Histamine and H1-Antihistamines in Allergic Disease PDF

Histamine and H1-Antihistamines
in Allergic Disease
Second Edition
Revised and Expanded
edited by
F. Estelle R. Simons
University of Manitoba
Winnipeg, Manitoba, Canada
Marcel Dekker, Inc. New York • Basel

TM
Copyright © 2002 by Marcel Dekker, Inc. All Rights Reserved.

The first edition was published as Histamine and H1-Receptor Antagonists in Allergic
Disease (Marcel Dekker, 1996).
ISBN: 0-8247-0628-5
This book is printed on acid-free paper.
Headquarters
Marcel Dekker, Inc.
270 Madison Avenue, New York, NY 10016
tel: 212-696-9000; fax: 212-685-4540
Eastern Hemisphere Distribution

Marcel Dekker AG
Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland
tel: 41-61-261-8482; fax: 41-61-261-8896
World Wide Web

http:/ /www.dekker.com
The publisher offers discounts on this book when ordered in bulk quantities. For more
information, write to Special Sales/Professional Marketing at the headquarters address
above.
Copyright  2002 by Marcel Dekker, Inc. All Rights Reserved.
Neither this book nor any part may be reproduced or transmitted in any form or by any
means, electronic or mechanical, including photocopying, microfilming, and recording,
or by any information storage and retrieval system, without permission in writing from
the publisher.
Current printing (last digit):

10 9 8 7 6 5 4 3 2 1
PRINTED IN THE UNITED STATES OF AMERICA

Dedicated with deepest gratitude to my father,
Francis Raymond Edward Davies
(1910–1995)
Series Introduction
Although 60 years have passed since antihistamines were first developed, new
and exciting observations are still coming forward, new antihistamines are still
being developed, and new uses for existing products are still being established.
Thus, it is timely to produce the second edition of this very successful
volume by F. Estelle R. Simons, M.D. Dr. Simons is widely considered the clini-
cal expert in the use of antihistamines, and she warrants being the creator and
editor of this useful book. This revised edition contains new chapters, new con-
cepts, and information about new products. This book will be exciting reading
for those interested in the study of allergy.
Michael A. Kaliner, M.D.
v
Preface
‘‘Yet all experience is an arch wherethro’

Gleams that untravell’d world . . .’’
Tennyson
Since the first edition of this successful medical textbook was published in 1996,
high-level interest in histamine as a chemical mediator of inflammation has con-
tinued, and H1-antihistamines such as cetirizine, fexofenadine, and loratadine re-
main the most widely used medications worldwide for allergic disorders, particu-
larly for allergic rhinoconjunctivitis and urticaria.
Several new second-generation, nonsedating H1-antihistamines have been
approved for use during the past few years. These medications include ebastine,
mizolastine, desloratadine, and levocetirizine, soon to be followed by epinastine,
tecastemizole, and others. New topical H1-antihistamine formulations such as
azelastine, levocabastine, ketotifen, emedastine, and olopatadine have also been
introduced for intranasal and ocular use. Two H1-antihistamines, astemizole and
terfenadine, which are no longer approved by regulatory agencies due to their
potential cardiac toxicity, have now almost entirely disappeared from the scene.
Histamine and H1-Antihistamines in Allergic Disease, Second Edition,
Revised and Expanded, reflects these important developments. It provides an up-
to-date, comprehensive analysis of the benefits of this important class of medica-
tions, including their broad antiallergic effects, and it contrasts the excellent
safety profiles of the relatively nonsedating second-generation H1-antihistamines
with those of the sedating first-generation H1-antihistamines.
We sincerely thank the scientists and clinician scientists who have helped
to make this new edition a reality—not only for their contributions to the book,
but also for their sustained contributions to improving the evidence base for H1-
antihistamine use in the treatment of allergic disease.
University of Manitoba
vii
Contents
Series Introduction v
Preface vii
Contributors xi
Introduction xiii
Part I. Histamine and Histamine Receptors
1. Histamine in Health and Disease 1

M. Susana Repka-Ramirez and James M. Baraniuk
2. Histamine Receptors: Specific Ligands, Receptor Biochemistry,

and Signal Transduction 27
Remko A. Bakker, Hendrik Timmerman, and Rob Leurs
Part II. H1-Antihistamines: Basic Science
3. Structure and Classification of H1-Antihistamines and Overview

of Their Activities 65
Giovanni Passalacqua, G. Walter Canonica,
and Jean Bousquet
4. Antiallergic Anti-Inflammatory Effects of H1-Antihistamines

in Humans 101
Paraya Assanasen and Robert M. Naclerio
5. Clinical Pharmacology of H1-Antihistamines 141

F. Estelle R. Simons and Keith J. Simons
ix
x Contents
Part III. H1-Antihistamines: Clinical Science
6. Antihistamines in Rhinoconjunctivitis 179

Peter Howarth
7. H1-Antihistamines in Asthma 221

James L. Lordan and Stephen T. Holgate
8. Antihistamines in Urticaria and Angioedema 249

Anne Kobza Black and Malcolm W. Greaves
9. Histamine and Antihistamines in Anaphylaxis 287

Stephen L. Winbery and Philip L. Lieberman
10. Cost-Effectiveness of H1-Antihistamines 319

Michael S. Blaiss
Part IV. H1-Antihistamines: Potential Adverse Effects
11. H1-Antihistamines and the Central Nervous System 337

Michael J. Welch, Eli O. Meltzer, and F. Estelle R. Simons
12. Potential Cardiac Toxicity of H1-Antihistamines 389

Yee Guan Yap and A. John Camm
Part V. H1-Antihistamines: Special Populations
13. H1-Antihistamines in Pregnancy and Lactation 421

Michael Schatz
14. H1-Antihistamines in Children 437

15. H1-Antihistamines in the Elderly 465

Michael A. Kaliner
Index 483
Contributors
Paraya Assanasen, M.D. University of Chicago, Chicago, Illinois
Remko A. Bakker, M.Sc. Leiden/Amsterdam Center for Drug Research, Vrije

Universiteit, Amsterdam, The Netherlands
James N. Baraniuk, M.D. Georgetown University, Washington, D.C.
Michael S. Blaiss, M.D. University of Tennessee Center for the Health Sci-
ences College of Medicine, Memphis, Tennessee
Jean Bousquet, M.D. Montpellier University, Montpellier, France
A. John Camm, M.D., F.R.C.P., F.A.C.S., F.E.S.C. St. George’s Hospital

Medical School, London, England
G. Walter Canonica, M.D. Genoa University, Genova, Italy
Malcolm W. Greaves, M.D., Ph.D., F.R.C.P. National University of Malay-

sia, Kuala Lumpur, Malaysia
Stephen T. Holgate, B.Sc., M.D., D.Sc., F.R.C.P., F.R.C.Path., F.I. Biol.,

F.Med.Sci University of Southampton, Southampton, England
Peter Howarth, B.Sc. (Hons.), D.M., F.R.C.P. University of Southampton,

Southampton, England
Michael A. Kaliner, M.D. Institute for Allergy and Asthma, Wheaton and
Chevy Chase, Maryland
xi
xii Contributors
Anne Kobza Black, M.D. Guy’s, King’s & St. Thomas’ School of Medicine,
London, England
Rob Leurs, Ph.D. Leiden/Amsterdam Center for Drug Research, Vrije Uni-
versiteit, Amsterdam, The Netherlands
Philip L. Lieberman, M.D. University of Tennessee College of Medicine,

Memphis, Tennessee
James L. Lordan, M.B., M.R.C.P.I., B.Sc., D.C.H., D.M.E., D.Obs. Univer-

sity of Southampton, Southampton, England
Eli O. Meltzer, M.D. Allergy and Asthma Medical Group and Research Cen-
ter, University of California, San Diego, San Diego, California
Robert M. Naclerio, M.D. University of Chicago, Chicago, Illinois
Giovanni Passalacqua, M.D. Genoa University, Genoa, Italy
M. Susana Repka-Ramirez, M.D. Georgetown University, Washington, D.C.
Michael Schatz, M.D., M.S. Kaiser-Permanente Medical Center, San Diego,

California
F. Estelle R. Simons, M.D., F.R.C.P. University of Manitoba, Winnipeg, Man-

itoba, Canada
Keith J. Simons, M.Sc., Ph.D. University of Manitoba, Winnipeg, Manitoba,

Canada
Hendrik Timmerman, Ph.D. Leiden/Amsterdam Center for Drug Research,

Vrije Universiteit, Amsterdam, The Netherlands
Michael J. Welch, M.D. Allergy and Asthma Medical Group and Research
Center, University of California, San Diego, San Diego, California
Stephen L. Winbery, M.D., Ph.D. Methodist Central Hospital Teaching Prac-

tice, Memphis, Tennessee
Yee Guan Yap, B. Med. Sci., M.B.B.S., M.R.C.P. St. George’s Hospital Med-
ical School, London, England
Introduction
Histamine and H1-Antihistamines in Allergic Disease, Second Edition, Revised

and Expanded, like the first edition, reviews the basic science of histamine, hista-
mine receptors, and antihistamines, and the clinical science—the benefits and
risks—of antihistamine use in allergic disease. It has been expanded to include
new chapters on ‘‘Cost-Effectiveness of Antihistamines,’’ ‘‘H1-Antihistamines
in Pregnancy and Lactation,’’ and ‘‘H1-Antihistamines in the Elderly.’’ The book
can be read in its entirety from cover to cover, since there is consistency and
minimal overlap among the chapters; or, individual chapters can be perused as
free-standing reviews of a particular aspect of histamine or H1-antihistamines.
In Chapter 1, ‘‘Histamine in Health and Disease,’’ the authors introduce
the concept that histamine is released in large amounts during the immediate
hypersensitivity response in the airways, skin, and other organs, where it up-
regulates a wide range of cellular responses and plays a primary role in allergic
inflammation.
In Chapter 2, ‘‘Histamine Receptors: Specific Ligands, Receptor Biochem-
istry, and Signal Transduction,’’ exciting new information about selective ligands
for the histamine receptors, including the recently discovered H3- and H4-recep-
tors, is introduced. Clinically relevant aspects of receptor biochemistry, molecular
biology, and signal transduction are presented. The constitutive nature of H1- and
H2-receptor signaling is described.
In Chapter 3, ‘‘Structure and Classification of H1-Antihistamines and Over-
view of Their Activities,’’ the authors review the history and chemistry of H1-
antihistamines, and provide an overview of their specific beneficial and adverse
effects. Second-generation H1-antihistamines that have been introduced during
the past few years are discussed in depth.
In Chapter 4, ‘‘Antiallergic Anti-Inflammatory Effects of H1-Antihista-
mines in Humans,’’ these wide-ranging activities are described in detail. Al-
though some antiallergic effects such as suppression of mediator release from
mast cells and basophils occur independently of the H1-receptor and may not be
xiii
xiv Introduction
clinically relevant, others, such as down-regulation of transcription by nuclear

factor kappa B and generation of cytokines and adhesion molecules, appear to
be H1-receptor-dependent and are probably of considerable clinical importance.
In Chapter 5, ‘‘Clinical Pharmacology of H1-Antihistamines,’’ the authors
focus on the second-generation medications, including cetirizine, desloratadine,
ebastine, fexofenadine, loratadine, and mizolastine. They explain how the differ-
ences in pharmacokinetics and pharmacodynamics among H1-antihistamines di-
rectly influence recommendations for dose and dose interval, and facilitate H1-
antihistamine use in children, the elderly, and other special groups. New clinical
pharmacology concepts, for example, population pharmacokinetics of H1-antihis-
tamines, and correlation of tissue H1-antihistamine concentrations with pharma-
codynamic activity, are introduced.
In Chapter 6, ‘‘Antihistamines in Rhinoconjunctivitis,’’ the important con-
tribution of histamine to allergic inflammation in the mucosa of the upper airways
and the conjunctivae, and the strong clinical evidence base for the use of H1-
antihistamines in treatment of allergic rhinoconjunctivitis, are covered in depth.
In this chapter, both oral second-generation H1-antihistamines and topical H1-
antihistamines for intranasal and/or ocular use are reviewed.
In Chapter 7, ‘‘H1-Antihistamines in Asthma,’’ the authors describe the
scientific rationale for the beneficial effects of H1-antihistamines in asthma,
which is due in large part to down-regulation of inflammatory cell recruitment.
The evidence supporting the beneficial effects of the second-generation H1-anti-
histamines in mild seasonal asthma in patients with concomitant allergic
rhinoconjunctivitis is presented. Combined H1-antihistamine and antileukotriene
treatment is discussed. The timely issue of the potential preventative effect of
antihistamines on the development of asthma in high-risk atopic infants is ad-
dressed.
In Chapter 8, ‘‘Antihistamines in Urticaria and Angioedema,’’ H1-antihista-
mine use in acute urticaria, chronic idiopathic urticaria, and the physical urticarias
is reviewed. The evidence base for the efficacy of various H1-antihistamines,
including the second-generation H1-antihistamines in urticaria, is presented in
tabular form for easy reference. The relatively minor role of H2-antihistamines
in the treatment of urticaria is also discussed.
In Chapter 9, ‘‘Histamine and Antihistamines in Anaphylaxis,’’ the authors
contrast the secondary adjunctive role of H1-antihistamines in the treatment of
anaphylaxis and anaphylactoid reactions, with their primary and very important
role in prevention of iatrogenic anaphylaxis and anaphylactoid reactions in pa-
tients at risk for reactions to radiocontrast media, drugs, anesthetics, and other
substances. The rationale for concurrent administration of H1- and H2-antihista-
mines in anaphylaxis and anaphylactoid reactions is reviewed.
In Chapter 10, ‘‘Cost-Effectiveness of Antihistamines,’’ the author con-
Introduction xv
firms that it no longer suffices to assess a medication’s clinical efficacy. It is also

necessary to evaluate cost-effectiveness and to perform comparative analyses of
the improvement in quality of life provided by the medication relative to other
options available.
In Chapter 11, ‘‘H1-Antihistamines and the Central Nervous System,’’ the
authors highlight the neurotransmitter effect of histamine in the central nervous
system (CNS) and review the evidence that first-generation H1-antihistamines,
even in low doses, cross the blood-brain barrier and can be identified on brain
H1-receptors by using positron emission tomography. More than 50 objective and
comprehensive studies contrasting the sedation and other adverse CNS effects
produced by first-generation sedating H1-antihistamines with the lack of CNS
effects of second-generation H1-antihistamines are summarized. The authors con-
clude that the first-generation H1-antihistamines are no longer medications of
choice for the outpatient treatment of allergic disorders, due to their common,
often subclinical, CNS adverse effects.
In Chapter 12, ‘‘Potential Cardiac Toxicity of H1-Antihistamines,’’ the
mechanisms underlying drug-induced QT interval prolongation and arrhythmias,
including torsade de pointes, are outlined. The physicochemical properties and
potassium ion channel blockade properties of H1-antihistamines leading to QT
prolongation and, occasionally, to torsade de pointes are reviewed. Fortunately,
these are not class effects. Most second-generation H1-antihistamines, such as
cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, and mizolas-
tine, have a well-documented low potential for cardiac toxicity. The regulatory
agency perspective on cardiac safety testing of H1-antihistamines and other new
chemical entities (new active substances) in development is presented.
In Chapter 13, ‘‘H1-Antihistamines in Pregnancy and Lactation,’’ the au-
thor provides a general overview of potential drug effects on the fetus, and dis-
cusses the risks of uncontrolled allergic disease during pregnancy and lactation
in the context of H1-antihistamine use during these important life stages. Clear
recommendations for choice of drugs are made based on the best evidence avail-
able. The concept of obtaining informed consent for H1-antihistamine treatment
during pregnancy is introduced.
In Chapter 14, ‘‘H1-Antihistamines in Children,’’ the challenges of study-
ing these medications in infants and young children are outlined, and recent stud-
ies of the second-generation H1-antihistamines in infants and children are re-
viewed. In the landmark randomized, placebo-controlled, double-blind Early
Treatment of the Atopic Child (ETAC) Study, the H1-antihistamine cetirizine,
given for 18 months to high-risk 1-year-olds with atopic dermatitis, delayed
asthma development in dust mite– and grass pollen–sensitized children, had a
topical steroid-sparing effect in atopic dermatitis, and reduced acute urticaria. As
the new nonsedating H1-antihistamines become more widely available in pediatric
xvi Introduction
formulations, the old sedating H1-antihistamines, which are still an important

cause of toxicity and fatality in the vulnerable pediatric population, will eventu-
ally disappear from outpatient use.
Finally, in Chapter 15, ‘‘H1-Antihistamines in the Elderly,’’ the author ex-
plores the use of these medications in elderly patients with allergic disorders,
who comprise another vulnerable population. He describes the anticholinergic
effects and alpha-adrenergic blockade produced by first-generation H1-antihista-
mines when given in usual doses to elderly individuals, potentially leading to
urinary problems, supraventricular tachycardia, peripheral vasodilation, postural
hypertension, reflex tachycardia, sedation, confusion, memory loss, and falls. He
also discusses polypharmacy and drug–drug interactions in the elderly.
Throughout the book, the terms ‘‘H1-antihistamine’’ and ‘‘H1-receptor an-
tagonist’’ are used interchangeably, although the former is perhaps more appro-
priate due to recent discovery of the constitutive nature of H1-receptor signaling.
Also, the terms ‘‘second-generation,’’ ‘‘new generation,’’ ‘‘nonsedating,’’ and
‘‘low-sedating’’ are used interchangeably to refer to the H1-antihistamines intro-
duced since the early 1980s which do not cross the blood-brain barrier to a sig-
nificant extent and do not cause sedation or psychomotor impairment.
In summary, Histamine and H1-Antihistamines in Allergic Disease, Second
Edition, Revised and Expanded, again provides a unique, global perspective on
histamine, histamine receptors, and H1-antihistamines. We thank all our contribu-
tors who are advancing research in the areas of histamine, histamine receptors,
and H1-antihistamines. We also gratefully acknowledge the support of Dr. Janet
R. Roberts and Lori L. McNiven at the University of Manitoba, and of Elyce
Misher and her colleagues at Marcel Dekker, Inc.
The University of Manitoba
1
Histamine in Health and Disease
M. Susana Repka-Ramirez and James N. Baraniuk

Georgetown University, Washington, D.C.
I. INTRODUCTION
Histamine, by far the most important mediator of acute allergic symptoms, and
the earliest recognized mediator of the immediate hypersensitivity response, was
discovered as a potent vasodilator substance by Dale and Laidlaw in 1910 (1).
In 1953 it was associated with tissue mast cells by Riley and West (2). Human
mast cells contain 2–5 pg histamine per cell. It is unclear if there are differences
in histamine content in different mast cell subsets (Table 1). Rapid advances in
molecular biology have led to the discovery of H 1-, H 2-, and H 3-receptors that
mediate the complex histamine-induced actions. In this chapter we discuss con-
cepts of the synthesis and metabolism, localization, receptors, effects, and the role
of histamine in various syndromes in which basophil and mast cell degranulation
occurs.
II. HISTAMINE
A. Histamine Synthesis and Catabolism
Histamine, 2-(4-imidazolyl)ethylamine or 5β-amino-ethylimidazole, is formed
by decarboxylation of histidine by the pyridoxalphosphate-dependent enzyme 1-
Although the research described in this chapter has been funded wholly or in part by the United
States Environmental Protection Agency through grant number R825814 to James N. Baraniuk, M.D.,
it has not been subjected to the agency’s required peer and policy review and therefore does not
necessarily reflect the views of the Agency and no official endorsement should be inferred.
1
2 Repka-Ramirez and Baraniuk
Table 1 Distribution of Human Mast Cell Subtypes
Human mast cell

subtypes in
various tissues (%)
MCT MCTC
Skin 12 88
Small intestine
mucosa 98 2
submucosa 13 87
Lung bronchi/bronchioles
subepithelium 77 23
alveoli 93 7
dispersed cells 90 10
Source: Data from Ref. 5.

T, tryptase; C, chymase.
histidine decarboxylase (3). It is stored preformed in cytoplasmic granules of

mast cells and basophils, and within platelets of some species. Intracellular pro-
duction of histamine is necessary for human platelet aggregation. Histamine syn-
thesis occurs in other cells, such as histaminocytes in rat gastric mucosa (4). Mast
cells are generally found in mucosal linings, or deeper in tissues around vessels,
nerves, and lymphatics. High densities have been measured in the conjunctiva,
skin (3–12 ⫻ 103 mast cells/mm3), upper and lower airway mucosa (0.1–0.5%
of all cells), the gastrointestinal mucosa (up to 20 ⫻ 103 /mm3), and the reproduc-
tive tract (5). Subsets of tryptase-positive ‘‘mucosal’’ mast cells (MCT ) and tryp-
tase and chymase-double-positive ‘‘connective tissue’’ mast cells (MCCT ) may
have different amounts of stored histamine (Table 1). In the heart, the histamine
is localized in mast cells of the right atrium and in walls of coronary blood vessels
(6). Plasma histamine levels following tissue mast cell degranulation rise between
2.5 and 5 min, and return to baseline by 15–30 min. Histamine is also elevated
in tears (5 ng/mL), and in nasal and bronchoalveolar lavage fluids after challenge
provocations. Urinary histamine is elevated in patients with idiopathic hyper-
eosinophilia, mastocytosis, and occasionally in Zollinger-Ellison syndrome and
pregnancy (7). Histamine can also be generated in cell culture systems of lym-
phocytes, tumor cells, and embryological tissues.
Plasma histamine is rapidly and extensively metabolized (Fig. 1). Between
50 and 70% is metabolized to N-methylhistamine and N-methylimidazoleacetic
acid, and 30 and 50% to imidazole acetic acid (7). Only 2–3% of urine histamine
is in a nonmetabolized state.
Histamine in Health and Disease 3
Figure 1 Histamine synthesis and catabolism. Percentage recovery was calculated fol-
lowing intradermal administration of [14C]histamine in human males. (Reprinted from
Ref. 3.)
B. Central Nervous System

Central nervous system (CNS) sources of histamine include the lateral hypothala-
mic nuclei projecting to the telencephalon, diencephalon, and lower brainstem.
Histaminergic neurons are present homogeneously throughout all laminar and
interlaminar zones of the pregeniculate nucleus and dorsolateral geniculate nu-
cleus (8). Their axons branch infrequently, and possess varicosities along their
length that do not form conventional synapses with other neurons. This suggests
that the histamine may be released into the interstitial space, where it may modu-
late state-dependent thalamic activity without necessarily producing neurotrans-
mission to specific neural pathways.
Histamine receptors are found throughout the human frontal cortex by posi-
tron emission tomography (PET) (9). H 1-receptor occupancy by H 1-antagonists
is significantly correlated with sleepiness and impaired cognitive performance.
This is consistent with the slow wave sleep-inducing effects of first-generation
H 1-antagonists, which show a rank potency of promethazine ⬎ chlorpheniramine
⬎ diphenhydramine ⫽ pyrilamine (10). The ranking for increase in sleep duration
is chlorpheniramine ⬎ promethazine ⬎ diphenhydramine ⫽ pyrilamine. These
activities are at odds with the effects of long-term intraventricular infusion of
chlorpheniramine in aged Brown-Norway rats, in which this drug improves maze
performance and reduces fear-related behaviors (11). Proposed explanations for
these results include the anticholinergic effect of chlorpheniramine (12) or hyper-
activation of the central histaminergic neural system during senescence that leads
to an increase in hypomnesia and hyperanxiety (11). Histamine H 1-receptor
knock-out mice have changes in arousal, sleep–wake patterns, locomotion, noci-
ception, and aggressive behavior compared to healthy littermates, suggesting
roles for histamine and/or the histaminergic neural systems in these activities
(9).
In assessing the issue of sedation, it is important to remember that allergic
rhinitis (AR) itself leads to sedation, inattentiveness, and loss of vigilance that
is readily improved by administration of second-generation antihistamines (13).
Thus, it may be important to test the effects of antihistamines on these CNS
symptoms in subjects with active AR rather than in healthy subjects in order to
assess AR-specific fatigue vs. drug-related effects. These findings are consistent
with an ‘‘allergic fatigue’’ syndrome that has been postulated but poorly charac-
terized to date (14).
C. IgE-Mediated Histamine Release

A variety of stimuli may induce mast cells and basophil degranulation and exo-
cytosis which may or may not be IgE-dependent. For IgE-dependent triggers,
cross-linking of at least two IgE molecules bound to high-affinity IgE receptors
(FCεRIαβγ) by multivalent antigens is necessary. IgE binds to the α subunit,

while the βγ subunits form a tyrosine kinase that leads to activation of additional
enzymes including other tyrosine kinases, serine proteases, phospholipase C
(PLC), methyltransferases, and adenylate cyclase. PLC begins the hydrolysis of
membrane inositol phospholipids and the release of inositol-1,4,5-triphosphate
(IP3 ) and 1,2-diacylglycerol (DAG). IP3 functions as a second messenger for the
mobilization of intracellular calcium. The DAG and Ca2⫹, in turn, activate protein
kinase (PKC) (15). Changes in intracellular calcium are thought to initiate the
transport of preformed granules to the cell surface, their hydration, and the exo-
cytosis of their contents.
D. Non-IgE-Mediated Histamine Release

Non-IgE-mediated histamine release can be initiated by highly charged or amphi-
pathic molecules including opioids such as morphine and codeine, and by intrave-
nous contrast media, calcium ionophore, anaphylatoxins (C3a, C4a, C5a), sub-
stance P, vancomycin, quinolones, and numerous cytokines (Table 2). Substances
that inhibit histamine release include cromolyn, nedocromil, transforming growth
factor-β1(TGF-β1), antisense oligonucleotides to TGF-β1 and FcεR1α, and β2-
adrenergic agonists.
Table 2 IgE-Independent Histamine-Releasing Factors
Direct agonists Augment histamine release Inhibit histamine release
IL-1 IL-1α, IL-1β Cromolyn

MCP-1 IL-3 Nedocromil
MCP-3 IL-5 TGF-β1
MIP-1α IL-6 TGF-β1 antisense
IL-7 oligonucleotides
c-kit ligand FcεR1α antisense
C3a, C5a oligonucleotides
Opioids β-agonists isoprenaline ⬎
Vancomycin salmeterol ⬎ albuterol
Intravenous contrast dye ‘‘Sainte’’ and ‘‘Val
High dosages of d’Orb’’ waters
substance P H 1-antihistamines
Mast cell degranulating
peptide
IL, interleukin; MCP, monocyte chemotactive protein; MIP, monocyte inhibitory protein; C, comple-
ment; TGF, transforming growth factor; FcεR1α, high-affinity IgE receptor.
III. HISTAMINE RECEPTORS

A. H 1-Receptors
The H 1-histamine receptor was identified pharmacologically in 1966 (Chap. 2).
After being cloned, the deduced protein of 487 amino acids showed similarity
to G-protein-coupled receptors (16). Members of this ‘‘rhodopsin receptor fam-
ily’’ have seven transmembrane segments, an extracellular N-terminal, two extra-
cellular loops, two intracellular loops, and a C-terminal tail. These receptors gen-
erate intracellular messages by activating guanosine triphosphate (GTP)-binding
protein (G-proteins).
Binding of histamine to the H 1-receptor has been studied by site-directed
mutagenesis and three-dimensional (3D) computer modeling of the receptor (17).
The histamine binding site consists of five amino acids. There may be two sepa-
rately defined components of the binding site, with one region responsible for
rewinding the α-helix of the fifth transmembrane region. This, in turn, has been
postulated to lead to subsequent conformational changes resulting in intracellular
G-protein activation, and cellular activation. This mechanism is different from
both β 2-adrenergic receptor and H 2-receptor interactions. H 1-receptor activation
leads to rapid, transient effects, suggesting that continued release of histamine
is required for prolonged histamine-induced symptom production.
H 1-receptor mRNA is upregulated in allergic rhinitis (18). H 1-receptors are
present on endothelial cells, where they act to induce vascular permeability and
the watery rhinorrhea of allergic rhinitis (19; see Table 3). Consistent with this
finding, allergic sensitization of guinea pigs increases H 1-receptor density and
vasodilator responses to histamine provocation (20). Histamine has been thought
to stimulate mucus production directly; however, histamine does not induce exo-
cytosis of mucus in human nasal mucosal explants in vitro (21).
B. H 2-Receptors
Stimulation of H 2-receptors leads to a slower but more sustained response (3).
Burimamide, the first H 2-receptor ligand, has been used to define the difference
between H 1- and H 2-receptors (22). H 2-receptor stimulation induces a rise in
cyclic adenosine 3′,5′,monophosphate (cAMP) and secondary rise in intracellular
calcium concentrations in the gastric mucosa, vascular smooth muscle, brain,
adipocytes, basophils, neutrophils, and other tissues (23). H 2-receptor stimulation
plays a minor role in vasodilation, but may mediate a substantial portion of the
chronotropic and inotropic cardiac effects of histamine in conditions such as ana-
phylaxis. H 2-receptor stimulation has also been related to tracheobronchial airway
mucus secretion, inhibition of basophil histamine release, stimulation of suppres-
sor T cells, and inhibition of neutrophil chemotaxis and enzyme release (3). The
Table 3 Summary of Actions of Histamine at H 1-, H 2-, and H 3-Receptors
H 1-receptor H 2-receptor H 3-receptor
Vessels Vasodilation Vasodilation Vasodilation?

↑ Vascular permea- No ↑ permeability Indirect ↓ permea-
bility bility
Adhesion ↑ Leukocyte adhe- No significant ef- No effect
sion through fect
multiple mecha-
nisms
Bronchial smooth Contraction No effect No effect
muscle
Glands No effect on exo- Possible bronchial No effect
cytosis of mucus mucus secretion
Neurons Activate nocicep- No effect Inhibit neural activa-
tive ‘‘itch’’ tion leading to re-
nerves duced neurotrans-
mitter release
Atrioventricular ↓ Conduction time Positive chrono- Potential inhibi-
node conduction (tachycardia) tropic and ino- tory autore-
tropic effectsa ceptor effects
on cardiac in-
nervation
Transduction PLC, guanylyl cy- Adenylyl cyclase Modulation of hyper-
clase, cGMP, and cAMP polarizing potas-
NO sium channels?
a
Rapid infusion of cimetidine or ranitidine can lead to bradycardia, hypotension, and asystole.
PLC, phospholipase C; cGMP, cyclic guanosine 3′,5′monophosphate; cAMP, cyclic adenosine
3′,5′monophosphate; NO, nitric oxide.
H 2-receptor plays a major role in stomach parietal cell hydrogen ion production
and in esophageal contraction.
Both H 1- and H 2-receptor mRNA have been identified by reverse tran-
scriptase polymerase chain reaction (RT-PCR) in the human nasal mucosa (24).
Even though histamine plays little or no role in the control of vasomotor tone
under normal conditions, a synergy between H 1- and H 2-antagonists has been
demonstrated in the cardiovascular system. The combination significantly blunts
the fall in diastolic blood pressure and pulse pressure associated with infusion
of low-dosage histamine (25). H 2-antagonists alone do not affect results of allergy
skin tests, but concomitant administration with an H 1-antagonist may augment
the inhibitory effect of the H 1-antagonist.
A further interaction is seen in cultured endothelial cells. Histamine causes

a transient decrease in H 1-receptor mRNA and a rapid and prolonged decrease in
H 2-receptor mRNA (26). The latter effect may occur via an H 1-receptor-mediated
transduction pathway. This interaction has relevance to tachyphylaxis of H 1- and
H 2-receptors, since continuous exposure to histamine, as in ongoing mast cell
degranulation states, may lead to tachyphylaxis of H 2-receptor-mediated events
but continued expression of H 1-receptor mRNA. These preliminary studies on
gene expression must be followed by an examination of the function of H 1- and
H 2-receptors, since uncoupling from G-protein transducing systems may still oc-
cur for H 1-receptors despite the continued generation of H 1-receptor mRNA.
C. H 3-Receptors
In 1983, Arrang et al. defined a new histamine receptor (H 3) in rat cerebral cortex
(27). The H 3-receptor also belongs to the G-protein-coupled receptor superfamily
(28). The localization and pharmacology of this H 3-receptor are distinct from H 1-
and H 2-receptors. It has a presynaptic localization and is an autoreceptor mediat-
ing inhibition of histamine release and biosynthesis in histaminergic nerve termi-
nals in CNS (29). H 3-receptors have been observed in neurons of the cerebral
cortex, amygdala, hippocampus, striatum, thalamus, and hypothalamus (30),
where they appear to act as ‘‘inhibitory autoreceptors’’ that reduce neural activity
(31). Presynaptic H 3-receptors may participate in the pathophysiology of head-
ache and cardiac ischemia. Post-synaptic H 3-receptors on peripheral neurons of
the gastrointestinal and respiratory tracts may regulate the release of a variety of
neurotransmitters (28). H 3-receptors have been detected in several vascular beds
and may cause vasodilation.
H 3-receptor activity is currently subject to intense investigation in humans.
In 1998, Hey et al. demonstrated that histamine may cause nasal congestion
through activation of inhibitory prejunctional H 3-receptors on sympathetic
nerves, leading to decreased norepinephrine release and subsequent ‘‘default’’
vasodilation with nasal vascular engorgement. They demonstrated that a combi-
nation of H 1- and H 3-receptor antagonists could reduce nasal airflow resistance
and increase nasal cavity airspace volumes (measured by acoustic rhinometry)
in several feline models. They proposed that a dual H 1-/H 3-antagonist could pro-
vide relief for allergic nasal congestion (32).
IV. HISTAMINE PRODUCTION BY BACTERIA
The bacterial enzyme histidine decarboxylase catalyzes the conversion of histi-

dine into histamine. Bacterial infection of food can lead to excessive levels of
histamine that can be a cause of food poisoning (scombroid) (33). Histamine
generated at sites of infection may modulate local inflammatory reactions. Chla-

mydia pneumoniae induce or enhance histamine release from basophil leukocytes
(34). Helicobacter pylori may trigger mast cell degranulation and promote gastric
mucosal inflammation (35). Nasal inoculation of hamsters with Mycoplasma
pneumoniae potentiates the contractile responses to histamine in the bronchi, pos-
sibly through a reduction of endogenous histamine N-methyltransferase activity
(36). Other respiratory bacterial species that produce significant amounts of hista-
mine include Moraxella catarrhalis, Haemophilus parainfluenzae, and Pseudom-
onas aeruginosa.
V. HISTAMINE IN ALLERGIC DISEASES

A. General Principles
After its release, histamine contributes to the pathophysiology of asthma, allergic
rhinitis and conjunctivitis, anaphylactic shock, and urticaria. Histamine partici-
pates in both the early- and late-phase allergic responses (37), playing important
and prominent roles in cytokine release and in the adhesion process.
The immediate- or early-phase reaction begins with the explosive degranu-
lation of mast cells that follows exposure to allergen (Fig. 2). In the nose, hista-
mine and other mediators rapidly lead to itching, sneezing, nasal discharge, and
mucosal swelling with increased nasal airway resistance (21, 38).
Figure 2 Mast cell degranulation.

B. Endothelial Cell Interactions

Histamine-induced contraction of postcapillary venule endothelial cells opens
gaps, which permits the hydrostatic intravascular pressure to force plasma into
the interstitial space. These effects are mediated by phosphorylation of vascular
endothelial (VE) cadherin with dissociation of VE-cadherin from the actin cy-
toskeleton (39). The rapid and transient (⬍3 min) increase in endothelial perme-
ability also involves calcium ion release, calmodulin, and phosphorylation of
myosin light chains (40). Thrombin accentuates this transepithelial flux by activa-
tion of a tyrosine kinase activity, RhoA, and by increasing the sensitivity of cal-
cium release to low levels of histamine. Under these conditions of reduced endo-
thelial barrier function, a hydrostatic vascular pressure of 5 cm H 2O is capable of
driving fluid from vessels through the interstitium, across the epithelial basement
membrane, and between epithelial cells and their tight junctions into the nasal
lumen (41). This is a nondamaging reversible event driven by the increase in
hydrostatic pressure. Plasma exudation may occur without significant tissue
edema. Histamine causes plasma extravasation by at least two mechanisms. First,
it may cause increased leukocyte adhesion and infiltration that can be inhibited
by exogenous nitric oxide (NO) and 9-Br-cGMP (42). Second, there may be an
adhesion-independent mechanism that can be blocked only by NO. Both of these
potential mechanisms offer novel targets for future therapeutic drugs.
Histamine also acts synergistically with bradykinin, leukotrienes, and
platelet-activating factor (PAF) to activate the endothelial cells of postcapillary
venules, inducing vasodilation, vascular permeability, and cellular adhesion.
These and other immediate consequences of histamine release are greater than
the combined immediate effects of tryptase, prostaglandin D2 (PGD2 ), prostaglan-
din F2 (PGF2 ), mast cell kininogenase-mediated bradykinin, tumor necrosis factor
α (TNF-α), interleukin 4 (IL-4), IL-5, IL-6, TGF-β, and IL-13 production (43).
This is clear from antihistamine studies, since H 1-antagonists reduce early allergic
response symptoms by 50–60% (44). Leukotrienes and chymase stimulate glan-
dular exocytosis and mucus secretion during the early allergic response, yet this
is outweighed by the mucus secretion induced via H 1-receptor-stimulated noci-
ceptive nerve recruitment of parasympathetic reflexes and cholinergic glandular
secretion (21, 45, 46).
C. Recruitment Phase
In allergen provocation models, the early allergic response phase is self-limited,
and followed by a relatively symptom-free period. During this ‘‘recruitment
phase’’ the cytokines and chemokines released as part of the early phase stimulate
endothelial cell adhesion marker expression and the diapedesis of the unique set
of inflammatory leukocytes that characterize atopic inflammation. Increased lev-
els of IL-4 and expression of vascular cell adhesion molecule 1 (VCAM-1) are
critical for the late-phase response (47). Histamine stimulates endothelial cell
production of IL-6 and IL-8 that increases the adhesion of leukocytes to the endo-
thelium and epithelium (48). Histamine increases IL-8 mRNA expression sixfold
and monocyte chemotactic protein (MCP)-1 mRNA twofold by stimulating tran-
scription of the endothelial cell transcription factor nuclear factor of activated T
cell (NFAT) (49). These effects are potentiated by TNF-α that is also stimulated
during the immediate and late phases. In vitro, both H 1- and H 2-, but not H 3-,
receptors participate in neutrophil adhesion of human umbilical cord endothelial
cells (50). Second messengers appear to include PLC-derived IP3, DAG, calcium
ions, NO, and cGMP. Increases in cAMP may counter this adhesion event. Diesel
exhaust particulates may also potentiate these effects, since they can upregulate
H 1-receptor mRNA and histamine-induced IL-8 and granulocyte macrophage col-
ony-stimulating factor (GM-CSF) production from cultured human nasal epithe-
lial and endothelial cells in vitro (51). The recruited eosinophils, basophils, and
other leukocytes in turn perpetuate the inflammatory process by the liberation of
their own mediators (late-phase response).
Upregulation of leukocyte–endothelial cell interactions is not a universal
consequence of histamine, however. In rat models, only Brown-Norway rats dem-
onstrate upregulation of leukocyte adhesion after histamine exposure (52). It is
curious that Brown-Norway rats are a preferred model for allergen-induced eosin-
ophilia and bronchial hyperresponsiveness. It will be of interest to determine if
mast cells, histamine release, eosinophil–endothelial binding, and tissue eosino-
philia are uniquely linked by a single underlying molecular mechanism that is
present in this, but not other, rat strains.
Antihistamines may exert their anti-inflammatory effects by decreasing his-
tamine-induced adhesion and thereby reducing inflammatory cell influx into the
tissues (53). This, in turn, would mean a reduction in mediator release from these
cells, and so a diminution in symptoms. While an attractive hypothesis, it is still
unclear if these effects are sufficient to alter the long-term outcomes of chronic
allergic diseases. Competition between versus in PLC, nitric oxide synthase
(NOS), and GC activity induced by histamine and β2-adrenergic agonist induced
increases in cAMP may represent one anti-inflammatory action of β2-agonists on
histamine-induced inflammation (50). Intranasal glucocorticoids can also reduce
histamine-related hyperresponsiveness in chronic allergic rhinitis, perhaps by in-
terfering with many of these transcription pathways, normalizing endothelial and
leukocyte adhesion marker expression, and reducing mediator release (54, 55).
D. Late-Phase Response
During the late-phase response, histamine is released without a change in tryp-
tase, suggesting release from basophils rather than a secondary degranulation of
mast cells (45, 46, 56, 57). Histamine’s effects in the late phase are likely to be
essentially the same as those described above for the early allergic response.
VI. HISTAMINE AND ASTHMA
Atopic subjects with asthma experience an immediate allergic response caused

by allergen-specific IgE-mediated histamine release (58). Histamine and leuko-
trienes are the major mediators of allergen-induced contraction in the human
airways. Passive sensitization with IgE in vitro induces an increase in histamine
and leukotriene release and responsiveness (59). Histamine and leukotriene C4
(LTC4 ) participate in the initiation mechanism of atopic asthma, but apparently
only LTC4 plays a role in nonatopic asthma (60). Plasma histamine concentrations
are elevated during early and late responses to inhaled allergens, and may also
increase during spontaneous acute asthma episodes (61).
Asthma is characterized by smooth muscle spasm, mucosal edema, in-
flammation, and mucus hypersecretion. Bronchospasm and mucosal edema can
be caused by H 1-receptor stimulation, while H 2- and possibly H 1-activation may
contribute to mucus secretion. Histamine interacts directly with the endothelial
cells to induce permeability and increase IL-6, IL-8, and lipid mediators (PGI2,
PAF, and LTB4) (62).
Antihistamines have some beneficial effects on airflow obstruction in aller-
gic asthma, but are not as effective as low-dosage inhaled glucocorticoids for
long-term therapy (Chap. 7). More interesting is the recent finding that a combina-
tion of an H 1-antagonist (loratadine) and LTD4-receptor antagonist (zafirlukast) in
high doses could block both early- and late-phase bronchial obstruction following
allergen inhalation (63). This suggests that histamine and leukotrienes, or media-
tors secondarily generated by them, are largely responsible for changes in airway
caliber after allergen inhalation. This combination of medications did not have a
synergistic effect in blocking exercise-induced bronchospasm (64). It remains to
be seen if it would be effective throughout a pollen season in persistent atopic
asthma as it is in seasonal allergic rhinitis (65), or if it would prevent airway
remodeling and irreversible airway changes over the longer term.
Histamine is a potent bronchoconstrictor, and is commonly used to assess
bronchial hyperresponsiveness. This appears to be a direct effect of inhaled hista-
mine on the smooth muscle; however, in other model provocation systems, such
as hypertonic saline, mast cell degranulation and histamine release have been
postulated to play central roles in bronchoconstriction, based largely on studies
with first-generation antihistamines that have significant anticholinergic activity.
Recent evidence indicates that inhalation of hypertonic saline is associated with
a decrease in bronchoalveolar lavage endothelin levels with no changes in hista-
mine, tryptase, or PGD2 (66). These data suggest that hypertonic saline does not
directly stimulate epithelial production of the potent bronchoconstrictor endo-

thelin, and does not lead to mast cell degranulation. Rather, other mechanisms
must be postulated, such as direct activation of sensory afferent nerves that may
lead to bronchoconstriction via axon response release of neuropeptides such as
neurokinin A and substance P (67), and recruitment of local parasympathetic
reflexes and cholinergically mediated smooth muscle contraction. This is further
suggested by the effects of β2-agonists on mast cell degranulation and bronchodi-
lation. Isoproterenol, but not formoterol, terbutaline, or salbutamol, inhibits hu-
man bronchial mast cell degranulation in vitro, while all of these drugs can over-
come histamine-induced bronchoconstriction in vivo (68).
VII. HISTAMINE, SINUSITIS, AND NASAL POLYPS
The response of the sinus mucosa to histamine is lower in magnitude than that
of the nose. Sinus challenge with histamine resulted in significant increases in
vascular permeability within the sinus cavity, but no significant change in para-
sympathetic reflex-mediated nasal secretions (69). This indicates the presence of
H 1-receptors on sinus mucosal vessels; however, this mucosa is much thinner than
that covering the inferior or middle turbinates, hence less vascular leak would be
anticipated. The levels of histamine in aspirin-induced, asthma-related polyps
were significantly lower than in nasal polyps related to allergy and infection (70).
This argues against a strong role for mast cells in nasal polyposis unless there
is concomitant atopic disease.
VIII. HISTAMINE AND ALLERGIC RHINITIS
To appreciate best the many effects of histamine in human nasal mucosa, it is

important to understand how the nose runs, and what runs in a runny nose (71).
The epithelium lies above the region of postcapillary venules, the site of vascular
leak and leukocyte diapedesis.
Submucosal glands form the next ‘‘layer’’ and contain both seromucous
and mucous cells. Seromucous cells secrete many nonspecific antimicrobial fac-
tors, neutral mucins such as MUC7, and hyaluronan. Mucus and goblet cells
secrete acid mucins such as MUC5B and MUC5/AC (72). MUC5/5AC mRNA
levels are 5–10-fold higher than those of MUC1 and MUC2 in patients with
allergic rhinitis, cystic fibrosis, and normal subjects. MUC2 mRNA levels are
similar in all subjects, while MUC5/5AC levels are significantly reduced in pa-
tients with cystic fibrosis.
The venous sinusoids are the erectile machinery that regulates the thickness
of the nasal lining. They are located deep in the mucosa. Dilation of arteriovenous
anastomoses combined with closure of venous outlet vessels increases the blood
flow into the sinusoids, causing them to swell. This thickens the mucosa, and
reduces nasal air flow. Sympathomimetic drugs contract both the arteriovenous
anastomoses and sinusoid wall myoepithelial cells to decrease blood flow, reduce
the volume of swollen sinusoids, thin the mucosa, and restore nasal patency.
The components of nasal secretions have three major sources: vascular leak
via the postcapillary venules, glandular exocytosis, and leukocyte infiltration.
Vascular leak accounts for about one-third of nasal secretion protein in healthy
subjects, and is increased in patients with allergic rhinitis and rhinovirus infec-
tions. Glandular exocytosis accounts for about two-thirds of the total protein in
nasal secretions in healthy subjects, with half this amount from seromucous cells
and half from mucous cells. Glandular products are increased in nasal secretions
from patients with allergic rhinitis, rhinovirus infections, cystic fibrosis, and acute
sinusitis. It has been proposed that the relative proportions of seromucous and
mucous cells in glands are modulated in inflammatory states, but as yet there
is little experimental evidence from human diseases. In models of ovalbumin-
immunized mice, IL-4 appears to promote goblet cell hyperplasia and mucus
hypersecretion. IL-13 stimulated goblet cell hyperplasia in an IL-13-overexpres-
sion murine model (73). Leukocyte infiltration from the epithelium into the nasal
lumen is prominent in allergic (eosinophils) and infectious (neutrophils) rhinitis.
The effects of histamine on these processes have been widely studied. His-
tamine induces prominent vascular leakage after nasal provocation. This appears
to be a direct effect on endothelial cells, since histamine H 1-receptors are densely
localized to these cells. Histamine induces itching by activating type C nocicep-
tive nerves. These may generate axon responses with the release of substance P,
calcitonin gene-related peptide, and other neuropeptides (74). Activation of these
trigeminal neurons recruits parasympathetic reflexes that release acetylcholine,
which is responsible for the glandular exocytosis that follows histamine provoca-
tion in vivo (75). In vitro, histamine does not stimulate glandular exocytosis from
nasal explants. In contrast, histamine H 2-receptors may be responsible for exo-
cytosis from bronchial explants in humans and other species. Histamine may
activate epithelial and inflammatory cells based upon in vitro experiments, but
effects on these cells are difficult to appreciate in vivo because of the overwhelm-
ing vascular permeability and nociceptive nerve events.
Based on this framework, the effects of H 1-antihistamines should be clear.
They will reduce vascular leak, itch, and recruitment of parasympathetic glandu-
lar secretion. Antihistamines account for amelioration of 50–60% of the symp-
toms of immediate allergic reactions, explaining their widespread popularity, but
also their inability to block all allergic rhinitis symptoms. These other effects are
mediated by bradykinin, leukotrienes, prostaglandins, neuropeptides, and, in the
chronic situation, cytokines and other mediators. H 1-antagonists and leukotriene
modifiers have a synergistic effect in allergic rhinitis treatment (65). As other

mediators are identified, additional antagonists may be developed.
Adjunctive treatments include α-adrenergic agonists that reduce the thick-
ness of the nasal mucosa and improve nasal patency, but apparently they have no
effect on vascular leak in allergic rhinitis or rhinovirus infections. Anticholinergic
agents reduce glandular hypersecretion.
IX. HISTAMINE AND VERNAL CONJUNCTIVITIS
The classic clinical symptoms of allergic conjunctivitis, itching and lacrimation,

are caused by histamine, and the histamine levels in tears can be monitored along
with the clinical symptoms in this disorder (76). Histamine may affect extracellu-
lar matrix production and cell growth in vernal conjunctivitis (VC), increasing
proliferation, migration, and collagen production in VC fibroblasts, so histamine
may be at least partially responsible for fibroblast stimulation (77). The enzymatic
degradation of histamine in tears and plasma is significantly decreased in patients
with VC compared with control subjects, suggesting that this dysfunction may
be an important factor in the pathophysiology of VC (78). Tear histaminase activ-
ity is different during the early and late phases of allergen conjunctival provoca-
tion tests. Greater histaminase activity occurs during the late-phase reaction,
while the lower enzymatic activity during the immediate phase may contribute
to the observed surge of histamine release (79). Histamine-stimulated cytokine
secretion by conjunctival epithelial cells is attenuated by compounds with H 1-
antagonist activity. Topical ocular drugs with antihistaminic activity offer thera-
peutic improvement by inhibiting proinflammatory cytokine secretion. Olopata-
dine, emedastine, and levocabastine seem to be more potent than pheniramine
and antazoline (80).
X. HISTAMINE AND OTITIS MEDIA
Evidence has accumulated for the role of immunological mechanisms in the

pathogenesis of otitis media with effusion. Infection and eustachian tube obstruc-
tion play an important role. Viruses and bacterial infections increase mast cell
numbers and histamine release into the middle ear fluid (81). Higher histamine
levels are observed in effusions positive for Haemophilus influenzae (82), sug-
gesting that both mast cells and the organisms generate the histamine. Histamine
concentrations are also increased in the adenoids of children with otitis media,
and lymphoid hyperplasia or mast cell degranulation in the nasopharynx may
contribute to edema with occlusion of the medial eustachian tube (83).
Histamine induces mucociliary dysfunction of the tubotympanum that con-

tributes to the increased negative pressure in the middle ear, improper ventilation,
and resulting eustachian tube insufficiency (84). Injection of histamine into the
guinea pig middle ear produces dilation and endothelial disjunction in capillaries,
leading to mucosal edema (85). Within the endothelial cells, this has been associ-
ated with an increased density of cytoplasmic vesicle-like structures that may
represent pinocytotic vesicles (86).
Histamine and bradykinin (BK) work in parallel through H 1- and BK B 2-
receptors, respectively, to activate intracellular calcium-dependent mechanisms
that lead to apical chloride secretion in a cultured gerbil middle ear epithelium
model (85). The release of these mediators can both initiate tissue destruction
and stimulate tissue repair (87). An imbalance or prolongation of these processes
may lead to chronic middle ear dysfunction.
XI. HISTAMINE AND ANAPHYLAXIS
A dramatic and devastating form of atopic disease is this systemic manifestation

of immediate hypersensitivity. All of the symptoms of anaphylaxis can be repro-
duced by histamine. Histamine promotes increased vascular permeability and
vascular smooth muscle relaxation, which leads to vasodilation, reduction of cir-
culating blood volume, and fall in blood pressure, leading to hypovolemic shock.
Laryngeal edema is due in large part to vascular leak with occlusion of the glottic
airway. Bronchial smooth muscle contraction, airway edema, neurogenic and di-
rect bronchorrhea contribute to airway plugging and bronchospasm with as-
phyxia. Stimulation of gastrointestinal smooth muscle along with plasma extrava-
sation and glandular secretion lead to vomiting, tenesmus, and diarrhea. In
anaphylaxis H 1-antagonists are useful adjunctive treatment for itching and the
urticarial component of the reaction, but systemic vasodilator and bronchocon-
strictor reactions require the vasoconstricting and bronchodilating effects of epi-
nephrine (3) (Chap. 9).
XII. ANAPHYLACTOID REACTIONS
Anaphylactoid reactions are clinically similar to anaphylaxis, but they are not
initiated by allergen–IgE interactions. They are generally caused by highly
charged or amphipathic molecules such as intravenous contrast dye and vanco-
mycin (red man syndrome). A wide range of peptides, drugs, complement fac-
tors (e.g., C3a and C5a released by immune complex formation as in serum
sickness), and other IgE-independent mechanisms can trigger histamine, arachi-
donic acid metabolite, or cytokine release (Table 2). The role of histamine and
of H 1- and H 2-antagonists in anaphylactoid reactions is similar to their role in

anaphylaxis (Chap. 9).
XIII. HISTAMINE AND URTICARIA
Histamine is the best known chemical mediator that arises from the activation
of mast cells and basophils to elicit the classic triple response of Lewis (88).
Drawing a probe across the skin leads to very transient local endothelial cell
swelling, leading to a sudden decrease in superficial blood flow (‘‘white line’’),
local increased vascular permeability (edema, ‘‘tumor’’), and nociceptive nerve
stimulation resulting in a local axon response with the release of calcitonin gene-
related peptide (CGRP) that causes local erythema (rubor), heat (calor), and cen-
trally mediated pain/itch (‘‘dolor’’) (89). Other vasoactive mediators that may
contribute to vasodilation are PGD 2 , LTC 4 , LTD 4 , PAF, and bradykinin (3). For
decades this model of cutaneous histamine release has shaped therapy for urti-
caria; however, a variety of mechanisms may initiate the histamine release in
physical, solar, cold-induced, and other types of urticaria. The central role of
histamine in urticaria and angioedema is demonstrated clinically by the beneficial
responses that occur when treated exclusively with H 1-antihistamines. Old, sedat-
ing, first-generation H 1-antagonists that have ‘‘nonspecific’’ pharmacological
properties (e.g., cyproheptadine, diphenhydramine, or hydroxyzine) are still
sometimes used in urticaria despite their poor benefit-to-risk ratio. While the
vascular leak (edema) and itch (neurogenically mediated itch ⫹ flare) are medi-
ated primarily by H 1-receptors, other factors also contribute. The histamine re-
lease may be only a marker of mast cell degranulation. Neither old nor new
antihistamines are likely to modify the primary pathogenesis of the urticaria,
although they effectively relieve symptoms and signs (Chap. 8).
Recently, an autoimmune hypothesis of chronic idiopathic urticaria has
emerged. IgG 1 and IgG 3 autoantibodies that bind to the Fcε–RI–α subunit may
fix complement and activate the classic cascade (90). The autoimmune nature is
further suggested by the frequent coexistence of autoantibodies to thyroglobulin
and/or thyroid peroxidase. This hypothesis offers the potential for future innova-
tive therapies for this common clinical disorder, which may frustrate patients and
physicians alike.
XIV. HISTAMINE AND THE COMMON COLD
Human rhinoviruses account for the majority of common colds, although para-
influenza virus, adenovirus, respiratory syncytial virus, influenza, and other vi-
ruses may also be causative factors. Viral replication may occur in the adenoidal
tissue and spread anteriorly and posteriorly. Until recently, bradykinin was the
only mediator found to be consistently elevated in nasal secretions in upper respi-
ratory tract infections (91). Vascular leak and symptom severity parallel each
other over the first 3 days of infection, only to subside as glandular secretion
becomes more prominent. Additional mediators such as histamine, interleukins
and prostaglandins, and stimulation of parasympathetic reflexes exacerbate the
vasodilation of nasal blood vessels, plasma transudation, glandular secretion, and
other pathophysiological processes (92). Nociceptive nerve stimulation triggers
sensations of irritation, sore throat, nasal congestion and obstruction, and sneeze and
cough reflexes (93). Computed tomography scans demonstrate the accumulation of
secretions in the maxillary and other paranasal sinuses after 4 days. This may repre-
sent a sterile transudate. It generally resolves completely within 6 weeks.
Rhinovirus infection has been causally linked with changes in lower air-
ways physiology and asthma exacerbations. Rhinoviral colds are associated with
a bronchial mucosal lymphocytic and eosinophilic infiltrate that may be related
to changes in airway responsiveness and asthma exacerbations (94). Trigg et al.
compared bronchial inflammation and the common cold in atopic and nonatopic
subjects. They found that lower airways inflammation was present in allergic and
nonallergic normal subjects with colds, but atopic subjects were less likely to
have positive results of virological tests and more likely to show activated eosino-
philia in the lower airway, even though they had similar symptoms (95). The
increased severity in atopic subjects suggested a potential role for histamine in
this process; however, studies of antihistamines in this setting have produced
mixed results. First-generation antihistamines do appear to decrease rhinorrhea,
but this may be because of their anticholinergic properties (96), which also con-
tribute to their adverse effects.
XV. SUMMARY
Histamine is a potent vasoactive agent, bronchial smooth muscle constrictor, and

stimulant of nociceptive itch nerves. Activation of H 1-receptors plays a central
role in the immediate allergic reaction, but has less of an impact in chronic aller-
gic disorders where inflammatory infiltrates, additional mediators such as LTC 4 /
D 4 /E 4 and cytokines, and structural remodeling occur.
Histamine, through its H 1-receptor-mediated activities, appears to be pri-
marily a proinflammatory agent, yet it does have some homeostatic functions in
gastric acid production (H 2-receptors) and the central nervous system (predomi-
nantly H 3-receptors) (97, 98). The realization that first-generation antihistamines
often had mixed pharmacological properties (e.g., anticholinergic actions) and
crossed the blood–brain barrier led to the development of the second-generation
drugs, which are more selective for H 1-receptors, have less access to the central
nervous system, and, therefore, a more favorable benefit-to-risk ratio (therapeutic

index). The potential for combined H 1 –H 3-antagonists remains to be fully ex-
plored, but offers another exciting opportunity for this ever-expanding family of
beneficial drugs.
ACKNOWLEDGMENTS
This work was supported by U.S. Public Health Service Award AI42403 and
Environmental Protection Agency Award R825814.
REFERENCES
1. Dale HH, Laidlaw PP. The physiologic action of B-imidazolylethylamine. J Physiol

1910; 41:318–344.
2. Riley JF, West DB. Histamine and tissue mast cells. J Physiol 1953; 120:528–537.
3. White MV, Kaliner MA. Histamine in allergic diseases. In: Simons FER, ed. Hista-
mine and H 1-Receptor Antagonists in Allergic Disease. New York: Marcel Dekker,
1996:61–90.
4. Soll AH, Lewin KJ, Beaven MA. Isolation of histamine-containing cells from rat
gastric mucosa: biochemical and morphologic differences from mast cells. Gastroen-
terology 1981; 80:717–727.
5. Metcalfe DD. Effector cell heterogeneity in immediate hypersensitivity reactions.
Clin Rev Allergy 1983; 1:311–325.
6. Wolff AA, Gross SS, Levi R. Histamine receptors: Involvement in cardiac function
and dysfunction. In: Settipane GA, ed. H 1 and H 2 Histamine Receptors. Providence,
RI: Ocean Side Publications, 1988–1989:61–64.
7. White MV, Slater JE, Kaliner MA. Histamine and asthma. Am Rev Respir Dis 1987;
135:1165–1176.
8. Wilson JR, Manning KA, Forestner DM, Counts SE, Uhlrich DJ. Comparison of
cholinergic and histaminergic axons in lateral geniculate complex of the macaque
monkey. Anat Rec 1999; 255:295–305.
9. Yanai K, Okamura N, Tagawa M, Itoh M, Watanabe T. New findings in pharmaco-
logical effects induced by antihistamines: from PET studies to knock-out mice. Clin
Exp Allergy 1999; 29(suppl 3):29–36.
10. Saitou K, Kaneko Y, Sugimoto Y, Chen Z, Kamei C. Slow wave sleep-inducing
effects of first generation H 1-antagonists. Biol Pharm Bull 1999; 22:1079–1082.
11. Hasenohrl RU, Weth K, Huston JP. Intraventricular infusion of the histamine H(1)
receptor antagonist chlorpheniramine improves maze performance and has anxio-
lytic-like effects in aged hybrid Fischer 344xBrown Norway rats. Exp Brain Res
1999; 128:435–440.
12. Fang S-Y, Druce HM, Baraniuk JN. Anticholinergic properties of brompheniramine,
chlorpheniramine and atropine in human nasal mucosa in vitro. Am J Rhinol 1998;
12:131–133.
13. Spaeth J, Klimek L, Mosges R. Sedation in allergic rhinitis is caused by the condition
and not by antihistamine treatment. Allergy 1996; 51:893–906.
14. Baraniuk JN, Clauw JD, Gaumond E. Rhinitis symptoms in chronic fatigue syn-
drome. Ann Allergy Asthma Immunol 1998; 81:359–365.
15. Lawlor G, Fischer T, Adelman D. Immediate hypersensitivity: approach to diagno-
sis. Man Allergy Immunol 1995; 2:18–39.
16. de Backer MD, Gommeren W, Moereels H, Nobels G, Van Gompel P, Leysen JE,
Luyten WH. Genomic cloning, heterologous expression and pharmacological char-
acterization of a human histamine H 1-receptor. Biochem Biophys Res Commun
1993; 197:1601–1608.
17. Fukui H, Ohta K, Yamamoto D. Ligand recognition and activation mechanism of
histamine H 1-receptor. Nippon Yakurigaku Zasshi 1999; 113:289–297.
18. Iriyoshi N, Takeuchi K, Yuta A, Ukai K, Sakakura Y. Increased expression of hista-
mine H 1-receptor mRNA in allergic rhinitis. Clin Exp Allergy 1996; 26:379–385.
19. Okayama M, Baraniuk JN, Hausfeld JN, Merida M, Kaliner MA. Characterization
and autoradiographic localization of histamine H 1-receptors in human nasal turbi-
nates. J Allergy Clin Immunol 1992; 89:1144–1150.
20. Ohkawa C, Ukai K, Miyahara Y, Takeuchi K, Sakakura Y. Histamine H 1-receptor
and reactivity of the nasal mucosa of sensitized guinea pigs. Auris Nasus Larynx
1999; 26:293–298.
21. Raphael GD, Meredith SD, Baraniuk JN, Druce HM, Banks SM, Kaliner MA. The
pathophysiology of rhinitis. II. Assessment of the sources of protein in histamine-
induced nasal secretions. Am Rev Respir Dis 1989; 139:791–800.
22. Black JW, Duncan WAM, Durant GJ, Ganellin CR, Parsons EM. Definition and
antagonism of histamine H 2-receptors. Nature 1972; 236:385–390.
23. Hill SJ. Distribution, properties, and functional characteristics of three classes of
histamine receptor. Pharmacol Rev 1990; 42:45–83.
24. Uddman R, Moller S, Cardell LO, Edvinsson L. Expression of histamine H 1- and
H 2-receptors in human nasal mucosa. Acta Otolaryngol 1999; 119:588–591.
25. Kaliner M, Singler R, Summers R, et al. Effects of infused histamine: analysis of
the effects of H 1- and H 2-histamine receptor antagonists on cardiovascular and pul-
monary responses. J Allergy Clin Immunol 1981; 68:365–371.
26. Schaefer U, Schmitz V, Schneider A, Neugebauer E. Histamine induced homologous
and heterologous regulation of histamine receptor subtype mRNA expression in cul-
tured endothelial cells. Shock. 1999; 12:309–315.
27. Arrang JM, Garbarg M, Schwartz JC. Auto-inhibition of brain histamine release
mediated by a novel class (H 3 ) of histamine receptor. Nature 1983; 302:832–
837.
28. Malinowska B, Godlewski G, Schlicker E. Histamine H 3-receptors—general charac-
terization and their function in the cardiovascular system. J Physiol Pharmacol 1998;
49:191–211.
29. Schwartz JC, Arrang JM, Garbarg M, Korner M. Properties and roles of the three
subclasses of histamine receptors in brain. J Exp Biol 1986; 124:203–224.
30. Onodera K, Miyazaki S. The roles of histamine H 3-receptors in the behavioral disor-
ders and neuropsychopharmacological aspects of its ligands in the brain. Nippon
Yakurigaku Zasshi 1999; 114:89–106.
31. Rozneicki JJ, Letourneau R, Sugiultzoglu M, Spanos C, Gorbach J, Theoharides

TC. Differential effect of histamine 3 receptor-active agents on brain, but not perito-
neal, mast cell activation. J Pharmacol Exp Ther 1999; 290:1427–1435.
32. McLeod RL, Mingo GG, Herczku C, DeGennaro-Culver F, Kreutner W, Egan RW,
Hey JA. Combined histamine H 1- and H 3-receptor blockade produces nasal deconges-
tion in an experimental model of nasal congestion. Am J Rhinol 1999; 13:391–399.
33. Actis LA, Smoot JC, Barancin CE, Findlay RH. Comparison of differential plating
media and two chromatography techniques for the detection of histamine production
in bacteria. J Microbiol Methods 1999; 39:79–90.
34. Larsen FO, Norn S, Mordhorst CH, Skov PS, Milman N, Clementsen P. Chlamydia
pneumoniae and possible relationship to asthma. Serum immunoglobulins and hista-
mine release in patients and controls. APMIS 1998; 106:928–934.
35. Yamamoto J, Watanabe S, Hirose M, Osada T, Ra C, Sato N. Role of mast cells
as a trigger of inflammation in Helicobacter pylori infection. J Physiol Pharmacol
1999; 50:17–23.
36. Tamaoki J, Araake M, Chiyotani A, Isono K, Nagai A. Airway hyperresponsiveness
to histamine in mycoplasmal infection: role of histamine N-methyltransferase. Eur
J Pharmacol 1998; 347:257–260.
37. Pietrzkowicz M, Grzelewska-Rzymowska I. Histamine as a mediator of allergic in-
flammation. Pol Merkuriusz Lek 1999; 6:232–235.
38. Baraniuk JN. Pathogenesis of allergic rhinitis. J Allergy Clin Immunol 1997; 99:
S763–S772.
39. Andriopoulou P, Navarro P, Zanetti A, Lampugnani MG, Dejana E. Histamine in-
duces tyrosine phosphorylation of endothelial cell-to-cell adherens junctions. Arte-
rioscler Thromb Vasc Biol 1999; 19:2286–2297.
40. van Nieuw Amerongen GP, Draijer R, Vermeer MA, van Hinsbergh VW. Transient
and prolonged increase in endothelial permeability induced by histamine and throm-
bin: role of protein kinases, calcium, and RhoA. Circ Res 1998; 83:1115–1123.
41. Erjefalt I, Persson CGA. Allergen, bradykinin, and capsaicin increase outward but
not inward macromolecular permeability of guinea-pig tracheobronchial mucus. Clin
Exp Allergy 1991; 21:217–224.
42. Johnston B, Gaboury JP, Suematsu M, Kubes P. Nitric oxide inhibits microvascular
protein leakage induced by leukocyte adhesion-independent and adhesion-dependent
inflammatory mediators. Microcirculation 1999; 6:153–162.
43. Naclerio RM, Baroody FM, Kagey-Sobotka A, Lichtenstein LM. Basophils and eo-
sinophils in allergic rhinitis. J Allergy Clin Immunol 1994; 94:1303–1309.
44. Togias A, Naclerio RM, Proud D, Pipkorn U, Bascom R, Iliopoulos O, Kagey-So-
botka A, Norman PS, Lichtenstein LM. Studies on the allergic and nonallergic nasal
inflammation. J Allergy Clin Immunol 1988; 81:782–790.
45. Sommerhoff CP, Caughey GH, Finkbeiner WE, Lazarus SC, Basbaum CB, Nadel
JA. Mast cell chymase: a potent secretagogue for airway gland serous cells. J Immu-
nol 1989; 142:2450–2456.
46. Holgate ST, Bradding P, Sampson AP. Leukotriene antagonists and synthesis inhibi-
tors: new directions in asthma therapy. J Allergy Clin Immunol 1996; 98:1–13.
47. Fernvik E, Hallden G, Lundahl J, Raud J, Alkner U, van Hage-Hamsten M, Gronneb-
erg R. Allergen-induced accumulation of eosinophils and lymphocytes in skin cham-
bers is associated with increased levels of interleukin-4 and sVCAM-1. Allergy

1999; 54:455–463.
48. Bachert C. Histamine—a major role in allergy? Clin Exp Allergy 1998; 28(Suppl
6):15–17.
49. Boss V, Wang X, Koppelman LF, Xu K, Murphy TJ. Histamine induces nuclear
factor of activated T cell-mediated transcription and cyclosporin A-sensitive in-
terleukin-8 mRNA expression in human umbilical vein endothelial cells. Mol Phar-
macol 1998; 54:264–272.
50. Schaefer U, Schneider A, Rixen D, Neugebauer E. Neutrophil adhesion to histamine
stimulated cultured endothelial cells is primarily mediated via activation of phospho-
lipase C and nitric oxide synthase isozymes. Inflamm Res 1998; 47:256–264.
51. Terada N, Hamano N, Maesako KI, Hiruma K, Hohki G, Suzuki K, Ishikawa K,
Konno A. Diesel exhaust particulates upregulate histamine receptor mRNA and in-
crease histamine-induced IL-8 and GM-CSF production in nasal epithelial cells and
endothelial cells. Clin Exp Allergy 1999; 29:52–59.
52. Tromp SC, Tangelder GJ, Slaaf DW, Reneman RS, van Velzen S, Engels W, van
Breda E, oude Egbrink MG. The role of mast cells and histamine in leukocyte-
endothelium interactions in four rat strains. Pflugers Arch 1998; 436:255–261.
53. Devalia JL, Davies RJ. Effect of antihistamines on epithelial cells. Clin Exp Allergy
1999; 29(Suppl 3):64–68.
54. Baroody FM, Cruz AA, Lichtenstein LM, Kagey-Sobotka A, Proud D, Naclerio RM.
Intranasal beclomethasone inhibits antigen-induced nasal hyperresponsiveness to
histamine. J Allergy Clin Immunol 1992; 90:373–376.
55. Baraniuk JN. Mechanisms of rhinitis. In: Lasley MV, Altman LC, eds. Rhinitis.
Philadelphia: Immunology and Allergy Clinics of North America, May 2000.
56. Terada N, Konno A, Togawa K. Biochemical properties of eosinophils and their
preferential accumulation mechanism in nasal allergy. J Allergy Clin Immunol 1994;
94:629–642.
57. Gosset P, Malaquin F, Delneste Y, Wallaert B, Capron A, Joseph M, Tonnel AB.
Interleukin-6 and interleukin-1α production is associated with antigen-induced late
nasal response. J Allergy Clin Immunol 1993; 92:878–890.
58. Menardo JL, Horak F, Danzig MR, Czarlewski W. A review of loratadine in
the treatment of patients with allergic bronchial asthma. Clin Ther 1997; 19:1278–
1293.
59. Schmidt D, Ruehlmann E, Branscheid D, Magnussen H, Rabe KH. Passive sensitiza-
tion of human airways increases responsiveness to leukotriene C4. Eur Respir J
1991; 14:315–319.
60. Mitsunobu F, Mifune T, Hosaki Y, Ashida K, Yokota S, Tsugeno H, Tanizaki Y.
Different roles of histamine and leukotriene C4 in the airways between patients with
atopic and nonatopic asthma. J Asthma 1998; 4:367–372.
61. Simons FE. Is histamine H 1-receptor antagonist therapy useful in clinical asthma?
Clin Exp Allergy 1999; 3:98–104.
62. Akagi M. Histamine in the pathogenesis of asthma. Nippon Yakurigaku Zasshi 1998;
111:217–222.
63. Roquet A, Dahlen B, Kumlin M, Ihre E, Anstren G, Binks S, Dahlen SE. Combined
antagonism of leukotrienes and histamine produces predominant inhibition of aller-
gen-induced early and late phase airway obstruction in asthmatics. Am J Respir Crit
Care Med 1997; 6:1856–1863.
64. Dahlén B, Roquet A, Inman M, Larssen F, Karlsson O, Hemmings R, Naya I,
Anstrén G, O’Byrne P, Dahlén S-E. The contribution of histamine and leukotrienes
to exercise induced airway obstruction in asthmatics. Am J Resp Crit Care Med
2000; 161:A613.
65. Meltzer EO, Malmstrom K, Lu S, Prenner BM, Wei LX, Weinstein SF, Wolfe JD,
Reiss TF. Concomitant montelukast and loratadine as treatment for seasonal allergic
rhinitis: a randomized, placebo-controlled clinical trial. J Allergy Clin Immunol
2000; 105:917–922.
66. Makker HK, Springall DR, Redington AE, Ghatei MA, Bloom SR, Polak JM, How-
arth PH, Holgate ST. Airway endothelin levels in asthma: influence of endobronchial
hypertonic saline challenge. Clin Exp Allergy 1999; 29:241–247.
67. Baraniuk JN, Ali M, Yuta A, Fang S-Y, Naranch K. Hypertonic saline nasal pro-
vocation stimulates nociceptive nerves, substance P release, and glandular
mucous exocytosis in normal humans. Am J Respir Crit Care Med 1999; 160:655–
662.
68. Chong LK, Peachell PT. Beta-adrenoceptor reserve in human lung: a comparison
between airway smooth muscle and mast cells. Eur J Pharmacol 1999; 378:115–
122.
69. Baroody FM, Gungor A, deTineo M, Haney L, Blair C, Nacleiro RM. Comparison
of the response to histamine challenge of the nose and the maxillary sinus: effect
of loratadine. J Appl Physiol 1999; 87:1038–1047.
70. Ogino S, Abe Y, Irifune M, Harada T, Matsunaga T, Imamura I, Fukui H. Histamine
metabolism in nasal polyps. Ann Otol Rhinol Laryngol 1993; 102:152–156.
71. Raphael GD, Baraniuk JN, Kaliner MA. How and why the nose runs. J Allergy Clin
Immunol 1991; 87:457–467.
72. Voynow JA, Selby DM, Rose MC. Mucin gene expression (MUC1, MUC2, and
MUC5/5AC) in nasal epithelial cells of cystic fibrosis, allergic rhinitis, and normal
individuals. Lung 1998; 176:345–354.
73. Wills-Karp M, Luyimbazi J, Xu X, Schofeield B, Neben TY, Karp CL, Donaldson
DD. Interleukin-13: central mediator of allergic asthma. Science 1998; 282:2258–
2261.
74. Mosimann BL, White MV, Hohman RJ, Goldrich MS, Kaulbach HC, Kaliner MA.
Substance P, calcitonin-gene related peptide, and vasoactive intestinal peptide in-
crease in nasal secretions after allergen challenge in atopic patients. J Allergy Clin
Immunol 1993; 92:95–104.
75. Spector S, Dockhorn W, Georgitis J, Wood C, Meltzer E, Kaliner M, Baraniuk JN,
Naclerio R, Druce H. Intranasal anticholinergic treatment of nasal disorders. J Al-
lergy Clin Immunol 1992; 90:1082–1086.
76. Struck HG, Wicht A, Ponicke K, Lautenschlager C, Lubbe D. Histamine in tears
in allergic rhinoconjunctivitis. Ophthalmology 1998; 95:241–246.
77. Leonardi A, Radice M, Fregona IA, Plebani M, Abatangelo G, Secchi AG. Histamine
effects on conjunctival fibroblasts from patients with vernal conjunctivitis. Exp Eye
Res 1999; 68:739–746.
78. Abelson MB, Leonardi AA, Smith LM, Fregona IA, George MA, Secchi AG. Hista-
minase activity in patients with vernal keratoconjunctivitis. Ophthalmology 1995;

102:1958–1963.
79. Leonardi AA, Smith LM, Fregona IA, Salmaso M, Secchi AG. Tear histamine and
histaminase during the early (EPR) and late (LPR) phases of the allergic reaction
and the effects of lodoxamide. Eur J Ophthalmol 1996; 6:106–112.
80. Yanni JM, Weimer LK, Sharif NA, Xu SX, Gamache DA, Spellman JM. Inhibition
of histamine-induced human conjunctival epithelial cell responses by ocular allergy
drugs. Arch Ophthalmol 1999; 117:643–647.
81. Chonmaitree T, Patel JA, Lett-Brown MA, Uchida T, Garofalo R, Owen MJ, Howie
VM. Virus and bacteria enhance histamine production in middle ear fluids of chil-
dren with acute otitis media. J Infect Dis 1994; 169:1265–1270.
82. Skoner DP, Stillwagon PK, Casselbrandt ML, Tanner EP, Doyle WJ, Fireman P.
Inflammatory mediators in chronic otitis media with effusion. Arch Otolaryngol
Head Neck Surg 1988; 114:1131–1133.
83. Berger G, Ophir D. Possible role of adenoid mast cells in the pathogenesis of secre-
tory otitis media. Ann Otol Rhinol Laryngol 1994; 103:632–635.
84. Esaki Y, Ohashi Y, Furuya H, Sugiura Y, Ohno Y, Okamoto H, Nakai Y. Histamine-
induced mucociliary dysfunction and otitis media with effusion. Acta Otolaryngol
Suppl 1991; 486:116–134.
85. Boisvert P, Wasserman SI, Schiff M, Ryan AF. Histamine-induced middle ear effu-
sion and mucosal histopathology in the guinea pig. Ann Otol Rhinol Laryngol 1985;
94:212–216.
86. Goldie P, Hellstrom S. Identification and characterization of middle ear vascular
leakage sites in experimental otitis media. Ann Otol Rhinol Laryngol 1990; 99:810–
816.
87. Sankovic S, Dergenc R, Bojic P. Mastocytes in chronic inflammation of middle ear
mucosa. Srp Arh Celok Lek 1999; 127:35–38.
88. Lewis T. The Blood Vessels of the Human Skin and Their Responses. London: Shaw
and Sons, 1927.
89. Alonso Lebrero E. Round Table. Urticaria and angioedema: introduction and classi-
fication. Allergol Immunopathol 1999; 27:71–73.
90. Ferrer M, Nakazawa K, Kaplan AP. Complement dependence of histamine release
in chronic urticaria. J Allergy Clin Immunol 1999; 104:169–172.
91. Naclerio RM, Proud D, Lichtenstein LM, Kagey-Sobotka A, Hendley JO, Sorrentino
J, Gwaltney JM. Kinins are generated during experimental rhinovirus colds. J Infect
Dis 1988; 157:133–142.
92. Gwaltney J Jr. Pathogenesis of rhinovirus colds: implications for management. Pro-
gram and abstracts of the Second International Symposium on Influenza and Other
Respiratory Viruses; December 10–12, 1999; Grand Cayman, Cayman Islands, Brit-
ish West Indies.
93. Gwaltney JM. Rhinovirus infection of the normal human airway. Am J Respir Crit
Care Med 1995; 152:S36–39.
94. Fraenkel DJ, Bardin PG, Sanderson G, Lampe F, Johnston SL, Holgate ST. Lower
airways inflammation during rhinovirus colds in normal and in asthmatic subjects.
Am J Respir Crit Care Med 1995; 151:879–886.
95. Trigg CJ, Nicholson KG, Wang JH, Ireland DC, Jordan S, Duddle JM, Hamilton
S, Davies RJ. Bronchial inflammation and the common cold: a comparison of atopic
and non-atopic individuals. Clin Exp Allergy 1996; 26:665–676.
96. Gwaltney JM Jr, Druce HM. Efficacy of bronpheniramine maleate for the treatment
of rhinovirus colds. Clin Infect Dis 1997; 25:1188–1194.
97. Irani AA, Schechter NM, Craig SS, DeBlois G, Schwartz LB. Two types of human
mast cells that have distinct neutral protease compositions. Proc Natl Acad Sci USA
1986; 83:4464–4468.
98. Yang OZ, Hatton GI. H 3-histamine receptors activate K⫹ channels to hyperpolarize
magnocellular histaminergic neurons of rat posterior hypothalamus. Soc Neurosci
Abstr 1991; 17:409.
2
Histamine Receptors: Specific
Ligands, Receptor Biochemistry,
and Signal Transduction
Remko A. Bakker, Hendrik Timmerman, and Rob Leurs

Vrije Universiteit, Amsterdam, The Netherlands
I. INTRODUCTION
The monoamine histamine is an important chemical messenger that regulates a

wide variety of physiological responses in the brain and peripheral organs. In
the central nervous system (CNS) this amine is synthesized in a restricted popula-
tion of neurons located in the tuberomammillary nucleus of the posterior hypo-
thalamus. These neurons project diffusely to most cerebral areas and have been
implicated in various functions of the brain of mammalian species (e.g., sleep/
wakefulness, hormonal secretion, cardiovascular control) (1–3). In various pe-
ripheral tissues histamine is stored in mast cells, basophils, enterochromaffin
cells, and probably also in specific neurons. In the gastric mucosa, histamine
release from enterochromaffin cells stimulates the gastric acid secretion by pari-
etal cells, whereas histamine release after mast cell degranulation leads to various
allergic phenomena conditions in skin and airway preparations (3, 4). Initially,
research in the histamine field focused completely on the role of histamine in
allergic diseases. This intensive research resulted in the development of several
potent ‘‘antihistamines’’ (e.g., mepyramine), which were useful in inhibiting
many symptoms of allergic disorders. The observation that these ‘‘antihista-
mines’’ could not antagonize all histamine effects led Ash and Schild in 1966
to hypothesize the existence of at least two distinct receptor subtypes (5). In
1972 this hypothesis became generally accepted, when Black and his co-workers
succeeded in synthesizing a series of new compounds (e.g., burimamide), which
antagonized the effects of histamine on the stomach and heart (6). These H 2-
27
28 Bakker et al.
receptor antagonists proved to be useful in the therapy of gastric ulcers. The

identification of the presynaptic H 3-receptor as a new receptor subtype in 1983
by Arrang and colleagues (7) gave rise to a new field of interest. The H 3-receptor
is now regarded as a general regulatory system and a potential target for new
therapeutic interventions (8). The use of genomic databases has recently resulted
in the identification of a new histamine receptor, the histamine H 4-receptor (8a).
In view of its expression profile, this receptor is suggested to be a new target in
the regulation of immune function.
In this chapter we will review the molecular pharmacological properties of
the various histamine receptor subtypes. Attention will be given to the specific
pharmacological tools used, the biochemical aspects of the receptor proteins, and
the different biochemical processes triggered in various target cells/tissues after
receptor activation.
II. SELECTIVE LIGANDS FOR THE HISTAMINE

RECEPTORS
In this section we will describe the various histaminergic agents that can be used
for the study of the four histamine receptor subtypes. For a detailed description
of the medicinal chemistry of the histamine receptor ligands, the reader is referred
to recent reviews (9–14).
A. Histamine H 1-Receptor Ligands

Many pharmacological tools are available for the study of the H 1-receptor, al-
though highly potent receptor agonists are not yet available. For many years the
substituted 2-phenylhistamines (e.g., 2-(3-trifluoromethylphenyl)histamine) (Fig.
1) have been the best choice. These agonists show relatively high affinity for the
H 1-receptor, but appear to possess only limited potency (11). Recently, however,
Schunack’s laboratory introduced histaprodifens as a new class of highly active
H 1-agonists (15), which are clearly more potent than histamine (Fig. 1). Many
potent and selective receptor antagonists are available for the study of H 1-recep-
tors (9); however, one should be aware of the possible antagonistic properties at
muscarinic and serotoninergic receptors and of the local anesthetic properties of
several classic H 1-receptor antagonists at concentrations usually much higher than
those needed for blocking the H 1-receptor. Currently, mepyramine (pyrilamine)
(Fig. 1) is the most commonly used H 1-receptor antagonist (pA 2 ⫽ 9) for pharma-
cological studies. The d- and l-enantiomers of chlorpheniramine are also very
useful for receptor classification. These compounds penetrate the brain readily
and can thus be used for in vivo CNS studies. New H 1-receptor antagonists have
been developed (e.g., cetirizine and loratadine) (Fig. 1), which do not cross the
blood–brain barrier and are of therapeutic importance in allergic disorders (9).
Histamine Receptors 29
Figure 1 Structures of various selective histamine H 1-receptor agonists and antagonists.
Classification of the H 1-antagonists has recently been changed. As described in

the section on signal transduction, the H 1-receptor shows considerable constitu-
tive activity, which can be inhibited by most H 1-antagonists, thus acting as inverse
agonists (16).
[ 3 H] mepyramine is the best available radioligand for labeling H 1-receptors,
although the compound might be taken up in cells (17) and has been shown to
label various non-H 1-receptor binding sites (e.g., in rat liver) (18). If a very high
sensitivity is required, the iodinated ligand [125l] iodobolpyramine (24) is of in-
terest. [ 3 H]doxepin (19) and the quaternary radioligand [ 3 H] (⫹)N-methyl-4-
methyldiphenhydramine, have also been used to label H 1-receptors, although not
to a large extent (20, 21). [11C]Doxepin has been used successfully to label H 1-
receptors in the human brain in positron emission tomographic (PET) studies
(22). Finally, [ 3 H](⫺)trans-phenyl-3-aminotetralin has recently been reported as
a novel H 1-receptor radioligand (23, 24). This ligand binds with high affinity to
binding sites with H 1-receptor pharmacology, but for still unknown reasons the
number of [ 3 H](⫺)trans-phenyl-3-aminotetralin binding sites is much lower than
the number labeled with [ 3 H]mepyramine.
B. Histamine H 2-Receptor Ligands

For the histamine H 2-receptor, both agonists and antagonists are available for a
proper pharmacological characterization. Amthamine (2-amino-5-(2-amino-
ethyl)-4-methylthiazole) (Fig. 2) is the best choice for a selective H 2-agonist. It
combines a high H 2-receptor selectivity with a potency slightly higher than that of
30 Bakker et al.
histamine (25). Many compounds with potent H 2-receptor antagonistic properties

have been described (see 12, 26, 27 for extensive reviews). Nowadays, com-
pounds such as cimetidine, ranitidine, and tiotidine are usually applied as selec-
tive tools for functional studies of the H 2-receptor (Fig. 2). As in the case of the
H 1-antagonists, the recognition of constitutive activity of the H 2-receptor (see the
signal transduction section) resulted in the reclassification of cimetidine, ranitid-
ine, and tiotidine as inverse agonists and burimamide as a neutral antagonist (28)
or a weak partial agonist (29). Although [ 3 H]tiotidine has been used for labeling
H 2-receptors in various tissues, the high level of nonspecific binding has led to
the development of [ 125 I]iodoaminopotentidine (30). This iodinated H 2-receptor
radioligand labels H 2-receptors with high affinity and provides a sensitive method
for the detection of H 2-receptor expression.
C. Histamine H 3-Receptor Ligands

Soon after the initial description of the H 3-receptor (17), Arrang et al. de-
scribed highly potent and selective ligands for this receptor subtype (31); (R)-
α-methylhistamine and thioperamide, an H 3-receptor agonist and an antagonist,
respectively, are valuable tools for receptor identification (Fig. 3), although they
have recently been reported to interact with the H 4-receptor as well. The use
of (R)-α-methylhistamine in combination with its less active enantiomer (S)-α-
methylhistamine is very effective for the characterization of H 3-receptor-medi-
ated effects. Recently, the dimethylated histamine analog (R)-α,β-dimethylhis-
tamine has also been shown to be a potent H 3-receptor agonist (32). In addition,
isothiourea analogs of histamine resulted in the development of potent H 3-recep-
tor agonists and antagonists (33).
The unsubstituted isothiourea analog S-[2-(4(5)-imidazolyl)ethyl]iso-
thiourea (VUF 8325 or imetit) (Fig. 3) is a very potent agonist (34–36). In addi-
tion, immepip (4(5)-1H-imidazolylmethylpiperidine) (Fig. 3) with the side chain
incorporated in a piperidine ring was shown to possess high H 3-agonistic po-

tency (38). In contrast to immepip, (R)-α-methylhistamine shows some α 2- and
H 1-agonistic activity, whereas imetit shows reasonable 5-HT 3-agonistic activity
(37, 39). Yet immepip acts as an H 4-receptor agonist as well.
A wide variety of potent H 3-antagonists have been described to date (13).
Thioperamide (Fig. 3) (pA 2 ⫽ 8.4) (31) and clobenpropit (Fig. 3) (pA 2 ⫽ 9.9)
(35), developed some years ago, are often considered to be the standard H 3-
antagonists. Thioperamide also acts as an H 4-receptor antagonist, whereas cloben-
propit surprisingly acts as an H 4-receptor agonist. One should be aware that clobe-
npropit does not easily penetrate the blood–brain barrier in rats (40) and mice
(41), whereas thioperamide also interacts with cytochrome P-450 (42, 43) and
5-HT 3 and sigma receptors (39). It is also important to mention that GT-2331
(Fig. 3) (K i ⫽ 0, 15 nM), also known as Perceptin (13), is currently under clinical
evaluation and might be the first clinically useful drug to target the H 3-receptor.
Due to the availability of various compounds with a very high H 3-receptor
affinity, it is not surprising that currently a variety of radioligands for the H 3-
receptor are also available. With the initial description of (R)-α-methylhistamine
as a selective ligand for the H 3-receptor (31), the tritiated compound was reported
as a suitable radioligand for the H 3-receptor (31). To overcome the low specific
activity of [ 3 H](R)-α-methylhistamine, [ 3 H]Nα-methylhistamine was labeled to
a threefold higher specific activity and has been used successfully to label H 3-
receptors (44). [ 125 I]Iodoproxyfan can be used as a highly sensitive agonist ra-
dioligand, although it was originally introduced as an iodinated antagonist (45).
A variety of radiolabeled H 3-antagonists have been reported in the literature.
[ 3 H]Thioperamide (43) and [ 3 H]S-methylthioperamide (46) have been used to
probe the H 3-receptor, but exhibit complex behavior which is probably related to
the interaction of the radioligand with cytochrome P-450 isoenzymes (43). In con-
32 Bakker et al.
trast, the guanidine analog of thioperamide, [ 3 H]GR168320 (47), and [ 3 H]cloben-

propit (48) are quite well validated and function as high-affinity radioligands for
H 3-receptors in the brain or intestine. [ 125 I]Iodophenpropit, a clobenpropit analog,
can be used as a highly sensitive H 3-receptor radioligand (49).
D. Histamine H 4-Receptor Ligands

Heterologous expression of the H 4-receptor in cells confers the ability to bind
[ 3H]histamine with high affinity (KD ⫽ 5 nM). Pharmacologically the H 4-receptor
resembles to some extent the histamine H 3-receptor in that it binds many of the
known H 3-agonists and antagonists, albeit with a different rank order of affinity
and potency. Oda and colleagues have shown that the histamine H 4-receptor can
bind and be activated by histamine, but also by the H 3-receptor ligands as R-(α)-
methylhistamine, N-(α)-methylhistamine, clozapine, imetit, immepip, and inter-
estingly also by the H 2-receptor antagonist burimamide and the H 3-receptor an-
tagonist clobenpropit (49a).
The H 4-receptor does not bind H 1- and H 2-receptor antagonists such as
diphenhydramine, loratadine, ranitidine, and cimetidine, but has modest affinity
for the H 2-receptor agonist, dimaprit (377 nM) (49b).
III. MOLECULAR ASPECTS OF THE HISTAMINE

RECEPTORS
In this section we describe the three histamine-receptor subtypes that were tradi-
tionally characterized by pharmacological techniques, and subsequently, with the
availability of modern molecular biological approaches, have also been identified
by gene cloning. We now have a detailed understanding of the receptor proteins
and their function at the molecular level.
A. The H 1-Receptor
1. Receptor Biochemistry
Using [ 125 I]iodoazidophenpyramine, Ruat et al. irreversibly labeled H 1-receptor
proteins in rat, guinea pig, and mouse brain (50, 51). Following sodium dodecyl
sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) analysis of the labeled
proteins, two main polypeptides (56 and 41–47 kDa) were found to be specifi-
cally labeled (51). Based on experiments with protease inhibitors, it was sug-
gested that the H 1-receptor is a 56 kDa peptide, whereas the other labeled peptide
was probably a result of protease action (51). Using [ 3 H]azidobenzamide, Yama-
shita et al. recently found receptor peptides of similar size (53–58 kDa) to be
labeled in bovine adrenal medulla membranes (52). Whereas the 56 kDa peptide
was also found in guinea pig lung and ileum, a peptide with a substantially higher
molecular weight (68 kDa) was labeled in guinea pig heart tissue (50). Although
at present no pharmacological differences have been observed between the H 1-
receptors from guinea pig heart and brain tissue, these results suggest the occur-
rence of several isoforms for the H 1-receptor. Also, the molecular weight found
for the H 1-receptor after photoaffinity labeling is in sharp contrast with the re-
ported weight (38–40 kDa) of a purified [ 3 H]mepyramine-binding protein from
DDT1-MF2 smooth muscle cells (53, 54). Since several highly potent H 1-receptor
antagonists possess only a moderate affinity for this binding protein, it is not yet
clear whether the binding of [ 3 H]mepyramine to these cells really represents H 1-
receptor binding (53).
2. Molecular Biology of the H 1-Receptor

Recently, Yamashita et al. cloned the gene encoding the bovine H 1-receptor (55)
by expression cloning. The H 1-receptor cDNA encodes for a 491 amino acid
receptor protein (apparent molecular weight 56 kDa) with all of the structural
features of a G-protein-coupled receptor (GPCR), 7 transmembrane domains
(TMs), N-terminal glycosylation sites, and phosphorylation sites for protein ki-
nase A and C (55). Based on biochemical studies, it is known that the H 1-receptor
protein from guinea pig brain is glycosylated (56). Therefore, the predicted mo-
lecular weight of 56 kDa is almost certainly an underestimate.
Using the sequence information of the bovine H 1-receptor gene, the genes
for the rat (57), guinea pig (58), mouse (59), and human (60–63) H 1-receptor
have now also been cloned. De Backer et al. recently identified a previously
unknown intron of approximately 5.8 kb in the 5′ untranslated region immediately
upstream of the start codon (64). Several groups have individually mapped the
H 1-receptor gene to chromosome 3, and have localized the gene on bands 3p14–
p21 (65), or band 3p25 (61, 64). In the promotor region of the H 1-receptor, several
potential transcription factor binding sites were identified, including glucocorti-
coid response element (GRE), Sp1, AP1, AP2, and NF-κB. Several of these tran-
scription factors are involved in the regulation of inflammatory genes as well as
in pathophysiological conditions that induce the expression of the H 1-receptor
(64). In this respect, the observed effect of dexamethasone on H 1-receptor func-
tion (66) and expression (67) is clearly of interest as well. The expression of the
histamine H 1-receptor gene is repressed by binding of the human TR2 orphan
receptor, a member of the steroid/thyroid hormone receptor family, to the 3′
flanking region of the receptor (68).
The H 1-receptor protein is encoded by a single exon and contains 486 (rat
[57]), 488 (guinea pig [58, 69], mouse [59]), 491 (bovine [55]), or 487 (human
[61–63]) amino acids. The homology among the several receptor proteins is quite
high in the transmembrane domains (90%), but is significantly lower in the intra-
cellular and extracellular domains. The various cloned genes are real species
homologs, although some small changes in pharmacology are evident (55, 58, 63).
34 Bakker et al.
Figure 4 Molecular model of histamine docked into the guinea pig histamine H 1-recep-
tor according to information from site-directed mutagenesis studies using AMBER 4.1
molecular dynamics simulations (15). Five of seven helices (II–VI) in the transmembrane
region of the histamine H 1-receptor are shown in yellow (see color plate). In this model,
three residues in the ligand-binding pocket (Asp116 in helix III [71], Lys200 in helix V [74,
75], and Asn207 in helix V [72]) contribute to the binding of histamine via intermolecular
hydrogen bonds.
With the availability of the cloned genes, detailed information on the recep-
tor–ligand interaction can now be obtained. From site-directed mutagenesis stud-
ies of various other aminergic receptors, it is generally accepted that the binding
of biogenic amines mainly occurs within the transmembrane (TM) domains (70).
The H 1-receptor also binds agonists and antagonists within the TM domains. Fig-
ure 4 shows the current concepts regarding the interaction of histamine with the
TM domains 3 and 5. The protonated amine function of histamine interacts with
the aspartate residue in the TM domain TM3 (71, 72), whereas the imidazole ring
makes hydrogen bond contacts with an asparagine and lysine residue in TM5 (73,
74). The asparagine residue appears to be very important for the interaction with
histamine and 2-methylhistamine (73), but seems to be only of minor importance
for 2-(3-bromophenyl) histamine. As was already suggested on the basis of phar-
macochemical studies (33), the aromatic 2-substituent apparently interacts in a
specific way with the H 1-receptor (15), and this interaction results in high-affinity
binding to the receptor protein. More detailed studies should identify the amino
acid residues of the H 1-receptor protein involved in the interaction with the aro-
matic ring of the 2-phenylhistamines and/or histaprodifens.
The binding site of the H 1-antagonists was recently investigated in detail
(71, 75). The H 1-agonists, like the antagonists, use the conserved aspartate residue
in TM3 as a counterion for their protonated amine function (71). The combination
of this information and a pharmacophore model derived for a variety of rigid H 1-
antagonists (76) led to the prediction that the binding site of the H 1-antagonists
is located between TMs 3, 4, and 6 (75). Mutagenesis studies revealed trypto-
phane167 (TM4) and phenylalanine433 and phenylalanine435 to be involved in the
binding of the aromatic rings of mepyramine. In addition, using the same model,
an additional recognition site (lysine200 in TM5) was found for the acidic side
chain in the relatively nonsedating H 1-antagonists acrivastine and cetirizine (75).
Since the acid group was previously thought to be responsible only for limiting
brain penetration (and thus sedation), these results illustrate nicely the impact of
molecular biology.
The ultimate example of the power of molecular biology is exhibited in
the generation of histamine H 1-receptor knockout mice by the method of gene
targeting (77, 78). Targeted disruption of the H 1-receptor gene leads to a loss of
both [ 3 H]mepyramine (77, 78) and [ 3 H]doxepin (77) binding in the brain. The
knock-out mice are very useful for clarification of the role of the H 1-receptors
in behavior. The initial studies confirmed results obtained with classic pharmaco-
logical studies: histamine modulates various neurophysiological functions such
as locomotor activity, emotion, memory and learning, nociception, and aggressive
behavior through histamine H 1-receptors (79).
B. The H 2-Receptor Protein

Detailed biochemical information about the H 2-receptor has been obtained by
photoaffinity labeling studies. Using [ 125 I]iodoazidopotentidine, Ruat et al. (30)
showed that the H 2-receptor binding peptide is probably a 59 kDa protein, al-
though the purification of a [ 3 H]tiotidine binding protein from human gastric
tumor HGT-1 cells resulted in the identification of a 70 kDa protein (80). The
H 2-receptor nature of the [ 3 H]tiotidine-binding protein from these cells has not,
however, been defined clearly. Although it was once generally accepted that G-
protein-coupled receptors (GPCRs) function as monomeric entities, a growing
body of evidence suggests that receptor dimers form and play a role in receptor
function. H 2-receptor oligomer formation has been observed after overexpression
in Sf9 cells (81, 82); however, further detailed investigations are required to
36 Bakker et al.
determine whether these oligomers arise from receptor aggregation (82) or repre-
sent true receptor dimers.
2. Molecular Biology of the H 2-Receptor

The gene and cDNA encoding the H 2-receptor have been identified in several
species including humans (83–85). Using the polymerase chain reaction with
degenerate oligonucleotides based on the known sequence homology of various
G-protein-coupled receptors, and canine gastric parietal cDNA, Gantz et al. ob-
tained the intronless gene encoding the canine H 2-receptor (83). Based on infor-
mation about the canine cDNA, the nucleotide sequence encoding the rat and
human H 2-receptor were rapidly identified (84, 85). The various sequences show
considerable homology (80–90%) and are probably real species homologs (83–
85). In parallel with recent advances in the understanding of the genetic makeup
of the histamine H 1-receptor gene, the location of the human histamine H 2-recep-
tor gene has also been characterized (86). The H 2-receptor gene has been assigned
to human chromosome 5 (86) and is regulated in a complex manner.
The proximal promoter region lacks an apparent TATA box (87, 88), and
multiple transcription-initiation sites of the human histamine H 2-receptor have
been identified that may be important for tissue-specific receptor expression (88).
Also, the promoter region of the human H 2-receptor gene contains several sites
for potential transcriptional regulation, including AP2 and CRE sites, and GATA
motifs (87).
The H 2-receptor genes encode for a histamine receptor protein of 359 amino
acids in the dog (83), human (85), and guinea pig (86) or 358 in the rat (84) and
mouse (89), with many of the structural features of G-protein-coupled receptors
and an apparent molecular weight of approximately 40 kDa. Since in the N-termi-
nal extracellular tail a consensus sequence for N-linked glycosylation is present,
the actual molecular weight of the receptor will be significantly higher.
With respect to receptor recognition, the H 2-receptor uses the conserved
aspartate residue in TM3 for the binding of histamine and H 2-receptor antagonists
(90). Initial studies indicate that the threonine and aspartate residues in TM5 of
the H 2-receptor are likely to interact with histamine and the antagonist [ 3 H]tioti-
dine. Based on studies of other biogenic amine receptors, however, the interaction
of the two residues with the antagonist is rather unexpected and certainly deserves
future attention.
C. The H 3-Receptor Protein

Detailed biochemical studies of the histamine H 3-receptor have been hampered
by the low abundance of this receptor protein and the lack of highly sensitive
radioligands. Using [ 3 H]histamine, the H 3-receptor was solubilized from bovine
brain tissue, and size-exclusion chromatography revealed an apparent molecular

weight of 220 kDa (91). Due to the protein-associated digitonin, this value is
clearly overestimated. Recently, a value of 70 kDa has been reported as the mo-
lecular weight for a putative human H 3-receptor (92), purified from human gastric
tumoral cell line HGT-1; however, no clear pharmacological profile of this puta-
tive receptor protein was obtained.
2. Molecular Biology
Although the intronless genes encoding the H 1- and H 2-receptors were cloned in
1991 (55, 83), the molecular architecture of the H 3-receptor was unknown until
recently, when Lovenberg et al. showed that, like the H 1- and H 2-receptor, the
H 3-receptor belongs to the large superfamily of GPCRs (93). A potential GPCR-
related expressed sequence tag (EST)-sequence was identified in silico in a search
for orphan GPCRs and used to clone a full-length cDNA from a human thalamus
cDNA library. The cDNA contained an open reading frame (ORF) of 445 amino
acids with all the features of a GPCR for a small biogenic amine (93, 94), which
turned out to be the H 3-receptor. The H 3-receptor protein shows very low homol-
ogy with other GPCRs. Overall homology between the H 3-receptor and the H 1-
and H 2- receptor amounts to only 22% and 20%, respectively. Within the trans-
membrane (TM) domains the homology is somewhat higher (H 1, 27%; H 2 33%),
although still not very high. This remarkable divergence probably explains why
the H 3-receptor gene was not cloned by homology screening with H 1- or H 2-
receptor-specific probes. Using the information on the human H 3-receptor cDNA,
the rat (445 amino acids) and guinea pig (445 amino acids) cDNAs have been
identified recently (95, 96).
For the human, rat, and guinea pig H 3-receptor, various isoforms have been
identified. The various H 3-isoforms are generated as a result of alternative splic-
ing and show differential brain expression (96a–96d) and signaling properties
(96a, 96d), in addition, also non-functional truncated receptors have been identi-
fied (96a–96d).
So far, no data are available on the ligand-binding site or the generation of
knock-out mice; however, in view of the growing interest in the therapeutic po-
tential of H 3-ligands, these studies will certainly be performed in the near future.
D. The H 4-Receptor Protein

As part of a directed effort to discover novel G-protein-coupled receptors through
homology searching of genomic databases, a novel orphan G-protein-coupled
receptor gene was identified on chromosome 18 that has significant homology
to the recently identified histamine H 3-receptor cDNA (8a, 49a, 49b, 96e–96g).
Although the H 4-receptor shows little overall sequence homology to any of the
other histamine receptors cloned to date, it exhibits an approximately 60% homol-
38 Bakker et al.
ogy within the transmembrane domains of the H 3-receptor. The human H 4-recep-
tor gene exhibits an exon/intron arrangement nearly identical to that of the
H 3-receptor gene (49b). In view of several reports on the existence of multiple
H 3-receptor isoforms (96a–96d), the recent report on H 4-receptor isoforms is per-
haps not surprising (96h).
By means of RT-PCR low expression of the H 4-receptor is reported in a
wide variety of peripheral tissues (8), and expression is predominantly found in
eosinophils (8a, 49a, 49b, 96) and in tissues likely to contain high concentrations
of blood cells, such as bone marrow and lung (49b, 96e, 96f ). In contrast to the
H 3-receptor, expression was not detected in the brain, although in situ hybridiza-
tion analysis showed that mouse H 4-receptor mRNA is selectively expressed in
the hippocampus (96f ). The unique expression profile of the H 4-receptor suggests
it may be a therapeutic target for the regulation of immune function.
IV. TRANSMEMBRANE SIGNALING
In this section we describe the signal transduction pathways activated by the

histaminergic receptor subtypes. Along with the identification of an increasing
number of G-proteins and effector systems, histamine receptors have been shown
to activate a variety of signal transduction systems. Detailed knowledge of the
intracellular pathways activated by histamine is indispensable for a proper under-
standing of the action of histamine in (patho)physiological processes.
A. Signal Transduction of the H 1-Receptor

The histamine H 1-receptor is, among other G-protein-coupled receptors, a Ca 2⫹-
mobilizing receptor. It is widely accepted that activation of Ca 2⫹-mobilizing recep-
tors is associated with the phospholipase C-(PLC) catalyzed hydrolysis of mem-
brane inositide phospholipids. Activation of the histamine H 1-receptor (Fig. 5)
leads to the hydrolysis of phosphatidyl 4,5-biphosphate (Pl(4,5)P 2) resulting in
the formation of inositol (1,4,5)triphosphate (Ins(1,4,5)P 3) and 1,2-diacylglycerol
(DAG). Ins(1,4,5)P 3-receptors in the endoplasmic reticulum (ER) mediate the sub-
sequent release of Ca 2⫹ from the ER, thereby raising [Ca 2⫹ ] i , whereas the released
DAG activates protein kinase C (PKC). For a detailed description of the various
functions of the second messengers Ins(1,4,5)P 3, Ca 2⫹, DAG, and their downstream
effectors, the interested reader is referred to comprehensive reviews (99–101).
Recent advances in molecular biology have led to the discovery of a pleth-
ora of previously unknown signaling proteins, and rapid progress in the under-
standing of mechanisms of signal transduction has been made. In parallel with
this progress, the H 1-receptor is also found to couple to G-proteins other than
members of the G q/11 family, and the βγ subunits that are released upon receptor
activation are suggested to be involved in the H 1-receptor-mediated responses.
Figure 5 Histamine activates various signal transduction pathways via interaction with
the G-protein-coupled histamine receptors (H 1-, H 2-, H 3-, and H 4-). Activated histamine
H 1-receptors will activate the phosphoinositide pathway by activating G-proteins belong-
ing to the G q/11 family of G-proteins, which will result in the activation of PLC and the
subsequent formation of DAG and InsP 3. Histamine H 2-, H 3-, and H 4-receptor activation
will affect the adenylyl cyclase cascade. Adenylyl cyclase is activated upon H 2-receptor
activation to generate cAMP from ATP. Activation of the H 3-receptor will inhibit adenylyl
cyclase and lower cAMP levels.
1. Stimulation of Phospholipase C
Histamine has been shown to induce production of inositol phosphates in several
tissues, including brain, airway smooth muscle, intestinal smooth muscle, vascu-
lar smooth muscle, and heart (2, 102–106). Guinea pig brain regions with the
highest density of H 1-receptors display the largest phosphoinositide response
(107, 108); however, in some tissues (guinea pig ileum and neonatal brain) the
H 1-response to histamine itself appeared to be masked by an H 1-antagonist-insen-
sitive component (109, 110).
In membrane preparations of rat cerebral cortex and 1321N1 astrocytoma
cells, H 1-receptor-stimulated phospholipid hydrolysis was found to be dependent
on the presence of guanine nucleotides (103, 106). Studies in 1321N1 astrocy-
toma cells (106), HeLa cells (111), and CHO cells stably expressing H 1-receptors
(112) showed the inositol phosphate response to be mediated by a pertussis toxin-
insensitive G-protein. Furthermore, histamine increased the incorporation of [α-
40 Bakker et al.
32
P]GTP azidoanilide into G q/11-like proteins in H 1-receptor-expressing Sf9 cells
(113) as well as in membranes prepared from guinea pig heart (114). In addition,
antibodies to the α q subfamily of G-proteins have been shown to inhibit the hista-
mine stimulation of Pl(4,5)P 2 hydrolysis in 1321N1 cells (115), implicating the
involvement of Gα q/11 in the H 1-receptor response.
Activation of PLC will not only generate Ins(1,4,5)P 3 and result in the
release and cellular influx of Ca 2⫹, but will also result in the formation of DAG.
DAG in turn will activate other effectors such as isoforms of PKC and protein
kinase D (PKD). Activated PKC has many cellular functions, including desensiti-
zation of the H 1-receptor by receptor phosphorylation (116, 117) and transcrip-
tional downregulation of histamine H 1-receptor expression (118). More recently,
the histamine H 1-receptor-mediated production of diacylglycerol has been shown
to mediate an influx in [Ca 2⫹ ] i by activating transient receptor potential (TRPC)
channels, homologs of Drosophila TRP proteins (119), which are thought to me-
diate capacitative Ca 2⫹ entry (120). Histamine activated the human TRPC6, a
nonselective cation channel that is activated in a Ca 2⫹-store-depletion-indepen-
dent mechanism by diacylglycerol, independently of protein kinase C in cotrans-
fected Chinese hamster ovary (CHO)-K1 cells (119).
2. Calcium Signaling
One of the physiological consequences of the production of inositol phosphates
is the elevation of intracellular Ca 2⫹. The histamine H 1-receptor has been widely
used to study the mechanism of Ca 2⫹ release from intracellular stores and the
extracellular Ca 2⫹ influx. The histamine-induced Ca 2⫹ response is characterized
by a rapid transient rise of the intracellular Ca 2⫹ concentration, which is followed
by a sustained elevation of the Ca 2⫹ concentration. Experiments in Ca 2⫹-free
medium and with inorganic Ca 2⫹ antagonists suggest that the sustained response
is highly dependent on the influx of extracellular calcium, whereas the transient
increase is caused by the release of Ca 2⫹ from intracellular Ca 2⫹ stores (112, 121–
129). In addition, histamine H 1-receptor stimulation has been shown to result in
a slight increase in the amplitude of the [Ca 2⫹ ] i transient rise due to H 1-receptor-
mediated inhibition of the outward K⫹ current (130).
The Ca 2⫹ signal exhibits a high degree of spatiotemporal complexity in
which intracellular organelles play a key role. Ca 2⫹-signal compartmentalization
after histamine stimulation (131) has been described for various intracellular
compartments, including the cytosol (132–135), the endoplasmic reticulum (136,
137), the mitochondria (133, 138, 139), the Golgi apparatus (140), and the nu-
cleus (141, 142).
Histamine not only results in the rise of intracellular Ca 2⫹ in various com-
partments but also influences Ca 2⫹ oscillations (143, 144). Ins(1,4,5)P 3-receptors
in the ER bind Ins(1,4,5)P 3 and release calcium from the lumen. Repetitive
phosphorylation/dephosphorylation of the Ins(1,4,5)P 3-receptor by calmodulin-
dependent kinase II (CaMKII) in histamine-stimulated HeLa cells has been

shown to control sustained Ca 2⫹ oscillation in these cells (143). In addition,
Ins(1,3,4,5)P 4, a metabolite of Ins(1,4,5)P 3, modulates Ca 2⫹ entry across the
plasma membrane, is known to alter frequency and amplitude of intracellular
Ca 2⫹ oscillations in HeLa cells (145, 146), and was recently found to regulate
calcium oscillations in histamine-stimulated HeLa cells (147). These [Ca 2⫹ ] i os-
cillations, rather than an increase in amplitude of the [Ca 2⫹ ] i transient (148), have
been implicated in the regulation of gene expression (143, 149–151), which may
depend on the phosphorylation/dephosphorylation of transcription factors that
vary specifically according to distinct Ca 2⫹ frequency. Histamine has been shown
to activate the transcription factor nuclear factor of activated T cells (NFAT) in a
cyclosporin-A-sensitive manner in human umbilical vein endothelial cells (152).
Furthermore, histamine has also been shown to activate the transcription factor
nuclear factor kappa B (NF-κB) in human aortic endothelial cells (143) and in
epithelial cells (153). Although activation of NF-κB in endothelial cells appears
to occur secondarily to PLC-mediated [Ca 2⫹ ] i oscillations (143), the H 1-receptor
mediated activation of NF-κB in epithelial cells seems to involve the generation
of arachidonic acid metabolites (153).
3. Other H 1-Receptor Signaling Pathways

Since Ca 2⫹ is involved in the regulation of many cellular functions, the increase
of intracellular Ca 2⫹ concentration can explain a wide variety of pharmacological
responses induced after stimulation of the H 1-receptor. First, elevation of intracel-
lular Ca 2⫹ levels leads to further stimulation of PLC, most likely the PLC-β sub-
type, since it is known to be sensitive to Ca 2⫹ (154). Correspondingly, the hista-
mine-induced production of inositol phosphates in both brain and tracheal slices
(155, 156) and CHO cells stably expressing the guinea pig H 1-receptor (112) has
been shown to be highly dependent on the influx of extracellular Ca 2⫹. In addition
to the effects on the inositol phospholipid-signaling systems, histamine H 1-recep-
tor activation also leads to the activation of other signaling pathways, many of
which appear to be secondary to changes in intracellular calcium concentration
or the activation of protein kinase C. Yet it appears that PLC-independent path-
ways can also regulate responses, such as the modulation of cAMP and phospho-
lipase A 2 activity. How H 1-receptor activation leads to these responses will be
discussed in detail below.
4. Activation of Nitric Oxide Synthase

Histamine-induced increase of Ca 2⫹ can elevate nitric oxide synthase activity to
induce nitric oxide production via a Ca 2⫹ /calmodulin-dependent pathway, with
subsequent activation of soluble guanylyl cyclase in a variety of cell types. In
various vascular preparations, the endothelium-dependent relaxation observed
upon H 1-receptor activation is found to be related to the production of nitric oxide
42 Bakker et al.
(157–161). In cultured bovine aortic cells the actual generation of nitric oxide
could be measured after stimulation with histamine (162). In a variety of airway
and heart preparations, H 1-receptor activation was shown to induce the production
of cGMP, which may be ascribed to generation of nitric oxide (163–168). More
recently, histamine was found to induce the association of heat-shock protein 90
with endothelial nitric oxide synthase (eNOS) and subsequently to activate eNOS
in human umbilical vein endothelial cells (HUVEC) (169). Thus, vascular re-
sponses to histamine may be explained by the generation of nitric oxide, which
appears to be highly dependent on the mobilization of intracellular Ca 2⫹.
5. Activation of Phospholipase A 2 and Subsequent Arachidonic

Acid Release
Another consequence of the histamine-induced mobilization of Ca 2⫹ is the release
of arachidonic acid and the generation of arachidonic acid metabolites such as
prostacyclin and thromboxane A 2 (112, 170, 171). The formation of arachidonic
acid metabolites has been implicated in the regulation of NF-κB-mediated gene
transcription by the H 1-receptor (153).
In HeLa cells endogenously expressing the human H 1-receptor as well as
in CHO-K1 transfected with the guinea pig H 1-receptor, the release of arachidonic
acid appeared to be phospholipase-A 2-dependent (112). In contrast to the phos-
pholipase-A 2-dependent, pertussis toxin-insensitive release of arachidonic acid
in HeLa cells (112), histamine stimulation of the transfected CHO cells resulted
in a partially sensitive phospholipase A 2 activation (112).
Murayama et al. (172) reported the histamine-induced, pertussis toxin-sen-
sitive release of arachidonic acid in the absence of inositol phosphate generation
in both human and rabbit platelets. Therefore, the H 1-receptor-mediated activa-
tion of phospholipase A 2 in transfected CHO cells may be ascribed to elevation
of the intracellular Ca 2⫹ concentration (as in HeLa cells) and, via interaction of
phospholipase A 2, with a pertussis toxin-sensitive G-protein (as in platelets).
6. Stimulation of Phospholipase D
Activation of phospholipase D (PLD) by the H 1-receptor may occur secondarily
to the activation of PLC by the liberation of DAG and subsequent activation of
PKC. PLD mediates the hydrolysis of phosphatidylcholine and other phospholip-
ids, to generate phosphatidic acid. The activation of PLD is believed to serve
diverse functions in signal transduction, membrane vesicle trafficking, and cy-
toskeletal dynamics, and to play an important role in the regulation of cell func-
tion and cell fate (see Ref. 173 for a recent review on PLD).
Agonist-induced PLD activation involves PKC activation and is dependent
on an increase in intracellular Ca 2⫹ (174); however, part of the histamine-stimu-
lated PLD activity may occur in the absence of PKC activation (174, 175). In
addition to binding to G q/11 proteins, the H 1-receptor has recently been shown to
mediate PLD activation in 1321N1 human astrocytoma cells via the small G-
protein ARF (176).
7. Changes in Intracellular cAMP Levels

The histamine H 1-receptor is also reported to mediate substantial changes in intra-
cellular levels of cAMP. The H 1-receptor acts to amplify cAMP responses from
histamine H 2-, adenosine A 2-, and vasoactive intestinal polypeptide receptors
(177–182); however, in various carcinomas, the H 1-receptor was found to couple
to elevation of cAMP in the absence of Ins(1,4,5)P 3 formation (183, 184). The
exact mechanism involved in the elevation of cAMP remains to be determined;
a role for both Ca 2⫹ and protein kinase C has been suggested (185). Neither
protein kinase C nor Ca 2⫹ accounted for the observed elevation of cAMP levels
in guinea-pig H 1-receptor-expressing CHO cells (112). The latter observations
could possibly be explained by stimulation of adenylyl cyclase by G-protein βγ-
subunits.
8. Coupling to G i/o-Proteins
In contrast to the H 1-receptor-mediated increase in intracellular levels of cAMP,
a phenomenon generally associated with coupling to G-proteins, differentiated
HL-60 cells have been found to express H 1-receptors coupled to both pertussis-
toxin (PTX)-insensitive G-proteins and PTX-sensitive G i-proteins (186, 187).
PTX partially inhibited the stimulatory effect of histamine on [Ca 2⫹ ] i (187), indi-
cating a role for G i/o-proteins in the Ca 2⫹ response. Modulation of a nonselective
cation current through coupling of the H 1-receptor to G i/o-proteins has also been
reported (188).
9. Constitutive H 1-Receptor Signaling

Recently, we have found the human histamine H 1-receptor to be constitutively
active (16). Overexpression of the receptor in SV40-immortalized African green
monkey kidney (COS-7) cells results in an agonist-independent production of
Ins(1,4,5)P 3, which can be inhibited by inverse H 1-agonists formerly known as
H 1-antagonists (Fig. 6). Among these are well-known, clinically useful H 1-antag-
onists such as cetirizine, loratadine, and epinastine. The recognition of inverse
agonism by H 1-antagonists provides an extremely important insight into the ac-
tion of these drugs at the H 1-receptor. The (patho)physiological significance of
basal H 1-receptor activity is as yet unknown, but in view of the reported regula-
tory mechanisms induced by inverse agonists (28, 189), one could speculate that
neutral antagonists might have some therapeutic benefit. However, neutral H 1-
antagonists have not, as yet, been identified.
44 Bakker et al.
Figure 6 Constitutive activity of the human histamine H 1-receptor and inverse agonism
of H 1-antagonists. (A) Effect of mepyramine on the basal [ 3 H]inositolphosphate accumu-
lation in COS-7 cells expressing the human histamine H 1-receptor (䊉) and on mock
transfected cells (䊊). The stereoisomers of cetirizine, (R)- (■) and (S)-cetirizine (䊐),
stereospecifically inhibit basal [ 3 H]inositolphosphate accumulation. (B) Correlation graph
of the plC 50 values obtained for the inverse agonists in the [ 3 H]inositolphosphate accumu-
lation assay vs. the pK 1 values obtained by [ 3 H]mepyramine displacement in COS-7 cells
expressing the human histamine H 1-receptor. (Data from Ref. 16.)
10. Conclusions
The H 1-receptor is primarily coupled to a PLC-dependent inositol phosphate path-
way via a G q/11-protein. In addition to binding to G q/11, the H 1-receptor can also
couple to G i/o-proteins and has recently been shown to activate phospholipase D
by activation of small G-proteins (176).
B. Signal Transduction of the H 2-Receptor

It is generally accepted that the histamine H 2-receptor is coupled to the adenylate
cyclase system (Fig. 5). A large number of reports have shown that histamine
increases the levels of cAMP in the brain, stomach, heart, and other tissues of
several species, including humans (2, 166, 190–198).
1. Stimulation of Adenylyl Cyclase

The H 2-receptor activates adenylyl cyclase in membrane fractions in a guanyl-
nucleotide-sensitive manner (197). Direct evidence for the involvement a G s-
protein in the H 2-receptor-mediated response comes from the observation of an
enhanced GTP azidoanilide-labeling of G s-like proteins in H 2-receptor-express-
ing Sf9 cells (113).
Ozawa and co-workers suggested that an H 2-receptor-stimulated phospho-
lipid methylation is involved in the activation of adenylyl cyclase (191, 198). In
both rat brain (191, 199) and guinea pig heart (198), histamine was shown to
stimulate the phospholipid methylation rapidly. The cAMP response in both tis-
sues was significantly slower and completely dependent on the presence of the
methyl-donor S-adenosyl-L-methionine and reduced by an inhibitor of the phos-
pholipid methyltransferases (191, 198). Moreover, in rat brain the regional distri-
bution of histamine-induced phospholipid methylation closely paralleled the H 2-
receptor-mediated cAMP response (191). These data suggest the necessity of the
phospholipid response for an effective G-protein-receptor coupling to adenylyl-
cyclase activation.
2. Other H 2-Receptor Signaling Pathways

Although the linkage of the H 2-receptor to the adenylate cyclase is well accepted,
some findings argue against a universal role of cAMP. In guinea pig brain the
regional distribution of H 2-receptor-binding sites does not parallel the observed
H 2-receptor-mediated cyclase activation (30). Also, Haas et al. (200) observed a
denervation hypersensitivity to histamine at the electrophysiological level,
whereas under the same conditions the cAMP response was unaltered.
In addition to the activation of adenylyl cyclase, presumably by activating
G s-type G-proteins, there are reports of H 2-receptor coupling to other signaling
46 Bakker et al.
systems. In differentiated HL-60 cells (201–203), parietal cells (204), human

keratinocytes (205), and HEPA, COS-7, and HEK-293 cells transfected with the
canine H 2-receptor (114, 206, 207), an H 2-receptor-mediated increase of the intra-
cellular Ca 2⫹ concentration was observed. The increase of intracellular Ca 2⫹ was
found to result from the release of Ca 2⫹ from intracellular stores (114, 202, 206).
The H 2-receptor-dependent Ca 2⫹ mobilization is probably due to the activation
of phospholipase C, since histamine was also found to increase the levels of
Ins(1,4,5)P 3 (114, 183, 184, 206, 208–212), and activation of both PKCα and
PKCβ (207). The physiological role of stimulation of PLC by the H 2-receptor is
unknown; however, a role in H 2-receptor desensitization (213) and cell prolifera-
tion is suggested (207, 214).
G-proteins are likely to be involved in the activation of PLC since the
increase of Ins(1,4,5)P 3 levels in both HL-60 and HEPA cells lines were found
to be inhibited by cholera toxin but not by pertussis toxin (202, 206). Reports
in hamster DDT1 MF-2 cells and bovine trachea smooth muscle have demon-
strated a cAMP-mediated inhibition of the production of inositol phosphates
(215–217). The crosstalk between the cAMP cascade and phosphoinositide sys-
tem could well explain the observed inhibitory effects induced by cholera toxin
(206, 210); yet, in the HEPA cells, forskolin did not inhibit the histamine-induced
effects, suggesting the involvement of another mechanism (206). H 2-receptor-
mediated Ins(1,4,5)P 3 formation has also been observed in the absence of cAMP
accumulation (209). A PTX-insensitive histamine-induced stimulation of PLC
has also been observed in COS-7 cells transfected with cDNA encoding the H 2-
receptor (114). In addition, coexpression of G q/11-family members of G-proteins,
but not G i- or G s-, lead to a further H 2-receptor-mediated increase in Ins(1,4,5)P 3
formation. Further, histamine stimulated the H 1- and H 2-receptor-mediated incor-
poration of [α-32P]GTP azidoanilide into G q/11-like proteins in membranes pre-
pared from guinea pig heart (114).
Therefore, in addition to elevation of cAMP levels, the H 2-receptor is thought
to activate phospholipase-C-signaling pathways via a separate GTP-dependent
mechanism (206, 211, 212). Although these results indicate a direct coupling of the
H 2-receptor to both G s- and G q/11-proteins, histamine failed to elicit Ins(1,4,5)P 3
formation in CHO cells permanently expressing the rat H 2-receptor (112), raising
the possibility that the coupling to G q/11 is cell-type-specific. Moreover, allelic varia-
tion of the human histamine H 2-receptor gene (218) may play a role in the observed
atypical coupling to second messengers in transformed cells (183).
Another cAMP-independent response was described for the cloned rat H 2-
receptor expressed in CHO cells (219). In addition to massive production of cAMP
upon H 2-receptor activation, inhibition of the release of arachidonic acid induced
by either constitutive purinergic receptors or a Ca 2⫹-ionophore was observed. At
present, the actual mechanism for this response is unknown. One should, however,
be aware that ambiguous receptor coupling might be due to the high level of receptor
expression in these cells. In contrast, expression of the gene encoding the human
H 2-receptor in CHO cells was shown to be functionally coupled to adenylate cy-

clase, but did not influence the inositol phosphate turnover or arachidonic acid
release (220). The observed sequence differences, in particular in the intracellular
domains between the rat and human receptor (84, 221) might also be a possible
explanation for the observed differences in signal transduction.
3. Constitutive H 2-Receptor Signaling

Preceding our findings concerning constitutive signaling by the histamine H 1-
receptor (16), we have shown constitutive activity of the histamine H 2-receptor
(28, 29, 222, 223). Expression of the H 2-receptor in CHO cells results in agonist-
independent elevation of cAMP levels (28, 29). In addition, constitutive H 2-recep-
tor activity enhances forskolin-induced cAMP production (222). Various inverse
H 2-receptor agonists have now been identified, and among these are well-known
therapeutic agents. The (patho)physiological significance of constitutive H 2-re-
ceptor activity and the H 2-receptor upregulation resulting from prolonged inverse
H 2-agonist treatment (28) are as yet unknown.
4. Conclusions
As previously seen for the H 1-receptor, various intracellular mediators are likely
to be involved in the H 2-receptor-mediated effects. The H 2-receptor is primarily
coupled to the adenylyl-cyclase-dependent production of cAMP. It appears, how-
ever, that in some cell types the breakdown of phosphoinositides, the intracellular
Ca 2⫹ levels, and phospholipase A 2 activity can be regulated by cAMP-indepen-
dent pathways.
C. Signal Transduction of the H 3-Receptor

The recent cloning of the histamine H 3-receptor by Lovenberg and colleagues
(93) has shown that the H 3-receptor indeed belongs to the family of G-protein-
coupled receptors. Binding studies (49, 91, 92, 224–228), as well as inhibitory
effects induced by pertussis toxin and cholera toxin (92, 229–231), had already
supported the involvement of a G i/o-protein in the H 3-receptor-mediated responses
(Fig. 5). In agreement with these observations, an inhibition of cAMP accumula-
tion in response to histamine was observed in forskolin-stimulated mouse L cells,
human SK-N-MC neuroblastoma cells, and rat C6 glioma cells expressing the
human histamine H 3-receptor (93). The effect was mimicked by the selective
H 3-agonist (R)-α-methylhistamine, unmasking the H 3-receptor as a G i-coupled
GPCR, which confirms previous findings of a PTX-sensitive G-protein coupling
of the H 3-receptor (227, 228, 230, 232).
Availability of the H 3-receptor cDNA will allow a more detailed investigation
of the signaling properties of this receptor. Recent studies have shown coupling of
the H 3-receptor to MARK pathway (96b) and the Na⫹ /H⫹ exchanger (232a).
48 Bakker et al.
D. Signal Transduction of the H 4-Receptor

Heterologous expression of the H 4-receptor in a variety of cells indicates this
member of the histamine receptor family is also a G-protein-coupled receptor,
and that it can couple to both G i/o- and to G 15/16-proteins. H 4-receptor-expressing
cells respond to histamine and inhibit forskolin-induced cAMP accumulation (8a,
49b, 96e), potently stimulate [ 35S]GTPγS binding (49a), and result in a pertussis
toxin-sensitive phosphorylation of MAP kinase (49a), indicating the involvement
of G i/o proteins.
Coexpression studies using either Gα 15 or Gα 16 (8a, 49a), or chimeric G-
proteins Gα q/i1,2 or Gα q/i3 in which the last five C-terminal amino acids of Gα q
have been replaced with those of the α-subunits Gα i1,2 or Gα i3 (49a), have shown
activation of the H 4-receptor to mobilize [Ca 2⫹ ]i. As the receptor is predominantly
expressed in leukocytes, coupling of the receptor to G 15/16-proteins, linking recep-
tor-activation to the phospholipase C pathway to generate inositolphosphates,
diacylglycerol and [Ca 2⫹ ]i, may also represent a natural second messenger path-
way of the H 4-receptor (8a).
V. MISCELLANEOUS HISTAMINE RECEPTORS
Apart from the G-protein-coupled histamine H 1-, H 2-, and H 3-receptors, several
other histamine receptors have been described. Patch-clamp studies on hista-
mine receptors in invertebrate neurons have identified a ligand-gated chloride channel
at a photoreceptor synapse of the housefly (233). Furthermore, similar histamine-
gated chloride channels have been detected in lobster olfactory neurons (234). The
histamine-gated chloride channels in the large monopolar cell, a retinal neuron, have
been utilized to estimate the metabolic cost of neural information (235).
Recently, three histamine-binding proteins have been cloned from the tick
Rhipicephalyus appendiculatus (236). These high-affinity histamine-binding pro-
teins (HBPs) appear to possess two histamine-binding sites, as determined from
the crystal structure of a histamine-bound HBP. They may sequester histamine
at the wound site of the host to outcompete histamine receptors for histamine,
thus overcoming their host’s inflammatory and immune responses (236).
There is as yet no indication of the presence of mammalian counterparts
for these ligand-gated ion channels or histamine-binding proteins. It therefore
remains an intriguing possibility that the family of mammalian histamine recep-
tors consists of ligand-gated ion channels, G-protein-coupled receptors, in addi-
tion to histamine-binding proteins.
VI. SUMMARY
During the past few years, there has been a tremendous increase in our under-
standing of the histamine receptors. Important progress has been made in the
development of H 1-receptor agonists and the rationalization of H 1-receptor–li-

gand interaction. The recent observation of constitutive H 1- and H 2-receptor activ-
ity has led to a reclassification of H 1- and H 2-antagonists. For the H 3-receptor,
a wide variety of selective and potent ligands are currently available and await
clinical application. The recent cloning of the H 3-receptor gene and the antici-
pated generation of transgenic mice will facilitate this development. Within the
field of signal transduction, a previously unanticipated complexity has been un-
ravelled. With the cloning of the H 3-receptor gene, a similar complexity is to be
expected.
REFERENCES
1. Hough LB. Cellular localization and possible functions for brain histamine: recent
progress. Prog Neurobiol 1988; 30:469–505.
2. Schwartz JC, Arrang JM, Garbarg M, Pollard H, Ruat M. Histaminergic transmis-
sion in the mammalian brain. Physiol Rev 1991; 71:1–51.
3. Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley NP, Young JM, Schu-
nack W, Levi R, Haas HL. International Union of Pharmacology. XIII. Classifica-
tion of histamine receptors. Pharmacol Rev 1997; 49:253–278.
4. Barnes PJ. Histamine receptors in the respiratory tract. In: Schwartz JC, Haas HL,
eds. The Histamine Receptor. New York: Wiley-Liss, 1992:253–270.
5. Ash AS, Schild HO. Receptors mediating some actions of histamine. Br J Pharma-
col 1966; 27:427–439.
6. Black JW, Duncan WA, Durant CJ, Ganellin CR, Parsons EM. Definition and an-
tagonism of histamine H 2-receptors. Nature 1972; 236:385–390.
7. Arrang JM, Garbarg M, Schwartz JC. Auto-inhibition of brain histamine release
mediated by a novel class (H 3) of histamine receptor. Nature 1983; 302:832–837.
8. Leurs R, Blandina P, Tedford C, Timmerman H. Therapeutic potentials of histamine
H 3-receptor agonists and antagonists. Trends Pharmacol Sci 1998; 19:177–183.
8a. Oda T, Morikawa N, Saito Y, Masuho Y, Matsumoto S. Molecular cloning and
characterization of a novel type of histamine receptor preferentially expressed in
leukocytes. J Biol Chem 2000; 275:36781–36786.
9. Zhang M-Q, Leurs R, Timmerman H. Histamine H 1-receptor antagonists. In: Wolff
ME, ed. Burger’s Medical Chemistry and Drug Discovery. New York: John Wi-
ley & Sons, 1997:495–559.
10. van der Goot H, Timmerman H. Selective ligands as tools to study histamine recep-
tors. Eur J Med Chem 2000; 35:5–20.
11. Zingel V, Leschke C, Schunack W. Developments in histamine H 1-receptor ago-
nists. Prog Drug Res 1995; 44:49–85.
12. van der Goot H, Bast A, Timmerman H. Structural requirements for histamine H 2-
agonists and H 2-antagonists. In: Uvnäs B, ed. Handbook of Experimental Pharma-
cology. Berlin: Springer-Verlag, 1991:573–748.
13. Phillips JG, Ali SM. Medicinal chemistry of histamine H 3-receptor antagonists. In:
Leurs R, Timmerman H, eds. The Histamine H 3-Receptor: A Target for New Drugs.
Amsterdam: Elsevier, 1998:197–222.
50 Bakker et al.
14. Krause M, Stark H, Schunack W. Medicinal chemistry of histamine H 3 receptor

agonists. In: Leurs R, Timmerman H, eds. The Histamine H 3-Receptor: A Target
for New Drugs. Amsterdam: Elsevier, 1998; 175–196.
15. Elz S, Kramer K, Pertz HH, Detert H, ter Laak AM, Kühne R, Schunack W. Hista-
prodifens: synthesis, pharmacological in vitro evaluation, and molecular modeling
of a new class of highly active and selective histamine H 1-receptor agonists. J Med
Chem 2000; 43:1071–1084.
16. Bakker RA, Wieland K, Timmerman H, Leurs R. Constitutive activity of the hista-
mine H 1 receptor reveals inverse agonism of histamine H 1-receptor antagonists.
Eur J Pharmacol 2000; 387:R5–R7.
17. Maloteaux JM, Gossuin A, Waterkeyn C, Laduron PM. Trapping of labelled ligands
in intact cells: a pitfall in binding studies. Biochem Pharmacol 1983; 32:2543–2548.
18. Leurs R, Bast A, Timmerman H. High affinity, saturable [ 3 H]mepyramine binding
sites on rat liver plasma membrane do not represent histamine H 1-receptors. A
warning. Biochem Pharmacol 1989; 38:2175–2180.
19. Tran VT, Lebovitz R, Toll L, Snyder SH. [ 3 H]doxepin interactions with histamine
H 1-receptors and other sites in guinea pig and rat brain homogenates. Eur J Pharma-
col 1981; 70:501–509.
20. Treherne JM, Young JM. Temperature-dependence of the kinetics of the binding of
[ 3 H]-(⫹)-N-methyl-4-methyldiphenhydramine to the histamine H 1-receptor: com-
parison with the kinetics of [ 3 H]-mepyramine. Br J Pharmacol 1988; 94:811–822.
21. Treherne JM, Young JM. [ 3 H]-(⫹)-N-methyl-4-methyldiphenhydramine, a quater-
nary radioligand for the histamine H 1-receptor. Br J Pharmacol 1988; 94:797–810.
22. Yanai K, Watanabe T, Yokoyama H, Meguro K, Hatazawa J, Itoh M, Iwata R,
Ishiwata K, Takahashi T, Ido T. Histamine H 1-receptors in human brain visualized
in vivo by [11C]doxepin and positron emission tomography. Neurosci Lett 1992;
137:145–148.
23. Booth RG, Owens CE, Brown RL, Bucholtz EC, Lawler CP, Wyrick SD. Putative
σ 3 sites in mammalian brain have histamine H 1-receptor properties: evidence from
ligand binding and distribution studies with the novel H 1-radioligand [ 3 H]-(⫺)-
trans-1-phenyl-3-aminotetralin. Brain Res 1999; 837:95–105.
24. Bucholtz EC, Brown RL, Tropsha A, Booth RG, Wyrick SD. Synthesis, evaluation,
and comparative molecular field analysis of 1-phenyl-3-amino-1,2,3,4-tetrahydronaph-
thalenes as ligands for histamine H 1-receptors. J Med Chem 1999; 42:3041–3054.
25. Eriks JC, van der Goot H, Sterk GJ, Timmerman H. Histamine H 2-receptor agonists.
Synthesis, in vitro pharmacology, and qualitative structure-activity relationships of
substituted 4- and 5-(2-aminoethyl)thiazoles. J Med Chem 1992; 35:3239–3246.
26. Ganellin CR. Pharmacochemistry of H 1- and H 2-receptors. In: Schwartz JC, Haas
H, eds. The Histamine Receptor. New York: Wiley-Liss, 1992:1–56.
27. Leurs R, van der Goot H, Timmerman H. Histaminergic agonists and antagonists:
recent developments. In: Testa B, eds. Advances in Drug Research, Vol. 20. Lon-
don: Academic Press, 1991:217–304.
28. Smit MJ, Leurs R, Alewijnse AE, Blauw J, van Nieuw Amerongen GP, van De
Vrede Y, Roovers E, Timmerman H. Inverse agonism of histamine H 2-antagonist
accounts for upregulation of spontaneously active histamine H 2-receptors. Proc Natl
Acad Sci USA 1996; 93:6802–6807.
29. Alewijnse AE, Smit MJ, Hoffmann M, Verzijl D, Timmerman H, Leurs R. Consti
tutive activity and structural instability of the wild-type human H 2-receptor. J Neu-
rochem 1998; 71:799–807.
30. Ruat M, Traiffort E, Bouthenet ML, Schwartz JC, Hirschfeld J, Buschauer A, Schu-
nack W. Reversible and irreversible labeling and autoradiographic localization of
the cerebral histamine H 2-receptor using [ 125 I]iodinated probes. Proc Natl Acad Sci
USA 1990; 87:1658–1662.
31. Arrang JM, Garbarg M, Lancelot JC, Lecomte JM, Pollard H, Robba M, Schunack
W, Schwartz JC. Highly potent and selective ligands for histamine H 3-receptors.
Nature 1987; 327:117–123.
32. Lipp R, Arrang JM, Buschmann J, Garbarg M, Luger P, Schunack W, Schwartz JC.
Novel chiral H 3-receptor agonists. In: van der Goot HTaH, ed. New Perspectives in
Histamine Research. Basel: Birkhauser Verlag, 1991:277–282.
33. Leurs R, Timmerman H. The histamine H 3-receptor: a target for developing new
drugs. In: Jucker E, ed. Progress in Drug Research. Basel: Birkhauser 1992:127–165.
34. Howson W, Parsons ME, Raval P, Swayne GTG. Two novel, potent and selective
histamine H 3-receptor agonists. Bioorg Med Chem Lett 1992; 2:77–78.
35. van der Goot H, Schepers MJP, Sterk GJ, Timmerman H. Isothiourea analogues
of histamine as potent agonists or antagonists of the histamine H 3-receptor. Eur J
Med Chem 1992; 27:511–517.
36. Garbarg M, Arrang JM, Rouleau A, Ligneau X, Tuong MDT, Schwartz JC, Ganel-
lin CR. S-[2-(4-Imidazolyl)ethyl]isothiourea, a highly specific and potent histamine
H 3-receptor agonist. J Pharmacol Exp Ther 1992; 263:304–310.
37. Coruzzi G, Gambarelli E, Bertaccini G, Timmerman H. Cardiovascular effects of
selective agonists and antagonists of histamine H 3-receptors in the anaesthetized
rat. Naunyn Schmiedeberg’s Arch Pharmacol 1995; 351:569–575.
38. Vollinga RJ, de Koning JP, Jansen FP, Leurs R, Menge WMPB, Timmerman H.
A new potent and selective histamine H 3-receptor agonist, 4-(1H-imidazol-4-
ylmethyl)piperidine. J Med Chem 1994; 37:332–333.
39. Leurs R, Tulp MT, Menge WMBP, Adolfs MJP, Zuiderveld OP, Timmerman H.
Evaluation of the receptor selectivity of the H 3-receptor antagonists, iodophenpropit
and thioperamide: an interaction with the 5HT 3-receptor revealed. Br J Pharmacol
1995; 116:2315–2321.
40. Barnes JC, Brown JD, Clarke NP, Clapham J, Evans DJ, O’Shaughnessy CT. Phar-
macological activity of VUF 9153, an isothiourea histamine H 3-receptor antagonist.
Eur J Pharmacol 1993; 250:147–152.
41. Mochizuki T, Jansen FP, Leurs R, Windhorst AD, Yamatodani A, Maeyama K,
Timmerman H. Brain penetration of the histamine H 3-receptor antagonists thiopera-
mide and clobenpropit in rat and mouse, determined with ex vivo [ 125 I]iodophen-
propit binding. Brain Res 1996; 743:178–183.
42. Labella FS, Queen G, Glavin G, Durant G, Stein D, Brandes LJ. H 3-receptor antagonist,
thioperamide, inhibits adrenal steroidogenesis and histamine binding to adrenocortical
microsomes and binds to cytochrome-P450. Br J Pharmacol 1992; 107:161–164.
43. Alves-Rodrigues A, Leurs R, Wu TS, Prell GD, Foged C, Timmerman H. [ 3 H]-
thioperamide as a radioligand for the histamine H 3-receptor in rat cerebral cortex.
Br J Pharmacol 1996; 118:2045–2052.
44. West RE, Zweig A, Shih NY, Siegel MI, Egan RW, Clark MA. Identification of
two H 3-histamine receptor subtypes. Mol Pharmacol 1990; 38:610–613.
52 Bakker et al.
45. Ligneau X, Garbarg M, Vizuette ML, Diaz J, Purand K, Stark H, Schunack W,

Schwartz JC. [ 125 I]iodoproxyfan, a new antagonist to label and visualize cerebral
histamine H 3-receptors. J Pharmacol Exp Ther 1994; 271:452–459.
46. Yanai K, Ryu JH, Sakai N, Takahashi T, Iwata R, Ido T, Murakami K, Watanabe
T. Binding characteristics of a histamine H 3-receptor antagonist, [ 3 H]S-methyl-
thioperamide: comparison with [ 3 H](R)α-methylhistamine binding to rat tissues.
Jpn J Pharmacol 1994; 65:107–112.
47. Brown JD, O’Shaughnessy CT, Kilpatrick GJ, Scopes DIC, Beswick P, Clitherow
JW, Barnes JC. Characterisation of the specific binding of the histamine H 3-receptor
antagonist radioligand [ 3 H]GR168320. Eur J Pharmacol 1996; 311:305–310.
48. Harper EA, Shankley NP, Black JW. Characterization of the binding of [ 3 H]-clo-
benpropit to histamine H 3-receptors in guinea-pig cerebral cortex membranes. Br
J Pharmacol 1999; 128:881–890.
49. Jansen FP, Wu TS, Voss HP, Steinbusch HW, Vollinga RC, Rademaker B, Bast
A, Timmerman H. Characterization of the binding of the first selective radiolabelled
histamine H 3-receptor antagonist, [ 125 I]-iodophenpropit, to rat brain. Br J Pharma-
col 1994; 113:355–362.
49a. Morse KL, Behan J, Laz TM, West RE, Greenfeder SA, Anthes JC, Umland S, Wan
Y, Hipkin RW, Gonsiorek W, Shin N, Gustafson EL, Qiao X, Wang S, Hedrick JA,
Greene J, Bayne M, Monsma FJ. Cloning and characterization of a novel human
histamine receptor. J Pharmacol Exp Ther 2001; 296:1058–1066.
49b. Liu C, Ma XJ, Jiang X, Wilson SJ, Hofstra CL, Blevitt J, Pyati J, Li X, Chai W,
Carruthers N, Lovenberg TW. Cloning and pharmacological characterization of a
fourth histamine receptor (H 4 ) expressed in bone marrow. Mol Pharmacol 2001;
59:420–426.
50. Ruat M, Bouthenet ML, Schwartz JC, Ganellin CR. Histamine H 1 receptor in the
heart: unique electrophoretic mobility and autoradiograhic localization. J Neuro-
chem 1990; 55:379–385.
51. Ruat M, Schwartz JC. Photoaffinity labelling and elektrophoretic identification of
the H 1-receptor: comparison of several brain regions and animal species. J Neuro-
chem 1989; 53:335–339.
52. Yamashita M, Ito S, Sugama K, Fukui H, Smith B, Nakanishi K, Wada H. Biochem-
ical characterization of histamine H 1-receptors in bovine adrenal medulla. Biochem
Biophys Res Commun 1991; 177:1233–1239.
53. Mitsuhashi M, Payan DG. Solubilization and characterization of the pyrilamine-
binding protein from cultured smooth muscle cells. Mol Pharmacol 1989; 35:751–
759.
54. Mitsuhashi M, Payan DG. Receptor glycosylation regulates the affinity of histamine
H 1-receptors during smooth muscle cell differentiation. Mol Pharmacol 1989; 35:
311–318.
55. Yamashita M, Fukui H, Sugama K, Horio Y, Ito S, Mizuguchi H, Wada H. Expres-
sion cloning of a cDNA encoding the bovine histamine H 1-receptor. Proc Natl Acad
Sci USA 1991; 88:11515–11519.
56. Garbarg M, Yeramian E, Körner M, Schwartz JC. Biochemical studies of cerebral
H 1-receptors. In: Ganellin CR, Schwartz JC, eds. Frontiers in Histamine Research.
Oxford: Pergamon Press, 1985:9–25.
57. Fujimoto K, Horio Y, Sugama K, Ito S, Liu YQ, Fukui H. Genomic cloning of the
rat histamine H 1-receptor. Biochem Biophys Res Commun 1993; 190:294–301.
58. Traiffort E, Leurs R, Arrang JM, Tardivel-Lacombe J, Diaz J, Schwartz JC, Ruat
M. Guinea pig histamine H 1-receptor. I. Gene cloning, characterization, and tis-
sue expression revealed by in situ hybridization. J Neurochem 1994; 62:507–518.
59. Inoue I, Taniuchi I, Kitamura D, Jenkins NA, Gilbert DJ, Copeland NG, Watanabe
T. Characteristics of the mouse genomic histamine H 1-receptor gene. Genomics
1996; 36:178–181.
60. Chowdhury BA, Kaliner MA, Strader CM. Cloning of a gene encoding the human
H 1-receptor. Soc Neurosci Abstr 1993; 19:84.
61. Fukui H, Fujimoto K, Mizuguchi H, Sakamoto K, Horio Y, Takai S, Yamada K,
Ito S. Molecular cloning of the human histamine H 1-receptor gene. Biochem Bio-
phys Res Commun 1994; 201:894–901.
62. Moguilevsky N, Varsalona F, Noyer M, Gillard M, Guillaume JP, Garcia L, Szpirer
C, Szpirer J, Bollen A. Stable expression of human H 1-histamine-receptor cDNA
in Chinese hamster ovary cells. Pharmacological characterisation of the protein,
tissue distribution of messenger RNA and chromosomal localisation of the gene.
Eur J Biochem 1994; 224:489–495.
63. De Backer MD, Gommeren W, Moereels H, Nobels G, van Gompel P, Leysen
JE, Luyten WH. Genomic cloning, heterologous expression and pharmacological
characterization of a human histamine H 1-receptor. Biochem Biophys Res Commun
1993; 197:1601–1608.
64. De Backer MD, Loonen I, Verhasselt P, Neefs JM, Luyten WH. Structure of the
human histamine H 1-receptor gene. Biochem J 1998; 335:663–670.
65. Le Coniat M, Traiffort E, Ruat M, Arrang JM, Berger R. Chromosomal localization
of the human histamine H 1-receptor gene. Hum Genet 1994; 94:186–188.
66. Hardy E, Farahani M, Hall IP. Regulation of histamine H 1-receptor coupling by
dexamethasone in human cultured airway smooth muscle. Br J Pharmacol 1996;
118:1079–1084.
67. Karlstedt K, Sallmen T, Eriksson KS, Lintunen M, Couraud PO, Joo F, Panula P.
Lack of histamine synthesis and down-regulation of H 1- and H 2-receptor mRNA
levels by dexamethasone in cerebral endothelial cells. J Cereb Blood Flow Metab
1999; 19:321–330.
68. Lee HJ, Lee YF, Chang C. Identification of the histamine H 1-receptor gene as a
differentially repressed target of the human TR2 orphan receptor. Mol Cell Bio-
chem 1999; 194:199–207.
69. Horio Y, Mori Y, Higuchi I, Fujimoto K, Ito S, Fukui H. Molecular cloning of the
guinea-pig histamine H 1-receptor gene. J Biochem (Tokyo), 1993; 114:408–
414.
70. Savarese TM, Fraser CM. In vitro mutagenesis and the search for structure–func-
tion relationships among G protein-coupled receptors. Biochem J 1992; 283:1–19.
71. Ohta K, Hayashi H, Mizuguchi H, Kagamiyama H, Fujimoto K, Fukui H. Site-
directed mutagenesis of the histamine H 1-receptor: roles of aspartic acid107, aspara-
gine198 and threonine194. Biochem Biophys Res Commun 1994; 203:1096–1101.
72. ter Laak AM, Timmerman H, Leurs R, Nederkoorn PHJ, Smit MJ, Donne-Op den
Kelder GM. Modelling and mutation studies on the histamine H 1-receptor agonist
54 Bakker et al.
binding site reveal different binding modes for H 1-agonists: Asp116 (TM3) has a consti-
tutive role in receptor stimulation. J Comput Aided Mol Des 1995; 9:319–330.
73. Leurs R, Smit MJ, Tensen CP, Ter Laak AM, Timmerman H. Site-directed mutagenesis
of the histamine H 1-receptor reveals a selective interaction of asparagine207 with sub-
classes of H 1-receptor agonists. Biochem Biophys Res Commun 1994; 201:295–301.
74. Leurs R, Smit MJ, Meeder R, ter Laak AM, Timmerman H. Lysine200 located in the
fifth transmembrane domain of the histamine H 1-receptor interacts with histamine
but not with all H 1-agonists. Biochem Biophys Res Commun 1995; 214:110–117.
75. Wieland K, ter Laak AM, Smit MJ, Kühne R, Timmerman H, Leurs R. Mutational
analysis of the antagonist-binding site of the histamine H 1-receptor. J Biol Chem
1999; 274:29994–30000.
76. ter Laak AM, Venhorst J, Donne-Op den Kelder GM, Timmerman H. The histamine
H 1-receptor antagonist binding site. A stereoselective pharmacophoric model based
upon (semi-)rigid H 1-antagonists and including a known interaction site on the re-
ceptor. J Med Chem 1995; 38:3351–3360.
77. Inoue I, Yanai K, Kitamura D, Taniuchi I, Kobayashi T, Niimura K, Watanabe T,
Watanabe T. Impaired locomotor activity and exploratory behavior in mice lacking
histamine H 1-receptors. Proc Natl Acad Sci USA 1996; 93:13316–13320.
78. Yanai K, Son LZ, Endou M, Sakurai E, Watanabe T. Targeting disruption of hista-
mine H 1-receptors in mice: behavioral and neurochemical characterization. Life Sci
1998; 62:1607–1610.
79. Yanai K, Son LZ, Endou M, Sakurai E, Nakagawasai O, Tadano T, Kisara K, Inoue
I, Watanabe T, Watanabe T. Behavioural characterization and amounts of brain
monoamines and their metabolites in mice lacking histamine H 1-receptors. Neuro-
science 1998; 87:479–487.
80. Reyl-Desmars F, Cherifi Y, Le Romancer M, Pigeon C, Le Roux S, Lewin MJM.
Solubilization, purification et characterisation moleculaire de recepteur histami-
nique H 2 à partir des cellules tumorales gastrique humaines HGT-1. CR Acad Sci
Paris 1991; 312:221–224.
81. Fukushima Y, Asano T, Saitoh T, Anai M, Funaki M, Ogihara T, Katagiri H, Matsu-
hashi N, Yazaki Y, Sugano K. Oligomer formation of histamine H 2-receptors ex-
pressed in Sf9 and COS7 cells. FEBS Lett 1997; 409:283–286.
82. Beukers MW, Klaassen CH, De Grip WJ, Verzijl D, Timmerman H, Leurs R. Heter-
ologous expression of rat epitope-tagged histamine H 2-receptors in insect Sf9 cells.
Br J Pharmacol 1997; 122:867–874.
83. Gantz I, Schäffer M, Del Valle J, Logsdon C, Campbell V, Uhler M, Yamada T.
Molecular cloning of a gene encoding the histamine H 2-receptor. Proc Natl Acad
Sci USA 1991; 88:429–433.
84. Ruat M, Traiffort E, Arrang JM, Leurs R, Schwartz JC. Cloning and tissue expres-
sion of a rat histamine H 2-receptor gene. Biochem Biophys Res Commun 1991;
179:1470–1478.
85. Gantz I, Munzert G, Tashiro T, Schaffer M, Wang L, Del Valle J, Yamada T.
Molecular cloning of the human histamine H 2-receptor. Biochem Biophys Res
Commun 1991; 178:1386–1392.
86. Traiffort E, Vizuete ML, Tardivel-Lacombe J, Souil E, Schwartz JC, Ruat M. The guinea
pig histamine H 2-receptor: gene cloning, tissue expression and chromosomal localization
of its human counterpart. Biochem Biophys Res Commun 1995; 211:570–577.
87. Nishi T, Koike T, Oka T, Maeda M, Futai M. Identification of the promoter region
of the human histamine H 2-receptor gene. Biochem Biophys Res Commun 1995;
210:616–623.
88. Murakami H, Sun-Wada GH, Matsumoto M, Nishi T, Wada Y, Futai M. Human
histamine H 2-receptor gene: multiple transcription initiation and tissue-specific ex-
pression. FEBS Lett 1999; 451:327–331.
89. Kobayashi T, Inoue I, Jenkins NA, Gilbert DJ, Copeland NG, Watanabe T. Cloning,
RNA expression, and chromosomal location of a mouse histamine H 2-receptor
gene. Genomics 1996; 37:390–394.
90. Gantz I, Del Valle J, Wang LD, Tashiro T, Munzert G, Guo YJ, Konda Y, Yamada
T. Molecular basis for the interaction of histamine with the histamine H 2-receptor.
J Biol Chem 1992; 267:20840–20843.
91. Zweig A, Siegel MI, Egan RW, Clark MA, Shorr RG, West RE, Jr. Characterization
of a digitonin-solubilized bovine brain H 3-histamine receptor coupled to a guanine
nucleotide-binding protein. J Neurochem 1992; 59:1661–1666.
92. Cherifi Y, Pigeon C, Le Romancer M, Bado A, Reyl-Desmars F, Lewin MJ. Purifi-
cation of a histamine H 3-receptor negatively coupled to phosphoinositide turnover
in the human gastric cell line HGT1. J Biol Chem 1992; 267:25315–25320.
93. Lovenberg TW, Roland BL, Wilson SJ, Jiang X, Pyati J, Huvar A, Jackson MR,
Erlander MG. Cloning and functional expression of the human histamine H 3-recep-
tor. Mol Pharmacol 1999; 55:1101–1107.
94. Leurs R, Hoffmann M, Wieland K, Timmerman H. H 3-receptor gene is cloned at
last. Trends Pharmacol Sci 2000; 21:11–12.
95. Tardivel-Lacombe J, Rouleau A, Héron A, Morisset S, Pillot C, Cochois V,
Schwartz JC, Arrang JM. Cloning and cerebral expression of the guinea pig hista-
mine H 3-receptor: evidence for two isoforms. Neuroreport 2000; 11:755–759.
96. Lovenberg TW, Pyati J, Chang H, Wilson SJ, Erlander MG. Cloning of rat hista-
mine H 3-receptor reveals distinct species pharmacological profiles. J Pharmacol
Exp Ther 2000; 293:771–778.
96a. Tardivel-Lacombe J, Rouleau A, Héron A, Morisset S, Pillot C, Cochois V,
Schwartz JC, Arrang JM. Cloning and cerebral expression of the guinea pig hista-
mine H 3-receptor: evidence for two isoforms. Neuroreport 2000; 11:755–759.
96b. Drutel G, Peitsaro N, Karlstedt K, Wieland K, Smit MJ, Timmerman H, Panula P,
Leurs R. Identification of rat H 3-receptor isoforms with different brain expression
and signaling properties. Mol Pharmacol 2001; 59:1–8.
96c. Morisset S, Sasse A, Gbahou F, Heron A, Ligneau X, Tardivel-Lacombe J,
Schwartz JC, Arrang JM. The rat H 3-receptor: gene organization and multiple iso-
forms. Biochem Biophys Res Commun 2001; 280:75–80.
96d. Cogé F, Guénin SP, Audinot V, Renouard-Try A, Beauverger P, Macia C, Ouvry
C, Nagel N, Rique H, Boutin JA, Galizzi JP. Genomic organization and character-
ization of splice variants of the human histamine H 3-receptor. Biochem J 2001;
355:279–288.
96e. Nakamura T, Itadani H, Hidaka Y, Ohta M, Tanaka K. Molecular cloning and
characterization of a new human histamine receptor, HH4R. Biochem Biophys Res
Commun 2000; 279:615–620.
96f. Zhu Y, Michalovich D, Wu HL, Tan KB, Dytko GM, Mannan IJ, Boyce R, Alston
J, Tierney LA, Li X, Herrity NC, Vawter L, Sarau HM, Ames RS, Davenport CM,
56 Bakker et al.
Hieble JP, Wilson S, Bergsma DJ, Fitzgerald LR. Cloning, expression, and pharma-
cological characterization of a novel human histamine receptor. Mol Pharmacol
2001; 59:434–441.
96g. Nguyen T, Shapiro DA, George SR, Setola V, Lee DK, Cheng R, Rauser L, Lee
SP, Lynch KR, Roth BL, O’Dowd BF. Discovery of a novel member of the hista-
mine receptor family. Mol Pharmacol 2001; 59:427–433.
96h. Gallagher MJ, Yates SL, Tedford CE. Cloning and expression of isoforms of the
human H 4-histamine receptor. Soc Neurosci Abstr 27, 2001.
97. Harper EA, Shankley NP, Black JW. Evidence that histamine homologues discrimi-
nate between H 3-receptors in guinea-pig cerebral cortex and ileum longitudinal
muscle myenteric plexus. Br J Pharmacol 1999; 128:751–759.
98. Leurs R, Kathmann M, Vollinga RC, Menge WMPB, Schlicker E, Timmerman H.
Histamine homologues discriminating between two functional H 3-receptor assays. Evi-
dence for H 3-receptor heterogeneity? J Pharmacol Exp Ther 1996; 276:1009–1015.
99. Bootman MD, Berridge MJ. The elemental principles of calcium signalling. Cell
1995; 83:675–678.
100. Topham MK, Prescott SM. Mammalian diacylglycerol kinases, a family of lipid
kinases with signaling functions. J Biol Chem 1999; 274:11447–11450.
101. Kiselyov K, Muallem S. Fatty acids, diacylglycerol, Ins(1,4,5)P 3 receptors and Ca 2⫹
influx. Trends Neurosci 1999; 22:334–337.
102. Barnes PJ. Histamine receptors in the lung. In: Timmerman H, van der Goot H, eds.
New Perspectives in Histamine Research. Basel: Birkhauser Verlag, 1991:103–122.
103. Claro E, Garcia A, Picatoste F. Carbachol and histamine stimulation of guanine-
nucleotide-dependent phosphoinositide hydrolysis in rat brain cortical membranes.
Biochem J 1989; 261:29–35.
104. Donaldson J, Hill SJ. Histamine-induced hydrolysis of polyphosphoinositides in
guinea-pig ileum and brain. Eur J Pharmacol 1986; 124:255–265.
105. Sakuma I, Gross SS, Levi R. Positive inotropic effect of histamine on guinea pig
left atrium: H 1-receptor-induced stimulation of phosphoinositide turnover. J Phar-
macol Exp Ther 1988; 247:466–472.
106. Orellana S, Solski PA, Brown JH. Guanosine 5′-O-(thiotriphosphate)-dependent
inositol trisphosphate formation in membranes in inhibited by phorbol ester and
protein kinase C. J Biol Chem 1987; 262:1638–1643.
107. Daum PR, Downes CP, Young JM. Histamine-induced inositol phospholipid break-
down mirrors H 1-receptor density in brain. Eur J Pharmacol 1983; 87:497–498.
108. Carswell H, Young JM. Regional variation in the characteristics of histamine H 1-
agonist mediated breakdown of inositol phospholipids in guinea-pig brain. Br J
Pharmacol 1986; 89:809–817.
109. Bailey SJ, Lippe IT, Holzer P. Effect of the tachykinin antagonist, [D-Pro4, D-
Trp7,9,10] substance P-(4-11), on tachykinin- and histamine-induced inositol phos-
phate generation in intestinal smooth muscle. Naunyn Schmiedebergs Arch Phar-
macol 1987; 335:296–300.
110. Claro E, Garcia A. Picatoste F. Histamine-stimulated phosphoinositide hydrolysis
in developing rat brain. Mol Pharmacol 1987; 32:384–390.
111. Tilly BC, Lambrechts AC, Tertoolen LG, de Laat SW, Moolenaar WH. Regulation
of phosphoinositide hydrolysis induced by histamine and guanine nucleotides in
human HeLa carcinoma cells. Calcium and pH dependence and inhibitory role of
protein kinase C. FEBS Lett 1990; 265:80–84.
112. Leurs R, Traiffort E, Arrang JM, Tardivel-Lacombe J, Raut M, Schwartz JC.
Guinea pig histamine H 1 receptor. II. Stable expression in Chinese hamster ovary
cells reveals the interaction with three major signal transduction pathways. J Neuro-
chem 1994; 62:519–527.
113. Leopoldt D, Harteneck C, Nürnberg B. G proteins endogenously expressed in Sf
9 cells: interactions with mammalian histamine receptors. Naunyn Schmiedebergs
Arch Pharmacol 1997; 356:216–224.
114. Kühn B, Schmid A, Harteneck C, Gudermann T, Schultz G. G. proteins of the G q
family couple the H 2-histamine receptor to phospholipase C. Mol Endocrinol 1996;
10:1697–1707.
115. Gutowski S, Smrcka A, Nowak L, Wu DG, Simon M, Sternweis PC. Antibodies
to the α q subfamily of quanine nucleotide-binding regulatory protein α subunits
attenuate activation of phosphatidylinositol 4,5-bisphosphate hydrolysis by hor-
mones. J Biol Chem 1991; 266:20519–20524.
116. Smit MJ, Bloemers SM, Leurs R, Tertoolen LG, Bast A, de Laat SW, Timmerman
H. Short-term desensitization of the histamine H 1 receptor in human HeLa cells:
involvement of protein kinase C dependent and independent pathways. Br J Phar-
macol 1992; 107:448–455.
117. Fujimoto K, Ohta K, Kangawa K, Kikkawa U, Ogino S, Fukui H. Identification
of protein kinase C phosphorylation sites involved in phorbol ester-induced desensi-
tization of the histamine H 1 receptor. Mol Pharmacol 1999; 55:735–742.
118. Pype JL, Mak JC, Dupont LJ, Verleden GM, Barnes PJ. Desensitization of the histamine
H 1-receptor and transcriptional down-regulation of histamine H 1-receptor gene expres-
sion in bovine tracheal smooth muscle. Br J Pharmacol 1998; 125:1477–1484.
119. Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, Schultz G.
Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature
1999; 397:259–263.
120. Birnbaumer L, Zhu X, Jiang M, Boulay G, Peyton M, Vannier B, Brown D, Platano,
D Sadeghi H, Stefani E, Birnbaumer M. On the molecular basis and regulation of
cellular capacitative calcium entry: roles for Trp proteins. Proc Natl Acad Sci USA
1996; 93:15195–15202.
121. Johnson CL, Johnson CG, Bazan E, Garver D, Gruenstein E, Ahluwalia M. Hista-
mine receptors in human fibroblasts: inositol phosphates, Ca 2⫹, and cell growth.
Am J Physiol 1990; 258:C533–543.
122. Matsumoto T, Kanaide H, Nishimura J, Shogakiuchi Y, Kobayashi S, Nakamura
M. Histamine activates H 1-receptors to induce cytosolic free calcium transients in
cultured vascular smooth muscle cells from rat aorta. Biochem Biophys Res Com-
mun 1986; 135:172–177.
123. Rotrosen D, Gallin JI. Histamine type 1 receptor occupancy increases endothelial
cytosolic calcium, reduces F-actin, and promotes albumin diffusion across cultured
endothelial monolayers. J Cell Biol 1986; 103:2379–2387.
124. Brown RD, Prendiville P, Cain C. α 1-Adrenergic and H 1-histamine receptor control
of intracellular Ca 2⫹ in a muscle cell line: the influence of prior agonist exposure
on receptor responsiveness. Mol Pharmacol 1986; 29:531–539.
58 Bakker et al.
125. Jacob R, Merritt JE, Hallam TJ, Rink TJ. Repetitive spikes in cytoplasmic calcium
evoked by histamine in human endothelial cells. Nature 1988; 335:40–45.
126. Kotlikoff MI, Murray RK, Reynolds EE. Histamine-induced calcium release and
phorbol antagonism in cultured airway smooth muscle cells. Am J Physiol 1987;
253:C561–566.
127. McDonough PM, Eubanks JH, Brown JH. Desensitization and recovery of musca-
rinic and histaminergic Ca 2⫹ mobilization in 1321N1 astrocytoma cells. Biochem
J 1988; 249:135–141.
128. Oakes SG, Iaizzo PA, Richelson E, Powis G. Histamine-induced intracellular free
Ca 2⫹, inositol phosphates and electrical changes in murine N1E-115 neuroblastoma
cells. J Pharmacol Exp Ther 1988; 247:114–121.
129. Tilly BC, Tertoolen LG, Lambrechts AC, Remorie R, de Laat SW, Moolenaar WH.
Histamine-H 1-receptor-mediated phosphoinositide hydrolysis, Ca 2⫹ signalling and
membrane-potential oscillations in human HeLa carcinoma cells. Biochem J 1990;
266:235–243.
130. Yoshimoto K, Hattori Y, Houzen H, Kanno M, Yasuda K. Histamine H 1-receptor-
mediated increase in the Ca 2⫹ transient without a change in the Ca 2⫹ current in electri-
cally stimulated guinea-pig atrial myocytes. Br J Pharmacol 1998; 124:1744–1750.
131. Inagaki N, Fukui H, Ito S, Yamatodani A, Wada H. Single type-2 astrocytes show
multiple independent sites of Ca 2⫹ signaling in response to histamine. Proc Natl
Acad Sci USA 1991; 88:4215–4219.
132. Brini M, Marsault R, Bastianutto C, Alvarez J, Pozzan T, Rizzuto R. Transfected
aequorin in the measurement of cytosolic Ca 2⫹ concentration ([Ca 2⫹ ] c). A critical
evaluation. J Biol Chem 1995; 270:9896–9903.
133. Jou MJ, Peng TI, Sheu SS. Histamine induces oscillations of mitochondrial free
Ca 2⫹ concentration in single cultured rat brain astrocytes. J Physiol (Lond) 1996;
497:299–308.
134. Baird GS, Zacharias DA, Tsien RY. Circular permutation and receptor insertion
within green fluorescent proteins. Proc Natl Acad Sci USA 1999; 96:11241–11246.
135. Miyawaki A, Griesbeck O, Heim R, Tsien RY. Dynamic and quantitative Ca 2⫹
measurements using improved cameleons. Proc Natl Acad Sci USA 1999; 96:
2135–2140.
136. Montero M, Barrero MJ, Alvarez J. [Ca 2⫹ ] microdomains control agonist-induced
Ca 2⫹ release in intact HeLa cells. FASEB J 1997; 11:881–885.
137. Barrero MJ, Montero M, Alvarez J. Dynamics of [Ca 2⫹ ] in the endoplasmic reticu-
lum and cytoplasm of intact HeLa cells. A comparative study. J Biol Chem 1997;
272:27694–27699.
138. Rizzuto R, Simpson AW, Brini M, Pozzan T. Rapid changes of mitochondrial
Ca 2⫹ revealed by specifically targeted recombinant aequorin. Nature 1992; 358:
325–327.
139. Rizzuto R, Pinton P, Carrington W, Fay FS, Fogarty KE, Lifshitz LM, Tuft RA,
Pozzan T. Close contacts with the endoplasmic reticulum as determinants of mito-
chondrial Ca 2⫹ responses. Science 1998; 280:1763–1766.
140. Pinton P, Pozzan T, Rizzuto R. The Golgi apparatus is an inositol 1,4,5-trisphos-
phate-sensitive Ca 2⫹ store, with functional properties distinct from those of the en-
doplasmic reticulum. EMBO J 1998; 17:5298–5308.
141. Lipp P, Thomas D, Berridge MJ, Bootman MD. Nuclear calcium signalling by
individual cytoplasmic calcium puffs. EMBO J 1997; 16:7166–7173.
142. Brini M, Murgia M, Pasti L, Picard D, Pozzan T, Rizzuto R. Nuclear Ca 2⫹ concen-
tration measured with specifically targeted recombinant aequorin. EMBO J 1993;
12:4813–4819.
143. Hu Q, Deshpande S, Irani K, Ziegelstein RC. [Ca 2⫹ ]i Oscillation frequency regu-
lates agonist-stimulated NF-κB transcriptional activity. J Biol Chem 1999; 274:
33995–33998.
144. Bootman MD, Taylor CW, Berridge MJ. The thiol reagent, thimerosal, evokes Ca 2⫹
spikes in HeLa cells by sensitizing the inositol 1,4,5-trisphosphate receptor. J Biol
Chem 1992; 267:25113–25119.
145. Bootman MD, Young KW, Young JM, Moreton RB, Berridge MJ. Extracellular
calcium concentration controls the frequency of intracellular calcium spiking inde-
pendently of inositol 1,4,5-trisphosphate production in HeLa cells. Biochem J 1996;
314:347–354.
146. Zhu DM, Tekle E, Chock PB, Huang CY. Reversible phosphorylation as a control-
ling factor for sustaining calcium oscillations in HeLa cells: involvement of cal-
modulin-dependent kinase II and a calyculin A-inhibitable phosphatase. Biochem-
istry 1996; 35:7214–7223.
147. Zhu DM, Tekle E, Huang CY, Chock PB. Inositol tetrakisphosphate as a frequency
regulator in calcium oscillations in HeLA cells. J Biol Chem 2000; 275:6063–6066.
148. Timmerman LA, Clipstone NA, Ho SN, Northrop JP, Crabtree GR. Rapid shuttling
of NF-AT in discrimination of Ca 2⫹ signals and immunosuppression. Nature 1996;
383:837–840.
149. Li W, Llopis J, Whitney M, Zlokarnik G, Tsein RY. Cell-permeant caged InsP 3
ester shows that Ca 2⫹ spike frequency can optimize gene expression. Nature 1998;
392:936–941.
150. Dolmetsch RE, Xu K, Lewis RS. Calcium oscillations increase the efficiency and
specificity of gene expression. Nature 1998; 392:933–936.
151. Dolmetsch RE, Lewis RS, Goodnow CC, Healy JI. Differential activation of tran-
scription factors induced by Ca 2⫹ response amplitude and duration. Nature 1997;
386:855–858.
152. Boss V, Wang X, Koppelman LF, Xu K, Murphy TJ. Histamine induces nuclear
factor of activated T cell-mediated transcription and cyclosporin A-sensitive in-
terleukin-8 mRNA expression in human umbilical vein endothelial cells. Mol Phar-
macol 1998; 54:264–272.
153. Aoki Y, Qiu D, Zhao GH, Kao PN. Leukotriene B 4 mediates histamine induction
of NF-κB and IL-8 in human bronchial epithelial cells. Am J Physiol 1998; 274:
L1030–1039.
154. Cockcroft S, Thomas GM. Inositol-lipid-specific phospholipase C isoenzymes and
their differential regulation by receptors. Biochem J 1992; 288:1–14.
155. Alexander SP, Hill SJ, Kendall DA. Differential effects of elevated calcium ion
concentrations on inositol phospholipid responses in mouse and rat cerebral cortical
slices. Biochem Pharmacol 1990; 40:1793–1799.
156. Baird JG, Chilvers ER, Kennedy ED, Nahorski SR. Changes in extracellular cal-
cium within the physiological range influence receptor-mediated inositol phosphate
60 Bakker et al.
responses in brain and tracheal smooth muscle slices. Naunyn Schmiedebergs Arch
Pharmacol 1989; 339:247–251.
157. Satoh H, Inui J. Endothelial cell-dependent relaxation and contraction induced by
histamine in the isolated guinea-pig pulmonary artery. Eur J Pharmacol 1984; 97:
321–324.
158. Schoeffter P, Godfraind T. Characterization of histamine-induced contraction in
rat isolated aorta. Eur J Pharmacol 1991; 197:193–200.
159. Toda N. Mechanism of histamine actions in human coronary arteries. Circ Res
1987; 61:280–286.
160. van de Voorde J, Leusen I. Effect of histamine on aorta preparations of different
species. Arch Int Pharmacodyn Ther 1984; 268:95–105.
161. Jansen-Olesen I, Ottosson A, Cantera L, Strunk S, Lassen LH, Olesen J, Mortensen,
A, Engel U, Edvinsson L. Role of endothelium and nitric oxide in histamine-
induced responses in human cranial arteries and detection of mRNA encoding
H 1- and H 2-receptors by RT-PCR. Br J Pharmacol 1997; 121:41–48.
162. Schmidt HH, Zernikow B, Baeblich S, Bohme E. Basal and stimulated formation
and release of L-arginine-derived nitrogen oxides from cultured endothelial cells.
J Pharmacol Exp Ther 1990; 254:591–597.
163. Yuan Y, Granger HJ, Zawieja DC, DeFily DV, Chilian WM. Histamine increases
venular permeability via a phospholipase C-NO synthase-guanylate cyclase cas-
cade. Am J Physiol 1993; 264:H1734–1739.
164. Sertl K, Casale TB, Wescott SL, Kaliner MA. Immunohistochemical localization
of histamine-stimulated increases in cyclic GMP in guinea pig lung. Am Rev Respir
Dis 1987; 135:456–462.
165. Leurs R, Brozius MM, Jansen W, Bast A, Timmerman H. Histamine H 1-receptor-
mediated cyclic GMP production in guinea-pig lung tissue is an L-arginine-depen-
dent process. Biochem Pharmacol 1991; 42:271–277.
166. Hattori Y, Sakuma I, Kanno M. Differential effects of histamine mediated by hista-
mine H 1- and H 2-receptors on contractility, spontaneous rate and cyclic nucleotides
in the rabbit heart. Eur J Pharmacol 1988; 153:221–229.
167. Duncan PG, Brink C, Adolphson RL, Douglas JS. Cyclic nucleotides and
contraction/relaxation in airway muscle: H 1- and H 2-agonists and antagonists. J
Pharmacol Exp Ther 1980; 215:434–442.
168. Casale TB, Rodbard D, Kaliner M. Characterization of histamine H 1-receptors on
human peripheral lung. Biochem Pharmacol 1985; 34:3285–3292.
169. Garcı́a-Cardeña G, Fan R, Shah V, Sorrentino R, Cirino G, Papapetropoulos A,
Sessa WC. Dynamic activation of endothelial nitric oxide synthase by Hsp90. Na-
ture 1998; 392:821–824.
170. Resink TJ, Grigorian G, Moldabaeva AK, Danilov SM, Buhler FR. Histamine-
induced phosphoinositide metabolism in cultured human umbilical vein endothelial
cells. Association with thromboxane and prostacyclin release. Biochem Biophys
Res Commun 1987; 144:438–446.
171. Baenziger NL, Force LE, Becherer PR. Histamine stimulates prostacyclin synthesis
in cultured human umbilical vein endothelial cells. Biochem Biophys Res Commun
1980; 92:1435–1440.
172. Murayama T, Kajiyama Y, Nomura Y. Histamine-stimulated and GTP-binding pro-
teins-mediated phospholipase A 2 activation in rabbit platelets. J Biol Chem 1990;

265:4290–4295.
173. Liscovitch M, Czarny M, Fiucci G, Tang X. Phospholipase D: molecular and cell
biology of a novel gene family. Biochem J 2000; 345:401–415.
174. Natarajan V, Garcia JG. Agonist-induced activation of phospholipase D in bovine
pulmonary artery endothelial cells: regulation by protein kinase C and calcium. J
Lab Clin Med 1993; 121:337–347.
175. Dawson G, Dawson SA, Post GR. Regulation of phospholipase D activity in
a human oligodendroglioma cell line (HOG). J Neurosci Res 1993; 34:
324–330.
176. Mitchell R, McCulloch D, Lutz E, Johnson M, MacKenzie C, Fennell M, Fink G,
Zhou W, Sealfon SC. Rhodopsin-family receptors associate with small G proteins
to activate phospholipase D. Nature 1998; 392:411–414.
177. Palacios JM, Garbarg M, Barbin G, Schwartz JC. Pharmacological characterization
of histamine receptors mediating the stimulation of cyclic AMP accumulation in
slices from guinea-pig hippocampus. Mol Pharmacol 1978; 14:971–982.
178. Al-Gadi M, Hill SJ. The role of calcium in the cyclic AMP response to histamine
in rabbit cerebral cortical slices. Br J Pharmacol 1987; 91:213–222.
179. Donaldson J, Brown AM, Hill SJ. Temporal changes in the calcium-dependence
of the histamine H 1-receptor-stimulation of cyclic AMP accumulation in guinea-
pig cerebral cortex. Br J Pharmacol 1989; 98:1365–1375.
180. Garbarg M, Schwartz JC. Synergism between histamine H 1- and H 2- receptors in
the cAMP response in guinea pig brain slices: effects of phorbol esters and calcium.
Mol Pharmacol 1988; 33:38–43.
181. Magistretti PJ Schorderet M. Norepinephrine and histamine potentiate the increases
in cyclic adenosine 3′:5′-monophosphate elicited by vasoactive intestinal polypep-
tide in mouse cerebral cortical slices: mediation by α 1-adrenergic and H 1-histamin-
ergic receptors. J Neurosci 1985; 5:362–368.
182. Marley PD, Thomson KA, Jachno K, Johnston MJ. Histamine-induced increases
in cyclic AMP levels in bovine adrenal medullary cells. Br J Pharmacol 1991; 104:
839–846.
183. Fitzsimons C, Molinari B, Duran H, Palmieri M, Davio C, Cricco G, Bergoc R,
Rivera E. Atypical association of H 1- and H 2-histamine receptors with signal trans-
duction pathways during multistage mouse skin carcinogenesis. Inflamm Res 1997;
46:292–298.
184. Davio CA, Cricco GP, Bergoc RM, Rivera ES. H 1- and H 2-histamine receptors in
N-nitroso-N-methylurea (NMU)-induced carcinomas with atypical coupling to sig-
nal transducers. Biochem Pharmacol 1995; 50:91–96.
185. Hill SJ, Donaldson J. The H 1-receptor and inositol phospholipid hydrolysis. In: Schwartz
JC, Haas H, eds. The Histamine Receptor. New York: Wiley-Liss, 1992:109–128.
186. Klinker JF, Wenzel-Seifert K, Seifert R. G-protein-coupled receptors in HL-60 hu-
man leukemia cells. Gen Pharmacol 1996; 27:33–54.
187. Seifert R, Grunbaum L, Schultz G. Histamine receptors in HL-60 monocytes are
coupled to Gi-proteins and pertussis toxin-insensitive G-proteins and mediate acti-
vation of Ca 2⫹ influx without concomitant Ca 2⫹ mobilization from intracellular
stores. Naunyn Schmiedebergs Arch Pharmacol 1994; 349:355–361.
62 Bakker et al.
188. Wang YX, Kotlikoff MI. Signalling pathway for histamine activation of non-
selective cation channels in equine tracheal myocytes. J Physiol (Lond) 2000; 523:
131–138.
189. Berg KA, Stout BD, Cropper JD, Maayani S, Clarke WP. Novel actions of inverse
agonists on 5-HT 2C-receptor systems. Mol Pharmacol 1999; 55:863–872.
190. Hegstrand LR, Kanof PD, Greengard P. Histamine-sensitive adenylate cyclase in
mammalian brain. Nature 1976; 260:163–165.
191. Ozawa K, Segawa T. Histamine increases phospholipid methylation and H 2-receptor-
adenylate cyclase coupling in rat brain. J Neurochem 1988; 50:1551–1558.
192. Ozawa K, Fujishima Y, Segawa T. Histamine H 2-receptor in atrium: signal trans-
duction and response. Agents Actions Suppl 1991; 33:295–300.
193. Bristow MR, Cubicciotti R, Ginsburg R, Stinson EB, Johnson C. Histamine-medi-
ated adenylate cyclase stimulation in human myocardium. Mol Pharmacol 1982;
21:671–679.
194. Sarem-Aslani A, Ratge D, Bigge HH, Walker S, Klotz U, Wisser H. A method to
assess histamine-induced cyclic AMP production in isolated gastric mucosal cells
from human biopsies. Pharmacology 1991; 42:327–332.
195. Agullo L, Picatoste F, Garcia A. Histamine stimulation of cyclic AMP accumula-
tion in astrocyte-enriched and neuronal primary cultures from rat brain. J Neuro-
chem 1990; 55:1592–1598.
196. Foreman JC, Norris DB, Rising TJ, Webber SE. A study of the H 2-receptor for
histamine stimulating adenylate cyclase in homogenates of guinea-pig lung paren-
chyma. Br J Pharmacol 1986; 87:37–44.
197. Johnson CL. Histamine receptors and cyclic nucleotides. In Schwartz JC, Haas H,
eds. The Histamine Receptor New York: Wiley-Liss, 1992:129–143.
198. Ozawa K, Fujishima Y, Segawa T. Histamine H 2-receptor in atrium: signal trans-
duction and response. In Timmerman H, van der Goot H, eds. New Perspectives
in Histamine Research. Basel: Birkhauser Verlag, 1991:265–300.
199. Ozawa K, Nomura Y, Segawa T. Histamine acting on H 2-receptors stimulates phos-
pholipid methylation in synaptic membranes of rat brain. J Neurochem 1987; 48:
1392–1398.
200. Haas HL, Wolf P, Palacios JM, Garbarg M, Barbin G, Schwartz JC. Hypersensitiv-
ity to histamine in the guinea-pig brain: microiontophoretic and biochemical stud-
ies. Brain Res 1978; 156:275–291.
201. Seifert R, Höer A, Schwaner I, Buschauer A. Histamine increases cytosolic Ca 2⫹
in HL-60 promyelocytes predominantly via H 2-receptors with a unique agonist/
antagonist profile and induces functional differentiation. Mol Pharmacol 1992; 42:
235–241.
202. Mitsuhashi M, Mitsuhashi T, Payan DG. Multiple signaling pathways of histamine
H 2-receptors. Identification of an H 2-receptor-dependent Ca 2⫹ mobilization path-
way in human HL-60 promyelocytic leukemia cells. J Biol Chem 1989; 264:18356–
18362.
203. Gespach C, Saal F, Cost H, Abita JP. Identification and characterization of surface
receptors for histamine in the human promyelocytic leukemia cell line HL-60. Com-
parison with human peripheral neutrophils. Mol Pharmacol 1982; 22:547–553.
204. Negulescu PA, Machen TE. Intracellular Ca⫹⫹ regulation during secretagogue stim-
ulation of the parietal cell. Am J Physiol 1988; 254:C130–140.
205. Koizumi H, Ohkawara A. H 2-histamine receptor-mediated increase in intracellular

Ca 2⫹ in cultured human keratinocytes. J Dermatol Sci 1999; 21:127–132.
206. Del Valle J, Wang L, Gantz I, Yamada T. Characterization of H 2 histamine receptor:
linkage to both adenylate cyclase and [Ca 2⫹ ] i signaling systems. Am J Physiol 1992;
263:G967–972.
207. Wang LD, Hoeltzel M, Butler K, Hare B, Todisco A, Wang M, Del Valle J. Activa-
tion of the human histamine H 2-receptor is linked to cell proliferation and c-fos
gene transcription. Am J Physiol 1997; 273:C2037–2045.
208. Legnazzi BL, Monczor F, Rivera E, Bergoc R, Davio C. Histamine receptors in
human epithelial cells—characterization of the receptor G-protein-effector system.
Inflamm Res 1998; 47(Suppl 1):S40–41.
209. Fitzsimons C, Duran H, Engel N, Molinari B, Rivera E. Changes in H 2-receptor
expression and coupling during Ca 2⫹-induced differentiation in mouse epidermal
keratinocytes. Inflamm Res 1999; 48(Suppl 1):S73–74.
210. Fitzsimons C, Durán H, Labombarda F, Molinari B, Rivera E. Histamine receptors
signalling in epidermal tumor cell lines with H-ras gene alterations. Inflamm Res
1998; 47(Suppl 1):S50–51.
211. Wang LD, Hoeltzel M, Gantz I, Hunter R, Del Valle J. Characterization of the
histamine H 2-receptor structural components involved in dual signaling. J Pharma-
col Exp Ther 1998; 285:573–578.
212. Wang L, Gantz I, Del Valle J. Histamine H 2-receptor activates adenylate cyclase and
PLC via separate GTP-dependent pathways. Am J Physiol 1996; 271:G613–620.
213. Fukushima Y, Asano T, Katagiri H, Aihara M, Saitoh T, Anai M, Funaki M, Ogi-
hara T, Inukai K, Matsuhashi N, Oka Y, Yazaki Y, Sugano K. Interaction between
the two signal transduction systems of the histamine H 2-receptor: desensitizing and
sensitizing effects of histamine stimulation on histamine-dependent cAMP produc-
tion in Chinese hamster ovary cells. Biochem J 1996; 320:27–32.
214. Del Valle J, Gantz I. Novel insights into histamine H 2-receptor biology. Am J Phys-
iol 1997; 273:G987–996.
215. Dickenson JM, White TE, Hill SJ. The effects of elevated cyclic AMP levels on
histamine-H 1-receptor-stimulated inositol phospholipid hydrolysis and calcium mo-
bilization in the smooth-muscle cell line DDT1MF-2. Biochem J 1993; 292:409–
417.
216. Hall IP, Hill SJ. β-Adrenoceptor stimulation inhibits histamine-stimulated inositol
phospholipid hydrolysis in bovine tracheal smooth muscle. Br J Pharmacol 1988;
95:1204–1212.
217. Hall IP, Donaldson J, Hill SJ. Inhibition of histamine-stimulated inositol phospho-
lipid hydrolysis by agents which increase cyclic AMP levels in bovine tracheal
smooth muscle. Br J Pharmacol 1989; 97:603–613.
218. Orange PR, Heath PR, Wright SR, Pearson RC. Allelic variations of the human
histamine H 2-receptor gene. Neuroreport 1996; 7:1293–1296.
219. Traiffort E, Ruat M, Arrang JM, Leurs R, Piomelli D, Schwartz JC. Expression of
a cloned rat histamine H 2-receptor mediating inhibition of arachidonate release and
activation of cAMP accumulation. Proc Natl Acad Sci USA 1992; 89:2649–2653.
220. Leurs R, Smit MJ, Menge WM, Timmerman H. Pharmacological characterization
of the human histamine H 2-receptor stably expressed in Chinese hamster ovary
cells. Br J Pharmacol 1994; 112:847–854.
64 Bakker et al.
221. Gantz I, Schäffer M, Del Valle J, Logsdon C, Campbell V, Uhler M, Yamada T.

Molecular cloning of a gene encoding the histamine H 2-receptor. Proc Natl Acad
Sci USA 1991; 88:5937.
222. Alewijnse AE, Smit MJ, Rodriguez Pena MS, Verzijl D, Timmerman H, Leurs R.
Modulation of forskolin-mediated adenylyl cyclase activation by constitutively ac-
tive G s-coupled receptors. FEBS Lett 1997; 419:171–174.
223. Alewijnse AE, Timmerman H, Jacobs EH, Smit MJ, Roovers E, Cotecchia S, Leurs
R. The effect of mutations in the DRY motif on the constitutive activity and struc-
tural instability of the histamine H 2-receptor. Mol Pharmacol 2000; 57:890–898.
224. Arrang JM, Roy J, Morgat JL, Schunack W, Schwartz JC. Histamine H 3-receptor
binding sites in rat brain membranes: modulations by guanine nucleotides and diva-
lent cations. Eur J Pharmacol 1990; 188:219–227.
225. West RE, Jr., Zweig A, Granzow RT, Siegel MI, Egan RW. Biexponential kinetics
of (R)-α-[ 3 H]methylhistamine binding to the rat brain H 3-histamine receptor. J
Neurochem 1990; 55:1612–1616.
226. Cumming P, Shaw C, Vincent SR. High affinity histamine binding site is the H 3-
receptor: characterization and autoradiographic localization in rat brain. Synapse
1991; 8:144–151.
227. Clark MA, Korte A, Egan RW. Guanine nucleotides and pertussis toxin reduce the
affinity of histamine H 3-receptors on AtT-20 cells. Agents Actions 1993; 40:129–
134.
228. Clark EA, Hill SJ. Sensitivity of histamine H 3-receptor agonist-stimulated
[ 35S]GTPγ[S] binding to pertussis toxin. Eur J Pharmacol 1996; 296:223–225.
229. Takeshita Y, Watanabe T, Sakata T, Munakata M, Ishibashi H, Akaike N. Hista-
mine modulates high-voltage-activated calcium channels in neurons dissociated
from the rat tuberomammillary nucleus. Neuroscience 1998; 87:797–805.
230. Nozaki M, Sperelakis N. Pertussis toxin effects on transmitter release from perivas-
cular nerve terminals. Am J Physiol 1989; 256:H455–459.
231. Oike M, Kitamura K, Kuriyama H. Histamine H 3-receptor activation augments
voltage-dependent Ca 2⫹ current via GTP hydrolysis in rabbit saphenous artery. J
Physiol (Lond) 1992; 448:133–152.
232. Endou M, Poli E, Levi R. Histamine H 3-receptor signaling in the heart: possible
involvement of G i /G o proteins and N-type Ca 2⫹ channels. J Pharmacol Exp Ther
1994; 269:221–229.
232a. Silver RB, Mackins CJ, Smith NC, Koritchneva IL, Lefkowitz K, Lovenberg TW,
Levi R. Coupling of histamine H 3-receptors to neuronal Na⫹ /H ⫹ exchange: a novel
protective mechanism in myocardial ischemia. Proc Natl Acad Sci USA 2001; 98:
2855–2859.
233. Hardie RC. A histamine-activated chloride channel involved in neurotransmission
at a photoreceptor synapse. Nature 1989; 339:704–706.
234. McClintock TS, Ache BW. Histamine directly gates a chloride channel in lobster
olfactory receptor neurons. Proc Natl Acad Sci USA 1989; 86:8137–8141.
235. Laughlin SB, de Ruyter van Steveninck RR, Anderson JC. The metabolic cost of
neural information. Nat Neurosci 1998; 1:36–41.
236. Paesen GC, Adams PL, Harlos K, Nuttall PA, Stuart DI. Tick histamine-binding pro-
teins: isolation, cloning, and three-dimensional structure. Mol Cell 1999; 3:661–671.
3
Structure and Classification
of H 1-Antihistamines
and Overview of Their Activities
Giovanni Passalacqua and G. Walter Canonica

Genoa University, Genoa, Italy
Jean Bousquet
Montpellier University, Montpellier, France
I. INTRODUCTION
Histamine, an ubiquitous cell-to-cell messenger, was identified in 1910 by Dale

and Laidlaw (1) and has been recognized since the 1920s as a major mediator of
allergic disorders such as rhinitis, asthma, urticaria, and anaphylaxis. The precise
mechanism of action of histamine remained unknown until 1966, when the H 1-
histamine receptor was identified (2). Knowledge about the histaminergic system
evolved with the subsequent discovery of the H 2-receptor (3), involved in gastric
acid secretion, and the H 3-receptor (4) represented most prominently in the central
nervous system (CNS) in humans.
Histamine is released from basophils and mast cells following an IgE-medi-
ated allergic reaction. The resulting inflammatory response is far more complex
than previously thought, since many cell types and a wide array of inflammatory
mediators including arachidonic acid metabolites, toxic proteins, cytokines, growth
factors, and neuromediators are involved. Thus, it is difficult to explain why a drug
that only acts on the H 1-receptor can be effective in controlling symptoms induced
by an allergic reaction, unless additional anti-inflammatory properties are present.
H 1-antihistamines (H 1-blockers or H 1-receptor antagonists) were discov-
ered by Bovet and Staub at the Institut Pasteur in 1937 (5). Although the first
65
66 Passalacqua et al.
compounds were too weak and too toxic for clinical use, their discovery led to
further research and, in 1942, to the development of phenbenzamine (Antegan),
the first H 1-antagonist used in the treatment of allergic diseases (6). Within a few
years, three other H 1-antihistamines were synthesized: pyrilamine maleate (7),
diphenhydramine (8), and tripelennamine (9), which are still in use today. Despite
their pronounced side effects, these were the first really useful drugs for the symp-
tomatic relief of allergic diseases. During the past 15 years, pharmacological
research has produced several compounds with an improved benefit-to-risk ratio
(therapeutic index) suitable for once-daily dosing: the so-called second-genera-
tion H 1-antihistamines, as opposed to the older first-generation H 1-antihistamines.
This class of drugs has recently been the focus of considerable medical scientific
interest, for two rather different reasons: its multiple antiallergic properties, and
its potential cardiotoxic effects. These topics are the source of much current inter-
est because of the widespread use of H 1-antihistamines in medical practice.
II. CHEMISTRY OF H1-ANTIHISTAMINES
Histamine consists of a single heterocyclic ring (imidazole) connected directly to

the ethylamine group. The unsubstituted amino-terminal H 1-antihistamines bear
much less structural resemblance to histamine than do the H 2-antagonists. H 1-
antihistamines are nitrogenous bases containing an aliphatic side chain, sharing
with histamine the common core structure of a substituted ethylamine (10). The
ethylamine side chain is essential for H 1-antagonism. A methyl group in the 2
position increases, and the same group in the 4 position decreases, the relative
affinity of a compound for H 1-receptors in contrast with H 2-receptors (3). The
side chain is attached to one, or more often two, cyclic or heterocyclic rings
that may be pyridine, piperidine, pyrrolidine, piperazine, phenothiazine, or even
imidazole (AR1, AR2). These rings are connected via a nitrogen, carbon, or oxy-
gen linkage (X) to the ethylamine group. Unlike that of histamine, the nitrogen
of this ethylamine group is tertiary with two substituents (R1 and R2) (Fig. 1).
A study of the structure–activity relationship indicates that not all compounds
with an aliphatic side chain have antihistamine activity (11). Three features of
H 1-antihistamines are of importance. First, the presence of multiple aromatic or
heterocyclic rings and alkyl substituents in these antagonists results in their lipo-
philic properties, in contrast to histamine and H 2-antagonists, which are hydro-
philic compounds. Second is the basicity of the nitrogen group as the nearer the
pKa is to 8.6 the more potent the compound is. Third is the nature of the linkage
atom X used to categorize the numerous H 1-antihistamines into six major classes
(Fig. 2). The geometries of H 1-antagonists have been studied by x-ray crystallog-
raphy and data have been compared with those obtained by minimizing the con-
formational energy of the molecules according to a simplified model of force
Figure 1 Structural comparison between histamine (top) and the general formula for
H 1-antihistamines (bottom). (From Ref. 10.)
Figure 2 The six major groups of H 1-antihistamines.

field. Both approaches agree in indicating unique stereochemical requirements

for optimum H 1-antihistaminic activity (12).
Some second-generation H 1-antihistamines have a chemical structure that
differs considerably from that of old H 1-antihistamines, thereby explaining some
of the properties of the new compounds (Fig. 3). Fexofenadine and levocabastine
contain a piperidine ring but they cannot be directly ascribed to this class (13).
Figure 3 Structural formula of some new-generation H 1-antihistamines.

Structure and Classification 69
Loratadine is related to azatadine, whereas cetirizine is a metabolite of hydroxy-

zine and acrivastine is structurally related to triprolidine.
An additional group of compounds includes azelastine, ketotifen, and oxa-
tomide. Although most H 1-antihistamines possess antiallergic properties, these
compounds have been directly developed to be both H 1-antihistamines and inhibi-
tors of mediator release from inflammatory cells.
Tricyclic antidepressants have a common three-ring molecular core and are
classified by the type of amine on the side chain into tertiary (doxepin, amitripty-
line, and trimipramine) and secondary (protriptyline, nortriptyline, and desipra-
mine) amine tricyclics (14). These compounds were initially developed for
possible use as H 1-antihistamines but they were found to have potent mood-
elevating effects and have subsequently been used for the treatment of de-
pression (15); however, they possess a potent inhibitory activity on histamine-
and allergen-induced skin tests (16).
III. PHARMACOLOGICAL EFFECTS

OF H 1-ANTIHISTAMINES
A. Effects Related to H 1-Receptor-Mediated Responses
The pharmacological effects of H 1-antihistamines derive primarily from inhibi-
tion of histamine action at H 1-receptors. The major effects of histamine that are
inhibited by H 1-antihistamines are smooth muscle contraction, increase in vascu-
lar permeability, possibly by direct action on endothelial cells (17), sensory nerve
stimulation, and pruritus. H 1-antihistamines act by binding to H 1-histamine recep-
tors. Unlike histamine, binding of the antagonists to the receptors does not elicit
a tissue response. The presence of H 1-antihistamines at the receptor prevents
histamine from binding and histaminic responses are therefore blocked. The first-
generation classic H 1-antihistamines act competitively with histamine at the re-
ceptor level and their binding is readily reversible. They can be displaced by
high levels of histamine or when they dissociate from the receptor. Doses of
H 1-antihistamines must therefore be high enough to compete effectively with
histamine for the H 1-receptor; however, the incidence and severity of side effects
increase with dose, thus limiting the use of first-generation H 1-antihistamines
(18). Second-generation H 1-antihistamines bind in a noncompetitive manner with
the H 1-receptor (19, 20). These new compounds dissociate slowly from the hista-
mine H 1-receptor, and are not displaced easily by histamine from the receptor
site.
Objective dose–response studies of H 1-receptor activity in the skin have
been performed using suppression of the histamine-induced wheal and flare re-
actions. Results with second-generation H 1-antihistamines indicate a dose-
dependent increase in histamine skin test suppression. Few dose–response
studies of H 1-antihistamines in allergic rhinitis or chronic urticaria have been

published. Recommended doses for H 1-antihistamines appear to be optimal with
regard to safety and should not be exceeded as, with the exception of fexofena-
dine, the incidence of adverse effects may increase when higher doses are used.
Also, even if higher doses are given, complete symptom relief may not occur in
all patients since total H 1-blockade still leaves the effects of other chemical medi-
ators of inflammation unopposed (21).
B. Antiallergic Activities
Histamine is not the only mediator released during allergic reactions. The rank
order of relative H 1-antagonism by H 1-antihistamines was studied by Simons et
al. using skin tests with histamine. The order from the most effective to the least
effective was found to be cetirizine, 10 mg; terfenadine, 120 mg; terfenadine, 60
mg; loratadine, 10 mg; astemizole, 10 mg; chlorpheniramine, 4 mg; and placebo
(22). Other studies confirmed this ranking (23); however, when these drugs are
compared in placebo-controlled clinical trials in which the outcomes are subjec-
tive relief of ocular, nasal or skin symptoms, it is usually impossible to differenti-
ate their clinical efficacy (24–32). Skin test reactivity does not correlate with
symptoms during nasal challenge (33) or the pollen season (34). This suggests
that the clinical activity of these drugs involves other properties besides H 1-
blocking activity, or alternatively that an incomplete H 1-blockade is sufficient
for clinical efficacy. Moreover, the blockade of the release of histamine by a
synthesis inhibitor was unable to suppress symptoms significantly during nasal
challenge (35).
Thus, it appears that properties in addition to H 1-blockade are desirable for
drugs that relieve the symptoms of the allergic reaction. Over the past 15 years,
it has become clear that most first- and second-generation H 1-antihistamines have
such antiallergic properties (36), although the properties differ depending on the
H 1-antihistamine and the cells and experimental conditions used (37–41). In
vitro, high concentrations of H 1-antihistamines are able to block mediator release
from basophils and human mast cells (42–46) by mechanisms that are not yet
completely understood (47).
These antiallergic effects can also be seen in vivo in skin, nasal, lung, and
ocular challenge studies. Using nasal challenge with allergen, it has been ob-
served that azatadine, loratadine, and terfenadine reduce histamine, PGD2, and
kinin release during challenge (48–51). Cetirizine was found to reduce tryptase
levels in nasal secretions (52). Azelastine (53) and cetirizine (51) decrease release
of leukotrienes. On the other hand, the effects of ketotifen were disappointing
in this particular model since mediator release was not blocked as expected (54).
Ebastine reduced cytokine production (37). Cetirizine, at least in some studies
in the skin, reduced eosinophil chemotaxis after allergen challenge (55–59), but
had no effect on eosinophils after allergen bronchial (60) or nasal challenge (61).
Moreover, terfenadine, cetirizine, and loratadine decreased the expression of in-
tracellular-adhesion molecule-1 (ICAM-1) on cells from conjunctival or nasal
secretions during allergen challenge (62–66) or natural allergen exposure to pol-
lens (67–72) or mites (73).
The extent of these antiallergic effects is not completely understood, yet
these studies have led to the concept of antiallergic drugs with H 1-blocking prop-
erties (36, 74). It would be premature to attempt to reclassify the H 1-antihista-
mines according to their antiallergic properties because these have not been fully
investigated. Their relative contribution to the overall therapeutic effectiveness
of each H 1-antihistamine is unknown (75).
Due to their variable H 1-blocking activity and antiallergic effects and pos-
sibly due to differences in lipophilicity and tissue deposition, the various H 1-
antihistamines are not equally effective in reducing skin, nose, eye, or lung
symptoms. Moreover, it appears that not all H 1-antihistamines have identical
effects in various patients, since nonresponders to one may respond favorably to
another (76).
C. Adverse Effects Unrelated to H 1-Activity

Most, if not all, first-generation H 1-antihistamines possess pharmacological ef-
fects that are not related to H 1-activity. Many H 1-antihistamines block cholinergic
muscarinic receptors in a dose-dependent manner. Quantitative evaluation of anti-
muscarinic effects of antihistamines (H 1- and H 2-receptor antagonists) was car-
ried out using a receptor-binding assay. Mequitazine, cyproheptadine, clemastine,
diphenylpyraline, promethazine, homochlorcyclizine, and alimemazine had high
affinities for the muscarinic receptors (Ki ⫽ 5.0–38 nM). Another group of H 1-
receptor antagonists (mepyramine, terfenadine, methapyralene, azelastine, hydro-
xyzine, and meclizine) exhibited low affinities for the muscarinic receptors (Ki
⫽ 3,600–30,000 nM) (77). Based on molecular cloning studies, five different
muscarinic receptor subtypes exist: m1, m2, m3, m4, and m5. Stanton et al. (78)
determined the affinity and selectivity of binding for three H 1-antihistamines us-
ing Chinese hamster ovarian cells (CHO-K1) transfected with genes for the hu-
man muscarinic receptor subtypes. The compounds studied showed no significant
selectivity among the five cloned subtypes in vivo. The most common anticholin-
ergic side effects at usual dosages consist of dryness of the mouth and of the
mucous membranes of the nose and the throat. In susceptible individuals, urinary
retention and blurred vision may occur. At higher doses, more severe anticholin-
ergic effects may be observed.
Some H 1-antihistamines have local anesthetic effects, possess membrane-
stabilizing or quinidine-like effects on cardiac muscle, and are responsible for a
prolongation of the refractory period in the myocardium and torsade de pointes
(79). These effects have been highlighted recently by the potentially fatal cardio-
toxicity of the H 1-antihistamines astemizole and terfenadine. The cardiac effects
of H 1-antihistamines are reviewed in Chapter 12.
Certain H 1-antihistamines, particularly promethazine, possess α-adrenergic
receptor-blocking properties. Some H 1-antihistamines increase adrenergic effects
by cocaine-like activity, decreasing transmitter reuptake. Other H 1-antihistamines
possess antiserotonin (80) or antidopamine effects (phenothiazines) (81).
Several but not all H 1-antihistamines are analgesic agents or adjuvants.
They include diphenhydramine, hydroxyzine, orphenadrine, pyrilamine, phenyl-
toloxamine, promethazine, methdilazine, and tripelennamine. More than one
mechanism of action exists for them. Considerable evidence suggests that hista-
minergic and serotoninergic central pathways are involved in nociception and
that H 1-antihistamine drugs can modulate these responses. The evidence for a
role for norepinephrine and dopamine and the effects of H 1-antihistamines on
their pathways is less well established (82).
Histamine H 1-receptors are involved in the development of the symptoms
of motion sickness, including emesis. On provocative motion stimulus, a signal
for sensory conflict activates the histaminergic neuron system and the histaminer-
gic descending impulse then stimulates H 1-receptors in the emetic center of the
brainstem. The histaminergic input to the emetic center via H 1-receptors is inde-
pendent of dopamine D2-receptors in the chemoreceptor trigger zone and seroto-
nin 5HT3-receptors in the visceral afferents that are also involved in the emetic
reflex. H 1-antihistamines block emetic H 1-receptors to prevent motion sickness.
Acetylcholine muscarinic receptors are involved in the generation of signals for
sensory conflict. Anticholinergic drugs prevent motion sickness by modifying
the neural store to facilitate habituation to provocative motion stimuli (83–85).
D. Central Nervous System Side Effects

In the CNS (86), histamine is considered to be both a local hormone and a neuro-
transmitter and is synthesized primarily by neurons and mast cells. The three
types of receptors are present in the CNS but differ in their localization, biochemi-
cal machinery, function, and affinities for histamine. H 1-receptors, visualized by
autoradiography, are widespread throughout the CNS. The most important physi-
ological role of histamine at H 1-receptors in the CNS is to control vigilance in
the waking state. The most common side effects of first-generation H 1-antihista-
mines are sedation, impaired coordination, dizziness, lassitude and inability to
concentrate, and, occasionally, paradoxical stimulation. Sedation ranging from
mild drowsiness to deep sleep can occur frequently, even at the usual therapeutic
doses. The CNS side effects of H 1-antihistamines can be attributed either to the
poor selectivity for the H 1-receptor or to the capacity to cross the blood–brain
barrier (87). This latter concept involves a number of different factors: lipophilic-
ity (88, 89), ionization, binding to serum proteins, and presence of active transpor-
tation. Second-generation relatively nonsedative H 1-antihistamines do not cross
this barrier to the same extent as their predecessors. Moreover, there is a highly
significant correlation between the sedation caused by H 1-antihistamines and the
level of their binding to brain receptors (90). Nonsedative H 1-antihistamines may
have a reduced affinity for CNS histamine receptors (91, 92).
The second-generation H 1-antihistamines are mostly devoid of CNS side
effects (93). A battery of cognitive and psychomotor tests has been used to assess
both objective and subjective sedative effects of these medications. They include
tests of psychomotor performance, sensorimotor coordination, speed, information
processing, sensory skills, as well as physiological measures and subjective rating
scales. At therapeutic doses, most of the new compounds are relatively free from
sedative effects (for review see 94–99), and, unlike the first-generation H 1-
antihistamines (100), do not exacerbate the CNS effects of alcohol and vice versa
(101–103).
Elderly patients present a greater risk for CNS side effects and first-genera-
tion H 1-antihistamines should no longer be used in this population (104)
(Chap. 15).
E. Cardiac Side Effects

During the past 15 years, arrhythmogenic effects and fatalities have been attrib-
uted to terfenadine and astemizole (96, 105, 106), which have been withdrawn
in several countries due to their potential cardiotoxicity. This is not a class effect.
It is a quinidine-like action that involves an abnormal prolongation of the QT
interval (107), possibly leading to torsade de pointes, ventricular tachycardia,
atrioventricular block, and cardiac arrest (79, 108–140). The molecular mecha-
nism sustaining the cardiotoxic action is the blockade of some potassium channels
on ventricular myocytes, namely Ikr and Ik1, which are responsible for the inward
rectifier current (141–143). The proclivity to block ion channels depends upon
the molecular structure of the drug and is maximal for terfenadine and astemizole.
The blockade of these channels may occur, and become clinically significant, in
the case of increased plasma concentration of the drug due to an overdose or to
impaired metabolism.
There is a dose-dependent effect on cardiac toxicity and this is of relevance
for drugs metabolized by the P-450 cytochrome system. The concomitant admin-
istration of compounds that compete with the enzyme (macrolide antibiotics, im-
idazole antifungals) may reduce metabolism of the H 1-antihistamine and increase
its plasma concentration. Loratadine (144–146) and ebastine (147, 148), although
metabolized in the liver, do not appear to possess the intrinsic capacity to block
ion channels. On the other hand, cetirizine (149) and fexofenadine (150, 151)
are eliminated mostly unchanged. Mizolastine is extensively metabolized. In
doses up to 40 mg (four times the therapeutic dose) there is no evidence of an
effect on ventricular repolarization in healthy volunteers (153).
F. Gastrointestinal Disturbances
Gastrointestinal disturbances including nausea, vomiting, diarrhea, loss of appe-
tite, and epigastric distress are produced by some members of the ethylenedi-
amine class.
G. Tumor Promotion
The potential tumor-promoting effects of some H 1-antihistamines were reported
in a single study in mice injected in the intraperitoneal space with melanoma or
fibrosarcoma cells (154), but these results have not been confirmed. Moreover,
results obtained in rodents are not directly applicable to humans because of the
experimental conditions and the different cellular metabolic systems involved (155,
156). During 60 years of use there has been no clinical evidence of tumor-promoting
effects of the commercially available H 1-antihistamines (157). Therefore, this
should not be considered to be a possible side effect of H 1-antihistamines.
IV. FIRST-GENERATION H 1-ANTIHISTAMINES
First-generation H 1-antihistamines are usually classified into six different groups

based on their chemical structure. In addition to their H 1-antagonist effects, they
have anticholinergic and antiserotonin effects that contribute to their adverse ef-
fect profiles.
A. Group I: Ethylenediamines
These include pyrilamine, antazoline, methapyrilene (158), and tripelennamine.
These drugs have relatively weak CNS effects but gastrointestinal side effects
are common. Methapyrilene was found to possess carcinogenic properties (159)
and is no longer available for use.
B. Group II: Ethanolamines

These include diphenhydramine (8, 160), bromodiphenhydramine, carbinoxa-
mine (161), clemastine (162), doxylamine, and phenyltoloxamine (163). These
drugs have significant anticholinergic side effects and cause overt sedation in
about half of users. The incidence of gastrointestinal side effects is relatively

low. Diphenhydramine is sometimes used as a sedative (due to its antihistamine
effects) or to improve voluntary movements in patients with Parkinson’s disease
(due to its anticholinergic effects).
C. Group III: Alkylamines

These include chlorpheniramine (164, 165), brompheniramine (166), dexbrom-
pheniramine, dexchlorpheniramine, dimethindene (167–169), pheniramine, and
triprolidine (170), which cause overt sedation in about 40% of users.
D. Group IV: Phenothiazines

Among these are promethazine, mequitazine, methdilazine, and trimeprazine
(171). Sedative and anticholinergic side effects are common with these drugs,
which are now primarily used as antiemetics (172). Mequitazine is effective in
the treatment of allergic rhinitis (26) but it is moderately sedative (173, 174) and
possesses anticholinergic effects (175, 176).
E. Group V: Piperazines
These include cyclizine (170, 177), buclizine, chlorcyclizine, hydroxyzine (178,
179), and meclizine, and induce mild to moderate sedation and anticholinergic
side effects in most users. Cyclizine, buclizine, and meclizine are used for treating
motion sickness or vertigo. Hydroxyzine is used as an H 1-antagonist (180, 181)
as well as a sedative, tranquilizer, and antiemetic.
F. Group VI: Piperidines

Among these are cyproheptadine (180, 181) and azatadine (182–184). These
drugs possess sedative and anticholinergic side effects. Cyproheptadine is used
as an appetite stimulant. Conflicting observations concerning the action of cypro-
heptadine on pituitary function have been reported in the literature. This may be
a reflection of the diversity of pharmacological actions of this drug, which include
a potent antiserotonin activity (185, 186).
First-generation H 1-antihistamines should no longer be used for allergic
rhinitis or chronic urticaria treatment owing to their side effects, among which
sedation, impaired driving performance (187, 188), and anticholinergic activity
are the most important. Tachyphylaxis in response to chlorpheniramine may oc-
cur (189–191), in contrast to the second-generation H 1-antihistamines, for which
tachyphylaxis has not been reported (192, 193).
V. SECOND-GENERATION H 1-ANTIHISTAMINES
Second-generation H 1-antihistamines have been developed over the last 15 years

and can be differentiated from the first-generation H 1-antihistamines by many
properties, two of which are of great importance: the kinetics of their binding to
and dissociation from the H 1-receptor and their lack of appreciable CNS and
anticholinergic side effects. Some of these drugs have been formulated for topical
use on the nasal mucosa and conjunctiva.
A. General Properties
Ideally, second-generation H 1-antihistamines should incorporate the properties
discussed below.
1. Pharmacological Properties
Agents should provide potent and noncompetitive H 1-receptor blockade as well
as antiallergic activities.
2. Side Effects
Formulations should cause no or little sedation, have no anticholinergic effect,
and cause neither weight gain nor cardiac side effects.
3. Pharmacokinetics
The ideal agent should have a rapid onset of action and food should not interfere
with its absorption. It should have a long duration of action (24 h) after once-
daily administration. It should not cause development of tachyphylaxis (192, 193)
and should not interact with cytochrome P-450. All the newer H 1-antihistamines
(except cetirizine and fexofenadine) undergo hepatic metabolism via the cyto-
chrome P-450 system and most are transformed into active metabolites. Cyto-
chrome P-450 (CYP3A) is involved in the metabolism of many chemically di-
verse drugs administered to humans (194, 195). Moreover, its localization in high
concentrations both in the small intestinal epithelium and liver makes it a major
contributor to presystemic first-pass elimination following oral drug administra-
tion. Drug interactions involving enzyme inhibition or induction are common
following the coadministration of two or more CYP3A substrates (196).
4. Clinical Activities
The new H 1-antihistamines are highly selective for H 1-receptors and therefore
they are effective in reducing itching, sneezing, and watery rhinorrhea in allergic
rhinitis (for review on clinical efficacy, see Refs. 197–202), but they are less
effective in treating nasal congestion (203). It is important to note that an H 1-

antihistamine, when administered orally, also exerts its effects on nonnasal symp-
toms such as allergic conjunctivitis and the mild asthma which is often associated
with allergic rhinitis. It has been shown that long-term continuous treatment with
H 1-antihistamines is more advantageous and effective than ‘‘on demand’’ treat-
ment (204). In addition to improving lower respiratory tract symptoms (205),
these agents may delay asthma onset in a subset of infants with house dust mite
or grass pollen sensitization (206).
Some H 1-antihistamines (azelastine, ketotifen, levocabastine) can be ad-
ministered locally to the nose or the eyes. The major advantage of delivering
drugs directly to the nasal mucosa or the conjunctiva is that high concentrations
can be delivered more effectively into the target organ. Topical H 1-antihistamines
have a rapid onset of action (within 15 min) at low dosage, but their actions are
limited to the treated organ. Topical H 1-antihistamines usually require twice-daily
(bid) administration to maintain a satisfactory clinical effect. Their use may there-
fore be recommended for mild organ-limited disease and as an ‘‘on demand’’
treatment in addition to regular medication (207).
B. Specific Properties
Second-generation H 1-antihistamines have similar efficacy, but differ in their
clinical pharmacology and safety profiles. Additional H 1-antihistamines in vari-
ous stages of development at this time include desloratadine, emedastine, epinas-
tine, levocetirizine, and tecastemizole (208).
1. Acrivastine
Acrivastine is a side-chain-reduced relative of the first-generation antihistamine
triprolidine. It is a very short-acting histamine H 1-receptor antagonist with a rapid
onset of action. Randomized controlled trials have shown acrivastine (usually 8
mg three times daily) to be an effective antihistamine in the treatment of chronic
urticaria (209) and allergic rhinitis (210). Acrivastine was found to cause less
drowsiness than clemastine (211), but it does seem to have some sedative effects
(212) and CNS interactions with alcohol have been observed (213). Because of
its rapid onset of action, acrivastine is useful for ‘‘on demand’’ therapy in patients
with intermittent symptoms (214).
2. Astemizole
Astemizole [1-(4-fluorophenylmethyl)-N-1(2-(4-methoxyphenyl)ethyl)-4-
piperidinyl-1H-benzamidazole-2-amine] is a long-acting, highly selective H 1-
antagonist with no CNS or anticholinergic effects (20, 215, 216). Due to its
potential cardiac toxicity, it has been withdrawn from the market in most coun-
tries.
3. Cetirizine
Cetirizine, [2-[(4-chlorophenyl)phenylmethyl-1-piperazinyl)ethoxy] acetic acid
dihydrochloride, a piperazine derivative and carboxylated metabolite of hy-
droxyzine, is a specific and long-acting histamine H 1-receptor antagonist. The H 1-
blocking activity of cetirizine is extremely potent (22). It also inhibits eosinophil
chemotaxis during the allergic response in the skin (217–219) but not in the nose.
Cetirizine is not extensively metabolized in the liver and no cardiac side effects
have been reported. Randomized controlled trials indicate that cetirizine 10 mg
daily is an effective treatment for seasonal and perennial allergic rhinitis (220–
230) and for allergic conjunctivitis (231, 232). It also has a role in the treatment
of certain forms of physical urticaria, atopic dermatitis, and reactions to mosquito
bites (233). It is associated with a significantly lower incidence of sedation than
hydroxyzine; however, when sedation was subjectively assessed, cetirizine ap-
peared to be more sedating than placebo or other second-generation H 1-antihista-
mine such as loratadine in some, but not all, double-blind studies (234). In con-
trast, when assessed objectively in pharmacodynamic comparisons, cetirizine
rarely had more CNS effects than placebo or other second-generation histamine
H 1-antagonists (197, 235).
4. Ebastine
Ebastine, 4-diphenylmethoxy-1-[3-(4-ter-butylbenzoyl)-propyl piperidine, a pi-
peridine derivative, and its active metabolite carebastine are selective H 1-receptor
antagonists (236) devoid of any other noticeable receptor binding. Ebastine has
less affinity for central than for peripheral H 1-receptors. Randomized controlled
trial have shown that, administered at a dosage of 10 mg daily, ebastine was
effective in the treatment of seasonal (237–239) and perennial allergic rhinitis
(240, 241). However, a dosage of 20 mg daily was found to be more effective
and a dual dosage has been suggested; 10 mg for seasonal (242) and 20 mg for
perennial rhinitis (241, 243). Administered at a dosage of 10 or 20 mg daily,
ebastine was not found to induce sedation (244). No interactions with alcohol
(245) have been reported. Ebastine appears to be free from cardiovascular side
effects at dosages of 10 mg or 20 mg daily (246).
5. Fexofenadine
Fexofenadine is the pharmacologically active metabolite of terfenadine (247). It
is a potent H 1-antihistamine in skin test models (198, 248, 249). Its pharmacoki-
netics have been studied in adults and children (250) and support once-daily
dosing. Randomized controlled trials have found that fexofenadine is effective

in seasonal allergic rhinitis and urticaria (151, 225, 251–253). Fexofenadine is
nonsedating in dosages up to 240 mg daily (151, 225, 251, 252) and does not
impair driving performance. It does not potentiate alcohol sedative effects or have
any cardiac side effects in dosages up to 690 mg twice daily for 28 days (254).
6. Levocabastine
Levocabastine (3S-(1(cis)-3α, 4β))-1[-[4-cyano-4(4-fluorophenyl)cyclohexyl]-
3-methyl-4-phenyl-4-piperidine carboxylic acid monochloride] is a cyclohexyl-
piperidine derivative shown to possess long-lasting H 1-antagonism and anti-
allergic properties (255). It has only been developed for nasal mucosal and
conjunctival administration due to its sedative effects. In controlled trials, levoca-
bastine was effective and well tolerated in the treatment of allergic rhinitis and
allergic conjunctivitis. Randomized controlled trials have demonstrated that levo-
cabastine is superior to placebo and at least as effective as sodium cromoglycate
in alleviating symptoms of seasonal allergic rhinitis (256–261) and conjunctivitis
(262–268); however, it is less effective than topical corticosteroids in relieving
rhinorrhea and nasal congestion. The incidence of adverse effects associated with
topical levocabastine therapy is low and similar to that observed with placebo
or sodium cromoglycate (269). No sedation was observed after use of eye drops
(270).
7. Loratadine
Loratadine (ethyl-4 (8-chloro-5,6-dihydro-11H-benzo (5-6)-cyclo-hepta (1,2-b)
pyridine 11-ylidene)-1 piperidine carboxylate) has high selectivity for peripheral
histamine H 1-receptors (271). It is rapidly metabolized into an active metabolite,
descarboethoxyloratadine. Although it is metabolized by the cytochrome
CYP3A4 system in the liver, an alternative pathway CYP2D6 is available and
no accumulation has been reported. Randomized controlled trials have shown
that loratadine (10 mg daily) is a well-tolerated and effective H 1-antagonist in
seasonal and perennial allergic rhinitis and chronic urticaria (24–28, 34, 272–
277). No sedative effect of loratadine is observed at recommended dosages (92,
188, 278, 279). No cardiac side effects have been observed.
8. Mizolastine
Mizolastine, an H 1-antihistamine (153, 280) without anticholinergic effects (281,
282), has antiallergic and anti-inflammatory effects in animals (283–285) and
healthy volunteers. Randomized controlled trials have shown that mizolastine is
effective in the treatment of seasonal and perennial allergic rhinitis (200, 286–
289). Mizolastine 10 mg daily is generally well tolerated, with the most common
adverse events, including sedation, being similar to those reported after placebo.
The incidence of prolonged QTc interval was similar in mizolastine- and placebo-
treated subjects (153, 290), although mizolastine is contraindicated in those with
cardiac disease or hepatic impairment or in those receiving erythromycin, ketoco-
nazole, or class I or III antiarrhythmic agents.
9. Terfenadine
Terfenadine (alpha-[4-(1,1-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1-
piperidinebutanol) is a selective histamine H 1-receptor antagonist devoid of CNS
and anticholinergic activity (291). Due to its potential cardiac toxicity, terfena-
dine has been withdrawn from use in most countries (292).
VI. OTHER H 1-ANTIHISTAMINES

A. Azelastine
Azelastine [(4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1-(2H)-
phthalazinone hydrochloride)] demonstrates H 1-receptor antagonist activity and
also inhibits mediator release from mast cells and other cells involved in the
allergic inflammation following antigenic and nonantigenic stimuli (293–300).
Azelastine antagonizes histamine- and leukotriene-induced bronchospasm in ani-
mal studies and reduces airway responsiveness to inhaled antigen or distilled
water and exercise challenge. Randomized controlled trials have shown that
orally administered azelastine in dosages up to 4 mg daily significantly relieved
symptoms in patients with seasonal (301) or perennial allergic rhinitis (302). In
addition, azelastine administered as a topical intranasal (303–306) or ophthalmic
formulation (307–310) is effective in alleviating symptoms of seasonal and pe-
rennial allergic rhinitis and conjunctivitis. As an antiasthmatic agent, azelastine
4 mg twice daily orally is superior to placebo and comparable to oral ketotifen
2 mg daily and sustained-release theophylline 700 mg daily. Azelastine is gener-
ally well tolerated: the most common adverse effects, altered taste perception
and drowsiness, are less frequent after topical application than after oral adminis-
tration (297).
B. Ketotifen
Ketotifen [(4-/1-methyl-4-piperidylidene/-4H-benzo[4,5]cyclohepta[1,2-b] thio-
phen-10(9H)-1-one hydrogen fumarate)] is an H 1-antagonist with antiallergic
properties. After 6–12 weeks of administration, ketotifen significantly reduces
respiratory symptoms and the need for concomitant antiasthmatic drugs in pa-
tients with mild to moderate bronchial asthma; however, improvement in lung
function is generally minimal. Ketotifen has shown efficacy in patients with

atopic dermatitis, seasonal or perennial rhinitis, allergic conjunctivitis, and
chronic or acute urticaria. Side effects include sedation and weight gain (311).
C. Oxatomide
Oxatomide, ((diphenylmethyl-4-piperazinyl-1)-3 propyl)-1,3 H benzimidazo-
lone-2, is an orally active H 1-histamine receptor antagonist that also inhibits me-
diator release (312). It is mostly used in the treatment of chronic urticaria. Some
patients responding to oxatomide were said to have been unresponsive to previ-
ously administered antihistamines. Sedation is a common side effect, as is weight
gain (313).
VII. SUMMARY: FUTURE OF H 1-ANTIHISTAMINES
With cloning of the gene encoding the histamine H 1-receptor (314–316), a new
area of histamine research has become reality. It seems feasible to study the target
of the therapeutically important H 1-antihistamines. Expression of the genes in
mammalian cells allows detailed investigations of the various signal transduction
routes of the histamine H 1-receptor (317). Moreover, using molecular biological
techniques, it is now possible to investigate ligand–receptor interaction at the
molecular level (318, 319). It is expected that these new developments will pro-
vide fundamental information about ligand interaction with the H 1-receptor (320).
REFERENCES
1. Dale H, Laidlaw P. The physiological action of β-imidazolethylamine. J Physiol

(London) 1910; 41:318–344.
col 1966; 27:427–439.
3. Black JW, Duncan WA, Durant CJ, Ganellin CR, Parsons EM. Definition and an-
tagonism of histamine H 2-receptors. Nature 1972; 236:385–390.
4. Arrang JM, Garbarg M, Lancelot JC, Lecomte JM, Pollard H, Robba M, Schunack
W, Schwartz J. Highly potent and selective ligands for histamine H 3-receptors.
Nature 1987; 327:117–123.
5. Staub A, Bovet D. Actions de la thymoethyl-diethylamine (929F) et des éthers
phénoliques sur le choc anaphylactique du cobaye. CR Soc Biol 1937; 128:818–
825.
6. Halpern B. Les antihistaminiques de synthèse: essai de chimiothérapie des états
allergiques. Arch Int Pharmacodyn Ther 1942; 68:339–345.
7. Bovet D, Horclois R, Walthert F. Propriétés antihistaminiques de la N-p-mé-
thoxybenzyl-N-diméthylaminoéthyl alpha aminopyridine. CR Soc Biol 1944; 138:

99–108.
8. Lowe E, MacMillan R, Katser M. The antihistamine properties of Benadryl, beta-
dimethyl-aminoethyl benzhydryl ether hydrochloride. J Pharmacol Exp Ther 1946;
86:229.
9. Yonkman F, Chess D, Mathieson D, Hansen N. Pharmacodynamic studies of a
new antihistamine agent, N′-pyridyl-N′-benzyl-N-dimethylethylene diamine HCl,
pyribenzamine HCl. I. Effects on salivation, nictitating membrane, lachrymation,
pupil and blood pressure. J Pharmacol Exp Ther 1946; 87:256.
10. Trzeciakowski J, Levi R. Antihistamines. In: Middleton E Jr, Reed CE, Ellis EF,
eds. Allergy, Principles and Practice, 2nd ed. St Louis, MO: Mosby, 1983:575–
592.
11. Marshall P. Some chemical and physical properties associated with histamine an-
tagonism. Br J Pharmacol 1955; 10:270.
12. Borea PA, Bertolasi V, Gilli G. Crystallographic and conformational studies on
histamine H 1-receptor antagonists. IV. On the stereochemical vector of antihista-
minic activity. Arzneimittelforschung 1986; 36:895–899.
13. Simons FER. Antihistamines. In: Middleton E, Jr, Reed CE, Ellis EF, Adkinson
NF, Jr, Yunginger JW, Busse WW, eds. Allergy, Principles and Practice, 5th ed.
St Louis, MO: Mosby, 1998:612–637.
14. Richelson E. Pharmacology of antidepressants. Psychopathology 1987; 20(Suppl
1):1–12.
15. Richelson E. Tricyclic antidepressants and histamine H 1-receptors. Mayo Clin Proc
1979; 54:669–674.
16. Sullivan TJ. Pharmacologic modulation of the whealing response to histamine in
human skin: identification of doxepin as a potent in vivo inhibitor. J Allergy Clin
Immunol 1982; 69:260–267.
17. Niimi N, Noso N, Yamamoto S. The effect of histamine on cultured endothelial
cells. A study of the mechanism of increased vascular permeability. Eur J Pharma-
col 1992; 221:325–331.
18. Carruthers SG, Shoeman DW, Hignite CE, Azarnoff DL. Correlation between
plasma diphenhydramine level and sedative and antihistamine effects. Clin Pharma-
col Ther 1978; 23:375–382.
19. Cheng HC, Woodward JK. A kinetic study of the antihistaminic effect of terfena-
dine. Arzneimittelforschung 1982; 32:1160–1166.
20. Van-Wauwe J, Awouters F, Neimegeers CJ, Janssens F, Van-Nueten JM, Janssen
PA. In vivo pharmacology of astemizole, a new type of H 1-antihistaminic com-
pound. Arch Int Pharmacodyn Ther 1981; 251:39–51.
21. Simons FER. H 1-receptor antagonists: does a dose–response relationship exist?
Ann Allergy 1993; 71:592–597.
22. Simons FER, McMillan JL, Simons KJ. A double-blind, single-dose, crossover
comparison of cetirizine, terfenadine, loratadine, astemizole, and chlorpheniramine
versus placebo: suppressive effects on histamine-induced wheals and flares during
24 hours in normal subjects. J Allergy Clin Immunol 1990; 86:540–547.
23. Grant JA, Danielson L, Rihoux JP, DeVos C. A double-blind, single-dose, cross-
over comparison of cetirizine, ebastine, epinastine, fexofenadine, terfenadine, and
loratadine versus placebo: suppression of histamine-induced wheal and flare re-

sponse for 24 h in healthy male subjects. Allergy 1999; 54:700–707.
24. Bruttmann G, Pedrali P. Loratadine (SCH29851) 40 mg once daily versus terfena-
dine 60 mg twice daily in the treatment of seasonal allergic rhinitis. J Int Med Res
1987; 15:63–70.
25. Bruttmann G, Charpin D, Germouty J, Horak F, Kunkel G, Wittmann G. Evaluation
of the efficacy and safety of loratadine in perennial allergic rhinitis. J Allergy Clin
Immunol 1989; 83:411–416.
26. Skassa-Brociek W, Bousquet J, Montes F, Verdier M, Schwab D, Lherminier M,
Michel FB. Double-blind placebo-controlled study of loratadine, mequitazine, and
placebo in the symptomatic treatment of seasonal allergic rhinitis. J Allergy Clin
Immunol 1988; 81:725–730.
27. Horak F, Bruttmann G, Pedrali P, Weeke B, Frolund L, Wolff HH, Christophers E.
A multicentric study of loratadine, terfenadine and placebo in patients with seasonal
allergic rhinitis. Arzneimittelforsch 1988; 38:124–128.
28. Oei HD. Double-blind comparison of loratadine (SCH 29851), astemizole, and pla-
cebo in hay fever with special regard to onset of action. Ann Allergy 1988; 61:
436–439.
29. Belaich S, Bruttmann G, DeGreef H, Lachapelle JM, Paul E, Pedrali P, Tennstedt
D. Comparative effects of loratadine and terfenadine in the treatment of chronic
idiopathic urticaria. Ann Allergy 1990; 64:191–194.
30. Monroe EW. Relative efficacy and safety of loratadine, hydroxyzine, and placebo
in chronic idiopathic urticaria and atopic dermatitis. Clin Ther 1992; 14:17–21.
31. Boggs PB, Ellis CN, Grossman J, Washburne WF, Gupta AK, Ball R, Shulan D.
Double-blind, placebo-controlled study of terfenadine and hydroxyzine in patients
with chronic idiopathic urticaria. Ann Allergy 1989; 63:616–620.
32. Breneman D, Bronsky EA, Bruce S, Kalivas JT, Klein GL, Roth HL, Tharp MD,
Treger C, Soter N. Cetirizine and astemizole therapy for chronic idiopathic urti-
caria: a double-blind, placebo-controlled, comparative trial. J Am Acad Dermatol
1995; 33:192–198.
33. Persi L, Demoly P, Harris AG, Tisserand B, Michel FB, Bousquet J. Comparison
between nasal provocation tests and skin tests in patients treated with loratadine
and cetirizine. J Allergy Clin Immunol 1999; 103:591–594.
34. Bousquet J, Czarlewski W, Cougnard J, Danzig M, Michel FB. Changes in skin-
test reactivity do not correlate with clinical efficacy of H 1-blockers in seasonal
allergic rhinitis. Allergy 1998; 53:579–585.
35. Pipkorn U, Granerus G, Proud D, Kagey-Sobotka A, Norman PS, Lichtenstein LM,
Naclerio RM. The effect of a histamine synthesis inhibitor on the immediate nasal
allergic reaction. Allergy 1987; 42:496–501.
36. Bousquet J, Campbell A, Michel FB. Antiallergic activities of antihistamines. In:
Church MK, Rihoux JP, eds. Therapeutic index of antihistamines. Lewiston, NY:
Hogrefe & Huber, 1992:57–96.
37. Campbell A, Michel FB, Bremard-Oury C, Crampette L, Bousquet J. Overview of
allergic mechanisms. Ebastine has more than an antihistamine effect. Drugs 1996;
52(Suppl 1):15–19.
38. Crampette L, Mainprice B, Bloom M, Bousquet J, Campbell AM. Inhibition of
mediator and cytokine release from dispersed nasal polyp cells by terfenadine. Al-
lergy 1996; 51:346–349.
39. Abdelaziz MM, Devalia JL, Khair OA, Bayram H, Prior AJ, Davies RJ. Effect of
fexofenadine on eosinophil-induced changes in epithelial permeability and cytokine
release from nasal epithelial cells of patients with seasonal allergic rhinitis. J Al-
40. Paolieri F, Battifora M, Riccio AM, Bertolini C, Cutolo M, Bloom M, Ciprandi G,
Canonica GW, Bagnasco M. Terfenadine and fexofenadine reduce in vitro ICAM-1
expression on human continuous cell lines. Ann Allergy Asthma Immunol 1998;
81:601–607.
41. Raptopoulou-Gigi M, Ilonidis G, Orphanou-Koumerkeridou H, Preponis C, Sidiro-
poulos J, Lazarides T, Goulis G. The effect of loratadine on activated cells of the
nasal mucosa in patients with allergic rhinitis. J Invest Allergol Clin Immunol 1993;
3:192–197.
42. Temple DM, McCluskey M. Loratadine, an antihistamine, blocks antigen- and
ionophore-induced leukotriene release from human lung in vitro. Prostaglandins
1988; 35:549–554.
43. Campbell AM, Chanez P, Marty-Ane C, Albart B, Bloom M, Michel FB, Godard
P, Bousquet J. Modulation of eicosanoid and histamine release from human dis-
persed lung cells by terfenadine. Allergy 1993; 48:125–129.
44. Faraj BA, Jackson RT. Effect of astemizole on antigen-mediated histamine release
from the blood of patients with allergic rhinitis. Allergy 1992; 47:630–634.
45. Miadonna A, Milazzo N, Lorini M, Marchesi E, Tedeschi A. Antiallergic activity
of loratadine: inhibition of leukotriene C4 release from human leucocytes. Clin Exp
Allergy 1995; 25:364–370.
46. Genovese A, Patella V, De-Crescenzo G, De-Paulis A, Spadaro G, Marone G. Lor-
atadine and desethoxylcarbonyl-loratadine inhibit the immunological release of me-
diators from human Fc epsilon RI⫹ cells. Clin Exp Allergy 1997; 27:559–567.
47. Foreman J, Rihoux J. The antiallergic activity of H 1-histamine receptor antagonists
in relation to their action on cell calcium. In: Church MK, Rihoux JP, eds. Thera-
peutic Index of Antihistamines. Lewiston, NY: Hogrefe & Huber, 1992:32–46.
48. Bousquet J, Lebel B, Chanal I, Morel A, Michel FB. Antiallergic activity of H 1-
receptor antagonists assessed by nasal challenge. J Allergy Clin Immunol 1988;
82:881–887.
49. Andersson M, Nolte H, Baumgarten C, Pipkorn U. Suppressive effect of loratadine
on allergen-induced histamine release in the nose. Allergy 1991; 46:540–546.
50. Naclerio RM, Kagey-Sobotka A, Lichtenstein LM, Freidhoff L, Proud D. Terfena-
dine, an H 1-antihistamine, inhibits histamine release in vivo in the human. Am Rev
Respir Dis 1990; 142:167–171.
51. Togias AG, Proud D, Kagey-Sobotka A, Freidhoff L, Lichtenstein LM, Naclerio
RM. In vivo and in vitro effects of antihistamines on mast cell mediator release:
a potentially important property in the treatment of allergic disease. Ann Allergy
1989; 63:465–469.
52. Jacobi HH, Skov PS, Poulsen LK, Malling HJ, Mygind N. Histamine and tryptase in
nasal lavage fluid after allergen challenge: effect of 1 week of pretreatment with intrana-
sal azelastine or systemic cetirizine. J Allergy Clin Immunol 1999; 103:768–772.
53. Shin MH, Baroody F, Proud D, Kagey-Sobotka A, Lichtenstein LM, Naclerio RM.
The effect of azelastine on the early allergic response. Clin Exp Allergy 1992; 22:
289–295.
54. Majchel AM, Proud D, Kagey-Sobotka A, Lichtenstein LM, Naclerio RM. Ketoti-
fen reduces sneezing but not histamine release following nasal challenge with anti-
gen. Clin Exp Allergy 1990; 20:701–705.
55. Michel L, De-Vos C, Rihoux JP, Burtin C, Benveniste J, Dubertret L. Inhibitory
effect of oral cetirizine on in vivo antigen-induced histamine and PAF-acether re-
lease and eosinophil recruitment in human skin. J Allergy Clin Immunol 1988;82:
101–109.
56. Fadel R, Herpin-Richard N, Rihoux JP, Henocq E. Inhibitory effect of cetirizine
2HCl on eosinophil migration in vivo. Clin Allergy 1987; 17:373–379.
57. Charlesworth EN, Kagey-Sobotka A, Norman PS, Lichtenstein LM. Effect of cetiri-
zine on mast cell-mediator release and cellular traffic during the cutaneous late-
phase reaction. J Allergy Clin Immunol 1989; 83:905–912.
58. Taborda-Barata L, Jacobson M, Walker S, Njuki F, Ying S, Randev P, Durham
SR, Kay AB. Effect of cetirizine and prednisolone on cellular infiltration and cytok-
ine mRNA expression during allergen-induced late cutaneous responses. Clin Exp
Allergy 1996; 26:68–78.
59. Zweiman B, Atkins PC, Moskovitz A, von Allmen C, Ciliberti M, Grossman S.
Cellular inflammatory responses during immediate, developing, and established
late-phase allergic cutaneous reactions: effects of cetirizine. J Allergy Clin Immunol
1997; 100:341–347.
60. Bentley AM, Walker S, Hanotte F, De-Vos C, Durham SR. A comparison of the
effects of oral cetirizine and inhaled beclomethasone on early and late asthmatic
responses to allergen and the associated increase in airways hyperresponsiveness.
61. Klementsson H, Andersson M, Pipkorn U. Allergen-induced increase in nonspecific
nasal reactivity is blocked by antihistamines without a clear-cut relationship to eo-
sinophil influx. J Allergy Clin Immunol 1990; 86:466–472.
62. Ciprandi G, Buscaglia S, Pronzato C, et al. New targets for antiallergic agents. In:
Langer S, Church M, Vargaftig B, Nicosia S, eds. New Targets for Antiallergic
Agents. Basel: Karger, 1993:115–127 (Int Acad Biomed Drug Res, vol 6).
63. Canonica GW, Ciprandi G, Buscaglia S, Pesce G, Bagnasco M. Adhesion mole-
cules of allergic inflammation: recent insights into their functional roles. Allergy
1994; 49:135–141.
64. Ciprandi G, Buscaglia S, Pesce G, Passalacqua G, Rihoux JP, Bagnasco M, Can-
onica GW. Cetirizine reduces inflammatory cell recruitment and ICAM-1 (or
CD54) expression on conjunctival epithelium in both early- and late-phase reactions
after allergen-specific challenge. J Allergy Clin Immunol 1995; 95:612–621.
65. Ciprandi G, Buscaglia S, Pronzato C, Benvenuti C, Cavalli E, Bruzzone F, Can-
onica GW. Oxatomide reduces inflammatory events induced by allergen-specific
conjunctival challenge. Ann Allergy Asthma Immunol 1995; 75:446–452.
66. Ciprandi G, Buscaglia S, Catrullo A, Pesce G, Fiorino N, Montagna P, Bagnasco
M, Canonica GW. Azelastine eye drops reduce and prevent allergic conjunctival
reaction and exert anti-allergic activity. Clin Exp Allergy 1997; 27:182–191.
67. Ciprandi G, Pronzato C, Ricca V, Varese P, Del-Giacco GS, Canonica GW.

Terfenadine exerts antiallergic activity reducing ICAM-1 expression on nasal
epithelial cells in patients with pollen allergy. Clin Exp Allergy 1995; 25:871–
878.
68. Ciprandi G, Pronzato C, Passalacqua G, Ricca V, Grogen J, Mela GS, Varese P,
Bertolini C, Bagnasco M, Canonica GW. Topical azelastine reduces eosinophil acti-
vation and intercellular adhesion molecule-1 expression on nasal epithelial cells:
an antiallergic activity. J Allergy Clin Immunol 1996; 98:1088–1096.
69. Ciprandi G, Pronzato C, Ricca V, Passalacqua G, Danzig M, Canomira GW. Lora-
tadine treatment of rhinitis due to pollen allergy reduces ICAM-1 expression. Clin
Exp Allergy 1997; 27:1175–1183.
70. Ciprandi G, Tosca M, Ricca V, Passalacqua G, Riccio AM, Bagnasco M, Canonica
GW. Cetirizine treatment of rhinitis in children with pollen allergy: evidence of its
antiallergic activity. Clin Exp Allergy 1997; 27:1160–1166.
71. Ciprandi G, Catrullo A, Cerqueti P, Tosca M, Fiorino N, Canonica GW. Loratadine
reduces the expression of ICAM-1. Allergy 1998; 53:545–546.
72. Campbell A, Chanal I, Czarlewski W, Michel FB, Bousquet J. Reduction of soluble
ICAM-1 levels in nasal secretion by H 1-blockers in seasonal allergic rhinitis. Al-
lergy 1997; 52:1022–1025.
73. Fasce L, Ciprandi G, Pronzato C, Cozzani S, Tosca MA, Grimaldi I, Canonica
GW. Cetirizine reduces ICAM-1 on epithelial cells during nasal minimal persistent
inflammation in asymptomatic children with mite-allergic asthma. Int Arch Allergy
Immunol 1996; 109:272–276.
74. Ciprandi G, Passalacqua G, Canonica GW. Effects of H 1-antihistamines on adhe-
sion molecules: a possible rationale for long-term treatment. Clin Exp Allergy 1999;
29(Suppl 3):49–53.
75. Simons FER. The antiallergic effects of antihistamines (H 1-receptor antagonists).
J Allergy Clin Immunol 1992; 90:705–715.
76. Carlsen KH, Kramer J, Fagertun HE, Larsen S. Loratadine and terfenadine in peren-
nial allergic rhinitis. Treatment of nonresponders to the one drug with the other
drug. Allergy 1993; 48:431–436.
77. Kubo N, Shirakawa O, Kuno T, Tanaka C. Antimuscarinic effects of antihista-
mines: quantitative evaluation by receptor-binding assay. Jpn J Pharmacol 1987;
43:277–282.
78. Stanton T, Bolden-Watson C, Cusack B, Richelson E. Antagonism of the five
cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by anti-
depressants and antihistaminics. Biochem Pharmacol 1993; 45:2352–2354.
79. Roden DM. Torsade de pointes. Clin Cardiol 1993; 16:683–686.
80. Van-Nueten JM, Xhonneux R, Janssen PAJ. Preliminary data on antiserotonin ef-
fects of oxatomide, a novel anti-allergic compound. Arch Int Pharmacodyn Ther
1978; 232:217–220.
81. Campbell M, Bateman DN. Pharmacokinetic optimisation of antiemetic therapy.
Clin Pharmacokinet 1992; 23:147–160.
82. Rumore MM, Schlichting DA. Analgesic effects of antihistaminics. Life Sci 1985;
36:403–416.
83. Takeda N, Morita M, Hasegawa S, Horii A, Kubo T, Matsunaga T. Neuropharma-
cology of motion sickness and emesis. a review. Acta Otolaryngol Suppl Stockh
1993; 501:10–15.
84. Mitchelson F. Pharmacological agents affecting emesis. A review (Part I). Drugs
1992; 43:295–315.
85. Mitchelson F. Pharmacological agents affecting emesis. A review (Part II). Drugs
1992; 43:443–463.
86. Timmerman H. Histamine receptors in the central nervous system. Pharm Weekbl
Sci 1989; 11:146–150.
87. Timmerman H. Factors involved in the incidence of central nervous system effects
of H 1-blockers. In: Church MK, Rihoux JP, eds. Therapeutic Index of Antihista-
mines. Lewiston, NY: Hogrefe & Hubers, 1992:19–31.
88. Goldberg MJ, Spector R, Chiang CK. Transport of diphenhydramine in the central
nervous system. J Pharmacol Exp Ther 1987; 240:717–722.
89. Timmerman H. Why are non-sedating antihistamines non-sedating? Clin Exp Al-
lergy 1999; 29(Suppl 3):13–18.
90. Schwartz JC, Barbin G, Duchemin AM, Garbarg M, Palacios JM, Quach TT, Rose
C. Histamine receptors in the brain: characterization by binding studies and bio-
chemical effects. Adv Biochem Psychopharmacol 1980; 21:169–182.
91. Janssens MM, Howarth PH. The antihistamines of the nineties. Clin Rev Allergy
1993; 11:111–153.
92. Ahn HS, Barnett A. Selective displacement of [3H]mepyramine from peripheral
vs. central nervous system receptors by loratadine, a non-sedating antihistamine.
Eur J Pharmacol 1986; 127:153–155.
93. Gengo FM, Manning C. A review of the effects of antihistamines on mental pro-
cesses related to automobile driving. J Allergy Clin Immunol 1990; 86:1034–
1039.
94. Passalacqua G, Scordamaglia A, Ruffoni S, Parodi MN, Canonica GW. Sedation
from H 1-antagonists: evaluation methods and experimental results. Allergol Immu-
nopathol Madr 1993; 21:79–83.
95. O’Hanlon JF, Ramaekers JG. Antihistamine effects on actual driving performance
in a standard test: a summary of Dutch experience, 1989–94. Allergy 1995; 50:
234–242.
96. Passalacqua G, Bousquet J, Barhert C, Church MK, Bindslev-Jensen C, Nagy L,
Szemere P, Davies RJ, Durham SR, Morak F, Kontou-Fili K, Van Couwenberge
P, Canonica GW. The clinical safety of H1 receptor antagonists. EAACI Position
Paper. Allergy 1996; 51:666–675.
97. Hindmarch I, Shamsi Z. Antihistamines: models to assess sedative properties, as-
sessment of sedation, safety and other side-effects. Clin Exp Allergy 1999;
29(Suppl 3):133–142.
98. Hindmarch I, Shamsi Z, Stanley N, Fairweather DB. A double-blind, placebo-
controlled investigation of the effects of fexofenadine, loratadine and promethazine
on cognitive and psychomotor function. Br J Clin Pharmacol 1999; 48:200–206.
99. Simons FER. Non-cardiac adverse effects of antihistamines (H 1-receptor antago-
nists). Clin Exp Allergy 1999; 29(Suppl 3):125–132.
100. Burns M, Moskowitz H. Effects of diphenhydramine and alcohol on skills perfor-
mance. Eur J Clin Pharmacol 1980; 17:259–266.
101. Bateman DN, Chapman PH, Rawlins MD. Lack of effect of astemizole on ethanol
dynamics or kinetics. Eur J Clin Pharmacol 1983; 25:567–568.
102. Bhatti JZ, Hindmarch I. The effects of terfenadine with and without alcohol on an
aspect of car driving performance. Clin Exp Allergy 1989; 19:609–611.
103. Doms M, Vanhulle G, Baelde Y, Coulie P, Dupont P, Rihoux JP. Lack of potentia-
tion by cetirizine of alcohol-induced psychomotor disturbances. Eur J Clin Pharma-
col 1988; 34:619–623.
104. Simons FER, Fraser TG, Maher J, Pillay N, Simons KJ. Central nervous system
effects of H 1-receptor antagonists in the elderly. Ann Allergy Asthma Immunol
1999; 82:157–160.
105. Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions
of terfenadine. JAMA 1993; 269:1532–1536.
106. Barbey JT, Anderson M, Ciprandi G, Frew AJ, Morad M, Priori SG, Ongini E,
Affrime MB. Cardiovascular safety of second-generation antihistamines [In Pro-
cess Citation]. Am J Rhinol 1999; 13:235–243.
107. Woosley RL, Sale M. QT interval: a measure of drug action. Am J Cardiol 1993;
72:36B–43B.
108. Biglin KE, Faraon MS, Constance TD, Lieh-Lai M. Drug-induced torsades de
pointes: a possible interaction of terfenadine and erythromycin [letter]. Ann Phar-
macother 1994; 28:282.
109. Craft TM. Torsade de pointes after astemizole overdose. Br Med J Clin Res Ed
1986; 292:660.
110. Feroze H, Suri R, Silverman DI. Torsades de pointes from terfenadine and sotalol
given in combination. Pacing Clin Electrophysiol 1996; 19:1519–1521.
111. Fournier P, Pacouret G, Charbonnier B. [A new cause of torsades de pointes: com-
bination of terfenadine and troleandomycin]. Ann Cardiol Angiol Paris 1993; 42:
249–252.
112. Goss JE, Ramo BW, Blake K. Torsades de pointes associated with astemizole (His-
manal) therapy [letter]. Arch Intern Med 1993; 153:2705.
113. Hasan RA, Zureikat GY, Nolan BM. Torsade de pointes associated with astemizole
overdose treated with magnesium sulfate. Pediatr Emerg Care 1993; 9:23–25.
114. Herings RM, Stricker BH, Leufkens HG, Bakker A, Sturmans F, Urquhart J. Public
health problems and the rapid estimation of the size of the population at risk. Tor-
sades de pointes and the use of terfenadine and astemizole in The Netherlands.
Pharm World Sci 1993; 15:212–218.
115. Hey JA, del-Prado M, Kreutner W, Egan RW. Cardiotoxic and drug interaction
profile of the second generation antihistamines ebastine and terfenadine in an exper-
imental animal model of torsade de pointes. Arzneimittelforsch 1996; 46:159–163.
116. Hsieh MH, Chen SA, Chiang CE, Tai CT, Lee SH, Wen ZC, Chang MS. Drug-
induced torsades de pointes in one patient with congenital long QT syndrome. Int
J Cardiol 1996; 54:85–88.
117. Katyal VK, Choudhary D. Occurrence of torsade de pointes with use of astemizole
[published erratum appears in Indian Heart J 1994; 46:358]. Indian Heart J 1994;
46:181–182.
118. Kelloway JS, Pongowski MA, Schoenwetter WF. Additional causes of torsades de
pointes [letter; comment]. Mayo Clin Proc 1995; 70:197.
119. Koh KK, Rim MS, Yoon J, Kim SS. Torsade de pointes induced by terfenadine
in a patient with long QT syndrome. J Electrocardiol 1994; 27:343–346.
120. Kulkarni SM, Agarwal HK, Shaikh AA. Torsade de pointes complicating treatment
with astemizole. Indian Heart J 1994; 46:179–180.
121. MacConnell TJ, Stanners AJ. Torsades de pointes complicating treatment with ter-
fenadine [letter] [see comments]. Br Med J 1991; 302:1469.
122. Mathews DR, McNutt B, Okerholm R, Flicker M, McBride G. Torsades de pointes
occurring in association with terfenadine use [letter; comment]. JAMA 1991; 266:
2375–2376.
123. Matsis PP, Easthope RN. Torsades de pointes ventricular tachycardia associated
with terfenadine and paracetamol self medication. N Z Med J 1994; 107:402–403.
124. McLeod AA, Thorogood S, Barnett S. Torsades de pointes complicating treatment
with terodiline [letter]. Br Med J 1991; 302:1469.
125. Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, Cantilena LR, Jr.
Torsades de pointes occurring in association with terfenadine use. JAMA 1990;
264:2788–2790.
126. Ng PW, Chan WK, Chan TY. Torsade de pointes during the concomitant use of
terfenadine and cimetidine [letter]. Aust N Z J Med 1996; 26:120–121.
127. Paris DG, Parente TF, Bruschetta HR, Guzman E, Niarchos AP. Torsades de pointes
induced by erythromycin and terfenadine. Am J Emerg Med 1994; 12:636–638.
128. Pohjola-Sintonen S, Viitasalo M, Toivonen L, Neuvonen P. Itraconazole prevents
terfenadine metabolism and increases risk of torsades de pointes ventricular tachy-
cardia. Eur J Clin Pharmacol 1993; 45:191–193.
129. Rao KA, Adlakha A, Verma-Ansil B, Meloy TD, Stanton MS. Torsades de pointes
ventricular tachycardia associated with overdose of astemizole [see comments].
Mayo Clin Proc 1994; 69:589–593.
130. Sakemi H, VanNatta B. Torsade de pointes induced by astemizole in a patient with
prolongation of the QT interval. Am Heart J 1993; 125:1436–1438.
131. Saviuc P, Danel V, Dixmerias F. Prolonged QT interval and torsade de pointes
following astemizole overdose. J Toxicol Clin Toxicol 1993; 31:121–125.
132. Simons FER, Kesselman MS, Giddins NG, Pelech AN, Simons KJ. Astemizole-
induced torsade de pointes [letter]. Lancet 1988; 2:624.
133. Snook J, Boothman-Burrell D, Watkins J, Colin-Jones D. Torsade de pointes ven-
tricular tachycardia associated with astemizole overdose. Br J Clin Pract 1988; 42:
257–259.
134. Stratmann HG, Kennedy HL. Torsades de pointes associated with drugs and toxins:
recognition and management. Am Heart J 1987; 113:1470–1482.
135. Tran HT. Torsades de pointes induced by nonantiarrhythmic drugs [published erra-
tum appears in Conn Med 1994 Aug; 58(8):494]. Conn Med 1994; 58:291–295.
136. Tsai WC, Tsai LM, Chen JH. Combined use of astemizole and ketoconazole re-
sulting in torsade de pointes. J Formos Med Assoc 1997; 96:144–146.
137. Vorperian VR, Zhou Z, Mohammad S, Hoon TJ, Studenik C, January CT. Torsade
de pointes with an antihistamine metabolite: potassium channel blockade with des-
methylastemizole. J Am Coll Cardiol 1996; 28:1556–1561.
138. Warin RP. Torsades de pointes complicating treatment with terfenadine [letter;
comment]. Br Med J 1991; 303:58.
139. Wiley JF, Henretig FM. Torsade de pointes [letter]. Pediatr Emerg Care 1993; 9:
326–327.
140. Zimmermann M, Duruz H, Guinand O, Broccard O, Levy P, Lacatis D, Bloch A.
Torsades de pointes after treatment with terfenadine and ketoconazole. Eur Heart
J 1992; 13:1002–1003.
141. Berul CI, Morad M. Regulation of potassium channels by nonsedating antihista-
mines. Circulation 1995; 91:2220–2225.
142. Roy ML, Dumaine R, Brown AM. HERG, a primary human ventricular target of
the nonsedating antihistamine terfenadine [see comments]. Circulation 1996; 94:
817–823.
143. Taglialatela M, Castaldo P, Pannaccione A, Giorgio G, Genovese A, Marone G,
Annunziato L. Cardiac ion channels and antihistamines: possible mechanisms of
cardiotoxicity. Clin Exp Allergy 1999; 29(Suppl 3):182–189.
144. Brannan MD, Reidenberg P, Radwanski E, Shneyer L, Lin CC, Cayen MN, Affrime
MB. Loratadine administered concomitantly with erythromycin: pharmacokinetic
and electrocardiographic evaluations. Clin Pharmacol Ther 1995; 58:269–278.
145. Hey JA, del-Prado M, Sherwood J, Kreutner W, Egan RW. Comparative analysis
of the cardiotoxicity proclivities of second generation antihistamines in an experi-
mental model predictive of adverse clinical ECG effects. Arzneimittelforschung
1996; 46:153–158.
146. Hey JA, del-Prado M, Sherwood J, Kreutner W, Egan RW. The guinea pig model
for assessing cardiotoxic proclivities of second generation antihistamines [letter].
Arzneimittelforsch 1996; 46:834–837.
147. Moss AJ, Chaikin P, Garcia JD, Gillen M, Roberts DJ, Morganroth J. A review
of the cardiac systemic side-effects of antihistamines: ebastine. Clin Exp Allergy
1999; 29(Suppl 3):200–205.
148. Roberts DJ, Gispert J. The non-cardiac systemic side-effects of antihistamines:
ebastine. Clin Exp Allergy 1999; 29(Suppl 3):151–155.
149. Carmeliet E. Effects of cetirizine on the delayed K⫹ currents in cardiac cells: com-
parison with terfenadine. Br J Pharmacol 1998; 124:663–668.
150. Pratt CM, Mason J, Russell T, Reynolds R, Ahlbrandt R. Cardiovascular safety of
fexofenadine HCl. Am J Cardiol 1999; 83:1451–1454.
151. Bernstein DI, Schoenwetter WF, Nathan RA, Storms W, Ahlbrandt R, Mason J.
Efficacy and safety of fexofenadine hydrochloride for treatment of seasonal allergic
rhinitis. Ann Allergy Asthma Immunol 1997; 79:443–448.
152. Chaufour S, Le Coz F, Denolle T, Dubruc C, Cimarosti I, Deschamps C, Ulliac
N, Delhotal-Landes B, Rosenzweig P. Lack of effect of mizolastine on the safety
and pharmacokinetics of digoxin administered orally in repeated doses to healthy
volunteers. Int J Clin Pharmacol Ther 1998; 36:286–291.
153. Chaufour S, Caplain H, Lilienthal N, L’heritier C, Deschamps C, Dubruc C, Rosen-
zweig P. Study of cardiac repolarization in healthy volunteers performed with mizo-
lastine, a new H 1-receptor antagonist. Br J Clin Pharmacol 1999; 47:515–520.
154. Brandes LJ, Warrington RC, Arron RJ, Bogdanovic RP, Fang W, Queen GM, Stein
DA, Tong J, Zaborniak CLF, LaBella FS. Enhanced cancer growth in mice adminis-
tered daily human-equivalent doses of some H 1-antihistamines: predictive in vitro
correlates [see comments]. J Natl Cancer Inst 1994; 86:770–775.
155. Weed D. Between science and technology: the case of antihistamines and cancer.
J Natl Cancer Inst 1994; 86:740–741.
156. FDA reviews antihistamine mouse study. FDA Talk May 17 1994.
157. Weiss SR, McFarland BH, Burkhart GA, Ho PTC. Cancer recurrences and second-
ary primary cancers after use of antihistamines or antidepressants. Clin Pharmacol
Ther 1998; 63:594–599.
158. Calandre EP, Alferez N, Hassanein K, Azarnoff DL. Methapyrilene kinetics and
dynamics. Clin Pharmacol Ther 1981; 29:527–532.
159. Lijinsky W, Reuber MD, Blackwell BN. Liver tumors induced in rats by oral adminis-
tration of the antihistaminic methapyrilene hydrochloride. Science 1980; 209:817–819.
160. Simons KJ, Watson WTA, Martin TJ, Chen XY, Simons FER. Diphenhydramine:
pharmacokinetics and pharmacodynamics in elderly adults, young adults, and chil-
dren. J Clin Pharmacol 1990; 30:665–671.
161. Seppala T, Nuotto E, Korttila K. Single and repeated dose comparison of three
antihistamines and phenylpropanolamine: psychomotor performance and subjective
appraisals of sleep. Br J Clin Pharmacol 1981; 12:179–188.
162. Clemastine (Tavist)—a new antihistamine. Med Lett Drugs Ther 1979; 21:24.
163. Falliers CJ, Redding MA, Katsampes CP. Inhibition of cutaneous and mucosal al-
lergy with phenyltoloxamine Ann Allergy 1978; 41:140–144.
164. Kotzan JA, Vallner JJ, Stewart JT, Brown WJ, Viswanathan CT, Needham TE,
Dighe SV, Malinowski R. Bioavailability of regular and controlled-release chlor-
pheniramine products. J Pharm Sci 1982; 71:919–923.
165. Rumore MM. Clinical pharmacokinetics of chlorpheniramine. Drug Intell Clin
Pharm 1984; 18:701–707.
166. Simons FER, Frith EM, Simons KJ. The pharmacokinetics and antihistaminic ef-
fects of brompheniramine. J Allergy Clin Immunol 1982; 70:458–464.
167. De Graeve J, Van Cantfort J, Gilard P, Wermeille MM. Identification of the molecu-
lar structure of the phenolic primary metabolite of dimetindene in animals and man.
Arzneimittelforsch 1989; 39:551–555.
168. Bhatt AD, Vaidya AB, Sane SP, Sahani S, Koya R, Rajaseharan A, Perumal SV,
Chauhan CK, Pathak KJ, Sainath BR, et al. Comparative effect of dimethindene
maleate and chlorpheniramine maleate on histamine-induced weal and flare. J Int
Med Res 1991; 19:479–483.
169. Towart R, Sautel M, Moret E, Costa E, Theraulaz M, Weitsch AF. Investigation of
the antihistaminic action of dimethindene maleate (Fenistil) and its optical isomers.
Agents Actions Suppl 1991; 33:403–408.
170. Hamilton M, Bush M, Bye C, Peck AW. A comparison of triprolidine and cyclizine
on histamine (H 1) antagonism, subjective effects and performance tests in man. Br
J Clin Pharmacol 1982; 13:441–444.
171. McGee JL, Alexander MR. Phenothiazine analgesia—fact or fantasy? Am J Hosp
Pharm 1979; 36:633–640.
172. Hals PA, Hall H, Dahl SG. Muscarinic cholinergic and histamine H 1-receptor bind-
ing of phenothiazine drug metabolites. Life Sci 1988; 43:405–412.
173. Hugonot L, Hugonot R, Beaumont D. A double-blind comparison of terfenadine
and mequitazine in the symptomatic treatment of acute pollinosis. J Int Med Res
1986; 14:124–130.
174. Nicholson AN, Stone BM. The H 1-antagonist mequitazine: studies on performance
and visual function. Eur J Clin Pharmacol 1983; 25:563–566.
175. Martinez-Mir I, Estan L, Rubio E, Morales-Olivas FJ. Antihistaminic and anticho-
linergic activities of mequitazine in comparison with clemizole. J Pharm Pharmacol
1988; 40:655–656.
176. Renzetti AR, Barone D, Criscuoli M. High-affinity binding of mequitamium iodide
(LG 30435) to muscarinic and histamine H 1-receptors. Eur J Pharmacol 1990; 182:
413–420.
177. Novack GD, Stark LG, Peterson SL. Anticonvulsant effects of benzhydryl pipera-
zines on maximal electroshock seizures in rats. J Pharmacol Exp Ther 1979; 208:
480–484.
178. Schaaf L, Hendeles L, Weinberger M. Suppression of seasonal allergic rhinitis
symptoms with daily hydroxyzine. J Allergy Clin Immunol 1979; 63:129–133.
179. Simons FER, Simons KJ, Frith EM. The pharmacokinetics and antihistaminic ef-
fects of the H 1-receptor antagonist hydroxyzine. J Allergy Clin Immunol 1984; 73:
69–75.
180. Klein GL, Galant SP. A comparison of the antipruritic efficacy of hydroxyzine and
cyproheptadine in children with atopic dermatitis. Ann Allergy 1980; 44:142–145.
181. Harvey RP, Wegs J, Schocket AL. A controlled trial of therapy in chronic urticaria.
182. Hillas JL, Somerfield SD, Wilson JD, Aman MG. Azatadine maleate in perennial
allergic rhinitis: effects on clinical symptoms and choice reaction time. Br J Clin
Pharmacol 1980; 10:573–577.
183. Luscombe DK, Nicholls PJ, Spencer PS. Effect of azatadine on human perfor-
mance. Br J Clin Pract 1980; 34:75–79.
184. Wilson JD, Hillas JL, Somerfield SD. Azatadine maleate (Zadine): evaluation in
the management of allergic rhinitis. N Z Med J 1981; 94:79–81.
185. Kletzky OA, Marrs RP, Nicoloff JT. Effects of cyproheptadine on insulin-induced
hypoglycaemia secretion of PRL, GH and cortisol. Clin Endocrinol Oxf 1980; 13:
231–234.
186. Gross MD, Grekin RJ, Gniadek TC, Villareal JZ. Suppression of aldosterone by
cyproheptadine in idiopathic aldosteronism. N Engl J Med 1981; 305:181–
185.
187. Warren R, Simpson H, Hilchie J, Cimbura G, Lucas D, Bennett R. Drugs detected
in fatally injured drivers in the Province of Ontario. In: Goldberg L, ed. Alcohol,
Drugs, and Traffic Safety. Stockholm: Almquist and Wiksell, 1981:203–217.
188. O’Hanlon JF. Antihistamines and driving safety. Cutis 1988; 42:10–13.
189. Bantz EW, Dolen WK, Chadwick EW, Nelson HS. Chronic chlorpheniramine ther-
apy: subsensitivity, drug metabolism, and compliance. Ann Allergy 1987; 59:341–
346.
190. Long WF, Taylor RJ, Wagner CJ, Leavengood DC, Nelson HS. Skin test suppres-
sion by antihistamines and the development of subsensitivity. J Allergy Clin Immu-
nol 1985; 76:113–117.
191. Taylor RJ, Long WF, Nelson HS. The development of subsensitivity to chlorphenir-
amine. J Allergy Clin Immunol 1985; 76:103–107.
192. Simons FER, Watson WTA, Simons KJ. Lack of subsensitivity to terfenadine
during long-term terfenadine treatment. J Allergy Clin Immunol 1988; 82:1068–

1075.
193. Bousquet J, Chanal I, Skassa-Brociek W, Lemonier C, Michel FB. Lack of subsen-
sitivity to loratadine during long-term dosing during 12 weeks. J Allergy Clin Im-
munol 1990; 86:248–253.
194. Guengerich FP. Role of cytochrome P450 enzymes in drug-drug interactions. Adv
Pharmacol 1997; 43:7–35.
195. Thummel KE, Wilkinson GR. In vitro and in vivo drug interactions involving hu-
man CYP3A. Annu Rev Pharmacol Toxicol 1998; 38:389–430.
196. Renwick AG. The metabolism of antihistamines and drug interactions: the role of
cytochrome P450 enzymes. Clin Exp Allergy 1999; 29(Suppl 3):116–124.
197. Campoli-Richards DM, Buckley MM, Fitton A. Cetirizine. A review of its pharma-
cological properties and clinical potential in allergic rhinitis, pollen-induced
asthma, and chronic urticaria. Drugs 1990; 40:762–781.
198. Markham A, Wagstaff AJ. Fexofenadine. Drugs 1998; 55:269–274.
199. Wiseman LR, Faulds D. Ebastine. A review of its pharmacological properties and
clinical efficacy in the treatment of allergic disorders. Drugs 1996; 51:260–277.
200. Leynadier F, Bousquet J, Murrieta M, Attali P. Efficacy and safety of mizolastine
in seasonal allergic rhinitis. The Rhinase Study Group. Ann Allergy Asthma Immu-
nol 1996; 76:163–168.
201. Janssens MM. Astemizole. A nonsedating antihistamine with fast and sustained
activity. Clin Rev Allergy 1993; 11:35–63.
202. Sorkin EM, Heel RC. Terfenadine. A review of its pharmacodynamic properties
and therapeutic efficacy. Drugs 1985; 29:34–56.
203. Weiner JM, Abramson MJ, Puy RM. Intranasal corticosteroids versus oral H 1 recep-
tor antagonists in allergic rhinitis: systematic review of randomised controlled
trials. Br Med J 1998; 317:1624–1629.
204. Ciprandi G, Passalacqua G, Mincarini M, Ricca V, Canonica GW. Continuous ver-
sus on demand treatment with cetirizine for allergic rhinitis. Ann Allergy Asthma
Immunol 1997; 79:507–511.
205. Ciprandi G, Ricca V, Tosca M, Landi M, Passalacqua G, Canonica GW. Continuous
antihistamine treatment controls allergic inflammation and reduces respiratory mor-
bidity in children with mite allergy. Allergy 1999; 54:358–365.
206. ETAC Study-Group. Allergic factors associated with the development of asthma
and the influence of cetirizine in a double-blind, randomised, placebo-controlled
trial: First results of ETAC. Pediatr Allergy Immunol 1998; 9:116–124.
207. Weiler JM, Meltzer EO. Azelastine nasal spray as adjunctive therapy to azelastine
tablets in the management of seasonal allergic rhinitis. Ann Allergy Asthma Immu-
nol 1997; 79:327–332.
208. Kreutner W, Hey JA, Anthes J, Barnett A, Tozzi S. Preclinical pharmacology of
desloratadine, a selective and nonsedating histamine H 1-receptor antagonist. 1st
communication: receptor selectivity, antihistaminic activity, and antiallergenic ef-
fects. Arzneimittelforsch 2000; 50:345–352.
209. Gibson JR, Manna VK, Salisbury J. Acrivastine: a review of its dermatopharmacol-
ogy and clinical activity. J Int Med Res 1989; 17(Suppl 2):28B–34B.
210. Bojkowski CJ, Gibbs TG, Hellstern KH, Major EWT, Mullinger B. Acrivastine in
allergic rhinitis: a review of clinical experience. J Int Med Res 1989; 17(Suppl 2):
54B–68B.
211. Juhlin L, Gibson JR, Harvey SG, Huson LW. Acrivastine versus clemastine in the
treatment of chronic idiopathic urticaria. A double-blind, placebo-controlled study.
Int J Dermatol 1987; 26:653–654.
212. Simons FER. The therapeutic index of newer H 1-receptor antagonists. Clin Exp
Allergy 1994; 24:707–723.
213. Cohen AF, Hamilton MJ, Peck AW. The effects of acrivastine (BW825C), diphen-
hydramine and terfenadine in combination with alcohol on human CNS perfor-
214. Brogden RN, McTavish D. Acrivastine. A review of its pharmacological properties
and therapeutic efficacy in allergic rhinitis, urticaria and related disorders [published
erratum appears in Drugs 1991 Oct; 42(4):639]. Drugs 1991; 41:927–940.
215. Laduron PM, Janssen PFM, Gommeren W, Leysen JE. In vitro and in vivo binding
characteristics of a new long-acting histamine H 1-antagonist, astemizole. Mol Phar-
macol 1982; 21:294–300.
216. Awouters FHL, Niemegeers CJE, Janssen PAJ. Pharmacology of the specific hista-
mine H 1-antagonist astemizole. Arzneimittelforsch 1983; 33:381–388.
217. Rihoux JP, Mariz S. Cetirizine. An updated review of its pharmacological proper-
ties and therapeutic efficacy. Clin Rev Allergy 1993; 11:65–88.
218. Walsh GM, Moqbel R, Hartnell A, Kay AB. Effects of cetirizine on human eosino-
phil and neutrophil activation in vitro. Int Arch Allergy Appl Immunol 1991; 95:
158–162.
219. De-Vos C. H 1-antagonists and inhibitors of eosinophil accumulation. Clin Exp Al-
lergy 1991; 21(Suppl 1):277–281.
220. Falliers CJ, Brandon ML, Buchman E, Connell JT, Dockhorn R, Leese PT, Miller
J, Wasserman SI, Zeterberg JM, Altman R, Love S, Samuels LL. Double-blind
comparison of cetirizine and placebo in the treatment of seasonal rhinitis. Ann Al-
lergy 1991; 66:257–262.
221. Wasserman SI, Broide DH, Marquardt DL. Cetirizine therapy for seasonal allergic
rhinitis: alternative dosage schedules. Clin Ther 1991; 13:707–713.
222. Mansmann HC, Jr., Altman RA, Berman BA, Buchman E, Dockhorn RJ, Leese
PT, Love SJ, Middleton E, Jr. Efficacy and safety of cetirizine therapy in perennial
allergic rhinitis. Ann Allergy 1992; 68:348–353.
223. Lockey RF, Widlitz MD, Mitchell DQ, Lumry W, Dockhorn R, Woehler T, Gross-
man J. Comparative study of cetirizine and terfenadine versus placebo in the symp-
tomatic management of seasonal allergic rhinitis. Ann Allergy Asthma Immunol
1996; 76:448–454.
224. Pearlman DS, Lumry WR, Winder JA, Noonan MJ. Once-daily cetirizine effective in
the treatment of seasonal allergic rhinitis in children aged 6 to 11 years: a randomized,
double-blind, placebo-controlled study. Clin Pediatr Phila 1997; 36:209–215.
225. Howarth PH, Stern MA, Roi L, Reynolds R, Bousquet J. Double-blind, placebo-
controlled study comparing the efficacy and safety of fexofenadine hydrochloride
(120 and 180 mg once daily) and cetirizine in seasonal allergic rhinitis. J Allergy
Clin Immunol 1999; 104:927–933.
226. Bruttmann G, Arendt C, Berheim J. Double-blind, placebo-controlled comparison
of cetirizine 2HCl and terfenadine in atopic perennial rhinitis. Acta Ther 1989; 15:
99–109.
227. Baelde Y, Dupont P. Cetirizine in children with chronic allergic rhinitis. A multi-
centre double-blind study of two doses of cetirizine and placebo. Drug Invest 1992;
4:466–472.
228. Jobst S, van-den-Wijngaart W, Schubert A, van-de-Venne H. Assessment of the
efficacy and safety of three dose levels of cetirizine given once daily in children
with perennial allergic rhinitis. Allergy 1994; 49:598–604.
229. Aaronson DW. Evaluation of cetirizine in patients with allergic rhinitis and peren-
nial asthma. Ann Allergy Asthma Immunol 1996; 76:440–446.
230. Bousquet J, Duchateau J, Pignat JC, Fayol C, Marquis P, Mariz S, Ware JE, Valen-
tin B, Burtin B. Improvement of quality of life by treatment with cetirizine in pa-
tients with perennial allergic rhinitis as determined by a French version of the SF-
36 questionnaire. J Allergy Clin Immunol 1996; 98:309–316.
231. Schoeneich M, Pecoud AR. Effect of cetirizine in a conjunctival provocation test
with allergens. Clin Exp Allergy 1990; 20:171–174.
232. Panayotopoulos SM, Panayotopoulou ES. Efficacy of cetirizine in the treatment of
seasonal allergic rhinoconjunctivitis. Ann Allergy 1990; 65:146–148.
233. Reunala T, Brummer-Korvenkontio H, Karppinen A, Coulie P, Palosuo T. Treat-
ment of mosquito bites with cetirizine. Clin Exp Allergy 1993; 23:72–75.
234. Ramaekers JG, Uiterwijk MMC, O’Hanlon JF. Effects of loratadine and cetirizine
on actual driving and psychometric test performance, and EEG during driving. Eur
235. Spencer CM, Faulds D, Peters DH. Cetirizine. A reappraisal of its pharmacological
properties and therapeutic use in selected allergic disorders. Drugs 1993; 46:1055–1080.
236. Simons FER, Watson WTA, Simons KJ. Pharmacokinetics and pharmacodynamics
of ebastine in children. J Pediatr 1993; 122:641–646.
237. de-Molina M, Cadahia A, Cano L, Sanz A. Efficacy and tolerability of ebastine at
two dose levels in the treatment of seasonal allergic rhinitis. Drug Invest 1989; 1:
40–46.
238. Ankier SI, Warrington SJ. A double-blind placebo-controlled study of the efficacy
and tolerability of ebastine against hayfever in general practice patients. J Intern
Med 1989; 226:453–458.
239. Storms WW. Clinical studies of the efficacy and tolerability of ebastine 10 or 20
mg once daily in the treatment of seasonal allergic rhinitis in the US. Drugs 1996;
52(Suppl 1):20–25.
240. Picado Valles C, Cadahia Garcia A, Cistero Bahima A, Cano Cantudo L, Sanz
Amaro A, Zayas Sanza JM. Ebastine in perennial allergic rhinitis. Ann Allergy
1991; 67:615–618.
241. Bousquet J, Gaudano EM, Palma Carlos AG, Staudinger H. A 12-week, placebo-
controlled study of the efficacy and safety of ebastine, 10 and 20 mg once daily,
in the treatment of perennial allergic rhinitis. Multicentre Study Group. Allergy
1999; 54:562–568.
242. Cohen B, Gehanno P. Comparison of the efficacy of ebastine 10 mg and 20 mg
once daily with that of cetirizine 10 mg once daily in adults with seasonal allergic
rhinitis. A multicentre double-blind study. Drugs 1996; 52(Suppl 1):26–29.
243. Bousquet J. Antihistamines in severe/chronic rhinitis. Clin Exp Allergy 1998;

28(Suppl 6):49–53.
244. Hopes H, Meuret GH, Ungethum W, Leopold G, Wiemann H. Placebo controlled
comparison of acute effects of ebastine and clemastine on performance and EEG.
Eur J Clin Pharmacol 1992; 42:55–59.
245. Mattila MJ, Kuitunen T, Pletan Y. Lack of pharmacodynamic and pharmacokinetic
interactions of the antihistamine ebastine with ethanol in healthy subjects. Eur J
Clin Pharmacol 1992; 43:179–184.
246. Llenas J, Bou J, Massingham R. Preclinical safety studies with ebastine. II. Pharma-
cologic effects on the cardiovascular system. Drugs Today 1992; 28 (Suppl B):29–
34.
247. Russell T, Stoltz M, Weir S. Pharmacokinetics, pharmacodynamics, and tolerance
of single- and multiple-dose fexofenadine hydrochloride in healthy male volunteers.
Clin Pharmacol Ther 1998; 64:612–621.
248. Simons FER, Simons KJ. Peripheral H 1-blockade effect of fexofenadine. Ann Al-
lergy Asthma Immunol 1997; 79:530–532.
249. Fexofenadine. Med Lett Drugs Ther 1996; 38:95–96.
250. Simons FER, Bergman JN, Watson WTA, Simons KJ. The clinical pharmacology
of fexofenadine in children. J Allergy Clin Immunol 1996; 98:1062–1064.
251. Bronsky EA, Falliers CJ, Kaiser HB, Ahlbrandt R, Mason JM. Effectiveness and
safety of fexofenadine, a new nonsedating H 1-receptor antagonist, in the treatment
of fall allergies. Allergy Asthma Proc 1998; 19:135–141.
252. Casale TB, Andrade C, Qu R. Safety and efficacy of once-daily fexofenadine HCl
in the treatment of autumn seasonal allergic rhinitis. Allergy Asthma Proc 1999;
20:193–198.
253. Meltzer EO, Casale TB, Nathan RA, Thompson AK. Once-daily fexofenadine HCl
improves quality of life and reduces work and activity impairment in patients with
seasonal allergic rhinitis. Ann Allergy Asthma Immunol 1999; 83:311–
317.
254. Vermeeren A, O’Hanlon JF. Fexofenadine’s effects, alone and with alcohol, on
actual driving and psychomotor performance. J Allergy Clin Immunol 1998; 101:
306–311.
255. Awouters F, Niemegeers CJE, Jansen T, Megens AAHP, Janssen PAJ. Levocabas-
tine: pharmacological profile of a highly effective inhibitor of allergic reactions.
Agents Actions 1992; 35:12–18.
256. Schata M, Jorde W, Richarz-Barthauer U. Levocabastine nasal spray better than
sodium cromoglycate and placebo in the topical treatment of seasonal allergic rhini-
tis. J Allergy Clin Immunol 1991; 87:873–878.
257. Palma-Carlos AG, Palma-Carlos ML, Rombaut N. The effect of levocabastine nasal
spray in nasal provocation tests. Int J Clin Pharmacol Res 1988; 8:25–30.
258. Kolly M, Pecoud A. Comparison of levocabastine, a new selective H1-receptor an-
tagonist, and disodium cromoglycate, in a nasal provocation test with allergen. Br
259. Dahl R, Pedersen B, Larsen B. Intranasal levocabastine for the treatment of seasonal
allergic rhinitis: a multicentre, double-blind, placebo-controlled trial. Rhinology
1995; 33:121–125.
260. Hampel FC, Jr., Martin BG, Dolen J, Travers S, Karcher K, Holton D. Efficacy
and safety of levocabastine nasal spray for seasonal allergic rhinitis. Am J Rhinol
1999; 13:55–62.
261. de-Graaf-in-’t-Veld T, Garrelds IM, van-Toorenenbergen AW, Mulder PGH, Gerth
van Wijk R, Boegheim JP. Effect of topical levocabastine on nasal response to
allergen challenge and nasal hyperreactivity in perennial rhinitis. Ann Allergy
Asthma Immunol 1995; 75:261–266.
262. Janssens M, Blockhuys S. Tolerability of levocabastine eye drops. Doc Ophthalmol
1993; 84:111–118.
263. Davies BH, Mullins J. Topical levocabastine is more effective than sodium cromo-
glycate for the prophylaxis and treatment of seasonal allergic conjunctivitis. Allergy
1993; 48:519–524.
264. Pipkorn U, Bende M, Hedner J, Hedner T. A double-blind evaluation of topical
levocabastine, a new specific H 1-antagonist in patients with allergic conjunctivitis.
Allergy 1985; 40:491–496.
265. Azevedo M, Castel-Branco MG, Oliveira JF, Ramos E, Delgado L, Almeida J.
Double-blind comparison of levocabastine eye drops with sodium cromoglycate
and placebo in the treatment of seasonal allergic conjunctivitis. Clin Exp Allergy
1991; 21:689–694.
266. Janssens MM, Vanden-Bussche G. Levocabastine: an effective topical treatment
of allergic rhinoconjunctivitis. Clin Exp Allergy 1991; 21(Suppl 2):29–36.
267. Odelram H, Bjorksten B, Klercker T, Rimas M, Kjellman NI, Blychert LO. Topical
levocabastine versus sodium cromoglycate in allergic conjunctivitis. Allergy 1989;
44:432–436.
268. Zuber P, Pecoud A. Effect of levocabastine, a new H 1-antagonist, in a conjunctival
provocation test with allergens. J Allergy Clin Immunol 1988; 82:590–594.
269. Dechant KL, Goa KL. Levocabastine. A review of its pharmacological properties
and therapeutic potential as a topical antihistamine in allergic rhinitis and conjuncti-
vitis. Drugs 1991; 41:202–224.
270. Arriaga F, Rombaut N. Absence of central effects with levocabastine eye drops.
Allergy 1990; 45:552–554.
271. Roman IJ, Danzig MR. Loratadine. A review of recent findings in pharmacology,
pharmacokinetics, efficacy, and safety, with a look at its use in combination with
pseudoephedrine. Clin Rev Allergy 1993; 11:89–110.
272. Dockhorn RJ, Bergner A, Connell JT, Falliers CJ, Grabiec SV, Weiler JM,
Shellenberger MK. Safety and efficacy of loratadine (Sch-29851): a new non-
sedating antihistamine in seasonal allergic rhinitis. Ann Allergy 1987; 58:407–
411.
273. Kemp J, Bahna SL, Chervinsky P, Rachelefsky GS, Seltzer JM. A comparison of
loratadine, a new nonsedating antihistamine, with clemastine and placebo in pa-
tients with fall seasonal allergic rhinitis. Am J Rhinol 1987; 3:151–154.
274. Gutkowski A, Bedard P, Del Carpio J, Herbert J, Prevost M, Schultz J, Turenne
Y, Yeadon C. Comparison of the efficacy and safety of loratadine, terfenadine, and
placebo in the treatment of seasonal allergic rhinitis. J Allergy Clin Immunol 1988;
81:902–907.
275. Del-Carpio J, Kabbash L, Turenne Y, Prevost M, Hebert J, Bedard PM, Nedilski
M, Gutkowski A, Schultz J. Efficacy and safety of loratadine (10 mg once daily),

terfenadine (60 mg twice daily), and placebo in the treatment of seasonal allergic
rhinitis. J Allergy Clin Immunol 1989; 84:741–746.
276. Frolund L, Etholm B, Irander K, Johannessen TA, Odkvist L, Ohlander B, Weeke
B. A multicentre study of loratadine, clemastine and placebo in patients with peren-
nial allergic rhinitis. Allergy 1990; 45:254–261.
277. Clissold SP, Sorkin EM, Goa KL. Loratadine. A preliminary review of its pharma-
codynamic properties and therapeutic efficacy. Drugs 1989; 37:42–57.
278. Roth T, Roehrs T, Koshorek G, Sicklesteel J, Zorick F. Sedative effects of antihista-
mines. J Allergy Clin Immunol 1987; 80:94–98.
279. van Cauwenberge PB. New data on the safety of loratadine. Drug Invest 1992; 4:
283–291.
280. Ascalone V, Guinebault P, Rouchouse A. Determination of mizolastine, a new anti-
histaminic drug, in human plasma by liquid–liquid extraction, solid-phase extrac-
tion and column-switching techniques in combination with high-performance liquid
chromatography. J Chromatogr 1993; 619:275–284.
281. Danjou P, Molinier P, Berlin I, Patat A, Rosenzweig P, Morselli PL. Assessment
of the anticholinergic effect of the new antihistamine mizolastine in healthy sub-
jects. Br J Clin Pharmacol 1992; 34:328–331.
282. Rosenzweig P, Thebault JJ, Caplain H, Dubruc C, Bianchetti G, Fuseau E, Morselli
PL. Pharmacodynamics and pharmacokinetics of mizolastine (SL 85.0324), a new
nonsedative H 1-antihistamine. Ann Allergy 1992; 69:135–139.
283. Benavides J, Schoemaker H, Dana C, Claustre Y, Delahaye M, Prouteau M, Ma-
noury P, Allen J, Scatton B, Langer SZ, et al. In vivo and in vitro interaction of
the novel selective histamine H 1-receptor antagonist mizolastine with H 1 receptors
in the rodent. Arzneimittelforsch 1995; 45:551–558.
284. Levrier J, Duval D, Prouteau M, Berry C, Lloyd KG, Scatton B. Anti-anaphylactic
activity of the novel selective histamine H 1-receptor antagonist mizolastine in the
rodent. Arzneimittelforsch 1995; 45:559–568.
285. Pichat P, Angel I, Arbilla S. Anti-inflammatory properties of mizolastine after oral
administration of arachidonic acid-induced cutaneous reaction in the rat. Arzneimit-
telforsch 1998; 48:173–178.
286. Stern M, Blondin-Ertzbischoff P, Murrieta-Aguttes M, Hardwicke C, Emmerson
EB, Judd MS. Rapid and sustained efficacy of mizolastine 10 mg once daily in
seasonal allergic rhinitis. J Int Med Res 1998; 26:292–303.
287. Sabbah A, Daele J, Wade AG, Ben-Soussen P, Attali P. Comparison of the efficacy,
safety, and onset of action of mizolastine, cetirizine, and placebo in the management
of seasonal allergic rhinoconjunctivitis. MIZOCET Study Group. Ann Allergy
288. Bellioni P, Catalano B, Cervellera G, Filiaci F, Mira E, Carraro A. Comparison of
mizolastine with loratadine in the treatment of perennial allergic rhinitis. Rhinology
1996; 34:101–104.
289. Bachert C, Brostoff J, Scadding GK, Tasman J, Stalla-Bourdillon A, Murrieta M.
Mizolastine therapy also has an effect on nasal blockade in perennial allergic rhino-
conjunctivitis. Allergy 1998; 53:969–975.
290. Delauche-Cavallier MC, Chaufour S, Guerault E, Lacroux A, Murrieta M, Wajman
A. QT interval monitoring during clinical studies with mizolastine, a new H 1 anti-

histamine. Clin Exp Allergy 1999; 29(Suppl 3):206–211.
291. Carr AA, Meyer DR. Synthesis of terfenadine. Arzneimittelforsch 1982; 32:1157–
1159.
292. FDA announces plan to halt marketing of terfenadine [news]. Am J Health Syst
Pharm 1997; 54:342.
293. Achterrath-Tuckermann U, Simmet T, Luck W, Szelenyi I, Peskar BA. Inhibition
of cysteinyl-leukotriene production by azelastine and its biological significance.
294. Little MM, Wood DR, Casale TB. Azelastine inhibits stimulated histamine release
from human lung tissue in vitro but does not alter cyclic nucleotide content. Agents
Actions 1989; 28:16–21.
295. Casale TB. The interaction of azelastine with human lung histamine H 1, beta, and
muscarinic receptor-binding sites. J Allergy Clin Immunol 1989; 83:771–776.
296. Busse W, Randlev B, Sedgwick J. The effect of azelastine on neutrophil and eosino-
phil generation of superoxide. J Allergy Clin Immunol 1989; 83:400–405.
297. McTavish D, Sorkin EM. Azelastine. A review of its pharmacodynamic and phar-
macokinetic properties, and therapeutic potential. Drugs 1989; 38:778–800.
298. Fields DA, Pillar J, Diamantis W, Perhach JL, Jr., Sofia RD, Chand N. Inhibition
by azelastine of nonallergic histamine release from rat peritoneal mast cells. J Al-
299. Chand N, Pillar J, Diamantis W, Sofia RD. Inhibition of IgE-mediated allergic
histamine release from rat peritoneal mast cells by azelastine and selected antialler-
gic drugs. Agents Actions 1985; 16:318–322.
300. Chand N, Pillar J, Diamantis W, Sofia RD. Inhibition of allergic histamine release
by azelastine and selected antiallergic drugs from rabbit leukocytes. Int Arch Al-
lergy Appl Immunol 1985; 77:451–455.
301. Weiler JM, Donnelly A, Campbell BH, Connell JT, Diamond L, Hamilton LH, Rosen-
thal RR, Hemsworth GR, Perhach JL, Jr. Multicenter, double-blind, multiple-dose,
parallel-groups efficacy and safety trial of azelastine, chlorpheniramine, and placebo
in the treatment of spring allergic rhinitis. J Allergy Clin Immunol 1988; 82:801–811.
302. Meltzer EO, Storms WW, Pierson WE, Cummins LH, Orgel HA, Perhach JL, Hems-
worth GR. Efficacy of azelastine in perennial allergic rhinitis: clinical and rhinoma-
nometric evaluation. J Allergy Clin Immunol 1988; 82:447–455.
303. Dorow P, Aurich R, Petzold U. Efficacy and tolerability of azelastine nasal spray
in patients with allergic rhinitis compared to placebo and budesonide. Arzneimit-
telforsch 1993; 43:909–912.
304. Ratner PH, Findlay SR, Hampel F, Jr., van-Bavel J, Widlitz MD, Freitag JJ. A
double-blind, controlled trial to assess the safety and efficacy of azelastine nasal
spray in seasonal allergic rhinitis. J Allergy Clin Immunol 1994; 94:818–825.
305. Davies RJ, Lund VJ, Harten-Ash VJ. The effect of intranasal azelastine and beclo-
methasone on the symptoms and signs of nasal allergy in patients with perennial
allergic rhinitis. Rhinology 1993; 31:159–164.
306. Herman D, Garay R, Le-Gal M. A randomized double-blind placebo-controlled
study of azelastine nasal spray in children with perennial rhinitis. Int J Pediatr Oto-
rhinolaryngol 1997; 39:1–8.
307. Giede-Tuch C, Westhoff M, Zarth A. Azelastine eye-drops in seasonal aller-

gic conjunctivitis or rhinoconjunctivitis. A double-blind, randomized, placebo-
controlled study. Allergy 1998; 53:857–862.
308. Lenhard G, Mivsek-Music E, Perrin-Fayolle M, Obtulowicz K, Secchi A. Double-
blind, randomised, placebo-controlled study of two concentrations of azelastine eye
drops in seasonal allergic conjunctivitis or rhinoconjunctivitis. Curr Med Res Opin
1997; 14:21–28.
309. Sabbah A, Marzetto M. Azelastine eye drops in the treatment of seasonal allergic
conjunctivitis or rhinoconjunctivitis in young children. Curr Med Res Opin 1998;
14:161–170.
310. Horak F, Berger UE, Menapace R, Toth J, Stubner PU, Marks B. Dose-dependent
protection by azelastine eye drops against pollen-induced allergic conjunctivitis. A
double-blind, placebo-controlled study. Arzneimittelforsch 1998; 48:379–384.
311. Grant SM, Goa KL, Fitton A, Sorkin EM. Ketotifen. A review of its pharmacody-
namic and pharmacokinetic properties, and therapeutic use in asthma and allergic
disorders [published erratum appears in Drugs 1991 Feb; 41:192]. Drugs 1990; 40:
412–448.
312. Church MK, Gradidge CF. Oxatomide: inhibition and stimulation of histamine re-
lease from human lung and leucocytes in vitro. Agents Actions 1980; 10:4–7.
313. Richards DM, Brogden RN, Heel RC, Speight TM, Avery GS. Oxatomide. A re-
view of its pharmacodynamic properties and therapeutic efficacy. Drugs 1984; 27:
210–231.
314. Yamashita M, Fukui H, Sugama K, Horio Y, Ito S, Mizuguchi H, Wada H. Expres-
sion cloning of a cDNA encoding the bovine histamine H 1-receptor. Proc Natl Acad
Sci USA 1991; 88:11515–11519.
315. Timmerman H. Cloning of the H 1-histamine receptor. Trends Pharmacol Sci 1992;
13:6–7.
316. De Backer MD, Gommeren W, Moereels H, Nobels G, Van Gompel P, Leysen JE,
Luyten WHML. Genomic cloning, heterologous expression and pharmacological
characterization of a human histamine H 1-receptor. Biochem Biophys Res Commun
1993; 197:1601–1608.
317. Smit MJ, Hoffmann M, Timmerman H, Leurs R. Molecular properties and signal-
ling pathways of the histamine H 1-receptor. Clin Exp Allergy 1999; 29(Suppl 3):
19–28.
318. ter Laak AM, Timmerman H, Leurs R, Nederkoorn PH, Smit MJ, Donne-Op den
Kelder GM. Modelling and mutation studies on the histamine H 1-receptor agonist
binding site reveal different binding modes for H 1-agonists: Asp116 (TM3) has a
constitutive role in receptor stimulation. J Comput Aided Mol Des 1995; 9:319–330.
319. Wieland K, Laak AM, Smit MJ, Kuhne R, Timmerman H, Leurs R. Mutational
analysis of the antagonist-binding site of the histamine H 1-receptor. J Biol Chem
1999; 274:29994–30000.
320. Holgate ST, Church MK, Howarth PH, Simons FER, Campbell A, Dunn N,
Routledge P, Hindmarch I, Timmerman H, Camm J, Friedmann P, Canonica W,
Scadding G, Devalia J, Renwick A. Antihistamines: back to the future. Summary
of the conclusions. BSACI. British Society for Allergy and Clinical Immunology.
Clin Exp Allergy 1999; 29(Suppl 3):iv–vi.
4
Antiallergic Anti-Inflammatory Effects
of H1-Antihistamines in Humans
Paraya Assanasen and Robert M. Naclerio

University of Chicago, Chicago, Illinois
I. INTRODUCTION
There is increasing evidence that some H 1-receptor antagonists possess a variety

of activities not explained by H 1-antagonism. These antiallergic, anti-inflamma-
tory activities can be studied in vitro, in vivo, and ex vivo. In vivo (in humans)
allergen challenge of the skin, nose, lung, and eye has been useful in studying
the role of anti-inflammatory properties. The clinical significance of antiallergic,
anti-inflammatory effects beyond H 1-receptor blockade is currently an important
area of investigation.
In this chapter, we begin by describing the pathophysiology of nasal allergic
inflammation and a human nasal model for the study of the antiallergic anti-
inflammatory effects of antihistamines. Different H 1-antagonists and available
human data on these effects of antihistamines are then reviewed.
II. PATHOPHYSIOLOGY OF ALLERGIC INFLAMMATION
To understand the antiallergic, anti-inflammatory effects of H 1-receptor antago-

nists, it is necessary to appreciate the pathophysiology of allergic inflammation,
which begins with a sensitization phase followed by a clinical phase (Fig. 1).
Individuals with a genetic predisposition to allergic disease develop IgE antibod-
ies to allergens after exposure, called ‘‘sensitization.’’ Allergens are processed
by antigen-presenting cells (macrophages, dendritic cells) and presented to T-
101
102 Assanasen and Naclerio
Figure 1 Simplified schematic representation of the development of allergic rhinitis.

During phase 1, persons become sensitized to an allergen, and during phase 2 clinical
disease develops. The majority of patients have an early response on exposure to allergen.
The early response is dominated by activation of the mast cells and release of mediators.
After the early response, most patients have cellular infiltration of the nasal mucosa that
causes late inflammatory events. These include the spontaneous recurrence of release of
mediators (late-phase reaction), hyperresponsiveness to irritants, and increased respon-
siveness to allergen (priming). The circles indicate the heterogeneity of these late inflam-
matory events. The inflammation can resolve spontaneously, cause a complication, or po-
tentially lead to an irreversible form of chronic rhinitis. (From Naclerio RM. N Engl J
Med 1991; 325: 860–869.)
helper cells (Th: CD4⫹) and, in turn, B cells. Interleukins (IL), especially IL-4
and IL-13 from Th2 lymphocytes, favor IgE synthesis by B cells. Allergen-spe-
cific IgE binds to high-affinity receptors on mast cells and basophils and to low-
affinity receptors on other cells, including monocytes, eosinophils, and platelets
(2–5).
The early-phase response (EPR) begins when subsequent exposure to an
allergen leads to cross-linking of adjacent IgE molecules, and mast cells degranu-
late, releasing multiple inflammatory mediators such as histamine, leukotriene
C4 (LTC4 ), and prostaglandin D2 (PGD2 ) (6). In allergic rhinitis, the mediators
stimulate the nasal end organs (nerves, glands, and blood vessels) to produce
itching, sneezing, rhinorrhea, and congestion. These symptoms usually resolve
spontaneously, but may return 3–10 h after allergen challenge.
Spontaneous recurrence of symptoms occurs in approximately 50% of per-
sons with seasonal allergic rhinitis (7). The dominant symptom in this late-phase
response (LPR) is nasal congestion. On histological examination, the LPR is
Antiallergic Anti-Inflammatory Effects 103
characterized by cellular influx of eosinophils, neutrophils, basophils, mononu-

clear cells, and T cells. The principal cells entering nasal secretions are eosino-
phils, whereas Th lymphocytes predominate in the submucosa, suggesting that
secretions and the nasal mucosa are distinct compartments with different cellular
arrays and cytokine profiles (8). Eosinophils can contribute mediators, neurotox-
ins, and peroxidases to the inflammatory milieu of the LPR. Activated basophils
rather than mast cells cause histamine release during the LPR (9). Recruited baso-
phils can also serve as targets during subsequent allergen exposure. In addition
to the mediators secreted by these inflammatory cells, cytokines such as IL-4
produced by mast cells (10), IL-3, IL-4, IL-5, granulocyte macrophage-colony
stimulating factor (GM-CSF) by Th2 lymphocytes, and IL-6 by epithelial cells
(11) are released to orchestrate and regulate the inflammatory response. Neuronal
reflexes also play a role in the allergic response, by mediating local responses
to mediators and possibly by playing a part in the activation of T lymphocytes
(12). Recruitment of cells such as eosinophils and activated T lymphocytes is
mediated, in part, by interactions between adhesion molecules both on the cells
themselves and on vascular endothelial cells, with cytokines playing a variety of
regulating roles in these interactions.
A series of events occurs during the migration of circulating leukocytes in
response to inflammatory stimuli: leukocyte activation, vascular endothelial cell
expression of adhesion molecules, adhesion of leukocytes to vascular endothe-
lium, rolling of leukocytes along the vessel wall, transendothelial migration into
the mucosa, and migration across the epithelium into nasal secretions. Important
adhesion molecules expressed on endothelial cells include intercellular adhesion
molecule-1 (ICAM-1), E-selectin, and vascular cell adhesion molecule-1
(VCAM-1). Their ligands on eosinophils include lymphocyte function-associated
antigen-1 (LFA-1) and macrophage antigen-1 (Mac-1) for ICAM-1, very late
antigen-4 (VLA-4) for VCAM-1, and sialyl-Lewis X for E-selectin. These adhe-
sion molecules and their coreceptors participate in the migratory process. Once
inflammatory cells have left the vascular compartment, they make their way
through the extracellular matrix to the site of inflammatory reaction, and finally,
to the mucosal surfaces.
It has recently been found that epithelial cells contribute to the pathophysi-
ology of the allergic inflammation at the mucosal level, besides providing a natu-
ral barrier against particulates, bacteria, and allergen. For example, epithelial cells
can synthesize and release a wide range of mediators, including IL-1, IL-1β, IL-
6, IL-8, GM-CSF, tumor necrosis factor (TNF)-α, monocyte chemotactic protein
(MCP)-1, and regulated on activation, normal T-cell expressed and secreted
(RANTES) (13).
A number of studies have suggested an increase in levels of adhesion mole-
cule expression on the nasal epithelium during allergic inflammation. Nasal epi-
thelial cells of patients with allergic rhinitis express increased ICAM-1 after ei-
ther seasonal exposure (14) or allergen challenge (15). Asymptomatic patients

sensitive to house dust mites express ICAM-1 on nasal and conjunctival epithelial
cells (16). Moreover, a number of inflammatory cytokines, such as interferon
(IFN)-γ, TNF-α, IL-1β, IL-4 (17, 18), and eosinophil cationic protein (ECP) and
major basic protein (MBP) (19), can induce upregulation of epithelial ICAM-1
expression in vitro. The increased epithelial ICAM-1 by ECP and MBP might indi-
cate a feedback mechanism responsible for epithelial damage and shedding via
eosinophil products (13). An increase in the epithelial expression of ICAM-1 is an
early signal of the development of inflammation and can be monitored as such.
Allergic inflammation not only involves an EPR and LPR but also leads
to increased sensitivity to allergen, known as the priming effect. The increased
responsiveness after allergen provocation reverses spontaneously when allergen
exposure ceases. Priming mechanisms probably involve cellular infiltration, in-
creased mediator production, and increased end-organ responsiveness. Influx of
inflammatory cells is hypothesized to alter the mucosal penetration of allergen,
to provide additional targets for allergen stimulation, to increase the generation
of inflammatory mediators, and to increase end-organ responsiveness. Patients
with allergic rhinitis also show hyperresponsiveness to nonantigenic stimuli such
as histamine, cold, dry air, and methacholine (12, 20, 21). Several studies show
a dissociation between nasal hyperresponsiveness to methacholine after allergen
challenge and the influx of eosinophils into nasal secretions (21–23). These stud-
ies suggest that the allergen-induced increase in nonspecific responsiveness is a
complex phenomenon. It probably reflects interactions among inflammatory cel-
lular influx, epithelial injury, and increased end-organ responsiveness and is not
dependent solely on eosinophil influx into the nasal mucosa.
In summary, allergic inflammation can be characterized as an initial sensiti-
zation phase, in which allergen presentation results in antibody (IgE) formation,
and a clinical disease phase, in which symptoms develop during exposure to
allergen. The clinical condition involves an early- and late-phase inflammatory
reaction. The former involves mast cell degranulation, and the latter is associated
with cellular infiltration and release of cytokines into the nasal mucosa. The pro-
duction of cytokines and the interactions of mediators result in an extremely
complex network, directing adhesion molecule expression, production of chemo-
attractants, and subsequent recruitment of inflammatory cells that affect the re-
sponse to additional allergenic and nonallergenic stimuli.
III. HUMAN MODELS FOR THE STUDY OF ANTIALLERGIC

EFFECTS OF ANTIHISTAMINES
Nasal challenge with allergen has helped us to understand the pathophysiology

of allergic inflammation and the action of H 1-antihistamines and other medica-
tions, and facilitates quantitative assessments of the release of inflammatory me-

diators during the early and late nasal allergic response (24). Nasal provocation
involves direct application of allergen to the nasal mucosa and observation of
the response both objectively and subjectively. It can be performed easily and
frequently and has several advantages over other types of provocation challenge.
First, the human nasal mucosa is the organ in which allergic rhinitis occurs. Sec-
ond, the technique examines the organ in its entirety, not isolating any single
element. Third, the human condition is not necessarily mimicked in animal mod-
els. Fourth, nasal challenge is a simple, safe, reliable, and reproducible tool for
evaluating the effectiveness and possible mode of action of medications used in
the treatment of allergic rhinitis.
A. General Considerations
Several methods for the provocation and measurement of the nasal response have
been used in recent years. Each technique or model has its own advantages and
disadvantages. For experimental research, quantitative measurements with high
reproducibility are essential (25). The interpretation of the results demands basic
knowledge of the techniques employed, as well as of the study design. All provo-
cation studies require careful selection of participants, including an assessment
of the disease state by using subjective and objective parameters. The participants
should be free of other underlying diseases and should not be taking any medica-
tions that may confound the interpretation of results. We prefer to challenge pa-
tients with seasonal allergic rhinitis out of season, because pollen exposure can
prime their mucosa and affect the laboratory responses in vivo during the season
and for weeks afterward. They should be studied during the asymptomatic stage
several weeks after termination of the pollen season, and at least 2 weeks should
pass between challenges, to avoid the priming effect.
Nasal challenges with histamine or methacholine have been used to assess
the nonspecific hyperreactivity of the nasal mucosa after allergen challenge. Both
histamine and methacholine induce a dose-dependent increase in secretion
weights on the challenged (ipsilateral) side, whereas only histamine induces a
contralateral reflex rhinorrhea (26). The use of a control group is essential for
assessment of the ‘‘placebo effect’’ or other potential confounding environmental
factors (27).
B. Allergen
Precise quantification of the amount of allergen to be used for challenge is essen-
tial. The purity and stability of the allergen must be known. Allergens are usually
given as aqueous solutions, powder, or pollen grains mixed with lactose in cap-
sules. We prefer to use standardized and lyophilized extracts. Aqueous extracts
must be stored appropriately as their potency may decrease rapidly. Optimal aller-
gen concentrations, which vary for seasonal and perennial allergens, should be
selected. In general, the amount of administered allergen that causes asymptom-
atic individuals to respond is far greater than that required during several days
of natural pollen exposure, mostly because of the priming effect that occurs dur-
ing natural exposure.
C. Delivery System
Delivery systems for liquid extracts commonly include nebulizers, atomizers,
metered-dose inhalers, direct instillation, and placement of extract-soaked paper
discs in the nose. The choice of a delivery system depends on the question being
addressed by the experiment. It must be reproducible, and its effect on the param-
eters being measured must be known. The diluent used for the allergen extract
and preservatives such as glycerol, benzalkonium chloride, or phenol may induce
nonspecific nasal reactions. The diluent is often administered before the allergen
exposure so that its effect can be studied. In addition, with all delivery systems,
an attempt should be made to minimize the exposure of the lower airways to
allergen, because allergen deposited in the lower airway can cause bronchocon-
striction.
D. Assessment of the Response

1. Subjective
The subjective assessment of symptoms by either participants or the observer
can be recorded using different techniques, such as symptom scores or a visual
analog scale. Congestion, rhinorrhea, and itching are easy to self-assess and yield
valuable information. Sneezes counted by the investigator provide an objective
symptom index. At least one additional objective measurement of the nasal re-
sponse should be used to strengthen the validity of any observations.
2. Outcomes Evaluated
Nasal Airway Resistance. Nasal congestion is one of the cardinal symp-
toms of allergic inflammation and the major symptom of the LPR following aller-
gen challenge.
Rhinomanometry measures nasal airway resistance (NAR) by quantita-
tively measuring nasal airflow and pressure. Active anterior rhinomanometry is
used most frequently as it is well tolerated by patients. Posterior rhinomanometry
is preferable because it does not distort the nasal valve, but only about 85%
of volunteers can successfully perform this maneuver (28). The physiological
fluctuation in nasal resistance, termed the nasal cycle, may interfere with nasal
monitoring in the nasal provocation test (29). A large number of subjects and/
or a large change in resistance are needed to overcome the variations in this
measurement.
Inspiratory Nasal Peak Flow. This is the simplest technique for detecting
changes in nasal patency for repeated measurements before and after nasal chal-
lenge. It can also be performed at home for monitoring nasal congestion as a
response to treatment. Peak flow measurements are less reproducible than rhino-
manometry measurements (30).
Nasal Volume. The geometric cross-sectional area and nasal volume can
be measured using acoustic rhinometry. This rapidly performed test, which does
not assess flow, complements NAR measurement and provides information about
the site of obstruction. It is also affected by nasal cycle.
Measurement of Mucosal Swelling. Rhinostereometry is an optical
method that exclusively measures changes in nasal swelling using stereotactic
measurement of one defined point through an eyepiece of a microscope to evalu-
ate changes in mucosal edema. Although it is highly accurate, correlation with
the subjective symptom of nasal obstruction is poor (31).
Nasal Secretions. Several methods have been used for collecting and
quantifying nasal secretions: suction, blowing, dripping, washing, lavage, and
absorption. Blown secretions can be quantified by weighing of paper tissues. The
amount of nasal secretions can also be obtained by the placement of discs or
other substances on the nasal mucosa to determine the weight of secretions gener-
ated during a fixed period of time. Nasal lavage samples epithelial lining fluid
(ELF) from a large mucosal area, whereas discs sample a localized area. The
volume of ELF in the lavage fluid can be estimated by using urea as a marker
(32). Nasal secretions can be processed for assessment of both their cellular and
their biochemical contents.
Biological Markers. Biological markers can be measured in collected se-
cretions to monitor changes in the underlying pathophysiology. These markers
include inflammatory mediators, cytokines, plasma proteins and glandular secre-
tory products. It is important to know the stability of each marker after recovery,
the sensitivity and specificity of each assay, and the potential cellular sources
of the markers when interpreting the results. The changes in markers reflect
their levels on the mucosal surface, but may not reflect levels in the underlying
tissue.
Cells. Cells can be obtained from the nasal cavity using various tech-
niques. The epithelial layer can be scraped or brushed for evaluation of specific
areas of the nasal cavity. Obtaining blown secretions is simple and painless; how-
ever, the specimen only reflects secretions and usually yields few cells. Nasal
lavage samples secretions from the entire nasal cavity. It provides a technique
for simultaneous measurement of cells and biological markers. Nasal biopsy sam-
ples provide information about structural elements and cellular contents of the
epithelial layer and the deeper submucosa. A wide range of histochemical or
immunohistochemical techniques can be employed for light microscopy to pro-
vide a more detailed evaluation of the cellular content. As an alternative, samples
may be processed specifically for either transmission or scanning electron micros-
copy.
IV. ANTIALLERGIC EFFECTS OF H 1-ANTIHISTAMINES
Human in vivo models provide an excellent opportunity to evaluate both the H 1-

receptor antagonism and the other anti-inflammatory effects of antihistamines.
In this section, we describe studies of the antiallergic activities of antihistamines.
A. Acrivastine
Acrivastine, which is related to triprolidine, is a short-acting H 1-antagonist with
a rapid onset of action. Lau and colleagues studied the effect of acrivastine on
histamine release from rat peritoneal mast cells and found it to be ineffective in
inhibiting anti-IgE- or calcium ionophore A 23187-induced histamine release at
concentrations from 10⫺9 M to 10⫺4 M (33). Acrivastine was, however, demon-
strated to inhibit PAF-induced airway hyperreactivity in guinea pigs (34). The
mechanism responsible for this finding is unclear, but is not related to H 1-antago-
nism. Antiallergic activities of acrivastine have not been studied in humans.
B. Astemizole
Astemizole, a benzimidazole–aminopiperidine compound, is a long-acting,
highly selective H 1-antagonist with no central nervous system (CNS) or anticho-
linergic effects. Because of its rare but potentially serious cardiac side effects,
it has been removed from the market. It significantly decreased IL-1 levels in
nasal lavage fluid and also decreased IL-8 and LTB4 levels (35, 36).
C. Azatadine
Azatadine, a tricyclic antihistamine of the piperidine class, is an effective H 1-
receptor antagonist for relieving the histamine-mediated symptoms of seasonal
allergic rhinitis (37). In vitro experimentation with azatadine base showed that
it inhibited histamine and LTC4 release from human lung mast cells by 45 and
85%, respectively, when used at a concentration of 10⫺3 M (38). Concentrations

less than 10⫺4 M had no significant effect. Because these concentrations would
be difficult to obtain from oral administration of the drug, Togias and colleagues
investigated topical intranasal delivery of azatadine 0.5 mg in a double-blind,
placebo-controlled, crossover study in eight allergic individuals (39). Azatadine
significantly inhibited allergen-induced sneezes, and increases in histamine, N-
alpha-tosyl-L-arginine methyl ester (TAME)-esterase activity, and kinins in nasal
lavage fluids collected after allergen challenge. These observations were consis-
tent with the notion that azatadine, given in sufficient concentration, was capable
of inhibiting mast cell histamine release in vitro and in vivo.
D. Azelastine
Azelastine, a phthalazinone compound, can be administered orally or as an intra-
nasal spray. In addition to histamine H 1-receptor blockade, it has inhibitory ef-
fects on cells and chemical mediators of the inflammatory response in vitro (40–
45). For example, it inhibits histamine release from human basophils (41) and
from animal (43, 44) and human lung mast cells (45) in vitro. Anti-inflammatory
effects of azelastine have also been shown in vivo. Shin and colleagues performed
a double-blind, placebo-controlled, crossover study comparing the effect of treat-
ment with oral azelastine or placebo on the EPR to nasal challenge with allergen
in 13 asymptomatic allergic subjects (46). Pretreatment with a single oral 2 mg
dose of azelastine resulted in a dramatic reduction in the number of sneezes as
well as in the levels of TAME-esterase activity, LTC4 , and kinins without a sig-
nificant reduction of histamine and PGD2 compared to placebo. These results
suggest that azelastine blocked the effects of histamine on nerves and blood ves-
sels.
An interesting finding in this study was the inhibition of leukotriene pro-
duction by azelastine. This finding probably reflects the fact that the concentra-
tion of azelastine in vivo was sufficient to inhibit only LTC4 , but not histamine
release, because in vitro studies showed that azelastine inhibited LTC4 release at
a dose lower than that required to inhibit histamine release (39, 47). Alternatively,
since mast cell activation was not inhibited, eosinophils, macrophages, and endo-
thelial cells may have contributed to the production of LTC4. Another possible
explanation is that azelastine may have some 5-lipoxygenase inhibitory activity
that leads to a preferential reduction of leukotriene generation in nasal mast cells
(48, 49). Because histamine itself does not affect LTC4 production (50), this is
not an H 1-receptor blockade effect. These results emphasize the importance of
correlating in vivo and in vitro results, and the greater complexity of in vivo
systems.
IL-4 from CD4⫹ lymphocytes and CD23 antigen from B lymphocytes are
important triggering mechanisms in cells producing IgE antibodies (51, 52). Ito
and colleagues studied the effect of azelastine on IL-4 and soluble CD23
(s-CD23), the soluble component of membrane-type CD-23, in subjects with al-
lergic rhinitis. They performed a randomized, placebo-controlled, parallel trial
in allergic subjects who were treated with either azelastine (orally 2 mg daily)
or placebo for 4 weeks during the allergy season (53). Compared to placebo,
azelastine significantly decreased symptoms and the levels of IL-4 and s-CD23
from baseline.
Ciprandi and colleagues studied the effect of azelastine nasal spray on the
EPR and LPR to nasal challenge with allergen in 20 subjects with pollen allergy
in a randomized, double-blind, placebo-controlled, parallel study (54). Azelastine
significantly decreased the total symptom score, as well as eosinophil and neutro-
phil infiltration and ICAM-1 expression during both EPR and LPR (Table 1).
Furthermore, ECP levels in nasal lavage fluid decreased significantly during the
LPR. The antiallergic effect of intranasal azelastine was more prominent and
effective when treatment was used continuously, rather than as needed (55). Us-
ing a conjunctival provocation model, Ciprandi and colleagues also demonstrated
the antiallergic activity of azelastine eye drops on the EPR and LPR to conjuncti-
val challenge with allergen (56). In contrast, Pelucchi and colleagues failed to
show an inhibitory effect of intranasal azelastine on the number of eosinophils
recovered in nasal lavage in allergic subjects during the pollen season (57).
A possible explanation for its antiallergic effect in the LPR is that azelastine
may downregulate ICAM-1 expression by acting on epithelial cells directly, or
by acting on mast cells or other cells that are able to release factors that upregulate
ICAM-1 expression (58).
Jacobi and colleagues studied the effect of a 1-week pretreatment with in-
tranasal azelastine or systemic cetirizine on allergen-induced release of mast cell
mediators from the human nasal mucosa (59). They performed a randomized,
double-blind, placebo-controlled, three-way crossover study on 11 allergic sub-
jects and 5 nonallergic subjects. Each subject was treated with azelastine nasal
spray, 0.14 mg per nostril twice daily, cetirizine 10 mg once daily, or placebo
for 1 week. There were significant increases in the number of sneezes and the
levels of histamine and tryptase in lavage fluid after allergen challenge. Both
azelastine and cetirizine significantly reduced allergen-induced sneezing and the
associated increases in histamine and tryptase levels (Fig. 2). Reduced levels of
mast cell mediators in nasal lavage fluid may result from a reduced release of
mediators from mast cells and/or a reduced transfer of released mediators from
the nasal mucosa to lavage fluid. The fact that antihistamines reduce histamine-
induced plasma exudation and secretion from nasal glands supports the latter
concept (26). The discrepancies between this study and that of Shin and col-
leagues may be related to the differences in study population and methods (e.g.,
allergen concentrations, or route of administration).
Table 1 Results of Parameters Measured During Early- and Late-Phase Response After Nasal Challenge with Allergen
Early-phase response Late-phase response
Parameter Time Azelastine Placebo p value Azelastine Placebo p value
Total symptom score T0 10 (7–12) 10 (8–11) NS 3 (1–3) 3 (2–3) NS

T7 7 (3–10) 10 (8–12) 0.01 1 (1–2) 3 (2–3) 0.01
Neutrophils T0 45 (28–80) 39 (22–70) NS 39 (18–63) 28 (19–63) NS
T7 28 (10–49) 37 (24–63) 0.01 20 (10–79) 26 (18–60) 0.01
Eosinophils T0 13.5 (9–22) 12 (5–21) NS 17 (10–26) 16 (10–26) NS
T7 8.5 (4–15) 14 (6–19) 0.03 11 (8–20) 17 (12–25) 0.01

ICAM-1 positivity T0 4 (2–4) 3.5 (3–4) NS 2 (1–3) 2 (1–3) NS
T7 2 (1–2) 3 (3–4) 0.001 1 (0–3) 2 (1–3) 0.05
ECP (µg/L) T0 33 (20–43) 30 (19–42) NS 40 (27–50) 40 (25–52) NS
T7 29 (19–35) 30 (20–41) NS 25 (11–37) 41 (30–56) 0.01
Twenty asymptomatic subjects with allergic rhinitis were studied in a randomized, double-blind, placebo-controlled, parallel trial. Numbers represent the
median values (range) after allergen challenge. T0, allergen challenge performed at baseline; T7, allergen challenge, which was done 1 week after T0,
performed 30 min after subjects received either azelastine (0.137 mg intranasally) or placebo; ICAM-1, intercellular adhesion molecule-1; ECP, eosinophil
cationic protein; NS, not significant.
Source: Ref. 54.
111
Figure 2 Effect of 1 week pretreatment with intranasal azelastine, oral cetirizine, and
placebo on the early allergic response. Eleven asymptomatic subjects with allergic rhinitis
were treated with azelastine nasal spray (0.14 mg per nostril twice daily), cetirizine tablets
(10 mg daily), or placebo 1 week prior to allergen challenge in a randomized, double-
blind, placebo-controlled, three-way crossover trial. The challenge protocol is shown on
the abscissa. The nasal challenge was begun with 0.9% NaCl solution as a control chal-
lenge, followed by three incremental dosages of allergen. The median values of number
of sneezes and the levels of histamine and tryptase in nasal lavage fluid are shown. Pre-
treatment with azelastine or cetirizine significantly inhibited the allergen-induced sneezes
and the increase in the levels of tryptase and histamine compared with placebo. SQU,
standardized quality units. (From Ref. 59.)
E. Cetirizine
Cetirizine, a piperazine derivative and the carboxylated metabolite of hydroxy-
zine, is a specific H 1-receptor antagonist. To evaluate the effects of cetirizine
on mediator release during the early allergic response, Naclerio and colleagues
performed a double-blind, placebo-controlled, crossover study in 10 asymptom-
atic patients with seasonal allergic rhinitis, comparing pretreatment with cetiri-
zine 20 mg daily for three doses, or placebo, on the response to nasal challenge
with allergen (60). After pretreatment with placebo, the volunteers sneezed in
response to antigen stimulation, and there was a dose-dependent increase in the
levels of histamine, TAME-esterase activity, albumin, LTC4 , and PGD2 in the
recovered nasal lavage fluid. After cetirizine pretreatment, there was a significant
reduction in the number of sneezes, TAME-esterase activity, LTC4 , and albumin,
whereas the histamine and PGD2 levels were not reduced. These findings support
the notion that cetirizine competes with histamine for H 1-receptors on nerves
(reduced sneezing) and blood vessels (decreased vascular permeability). The inhi-
bition of leukotriene production by cetirizine could be explained in the same way
as discussed above for azelastine.
In another study, the effect of cetirizine on histamine-induced changes in
lavage protein concentration was studied in 10 healthy volunteers in a random-
ized, double-blind, placebo-controlled manner (61). The increase in lavage total
protein and albumin concentration after histamine challenge was almost com-
pletely abolished by cetirizine compared to placebo. This finding supports the
concept that the increase in albumin after allergen challenge is mediated by hista-
mine acting through H 1-receptors on blood vessels, resulting in plasma leakage,
which is inhibited by cetirizine.
The effect of cetirizine on accumulation of inflammatory cells has also
been studied in the skin and upper airways. Double-blind, placebo-controlled,
crossover studies evaluating its effect on the cutaneous allergic response have
shown that it reduces eosinophilic infiltration at the site of allergen challenge in
a skin chamber challenge model (62), and also in a similar study in which it
decreased eosinophil infiltration by approximately 80% in ragweed-sensitive sub-
jects (63). Furthermore, cetirizine has been shown to inhibit cellular recruitment,
particularly eosinophils, into bronchial washings from asthmatic subjects with an
early and late response (64). Klementsson and colleagues evaluated the effect of
cetirizine (10 mg daily), terfenadine (60 mg twice daily), and placebo on eosino-
phil infiltration into nasal secretions and on allergen-induced nonspecific nasal
hyperreactivity after nasal allergen challenge (65). The allergen challenge in-
creased surface eosinophils, which were unaffected by both active drugs. Why
cetirizine prevents the selective recruitment of eosinophils to the skin, but not to
the nasal mucosa, is unknown. A surprising finding was that both antihistamines
inhibited the increased nonspecific nasal reactivity induced by methacholine 24
Table 2 Effect of Terfenadine and Cetirizine on Nasal Symptoms After Allergen

Challenge and on Allergen-Induced Nonspecific Nasal Hyperreactivity to Methacholine
Parameter Placebo Terfenadine Cetirizine
Total nasal symptom score 4.8 ⫾ 0.63 2.2 ⫾ 0.49** 2.13 ⫾ 0.51**
Volume of nasal secretion (mL) 0.3 ⫾ 0.06 0.2 ⫾ 0.05 0.27 ⫾ 0.06
after methacholine challenge
(before allergen challenge)
Volume of nasal secretion (mL) 0.36 ⫾ 0.07 0.25 ⫾ 0.08* 0.27 ⫾ 0.05*
after methacholine challenge
(24 h after allergen challenge)
Fifteen asymptomatic subjects with allergic rhinitis were treated with terfenadine (60 mg twice daily),
cetirizine (10 mg daily), or placebo for 5 days before allergen challenge in a randomized, double-
blind, placebo-controlled trial. Methacholine challenge was performed before and 24 h after allergen
challenge for assessment of nasal hyperresponsiveness. The data are mean ⫾ SEM of 15 subjects.
*p ⬍ 0.05; **p ⬍ 0.01 compared to placebo.
Source: Ref. 65.
h after allergen challenge (Table 2). This study suggests that the allergen-induced
increase in nonspecific responsiveness is a complex phenomenon not dependent
solely on eosinophil influx into the nasal mucosa. In addition, histamine stimula-
tion of the nasal mucosa does not increase the reactivity to methacholine 24 h later
(50), suggesting that histamine released from mast cells after allergen challenge is
not responsible for increased methacholine responsiveness. Thus, the mechanism
by which these two antihistamines reduce nasal hyperresponsiveness is unrelated
to H 1-antagonist activity.
Ciprandi and colleagues investigated the antiallergic activity of cetirizine
in 20 allergic children with allergic rhinoconjunctivitis during the pollen season
(66). Cetirizine significantly reduced clinical symptoms, inflammatory cell in-
filtrates, ICAM-1 expression on nasal epithelial cells, and soluble ICAM-1
(sICAM-1) and ECP in nasal lavages (Fig. 3). In another study comparing lora-
tadine and cetirizine during natural allergen exposure, similar findings were
obtained (67). These data suggest that cetirizine has inhibitory effects on ex-
pression of adhesion molecules, and on cellular influx, as well as on eosinophil
mediators.
Even when asymptomatic, individuals who suffer from house dust mite
allergy have both conjunctival and nasal mucosal inflammation, characterized by
infiltration of inflammatory cells (eosinophils and neutrophils) and by ICAM-1
expression on epithelial cells (16). In one randomized, double-blind, placebo-
controlled, parallel study, Fasci et al. investigated the effect of 2-weeks treatment
with cetirizine on chronic, naturally occurring inflammation in 20 children, all of
whom had allergic asthma associated with mite sensitivity and had been symptom-
Figure 3 Effect of cetirizine on nasal allergic inflammation during natural pollen expo-
sure. In a double-blind, placebo-controlled, parallel design, 20 allergic children were
treated with either cetirizine (0.15 mg/kg daily) or placebo for 4 weeks during the pollen
season. Nasal lavages were performed before and after treatment. Cell counts and mediator
levels (ECP and soluble ICAM-1) were measured in nasal lavage. Expression of ICAM-
1 on nasal epithelial cells was also evaluated by a five-point rating scale. Individual data
for each parameter are shown. Compared with placebo, cetirizine significantly decreased
eosinophil counts (a), ICAM-1 positivity on nasal epithelium (b), and levels of sICAM-
1 (c) and ECP (d) in nasal lavage fluid. The solid horizontal bars represent median values.
Pre, pretreatment; post, after 4 weeks of treatment. The intragroup comparisons are shown
in the upper part of the each graph (p value, NS). NS, not significant. (From Ref. 66.)
free for at least 2 months (68). In contrast to patients treated with placebo, cetirizine-
treated children showed a significant reduction in ICAM-1 on epithelial cells in
nasal scrapings. There was also a trend to a reduction in eosinophil and neutrophil
numbers, consistent with the above finding. It can be speculated that longer treat-
ment might have diminished the inflammatory cell infiltration even further.
A soluble form of ICAM-1 (sICAM-1), thought to consist of extracellular
parts of membrane ICAM-1, has been identified in nasal lavage fluid samples of
patients with allergic rhinitis (69, 70). It is assumed to be generated by local
production in the nasal mucosa, followed by release into nasal secretions. The
cells of origin and the mechanisms for releasing the soluble components of these
adhesion molecules are unknown, but either shedding or enzymatic cleavage from
nasal epithelial cell surface could be involved (71). There is a significant correla-
tion between cell membrane expression of ICAM-1 and of sICAM-1, suggesting
that the measurement of sICAM-1 in secretions reflects the expression of ICAM-
1 at the cell-surface level (66, 72).
In a 2-week study, the effects of cetirizine (10 mg daily) and loratadine (10
mg daily) on the release of sICAM-1 in nasal secretions were compared in patients
with allergic rhinitis during the grass pollen season (73). Cetirizine and loratadine
significantly reduced the sICAM-1 released in nasal secretions, whereas the levels
in the control group of untreated patients were unchanged. In vitro evidence of
inhibitory effects of cetirizine on eosinophil adhesion on human endothelial cells
(74) and on eosinophil chemotaxis (75, 76) supports these findings.
F. Ebastine
Ebastine, a piperidine derivative, and its metabolite, carebastine, are selective
H 1-receptor antagonists devoid of any other known receptor binding (77). Camp-
bell and colleagues studied the antiallergic effect of ebastine in both in vitro and
in vivo models (78). They used nasal polyp cells to examine the effects of ebastine
on the release of LTC4 , LTD4 , and PGD2 in vitro after stimulation by anti-IgE,
and on the spontaneous release of cytokines (GM-CSF, TNF-α, and IL-8). Ebastine
at concentrations ranging from 0.1 to 10 µmol/L significantly inhibited the release
of PGD2 , LTC4 , and LTD4 in a dose-dependent manner. In addition, ebastine at
10 µmol/L significantly inhibited the release of GM-CSF, TNF-α, and IL-8.
The same investigators performed a randomized, double-blind, placebo-
controlled, crossover study comparing the antiallergic effects of ebastine (10 and
20 mg daily) and placebo on the release of inflammatory mediators after allergen
challenge in 12 asymptomatic patients with seasonal allergic rhinitis (78). They
found that ebastine dosages of 10 and 20 mg induced a significant increase in
the mean threshold number of pollen grains required to induce a positive response
compared with placebo. Ebastine significantly reduced the release of GM-CSF
in a dose-dependent manner; however, levels of LTC4 , LTD4 , PGD2 , TNF-α,
and IL-8 were not significantly affected. These data suggest that ebastine exerts
its anti-inflammatory effect by inhibiting the release of PGD2 , LTC4 , LTD4 , and
cytokines from nasal polyp cells in vitro and by decreasing the release of GM-
CSF in vivo.
G. Fexofenadine
Fexofenadine, the carboxylic acid metabolite of terfenadine, is a new second-
generation antihistamine that is nonsedating and does not cause QT prolongation.
Paolieri and colleagues evaluated the effect of fexofenadine on ICAM-1 expres-
sion of a human continuously cultured conjunctival epithelial cell line (WK) and
a fibroblast cell line (HEL) (79). They found that fexofenadine in a concentra-
tion of 50 µ/mL significantly decreased ICAM-1 basal expression on WK cells,
sICAM-1 levels in IFN-γ-stimulated WK cells, and IFN-γ-induced ICAM-1 up-
regulation on HEL. A dose-dependent decrease of spontaneous IL-6 release was
also observed. This study shows that fexofenadine exerts an anti-inflammatory
effect directly on epithelial cells and fibroblasts, reducing ICAM-1 expression
and sICAM-1.
Abdelaziz and colleagues cultured epithelial cells from nasal biopsy speci-
mens from patients with seasonal allergic rhinitis outside the pollen season and
studied the effect of fexofenadine on eosinophil-induced release of proinflamma-
tory mediators, on eosinophil chemotaxis, and on adherence to endothelial cells
in response to conditioned medium from human nasal epithelial cell (HNEC)
cultures (80). Incubation of HNECs in the presence of eosinophils significantly
increased the release of RANTES, IL-8, GM-CSF, and sICAM-1 from HNECs.
Fexofenadine treatment (10⫺9 –10⫺3 mol/L) significantly attenuated the eosino-
phil-induced release of IL-8, GM-CSF, and sICAM-1 from the HNECs. More-
over, conditioned medium from HNECs significantly altered the activity of eosin-
ophils, as indicated by increased release of ECP, and increased both eosinophil
chemotaxis and adherence to endothelial cells. Addition of 10⫺6 –10⫺3 mol/L
fexofenadine to the conditioned medium significantly decreased eosinophil che-
motaxis and adherence to endothelial cells. In vivo, fexofenadine also modulates
the release of inflammatory mediators, cytokines, and adhesion molecules.
H. Ketotifen
In addition to being a competitive (81) and noncompetitive H 1-receptor antagonist
(82), ketotifen inhibits the release of histamine from rat peritoneal mast cells
(83). It also inhibits both histamine and leukotriene release from human basophil
leukocytes stimulated by both anti-IgE and low concentrations of calcium iono-
phore A23187 (84–86). Majchel and colleagues evaluated the effect of pretreat-
ment with ketotifen (1 and 2 mg twice daily) on the early response to nasal
challenge with allergen in a double-blind, crossover trial (87). Six weekly nasal
challenges followed by lavage were performed in 10 allergic subjects after 1 h
and 1, 2, 3, and 4 weeks of ketotifen administration. The number of sneezes
decreased significantly after a single dose of drug with both the 1 and 2 mg doses.
Increasing the duration of drug administration did not improve the results. Neither
dosage significantly reduced levels of histamine and TAME-esterase activity in
recovered nasal lavages. Despite the efficacy of ketotifen in inhibiting sneezing,
it did not block the release of histamine or TAME-esterase activity during the
EPR to allergen challenge. The authors concluded that ketotifen reduces allergic
symptoms by its antihistaminic activities rather than by inhibiting histamine re-
lease from mast cells. They could not exclude the possibility that ketotifen may
selectively inhibit release of other mast cell mediators, since they did not measure
other mediators.
Kato and colleagues investigated the effect of prophylactic treatment with
ketotifen on nasal symptoms, blood eosinophil counts, and serum ECP in subjects
with allergic rhinitis before and after the pollen season (88). Ten subjects who
received ketotifen (orally 2 mg daily) for 4 weeks before the start of the pollen
season (prophylactic treatment group) and 12 subjects who began their medica-
tion 12 days after the start of the season (post-symptomatic treatment group) were
enrolled in this study. Treatment with ketotifen was maintained until the end of
the season. Total subjective symptom scores, blood eosinophil count, and serum
ECP values were significantly higher during the season than during preseason.
There were significant decreases in these three parameters in the prophylactic
treatment group compared to the post-symptomatic treatment group.
The same group of authors demonstrated that prophylactic treatment with
topical ketotifen decreased the total symptom score, blood eosinophil counts, and
serum MBP during the season compared to post-symptomatic treatment (89).
These data suggest that blood eosinophils and levels of ECP and MBP in serum
of allergic individuals were upregulated during the season, and that ketotifen’s
antiallergic properties include inhibiting eosinophil recruitment and its activation
in the blood. It is of interest that topical administration of ketotifen could reduce
blood eosinophils and serum MBP, as plasma concentrations of ketotifen are
undetectable when it is applied intranasally. The decrease in mediator release
from mast cells in the nose by ketotifen might reduce local allergic inflammation,
which subsequently suppressed the systemic allergic response (89).
I. Levocabastine
Levocabastine, a cyclohexyl piperidine derivative, is a selective H 1-receptor an-
tagonist developed for nasal and ocular administration. It is effective and well
tolerated in the treatment of allergic rhinitis (90). It has been shown to reduce
the severity of the immediate nasal response to allergen significantly when admin-
istered 5 min before the challenge, and its protective effect persists for 24 h after
administration (91).
To study the anti-inflammatory effect of levocabastine on the EPR and LPR
to nasal challenge with allergen in vivo, de Graaf and colleagues evaluated 21
house dust mite-allergic rhinitis patients in a double-blind, placebo-controlled,
two-way crossover study (92). Subjects who had EPR but no LPR on nasal chal-
lenge received either topical intranasal levocabastine (400 µg daily) or placebo
for 1 week. Levocabastine significantly reduced the symptom score, but did not
reduce albumin or tryptase levels in nasal lavage fluid or hyperresponsiveness
to methacholine. In agreement with these data, another study failed to show the
inhibition of an allergen-induced increase in albumin levels by levocabastine (400
µg daily) during the early response to nasal challenge with birch allergen extract
(93). Bachert and colleagues also demonstrated no significant differences in aller-
gen-challenge-induced increments of albumin levels in nasal secretions after
levocabastine (400 µg daily) treatment, compared to placebo (94). These findings
suggest that after allergen challenge the principal effect of levocabastine is its
H 1-antagonist effect.
In a contrasting single-blind, placebo-controlled study, the effect of 8 days
pretreatment with levocabastine (intranasally 800 µg daily) was investigated in
12 asymptomatic subjects with allergic rhinitis (95). There were significant in-
creases in albumin levels and inflammatory cells in lavage fluid after allergen
challenge in the placebo group, but not in the levocabastine-treated group (Fig.
4). Levocabastine significantly decreased nasal symptoms, albumin, and inflam-
matory cell influx (neutrophils, eosinophils, metachromatic cells) after allergen
challenge compared to placebo (Fig. 4). The differences in study population,
methods and levocabastine dosages may explain the apparent discrepancies be-
tween this study and earlier ones.
J. Loratadine
Loratadine is a tricyclic, selective H 1-receptor antagonist without anticholinergic
or sedative properties. In vitro it decreases antigen- and calcium ionophore-
induced histamine and LTC4 release from mast cell lines (96). The antiallergic
activity of loratadine may be mediated by blockade of calcium influx into the
cells (96). To study its antiallergic properties in vivo, Bousquet and colleagues
performed a three-way crossover study comparing the effect of 1-week treatment
with loratadine (10 mg daily), terfenadine (60 mg twice daily), or placebo on
mediator release during the immediate response to nasal challenge with allergen
in 14 individuals allergic to pollen (97). Both active drugs suppressed symptoms
and the release of histamine and PGD2 , suggesting that they affected mast cell
activation. Using a similar model, Andersson showed a significant reduction in
the release of histamine and TAME-esterase activity during the early allergic
Figure 4 Effect of intranasal levocabastine on nasal challenge with allergen. Twelve

asymptomatic subjects with allergic rhinitis were treated with placebo or intranasal levoca-
bastine (800 µg daily) for 8 days before nasal allergen challenge in a randomized, single-
blind, placebo-controlled, crossover study. Nasal lavages were performed 20 h before and
2 h after allergen provocation. Levels of albumin and inflammatory cells in nasal lavage
fluid were evaluated. The albumin levels (a) and the number of inflammatory cells (total
cells, eosinophils, and neutrophils) (b) in nasal lavage fluid before and 2 h after allergen
challenge are shown. The data are shown as mean ⫾ SEM. Pretreatment with levocabas-
tine significantly decreased albumin levels, total cells, eosinophils, and neutrophils com-
pared to placebo. Filled bars, levocabastine; open bars, placebo; AC, allergen challenge;
Ag, allergen; *p ⬍ 0.05 vs. placebo; †p ⬍ 0.05 vs. before AC. (From Ref. 95.)
reaction after loratadine treatment (98). These studies show that loratadine is able
to block the release of mediators during the immediate nasal allergic reaction;
however, loratadine did not significantly inhibit the histamine concentration after
allergen administration to the skin (99, 100).
In a double-blind, placebo-controlled, crossover study in 14 patients aller-
gic to ragweed or grass, loratadine (10 mg daily for 1 week before allergen chal-
lenge) markedly inhibited the sneezing response (101). Release of histamine or
PGD2 was not decreased significantly. Loratadine had some inhibitory effects on
the release of LTC4 , albumin, and kinin, but these were not statistically signifi-
cant. Baroody and colleagues performed another double-blind, placebo-con-
trolled, three-way crossover study comparing the effects of 1 week pretreatment
with loratadine, 10 mg once daily, terfenadine, 60 mg twice daily, or placebo on

the early response to nasal challenge with allergen, the subsequent cellular influx,
and the increased responsiveness to methacholine 24 h later (23). Both loratadine
and terfenadine treatment resulted in significant reductions in allergen-induced
sneezing and in the levels of histamine, kinins, albumin, and TAME-esterase
activity in recovered nasal lavage, with no significant differences between the
treatments (Fig. 5). Neither treatment decreased the levels of tryptase, PGD2 , or
LTC4. There was a significant increase in total eosinophils 24 h after allergen
challenge in the placebo group, and this was not affected by loratadine or terfena-
dine treatment. A significant increase in reactivity to methacholine, as assessed
by weights of secretions, was found 24 h after allergen challenge compared to
screening challenge, and both antihistamines prevented this. These results suggest
that loratadine may not only antagonize the effects of histamine following its
release from mast cells after the early response to nasal challenge with allergen,
but also inhibit subsequent cellular influx and allergen-induced hyperresponsive-
ness of the nasal mucosa.
Raptopoulou-Gigi and colleagues treated patients with allergic rhinitis with
either loratadine, 10 mg daily, or placebo for 1 month during a high-pollen-count
period (102). Loratadine-treated patients had significantly lower symptom scores
and, at the end of treatment, the numbers of cells expressing IL-2R, HLA-DR, and
proliferating cell nuclear antigen (PCNA) in the nasal biopsies were significantly
decreased in the loratadine-treated group. How loratadine exerted its inhibitory
effect on the activation of T cells is unknown. Furthermore, Greiff and colleagues
(103) have investigated the effect of treatment with loratadine 20 mg daily for
5 days on allergen-induced changes in the level of tryptase and α2-macroglobulin
in 12 subjects with allergic rhinitis in a randomized, double-blind, placebo-con-
trolled, crossover trial. Loratadine significantly decreased nasal symptoms as well
as the release of tryptase and α2-macroglobulin during the EPR, but did not
affect the number of eosinophils during the LPR. The reduction in both mediators
suggests that loratadine inhibits mast cell activation and modulates the permeabil-
ity of the microvasculature in the nasal mucosa.
Ciprandi and colleagues (67) conducted a randomized, double-blind, paral-
lel study in 20 seasonal allergic rhinitis subjects examining the effect of 2 weeks
treatment with loratadine 10 mg daily and cetirizine 10 mg daily on cellular
infiltration and expression of adhesion molecules after natural allergen exposure.
Loratadine and cetirizine significantly reduced symptoms, eosinophil and meta-
chromatic cell infiltration, levels of ECP and histamine in nasal lavage fluid, and
ICAM-1 expression on nasal epithelial cells compared to the pretreatment base-
line (Table 3). The reduction of ICAM-1 expression on the conjunctival epithe-
lium by loratadine was also shown in a study of allergen-specific conjunctival
challenge (104). Loratadine and its metabolite desloratadine decrease histamine-
induced expression of ICAM-1 on nasal epithelial cells in vitro significantly
Figure 5 Effects of loratadine and terfenadine on nasal challenge with allergen. In a

double-blind, placebo-controlled, three-way crossover study, 14 asymptomatic allergic in-
dividuals were treated with loratadine 10 mg daily, terfenadine 60 mg twice daily, or
placebo for 1 week. Nasal challenge and lavage were then performed. Twenty-four hours
later, the lavage was repeated, and methacholine challenge was performed to assess aller-
gen-induced increased nasal hyperresponsiveness. Mediator levels were measured in nasal
lavage fluid. The net changes from the diluent challenge for each parameter are shown
as mean ⫾ SEM. Compared with placebo, both loratadine and terfenadine significantly
decreased allergen-induced sneezing and the levels of histamine, kinins, TAME-esterase
activity, and albumin in recovered nasal lavage, with no significant differences between
the two treatments. *p ⬍ 0.05 vs. placebo; TAME, N-α-tosyl L-arginine methyl ester.
(From Ref. 23.)
Table 3 Effect of Loratadine and Cetirizine on Chronic Naturally Occurring Allergic Inflammation
Loratadine Cetirizine
Parameters Before After p value Before After p value
Clinical score 13 (11–16) 2 (0–7) 0.002 14 (11–18) 2 (0–8) 0.002

ICAM-1 positivity 2 (1–3) 0 (0–1) 0.02 2 (1–2) 0.5 (0–1) 0.01
Neutrophils 4 (2–5) 3 (1–4) NS 4 (1–5) 3 (1–4) 0.015
Eosinophils 3 (2–6) 2.5 (1–5) 0.016 3 (1–4) 2 (1–4) 0.03
Metachromatic cells 2 (1–4) 1 (1–2) 0.01 3 (1–4) 1 (1–3) 0.001

ECP (µg/L) 38.5 (30–51) 26 (15–31) 0.002 28 (19–45) 21 (16–32) 0.01
EPO (µg/L) 50 (29–63) 41 (19–58) 0.006 45 (31–61) 33 (19–55) 0.002
MPO (µg/L) 81 (50–133) 96 (52–238) NS 88 (53–137) 93 (32–144) NS
Histamine (µg/L) 0.2 (0.1–3.7) 0.1 (0–0.7) 0.01 0.1 (0.1–2.8) 0.1 (0–0.7) 0.02
In a randomized, double-blind, parallel design, 20 subjects with allergic rhinoconjunctivitis were treated with either loratadine 10 mg daily or cetirizine 10
mg daily for 2 weeks during natural allergen exposure. The parameters were compared before and after treatment. The data are presented as median (range).
Cells and mediators were measured in nasal lavage fluid. ICAM-1, intercellular adhesion molecule-1; ECP, eosinophil cationic protein; EPO, eosinophil
peroxidase; MPO, myeloperoxidase; NS, not significant.
Source: Ref. 67.
123
(105). These studies demonstrate that loratadine provides an antiallergic effect

by modulating ICAM-1 expression on epithelial cells. The different results, com-
pared with earlier studies, could be related to differences in the design, tech-
niques, and outcome measures used.
Miadonna and colleagues studied 10 subjects with allergic rhinitis due to
dust mites, who were treated with loratadine (10 mg daily) and with placebo for
1 week, in a double-blind, crossover trial (106). Subjects treated with placebo
had nasal symptoms after allergen challenge, followed by a significant increase
in histamine concentration in nasal lavage fluid collected 5 min after stimulation.
Loratadine significantly reduced allergen-induced nasal symptoms and histamine
release in the 5 min, 10 min, and 20 min postchallenge lavages (Table 4). The
results of this study are consistent with those of earlier studies (23, 97, 98). Fur-
thermore, ex vivo basophil histamine release induced by anti-IgE (10 µg/mL),
formyl methionyl leucyl phenylalanine (fMLP) (1 µm), and Ca 2⫹ ionophore
A23187 (1 µ) was reduced significantly after treatment with loratadine. The most
interesting feature is that loratadine also inhibited histamine release from baso-
phils activated by different agents. Although anti-IgE, fMLP, and Ca 2⫹ ionophore
A23187 have different mechanisms of action, they all cause an increase in intra-
cellular Ca 2⫹ concentration. A previous study has shown that one possible mecha-
Table 4 Effect of Loratadine on Histamine Levels in Early Allergic

Inflammation
Nasal lavage Placebo Loratadine p value
Prechallenge
1st 6.5 (2–25) 6.5 (2–40) NS
5th 0.5 (0–1) 0.5 (0–2) NS
Postchallenge
5 min 4 (1–28) 0.5 (0–3) ⬍0.01
10 min 0.5 (0–5) 0 (0–1) ⬍0.001
20 min 0 (0–2) 0 (0–0) ⬍0.01
30 min 0 (0–1) 0 (0–0) NS
60 min 0 (0–0) 0 (0–0) NS
Ten asymptomatic subjects with allergic rhinitis were treated with loratadine 10 mg daily
and with placebo for 1 week before allergen challenge. Nasal lavages were done before
and after challenge with the relevant allergen after each treatment period. Five nasal la-
vages were performed at 4-min intervals before allergen challenge in order to obtain low
and uniform prechallenge histamine levels (1st: first prechallenge lavage; 5th: fifth pre-
challenge lavage). Nasal lavages were repeated 5, 10, 20, 30, and 60 min after allergen
challenge. Results are histamine levels in nasal lavage fluids (ng/mL) before and after
allergen challenge. The data are median (range) for 10 subjects. NS, not significant.
Source: Ref. 106.
nism by which an antiallergic drug can inhibit histamine release is through induc-
tion of membrane stabilization (107). It is reasonable to speculate that the
inhibitory effect of loratadine on basophil histamine release is related to its effect
on membrane stabilization, transmembrane Ca 2⫹ influx, and intracellular Ca 2⫹
increase.
K. Mizolastine
Mizolastine, a novel benzimidazole derivative, is highly selective for histamine
H 1-receptors and has no anticholinergic, antiadrenergic, or antiserotoninergic ac-
tivity. At a dosage of 10 mg daily it reduces the symptoms associated with seasonal
and perennial allergic rhinitis (108, 109). Anti-inflammatory properties of mizolas-
tine were demonstrated in animal experiments (110, 111). Levrier and colleagues
studied the antiallergic activities of mizolastine in actively sensitized guinea pigs
and passively sensitized rats (110). Mizolastine significantly reduced allergen-
induced release of histamine from mast cells in bronchoalveolar lavage fluid of
guinea pigs and in the peritoneal fluid of sensitized rats. This study suggests a
potential mast cell inhibitory role for this agent in allergen-induced reactions.
Pichat and colleagues studied the effects of mizolastine, loratadine, terfena-
dine, and pyrilamine on arachidonic acid (AA)-induced edema in the rat paw
(111). Mizolastine significantly inhibited AA-induced paw inflammation in a
dose-dependent manner, whereas other antihistamines failed to inhibit the in-
flammatory action of AA. These data suggest inhibitory effects of mizolastine
on AA-induced inflammation. Mizolastine is one of the newest antihistamines
and there are few published data on its antiallergic effects in humans.
L. Oxatomide
Oxatomide is an H 1-receptor antagonist chemically related to cinnarizine, with
potent antihistaminic activity and inhibitor effects on mast cell degranulation
(112). In addition, oxatomide exerts some antiserotonin, anticholinergic activity,
and anti-slow-reacting substance of anaphylaxis (SRSA) in in vitro and in vivo
models (113). Preincubation of basophils with oxatomide (10⫺7 –10⫺5 mol/L) con-
centration dependently inhibited the immunological release of histamine and
LTC4 before anti-IgE challenge (114). Oxatomide (10⫺7 –10⫺5 mol/L) also re-
duced histamine, tryptase, and LTC4 release from human lung mast cells (HLMC)
activated by anti-IgE.
The efficacy of oxatomide (30 mg daily) in the treatment of seasonal aller-
gic rhinitis and/or conjunctivitis has been demonstrated in a double-blind,
placebo-controlled study (115).
To study the effect of 4 weeks of treatment with azelastine (orally 1 mg
twice a day) and oxatomide (orally 30 mg twice a day) on substance P (SP)
126
Table 5 In Vivo Studies of the Effect of H 1-Antihistamines on Nasal Allergic Inflammation Either After Nasal Challenge with
Allergen or During Natural Allergen Exposure
Hyperresponsiveness
Drug Early phase Late phase in vivo
Azatadine
Togias et al. (39) NCA ↓ Histamine, TAME-esterase, NE NE
kinin
Azelastine
(Intranasal)
Pelucchi et al. (57) NAE No effect: eosinophils —
Ciprandi et al. (54) NCA ↓ Neutrophils, eosinophils, ICAM- ↓ ECP in nasal lavage, neutro- NE
1 expression on nasal epithelial phils, eosinophils, ICAM-1 ex-
cells pression on nasal epithelial cells
Jacobi et al. (59) NCA ↓ Histamine, tryptase NE NE
Cetirizine
Naclerio et al. (60) NCA ↓ TAME-esterase, LTC 4 , albumin NE NE
No effect: histamine, PGD 2
Klementsson et al. (65) NCA NE No effect: eosinophils ↓ increased nonspe-
cific hyperreactiv-
ity to metha-
choline
Ciprandi et al. (68) NAE ↓ ICAM-1 expression on nasal epi- — —
thelial cells
Ciprandi et al. (66) NAE ↓ Neutrophils, eosinophils, ICAM- — —
1 expression on nasal epithelial
cells, sICAM-1, ECP
Assanasen and Naclerio
Campbell et al. (73) NAE ↓ sICAM-1 — —
Ciprandi et al. (67) NAE ↓ Eosinophils, neutrophils, meta- — —
chromatic cells, ICAM-1 expres-
sion on nasal epithelial cells,
ECP, EPO, histamine
Jacobi et al. (59) NCA ↓ Histamine, tryptase NE NE
Ebastine
Campbell et al. 1996 (78) NCA No effect: LTC 4 , LTD 4 , PGD 2 , ↓ GM-CSF -No effect: LTC 4 , NE
GM-CSF, TNF-α, IL-8 LTD 4 , PGD 2 , TNF-α, IL-8
Ketotifen
Majchel et al. (87) NCA No effect: TAME-esterase, his- NE NE
tamine
Kato et al. (88) NAE ↓ Blood eosinophil count, serum — —
ECP
Kato et al. (89) NAE — —
↓ Blood eosinophil count, serum

MBP
Levocabastine
(Intranasal)
Padgrak et al. (95) NCA NE ↓ albumin, neutrophils, eosino- NE
phils, metachromatic cells
Bachert et al. (94) NCA No effect: albumin NE NE
de Graaf et al. (92) NCA No effect: albumin, tryptase NE No effect
Svensson et al. (93) NCA No effect: albumin NE NE
Loratadine
Bousquet et al. (97) NCA ↓ Histamine, PGD 2 NE NE
Andersson et al. (98) NCA ↓ Histamine, TAME-esterase NE No effect
Naclerio et al. (101) NCA No effect: histamine, PGD 2 , NE NE
LTC 4 , albumin, kinin
Raptopoulou et al. (102) NAE ↓ IL-2R, HLA-DR, PCNA posi- — —
127
tive cells
128
Table 5 (Continued)
Hyperresponsiveness
Drug Early phase Late phase in vivo
Greiff et al. (103) NCA ↓ Tryptase, α2-macroglobulin No effect: eosinophils NE

Baroody et al. (23) NCA ↓ Histamine, kinin, albumin, No effect: eosinophils ↓ increased nonspe-
TAME-esterase cific hyperreactiv-
ity to metha-
choline
No effect: tryptase, PGD 2 , LTC 4
Ciprandi et al. (67) NAE ↓ Eosinophils, metachromatic — —
cells, ICAM-1 expression on na-
sal epithelial cells, ECP, EPO,
histamine
Campbell et al. (73) NAE ↓ sICAM-1 — —
Miadonna et al. (106) NCA ↓ Histamine NE NE
Oxatomide
Shinoda et al. (121) NAE ↓ SP — —
NCA, nasal challenge with allergen; NAE, natural allergen exposure; NE, not evaluated; IL, interleukin; LT, leukotriene; TAME, N-alpha-tosyl-L-arginine
methyl ester; GM-CSF, granulocyte macrophage colony-stimulating factor; ECP, eosinophil cationic protein; ICAM-1, intercellular adhesion molecule-1;
SP, substance P; sICAM-1, soluble intercellular adhesion molecule-1; EPO, eosinophil peroxidase; TNF, tumor necrosis factor; PG, prostaglandin; MBP,
major basic protein; HLA-DR, human leukocyte antigen-DR.
Assanasen and Naclerio
and vasoactive intestinal peptide (VIP) levels in nasal secretions, Shinoda and
colleagues performed a randomized, double-blind, parallel study in 40 subjects
with house dust allergy and 210 healthy subjects (116). Mean values of SP, but
not VIP, were significantly higher in the nasal allergy group than in the control
group. Patients with severe symptoms had significantly higher levels of SP and
VIP in nasal secretions than those in the control group. Oxatomide and azelastine
significantly reduced SP levels in nasal secretions, and VIP levels were sup-
pressed by 70%, although this did not achieve statistical significance.
The mechanism by which oxatomide decreases neuropeptides in nasal se-
cretions is unknown. Eosinophils from human peripheral blood were demon-
strated to contain significantly higher levels of SP and VIP than did neutrophils,
mononuclear leukocytes, and platelets (117). One possible mechanism for the
decrease of the neuropeptides in nasal secretions after oxatomide administration
might be the reduction of eosinophil infiltration into nasal secretions. This hy-
pothesis is supported by the study of Ciprandi and colleagues (118). Using
allergen-specific conjunctival challenge, they demonstrated that oxatomide sig-
nificantly decreased total numbers of inflammatory cells as well as the number
of single cell types (neutrophils, eosinophils, and lymphocytes) during the early-
and late-phase reactions.
M. Terfenadine
From an historical point of view, terfenadine was one of the first H 1-antagonists
to be investigated for antiallergic properties, and was one of the most compre-
hensively studied. Rarely, it caused cardiac toxicity, and regulatory approval
was withdrawn for it in most countries. In addition to its H 1-receptor antagonist
effects it also inhibits the anti-IgE-induced release of histamine, LTC4 , and PGD2
from human lung mast cells in vitro (119). After allergen challenge in subjects
with allergic rhinitis, pretreated with terfenadine, the following have been re-
ported: reduced symptoms, decreased histamine, kinins, albumin and TAME-
esterase activity, decreased inflammatory cell infiltrates and ICAM-1 expression
on nasal epithelial cells, and ECP in lavage fluid (120–125).
V. SUMMARY
Data from in vitro, in vivo, and ex vivo studies suggest that second-generation
antihistamines have a number of antiallergic, anti-inflammatory properties that
appear to be independent of their H 1-blockade activity. First-generation antihista-
mines also have antiallergic, anti-inflammatory properties, as suggested by the
studies with azatadine, chlorpheniramine, mepyramine, and promethazine; most
other first-generation antihistamines have not been studied for these properties.
In vitro studies have shown that H 1-antihistamines reduce the release of pro-
inflammatory mediators from mast cells and basophils, the chemotaxis and ac-
tivation of inflammatory cells (especially eosinophils), and the expression of
adhesion molecules induced by immunological and nonimmunological stimuli in
epithelial cell lines. Nasal allergen challenge models have similarly demonstrated
that H 1-antihistamines inhibit mediator release from mast cells and basophils, and
that they decrease inflammatory cell infiltration and the expression of adhesion
molecules on epithelial cells. The results of published studies of the effects of
H 1-antihistamines on nasal allergic inflammation in humans have been summa-
rized in this chapter. Recent investigations indicate that H 1-antihistamines may
modulate airway inflammation by downregulating the activity of airway epithelial
cells, which have an important role in allergic airway inflammation. The modula-
tion of adhesion molecules and of inflammatory cell infiltration by H 1-antihista-
mines may be beneficial during long-term treatment in patients with allergic rhini-
tis. The rationale for this hypothesis is the persistence of inflammation on the
nasal epithelial cells even when patients are symptom-free (16). All of the events
affected by H 1-antihistamines are important in the allergic inflammation cascade.
The underlying mechanisms for such effects remain unclear, but are unrelated
to H 1-antagonist activity. Several studies have demonstrated that H 1-antihista-
mines can form an ionic association with cell membranes and inhibit calcium
ion influx into the mast cell or basophil plasma membrane, or inhibit Ca 2⫹ release
within the cells, and may therefore influence the signal transduction pathways.
However, these effects appear to occur at concentrations higher than those
achieved in therapeutic practice (126–128). It has recently been hypothesized
that the anti-inflammatory activity of H 1-antihistamines may be a consequence
of their ability to influence the activation of genes responsible for the expression
and synthesis of proinflammatory mediators (129).
The contribution of the antiallergic effects of H 1-receptor antagonists to
their clinical efficacy is not fully understood. There have been no data suggesting
that H 1-antihistamines with well-documented antiallergic properties are superior
to the others for which such properties have not been as extensively investigated.
Additional studies are needed to elucidate the mechanisms(s) by which H 1-anti-
histamines exert anti-inflammatory effects. This knowledge might lead to the
development of novel therapies with more potent and specific anti-inflammatory
effects.
ACKNOWLEDGMENTS
This work was supported in part by NIH grant DC 02714 and Anandamahidol
King Scholarship.
REFERENCES
1. Slater JW, Zechnich AD, Haxby DG. Second-generation antihistamines: a compar-

ative review. Drugs 1999; 57:31–47.
2. Tada T, Ishizaka K. Distribution of gamma E-forming cells in lymphoid tissues of
the human and monkey. J Immunol 1970; 104:377–387.
3. Grangette C, Gruart V, Ouaissi MA, Rizvi F, Delespesse G, Capron A, Capron M.
IgE receptor on human eosinophils (FCεRII): comparison with B cell CD23 and
association with an adhesion molecule. J Immunol 1989; 143:3580–3588.
4. Melewicz FM, Spiegelberg HL. Fc receptors for IgE on a subpopulation of human
peripheral blood monocytes. J Immunol 1980; 125:1026–1031.
5. Cines DB, van der Keyl H, Levinson AI. In vitro binding of an IgE protein to
human platelets. J Immunol 1986; 136:3433–3440.
6. Gomez E, Corrado OJ, Baldwin DL, Swanston AR, Davies RJ. Direct in vivo evi-
dence for mast cell degranulation during allergen-induced reactions in man. J Al-
7. Iliopoulos O, Proud D, Adkinson NF Jr, Norman PS, Kagey-Sobotka A, Lich-
tenstein LM, Naclerio RM. Relationship between the early, late, and rechallenge
reaction to nasal challenge with antigen: observations on the role of inflammatory
mediators and cells. J Allergy Clin Immunol 1990; 86:851–861.
8. Lim MC, Taylor RM, Naclerio RM. The histology of allergic rhinitis and its com-
parison to cellular changes in nasal lavage. Am J Respir Crit Care Med 1995; 151:
136–144.
9. Naclerio RM, Proud D, Togias AG, Adkinson NF Jr, Meyers DA, Kagey-Sobotka
A, Plaut M, Norman PS, Lichtenstein LM. Inflammatory mediators in the late anti-
gen-induced rhinitis. N Engl J Med 1985; 313:65–70.
10. Bradding P, Feather IH, Howarth PH, Mueller R, Roberts JA, Britten K, Bews
JPA, Hunt TC, Okayama Y, Heusser CH, Bullock GR, Church MK, Holgate ST.
Interleukin-4 is localized to and released by human mast cells. J Exp Med 1992;
176:1381–1386.
11. Howarth PH. The cellular basis for allergic rhinitis. Allergy 1995; 50(suppl 23):
6–10.
12. Naclerio RM. Pathophysiology of perennial allergic rhinitis. Allergy 1997;
52(suppl 36):7–13.
13. Papi A. Epithelial ICAM-1 regulation and its role in allergy. Clin Exp Allergy
1997; 27:721–724.
14. Ciprandi G, Pronzato C, Ricca V, Bagnasco M, Canonica GW. Evidence of intercel-
lular adhesion molecule-1 expression on nasal epithelial cells in acute rhinoconjunc-
tivitis caused by pollen exposure. J Allergy Clin Immunol 1994; 94:738–746.
15. Ciprandi G, Pronzato C, Ricca V, Passalacqua G, Bagnasco M, Canonica GW.
Allergen-specific challenge induces intercellular adhesion molecule-1 (ICAM-1 or
CD54) on nasal epithelial cells in allergic subjects. Relationships with early and
late inflammatory phenomena. Am J Respir Crit Care Med 1994; 150:1653–1659.
16. Ciprandi G, Buscaglia S, Pesce G, Pronzato C, Ricca V, Parmiani S, Bagnasco M,
Canonica GW. Minimal persistent inflammation is present at the mucosal level in
patients with asymptomatic rhinitis and mite allergy. J Allergy Clin Immunol 1995;
96:971–979.
17. Tosi MF, Stark JM, Smith CW, Hamedani A, Gruenert DC, Infeld MD. Induction
of ICAM-1 expression on human airway epithelial cells by inflammatory cytokines:
effects on neutrophil-epithelial cell adhesion. Am J Respir Cell Mol Biol 1992; 7:
214–221.
18. Rothlein R, Czajkowski M, O’Neill MM, Marlin SD, Mainolfi E, Merluzzi VJ.
Induction of intercellular adhesion molecule-1 on primary and continuous cell lines
by pro-inflammatory cytokines: regulation by pharmacologic agents and neutraliz-
ing antibodies. J Immunol 1988; 141:1665–1669.
19. Altman LC, Ayars GH, Baker C, Luchtel DL. Cytokines and eosinophil-derived
cationic proteins upregulate intercellular adhesion molecule-1 on human nasal epi-
thelial cells. J Allergy Clin Immunol 1993; 92:527–536.
20. Walden SM, Proud D, Lichtenstein LM, Kagey-Sobotka A, Naclerio RM. Antigen-
provoked increase in histamine reactivity: observations on mechanisms. Am Rev
Respir Dis 1991; 144:642–648.
21. Klementsson H, Andersson M, Baumgarten CR, Venge P, Pipkorn U. Changes
in non-specific nasal reactivity and eosinophil influx and activation after allergen
challenge. Clin Exp Allergy 1990; 20:539–547.
22. Klementsson H, Svensson C, Andersson M, Venge P, Pipkorn U, Persson CG.
Eosinophils, secretory responsiveness and glucocorticoid-induced effects on the na-
sal mucosa during weak pollen season. Clin Exp Allergy 1991; 21:705–710.
23. Baroody FM, Lim MC, Proud D, Kagey-Sobotka A, Lichtenstein LM, Naclerio
RM. Effects of loratadine and terfenadine on the induced nasal allergic reaction.
Arch Otolaryngol Head Neck Surg 1996; 122:309–316.
24. Naclerio RM, Meier HL, Kagey-Sobotka A, Adkinson NF Jr, Meyers DA, Norman
PS, Lichtenstein LM. Mediator release after nasal airway challenge with allergen.
Am Rev Respir Dis 1983; 128:597–602.
25. Andersson M, Greiff L, Svensson C, Persson C. Various methods for testing nasal
responses in vivo: a critical review. Acta Otolaryngol Stockh 1995; 115:705–713.
26. Baroody FM, Wagenmann M, Naclerio RM. Comparison of the secretory response
of the nasal mucosa to methacholine and histamine. J Appl Physiol 1993; 74:2661–
2671.
27. Spector SL. The placebo effect is nothing to sneeze at. J Allergy Clin Immunol
1992; 90:1042–1043.
28. Cole P. Rhinomanometry 1988: practice and trends. Laryngoscope 1989; 99:311–
315.
29. Pirila T, Talvisara A, Alho OP, Oja H. Physiological fluctuations in nasal resistance
may interfere with nasal monitoring in the nasal provocation test. Acta Otolaryngol
(Stockh) 1997; 117:596–600.
30. Clement PAR, Hirsch C. Rhinomanometry: a review. Otol Rhinol Laryngol 1984;
46:173–191.
31. Graf P, Juto JE. Correlation between objective nasal mucosal swelling and esti-
mated stuffiness during long-term use of vasoconstrictors. Otol Rhinol Laryngol
1994; 56:334–339.
32. Kaulbach HC, White MV, Igarashi Y, Hahn BK, Kaliner MA. Estimation of nasal
epithelial lining fluid using urea as a marker. J Allergy Clin Immunol 1993; 92:
457–465.
33. Lau HY, Tsang CW, Wong PP. Effects of acrivastine, azelastine, cetirizine and
noberastine on rat peritoneal mast cells. Inflamm Res 1995; 44(suppl 1):S30–31.
34. Hoshiko K, Chapman ID, Morley J. Histamine (H 1) antagonists and airway hyper-
reactivity in the guinea pig. Agents Actions 1991; 34(suppl):323–333.
35. Frieri M, Madden J, Zitt M, Kumar NS, Knapik M. Late phase inflammation during
nasal grass and ragweed challenge in a double-blind, placebo-controlled trial with
astemizole. Am J Rhinol 1995; 9:169–173.
36. Kumar NS, Schaefer PA, Lark G, Frieri M. Late phase response during nasal chal-
lenge: effect of astemizole on leukotriene B4 levels. Allergy Asthma Proc 1996;
17:93–99.
37. Katelaris C. Comparative effects of loratadine and azatadine in the treatment of
seasonal allergic rhinitis. Asian Pac J Allergy Immunol 1990; 8:103–107.
38. Lichtenstein LM, Gillespie E. The effects of the H 1- and H 2-antihistamines on ‘‘al-
lergic’’ histamine release and its inhibition by histamine. J Pharmacol Exp Ther
1975; 192:441–450.
39. Togias AG, Naclerio RM, Warner J, Proud D, Kagey-Sobotka A, Nimmagadda I,
Norman PS, Lichtenstein LM. Demonstration of inhibition of mediator release from
human mast cells by azatadine base: in vivo and in vitro evaluation. JAMA 1986;
255:225–229.
40. Hamasaki Y, Shafigeh M, Yamamoto S, Sato R, Zaitu M, Muro E, Kobayashi I,
Ichimaru T, Tasaki H, Miyazaki S. Inhibition of leukotriene synthesis by azelastine.
Ann Allergy Asthma Immunol 1996; 76:469–475.
41. Little MM, Casale TB. Azelastine inhibits IgE-mediated human basophil histamine
release. J Allergy Clin Immunol 1989; 83:862–865.
42. Morita M, Ohshima Y, Akutagawa H, Uenoyama Y, Nambu M, Mayumi M, Mi-
kawa H. Inhibitory effects of azelastine hydrochloride on Ca 2⫹ influx, actin poly-
merization and release of eosinophil cationic protein of an eosinophilic leukemia
cell line EoL-1. Curr Med Res Opin 1993; 13:163–174.
43. Fields DA, Pillar J, Diamantis W, Perhach JL Jr, Sofia RD, Chand N. Inhibition
by azelastine of nonallergic histamine release from rat peritoneal mast cells. J Al-
44. Chand N, Pillar J, Diamantis W, Perhach JL Jr, Sofia RD. Inhibition of calcium
ionophore (A23187)-stimulated histamine release from rat peritoneal mast cells by
azelastine: implications for its mode of action. Eur J Pharmacol 1983; 96:227–233.
45. Little MM, Wood DR, Casale TB. Azelastine inhibits stimulated histamine release
from human lung tissue in vitro but does not alter cyclic nucleotide content. Agents
Actions 1989; 28:16–21.
46. Shin M-H, Baroody FM, Proud D, Kagey-Sobotka A, Lichtenstein LM, Naclerio
RM. The effect of azelastine on the early allergic response. Clin Exp Allergy 1992;
22:289–295.
47. Daniels C, Temple DM. The inhibition by azatadine of the immunological release
of leukotrienes and histamine from human lung fragments. Eur J Pharmacol 1986;
123:463–465.
48. Chand N, Diamantis W, Sofia RD. Modulation of in vitro anaphylaxis of guinea
pig isolated tracheal segments by azelastine, inhibitors of arachidonic acid metabo-

lism, and selected antiallergic drugs. Br J Pharmacol 1986; 87:443–448.
49. Achterrath-Tuckermann U, Simmet T, Luck W, Szelenyi I, Peskar BA. Inhibition
of cysteinyl-leukotriene production by azelastine and its biological significance.
50. Majchel AM, Proud D, Hubbard WC, Naclerio RM. Histamine stimulation of the
nasal mucosa does not induce prostaglandin or leukotriene generation or induce
methacholine hyperresponsiveness. Int Arch Allergy Appl Immunol 1991; 95:149–
155.
51. Finkelman FD, Urban JF Jr, Beckmann MP, Schooley KA, Holmes JM, Katona
IM. Regulation of murine in vivo lgG and lgE responses by a monoclonal anti-IL-
4 receptor antibody. Int Immunol 1991; 3:599–607.
52. Paul WE. Interleukin-4: a prototypic immunoregulatory lymphokine. Blood 1991;
77:1859–1870.
53. Ito H, Nakamura Y, Takagi S, Sakai K. Effects of azelastine on the level of serum
interleukin-4 and soluble CD23 antigen in the treatment of nasal allergy. Arzneim-
Forsch Drug Res 1998; 48:1143–1147.
54. Ciprandi G, Pronzato C, Passalacqua G, Ricca V, Grögen J, Mela GS, Varese P,
55. Ciprandi G, Ricca V, Passalacqua G, Truffelli T, Bertolini C, Fiorino N, Ricco
AM, Bagnasco M, Canonica GW. Seasonal rhinitis and azelastine: long- or short-
term treatment? J Allergy Clin Immunol 1997; 99:301–307.
56. Ciprandi G, Buscaglia S, Catrullo A, Pesce G, Fiorino N, Montagna P, Bagnasco
M, Canonica GW. Azelastine eye drops reduce and prevent allergic conjunctival
reaction and exert anti-allergic activity. Clin Exp Allergy 1997; 27:182–191.
57. Pelucchi A, Chiapparino A, Mastropasqua B, Marazzini L, Hernandez A, Foresi
A. Effect of intranasal azelastine and beclomethasone dipropionate on nasal
symptoms, nasal cytology, and bronchial responsiveness to methacholine in aller-
gic rhinitis in response to grass pollens. J Allergy Clin Immunol 1995; 95:
515–523.
58. Altman LC, Ayars GH, Baker C, Luchtel DL. Cytokines and eosinophil-derived
cationic proteins upregulate intercellular adhesion molecule-1 on human nasal epi-
thelial cells. J Allergy Clin Immunol 1993; 92:527–536.
59. Jacobi HH, Skov PS, Poulsen LK, Malling H-J, Mygind N. Histamine and tryptase
in nasal lavage fluid after allergen challenge: effect of 1 week of pretreatment with
intranasal azelastine or systemic cetirizine. J Allergy Clin Immunol 1999; 103:768–
772.
60. Naclerio RM, Proud D, Kagey-Sobotka A, Freidhoff L, Norman PS, Lichtenstein
LM. The effect of cetirizine on early allergic response. Laryngoscope 1989; 99:
596–599.
61. Wood-Baker R, Lau L, Howarth PH. Histamine and the nasal vasculature: the in-
fluence of H 1- and H 2-histamine receptor antagonism. Clin Otolaryngol 1996; 21:
348–352.
62. Michel L, De Vos C, Rihoux J-P, Burtin C, Benveniste J, Dubertret L. Inhibitory
effect of oral cetirizine on in vivo antigen-induced histamine and PAF-acether re-

lease and eosinophil recruitment in human skin. J Allergy Clin Immunol 1988; 82:
101–109.
zine on mast cell mediator release and cellular traffic during the cutaneous late-
64. Redier H, Chanez P, De Vos C, Rifai N, Clauzel AM, Michel F-B, Godard P.
Inhibitory effect of cetirizine on the bronchial eosinophil recruitment induced by
allergen inhalation challenge in allergic patients with asthma. J Allergy Clin Immu-
nol 1992; 90:215–224.
65. Klementsson H, Andersson M, Pipkorn U. Allergen-induced increase in non-spe-
cific nasal reactivity is blocked by antihistamines without a clear-cut relationship
to eosinophil influx. J Allergy Clin Immunol 1990; 86:466–472.
67. Ciprandi G, Pronzato C, Ricca V, Passalacqua G, Danzig M, Canonica GW. Lora-
tadine treatment of rhinitis due to pollen allergy reduces epithelial ICAM-1 expres-
sion. Clin Exp Allergy 1997; 27:1175–1183.
Immunol 1996; 109:272–276.
69. Kato M, Hattori T, Kitamura M, Beppu R, Yanagita N, Nakashima I. Soluble
ICAM-1 as a regulator of nasal allergic reaction under natural allergen provocation.
70. Kato M, Hattori T, Matsumoto Y, Nakashima I. Dynamics of soluble adhesion
molecule levels in patients with pollinosis. Arch Otolaryngol Head Neck Surg 1996;
122:1398–1400.
71. Canonica GW, Ciprandi G, Buscaglia S, Pesce G, Bagnasco M. Adhesion mole-
cules of allergic inflammation: recent insights into their functional roles. Allergy
1994; 49:135–141.
72. Budnik A, Grewe M, Gyufko K, Krutmann J. Analysis of the production of soluble
ICAM-1 molecules by human cells. Exp Hematol 1996; 24:352–359.
ICAM-1 levels in nasal secretions by H 1-blockers in seasonal allergic rhinitis. Al-
lergy 1997; 52:1022–1025.
74. Kyan-Aung U, Hallsworth M, Haskard D, De Vos C, Lee TH. The effects of cetiri-
zine on the adhesion of human eosinophils and neutrophils to cultured human um-
bilical vein endothelial cells. J Allergy Clin Immunol 1992; 90:270–272.
75. Sehmi R, Walsh GM, Hartnell A, Barkans J, North J, Kay AB, Moqbel R. Modula-
tion of human eosinophil chemotaxis and adhesion by anti-allergic drugs in vitro.
Pediatr Allergy Immunol 1993; 4(suppl 4):13–18.
76. Leprevost C, Capron M, De Vos C, Tomassini M, Capron A. Inhibition of eosino-
phil chemotaxis by a new antiallergic compound (cetirizine). Int Arch Allergy Appl
Immunol 1988; 87:9–13.
78. Campbell A, Michel FB, Bremard-Oury C, Crampette L, Bousquet J. Overview of
allergic mechanisms: ebastine has more than an antihistamine effect. Drugs 1996;
52(suppl 1):15–19.
79. Paolieri F, Battifora M, Riccio AM, Bertolini C, Cutolo M, Bloom M, Ciprandi G,
Canonica GW, Bagnasco M. Terfenadine and fexofenadine reduce in vitro ICAM-1
expression on human continuous cell lines. Ann Allergy Asthma Immunol 1998;
81:601–607.
80. Abdelaziz MM, Devalia JL, Khair OA, Bayram H, Prior AJ, Davies RJ. Effect of
fexofenadine on eosinophil-induced changes in epithelial permeability and cytokine
release from nasal epithelial cells of patients with seasonal allergic rhinitis. J Al-
81. Trzeciakowski JP, Mendelsohn N, Levi R. Antihistamines. In: Middleton E, Reed
C, Ellis E, Adkinson NF Jr, Yunginger JW, eds. Allergy: Principles and Practice.
St Louis: CV Mosby, 1988:723–725.
82. Rafferty P, Holgate ST. Histamine and its antagonists in asthma. J Allergy Clin
Immunol 1989; 84:144–151.
83. Martin M, Romer D. Anti-anaphylactic properties of ketotifen in animal experi-
ments. Triangle 1978; 17:141–147.
84. Tomioka H, Yoshida S, Tanaka M, Kumagai A. Inhibition of chemical mediator
release from human leukocytes by a new antiasthma drug HC20-511 (ketotifen).
Monogr Allergy 1979; 14:313–317.
85. Radermecker M. Inhibition of allergen-mediated histamine release from human
cells by ketotifen and oxatomide: comparison with other H 1-antihistamines. Respi-
ration 1981; 41:45–55.
86. Wilhelms OH. Inhibition profiles of picumast and ketotifen on the in vitro release
of prostanoids, slow-reacting substances of anaphylaxis, histamine, and enzyme
from human leukocytes and rat alveolar macrophages. Int Arch Allergy Appl Im-
munol 1987; 82:547–549.
87. Majchel AM, Proud D, Kagey-Sobotka A, Lichtenstein LM, Naclerio RM. Ketoti-
fen reduces sneezing but not histamine release following nasal challenge with anti-
gen. Clin Exp Allergy 1990; 20:701–705.
88. Kato M, Hattori T, Takahashi M, Yanagita N, Nakashima I. Eosinophil cationic
protein and prophylactic treatment in pollinosis in natural allergen provocation. Br
J Clin Pract 1994; 48:299–301.
89. Kato M, Hattori T, Kitamura M, Beppu R, Yanagita N, Nakashima I. Major basic
protein and topical administration of ketotifen in pollinosis under natural allergen
provocation. Otol Rhinol Laryngol 1995; 57:269–272.
90. Hampel FC Jr, Martin BG, Dolen J, Travers S, Karcher K, Holton D. Efficacy and
safety of levocabastine nasal spray for seasonal allergic rhinitis. Am J Rhinol 1999;
13:55–62.
91. Corren J, Rachelefsky G, Spector S, Schanker H, Siegel S, Holton D, Karcher K,
Travers S. Onset and duration of action of levocabastine nasal spray in atopic patients
under nasal challenge conditions. J Allergy Clin Immunol 1999; 103:574–580.
92. de Graaf-in’t Veld T, Garrelds IM, van Toorenenbergen AW, Mulder PG, Gerth
van Wijk R, Boegheim JP. Effect of topical levocabastine on nasal response to

allergen challenge and nasal hyperreactivity in perennial rhinitis. Ann Allergy
93. Svensson C, Andersson M, Greiff L, Blychert LO, Persson CG. Effects of topical
budesonide and levocabastine on nasal symptoms and plasma exudation responses
in seasonal allergic rhinitis. Allergy 1998; 53:367–374.
94. Bachert C, Wagenmann M, Vossen-Holzenkamp S. Intranasal levocabastine pro-
vides fast and effective protection from nasal allergen challenge. Rhinology 1996;
34:140–143.
95. Pazdrak K, Gorski P, Ruta U. Inhibitory effect of levocabastine on allergen-induced
increase of nasal reactivity to histamine and cell influx. Allergy 1993; 48:598–
601.
96. Kreutner W, Chapman RW, Gulbenkian A, Siegel MI. Antiallergic activity of lora-
tadine, a non-sedating antihistamine. Allergy 1987; 42:57–63.
97. Bousquet J, Lebel B, Chanal I, Morel A, Michel FB. Antiallergic activity of H 1-
82:881–887.
98. Andersson M, Nolte H, Baumgarten C, Pipkorn U. Suppressive effect of loratadine
on allergen-induced histamine release in the nose. Allergy 1991; 46:540–546.
99. Roquet A, Raud J, Hallden G, van Hage-Hamsten M, Hed J, Hansson LO, Zetter-
strom O, Gronneberg R. Effects of loratadine on anti-IgE-induced inflammation,
histamine release, and leukocyte recruitment in skin of atopics. Allergy 1995; 50:
414–420.
100. Perzanowska M, Malhotra D, Skinner SP, Rihoux JP, Bewley AP, Petersen LJ,
Church MK. The effect of cetirizine and loratadine on codeine-induced histamine
release in human skin in vivo assessed by cutaneous microdialysis. Inflamm Res
1996; 45:486–490.
101. Naclerio RM. Effects of antihistamines on inflammatory mediators. Ann Allergy
1993; 71:292–295.
102. Raptopoulou-Gigi M, Ilonidis G, Orphanou-Koumerkeridou H, Preponis C, Sidiro-
poulos J, Lazaridis T, Goulis G. The effect of loratadine on activated cells of the
nasal mucosa in patients with allergic rhinitis. J Investig Allergol Clin Immunol
1993; 3:192–197.
103. Greiff L, Persson CGA, Svensson C, Enander I, Andersson M. Loratadine reduces
allergen-induced mucosal output of α2-macroglobulin and tryptase in allergic rhini-
105. Vignola AM, Crampette L, Mondain M, Sauvere G, Czarlewski W, Bousquet J,
Campbell AM. Inhibitory activity of loratadine and descarboethoxyloratadine on
expression of ICAM-1 and HLA-DR by nasal epithelial cells. Allergy 1995; 50:
200–203.
106. Miadonna A, Cottini M, Milazzo N, Tosi D, Danzig M, Tedeschi A. In vivo and
ex vivo inhibitory effects of loratadine on histamine release in patients with allergic
rhinitis. Allergy 1998; 53:1183–1188.
107. Akagi M, Mio M, Tasaka K. Histamine release inhibition and prevention of the
decrease in membrane fluidity induced by certain anti-allergic drugs: analysis of

the inhibitory mechanism of NCO-650. Agents Actions 1983; 13:149–156.
nol 1996; 76:163–168.
1996; 34:101–104.
110. Levrier J, Duval D, Prouteau M, Voltz C, Berry CN, Lloyd KG, Scatton B. Anti-
anaphylactic activity of the novel selective histamine H 1 receptor antagonist mizo-
lastine in the rodent. Arzneim-Forsch Drug Res 1995; 45:559–568.
administration on arachidonic acid-induced cutaneous reaction in the rat. Arzneim-
Forsch Drug Res 1998; 48:173–178.
112. Church MK, Gradidge CF. Oxatomide: inhibition and stimulation of histamine re-
lease from human lung and leukocytes in vitro. Agents Action 1980; 10:4–7.
113. Richards DM, Brogden RN, Heel RC, Speight TM, Avery GS. Oxatomide. A re-
view of its pharmacodynamic properties and therapeutic efficacy. Drugs 1984; 27:
210–231.
114. Patella V, de Crescenzo G, Marino O, Spadaro G, Genovese A, Marone G. Oxatom-
ide inhibits the release of proinflammatory mediators from human basophils and
mast cells. Int Arch Allergy Immunol 1996; 111:23–29.
115. Wood SF, Barber JH. Oxatomide in the management of hay fever—a placebo-
controlled, double-blind study in general practice. Clin Allergy 1981; 11:491–497.
116. Shinoda M, Watanabe N, Suko T, Mogi G, Takeyama M. Effects of anti-allergic
drugs on substance-P and vasoactive intestinal peptide in nasal secretions. Am J
Rhinol 1997; 11:237–241.
117. Aliakbari J, Sreedharan SP, Turck CW, Goetzl EJ. Selective localization of vaso-
active intestinal peptide and substance P in human eosinophils. Biochem Biophys
Res Commun 1987; 148:1440–1445.
119. de Weck AL, Derer T, Bischoff SC, Takafugi S. The effect of terfenadine on the
immediate and late-phase reactions mediated by immunoglobulin E. Int Arch Al-
lergy Immunol 1993; 101:326–332.
Respir Dis 1990; 142:167–171.
121. Wagenmann M, Baroody FM, Kagey-Sobotka A, Lichtenstein LM, Naclerio RM.
The effect of terfenadine on unilateral nasal challenge with allergen. J Allergy Clin
Immunol 1994; 93:594–605.
122. Ciprandi G, Pronzato C, Ricca V, Varese P, Del Giacco GS, Canonica GW. Terfen-
adine exerts antiallergic activity reducing ICAM-1 expression on nasal epithelial
cells in patients with pollen allergy. Clin Exp Allergy 1995; 25:871–878.

124. Bradding P, Feather IH, Wilson S, Bardin PG, Heusser CH, Holgate ST, Howarth
PH. Immunolocalization of cytokines in the nasal mucosa of normal and perennial
rhinitic subjects: the mast cell as a source of IL-4, IL-5, and IL-6 in human allergic
mucosal inflammation. J Immunol 1993; 151:3853–3865.
125. Thornhill MH, Haskard DO. IL-4 regulates endothelial cell activation by IL-1, tu-
mor necrosis factor, or IFN-γ. J Immunol 1990; 145:865–872.
126. Middleton E Jr, Ferriola P, Drzewiecki G, Sofia RD. The effect of azelastine and
some other antiasthmatic and antiallergic drugs on calmodulin and protein kinase
C. Agents Actions 1989; 28:9–15.
127. Letari O, Miozzo A, Folco G, Belloni PA, Sala A, Rovati GE, Nicosia S. Effects
of loratadine on cytosolic Ca 2⫹ levels and leukotriene release: novel mechanisms
of action independent of the anti-histamine activity. Eur J Pharmacol 1994; 266:
219–227.
128. Fischer MJ, Paulussen JJ, Kok-Van Esterik JA, Van der Heijden VS, De Mol NJ,
Janssen LH. Effects of the anti-allergics astemizole and norastemizole on Fc epsilon
RI receptor-mediated signal transduction processes. Eur J Pharmacol 1997; 322:
97–105.
129. Yoneda K, Yamamoto T, Ueta E, Osaki T. Suppression by azelastine hydrochloride
of NF-κB activation involved in generation of cytokines and nitric oxide. Jpn J
Pharmacol 1997; 73:145–153.
5
Clinical Pharmacology
of H1-Antihistamines
F. Estelle R. Simons and Keith J. Simons

University of Manitoba, Winnipeg, Manitoba, Canada
I. INTRODUCTION
H1-antagonists have similar efficacy in the treatment of patients with allergic

rhinitis or urticaria; however, they are diverse with regard to their chemical struc-
ture (Fig. 1), clinical pharmacology, and potential for toxicity (1). The scientific
foundation for using these medications with optimal effectiveness in all patient
populations, including the very young, the elderly, and those with hepatic or
renal dysfunction, or those taking other medications concurrently, is provided by
results of pharmacokinetic and pharmacodynamic studies (2).
The pharmacokinetics and pharmacodynamics of some of the old H1-antag-
onists (brompheniramine, chlorpheniramine, diphenhydramine, hydroxyzine, and
triprolidine) have been reviewed previously (3–11) (Fig. 2). Many of these medi-
cations have a surprisingly long terminal elimination half-life (t1/2 β); for exam-
ple, chlorpheniramine, brompheniramine, and hydroxyzine have mean t1/2 β val-
ues of 24, 25, and 21 h, respectively. In contrast, diphenhydramine has a mean
t1/2 β of 9.5 h, and the value for triprolidine is 1.7 ⫾ 0.5 h. The pharmacokinetics
and pharmacodynamics of other first-generation H1-antagonists have never been
adequately studied. The pharmacokinetics and pharmacodynamics of two of the
nonsedating H1-antagonists, astemizole and terfenadine, while extensively stud-
ied, are mainly of historical interest. These medications have been removed
from the pharmaceutical register by governmental regulatory agencies because
of their susceptibility to interactions with other medications eliminated by the
cytochrome P-450 system, and their potential cardiac toxicity (12, 13). These
141
142 Simons and Simons
Figure 1 Chemical structures of selected H1-antihistamines. All are administered by

mouth except for levocabastine, which is applied topically to the nasal mucosa or conjunc-
tiva; and azelastine, which is commonly administered intranasally, although available in
an oral formulation in a few countries. Azelastine, ebastine, loratadine, and mizolastine
are extensively metabolized; in contrast, acrivastine, cetirizine, desloratadine, fexofena-
dine, and levocabastine are not extensively metabolized.
Clinical Pharmacology 143
Figure 2 Temporal relationships between the pharmacokinetics and pharmacodynamics

of four H1-antihistamines. Information was obtained in prospective, randomized, double-
blind, single-dose studies in children. After oral dosing, plasma concentrations of (a) di-
phenhydramine, (b) brompheniramine, (c) carebastine (the active metabolite of ebastine)
and (d) cetirizine were monitored for at least 24 h, along with suppression of the histamine-
induced wheal and flare. Following ingestion of cetirizine and ebastine, wheal-and-flare
suppression was maintained even after H1-antihistamine concentrations became negligible.
These temporal relationships are characteristic of most H1-antihistamines studied to date
using this model. (From Refs. 9, 11, 46, 77.)
Figure 2 Continued
medications, and the first-generation H1-antagonists, will not be discussed further

here.
In this chapter, we focus on the new second-generation H1-antagonists,
highlighting comparative studies (14–18) and reviewing the following medica-
tions in detail: acrivastine (19–25), azelastine (26–39), cetirizine (40–62), deslor-
atadine (63–72), ebastine (73–86), fexofenadine (87–102), levocabastine (103–

107), loratadine (108–133), and mizolastine (134–147).
Information about these medications was obtained by searching the Med-
line database, by reviewing Current Contents on Diskette, and, for the newest
H1-antagonists, by hand-searching for relevant recent abstracts and accessing
manufacturers’ data on file. Considerable pharmacokinetic and pharmacody-
namic information about some of the new H1-antagonists remains unpublished
in peer-reviewed journals, despite the fact that these medications were introduced
more than a decade ago.
II. OVERVIEW OF PHARMACOKINETICS

AND PHARMACODYNAMICS
A. Measurement of H1-Antihistamines in Body Fluids
H1-antagonists are generally present in low concentrations in plasma (20, 28, 41,
42, 109, 110, 136) and are not routinely measured. During the past few years,
new assays, including gas–liquid chromatography (GLC) and high-performance
liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) have
been developed. This has facilitated detection of minute concentrations of H1-
antagonists in plasma and tissues, identification of parent compounds and their
metabolites (Table 1), pharmacokinetic studies (Figs. 2, 3), and medication inter-
action studies. The comparative pharmacokinetics of new H1-antagonists in
healthy young adults are shown in Table 2.
After oral administration, H1-antagonists are generally well absorbed, with
peak plasma concentrations being reached within a few hours after administration
to fasting individuals. Many new H1-antagonists appear to be extensively distrib-
uted into body tissues and bound to plasma proteins. Volumes of distribution (Vd)
measured pharmacokinetically are seldom corrected for absolute bioavailability,
because few of the new H1-antagonists can be administered to humans in intrave-
nous formulations for comparison with oral formulations. Pharmacokinetic dispo-
sition is characterized by open two-compartment models and H1-antagonist kinet-
ics are generally linear over the dosage ranges studied (Fig. 2). The t1/2 β values
range from 2 to 24 h.
The basic information obtained on H1-antagonists in traditional phar-
macokinetic studies, performed in healthy young adults without concomitant
disease and taking no other medications, can be usefully compared with the
population pharmacokinetic data obtained during phase II and III clinical trials.
These trials involve hundreds or even thousands of volunteers with allergic disor-
ders who differ in age, sex, race, and body weight, in whom blood samples
obtained at intervals for chemistry tests can also be used for measurement of
146
Table 1 Assays for New H1-Antihistamines in Plasma
Drug (active metabolite) Assay Limit of quantitation Comments
Acrivastine RIA 0.1–0.25 µg/Lb —

GLC-MSa 2 µg/L CV: 15% at 4 µg/L; 35% at 2 µg/L
Azelastine (desmethylazelastine) RIA — —
HPLC-FL 0.3 µg/L (0.5 µg/L)
Cetirizine HPLC-UV 3 µg/L 5–200 µg/L, CV ⬍ 6%
GLC
Desloratadine (3-hydroxydesloratadine) GLC-NP 0.025 µg/L
HPLC/MS/MS
Ebastine c (carebastine) (HPLC-UV) (3x baseline, 20 µg/L) (linear 50–700 µg/L)
(GLC-MS) CV: (3.8% at 500 µg/L; 7.6% at 75 µg/L)
or (5.3% at 250 µg/L; 12.5% at 25
µg/L)
Fexofenadine HPLC-FL — Precision 5.9–9.7%
HPLC-MS 1 µg/L linear 1–500 µg/L
Levocabastine RIA specific 0.1 mg/L (plasma) —
0.5 µg/L (urine)
Loratadine (descarboethoxyloratadine) RIAa 0.3 µg/L linear 0.1–20 µg/L
(HPLC-FL) a (0.6 µg/L) (linear 0.6–24 µg/L)
Mizolastinec HPLC 0.5 µg/L solid-phase extraction; 15–300 µg/L, CV
⬃6%
CV, coefficient of variation; FL, fluorimetric; GLC, gas–liquid chromatography; HPLC, high-performance liquid chromatography; MS, mass spectrometry;
RIA, radioimmunoassay; UV, ultraviolet; NP, nitrogen phosphorous detector.
a
Can differentiate between parent compound and metabolites.
b
Cannot differentiate between parent compound and metabolites.
c
Not available in the United States at time of publication.
Simons and Simons
Figure 3 Population pharmacokinetic analyses. The marginal discrete distribution of

the oral clearance of mizolastine, estimated by the nonparametric maximum likelihood
method in the learning sample (population), and its smoothed representation, is shown.
A two-compartment open model with zero-order absorption was used to describe the phar-
macokinetics of mizolastine after oral administration. A heteroscedastic variance model
was assumed. The eight covariates introduced were sex, pharmaceutical dosage form, age,
body weight, serum creatinine concentration, renal creatinine clearance, aspartate transam-
inase, and alanine transaminase. The pharmacokinetic parameters of mizolastine in pa-
tients with allergic disorders were similar to those obtained in young healthy volunteers,
and no particular high-risk group of patients was identified. (From Ref. 142.)
H1-antagonist concentrations. This facilitates assessment of the possible influ-

ences of clinical and biological covariates (including dosage form, age, sex, race,
body weight, and, theoretically, hepatic and renal function, and medication
interactions) on kinetic parameters (142) (Fig. 3). The studies may contribute to
identification of subgroups of individuals who require special dosage regimens.
Several validation techniques have been proposed, and standards are available
from the FDA. It is important to recognize, however, that patients with systemic
disorders other than allergic disorders, including those with impaired hepatic or
renal function, and those who regularly use medications in addition to the H1-
Table 2 Single-Dose Pharmacokinetics of Representative H1-Anthistamines in Healthy Nonallergic Young Adults
Protein AUC Ae24 in
148
Drug (active Cmax (µg/L)/ Vd b binding (µg/L/h)/ urine/
metabolite) tmax (h) a dose (mg) t1/2β (h) Cl/F (L/h/kg) b (L/kg) (%) dose (mg) feces (%)
Acrivastine 1.4 ⫾ 0.4 73/4 1.4–3.1 0.26 ⫾ 0.036 0.64 50 0.64/4 59/0
(none)c
Azelastine 5.3 ⫾ 1.6 1.5–12.5 µg-eq/L/4 22–27.6 0.54 ⫾ 0.19 14.5 78–88 47.3–405.9 2(3)/0
(desmethyl- (20.5) (54 ⫾ 15) µg-eq/4 (oral)
azelastine)
Cetirizine (none) 1.0 ⫾ 0.5 257/10 6.5–10 0.06 ⫾ 0.012 0.56 93 2.9/10 60/0
580/20 5.8/20
Desloratadine — 3/7.5 21–31 — — — 104/7.5 —
Ebastined (care- (2.6–5.7) (90–120)/10 (10.3– n/a (90–143 L) (98) (1.75–2.94)/10 (75–95)/0
bastine) (3.6 ⫾ 1.1) 19.3)
Fexofenadine 1–3 290–500/120,80 14.4 1.10 ⫾ 0.144 5.8 ⫾ 0.7 60–70 1.9–3.1/ 12/80
(none) 286/60–180 120,180
Levocabastine 1–2 1.4–2.2 po 35–40 1.8 L/h 1.14 55 — 65–70/20
(none) 0.26–0.29 n, o (po, iv)
33 (n, o)
Loratadine (des- 1.2 ⫾ 0.3 24.3–30.5/40 7.8 ⫾ 4.2 8.52 ⫾ 3.36 119 98 0.04–0.14/40 trace
carboethoxy- (1.5 ⫾ 0.7) (6.7–30.5)/40 (24 ⫾ 9.8) (n/a) (73–76) (0.14–0.39)/40
loratadine)
Mizolastined 1.5 276/10 12.9 0.69 1.4 98 — 0.5/0
(none)
Results are given as mean ⫾ standard deviation.

a
Time from oral intake to peak plasma concentration.
b
Clearance and volume of distribution measured pharmacokinetically, seldom corrected for bioavailability because few of the new H1-antagonists are available
in intravenous formulations for comparison with oral formulations.
c
Acrivastine has a propionic acid derivative metabolite that has not been studied in humans.
d
Ae24, amount of parent compound excreted unchanged in 24 h; AUC, area under the concentration-time curve; Cmax , peak plasma drug concentration after
single dose administration; Cl/F, apparent oral clearance; n, nasal; n/a, minimal published data available; o, ocular; po, oral; tmax , time from oral intake to
Simons and Simons
peak plasma drug concentration; t1/2β, terminal elimination half-life; Vd, volume of distribution.
antagonists being studied, are generally excluded from phase II and III clinical
trials.
B. Pharmacokinetics
1. Extensively Metabolized H1-Antihistamines
Some new H1-antagonists such as azelastine, ebastine, loratadine, and mizolastine
undergo extensive metabolism in the cytochrome P-450 (CYP-450) system in
the liver and/or gastrointestinal tract, which can affect rate and/or extent of ab-
sorption due to gut metabolism, active transport, and first-pass hepatic extraction.
After ordinary single oral doses, the plasma concentration of the parent compound
is low, in contrast with a high concentration of the metabolite(s). Compared with
the values found in healthy young adults, t1/2 β values for these H1-antagonists
may differ in children (10, 11, 77, 115, 116), the elderly (32, 78, 117, 139), in
patients with hepatic dysfunction (34, 80), or renal insufficiency (34, 79, 118),
or those concomitantly receiving macrolide antibiotics, imidazole antifungals,
cimetidine, or other medications eliminated by the CYP-450 system (33, 83, 107,
123–126, 140). A reduction of the dose or an increased interval between doses
may be required (Table 3).
For research purposes, patients who are extensive metabolizers or poor
metabolizers can be identified by phenotyping hepatic enzymes, such as CYP3A4
or CYP2D6 in vitro or in vivo. H1-antagonist metabolism and medication interac-
tions can also be studied in vitro using human liver tissue slices, hepatocytes,
hepatoma cells, microsomal preparations, or purified recombinant fusion proteins
containing CYP-450, with some accuracy in prediction of the in vivo response
(82, 121, 122).
2. H1-Antihistamines Excreted Largely Unchanged

Other new H1-antagonists, such as acrivastine, cetirizine, desloratadine, fexofena-
dine, and levocabastine, are not metabolized as extensively in the CYP-450 sys-
tem; indeed, fexofenadine is excreted largely unchanged. These medications are
unlikely to compete for elimination with other medications metabolized in this
system and are also less likely to be implicated in causing adverse medication
interactions (Table 3). Fexofenadine is primarily eliminated unchanged in the
feces after biliary excretion. More than 50% of a dose of acrivastine, cetirizine,
and levocabastine is eliminated unchanged in the urine. Although the elimination
of acrivastine, fexofenadine, and levocabastine may be reduced in patients with
impaired renal function (95, 106), and the elimination of cetirizine may be re-
duced in those with either impaired renal or hepatic function (51–54), the magni-
tude of the increases in maximum plasma drug concentrations (Cmax) and area
Table 3 Pharmacokinetics of H1-Antihistamines: Potential Increase in Elimination Half-Life in Special Populations
Population in which Interactions with other
150
Hepatic Renal dosage adjustment is medications eliminated via

Drug Elderly dysfunction dysfunction requireda CYP system
Acrivastine t1/2β
↑ (35%) — — none unlikely
AUC doubled
Azelastine
nasal — — — none unlikely
(oral) b (t1/2β ↑) (t1/2β ↑, minimal) — (elderly) possible (cimetidine, ketocona-
zole)
Cetirizine dependent on t1/2β ↑ to 14 h t1/2β ↑ to 20 h hepatic or renal unlikely
renal function dysfunction/geriatric
Desloratadine n/a n/a n/a n/a unlikely; however, systemic bio-
availability is increased
Ebastine b — t1/2β ↑ t1/2β ↑, 23–26 hepatic dysfunction, no possible (ketoconazole, erythromy-
27.2 vs 18.7 vs 17–19 change in Cmax or cin)
AUC
Fexofenadine ↑ Cmax 68% ↑ Cmax ↑ Cmax none (UK) systemic bioavailability ↑ by
t1/2β ↑ 10.4% t1/2β ↑, minimal t1/2β ↑ to renal dysfunction 107% (erythromycin) and 164%
19–24 h (US): lower initial (ketoconazole); bioavailability
dose ↓ by antacid
Levocabastine
nasal b n/a n/a n/a unlikely
(oral) — — (t1/2β ↑ to 95 h) (renal dysfunction)
Loratadine t1/2β ↑, not t1/2β ↑, not no significant ↑ hepatic/renal dysfunc- unlikely; loratadine is also elimi-
clinically clinically in t1/2β; AUC tion nated via CYP2D6
significant significant doubles
Mizolastineb t1/2β ↑ ↓ Cmax , ↑ tmax t1/2β ↑ 47% none possible, no effect identified in
↓ Cmax population pharmacokinetics
a
Dosage adjustment required only in patients with moderate/severe hepatic or renal dysfunction: Child’s class III hepatic disease or renal insufficiency with
glomerular filtration rate ⬍30 mL/min.
Simons and Simons
b
AUC, area under the concentration–time curve; Cmax , peak plasma drug concentration after single-dose administration; CYP, cytochrome P-450; tmax , time
to reach peak concentration following drug administration; t1/2β, elimination half-life; ↑, increase; ↓, decrease.
under the concentration–time curve (AUC) is such that dosage adjustments usu-
ally are not necessary (34, 51–54, 95, 96, 106).
Fixed-dose H1-antagonist/pseudoephedrine combination medications are
widely used, and medication interaction studies with H1-antagonists and pseudo-
ephedrine are, therefore, of interest. This is especially true of the H1-antagonists
that are eliminated largely unchanged in the urine, since this is also the primary
route of elimination for pseudoephedrine (23, 113, 120).
C. Pharmacodynamics
1. Wheal-and-Flare Model
Understanding the relationship between plasma H1-antagonist concentration and
the intensity of the H1-antagonist effect is facilitated by objective assessments of
the suppression of the histamine-induced wheal-and-flare response in the skin
(14, 15, 18, 24, 25, 35, 36, 38, 46, 49, 55–59, 77, 85, 93, 98–100, 127–132, 143–
145, 147), or the antigen-induced wheal-and-flare response, to which histamine is
the major contributor. H1-antagonists decrease the size of the wheal directly by
decreasing postcapillary venule permeability and leakage of plasma protein, and
they decrease the size of the flare indirectly by blocking the histamine-induced
axon reflex. Using a standardized wheal-and-flare bioassay, dose–response
curves can be identified for an H1-antagonist. Significant differences in onset,
potency, and duration of activity among H1-antagonists can be identified during
the first 24 h after administration (14, 15) (Figs. 2, 4).
2. Allergic Rhinitis Model

In contrast to the differences detected by using the wheal-and-flare model, clinical
evaluations over several weeks using subjective symptom scores in patients with
allergic rhinoconjunctivitis tend to demonstrate similarities in dose–response to
the same H1-antagonists, and in efficacy and effectiveness among H1-antagonists.
Although the unique ability of H1-antagonists to suppress the wheal-and-
flare response is used as the end point in most pharmacodynamic studies, in other
studies their ability to suppress the histamine- or allergen-induced response in
the nose, eye, or lower airways has been used (16, 17, 37–39, 62, 86, 101, 132,
133). In patients with allergic rhinitis, after intranasal histamine or allergen chal-
lenge, pretreatment with an H1-antagonist prevents symptoms. In these studies,
direct evidence of histamine blockade on postcapillary venules and prevention
of vascular leak can be obtained by measuring α2-macroglobulin in nasal secre-
tions (16) (Fig. 5).
Figure 4 Cutaneous antihistaminic effects of cetirizine, ebastine, epinastine, fexofena-

dine, terfenadine, and loratadine. In a randomized, double-blind, crossover study, cetirizine
10 mg, ebastine 10 mg, epinastine 20 mg, fexofenadine 60 mg, terfenadine 60 mg, lorata-
dine 10 mg, or placebo was given to 14 healthy men. Wheal-and-flare inhibition was
assessed using epicutaneous tests with histamine phosphate 100 mg/mL and measurement
of the least-squares mean surface area of the resulting wheal and flare, before and up to
24 h after a single dose. Epinastine had the fastest onset of action, inhibiting the wheal
(shown) and flare (not shown) significantly compared to placebo and to all other active
treatments at 0.5 and 1 h. (From Ref. 15.)
3. Onset of Action and Peak Action

The pharmacodynamics of H1-antagonists are medication- and dose-dependent.
The Cmax of the H1-antagonists in target organs such as the skin is achieved rapidly
after oral administration (Fig. 6). It correlates well with onset of H1-antagonist
activity, and amount of H1-antagonist activity, as evidenced by suppression of
the histamine-induced wheals and flares (14, 15) (Table 4; Figs. 2, 4, 6). Peak
suppression of the histamine-induced wheals and flares by H1-antagonists gener-
ally occurs 5–8 h after oral administration of a single dose, later than the Cmax
(14, 15). Maximum H1-blockade usually persists for hours even after plasma
concentrations have declined to the lowest limits of analytical detection. For some
medications, such as cetirizine and fexofenadine, this persistent effect is associ-
ated with high tissue/plasma concentration ratios (56, 99) (Fig. 6). For other
medications, such as ebastine and loratadine, the presence of active metabo-
Figure 5 H1-activity on the nasal mucosa produced by intranasal and oral H1-antihista-
mines. In a double-blind, single-dose, crossover study, healthy individuals received either
azelastine nasal spray 0.254 mg/nasal cavity, or oral cetirizine 10 mg, or placebo. Hista-
mine challenges (40 and 400 µg/L) were given 1 h before, and 1, 6, 9, 12, and 24 h after,
treatment. α2-Macroglobulin in the nasal lavage fluid was measured as a marker of in-
creased vascular permeability and exudation of bulk plasma onto the nasal mucosa. From
1 to 12 h after administration, azelastine or cetirizine, but not placebo, decreased the hista-
mine-induced mucosal exudation of plasma, as shown by a significant decrease in the α2-
macroglobulin marker (1 h results shown). (From Ref. 16.)
lites in tissue is probably important, although they have not been directly mea-
sured there.
4. Duration of Action and Residual Action

The duration of action of a single dose of an H1-antagonist, assessed objectively
from suppression of the histamine- or allergen-induced wheals and flares in the
skin, or subjectively by suppression of nasal symptoms after allergen challenge,
is more prolonged than might be expected from consideration of plasma H1-antag-
onist concentrations and t1/2 β values. For many H1-antagonists, the duration of
action is at least 24 h (Figs. 2, 4, 6), facilitating once-daily administration (Tables
Figure 6 Correlation of skin and plasma H1-antihistamine concentrations during multi-

ple-dose administration. In a randomized, double-blind, multiple-dose, crossover study,
fexofenadine 120 mg/day was administered for 1 week, during which skin and plasma
fexofenadine concentrations were monitored, and wheal-and-flare areas were measured
after epicutaneous tests with histamine phosphate 1 mg/mL. The tests were performed at
baseline and 1, 3, 6, 9, and 24 h after the initial dose of fexofenadine 120 mg. On each
of 6 subsequent consecutive days, participants took fexofenadine 120 mg at 2100 h, and
all the tests were repeated at 168 h (steady state), exactly 12 h after the seventh and last
dose. Values are means ⫾ standard error of the mean; * indicates significantly different
from predose values (p ⬍ 0.05). Fexofenadine achieves excellent concentrations in the
skin and excellent wheal-and-flare suppression, in contrast to the comparator H 1-antihista-
mine diphenhydramine 50 mg/day (not shown). (From Ref. 99.)
4, 5). For some H1-antagonists, the duration of action may be even longer in the
elderly and in patients with hepatic or renal dysfunction, and may necessitate a
reduced dosage or dose frequency of some H1-antagonists in these populations
(Table 3).
The residual action of an H1-antagonist is defined as the pharmacological
effects that last for days or weeks after the medication has been discontinued. This
is clinically relevant information because it defines the time during which an H1-
antagonist must be discontinued before allergen skin tests or inhalation challenge
tests with allergen or histamine can be performed with acceptable clinical accuracy.
Most H1-antagonists need to be discontinued 2–7 days before these tests.
5. Peripheral H1-Activity Does Not Diminish During Regular

Administration
Loss of effectiveness of the peripheral H1-receptor blocking activity of H1-antago-
nists during regular daily administration has not been found in rigorously con-
Table 4 Pharmacodynamics of Representative H1-Antihistamines
Suppression of skin wheal and flare
Single dose Regular administration
Residual
Clinical Pharmacology
Duration effect after Tachyphylaxis Other organs in which

Onset of action stopping during regular pharmacodynamic studies
Drug and dose (h) (h) (days) administration have been performed
Acrivastine 8 mg 0.5 8 n/a no Nose, eyes, lower airways

Azelastine: nasala — — — no Nose
(oral)c 4 mg (4) (12) (7) (no) (lower airways)
Cetirizine 10 mg 0.7 ⱖ24 3 nob Nose, lower airways
Desloratadine n/a n/a n/a n/a n/a
Ebastinec 10 mg 1 ⱖ24 3 no Nose, eyes, lower airways
Fexofenadine 60 mg 2 24 2 no Nose
Levocabastine (nasal,c eye) a — — — no Nose, eyes
Loratadine 10 mg 3 24 7 nob Nose, lower airways
Mizolastinec 10 mg 1 24 n/a nob —
a
Wheal-and-flare suppression does not occur after application to the nasal mucosa or eye, due to minimal systemic absorption.
b
Excellent published wheal-and-flare data.
c
n/a, minimal published information available.
155
156
Table 5 Formulations and Dosages of Representative H1-Antihistamines

Generic/proprietary namea Formulation Recommended dosage
Acrivastine (Semprex) b Tablets 8 mg Adult 8 mg tid

Azelastine (Astelin) Nasal solution 0.1% (0.137 µg/spray) Adult intranasal: 2 sprays per nostril
Tablets 2 mg c bid; oral: 2–4 mg bid
Cetirizine (Zyrtec, Reactine) b Tablets 10 mg Adult: 5–10 mg od
Syrup 5 mg/5 mL Pediatric (6–11 yrs): 5–10 mg od
Desloratadine Tablets 5 mg Adult: 5 mg od
Ebastine (Ebastel) c Tablets 10 mg Adult: 10–20 mg od
Pediatric (6–12 yrs): 5 mg od
Pediatric (2–5 yrs): 2.5 mg od
Fexofenadine (Allegra, Telfast) b Tablets 60 mg, 120 mg, 180 mg Adult: 60 mg bid or 120 or 180 mg od
Levocabastine (Livostin) Intranasal microsuspension 50 µg/spray c Adult nasal: 2 sprays/nostril bid-qid
Ophthalmic suspension 0.05% (0.5 mg/mL) Ophthalmic: 1 drop in each eye bid-qid
Loratadine (Claritin)b Tablets 10 mg Adult: 10 mg od
Rapidly disintegrating tablets (Reditabs) Pediatric (6–10 yrs): 10 mg od
10 mg
Syrup 5 mg/5 mL Pediatric (2–9 yrs): 5 mg od
Mizolastine (Mizollen) c Tablets 10 mg Adult: 10 mg od
a
Only the most commonly used proprietary names are listed.
b
Available with pseudoephedrine; acrivastine is only available in fixed-dose combination with pseudoephedrine hydrochloride, 120 mg.
c
Not available in the U.S. at time of publication.
od, once daily; bid, twice daily; tid, three times daily; qid, four times daily.
Simons and Simons
trolled, double-blind studies of up to 12 weeks duration in which H1-activity has

been monitored objectively using the suppression of skin wheals and flares (46,
131, 147) (Fig. 7). Nor has loss of H1-activity been found in clinical studies of
up to 6 weeks duration during which suppression of urticaria lesions or perennial
allergic rhinitis symptoms has been monitored subjectively (1). The apparent
tachyphylaxis to some H1-antagonists demonstrated in a few lower-airway studies
or central nervous system (CNS) studies may be due to study design and to the
variable effects of the specific H1-antagonist being tested in these organs, since
H1-receptors do not differ in skin, upper airways, lower airways, and CNS.
Figure 7 H1-activity does not diminish during regular daily administration of an H1-
antihistamine. In a double-blind, placebo-controlled, parallel study in 60 patients with
atopy, mizolastine 10 mg/day was given for 8 weeks. Epicutaneous (puncture) tests with
histamine chlorhydrate 10 mg/mL, codeine phosphate 9%, or allergen (five incremental
concentrations of orchard grass pollen or house dust mite) were performed 2 h after the
mizolastine or placebo dose on 6 test days at least 1 week apart (7 days before the first
dose, immediately before the first dose, and on the 7th, 28th, 42nd, and 56th day of admin-
istration). Suppression of the wheals and flares induced by all three agents was maintained
throughout the study. The figure shows the changes from baseline in patients with allergen-
induced skin reactions during placebo and mizolastine treatment, all concentrations of
both types of treatment being considered together (intergroup comparisons by MANOVA,
p ⫽ 0.0001). The model incorporates treatment, allergen, and interaction. (From Ref. 147.)
III. NEW H1-ANTIHISTAMINES: DIVERSE

PHARMACOKINETICS AND PHARMACODYNAMICS
A detailed review of the pharmacokinetics and pharmacodynamics of selected

new H1-antagonists follows. The medications are discussed in alphabetical order.
A. Acrivastine
1. Pharmacokinetics
Absorption of acrivastine (19–25) is rapid after oral administration. In healthy
individuals, the mean Cmax is 73 µg/L, achieved at a mean time of 1.4 ⫾ 0.4 h
after administration of acrivastine 4 mg (Table 2). Absorption is not significantly
decreased by the concomitant ingestion of food. During administration of acrivas-
tine three times daily for 7 days, accumulation does not occur (19–23).
The mean apparent Vd is 0.64 and 0.75 L/kg after single and multiple
doses, respectively. Acrivastine is approximately 50% protein-bound.
The principal acrivastine metabolite, a propionic acid analog formed by
reduction of the acrylic acid side chain, accounts for about 10% of the total
plasma concentration and for between 15 and 17% of the dose recovered in the
urine. It is more active than the parent compound in vitro. Unchanged acrivastine
accounts for 59% of the administered dose recovered in the urine. After a single
8 mg dose of [14C]acrivastine, 88% of the ingested radioactivity is recovered in
the urine within 48 h; the remainder is excreted in the feces within 5 days.
After single or repeated doses, the apparent total body clearance is 0.26 L/
h/kg and t1/2 β ranges between 1.4 and 3.1 h. The mean t1/2 β of the metabolite
is 2.3 h (19, 21, 22).
In 36 elderly volunteers (aged 65–75 years) receiving acrivastine 8 mg or
16 mg three times daily for 22 doses, a 25% decrease in clearance, a 35% increase
in t1/2 β and time to Cmax (tmax), and a doubling of the AUC have been reported
(Table 3). There is minimal information about the pharmacokinetics of acrivas-
tine in children or in patients with impaired renal or hepatic function. Acrivastine
is generally formulated in a fixed-dose combination with pseudoephedrine; there
are no pharmacokinetic interactions between the H1-antagonist and the deconges-
tant. There is also minimal information on interactions between acrivastine and
other coadministered medications (19, 23).
2. Pharmacodynamics
After administration of acrivastine, suppression of the histamine-induced wheal
and flare begins within 30 min (Table 4), and peaks at between 1.5 and 2 h (19,
24, 25). The duration of action is shorter than that of any other new H1-antagonist.
Acrivastine 4 mg, but not 2 mg, reduces the response to histamine in nasal chal-
lenge studies. Acrivastine 8 mg reduces the conjunctival response to histamine.

In patients with asthma, acrivastine protects against histamine-induced broncho-
constriction. No studies on the potential development of tachyphylaxis to acrivas-
tine have been published.
B. Azelastine
1. Pharmacokinetics
It is not possible to perform pharmacokinetic studies after the administration
of a single dose of the nasal formulation of azelastine (26–39), as the plasma
concentrations of the parent compound and its pharmacologically active major
metabolite, desmethylazelastine, are below 0.25 µg/L, the lowest limit of detec-
tion using the HPLC assay available (Table 1). Using the older radioimmunoas-
say, at steady-state, after intranasal administration of 0.56 mg (4 puffs) daily for
29 days, the Cmax is 0.306 µg/L, the tmax is 2.5 h, and the steady-state plasma
concentration is 0.26 µg/L in healthy individuals and 0.65 µg/L in those with
allergic rhinitis. These plasma concentrations are considerably lower than the
Cmax of 1.5–12.5 µg/L achieved 4–5 h after azelastine 4 mg by mouth (Table 2).
Systemic bioavailability is 40%; after intranasal administration, systemic expo-
sure is estimated as six to eight times lower than after oral administration of
azelastine 4 mg.
Using the new HPLC assay and measuring only the parent compound azel-
astine, the Cmax is 5.9 µg/L, and tmax is 5.3 h.
The Vd of azelastine at steady-state is 14.5 ⫾ 4.0 L/kg and it is 78–88%
bound to plasma proteins.
Azelastine is almost completely metabolized by hepatic oxidation. After
intranasal administration to steady-state, plasma concentrations of desmethyl-
azelastine account for 20–50% of total measurable concentrations of azelastine
and its metabolites. Additional metabolites include the 2- and 7-acid derivatives
formed by oxidation and subsequent azepinyl ring opening. Following adminis-
tration of a single oral dose of [14C]azelastine, 75% of the radioactivity is recov-
ered within 120 h: 50% in the feces and 25% in the urine. HPLC analysis of
urine reveals that 2% of an azelastine dose is eliminated as parent compound
and 3% as desmethylazelastine.
The pharmacokinetics of azelastine are similar when determined after oral
or intravenous administration. In single-dose studies, the t1/2β is 22 ⫾ 4 h for
azelastine and 54 ⫾ 15 h for desmethylazelastine. At steady-state after multiple
oral doses of 4 mg twice daily, the t1/2β is reported as 35.5 h (27, 29–31).
There is minimal information on the pharmacokinetics of the nasal or oph-
thalmic formulations of azelastine in children, in patients with hepatic or renal
dysfunction, or in those concomitantly taking other medications. The pharmaco-
kinetics of orally administered azelastine have been studied in the elderly (mean
age, 70 years) in whom elimination is decreased, leading to a doubling of plasma
concentrations during multiple doses; a 50% reduction of the oral dose is required
in this population (32) (Table 3). In patients with mild or moderate hepatic or
renal dysfunction, azelastine elimination is not greatly affected and dose reduc-
tions are not considered necessary (34).
2. Pharmacodynamics
Azelastine administered intranasally before challenge with histamine or allergen
decreases sneezing and other symptoms (16, 26, 27, 35–39) and also decreases
α2-macroglobulin concentrations in nasal lavage fluid, providing direct evidence
of histamine blockade on postcapillary venules and prevention of vascular leak
(16) (Fig. 5). Azelastine nasal spray administration, 0.14 mg/nostril twice daily
for 1 week, has no suppressive effect on histamine-induced wheals and flares in
the skin, suggesting that there is little systemic absorption.
Orally administered azelastine has a dose-related suppressive effect on his-
tamine-induced wheals and flares (Table 4), on histamine-induced nasal obstruc-
tion as measured by posterior rhinomanometry, and on histamine-induced bron-
choconstriction in patients with asthma in whom it also has a dose-related
bronchodilator effect. Tachyphylaxis to azelastine has not been reported.
C. Cetirizine
1. Pharmacokinetics
After oral administration of a 10 or 20 mg dose, cetirizine (40–62) is rapidly
absorbed from the gastrointestinal tract, with a mean Cmax of 257 and 580 µg/L,
respectively, achieved in 1 h (Table 2). Concurrent ingestion of food may de-
crease the rate but not the extent of absorption.
The Vd of cetirizine, 0.56 L/kg, is low compared with that of the other
H1-antagonists. At 24 h after a single dose and at steady-state, skin cetirizine
concentrations are similar to, or exceed, serum concentrations (56). Plasma pro-
tein binding is reported to be 93% at plasma concentrations of 25–1000 µg/L.
Approximately 60% of the administered dose is recovered unchanged in
the urine within 24 h. Renal excretion involves an active transport mechanism.
Steady-state concentrations are achieved within 3 days. During long-term admin-
istration, no accumulation occurs and the rate of elimination does not change
(40, 43–45).
After administration of [ 14C]cetirizine, more than 90% of plasma radioac-
tivity is attributed to unchanged cetirizine at 2 h, 80% at 10 h, and 70% at 24
h. Small amounts of a metabolite produced by oxidative O-dealkylation appear
in the plasma at 10 h and in the feces from 24 to 48 h. About 50% of the adminis-
tered radioactivity is excreted in the urine during the first 24 h after administra-
tion, and a further 10% is excreted in the next 4 days. The major source of urinary
radioactivity is unchanged cetirizine, accounting for 93% of the radioactivity dur-
ing the first 2 h after administration and 83% from 12 to 24 h postdose. The
remaining radioactivity is attributable to small amounts of unidentified metabo-
lites (43).
Mean t1/2β values for cetirizine are 6.5–10 h after a single 10 mg dose in
healthy adults. In children with a mean age of 8 years, the t1/2β is approximately
7 h (Fig. 2); in those with a mean age of 2–4 years, it is 4.9 h; and in infants
with a mean age of 12 months, it is 3.1 h. In infants and children, only 40% of
cetirizine is eliminated unchanged in the urine (46–49).
In the elderly (mean age, 75 ⫾ 11 years), the mean t1/2β of cetirizine is
11.8 h (Table 3); this slight prolongation is associated with significant reduction
in total body renal clearance and apparent nonrenal clearance, and is dependent
on renal function rather than age (50, 51).
In patients of any age with moderate renal dysfunction, the tmax is increased
to 2 h, and the t1/2β is increased to 20–20.9 h. Less than 10% of a dose of cetirizine
is removed by hemodialysis. In patients with impaired hepatic function, the clear-
ance rate is 0.018 L/h/kg (0.3 mL/min/kg), the fraction of the dose excreted
unchanged in the urine (32% after 96 h) is significantly reduced compared with
values obtained in healthy individuals, and the t1/2β is between 13.8 and 14.3 h.
These alterations in the pharmacokinetics are clinically relevant and dose reduc-
tion is suggested in these patients (51–54). Cetirizine elimination is not inhibited
by concomitant administration of other medications such as cimetidine (55).
2. Pharmacodynamics
Cetirizine 10 mg suppresses the histamine- or allergen-induced wheal and flare
response rapidly with a significant effect in 30 to 40 min, and a peak effect 4 to
8 h after administration (14–18, 40, 46, 49, 55–62) (Table 4). Significant suppres-
sion lasts for at least 24 h in adults and children; in infants, it only lasts for 12 h.
The comparative suppressive effects of cetirizine and other H1-antagonists have
been extensively studied (14, 15) (Fig. 4). Cetirizine is more effective than other
antihistamines in suppressing the wheals and flares induced by epicutaneous his-
tamine phosphate 1, 10, or even 100 mg/mL, the concentrations generally used
in this pharmacodynamic model.
Cetirizine also has favorable pharmacodynamics in the upper airway (16,
17) and lower airways (18, 62). It provides dose-dependent protection against
histamine-induced bronchospasm in patients with mild asthma (62).
Patients taking cetirizine regularly should discontinue it 3–4 days before
having skin tests with histamine or allergen. Tachyphylaxis to cetirizine has not
been reported.
D. Desloratadine
1. Pharmacokinetics
Plasma concentrations of desloratadine (63–72) and its active metabolite 3-hy-
droxy-desloratadine are determined by liquid chromatography/mass spectrometry
with a lower limit of quantitation of 0.025 µg/L (Table 1). Desloratadine has
excellent bioavailability in fasted and in fed subjects (64). It exhibits linear phar-
macokinetics over the dose range 5–20 mg. After a single dose of 7.5 mg and
after multiple dosing with 7.5 mg daily for 14 days, the Cmax is approximately
5.5–10.2 µg/L and the t1/2β is 21–31 h (Table 2). No dosage adjustment is needed
for race or sex (67). Although some increases in the AUC and in Cmax are observed
when desloratadine is administered concomitantly with either erythromycin or
ketoconazole, no clinically important pharmacokinetic changes and no electrocar-
diographic changes are observed (68, 69) (Table 3).
2. Pharmacodynamics
No wheal-and-flare studies with desloratadine have been published to date.
E. Ebastine
1. Pharmacokinetics
After oral administration, ebastine (73–86) undergoes extensive first-pass metab-
olism to its active carboxylic acid metabolite, carebastine. The parent compound
is present in extremely low concentrations in plasma, and pharmacokinetic stud-
ies are based on the measurement of carebastine (Table 1, Fig. 2). After ingestion
of ebastine 10 mg, the carebastine Cmax of 90–120 µg/L was obtained at 2.6–
5.7 h (Table 2), with some variations according to race. The values for the AUC
range from 1.75 to 2.94 mg/L/h. Extrapolating from plasma carebastine concen-
trations, ebastine seems to be readily absorbed and food ingestion increases bio-
availability.
Carebastine has a Vd of 90–143 L, and is 98% bound to plasma proteins.
In human studies, 40% of the radioactivity from labeled ebastine is recovered in
urine and 6% in feces over 24 h, increasing to 71% and 28%, respectively, over
312 h. The t1/2 β of carebastine is 10.3–19.3 h in single-dose studies and in multi-
ple-dose studies over 7 days. The pharmacokinetics of carebastine appear to be
linear following ebastine doses of 10–90 mg. During once-daily multiple-dose
administration of ebastine, the Cmax of carebastine increases 1.6–1.7-fold, but the
AUC24 does not change at steady state, reached by days 3–5 (73–76).
In a multiple-dose study in which ebastine 10 mg was given daily for 9
days to elderly adults age 65–75 years, no significant differences in mean steady-
state pharmacokinetic parameters were found, compared to young adults (Table
3). In children, the pharmacokinetics and pharmacodynamics of ebastine have

been well studied (77) (Fig. 2). Patients with hepatic or renal dysfunction may
have a significant increase in the t1/2 β of carebastine; however, they have no
significant increase in the Cmax or in the AUC of carebastine, and dosage adjust-
ments may not be necessary. Ebastine does not appear to interact with ethanol,
diazepam, or cimetidine. A significant increase in plasma carebastine concentra-
tions may occur when ketoconazole 400 mg/day or erythromycin 500 mg every
6 h are concomitantly administered with ebastine (83, 84).
2. Pharmacodynamics
Ebastine has a dose-related suppressive effect (15, 86) on the histamine-induced
wheals and flares over the range of 3–30 mg (61, 73, 77, 85). After a single dose,
the maximum suppressive effect occurs at 6–8 h, and significant suppression is
still present at 24 h (Table 4). The comparative suppressive effects of ebastine
and other new H1-antagonists are shown in Figure 4 (15).
A single oral dose of ebastine 10 mg or 30 mg, administered before bron-
chial challenge with histamine, shifts the dose–response curve 3- to 27-fold.
There is a good correlation between plasma carebastine concentrations and sup-
pression of the histamine-induced wheals and flares, or suppression of histamine-
induced bronchoconstriction. After a short course of ebastine, the residual effect
lasts for 3–4 days. Tachyphylaxis to ebastine has not been reported.
F. Fexofenadine
1. Pharmacokinetics
Fexofenadine (87–102) is readily absorbed when administered orally, with Cmax
reached between 1 and 2.6 h after administration (Table 2). Absorption is not
markedly affected by food (89). Bioavailability is reported as being at least 33%
(90). In equilibrium dialysis studies, 60–70% of plasma fexofenadine is protein-
bound, predominantly to albumin and α1-acid glycoprotein.
During the 24 h after a single dose of fexofenadine 120 mg, and at steady-
state, skin fexofenadine concentrations exceed plasma concentrations (99) (Fig.
6).
The primary pathways of elimination of fexofenadine are biliary and renal
excretion, and there is no evidence of significant biotransformation. In a study
in which healthy volunteers were given fexofenadine 60 mg twice daily for 4
days to achieve steady-state and then received a single 60 mg oral dose of
[ 14C]fexofenadine, 80% of the dose was recovered in an unchanged form in the
feces and 12% in the urine. The only other substances recovered in urine and
feces are azacyclonol, an inactive degradation product, and fexofenadine methyl
ester, which may be a true metabolite, a product of intestinal microflora activity,

or a minor synthetic impurity.
The t1/2 β of fexofenadine in healthy adults is 11–15 h and is similar in
children (91–94) (Table 2). In participants older than 65 years of age given a
single 80 mg dose, the mean Cmax is 68% higher and t1/2β 10.4% longer than in
younger adult males; however, the resulting plasma concentrations are consider-
ably below those observed in clinical trials in which fexofenadine dosages of up
to 800 mg daily have been administered (94) (Table 3).
In patients with renal disease, higher peak plasma fexofenadine concentra-
tions and slower elimination are observed in proportion to the severity of impair-
ment of renal function. Although renal clearance of fexofenadine decreases as
the severity of renal disease increases, there is little correlation between plasma
clearance and the severity of renal disease, and it is possible that decreased renal
elimination may be compensated to some extent by higher biliary clearance. He-
modialysis removes only 1.7% of the fexofenadine in blood. Hepatic impairment
does not affect the absorption or elimination of fexofenadine to any extent, with
mean plasma clearance, Cmax , t1/2β, and renal clearance all within 25% of that in
healthy individuals (95, 96).
When fexofenadine is coadministered with erythromycin or ketoconazole,
its systemic bioavailability increases by 107% and 164%, respectively. This has
been attributed to increased gastrointestinal absorption (seen with both erythro-
mycin and ketoconazole), decreased biliary excretion (erythromycin), or de-
creased gastrointestinal secretion (ketoconazole). The resulting increased plasma
concentrations are within the range of concentrations that are well tolerated in
clinical trials (87, 88, 102). Ingestion of fexofenadine within 15 min of ingestion
of an aluminum- and magnesium-containing antacid decreases bioavailability by
40% (87, 88).
2. Pharmacodynamics
The effectiveness of a single oral dose of fexofenadine (15, 87, 88, 93, 97, 101)
in inhibiting the histamine-induced skin wheal and flare response has been studied
over a dose range of 20–800 mg. Doses of ⱖ40 mg produce significant suppres-
sion of wheals and flares 2 h after administration (Table 4). An 80 mg dose of
fexofenadine is said to be equivalent to a 60 mg dose of the parent compound,
terfenadine. Peak suppression occurs from 3 to 12 h, and suppression is still
significant at 24 h. The comparative suppressive effects of fexofenadine and other
new H1-antagonists are shown in Figure 4 (15). In the skin wheal-and-flare model
and in the nasal challenge model, fexofenadine has a prompt onset of action (98–
101).
When fexofenadine is given for a week and then discontinued, the residual
effect lasts for only 2 days. Tachyphylaxis to fexofenadine has not been re-
ported.
G. Levocabastine
1. Pharmacokinetics
In healthy individuals, absorption of levocabastine (103–107) from nasal or oph-
thalmic formulations occurs within 1 to 2 h (Table 2) and bioavailability is
between 60 and 80%, and between 30 and 60%, respectively. Swallowed levoca-
bastine may contribute to the overall systemic availability of the nasal spray.
Steady-state plasma concentrations, achieved in 7–10 days, are approximately
10.4 µg/L after two nasal sprays (50 µg/spray) per nostril three times daily, and
1.6 µg/L after application of a 0.05% ophthalmic suspension, 1 drop (15 µg) per
eye three times daily. Steady-state plasma concentrations with the nasal spray
are lower in patients with allergic rhinitis (3.5 to 5.2 µg/L) than in healthy indi-
viduals; this is in contrast to azelastine, which is absorbed to a greater extent by
those with allergic rhinitis.
After application to the nasal mucosa or the eyes in nursing mothers, minute
amounts of levocabastine have been detected in breast milk.
The pharmacokinetics of levocabastine have also been studied after oral
and intravenous administration; these formulations are not used clinically because
of sedative effects. After oral administration, Cmax is attained within 2 h and sys-
temic bioavailability is 100–120%, indicative of a negligible first-pass effect. At
steady-state, intravenously administered levocabastine has a mean Vd of 82 L
(1.14 L/kg). The plasma protein binding is approximately 55%.
Levocabastine undergoes little hepatic metabolism; 65–70% of absorbed
levocabastine is excreted in the urine as unchanged drug and 10–20% appears
unchanged in the feces, probably because of biliary excretion. The remainder is
recovered in the urine as the acylglucuronide metabolite.
After single or repeated doses, the t1/2β of levocabastine is between 35 and
40 h, regardless of the route of administration. In patients with renal impairment,
orally administered levocabastine has an increased t1/2 β of 95 h and a 56% in-
crease in the AUC; urinary excretion of unchanged levocabastine is reduced (Ta-
ble 3). Although hemodialysis removes 10% of a dose of levocabastine, it does
not alter the effect of impaired renal clearance on pharmacokinetics. There is
minimal information on topically administered levocabastine in patients with re-
nal impairment and on levocabastine administered by any route in children, the
elderly, or in patients with hepatic impairment (106). No medication interactions
have been reported (107).
2. Pharmacodynamics
Topically applied levocabastine (103, 104) prevents histamine- or allergen-in-
duced nasal or conjunctival symptoms. Levocabastine nasal spray or levocabas-
tine eye drops administered regularly have no significant suppressive effects on
histamine-induced wheals and flares, suggesting that little systemic absorption

occurs when these formulations are applied topically (Table 4).
H. Loratadine
1. Pharmacokinetics
Loratadine is well absorbed following oral administration (108–126), with peak
plasma concentrations of 24.3–30.5 µg/L occurring 1–1.5 h after ingestion of a
40 mg dose (111–114) (Table 2). Concurrent ingestion of food decreases the rate
but not the extent of absorption. Steady-state is achieved by the fifth day of multi-
ple dosing.
Loratadine has a large Vd of 119 L/kg and is 97–99% plasma protein-
bound. It is extensively metabolized by hydroxylation by the CYP3A4 family to
descarboethoxyloratadine (DCL). After administration of single doses of 20–40
mg, its mean distribution and terminal elimination (t1/2 β) half-life values are 0.9–
1.0 h and 7.8–11 h, respectively. At steady-state, after administration of 40 mg
daily for 10 days, the distribution half-life does not change, and the t1/2 β is 14.4
h; little accumulation occurs. The major metabolite, DCL, has a mean t1/2 β of
17.3–24 h (14.4–18.7 h at steady-state). It is 73–76% protein-bound. It is further
converted to an inactive metabolite excreted primarily in the urine. Like its parent
compound, DCL has dose-proportional pharmacokinetics and does not accumu-
late to any extent during multiple-dose administration.
In children, the t1/2 β of DCL arising from loratadine in vivo is 13.8 h. In
healthy elderly individuals, the mean t1/2 β of loratadine and DCL are 18.2 and 17.5
h, respectively. In patients with impairment of renal or hepatic function, although
there may be increases in Cmax and AUC for loratadine and DCL, the rate of elimina-
tion is not significantly decreased (115–118). Loratadine is one of the few H1-
antagonists for which elimination in breast milk has been optimally investigated:
a 4 kg infant is estimated to receive 0.46% of a 10 mg maternal dose (119).
Potential pharmacokinetic interactions of loratadine and other medications
have been extensively studied (120–126). In the presence of CYP3A4 inhibitors,
loratadine is also metabolized by CYP2D6. Coadministration of ketoconazole
200 mg twice daily for 5 days in 12 healthy volunteers inhibited the metabolism
of a single 20 mg oral dose of loratadine, as did coadministration of erythromycin
or cimetidine; however, these findings are of minimal clinical relevance. The
pharmacokinetics of loratadine are not influenced by concomitant administration
of pseudoephedrine.
2. Pharmacodynamics
Loratadine 10 mg suppresses histamine-induced wheals and flares significantly
within a few hours, and the suppression lasts for 12–24 h (14, 15, 127–130)
(Table 4). The comparative suppressive effects of loratadine and other new H1-
antagonists are shown in Figure 4 (15). In the wheal-and-flare model, and in the
nasal challenge model (17), significant suppression begins a few hours later after
loratadine than after some other H1-antagonists; however, the data obtained in
studies with a duration of only 24 h are not necessarily reflected in allergic rhinitis
studies lasting several weeks. Loratadine also prevents the bronchoconstrictor
response to histamine or allergen (132, 133).
After a short course of loratadine, the residual effect lasts for less than 1
week. Tachyphylaxis to loratadine has not been reported (131).
I. Mizolastine
1. Pharmacokinetics
Mizolastine is rapidly absorbed with a mean Cmax of 276 µg/L and a median tmax
of 1.5 h (134–142) (Table 2). Bioavailability is 65.5% and is not affected by age
or concomitant ingestion of food or alcohol. Linear dose–response curves are
observed for Cmax and AUC over the dose range 5–20 mg. The Vd of mizolastine
after intravenous administration is 1.4 L/kg, reflecting its low lipophilicity (log
P ⫽ 2.9 at pH ⫽ 7.4). It is 98.4% protein-bound in plasma.
Mizolastine is extensively metabolized, with less than 0.5% of the adminis-
tered dose excreted unchanged in the urine. After administration of [ 14C]mizolas-
tine to humans, 84–95% of the radioactivity is excreted in the feces. The main
metabolic pathway is glucuronidation of the parent compound (66% of the admin-
istered dose). In vitro studies with specific metabolic inhibitors have shown
CYP3A4 and CYP2A6 to be responsible for the oxidation pathways. No active
metabolites have been identified (134, 135).
The distribution half-life is 1.9 h and the t1/2 β is 12.9 h. Systemic plasma
clearance is 0.69 L/h/kg and does not change with repeated once-daily oral ad-
ministration of mizolastine for 5 or 14 days. Steady-state is reached on the third
day of administration and accumulation does not occur (137, 138).
In the elderly (aged 66–77 years), Cmax is lower and apparent t1/2 β slightly
longer than in young healthy individuals (Table 3). In patients with renal disease,
the t1/2 β of mizolastine is prolonged by 47%, but values remain within the
range found in healthy young volunteers, and no dose adjustments are necessary
(139).
Mizolastine is not cleared by hemodialysis. In patients with hepatic cirrho-
sis, tmax is delayed and Cmax is 35% lower than in healthy volunteers, but the
t1/2 β is similar.
Mizolastine has no effect on the pharmacokinetics of theophylline, digoxin,
R⫺(⫹)⫺ and S⫺(⫺)⫺ warfarin or diltiazem. In the in vitro human hepatocyte
model, there are minimal interactions between mizolastine and ketoconazole, and
none between mizolastine and erythromycin; however, incubation of mizolastine
and ketoconazole with human microsomes results in inhibition of the biotransfor-

mation pathway (140, 141).
Population kinetics in 696 individuals in whom 960 plasma samples were
obtained have not identified any particular age, sex, or body weight group to be
at risk for mizolastine accumulation (142) (Fig. 3).
2. Pharmacodynamics
Mizolastine 10 mg suppresses histamine-induced wheals and flares significantly
within 1 h of administration (Table 4). Peak effect occurs from 3 to 12 h, and
suppression is still significant at 24 h (134, 135, 137, 143–147). Mizolastine has
been measured in skin blister fluid (143). It also produces dose-related bronchodi-
lation and protection against histamine-induced bronchoconstriction.
There is minimal information about the residual effects of mizolastine.
Tachyphylaxis to mizolastine has not been reported. The suppressive effect of
mizolastine on wheals and flares induced by histamine, codeine, or allergen re-
mains highly significant after 3 months of regular administration (147) (Fig. 7).
IV. SUMMARY AND FUTURE DIRECTIONS
We have reviewed pharmacokinetic and pharmacodynamic studies of the H1-

antagonists acrivastine, azelastine, cetirizine, desloratadine, ebastine, fexofena-
dine, levocabastine, loratadine, and mizolastine. The differences in the pharmaco-
kinetics and pharmacodynamics among these medications directly influence
recommendations for dosage and administration interval in patients with allergic
disorders, and facilitate their use in the very young, the elderly, and other unique
populations. The importance of these clinical pharmacology studies should not
be underestimated, since they provide the scientific rationale for administration
of H1-antagonists with optimal benefit and minimal risk.
The ideal H1-antagonist does not yet exist. New medications in this class
continue to be introduced at intervals. Pharmacokinetic and pharmacodynamic
studies of emedastine (148), epinastine (15), levocetirizine (149), tecastemizole
(150), rupatadine, and other new H1-antagonists will provide the scientific basis
for their use in clinical trials, as these types of studies have done for new
H1-antagonists currently in use worldwide.
REFERENCES
1. Simons FER. Antihistamines. In: Middleton E Jr, Reed CE, Ellis EF, Adkinson
NF Jr, Yunginger JW, Busse WW, eds. Allergy Principles and Practice. 5th Ed.
St. Louis: Mosby-Year Book, Inc., 1998:612–637.
2. Simons FER, Simons KJ. Clinical pharmacology of new histamine H1-receptor an-
tagonists. Clin Pharmacokinet 1999;36:329–352.
3. Simons KJ, Simons FER. H1-receptor antagonists: pharmacokinetics and clinical
pharmacology. In: Simons FER, ed. Histamine and H1-Receptor Antagonists in Al-
lergic Disease. New York: Marcel Dekker, 1996:175–213.
4. Paton DM, Webster DR. Clinical pharmacokinetics of H1-receptor antagonists (the
antihistamines). Clin Pharmacokinet 1985;10:477–497.
5. Desager J-P, Horsmans Y. Pharmacokinetic–pharmacodynamic relationships of H1-
antihistamines. Clin Pharmacokinet 1995;28:419–432.
6. Simons FER, Simons KJ, Frith EM. The pharmacokinetics and antihistaminic ef-
fects of the H1-receptor antagonist hydroxyzine. J Allergy Clin Immunol 1984; 73:
69–75.
7. Simons KJ, Watson WTA, Chen XY, Simons FER. Pharmacokinetic and pharma-
codynamic studies of the H1-receptor antagonist hydroxyzine in the elderly. Clin
Pharmacol Ther 1989; 45:9–14.
8. Simons FER, Watson WTA, Chen XY, Minuk GY, Simons KJ. The pharmacokinet-
ics and pharmacodynamics of hydroxyzine in patients with primary biliary cirrho-
sis. J Clin Pharmacol 1989; 29:809–815.
9. Simons FER, Frith EM, Simons KJ. The pharmacokinetics and antihistaminic ef-
fects of brompheniramine. J Allergy Clin Immunol 1982; 70:458–464.
10. Simons FER, Luciuk GH, Simons KJ. Pharmacokinetics and efficacy of chlorphe-
niramine in children. J Allergy Clin Immunol 1982; 69:376–381.
cytochrome P450 enzymes. Clin Exp Allergy 1999; 29 (suppl 3):116–124.
cardiotoxicity. Clin Exp Allergy 1999; 29 (suppl 3):182–189.
14. Simons FER, McMillan JL, Simons KJ. A double-blind, single-dose, crossover
comparison of cetirizine, terfenadine, loratadine, astemizole, and chlorpheniramine
versus placebo: suppressive effects on histamine-induced wheals and flares during
24 hours in normal subjects. J Allergy Clin Immunol 1990; 86:540–547.
15. Grant JA, Danielson L, Rihoux J-P, De Vos C. A double-blind, single-dose, cross-
over comparison of cetirizine, ebastine, epinastine, fexofenadine, terfenadine, and
sponse for 24 hours in healthy male subjects. Allergy 1999; 54:700–707.
16. Greiff L, Andersson M, Svensson C, Persson CG. Topical azelastine has a 12-hour
duration of action as assessed by histamine challenge-induced exudation of α2-
macroglobulin into human nasal airways. Clin Exp Allergy 1997; 27:438–444.
17. Day JH, Briscoe MP, Clark RH, Ellis AK, Gervais P. Onset of action and efficacy
of terfenadine, astemizole, cetirizine, and loratadine for the relief of symptoms of
allergic rhinitis. Ann Allergy Asthma Immunol 1997; 79:163–172.
18. Wood-Baker R, Holgate ST. The comparative actions and adverse effect profiles
of single doses of H1-receptor antihistamines in the airways and skin of subjects
with asthma. J Allergy Clin Immunol 1993; 91:1005–1014.
19. Brogden RN, McTavish D. Acrivastine. A review of its pharmacological properties

and therapeutic efficacy in allergic rhinitis, urticaria and related disorders. Drugs
1991; 41:927–940.
20. Chang SY, Nelson FR, Findlay JWA, Taylor LCE. Quantitative gas chromato-
graphic–mass spectrometric analysis of acrivastine and a metabolite in human
plasma. J Chromatogr 1989; 497:288–295.
21. Cohen AF, Hamilton MJ, Liao SHT, Findlay JWA, Peck AW. Pharmacodynamics
and pharmacokinetics of BW 825C: a new antihistamine. Eur J Clin Pharmacol
1985; 28:197–204.
22. Jallad NS, Garg DC, Fleck RJ, Poe SH, Blum MR, Findlay JWA, Liao SHT, Froso-
lono MF, Weidler DJ. Pharmacokinetics of acrivastine, a new H1-antagonist, fol-
lowing ascending doses. J Clin Pharmacol 1985; 25:629–637.
23. Liao SHT, Fleck RJ, Blum MR, Frosolono MF, Findlay JWA. Clinical pharmacoki-
netics and safety of acrivastine with pseudoephedrine in geriatric volunteers. J
Pharm Sci 1987; 76:S113.
24. Petersen LJ, Bindslev-Jensen C, Poulsen LK, Malling H-J. Time of onset of action
of acrivastine in the skin of pollen-allergic subjects. A double-blind, randomized,
placebo-controlled comparative study. Allergy 1994; 49:27–30.
25. Lahti A, Haapaniemi T. Initiation of the effects of acrivastine and cetirizine on
histamine-induced wheals and itch in human skin. Acta Derm Venereol (Stockh)
1993; 73:350–351.
26. McNeely W, Wiseman LR. Intranasal azelastine. A review of its efficacy in the
management of allergic rhinitis. Drugs 1998; 56:91–114.
27. McTavish D, Sorkin EM. Azelastine: a review of its pharmacodynamic and phar-
28. Pivonka J, Segelman FH, Hartman CA, Segl WE, Kucharczyk N, Sofia RD. Deter-
mination of azelastine and desmethylazelastine in human plasma by high-perfor-
mance liquid chromatography. J Chromatogr 1987; 420:89–98.
29. Tatsumi K, Ou T, Yamada H, Yoshimura H. Studies of metabolic fate of a new
antiallergic agent, azelastine (4-(p-chlorobenzyl)-2-[N-methylperhydroazepinyl-
(4)]-1-(2H)-phthalazinone hydrochloride). Jpn J Pharmacol 1980; 30:37–48.
30. Weliky I, Howard JR, Wichmann JK. Absolute bioavailability and pharmacokinet-
ics of azelastine. Pharm Res 1990; 7:S247.
31. Riethmüller-Winzen H, Peter G, Büker KM, Romeis P, Borbe HO. Tolerability,
pharmacokinetics and dose linearity of azelastine hydrochloride in healthy subjects.
Arzneim-Forsch Drug Res 1994; 44(II):1136–1140.
32. Peter G, Romeis P, Borbe HO, Büker KM, Riethmüller-Winzen H. Tolerability
and pharmacokinetics of single and multiple doses of azelastine hydrochloride in
elderly volunteers. Arzneim-Forsch Drug Res 1995; 45:576–581.
33. Morganroth J, Lyness WH, Perhach JL, Mather GG, Harr JE, Trager WF, Levy
RH, Rosenberg A. Lack of effect of azelastine and ketoconazole coadministration
on electrocardiographic parameters in healthy volunteers. J Clin Pharmacol 1997;
37:1065–1072.
34. Hirata-Dulas CAI, Awni WM, Weliky I, et al. Disposition of azelastine and des-
methylazelastine in patients with hepatic dysfunction and renal insufficiency.
Pharm Res 1992; 9 (suppl):S318.
35. Atkins P, Merton H, Karpink P, Weliky I, Zweiman B. Azelastine inhibition of

skin test reactivity in humans. J Allergy Clin Immunol 1985; 75:167.
36. De Weck AL, Derer T, Bahre M. Investigation of the anti-allergic activity of azelas-
tine on the immediate and late-phase reactions to allergens and histamine using
telethermography. Clin Exp Allergy 2000; 30:283–287.
37. Meltzer EO, Storms WW, Pierson WE, Cummins LH, Orgel HA, Perhach JL, Hem-
sworth GR. Efficacy of azelastine in perennial allergic rhinitis: clinical and rhino-
manometric evaluation. J Allergy Clin Immunol 1988; 82:447–455.
38. Rafferty P, Harrison PJ, Aurich R, Holgate ST. The in vivo potency and selectivity
of azelastine as an H1 histamine-receptor antagonist in human airways and skin. J
Allergy Clin Immunol 1988; 82:1113–1118.
39. Rafferty P, Ng WH, Phillips G, Clough J, Church MK, Aurich R, Ollier S, Holgate
ST. The inhibitory actions of azelastine hydrochloride on the early and late bron-
choconstrictor responses to inhaled allergen in atopic asthma. J Allergy Clin Immu-
nol 1989; 84:649–657.
40. Spencer CM, Faulds D, Peters DH. Cetirizine. A reappraisal of its pharmacological
properties and therapeutic use in selected allergic disorders. Drugs 1993; 46:1055–
1080.
41. Baltes E, Coupez R, Brouwers L, Gobert J. Gas chromatographic method for the
determination of cetirizine in plasma. J. Chromatogr 1988; 430:149–155.
42. Pandya KK, Bangaru RA, Gandhi TP, Modi IA, Modi RI, Chakravarthy BK. High-
performance thin-layer chromatography for the determination of cetirizine in hu-
man plasma and its use in pharmacokinetic studies. J Pharm Pharmacol 1996; 48:
510–513.
43. Wood SG, John BA, Chasseaud LF, Yeh J, Chung ML. The metabolism and phar-
macokinetics of 14C-cetirizine in humans. Ann Allergy 1987; 59:31–34.
44. Muscara MN, De Nucci G. Comparative bioavailability of single doses of tablet
formulations of cetirizine dihydrochloride in healthy male volunteers. Int J Clin
45. Pagliara A, Testa B, Carrupt P-A, Jolliet P, Morin C, Morin D, et al. Molecular
properties and pharmacokinetic behaviour of cetirizine, a zwitterionic H1-receptor
antagonist. J Med Chem 1998; 41:853–863.
46. Watson WTA, Simons KJ, Chen XY, Simons FER. Cetirizine: a pharmacokinetic
and pharmacodynamic evaluation in children with seasonal allergic rhinitis. J Al-
47. Desager JP, Dab I, Horsmans Y, Harvengt C. A pharmacokinetic evaluation of the
second-generation H1-receptor antagonist cetirizine in very young children. Clin
48. Pariente-Khayat A, Rey E, Dubois MC, Vauzelle-Kervroedan F, Pons G, D’Athis
P, Murat II, Pinelli ME, Saint-Maurice C, Olive G. Pharmacokinetics of cetirizine
in 2- to 6-year-old children. Int J Clin Pharmacol Ther 1995; 33:340–344.
49. Spicak V, Dab I, Hulhoven R, Desager J-P, Klanova M, de Longueville M, Har-
vengt C. Pharmacokinetics and pharmacodynamics of cetirizine in infants and tod-
dlers. Clin Pharmacol Ther 1997; 61:325–330.
50. Lefebvre RA, Rosseel MT, Bernheim J. Single dose pharmacokinetics of cetirizine
in young and elderly volunteers. Int J Clin Pharm Res 1988; 8:463–470.
51. Matzke GR, Yeh J, Awni WM, Halstenson CE, Chung M. Pharmacokinetics of
cetirizine in the elderly and patients with renal insufficiency. Ann Allergy 1987;
59:25–30.
52. Simons FER, Watson WTA, Minuk GY, Simons KJ. Cetirizine pharmacokinetics
and pharmacodynamics in primary biliary cirrhosis. J Clin Pharmacol 1993; 33:
949–954.
53. Horsmans Y, Desager JP, Hulhoven R, Harvengt C. Single-dose pharmacokinetics
of cetirizine in patients with chronic liver disease. J Clin Pharmacol 1993; 33:929–
932.
54. Awni WM, Yeh J, Halstenson CE, Opsahl JA, Chung M, Matzke GR. Effect of
haemodialysis on the pharmacokinetics of cetirizine. Eur J Clin Pharmacol 1990;
38:67–69.
55. Simons FER, Sussman GL, Simons KJ. Effect of the H2-antagonist cimetidine on
the pharmacokinetics and pharmacodynamics of the H1-antagonists hydroxyzine
and cetirizine in patients with chronic urticaria. J Allergy Clin Immunol 1995; 95:
685–693.
56. Simons FER, Murray HE, Simons KJ. Quantitation of H1-receptor antagonists in
skin and serum. J Allergy Clin Immunol 1995; 95:759–764.
57. Petersen LJ, Church MK, Rihoux J-P, Skov PS. Measurement of interstitial cetiri-
zine concentrations in human skin: correlation of drug levels with inhibition of
histamine-induced skin responses. Allergy 1999; 54:607–611.
58. Rivest J, Despontin K, Ghys L, Rihoux JP, Lachapelle JM. Pharmacological modu-
lation by cetirizine and ebastine of the cutaneous reactivity to histamine. Dermato-
logica 1991; 183:208–211.
59. Sannita WG, Crimi E, Riela S, Rosadini G, Brusasco V. Cutaneous antihistaminic
action of cetirizine and dose-related EEG concomitants of sedation in man. Eur J
Pharmacol 1996; 300:33–41.
60. Perzanowska M, Malhotra D, Skinner SP, Rihoux J-P, Bewley AP, Petersen LJ,
1996; 45:486–490.
61. Leroy T, Tasset C, Valentin B, Van Neste D. Comparison of the effects of cetirizine
and ebastine on the skin response to histamine iontophoresis monitored with laser
Doppler flowmetry. Dermatology 1998; 197:146–151.
62. Brik A, Tashkin DP, Gong H Jr, Dauphinee B, Lee E. Effect of cetirizine, a new
histamine H1-antagonist, on airway dynamics and responsiveness to inhaled hista-
mine in mild asthma. J Allergy Clin Immunol 1987; 80:51–56.
63. Kreutner W, Hey JA, Anthes J, Barnett A, Young S, Tozzi S. Preclinical pharmacol-
ogy of desloratadine, a selective and nonsedating histamine H1-receptor antagonist:
1st communication: Receptor selectivity, antihistaminic activity, and anti-allergenic
effects. Arzneim-Forsch Drug Res 2000; 50:345–352.
64. Gupta S, Banfield C, Affrime M, Padhi D, Marbury T, Glue P. Oral bioavailability
of desloratadine is unaffected by food. Clin Pharmacokinet 2002; 41 (suppl 1):7–12.
65. Padhi D, Banfield C, Gupta S, Herron JM, Glue P, Affrime MB. Multiple-dose
pharmacokinetics, safety, and tolerance of desloratadine in healthy volunteers. J
Allergy Clin Immunol 2000; 104:S385.
66. Gupta S, Banfield C, Affrime M, Marco A, Cayen M, Herron J, et al. Desloratadine

demonstrates dose proportionality in healthy adults after single doses. Clin Pharma-
cokinet 2002; 41 (suppl 1):1–6.
67. Affrime M, Banfield C, Gupta S, Rosenberg M, Cohen A, Boutros T, et al. Effect
of race and sex on single- and multiple-dose pharmacokinetics of desloratadine.
Clin Pharmacokinet 2002; 41 (suppl 1):21–28.
68. Banfield C, Hunt T, Reyderman L, Statkavich P, Padhi D, Affrime M. Lack of
clinically relevant interaction between desloratadine and erythromycin. Clin Phar-
macokinet 2002; 41 (suppl 1):29–35.
69. Banfield C, Herron J, Keung A, Pahdi D, Affrime M. Desloratadine has no clini-
cally relevant electrocardiographic or pharmacodynamic interactions with ketocon-
azole. Clin Pharmacokinet 2002; 41 (suppl 1):37–44.
70. Cayen M, Wang E, Clement RP, Johnson WW. Effect of desloratadine on p-glyco-
protein transport system. Allergy 2000; 55 (suppl 63):282.
71. Geha RS, Meltzer EO. Desloratadine: A new, nonsedating, oral antihistamine. J
72. Banfield C, Padhi D, Glue P, Herron JM, Statkevich P, Affrime MB. Electrocardio-
graphic effects of multiple high doses of desloratadine. J Allergy Clin Immunol
2000; 104:S383.
73. Hurst M, Spencer CM. Ebastine. An update of its use in allergic disorders. Drugs
2000; 59:981–1006.
74. Yamaguchi T, Hashizume T, Matsuda M, Sakashita M, Fujii T, Sekine Y, Naka-
shima M, Uematsu T. Pharmacokinetics of the H1-receptor antagonist ebastine and
its active metabolite carebastine in healthy subjects. Arzneim-Forsch Drug Res
1994; 44:59–64.
75. Vincent J, Liminana R, Meredith PA, Reid JL. The pharmacokinetics, antihistamine
and concentration-effect relationship of ebastine in healthy subjects. Br J Clin Phar-
macol 1988; 26:497–502.
76. Marino EL, Jansat JM, March MA, Lastra CF. Parametrization by nonlinear regres-
sion analysis of the active acid metabolite of ebastine using different weighting
methods. Int J Clin Pharmacol Ther 1996; 34:546–549.
78. Huang M-Y, Argenti D, Wilson J, Heald D, Ziemniak J. Single dose and steady-
state pharmacokinetics of carebastine following administration of 10 mg ebas-
tine tablets once daily in healthy elderly and young adults. Pharm Res 1993; 10:
S–391.
79. Wilson J, Huang M-Y, Argenti D, Pandit B, Heald D, Ziemniak J. Comparative
pharmacokinetics of carebastine/ebastine in moderately renally impaired and
healthy volunteers following a single 10 mg dose of ebastine. Pharm Res 1993;
10:S–391.
80. Huang M-Y, Wilson J, Argenti D, Heald D, Ziemniak J. Comparative pharmacoki-
netics of ebastine/carebastine in liver cirrhosis and healthy volunteers following
administration of a 10 mg ebastine tablet. Pharm Res 1993; 10:S–390.
81. Pentikis HS, Huang M-Y, Dorr MB, Heald DL. The effect of food on the bioavail-
ability of ebastine. Am J Ther 1997; 4:80–84.
82. Hashizume T, Mise M, Terauchi Y, Luan O, Fujii T, Miyazaki H, et al. N-dealkyl-

ation and hydroxylation of ebastine by human liver cytochrome P450. Drug Metab
Dispos 1998; 26:566–571.
83. Gillen M, Pentikis H, Rhodes G, Aubeneau M, Scheinman S, Duvauchelle T, Mor-
ganroth J, Chaikin P. Pharmacokinetic and cardiac safety studies of ebastine and
loratadine administered with ketoconazole. J Clin Pharmacol 1998; 38:867.
84. Gillen M, Pentikis H, Rhodes G, Chaikin P, Morganroth J. Pharmacokinetic and
pharmacodynamic interaction of ebastine and erythromycin. J Clin Pharmacol
1998; 38:878.
85. Nelson HS, Bucher B, Buchmeier A, Oppenheimer J, Garcia J. Suppression of the
skin reaction to histamine by ebastine. Ann Allergy Asthma Immunol 1995; 74:
442–447.
86. Wood-Baker R, Holgate ST. Dose–response relationship of the H1-histamine antag-
onist, ebastine, against histamine and methacholine-induced bronchoconstriction in
patients with asthma. Agents Actions 1990; 30:284–286.
87. Simpson K, Jarvis B. Fexofenadine. A review of its use in the management of
seasonal allergic rhinitis and chronic idiopathic urticaria. Drugs 2000; 59:1–16.
88. Simons FER. Fexofenadine. J Drug Eval 2001; 1:13–33.
89. Stoltz M, Arumugham T, Lippert C, Yu D, Bhargava V, Eller M, et al. Effect of
food on the bioavailability of fexofenadine hydrochloride (MDL 16455A). Bio-
pharm Drug Disp 1997; 18:645–648.
90. Lippert C, Ling J, Brown P, Bunnaster S, Eller M, Cheng L, et al. Mass balance
and pharmacokinetics of MDL 16,455A in healthy, male volunteers. Pharm Res
1995; 12:S–390.
91. Russell T, Stoltz M, Weir S. Pharmacokinetics, pharmacodynamics, and tolerance
of single- and multiple-dose fexofenadine hydrochloride in healthy male volunteers.
Clin Pharmacol Ther 1998; 64:612–621.
92. Robbins DK, Castles MA, Pack DJ, Bhargava VO, Weir SJ. Dose proportionality
and comparison of single and multiple dose pharmacokinetics of fexofenadine
(MDL 16455) and its enantiomers in healthy male volunteers. Biopharm Drug Disp
1998; 19:455–463.
94. Rao N, Weilert DR, Grace MGA, et al. Pharmacokinetics of terfenadine-acid-
metabolite, MDL 16,455A, in healthy geriatric subjects. Pharm Res 1995; 12
(suppl):S386.
95. Robbins DK, Horton MW, Swan SK, et al. Pharmacokinetics of fexofenadine in
patients with varying degrees of renal impairment. Pharm Res 1996; 13:S431.
96. Lippert CL, Rao N, Eller M, et al. Pharmacokinetics of fexofenadine in liver dis-
eased patients. Pharm Res 1996; 13:S431.
97. Harris AG, Iezzoni DG, Hubbell JP, Chen R, Cornet P. Comparative pharmacoki-
netic and pharmacodynamic crossover study of Seldane tablets and Allegra cap-
sules. J Allergy Clin Immunol 1999; 103:S253.
98. Simons FER, Simons KJ. Peripheral H1-blockade effect of fexofenadine. Ann Al-
lergy Asthma Immunol 1997; 79:530–532.
99. Simons FER, Silver N, Gu X, Simons KJ. Skin concentrations of H1-receptor antag-
onists. J Allergy Clin Immunol 2001; 107:526–530.
100. Simons FER, Johnston L, Gu X, Simons KJ. Suppression of the early and late
cutaneous allergic responses using fexofenadine and montelukast. Ann Allergy
101. Day JH, Briscoe MP, Welsh A, Smith J, Mason J. Onset of action, efficacy, and
safety of a single dose of fexofenadine hydrochloride for ragweed allergy using an
environmental exposure unit. Ann Allergy Asthma Immunol 1997; 79:533–540.
102. Mason J, Reynolds R, Rao N. The systemic safety of fexofenadine HCl. Clin Exp
Allergy 1999; 29 (suppl 3):163–170.
103. Heykants J, Van Peer A, Van de Velde V, Snoeck E, Meuldermans W, Woesten-
borghs R. The pharmacokinetic properties of topical levocabastine. A review. Clin
Pharmacokinet 1995; 29:221–230.
vitis. Drugs 1991; 41:202–224.
105. Heykants J, Van Peer A, Woestenborghs R, Geuens I, Rombaut N, Vanden Bussche
G. Pharmacokinetics and bioavailability of levocabastine (50547) in man. Arch
Int Pharmacodyn Ther 1985; 274:329–330.
106. Zazgornik J, Huang ML, Van Peer A, Woestenborghs R, Heykants J, Stephen A.
Pharmacokinetics of orally administered levocabastine in patients with renal insuf-
ficiency. J Clin Pharmacol 1993; 33:1214–1218.
107. Pesco-Koplowitz L, Hassell A, Lee P, Zhou H, Hall N, Wiesinger B, Mechlinski
W, Grover M, Hunt T, Smith R, Travers S. Lack of effect of erythromycin and
ketoconazole on the pharmacokinetics and pharmacodynamics of steady-state intra-
nasal levocabastine. J Clin Pharmacol 1999; 39:76–85.
108. Haria M, Fitton A, Peters DH. Loratadine. A reappraisal of its pharmacological
properties and therapeutic use in allergic disorders. Drugs 1994; 48:617–637.
109. Martens J. Determination of loratadine and pheniramine from human serum by gas
chromatography-mass spectrometry. J Chromatogr B 1995; 673:183–188.
110. Johnson R, Christensen J, Lin C-C. Sensitive gas–liquid chromatographic method
for the determination of loratadine and its major active metabolite, descarboethoxy-
loratadine, in human plasma using a nitrogen–phosphorus detector. J Chromatogr
B 1994; 657:125–131.
111. Katchen B, Cramer J, Chung M, Gural R, Hilbert J, Luc V, et al. Disposition of
14
C-SCH 29851 in humans. Ann Allergy 1985; 55:393.
112. Hilbert J, Radwanski E, Weglein R, Perentesis G, Symchowicz S, Zampaglione N.
Pharmacokinetics and dose proportionality of loratadine. J Clin Pharmacol 1987;
27:694–698.
113. Nomeir AA, Mojaverian P, Kosoglou T, Affrime MB, Nezamis J, Radwanski E,
Lin C-C, Cayen MN. Influence of food on the oral bioavailability of loratadine
and pseudoephedrine from extended-release tablets in healthy volunteers. J Clin
Pharmacol 1996; 36:923–930.
114. Radwanski E, Hilbert J, Symchowicz S, Zampaglione N. Loratadine: multiple-dose
pharmacokinetics. J Clin Pharmacol 1987; 27:530–533.
115. Lin CC, Radwanski E, Affrime MB, Cayen MN. Pharmacokinetics of loratadine
in pediatric subjects. Am J Ther 1995; 2:504–508.
116. Salmun LM, Herron JM, Banfield C, Padhi D, Lorber R, Affrime MB. The pharma-
cokinetics, electrocardiographic effects, and tolerability of loratadine syrup in chil-
dren aged 2 to 5 years. Clin Ther 2000; 22:613–621.
117. Hilbert J, Moritzen V, Parks A, Radwanski E, Perentesis G, Symchowicz S, Zam-
paglione N. The pharmacokinetics of loratadine in normal geriatric volunteers.
J Int Med Res 1988; 16:50–60.
118. Matzke GR, Halstenson CE, Opsahl JA, Hilbert J, Perentesis G, Radwanski E,
Zampaglione N. Pharmacokinetics of loratadine in patients with renal insufficiency.
119. Hilbert J, Radwanski E, Affrime MB, Perentesis G, Symchowicz S, Zampaglione
N. Excretion of loratadine in human breast milk. J Clin Pharmacol 1988; 28:234–
239.
120. Kosoglou T, Radwanski E, Batra VK, Lim JM, Christopher D, Affrime MB. Phar-
macokinetics of loratadine and pseudoephedrine following single and multiple
doses of once- versus twice-daily combination tablet formulations in healthy adult
males. Clin Ther 1997; 19:1002–1012.
121. Yumibe N, Huie K, Chen K-J, Clement RP, Cayen MN. Identification of human
liver cytochrome P450s involved in the microsomal metabolism of the antihista-
minic drug loratadine. Int Arch Allergy Immunol 1995; 107:420.
122. Yumibe N, Huie K, Chen K-J, Snow M, Clement RP, Cayen MN. Identification
of human liver cytochrome P450 enzymes that metabolize the nonsedating antihis-
tamine loratadine. Formation of descarboethoxyloratadine by CYP3A4 and
CYP2D6. Biochem Pharmacol 1996; 51:165–172.
123. Brannan MD, Reidenberg P, Radwanski E, Shneyer L, Lin C-C, Cayen MN, Af-
frime MB. Loratadine administered concomitantly with erythromycin: pharmacoki-
netic and electrocardiographic evaluations. Clin Pharmacol Ther 1995; 58:269–
278.
124. Carr RA, Edmonds A, Shi H, Locke CS, Gustavson LE, Craft JC, Harris SI, Palmer
R. Steady-state pharmacokinetics and electrocardiographic pharmacodynamics of
clarithromycin and loratadine after individual or concomitant administration. Anti-
microb Agents Chemother 1998; 42:1176–1180.
125. Van Peer A, Crabbé R, Woestenborghs R, Heykants J, Janssens M. Ketoconazole
inhibits loratadine metabolism in man. Allergy 1993; 48:34.
126. Brannan MD, Affrime MB, Reidenberg P, Radwanski E, Linn CC. Evaluation of
the pharmacokinetics and electrocardiographic pharmacokinetics of loratadine with
concomitant administration of cimetidine. Pharmacotherapy 1994; 14:347.
127. Kassem N, Roman I, Gural R, Dyer JG, Robillard N. Effects of loratadine (SCH
29851) in suppression of histamine-induced skin wheals. Ann Allergy 1988; 60:
505–507.
128. Roman IJ, Kassem N, Gural RP, Herron J. Suppression of histamine-induced wheal
response by loratadine (SCH 29851) over 28 days in man. Ann Allergy 1986; 57:
253–256.
129. Kontou-Fili K, Paleologos G, Herakleous M. Suppression of histamine-induced
skin reactions by loratadine and cetirizine diHCl. Eur J Clin Pharmacol 1989; 36:
617–619.
130. Fadel R, Herpin-Richard N, Dufresne F, Rihoux J-P. Pharmacological modulation
by cetirizine and loratadine of antigen and histamine-induced skin weals and flares,
and late accumulation of eosinophils. J Int Med Res 1990; 18:366–371.
131. Bousquet J, Chanal I, Skassa-Brociek W, Lemonier C, Michel FB. Lack of subsen-
sitivity to loratadine during long-term dosing during 12 weeks. J Allergy Clin Im-
munol 1990; 86:248–253.
132. Town GI, Holgate ST. Comparison of the effect of loratadine on the airway and
skin responses to histamine, methacholine, and allergen in subjects with asthma.
133. Debelic M. Protection against histamine-induced bronchoconstriction by loratadine.
Allergol Immunopathol (Madr) 1992; 20:97–100.
134. Simons FER. Mizolastine: antihistaminic activity from preclinical data to clinical
evaluation. Clin Exp Allergy 1999; 29 (suppl 1):3–8.
135. Arbilla S, Besserve A, Chaufour S, Chodorge-Coulon F, Delauche-Cavillier MC,
Dubruc C, Grippon P, Guérault E, Kerr A, Levy D, Manoury P, Murrieta-Aguttes
M, O’Connor S. Core Scientific Brochure. Synthélabo Groupe, Medical and Regu-
latory Affairs Direction, 1998.
136. Ascalone V, Guinebault P, Rouchouse A. Determination of mizolastine, a new anti-
histaminic drug, in human plasma by liquid-liquid extraction, solid-phase extrac-
tion, and column-switching techniques in combination with high-performance liq-
uid chromatography. J Chromatogr 1993; 619:275–284.
137. Rosenzweig P, Thebault JJ, Caplain H, Dubruc C, Bianchetti G, Fuseau E, Morselli
PL. Pharmacodynamics and pharmacokinetics of mizolastine (SL 85.0324), a new
nonsedative H 1-antihistamine. Ann Allergy 1992; 69:135–139.
138. Mesnil F, Dubruc C, Mentre F, Huet S, Mallet A, Thenot JP. Pharmacokinetic
analysis of mizolastine in healthy young volunteers after single oral and intravenous
doses: noncompartmental approach and compartmental modeling. J Pharmacokinet
Biopharm 1997; 25:125–147.
139. Patat A, Gram LF, Dubruc C, Brohier S, Cabanis MJ, Rosenzweig P. Effects of
mizolastine, a new antihistamine, on psychomotor performance and memory in
elderly subjects. Int Clin Psychopharmacol 1994; 9:101–108.
140. Chaufour S, Holt B, Jensen R, Dubruc C, Deschamp C, Rosenzweig P. Interaction
study between mizolastine, a new H1-antihistamine, and erythromycin. Clin Phar-
macol Ther 1998; 63:214.
141. Chaufour S, Le Coz F, Denolle T, Dubruc C, Cimarosti I, Deschamps C, Ulliac
N, Delhotal-Landes B, Rosenzweig P. Lack of effect of mizolastine on the safety
and pharmacokinetics of digoxin administered orally in repeated doses to healthy
volunteers. Int J Clin Pharmacol Ther 1998; 36:286–291.
142. Mesnil F, Mentre F, Dubruc C, Thenot JP, Mallet A. Population pharmacokinetic
analysis of mizolastine and validation from sparse data on patients using the nonpar-
ametric maximum likelihood method. J Pharmacokinet Biopharm 1998; 26:133–
161.
143. Chosidow O, Dubruc C, Danjou P, Fuseau E, Espagne E, Bianchetti G, Thenot JP,
Herson S, Rosenzweig P, Revuz J. Plasma and skin suction-blister-fluid pharmaco-

kinetics and time course of the effects of oral mizolastine. Eur J Clin Pharmacol
1996; 50:327–333.
144. Pinquier J-L, Caplain H, Cabanis M-J, Dubruc C, Stalla-Bourdillon A, Rosenzweig
P. Inhibition of histamine-induced skin wheal and flare after 5 days of mizolastine.
145. Rosenzweig P, Caplain H, Chaufour S, Ulliac N, Cabanis MJ, Thebault JJ. Compar-
ative wheal and flare study of mizolastine vs terfenadine, cetirizine, loratadine and
placebo in healthy volunteers. Br J Clin Pharmacol 1995; 40:459–465.
146. Prakash A, Lamb HM. Mizolastine: a review of its use in allergic rhinitis and
chronic idiopathic urticaria. Biodrugs 1998; 10:41–63.
147. Bousquet J, Chanal I, Murrieta M, Stalla-Bourdillon A. Lack of subsensitivity to
mizolastine over 8-week treatment. Allergy 1996; 51:251–256.
148. Jansen B, Graselli U, Dallinger S, Kiss B, Wacheck V, Schlagbauer-Wadl H, As-
sandri A, Müller M. Pharmacokinetics and pharmacodynamics of the novel H1-
receptor antagonist emedastine in healthy volunteers. Eur J Clin Pharmacol 2000;
55:837–841.
149. Devalia JL, De Vos C, Hanotte F, Baltes E. A randomized, double-blind, crossover
comparison among cetirizine, levocetirizine, and ucb 28557 on histamine-induced
cutaneous responses in healthy adult volunteers. Allergy 2001; 56:50–57.
150. Handley DA. Advancement of the third-generation of antihistamines. Pediatr
Asthma Allergy Immunol 1999; 13:163–168.
6
Antihistamines in
Rhinoconjunctivitis
Peter Howarth
University of Southampton, Southampton, England
I. INTRODUCTION
H1-receptor antagonists have been the mainstay of therapy for allergic rhinitis
since they were first introduced for clinical use, following the demonstration by
Staub and Bovet in 1937 that this class of compounds, newly developed at that
time, protected against allergen-induced anaphylaxis (1). The experimental use
of antihistamines in allergic disease was a natural sequel to the suggestion by
Dale that histamine was central to immediate anaphylaxis (2) and the demon-
strated release of histamine following allergen exposure in vitro (3, 4). The rela-
tionship between rhinitis and conjunctivitis symptoms and allergen (grass pollen)
exposure in ‘‘hay fever’’ sufferers was established at the end of the 19th century
(5).
Although observational studies reported symptom relief in allergic rhino-
conjunctivitis with use of the earliest antihistamines, the widespread acceptance
of these medications was limited by their adverse pharmacological effects such
as sedation, dry mouth, and blurred vision. In addition, there was concern that
asthma, a condition often associated with rhinitis, might be worsened by anti-
histaminic therapy (6, 7). This concern was compounded by the reports from
in vitro studies that antihistamines might potentiate mast cell degranulation (8).
Careful subsequent studies, however, did not confirm the bronchoconstrictor
effects of H1-antihistamines. Indeed they suggested that bronchodilatation (9,
10) and the in vitro effects identified only at high (suprapharmacological) con-
179
180 Howarth
centrations were found to be unrelated to the H1-receptor-inhibitory effects (11,

12).
In general, an ethylamine chain is common to all H1-receptor antagonists.
However, it was realized that many of the additional properties of this class of
compounds, with the exception of sedation, were related to side chain radical
structure. Thus with structural engineering it was possible to synthesize H1-anti-
histamines without the anticholinergic (13), antiserotoninergic (14), alpha-adren-
ergic receptor antagonistic (15), or local anesthetic (16) activity evident in early
compounds. Although these approaches resulted in the synthesis of improved
compounds, the major breakthrough in the development of H1-antihistamines for
clinical use came with the serendipitous synthesis of the H1-antihistamine terfena-
dine. This agent, while retaining peripheral H1-receptor antagonistic activity, was
devoid of central nervous system (CNS) antihistaminic effects and thus did not
induce sedation or impair psychomotor function (17). Furthermore, it had no H2-
receptor antagonism, no alpha- or beta-adrenergic activity, no antiserotonin ef-
fect, and no antimuscarinic effect (18). Thus, in 1981 it was introduced as the
first oral nonsedating antihistamine for the treatment of rhinoconjunctivitis and
represented a major advance in the use of H1-antihistamines in the treatment of
this condition. Astemizole (1983), cetirizine (1988), and loratadine (1989) fol-
lowed subsequently as orally administered nonsedating H1-antihistamines. Dur-
ing the 1990s, additional nonsedating antihistamines were launched including
fexofenadine, mizolastine, and ebastine. Others such as desloratadine, levocetiri-
zine, and tecastemizole are under advanced development for the treatment of
rhinoconjunctivitis and are licensed for use in some countries. Topical H1-antihis-
tamines such as levocabastine, azelastine, and ketotifen have also been developed.
Current guidelines for the management of rhinitis, such as the World Health
Organization ARIA Guidelines, advocate H1-antihistamines as first-line therapy
for intermittent (seasonal) disease and also as an initial treatment option in mild/
moderate persistent (perennial) disease in which nasal obstruction is not a promi-
nent symptom (19).
In this review of H1-antagonists and rhinoconjunctivitis, we discuss the
current understanding of mucosal inflammation and histamine release in rhino-
conjunctivitis, the role of histamine in disease generation and its receptor speci-
ficity, the influence of H1-receptor blockade on experimental and clinical rhino-
conjunctivitis, the clinical use and comparative effects of different H1-receptor
antagonists, the adverse effects of antihistamines, and the newer developments
in this field. Although much information was gathered in relationship to the
early second-generation H1-antihistamines terfenadine and astemizole, since
these are no longer used clinically because of their potential adverse cardiac ef-
fects, this chapter will focus largely on the later second-generation antihista-
mines.
Rhinoconjunctivitis 181
II. MUCOSAL INFLAMMATION AND HISTAMINE RELEASE

A. Rhinitis
Allergic rhinitis is characterized by mucosal inflammation associated with epithe-
lial accumulation of mast cells, basophils, and eosinophils along with endothelial
and epithelial cell activation, expansion of dendritic antigen-presenting cells and,
in persistent disease, T-lymphocyte accumulation and activation (20). The end-
organ effects of nasal itch, sneeze, rhinorrhea, and nasal obstruction arise due to
mediator release from activated effector cells, primarily mast cells, basophils,
and eosinophils.
Histamine is a major granule constituent of both tissue mast cells and circu-
lating basophils (23). Immunological activation of mast cells and basophils in-
duces histamine release amounting to 3–5 ng/106 cells and 1 ng/106 cells, respec-
tively. This far exceeds the reported ability of both mast cells and basophils to
generate leukotriene C4 (LTC4) on immunological activation (each 60 ng/106
cells) and the ability of mast cells to generate prostaglandin2 (PGD2) or platelet-
activating factor (PAF; 60 ng/106 cells and 2 pmol/106 cells, respectively). Thus,
histamine is quantitatively the major mediator generated on immunological acti-
vation by both mast cells and basophils.
Within the nose, mast cells represent the primary source of histamine (21).
Recent studies on nasal polyps and turbinate tissue reveal a tissue histamine con-
tent of 6.4 µg/g wet weight and 3.9 µg/g wet weight, respectively, with histamine
release induced by anti-IgE and calcium ionophore but not formyl-methionyl-
leucyl-phenylalanine (FMLP). Because FMLP is a potent histamine secretagogue
from human basophils, this suggests that basophils, unlike mast cells, are not a
constitutive component in nasal tissue. In allergic rhinitis, basophils are only
identified in nasal secretions (20) and thus represent a lesser component of the
histamine release in this condition.
Nasal lavage has been used to recover tissue lining fluid from the nose and
to enable mediator measurements to be made. Although increments in histamine
concentrations in nasal lavage fluid can be identified when repeated lavage is
undertaken prior to allergen challenge, in order to obtain a low prechallenge
baseline (22), single lavage measurements in naturally occurring allergic rhinitis
have surprisingly not identified a disease-related difference (23). This lack of
increase in allergic rhinitis may occur on account of both histamine generation
in the normal nose by alternative sources such as bacteria (24) and the rapid
degradation of histamine in active rhinitis by histaminase in the nasal cavity. The
latter may be derived either from the circulation in association with plasma pro-
tein leakage or possibly released in association with eosinophil activation (25).
Alternative methods have therefore been used to document mast cell de-
granulation in allergic rhinitis. Ultrastructural changes of degranulation are re-
182 Howarth
ported following nasal allergen challenge by use of transmission electron micro-

scopic (EM) examination of nasal biopsies (26). Using this same technique, and
quantifying all granules present in each mast cell as intact or degranulating, we
have identified ultrastructural evidence of mast cell degranulation in naturally
occurring seasonal allergic rhinitis. These results are confirmed by measurement
of alternative markers of mast cell degranulation to histamine in nasal lavage,
such as tryptase, which is less susceptible to metabolism and allows seasonal
increments to be identified in naturally occurring allergic rhinitis.
B. Conjunctivitis
The cellular changes in allergic conjunctivitis are similar to those identified in
allergic rhinitis, involving mast cells, eosinophils, and T lymphocytes. In the
healthy conjunctiva, although eosinophils are rarely evident, mast cells are a nor-
mal constituent with an estimated 5000–6000 mast cells/mm3, usually found be-
low the basement membrane in the substantia propria (27). Mast cells are not
usually found in the normal epithelium of the bulbar or tarsal conjunctiva (28,
29). In allergic conjunctivitis mast cells increase in number and infiltrate into the
epithelium (29, 30). Eosinophils are also recruited into the conjunctival tissue
and can be identified both in the substantia propria and the epithelium (29). T
lymphocytes are found in the epithelium and substantia propria of normal con-
junctiva (28), consistent with their ‘‘immunological policing role.’’ As in rhinitis,
their levels are only increased in severe chronic disease, such as keratoconjuncti-
vitis (31). T cells, cloned from conjunctival biopsies of patients with vernal kera-
toconjunctivitis, have been shown to have a cytokine profile compatible with a
T helper (Th2) subset (32).
Histamine is present in normal tears (5 ng/mL) and levels are elevated
in vernal keratoconjunctivitis (16 ng/mL), in which there is severe conjunctival
inflammation (33). As in rhinitis, it has been more difficult to detect histamine
increments in milder forms of conjunctivitis or indeed after conjunctival allergen
challenge; however, it has been demonstrated that histaminase is present in hu-
man tears. With inactivation of this enzyme, it has been possible to demonstrate
acute increments in tear levels of histamine following conjunctival allergen chal-
lenge in sensitized individuals (33).
III. ROLE OF HISTAMINE AND RECEPTOR SPECIFICITY

IN RHINOCONJUNCTIVITIS
A. Rhinitis
Nasal challenge with histamine has been used to investigate the role of histamine
in the nose. Nasal insufflation of histamine mimics acute allergic rhinitis in induc-
ing immediate nasal itching, sneezing, and rhinorrhea as well as causing nasal
obstruction (34). Following single-nostril application of histamine, the rhinorrhea
is bilateral, indicative of reflex neuronal stimulation. The nasal itching and sneez-
ing are also neuronally mediated, due to stimulation of histamine-sensitive affer-
ent receptors, while nasal obstruction is vascular in origin. Histamine exerts sev-
eral different effects on the nasal vasculature. It increases mucosal blood flow
(35), enhances vascular permeability (36), inducing plasma protein exudation
from fenestrated superficial capillaries, and produces nasal venous engorgement
through its regulatory effects on the nasal capacitance vessels. By increasing
turbinate volume, this latter effect reduces nasal airflow and increases nasal air-
ways resistance.
The neuronal effects of histamine are H1-receptor-mediated: specific H1-
receptor antagonism prevents histamine-induced nasal itch, sneeze, and rhinor-
rhea (37). The receptor regulation of the nasal vascular effects is less precise. H1-
receptor blockade can prevent histamine-induced nasal vascular plasma protein
leakage (Fig. 1), suggesting a specific H1-receptor effect in this regard (36). Hista-
Figure 1 The influence of topical azelastine (0.254 mg per nasal cavity), topical pla-
cebo, and oral cetirizine (10 mg) on histamine- (40 µg/ml and 400 µg/ml delivered in
nasal pool device) induced increments in α2-macroglobulin as an index of induced plasma
protein exudation in 12 healthy subjects. ■, azelastine; , cetirizine; 䊐, placebo. *p ⬍
0.05, **p ⬍ 0.01. Challenge was undertaken 1 h after drug pretreatment. (From Ref.
36.)
184 Howarth
mine H2-receptor antagonism can also partially reduce plasma protein exudation
(38). This effect may be indirect due to a regulatory effect on mucosal blood flow,
however, since within the skin, H2-receptor stimulation causes vasodilatation and
within the nose H2-receptor antagonism reduces the increase in mucosal blood
flow in response to allergen (39). An H2-receptor antagonist, by reducing mucosal
blood flow, would indirectly limit the potential plasma protein exudation from
the superficial mucosal capillaries.
Both H1- and H2-receptor antagonists also modify histamine-induced nasal
obstruction (38). Their combined effects have been reported to be greater than
with either administered alone, although, in general, there is little additional
benefit, particularly in reducing histamine-induced nasal blockage (38, 40).
This limited effect in inhibiting histamine-induced nasal blockage could relate
to the histamine-induced kinin generation shown to occur within the nose (41);
however, since kinins also induce nasal blockage (42) as well as promoting
plasma protein leakage (43), this is unlikely as H1-receptor blockade completely
inhibits plasma protein extravasation (38). More probable is an effect of histamine
on H3-receptors. In rodents, H3-receptors have been identified on presynaptic peri-
vascular nerve terminals, where they regulate sympathetic tone (44). Since the
nasal vasculature is under sympathetic tone, with stimulation inducing constric-
tion, inhibition of this effect by H3-receptor activation would lead to vasodila-
tation and nasal venous engorgement. Thus, the nasal obstruction that is not
H1- or H2-receptor-mediated following nasal histamine insufflation is likely to be
H3-receptor-mediated.
Histamine may also contribute to the recruitment of cells that characterize
allergic mucosal inflammation. In cultured human umbilical vein endothelial
cells, histamine upregulates the expression of the cell adhesion molecule P-selec-
tin (45). It has been proposed that P-selectin, which induces a rolling margination
of leukocytes when upregulated on the vascular endothelium, is critical to tissue
eosinophil recruitment (46). In vivo studies in rodents have demonstrated that
histamine-induced rolling margination is inhibited by a P-selectin antibody and
that the mobilization of P-selectin onto the vascular endothelium by histamine
is mediated by H1- rather than H2-receptors (47). Histamine H1-receptors also
appear to be relevant to the epithelial expression of the adhesion molecule, inter-
cellular adhesion molecule-1 (ICAM-1), since terfenadine has been shown to
reduce epithelial ICAM-1 expression in pollen-sensitive patients during seasonal
pollen exposure (48). In addition to promoting eosinophil–endothelial adherence,
histamine will contribute to eosinophil activation (49). This action is H3-receptor-
mediated: the H3-receptor antagonist thioperamide, but not the H1- or H2- receptor
antagonists pyrilamine or cimetidine, respectively, prevents histamine-induced
eosinophil activation (49). It is thus apparent that histamine can contribute to
many of the features of allergic rhinitis.
B. Conjunctivitis
Instillation of histamine into the conjunctival sac reproduces many of the features
of allergic conjunctivitis. Itching, lacrimation, hyperemia, and conjunctival
edema occur rapidly after histamine instillation. Investigation of the effects of
the topical H1-receptor antagonist levocabastine identified that itching, tearing,
redness, and conjunctival edema are all H1-receptor-mediated (50). In guinea pigs,
the inhibition of histamine-induced conjunctival edema by levocabastine has been
shown to be dose-related (51). Within the conjunctiva there is also an H2-receptor-
mediated effect of histamine on blood flow (52). As such, the hyperemia and
conjunctival edema are in part H2-receptor-determined. No details exist concern-
ing H3-receptors and the conjunctiva. The pertinence of histamine to tissue cell
recruitment and activation in allergic conjunctivitis is as described previously for
rhinitis.
IV. ANTIHISTAMINES AND EXPERIMENTAL ALLERGIC

RHINOCONJUNCTIVITIS
Allergen challenge in sensitized individuals has been used to investigate the ef-
fects of oral and topical antihistamine preparations in both the nose and the eye.
Nasal allergen challenge, either with an aqueous extract or with pollen grains,
induces an immediate response characterized by nasal itch, sneeze, rhinorrhea,
and nasal obstruction. The nasal blockage is often long-lasting but the biphasic
obstructive response that typifies the immediate and late responses in the lower
airways is not as readily discernible in the upper airways. A symptomatic late-
phase response is not a characteristic finding following ocular allergen challenge.
There are, however, biochemical and cellular measures indicative of events ex-
tending beyond the immediate response.
During the immediate nasal response to allergen, an increase in histamine,
tryptase, prostaglandin D2, and kinins is evident, consistent with mast cell degran-
ulation, while further increments in histamine and kinins but not prostaglandin
D2 or tryptase are apparent 6–10 h postchallenge (22). The late changes in hista-
mine, but not the other mast cell markers, is indicative of basophil activation.
Consistent with this, an accumulation of basophils is evident within nasal lavage
during the late response (53), although the most marked cellular change 24 h
post-allergen challenge relates to eosinophil influx (54, 55), which is associated
with concomitant allergen-induced nasal hyperresponsiveness.
A. Onset of Action
Treatment with H1-receptor antagonists modifies the response to allergen chal-
lenge in both the nose and the eye (39, 56). The onset of relief of symptoms
186 Howarth
after a single dose is more rapid with topical than oral medication. Topical levoca-
bastine is reported to afford protection within 5 min of application (56). Oral H1-
antagonists have to be absorbed into the circulation before distribution to the
target organ, in this case the nose and eye, and thus have a slower onset of action.
In pollen chamber challenge studies, in which individuals or groups of individuals
are exposed to a regulated amount of pollen for a prolonged duration, sometimes
with repeated daily priming exposures prior to the actual study, relief of symp-
toms has been reported to be significant within an hour of ingestion for fexofena-
dine (57) and cetirizine (58) but to take longer (3 h) for loratadine (58). A recent
study with one of the active metabolites of loratadine, desloratadine, reveals phar-
macological heterogeneity in the effects of H1-receptor antagonism on the nasal
response to allergen. By implication, this would point to heterogeneity in the
involvement of histamine in the nasal obstructive response to allergen. Fourteen
of 28 subjects (50%) were found to have a major improvement in allergen-in-
duced nasal obstruction (mean 50% reduction at 2 h) with desloratadine in a
pollen chamber challenge study (59); thus allergen-induced nasal obstruction may
only be histamine-dependent in a proportion of rhinitics. When assessed 3 h after
ingestion, cetirizine has been shown to afford greater protection than terfenadine,
loratadine, or astemizole (60). A more rapid onset of effect of cetirizine compared
to loratadine has also been reported from nasal histamine challenge studies (61).
The use of a pollen chamber for group allergen nasal challenge may be a
more sensitive method of evaluation than individual nasal allergen challenge. For
example, one study investigating the protective effect of loratadine and cetirizine
on nasal allergen challenge (62) found these H1-antihistamines to be comparable,
in a placebo-controlled evaluation, in the magnitude of their displacement of the
threshold pollen grain challenge required to induce a positive nasal challenge.
By contrast, a pollen chamber challenge study in which symptoms were induced
and relief evaluated (58), identified a significantly greater effect of cetirizine
(36.7% mean reduction in total symptom scores) than either loratadine (15.4%
reduction) or placebo (12.0% reduction). This study addressed relief after single-
dose therapy, whereas the allergen challenge study referred to above (62) in-
vestigated the protective effect after 7 days of treatment. This study, in which
loratadine and cetirizine were reported to afford comparable protection against
allergen-induced rhinitis, also tested these drugs’ effects on skin wheal responses
to histamine and allergen. Cetirizine had a significantly greater effect on the hista-
mine-induced skin wheal response than loratadine, whereas they had an equal
effect in inhibiting the allergen-induced skin wheal responses. An interpretation
of these findings is that an effect of loratadine on allergen-induced mediator re-
lease makes up for its relative lack of potency as an end-organ H1-receptor antago-
nist. Such an ‘‘antiallergic’’ effect may only be achieved at steady state and may
not be evident in single-dose studies.
B. Extent and Duration of Effect

In general, allergen-challenge studies reveal that it is predominantly the H1-recep-
tor-mediated events (e.g., nasal itch, sneeze, and rhinorrhea) that are reduced by
H1-antihistamine therapy (39), with less effect on the nasal obstructive response.
Some studies report some reduction in allergen-induced nasal obstruction in com-
parison to placebo (56). Many others have failed to find any effect of either H1-
receptor or H2-receptor blockade (63–65). Studies in which objective monitoring
of nasal obstruction has been undertaken, by either rhinomanometry or nasal
inspiratory peak flow, have failed to identify clear effects of H1-receptor antago-
nism on allergen-induced increases in nasal airways resistance or reduction in
nasal airflow (63–65), despite clear effects of such treatment on sneezing and
rhinorrhea. These nasal obstructive effects relate to the indirect and direct actions
of mediators on the state of engorgement of the venous sinusoids, and indicate
that histamine is not prominently involved in this vascular response to allergenic
challenge, at least through H1-receptor-mediated mechanisms. Histamine may,
however, contribute to the microcirculatory response to allergen within the nose.
Figure 2 Duration of action of intranasal levocabastine in reducing allergen-induced

increments in total nasal symptom score (NSS). Results presented as mean (⫾ SD) total
NSS after levocabastine (LEV) administration and allergen challenge. *Symptom scores
were significantly lower than placebo (p ⬍ 0.05). (From Ref. 65.)
188 Howarth
Objective recording of nasal mucosal microcirculatory blood flow by laser Dopp-

ler flowmetry has shown that allergen challenge reduces this superficial capillary
blood flow within the nose and that this effect is inhibited by H1- but not H2-
receptor antagonism (66). No evidence of an additive effect of H1- and H2-recep-
tor antagonism was evident in this study.
Although laboratory allergen challenge studies could be used as a model
to investigate the duration of effect, few studies have assessed duration of antihis-
taminic effect at the organ site. Usually they have investigated the H1-receptor
inhibitory effect at a single time point, the choice of time point being derived
from time course studies performed on skin wheal and flare responses. Topical
levocabastine therapy (0.05% solution) has, however, been shown to reduce aller-
gen-induced conjunctival itch, hyperemia, tearing, and chemosis 10 min and 4
h after initial application (67), and also to be effective in the nose, within 5 min
of administration (56, 65) (Fig. 2). In separate studies it was found to remain
protective at 12 h and 24 h after single-dose administration (65) (Fig. 2).
V. ANTIALLERGIC ACTIVITIES OF H1-ANTIHISTAMINES

IN RHINOCONJUNCTIVITIS
Nasal allergen challenge has also been used to investigate the antiallergic proper-
ties of H1-antihistamines in vivo. These investigations are based on the in vitro
findings that H1-antihistamines inhibit anti-IgE-induced histamine release from
human lung fragments at low concentrations, although at high concentrations
they enhance histamine liberation (11). Comparative in vitro studies suggest that
this effect does not relate to H1-receptor antagonist potency but more to the lipo-
philicity of the compound. H1-antihistamines with low lipophilicity have a lesser
effect on histamine liberation than those with greater lipophilicity. This ‘‘antial-
lergic’’ potential of antihistamines has been extended by other in vitro studies
reporting inhibition of LTC4 and leukotriene D4 (LTD4) release from dispersed
human lung cells and from eosinophils, modification of macrophage function,
inhibition of both neutrophil and basophil activation, and alteration in platelet
cytotoxicity (68).
When administered orally at standard clinical doses, the piperidine antihis-
tamines azatadine, terfenadine, and loratadine have all been shown to reduce the
allergen-induced increment in nasal lavage concentrations of histamine and kinins
(69–71). Where measured, this protective effect is also associated with a reduc-
tion in induced increments in albumin. Cetirizine is without effect on histamine
release (63), although it does decrease allergen-induced changes in LTC4 and
LTD4 (80). The interpretation of these findings is complicated: kinins are likely
to be generated in association with plasma protein extravasation (41). Thus the
inhibitory action of antihistamines may reflect purely an H1-mediated action on
vascular permeability, with the inhibitory action on the histamine increase re-
flecting reduced tissue availability of histamine on account of the reduced tissue
fluid exudation. Against such an explanation, however, is the reported lack of
inhibitory effect of cetirizine on the histamine rise in the presence of an inhibition
of the allergen-induced albumin changes (72).
Evidence in support of an additional action for loratadine over and above
end-organ H1-receptor antagonism has been derived indirectly from comparisons
of loratadine with cetirizine in nasal and skin challenge studies (62). In these
studies, cetirizine had greater activity against histamine-induced skin wheal for-
mation than loratadine, but equal activity against allergen-induced skin wheal
and nasal responses. This difference was interpreted as being indicative of a dual
activity of loratadine, involving both end-organ H1-receptor antagonism and inhi-
bition of tissue histamine release. Such an interpretation would be consistent with
the nasal lavage studies (70–71) but is in contrast to a careful skin study using
a microdialysis technique to sample venous blood draining the skin wheal site
directly (73). This placebo-controlled study failed to detect any effect of lorata-
dine on induced histamine release. There may be several explanations for these
discrepant skin and nasal findings. First, there may be target organ differences
in the mast cell sensitivity to the effects of loratadine, although there is no evi-
dence for this. Target site discrepancies may also relate to the inducing stimulus
being stronger in the skin and thus less amenable to inhibition. A third consider-
ation is that the increase in histamine within the nasal lumen following allergen
challenge is, in part, a reflection of basophil activation and that this component,
rather than a mast cell component, is inhibited by loratadine. Consistent with
such a possibility is the failure to detect any significant effect of loratadine on
allergen-induced increments within the nose of tryptase and PGD2 (70), two mast
cell–derived mediators, and the ex vivo identification that loratadine inhibits IgE-
mediated basophil activation (71).
In addition to the assessment of the impact of antihistamine therapy on cell
activation, in vivo studies have investigated the ability of H1-receptor antagonists
to modify plasma protein leakage, eosinophil recruitment and activation, and epi-
thelial activation. Clemastine pretreatment does not modify allergen-induced na-
sal vascular responses (74). No effect on either eosinophil recruitment or eosino-
phil activation has been found with loratadine (70) or cetirizine, either alone or
in combination with the H2-receptor antagonist cimetidine (63), in the allergen
nasal challenge model. A number of H1-antihistamines have, however, been
found to modify epithelial activation. Nasal allergen challenge is associated with
increased epithelial expression of the adhesion molecule ICAM-1 and the appear-
ance in the lavage of the shed form of this, soluble ICAM-1 (sICAM-1). In the
nose, topical azelastine pretreatment has been found to inhibit this response (75)
as has topical levocabastine (76), as well as oral therapy with cetirizine (77),
oxatomide (78), and loratadine (79) in the conjunctiva with topical allergen chal-
190 Howarth
lenge to the eye. These findings have been extended into naturally occurring
disease, with topical azelastine (80) and oral cetirizine (81–83) and loratadine
(81–82). All of these are reported either to downregulate epithelial ICAM-1 ex-
pression or to reduce the recovery of sICAM-1. The relevance of this to the
modification of allergic rhinitis or conjunctivitis is undefined, but increasingly
the epithelium is considered to play an important role in cell recruitment through
the release of chemokines. In vitro, fexofenadine has been found to modify epi-
thelial–eosinophil interactions and the release of the chemokines regulated on
activation, normal T-cell expressed and secreted (RANTES) and interleukin 8
(IL-8), as well as the cytokine granulocyte macrophage colony-stimulating factor
(GM-CSF) and the adhesion molecule ICAM-1 from epithelial cells (84).
These findings have been extended by reports from some workers that cetir-
izine and loratadine can inhibit both eosinophil recruitment and activation in the
nose in naturally occurring disease (82, 83). One of these studies is uncontrolled
(82) and therefore difficult to evaluate. The other, with cetirizine is a placebo-
controlled evaluation in seasonal allergic disease demonstrating a clear effect of
active therapy (83). These findings are compatible with studies in the skin, using
a skin blister model in which cetirizine inhibits allergen-induced eosinophil re-
cruitment (85). Other nasal and skin studies have not identified an effect of cetiri-
zine on either acute allergen-induced eosinophil recruitment or mucosal eosino-
phil accumulation in naturally occurring disease (54, 85, 86). An inability to
identify additional benefit with ‘‘antiallergic’’ antihistamines brings into question
the relevance of these findings to cell recruitment and activation, a difficulty
that is also reflected in naturally occurring disease in which most modern H1-
antihistamines appear equally efficacious when used at standard clinical doses
(see below). Subtle differences between therapies may need very large numbers
of patients to be clinically discernible, due to the variability of the disease expres-
sion. Also, as in some H1-antihistamines, the effect may appear primarily related
to inhibition of histamine release, rather than a broader effect on cell activation,
and consequently no real additional biological benefit is accrued over the H1-
receptor antagonism alone.
VI. ORAL H1-ANTIHISTAMINES AND NATURALLY

OCCURRING RHINOCONJUNCTIVITIS
A. Seasonal (Intermittent) Allergic Disease
Minor differences exist among clinical trials, attributable to the number of pa-
tients enrolled, local environmental factors, patient selection, and individual pa-
tient variability; however, in general, H1-antihistamines modify nasal itch, sneeze,
and rhinorrhea in seasonal allergic rhinitis with little or no effect on nasal obstruc-
tion (87–90). The effect on the H1-responsive symptoms is only partial (40%–
60% reduction) since histamine is not the sole contributor to the generation of
these symptoms (91). Oral H1-antihistamines also modify the conjunctival symp-
toms of itch, watering, and redness (92, 93). The effect on conjunctival symptoms
may be less marked than on rhinitis symptoms, possibly on account of a higher
local allergen load in the eye. Topical H1-antihistamines have a similar profile
(94) and while theoretically they may achieve a higher local concentration
(thereby creating a greater effect), comparative trials of topical H1-antihistamine
therapy with oral H1-antihistamine therapy report a similar overall effect in reduc-
ing ocular symptoms (95).
Due to the potential for first-generation H1-antihistamines to cause subclini-
cal central nervous system (CNS) adverse effects, interfering with performance
at work and school, and in some individuals, frank somnolence, these H1-receptor
antagonists are no longer recommended for use, with the second-generation non-
sedating H1-antihistamines being preferred.
Few details will be given regarding terfenadine and astemizole, since these
second-generation H1-antihistamines are no longer approved for use in many
countries because of their potential to cause serious cardiac arrhythmias.
1. Placebo-Controlled Studies
Cetirizine. Cetirizine, a piperazine derivative and carboxylated metabo-
lite of hydroxyzine, is a potent H1-receptor antagonist. Placebo-controlled com-
parative studies of cetirizine 5 mg daily (96), 10 mg daily (96, 97), and 10 mg
twice daily (98) have been conducted and all dosages are found to be effective
in seasonal allergic rhinitis. A subsequent study compared 5 mg, 10 mg, and 20
mg cetirizine dosages with placebo in seasonal allergic rhinitis and found all
active treatments to be effective (Fig. 3), with no significant dose–response rela-
tionship (89). A study using a syrup preparation in children aged 6–11 years
found 5 mg no different from placebo, while the 10 mg dosage was significantly
more effective (99). Cetirizine is marketed at a dosage of 10 mg daily for the
treatment of seasonal allergic rhinoconjunctivitis. In the placebo-controlled trials,
cetirizine, like other H1-antihistamines, is effective for relief of nasal pruritus,
runny nose, and sneezing but less effective for nasal obstruction or lacrimation,
although effects are evident in studies with sufficient power (100). Cetirizine
affords better relief when taken on a daily basis rather than on an as-needed basis
(101).
Desloratadine. Desloratadine is an active metabolite of loratadine that
has been developed for clinical use in its own right. It has a high affinity for H1-
receptor binding. Details in a review article suggest a relative selectivity for the
H1-receptor, with 15–50 times the dosage being required to demonstrate antago-
nism of the H2-receptor or muscarinic receptors (102). A recent abstract does,
however, indicate that the selectivity ratio for H1- to muscarinic M2-receptors is
192 Howarth
Figure 3 The influence of three separate dosages of cetirizine on mean daily symptom
scores, in comparison to placebo, in a double-blind, randomized, parallel-group study de-
sign involving 419 patients with seasonal allergic rhinitis. Treatment was given once daily
for 1 week. Cetirizine was significantly (p ⱕ 0.05) more effective than placebo on all
days, but no dose–response relationship was evident. (From Ref. 89.)
only 5 in comparison to 11 for loratadine and 600 for fexofenadine (103). This
indicates a broader receptor antagonistic profile for desloratadine than either its
parent compound or a comparable H1-receptor antagonist. At the time of writing,
no peer-reviewed original articles relating to desloratadine in allergic rhinitis
were available, although data are available in abstracts from presentations at
meetings, a supplement publication, and a review article (104).
The supplement referred to focused on the effects of desloratadine in reliev-
ing nasal congestion (59). Clinical trials in patients with seasonal allergic rhinitis
identified, in comparison to placebo, that desloratadine not only relieved nasal
itch, sneeze, and rhinorrhea but also improved nasal obstruction. This was re-
ported by the Desloratadine Study Group (105) in a double-blind, randomized
study design involving 346 patients and a 2-week treatment period with deslora-
tadine 5 mg once daily or placebo. Desloratadine treatment led to a 25% reduction
in the nasal congestion score in comparison to placebo ( p ⫽ 0.04). A separate
abstract from the same group reported that this reduction was statistically signifi-
cant, compared to baseline, within 12 h of initial administration (106). A third
abstract from the Desloratadine Study Group reported the influence of treatment
on quality of life (QOL) using the rhinitis health-related quality-of-life question-

naire (RQLQ). After 14 days treatment with desloratadine 5 mg or 7.5 mg once
daily, the abstract indicates that five of the RQLQ domains improved (practical
problems, nasal symptoms, eye symptoms, activities, overall) in the group treated
with 5 mg (107). No level of statistical significance in comparison to placebo
and no details of the effect of the 7.5 mg dose are provided, so it is not possible
to evaluate this information in comparison with other published studies on QOL.
Loratadine. Loratadine is a piperidine derivative. Placebo-controlled,
double-blind, randomized trials of loratadine in seasonal allergic rhinitis have
confirmed the efficacy of this H1-antihistamine at a dosage of 10 mg daily (40,
108–100) (Fig. 4). Loratadine is less effective in relieving nasal obstruction than
the other nasal symptoms of rhinitis (111). The choice of 10 mg daily is supported
by the findings of a study that investigated the effect of 40 mg daily loratadine
in seasonal allergic rhinitis and suggested that this dosage was no more effective
and carried the potential risk of sedation (112). Loratadine is also effective in
the relief of conjunctival symptoms in seasonal allergic rhinitis.
Figure 4 Mean change from baseline in 24-h reflective symptom scores for sneezing,
itchy nose/palate, rhinorrhea, itchy red eyes, and nasal congestion following treatment
with fexofenadine 120 mg once daily (n ⫽ 232, ■), loratadine 10 mg once daily (n ⫽
228, ), and placebo (n ⫽ 225, 䊐) over a 2-week treatment period in seasonal allergic
rhinitis. *p ⬍ 0.05, **p ⬍ 0.01, ***p ⬍ 0.005, ****p ⬍ 0.001, *****p ⬍ 0.0001 in
comparison to placebo; p ⬍ 0.05 for comparison between fexofenadine and loratadine:
itchy red eyes and nasal congenstion. No details of baseline starting score for individual
symptoms are provided in the publication. NS, not significant. (From Ref. 139.)
194 Howarth
Fexofenadine. Fexofenadine is the pharmacologically active metabolite

of terfenadine. It does not undergo hepatic metabolism and is thus free of the
hepatic drug interactions associated with terfenadine. In addition, fexofenadine
has no intrinsic cardiac activity in vivo. A number of large multicenter, double-
blind, randomized, placebo-controlled studies have evaluated the effect of fexo-
fenadine in grass pollen– and ragweed pollen–induced seasonal allergic rhinitis
(100, 113–115). These identify its significant benefit in relieving nasal itch,
sneeze, and rhinorrhea as well as conjunctival itch and watering. There is a clear,
although smaller, effect in relieving nasal obstruction (Fig. 4).
Dose-ranging studies have investigated both twice-daily and once-daily
treatment regimens. Initial studies focused on twice-daily therapy in fall seasonal
allergic rhinitis with placebo-controlled comparisons against 40 mg, 60 mg, and
120 mg twice daily (113) and 60 mg, 120 mg, and 240 mg twice daily (114).
All dosages of fexofenadine were found to be significantly better than placebo
in improving nasal and conjunctival symptoms over a 2-week treatment period.
There was no clear dose–response effect at dosages above 60 mg twice daily
(114); thus fexofenadine was initially launched in the United States at a recom-
mended dosage of 60 mg twice daily although once-daily studies were underway.
Such studies in the United States in ragweed-sensitive rhinitics (115) and in Eu-
rope in grass pollen–sensitive rhinitics (100) compared once-daily treatment with
fexofenadine 120 mg and 180 mg to placebo. The emphasis was not only on the
overall effect over 24 hours but also on the level of protection afforded at trough
drug levels, immediately prior to the daily dosing, to ensure that once-daily treat-
ment did truly provide 24 hours symptom relief. These evaluations found that
once-daily fexofenadine was indeed protective throughout the 24 hours and that
both 120 mg daily and 180 mg daily were significantly better than placebo in
improving both rhinitis and conjunctivitis. There was no statistical difference
between the 120 mg and the 180 mg dosages. Fexofenadine was licensed for use,
following recommendations from the appropriate licensing authorities, as a once-
daily treatment for seasonal allergic rhinitis at 120 mg in Europe and 180 mg in
the United States. Both the 120 mg daily and the 180 mg daily dosages have
been shown to improve quality of life in patients with seasonal allergic rhinitis,
ameliorating both work and activity impairment (116).
Mizolastine. Mizolastine has also been developed as a once-daily medica-

tion. An early placebo-controlled study in 494 patients with seasonal allergic
rhinitis compared the efficacy of 5, 10, and 15 mg once-daily dosages. The two
higher dosages had a significant effect in relieving total nasal and ocular symp-
toms after 7 days of treatment (117). Further evaluations focusing on the 10 mg
daily dose have confirmed the benefit of mizolastine in reducing nasal itch,
sneeze, and rhinorrhea in seasonal disease (118–120). Onset of symptom relief
began as early as 2 hours after dosing (118) in established disease (Fig. 5).
Figure 5 The onset of symptom relief following oral administration of mizolastine 10

mg (n ⫽ 122, 䊉), cetirizine 10 mg (n ⫽ 125, 䊐), and placebo (n ⫽ 128, 䉱) in seasonal
allergic rhinitis. p ⬍ 0.05 and p ⬍ 0.01 vs. placebo, respectively. Starting baseline total
symptom scores were 13.4 ⫾ 4.2, 13.2 ⫾ 4.4, and 13.1 ⫾ 4.3 for mizolastine, cetirizine,
and placebo, respectively. Results represented a mean group decrease from pretreatment
baseline. (From Ref. 118.)
Prophylactic therapy, initiated before symptom development, delayed the onset

of seasonal disease in comparison to placebo (120). An open-label effectiveness
study, involving 5408 patients with seasonal allergic rhinitis, reported that symp-
toms improved in 93% of patients receiving mizolastine 10 mg once a day over
a 14-day treatment period, and that symptoms decreased by at least 50% in 86%
of patients (121).
Ebastine. Ebastine is a piperidine derivative in the same class of H1-anti-
histamines as azelastine, terfenadine, and loratadine. It, too, has been developed
as a once-daily medication at a dosage of 10 mg. Placebo-controlled studies have
confirmed its clinical effect in significantly reducing nasal itch, sneeze, and rhi-
norrhea, but no effect on nasal obstruction (122). Several studies have compared
ebastine at the 10 and 20 mg dosage in the treatment of seasonal allergic rhinitis
(123, 124) and have suggested that 10 mg may not afford 24 hour symptom re-
lief. A 10 mg dose taken at night was found to be no more effective than pla-
cebo, while 10 mg taken in the morning (123). Ebastine in a dosage of 20 mg,
196 Howarth
whether taken in the morning or in the evening, was superior to placebo. There
was no statistical significance between the 10 and 20 mg treatment groups, but
it has been proposed that 10 mg ebastine be used for mild rhinitis and the higher
dosage for more severe disease (123, 124).
Others. Acrivastine is related to the H1-antihistamine triprolidine. It does
not have advantages over the once-daily nonsedating H1-antihistamines since it
has a short half-life, needing to be taken three times a day (8 mg three times
daily), and has CNS effects (125), especially in association with alcohol (126).
It is effective in the treatment of seasonal allergic rhinitis (127, 128). Emedastine
has been developed for ocular application (129, 130) and tested in a conjunctival
challenge model (131). No placebo-controlled clinical trials have been published
with either this H1-antihistamine or another H1-antihistamine under development,
epinastine (132). Levocetirizine is being developed for clinical use (40), based
on the findings that cetirizine is a racemic mixture of two enantiomers: levocetiri-
zine (R-enantiomer) and dextrocetirizine (S-enantiomer), and that histamine nasal
challenge studies indicate that the H1-receptor antagonistic activity resides with
the R-enantiomer. No trial reports are published as yet relating to its efficacy in
seasonal allergic rhinitis (SAR). A further novel H1-receptor antagonist, rupata-
dine, has been found to be clinically effective in SAR when given at a dosage
of 10 mg once daily (133).
2. Comparative Studies
Comparisons have been made between nonsedating H1-antihistamines and seda-
tive H1-antihistamines such as chlorpheniramine and pheniramine, other nonse-
dating H1-receptor antagonists, and other classes of medication used for allergic
rhinitis.
While sedating and nonsedating H1-antihistamines often have similar clini-
cal efficacy, the two generations of H1-receptor antagonists are clearly distin-
guishable by their sedative adverse effect profile. The nonsedating H1-antihista-
mines have a much more favorable risk/benefit profile. A recent study compared
a sustained-release formulation of brompheniramine with loratadine and found
that brompheniramine 12 mg twice daily was clinically more effective in reliev-
ing nasal and ocular symptoms than loratadine 10 mg once daily (134). This
dosage of brompheniramine was, however, clearly sedative (134). A comparative
evaluation of cetirizine and chlorpheniramine similarly found that while both
treatments were effective in the clinical control of allergic rhinitis, the first-gener-
ation H1-antihistamine chlorpheniramine caused sedation in 40.5% of patients but
only 11.6% of cetirizine-treated patients reported sedation (135). Comparisons of
second-generation H1-antihistamines have, in general, not found any major clini-
cal differences over 1–2 week study periods (100, 110, 118, 124, 136–139).
Fexofenadine, when administered in a dose of 120 mg once daily, is comparable

to cetirizine 10 mg daily in relieving both nasal and ocular symptoms (100).
A recent comparative study of fexofenadine 120 mg once daily and lorata-
dine 10 mg once daily with placebo in 688 patients with SAR revealed, however,
that while these H1-antihistamines were both effective in reducing symptoms in
comparison to placebo, there were differences in their profile of effect (139). The
two active treatments both improved nasal itch, sneeze, and rhinorrhea compara-
bly but only fexofenadine improved nasal obstruction (Fig. 4). This improvement
was statistically greater than that with either placebo or loratadine. Fexofenadine
also significantly improved the RQLQ index more than either placebo or loratad-
ine. This suggests a potential for fexofenadine to modify disease in addition to
its H1-receptor antagonism. An analysis of the quality-of-life data using the num-
ber of patients needed to treat (NNT) as an endpoint revealed that 8.4 patients
needed to be treated with fexofenadine for one patient to have a clinically impor-
tant improvement in quality of life as compared with loratadine, and 7.2 patients
in relationship to placebo therapy. The equivalent calculation for loratadine was
that 57.2 patients needed to be treated with loratadine to see an improvement in
QOL over placebo (139). The use of such NNT analysis with a standardized QOL
score from other studies would facilitate an evaluation of comparable efficacy of
differing treatments. These findings of an improvement in QOL with fexofena-
dine confirm other findings (116, 140).
A range of studies have found that topical intranasal corticosteroid therapy
is more effective than systemic antihistamine therapy in allergic rhinitis (141–
144) (Fig. 6). This has been confirmed by a meta-analysis of a range of compara-
tive studies between H1-antihistamines and nasal steroids which showed that reg-
ular use of intranasal corticosteroids is more efficacious in reducing symptoms
then regular H1-antihistamine therapy (145). While this would be anticipated for
nasal obstruction, the meta-analysis identified that this was also the case for nasal
itch, rhinorrhea, and sneezing.
Although it might be anticipated, on account of their systemic bioavailabil-
ity, that oral H1-antihistamines would have additional activity in reducing ocular
as well as nasal symptoms over topical treatment to the nose, the meta-analysis
revealed that topical nasal steroids and oral H1-antihistamines have comparable
effects in reducing eye symptoms in seasonal allergic rhinitis. This may relate
to systemic bioavailability of steroids from the nose, or possibly to improved
nasolacrimal drainage with improvement in nasal obstructive responses. The for-
mer is more likely since, even with a standard dose, evidence for systemic effects
has been found with nasal steroid therapy (146), although this appears drug-
rather than class-specific (147). As expected, a decongestant has a greater effect
on nasal obstruction than an H1-antihistamine (148), although the profile of effect
is limited to nasal blockage. Comparative studies between oral H1-antihistamines
198 Howarth
Figure 6 Influence of intranasal fluticasone 200 µg/day (n ⫽ 121) and oral loratadine
10 mg daily (n ⫽ 119) on symptoms in seasonal allergic rhinitis. Results are presented
as median percentage of symptom-free days for each of the nasal and conjunctival symp-
toms scored over the 4-week treatment period. (From Ref. 144.)
and topical cromoglycate identify that both therapeutic approaches have compara-
ble clinical benefit, although the frequency of treatment regimens differs and
would favor H1-antihistamines on the basis of compliance with regular medica-
tion.
B. Perennial (Persistent) Allergic Rhinitis

As for seasonal allergic rhinitis, H1-antihistamines are effective in the treatment
of this condition. With chronic persistent disease, however, nasal obstruction is
often a more prominent symptom while nasal itch is less common. The benefit
from H1-antihistamines may therefore be less marked than that reported in sea-
sonal allergic disease and time to treatment improvement may be more prolonged.
Indeed an early study in perennial disease found no treatment benefit (149). Due
to these differences from seasonal disease, patient selection is often more rigor-
ous, with exclusion of patients in whom nasal obstruction is the most troublesome
symptom, or the results are biased by the exclusion of this symptom from an
overall rhinitis evaluation score.
1. Placebo-Controlled Studies
Significant clinical benefit over placebo has been reported with cetirizine 10 mg
daily (150–152), loratadine 10 mg daily (153), and mizolastine 10 mg daily (154).
Symptom improvement can progressively increase during 28 days of treatment
(153) and these trials report the most marked benefit for nasal pruritus, sneezing,
and rhinorrhea, with a lesser effect on nasal obstruction. The lack of benefit on
nasal obstruction was highlighted in one study in which the nasal corticosteroid
beclomethasone dipropionate was administered after the use of regular antihista-
mine treatment. This identified a further reduction in symptoms, in particular,
blocked nose (155). Both cetirizine (152) and mizolastine (154) have, however,
been found to significantly improve nasal obstruction and this symptomatic bene-
fit has also been matched by a significant improvement in rhinoscopic appearance
with mizolastine (154). The improvement in perennial rhinitic symptoms with
cetirizine is associated with an improvement in quality of life (152). In a 26-
week treatment period, a higher dosage of cetirizine (20 mg daily) was found
not only to improve rhinitis, including nasal obstruction, but also to improve
lower airway symptoms, increase peak flow, and reduce the requirement for as-
needed beta-agonist therapy in subjects with coexisting asthma (156). To date,
there are no published placebo-controlled trials of desloratadine, fexofenadine,
or levocetirizine in perennial allergic rhinitis.
2. Comparative Studies with H1-Antihistamines

As for seasonal allergic disease, comparative studies among the nonsedating H1-
antihistamines indicate that at standard dosages they have similar clinical effi-
cacy. A comparative evaluation reported cetirizine to be more effective over the
first week of treatment than ebastine (157), although this difference was not evi-
dent after 4 weeks of treatment. No difference is evident between mizolastine or
loratadine in reducing nasal or ocular symptoms in perennial allergic rhinitis over
4 weeks of treatment (158).
With respect to comparisons with older H1-antihistamines, a 6-month trial
of loratadine, 10 mg once daily, and clemastine, 1 mg twice daily, reported com-
parable effects. Good or excellent responses were considered to have occurred
in 63% of patients treated with loratadine and 64% of those receiving clemastine
(159). The clemastine-treated patients did, however, experience more sedation
(28%) than those receiving loratadine (4%). A similar difference in sedative pro-
file was reported in a separate study of loratadine and clemastine (160). The
persistence of benefit with both loratadine and clemastine over the 6-month treat-
ment period indicates that there is no tachyphylaxis to the effects of these H1-
antihistamines.
200 Howarth
3. Comparative Studies with Other Agents

Fewer studies have been undertaken in perennial disease than in seasonal disease.
Topical nasal corticosteroid therapy is more effective than H1-antihistaminic ther-
apy (161–163). Studies have been undertaken with a combination of an H1-anti-
histamine and an oral decongestant in comparison to an H1-antihistamine alone
(see combination therapy section). No good comparisons exist with respect to
cromoglycate preparations.
VII. TOPICAL H1-ANTIHISTAMINES AND NATURALLY

OCCURRING RHINOCONJUNCTIVITIS
Two H1-antihistamines have been developed primarily for topical application:

levocabastine for nasal and ocular administration and azelastine for nasal admin-
istration (51, 164). Dimethindene has been tested in an allergen challenge model
but not as yet in clinical disease (165). Clinical data are available for olopatadine
(166) and ketotifen (166). Antihistamines such as azelastine, ketotifen, and levo-
cabastine may be sedating when administered orally but are free from this adverse
effect when administered topically due to the smaller dose required to achieve
clinical benefit. The nasal dosage for levocabastine and azelastine is 0.1 mg and
0.14 mg to each nostril twice daily, respectively. The conjunctival dosage of
levocabastine is 0.03 mg administered to each eye twice daily. The nasal efficacy
of these topical H1-antihistamines has been demonstrated under challenge condi-
tions (39, 56, 67). They have a rapid onset of action (10–15 min) and are effective
for up to 12 h. These findings have been confirmed in the eye using conjunctival
challenge (56, 65). Concern that the effect of topical therapy might be limited
by rhinorrhea has not been substantiated. Experimentally induced rhinorrhea with
methacholine and nasal washing 30 seconds after nasal levocabastine therapy has
not been found to reduce its efficacy in inhibiting histamine-induced sneezing
and rhinorrhea (167).
A. Rhinitis
Both levocabastine and azelastine administered topically are most effective
against nasal itch, sneeze, and rhinorrhea. In some studies nasal obstruction is
also reduced by azelastine (168–171). There are a number of published placebo-
controlled trials in seasonal allergic rhinitis (172–174), but the majority of studies
report comparison with active medications such as H1-antihistamines (169, 170,
175–177), cromoglycate (172, 178), or nasal corticosteroids (176, 179). One pla-
cebo-controlled study reported no effect of levocabastine on nasal obstruction in
Mountain Cedar-sensitive patients with seasonal allergic rhinitis, when used at
a dosage of 0.2 mg twice daily (1 spray into each nostril twice daily), despite
clear effects on the neurally medicated symptoms of itch, sneeze, and rhinorrhea
(173). In patients with seasonal allergic rhinitis, regular therapy with topical nasal
azelastine is more effective than on-demand use, with effects on nasal inflamma-
tion (ICAM-1 expression on epithelial cells) as well as clinical parameters (80).
Half the standard daily dosage (0.28 mg/day) was also found in this study to be
as effective as the standard dosage (0.56 mg/day), although there was signifi-
cantly greater use of rescue medication in the lower-dosage treatment group.
Azelastine, administered as a nasal spray (180), is more effective than either oral
azelastine or terfenadine in relieving nasal obstruction, while producing compara-
ble relief of other nasal symptoms. Levocabastine is reported to be more effective
than a topical antihistamine/decongestant (antazoline/naphazoline) preparation
(176) or topical cromoglycate (172, 178) in the treatment of seasonal allergic
rhinitis.
The two comparative studies of levocabastine (0.5 mg/mL, two sprays each
nostril four times daily) and cromoglycate (20 mg/mL, two sprays each nostril
four times daily) involving 114 patients over 2 weeks found significantly fewer
symptoms with levocabastine therapy (76% of patients improving vs. 46% on
cromoglycate) (181), which was paralleled by more symptom-free days in the
levocabastine-treated patients (172). An open comparison of the onset of action
of topical levocabastine and nedocromil to both the nose and eye reported that
more than 80% of patients with seasonal allergic rhinitis reported symptom relief
with both medications within 1 h. This amounted to approximately a 50% reduc-
tion in symptom severity (182).
While both levocabastine (176) and azelastine (179) nasal sprays are re-
ported to be as efficacious as topical nasal steroid administration, the comparative
studies are limited and further studies are required before valid comparison can
be made. One study of patients with seasonal allergic rhinitis taking nasal steroids
or oral antihistamines who remained symptomatic after a 1- to 2-week washout
period compared double-dose azelastine (1.1 mg/day) with the combination of
loratadine 10 mg daily and nasal beclomethasone dipropionate 200 µg twice
daily. After 1 week of treatment there was no statistical difference between the
treatments, and azelastine was concluded to be as effective as the combination
therapy (179). Such studies are likely to be misleading: in essence, this represents
predominantly a comparison of azelastine and loratadine, since the effects of the
nasal steroid will not be fully expressed within the timeframe of such a study.
Another study that assessed nasal nitric oxide measurements as a marker of nasal
inflammation, found a significant effect with nasal steroid therapy but not with
topical levocabastine (183).
Studies in perennial rhinitis are limited. One preliminary 2-week study re-
ported improvement in sneezing and rhinorrhea with topical levocabastine, in
comparison with placebo, which could not be improved further by the addition
202 Howarth
of topical nasal beclomethasone dipropionate. Nasal blockage did respond to the

additional therapy (184). Another 6-week study of azelastine nasal spray therapy
(0.14 mg per nostril twice daily; total dosage 0.56 mg) reported a significant
effect, in comparison to placebo, on all nasal symptoms, including nasal obstruc-
tion in children with perennial allergic rhinitis (174).
B. Conjunctivitis
Levocabastine (0.5 mg/mL, one drop in each eye twice daily) has been shown
to be superior to placebo for the treatment of itchy eyes, runny eyes, and red
eyes associated with seasonal allergic conjunctivitis (185). Relief of symptoms
is rapid, occurring within 15 min of application (168). Topical levocabastine (0.5
mg/mL) appears to be more efficacious than topical cromoglycate (20 mg/mL)
when both preparations are administered four times daily for seasonal allergic
conjunctivitis over a 4-week period (186, 187). Patient diary card recordings
identified fewer symptoms in the levocabastine-treated patients (181). In one of
the studies, the proportion of patients virtually symptom-free on high pollen count
days was greater in the levocabastine (33%)- than in the cromoglycate (6%)-
treated patients (187).
VIII. ADVERSE EFFECTS
The use of medication for treatment of a condition is based both on its beneficial
effects and on its adverse effects potential. The major advantage of the second-
generation oral H1-antihistamines, which considerably improved their risk/benefit
profile, was their absence of CNS sedative effects when used at standard clinical
dosages. With loratadine, fexofenadine, mizolastine, and ebastine, the reported
side effects of tiredness and drowsiness are no different from placebo at the rec-
ommended dosage level (188–190). This clinical reporting is substantiated by
laboratory assessment incorporating reaction time analysis, the performance of
complex sensorimotor tasks such as simulated car driving, sleep latency studies,
and electroencephalographic (EEG) monitoring (191–198). The topical H1-antag-
onist levocabastine has also been shown to be devoid of adverse CNS effects by
using such methods (199). When the dosage of loratadine and mizolastine is
increased above the standard 10 mg once daily, there are reports of cognitive
or psychomotor performance test impairment (190). Cetirizine is labeled as a
nonsedating H1-antihistamine in Europe and as a sedating antihistamine in the
United States. Many studies with cetirizine show no difference from placebo in
the reporting of drowsiness or sleepiness, although some do at the standard dos-
age (reviewed in 190) and there are reported EEG abnormalities (200).
Cetirizine is only 40% metabolized in adults and is thus relatively uninflu-

enced by impaired hepatic function. Loratadine, while sharing the same cyto-
chrome P-450 isoenzyme (CYP3A) as astemizole and terfenadine (201), is also
metabolized by an alternative isoenzyme (CYP2D) (202) and no adverse cardiac
effects are recorded with this H1-antihistamine (203). Of the newer H1-antihista-
mines, ebastine is metabolized by cytochrome P-450 isoenzymes. At higher dos-
ages or in interaction with agents such as ketoconazole, there is the potential for
QTc prolongation (204), although there are no adverse effects at standard dosage.
Mizolastine is also metabolized in part by liver cytochrome P-450 isoenzymes
and care has to be taken in relationship to drug interactions and hepatic impair-
ment; however, the tendency for QTc prolongation is considerably less with this
H1-antihistamine than with terfenadine, and no adverse cardiac effects are seen
at standard dosage (205). Fexofenadine is not metabolized hepatically and ap-
pears very safe from the cardiac perspective based on in vitro and in vivo studies.
No effect of fexofenadine on QTc intervals has been found when administered
either at 480 mg/day for 2 weeks to patients or at either 800 mg/day for 6 days
or 240 mg/day for a year to healthy volunteers (206).
Topical H1-antihistamines are associated with very low plasma levels and,
in standard doses, they generally do not induce systemic effects. The main ad-
verse effect of topical therapy is either nasal or ocular irritation (168, 172, 186).
This affects approximately 5% of patients receiving the nasal spray and 16% of
those receiving eye drops (168). This profile of adverse reaction reporting is
equally associated with placebo application (6% and 16%, respectively) and does
not appear related to the drug per se. Detailed ophthalmological studies have not
revealed any structural or functional adverse effect with regular use (177).
IX. NEW DEVELOPMENTS AND SPECIAL

CONSIDERATIONS
A. H1-Antihistamine/Decongestant Combination Therapy
The lack of effect of H1-antihistamines on nasal obstruction, whether orally or
topically administered, has led to the development of combination products con-
taining both H1-antihistamines and decongestants. For decades, two oral alpha-
adrenergic agonists, pseudoephedrine and phenylpropanolamine, have been com-
monly used as decongestants. Recently, a review of adverse effects related to the
intake of ephedra alkaloids instigated by the U.S. Food and Drug Administration
(FDA) revealed deaths due to cardiovascular and CNS events (207), and the
FDA has requested that pharmaceutical companies stop marketing products that
contain phenylpropanolamine (208).
There is also concern over the use of pseudoephedrine due to the potential
204 Howarth
for serious cardiac adverse effects (209); however, modified-release formulations

for the combination preparations provide a sustained release and appear safe from
the cardiovascular viewpoint.
Clinical trials in perennial allergic rhinitis have been undertaken with com-
binations of pseudoephedrine and the newer nonsedating H1-antihistamines. The
advantage of a combination approach over an H1-antihistamine alone in improv-
ing nasal obstruction has been shown in large studies involving administration
of pseudoephedrine (120 mg) with fexofenadine (5 mg), loratadine (5 mg), or
cetirizine (5 mg) used in twice-daily dosing regimens (210–212). Studies in chil-
dren with the loratadine and pseudoephedrine combination given on a dose/kg
basis (213) and nasal allergen challenge studies involving a cetirizine/pseudoe-
phedrine combination (214) have also shown the benefit of the combination in
relieving nasal symptoms, in particular, nasal obstruction in comparison to the
H1-antihistamine alone. It has also been possible with the combination product
to demonstrate an objective improvement in nasal obstruction by measuring na-
sal peak inspiratory flow (215). Acrivastine-D, a combination of 8 mg acrivastine
and 60 mg pseudoephedrine, taken three times daily, has also been found to
improve nasal symptoms and nasal airflow in comparison to placebo (216).
The improved ability to demonstrate clinical benefit of the combination
product over the individual components in more recent studies can be attributed
to improved study design and to larger sample size. Multicenter studies of lorata-
dine-D, involving over 800 patients (146, 217), and fexofenadine-D, involving
651 patients (210), have shown that it is possible to separate the effect of the
component medications and demonstrate a significant effect of the combination
product (Fig. 7). Such studies also have demonstrated a significant effect of the
combination over and above the additive effects of the two products (212).
The formulation may also be critical to the acceptance of these preparations.
Loratadine-D, which is a combination of 5 mg loratadine and 120 mg pseudo-
ephedrine in a Retab tablet formulation, such that there is an immediate-release
coating of 5 mg loratadine and 60 mg pseudoephedrine, has a low adverse effect
profile. Nervousness after loratadine-D administration (4–7%) is more common
than with placebo (1–2%). The comparable figure for fexofenadine-D is 1.7%.
The combination product is, however, associated with a higher prevalence of
insomnia (12.8% for fexofenadine-D vs. 1.8% for fexofenadine alone) (210).
B. Other Combinations
The addition of regular therapy with a nedocromil sodium nasal spray to oral
therapy with astemizole has been found to provide improved control in ragweed
seasonal allergic rhinitis, despite greater use of rescue medication in the astemi-
zole-treated group (218). In patients with perennial rhinitis (both allergic and
Figure 7 Comparative study of the effects of fexofenadine 60 mg twice daily, pseudo-

ephedrine sustained-release 120 mg twice daily, or a combination of the two over a 2-week
treatment period. This randomized, double-blind, parallel-group study design involved 651
patients allergic to ragweed. The combination product was more effective than fexofena-
dine alone in reducing the 7.0 pm reflective nasal congestion score (NCS). Baseline NCS
scores were between 2.32 and 2.36 for the 3 treatment groups. (From Ref. 210.)
nonallergic) in whom rhinorrhea is a prominent symptom, the addition of regular

therapy three times a day with an ipratropium bromide nasal spray has been found
to decrease both the severity and duration of rhinorrhea when used in combination
with terfenadine compared to terfenadine treatment alone (219).
C. Common Cold
Nasal lavage studies in the common cold have failed to demonstrate histamine
release and nonsedating H1-antihistamines have not been found to be effective
(220, 221). One study of loratadine-D vs. placebo has, however, reported that
loratadine-D, administered twice daily, is more effective than placebo in relieving
symptoms, with improvement not only in nasal obstruction, as might be antici-
pated with pseudoephedrine, but also in sneezing and rhinorrhea (222). In view
of the previous lack of effect of H1-receptor antagonism alone, assessment of
pseudoephedrine alone administered by the same method is now required to as-
sess whether modification of nasal obstruction itself may modify other sequelae,
or whether such a combination is essential for benefit.
206 Howarth
D. Nonallergic Rhinitis
Some patients with rhinitis who are skin-test negative have nasal eosinophilia
(NARES) and may benefit from H1-antihistamine therapy. So may individuals
who experience cold air–induced rhinorrhea, as in these individuals there is evi-
dence of mast cell degranulation (223, 224). Clinical trials have thus reported
some benefit with H1-antihistamines in nonallergic rhinitis patients. Subanalysis
reveals that patients in whom sneezing is the most prominent symptom respond
best to this mode of therapy (155, 225).
X. SUMMARY
In allergic rhinoconjunctivitis, histamine is known to contribute predominantly

to nasal itch, sneeze, rhinorrhea, conjunctival itch, and lacrimation and these
symptoms benefit most from H1-antihistamine therapy. The discovery in the early
1980s of nonsedating H1-receptor antagonists contributed dramatically to the
more widespread acceptance of this mode of therapy. This also led to the under-
taking of well-designed clinical trials that have added significantly to our
understanding of allergic rhinitis. Oral treatment modifies both nasal and ocular
symptoms and provides effective control throughout a 24-h period with once- or
twice-daily medication. The advent of topical H1-receptor antagonists offers a
wider choice of treatments and provides equal or greater efficacy with lower
systemic bioavailability. While having a major impact on rhinoconjunctivitis
symptoms, H1-antihistamines do not fully modify disease since histamine is not
the only contributor to symptom generation in allergic rhinoconjunctivitis. While
the search for oral H1-antihistamines with more widespread ‘‘antiallergic’’ activ-
ity continues, the currently available medications modify predominantly hista-
mine-regulated events despite in vitro evidence of greater potential. The develop-
ment of these new medications may be the next significant advance in this mode
of treatment.
REFERENCES
1. Staub AM, Bovet D. Action de la thymoxyethyldiethylamine (929F) et des ethers

phenoliques sur le choc anaphylactique. CR Soc Biol 1937; 125:818–821.
2. Dale HH. Some chemical factors in the control of the circulation. Croonian lectures.
Lancet 1929; 1233–1237, 1285–1290.
3. Bartosch R, Feldberg W, Nagel E. Das Freiwerden eines histaminin-ahnlichen Stof-
fes bei der anaphylaxic des Mierschweinchens. Pflugers Arch Ges Physiol 1932;
230:129–153.
4. Dragstedt CA, Mead FB. The role of histamine in canine anaphylactic shock. J
Pharmacol Exp Ther 1936; 57:419–426.
5. Blackley CH. Experimental Research on the Causes and Nature of Catarrhus Aesti-
vus. London: Bailliere Tindall and Cox, 1873.
6. Levy L, Seabury JH. Spirometric evaluation of Benadryl in asthma. J Allergy 1947;
18:244–250.
7. Herxheimer H. Antihistamines in bronchial asthma. Br Med J 1949; 2:901–905.
8. Mota I, Da Silva WD. The anti-anaphylactic and histamine releasing properties of
the antihistamines. Their effect on the mast cell. Br J Pharmacol 1960; 15:396–
404.
9. Kemp JP, Meltzer EO, Orgel HA, Welch MJ, Bucholtz GA, Middleton E, Spector
SL, Newton JJ, Perhach JL Jr. A dose-response study of the bronchodilator action
of azelastine in asthma. J Allergy Clin Immunol 1987; 79:893–899.
10. Brik A, Tashkin DP, Gong H Jr, Dauphinee B, Lee E. Effect of cetirizine, a new
histamine H1-antagonist, on airway dynamics and responsiveness to inhaled hista-
mine in mild asthma. J Allergy Clin Immunol 1987; 80:51–56.
11. Church MK, Gradidge CF. Inhibition of histamine release from human lung in vitro
by antihistamines and related drugs. Br J Pharmacol 1980; 69:663–667.
12. Lichtenstein LM, Gillespie E. The effects of the H1 and H2 antihistamines on aller-
gic histamine release and its inhibition by histamine. J Pharmacol Exp Ther 1975;
192:441–450.
13. Pandit PR, Kulkarni SD, Joglekar GV. Study of the relationship between antihista-
minic, anticholinergic and central depressant properties of various antihistaminics.
Indian J Med Sci 1973; 27:920–924.
14. Stone CA, Wenger H, Ludden CT, Stavorski JM, Ross CA. Antiserotinin–antihista-
minic properties of cyproheptadine. J Pharmacol Exp Ther 1961; 131:73–84.
15. Byck R. Drugs and the treatment of psychiatric disorders. In: Goodman, Gilman,
eds. The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan,
1975:152–200.
16. Casterline CL, Evans R. Further studies on the mechanism of human histamine-
induced asthma: The effect of an aerosolized H1-receptor antagonist (diphenhydra-
mine). J Allergy Clin Immunol 1977; 59:420–424.
17. Moser L, Huther KJ, Koch-Weser J, Lundt PV. Effects of terfenadine and diphenhy-
dramine alone or in combination with diazepam or alcohol on psychomotor perfor-
mance and subjective feelings. Eur J Clin Pharmacol 1978; 14:417–423.
18. Cheng HC, Woodward JK. Antihistaminic effect of terfenadine: a new piperidine-
type antihistamine. Drug Dev Res 1982; 2:181–196.
19. Bousquet J, Van Cauwenberge P, Khaltaev N, et al. Allergic rhinitis and its impact
on asthma. J Allergy Clin Immunol 2001; 108(Suppl 5):S147–S334.
20. Howarth PH. The cellular basis for allergic rhinitis. Allergy 1995; 50 (Suppl 23):
6–10.
21. Howarth PH, Wilson S, Lau L, Rajakulasingam K. The nasal mast cell and rhinitis.
Clin Exp Allergy 1991; 21 (Suppl 2):3–8.
22. Naclerio RM, Proud D, Togias AG, Adkinson NF Jr, Meyers DA, Kagey-Sobotka
A, Plaut M, Norman PS, Lichtenstein LM. Inflammatory mediators in late antigen
induced rhinitis. N Engl J Med 1985; 313:65–70.
208 Howarth
23. Knani J, Campbell A, Enander I, Peterson CG, Michel FB, Bousquet J. Indirect
evidence of nasal inflammation assessed by titration of inflammatory mediators and
enumeration of cells in nasal secretions of patients with chronic rhinitis. J Allergy
Clin Immunol 1992; 90:880–889.
24. Devalia JL, Grady D, Harmanyeri Y, Tabaqchali S, Davies RJ. Histamine synthesis
by respiratory tract micro-organisms: possible role in pathogenicity. J Clin Pathol
1989; 42:516–522.
25. Bainton DF, Farquhar MG. Segregation and packaging of granule enzymes in eo-
sinophilic leukocytes. J Cell Biol 1970; 45:54–73.
26. Gomez E, Corrado OJ, Baldwin DL, Swanston AR, Davies RJ. Direct in vivo evi-
dence for mast cell degranulation during allergen-induced reactions in man. J Al-
27. Allansmith MR. The Eye and Immunology. St. Louis: CV Mosby, 1982 p 47.
28. Allansmith MR, Greiner JV, Baird RS. Number of inflammatory cells in the normal
conjunctiva. Am J Ophthalmol 1978; 86:250–259.
29. Morgan SJ, Williams JH, Walls AF, Holgate ST. Mast cell hyperplasia in atopic
keratoconjunctivitis. An immunohistochemical study. Eye 1991; 5:729–735.
30. Irani AM, Butrus SI, Tabbara KF, Schwartz LB. Human conjunctival mast cells:
distribution of MCT and MCTC in vernal conjunctivitis and giant papillary conjuncti-
vitis. J Allergy Clin Immunol 1990; 86:34–40.
31. Foster CS, Rice BA, Dutt JE. Immunopathology of atopic keratoconjunctivitis.
Ophthalmology 1991; 98:1190–1196.
32. Romagnani S, Maggi E, Parronchi P, Macchia D, Piccinni MP, Ricci M. Increased
numbers of Th2-like CD4⫹ T cells in target organs and in the allergen-specific
repertoire of allergic patients. Possible role of IL-4 produced by non-T cells. Int
Arch Allergy Appl Immunol 1991; 94:133–136.
33. Abelson MB, Baird RS, Allansmith MR. Tear histamine levels in vernal conjuncti-
vitis and other ocular inflammations. Ophthalmology 1980; 87:812–814.
34. Mygind N, Secher C, Kirkegaard J. Role of histamine and antihistamines in the
nose. Eur J Resp Dis Suppl 1983; 128:16–20.
35. Rajakulasingam K, Mani R, Church MK, Holgate ST, Howarth PH. Changes in
mucosal blood flow and airways resistance after nasal challenge with bradykinin
and histamine. Thorax 1992; 47:894A.
36. Greiff L, Andersson M, Svensson C, Persson CGA. Topical azelastine has a 12-
hour duration of action as assessed by histamine challenge-induced exudation of
α2-macroglobulin into human nasal airways. Clin Exp Allergy 1997; 27:438–444.
37. Wong L, Hendeles L, Weinberger M. Pharmacologic prophylaxis of allergic rhini-
tis: relative efficacy of hydroxyzine and chlorpheniramine. J Allergy Clin Immunol
1981; 67:223–228.
38. Wood-Baker R, Lau L, Howarth PH. Histamine and the nasal vasculature: the in-
fluence of H1- and H2-histamine receptor antagonism. Clin Otolaryngol 1996; 21:
348–352.
39. Holmberg K, Pipkorn U, Bake B, Blychert L-O. Effects of topical treatment with
H1- and H2-antagonists on clinical symptoms and nasal vascular reactions in patients
with allergic rhinitis. Allergy 1989; 44:281–227.
40. Wang DY, Hanotte F, De Vos C, Clement P. Effect of cetirizine, levocetirizine and
dextrocetirizine on histamine-induced nasal response in healthy adult volunteers.

Allergy 2001; 56:339–343.
41. Svensson C, Baumgarten CR, Pipkorn U, Alkner U, Persson CG. Reversibility and
reproducibility of histamine induced plasma leakage in nasal airways. Thorax 1989;
44:13–18.
42. Rajakulasingam K, Polosa R, Holgate ST, Howarth PH. Comparative nasal effects
of bradykinin, kallidin and [Des-Arg9]-bradykinin in atopic rhinitic and normal vol-
unteers. J Physiol 1991; 437:577–587.
43. Rajakulasingam K, Polosa R, Lau LC, Church MK, Holgate ST, Howarth PH. Nasal
effects of bradykinin and capsaicin: influence on plasma protein leakage and role
of sensory neurons. J Appl Physiol 1992; 74:1418–1424.
44. Ishikawa S, Sperelakis N. A novel class (H3) of histamine receptors on perivascular
nerve terminals. Nature 1987; 327:158–160.
45. Lorant DE, Patel KD, McIntyre TM, McEver RP, Prescott SM, Zimmerman GA.
Coexpression of GMP-140 and PAF by endothelium stimulated by histamine or
thrombin. A juxtacrine system for adhesion and activation of neutrophils. J Cell
Biol 1991; 115:223–234.
46. Symon FA, Walsh GM, Watson SR, Wardlaw AJ. Eosinophil adhesion to nasal
polyp endothelium is P-selectin-dependent. J Exp Med 1994; 180:371–376.
47. Asako H, Kurose I, Wolf R, DeFrees S, Zheng ZL, Phillips ML, Paulson JC,
Granger DN. Role of H1-receptors and P-selectin in histamine-induced leukocyte
rolling and adhesion in post capillary venules. J Clin Invest 1994; 93:1508–1515.
48. Canonica GW, Ciprandi G, Pronzato C, Paolieri F, Scordamaglia A, Bagnasco M.
Role of adhesion molecules in allergic rhinitis. In: A Bascomb, J Sastre, eds. Pro-
ceedings XVI European Congress of Allergology and Clinical Immunology. Bolo-
gna: Monduzzi Editore 1995:127–142.
49. Raible DG, Schulman ES, Di Muzio J, Cardillo R, Post TJ. Mast cell mediators
prostaglandin D2 and histamine activate human eosinophils. J Immunol 1992; 148:
3536–3542.
50. Abelson MB, Smith LM. Levocabastine: evaluation in the histamine and compound
48/80 models of ocular allergy in humans. Ophthalmology 1988; 95:1494–1497.
51. Dechant KL, Goa KL. Levocabastine: a review of its pharmacological properties
vitis. Drugs 1991; 41:202–224.
52. Abelson MB, Udell IJ. H2 receptors in the human ocular surface. Arch Ophthalmol
1981; 99:302–304.
53. Bascom R, Wachs M, Naclerio RM, Pipkorn U, Galli SJ, Lichtenstein LM. Basophil
influx occurs after nasal antigen challenge: effects of topical corticosteroid pretreat-
ment. J Allergy Clin Immunol 1988; 81:580–589.
54. Klementsson H, Andersson M, Pipkorn U. Allergen-induced increase in non-spe-
cific nasal reactivity is blocked by antihistamines without a clear-cut relationship
to eosinophil influx. J Allergy Clin Immunol 1990; 86:466–472.
55. Iliopoulos O, Proud D, Adkinson NF Jr, Norman PS, Kagey-Sobotka A, Lich-
tenstein LM, Naclerio RM. Relationship between the early, late, and rechallenge
reaction to nasal challenge with antigen: observations on the role of inflammatory
mediators and cells. J Allergy Clin Immunol 1990; 86:851–861.
210 Howarth
56. Palma-Carlos AG, Palma-Carlos ML, Rombaut N. The effect of levocabastine nasal
spray in nasal provocation tests. Int J Clin Pharmacol Res 1988; 8:25–30.
57. Day JH, Briscoe MP, Welsh A, Smith J, Mason J. Onset of action, efficacy and
safety of a single dose of fexofenadine hydrochloride for ragweed allergy using an
environmental exposure unit. Ann Allergy Asthma Immunol 1997; 79:533–540.
58. Bousquet J, Czarlewski W, Cougnard J, Danzig M, Michel FB. Changes in skin-test
reactivity do not correlate with clinical efficacy of H1-blockers in seasonal allergic
59. Bachert C. Decongestant efficacy of desloratadine in patients with seasonal allergic
rhinitis. Allergy 2001; 56(Suppl 65):14–20.
60. Day JH, Briscoe MP, Clark RH, Ellis AK, Gervais P. Onset of action and efficacy
of terfenadine, astemizole, cetirizine, and loratadine for the relief of symptoms of
allergic rhinitis. Ann Allergy Asthma Immunol 1997; 79:163–172.
61. Frossard N, Lacronique J, Melac M, Benabdesselam O, Braun JJ, Glasser N, Pauli
G. Onset of action in the nasal antihistaminic effect of cetirizine and loratadine in
patients with allergic rhinitis. Allergy 1997; 52:205–209.
62. Persi L, Demoly P, Harris AG, Tisserand B, Michel FB, Bousquet J. Comparison
between nasal provocation tests and skin tests in patients treated with loratadine
and cetirizine. J Allergy Clin Immunol 1999; 103:591–594.
63. Wang D, Clement P, Smith J. Effect of H1 and H2 antagonists on nasal symptoms
and mediator release in atopic patients after nasal allergen challenge during the
pollen season. Acta Otolaryngol Stockh 1996; 116:91–96.
64. Bachert C, Wagenmann M, Vossen-Holzenkamp S. Intranasal levocabastine pro-
vides fast and effective protection from nasal allergen challenge. Rhinology 1996;
34:140–143.
65. Corren J, Rachelefsky G, Spector S, Schanker H, Siegel S, Holton D, Karcher K,
Travers S. Onset and duration of action of levocabastine nasal spray in atopic pa-
tients under nasal challenge conditions. J Allergy Clin Immunol 1999; 103:574–
580.
66. Juliusson S, Bende M. Effect of systemically administered H1- and H2-receptor
antagonists on nasal blood flow as measured with laser Doppler flowmetry in a
provoked allergic reaction. Rhinology 1996; 34:24–27.
67. Abelson MB, George MA, Schaefer K, Smith LM. Evaluation of the new ophthal-
mic antihistamine 0.05% levocabastine, in the clinical allergen challenge model of
allergic rhinitis conjunctivitis. J Allergy Clin Immunol 1994; 94:458–464.
68. Bousquet J, Campbell A, Michel F-B. Antiallergic activities of antihistamines. In:
Church MK, Rihoux J-P, eds. Therapeutic Index of Antihistamines. Lewiston, NY:
Hogrefe and Huber, 1992:57–96.
69. Togias AG, Naclerio RM, Warner J, Proud D, Kagey-Sobotka A, Nimmagadda I,
human mast cells by azatadine base. In vivo and in vitro evaluation. JAMA 1986;
255:225–229.
70. Baroody FM, Lim MC, Proud D, Kagey-Sobotka A, Lichtenstein LM, Naclerio
RM. Effects of loratadine and terfenadine on the induced nasal allergic reaction.
Arch Otolaryngol Head Neck Surg 1996; 122:309–316.
71. Miadonna A, Cottini M, Milazzo N, Tosi D, Danzig M, Tedeschi A. In vivo and
ex vivo inhibitory effects of loratadine on histamine release in patients with allergic

72. Naclerio RM, Proud D, Kagey-Sobotka A, Freidhoff L, Norman PS, Lichtenstein
LM. The effect of cetirizine on early allergic response. Laryngoscope 1989; 99:
596–599.
73. Perzanowska M, Malhotra D, Skinner SP, Rihoux J-P, Bewley AP, Petersen L-J,
1996; 45:486–490.
74. Chung JH, deTineo ML, Naclerio RM, Sorrentino JV, Winslow CM, Baroody FM.
Low dose clemastine inhibits sneezing and rhinorrhea during the early nasal allergic
reaction. Ann Allergy Asthma Immunol 1997; 78:307–312.
75. Ciprandi G, Pronzato C, Passalacqua G, Ricca V, Grogen J, Mela GS, Varese P,
76. Buscaglia S, Paolieri F, Catrullo A, Fiorino N, Riccio AM, Pesce G, Montagna P,
Bagnasco M, Ciprandi G, Canonica GW. Topical ocular levocabastine reduces
ICAM-1 expression both in vitro and in vivo. Clin Exp Allergy 1996; 26:1188–1196.
77. Ciprandi G, Buscaglia S, Pesce GP, Passalacqua G, Rihoux JP, Bagnasco M, Can-
CD54) expression on conjunctival epithelium both in early- and late-phase reactions
80. Ciprandi G, Ricca V, Passalacqua G, Truffelli T, Bertolini C, Fiorino N, Riccio
AM, Bagnasco M, Canonica GW. Seasonal rhinitis and azelastine. Long- or short-
term treatment? J Allergy Clin Immunol 1997; 99: 301–307.
ICAM-1 levels in nasal secretion by H1-blockers in seasonal allergic rhinitis. Al-
lergy 1997; 52:1022–1025.
82. Ciprandi G, Pronzato C, Ricca V, Passalacqua G, Danzig M, Canonica GW. Lora-
tadine treatment of rhinitis due to pollen allergy reduces epithelial ICAM-1 expres-
sion. Clin Exp Allergy 1997; 27:1175–1183.
zine on mast cell mediator release and cellular traffic during the cutaneous late-
85. Bousquet J, Czarlewski W, Cougnad J, Danzig M, Michel FB. Changes in skin-
test reactivity do not correlate with chemical efficacy of H1-blockers in seasonal
allergic rhinitis. Allergy 1998; 53:579–585.
212 Howarth
86. Howarth PH, Wilson SJ, Brewster H. The influence of cetirizine on symptom gener-
ation and nasal eosinophilia in seasonal allergic rhinitis. J Allergy Clin Immunol
1991; 87:151.
87. Howarth PH, Emanuel MB, Holgate ST. Astemizole, a potent histamine H1-receptor
antagonist: effect in allergic rhinoconjunctivitis, on antigen and histamine induced skin
weal responses and relationship to serum levels. Br J Clin Pharmacol 1984; 18:1–8.
88. Kemp JP, Buckley CE, Gershwin ME, Buchman E, Cascio FL, Chretien JH, Foster
TS, Gordon WE, Jakle C, Klemawesch SJ, et al. Multicenter, double-blind, placebo
controlled trial of terfenadine in seasonal allergic rhinitis and conjunctivitis. Ann
Allergy 1985; 54:502–509.
lergy 1991; 66:257–262.
90. Dockhorn RJ, Bergner A, Connell JT, Falliers CJ, Grabiec SV, Weiler JM, Shel-
lenberger MK. Safety and efficacy of loratadine (Sch-29851): a new non-sedating
antihistamine in seasonal allergic rhinitis. Ann Allergy 1987; 58:407–411.
91. Howarth PH, Holgate ST. Comparative trial of two non-sedative H1-antihistamines,
terfenadine and astemizole for hay fever. Thorax 1984; 39:668–672.
92. Beswick KB, Kenyon GS, Cherry JR. A comparative study of beclomethasone di-
propionate aqueous nasal spray with terfenadine tablets in seasonal allergic rhinitis.
Curr Med Res Opin 1985; 9:560–567.
93. Wood SF. Oral antihistamine or nasal steroid in hay fever: a double-blind, double-
dummy comparative study of once-daily oral astemizole vs twice daily nasal beclo-
methasone dipropionate. Clin Allergy 1986; 16:195–201.
94. Njaa F, Baekken T, Bjammer D, et al. Levocabastine compared with sodium cro-
moglycate eyedrops in children with both birch and grass pollen allergy. Pediatr
Allergy Immunol 1992; 3:39–42.
95. The Livostin Study Group. A comparison of topical levocabastine and oral terfena-
dine in the treatment of allergic rhinoconjunctivitis. Allergy 1993; 48:530–534.
96. Kaiser H, Weisberg S, Morris R, Mansmann H Jr, Mitchell D, Settipane G, Tinkel-
man D, Altman R, Love S, Samuel L. A comparison of cetirizine and chlorphenira-
mine vs placebo in the treatment of seasonal allergic rhinitis. J Allergy Clin Immu-
nol 1989; 83:306A.
97. Broide DH, Love S, Altman R, Wasserman SI. Evaluation of cetirizine in the treatment
of patients with seasonal allergic rhinitis. J Allergy Clin Immunol 1988; 81:176.
98. Panayotopoulos SM, Panayotopoulos ES. The efficacy of cetirizine in the treatment
of pollinosis. A correlation with the daily pollen count of atmospheric air. A double-
blind, placebo controlled study. Acta Ther 1988; 14:347–353.
99. Pearlman DS, Lumry WR, Winder JA, Noonan MJ. Once-daily cetirizine effective
in the treatment of seasonal allergic rhinitis in children aged 6–11 years: a random-
ised, double-blind, placebo-controlled study. Clin Pediatr 1997; 36:209–215.
100. Howarth PH, Stern MA, Roi L, Reynolds R, Bousquet J. Double-blind, placebo
Clin Immunol 1999; 104:927–933.
101. Ciprandi G, Passalacqua G, Mincarini M, Ricca V, Canonica GW. Continuous ver-

sus on demand treatment with cetirizine for allergic rhinitis. Ann Allergy Asthma
Immunol 1997; 79:507–511.
102. Henz BM. The pharmacologic profile of desloratadine: a review. Allergy 2001;
56(Suppl 65):7–13.
103. Ellis J, Seidenberg M. Desloratadine is a potent antagonist at muscarinic acetylcho-
line receptors, but fexofenadine is not. Allergy 2001; 56(Suppl 68):202–203.
104. Geha RS, Meltzer EO. Desloratadine: a new, nonsedating, oral antihistamine. J
105. Corren J. Desloratadine 5 mg once daily reduces nasal congestion in patients with
seasonal allergic rhinitis. ACI Int 2000; (Suppl 2):14.
106. Baena-Cagnani CE. Desloratadine activity in concurrent seasonal allergic rhinitis
and asthma. Allergy 2001; 56(Suppl 65):21–27.
107. Baena-Cagnani CE. Quality of life improves in seasonal allergic rhinitis patients
treated with desloratadine. ACI Int 2000; (Suppl 2):165.
108. Skassa-Brociek W, Bousquet J, Montes F, Verdier M, Schwab D, Lherminier M,
Michel FB. Double-blind, placebo controlled study of loratadine, mequitazine and
placebo in the symptomatic treatment of seasonal allergic rhinitis. J Allergy Clin
Immunol 1988; 81:725–730.
109. Kemp J, Bahna S, Chervinsky P, et al. A comparison of loratadine, a new nonsedat-
ing antihistamine, with clemastine and placebo in patients with fall seasonal allergic
rhinitis. Am J Rhinol 1987; 3:151–154.
110. Horak F, Bruttmann G, Pedrali P, Weeke B, Frolund L, Wolff HH, Christophers E.
A multicenter study of loratadine, terfenadine and placebo in patients with seasonal
allergic rhinitis. Arzneimittelforsch 1988; 38:124–128.
111. Clissold SP, Sorkin EM, Goa KL. Loratadine: a preliminary review of its pharmaco-
dynamic properties and therapeutic efficacy. Drugs 1989; 37:42–57.
112. Bruttmann G, Pedrali P. Loratadine (SCH 29851) 40 mg once daily vs terfenadine
60 mg twice daily in the treatment of seasonal allergic rhinitis. J Int Med Res 1987;
15:63–70.
113. Bronsky EA, Falliers CJ, Kaiser HB, Ahlbrandt R, Mason JM. Effectiveness and
safety of fexofenadine, a new nonsedating H1-receptor antagonist, in the treatment
of fall allergies. Allergy Asthma Proc 1998; 19:135–141.
114. Bernstein DI, Schoenwetter WF, Nathan RA, Storms W, Ahlbrandt R, Mason J.
Efficacy and safety of fexofenadine hydrochloride for treatment of seasonal allergic
rhinitis. Ann Allergy Asthma Immunol 1997; 79:443–448.
115. Casale TB, Andrade C, Qu R. Safety and efficacy of once daily fexofenadine HCl
in the treatment of autumn seasonal allergic rhinitis. Allergy Asthma Proc 1999;
20:193–198.
116. Meltzer EO, Casale TB, Nathan RA, Thompson AK. Once-daily fexofenadine HCl
improves quality of life and reduces work and activity impairment in patients with
seasonal allergic rhinitis. Ann Allergy Asthma Immunol 1999; 83:311–317.
nol 1996; 76:163–168.
118. Sabbah A, Daele J, Wade AG, Ben-Soussen P, Attali P. Comparison of the efficacy,
214 Howarth
safety, and onset of action of mizolastine, cetirizine, and placebo in the management
of seasonal allergic rhinoconjunctivitis. MIZOCET Study Group. Ann Allergy
119. Bousquet J. Rapid symptom relief in rhinitis. Clin Exp Allergy 1999; 29(suppl 1):
25–29.
120. Stern MA, Darnell R, Tudor D. Can an antihistamine delay appearance of hay fever
symptoms when given prior to pollen season? Allergy 1997; 52:440–444.
121. Bachert C, Vovolis V, Margari P, Murrieta-Aguttes M, Santoni JP. Mizolastine in
the treatment of seasonal allergic rhinoconjunctivitis: A European clinical experi-
ence with 5408 patients managed in daily practice (PANEOS SAR Study). Allergy
2001; 56:653–659.
122. Pelaez A. Clinical efficacy of ebastine in the treatment and prevention of seasonal
allergic rhinitis. Drugs 1996; 52(suppl 1):35–8.
123. Callier J, Engelen RF, Ianniello I, Olzen R, Zeisner M, Amery WK. Astemizole
(R43512) in the treatment of hay fever: An international double-blind study com-
paring a weekly treatment (10 mg and 25 mg) with placebo. Curr Ther Res 1981;
29:24–35.
124. Cohen R, Gehanno P. Comparison of the efficacy of ebastine 10 mg and 20 mg
once daily with that of cetirizine 10 mg once daily in adults with seasonal allergic
rhinitis. A multi-centre double-blind study. Drugs 1996; 52(suppl 1):26–29.
125. Ramaekers JG, O’Hanlon JF. Acrivastine, terfenadine and diphenhydramine effects
on driving performance as a function of dose and time after dosing. Eur J Clin
Pharmacol 1994; 47:261–266.
127. Gibbs TG, McDonnell KA, Stokes T, Graham AA. Acrivastine in two doses com-
pared with placebo in a multicentre, parallel group study for the treatment of sea-
sonal allergic rhinitis. Br J Clin Pract 1989; 43:11–14.
128. Gibbs TG, Irander K, Salo OP. Acrivastine in seasonal allergic rhinitis: two ran-
domised crossover studies to evaluate efficacy and safety. J Int Med Res 1988; 16:
413–419.
129. Sharif NA, Su SX, Yanni JM. Emedastine: a potent, high affinity histamine H1-
receptor-selective antagonist for ocular use: receptor binding and second messenger
studies. J Ocul Pharmacol 1994; 10:653–664.
130. Yanni JM, Stephens DJ, Parnell DW, Spellman JM. Preclinical efficacy of emedas-
tine, a potent, selective histamine H1 antagonist for topical ocular use. J Ocular
Pharmacol 1994; 10:665–675.
131. Discepola M, Deschenes J, Abelson M. Comparison of the topical ocular antialler-
gic efficacy of emedastine 0.05% ophthalmic solution to ketorolac 0.5% ophthalmic
solution in a clinical model of allergic conjunctivitis. Acta Ophthamol Scand Suppl
1999; 228:43–46.
132. Grant JA, Danielson L, Rihoux JP, DeVos C. A double-blind, single-dose, cross-
over comparison of cetirizine, ebastine, epinastine, fexofenadine, terfenadine and
sponse for 24 hours in healthy male subjects. Allergy 1999; 54:700–707.
133. Izqwierde I, Lurigados C, Perez I, Forn J. Rupatidine exhibits a better profile than
ebastine in patients with seasonal allergic rhinitis. Allergy 2001; 56 (Suppl 68):
200.
134. Druce HM, Thoden WR, Mure P, Furey SA, Lockhart EA, Xie T, Galant S, Prenner
BM, Weinstein S, Ziering R, Brandon ML. Brompheniramine, loratadine and pla-
cebo in allergic rhinitis: a placebo-controlled comparative clinical trial. J Clin Phar-
macol 1998; 38:382–389.
135. Harvey RP, Comer C, Sanders B, Westley R, Marsh W, Shapiro H, Wiener M.
Model for outcomes assessment of antihistamine use for seasonal allergic rhinitis.
136. Herman D, Arnaud A, Dry J, et al. Clinical effectiveness and safety of loratadine
vs cetirizine in the treatment of seasonal allergic rhinitis. Clin Exp Allergy 1990;
20:56.
137. Backhouse CI, Renton R, Fidler C, Rosenberg RM. Multicentre, double-blind com-
parison of terfenadine and cetirizine in patients with seasonal allergic rhinitis. Br
J Clin Pract 1990; 44:88–91.
138. Stelmach WJ, Rush DR, Pocucker PC, et al. A large scale, office based study evalu-
ates the use of a new class of non-sedating antihistamines. J Am Board Fam Pract
1990; 3:241–252.
139. Van Cauwenberge P, Juniper EF. Comparison of the efficacy, safety and quality of
life provided by fexofenadine hydrochloride 120 mg, loratadine 10 mg and placebo
administered once daily for the treatment of seasonal allergic rhinitis. Clin Exp
Allergy 2000; 30:891–899.
140. Tanner LA, Reilly M, Meltzer EO, Bradford JE, Mason J. Effect of fexofenadine
HCl on quality of life and work, classroom and daily activity impairment in patients
with seasonal allergic rhinitis. Am J Manag Care 1999; 5(suppl 2):S235–S247.
141. D’Ambrosio FP, Gangemi S, Merendino RA, Arena A, Ricciardi L, Bagnato GF.
Comparative study between fluticasone propionate and cetirizine in the treatment
of allergic rhinitis. Allergol Immunopathol Madr 1998; 26:277–282.
142. Ratner PH, van-Bavel JH, Martin BG, Hampel FC Jr, Howland WC 3rd, Rogenes
PR, Westlund RE, Bowers BW, Cook CK. A comparison of the efficacy of flutica-
sone propionate aqueous nasal spray and loratadine, alone and in combination, for
the treatment of seasonal allergic rhinitis. J Fam Pract 1998; 47:118–125.
143. Gehanno P, Desfougeres JL. Fluticasone propionate aqueous nasal spray compared
with oral loratadine in patients with seasonal allergic rhinitis. Allergy 1997; 52:
445–450.
144. Jordana G, Dolovich J, Briscoe MP, JH Day, MA Drouin, M Gold, R Robson, N
Stepner, W Yang. Intranasal fluticasone propionate versus loratadine in the treat-
ment of adolescent patients with seasonal allergic rhinitis. J Allergy Clin Immunol
97:588–595, 1996.
145. Weiner JM, Abramson MJ, Puy RM. Intranasal corticosteroids versus oral H1-
receptor antagonists in allergic rhinitis. Systematic review of randomised controlled
trials. Br Med J 1998; 317:1624–1629.
146. Dockhorn RJ, Shellenberger MK, Hassanien R, Trachelman L. Efficacy of SCH 434
(loratadine plus pseudoephedrine) vs components and placebo in seasonal allergic
rhinitis. J Allergy Clin Immunol 1988; 81:178.
216 Howarth
147. Skoner DP, Rachelefsky GS, Meltzer EO, Chervinsky P, Morris RM, Seltzer JM,
Storms WW, Wood RA. Detection of growth suppression in children during treat-
ment with intranasal beclomethasone dipropionate. Pediatrics 2000; 105:E23.
148. Schenkel EJ, Skoner DP, Bronsky EA, Miller SD, Pearlman DS, Rooklin A, Rosen
JP, Ruff ME, Vandewalker ML, Wanderer A, Damaraju CV, Nolop KB, Mesarina-
Wicki B. Absence of growth retardation in children with perennial allergic rhinitis
after one year of treatment with mometasone furoate aqueous nasal spray. Pediatrics
2000; 105:E22.
149. Brostoff J, Lockhart JDF. Controlled trial of terfenadine and chlorpheniramine
maleate in perennial rhinitis. Postgrad Med J 1982; 58:422–423.
150. Renton R, Fidler C, Rosenberg R. Multicentre crossover study of the efficacy and
tolerability of terfenadine, 120 mg, versus cetirizine 10 mg, in perennial allergic
rhinitis. Ann Allergy 1991; 67:416–420.
151. Berman B, Buchman E, Dockhorn R, Leese P, Mansmann H, Middleton E. Cetiri-
zine therapy of perennial allergic rhinitis. J Allergy Clin Immunol 1988; 81:177.
152. Bousquet J, Duchateau J, Pignat JC, Fayol C, Marquis P, Mariz S, Ware JE, Valen-
tin B, Burtin B. Improvement of quality of life by treatment with cetirizine in pa-
tients with perennial allergic rhinitis as determined by a French version of the SF-
36 questionnaire. J Allergy Clin Immunol 1996; 98:309–316.
153. Bruttmann G, Charpin D, Germouty J, Horak F, Kunkel G, Wittmann G. Evaluation
of the efficacy and safety of loratadine in perennial allergic rhinitis. J Allergy Clin
Immunol 1989; 83:411–416.
154. Bachert C, Brostoff J, Scadding GK, Tasman J, Stalla-Bourdillon A, Murrieta M.
Mizolastine therapy also has an effect on nasal blockade in perennial allergic rhino-
conjunctivitis. RIPERAN Study Group. Allergy 1998; 53:969–975.
155. Wihl J-A, Petersen BN, Gundersen G, Bresson K, Mygind N. Effect of the non-
sedative H1-receptor antagonist astemizole in perennial allergic and non-allergic
rhinitis. J Allergy Clin Immunol 1985; 75:720–727.
156. Aaronson DW. Evaluation of cetirizine in patients with allergic rhinitis and peren-
nial asthma. Ann Allergy Immunol 1996; 76:440–446.
157. Murris-Espin M, Melac M, Charpentier JC, Didier A. Comparison of efficacy and
safety of cetirizine and ebastine in patients with perennial allergic rhinitis. Ann
Allergy Asthma Immunol 1998; 80:399–403.
1996; 34:101–104.
159. Lockey RF, Fox RW. Loratadine (SCH 29851) 10 mg od vs clemastine 1 mg b.i.d. in
the treatment of perennial allergic rhinitis. Immunol Allergy Prac 1989; 11;423–429.
160. Frolund L, Etholm B, Irander K, Johannessen TA, Odkvist L, Ohlander B, Weeke
B. A multicentre study of loratadine, clemastine and placebo in patients with peren-
nial allergic rhinitis. Allergy 1990; 45:254–261.
161. Robinson AC, Cherry JR, Daly S. Double-blind, cross-over trial comparing beclo-
methasone dipropionate and terfenadine in perennial rhinitis. Clin Exp Allergy
1989; 19:569–573.
162. Harding SM, Heath S. Intranasal steroid aerosol in perennial rhinitis: comparison
with an antihistamine compound. Clin Allergy 1976; 6:369–372.
163. Sibbald B, Hilton S, D’Souza M. An open crossover trial comparing two doses of
astemizole and beclomethasone dipropionate in the treatment of perennial rhinitis.
Clin Allergy 1986; 16:203–211.
164. McTavish D, Sorkin EM. Azelastine: a review of its pharmacodynamic and phar-
165. Kyrein HJ, Horak F, Nirnberger G, Rehn D. Efficacy of intranasally applied dimethin-
dene maleate solution as spray in adult volunteers with symptoms of seasonal allergic
rhinitis in the Vienna challenge chamber. Arzneimittelforsch 1996; 46:794–799.
166. Aguilar AJ. Comparative study of clinical efficacy and tolerance in seasonal allergic
conjunctivitis management with 0.1% olopatadine hydrochloride versus 0.05%
ketotifen fumarate. Acta Opthalmol Scand 2000; 78 (Suppl 230):52–55.
167. Borum S, Nielsen K, Bisgaard H, Mygind N. Experimentally induced nasal hyper-
secretion does not reduce the efficacy of intranasal levocabastine. Rhinology 1998;
36:153–155.
168. Janssens MM, Vanden Bussche G. Levocabastine: an effective topical treatment
of allergic rhinoconjunctivitis. Clin Exp Allergy 1991; 21(Suppl 2):29–36.
169. Weiler JM, Meltzer EO, Dockhorn R, Widlitz MD, D’Eletto TA, Freitag JJ. A
safety and efficacy evaluation of azelastine nasal spray in seasonal allergic rhinitis.
J Allergy Clin Immunol 1991; 87:219.
170. Ratner PH, Findlay SR, van Bavel JH, Hampel F Jr, Freitag JJ. Azelastine nasal
spray: a two week safety/efficacy study in seasonal allergic rhinitis. Ann Allergy
1991; 66:91.
171. McNeely W, Wiseman LR. Intranasal azelastine. A review of its efficacy in the
management of allergic rhinitis. Drugs 1998; 56:91–114.
172. Schata M, Jorde W, Richarz-Barthauer U. Levocabastine nasal spray better than
sodium cromoglycate and placebo in the topical treatment of seasonal allergic rhini-
173. Hampel FC Jr., Martin BG, Dolen J, Travers S, Karcher K, Holton D. Efficacy and
safety of levocabastine nasal spray for seasonal allergic rhinitis. Am J Rhinol 1999;
13:55–62.
174. Herman D, Garay R, Le-Gal M. A randomised double-blind placebo controlled
175. La Force C, Dockhorn R, Prenner B, Chu T, Kraemer MJ, Widlitz M, D’Eletto T,
Freitag J. Safety and efficacy of azelastine nasal spray for seasonal allergic rhinitis:
A four week comparative trial. J Allergy Clin Immunol 1992; 89:182.
176. Bende M, Pipkorn U. Topical levocabastine, a selective H1-antagonist in seasonal
allergic rhinoconjunctivitis. Allergy 1987; 42:512–515.
177. Sohoel P, Freng BA, Kramer J, Poppe S, Rebo R, Korsrud FR, Garud O, Woxen OJ,
Olsen AK. Topical levocabastine compared with orally administered terfenadine for
the prophylaxis and treatment of seasonal allergic rhinoconjunctivitis. J Allergy
Clin Immunol 1993; 92:73–81.
178. Palma-Carlos AG, Chieira C, Conde TA, Robalo Cordeiro JA. Double-blind com-
parison of levocabastine nasal spray with sodium cromoglycate nasal spray in the
treatment of seasonal allergic rhinitis. Ann Allergy 1991; 67:394–398.
179. Berger WE, Fineman SM, Lieberman P, Miles RM. Double-blind trials of azelas-
218 Howarth
tine nasal spray monotherapy versus combination therapy with loratadine tablets
and beclomethasone nasal spray in patients with seasonal allergic rhinitis. Rhinitis
Study Groups. Ann Allergy Asthma Immunol 1999; 82:535–541.
180. Azelastine Product Monograph, 1988, pp. 16–22.
181. Knight A. The role of levocabastine in the treatment of allergic rhinoconjunctivitis.
Br J Clin Pract 1994; 48:139–143.
182. Kremer B, Tundermann A, Goldschmidt O. Onset of action, effectiveness and toler-
ance of levocabastine and nedocromil in topical therapy of seasonal allergic rhino-
conjunctivitis. The Deutsche Rhinitis Studiengruppe. Arzneimittelforsch 1998; 48:
924–930.
183. Baraldi E, Azzolin NM, Carra S, Dario C, Marchesini L, Zacchello F. Effect of
topical steroids on nasal nitric oxide production in children with perennial allergic
rhinitis: a pilot study. Respir Med 1998; 92:558–561.
184. van de Heyning PH, van Haesendonck J, Creten W, Rombaut N. Effect of topical
levocabastine on allergic and non-allergic perennial rhinitis; a double-blind study,
levocabastine vs. placebo, followed by an open prospective, single-blind study on
beclomethasone. Allergy 1988; 43:386–391.
185. Pipkorn U, Bende M, Hedner J, Hedner T. A double-blind evaluation of topical
levocabastine, a new specific H1-antagonist in patients with allergic conjunctivitis.
Allergy 1985; 40:491–496.
186. Azevedo M, Castel-Branco MG, Oliveira JF, Ramos E, Delgado L, Almeida J.
Double-blind comparison of levocabastine eye drops with sodium cromoglycate
and placebo in the treatment of seasonal allergic conjunctivitis. Clin Exp Allergy
1991; 21:689–694.
187. Davies BH, Mullins J. Topical levocabastine is more effective than sodium cromo-
glycate for the prophylaxis and treatment of seasonal allergic conjunctivitis. Allergy
1993; 48:519–524.
188. Meltzer EO. Comparative safety of H1-antihistamines. Ann Allergy 1991; 67:625–
633.
189. Simons FER. H1-receptor antagonists: comparative tolerability and safety. Drug
Safety 1994; 10:350–380.
29(Suppl 3):133–142.
191. Meador KJ, Loving DW, Thompson EE, Thompson WO. Differential cognitive effects
of terfenadine and chlorpheniramine. J Allergy Clin Immunol 1989; 84:322–325.
193. Hindmarch I, Bhatti JZ. Psychomotor effects of astemizole and chlorpheniramine,
alone and in combination with alcohol. Int Clin Psychopharmacol 1987; 2:117–119.
194. Seidel WF, Cohen S, Bliwise NG, Dement WC, Direct measurement of daytime
sleepiness after administration of cetirizine and hydroxyzine with a standardized
electroencephalographic assessment. J Allergy Clin Immunol 1990; 86:1029–1033.
195. Bradley CM, Nicholson AN. Studies on the central effects of the H1-antagonist
loratadine. Eur J Clin Pharmacol 1987; 32:419–421.
306–311.
197. Brookhuis KA, DeVries G, De Waard D. Acute and subchronic effects of the H1-
histamine receptor antagonist ebastine in 10, 20 and 30 mg dose and triprolidine
10 mg on car driving performance. Br J Clin Pharmacol 1993; 36:67–70.
198. Kerr JS, Dunmore C, Hindmarch I. The psychomotor and cognitive effects of a
new antihistamine, mizolastine, compared to terfenadine, triprolidine and placebo
in healthy volunteers. Eur J Clin Pharmacol 1994; 47:331–335.
199. Rombaut N, Bhatti JZ, Curran S, Hindmarch I. Effects of topical administration of
levocabastine on psychomotor and cognitive function. Ann Allergy 1991; 67:75–79.
200. Alford C, Bhatti JZ, Rombaut NEI, Curran S, Hindmarch IA. Comparison of anti-
histamines using EEG and questionnaire-based assessments. Med Sci Reg 1989;
17:421–423.
201. Yun CH, Okerholm RA, Guengerich FP. Oxidation of the antihistaminic drug ter-
fenadine in human liver microsomes: role of cytochrome P-450 3A(4) in N-dealkyl-
ation and C-hydroxylation. Drug Metab Dispos 1993; 21:403–409.
202. Yumibe N, Huie K, Chen KJ, Clement RP, Cayen MN. Identification of human
liver cytochrome P450s involved in the microsomal metabolism of the antihista-
minic drug loratadine. J Allergy Clin Immunol 1994; 93:234.
203. Affrime MB, Lorber R, Danzig M, Cuss F, Brannan MD. Three month evaluation
of electrocardiographic effects of loratadine in humans. J Allergy Clin Immunol
1993; 91:259.
204. Moss AJ, Chaikin P, Garcia JD, Gillen M, Roberts DJ, Morganroth J. A review
of the cardiac systemic side effects of antihistamines: ebastine. Clin Exp Allergy
1999; 29 (Suppl 3):200–205.
A. QT interval monitoring during clinical studies with mizolastine, a new H1-anti-
histamine. Clin Exp Allergy 1999; 29 (Suppl 3):206–211.
206. Pratt C, Brown AM, Rampe D, Mason J, Russell T, Reynolds R, Ahlbrandt R.
Cardiovascular safety of fexofenadine HCl. Clin Exp Allergy 1999; 29 (Suppl 3):
212–216.
207. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system
events associated with dietary supplements containing ephedra alkaloids. N Engl
J Med 2000; 21:1833–1838.
208. Mersfelder TL. Phenylpropanolamine and stroke: the study, the FDA ruling, the
implications. Cleve Clin J Med 2001; 68:208–209, 213–219, 223.
209. Pederson KJ, Kuntz DH, Garbe GJ. Acute myocardial ischemia associated with
ingestion of bupropion and pseudoephedrine in a 21-year-old man. Can J Cardiol
2001; 17:599–601.
210. Sussman GL, Mason J, Compton D, Steward J, Ricard N. The efficacy and safety
of fexofenadine HCl and pseudoephedrine, alone and in combination, in seasonal
allergic rhinitis. J Allergy Clin Immunol 1999; 104:100–106.
211. Corren J, Harris AG, Aaronson D, Beaucher W, Berkowitz R, Bronsky E, Chen R, Cher-
vinsky P, Cohen R, Fourre J, Grossman J, Meltzer E, Pedinoff A, Stricker W, Wanderer A.
Efficacy and safety of loratadine plus pseudoephedrine in patients with seasonal allergic
rhinitis and mild asthma. J Allergy Clin Immunol 1997; 100:781–788.
220 Howarth
212. Grosclaude M, Mees K, Pinelli ME, Lucas M, Van de Venne H. Cetirizine and
pseudoephedrine retard, given alone or in combination, in patients with seasonal
allergic rhinitis. Rhinology 1997; 35:67–73.
213. Serra HA, Alves O, Rizzo LF, Devoto FM, Ascierto H. Loratadine–pseudoephed-
rine in children with allergic rhinitis, a controlled double-blind trial. Br J Clin Phar-
macol 1998; 45:147–150.
214. Horak F, Toth T, Marks B, Stubner UP, Berger UE, Jager S, Burtin B, Duby C.
Efficacy and safety relative to placebo of an oral formulation of cetirizine and sus-
tained-release pseudoephedrine in the management of nasal congestion. Allergy
1998; 53:849–856.
215. Malka S, Partjdas A, Fuentes R. Estudio comparativo rhinomanometrico Y valova-
cion clinica de la combinacion de terfenadina and pseudofedrina vs carbinoxamina
and pseudoefedrina en rhinitis obstructive. Invest Med Int 1989; 16:313–136.
216. Bronsky E, Rogers C, Altman L, Ayars G, Falliers C, Milwee S, Frosolono M. A
comparison of acrivastine and pseudoephedrine, chlorpheniramine and pseudoe-
phedrine, and placebo in the treatment of perennial allergic rhinitis. J Allergy Clin
Immunol 1987; 79:191.
217. Storms WW, Bodman SF, Nathan RA, Chervinsky P, Banov CH, Dockhorn RJ, Jar-
moszuk I, Zeitz HJ, McGeady SJ, Pinnas JL, Greenstein S. SCH434: A new
antihistamine/decongestant for seasonal allergic rhinitis. J Allergy Clin Immunol 83:
1083–1090, 1989.
218. Bukstein DA, Biondi RM, Blumenthal MM, Dockhorn RJ, Filley WV, Fink J,
Goldstein S, Graft DF, Hirsch SR. Joos TH, Melamed J, Rowe MS, Townley RG.
Tilarin in combination with astemizole. Allergy 1996; 51 (Suppl 28):20–27.
219. Kinn AF Jr., Aaronson D, Korenblat P, Lumry W, Settipane G, Spector S, Woehler
T, Orda K, Wood CC. Ipratropium bromide nasal spray 0.03% provides additional
relief from rhinorrhea when combined with terfenadine in perennial rhinitis pa-
tients, a randomized, double-blind, active-controlled trial. Am J Rhinol 1998; 12:
441–449.
220. Smith MBH, Feldman W. Over-the-counter cold medications: a critical review of
clinical trials between 1950 and 1991. JAMA 1993; 269:2258–2263.
221. Gaffey MJ, Kaiser DL, Hayden FG. Ineffectiveness of oral terfenadine in natural
colds: evidence against histamine as a mediator of common cold symptoms. Pediatr
Infect Dis J 1988; 7:223–228.
222. Berkowitz RB, Connell JT, Dietz AJ, Greenstein SM, Tinkelman DG. The effec-
tiveness of the nonsedating antihistamine loratadine plus pseudoephedrine in the
symptomatic management of the common cold. Ann Allergy 1989; 63:336–339.
223. Togias AG, Naclerio RM, Proud D, Fish JE, Adkinson NF Jr, Kagey-Sobotka A,
Norman PS, Lichtenstein LM. Nasal challenge with cold, dry air results in release
of inflammatory mediators: possible mast cell involvement. J Clin Invest 1985; 76:
1375–1381.
224. Proud D, Bailey GS, Naclerio RM, Reynolds CJ, Cruz AA, Eggleston PA, Lich-
tenstein LM, Togias AG. Tryptase and histamine as markers to evaluate mast cell
activation during the responses to nasal challenge with allergen, cold, dry air and
hyperosmolar solutions. J Allergy Clin Immunol 1992; 89:1098–1110.
225. Wihl JA, Petersen BN, Mygind N. The role of histamine in non-allergic perennial
rhinitis. Acta Otolaryngol (Stockh) 1984; 214:99–102.
7
H 1-Antihistamines in Asthma
James L. Lordan and Stephen T. Holgate

University of Southampton, Southampton, England
I. INTRODUCTION
Epidemiological studies have documented an increase in the prevalence of asthma

and allergic diseases over the last 20 years, associated with an increase in morbid-
ity and mortality, as reflected by increased hospitalizations and increased use of
medications for asthma (1). Although treatment with inhaled corticosteroids and
as-needed short-acting β 2-adrenergic agonists maintains disease control in the
majority of asthmatics, some patients remain symptomatic and require additional
treatment with long-acting β 2-adrenergic agonists, theophylline, leukotriene re-
ceptor antagonists, or oral corticosteroids for control of symptoms (2). There are
a number of studies to support the involvement of histamine in the pathogenesis
of lower airway inflammation in asthma; however, the results of clinical trials
with first-generation H 1-antagonists showed limited efficacy. In most countries
H 1-antagonists have not traditionally been prescribed for the management of
asthma. Indeed, it was believed that the first-generation antihistamines could po-
tentially exacerbate asthma by drying airway secretions as a result of anticholiner-
gic side effects.
In this chapter, we will discuss the evidence for histamine release by mast
cells and basophils in the airway, review the involvement of histamine in airway
bronchoconstriction in response to known spasmogens, and detail the involve-
ment of histamine in the pathogenesis of asthma. We will also describe the bron-
chodilator and bronchoprotective properties of currently available H 1-antagonists,
and examine the ability of H 1-antagonists to delay the development of asthma in
221
222 Lordan and Holgate
high-risk atopic infants and the potential role of H 1-antagonists in the continuing
management of patients with chronic asthma.
II. MAST CELLS, BASOPHILS, HISTAMINE RELEASE,

AND THE INVOLVEMENT OF OTHER MEDIATORS
IN ASTHMA
Before discussing the involvement of histamine in the pathogenesis of asthma,

it is necessary to review the contribution of mast cells and basophils to the in-
flammatory process through the release of histamine and other mediators.
A. Mast Cells
In 1953, Riley and West identified the mast cell as a major source of histamine
(3). Stimuli that increased the numbers of mast cells in tissues were also noted
to result in increased release of histamine. The identification of circulating IgE
and the discovery of high-affinity IgE (FcεRI) receptors on mast cells supported
the hypothesis that allergen cross-linkage of IgE receptors on mast cells resulted
in mast cell degranulation, histamine release, and the characteristic bronchocon-
striction of asthma (4).
In healthy and asthmatic subjects, the airways have been shown to contain
numerous mast cells, which originate from CD34 ⫹ precursor cells, and are pre-
dominantly of the tryptase only phenotype (MC T ), as distinct from chymase-
positive, tryptase-positive mast cells (MC CT ) found in other tissues (5). The polar-
ization of airway mast cells to the MC T type is promoted by the presence of mast
cell growth factors derived from infiltrating Th2-type lymphocytes (interleukin
[IL]-3, IL-4, and IL-9), and stem cell factor released by the bronchial epithelium
and adjacent fibroblast/myofibroblast layer (6). Although some investigators have
not noted any difference in mast cell numbers in endobronchial biopsies (5, 7) or
bronchoalveolar lavage (BAL) fluid (8) between asthmatics and healthy subjects,
others have confirmed increased numbers in BAL fluid of stable asthmatics (9),
and endobronchial evidence of a further rise in mast cell numbers in parallel with
the extent of the late allergic response to allergen challenge (10, 11). In patients
with asthma, some mast cells show ultrastructural evidence of degranulation,
which is not found in healthy subjects, and become localized to the bronchial
epithelium after allergen challenge, where they are more likely to encounter in-
haled allergens or be activated by other noxious stimuli (12). Consistent with the
hypothesis of increased activation of mast cells in asthma is the observation that
mast cell mediator levels such as histamine, tryptase, and leukotrienes are in-
creased in BAL fluid in asthmatics after allergen challenge (13). Flint et al.
Asthma 223
showed increased numbers of mast cells containing histamine in BAL fluid of

asthmatics compared to healthy subjects, with an inverse relationship among
forced expiratory volume in 1 second (FEV 1), numbers of mast cells, and the
levels of histamine (12). Increased levels of histamine have been found in the
BAL fluid of subjects with active asthma, accompanied by increased levels of
other mast cell–derived products including prostaglandin (PG)D 2 , leukotriene
(LT) C4, and the protease, tryptase. Increased numbers of airway MC T cells have
been particularly associated with more severe forms of asthma. In the airway
inflammation of asthma, the mast cell has been confirmed as an important source
of cytokine release (IL-3, IL-4, IL-5, IL-6, IL-8, IL-13, IL-16 and tumor necrosis
factor [TNF-α]), both stored preformed in secretory granules and newly gener-
ated by transcriptional mechanisms in response to cross-linkage of Fc⑀RI recep-
tors and other stimuli (14–17).
B. Basophils
Until recently, it has been difficult to differentiate between mast cells and baso-
phils in tissues, since both cells contain metachromatic granules and stain posi-
tively for FcεRI receptors. Similar to mast cells, airway and circulating basophils
are derived from CD34 ⫹ cells. Upon activation by IgE-dependent or IgE-indepen-
dent mechanisms, basophils release a number of potent mediators, including his-
tamine, leukotrienes, proteoglycans, and cytokines such as IL-4 and IL-13 (18–
22). Earlier studies have applied morphological criteria including cell surface
expression of FcεRI receptors, the presence of metachromatic granules staining
negatively for trypsin, and multilobular nuclei to identify basophils in tissues.
Using these indirect criteria, increased numbers of basophils have been described
in the sputum of asthmatics during exacerbations. After subsegmental allergen
challenge with ragweed antigen in sensitized allergic asthmatics, Guo et al. re-
ported a 20- to 200-fold increase in the numbers of IgE-bearing, histamine-con-
taining cells in BAL fluid, 95% of which were considered to be basophils (23).
McFarlane and colleagues have recently developed a monoclonal antibody
(BB1) that stains antigens specific to basophils (24) and have used this antibody to
assess the role of basophils in the allergic airway responses of asthma. They have
confirmed increased numbers of basophils in bronchial biopsies of atopic asthma-
tics compared to healthy controls, atopic nonasthmatics, or even nonatopic asthma-
tics. They noted a further increase in the numbers of BB1-positive basophils at 24
hours after allergen challenge, coincident with the late allergic response, with a
proportion of these cells showing evidence of degranulation. The influx of basophils
into the airways was significantly lower than the numbers of eosinophils recruited,
suggesting that although basophils contribute to the development of the late allergic
response (LAR), eosinophils play a more important role.
III. INVOLVEMENT OF HISTAMINE IN

BRONCHOCONSTRICTOR RESPONSES IN ASTHMA
The initial isolation of histamine in 1907 by Windaus and Vogt (25), and the
recognition that anaphylactic challenge of lung tissue resulted in histamine re-
lease, stimulated the search for mediators involved in airflow dysfunction in pa-
tients with asthma (26). Early studies by Weiss et al. observed that the administra-
tion of intravenous or intramuscular histamine to patients with bronchial asthma
precipitated attacks of breathlessness associated with bronchial obstruction as
measured by decreased vital capacity (27). It was recognized that the bronchocon-
striction induced by histamine was unique to asthmatic subjects, was not observed
in healthy subjects, and could be abrogated by pretreatment of asthmatic subjects
with an early histamine receptor antagonist, β-dimethylaminoethyl-benzhydryl-
ether hydrochloride, which had shown effectiveness in animal studies and in aller-
gic rhinitis (28, 29).
It has been well documented that histamine is released in airway inflamma-
tion in asthma and it is possible to detect histamine or its metabolites in airway
fluids, peripheral blood, or urine of asthmatic subjects. In the circulation, hista-
mine release was initially localized to the granulocyte fraction of blood (30), and
it was later confirmed by Ishizaka et al. that basophils were responsible for hista-
mine release from blood stimulated in vitro with an anti-IgE antibody (31).
Barnes et al. showed that plasma histamine levels were increased in asthmatics
compared to healthy controls, atopic nonasthmatics, or chronic bronchitic sub-
jects (32). Plasma histamine release is noted to increase in atopic asthmatics
after allergen challenge, and in asthmatic subjects experiencing an exacerbation,
compared to stable asthmatics. The levels of histamine found correlate with the
severity of underlying disease (23). Patients receiving effective treatment for
asthma have also been shown to release lower levels of histamine than asthmatic
subjects with poorly controlled disease (33).
IV. BRONCHOCONSTRICTOR RESPONSES IN ASTHMA:

EFFECTS OF H 1-ANTIHISTAMINES
A number of studies have assessed the ability of H 1-antihistamine compounds

to prevent the bronchoconstriction induced by inhalation of known spasmogens
[histamine, methacholine, adenosine, and platelet-activating factor (PAF)]. The
bronchoconstrictor response to histamine inhalation in asthmatic subjects has
been widely applied as a measure of airway hyperresponsiveness, in which the
histamine inhalation challenge determines the concentration of histamine re-
quired to cause a 20% reduction in the forced expiratory volume in 1 second
(histamine PC 20 FEV 1). Wood-Baker and Holgate compared the effect of some
Asthma 225
H 1-antihistamines (including brompheniramine, cetirizine, chlorpheniramine,

clemastine, and cyproheptadine) on inhibition of bronchospasm induced by hista-
mine or methacholine inhalation in asthmatic subjects (34) (Fig. 1). Cetirizine
was most effective at inhibiting histamine-induced bronchospasm. None of the
H 1-antagonists protected against methacholine-induced bronchospasm (34).
Other investigators confirmed that cetirizine at three doses (5, 10, or 20 mg)
and hydroxyzine (25 mg) had a protective effect against the bronchoconstrictor
response to histamine, and also confirmed the significant bronchodilator effect
of both compounds (35).
The inhalation of adenosine or its 5′-nucleotides [adenosine monophos-
phate (AMP), adenosine diphosphate (ADP)] has been used to study the involve-
ment of histamine in asthma. The bronchoconstrictor response induced by inhala-
tion of adenosine results from the selective activation of A 2b receptors on mast
cells, resulting in mast cell degranulation, and the release of preformed mediators
including histamine (36–40). Histamine release in the airway fluids and blood
of atopic and asthmatic subjects is increased after inhalation of AMP or local
Figure 1 The protective effects of H 1-antihistamines against histamine-induced bron-

choconstriction. All antihistamines provided significant protection against histamine-in-
duced bronchoconstriction (black bars) and none provided protection against methacho-
line-induced bronchoconstriction (white bars). (From Ref. 34.)
endobronchial challenge with AMP, and the bronchoconstrictor responses can be

inhibited by prior treatment with a selective H 1-antagonist (41–43).
Inhalation of PAF has been shown to induce acute reversible bronchocon-
striction of a degree greater than histamine or leukotriene inhalation. A double-
blind, placebo-controlled trial has assessed the effects of cetirizine on PAF-in-
duced bronchoconstriction (measured by specific airway conductance, sGaw) in
10 subjects with mild asthma (44). Patients inhaled a dose of PAF titrated to
cause a 35% fall in sGaw, but cetirizine did not significantly inhibit the broncho-
constriction induced by PAF inhalation.
V. INVOLVEMENT OF HISTAMINE IN THE

BRONCHOCONSTRICTOR RESPONSE TO ALLERGEN
Histamine contributes to the development of airway hyperresponsiveness after

allergen challenge in asthma. Following inhalation allergen challenge, an increase
in the plasma histamine level is seen within minutes (41, 45, 46), associated with
a later increase in the level of the histamine metabolite, N-methyl histamine in
the urine (47), suggesting that histamine is involved in the development of the
early bronchoconstrictor response. Although pretreatment with an H 1-receptor
antagonist attenuates the first phase (0–7 min) of the early allergic response
(EAR) (48–50), it does not completely abolish it, implying that other mediators
such as leukotrienes or PGE 2 are also involved (51, 52).
The involvement of histamine in the LAR is even less certain. An increase
in the plasma histamine level coincident with the LAR has been reported (53),
but temporal relationships were not found among the airway changes, the rise in
plasma histamine, or the urinary excretion of the histamine metabolite, N-methyl
histamine (54). The influx of basophils described by McFarlane and others coinci-
dent with the late allergic response supports the involvement of basophils in this
process; however, H 1-antihistamines have had limited effectiveness at sup-
pressing the LAR, and do not reduce nonspecific airway hyperresponsiveness
(55–57).
Asthmatics have an enhanced baseline release of histamine in the peripheral
circulation and lungs compared to healthy or atopic nonasthmatic subjects, pre-
sumably as a result of basophil and mast cell degranulation. Increased histamine
levels are also noted following an exercise- or allergen-induced asthmatic attack
(58). Segmental allergen challenge has been shown to result in increased local
histamine release and bronchoconstriction in healthy and asthmatic subjects (59),
and there is a correlation between the increased levels of histamine in BAL fluid
and the increased bronchial hyperresponsiveness as assessed using methacholine
challenge (60).
A recent study suggests that leukotrienes play a more prominent role than
histamine in the development of the EAR and LAR after allergen challenge
Asthma 227
Figure 2 The allergen-induced reduction in FEV 1 during the early and late allergic
response to inhaled allergen in 12 asthmatic subjects after 1 week of treatment with pla-
cebo (open circles), zafirlukast 80 mg twice daily (closed circles), loratadine 10 mg twice
daily (open squares), or a combination of zafirlukast and loratadine (solid squares). The
pulmonary function is expressed as a percentage of the postdiluent FEV 1. (From Ref. 61.)
(Fig. 2). Roquet and colleagues noted that pretreatment of asthmatic subjects with
the selective cysteinyl leukotriene LT 1 receptor antagonist zafirlukast (80 mg
twice daily) reduced the extent of the EAR by 62% and the LAR by 55% (61)
(Fig. 2). The H 1-antagonist loratadine (10 mg twice daily) had a lower efficacy
and reduced the EAR and LAR by 25 and 40%, respectively. The combination
of the two agents was most effective, suppressing the EAR and LAR by 75 and
74%; however, a recent study by Dahlen et al. showed that high-dose loratadine
alone offered less protection against exercise-induced bronchoconstriction
(⫺9%) than high-dose zafirlukast alone (57%), or the combination of loratadine
and zafirlukast (65%) (62). Although it does appear that leukotrienes play a more
important role than histamine in the development of allergen- or exercise-induced
bronchoconstriction, these studies support the view that a combination of an anti-
histamine and an antileukotriene in high doses may represent a novel strategy
for the treatment of asthma.
VI. HISTAMINE AND H 1-ANTIHISTAMINES: PROPOSED

MECHANISMS OF ACTION AND INVOLVEMENT
IN INFLAMMATORY PROCESSES IN ASTHMA
Histamine is an important mediator of inflammation in asthma and has a number

of actions mediated through H 1-receptors, including vasodilation of postcapillary
venules and increased microvascular permeability leading to mucosal edema;

smooth muscle contraction and stimulation of parasympathetic reflexes leading
to bronchoconstriction; cough mediated by the stimulation of H 1-receptors on
afferent airway sensory nerve endings; and mucus hypersecretion as a result of
H 2-receptor activation on mucus glands (58).
A. Mechanism of Action of H 1-Antihistamines

Although H 1-antihistamines have been shown to have anti-inflammatory proper-
ties (Table 1), the precise mechanisms involved are unclear. Although many ac-
tions involve the activation of selective H 1-receptors on target cells, antihista-
mines may also effect responses by other mechanisms. Studies have suggested
that they may inhibit the influx of calcium into cells and interfere with signal
transduction pathways that are dependent on cytosolic calcium. Studies per-
formed by Arnold et al. on pulmonary epithelial cells (A549) and endothelial
cells suggest that many of the actions of cetirizine could be linked to the modulat-
ing effect of this H 1-antihistamine on the expression of the transcription factor
nuclear factor kappaB (NF-κB) (63, 64). Yoneda et al. also showed that azelastine
can block the activation of NF-κB and the expression of messenger (m)RNA
transcripts for IL-1β, IL-6, granulocyte macrophage colony-stimulating factor
(GM-CSF), and TNF-α in human peripheral blood leukocytes, lending support
Table 1 Anti-Inflammatory Actions of H 1-Antihistamines Relevant to Asthma
Cell Anti-inflammatory actions
Mast cells and basophils Inhibition of mediator release (histamine, leukotrienes, and
PGD 2)
Eosinophils Suppression of influx to airways after allergen challenge
Reduced chemotaxis
Reduced mediator release (superoxide radicals)
Neutrophils Reduced chemotaxis
Reduced release of mediators
Vascular endothelium Reduced expression of leukocyte adhesion molecules
(ICAM-1, VCAM-1) on vascular endothelium
Reduced NF-κB expression
Bronchial epithelium Reduced expression of activation markers, HLA-DR, and
ICAM-1
Reduced release of RANTES, IL-16, and soluble ICAM-1
Reduced expression of NF-κB
Antigen-presenting cells Possible reduction of antigen-presenting/antigen-processing
activity by APCs
ICAM-1, intercellular adhesion molecule-1; RANTES, regulated upon activation, normal T expressed
and secreted; HLA-DR, human leukocyte antigen-DR; NF-κB, nuclear factor kappa B; APC, antigen
presenting cell; VCAM-1, vascular cell adhesion molecule-1.
Asthma 229
to the hypothesis that H 1-antihistamines may inhibit the activation of genes re-
sponsible for the synthesis of proinflammatory mediators (64).
B. Mediator Release
The potential of various antihistamines to inhibit the generation of proinflamma-
tory mediators has been widely studied. Church et al. observed an inhibition of
anti-IgE-induced histamine release from human lung fragments by antihistamine
compounds at low concentrations, but a paradoxical increased release at higher
concentrations independent of the challenge used (65), suggesting inhibitory ef-
fects by mechanisms independent of the H 1-histamine receptor. Ketotifen has
shown poor inhibitory actions on histamine release by human lung mast cells,
but was noted to antagonize effectively the release of slow-reacting substance of
anaphylaxis (SRSA) (66). Azelastine has also been shown to inhibit histamine
and leukotriene release from human lung mast cells at concentrations of 3 µM
(67–69) while loratadine reduces leukotriene but not histamine release (70).
Ketotifen also inhibits the release of superoxide radicals by human neutro-
phils. In addition, inhibition of oxygen free radical production has been described
for ketotifen in human alveolar macrophages, and for azelastine, oxatomide, lora-
tadine, and cetirizine in human eosinophils. Of interest, the actions of cetirizine
were more pronounced in cells obtained from atopic subjects, with effective inhi-
bition of mediator release at lower concentrations in eosinophils obtained from
atopic donors than from nonatopic controls (71).
The airway epithelium is an important source of autacoid mediators, cyto-
kines, and chemokines, and plays an important role in regulating the inflamma-
tion, repair, and remodeling process in asthma (72). In vitro studies involving
the culture of bronchial epithelial cells transformed by virus 12-SV40 cells
(BEAS-2B) have confirmed that histamine is capable of activating the airway
epithelium with increased accumulation of intracellular calcium, an effect that
can be abrogated by the antihistamine diphenhydramine (73). Vignola et al. also
showed that histamine exposure increases the expression of the activation mark-
ers HLA-DR and ICAM-1 and the production of fibronectin by airway epithelial
cells, which can be inhibited by either the H 1-receptor antagonist pyrilamine or
the H 2-receptor antagonist ranitidine (74). More recently, it has been shown that
histamine augments the release of IL-16 (a potent chemokine for CD4 ⫹ lympho-
cytes and eosinophils) from airway epithelial cells in culture, particularly after
priming by IL-1β and TNF-α (75). These effects were inhibited by the protein
synthesis inhibitor cyclohexamide, and by dexamethasone, suggesting de novo
synthesis of IL-16 by mechanisms involving the activation of transcription fac-
tors, such as NF-κB (75). Bayram and colleagues observed an increased release
of IL-8, RANTES, and soluble ICAM-1 by primary bronchial epithelial cell
cultures after exposure to the air pollutant nitrogen dioxide (NO 2, 400 ppb),
and inhibition by loratadine or its metabolite SCH34117 (desloratadine) (76, 77)
(Fig. 3). Arnold et al. also confirmed that the release of IL-8 from bronchial
epithelial cells (A549) in response to TNF-α or phorbol 12-myristate 13-acetate
(PMA) exposure was inhibited by pretreatment with cetirizine, and was associ-
ated with a decreased amount of accessible DNA-binding sites of NF-κB as deter-
mined by flow cytometry automated cell sorting (FACS) analysis, providing fur-
ther evidence for the anti-inflammatory effects of H 1-antagonists (78).
C. Effects of H 1-Antihistamines on Inflammatory

Cell Recruitment
The accumulation and activation of inflammatory cells in the airways of asthma-
tics contribute significantly to the chronic inflammation and airway remodeling
of asthma. Histamine has been shown to promote the recruitment of inflammatory
cells to the airway by the upregulation of adhesion molecules on pulmonary vas-
cular endothelial cells. It is a potent stimulus for the transport of P-selectin from
the Weibel palisade bodies to the cell surface in the microvascular endothelium
(79). The interaction of P-selectin with its carbohydrate ligand expressed on cir-
culating T lymphocytes, eosinophils, and neutrophils promotes the initial rolling
and margination of leukocytes. In addition, cytokines released by mast cells pro-
mote the subsequent migration of inflammatory cells into the airways by aug-
menting the tight adherence and transendothelial migration of leukocytes, re-
sulting from increased expression of E-selectin and ICAM-1 (TNF-α, IL-1β, and
interferon-γ), and vascular cell adhesion molecule 1 (VCAM-1) (TNF-α, IL-4,
and IL-13).
In 1987, Fadel and colleagues showed that cetirizine inhibited the accumu-
lation of eosinophils at sites of allergen challenge in the skin of pollen-sensitive
subjects (80). Redier et al. also showed that the influx of eosinophils to the air-
ways, synchronous with the LAR after allergen challenge in allergic asthmatics,
is inhibited by prior treatment with cetirizine (55). Subsequent in vitro work
has shown that cetirizine effectively inhibits PAF-induced adherence of human
eosinophils to human umbilical vein endothelial cells (HUVEC) at extremely low
concentrations (81). Similar responses have also been noted in allergic diseases
of the eyes and skin. Cetirizine inhibits the increase in ICAM-1 expression on
epithelial conjunctival cells after conjunctival allergen challenge (82), suppresses
the allergen-induced expression of VCAM-1 in the skin of subjects with atopic
dermatitis (83), and decreases the expression of ICAM-1 on nasal epithelial cells
in children with mite-sensitive asthma (84).
There is also evidence from in vitro studies that antihistamines may have
a suppressive effect on the chemotaxis of inflammatory cells to sites of inflamma-
tion. In vitro studies by Gonzales et al. have shown that ketotifen inhibits the
chemotaxis of neutrophils at concentrations as low as 10 µg/mL (85). Results
with azelastine on neutrophil chemotaxis were equivocal, while the concentration
Asthma 231
Figure 3 The release of (a) RANTES and (b) sICAM-1 by primary bronchial epithelial
cell cultures after 24 h in vitro exposure to 400 ppb NO 2 in the presence or absence of
loratadine (0.25–25 µM). Expressed as median and range, n ⫽ 6 in each group. RANTES,
regulated upon activation, normal T expressed and secreted; sICAM-1, soluble intercellu-
lar adhesion molecule. (From Refs. 76, 77, and 122.)
of cetirizine required to inhibit neutrophil chemotaxis, above 35 µg/mL, was too

high to be of clinical relevance (86).
Cetirizine effectively inhibits eosinophil chemotaxis induced by PAF,
LTB 4, IL-8, and C5a, even at concentrations within the therapeutic range (87).
Ketotifen is reported to inhibit PAF-induced eosinophil chemotaxis at concentra-
tions lower than that required for inhibition of LTC 4 production. Other antihista-
mines have been shown to be less effective or ineffective at concentrations likely
to be achieved in vivo by doses used in clinical practice.
The accumulation of inflammatory cells at the site of inflammation is also
dependent on the rate at which the cells die or are removed from the tissue by
programmed cell death, or apoptosis. The apoptosis of eosinophils and mast cells
is delayed and survival increased by the cytokine IL-5 and stem cell factor (SCF),
respectively. The survival of eosinophils in the presence of IL-5 is reduced by
ketotifen, although relatively high concentrations are required (10 ⫺3 or 10 ⫺4 M)
to elicit the response (88).
It has been suggested that antihistamines may have some suppressive ef-
fects on the initial processing or presentation of antigen by antigen-presenting
cells. Ketotifen enhanced lymphocyte proliferation at concentrations up to 50
µM, but had inhibitory effects at higher concentrations (71). Todoroki and col-
leagues also reported a weak suppressive effect of azelastine on the induction of
IL-2 responsiveness by Dermatophagoides farinae antigen in peripheral blood
mononuclear cell cultures from patients with asthma (89).
VII. EFFECTS OF H 1-ANTIHISTAMINES

IN CLINICAL ASTHMA
As early as 1949, Herxheimer reported clinical improvement in an open study of

26 patients with mild to moderate asthma following treatment with mepyramine,
diphenhydramine, and promethazine (90). It was believed, however, that antihis-
tamines would thicken airway mucus, and concerns were expressed about the
frequent side effects of the first-generation H 1-antihistamines, in particular seda-
tion and dry mouth. Schuller et al. (91) reported that antihistamines could cause
bronchoconstriction and have a deleterious effect on lung function in children
with asthma. This led to a warning that they should not be used in the manage-
ment of asthma; however, in contrast to the extremely limited evidence that anti-
histamines cause bronchoconstriction, there are now considerable supportive data
for an H 1-antagonist bronchodilator effect (92). In a position statement, the Amer-
ican Academy of Allergy, Asthma and Immunology advised removal of the warn-
ing, and recommended that antihistamines should be prescribed if required for
patients with asthma, unless a previous adverse reaction had been documented
in a specific patient (93).
Asthma 233
In reviews of the role of H 1-antagonists in the management of asthma (94),

concerns have been expressed over the design of many of the studies performed
before 1996 including the absence of a double-blind, placebo-controlled (DBPC)
design, inadequate washout period for other medications, insufficient patient
numbers to detect a significant effect, and inadequate characterization of asthma
severity prior to inclusion in the study. Van Ganse and colleagues performed a
meta-analysis of clinical trials of antihistamines in the management of mild, mod-
erate, and severe asthma (95), in which 71 DBPC trials were reviewed, and 19
studies submitted for quality assessment (Fig. 4). The overall quality of studies
was low, with a mean score of 59%. Asthma was generally uncontrolled at inclu-
sion. The antihistamines assessed included azelastine, cetirizine, ketotifen, lora-
tadine, oxatomide, pemirolast, picumast, and terfenadine. H 1-antihistamines had
Figure 4 Meta-analysis of the efficacy of H 1-antihistamines in adults with asthma. The

antihistamines selected were azelastine (study number 7 in meta-analysis), cetirizine (15),
ketotifen (1, 2, 3, 5, 8,), loratadine (13), oxatomide (4), pemirolast (12), picumast (9), and
terfenadine (6, 10, 14). H 1-antihistamines and placebo had a similar effect on morning
and evening PEF and FEV 1. Sedation was reported more frequently than for placebo
(p ⬍ 0.001). (From Ref. 95.)
little effect on morning peak expiratory flow (PEF), evening PEF, or FEV 1. Seda-
tion was noted more frequently in the active treatment group compared to those
receiving placebo, and additional side effects of weight gain, altered taste, head-
ache, and dry mouth were recorded.
The second-generation H 1-antihistamines have many advantages over the
first-generation H 1-antihistamines in terms of specificity, safety, and side effect
profile. Similar to H 1-receptor effects in the upper airways and skin, there is no
evidence of tachyphylaxis to bronchodilator effect in the lower airway (96–105),
and no increase in asthma symptoms has been documented with continued use
of antihistamines (106, 107).
Some authors have suggested that antihistamines may have a corticoste-
roid-sparing effect in asthma (102) (Fig. 5a), but this has not been consistently
shown (103) (Fig. 5b).
A. Cetirizine
Cetirizine, a carboxylated metabolite of hydroxyzine, is a potent antihistamine
with documented bronchodilator and anti-inflammatory properties (108) and no
effect on calcium channels, serotoninergic, muscarinic, or dopaminergic receptors
(109). In a study of symptomatic grass pollen–sensitive asthmatics, treatment
with cetirizine 15 mg daily for 2 weeks led to a reduction in asthma symptoms,
and allowed a reduction in the concomitant use of β 2-agonists and inhaled cortico-
Figure 5 (a) Glucocorticosteroid-sparing effect of H 1-antihistamines in adults with

asthma. Azelastine reduced the requirement for inhaled corticosteroids (ICS) in adults
with chronic asthma. In a study of 193 subjects receiving azelastine (6 mg twice daily)
or placebo in combination with beclomethasone dipropionate (BDP; 6–16 inhalations/
day), BDP was reduced until maximum reduction or cessation was achieved. Subjects
were then evaluated for a maintenance period of 12 weeks at the reduced dosage of BDP.
A significantly greater reduction in BDP was achieved in the azelastine group (4.9 puffs/
day) than in patients receiving placebo (3.1 puffs/day; p ⬍ 0.01). (From Ref. 102.) (b)
Lack of a steroid-sparing effect by the H 1-antagonist, ketotifen, in children with asthma.
In a study of 52 children aged 6–13 years receiving maintenance treatment with ICS at
dosages less than 1000 µg/day, ketotifen (2 mg/day) or placebo was administered for 32
weeks, following a 4-week run-in period. From weeks 13 to 20, the dose of ICS was
reduced by 25% on alternate weeks to the minimum dose tolerated, and continued during
weeks 21–32 if tolerated. At baseline the mean ICS dosages were 432 µg/day and 408
µg/day in the ketotifen and placebo groups, respectively. Although the ketotifen-treated
children reported fewer symptoms compared to the placebo-treated group, there was no
significant difference in ICS doses (vertical axis) during weeks 21–32 in the ketotifen-
treated group (18% of baseline) compared to the placebo group (35% of baseline) (no.,
number). (From Ref. 103.)
Asthma 235
steroids (ICS) compared to placebo (110). Bousquet and colleagues reported that
cetirizine (10 or 15 mg twice daily) was more effective than terfenadine (60 mg
twice daily) in the control of asthma in 97 grass pollen–allergic subjects with
mild seasonal symptoms of recent onset. Spector et al. also confirmed a significant
bronchodilator effect of cetirizine in a DBPC trial of 13 patients with mild-to-
moderate asthma. After three different doses of cetirizine (5, 10, or 20 mg), they
noted a bronchodilator effect that was additive to, and lasted longer than that of,
salbutamol (101).
B. Azelastine
Azelastine has been shown to inhibit the release of both histamine and leuko-
trienes from human lung mast cells (71), and may also have some suppressive
effects on antigen processing or presentation (89). The efficacy of azelastine in
the management of persistent asthma has been assessed in a number of studies
(97, 102). In a DBPC trial of 24 asthmatic subjects by Gould et al. (97), treat-
ment with azelastine for 7 weeks resulted in a reduction in symptoms of cough
and wheeze, associated with improvements in peak flow readings, and a reduc-
tion in the use of rescue bronchodilator therapy. Busse et al. also noted that
azelastine reduced the requirements for inhaled corticosteroids in adults with
chronic asthma (102). In this study of 193 adults with asthma, subjects received
either azelastine 6 mg twice daily or placebo in combination with beclometha-
sone dipropionate 6–16 inhalations per day. The inhaled corticosteroid was then
reduced until maximum reduction or discontinuation was achieved and main-
tained for a 12-week period. The authors noted a significantly greater overall
median reduction in corticosteroid dose in the azelastine group compared with
placebo (4.9 puffs per day for azelastine compared to 3.1 puffs per day for pla-
cebo, p ⬍ 0.01), indicating a mild glucocorticoid-sparing effect of azelastine in
asthma (Fig. 5a).
C. Ketotifen
Studies assessing the role of ketotifen in asthma have shown variable efficacy, but
excessive drowsiness has been consistently reported. In a 1-month randomized
placebo-controlled study of ketotifen (1 mg and 2 mg) involving 50 atopic asth-
matics, Dyson and colleagues showed no improvement in PEF; also, there was
a significant reduction in reliever β 2-agonist use in the subgroup of patients not
maintained on ICS, but no improvement in patients requiring ICS therapy (111).
Fourteen percent of subjects either withdrew from the study or reduced the dose
of ketotifen due to excessive sedation. A 7-month DBPC study of ketotifen was
performed in 138 children aged 5–17 years with chronic asthma (112). After 10
Asthma 237
weeks of treatment, 60% of ketotifen-treated children were able to discontinue

theophylline therapy compared to 34% in the placebo group. Ketotifen-treated
children also reported a significant improvement in quality of life.
Lane et al. performed a multicenter DBPC study in 86 steroid-dependent
asthmatics to assess the steroid-sparing effects of ketotifen use (113). Subjects
had documented airflow obstruction and had been taking oral corticosteroids for
1 month prior to inclusion. After a run-in period of 2 weeks, oral corticosteroids
were reduced by 1 mg per week until subjects became symptomatic or were off
corticosteroids for 1 week. Ten patients (24%) were weaned from corticosteroids
in the ketotifen group compared to three subjects in the placebo group. The daily
requirement for oral prednisolone was reduced from 8.4 mg to 4.4 mg in the
active group. Drowsiness was the major adverse event, being reported in 5% of
patients taking ketotifen.
D. Loratadine
Loratadine has been variably successful in asthma treatment. Kroll et al. per-
formed an uncontrolled study of 25 patients with asthma and showed an improve-
ment in lung function, associated with a reduction in asthma symptoms and bron-
chodilator use after 6 weeks treatment with loratadine 10 mg daily (114);
however, the same dose of loratadine failed to show any effect on peak flow or
symptoms in a DBPC crossover trial involving 17 subjects with moderate asthma
(115).
VIII. ROLE OF H1-ANTIHISTAMINES IN PATIENTS WITH

ALLERGIC RHINITIS AND MILD SEASONAL ASTHMA
Allergic rhinitis and asthma are both relatively common disorders and the two
conditions commonly coexist. The upper and lower airways share a number of
epidemiological, physiological, immunopathological, and pharmacological simi-
larities, yet also exhibit distinct features as summarized by Simons (Table 2).
Poorly controlled allergic rhinitis has been shown to sustain asthma-like symp-
toms (116), and has been associated with a worsening of asthma control. Nasal
allergen challenge in subjects with allergic rhinitis and mild asthma results in
increased bronchial hyperreactivity to methacholine, which is reduced by prior
treatment with cetirizine (10 mg daily) (117). An improvement in symptoms of
allergic rhinitis and asthma has been documented for patients with coexistent
rhinitis and pollen-sensitive asthma after treatment with cetirizine at dosages as
low as 10 mg daily, in comparison with terfenadine (60 mg twice daily) which
only improved allergic rhinitis symptoms (118). Grant et al. performed a 6-week
randomized DBPC clinical trial of 186 patients with seasonal allergic rhinitis and
Table 2 Links Between the Upper and Lower Airways in Allergic Rhinitis and
Atopic Asthma
Epidemiology 30–50% of allergic rhinitis patients have clinical asthma. 80% of

asthmatics have undiagnosed or clinical allergic rhinitis.
Anatomy Nasal mucosa and bronchial mucosa are lined by ciliated colum-
nar epithelium.
Increased vascularity is characteristic of allergic rhinitis. Subepi-
thelial fibrosis and smooth muscle hypertrophy are characteris-
tic features of asthma.
Physiology Increased bronchial hyperresponsiveness is found in patients with
isolated allergic rhinitis.
Increased bronchial hyperresponsiveness is typical of asthma.
Immunopathology Inflammation of upper and lower airways, and infiltration by Th2
lymphocytes, activated eosinophils, degranulated mast cells,
and basophils.
Elevated IgE levels.
Increased expression of Th2-type cytokines (IL-4, IL-5, GM-
CSF), and chemokines (RANTES); and release of mediators
(histamine, leukotrienes).
Pharmacology Anti-inflammatory therapy with topical corticosteroids is the key
to management of both conditions.
Control of allergic rhinitis symptoms (topical corticosteroids, anti-
allergics, H1-antagonists) improves asthma symptoms.
Asthma may remain poorly controlled despite optimal treatment
in the presence of symptomatic allergic rhinitis.
α-Adrenergic agonists have a role as vasoconstrictors in allergic
rhinitis.
β2-Adrenergic agonists are important bronchodilator agents in
asthma.
IL-4, interleukin 4; GM-CSF, granulocyte macrophage colony stimulating factor; RANTES, regulated
upon activation, normal T expressed and secreted.
Source: Adapted from Ref. 94.
asthma (105) (Fig. 6). They reported a worsening of symptoms in the placebo
group during the study, whereas the patients treated with cetirizine (10 mg daily)
showed improvements in rhinitis and asthma symptoms. Although the use of
reliever bronchodilators was reduced, there was no significant improvement in
lung function in the cetirizine-treated group. More patients in the cetirizine-
treated group completed the trial, suggesting that cetirizine was safe, well toler-
ated, and effectively relieved symptoms in upper and lower airways disease, at
doses commonly used for the treatment of allergic rhinitis (105). These effects
Asthma 239
Figure 6 Effects of H 1-antihistamines in seasonal allergic rhinitis and mild asthma. (a)
There was a significant reduction in rhinitis symptoms from week 1 and during the pollen
season in cetirizine-treated patients. (b) Cetirizine significantly reduced asthma symptoms
during weeks 1, 2, 4, 5, and 6 of the study, but no significant improvements in PEF or
FEV 1 were noted. (From Ref. 105.)
of H 1-antagonists on upper and lower airways disease have also been confirmed
by Corren and colleagues in a DBPC trial in which they gave a combined prepara-
tion of loratadine 5 mg and pseudoephedrine sulfate 120 mg twice daily (104).
Compared to placebo, the combination was shown to improve pulmonary func-
tion and symptoms of allergic rhinitis and asthma in 193 patients with seasonal
allergic rhinitis and asthma.
IX. DO H 1-ANTIHISTAMINES HAVE A PREVENTATIVE

EFFECT ON THE DEVELOPMENT OF ASTHMA IN
HIGH-RISK ATOPIC INFANTS?
There has been considerable recent interest in the early-life origins of asthma.
Management strategies have been devised to prevent the later onset of asthma
in infants considered at high risk of asthma due to atopic status or positive history
of asthma in one or both parents. Allergen avoidance in early life has been advo-
cated as a possible strategy but is difficult to achieve and may not be effective.
Of particular interest are the results of studies suggesting that antihistamine ther-
apy may delay the subsequent development of asthma. Placebo-controlled studies
by Iikura et al. and Bustos et al. of 1 and 3 years’ duration, respectively, in infants
with atopic dermatitis, positive family history of asthma, and/or elevated IgE
levels suggest that ketotifen may delay the onset of asthma (119, 120). The Early
Treatment of the Atopic Child (ETAC) study reported similar effects with cetiri-
zine, which was shown to prevent the onset of asthma when administered to
grass- or house dust mite–sensitized infants (121). Although the precise mecha-
nisms involved in this process are not yet clear, it has been suggested that in-
flammatory mediators released from a primary site of atopy (e.g., the skin in
atopic dermatitis) may have distant actions on a secondary organ to upregulate
the expression of adhesion molecules on the pulmonary vascular endothelium,
priming the airways for the recruitment of inflammatory cells to the lungs, and
the later development of bronchial asthma. It is possible that cetirizine may act
to downregulate the activation state of the pulmonary vascular endothelium by
downregulating adhesion molecules through mechanisms involving NF-kB ex-
pression, and may prevent the airway inflammation from the outset (63).
X. SUMMARY
Histamine released from mast cells and basophils is an important mediator of

airway inflammation in asthma, particularly in the development of the early aller-
gic response. Although histamine has been shown to contribute significantly to
the bronchoconstrictor response to allergen or exercise, leukotrienes are likely
Asthma 241
to play a more prominent role in these responses in asthma. The improved speci-
ficity, tolerability, and safety profile of the second-generation H 1-antagonists as-
sociated with anti-inflammatory activities and bronchodilator activities, may con-
tribute to relieve the symptoms of the upper and lower airways in patients with
coexistent mild seasonal asthma and allergic rhinitis. Considering the global rise
in the prevalence of allergy and asthma, the suggestion that H 1-antagonists may
delay the onset of asthma in infants is of considerable interest and merits further
assessment. Although it is unlikely that monotherapy with most currently avail-
able H 1-antagonists will provide significant clinical benefit in asthma, the poten-
tial of combined antihistamine and antileukotriene therapy may prove useful,
particularly in subjects with poor compliance to inhaled corticosteroid therapy.
ACKNOWLEDGMENTS
Dr. Lordan is a clinical research fellow funded by a program grant from the
Medical Research Council, UK. Professor Holgate is MRC Clinical Professor of
Immunopharmacology. The authors thank Evelyn Lordan for her assistance and
support in preparation of the manuscript.
REFERENCES
1. ISAAC. Worldwide variation in prevalence of symptoms of asthma, allergic rhino-

conjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and
Allergies in Childhood (ISAAC) Steering Committee. Lancet 1998; 351:1225–
1232.
2. British Thoracic Society, NAC, Royal College of Physicians of London. The British
guidelines on asthma management: 1995 review and position statement. Thorax
1997; 52:S1–S20.
3. Riley JF, West GB. The presence of histamine in tissue mast cells. J Physiol 1953;
120:528–537.
4. Corne JM, Holgate ST. H 1-receptor antagonists in asthma. In: Simons FER ed.
Histamine and H 1-Receptor Antagonists in Allergic Disease. New York: Marcel
Dekker, Inc., 1996:251–271.
5. Djukanovı́c R, Wilson JW, Britten KM, Wilson SJ, Walls AF, Roche WR, Howarth
PH, Holgate ST. Quantitation of mast cells and eosinophils in the bronchial mucosa
of symptomatic atopic asthmatics and healthy control subjects using immunohisto-
chemistry. Am Rev Respir Dis 1990; 142:863–871.
6. Galli SJ, Wershil BK. The two faces of the mast cell. Nature 1996; 381:21–22.
7. MacFarlane AJ, Kon OM, Smith SJ, Zeibecoglou K, Khan LN, Barata LT, McEven
AR, Buckley MG, Walls AF, Meng Q, Humbert M, Barnes NC, Robinson DS,
Ying S, Kay AB. Basophils, eosinophils, and mast cells in atopic and non-atopic
asthma and in late-phase allergic reactions in the lung and skin. J Allergy Clin
Immunol 2000; 105:99–107.
8. Wenzel SE, Fowler AA, Schwartz LB. Activation of pulmonary mast cells by bron-
choalveolar allergen challenge. In vivo release of histamine and tryptase in atopic
subjects with and without asthma. Am Rev Respir Dis 1988; 137:1002–1008.
9. Wardlaw AJ, Dunnette S, Gleich GJ, Collins JV, Kay AB. Eosinophils and mast
cells in bronchoalveolar lavage in subjects with mild asthma. Relationship to bron-
chial hyperreactivity. Am Rev Respir Dis 1988; 137:62–69.
10. Howarth PH, Bradding P, Montefort S, Peroni D, Djukanovı́c R, Carroll MP, Hol-
gate ST. Mucosal inflammation and asthma. Am J Respir Crit Care Med 1994;
150:S18–22.
11. Crimi E, Chiaramondia M, Milanese M, Rossi GA, Brusasco V. Increased numbers
of mast cells in bronchial mucosa after the late-phase asthmatic response to aller-
gen. Am Rev Respir Dis 1991; 144:1282–1286.
12. Flint KC, Leung KB, Hudspith BN, Brostoff J, Pearce FL, Johnson NM. Bronchoal-
veolar mast cells in extrinsic asthma: a mechanism for the initiation of antigen
specific bronchoconstriction. Br Med J (Clin Res Ed) 1985; 291:923–926.
13. Diaz P, Gonzalez MC, Galleguillos FR, Ancic P, Cromwell O, Shepherd D, Durham
SR, Gleich GJ, Kay AB. Leukocytes and mediators in bronchoalveolar lavage dur-
ing allergen-induced late-phase asthmatic reactions. Am Rev Respir Dis 1989; 139:
1383–1389.
14. Bradding P, Okayama Y, Howarth PH, Church MK, Holgate ST. Heterogeneity of
human mast cells based on cytokine content. J Immunol 1995; 155:297–307.
15. Bradding P, Roberts JA, Britten KM, Montefort S, Djukanovic R, Mueller R, Heus-
ser CH, Howarth PH, Holgate ST. Interleukin-4, -5, and -6 and tumor necrosis
factor-alpha in normal and asthmatic airways: evidence for the human mast cell as
a source of these cytokines. Am J Respir Cell Mol Biol 1994; 10:471–480.
16. Okayama Y, Petit-Frere C, Kassel O, Semper A, Quint D, Tunon-de-Lara MJ, Brad-
ding P, Holgate ST, Church MK. IgE-dependent expression of mRNA for IL-4 and
IL-5 in human lung mast cells. J Immunol 1995; 155:1796–1808.
17. Laberge S, Pinsonneault S, Ernst P, Olivenstein R, Ghaffar O, Center DM, Hamid
Q. Phenotype of IL-16-producing cells in bronchial mucosa: evidence for the hu-
man eosinophil and mast cell as cellular sources of IL-16 in asthma. Int Arch Al-
lergy Immunol 1999; 119:120–125.
18. Ochensberger B, Rihs S, Brunner T, Dahinden CA. IgE-independent interleukin-
4 expression and induction of a late phase of leukotriene C4 formation in human
blood basophils. Blood 1995; 86:4039–4049.
19. MacGlashan D. Jr., White JM, Huang SK, Ono SJ, Schroeder JT, Lichtenstein LM.
Secretion of IL-4 from human basophils. The relationship between IL-4 mRNA
and protein in resting and stimulated basophils. J Immunol 1994; 152:3006–3016.
20. Sarmiento EU, Espiritu BR, Gleich GJ, Thomas LL. IL-3, IL-5, and granulocyte-
macrophage colony-stimulating factor potentiate basophil mediator release stimu-
lated by eosinophil granule major basic protein. J Immunol 1995; 155:2211–2221.
21. Ochensberger B, Daepp GC, Rihs S, Dahinden CA. Human blood basophils pro-
duce interleukin-13 in response to IgE-receptor–dependent and –independent acti-
vation. Blood 1996; 88:3028–3037.
Asthma 243
22. Li H, Sim TC, Alam R. IL-13 released by and localized in human basophils. J
Immunol 1996; 156:4833–4838.
23. Simon RA, Stevenson DD, Arroyave CM, Tan EM. The relationship of plasma
histamine to the activity of bronchial asthma. J Allergy Clin Immunol 1977; 60:
312–316.
24. McEuen AR, Buckley MG, Compton SJ, Walls AF. Development and characteriza-
tion of a monoclonal antibody specific for human basophils and the identification
of a unique secretory product of basophil activation. Lab Invest 1999; 79:27–
38.
25. Windaus A, Vogt W. Synthese des Iminazolylethylamins. Berd Deutsch Chem Ge-
sell 1907; 40:369.
26. Dale HH, Laidlaw PP. The physiological action of beta-iminazolylethylamine. J
Physiol 1910; 41:318–344.
27. Weiss S, Robb GP, Ellis LB. The systemic effects of histamine in man. Arch Intern
Med 1932; 49:360–396.
28. Curry JJ. The action of histamine on the respiratory tract in normal and asthmatic
subjects. J Clin Invest 1946; 25:785–791.
29. Curry JJ. The effect of antihistamine substances and other drugs on histamine bron-
choconstriction in asthmatic subjects. J Clin Invest 1946; 25:792–799.
30. Graham HT, Lowry OH, Wheelwright F, Lenz MA, Parish HH. Distribution of
histamine among leukocytes and platelets. Blood 1955; 10:467–481.
31. Ishizaka K, Ishizaka T, Terry WD. Antigenic structure of gamma-E-globulin and
reaginic antibody. J Immunol 1967; 99:849–858.
32. Barnes PJ, Ind PW, Brown MJ. Plasma histamine and catecholamines in stable
asthmatic subjects. Clin Sci (Colch) 1982; 62:661–665.
33. Akagi K, Townley RG. Spontaneous histamine release and histamine content in
normal subjects and subjects with asthma. J Allergy Clin Immunol 1989; 83:742–
749.
34. Wood-Baker R, Holgate ST. The comparative actions and adverse effect profile of
single doses of H 1-receptor antihistamines in the airways and skin of subjects with
asthma. J Allergy Clin Immunol 1993; 91:1005–1014.
35. Tashkin DP, Brik A, Gong H Jr. Cetirizine inhibition of histamine-induced bron-
chospasm. Ann Allergy 1987; 59:49–52.
36. Cushley MJ, Tattersfield AE, Holgate ST. Inhaled adenosine and guanosine on
airway resistance in normal and asthmatic subjects. Br J Clin Pharmacol 1983; 15:
161–165.
37. Polosa R, Holgate ST. Adenosine bronchoprovocation: a promising marker of aller-
gic inflammation in asthma? Thorax 1997; 52:919–923.
38. Feoktistov I, Polosa R, Holgate ST, Biaggioni I. Adenosine A 2b receptors: a novel
therapeutic target in asthma? Trends Pharmacol Sci 1998; 19:148–153.
39. Forsythe P, Ennis M. Adenosine, mast cells and asthma. Inflamm Res 1999; 48:
301–307.
40. Forsythe P, McGarvey LP, Heaney LG, MacMahon J, Ennis M. Adenosine induces
histamine release from human bronchoalveolar lavage mast cells. Clin Sci (Colch)
1999; 96:349–355.
41. Phillips GD, Ng WH, Church MK, Holgate ST. The response of plasma histamine
to bronchoprovocation with methacholine, adenosine 5′-monophosphate, and aller-

gen in atopic non-asthmatic subjects. Am Rev Respir Dis 1990; 141:9–13.
42. Polosa R, Ng WH, Crimi N, Vancheri C, Holgate ST, Church MK, Mistretta A.
Release of mast-cell-derived mediators after endobronchial adenosine challenge in
asthma. Am J Respir Crit Care Med 1995; 151:624–629.
43. Rafferty P, Beasley R, Holgate ST. The contribution of histamine to immediate
bronchoconstriction provoked by inhaled allergen and adenosine 5′ monophosphate
in atopic asthma. Am Rev Respir Dis 1987; 136:369–373.
44. Ghosh SK, Rafferty P, De Vos C, Patel KR. Effect of cetirizine, a potent H 1-antago-
nist, on platelet activating factor induced bronchoconstriction in asthma. Clin Exp
Allergy 1993; 23:524–527.
45. Howarth PH, Durham SR, Lee TH, Kay AB, Church MK, Holgate ST. Influence of
albuterol, cromolyn sodium and ipratropium bromide on the airway and circulating
mediator responses to allergen bronchial provocation in asthma. Am Rev Respir
Dis 1985; 132:986–992.
46. Busse WW, Swenson CA. The relationship between plasma histamine concentra-
tions and bronchial obstruction to antigen challenge in allergic rhinitis. J Allergy
Clin Immunol 1989; 84:658–666.
47. Dahlen SE, Kumlin M. Can asthma be studied in the urine? Clin Exp Allergy 1998;
28:129–133.
48. Wasserfallen JB, Leuenberger P, Pecoud A. Effect of cetirizine, a new H 1-antihista-
mine, on the early and late allergic reactions in a bronchial provocation test with
allergen. J Allergy Clin Immunol 1993; 91:1189–1197.
49. Holgate ST, Finnerty JP. Antihistamines in asthma. J Allergy Clin Immunol 1989;
83:537–547.
50. Howarth PH. Histamine and asthma: an appraisal based on specific H 1-receptor
antagonism. Clin Exp Allergy 1990; 20 (Suppl 2):31–41.
51. Beasley RC, Featherstone RL, Church MK, Rafferty P, Varley JG, Harris A,
Robinson C, Holgate ST. Effect of a thromboxane receptor antagonist on PGD2-
and allergen-induced bronchoconstriction. J Appl Physiol 1989; 66:1685–1693.
52. Kumlin M, Dahlen B, Bjorck T, Zetterstrom O, Granstrom E, Dahlen SE. Urinary
excretion of leukotriene E 4 and 11-dehydro-thromboxane B 2 in response to bron-
chial provocations with allergen, aspirin, leukotriene D 4, and histamine in asthma-
tics. Am Rev Respir Dis 1992; 146:96–103.
53. Durham SR, Lee TH, Cromwell O, Shaw RJ, Merrett TG, Merrett J, Cooper P,
Kay AB. Immunologic studies in allergen-induced late-phase asthmatic reactions.
54. DeMonchy JG, Keyzer JJ, Kauffman HF, Beaumont F, De Vries K. Histamine in
late asthmatic reactions following house-dust mite inhalation. Agents Actions 1985;
16:252–255.
55. Redier H, Chanez P, De Vos C, Rifai N, Clauzel AM, Michel FB, Godard P. Inhibi-
tory effect of cetirizine on the bronchial eosinophil recruitment induced by allergen
inhalation challenge in allergic patients with asthma. J Allergy Clin Immunol 1992;
90:215–224.
56. Hamid M, Rafferty P, Holgate ST. The inhibitory effect of terfenadine and flurbi-
profen on early and late-phase bronchoconstriction following allergen challenge in
atopic asthma. Clin Exp Allergy 1990; 20:261–267.
Asthma 245
57. Town GI, Holgate ST. Comparison of the effect of loratadine on the airway and
skin responses to histamine, methacholine, and allergen in subjects with asthma.
58. Grant JA. The clinical efficacy of antihistamines in the upper and lower airway.
Clin Exp Allergy 1997; 27(Suppl 2):38–46; discussion 54–56.
59. Casale TB, Wood D, Richerson HB, Zehr B, Zavala D, Hunninghake GW. Direct
evidence of a role for mast cells in the pathogenesis of antigen- induced broncho-
constriction. J Clin Invest 1987; 80:1507–1511.
60. Casale TB, Wood D, Richerson HB, Trapp S, Metzger WJ, Zavala D, Hunninghake
GW. Elevated bronchoalveolar lavage fluid histamine levels in allergic asthmatics
are associated with methacholine bronchial hyperresponsiveness. J Clin Invest
1987; 79:1197–1203.
61. Roquet A, Dahlen B, Kumlin M, Ihre E, Anstren G, Binks S, Dahlen SE. Combined
antagonism of leukotrienes and histamine produces predominant inhibition of aller-
gen-induced early and late phase airway obstruction in asthmatics. Am J Respir
Crit Care Med 1997; 155:1856–1863.
62. Dahlen B, Roquet A, Inman M, Larssen F, Karlsson O, Hemmings R, Naya I,
Anstren G, O’Byrne P, Dahlen S-E. The contribution of histamine and leukotrienes
to exercise-induced airway obstruction in asthmatics. Am J Respir Crit Care Med
2000; 161:A613.
63. Rihoux JP, Michel L, Arnold R, Konig W. Hypothetical mechanisms of action
of an H 1-antihistamine in asthma. Int Arch Allergy Immunol 1999; 118:380–
383.
64. Yoneda K, Yamamoto T, Ueta E, Osaki T. Suppression by azelastine hydrochloride
of NF-kappa B activation involved in generation of cytokines and nitric oxide. Jpn
J Pharmacol 1997; 73:145–153.
66. Ross WJ, Harrison RG, Jolley MR, Neville MC, Todd A, Verge JP, Dawson W,
Sweatman WJ. Antianaphylactic agents. 1. 2-(Acylamino)oxazoles. J Med Chem
1979; 22:412–417.
67. Manabe H, Ohmori K, Tomioka H, Yoshida S. Oxatomide inhibits the release of
chemical mediators from human lung tissues and from granulocytes. Int Arch Al-
lergy Appl Immunol 1988; 87:91–97.
68. Josephs LK, Gregg I, Mullee MA, Holgate ST. Nonspecific bronchial reactivity
and its relationship to the clinical expression of asthma. A longitudinal study. Am
Rev Respir Dis 1989; 140:350–357.
69. Schmutzler W, Delmich K, Eichelberg D, Gluck S, Greven T, Jurgensen H, Rie-
sener KP, Risse G, Pult P. The human adenoidal mast cell. Susceptibility to differ-
ent secretagogues and secretion inhibitors. Int Arch Allergy Appl Immunol 1985;
77:177–178.
70. Temple DM, McCluskey M. Loratadine, an antihistamine, blocks antigen- and io-
nophore-induced leukotriene release from human lung in vitro. Prostaglandins
1988; 35:549–554.
71. Church MK. Non-H 1-receptor effects of antihistamines. Clin Exp Allergy 1999;
29(Suppl.3):39–48.
72. Knobil K, Jacoby DB. Mediator functions of epithelial cells. In: Holgate ST, Busse
WW, eds. Inflammatory mechanisms in asthma. Lung Biology Health and Disease,
Vol. 117. New York: Marcel Dekker, Inc., 1998:469–495.
73. Noah TL, Paradiso AM, Madden MC, McKinnon KP, Devlin RB. The response
of a human bronchial epithelial cell line to histamine: intracellular calcium changes
and extracellular release of inflammatory mediators. Am J Respir Cell Mol Biol
1991; 5:484–492.
74. Vignola AM, Campbell AM, Chanez P, Lacoste P, Michel FB, Godard P, Bousquet
J. Activation by histamine of bronchial epithelial cells from nonasthmatic subjects.
Am J Respir Cell Mol Biol 1993; 9:411–417.
75. Arima M, Plitt J, Stellato C, Bickel C, Motojima S, Makino S, Fukuda T, Schleimer
RP. Expression of interleukin-16 by human epithelial cells. Inhibition by dexameth-
asone. Am J Respir Cell Mol Biol 1999; 21:684–692.
76. Bayram H, Devalia JL, Khair OA, Abdelaziz MM, Sapsford RJ, Czarlewski W,
Campbell AM, Bousquet J, Davies RJ. Effect of loratadine on nitrogen dioxide-
induced changes in electrical resistance and release of inflammatory mediators from
cultured human bronchial epithelial cells. J Allergy Clin Immunol 1999; 104:93–
99.
1999; 29 (Suppl 3):64–68.
78. Arnold R, Rihoux J, Konig W. Cetirizine counter-regulates interleukin-8 release
from human epithelial cells (A549). Clin Exp Allergy 1999; 29:1681–1691.
79. Kubes P. Mast cell activation and leucocyte responses. In: Bochner B, ed. Adhesion
molecules in allergic diseases. New York: Marcel Dekker, Inc., 1997:226–229.
80. Fadel R, Herpin-Richard N, Rihoux JP, Henocq E. Inhibitory effect of cetirizine
2HCl on eosinophil migration in vivo. Clin Allergy 1987; 17:373–379.
81. Sehmi R, Walsh GM, Hartnell A, Barkans J, North J, Kay AB, Moqbel R. Modula-
tion of human eosinophil chemotaxis and adhesion by anti-allergic drugs in vitro.
Pediatr Allergy Immunol 1993; 4(Suppl.4):13–18.
82. Ciprandi G, Buscaglia S, Pesce G, Passalacqua G, Rihoux JP, Bagnasco M, Can-
CD54) expression on conjunctival epithelium in both early- and late-phase reactions
83. Boone M, Renard N, Rihoux J, Song M. Adhesion molecule profiles in the skin
of atopic dermatitis and of allergic contact dermatitis before and after patch testing.
Pharmacological modification by cetirizine. Dublin: EADV, 1996.
GW. Cetirizine reduces ICAM-I on epithelial cells during nasal minimal persistent
Immunol 1996; 109:272–276.
85. Mitra RS, Shimizu Y, Nickoloff BJ. Histamine and cis-urocanic acid augment tu-
mor necrosis factor-alpha mediated induction of keratinocyte intercellular adhesion
molecule-1 expression. J Cell Physiol 1993; 156:348–357.
86. Van Epps DE, Kutvirt SG, Potter JW. In vitro effects of cetirizine and histamine
on human neutrophil function. Ann Allergy 1987; 59:13–19.
87. Leprevost C, Capron M, De Vos C, Tomassini M, Capron A. Inhibition of eosino-
phil chemotaxis by a new antiallergic compound (cetirizine). Int Arch Allergy Appl
Immunol 1988; 87:9–13.
Asthma 247
88. Hossain M, Okubo Y, Sekiguchi M. Effects of various drugs (staurosporine, herbi-

mycin A, ketotifen, theophylline, FK506 and cyclosporin A) on eosinophil viability.
Arerugi 1994; 43:711–717.
89. Todoroki I, Yoshizawa I, Kawano Y, Noma T. Suppressive effect of azelastine on
the induction of Df antigen-specific IL-2 responsiveness in lymphocytes from pa-
tients with bronchial asthma. Arerugi 1990; 39:1509–1514.
90. Herxheimer H. Antihistamines in bronchial asthma. Br Med J 1949; 2:901–905.
91. Schuller DE. Adverse effects of brompheniramine on pulmonary function in a sub-
set of asthmatic children. J Allergy Clin Immunol 1983; 72:175–179.
92. Popa VT. Bronchodilating activity of an H 1-blocker, chlorpheniramine. J Allergy
Clin Immunol 1977; 59:54–63.
93. Sly R, Kemp J, Anderson J, et al. The use of antihistamines in patients with asthma.
Position statement of the Committee on Drugs of the American Academy of Allergy
and Immunology. J Allergy Clin Immunol 1988; 82:481–482.
94. Simons FER. Is antihistamine (H 1-receptor antagonist) therapy useful in clinical
asthma? Clin Exp Allergy 1999; 29:98–104.
95. Van Ganse E, Kaufman L, Derde MP, Yernault JC, Delaunois L, Vincken W. Ef-
fects of antihistamines in adult asthma: a meta-analysis of clinical trials. Eur Respir
J 1997; 10:2216–24.
96. Cistero A, Abadias M, Lleonart R, Lafuente V, Pinto E, Torrent J, Jane F. Effect
of astemizole on allergic asthma. Ann Allergy 1992; 69:123–127.
97. Gould CAL, Ollier S, Aurich R, Davies RJ. A study of the clinical efficacy of
azelastine in patients with extrinsic asthma, and its effect on airway responsiveness.
Br J Clin Pharmacol 1988; 26:515–525.
98. Ekstrom T, Osterman K, Zetterstrom O. Lack of effect of loratadine on moderate
to severe asthma. Ann Allergy Asthma Immunol 1995; 75:287–289.
99. Rafferty P, Jackson L, Smith R, Holgate ST. Terfenadine, a potent histamine H 1-
receptor antagonist in the treatment of grass pollen-sensitive asthma. Br J Clin Phar-
macol 1990; 30:229–235.
100. Kjellman NI. Is there a place for antihistamines in the treatment of perennial
asthma? Pediatr Allergy Immunol 1993; 4 (Suppl 4):38–43.
101. Spector SL, Nicodemus CF, Corren J, Schanker HM, Rachelefsky GS, Katz RM,
Siegel SC. Comparison of the bronchodilatory effects of cetirizine, albuterol, and
both together versus placebo in patients with mild-to-moderate asthma. J Allergy
Clin Immunol 1995; 96:174–181.
102. Busse WW, Middleton E, Storms W, Dockhorn RJ, Chu TJ, Grossman J, Weiler
JM, Bronsky EA, Mansfield LE, Bell TD, Hemsworth GR, Perhach JL, D’Eletto
TA, Dam A. Corticosteroid-sparing effect of azelastine in the management of bron-
chial asthma. Am J Respir Crit Care Med 1996; 153:122–127.
103. Canny GJ, Reisman J, Levison H. Does ketotifen have a steroid-sparing effect in
childhood asthma? Eur Respir J 1997; 10:65–70.
104. Corren J, Harris AG, Aaronson D, Beaucher W, Berkowitz R, Bronsky E, Chen
R, Chervinsky P, Cohen R, Fourre J, Grossman J, Meltzer E, Pedinoff A, Stricker
W, Wanderer A. Efficacy and safety of loratadine plus pseudoephedrine in patients
with seasonal allergic rhinitis and mild asthma. J Allergy Clin Immunol 1997; 100:
781–788.
105. Grant JA, Nicodemus CF, Findlay SR, Glovsky MM, Grossman J, Kaiser H, Mel-
tzer EO, Mitchell DQ, Pearlman D, Selner J, Settipane G, Silvers W. Cetirizine in

patients with seasonal rhinitis and concomitant asthma: prospective, randomized,
placebo-controlled trial. J Allergy Clin Immunol 1995; 95:923–932.
106. Bousquet J, Emonot A, Germouty J, Molina C, Perrin-Fayolle M, Prod’homme A,
Sabbah A, Taytard A, Dupont P, Hulhoven R. Double-blind multicenter study of
cetirizine in grass-pollen-induced asthma. Ann Allergy 1990; 65:504–508.
107. Spector S, Lee N, McNutt B, Katz RM, Huster W, Siegel S, Rachelefsky G, Rohr
A. Effect of terfenadine in asthmatic patients. Ann Allergy 1992; 69:212–216.
108. Walsh G. The anti-inflammatory effects of cetirizine. Clin Exp Allergy 1994; 24:
81–85.
109. Snowman AM, Snyder SH. Cetirizine: actions on neurotransmitter receptors. J Al-
110. Bruttmann G, Pedrali P, Arendt C, Rihoux JP. Protective effect of cetirizine in
patients suffering from pollen asthma. Ann Allergy 1990; 64:224–228.
111. Dyson AJ, Mackay AD. Ketotifen in adult asthma. Br Med J 1980; 280:360–361.
112. Rackham A, Brown CA, Chandra RK, Ho P, Hoogerwerf PE, Kennedy RJ, Knight
A, Langer H, Milne J, Moote DW, Nickerson GH, Rosen L, Stephenson H, Broad-
head M, Lalonde Y, St-Pierre J-P. A Canadian multicenter study with Zaditen (keto-
tifen) in the treatment of bronchial asthma in children aged 5 to 17 years. J Allergy
Clin Immunol 1989; 84:286–296.
113. Lane DJ. A steroid sparing effect of ketotifen in steroid-dependent asthmatics. Clin
Allergy 1980; 10:519–525.
114. Kroll VM, Nothofer B, Werdermann K. Allergic bronchial asthma treated with
loratadine. Fortschr Med 1993; 111:76–78.
115. Dirksen A, Engel T, Frolund L, Heinig JH, Svendsen UG, Weeke B. Effect of a non-
sedative antihistaminic (loratadine) in moderate asthma. A double-blind controlled
clinical crossover-trial. Allergy 1989; 44:566–571.
116. Bucca C, Rolla G, Brussino L, De Rose V, Bugiani M. Are asthma-like symptoms
due to bronchial or extrathoracic airway dysfunction? Lancet 1995; 346:791–795.
117. Aubier M. Linking upper and lower airways. Ann Allergy Asthma Immunol 1999;
83:431–434.
118. Dijkman JH, Hekking PRM, Molkenboer JF, Nierop G, Vanderschueren R, Bern-
heim J, van Ganse EH. Prophylactic treatment of grass pollen-induced asthma with
cetirizine. Clin Exp Allergy 1990; 20:483–490.
119. Iikura Y, Naspitz CK, Mikawa H, Talaricoficho S, Baba M, Sole D, Nishima S.
Prevention of asthma by ketotifen in infants with atopic dermatitis. Ann Allergy
1992; 68:233–236.
120. Bustos GJ, Bustos D, Bustos GJ, Romero O. Prevention of asthma with ketotifen
in preasthmatic children: a three-year follow-up study. Clin Exp Allergy 1995; 25:
568–573.
121. Wahn U, for the ETAC study Group. Allergic factors associated with the develop-
ment of asthma and the influence of cetirizine in a double-blind, randomised, pla-
cebo-controlled trial: first results of ETAC. Pediatr Allergy Immunol 1998; 9:116–
124.
1999; 29 (Suppl 3): 69–71.
8
Antihistamines in Urticaria and
Angioedema
Anne Kobza Black

Guy’s, King’s, and St. Thomas’ School of Medicine, London, England
Malcolm W. Greaves
National University of Malaysia, Kuala Lumpur, Malaysia
I. INTRODUCTION
The urticarias and angioedemas form a group of disorders characterized by tran-

sient cutaneous swellings that are frequently itchy. Urticarial lesions (wheals,
hives) are superficial dermal swellings. In angioedema, the transient swellings
are deeper in the dermis, subcutaneous, and submucosal tissue. In most types of
urticaria, the wheals are pink or red with a pale center, and are often itchy, espe-
cially in the evenings and at night. They occur in varying shapes and sizes on
any part of the skin and generally last less than 24 hours, resolving through a
flat erythematous stage to normal-appearing skin. Angioedema frequently affects
the lips and eyelids, and sometimes the hands, feet, and tongue. Occasionally it
involves the submucosal tissue of the oropharynx, larynx, and gastrointestinal
tract. Lesions of angioedema may be red or skin-colored, are sometimes itchy,
and generally resolve within 48 hours. They are distressing and worrying for
patients, who fear the possibility of choking and impending death. In 40% of
patients, both urticaria and angioedema occur at some stage of their disease (1)
and are generally considered to be part of the same process. Angioedema without
urticaria occurs in 10% of patients, and is frequently intermittent.
Urticaria and angioedema, if severe, may be accompanied by systemic
symptoms including malaise, headache, nausea, vomiting, abdominal pain, and
arthralgia (2).
249
250 Kobza Black and Greaves
Urticaria/angioedema occur as ordinary urticaria (which affects 75% of

patients with urticaria seen in dermatology clinics), physical urticarias (15–20%)
(1), urticarial vasculitis (approximately 5%), and contact urticaria, which is un-
derdiagnosed. One uncommon form of angioedema without urticaria is C1 ester-
ase inhibitor deficiency angioedema. In ordinary urticaria, the onset of wheals
and the skin areas affected are unpredictable. Wheals last from several to 24
hours. In physical urticarias, a physical stimulus such as minor friction, sustained
pressure, heat, cold, exercise, sunlight, and even water induces reproducible
whealing. Wheals usually resolve within 1 hour, except for those of delayed pres-
sure urticaria. The clinical types and identifying characteristics of the urticarias
and angioedemas are listed in Table 1. Different types of urticaria often occur
together, for example, ordinary chronic urticaria and delayed pressure urticaria,
and different combinations of physical urticarias.
Urticarial vasculitis is an important condition to identify (3). Its wheals have
the histological characteristics of vasculitis (venulitis). The individual wheals may
be difficult to differentiate clinically from ordinary urticaria, but they often persist
for more than 24 hours, may be burning and tender as well as itchy, and infre-
quently bruise. Arthralgia, lethargy, and abdominal pain are more prominent sys-
temic features than in chronic ordinary urticaria. A suspected diagnosis of urticar-
ial vasculitis must be confirmed by histopathological examination of a wheal.
Table 1 Classification of Urticarias with or Without

Angioedema
Ordinary urticarias
Acute
Chronic idiopathic
Physical urticarias
Dermographism
Cholinergic urticaria
Cold urticaria
Solar urticaria
Delayed pressure urticaria
Aquagenic urticaria
Urticarial vasculitis
Contact urticaria
Angioedema: predominantly or alone
Idiopathic
Drug-induced (NSAIDs, angiotensin-converting enzyme
inhibitor)
C1 esterase inhibitor deficiency
Inherited
Acquired
NSAIDs, nonsteroidal anti-inflammatory drugs.

Urticaria and Angioedema 251
Contact urticaria is frequently unrecognized. Contact of the skin with a

provoking substance induces whealing at that site within minutes. It may be a
nonimmunological reaction occurring on first contact, or an immunological IgE-
mediated reaction. Immunological contact urticaria is more common in atopic
persons and may be severe.
The urticarias can also be classified into acute, in which the whole episode
persists for less than 6 weeks, and chronic, in which wheals are present on most
days for longer than 6 weeks. The classification is arbitrary and often urticaria
is present intermittently; however, a cause is more likely to be found in acute
ordinary urticaria. It is not generally appreciated that, due to appearance of the
swellings, associated itching and sometimes pain, and the unpredictability of on-
set, urticaria can severely interfere in the patient’s quality of life. The Nottingham
Profile questionnaire of general health used in patients with ordinary chronic
urticaria attending an urticaria clinic revealed that disability evidenced by lack
of energy, social isolation, emotional reactions, and sleep disruption was as severe
as that experienced by patients awaiting triple coronary bypass surgery (4). A
skin-disease-specific questionnaire revealed that patients with chronic ordinary
urticaria and pressure urticaria were comparably disabled to outpatients with ec-
zema and those with ordinary urticaria alone were comparably disabled to outpa-
tients with psoriasis (5).
II. PATHOPHYSIOLOGY
The physiological processes leading to urticaria and angioedema are thought to

be similar, with the exception of C1 esterase inhibitor deficiency and angiotensin-
converting enzyme (ACE)–induced angioedema (6). In the latter conditions bra-
dykinin is thought to be an important mediator; however, since ordinary angi-
oedema, which is usually intermittent, has not been extensively investigated, ad-
ditional or different factors may be present in some of these patients compared
to those who also exhibit urticaria. For practical purposes, the term urticaria will
be used to describe patients with and without angioedema.
Urticaria is due to vasodilation of the microvasculature (venules) with
plasma extravasation, associated with a variable dermal inflammatory infiltrate
of eosinophils, neutrophils, and mononuclear cells, depending on the type of urti-
caria and the stage of evolution of the wheal (7).
A central role has been ascribed to activation of the cutaneous mast cells,
with release of mediators, predominantly histamine but also other inflammatory
substances including prostaglandin D 2 , proteolytic enzymes, and cytokines such
as IL-4, IL-6, IL-8, and tumor necrosis factor α (TNF-α). Increased levels of
histamine in lesional compared to nonlesional skin have been detected in all forms
of urticaria using various techniques, including venous blood sampling, skin per-
fusion, skin chamber, and suction blister techniques. In the skin, histamine reacts
with H 1- and H 2-receptors to induce erythema and whealing, but H 1-receptors
are predominantly responsible for the flare and itching (8). So far no H 3-receptors
have been identified in human skin (9). Because there is subsensitivity to the
effects of histamine in the skin after 30 min (10) and wheals persist for many
hours, other mediators are also involved in the urticarial process. Upregulation
of the vascular adhesion molecules E selectin and VCAM occurs in chronic urti-
carial wheals and in delayed pressure urticaria (11), enabling leukocytes to tra-
verse the blood vessel walls in response to mast cell-derived chemoattractants
such as IL-6 and IL-8. The ensuing dermal inflammatory cells can release their
own repertoire of proinflammatory mediators, thus prolonging and amplifying
the whealing process.
In physical urticarias (except delayed pressure urticaria), wheals are short-
lived, often for less than 1 hour, and the reaction appears to be predominantly
mediated by histamine although other inflammatory mediators are also involved.
Urticarial vasculitis is usually considered to be due to immune complex
deposition in the skin and other organs (3).
III. PROGNOSIS
The prognosis of urticaria in any individual is unpredictable, with a general ten-

dency toward improvement. There is no evidence that antihistamine therapy alters
the long-term prognosis of urticaria; however, it suppresses the symptoms until
the urticarial process resolves spontaneously.
IV. GENERAL MANAGEMENT
A detailed history is vital (12) for categorizing the type of urticaria, and for
elucidating a cause, if one can be found, and aggravating factors, if any.
It is helpful to identify patients with physical urticarias, urticarial vasculitis,
and contact urticaria since their management will differ from that of the larger
group of patients with ordinary ‘‘idiopathic’’ chronic urticaria.
In patients with physical urticarias it is important to reduce the exposure
to precipitating factors. H 1-antihistamine therapy is generally helpful, except in
delayed pressure urticaria, which can be very resistant to this and other treat-
ments.
The suspicion of urticarial vasculitis must be confirmed by examination
of a biopsy specimen of a wheal, which shows a perivascular dermal inflamma-
tory cell infiltrate rich in neutrophils, with leukocytoclastic (fragmentation of the
nucleus of neutrophils), red cell extravasation, and fibrinoid necrosis of mi-
crovessel walls. Investigation of urticarial vasculitis includes the search for a

cause and for any organ involvement, and should include full blood counts,
complement C3 and C4 levels, urinalysis, renal and liver function tests, and
chest radiograph.
The treatment of ordinary urticarias is to eliminate a cause, which is more
likely to be found for acute urticaria than for chronic urticaria. Nonspecific aggra-
vating factors such as heat, alcohol, and stress should be minimized. Aspirin and
nonsteroidal anti-inflammatory drugs and codeine should be avoided in patients
with ordinary urticaria. Acetaminophen is usually a satisfactory substitute. ACE
inhibitors should be avoided in patients with ordinary and hereditary angioedema,
since these agents can aggravate these conditions severely.
If a particular dietary substance has been shown to cause or aggravate ordi-
nary urticaria in a reproducible placebo-controlled trial, it should be omitted from
the diet. Patients with severe oropharyngeal or laryngeal angioedema that causes
difficulty breathing should be prescribed epinephrine and instructed how to self-
administer it in an emergency.
In the management of urticarias it is very important to explain the condition
Table 2 Management of Urticaria
General measures
Avoid cause, if known
Avoid aggravating factors: NSAIDs, tight clothes
Reduce heat, stress, alcohol
Provide explanation and reassurance
Drug therapy
Second-generation low-sedation H 1-antihistamines: treatment of choice
Sedating antihistamine at night (on an empirical basis)
H 2-antihistamine for trial period
Mast cell stabilizers: terbutaline, nifedipine (usually disappointing)
Oral corticosteroids
Acute exacerbations of chronic ordinary urticaria
Exacerbations of delayed pressure urticaria
Urticarial vasculitis
Avoid long-term administration for chronic urticaria, if possible
Anabolic steroids for prophylaxis of hereditary C1 esterase deficiency
Immunomodulation: For severe cases not responding to conventional therapy, admin-
istered in specialized units
Oral cyclosporin
Intravenous high-dose immunoglobulin
Plasmapheresis
NSAID, nonsteroidal anti-inflammatory drug; C1, complement 1.

to an anxious patient. Patients will expect that their urticaria is due to a food
allergy, but in chronic urticaria this is seldom the case.
In many patients with acute urticaria and the vast majority of those with
chronic ordinary urticarias, no external cause can be found. Although urticaria
is distressing and unsightly, usually it does not harm general health.
Because the main mediator is histamine, H 1-antihistamines have been and
remain the symptomatic treatment of choice for urticaria and angioedema until
there is spontaneous remission. Patients are worried about the long-term use of
antihistamines; therefore, the benefits, possible side effects, and the relatively
good long-term safety record of the second-generation drugs must be explained.
The place of antihistamine therapy is set in context of the overall manage-
ment of urticaria in Table 2.
V. TREATMENT TRIALS
A. Design
First, the pharmacodynamics of histamine-induced wheal-and-flare suppression
are studied. This is useful for ascertaining onset, potency, and duration of action;
however, in one study, an H 1-antagonist administered at a dosage that totally
suppressed histamine-induced whealing only caused 60% improvement in spon-
taneous urticarial wheals (13).
The objective assessment of H 1-receptor antagonist treatment of urticarias
has been difficult. Because urticaria is a heterogeneous group of conditions,
which may vary in response to therapy, the treated group should be defined pre-
cisely as to whether they have chronic ordinary or physical urticaria. This has
not been done in all studies. Urticaria occurs in patients of all ages, but most
studies have been performed in adults.
The course of chronic urticaria is notoriously unpredictable, with a ten-
dency to improvement. This makes crossover studies unreliable. As there is a
marked placebo effect, a placebo should always be incorporated into the design.
Trials should clearly identify the response of individual symptoms and
signs of urticaria (itching, erythema, whealing) in addition to a global response.
There is no direct objective method to assess itching, one of the most distressing
aspects of urticaria, but it can be evaluated subjectively using a point scale of
severity or a visual analog scale. Indirect objective assessments based on
scratching are rarely included. Whealing is evaluated by various methods includ-
ing reduction in the numbers of wheals (grouped on a point scale), percentage
of patients in whom urticaria cleared or was greatly improved, or a point scale
of global improvement scored by subject/and or investigator. Assessments of the
effect of treatment on systemic symptoms and quality of life should be included.
The challenges involved in designing clinical trials of antihistamine treat-
ment in urticaria that lead to outcomes that can be analyzed statistically in a

satisfactory manner have been reviewed (14).
Even if a trial is well designed and conducted, there is difficulty in compar-
ing the results of different trials because the population studied, dose and total
time of administration of an individual antihistamine, and methods of assessing
improvement vary.
B. Studies of Antihistamine Therapy

In this chapter we review the controlled studies of H 1-antihistamine therapy in
patients with acute urticaria, chronic ordinary urticaria, and physical urticarias
alone and in combination with H 2-receptor antagonists. We include a short section
on the use of H 1-antihistamine therapy in urticarial vasculitis.
VI. ACUTE URTICARIA
Acute urticaria may follow a viral upper respiratory tract infection, may be due
to an IgE-mediated reaction to food or drugs such as penicillin, or may be an
anaphylactoid (pseudoallergic) reaction to a nonsteroidal anti-inflammatory med-
ication. These aspirin-like drugs divert prostaglandin production by the cyclo-
oxygenase pathway into leukotriene production via the lipoxygenase pathway.
In a hospital setting, a cause is found in fewer than 50% of patients with acute
urticaria (15).
The optimal treatment of acute urticaria is with second-generation low-
sedation antihistamines, but there are no controlled trials comparing these medi-
cations. Epinephrine treatment of severe angioedema with localized difficulty
breathing or swallowing or widespread urticaria is described in Chapter 9 on
anaphylaxis.
One study compared the treatment of acute urticaria with either loratadine
10 mg/day or prednisolone 40 mg/day for 3 days in 109 patients (15). All patients
were evaluated until remission. Complete remission occurred in 94% of patients
after prednisolone therapy compared to 66% after loratadine treatment. As a prac-
tical step, however, low-sedation antihistamines are begun at the same time as
a short course of oral steroids, and continued as long as acute urticaria persists.
VII. CHRONIC ‘‘IDIOPATHIC’’ URTICARIA
Chronic idiopathic urticaria (CIU) can be conventionally defined as daily or al-

most daily wheals for 6 weeks or more. Individual wheals last for more than 1
hour, (differenting them from the wheals of all physical urticarias except delayed
pressure urticarias), and less than 24 hours (differentiating them from the wheals
of urticarial vasculitis, which last individually longer than 24 hours according to
generally accepted criteria). Normally the wheals of CIU leave no marks on the
skin except for those caused by rubbing. Delayed pressure urticaria occurs con-
currently with CIU in about 40% of patients (16). The well-recognized treatment-
resistant character of delayed pressure urticaria may at least partly explain the
seemingly poor response of some patients with CIU to antihistamine therapy.
The wheals of delayed pressure urticaria, in addition to persisting for 36–48
hours, are often painful, occur at pressure sites such as the palms, soles and
waistbands, and may be indurated on palpation, which may lead to the erroneous
diagnosis of urticarial vasculitis. Histological examination of a skin biopsy of
a wheal can facilitate the correct diagnosis. Other physical urticarias, such as
symptomatic dermographism and cholinergic urticaria, may coexist with CIU.
About 40% of patients with CIU have associated angioedema, which affects
skin and mucus membranes (1). Pruritus is an invariable feature of CIU, although
it may be a lesser or greater cause of disability in different patients. Itching may
occur at any time but is most prevalent in the evening and at night (2).
Systemic symptoms are not very common in CIU and, when they occur,
should raise the possibility that the correct diagnosis is urticarial vasculitis. Joint
pains are common in patients with CIU in whom delayed pressure urticaria is a
feature. The natural history of CIU is poorly documented. The best data, available
on 554 hospital patients, suggest that 50% of patients with urticaria alone will
have achieved remission within 6 months to 1 year and 50% of those with associ-
ated angioedema within 2–5 years. In some patients urticaria can be persistent
and up to 20% can still be affected in 20 years (1).
A. Pathophysiological Mechanisms
The underlying pathophysiology of CIU is noncontroversial. The numbers of
dermal mast cells are not increased. Promiscuous activation of these cells leads
to the release of histamine and other mediators, which cause vasodilation and
perivascular accumulation of eosinophils, neutrophils, and mononuclear cells,
aided by increased adhesion molecule expression in the postcapillary venules.
The cause of the unwanted dermal mast cell activation is less clear.
Most patients with CIU, their relatives, and very often their physicians as
well, believe that dietary factors are causative. In contrast to acute urticaria, how-
ever, food items can rarely be implicated as culprits of CIU (17) and exclusion
diets rarely lead to remission of hives (18). Chronic infections and infestations
including candidiasis (19), bacterial sinusitis (20), and most recently Helicobacter
pylori infection (21) have been proposed to be causative. The weight of evidence,
recently comprehensively reviewed, is against a direct role for these agents (22);
however, the possibility that H. pylori could play an indirect role in genetically
predisposed individuals with autoimmune urticaria (see below) cannot be ex-

cluded.
It is now generally acknowledged that the whealing in some, but not all,
patients with CIU has an autoimmune basis. It has been recognized that there is
a positive association with thyroid disease (23). In 1989 Grattan reported the
recovery of a mediator in the serum of some patients with CIU but not in those
with physical urticarias or in healthy individuals (24). Subsequent analysis of
this factor showed it to be composed of IgG autoantibodies against the high-
affinity IgE receptor (FcεRI) expressed on human basophils and mast cells, or less
commonly against IgE itself (25, 26). That these autoantibodies are functional and
are therefore involved in the pathogenesis of the disease is indicated by their
ability to evoke histamine release from mast cells and basophils, to cause
whealing in the skin, by the positive correlation between serum autoantibody titer
and disease activity, and by the beneficial clinical effect of suppression or re-
moval of autoantibodies (27, 28). The importance of the anti-FcεRI autoantibod-
ies in CIU has been confirmed independently by several groups (29, 30–32). It
turns out that, depending on the patient population, between 30 and 50% of CIU
patients have functional autoantibodies.
B. Diagnosis
A careful history is important. If the diagnosis of a physical urticaria has been
made, further investigation should focus only on the physical urticaria and need
not involve tests for circulating autoantibodies or food additive reactivity. In some
patients without physical urticaria, it may be worthwhile carrying out a placebo-
controlled food additive challenge, which is the gold standard for diagnosis of
food additive reactivity (33, 34). An autologous serum skin test can be carried
out to screen patients for autoimmune urticaria (antiFcεRI or anti-IgE), but it is
time-consuming and needs to be interpreted by someone experienced in per-
forming the test (35). Positive results need to be confirmed by demonstrating in
vitro histamine release from basophils of low- and high-IgE occupancy donors,
with inhibition by human recombinant FcεRIα or monoclonal IgE (26). Some
laboratories use Western blotting or enzyme-linked immunosorbent assays
(ELISAs) (29, 32), but since these methods also detect immunoreactive but non-
functional anti-FCεRI autoantibodies, false-positive results may occur in auto-
immune connective tissue and immunobullous disease (32).
The cause of CIU remains elusive in at least 40% of all patients despite
investigations along the lines recommended here. As discussed previously,
searching for infections, infestations, and food allergies is usually not helpful;
however, it is worthwhile to identify histamine-releasing autoantibodies in se-
verely affected patients in whom plasmapheresis or intravenous immunoglobulin
therapy may be indicated.
VIII. TREATMENT OF CHRONIC IDIOPATHIC URTICARIA
General measures provide significant symptomatic relief in some patients. Over-

tiredness, stress of traveling, overindulgence in alcohol, and wearing tightly fit-
ting garments (especially woollen fabric) all cause exacerbations and/or enhance-
ment of itching. Patients also need to be reassured that CIU is not an outward
manifestation of cancer, human immunodeficiency virus (HIV), or other infec-
tion, that the disease is usually self-limiting, running an average course of 2–3
years, and that it is not inherited from an affected parent. Drugs that may exacer-
bate CIU and therefore need to be avoided include aspirin, morphine, morphine-
like drugs, and dextran. Pruritus is especially troublesome at night (2). A tepid
shower taken before retiring to bed may be timely and the bedroom should be
cool. Many patients find application of 1% menthol in aqueous cream to be sooth-
ing, although its beneficial effects are short-lived (about 30 min).
A. General Principles of CIU Antihistamine Treatment

The redness and whealing of CIU are probably caused by a number of mast cell–
or basophil-derived mediators, but histamine clearly plays a major role, especially
in itching, due to the action of histamine on H 1-receptors (36). Histamine-evoked
redness and whealing involve both H 1- and H 2-receptors (37,38). Combined treat-
ment with H 1- and H 2-antihistamines has been proposed and found to be effective
(39), but it is doubtful if the advantage gained is clinically useful. Some combina-
tions, for example, hydroxyzine and cimetidine, in which a pharmacokinetic inter-
action as well as a synergistic end-organ response occur, appear to work better
than other combinations, for example, cetirizine and cimetidine (40).
H 1-antihistamine treatment is the cornerstone of drug therapy of CIU and
ameliorates the symptoms, especially itching, by blocking the actions of dermal
or mast cell–derived histamine. The newer low-sedation antihistamines enable
this purpose to be fulfilled with few or no side effects.
One of the earliest studies of the use of antihistamines in CIU was reported
in the Proceedings of the Staff Meetings of the Mayo Clinic in 1946. Thirty-five
patients with chronic urticaria were treated with diphenhydramine 50–100 mg
three or four times daily. The skin lesions disappeared in 25 of these and were
greatly improved in 7 others. In all but one patient the wheals recurred when a
placebo tablet was substituted for diphenhydramine (40a). Arrays of side effects
such as drowsiness and atropine-like symptoms, including dry mouth and blurred
vision, were noted.
Subsequently, H 1-antihistamines became the treatment of choice in CIU.
As detailed in Chapter 3 antihistamines are currently classified as first-generation
(chlorpheniramine, hydroxyzine, diphenhydramine, promethazine) and second-
generation (cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, mi-

zolastine) (41).
First-generation antihistamines are invariably accompanied by sedative and
atropine-like side effects due to penetration of the blood–brain barrier. Second-
generation antihistamines are at least as potent as their predecessors, but cause
minimal or no sedation.
It is widely and correctly believed that the clinical efficacy of antihista-
mines in CIU is attributable to antagonism of histamine at the H 1-receptor; how-
ever, additional so-called antiallergic activity may play a part, especially at higher
dosages (42, 43). This activity, which is independent of H 1-receptors, is probably
due to the stabilizing effect on plasma membranes of mast cells and basophils.
The importance of regular antihistamine dosing in the treatment of CIU
needs to be emphasized (44). Apparent failures of antihistamine treatment can
often be attributed to intermittent, instead of continuous, usage: indeed, studies
in allergic rhinitis support the value of uninterrupted administration (45). Whether
this increased efficacy involves the above-mentioned H 1-receptor-independent
antiallergic action is unclear. H 1-antihistamines are more effective in alleviating
pruritus than in reducing the frequency and severity of whealing. It is important
to determine from the CIU patient’s history the period(s) of the day and night
when the itching is most troublesome so that the timing of the antihistamine dose
is appropriate. Most patients find pruritus is most intense in the evening and at
night (2), although whealing may be most troublesome first thing in the morning
and throughout the day. Some physicians recommend a low-sedation antihista-
mine early in the morning with a sedative antihistamine in the evening; however,
this approach needs to be tested in a randomized, double-blind, placebo-con-
trolled trial and the patient needs to be warned that cognitive function and reflexes
may be impaired the following morning, although the sedative effect of the first-
generation H 1-antihistamine is no longer evident. Tolerance is frequently claimed
by patients and physicians to develop after a few days of continuous administra-
tion of H 1-antihistamines, but the most likely cause of dwindling efficacy is poor
compliance (44).
More than 20 H 1-antihistamines are currently available. Since it is difficult
to predict the response of a given patient, and since the efficacy of individual
members of the first- and second-generation H 1-groups is not greatly different,
a self-assessment method has proved useful (46).
B. First-Generation H 1-Antihistamines
There is no precise definition of first-generation antihistamines, but members
of the group were generally licensed before 1981 and characteristically cause
marked drowsiness and atropine-like (anticholinergic) side effects, leading to
impaired psychomotor function and perhaps to poor compliance. The sedative

actions of the group may be useful in some circumstances. Some of the first-
generation H 1-antihistamines widely used in the context of CIU are discussed
below.
1. Hydroxyzine
Like other members of its class, hydroxyzine penetrates the endothelial lining of
the capillaries of the central nervous system (CNS) and causes marked sedation.
It also has marked atropine-like (anticholinergic) activity. Nevertheless it remains
one of the most widely used H 1-antihistamines in the treatment of CIU, since it
is potent, inexpensive, and its soporific effect can be put to good use. It has an
elimination half-life of 14 to 20 hours in adults. Hydroxyzine is best given in
the evening to allay nocturnal pruritus. The dosage is 25–75 mg (one to three
25 mg tablets). The sedative action assists in providing patients with a full night’s
sleep and also allays anxiety associated with severe protracted urticaria and angio-
edema. The patient must be warned that computer skills and car driving may be
impaired in the morning from the evening dose of hydroxyzine, and that
consumption of alcohol must be avoided. Hydroxyzine plasma levels and wheal-
suppressive activity increase significantly when it is coadministered with cimeti-
dine.
2. Chlorpheniramine
Chlorpheniramine has, like hydroxyzine, marked sedative and anticholinergic
side effects, low cost, and rapidity of action. It is prescribed orally for adults at
a dosage of 4 mg (one tablet every 6 hours). By injection it can be prescribed
at a dose of 10–20 mg. The cautions with its use are the same as for hydroxyzine.
3. Doxepin
Tricyclic antidepressants, including doxepin, were introduced as antihistamines
although they were rapidly ‘‘adopted’’ for psychiatric use owing to their mood-
elevating properties. Doxepin is a potent H 1-antihistamine with a high affinity
for H 1-receptors. It also possesses significant H 2-antihistaminic activity (47). In
a double-blind, crossover study of 50 patients with CIU, doxepin 10 mg three
times a day conferred a more favorable response than diphenhydramine 25 mg
three times a day (48). The dosage can be gradually increased up to 75 mg a day
in divided doses; however, because it has a half-life of 19 hours, doxepin is best
used as a single evening dose of 10–75 mg in adults. On an empirical basis, it
is sometimes combined with a morning dose of a low-sedation antihistamine such
as loratadine, fexofenadine, or mizolastine (see below). It is very useful in pa-
tients with severe CIU that is unresponsive to low-sedation antihistamines alone.
Such patients frequently become anxious and depressed, and respond to doxe-
pin’s anxiolytic and mood-elevating actions. Doxepin is also available in a topical
cream formulation in a concentration of 5%, but its topical use in CIU presents
no real advantages over systemic antihistamines, since drowsiness due to percuta-
neous absorption is common. Doxepin needs to be used cautiously. It has sedative
and anticholinergic side effects. Concurrent alcohol consumption should be
avoided. Doxepin should not be coadministered with any other medication that
potentially prolongs the QT interval (e.g., cimetidine), as this may lead to cardiac
arrhythmias. Doxepin enhances the hypertensive actions of epinephrine and other
sympathomimetics and should not be used with monoamine oxidase–inhibiting
drugs. It should not be used during breast feeding. Doxepin is not recommended
in children.
4. Ketotifen
Pharmacologically this compound has a range of interesting actions. In addition
to its ability to produce H 1-blockade, it inhibits release of histamine and other
mediators from mast cells and basophils in vitro (49). Its mast cell and basophil
stabilizing-action may be at least partly due, at the molecular level, to inhibition
of transmembrane calcium transport. Ketotifen causes a number of side effects,
including sedation and atropine-like effects (dry mouth, blurred vision, constipa-
tion). Whether its mast cell–stabilizing properties are clinically significant is un-
clear. We were unable to demonstrate any reduction of urinary excretion of hista-
mine or its metabolites in patients with cutaneous mastocytosis treated with
ketotifen (50); however, plasma histamine levels have been demonstrated to be
reduced in patients with physical urticarias (51).
There have been a number of studies of its usefulness in chronic urticaria.
A Japanese study compared ketotifen 1 mg daily, clemastine (a first-generation
H 1-antihistamine) 2 mg, and placebo in 305 patients with chronic idiopathic
urticaria in a double-blind trial (52). Significantly greater relief of pruritus and
whealing was observed in patients receiving ketotifen than clemastine or placebo.
The frequency of side effects (20–21% of patients) was the same in the ketotifen-
and clemastine-treated patients. A number of other reports, mainly anecdotal,
also support its use in the treatment of chronic idiopathic urticaria (53).
C. Second-Generation Low-Sedation H 1-Antihistamines

These agents impair CNS function significantly less than the ‘‘first-generation’’
compounds due to their low blood–brain barrier penetration. Some members of
this group, including cetirizine, retain some sedative activity. Low-sedation anti-
histamines can therefore be administered safely with alcohol and other CNS de-
pressants. They also possess little or no atropine-like (anticholinergic) side ef-

fects. They have no H 2-receptor antagonistic activity. Currently the most widely
used are cetirizine, loratadine, mizolastine, and fexofenadine, which are reviewed
individually below. Results of studies are summarized in Table 3.
1. Cetirizine
Cetirizine is the carboxylated metabolite of the first-generation H 1-antihistamine
hydroxyzine (see above). It is long-acting (up to 24 hours) with a rapid onset
and potent activity at the H 1-receptor. It possesses significant antiallergic activity,
especially in inhibiting eosinophil chemotaxis (54), although the clinical rele-
vance of this action of cetirizine in patients with CIU is unclear. It has no cardiac
toxicity. In adults, the licensed dosage is 10 mg daily or 5 mg twice daily. There
is an oral solution (5 mg/mL) for children 2 years and older.
Several studies of the efficacy of cetirizine in CIU have been published.
An early multicenter double-blind study in 219 patients compared cetirizine 5–
20 mg daily with hydroxyzine 25–75 mg daily and placebo (55). The results
showed equivalence with hydroxyzine in terms of clinical efficacy and superiority
with regard to severity of side effects, which with cetirizine were no greater than
placebo. It is a criticism of this and most other clinical studies of antihistamines
in CIU that the criteria for diagnosis of CIU are not clearly set out, and the
question arises as to how many patients recruited actually had predominantly
physical urticaria. A subsequent smaller placebo-controlled study in which 30
patients with CIU received 10–20 mg cetirizine daily also showed a significant
benefit (56). Cetirizine is as effective as another low-sedation antihistamine, lora-
tadine, as suggested by a double-blind placebo-controlled study of 116 patients
with chronic urticaria (57). These results are summarized in Table 3.
2. Loratadine
Loratadine is a long-acting minimal-sedation H 1-antihistamine with little or no
affinity for cholinergic or alpha-adrenergic receptors and no cardiotoxicity. It is
widely used in the treatment of CIU because of its efficacy and low frequency
of adverse reactions, leading to a high degree of patient compliance. In addition
to its H 1-antagonist activity, it has antiallergic action independent of the H 1-recep-
tors. This action includes ‘‘stabilization’’ of the mast cell membrane, leading to
reduced secretion of mast cell–derived mediators including eicosanoids, suppres-
sion of adhesion molecule expression, and inhibition of vasopermeability (58).
There is convincing evidence that loratadine in therapeutic dosages suppresses
mediator release into nasal secretions in patients with seasonal allergic rhinitis
(59). To what extent these actions form a part of the therapeutic response to
loratadine in the skin of patients with CIU, at least at a therapeutic dosage of 10
mg daily, is uncertain.
Several well-controlled clinical trials attest to the value of loratadine in

CIU. In one of the first studies (60), in 187 patients with CIU, loratadine 10 mg
daily was as effective as terfenadine 60 mg and both active medications were
significantly more effective than placebo. Adverse side effects were few and simi-
lar among the treatments.
In other studies, loratadine has been compared to hydroxyzine (61–63).
In one of these, 172 patients were assigned to receive loratadine 10 mg daily,
hydroxyzine 25 mg three times daily, or placebo. The study was stated to be
double-blind but, given the pronounced soporific effects of hydroxyzine, some
patients were likely able to discriminate among the three treatments. Neverthe-
less, two-thirds of patients in each of the active drug groups showed marked or
complete relief of symptoms. There was no clear difference between the two
active treatments with regard to response, although those receiving hydroxy-
zine noted greater sedation. Loratadine has been compared with other so-called
second-generation H 1-antihistamines, as described previously (57) (Table 3).
3. Mizolastine
Mizolastine, a relative newcomer to the ranks of the so-called second-generation
low-sedation H 1-antihistamines, has no anticholinergic and minimal sedative ef-
fects. It is also claimed to have anti-inflammatory action independent of its affin-
ity for the H 1-receptor. In the rat, it inhibits transformation of arachidonic acid
to its lipoxygenase transformation products, the pro-inflammatory leukotrienes
and related fatty acids (64). To what extent this is relevant to the actions of the
drug in humans is uncertain. A recently published report (65) in 247 patients
with CIU compared mizolastine 10 mg daily with loratadine 10 mg daily and
placebo. Mizolastine was more effective in suppressing symptoms and signs of
CIU than placebo and equivalent to loratadine. Angioedema, when present, was
similarly ameliorated. Adverse effects were no different from those occurring
with placebo for either active drug.
A smaller study involving 56 patients with CIU compared mizolastine with
placebo (66). The results showed that mizolastine produced a greater decrease
in itching, whealing, and erythema than placebo. Drowsiness and anticholinergic
side effects were not significantly different between mizolastine and placebo.
Further details of these studies are summarized in Table 3. Overall, mizolastine
appears to be equally, but not more, effective than loratadine and cetirizine in
the management of CIU.
4. Fexofenadine
Fexofenadine is an effective low-sedation antihistamine. It has no cardiotoxic
side effects, causes no drowsiness or impairment of cognitive function, and can
be safely administered with cytochrome P-450-inhibiting drugs. Its pharmacolog-
264
Table 3 Treatment of Chronic Ordinary Urticaria with Low-Sedation H1-Antihistamines

Study design
Treatments Nos and length Assessment Result Side effects Comments Reference
Cetirizine 10 mg 219 Randomized, double- P, E, W, ordinal Cetirizine ⬃ hy- Severe somnolence: Was double-blinding 55
daily, hydroxyzine blind, parallel, 4 scale, symptoms, droxyzine ⬎ pla- Placebo 3% compromised?
25–75 mg daily, wks VAS cebo Cetirizine 6%
placebo Cetirizine more effec- Hydroxyzine 15%
tive on itch than
wheal size
Cetirizine 10 mg 30 Double-blind, cross- P, E, W, ordinal Cetirizine more effec- Small numbers 56
daily, placebo over, 4 wks tive than placebo
Cetirizine 10 mg, lor- 116 Randomized, double- P, E, W, size of W, Cetirizine and lorata- Dizziness, drowsiness: Loratadine signifi- 57
atadine 10 mg, pla- blind, parallel, 4 ordinal dine ⬎P1 Cetirizine 20% cantly more rapid
cebo; all daily wks At 4 wks free of Loratadine 16% in action than cetir-
symptoms: Placebo 8% izine
Loratadine 63%
Cetirizine 45%
Placebo 13%
Fexofenadine 60, 222 Randomized, double- P, W, ordinal: overall Fe 180, 240 mg ⬎P1 Drowsiness and 68
120, 180, 240 mg blind, parallel, in total other side effects:
daily; placebo 6 wks symptom score fexofenadine ⬃
daily All doses ⬎ decrease placebo
pruritus
Kobza Black and Greaves
Fexofenadine 20, 60, 439 Randomized, P, W, ordinal All doses of fexofena- Frequency of seda- Quality-of-life indi- 69
120, 240 mg twice multicenter, dou- dine ⬎ placebo for tion not stated ces also showed
daily or placebo ble-blind, parallel, P and mean total improvement on
twice daily 4 wks symptom score fexofenadine
Loratadine 10 mg 187 Randomized, double- P, E, W, ordinal, over- Loratadine ⬎ terfena- Active drugs had mini- 60
daily, terfenadine a, blind, parallel, 4 all improvement dine ⬎ placebo mal side effects, no
60 mg twice daily, weeks Marked relief: greater than pla-
placebo Loratadine 64% cebo
Terfenadine 52%
Placebo 25%
Loratadine 10 mg 172 Randomized, double- P, W, ordinal, overall Loratadine ⬃ hy- Sedation: Hydroxyzine caused 63
daily, hydroxyzine blind, parallel, 4 efficacy droxyzine ⬎ P1 Loratadine 7% marked drowsiness
Urticaria and Angioedema
25 mg three times weeks At 4 wks patients with Hydroxyzine 49% and dry mouth; lora-
daily, or placebo marked relief: Placebo 3% tadine caused ⬃ se-
Loratadine 65% dation to placebo.
Hydroxyzine 66% Was double-blind-
Placebo 41% ing compromised?
Mizolastine 10 mg, 247 Randomized, P, number and size of Mizolastine ⬃ loratad- Drowsiness more fre- 65
loratadine 10 mg, multicenter, dou- W, ordinal ine; sig more quent with mizolas-
placebo; all daily ble-blind, parallel, effective than tine than loratadine
4 wks placebo or placebo
Mizolastine 10 mg 56 Randomized, two- P, E, W, ordinal Mizolastine sig more Slightly more drowsi- 66
daily, placebo center, double- effective than pla- ness with mizolas-
blind, parallel, 4 cebo tine
wks
a
Terfenadine has been withdrawn in most countries. VAS, visual analog scores; Pl, placebo; ⬎ significantly better; ⬃ essentially equivalent; P, pruritus,
E, erythema, W, wheal; sig, significantly; Nos, number of participants; Fe, fexofenadine.
265
ical and pharmacokinetic properties have recently been reviewed (67). In the
treatment of CIU, fexofenadine is administered at a dosage of 180 mg (one tablet)
daily. It is licensed in some countries for children under the age of 12 years. In
a dose-ranging study, daily fexofenadine doses of 60 mg, 120 mg, 180 mg, and
240 mg were compared to placebo (68). Two hundred and twenty-two patients
with CIU were randomly allocated to one or another of these daily dose regimens
on a double-blind basis. The 180 mg and 240 mg doses produced significant
improvement in total symptom score. Lower doses caused an improvement in
scores for itching. As a result of this study, the authors recommended the 180 mg
daily dose for the patients with CIU. Adverse side effects were trivial and no
greater than with placebo at any of the dosages used.
In another randomized, double-blind, placebo-controlled, dose-ranging
multicenter study, the fexofenadine doses given were 20, 60, 120, or 240 mg
twice daily (69). All four doses were more effective than placebo with regard to
amelioration of pruritus, whealing, and total symptom score (Fig. 1). It is interest-
ing that patients receiving fexofenadine experienced less drowsiness than those
receiving placebo. The authors concluded that dosages of fexofenadine of 60 mg
twice daily or more were most effective. Quality-of-life indices were measured
and showed an overall improvement in fexofenadine-treated patients in whom
urticaria interfered significantly less with daily activities and with sleep than it
did in placebo-treated patients.
Overall, fexofenadine appears to be an effective H 1-antihistamine with a
very low frequency of unwanted side effects and no sedation or cardiotoxicity.
D. H 2-Antihistamines
Studies on the responses of human skin blood vessels led to the conclusion that
H 2- as well as H 1-receptors were present on these vessels (8, 36, 37). Activation
of H 1- and H 2-receptors induced erythema and whealing, but H 2-activation had
little effect on flare and itching. Cimetidine, an H 2-receptor antagonist, in combi-
nation with chlorpheniramine, caused a significantly greater inhibition of hista-
mine-induced erythema than either drug alone (38). This raised the possibility
that the combination of H 1- and H 2-antihistamines might be more effective than
either drug alone in the treatment of urticaria.
The earliest study of H 1- and H 2-antihistamines in urticaria by Commens
and Greaves included 19 patients with chronic idiopathic urticaria who were
allocated on a randomized, double-blind basis to three consecutive treatments for
2 weeks consisting of a combination of chlorpheniramine 4 mg and cimetidine
400 mg each four times a day, chlorpheniramine 4 mg four times a day, and
placebo four times a day (39) (Table 4). There was a significant reduction in
whealing and itching with chlorpheniramine treatment, alone and when combined
Figure 1 Fexofenadine in the treatment of chronic idiopathic urticaria. In a randomized,

double-blind, placebo-controlled, parallel-group study, 439 patients with moderate to se-
vere itching and hives received either fexofenadine 20 mg, 60 mg, 120 mg, or 240 mg,
or placebo twice daily. The severity of itching, number of wheals, and interference with
sleep/normal daily activities because of hives were assessed reflectively over the previous
12 hours. All four doses of fexofenadine were statistically superior to placebo for reducing
mean pruritus score, mean new wheal score, and mean total symptom score (sum of itch
and wheal scores). The decrease in the average mean total symptom score from baseline
over the 4 weeks, compared to placebo, is shown. All doses of fexofenadine were statisti-
cally superior to placebo (p ⱕ 0.0010). A dose–response is seen, with the results being
better in the 60, 120, and 240 mg groups than in the 20 mg group. (From Ref. 69.)
with cimetidine, compared to placebo; however, there was no statistically sig-

nificant difference between the two active treatment regimens.
The effect of combining an H1- and H2-antagonist was studied in 18 subjects
with chronic idiopathic urticaria whose disease was inadequately controlled by
traditional therapy. In a double-blind crossover study consisting of two treatment
periods of 2 weeks duration, a combination of hydroxyzine 20 mg and cimetidine
300 mg each given four times daily, was compared with hydroxyzine 20 mg four
times daily and placebo. The severity of itching, and wheal numbers, frequency,
and size were significantly reduced by the combination of hydroxyzine and cimet-
idine, compared to hydroxyzine alone (70).
Nineteen patients with refractory chronic urticaria were sequentially treated
in a double-blind, randomized, serial fashion with hydroxyzine 25 mg four times
268
Table 4 Treatment of Chronic Ordinary Urticaria with H 1- and H 2-Antihistamines

Study design
Treatments Nos and length Assessments Results Side effects Reference
Chlorpheniramine 4 19 Randomized, P, W, ordinal scale Ch ⫹ Ci ⬃ Ch ⫹ Sedation: chlorphen- 39

mg qid alone or double-blind, P1 iramine with or
in combination crossover, 2 without cimeti-
with cimetidine wks dine, 12 patients;
200 mg qid ver- placebo, 2 pa-
sus placebo tients
Hydroxyzine 25 mg 19 Randomized, P, W, ordinal Hy ⫹ Ci ⬎ Hy ⬃ 71
qid alone and double-blind, Hy ⫹ Terbut ⬃
with one of the serial, 7–10 days Hy ⫹ Ch ⬃
following: ter- Hy ⫹ Cy (symp-
butaline 2.5 mg tom scores)
qid, cyprohepta-
dine 4 mg qid,
chlorpheniramine
4 mg qid, cimeti-
dine 300 mg qid
Hydroxyzine 20 mg 18 Randomized, P, W, ordinal Hy ⫹ Ci ⬎ Hy, Ci 70
qid, cimetidine double-blind, 14
300 mg qid, com- days
bination
Chlorpheniramine 4 15 Double-blind, cross- P, W, persistence 4 patients: Ch ⫹ Ci 72
mg qid, cimeti- over, 4 wks, wash- of W, ordinal ⬎ Ch, Ci
dine 200 mg qid, out 1 wk 4 patients: Ch ⬎
combination Ch ⫹ Ci or Ci
5 patients: no differ-
ence
Chlorpheniramine 4 20 Randomized, P, W, ordinal Ch ⬃ Ch ⫹ Ci 73
mg qid, cimeti- double-blind,
dine 400 mg qid, serial: 2 wks
combination
Chlorpheniramine 4 40: those not re- Randomized, P, E, W, ordinal Ch ⫹ Ra ⬎ Ch 74
mg qid: increase sponding to Ch double-blind,

to max effect; parallel, 8 wks
with placebo or
cimetidine 400
mg qid
Terfenadine a 60 mg 45 Randomized, P, W, ordinal Ch ⫹ Ra ⬎ Ch 75
bid, ranitidine double-blind,
150 mg bid, parallel, 9 days
combination
a
Terfenadine has been withdrawn in most countries.
P, pruritus; E, erythema; W, wheal; Ch, chlorpheniramine; Ci, cimetidine; Hy, hydroxyzine; Ra, ranitidine; Terbut, terbutaline; Pl, placebo; ⬃, essentially
equal; Cy, cyproheptadine; ⬎, significantly better; nos, number of participants; bid, twice daily; qid, four times daily.
269
daily for 7–10 days, in sequential combination with placebo, terbutaline 2.5 mg
four times daily, cyproheptadine 4 mg four times daily, chlorpheniramine 4
mg four times daily, or cimetidine 300 mg four times daily. The hydroxyzine–
cimetidine combination significantly improved itching and number of wheals
compared to all other combinations (71).
Combination treatment with H 1- and H 2-antagonists was studied in 15 se-
lected patients with chronic urticaria in a randomized, crossover, double-blind
study. Chlorpheniramine 4 mg four times daily, chlorpheniramine 4 mg and ci-
metidine 400 mg four times daily in combination, and placebo were administered
for 4 weeks with a 1 week washout period. The number and persistence of wheals
and the presence of itching were scored daily on an ordinal scale. The group as
a whole showed no difference in number and persistence of wheals between the
antihistamine- and placebo-treated groups; however, four patients fared signifi-
cantly better on combined antihistamine therapy, so the authors suggested that
the combined H 1- and H 2-antihistamine treatment might show modest benefit in
some patients (72).
A study by Cook and Shuster assessed the severity of 20 patients with
chronic idiopathic urticaria without therapy (73). They were then allocated in
a double-blind randomized manner to three blocks of 2 weeks’ treatment with
cimetidine and placebo, chlorpheniramine and placebo, and cimetidine and chlor-
pheniramine. Both H 1-receptor blockade alone and in combination with H 2-
receptor blockade produced a significant reduction in whealing and itching, but
there was no significant difference among the treatments.
In a multicenter study, 120 patients with chronic idiopathic urticaria were
treated with chlorpheniramine for 6 weeks, commencing at 4 mg four times daily.
The dosage was increased until symptoms were controlled, or to the maximum
tolerated. Forty-three patients did not respond, but chlorpheniramine was contin-
ued in all. Forty were randomly allocated to receive in addition either cimetidine
400 mg four times a day or placebo four times a day, and assessed for 8 weeks.
The most important change was reduction in total symptom score compared to
baseline. Chlorpheniramine and cimetidine in combination were significantly
more effective than chlorpheniramine alone at both 4 and 8 weeks (74).
These studies do not demonstrate any consistent efficacy of a combination
of an H 1- and H 2-antihistamine over an H 1-antihistamine alone. It has been sug-
gested that any modest improvement with the combination may not only have
been due to the blockade of H 2-receptors on blood vessels, but also to increased
levels of chlorpheniramine or hydroxyzine, which could have occurred because
cimetidine inhibits the enzyme complex cytochrome P-450, which metabolizes
chlorpheniramine and hydroxyzine and elevates the H 1-antihistamine plasma and
tissue concentrations (40).
In another study, however, 25 patients with chronic urticaria were treated
with the low-sedation antihistamine terfenadine (subsequently withdrawn) in
combination with a newer H 2-blocker, ranitidine, which is less inhibitory of cyto-

chrome P-450 and less antiandrogenic (75). Forty-five patients with CIU, after
2–5 days of placebo washout, were randomized into three double-blind parallel
groups to receive 9 days of treatment with terfenadine 60 mg twice daily, ranitid-
ine 150 mg twice a day, or a combination of both. The reduction in itching was
significantly greater with the H 1- and H 2-combination (maximum by 2 days) than
with terfenadine alone, while ranitidine alone had no effect. There was a similar
trend regarding whealing.
Overall, there may be modest, unpredictable improvement in an small sub-
group of patients with CIU treated with a combination of H 1- and H 2-antihista-
mines, compared to H 1-antihistamines alone. It is worth trying this combination
in patients not responding to adequate H 1-antihistamine therapy alone, for a lim-
ited period of time (4–6 weeks).
E. Antihistamine Therapy in the Context of Alternative

Systemic Treatment for CIU
Systemic corticosteroids are best reserved for the treatment of patients with se-
vere and disabling CIU, with or without angioedema, in which H 1-antihistamine
treatment has failed to bring about control. They are best used as short, tapering
courses: for example, prednisolone 40 mg daily reduced by 5 mg daily every 5
days to zero. Such regimens are rapidly effective in the short term and are useful
for tiding a patient over a critical personal or occupational event such as an exami-
nation, a wedding, or an overseas assignment. In the longer term, however, sys-
temic corticosteroids are usually unsatisfactory since they ultimately achieve poor
control, lead to rebound urticaria upon withdrawal, and cause troublesome toxic-
ity. These undesirable effects can be mitigated by use of a regimen advocated
by Kaplan (76). It consists of prednisolone 40 mg daily for 3 days, and then a
decrease in the dosage by 5 mg per day to 25 mg daily. Subsequently the dosage
is reduced by 5 mg on alternate days only, until eventually the patient is main-
tained on 25 mg on alternate days. After that, the maintenance dose is reduced
by 5 mg every 2 weeks so that about 3 months would be required for total with-
drawal of the steroid. Systemic corticosteriods are best given as a single morning
dose, and H 1-antihistamines must be continued during corticosteroid treatment.
Patients with autoimmune CIU (see above) who are severely disabled and
poorly responsive to antihistamines can be offered intravenous immunoglobulin
infusions (28) or even plasmapheresis (9) in addition to their H 1-antihistamine
treatment. Cyclosporin can also be used as an alternative to systemic corticoste-
roids (77); again, H 1-antihistamine treatment should be administered concur-
rently. In the authors’ experience, the majority of patients with CIU can be man-
aged successfully without recourse to corticosteroids or other immunosuppressive
modalities.
IX. PHYSICAL URTICARIAS
In this group of urticarias, reproducible whealing occurs in response to a physical

stimulus. Except in delayed-pressure urticaria, wheals usually occur within min-
utes and resolve within 1 hour. Physical urticarias often occur in young adults. If
suspected from the history, appropriate challenge tests will confirm the diagnosis.
Blood tests are rarely necessary, and allergy testing is inappropriate. If an individ-
ual is markedly affected and/or the stimulus is severe, angioedema and systemic
symptoms of flushing, headache and syncope may occur.
A. Dermographism
Symptomatic dermographism is the most common physical urticaria (Table 5).
It is an abnormal itching, whealing response to moderate friction of the skin (78).
A reproducible stimulus can be quantified by using a calibrated spring-loaded
stylus (dermographometer), stroked firmly along the skin of the back, and measur-
ing the width of the wheal produced. In symptomatic dermographism, itching and
whealing occur within minutes below a 36 g/mm 2 setting of the stylus. Patients
generally have very itchy uncomfortable skin, and show wheals, often linear,
within minutes of scratching. Dermographism is usually idiopathic and not asso-
ciated with systemic disease.
In symptomatic dermographism, the reproducible whealing response can
be assessed objectively, so this has been used to test whether a combination of
H 1- and H 2-antihistamines was superior to H 1-antihistamines alone; however, the
results obtained may not be applicable to ordinary chronic urticaria.
A double-blind trial in 33 patients with symptomatic dermographism
showed that hydroxyzine 75 mg daily decreased whealing to a significantly
greater degree than chlorpheniramine 12 mg daily, and was preferred by patients
(79).
A double-blind, randomized trial of antihistamine therapy using chlor-
pheniramine 4 mg, cimetidine 400 mg, and their combination four times daily
in successive 2-week periods was carried out in 10 patients with dermographism
(80). The mean diameters induced by the stylus at 49.0 and 73.5 g/mm 2 after 10
min were measured after each treatment period. There was significant overall
improvement with the combination treatment, but chlorpheniramine given alone
produced no benefit. A similar study showed that only the combination of cimeti-
dine and chlorpheniramine significantly reduced dermographometer-induced
wheal and flare compared to either H 1- or H 2-antihistamine alone or to placebo
(81). In another study, a single low dose of chlorpheniramine (4 mg) successfully
reduced dermographometer-induced wheals (82); therefore, the combination of
H 1- and H 2-antihistamine was not necessarily superior to the H 1-antihistamine
chlorpheniramine.
Table 5 H 1- and H 2-Antihistamine Treatment of Physical Urticarias
Study design
Dermographism
Hydroxyzine 75 mg 33 Double-blind, 2 wks Dermographometer Hy ⬎ Ch 79
daily, chlorphe- wheal widths
niramine 12 mg
daily
Chlorpheniramine 4 16 Randomized, double- Dermographometer Ch ⫹ Ci ⬎ Ch 80
mg qid, cimeti- blind, sequential, wheal widths ( p ⬍.025)
dine 400 mg qid, 2 weeks Ci worsened
combination
Chlorpheniramine 4 12 Randomized, double- Dermographo- Hydroxyzine: the Trimeprazine and 78
mg qid, mepyra- blind, crossover, 5 meter wheals most effective cyproheptadine
mine 50 mg tid, days treatment, 2 most sedating
promethazine 50 days washout
mg nocte, ketoti-
fen 1 mg bid, cy-
proheptadine 4
mg qid, trimepraz-
ine 10 mg tid, pre-
treatment
Chlorpheniramine 4 19 Randomized, double- Dermographometer Ch ⫹ Ci ⬎ Pl 81
mg qid, cimeti- blind, crossover; wheal widths ( p ⬍ 0.01)
dine 400 mg qid, each combination,
combination, 48 h, 5 days free
placebo
Chlorpheniramine 4 20 Randomized, double- Whealing response Ch ⫹ Ci ⬎ Ci 82
mg, cimetidine blind, sequential to dermogra-
400 mg, or combi- phometer
273
nation 2 h before
assessment
274
Table 5 H 1- and H 2-Antihistamine Treatment of Physical Urticarias
Study design
Cetirizine 10 mg: one 10 Open study 4 h after Ce, der- 8 patients 83

dose mographometer whealing ab-
wheals sent; 2 patients
reduced
Cetirizine 10 mg: 19 Randomized, double- Dermographo- Significant reduc- 84
placebo daily blind, crossover, 7 meter wheals tion in itch and
days wheal by Ce
compared to Pl
Cetirizine 10 mg at 19 Randomized, double- Dermographo- Ce ⫹ Ra ⬎ Ce 85
night, combined blind, crossover, 7 meter whealing Small reduction in
with ranitidine 150 days, 3 days wash- threshold wheal but no
mg bid out symptomatic
relief
Cholinergic urticaria
Acrivastine 8 mg, hy- 10 Randomized, double- Exercise-induced Ac ⬃ Hy ⬎ Pl 87
droxyzine 20 mg, blind, crossover, 5 itch, VAS,
placebo each tid days, 2 days wash- wheal numbers
out
Cetirizine 10 mg, 20 24 Randomized, double- P, E, W, diary Ce improved P 2 patients: tired- 88
mg, placebo daily blind, crossover, 3 card, ordinal and W ⬎ Pl ness on Ce 20
weeks each, pla- days improved ( p ⬍ 0.01) Ce mg daily
cebo between Ce 20 mg ⬎ 10 mg
treatments for whealing only

Cold urticaria
Cinnarizine 10 mg, 10(9) Both studies double- Subjective prefer- 8/9 preferred dox- 92
doxepin 10 mg, pla- blind, crossover, 2 ence, wheal re- epin
cebo all tid weeks, 1 week sponse to ice Suppression
Cyproheptadine 4 mg, 12 washout, 1 week, cube, ordinal Cy 53%
doxepin 10 mg, hy- 1 week washout Do 61%
droxyzine 10 mg, Hy 56%
placebo all tid Pl 3%
Cyproheptadine 0.25 6 child Randomized, cross- Ice cube test re- Improvement: Cy Ketotifen ⬍ Cy 91
mg/kg, ketotifen 1 over study, 4 wks, sponse 85 ⬃ Ke ⫽
mg bid 2 wks washout 88%
Cyproheptadine 4 mg 18 Randomized, double- Ice cube test, Ac ⬎ Cy Cy ⬎ sedating Ac 93
tid, acrivastine 8 blind, crossover wheal areas

mg tid, placebo tid
Cetirizine 10 mg 12 Open, one dose Ice cube test, 4 h 5 patients no 83
later: subjective, wheal, de-
ordinal creased in
others
Solar urticaria
Cetirizine 10 mg 6 Randomized, double- Phototest for mini- 4 patients: Ce ⬃ 95
daily, terfena- blind, sequential mum whealing Te in raising
dine a 60 mg bid for 2 days dose wheal thresh-
old, 2 patients:
no effect
Delayed pressure ur-
ticaria
Cetirizine 10 mg tid, 11 Double-blind, cross- Pressure-induced Ce ⬎ Pl on wheal 100
placebo over, 1 week, 2 wheals, area areas (p ⬍ 0.01)
weeks washout
a
Terfenadine has been withdrawn in most countries.
P, pruritus; E, erythema; W, wheal; Ch, chlorpheniramine; Ci, cimetidine; Ra, ranitidine; Ac, acrivastine (not available in US); Ce, cetirizine; Do, doxepin;
275
Cy, cyproheptadine; Hy, hydroxyzine; Pl, placebo; Te, terfenadine; ke, ketotifen; ⬎, significantly better; ⬃, equivalent response; p, probability; VAS, visual
analog score; h, hours; Nos, number of participants; bid, twice daily; tid, three times daily; qid, four times daily; nocte, at night.
In a double-blind, randomized, controlled trial, eight different sedating anti-

histamines (Table 4) were given for 5 days to 12 patients and assessments were
made of dermographometer-induced wheal widths. A combination of hydroxy-
zine and cimetidine was significantly superior to all other treatments, and was
associated with the fewest side effects (78).
An open study of 10 patients with dermographism showed that 4 hours
after administration of cetirizine 10 mg, dermographometer-induced whealing
was absent in eight patients and reduced in two (83). A randomized, double-
blind, crossover comparison of cetirizine 10 mg at night and placebo treatment for
1 week given to 19 dermographic patients also showed that cetirizine significantly
reduced dermographometer-induced itching and whealing (84).
The same investigators used a randomized, double-blind, crossover design
in 19 patients with dermographism to compare the effect of a combination of
cetirizine 10 mg at night and ranitidine 150 mg twice daily given for 7 days
with cetirizine alone and with placebo (85). With the addition of ranitidine, some
objective improvement in the increase in threshold whealing response could be
demonstrated; however, there was no significant improvement as assessed by
patients on linear analog scores for wheal, itch, or sleep. It was concluded that
these results did not justify the use of H 2-antagonists in dermographism and, by
implication, in chronic urticaria.
B. Cholinergic Urticaria
Cholinergic urticaria (heat bumps, prickly heat) (86) (Table 5), another common
type of urticaria grouped with the physical urticarias, occurs in up to 10% of
young adults. Within minutes, a rise in core body temperature caused by heating
induced by a hot bath, exercise, or stress induces multiple itchy small monomor-
phic wheals surrounded by a flare. The hives usually last less than 1 hour. Se-
verely affected patients may develop angioedema or a form of exercise-induced
anaphylaxis.
Challenge tests include exercise or a hot bath to induce the characteristic
wheals. The reproducibility of whealing after challenge is not as consistent as
dermographometer-induced whealing in dermographism; however, wheal counts
in a predefined area have been used as an objective measurement of the severity
of cholinergic urticaria.
Ten patients with cholinergic urticaria were tested in a randomized, double-
blind, crossover, placebo-controlled trial with hydroxyzine 20 mg three times
daily. Each treatment was taken for 5 days with a 3-day washout. There was a
significant reduction in the number of exercise-induced wheals with hydroxyzine
compared to placebo. One patient in each group reported drowsiness (87).
Cetirizine in doses of 10 mg and 20 mg was studied in a double-blind,
placebo-controlled, crossover trial involving 3-week treatment periods in 24 pa-
tients with cholinergic urticaria (88). Evaluation of the patients’ daily symptom
scores based on itching, erythema, and whealing showed a high level of improve-
ment with cetirizine, with only whealing showing a greater improvement at the
higher dose.
Although antihistamines are moderately effective in many patients with
cholinergic urticaria, some severely affected patients may not benefit signifi-
cantly. A controlled trial of danazol 200 mg three times a day significantly con-
trolled whealing in patients with cholinergic urticaria (89). Although this is an
unlicensed indication for this drug, it may be an option for short-term treatment
of the most severely affected patients.
C. Cold Urticaria
The most common form is acquired cold urticaria in which contact with cold air,
water, or objects induces itching, erythema, and wheals localized to the contact
site (90). Wheals develop within minutes and resolve within 1 hour. Exposure
of large areas of the body to cold, such as swimming in cold water, can induce
massive histamine release with risk of histamine shock and drowning. Patients
with cold urticaria must avoid such situations and have epinephrine available.
Confirmatory challenge testing is by application of a melting ice cube in
a plastic bag against the skin for 20 min, resulting in whealing at the site.
The condition usually occurs in children and young adults. It is idiopathic
in over 90% of cases. Rarely, it may be secondary to cold-reactive proteins such
as cryoglobulins, which should be measured especially if there are unusual associ-
ated features such as Raynaud’s disease or purpura. Some patients have cryoglo-
bulinemia secondary to lymphoproliferative malignancy.
Treatment of idiopathic cold urticaria is with H 1-antihistamines (Table 5).
Early studies showed that cyproheptadine was effective in cold urticaria; how-
ever, it is sedative and can cause headaches and inappropriate weight gain. Other
H 1-antihistamines with fewer side effects are as, or more, effective. For example,
a double-blind, crossover study in six children with cold urticaria showed that
ketotifen, a somewhat less sedating antihistamine, was as effective as cyprohepta-
dine (91). A double-blind comparison of cyproheptadine 4 mg, doxepin 10 mg,
cinnarizine 10 mg, and hydroxyzine, all administered three times daily, showed
similar efficacy of these H 1-antihistamines assessed by suppression of the ice
cube test. Doxepin was subjectively the most effective and, although sedating,
had the fewest side effects (92).
Another second-generation antihistamine, acrivastine, was more effective
in treating cold urticaria than cyproheptadine and was less sedating (93). Twelve
patients with cold urticaria were tested with an ice cube before and 4 hours after
administration of cetirizine 10 mg. The whealing response was abolished in five
patients and reduced in the others (83). These studies suggest that second-genera-
tion low-sedation antihistamines should be the first choice in the treatment of

cold urticaria.
D. Solar Urticaria
This is a rare condition in which itching, erythema, and whealing occur within
minutes in areas exposed to ultraviolet radiation and/or visible light. The wheals
resolve within 1 hour. Confirmation is an immediate whealing response to natural
sunlight or a solar simulator, but the monochromator, available in special photo-
biology units, will demonstrate the specific wavelengths responsible. Treatment
is difficult, but some patients respond to low-sedation H 1-antihistamines (94).
In a placebo-controlled, double-dummy, crossover study in six patients with so-
lar urticaria, terfenadine 60 mg twice daily (now withdrawn) or cetirizine 10 mg
daily was given for 2 days with a washout period of 7 days. Monochromator-
induced whealing was assessed 2 hours after the last dose of medication. At the
doses used, cetirizine and terfenadine were equally effective in raising the thresh-
old whealing response in four patients, but two patients failed to respond to either
(95) (Table 5). This is in keeping with the variable response to antihistamines
in solar urticaria (94). Treatment of patients failing to respond to H 1-antihista-
mines in combination with sunblocks includes photochemotherapy with ultravio-
let A (PUVA) (96) or even plasmapheresis (97) supervised in specialist photobi-
ology centers.
E. Delayed Pressure Urticaria

In this condition there is a whealing response to sustained pressure on the skin
occurring 30 minutes to 9 hours after the pressure has been applied. Lesions
occur at the waistline, on the soles after walking, and on the palms after using
tools. They are often painful and persist for more than 24 hours (98). As men-
tioned previously, 40% of patients with ordinary urticaria have an element of
pressure urticaria but, in some, delayed pressure is the major problem. A positive
challenge test consists of the development of an indurated wheal at 6 hours at
the site of a 4 kg weight resting on the skin (thigh or back) for 15 min or a 7 kg
weight suspended on a broad strap across the shoulders or thighs. The histology
of a delayed pressure–induced wheal shows a similar appearance to a wheal in
ordinary chronic urticaria, but there may be a more marked eosinophil infiltrate,
especially in the deeper dermis.
Cetirizine 10 mg three times daily, compared to placebo in a double-blind
study in 11 patients with delayed pressure urticaria, led to a significant reduction
of the weight-induced wheal area (99); however, since the weight per unit area
used for the challenge was not defined, a reliable comparison of the size of the
pressure-induced wheals was not possible (Table 5). In practical terms, the use
of high-dose cetirizine is disappointing, and other antihistamines are also not

effective (98).
Nonsteroidal anti-inflammatory drugs (NSAIDs) are claimed to be useful
(100) but indomethacin had little effect on the size of the induced wheals in a
double-blind trial (98). There is a case report of dapsone improving pressure
urticaria in five patients, but most patients are resistant to all treatments except
oral steroids. Short-term corticosteroid treatment for exacerbations can be used,
but often more than 30 mg/day prednisone may be necessary, and long-term
treatment should be avoided if possible.
F. Urticarial Vasculitis
Usually a cause cannot be identified for urticarial vasculitis (3). In a few patients
it may be due to an infection such as hepatitis B or C, or to a collagen vascular
disease such as lupus erythematosus or Sjögren’s disease. Investigation for pul-
monary, renal, or other systemic involvement should be undertaken.
There are no controlled trials of therapy. Most patients respond poorly to
H 1-antihistamine therapy; however, because the lesions are itchy these medica-
tions are usually continued and other medications added. The response is unpre-
dictable. Nonsteroidal anti-inflammatory drugs, such as dapsone 50–100 mg
daily, colchicine 0.5 mg twice to three times daily, and antimalarials have all
been used. Long-term oral corticosteroids may be necessary, but the dosage re-
quired for control may exceed prednisone 30 mg daily. Azathioprine can be used
for a steroid-sparing effect.
G. Angioedema Without Urticaria

This is the most frequent ordinary idiopathic angioedema, occasionally occurring
with physical or contact urticaria (101); however, it is vital to exclude the rare
C1 esterase deficiency angioedema with a screening test of serum complement
C4. If C4 levels are low, a functional measurement of C1 esterase inhibitor, if
also low, will confirm the diagnosis. These swellings do not respond to antihista-
mines, and life-threatening laryngeal swellings may also respond poorly to epi-
nephrine. Emergency treatment is with fresh frozen plasma or C1 esterase inhibi-
tor concentrate, if available. Prophylactic treatment is with oral anabolic steroids
such as danazol or antifibrinolytic agents.
X. SUMMARY
H 1-antihistamines are the cornerstone of symptomatic treatment in acute and

chronic urticaria, in which they not only relieve itching, but also reduce the num-
ber, size, and duration of urticarial lesions. Relief of whealing, flaring, and ery-
thema may be incomplete as the vascular effects of histamine are mediated to
its action at H 2-receptors as well as at H 1-receptors, and other vasoactive sub-
stances may also be involved.
In randomized, prospective, placebo-controlled, double-blind studies, the
new low-sedating H 1-antihistamines have been found to be effective and safe in
urticaria. Sedating antihistamines, although effective, place patients at risk for
adverse effects, including decreased psychomotor performance. The response to
H 1-antihistamines in some types of urticaria, for example, in urticarial vasculitis,
is unsatisfactory. An H 2-antihistamine administered concurrently with an H 1-anti-
histamine may modestly enhance relief of itching and wheal formation in some
patients with urticaria refractory to treatment with an H 1-antihistamine alone.
The available evidence does not justify the routine addition of H 2-antihistamine
treatment to H 1-antihistamine treatment.
REFERENCES
1. Champion RH, Roberts SOB, Carpenter RG, Roger JH. Urticaria and angioedema.
A review of 554 patients. Br J Dermatol 1969; 81:588–597.
2. Sabroe RA, Seed PT, Francis DM, Barr RM, Kobza Black A, Greaves MW.
Chronic idiopathic urticaria: Comparison of the clinical features of patients with
and without anti-FcεRI or anti-IgE autoantibodies. J Am Acad Dermatol 1999; 40:
443–450.
3. Kobza Black A. Urticarial vasculitis. Clin Dermatol 1999; 17:565–569.
4. O’Donnell BF, Lawlor F, Simpson J, Morgan M, Greaves MW. The impact of
chronic urticaria on the quality of life. Br J Dermatol 1997; 136:197–201.
5. Poon E, Seed PT, Greaves MW, Kobza Black A. The extent and nature of disability
in different urticarial conditions. Br J Dermatol 1999; 140:667–671.
6. Sabroe RA, Greaves MW. The pathogenesis of chronic idiopathic urticaria. Arch
Dermatol 1997; 133:1003–1008.
7. Sabroe RA, Poon E, Orchard GE, Lane D, Francis DM, Barr RM, Black MM,
Kobza Black A, Greaves MW. Cutaneous inflammatory cell infiltrate in chronic
idiopathic urticaria: comparison of patients with and without anti-FcεRI or anti-
IgE autoantibodies. J Allergy Clin Immunol 1999; 103:484–493.
8. Greaves MW, Davies MG. Histamine receptors in human skin: indirect evidence.
Br J Dermatol 1982; 107 (suppl 23):101–105.
9. Kavanagh GM, Sabroe RA, Greaves MW, Archer CB. The intradermal effects of
the H 3-receptor agonist R α-methyl-histamine in human skin. Br J Dermatol 1998;
138:622–626.
10. Greaves M, Shuster S. Responses of skin blood vessels to bradykinin, histamine
and 5-hydroxytryptamine. J Physiol (Lond) 1997; 193:255–267.
11. Barlow RJ, Ross EL, MacDonald D, Kobza Black A, Greaves MW. Adhesion mole-
cule expression and the inflammatory cell infiltrate in delayed pressure urticaria.
Br J Dermatol 1994; 131:341–347.
12. Kozel MMA, Mekkes JR, Bossuyt PMM, Bos JD. The effectiveness of a history-
based diagnostic approach in chronic urticaria and angioedema. Arch Dermatol
1998; 134:1575–1580.
13. Krause LB, Shuster S. H 1-receptor-active histamine not sole cause of chronic idio-
pathic urticaria. Lancet 1984; 2:929–930.
14. Corbett MF. The design of trials in urticaria. In: RH Champion, MW Greaves,
A Kobza Black, RJ Pye, eds. The Urticarias. Edinburgh: Churchill Livingstone,
1985:212–216.
15. Zuberbier T, Ifflandder J, Semmler C, Henz BM. Acute urticaria: clinical aspects
and therapeutic responsiveness. Acta Derm Venereol (Stockh) 1996; 76:295–
297.
16. Barlow RJ, Warburton F, Watson K, Kobza Black A, Greaves MW. Diagnosis and
incidence of delayed pressure urticaria in patients with chronic urticaria. J Am Acad
Dermatol 1993; 24:954–958.
17. Kobza Black A, Greaves MW, Champion RH, Pye RJ. The urticarias. 1990. Br J
Dermatol 1991; 124:100–108.
18. Greaves MW. Chronic urticaria. N Engl J Med 1995; 332:1767–1772.
19. James J, Warin RP. An assessment of the role of Candida albicans and food yeasts
in chronic urticaria. Br J Dermatol 1971; 84:227–237.
20. Jacobson KW, Branch LB, Nelson HS. Laboratory tests in chronic urticaria. JAMA
1980; 243:1644–1646.
21. Di Campli C, Gasbarrini A, Nucera E, Franceschi F, Ojetti V, Sanz Torre E, Schia-
vino D, Pola P, Patriarca G, Gasbarrini G. Beneficial effect of Helicobacter
pylori eradication on idiopathic chronic urticaria. Dig Dis Sci 1998; 43:1226–
1229.
22. Greaves MW. Chronic idiopathic urticaria (CIU) and Helicobacter pylori: not di-
rectly causative—but could there be a link? J Allergy Clin Immunol 2001; 13:23–
26.
23. Leznoff A, Sussman GL. Syndrome of idiopathic chronic urticaria and angioedema
with thyroid autoimmunity: a study of 90 patients. J Allergy Clin Immunol 1989;
84:66–71.
24. Grattan CEH, Wallington TB, Warin RP, Kennedy CTC, Bradfield JW. A serologi-
cal mediator in chronic idiopathic urticaria—a clinical, immunological and histo-
logical evaluation. Br J Dermatol 1986; 114:583–590.
25. Hide M, Francis DM, Grattan CEH, Hakimi J, Kochan JP, Greaves MW. Autoanti-
bodies against the high-affinity IgE receptor as a cause of histamine release in
chronic urticaria. N Engl J Med 1993; 328:1599–1604.
26. Niimi N, Francis DM, Kermani F, O’Donnell BF, Hide M, Kobza Black A, Winkel-
mann RK, Greaves MW, Barr RM. Dermal mast cell activation by autoantibodies
against the high-affinity IgE receptor in chronic urticaria. J Invest Dermatol 1996;
106:1001–1006.
27. Grattan CEH, Francis DM, Slater NGP, Barlow RJ, Greaves MW. Plasmapheresis
for severe, unremitting, chronic urticaria. Lancet 1992; 339:1078–1080.
28. O’Donnell BF, Barr RM, Black AK, Francis DM, Kermani F, Niimi N, Barlow
RJ, Winkelmann RK, Greaves MW. Intravenous immunoglobulin in autoimmune

chronic urticaria. Br J Dermatol 1998; 138:101–106.
29. Fiebiger E, Maurer D, Holub H, Reininger B, Hartmann G, Woisetschlager M,
Kinet JP, Stingl G. Serum IgG autoantibodies directed against the α chain of FcεRI:
a selective marker and pathogenetic factor for a distinct subset of chronic urticaria
patients? J Clin Invest 1995; 96:2602–2612.
30. Zweiman B, Valenzano M, Atkins PC, Tanus T, Getsy JA. Characteristics of hista-
mine-releasing activity in the sera of patients with chronic idiopathic urticaria. J
31. Tong LJ, Balakrishnan G, Kochan JP, Kinet JP, Kaplan AP. Assessment of autoim-
munity in patients with chronic urticaria. J Allergy Clin Immunol 1997; 99:461–
465.
32. Fiebiger E, Hammerschmid F, Stingl G, Maurer D. Anti-FcεRIα autoantibodies in
autoimmune-mediated disorders. Identification of a structure–function relationship.
J Clin Invest 1998; 101:243–251.
33. Supramaniam G, Warner JO. Artificial food additive intolerance in patients with
angio-oedema and urticaria. Lancet 1986; 2:907–909.
34. Pastorello EA. Evaluating new tests for the diagnosis of food allergy. Allergy 1995;
50:289–291.
35. Sabroe RA, Grattan CEH, Francis DM, Barr RM, Kobza Black A, Greaves MW.
The autologous serum skin test: a screening test for autoantibodies in chronic idio-
pathic urticaria. Br J Dermatol 1999; 140:446–452.
36. Davies MG, Greaves MW. Sensory responses of human skin to synthetic histamine
analogues and histamine. Br J Clin Pharmacol 1980; 9:461–465.
37. Greaves M, Marks R, Robertson I. Receptors for histamine in human skin blood
vessels: a review. Br J Dermatol 1977; 97:225–228.
38. Marks R, Greaves MW. Vascular reactions to histamine and compound 48/80 in
human skin: suppression by a histamine H 2-receptor blocking agent. Br J Clin Phar-
macol 1977; 4:367–369.
39. Commens CA, Greaves MW. Cimetidine in chronic idiopathic urticaria: a random-
ized double-blind study. Br J Dermatol 1978; 99:675–679.
40. Simons FER, Sussman GL, Simons KJ. Effect of the H 2-antagonist cimetidine on
the pharmacokinetics and pharmacodynamics of the H 1-antagonists hydroxyzine
and cetirizine in patients with chronic urticaria. J Allergy Clin Immunol 1995; 95:
685–693.
40a. O’Leary PA, Farber EM. Benadryl in the treatment of urticaria. Proc Staff Meetings
Mayo Clinic 1946; 20:429–432.
41. Handley DA, Magnetti A, Higgins AJ. Therapeutic advantages of third-generation
antihistamines. Exp Opin Invest Drugs 1998; 7:1045–1054.
43. Brunet C, Bedard P-M, Hebert J. Effect of H 1-antihistamine drug regimen on his-
tamine release by nonlesional skin mast cells of patients with chronic urticaria. J
44. Simons FER. Antihistamines. In: Middleton E Jr, Reed CE, Ellis EF, Adkinson
NF Jr, Yunginger JW, Busse WW, eds. Allergy: Principles and Practice. 5th ed.
St. Louis: Mosby-Year Book, Inc., 1998:612–637.
46. Greaves MW. Antihistamine treatment: a patient self-assessment method in chronic
urticaria. Br Med J 1981; 283:1435–1436.
47. Green JP, Maayani SS. Tricyclic antidepressant drugs block histamine H 2-receptors
in the brain. Nature 1977; 269:163–165.
48. Greene SL, Redd CE, Schroeter AL. Double-blind crossover study comparing dox-
epin with diphenhydramine for the treatment of chronic urticaria. J Am Acad Der-
matol 1985; 12:669–675.
49. Craps LP. Immunologic and therapeutic aspects of ketotifen. J Allergy Clin Immu-
nol 1985; 76:389–393.
50. Mallet AI, Norris P, Rendell NB, Wong E, Greaves MW. The effect of disodium
cromoglycate and ketotifen on the excretion of histamine and N T-methylimidazole
acetic acid in urine of patients with mastocytosis. Br J Clin Pharmacol 1989; 27:
88–91.
51. Huston DP, Bressler RB, Kaliner M, Sowell LK, Baylor MW. Prevention of mast-
cell degranulation by ketotifen in patients with physical urticarias. Ann Intern Med
1986; 104:507–510.
52. Kamide R, Niimura M, Ueda H, Imamura S, Yamamoto S, Yoshida H, Kukita
A. Clinical evaluation of ketotifen for chronic urticaria: multicenter double-blind
comparative study with clemastine. Ann Allergy 1989; 62:322–325.
53. Egan C, Rallis TM. Treatment of chronic urticaria with ketotifen. Arch Dermatol
1997; 133:147–149.
54. Spencer CM, Faulds D, Peters DH. Cetirizine: a reappraisal of its pharmacological
properties and therapeutic use in selected allergic disorders. Drugs 1993; 46:1055–
1080.
55. Kalivas J, Breneman D, Tharp M, Bruce S, Bigby M and nine other investigators.
Urticaria: clinical efficacy of cetirizine in comparison with hydroxyzine and pla-
cebo. J Allergy Clin Immunol 1990; 86:1014–1018.
56. L Juhlin. Cetirizine in the treatment of chronic urticaria. Clin Ther 1991; 13:81–
86.
57. Guerra L, Vincenzi C, Marchesi E, Tosti A, Pretto E, Bassi R, Ruetta Fabbian P,
De Costanza F. Loratadine and cetirizine in the treatment of chronic urticaria. J
Eur Acad Dermatol 1994; 3:148–152.
58. Bousquet J, Czarlewski W, Danzig MR. Antiallergic properties of loratadine: a
review. Adv Ther 1995; 12:283–298.
59. Bousquet J, Lebel B, Chanal I, Morel A, Michel F-B. Antiallergic activity of H 1-
82:881–887.
60. Belaich S, Bruttmann G, De Greef H, Lachapelle JM, Paul E, Pedrali P, Tennstedt
D. Comparative effects of loratadine and terfenadine in the treatment of chronic
idiopathic urticaria. Ann Allergy 1990; 64:191–194.
61. Monroe EW, Fox RW, Green AW, Izuno GT, Bernstein DI, Pleskow WW, Willis
I, Brigante JR. Efficacy and safety of loratadine (10 mg once daily) in the manage-
ment of idiopathic chronic urticaria. J Am Acad Dermatol 1988; 19:138–139.
62. Monroe EW. Relative efficacy and safety of loratadine, hydroxyzine and placebo
in chronic idiopathic urticaria and atopic dermatitis. Clin Ther 1992; 14:17–21.
63. Monroe EW, Bernstein DI, Fox RW, Grabiec SV, Honsinger RW, Kalivas JT, Katz
HI, Cuss F, Danzig MR, Garvin PR, Lutsky BN. Relative efficacy and safety of
loratadine, hydroxyzine and placebo in chronic idiopathic urticaria. Arzneim Forsch
Drug Res 1992; 42:1119–1121.
administration: arachidonic acid-induced cutaneous reaction in the rat. Arzneim
Forsch Drug Res 1998; 48:173–178.
65. Dubertret L, Aguttes MM, Tonet J. Efficacy and safety of mizolastine 10 mg in a
placebo-controlled comparison with loratadine in chronic idiopathic urticaria. Re-
sults of the MILOR study. J Eur Acad Dermatol Venereol 1999; 12:16–24.
66. Brostoff J, Fitzharris P, Dunmore C, Theron M, Blondin P. Efficacy of mizolastine,
a new antihistamine, compared with placebo in the treatment of chronic idiopathic
urticaria. Allergy 1996; 51:320–325.
67. Markham A, Wagstaff AJ. Fexofenadine. Drugs. 1998; 55:269–274.
68. Paul E, Berth-Jones J, Ortonne J-P, Stern M. Fexofenadine hydrochloride in the
treatment of chronic idiopathic urticaria: a placebo-controlled, parallel-group, dose-
ranging study. J Dermatol Treat 1998; 9:143–149.
69. Finn AF Jr, Kaplan AP, Fretwell R, Qu R, Long J. A double-blind placebo-
controlled trial of fexofenadine HCl in the treatment of chronic idiopathic urticaria.
70. Monroe EW, Cohen SH, Kalbfleisch J, Schulz CI. Combined H 1- and H 2-antihista-
mine therapy in chronic urticaria. Arch Dermatol 1981; 117:404–407.
71. Harvey RP, Wegs J, Schocket AL. A controlled trial of therapy in chronic urticaria.
72. Diller G, Orfanos CE. Management of idiopathic urticaria with H 1- ⫹ H 2-antago-
nists. A crossover double-blind long-term study. Z Hautkr 1983; 58:785–793.
73. Cook LJ, Shuster S. Lack of effect of cimetidine in chronic idiopathic urticaria.
Acta Dermato-Venereol (Stockh) 1983; 63:265–267.
74. Bleehen SS, Thomas SE, Greaves MW, Newton J, Kennedy CTC, Hindley F, Marks
R, Hazell M, Rowell NR, Fairiss GM, Cartwright PH, Glenny HP, Howland K.
Cimetidine and chlorpheniramine in the treatment of chronic idiopathic urticaria:
a multi-centre randomized double-blind study. Br J Dermatol 1987; 117:81–88.
75. Paul E, Bodeker RH. Treatment of chronic urticaria with terfenadine and ranitidine.
A randomized double-blind study in 45 patients. Eur J Clin Pharmacol 1986; 31:
277–280.
76. Kaplan AP. Chronic urticaria: possible causes, suggested treatment alternatives.
Postgrad Med 1983; 74:209–215, 218–222.
77. Grattan CEH, O’Donnell BF, Francis DM, Niimi N, Barlow RJ, Seed PT, Kobza
Black A, Greaves MW. Randomized double-blind trial of cyclosporin A in chronic
idiopathic urticaria. Br J Dermatol 2000; 143:365–372.
78. Breathnach SM, Allen R, Milford Ward A, Greaves MW. Symptomatic dermo-
graphism: natural history, clinical features, laboratory investigations and response

to therapy. Clin Exp Dermatol 1983; 8:463–476.
79. Matthews CNA, Kirby JD, James J, Warin RP. Dermographism: reduction in wheal
size by chlorpheniramine and hydroxyzine. Br J Dermatol 1973; 88:279–282.
80. Matthews CNA, Boss JM, Warin RP, Storari F. The effect of H 1- and H 2-histamine
antagonists on symptomatic dermographism. Br J Dermatol 1979; 101:57–61.
81. Kaur S, Greaves M, Eftekhari N. Factitious urticaria (dermographism): treatment
by cimetidine and chlorpheniramine in a randomized double-blind study. Br J Der-
matol 1981; 104:185–190.
82. Cook J, Shuster S. The effect of H 1- and H 2-receptor antagonists on the dermo-
graphic response. Acta Derm Venereol (Stockh) 1983; 63:260–262.
83. Juhlin L, de Vos C, Rihoux J-P. Inhibiting effect of cetirizine on histamine-induced
and 48/80-induced wheals and flares, experimental dermographism, and cold-
induced urticaria. J Allergy Clin Immunol 1987; 80:599–602.
84. Sharpe GR, Shuster S. The effect of cetirizine on symptoms and whealing in dermo-
graphic urticaria. Br J Dermatol 1993; 129:580–583.
85. Sharpe GR, Shuster S. In dermographic urticaria H 2-receptor antagonists have a
small but therapeutically irrelevant additional effect compared with H 1-antagonists
alone. Br J Dermatol 1993; 129:575–579.
86. Hirschmann JV, Lawlor F, English JSC, Louback JB, Winkelmann RK, Greaves
MW. Cholinergic urticaria. A clinical and histologic study. Arch Dermatol 1987;
123:462–467.
87. Kozba Black A, Aboobaker J, Gibson JR, Harvey SG, Marks P. Acrivastine versus
hydroxyzine in the treatment of cholinergic urticaria. A placebo-controlled study.
Acta Derm Venereol (Stockh) 1988; 68:541–544.
88. Zuberbier T, Aberer W, Burtin B, Rihoux J-P, Czarnetzki BM. Efficacy of cetirizine
in cholinergic urticaria. Acta Derm Venereol (Stockh) 1995; 75:147–149.
89. Wong E, Eftekhari N, Greaves MW, Milford Ward A. Beneficial effects of danazol
on symptoms and laboratory changes in cholinergic urticaria. Br J Dermatol 1987;
116:553–556.
90. Wanderer AA. Cold urticaria syndromes: historical background, diagnostic classi-
fication, clinical and laboratory characteristics, pathogenesis and management. J
91. Visitsunthorn N, Tuchinda M, Vichyanond P. Cold urticaria in Thai children: Com-
parison between cyproheptadine and ketotifen in the treatment. Asian Pac J Allergy
Immunol 1995; 13:29–35.
92. Neittaanmaki H, Myohanen T, Fraki JE. Comparison of cinnarizine, cyprohepta-
dine, doxepin, and hydroxyzine in the treatment of idiopathic cold urticaria: Use-
fulness of doxepin. J Am Acad Dermatol 1984; 11:483–489.
93. Neittaanmaki H, Fraki JE, Gibson JR. Comparison of the new antihistamine acri-
vastine (BW 825C) versus cyproheptadine in the treatment of idiopathic cold urti-
caria. Dermatologica 1988; 177:98–103.
94. Ferguson J. Idiopathic solar urticaria: natural history and response to non-sedative
therapy. A study of 26 cases. Br J Dermatol 1988; 119 (suppl 13):16.
95. Bilsland D, Ferguson J. A comparison of cetirizine and terfenadine in the manage-
ment of solar urticaria. Photodermatol Photoimmunol Photomed 1991; 8:62–64.
96. Parrish JA, Jaenicke KF, Morison WL, Momtaz K, Shea C. Solar urticaria: treat-
ment with PUVA and mediator inhibitors. Br J Dermatol 1982; 106:575–580.
97. Duschet P, Leyen P, Schwarz T, Hocker P, Greiter J, Gschnait F. Solar urticaria—
effective treatment by plasmapheresis. Clin Exp Dermatol 1987; 12:185–188.
98. Dover JS, Kobza Black A, Milford Ward A, Greaves MW. Delayed pressure urti-
caria: clinical features, laboratory investigations and response to therapy of 44 pa-
tients. J Am Acad Dermatol 1988; 18:1289–1298.
99. Sussman GL, Harvey RP, Schocket AL. Delayed pressure urticaria. J Allergy Clin
Immunol 1982; 70:337–342.
100. Kontou-Fili K, Maniatakou G, Demaka P, Gonianakis M, Palaiologos G, Aroni
K. Therapeutic effects of cetirizine in delayed pressure urticaria: clinicopathologic
findings. J Am Acad Dermatol 1991; 24:1090–1093.
101. Greaves M, Lawlor F. Angioedema: manifestations and management. J Am Acad
Dermatol 1991; 25:155–165.
9
Histamine and Antihistamines
in Anaphylaxis
Stephen L. Winbery
Methodist Central Hospital Teaching Practice,
Memphis, Tennessee
Philip L. Lieberman
University of Tennessee College of Medicine,
Memphis, Tennessee
I. INTRODUCTION
The incidence of severe systemic allergic reactions is increasing. Anaphylaxis

and anaphylactoid reactions are provoked by a variety of factors, some of which
are iatrogenic. Theoretically, most of these so-called allergic reactions are pre-
dictable and preventable; however, in real life, inadvertent exposure occurs.
When severe reactions happen, epinephrine injected intramuscularly is the first-
response medication of choice. H 1-receptor antagonists are secondary and play
a minor role in acute treatment. For the prevention of anaphylactoid and anaphy-
lactic reactions, particularly iatrogenic reactions, however, H 1-antagonists play
an important role. A brief review of the provoking factors for anaphylaxis and
anaphylactoid reactions is shown in Table 1.
In its strictest sense, the term anaphylaxis refers to an immediate systemic
reaction mediated by antigen–IgE-antibody-induced degranulation of mast cells
and basophils. An allergen is a multivalent, physiological cross-link between re-
ceptor-bound IgE molecules on the surface of mast cells and basophils.
In a medical setting anaphylactoid reactions are more common than true
anaphylaxis. The term anaphylactoid reaction refers to an event that is clinically
indistinguishable from anaphylaxis, but not due to IgE–antibody–antigen-in-
287
288 Winbery and Lieberman
Table 1 Provoking Factors for Anaphylaxis and

Anaphylactoid Reactions
I. Anaphylaxis: IgE-mediated reaction

Food
peanuts and tree nuts (often concealed in food, bakery goods, Asian cooking,
chocolate) (20)
seafood (shellfish and fish)
eggs
milk
grains
food additives (carmine, tartrazine, aniline) (21)
spices (paprika, cumin, anise, mustard)
Drugs
penicillins
cephalosporins
sulfonamides
Vaccines
MMR: bovine gelatin (22)
allergen immunotherapy
Venoms
Hymenoptera
fire ants
snakes
Human proteins
insulin, corticotropin, vasopressin
serum and seminal proteins
Latex
Idiopathic
Exercise (food or inhalant allergen cotriggers common)
II. Anaphylactoid
Direct release of mediators from mast cells and basophils
Drugs
opiates
paralytic agents
vancomycin
fluorescein
dextran
chlorhexidine (23)
Hyperosmolar solutions
Idiopathic
Exercise (see also anaphylaxis)
physical temperature
weather conditions (24)
Physical factors such as cold, sunlight
Anaphylaxis 289
Table 1 Continued
Disturbances in arachidonic acid metabolism

aspirin
other nonsteroidal anti-inflammatory drugs
Immune aggregates
gamma globulin
IgG- anti-IgA
antivenoms (25)
Cytotoxic
Transfusion reactions to cellular elements
Miscellaneous
Non-antigen–antibody-mediated complement activation
radiocontrast material
some protamine reactions
dialysis membranes
Activation of contact system
dialysis membranes
plasmapheresis
radiocontrast material
Source: From Refs. 1–24.
duced mast cell and basophil degranulation. The approximate incidence of ana-
phylaxis and anaphylactoid reactions is provided in Table 2.
The same vasoactive and inflammatory mediators, including histamine and
tryptase play a role in both types of clinical events. Measurement of serum tryp-
tase levels for mast cell degranulation may differentiate IgE-mediated from non-
IgE-mediated reactions but as yet are not widely used (26–28).
II. MEDIATORS OF ANAPHYLAXIS
Anaphylaxis and many anaphylactoid reactions are initiated by the release of

preformed chemical mediators of inflammation from granules in mast cells and
basophils. Histamine is only one of many mediators involved in the pathophysiol-
ogy of anaphylaxis (Table 3). Besides preformed mediators, activated mast cells
also synthesize and release mediators including arachidonic acid metabolites and
platelet-activating factor (PAF). Slow-reacting substance of anaphylaxis (SRS-
A) is a chemotactic mixture of leukotrienes LTB 4, LTC 4, LTD 4, and LTE 4. The
reaction is amplified as these chemotactic agents in turn recruit inflammatory
cells and their mediators.
Table 2 Approximate Incidence of Anaphylaxis and Anaphylactoid Reactions to

Selected Agents
Incidence for specific agents References
Penicillin
1–5 reactions per 10,000 patient treatments Idsoe et al. (1)
Cephalosporins
3–7% of patients with a history of penicillin allergy Saxon et al. (2)
and a positive skin test
N-acetylcysteine for acetaminophen overdose
50 patients in 17 months at one pediatric hospital Bailey and McGuigan (3)
Radiocontrast media
Estimated 2667 reactions with 500 deaths to hyperos- Cohan et al. (4)
molar agents
Severe reactions in 0.04% of patients receiving lower Katayama et al. (5)
osmolar agents
Plasmapheresis and cryofiltrationa
Plasmapheresis: 2 of 21 patients with 497 procedures Siami et al. (6)
Cryofiltration: 4 of 28 patients with 680 procedures
Drugs used during perioperative period
Penicillin, analgesics, nonsteroidal anti-inflammatory van der Klauw et al. (7)
drugs (NSAIDs)
Anesthetics—1: 13,000 Laxenaire (8)
Muscle relaxants—1: 6500
Australia: frequency between 1: 5000 and 1: 25,000 Fisher and More (9)
with mortality of 3.4%
France—1:4500 cases Hatton et al. (10)
MMR
28 patients reported since 1980 Kelso et al. (11)
Insect stings
0.4–3% of population is sensitive Golden (12)
Estimated 25–50 deaths per year Barnard (13)
39 of 138 patients with a previous history upon re- van der Linden et al. (14)
challenge
1: 2000 individuals is severely allergic Maher et al. (15)
Aspirin and NSAIDs
Anaphylactoid reactions occur in as many as 0.9% of Settipane et al. (16)
patients taking aspirin
35: 51,797 patients taking NSAIDs experienced shock Strom et al. (17)
Most common agent causing anaphylaxis in a series Kemp et al. (18)
of 267 adult cases
Allergen-specific immunotherapy
1: 100,000–1: 1,000,000 doses Klimet (19)
a
All patients who had reactions were taking ACE inhibitors.
MMR, measles, mumps, rubella; NSAID, nonsteroidal anti-inflammatory; ACE, angiotensin-con-
verting enzyme.
Anaphylaxis 291
Histamine’s principal role in anaphylaxis was established many years ago

when it was found to mimic anaphylaxis when infused intravenously. The multi-
plicity of mediators offers an explanation as to why antihistamines alone do not
control anaphylactic episodes. Histamine also has a regulatory role in the subse-
quent release and production of mediators after stimulation of mast cells by anti-
gen, since antihistamines can block allergen-induced increases in histamine and
other mediators. Also, there appears to be an interdependence of PAF and hista-
mine in anaphylactic reactions (30, 31). The role of antihistamines in anaphylactic
reactions is largely prophylactic. Once mediators are released, H 1-antagonists
are relatively ineffective for treatment of acute symptoms, except as adjunctive
treatment to parenteral epinephrine for relief of pruritus and urticaria.
A. The Late Phase of the Anaphylactic Response

After resolution of an anaphylactic event, symptoms may reappear within 3–
12 hours. This late response is likely due to recruitment of additional inflamma-
tory cells by chemotactic factors released from mast cells and/or basophils in
the initial reaction. Chemotactic factors promote adhesion, diapedesis, migration,
and activation of inflammatory cells (32).
B. Amplification of the Anaphylactic Response

Amplification of the acute anaphylactic event occurs through activation and re-
cruitment of inflammatory cells, neuropeptides, the contact (kallikrein) system,
complement, clotting, and the clot lysis systems.
Neuropeptides can be detected in nasal secretions of patients with allergic
symptoms. Sensory nerves release substance P and calcitonin gene-related pep-
tide (CGRP), while vasoactive intestinal peptide is released from parasympathetic
nerve endings. Both sets of nerves are probably stimulated in a nonspecific man-
ner by inflammation associated with allergic reactions (33). Substance P increases
vascular permeability and blood flow, which are mediated in part by histamine
acting on H 1-receptors (34).
Mast cell kininogenase and basophil kallikrein can activate the contact sys-
tem (35, 36). Tryptase has kallikrein-like activity and can activate complement
and cleave fibrinogen (37).
Circumstantial evidence for activation of complement as part of anaphylac-
tic reactions comes from the relationship between levels of C3a and severity of
the reaction in eight wasp-allergic patients challenged with wasp stings (14).
Several animal studies suggest that pesticides and other environmental pol-
lutants may augment histamine release from mast cells and contribute to both
the incidence and severity of allergic reactions (38).
292
Table 3 Mediators of Anaphylaxis
Mediator Action Signs and symptoms
Histamine Smooth muscle relaxation and contraction Vasodilation, hypotension, bronchospasm,

coronary artery spasm, increased gastro-
intestinal (GI) motility, diarrhea
Increase in capillary permeability Angioedema, urticaria, flushing
Positive inotropy Increased contractility
Positive chronotropy Tachycardia
Exocrine gland secretion Increased respiratory secretions
Stimulation of sensory nerves Pruritus
Stimulation of release or synthesis of most Potentiation of reaction, late-phase reaction
other mediators
Heparin Anticoagulation Coagulopathy, could have anti-inflamma-
tory effect, possible complement inhib-
ition
Prostaglandins (D 2 and F2α) Smooth muscle relaxation and contraction, Vasodilation, flushing, hypotension, bron-
peripheral vasodilation chospasm, coronary artery spasm, in-
creased GI motility, diarrhea
Mucus secretion Rhinorrhea, increased respiratory secre-
tions
Enhanced basophil mediator release Potentiation
Leukotrienes (B 4, C 4, D 4) Chemotaxis Potentiation
Contraction of airway smooth muscle Bronchospasm
Increased vascular permeability Vasodilation, efflux of inflammatory cells
Negative inotropic effect Hypotension, myocardial depression
Goblet and mucosal cell secretion Increased respiratory secretions
Winbery and Lieberman
Platelet-activating factor (PAF) Contraction of airway smooth muscle Bronchospasm
Increased vascular permeability Hypotension, flushing, urticaria, angi-
oedema
Neutrophil aggregation Inflammation
Anaphylaxis
Platelet aggregation Platelet activation

Lymphokines (IL-3, IL-5, TNF) Adherence, degranulation, and chemotaxis Potentiation, inflammation
of inflammatory cells
Eosinophilic chemotactic factor (ECF-A) Eosinophil chemotaxis Amplification, inflammation
Neutrophilic chemotactic factor (NCF) Neutrophil chemotaxis Amplification, inflammation
Neutral proteases Proteolysis Inflammation
Tryptase May cleave C3 to activate complement Amplification
Major basic protein (MBP) Stimulates histamine release Amplification
Arachidonic acid stimulating factors Production of lipoxygenase and cyclo-oxy- Amplification
genase products
Neuropeptides, substance P, and vasoactive Peripheral nerve stimulation Itching, pain
intestinal peptide (VIP)
Vasodilation Flushing, hypotension
Possible mast cell degranulation Amplification
Tumor necrosis factor-α Decreases histamine release from mast Inhibition of inflammation (29)
cells
293
C. Modulation by Histamine
Histamine may play a role in modulating anaphylaxis, as it binds to H 2-receptors
on basophils and mast cells, leading to inhibition of further histamine release by
the cyclic adenosine 3′,5′–monophosphate (cAMP)-dependent mechanism (39–
41). H 2-receptor agonists cause a dose-dependent inhibition of antigen-induced
histamine release from sensitized guinea pig hearts. This suggests histamine feed-
back inhibition of antigenic histamine release via H 2-receptors (42). In theory,
if histamine modulates the anaphylactic response via H 2-receptors, H 2-receptor
antagonists could have a detrimental effect on the treatment of anaphylaxis. This
has been reported with the use of H 2-antagonists alone in clinical settings (43).
As discussed below, the addition of H 2-antagonists may be of benefit in the treat-
ment or prevention of anaphylactic episodes and some authors have suggested
the addition of cyclo-oxygenase inhibitors when treating anaphylaxis (44).
III. HISTAMINE AND ANAPHYLAXIS
Histamine, an endogenous imidazole compound, is synthesized, stored, and re-

leased primarily by mast cells and circulating basophils. In 1949 MacIntosh and
Paton (45) showed that basic substances such as diamines, diamides, and diqua-
nides cause histamine release. Histamine is the mediator directly responsible for
many of the symptoms early in the course of anaphylaxis and may be indirectly
responsible for many of the late responses. Most of the signs and symptoms of
anaphylaxis can be produced by histamine infusion, and many can be blocked by
H 1- and/or H 2-histamine antagonists (46). Histamine infusion produces increased
permeability of the postcapillary venules, vasodilation, decreased total peripheral
resistance, and hence decreased blood pressure, myocardial depression, and warm
extremities. Emanuel has recently reviewed the historic discovery of histamine
and histamine antagonists (47).
The considerable species variation in response to histamine has led to con-
fusion in interpretation of experimental results. For instance, guinea pigs and
rabbits are extremely sensitive to both the respiratory and cardiovascular effects
of histamine and require a much lower lethal dose than the relatively insensitive
rat. There is strong species variability in the histamine-releasing ability of the
anaphylatoxins, C3a and C5a and compound 48/80. In most animals, histamine-
induced increases in microvascular permeability are mediated by H 1-receptors,
except in the hamster where these effects are mediated by H 2-receptors (48). The
human response tends to be somewhat intermediate, and sensitivity varies from
person to person and with different physiological milieux.
Modestly increased serum histamine levels (less than 1 ng/mL) are associ-
ated with metallic taste, headache, and nasal congestion. Higher levels cause
Anaphylaxis 295
generalized skin reactions, gastrointestinal stimulation, flushing, tachycardia, car-

diac arrhythmias, and hypotension. Life-threatening hypotension, ventricular fi-
brillation, bronchospasm, and cardiopulmonary arrest generally result from hista-
mine levels above 12 ng/mL (49).
It has been suggested that the clinical manifestations of histamine release
during anesthesia are different from those of classic systemic anaphylaxis because
of the effects of anesthetic agents and other drugs used perioperatively. Elevated
levels of histamine may produce untoward effects in the perioperative patient
even though the classic symptoms of anaphylaxis (urticaria, angioedema, bron-
chospasm, and hypotension) are not necessarily present. In patients undergoing
general anesthesia, elevated histamine levels, bradycardia, arrhythmias, hyper-
tension, and myocardial ischemia should be considered as evidence of an anaphy-
lactoid reaction (50, 51). Elevated levels of plasma histamine are associated with
arrhythmias, increased thrombosis, stress ulceration, increased intrapulmonary
shunt, death from shock, and adult respiratory distress syndrome. Plasma hista-
mine concentrations of 0.2–1.0 ng/mL must be accepted as elevated, and may
be clinically relevant despite the absence of classic signs and symptoms of ana-
phylaxis during anesthesia (52).
A. Histamine Receptors
Histamine stimulates H 1-, H 2-, and H 3-receptors to produce its characteristic re-
sponses (Table 4). Many of the actions of histamine are local and tissue-depen-
dent. H 1-receptor stimulation results in the breakdown of the second-messenger
inositol phosphate and calcium mobilization, and H 2-mediated responses are
mostly due to activation of adenylate cyclase; however, there is considerable
‘‘cross talk’’ between second messenger systems (54). The mechanisms responsi-
ble for many actions of histamine such as vascular smooth muscle dilation are not
understood and may involve release of epithelial factors. Histamine can stimulate
endothelial cells to produce nitric oxide, a smooth muscle relaxant factor (55,
56). In guinea pig lung tissue, histamine binds to H 1-receptors to produce a phos-
pholipase-C-dependent calcium mobilization that stimulates the conversion of
L-arginine to nitric oxide. Nitric oxide activates guanylate cyclase, leading to
production of 3′,5′-cyclic guanosine monophosphate (cGMP) (57).
The H 3-receptor is identified pharmacologically by its antagonist, thiopera-
mide. These receptors have been located on presynaptic nerve endings both per-
ipherally and in the central nervous system. H 3-receptors control acetylcholine
release at the level of the myenteric plexus in the guinea pig intestine (58), modify
peripheral neuropeptide release, modulate airway reactivity (59), and control his-
tamine synthesis in brain and lung tissue. H 3-receptors are on presynaptic termi-
nals of sympathetic effector nerves that innervate heart and systemic vasculature.
The H 3-receptor modulates norepinephrine release from systemic nerves and, in a
Table 4 Actions of Histamine Related to Anaphylaxis
H 1-receptor-mediated actions H 2-receptor-mediated actions

Elevation of cyclic GMP Increased intracellular cyclic AMP
Smooth muscle contraction Increased gastric acid and pepsin secretion
Increased endothelial permeability Decreased fibrillation threshold of cardiac
Stimulation of nerve endings muscle
Pruritus Positive inotropy
Vagal irritant receptors (cough and Positive chronotropy
bronchospasm) Increased amount of mucus secretion
Increased viscosity of mucus
Vasodilation H 1- and H 2-receptor-mediated actions
Direct
Vasodilation and flushing
Production of endothelium-derived
Increased vascular permeability
relaxing factors
Hypotension
Release of neuropeptides from nerve
Eosinophil chemotaxis
endings
Epinephrine secretion from adrenal
H 3-receptor-mediated actions
medulla
Increased rate of depolarization of the Modulation of peripheral and bronchial
sinoatrial node neurotransmission; possible
Slowed rate of atrioventricular conduction bronchospasm
Presynaptic terminals of sympathetic
effector nerves in heart and systemic
vasculature (53)
canine model of anaphylaxis, an H 3-receptor antagonist attenuated cardiovascular

collapse (53).
B. Anaphylaxis-Related Actions of Histamine

1. Vascular System
Histamine exerts a complex action on the vascular system. Its predominant action
is a net vasodilation from smooth muscle relaxation in arterioles, precapillary
sphincters, and venules, leading to a decrease in total peripheral resistance and
a fall in blood pressure. Intravenous histamine infusion produces a marked de-
crease in diastolic blood pressure and a widening of pulse pressure. Histamine
contracts postcapillary venules, which exposes permeable capillary membranes
to hydrostatic forces leading to edema. The initial flush from intradermally ad-
ministered histamine is due to local cutaneous vasodilation, while wheal forma-
tion is due to local edema. The vascular effects of histamine are mediated through
both H 1- and H 2-receptors, but predominantly through H 1-receptors.
Anaphylaxis 297
2. Nerves
Histamine directly stimulates nerve endings to produce pruritus. Local inflamma-
tion nonspecifically stimulates nerve endings to release neurotransmitters and
neuropeptides that can perpetuate and potentiate the actions of histamine and
other inflammatory mediators.
3. Heart and Coronary Arteries

Mast cells are present in cardiac muscle and coronary arteries. Histamine acts
on the heart to increase inotropy and chronotropy, probably through increasing
calcium influx in cardiac myocytes. H 2-receptors directly mediate most of the
increase in contractile force and in heart rate. H 1-receptors appear to mediate
effects on the conducting system and produce coronary artery vasospasm in pa-
tients with variant angina. H 1-receptor stimulation results in negative chrono-
tropic effects secondary to atrioventricular conduction delay. In experimental
animal models, histamine acting on H 1-receptors slows atrioventricular nodal
conduction and decreases fibrillation threshold. Dysrhythmia may result from a
combination of effects on conduction and ischemia from coronary artery vaso-
spasm (60). Anaphylactic reactions of isolated perfused guinea pig hearts are
characterized by a short initial cardiac stimulation, followed by precipitous con-
striction of coronary arteries and long-lasting impaired myocardial function. Va-
soactive anaphylactic mediators other than histamine are also involved in cardiac
malfunction occurring during the later phase of systemic and cardiac anaphylaxis.
H 1-receptor antagonist pretreatment generally prevents myocardial depression
and cardiac shock in experimental models of anaphylaxis. It has been thought
that H 2-receptor-mediated effects are of minor importance in cardiovascular man-
ifestations of anaphylaxis (61); however, histamine acting on H 2-receptors causes
pronounced stimulation of spontaneously active cardiac Purkinje fibers in sheep
hearts (62). In theory, H 2-antagonists could have detrimental effects by potentiat-
ing coronary artery vasoconstriction (63) or by reversing H 2-receptor-mediated
inhibition of cardiac histamine release (42). Thus far, investigators have not
shown detrimental effects of H 2-antagonists on cardiovascular function (61).
A prominent feature of antigen-induced mediator release in isolated rat and
guinea pig hearts is coronary artery vasoconstriction and ischemic myocardial
damage (63). In other experimental models histamine has a biphasic response
on coronary arteries. Vasodilation is produced in part by H 2-receptor-stimulated
synthesis of an endothelium-derived relaxing factor that has been postulated to be
nitric oxide. An inhibitor of nitric oxide synthesis, N-methyl-L-arginine, causes
pronounced coronary constriction in response to histamine. This suggests that
dysfunction in the formation of nitric oxide could precipitate histamine-induced
coronary artery vasospasm and myocardial infarction (64). Several studies have
demonstrated that H 1-receptor stimulation of epicardial coronaries causes con-
striction, whereas H 2-receptor activation induces dilation. In patients with normal

coronary arteries, direct coronary artery infusion of histamine acts via H 1-recep-
tors located in the endothelium to cause coronary artery dilation and decreased
coronary artery vascular resistance. H 2-receptors in vascular smooth muscle also
mediate coronary vasodilation, whereas H 1-receptors in vascular smooth muscle
induce vasoconstriction (65). Thus, the action of histamine on coronary arteries
is complex and there is considerable species variation.
4. Respiratory System
Histamine acts via H 1-receptors in the lower airways to constrict bronchial
smooth muscle, dilate or constrict vascular smooth muscle, cause microvascular
leak, and activate sensory nerves. In healthy individuals, histamine does not cause
significant bronchoconstriction, but patients with asthma and other lower airway
disorders are hypersensitive to its bronchoconstricting effects. H 1-receptors also
mediate an increase in airway fluid and electrolyte secretions and increased mu-
cous viscosity. In awake sheep, bronchial vasodilation is mediated primarily by
histamine acting on H 1-receptors (66). In experimental models, H 2-receptor stim-
ulation may actually relax constricted bronchial smooth muscle. This is probably
not clinically significant, since patients with asthma tolerate H 2-antagonists well
(67). Although most reports indicate that cimetidine and ranitidine do not cause
or potentiate bronchoconstriction in normal and asthmatic patients, in one study,
bronchoconstriction increased in 4 of 24 asthmatic patients treated with cimeti-
dine. In addition, isolated basophils from H 2-antagonist-treated asthmatic patients
showed enhanced histamine release (68). H 3-receptors in the lungs modulate chol-
inergic neurotransmission, neuropeptide release, and bronchoconstriction (59, 69).
5. Gastrointestinal System
Histamine plays a physiological role in stimulating gastric acid secretion through
H 2-receptors, and H 2-antagonists have been widely used to decrease gastric acid
secretion. Histamine also produces gastrointestinal smooth muscle contraction
and relaxation. These responses are caused by direct actions on smooth muscle
H 1- and H 2-receptors and indirect actions leading to release of several active
substances from the gut’s own intrinsic nervous system.
6. Measurement of Histamine Levels in the

Diagnosis of Anaphylaxis
Anaphylaxis is largely a clinical diagnosis based on clinical signs and symptoms
and history of exposure to a potential provoking agent. Atypical presentations
may be more common than previously thought and it may not always be possible
to identify the offending agent (18). Improved techniques allow histamine levels
Anaphylaxis 299
to be measured more accurately and quickly than ever before. Histamine begins
to rise in 5–10 min and may remain elevated for up to 60 min. Urine histamine
and histamine metabolites may stay elevated longer and are more stable (70).
Analysis of the histamine metabolite methylhistamine in urine can be valuable
in diagnosing anaphylaxis (71), especially when combined with the measurement
of tryptase concentrations (26).
IV. ANTIHISTAMINES
H 1-receptor antagonists were introduced into therapeutic use 60 years ago. Bind-
ing of the H 1-antagonist to the H 1-receptor does not produce a response but,
rather, blocks the actions of endogenous histamine at H 1-receptors. For the most
part, H 1-antagonist binding is competitive and reversible, with the exceptions of
astemizole, terfenadine, and loratadine. Antihistamines may be ranked on the
basis of potency; however, equal efficacy can usually be obtained by giving a
relatively larger dose of the less potent drug. Potency may be relevant when
considering the limitations of the effects of these agents beyond histamine recep-
tor blockade (72).
A. Second-Generation H 1-Antihistamines
The newer H 1-antagonists such as cetirizine, fexofenadine, and loratadine are
highly selective for the H 1-receptor and are generally well-tolerated at doses that
produce high levels of antihistaminergic activity. At the present time, none of
the second-generation H 1-antagonists is available for injection, but in one study
several of the agents were given intravenously to squirrel monkeys (73). These
newer agents have not yet been widely used for the treatment or prevention of
anaphylaxis in humans; however, like their predecessors, they prevent anaphy-
lactic death in experimental animal models. The improved selectivity and addi-
tional antiallergic properties of these drugs may be of benefit in the treatment of
anaphylaxis (73–76). Two of the new H 1-antagonists, terfenadine and astemizole,
are no longer used in most countries due to potential cardiac toxicity (72) (see
Chap. 12).
B. Nonhistamine Receptor Antiallergic

Properties of Antihistamines
Many of the first-generation antihistamines have antimuscarinic, antidopaminer-
gic, anti-alpha-adrenergic, and antiserotoninergic properties. The contribution of
these properties to the treatment of anaphylaxis is unknown and possibly of little
consequence. The H 1-antagonists not only block histamine interaction with the
H 1-receptor but also inhibit cell mediator release (77, 78), basophil migration
(79), and eosinophil recruitment (80). In therapeutic concentrations, H 1-antago-
nists such as chlorpheniramine, mepyramine, ketotifen, promethazine, diphenhy-
dramine, cyclizine, and oxatomide can inhibit IgE-induced histamine release (81).
At supratherapeutic concentrations, the H 1-antagonists can release histamine by
an antigen-independent direct cytotoxic effect on mast cells. The antiallergic ef-
fect to inhibit release of histamine from mast cells and basophils has been shown
with the second-generation H 1-antagonists as well, including terfenadine, loratad-
ine, cetirizine, azatadine, azelastine, ketotifen, and oxatomide (82–84). Their an-
tiallergic effects vary depending on the source of the mast cells and the stimulus
used (compound 48/80, IgE-antigen, substance P, Con A, or a calcium iono-
phore). The exact mechanism of inhibiting histamine release is unknown, but
may be due in part to the lipophilic and cationic nature of the H 1-antagonists.
Many H 1-antagonists are lipophilic, cationic drugs and may dissolve into the cell
membrane and produce stabilization to sodium ion and calcium ion flux; however,
there is imprecise correlation between lipophilicity and inhibition of histamine
release (82).
Several other antiallergic effects have been observed with the second-gen-
eration antihistamines including inhibition of allergen-induced eosinophil, baso-
phil, and neutrophil migration and inhibition of PAF-induced eosinophil accumu-
lation in the skin. There is a definite need for characterization of the antiallergic
properties of H 1-antagonists using double-blind, placebo-controlled human stud-
ies with strict criteria for measurement of plasma concentrations, standardization
of mediator assays, and reproducibility. The role of antiallergic effects of antihis-
tamines in the treatment of anaphylaxis, if any, has not been established and
further clinical investigation is warranted. The effects are reviewed in Chap-
ter 4.
V. ANTIHISTAMINES IN ANAPHYLAXIS
A. The Adjunctive Role of Antihistamines in Treatment
of Acute Anaphylaxis
It is important to emphasize early diagnosis of anaphylaxis along with prompt
treatment with epinephrine and volume expansion, realizing that antihistamines
are an adjunctive treatment (85). Histamine is only one of a number of mediators
that contribute to the pathophysiology of anaphylaxis, and H 1-antagonists are not
effective as single agents for the treatment of anaphylaxis.
Before the discovery of the H 1- and H 2-receptors, histamine was thought
to be the mediator of anaphylaxis because agents such as diphenhydramine
blocked or reversed histamine-induced hypotension and bronchospasm; however,
H 1-antihistamines alone were clinically ineffective in reversing all the symptoms
Anaphylaxis 301
of anaphylaxis and were of little benefit in severe anaphylaxis. We now know

that although histamine mediates anaphylactic signs and symptoms through both
H 1- and H 2-receptors, there are many other mediators of the anaphylactic re-
sponse. Antihistamines are not the major therapy for the anaphylactic event but
are helpful when given in addition to epinephrine as adjunctive treatment of pruri-
tus and urticaria. Intravenous or intramuscular diphenhydramine, 1–2 mg/kg, up
to 75 mg, should be given early and repeated every 4–6 h as long as anaphylactic
symptoms persist (86). Ranitidine, up to 50 mg, or cimetidine 200–300 mg ad-
ministered intramuscularly or intravenously, has been used adjunctively. Orally
administered H 2-antagonists may be of benefit in less serious anaphylactic reac-
tions. An important principle regarding the activity of H 1-antihistamines is that
their effect is delayed compared to peak plasma levels and lasts longer than ex-
pected from the elimination half-life of these drugs. For example, with hydroxy-
zine, maximal suppression of wheal and flare does not occur until 7 h after peak
serum concentrations have been reached (87). This may indicate that the peak
therapeutic effect of these agents is also delayed after a single dose. Another
disadvantage of antihistamine therapy in acute anaphylaxis is that H 1-antagonists
cannot reverse the consequences of H 1-receptor activation after the fact. They
are most effective if they block receptors before histamine binds. This offers a
tenable explanation as to why these agents are more effective as prophylactic
drugs for anaphylaxis than for treating the acute event.
B. Potential Deleterious Effects of H 1- and H 2-Antihistamines

in Acute Anaphylaxis
When antihistamines are used in the treatment of acute anaphylaxis, H 1-receptor
blockade may produce atrioventricular conduction delay, coronary artery vaso-
constriction, and initial hypotension (with intravenous administration). H 2-recep-
tor blockade may produce negative feedback inhibition of subsequent histamine
release. This emphasizes once again that antihistamines are not primary medica-
tions for the treatment of acute anaphylaxis. In general, the benefit of the addition
of antihistamines in acute anaphylaxis probably outweighs their potential risks.
The relative degree of these deleterious effects with newer antihistamines is not
yet known (88).
C. Prevention of Anaphylaxis with H 1- and H 2-Antihistamines

Pretreatment with antihistamines can prevent or attenuate anaphylaxis in experi-
mental models, whether antigen, exogenous histamine, or compound 48/80 trig-
gers the reaction. Pretreatment with either first- or second-generation antihista-
mines can prevent anaphylactic death and pulmonary, cardiac, hemodynamic,
and cutaneous manifestations of anaphylaxis in experimental animals (89, 90).
In patients, pretreatment with H 1-antagonists prevents bronchoconstriction to his-

tamine challenge, nonisotonic aerosols, and exercise (91–93), and also reduces
microvascular leak in the skin wheal response to histamine. Cetirizine has been
reported to protect against late-phase reactions to allergen provocation tests (94).
In a crossover trial with six healthy adult volunteers, 8 mg dimethindene and 400
mg cimetidine administered intravenously reversed hypotension and tachycardia
caused by intravenous histamine infusion (95). Pretreatment with antihistamines
has been used clinically to prevent anaphylaxis and anaphylactoid reactions in
patients at risk for reactions to radiocontrast media, volume expanders, plasma
exchange, fluorescein, other drugs, and during anesthesia. Antihistamines have
failed to prevent reactions to antivenoms for patients with snake bites (25).
1. Reactions to Radiocontrast Materials

Radiocontrast materials (RCM) have been used since 1929. Reactions to RCM
are heterogeneous and involve nonallergic mast cell degranulation and histamine
release as well as complement activation. In pigs, RCM cause release of histamine
from cardiac mast cells (96); however, studies with canine mastocytoma cells
suggest that direct release of histamine from mast cells does not completely ex-
plain the pathogenesis of RCM reactions. Although antihistamines are not the
primary drugs of choice for treatment of anaphylaxis, they play an important role
in the prevention of anaphylactoid reactions to RCM (97) in patients who have
experienced a previous reaction.
Zweiman and associates were the first to use an antihistamine for preven-
tion of RCM reactions in patients with a history of previous reactions. Diphenhy-
dramine (50 mg) was given intramuscularly prior to the administration of RCM.
There was a significant reduction in recurrence rates, which in the untreated previ-
ous reactors, ranged from 16% to a high of 44% (98–100). Since that time, the
pretreatment protocol has been refined (Table 5). Patterson and associates showed
that the addition of prednisone enhanced the clinical efficacy of the H 1-antagonist
(101)
Ephedrine (25 mg), added empirically to prevent hypotension with anaphy-
laxis, produced a further reduction in reaction rates (102). Ephedrine should not
be used in patients with ischemic heart disease, moderate-to-severe congestive
heart failure, and those being treated with monoamine oxidase inhibitors in whom
sympathomimetics are contraindicated.
H 2-antagonists have also been studied in this setting. Greenberger and asso-
ciates found that the addition of cimetidine reduced the efficacy of the pretreat-
ment protocol (102). In another study, patients undergoing intravenous urography
were stratified into four treatment groups. Group 1 received intravenous predniso-
lone alone; group 2 received clemastine; group 3 received clemastine and cimeti-
dine; and group 4 received only saline. There was a significant reduction in ana-
Anaphylaxis 303
Table 5 Prophylactic Regimen for Patients with History

of Reaction to RCM
Prednisone, 50 mg by mouth 13 h, 7 h, and 1 h before

Diphenhydramine, 50 mg intramuscularly, 1 h before
Ephedrine, 25 mg by mouth, 1 h before a
Ranitidine, 150 mg or cimetidine, 300 mg by mouth, 3 h
before b
a
Omit if patient has contraindication to sympathomimetics, includ-
ing ischemic heart disease, angina, and cardiac arrhythmias.
b
Optional (see text).
RCM, radiocontrast materials.
Source: Ref. 100.
phylactic signs and symptoms for patients in group 3 compared with the other
groups: the combination of an H 1- and H 2-antagonist was superior to an H 1-
antagonist alone. Although not all anaphylactic reactions were suppressed, there
were no severe reactions (103). In a third study involving 100 patients with previ-
ous reactions to RCM, the addition of an H 2-antagonist did not alter the results
of prophylaxis. Combined glucocorticoid–antihistamine treatment prevented the
majority of patients from having reactions and none had severe reactions (104).
At best, the results are inconclusive as to whether an H 2-antagonist is an effective
adjunctive agent to diphenydramine, prednisone, and ephedrine (105), therefore,
the use of an H 2-antagonist should be left to the discretion of the physician manag-
ing the patient.
The protocol for prevention of reactions to RCM in patients at risk should
be followed regardless of the route of administration of the RCM or the procedure
being performed. Reactions have been reported after hysterosalpingograms, my-
elograms, and retrograde pyelograms (106). The introduction of nonionic and
low-osmolar RCM has decreased the frequency, but not the severity, of adverse
events (107).
The risk of reactions to RCM in patients with previous reactions decreases
to 1% with the use of the prophylactic regimen plus the use of a low-osmolar
agent (105). The antihistamine/prednisone prophylactic regimen has been so suc-
cessful that it has been adopted for prevention of other anaphylactic reactions in
patients at risk in the following settings: plasma exchanges (108), general anes-
thesia (109), fluorescein administration (110). It has also been used in patients
with cold urticaria who must undergo bypass surgery (111). Based on studies in
ragweed-sensitized dogs, there has been some suggestion that the addition of
cyclo-oxygenase inhibitors to the RCM prophylactic regimen may be useful (44).
This prophylactic regimen has been demonstrated only to prevent anaphy-
laxis and anaphylactoid episodes. In two reported instances, it failed to prevent
recurrence of adult respiratory distress syndrome and noncardiac pulmonary

edema associated with RCM (112, 113).
2. Volume Expanders
A combination of H 1- and H 2-antagonists with a corticosteroid effectively pre-
vented reactions to urea-linked gelatin solutions used as volume expanders in
two studies. In one study, volunteers received intravenous infusions of the plasma
expander. Fifteen of 50 had anaphylactic symptoms compared to 0 of 50 in the
pretreated group. In the other study, 27 of 150 orthopedic patients had significant
reactions when pretreated with only intravenous saline. When pretreated with
dimethindene and cimetidine, 4 of 150 patients had reactions; in those pretreated
with chlorpheniramine plus cimetidine, 9 of 150 patients had reactions (114).
3. Plasma Exchange
Patients undergoing plasma exchange may experience anaphylactic reactions due
to multiple causes. Pretreatment using a modification of the program established
for the prevention of RCM reactions has been successful in preventing repeat
reactions (108). These reactions seem much more likely when patients are treated
concurrently with angiotensin-converting enzyme (ACE) inhibitors (6).
4. Fluorescein
Fluorescein is commonly employed as an intravenous microvascular contrast
agent by ophthalmologists and optometrists. In patients with previous reactions
to fluorescein, the incidence of reaction with subsequent exposure can be nearly
50% (115). A modification of the treatment regimen for RCM reactions has been
used to prevent recurrent reactions. The modification includes a 3-day regimen
of oral prednisone followed by 50 mg diphenhydramine with 400 mg cimetidine
1 h before the test (110).
5. Idiopathic Anaphylaxis
Even after exhaustive searches for avoidable provoking factors for anaphylaxis,
some triggers remain undetected. Patients with mild episodes of idiopathic ana-
phylaxis that occur fewer than three or four times per year probably do not need
preventive therapy. For moderate or severe episodes occurring more frequently,
the combination of an H 1- and H 2-antagonist should be considered on a daily
basis. The second-generation, nonsedating H 1-antagonists should be used in pref-
erence to potentially sedating drugs. When patients are refractory to antihistamine
therapy, glucocorticoids, albuterol, cromolyn, and ephedrine may be empirically
added (116). Adult and pediatric patients with idiopathic anaphylaxis have similar
clinical profiles and should be treated in a similar way (117).
Anaphylaxis 305
6. Anaphylaxis to Latex
Exposure to latex is widespread. Sources include condoms, balloons, gloves,
bladder catheterization with rubber tubing, intravenous injection ports and tubing,
ventilator tubing, electrocardiogram pads, and latex-cuffed enema tubes. In pa-
tients with latex allergy, perioperative prophylaxis with corticosteroids, H 1- and
H 2-antagonists, and ephedrine has been recommended; however, such a prophy-
lactic regimen, while useful, has not been as successful in preventing reactions
to latex as it is in preventing reactions to RCM in at-risk individuals, perhaps
due to differences in the inducing or causative mechanisms between RCM and
latex (118).
7. Exercise-Induced Anaphylaxis
Exercise-induced anaphylaxis was first described by Sheffer and Austen in 1980
(119). The mechanism responsible for anaphylaxis appears to be non-IgE-medi-
ated mast cell activation. Successful prophylaxis with antihistamine therapy is
not always achieved (120, 121). Of almost 300 patients, 56% reported improve-
ment with H 1-antagonist prophylaxis compared to 44% who improved by
avoiding extreme temperatures and 37% who improved by avoiding certain food
co-triggers (24).
8. Drug- and Anesthesia-Related Anaphylaxis

Drugs used perioperatively and for anesthesia are frequently implicated as causes
of anaphylaxis. Even in asymptomatic patients undergoing surgery and general
anesthesia, there is evidence of mediator release from mast cells (122). Histamine
is liberated from mast cells in the lung vasculature and the heart during pediatric
cardiopulmonary bypass (123). Basophil and mast cell release of histamine
appears to be the mechanism underlying adverse reactions to many anesthetic
agents. Propanidid, althesin, chemaphor, and opiates are examples of periopera-
tive substances that directly release histamine (41). Muscle relaxants, especially
atracurium, can release histamine from human lung and skin mast cells, but the
effect varies considerably from patient to patient (124, 125). With the exception
of buprenorphine, the majority of these drugs stimulate release of preformed me-
diators but do not generally stimulate synthesis of late mediators. In a study of
11 patients with previous reactions to anesthesia, patients were premedicated with
prednisone and diphenhydramine. In addition, in seven of these patients, sub-
stances to which they had positive skin tests were avoided. Only 1 of the 11
patients had any repeat reaction and none had anaphylaxis (109). Other studies
have demonstrated the clinical efficacy of antihistamine prophylaxis in periopera-
tive patients (126, 127). In general, H 1-antagonists can decrease the occurrence
and severity of anaphylactoid reactions to anesthesia.
After consideration of the evidence from patients undergoing anesthesia,

especially the fact that histamine may be elevated in the majority of asymptomatic
patients, it is tempting to recommend universal prophylactic antihistamine ther-
apy (41, 50, 128). Universal prophylaxis with H 1- and H 2-antagonists in the peri-
operative patient is controversial and many urge restraint. Endorsement of such
a policy should come only after large multicenter trials show unequivocal benefit.
For now, prophylactic regimens are indicated for those individuals at risk for
adverse reactions to procedures that cannot be avoided. Examples of patients at
risk may include those with previous reactions, atopy, multiple drug allergies,
previous bronchospasm, previous anaphylaxis (any cause), and certain tumors
(51).
9. Morphine
Morphine is used for preoperative analgesia and induction of anesthesia. Philbin
and associates investigated the relationship between plasma histamine levels, sys-
temic vascular resistance, and diastolic blood pressure in patients given 1 mg/
kg intravenous morphine before cardiac bypass surgery. In patients undergoing
bypass, intravenous morphine causes significant histamine release. Four groups
of 10 patients each were studied. Group 1 received placebo; group 2 received
cimetidine; group 3 received diphenhydramine; group 4 received both the H 1-
and H 2-antagonist. Patients in both groups 3 and 4 had significant decrease in
morphine-related reactions, but the combination therapy was more effective than
treatment with the H 1-antagonist alone. Thus, pretreatment with antihistamines
can attenuate the hemodynamic complications of intravenous morphine adminis-
tered to patients undergoing cardiac bypass (129).
In a postmortem study of heroin-related deaths, 32% of the decedents had
elevated mast cell tryptase levels. This suggests that a significant proportion of
heroin-related deaths are, at least in part, due to anaphylactoid reactions (130).
10. Vancomycin
Intravenous injection with vancomycin or polymixin causes non-immune dose-
dependent degranulation of mast cells and basophils leading to anaphylactoid
reactions. The reaction to vancomycin can be prevented by pretreatment with an
antihistamine (131).
11. Protamine
Protamine is being used increasingly in cardiac catheterization, cardiothoracic
and vascular surgical procedures, dialysis, and leukopheresis. It is also found in
some insulin preparations. Reactions to protamine can be IgE-mediated (132).
The incidence of reaction to protamine during cardiac bypass can be as high as
Anaphylaxis 307
10.7% (133). Patients with known sensitivity to protamine who must undergo
procedures in which hexadimethrine bromide cannot be substituted should be
pretreated with the prophylactic regimen used for reactions to RCM.
12. Chymopapain
Chymopapain, used topically for enzymatic debridement of surface lesions, is
known to induce anaphylactoid reactions. Antihistamines have been shown to be
effective in the prophylaxis of chymopapain-induced anaphylaxis. In a retrospec-
tive review of an uncontrolled trial, the combination of an H 1- and an H 2-antago-
nist was more effective than an H 1-antagonist alone for prevention of reaction
to chymopapain (134).
13. N-Acetylcysteine
N-acetylcysteine (NAC) is an antidote for acetaminophen overdose and in much
of the world, although not in the United States, is available for intravenous admin-
istration. In one study there were 50 cases of anaphylactoid reactions of varying
severity to NAC over 17 months in a pediatric hospital. The incidence of anaphy-
lactoid reactions to NAC has prompted clinicians to review the indications for
its use. Reactions to NAC can probably be prevented with H 1-antagonists (3).
D. The Case for Combination H 1- and

H 2-Antihistamine Therapy
In 1966 Ash and Schild (135) noticed that the classic antihistamines did not block
all of the actions of histamine, especially gastric acid secretion. This was followed
by the discovery of the H 2-histamine receptor subtype by Black et al. in 1972
(136). The combination of an H1- and H 2-receptor antagonist is generally needed
to reduce histamine-induced peripheral vasodilation, hypotension, and mucus se-
cretion maximally. Combinations of H 1- and H 2-antagonists are more effective
in preventing the decrease in diastolic blood pressure and the widening of pulse
pressure by histamine.
1. Experimental Evidence
In pentobarbitone-anesthetized rats, compound 48/80 produces an anaphylactoid
response that includes decreased mean arterial blood pressure, decreased left ven-
tricular pressure, and increased frequency of ventricular tachycardia and fibrilla-
tion. Either cimetidine or diphenhydramine reduced the frequency of ventricular
tachycardia and fibrillation, but only the combination of the H 1- and H 2-antago-
nists completely inhibited hypotension and decreased left ventricular pressure
and ventricular arrhythmia. (137). Numerous studies have shown that H 1- and
H 2-receptor antagonists produce a greater inhibition of histamine-induced cardio-

vascular reactions (129, 138). In a controlled trial using dog and piglet models
of anaphylaxis, the combination of the H 1- and H 2-antagonists dimethindene and
cimetidine was more effective than dimethindene alone and in combination with
famotidine or ranitidine (139, 140).
In a crossover study with six human volunteers, dimethindene and cimeti-
dine inhibited histamine-induced decrements in mean arterial pressure and cuta-
neous reactions (95). After administration of 1 mg/kg morphine intravenously
before bypass surgery, there is increased serum histamine, decreased diastolic
blood pressure, and decreased vascular resistance. Cimetidine plus diphenhydra-
mine was more effective than either antagonist alone in preventing these hemody-
namic effects during reactions to morphine (129). In a dorsal hand vein compli-
ance technique in human subjects, the venodilatory response to histamine is
mediated by both H 1- and H 2-receptor subtypes. This study provides compelling
evidence that combined H 1- and H 2-antagonist therapy may prevent hypotension
during anaphylaxis more effectively than an H 1-antagonist alone (141, 142).
The addition of an H 2-antagonist reversed symptoms in several patients
who were unresponsive to H 1-antagonists and/or ephedrine (143–145). The com-
bination of H 1- and H 2-antagonists is more effective than either alone for the
prevention of anaphylactic reactions to chymopapain, perioperative agents,
plasma expanders, and morphine (105). The combination of H 1- and H 2-antago-
nists for the prophylaxis of anaphylaxis may have additional effects other than
blocking the action of histamine at its receptors. The combination may exert a
mast cell–stabilizing effect or suppress immune cell function (41, 146). The use
of H 2-antagonists alone in patients who experience anaphylactoid reactions may
be associated with an increased risk of cardiac arrhythmia (43).
VI. SUMMARY
Anaphylaxis and anaphylactoid reactions are potentially fatal. These disorders are
sometimes iatrogenic, and increase with increased exposure to drugs, synthetic
substances, and medical procedures. Non-IgE-mediated anaphylactoid reactions
are common in medical settings and are clinically indistinguishable from anaphy-
laxis. These reactions may be unrecognized if a rigid classic definition of anaphy-
laxis is used.
Histamine is a primary mediator of anaphylaxis and signs and symptoms
of anaphylaxis can be reproduced by histamine infusion. Histamine triggers a
cascade of inflammatory mediators and modulates its own release.
H 1-antihistamines are adjunctive treatment therapy for acute anaphylaxis
and anaphylactoid reactions, in which many mediators of inflammation are in-
Anaphylaxis 309
volved. Compared with epinephrine, the first-response medication of choice, anti-

histamines have a slow onset of action, and they cannot block events that occur
subsequent to histamine binding to its receptors.
Antihistamines are an important component of regimens for the prevention
of anaphylaxis and anaphylactoid reactions in patients at risk, and may eventually
have more widespread application in the perioperative setting. In some instances,
such as with exercise-induced anaphylaxis and reactions to latex in sensitized
individuals, prophylaxis regimens are not always effective.
H 2-antagonists are not detrimental in the therapy of anaphylaxis and many
studies show a favorable outcome when combining H 1- and H 2-antagonist therapy
for prophylaxis. They should be added to therapy at the discretion of the treating
physician.
Because of decreased antimuscarinic and central nervous system side ef-
fects, the newer antihistamines can be given in high doses, allowing more com-
plete blockade of histamine receptors. These agents should lead to a reevaluation
of the usefulness of antihistamines in both the treatment of acute anaphylaxis
and in prophylactic regimens. The unavailability of parenterally administered
second-generation H 1-antagonists limits their usefulness in acute anaphylaxis and
perioperative prophylaxis.
REFERENCES
1. Idsoe O, Guthe T, Wilcox RR, de Weck AL. Nature and extent of penicillin side-
reactions with particular reference to fatalities from anaphylactic shock. Bull World
Health Organ 1968; 38:159–188.
2. Saxon A, Beall GN, Rohr AS, Adelman DC. Immediate hypersensitivity reactions
to beta-lactam antibiotics. Ann Intern Med 1987; 107:204–215.
3. Bailey B, McGuigan MA. Management of anaphylactoid reactions to intravenous
N-acetylcysteine. Ann Emerg Med 1998; 31:710–715.
4. Cohan RH, Dunnick NR, Bashore TM. Treatment of reactions to radiographic con-
trast material. AJR 1988; 151:263–270.
5. Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez P, Matsuura K. Adverse
reactions to ionic and nonionic contrast media. A report from the Japanese Commit-
tee on the Safety of Contrast Media. Radiology 1990; 175:621–628.
6. Siami GA, Siami FS, Morrow JD, Stone WJ. Cryofiltration apheresis and plasma
fractionation causing anaphylactoid reactions in patients receiving angiotensin con-
verting enzyme inhibitors. Ther Apher 1997; 1:325–329.
7. van der Klauw MM, Stricker BHCH, Herings RMC, Cost WS, Valkenburg HA,
Wilson JH. A population based case-cohort study of drug-induced anaphylaxis. Br
8. Laxenaire MC. [Epidemiology of anesthetic anaphylactoid reactions. Fourth
multicenter survey (July 1994–December 1996)]. Ann Fr Anesth Reanim 1999;

18:796–809.
9. Fisher MM, More DG. The epidemiology and clinical features of anaphylactic reac-
tions in anaesthesia. Anaesth Intensive Care 1981; 9:226–234.
10. Hatton F, Tiret L, Maujol L, N’Doye P, Vourc’h G, Desmonts JM, Otteni JC,
Scherpereel P. Enquête épidémiologique sur les anesthésies. Premiers resultats.
Ann Fr Anesth Reanim 1983; 2:331–386.
11. Kelso JM, Jones RT, Yunginger JW. Anaphylaxis to measles, mumps, and rubella
vaccine mediated by IgE to gelatin. J Allergy Clin Immunol 1993; 91:867–872.
12. Golden DBK. Epidemiology of allergy to insect venoms and stings. Allergy Proc
1989; 10:103–107.
13. Barnard JH. Studies of 400 Hymenoptera sting deaths in the United States. J Allergy
Clin Immunol 1973; 52:259–264.
14. van der Linden PWG, Hack CE, Poortman J, Vivie-kipp YC, Struyvenberg A, van
der Zwan JK. Insect-sting challenge in 138 patients: Relation between clinical se-
verity of anaphylaxis and mast cell activation. J Allergy Clin Immunol 1992; 90:
110–118.
15. Maher L, Reisman R, Yunginger J. ’Tis the season for stinging insect allergies.
Patient Care 1998; June:38–50.
16. Settipane GA, Chafee FH, Klein DE. Aspirin intolerance: II. A prospective study
in an atopic and normal population. J Allergy Clin Immunol 1974; 53:200–204.
17. Strom BL, Carson JL, Morse ML, West SL, Soper KA. The effect of indication
on hypersensitivity reactions associated with zomepirac sodium and other non-
steroidal antiinflammatory drugs. Arthritis Rheum 1987; 30:1142–1148.
18. Kemp SF, Lieberman PL, Wolf BL. A review of 267 cases of anaphylaxis in clinical
practice. J Allergy Clin Immunol 1993; 91:153.
19. Klimek L. [Therapeutic measures for anaphylactic reactions in the course of aller-
gen-specific immunotherapy]. Wien Med Wochenschr 1999; 149:429–432.
20. Borelli S, Anliker MD, Wuthrich B. [Peanut anaphylaxis: the problem of hidden
allergens]. Dtsch Med Wochenschr 1999; 124:1197–1200.
21. Beaudouin E, Kanny G, Lambert H, Fremont S, Moneret-Vautrin DA. Food ana-
phylaxis following ingestion of carmine. Ann Allergy Asthma Immunol 1995; 74:
427–430.
22. Sakaguchi M, Hori H, Hattori S, Irie S, Imai A, Yanagida M, Miyazawa H, Toda
M, Inouye S. IgE reactivity to alpha 1 and alpha 2 chains of bovine type 1 collagen
in children with bovine gelatin allergy. J Allergy Clin Immunol 1999; 104:695–
699.
23. Terazawa E, Nagase K, Masue T, Niwa Y, Fukao I, Shimonaka H, Yokoi T, Kon-
doh N, Dohi S. [Anaphylactic shock associated with a central venous catheter im-
pregnated with chlorhexidine and silver sulfadiazine.] Masui 1998; 47:556–561.
24. Shadick NA, Liang MH, Partridge AJ, Bingham C, Wright E, Fossel AH, Sheffer
AL. The natural history of exercise-induced anaphylaxis: survey results from a 10-
year follow-up study. J Allergy Clin Immunol 1999; 104:123–127.
25. Fan HW, Marcopito LF, Cordoso JL, Franca FO, Malaque CM, Ferrari RA, Theaks-
ton RD, Warrell DA. Sequential randomised and double-blind trial of promethazine
Anaphylaxis 311
prophylaxis against early anaphylactic reactions to antivenom for bothrops snake

bites. Br Med J 1999; 318:1451–1452.
26. Renz CL, Laroche D, Thurn JD, Finn HA, Lynch JP, Thisted R, Moss J. Tryptase
levels are not increased during vancomycin-induced anaphylactoid reactions. Anes-
thesiology 1998; 89:620–625.
27. Fernandez J, Blanca M, Moreno F, Garcia J, Segurado E, del Cano A, Aguilar F.
Role of tryptase, eosinophil cationic protein and histamine in immediate allergic
reactions to drugs. Int Arch Allergy Immunol 1995; 107:160–162.
28. Hogan AD, Shwartz LB. Markers of mast cell degranulation. Methods 1997; 13:
43–52.
29. Olejnik AK, Brzezinska-Blaszczyk E. Tumor necrosis factor alpha (TNF-alpha)
modulates rat mast cell reactivity. Immunol Lett 1998; 64:167–171.
30. Lohman IC, Halonen M. The effects of combined histamine and platelet-activating
factor antagonism on systemic anaphylaxis induced by immunoglobulin E in the
rabbit. Am Rev Respir Dis 1993; 147:1223–1228.
31. Takafuji S, Tadokora K, Ito K, Nakagawa T. Release of granule proteins from
human eosinophils stimulated with mast cell mediators. Allergy 1998; 53:951–6.
32. Pradalier A. Late-phase reaction in asthma: basic mechanisms. Int Arch Allergy
Immunol 1993; 101:322–325.
33. Mosimann BL, White MV, Hohman RJ, Goldrich MS, Kaulbach HC, Kaliner MA.
Substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide in-
crease in nasal secretions after allergen challenge in atopic patients. J Allergy Clin
Immunol 1993; 92:95–104.
34. Gyorfi A, Fazekas A, Posch E, Irmes F, Rosivall L. Role of histamine in the devel-
opment of neurogenic inflammation of rat oral mucosa. Agents Actions 1991; 32:
229–236.
35. Proud D, MacGlashan DW, Newball HH, Schulman ES, Lichtenstein LM. Immu-
noglobulin E-mediated release of a kininogenase from purified human lung mast
cells. Am Rev Respir Dis 1985; 132:405–408.
36. Newball HH, Berninger RW, Talamo RC, Lichtenstein LM. Anaphylactic release
of a basophil kallikrein-like activity. I. Purification and characterization. J Clin
Invest 1979; 64:457–465.
37. Holgate ST, Robinson C, Church MK. Mediators of immediate hypersensitivity.
In: Middleton Jr E, Reed CE, Ellis EF, Adkinson NF, Yunginger JW, Busse WW,
eds. Allergy Principles and Practice, 4th edition, vol. I. St. Louis, MO: Mosby-
Year Book, 1993:267–301.
38. Sato T, Taguchi M, Nagase H, Kito H, Niikawa M. Augmentation of allergic reac-
tions by several pesticides. Toxicology 1998; 126:41–53.
39. Lichtenstein LM, Gillespie E. The effects of the H 1- and H 2-antihistamines on aller-
gic histamine release and its inhibition by histamine. J Pharmacol Exp Ther 1975;
192:441–450.
40. Tauber R, Reimann HJ, Schmiedt E. Hat das Hastammeme. pathophysiologische
Bedeutung bei Nierentumoren? In Zioegler M, ed. Urologish-nephrologische Pro-
bleme 20 Tagung der Sudwestdeuschen Gesell Urol Konstanz Schmetzor, 1981:
176.
41. Ring J, Behrendt H. H 1- and H 2-antagonists in allergic and pseudoallergic diseases.

42. Blandina P, Brunelleschi S, Fantozzi R, Giannella E, Mannaioni PF, Masini E. The
antianaphylactic action of histamine H 2-receptor agonists in the guinea-pig isolated
heart. Br J Pharmacol 1987; 90:459–466.
43. Patterson LJ, Milne B. Latex anaphylaxis causing heart block: role of ranitidine.
Can J Anaesth 1999; 46:776–778.
44. Mink S, Becker A, Sharma S, Unruh H, Duke K, Kepron W. Role of autacoids in
cardiovascular collapse in anaphylactic shock in anesthetized dogs. Cardiovasc Res
1999; 43:173–182.
45. MacIntosh FC, Paton WDM. The liberation of histamine by certain organic bases.
J Physiol 1949; 109:190–219.
46. Kaliner M, Shelhamer JH, Ottesen EA. Effects of infused histamine: correlation
of plasma histamine levels and symptoms. J Allergy Clin Immunol 1982; 69:283–
289.
47. Emanuel MB. Histamine and the antiallergic antihistamines: a history of their dis-
coveries. Clin Exp Allergy 1999; 29 (Suppl 3):1–12.
48. Woodward DF, Ledgard SE. Histamine-induced microvascular permeability in-
creases in hamster skin: a response predominantly mediated by H 2-receptors.
49. Pearce FL. Biological effects of histamine: an overview. Agents Actions 1991; 33:
4–7.
50. Duda D, Lorenz W, Dick W, Celik I, Black A, Healy MJ, Black JW. Can clinically
relevant histamine release be accurately diagnosed in anaesthetised patients without
plasma histamine measurements? Randomised study with nested sampling aimed
to change paradigms. Inflamm Res 1998; 47(Suppl 1):S73–74.
51. Sitter H, Lorenz W, Duda D, Doenicke A. Causality-based diagnosis of histamine-
related cardiorespiratory disturbances in surgical patients. Inflamm Res 1998;
47(Suppl 1):S71–72.
52. Sitter H, Lorenz W, Doenicke A. The clinical and biological signs of histamine
release during induction of anaesthesia and preparation of the surgical patient: a
farewell party for the classical manifestations of anaphylaxis. Agents Actions 1992;
Special Conference Issue: C219–230.
53. Chrusch C, Sharma S, Unruh H, Bautista E, Duke K, Becker A, Kepron W, Mink
SN. Histamine H 3-receptor blockade improves cardiac function in canine anaphy-
laxis. Am J Respir Crit Care Med 1999; 160:1142–1149.
54. Hill SJ. Histamine receptors and interactions between second messenger transduc-
tion systems. Agents Actions 1991; 33:145–159.
55. Moncada S, Martin JF. Vasodilation—evolution of nitric oxide. Lancet 1993; 341:
1511.
56. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biologi-
cal activity of endothelium-derived relaxing factor. Nature 1987; 327:524–526.
57. Leurs R, Brozius MM, Jansen W, Bast A, Timmerman H. Histamine H 1-receptor-
mediated cyclic GMP production in guinea-pig lung tissue is an l-arginine-depen-
dent process. Biochem Pharmacol 1991; 42:271–277.
Anaphylaxis 313
58. Poli E, Stark H, Bertaccini G. Histamine H 3-receptor activation inhibits acetylcho-

line release from the guinea pig myenteric plexus. Agents Actions 1991; 33:167–
169.
59. Ichinose M, Bames PJ. Histamine H 3-receptors modulate antigen-induced broncho-
constriction in guinea pigs. J Allergy Clin Immunol 1990; 86:491–495.
60. Borchard U, Hafner D, Hirth C. Electrophysiological actions of histamine and H 1-,
H 2-receptor antagonists in cardiac tissue. Agents Actions 1986; 18:186–190.
61. Felix SB, Baumann G, Niemczyk M, Hashemi T, Ochsenfeld G, Ahmad Z, Shirani
S, Blomer H. Effects of histamine H 1- and H 2-receptor antagonists on cardiovascu-
lar function during systemic anaphylaxis in guinea pigs. Agents Actions 1991; 32:
245–252.
62. Thome U, Borchard U, Berger F, Hafner D. Electrophysiological characterization
of histamine receptor subtypes in sheep cardiac Purkinje fibres. Agents Actions
1992; Special Conference Issue:C325–328.
63. Vleeming W, van Rooij HH, Wemer J, Porsius AJ. Characterization and modulation
of antigen-induced effects in isolated rat heart. J Cardiovasc Pharmacol 1991; 18:
556–565.
64. Lamparter B, Gross SS, Levi R. Nitric oxide and the cardiovascular actions of
histamine. Agents Actions 1992; Special Conference Issue C187–C190.
65. Matsuyama K, Yasue H, Okumura K, Matsuyama K, Ogawa H, Morikami Y, Inot-
sume N, Nakano M. Effects of H 1-receptor stimulation on coronary arterial diame-
ter and coronary hemodynamics in humans. Circulation 1990; 81:65–71.
66. Parsons GH, Villablanca AC, Brock JM, Howard RS, Colbert SR, Nichol GM,
Chung KF. Bronchial vasodilation by histamine in sheep: characterization of recep-
tor subtype. J Appl Physiol 1992; 72:2090–2098.
67. Barker LA, Winbery SL. Histamine and antihistamines. In: Wingard LB, Brody
TM, Larner J, Minneman KP, eds. Human Pharmacology Molecular to Clinical,
3rd ed. New York: Mosby, 1998: 811–825.
68. Hofman J, Siergiejko Z, Bortkiewicz J, Rutkowski R, Chyrek-Borowska S. Bron-
chial hyper-reactivity in atopic patients during H 2-receptor blocker treatment.
69. Barnes PJ. Histamine receptors in the lung. Agents Actions 1991; 33:103–122.
70. Kaliner M, Dyer J, Merlin S, Shelton A, Greenhill A, Treadwell G, McKenna W,
Lieberman P. Increased urine histamine and contrast media reactions. Invest Radiol
1984; 19:116–118.
71. Watkins J, Wild G. Problems of mediator measurement for a national advisory
service to UK anaesthetists. Agents Actions 1990; 30:247–249.
72. Howarth PH. Assessment of antihistamine efficacy and potency. Clin Exp Allergy
1999; 29 (Suppl 3):87–97.
73. Barnett A, Kreutner W. Pharmacology of non-sedating H1-antihistamines. Agents
Actions 1991; 33:181–196.
74. Simons FER. Recent advances in H 1-receptor antagonist treatment. J Allergy Clin
Immunol 1990; 86:995–999.
75. Sutherland DC. Antihistamine agents: new options or just more drugs? Med J Austr
1989; 151:158–162.
76. Rimmer SJ, Church MK. The pharmacology and mechanisms of action of histamine
H 1-antagonists. Clin Exp Allergy 1990; 20(Suppl 2):3–17.
77. Nabe M, Agrawal DK, Sarmiento EU, Townley RG. Inhibitory effect of terfenadine
on mediator release from human blood basophils and eosinophils. Clin Exp Allergy
1989; 19:515–520.
Respir Dis 1990; 142:167–171.
zine on mast cell-mediator release and cellular traffic during the cutaneous late-
80. Fadel R, Herpin-Richard N, Rihoux JP, Henocq E. Inhibitory effect of cetirizine-
2-HCl on eosinophil migration in vivo. Clin Allergy 1987; 17:373–379.
83. Massey WA, Lichtenstein LM. The effects of antihistamines beyond H1-antagonism
in allergic inflammation. J Allergy Clin Immunol 1990; 86:1019–1024.
84. Togias AG, Naclerio RM, Wamer J, Proud D, Kagey-Sobotka A, Nimmagadda I,
human mast cells by azatadine base. JAMA 1986; 255:225–229.
85. Zull DN. Preventing fatalities from anaphylaxis: an emergency medicine physi-
cian’s perspective. Allergy Proc 1995; 16:113–114.
86. Marshall C, Lieberman P. Analysis of three pretreatment procedures to prevent
anaphylactoid reactions to radiocontrast in previous reactors. J Allergy Clin Immu-
nol 1989; 83:254.
87. Simons FER, Simons KJ. H 1-receptor antagonists: clinical pharmacology and use
in allergic disease. Pediatr Clin North Am 1983; 30:899–914.
88. Brown AF. Therapeutic controversies in the management of acute anaphylaxis. J
Accid Emerg Med 1998; 15:89–95.
89. Mota I, DaSilva WD. The anti-anaphylactic and histamine-releasing properties of
the antihistamines. Their effect on the mast cells. Br J Pharmacol 1960; 15:396–
404.
90. Wood-Baker R, Holgate ST. The comparative actions and adverse effect profile of
single doses of H 1-receptor antihistamines in the airways and skin of subjects with
asthma. J Allergy Clin Immunol 1993; 91:1005–1014.
91. Kreutner W, Chapman RW, Gulbenkian A, Siegel MI. Antiallergic activity of lora-
tadine, a non-sedating antihistamine. Allergy 1987; 42:57–63.
92. Eiser NM, Mills J, Snashall PD, Guz A. The role of histamine receptors in asthma.
Clin Sci 1981; 60:363–370.
93. Cookson WO. Bronchodilator action of the antihistaminic terfenadine. Br J Clin
Pharmacol 1987; 24:120–121.
94. Wasserfallen JB, Leuenberger P, Pecoud A. Effect of cetirizine, a new H 1-antihista-
mine, on the early and late allergic reactions in a bronchial provocation test with
allergen. J Allergy Clin Immunol 1993; 91:1189–1197.
Anaphylaxis 315
95. Tryba M, Zenz M, Thole H. Therapeutic efficacy of combined H 1- and H 2-receptor

antagonists on severe histamine-induced cardiovascular reactions in humans.
Agents Actions 1992; Special Conference Issue:C238–241.
96. Ennis M, Lorenz W, Nehring E, Schneider C. In vitro and in vivo studies of radio-
graphic contrast media-induced histamine release in pigs. Agents Actions 1991;
33:26–29.
97. Laroche D, Aimone-Gastin I, Dubois F, Huet H, Gerard P, Vergnaud MC, Mouton-
Faivre C, Gueant JL, Laxenaire MC, Bricard H. Mechanisms of severe immediate
reactions to iodinated contrast material. Radiology 1998; 209:183–190.
98. Zweiman B, Mishkin MM, Hildreth EA. An approach to the performance of con-
trast studies in contrast material-reactive persons. Ann Intern Med 1975; 83:159–
162.
99. Lieberman P. Anaphylactoid reactions to radiocontrast material. Clin Rev Allergy
1991; 9:319–338.
100. Lieberman P, Siegle RL, Treadwell G. Radiocontrast reactions. Clin Rev Allergy
1986; 4:229–245.
101. Patterson R, Pruzansky JJ, Dykewicz MS, Lawrence ID. Basophil–mast cell re-
sponse syndromes: a unified clinical approach. Allergy Proc 1988; 9:611–620.
102. Greenberger PA. Life-threatening idiopathic anaphylaxis associated with hyperim-
munoglobulinemia E. Am J Med 1984; 76:553–556.
103. Ring J, Rothenberger KH, Clauss W. Prevention of anaphylactoid reactions after
radiographic contrast media infusion by combined histamine H 1- and H 2-receptor
antagonists: results of a prospective controlled trial. Int Arch Allergy Appl Immunol
1985; 78:9–14.
104. Marshall GD, Lieberman PL. Comparison of three pretreatment protocols to pre-
vent anaphylactoid reactions to radiocontrast media. Ann Allergy 1991; 67:70–
74.
105. Lieberman P. The use of antihistamines in the prevention and treatment of ana-
phylaxis and anaphylactoid reactions. J Allergy Clin Immunol 1990; 86:684–
686.
106. Lieberman P. Anaphylactoid reactions to radiocontrast material. Immunol Allergy
Clin North Am 1992; 12:649–670.
107. Thomsen HS, Bush Jr WH. Treatment of the adverse effects of contrast media.
Acta Radiol 1998; 39:212–218.
108. Apter AJ, Kaplan AA. An approach to immunologic reactions associated with
plasma exchange. J Allergy Clin Immunol 1992; 90:119–124.
109. Moscicki RA, Sockin SM, Corsello BF, Ostro MG, Bloch KJ. Anaphylaxis during
induction of general anesthesia: subsequent evaluation and management. J Allergy
Clin Immunol 1990; 86:325–332.
110. Rohr AS, Pappano JE. Prophylaxis against fluorescein-induced anaphylactoid reac-
tions. J Allergy Clin Immunol 1992; 90:407–408.
111. Babe KS, Zebrowski M, Lieberman P, Kim R. Successful hypothermic cardiopul-
monary bypass in a patient with primary cold urticaria. Ann Allergy 1993;
70:90.
112. Madowitz JS, Schweiger MJ. Severe anaphylactoid reaction to radiographic con-
trast media. Recurrence despite premedication with diphenhydramine and predni-
sone. JAMA 1979; 241:2813–2815.
113. Borish L, Matloff SM, Findlay SR. Radiographic contrast media-induced noncar-
diogenic pulmonary edema: case report and review of the literature. J Allergy Clin
Immunol 1984; 74:104–107.
114. Lorenz W, Doenicke A. Anaphylactoid reactions and histamine release by intrave-
nous drugs used in surgery and anaesthesia. In Watkins J, Ward AM, eds. Adverse
Response to Intravenous Drugs. London: Academic Press, 1978:83–112.
115. Kwiterovich KA, Maguire MG, Murphy RP, Schachat AP, Bressler NM, Bressler
SB, Fine SL. Frequency of adverse systemic reactions after fluorescein angiogra-
phy. Results of a prospective study. Ophthalmology 1991; 98:1139–1142.
116. Greenberger PA. Idiopathic anaphylaxis. Immunol Allergy Clin North Am 1992;
12:571–583.
117. Ditto AM, Krasnick J, Greenberger PA, Kelly KJ, McGrath K, Patterson R. Pediat-
ric idiopathic anaphylaxis: experience with 22 patients. J Allergy Clin Immunol
1997; 100:320–326.
118. Pasquariello CA, Lowe DA, Schwartz RE. Intraoperative anaphylaxis to latex. Pe-
diatrics 1993; 91:983–986.
119. Sheffer AL, Austen KF. Exercise-induced anaphylaxis. J Allergy Clin Immunol
1980; 66:106–111.
120. Briner WW, Sheffer AL. Exercise-induced anaphylaxis. Med Sci Sports Exerc
1992; 24:849–850.
121. Saryan JA, O’Loughlin JM. Anaphylaxis in children. Pediatr Ann 1992; 21:590–
598.
122. LaRoche D, Vergnaud M, Sillard B, Sovfarapis H, Bricard H. Biochemical markers
of anaphylactoid reactions to drugs. Comparison of plasma histamine and tryptase.
Anesthesiology 1991; 75:945–949.
123. Withington DE, Elliot M, Man WK. Histamine release during paediatric cardiopul-
monary bypass. Agents Actions 1991; 33:200–202.
124. Marone G, Stellato C. Activation of human mast cells and basophils by general
anaesthetic drugs. In Assem E-SK, ed. Allergic Reactions to Anaesthetics. Clinical
and Basic Aspects. Basel: Karger, 1992:54–73.
125. Gueant JL, Aimone-Gastin I, Namouv F, Laroche D, Bellou A, Laxenaire MC.
Diagnosis and pathogenesis of the anaphylactic and anaphylactoid reactions to an-
aesthetics. Clin Exp Allergy 1998; 28(Suppl 4):65–70.
126. Tryba M, Zevounou F, Zenz M. Prevention of histamine-induced cardiovascular
reactions during the induction of anaesthesia following premedication with H 1- ⫹
H 2-antagonists intramuscularly. Br J Anaesth 1986; 58:478–482.
127. Lorenz W, Dick W, Junginger T, et al. Induction of anaesthesia and perioperative
risk: influence of antihistamine H 1- ⫹ H 2-prophylaxis and volume substitution with
Haemaccel-35 on cardiovascular and respiratory disturbances and histamine re-
lease. Theo Surg 1988; 3:55–77.
128. Lorenz W, Doenicke A. H 1- ⫹ H 2-blockade: a prophylactic principle in anaesthesia
and surgery against histamine-release responses of any degree of severity. Part I.
N Eng Reg Allergy Proc 1985; 6:37–57; Part II 1985; 6:174–194.
129. Philbin DM, Moss J, Akins CW, Rosow CE, Kono K, Schneider RC, Ver Lee TR,
Savarese JJ. The use of H 1- and H 2-histamine antagonists with morphine anesthesia:
a double-blind-study. Anesthesiology 1981; 55:292–296.
Anaphylaxis 317
130. Edston E, van Hage-Hamsten M. Anaphylactoid shock—a common cause of death

in heroin addicts? Allergy 1997; 52:950–954.
131. Williams PD, Laska DA, Shetler TJ, McGrath JP, White SL, Hoover DM. Vanco-
mycin-induced release of histamine from rat peritoneal mast cells and a rat basophil
cell line (RBL-1). Agents Actions 1991; 32:217–223.
132. Weiss ME, Nyhan D, Peng ZK, Horrow JC, Lowenstein E, Hirshman C, Adkinson
NF. Association of protamine lgE and lgG antibodies with life-threatening reactions
to intravenous protamine. N Eng J Med 1989; 320:886–892.
133. Weiler JM, Gellhaus MA, Carter JG, Meng RL, Benson PM, Hottel RA, Schillig
KB, Vegh AB, Clarke WR. A prospective study of the risk of an immediate adverse
reaction to protamine sulfate during cardiopulmonary bypass surgery. J Allergy
Clin Immunol 1990; 85:713–719.
134. Moss J, Roizen MF, Nordby EJ, Thisted R, Apfelbaum JL, Schreider BD, McDer-
mott DJ. Decreased incidence and mortality of anaphylaxis to chymopapain. Anesth
Analog 1985; 64:1197–1201.
col 1966; 27:427–439.
136. Black JW, Duncan WAM, Durant GJ, Ganellin CR, Parsons EM. Definition and
antagonism of histamine H 2-receptors. Nature 1972; 236:385–390.
137. Dai S. Circulatory depression and ventricular arrhythmias induced by compound
48/80 in anaesthetized rats. Agents Actions 1991; 34:316–323.
138. Lorenz W, Ennis M, Doenicke A, Dick W. Perioperative uses of histamine antago-
nists. J Clin Anesth 1990; 2:345–360.
139. Lorenz W, Kubo K, Stinner B, Sitter H, Hasse C, Dietz W, Schmal A, Krack W.
Studies on the effectiveness of H 1- ⫹ H 2-antagonist combinations in preventing
life-threatening anaphylactoid reactions in anaesthesia and surgery: problems with
selecting the animal model from clinical data and with ‘‘equi-effective’’ dose.
Agents Actions 1992; Special Conference Issue C231–237.
140. Lorenz W, Duda D, Dick W, Sitter H, Doenicke A, Black A, Weber D, Menke H,
Stinner B, Junginger T, Rothmund M, Ohmann C, Healy MJR, and the Trial Group
Mainz Marburg. Incidence and clinical importance of perioperative histamine re-
lease: randomized study of volume loading and antihistamines after induction of
anaesthesia. Lancet 1994; 343:933–940.
141. Dahl JB. Antihistamine prophylaxis and general anaesthesia. Lancet 1994; 343:
929–930.
142. Dachman WD, Bedarida G, Blaschke TF, Hoffman BB. Histamine-induced venodi-
lation in human beings involves both H 1- and H 2-receptor subtypes. J Allergy Clin
Immunol 1994; 93:606–614.
143. Vidovich RR, Heiselman DE, Hudock D. Treatment of urokinase-related anaphy-
lactoid reaction with intravenous famotidine. Ann Pharmacother 1992; 26:782–783.
144. De Soto H, Turk P. Cimetidine in anaphylactic shock refractory to standard therapy.
Anesth Analg 1989; 69:264–265.
145. Yarbrough JA, Moffitt JE, Brown DA, Stafford CT. Cimetidine in the treatment
of refractory anaphylaxis. Ann Allergy 1989; 63:235–238.
146. Brown AF. Anaphylactic shock: mechanisms and treatment. J Accid Emerg Med
1995; 12:89–100.
10
Cost-Effectiveness of H 1-Antihistamines
Michael S. Blaiss
University of Tennessee Center for the Health Sciences
College of Medicine, Memphis, Tennessee
I. INTRODUCTION
H 1-antagonists are commonly used in the treatment of seasonal and perennial

allergic rhinitis, allergic conjunctivitis, acute and chronic urticaria, atopic derma-
titis, asthma, and anaphylaxis. Allergic rhinitis and asthma affect a large percent-
age of the population. They are associated with high expenditures for medical
care and high indirect costs due to work and school absences and decreases in
productivity. These disorders lead to impaired quality of life for patients. With
the changes occurring in the health care arena and continued decrease in monetary
resources, cost and quality-of-life considerations must be assessed in addition to
clinical efficacy and safety when evaluating pharmacological treatments.
This chapter begins with a general overview of the discipline of phar-
macoeconomics. It continues with a review of studies assessing the cost and
quality-of-life considerations in prescribing H 1-antagonists for managing allergic
rhinoconjunctivitis, urticaria and angioedema, atopic dermatitis, asthma, and
anaphylaxis.
II. OVERVIEW OF PHARMACOECONOMICS
With the increasing emphasis on economics in health care there has been an
incentive to develop new ways to assess the value of health care treatment. This
has led to the development of the field of pharmacoeconomics, which can be
defined as the identification and measurement of the comparative value of differ-
319
320 Blaiss
ent pharmaceutical therapies in the management of a disease (1). When assessing

the value of a drug, one needs to look beyond the purchase price, and take into
account the drug’s total economic and health effect on the patient population. This
information can lead to improved decisions in caring for the individual patient and
in developing public health policy (2).
Costs in health care can be organized into two major categories: direct and
indirect (3). Direct costs include the monies spent during the course of managing
the disease (4, 5). Along with the cost of therapeutic agents, direct costs include
medical services, such as outpatient clinic, hospital, and emergency department
visits, physician fees, and laboratory procedures. Some direct costs can be non-
medical, including transportation for medical services and monies for research
and teaching. Other direct costs are ‘‘hidden.’’ These are monies spent directly
for other medical conditions that may have been brought about by the condition
being evaluated. Indirect costs encompass all the non-health care costs associated
with the illness. These include monies lost due to missing work and decreased
productivity due to the illness. Other indirect costs to measure include the mone-
tary value of missing school and unpaid caregivers’ time to look after a sick child.
In understanding economic assessments in medicine, it is important to un-
derstand the difference between efficacy and effectiveness studies. Efficacy stud-
ies measure results in controlled situations with a highly selected population.
This type of study is the double-blind, placebo-controlled procedure used to eval-
uate the effect of the medication and safety. In pharmacoeconomic studies, effec-
tiveness trials are done. This type of evaluation is ‘‘real-world,’’ in which routine
conditions in a more generalized population are used to assess outcomes of medi-
cation use.
Health care economists have developed several different techniques to
compare costs among different treatment modalities. The four most commonly
used assessments are cost-identification analysis, cost-benefit analysis, cost-ef-
fectiveness analysis, and cost-utility analysis (Table 1). A cost-identification anal-
Table 1 Economic Evaluations in Health Care
Cost-Identification
Costs are compared among different programs or treatments.
Cost-Benefit
Costs are compared to benefits from a program or treatment as defined by society.
Cost-Effectiveness
Costs are compared to clinical effects produced by different programs or treatments.
Cost-Utility
Costs are compared to quality-adjusted life years attained among different programs
or treatments.
Cost-Effectiveness 321
ysis compares costs when the safety and efficacy of any two or more treatments
are assumed to be equal. This technique should not be used if there is any question
of differences in outcomes observed with the different treatment modalities. A
common use of cost-identification analysis would be comparing a brand-name
drug with its generic equivalent.
Cost–benefit analysis is a comparison of costs and the accompanying out-
comes on a monetary basis (4). This technique requires placing a dollar value
on the outcomes produced, which could be very difficult depending on who is
setting the value of the benefits obtained. An example of cost–benefit analysis
would be a case in which one treatment that costs $500 a year produces outcomes
valued by society at $1500, while a second treatment that costs $250 a year
produces outcomes valued by society at $1000 per year. The second treatment
would have the highest cost–benefit for the outcomes obtained, since for each
dollar spent there was a $4 benefit ($1000 outcomes/$250 costs), while the first
treatment had a $3 benefit ($1500 outcomes/$500 costs). Difficulties from this
type of cost evaluation arise when one tries to put a monetary value on years of
life saved or improvements in psychosocial outcomes (2).
The cost-effectiveness analysis compares the costs of alternative treatments
in monetary units with the clinical results obtained with treatment (6). This analy-
sis uses a natural unit or health outcome such as life-years gained, symptom-free
days, or number of cures obtained for assessing outcomes. This method allows
for the development of the cost-effectiveness ratio: the cost to achieve a particular
outcome. An example would be one treatment that costs $1000 for 5 patients
and increases symptom-free days by 50% and a second treatment that costs $1500
for 5 patients and increases symptom-free days by 90%. Treatment A has a cost-
effectiveness ratio of 20 (1000/50) while treatment B’s ratio is 16.7 (1500/90).
Even though the second treatment is more costly, it is more cost-effective due
to the higher increase in symptom-free days for each dollar spent. In using cost-
effective analysis in comparing two treatments, there are four possible outcomes
(7) (Fig. 1). Quadrant I shows that treatment A is more effective and costs less
than treatment B. In this case treatment A is truly cost-effective. In quadrant III,
the scenario illustrates that treatment A is more costly and less effective than
treatment B; therefore, treatment B is more cost-effective. The next possibility,
quadrant II, shows that treatment A is less costly and less effective than treatment
B. In this scenario, treatment A may or may not be the most cost-effective de-
pending upon the particular clinical situation and resources available for treat-
ment. One would need to analyze the cost-effectiveness ratio to determine the
optimal therapy. Quadrant IV, the last possibility, shows that treatment A is more
costly and more effective. Again it would depend upon the clinical situation,
resources available, and assessment of the cost-effectiveness ratio, in determining
which treatment produces the best value.
The last method of assessing pharmacoeconomics costs is cost-utility anal-
322 Blaiss
Figure 1 Possible outcomes of cost-effectiveness analysis (see text for explanation).

(Adapted from Ref. 7.)
ysis. This technique compares monies spent to one component of outcomes,

health-related quality of life (HRQL) and has led to development of a patient-
weighted unit of measure: quality-adjusted life years (QALY) (8, 9). A key ele-
ment in the QALY methodology is that it weighs years of life by the patient’s
subjective health quality (10). Usually this form of cost analysis is applied in
national or regional health care policy decisions, especially when comparing costs
per QALY obtained between different treatments in determining funding for dif-
ferent programs. A difficulty in this type of cost evaluation is measuring the
patient’s perception of the disease and its subsequent change with treatment. This
has led to the development of psychometric questionnaires to assess the patient’s
HRQL to calculate the utility unit, QALY. (8).
One evaluates HRQL by using two different types of questionnaires: ge-
neric and disease-specific. Generic HRQL questionnaires are broad-based surveys
that can be used to assess quality of life over a variety of conditions and popula-
tions regardless of disease state. These surveys can compare quality of life among
different diseases and populations. Examples of generic quality-of-life question-
naires are the Sickness Impact Profile, the Quality of Well-Being Scale, and the
Medical Outcomes Study Short Form 36 (SF-36) and 12 (SF-12). The SF-36 was
developed as part of the Medical Outcomes Study and analyzes health status
using 36 questions to measure nine different health dimensions (11). Bousquet
used the SF-36 to assess the HRQL in patients with perennial allergic rhinitis to
Table 2 SF-36 Questionnaire Scores
Allergic
Healthy adults rhinitis patients
Health domain (n ⫽ 116) (n ⫽ 111)
Physical functioning 95.9 88.6*

Physical limitations 92.0 60.6*
Pain 90.3 76.9*
Social functioning 91.3 73.1*
Energy/fatigue 71.9 54.5*
Emotional limitations 86.7 64.2*
Mental health 73.4 64.8 †
General health perception 81.7 62.4*
Change in health 54.1 49.8
* p ⬍ 0.0001.
†
p ⬍ 0.0005.
pets or dust mites (12) and found that, in all but one health domain, patients with
perennial allergic rhinitis had significantly poorer quality of life than the healthy
controls (Table 2). Specific instruments used in the evaluation of quality of life
are usually focused on one particular interest such as a disease state, a distinct
patient population, or certain functions or problems. An example in allergic rhini-
tis is the Rhinitis Quality-of-Life Questionnaire (RQLQ) (13, 14) (Table 3). It
is scored on a six-point scale with a lower score indicating better quality of life.
Meltzer et al., using the RQLQ, showed that patients with rhinitis have impaired
quality of life compared to the healthy population (15).
Table 3 Domains of the Juniper and Guyatt Rhinoconjunctivitis Quality-of-

Life Questionnaire
1. Activities
2. Sleep
3. Nonspecific symptoms: fatigue, thirst, reduced productivity, tiredness, poor concen-
tration, headache, worn out
4. Practical problems: need to rub and blow nose/eyes repeatedly, inconvenience of
having to carry handkerchief
5. Nasal symptoms
6. Eye symptoms
7. Emotional problems: frustrated, impatient or restless, irritable, embarrassed by symp-
toms

324 Blaiss
III. ALLERGIC RHINITIS: ECONOMIC IMPACT
Up to 40% of the population suffers from allergic rhinitis (16, 17). A majority
of patients with allergic rhinitis are children, adolescents, and young adults (18).
Because patients are rarely, if ever, hospitalized, rarely require surgery or other
sophisticated interventions, and do not have their day-to-day survival threatened
by this entity, allergic rhinitis may be seen as a minor nuisance. It is now being
recognized as a costly condition in the health care arena. Costs of allergic rhinitis
can be classified into two major categories: direct and indirect. Direct costs are
monies spent in the care of the patient, while indirect costs are monies lost due
to the disease. An important aspect of allergic rhinitis costs is that this disease
can lead to or complicate other high-cost disorders such as asthma, sinusitis, otitis
media with effusion, and nasal polyposis. These conditions lead to an important
cost category: ‘‘hidden’’ direct costs. Table 4 illustrates the direct, ‘‘hidden’’
direct, and indirect costs associated with allergic rhinitis.
Table 4 Direct and Indirect Costs of Allergic Rhinitis
Direct costs
Physician/provider consultation
Laboratory testing: allergy skin tests, RAST, etc.
Costs of specific allergy therapy: environmental control, prescription and OTC medi-
cations, and immunotherapy
‘‘Hidden’’ direct costs
Costs for antibiotics, radiographs for diagnosis and emergency department visits for
sinusitis
Surgical costs for nasal polyposis and sinusitis
Medical and surgical costs for otitis media with effusion
Costs of worsening asthma and frequent upper respiratory infections
Orthodontic costs
Evaluation and treatment of ocular symptoms
Indirect costs
Sleep disorders and neuropsychiatric abnormalities
Activity limitation due to symptoms and effects of first-generation H 1-antagonists
Decreased decision-making capacity
Impaired psychomotor function
Poor concentration
Irritability
Fatigue
Decreased functioning at work and school
Increased motor vehicle accidents and school and workplace injuries

RAST, radio allergosorbent test; OTC, over-the-counter.
Recently several groups of investigators have evaluated the cost of allergic

rhinitis in the United States. In each of these studies cost was assessed in different
ways, leading to different cost estimates. McMenamin assessed the costs and
prevalence of this condition in 1990 by using the National Health Interview Sur-
vey (NHIS) to estimate the number of patients with allergic rhinitis and the Na-
tional Ambulatory Medical Care Survey (NAMCS) to estimate the type of physi-
cian treatments provided (19). His results suggested that the prevalence rate of
allergic rhinitis was 9.3%, with total costs in 1990 of $1.8 billion. Direct costs
totaled $1.16 billion with $881 million from physician costs and $276 million
from medication costs. Indirect costs from allergic rhinitis came to $639 million,
estimated from a loss of 3.4 million workdays.
Ross assessed the indirect cost of allergic rhinitis in the workplace (20).
Using the data from the United States Public Health Survey, he calculated that
allergic rhinitis affected 12.6 million people in the U.S. workforce in 1989. Next
he extrapolated the increase in the workforce through 1993 and calculated the
loss of productivity due to allergic rhinitis. For 1993, the loss of productivity in
the U.S. labor force was $2.39 billion in men and $1.4 billion in women. Because
such a high percentage of the workforce has allergic rhinitis, it is estimated from
his data that lost productivity due to this disorder may cost $1000 for each worker
in the United States per year.
Malone et al. produced another study addressing the burden of allergic
rhinitis on the national economy (21). By using data from the 1987 National
Medical Expenditure Survey, they calculated estimates of resource utilization,
medical expenditures, and lost productivity from allergic rhinitis and extrapolated
the data in 1994 dollars. They estimated that 39 million Americans had allergic
rhinitis in 1987, but only 12.3% obtained medical care from physicians. Allergic
rhinitis accounted for 811,000 missed workdays, 824,000 missed school days,
and 4,230,000 reduced activity days in 1987. The total cost of allergic rhinitis
in 1994 dollars was $1.23 billion.
Storms et al. (22) conducted a nationwide survey in 1993 to evaluate the
costs related to the management of allergic rhinitis in the United States. Patients
with ocular and/or nasal symptoms for 7 days or more during the previous 12
months were studied with regard to the amount of medical care services, includ-
ing spending on medication, over that 12-month period. Sixty-three percent of
the respondents consulted a physician in the previous 12 months, with an esti-
mated cost of $1.1 billion. The average per-person expenditure for prescription
medications was $56/year. The same amount was spent on nonprescription medi-
cations yearly, giving an estimated total cost in medications for allergic rhinitis
in the range of $2.4 billion.
Mackowiak developed an employer cost/benefit economic model for aller-
gic rhinitis (23). In looking at pharmaceutical costs he obtained data on drug
sales from various pharmaceutical companies for his model. The preliminary data
326 Blaiss
Table 5 Medical Expenditures Attributable to Allergic Rhinitis/Allergic

Conjunctivitis in the United States by Age of Patient and Airway Disorder (1996; in
millions of dollars)
Airway disorder ⱕ12 years ⱖ13 years Total
Allergic rhinitis/allergic conjunctivitis 356.6 1506.8 1863.4

Chronic otitis and eustachian tube disorders 1173.5 310.0 143.5
Sinusitis 176.0 841.2 1017.3
Asthma 253.3 751.4 1006.7
Acute upper respiratory tract infection 114.3 97.6 211.8
Pharyngitis and tonsillitis 76.5 89.3 165.7
Other conjunctivitis 41.6 46.3 88.0
Chronic rhinitis 30.3 32.0 62.3
Rhinorrhea 26.8 5.3 32.0
Total 2250.9 3679.9 5930.8
show direct costs of allergic rhinitis of $4.48 billion and indirect costs of $3.37
billion.
Ray et al. assessed direct expenditures for treatment of allergic rhinocon-
junctivitis in 1996, along with calculating the ‘‘hidden’’ direct costs of rhinitis,
such as sinusitis, asthma, acute upper respiratory tract infection, pharyngitis and
tonsillitis, nonatopic conjunctivitis, and chronic otitis media and eustachian tube
disorders (24). These investigators found that the primary diagnosis of rhinitis
led to direct costs of $1.9 billion (in 1996 dollars). Costs were estimated for
rhinitis as a secondary diagnosis and found to be $4.0 billion (Table 5). Although
all these studies took distinct approaches and used different methods in determin-
ing costs related to allergic rhinitis, it is clear that this disease has a significant
economic impact on the health care system.
IV. COST-EFFECTIVE MANAGEMENT

OF ALLERGIC RHINITIS
In allergic rhinitis, treatment consists of a threefold approach. First, avoidance

procedures should be instituted to decrease exposure to harmful allergens. Next,
appropriate pharmaceutical agents should be prescribed to help alleviate and pre-
vent chronic symptoms. Last, allergen vaccination may be needed to significantly
desensitize or possibly eliminate symptoms due to specific allergens. With the
large population of patients with allergic rhinitis and its high total cost, it is
important to be able to determine what treatment measures are truly cost-effective
in the management of this disorder.
V. MEDICAL MANAGEMENT OF ALLERGIC RHINITIS
The mainstays of pharmacological therapy for allergic rhinitis are oral H 1-antago-
nists and intranasal corticosteroids. Table 6 lists some first- and second-genera-
tion H 1-antagonists and their costs per day calculated from their average whole-
sale price and recommended frequency of daily dosing (25). The average
wholesale price is used to keep the data uniform in this analysis. It is important
to note that the true cost of the H 1-antagonist for the patient may vary because
certain health plans may have arrangements for discounts from pharmaceutical
companies and certain pharmacists charge more or less for a particular medica-
tion. Also, in many countries most H 1-antagonists, including the new nonsedating
ones, are available on a nonprescription basis. First-generation H 1-antagonists
have been in use for many years. These drugs are all effective in decreasing the
symptoms of allergic rhinitis such as rhinorrhea, sneezing, nasal itching, and
ocular symptoms and are the least expensive daily pharmacological therapy in
the management of allergic rhinitis (Table 6). They may not be the most cost-
effective, however, because many patients experience significant side effects that
may impair productivity (Chap. 11). These H 1-antagonists cross the blood–brain
barrier and may cause significant central nervous system sedation, impairment
of psychomotor function, and depression (26, 27). This sedation may be imper-
ceptible. In many states it is illegal to operate heavy machinery or a motor vehicle
while using these medications. Internationally, civilian and military aviation au-
thorities prohibit their use. The first-generation sedating H 1-antagonists have been
shown to have a detrimental effect on learning in children (28–30). Fireman
determined from pharmacy data from a health maintenance organization (HMO)
Table 6 Cost per Day from 2001 Drug Topics

Red Book Based on Average Wholesale Price of
H 1-Antihistamines at the Recommended Daily Dosage
Second-generation a
Fexofenadine (60 mg) $2.07
Loratadine (10 mg) $2.44
Cetirizine (10 mg) $1.92
First-generation
Diphenhydramine (50 mg) $0.56
Clemastine (2.68 mg) $1.35
Chlorpheniramine (8 mg) $0.21
Nasal spray
Azelastine $1.99
a
Costs in United States reflect prescription-only status of these
H 1-antihistamines.
Source: From Ref. 25.
328 Blaiss
that first-generation antihistamine usage was associated with significantly more

work-related injuries compared to control groups (31). He estimated the annual
cost of lost productivity to employers and society as the result of allergic rhinitis
and use of over-the-counter sedating H 1-antagonists to be greater than $4 billion.
The second-generation H 1-antagonists are relatively nonsedating. These are
also listed in Table 6. These agents are as effective in relief of symptoms as the
first-generation H 1-antagonists (32, 33). The advantages these H 1-antagonists
have over the first-generation agents include rare sedation (no greater than pla-
cebo at the indicated dosage, except for cetirizine which is slightly greater than
placebo) (34), no anticholinergic effects, lack of tolerance with prolonged use,
and decreased dosing frequency (35). These agents have been shown to improve
the quality of life in patients with allergic rhinitis (36–38).
Comparisons among the different second-generation H 1-antagonists have
generally failed to show any clinically significant difference in efficacy in man-
agement of allergic rhinitis (39). There are few comparative studies in cost-effec-
tiveness and quality of life among the second-generation agents. Harvey com-
pared cetirizine, terfenadine, and chlorpheniramine in a large managed care
setting and found that cetirizine was associated with the greatest improvement
in quality of life using the RQLQ (40).
Antihistamine nasal sprays (Table 6) are available for treatment of allergic
rhinitis. The cost is equivalent to that of oral second-generation H 1-antagonists
and their efficacy is similar (41, 42). The major side effects observed with azelas-
tine are somnolence and bitter taste.
No cost-effectiveness data have been published to date for ebastine and
mizolastine.
VI. COMPARATIVE STUDIES WITH OTHER AGENTS

IN ALLERGIC RHINITIS MANAGEMENT
Another important modality in the treatment of allergic rhinitis is intranasal corti-

costeroids. Table 7 summarizes the preparations available along with their daily
cost based on average wholesale price. In general, the daily cost of intranasal
corticosteroids is less than second-generation H 1-antagonists (see Tables 6 and
7). Several studies have compared the cost-effectiveness and quality of life asso-
ciated with these two major treatments for allergic rhinitis. Bronsky et al. com-
pared an intranasal corticosteroid, fluticasone, with a second-generation antihista-
mine, terfenadine, and placebo for treatment of seasonal allergic rhinitis in 348
patients (43). Patient-rated total nasal symptom scores throughout treatment and
total nasal airflow, measured by rhinomanometry, were significantly ( p ⬍ 0.05)
improved in the fluticasone-treated group compared with the terfenadine-treated
Table 7 Cost per Day from 2001 Drug Topics Red

Book Based on Average Wholesale Price of Intranasal
Corticosteroids at the Recommended Daily Dosage
Fluticasone propionate $1.87
Triamcinolone acetonide (aqueous) $1.41
Budesonide aqueous $1.66
Flunisolide $1.74
Mometasone furoate $1.83
Source: From Ref. 25.
group. Other clinical studies have shown that adults and adolescents with seasonal
allergic rhinitis had significantly better improvement with fluticasone nasal spray
than loratadine tablets (44, 45). Kozma compared cost-efficacy ratios for intrana-
sal fluticasone and terfenadine tablets within a sample of patients with seasonal
allergic rhinitis symptoms due to mountain cedar allergy (46). Costs measured
were the direct costs of the drugs used for therapy; efficacy was assessed using
patient ratings of symptoms and their overall assessment of response to treatment.
The cost-efficacy ratios for intranasal fluticasone once daily were more favorable
than the ratios for terfenadine 60 mg twice daily. Two cost-effectiveness studies
from Canada found fluticasone to be 2.5 times less costly daily than terfenadine
and 5.7 times less costly daily than loratadine (47).
Other intranasal corticosteroids and second-generation H 1-antagonists
have been compared in assessing clinical efficacy. Bernstein et al. conducted a
multicenter, double-blind, parallel-group study in 239 patients randomized to re-
ceive either triamcinolone nasal spray or astemizole tablets (48). Overall, triam-
cinolone spray was more effective than astemizole in reducing total nasal symp-
toms, nasal stuffiness, nasal itching, and sneezing. Schoenwetter et al. compared
the safety and efficacy of intranasal triamcinolone with oral loratadine in reliev-
ing symptoms of ragweed-induced seasonal allergic rhinitis (49). Improvement
in all rhinitis symptoms was significantly greater with triamcinolone than with
loratadine. Physicians’ global evaluations indicated that 78% of patients taking
triamcinolone had moderate to complete relief, compared with 58% of loratad-
ine-treated patients ( p ⱕ 0.0001). Schulz compared quality of life in patients
with allergic rhinitis using triamcinolone nasal spray or loratadine (50). At day
14, the patients using triamcinolone spray were significantly better ( p ⬍ 0.05)
in several different components of quality of life and overall quality of life as-
sessment. Ratner assessed use of loratadine tablets alone, fluticasone nasal spray
alone, and the combination in the management of seasonal allergic rhinitis. In
all aspects, fluticasone alone showed more clinical and quality-of-life improve-
330 Blaiss
ment than loratadine tablets. There was no added benefit to the combination of
loratadine tablets and fluticasone nasal spray compared to fluticasone nasal
spray alone.
Weiner performed a meta-analysis of articles comparing intranasal cortico-
steroids and nonsedating H 1-antagonists in the management of allergic rhinitis
(51). The conclusions gained from this study point out the greater improvement
in allergic rhinitis symptoms with intranasal corticosteroids, except in eye symp-
toms, for which both agents were equal. The authors were not truly able to analyze
cost-effectiveness from the studies, but did compare the mean daily cost of oral
corticosteroids in Australia (by asking pharmacists in four Australian states) with
the mean daily cost of intranasal corticosteroids. Their surveillance data found
that second-generation H 1-antagonists were 4.5 times more expensive daily than
intranasal corticosteroids. Stempel did an evidence-based analysis comparing
these agents in allergic rhinitis management and came to the same conclusion
(52). A study in South Africa found that intranasal corticosteroids were the least
costly in the management of allergic rhinitis (53).
In summary, these studies indicate that the intranasal corticosteroids are
more cost-effective than the second-generation H 1-antagonists in the management
of allergic rhinitis. It is important to remember that convenience and compliance
are deciding factors in chronic use of medication. Oral medications have a higher
compliance rate than inhaled agents (54). Also, these studies were primarily effi-
cacy-based, involving patients using the medications during short-term clinical
trials. In ‘‘real life’’ many patients only use these agents on an as-needed basis.
Informing patients of the pros and cons of each type of medication and allowing
them to participate in deciding on their pharmacological management may be
the best approach for highest compliance.
Allergen immunotherapy (vaccinations) is the administration of low, and
then sequentially increasing, dosages of allergens by subcutaneous injection in
patients with IgE-mediated diseases, such as allergic rhinitis, allergic asthma, and
insect sting anaphylaxis (55). It has been shown to be efficacious in the treatment
of patients with allergic rhinitis (56, 57). Sullivan reported that the average direct
costs for immunotherapy at Emory University were $800 for the first year and
$170 for next 2–4 years (58). The estimated costs for immunotherapy based on
the Medicare payment schedule are $1640, which includes 24 injections to main-
tenance dose, followed by monthly injections for 3–5 years and allergen extract
preparation for 10 allergens (59).
In determining the cost-effectiveness of allergen immunotherapy, Kumar
looked at costs of treatment and quality of life in patients with allergic rhinitis
prior to allergen immunotherapy and then assessed these variables yearly for 3
years of immunotherapy (60). The cost of care was $1129 ⫾ 321 in the year
prior to immunotherapy and $950 ⫾ 352 for the third year of allergen immuno-
therapy. This study suggests that allergen immunotherapy is no more costly by
the third year than allergy treatment without immunotherapy, with significant
improvement in quality of life. Direct comparisons of cost-effectiveness of immu-
notherapy and H 1-antagonists are not available.
VII. ATOPIC DERMATITIS
Management of patients with atopic dermatitis involves topical emollients, mild-

moderate-potency topical corticosteroids, and oral H 1-antagonists. In children in
whom a food allergen is implicated in the condition, removal of the offending
food can lead to significant improvement in skin manifestations. H 1-antagonists
can be beneficial in controlling the chronic pruritus accompanying this disorder.
Like allergic rhinitis, the prevalence of atopic dermatitis has been increasing in
the pediatric population. The onset in a majority of patients with atopic dermatitis
is in infancy, with 90% of patients presenting by 5 years of age. A recent estimate
of the annual total national cost for the treatment of childhood eczema in the
United States was $364 million (61). Su et al. evaluated the total costs of atopic
dermatitis in Australia based on degree of severity. The costs for medication per
year ranged from $200 Aus for mild disease to $469 Aus for severe disease. The
authors did not differentiate between different categories of medication in their
calculations; therefore, the exact contribution of H 1-antagonists’ cost in the total
medication’s cost is not known.
Studies comparing the cost-effectiveness of different H 1-antagonists in the
treatment of atopic dermatitis are lacking. Nunovo reported the use of single-
patient, double-blind controlled studies looking at efficacy of different H 1-antago-
nists (62). This work found that in both patient and physician preference, chlor-
pheniramine produced the most noticeable positive therapeutic effect on the pa-
tient’s mild but disturbing symptoms (pruritus and eye irritation) compared to
the nonsedating H 1-antagonists. Drowsiness was reported with chlorpheniramine.
Although it appears as if the sedative effect of the first-generation agents adds
to their benefit for nighttime control of pruritus and they bring significant cost
savings compared to the newer nonsedating H 1-antagonists, they have the disad-
vantage of producing adverse effects on patients’ school or work performance
and other daytime activities.
VIII. URTICARIA AND ANGIOEDEMA
Urticaria and angioedema (Chap. 8) can have a marked effect on the patient’s
quality of life. O’Donnell used a generic quality-of-life instrument, the Notting-
ham health profile, and showed that patients with delayed pressure urticaria had
scores showing restriction in the areas of mobility, sleep, and energy, and demon-
332 Blaiss
strated high scores in pain, social isolation, and altered emotional reactions (63).
H 1-antagonists are the first-line therapy for patients with both acute and chronic
urticaria and angioedema. First-generation agents are effective for many forms
of urticaria and angioedema, and recent studies have documented the value of
the second-generation H 1-antagonists in controlling symptoms (64–66). Research
is lacking in comparing the cost-effectiveness of H 1-antagonists in this condition
compared to other medications, although it is clear that their safety and efficacy
outweigh such treatments as corticosteroids, tricyclic antidepressants, and immu-
nosuppressive therapy, such as cyclosporine. At present there are no studies as-
sessing cost-effectiveness between the first- and second-generation H 1-antago-
nists in controlling urticaria and angioedema. As with all chronic diseases treated
with first-generation H 1-antagonists, one needs to weigh the decreased cost of
these agents compared to second-generation agents against the sedative and other
adverse effects seen with first-generation agents that can increase indirect costs.
IX. ASTHMA
Controversy exists on the role of H 1-antagonists in the management of asthma

(Chap. 7). Some studies suggest that H 1-antagonists, especially the second-gener-
ation compounds, may be efficacious in some patients (67, 68). A meta-analysis
by Van Ganse failed to confirm an advantage of treatment with these medications
(69). If further data suggest the efficacy of H 1-antagonists in the treatment of
asthma, studies evaluating the cost-effectiveness of these agents would be worth
pursuing because of the high direct and indirect costs associated with this disease
(70).
X. ANAPHYLAXIS
H 1-antagonists are considered adjunctive treatment to epinephrine injection in

patients with anaphylaxis. Their minimal contribution to the total cost of care in
patients with this life-threatening condition does not lend itself to studies assess-
ing cost-effectiveness among different H 1-antagonists in anaphylaxis manage-
ment.
XI. SUMMARY
In the health care arena, assessment of a medication’s clinical efficacy is no longer

enough. It is important to confirm the medication’s cost-effectiveness and the
improvement in quality of life it provides in relationship to other options in ther-
apy. H 1-antagonists are widely used in the treatment of many atopic disorders,
especially allergic rhinitis. This review has pointed out cost-effectiveness and
quality-of-life studies comparing the different H 1-antagonists among themselves,
and with other treatments used in allergic rhinitis, such as intranasal corticoste-
roids and allergen immunotherapy. Cost-effective analyses among H 1-antagonists
in other allergic diseases, such as atopic dermatitis, urticaria and angioedema,
and asthma, are lacking at this time.
REFERENCES
1. Drummond MF, Stoddart GL, Torrance GW. Methods for the Economic Evaluation
of Health Care Programmes. New York: Oxford University Press, 1987.
2. Sullivan SD. Cost and cost-effectiveness in asthma. Immunol Allergy Clin North
Am 1996; 16:819–839.
3. Blaiss M, Bukstein D, Davis M, Luskin A. Improving allergy and asthma care
through outcomes management. In: Davis M, ed. Managed Care Focus Series. Chi-
cago: American Academy of Allergy, Asthma, and Immunology, 1997.
4. Eisenberg JM. Clinical economics: a guide to the economic analysis of clinical prac-
tices. JAMA 1989; 262:2879–2886.
5. Luce BR, Manning WG, Siegel JE, Lipscomb J. Estimating costs in cost-effective-
ness analysis. In: Gold MR, Siegel JE, Russell LB, Weinstein MC, eds. Cost-Effec-
tiveness in Health and Medicine. New York: Oxford University Press, 1996:176–
213.
6. Gibaldi M, Sullivan SD. A look at cost-effectiveness. Pharmacotherapy 1994; 14:
399–414.
7. Rich MW, Nease RF. Cost-effectiveness analysis in clinical practice: the case of
heart failure. Arch Intern Med 1999; 159:1690–1700.
8. Patrick DL, Erickson P. Health Status and Health Policy: Quality of Life in Health
Care Evaluation and Resource Allocation. New York: Oxford University Press,
1993.
9. Nord E. The QALY—a measure of social value rather than individual utility? Health
Econ 1994; 3:89–93.
10. Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB. Recommendations
of the panel on cost-effectiveness in health and medicine. JAMA 1996; 276:1253–
1258.
11. Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36): I.
Conceptual framework and item selection. Med Care 1992; 30:473–483.
12. Bousquet J, Bullinger M, Fayol C, Marquis P, Valentin B, Burtin B. Assessment of
quality of life in patients with perennial allergic rhinitis with the French version of
the SF-36 Health Status Questionnaire. J Allergy Clin Immunol 1994; 94:182–188.
13. Juniper EF. Measuring health-related quality of life in rhinitis. J Allergy Clin Immu-
nol 1997; 99:S742–749.
14. Juniper EF, Guyatt GH, Griffith LE, Ferrie PJ. Interpretation of rhinoconjunctivitis
quality of life questionnaire data. J Allergy Clin Immunol 1996; 98:843–845.
334 Blaiss
15. Meltzer EO, Nathan RA, Selner JC, Storms W. Quality of life and rhinitic symptoms:
results of a nationwide survey with the SF-36 and RQLQ questionnaires. J Allergy
Clin Immunol 1997; 99:S815–819.
16. Sibbald B, Rink E. Epidemiology of seasonal and perennial rhinitis: clinical presen-
tation and medical history. Thorax 1991; 46:895–901.
17. Naclerio RM. Allergic rhinitis. N Engl J Med 1991; 325:860–869.
18. Arrighi HM, Maier WC, Redding GJ, Morray BH, Llewellyn CE. The impact of
allergic rhinitis in Seattle school children (abstract). J Allergy Clin Immunol 1995;
95:192.
19. McMenamin P. Costs of hay fever in the United States in 1990. Ann Allergy 1994;
73:35–39.
20. Ross RN. Allergic rhinitis, an expensive disease for American business. Am J Manag
Care 1996; 2:285–290.
21. Malone DC, Lawson KA, Smith DH, Arrighi HM, Battista C. A cost of illness study
of allergic rhinitis in the United States. J Allergy Clin Immunol 1997; 99:22–27.
22. Storms W, Meltzer EO, Nathan RA, Selner JC. The economic impact of allergic
rhinitis. J Allergy Clin Immunol 1997; 99:S820–824.
23. Mackowiak J. The health and economic impact of rhinitis—a roundtable discussion.
Am J Managed Care 1997; 3:S8–S18.
24. Ray NF, Baraniuk JN, Thamer M, Rinehart CS, Gergen PJ, Kaliner M, Josephs S,
Pung YH. Direct expenditures for the treatment of allergic rhinoconjunctivitis in
1996, including the contributions of related airway illnesses. J Allergy Clin Immunol
1999; 103:401–407.
25. 2001 Drug Topics Red Book. Montvale, NJ: Medical Economic Company, 1999.
26. Nolen TM. Sedative effects of antihistamines: safety, performance, learning, and
quality of life. Clin Ther 1997; 19:39–55.
27. Storms WW. Treatment of allergic rhinitis: effects of allergic rhinitis and antihista-
mines on performance. Allergy Asthma Proc 1997; 18:59–61.
28. Kemp JP. Special considerations in the treatment of seasonal allergic rhinitis in ado-
lescents: the role of antihistamine therapy. Clin Pediatr (Phila) 1996; 35:383–
389.
29. Simons FE. Learning impairment and allergic rhinitis. Allergy Asthma Proc 1996;
17:185–189.
30. Vuurman EF, van Veggel LM, Uiterwijk MM, Leutner D, O’Hanlon JF. Seasonal
allergic rhinitis and antihistamine effects on children’s learning. Ann Allergy. 1993;
71:121–126.
31. Fireman P. Treatment of allergic rhinitis: effect on occupation productivity and work
force costs. Allergy Asthma Proc 1997;18:63–67.
32. Busse WW. Role of antihistamines in allergic disease. Ann Allergy 1994; 72:371–
375.
33. Du Buske LM. Clinical comparison of histamine H 1-receptor antagonist drugs. J
Allergy Clin Immunol 1996; 98:S307–318.
34. Adelsberg BR. Sedation and performance issues in the treatment of allergic condi-
tions. Arch Intern Med 1997; 157:494–500.
35. Pedinoff AJ. Approaches to the treatment of seasonal allergic rhinitis. South Med
J 1996; 89:1130–1139.
36. Pariente PD, LePen C, Los F, Bousquet J. Quality-of-life outcomes and the use of
antihistamines in a French national population-based sample of patients with peren-

nial rhinitis. Pharmacoeconomics 1997; 12:585–595.
37. Mann RD, Pearce GL, Dunn N, Shakir S. Sedation with ‘‘non-sedating’’ antihista-
mines: four prescription-event monitoring studies in general practice. Br Med J 2000;
320:1184–1187.
38. Bousquet J, Duchateau J, Pignat JC, Fayol C, Marquis P, Mariz S, Ware JE, Valentin
B, Burtin B. Improvement of quality of life by treatment with cetirizine in patients
with perennial allergic rhinitis as determined by a French version of the SF-36 ques-
tionnaire. J Allergy Clin Immunol 1996; 98:309–316.
39. Slater JW, Zechnich AD, Haxby DG. Second-generation antihistamines: a compara-
tive review. Drugs 1999; 57:31–47.
41. Conde Hernandez DJ, Palma Aqilar JL, Delgado Romero J. Comparison of azelas-
tine nasal spray and oral ebastine in treating seasonal allergic rhinitis. Curr Med Res
Opin 1995; 13:299–304.
42. Gastpar H, Nolte D, Aurich R, Brendt P, Enzmann H, Giesemann G, Kunkel G,
Petzold U, Renz W, Schata M, et al. Comparative efficacy of azelastine nasal spray
and terfenadine in seasonal and perennial rhinitis. Allergy 1994; 49:152–158.
43. Bronsky EA, Dockhorn RJ, Meltzer EO, Shapiro G, Boltansky H, La Force C, Ran-
som J, Weiler JM, Blumenthal M, Weakley S, Wisniewski M, Field E, Rogenes P.
Fluticasone propionate aqueous nasal spray compared with terfenadine tablets in the
treatment of seasonal allergic rhinitis. J Allergy Clin Immunol 1996; 97:915–
921.
44. Gehanno P, Desfougeres JL. Fluticasone propionate aqueous nasal spray compared
with oral loratadine in patients with seasonal allergic rhinitis. Allergy 1997; 52:445–
450.
45. Jordana G, Dolovich J, Briscoe MP, Day JH, Drouin MA, Gold M, Robson R,
Stepner N, Yang W. Intranasal fluticasone propionate versus loratadine in the treat-
ment of adolescent patients with seasonal allergic rhinitis. J Allergy Clin Immunol
1996; 97:588–595.
46. Kozma CM, Schulz RM, Sclar DA, Kral KM, Mackowiak JI. A comparison of costs
and efficacy of intranasal fluticasone propionate and terfenadine tablets for seasonal
allergic rhinitis. Clin Ther 1996; 18:334–346.
47. Berka C, Chin W. Fluticasone propionate intranasal steroid: cost-effectiveness vs.
antihistamines. J Allergy Clin Immunol 1994; 93:165 (abstract).
48. Bernstein DI, Creticos PS, Busse WW, Cohen R, Graft DF, Howland WC, Lumry
WR, Pedinoff AJ, Rutner PH, Lim J, Stokes A, McNally C. Comparison of triamcin-
olone acetonide nasal inhaler with astemizole in the treatment of ragweed-induced
49. Schoenwetter W, Lim J. Comparison of intranasal triamcinolone acetonide with oral
loratadine for the treatment of patients with seasonal allergic rhinitis. Clin Ther 1995;
17:479–492.
50. Schulz RM, Smith DH, Lim J. Quality of life in patients with seasonal allergic rhini-
tis: triamcinolone acetonide aqueous nasal spray versus loratadine (abstract). Ann
Allergy Asthma Immunol 1997; 78:155.
336 Blaiss
51. Weiner JM, Abramson MJ, Puy RM. Intranasal corticosteroids vs oral H 1-receptor
antagonists in allergic rhinitis: systematic review of randomized controlled trials.
Br Med J 1998; 317:1624–1629.
52. Stempel DA, Thomas M. Treatment of allergic rhinitis: an evidence-based evaluation
of nasal corticosteroids versus nonsedating antihistamines. Am J Managed Care
1998; 4:89–96.
53. Wessels F, Green R, Luyt D. Cost of therapy for allergic rhinitis. S Afr Med J 1997;
87:141–145.
54. Kelloway JS, Wyatt RA, Adlis SA. Comparison of patients’ compliance with pre-
scribed oral and inhaled asthma medications. Arch Intern Med 1994; 154:1349–
1352.
55. Hedlin G. The role of immunotherapy in pediatric allergic disease. Curr Opin Pediatr
1995; 7:676–682.
56. Creticos PS. The role of immunotherapy in allergic rhinitis/allergic asthma. Allergy
Proc 1995; 16:297–302.
57. Donovan JP, Buckeridge DL, Briscoe MP, Clark RH, Day JH. Efficacy of immuno-
therapy to ragweed antigen tested by controlled antigen exposure. Ann Allergy
58. Sullivan TJ. Expert Care and Immunotherapy for Asthma. Chicago: American Col-
lege of Allergy, Asthma, and Immunology, 1996.
59. American Medical Association. Medicare RBRVS: The Physician’s Guide, 1995.
60. Kumar P, Kamboj S, Rao P. The cost of care and quality of life in patients with
allergic rhinitis on allergen immunotherapy. Allergy Clin Immunol Int 1997; 9:133–
135.
61. Lapidus CS, Schwarz DF, Honig PJ. Atopic dermatitis in children: who cares? Who
pays? J Am Acad Dermatol 1993; 28:699–703.
62. Nuovo J, Ellsworth AJ, Larson EB. Treatment of atopic dermatitis with antihista-
mines: lessons from a single-patient, randomized clinical trial. J Am Board Fam
Pract 1992; 5:137–141.
63. O’Donnell BF, Lawlor F, Simpson J, Morgan M, Greaves MW. The impact of
chronic urticaria on the quality of life. Br J Dermatol 1997; 136:197–201.
64. Monroe EW. Loratadine in the treatment of urticaria. Clin Ther 1997; 19:232–242.
65. Tharp MD. Cetirizine: a new therapeutic alternative for chronic urticaria. Cutis 1996;
58:94–98.
66. Soter NA. Treatment of urticaria and angioedema: low-sedating H 1-type antihista-
mines. J Am Acad Dermatol 1991; 24:1084–1087.
67. Malick A, Grant JA. Antihistamines in the treatment of asthma. Allergy 1997; 52:
55–66.
68. Grant JA, Nicodemus CF, Findlay SR, Glovsky MM, Grossman J, Kaiser H, Meltzer
EO, Mitchell DQ, Pearlman D, Selner J, Settipane G, Silvers W. Cetirizine in pa-
tients with seasonal rhinitis and concomitant asthma: prospective, randomized, pla-
cebo-controlled trial. J Allergy Clin Immunol 1995; 95:923–932.
69. Van Ganse E, Kaufman L, Derde MP, Yernault JC, Delaunois L, Vincken W. Effects
of antihistamines in adult asthma: a meta-analysis of clinical trials. Eur Respir J
1997; 10:2216–2224.
70. Weiss KB, Gergen PJ, Hodgson TA. An economic evaluation of asthma in the
United States. N Engl J Med 1992; 326:862–866.
11
H 1-Antihistamines and the Central
Nervous System
Michael J. Welch and Eli O. Meltzer

Allergy and Asthma Medical Group and Research Center and
University of California, San Diego, San Diego, California
I. INTRODUCTION
First-generation histamine-1-receptor (H 1-receptor) antagonists such as diphenhy-

dramine, triprolidine, hydroxyzine, and chlorpheniramine (chlorphenamine), fre-
quently cause somnolence, performance impairment, and other adverse central
nervous system (CNS) effects. Various subjective and objective methods have
been utilized to detect these adverse effects. Because the CNS changes induced
by H 1-antagonists are complex and cannot be reflected in one measurement, a
variety of assessments are required. Dosing strategies have been proposed to
circumvent these unwanted effects (pm dosing, relying on tolerance to CNS ef-
fects to develop) but their effectiveness is at best uncertain. Second-generation
H 1-antagonists such as loratadine, cetirizine, fexofenadine, ebastine, and mizolas-
tine represent a true advance in therapeutics. At manufacturers’ recommended
dosages, they result in little or no sedation in contrast to their predecessors, and do
not exacerbate the adverse CNS effects of alcohol or other CNS-active chemicals.
Differences among various agents within each generation of H 1-antagonists
in their effects on the CNS have been noted, and with certain of the second-
generation H 1-antagonists (e.g., acrivastine and cetirizine), these differences can
be clinically relevant. When given in higher than usual dosages by mouth, or
even when applied topically, some subjective and/or objective CNS abnormali-
ties have been noted with certain second-generation H 1-antagonists. Given the
337
338 Welch et al.
availability of the safer second-generation products, the future usefulness of the

older first-generation H 1-antagonists used orally in allergic disease is in doubt.
The need for a phase-out plan of the sedating first-generation H 1-antagonists will
likely become more clear as we collect further experience and information about
the advantageous benefit/risk ratio of the second-generation H 1-antagonists.
II. FIRST- VERSUS SECOND-GENERATION

H 1-ANTIHISTAMINES
Orally administered H 1-antagonists are an integral part of pharmacotherapy for

allergic disease. H 1-antagonists applied topically to mucosal surfaces are avail-
able as well. Use of the traditional or first-generation H 1-antagonists (Table 1)
has been limited by adverse CNS effects. Many allergic individuals choose to
suffer with their symptoms and ignore the benefits of H 1-antagonists rather than
endure the soporific effects of the old sedating medications in this class. Although
new or second-generation H 1-antagonists with less potential for CNS adverse
effects have become available (Table 2), the problems of somnolence and impair-
ment with H 1-antagonists continue to exist, and will likely continue for some
time. The reason is that the old sedating agents are present in numerous over-
the-counter (OTC) allergy and cold formulations, and are inexpensive and widely
used by millions of allergy sufferers throughout the world. It is estimated that
over 1.4 billion dollars per year is spent on OTC antihistamine-containing prod-
ucts in the United States alone (1). Because second-generation nonsedating H 1-
antagonists are available by prescription only in some countries, including the
United States, and are more costly than their predecessors, first-generation H 1-
Table 1 Selected First-Generation H 1-Antihistaminesa
Alkylamines Piperidines
Brompheniramine (Dimetane) Azatadine (Optimine)
Chlorpheniramine (Chlor-Trimeton) Cyproheptadine (Periactin)
Dexchlorpheniramine (Polaramine) Phenindamine (Nolahist)
Ethanolamines Piperazines
Carbinoxamine (Clistin) Hydroxyzine hydrochloride (Atarax)
Clemastine (Tavist) Hydroxyzine pamoate (Vistaril)
Dimenhydrinate (Dramamine) Meclizine (Antivert)
Diphenhydramine (Benadryl)
Doxylamine (Unisom)
Ethylenediamines
Tripelennamine (PBZ)
a
U.S. brand names are given in parentheses.
Effects on CNS 339
Table 2 Second-Generation H 1-Antihistaminesa
Generic name Brand name Comments
Fexofenadine Allegra
Loratadine Claritin
Cetirizine Zyrtec
Acrivastine Semprex D Available only as a combination
antihistamine-decongestant
Ebastine NA
Mizolastine NA
Ketotifen Zaditor Available only as ophthalmic drops in USA
Azelastine Astelin Available only as nasal spray and ophthalmic drops
in USA
Levocabastine Livostin Available only as ophthalmic drops
a
U.S. brand names are given.
antagonists are still being selected by consumers and recommended by some

physicians.
The most common and bothersome adverse effect of H 1-antagonists is CNS
depression or sedation, but other adverse nervous system effects may occur. Most
first-generation H 1-antagonists possess anticholinergic properties, and can cause
blurred vision, dry mouth, urinary retention, impotence, and gastrointestinal ef-
fects, mainly due to their peripheral nervous system activity. Central manifesta-
tions of their anticholinergic activities include hallucinations and psychosis, even
at therapeutic dosages (2). Some, such as promethazine, have alpha-adrenergic-
blocking ability. Others, such as cyproheptadine, are effective inhibitors of both
histamine and serotonin activity, and may cause appetite stimulation and weight
gain (3) or aggressive, violent behavior (4), both of which are thought to be
related to the drug’s effects on serotonin pathways. Rare adverse effects have
also been described either with chronic use or high-dosage acute use of first-
generation H 1-antagonists and include dyskinesia, muscle spasms, tremor, activa-
tion of epileptogenic foci, paresthesias, and various psychiatric disturbances such
as anxiety, confusion, hallucinations, and psychosis (5–7).
Second-generation H 1-antagonists were developed after a long and costly
search for H 1-antagonists that did not have sedative properties. The initial non-
sedating compound introduced for clinical use was terfenadine, the earliest of
what have been termed ‘‘second-generation’’ H 1-receptor antagonists. A number
of additional agents have since become available (e.g., acrivastine, astemizole,
loratadine, cetirizine, fexofenadine, ebastine, mizolastine, levocabastine, azelas-
tine). Second-generation, relatively nonsedating H 1-antagonists have been com-
pared with first-generation agents and placebo in an extensive number of con-
trolled subjective and objective studies. Findings from these studies confirm the
340 Welch et al.
clinical impression held by physicians: these second-generation H 1-antagonists

are better tolerated and safer than their predecessors (8–15). Specifically, second-
generation H 1-antagonists produce significantly less somnolence and other ad-
verse CNS effects than the first-generation H 1-antagonists, and do not exacerbate
the adverse CNS effects of alcohol and other CNS-active chemicals. They also
appear to have little or no affinity for muscarinic cholinergic receptors and there-
fore do not cause dry mouth or other anticholinergic effects (16, 17). Most do
not have antiserotoninergic activities, and do not cause appetite stimulation or
weight gain, although this has been reported in some patients after astemizole
and ketotifen administration (18, 19).
Over the last several years, two of the original second-generation H 1-antag-
onists (terfenadine and astemizole) have been removed from the market in most
countries. An extensive body of literature pertains to these two very important
and widely used H 1-antagonists. Because they are no longer available to patients,
they will not be discussed in detail in this chapter. However, they may be men-
tioned or referred to when needed for historical reasons, or because they were
used as comparators in studies of other H 1-antagonists.
III. THE BLOOD–BRAIN BARRIER AND MECHANISMS

OF CNS ADVERSE EFFECTS
The blood–brain barrier, formed by endothelial cells lining CNS capillaries, has
evolved to provide a stable chemical environment for neurons. Endothelial cells
in CNS capillaries are characterized by tight junctions, with cell membranes being
fastened along the length of their contact. The capillaries are encased by
astrocytes. Lipid-soluble molecules travel freely across these endothelial mem-
branes, but other chemicals need the help of pinocytosis, receptors, or specific
transport mechanisms (20).
Most first-generation H 1-antagonists readily penetrate the blood–brain bar-
rier (21). The variable propensity of these medications to cause somnolence and
other CNS effects now limits their use in the treatment of allergic disorders. In
other patient populations, some of these CNS effects are considered to be thera-
peutic; for example, the use of nonprescription dimenhydrinate for the treatment
of motion sickness and diphenhydramine or doxylamine as medications for in-
somnia.
The mechanisms by which the first-generation H 1-antagonists cause useful
and adverse CNS effects are still being elucidated. The role of histamine as a
neurotransmitter is now firmly established. Histamine has important neuromodu-
latory influences on CNS electrophysiology that determine normal thalamocorti-
cal function in the brain (22). The histaminergic system seems to be concerned
with mechanisms that favor vigilance during the wakeful state and the balance
Effects on CNS 341
between wakefulness and slow-wave activity during sleep (23). Histamine also
functions as a neuroregulator for higher brain functions (e.g., cognition, memory),
with deficits of the histaminergic system having been implicated as playing an
important role in major diseases such as Alzheimer’s, schizophrenia, and Down
syndrome (24–26). Histaminergic pathways are widespread. They originate from
the reticular formation and project diffusely to the cerebral cortex. Most first-
generation H 1-antagonists in therapeutic dosages lead to the occupation of a major
fraction of the cerebral H 1-receptors; hence, central effects in humans are thought
to be predominantly mediated by a blockade of endogenous histamine (22).
Yanai, (27) using positron emission tomography and comparing the histamine
H 1-receptor occupancy between chlorpheniramine and terfenadine, demonstrated
that first-generation H 1-antagonists in recommended doses occupied almost all
H 1-receptors in the brain and that the full occupancy of H 1-receptors was closely
related to their unwanted central side effects. Further proof that somnolence and
CNS dysfunction arise from H 1-antagonism alone within the CNS is based on
studies demonstrating that subjective and objective measurements of drowsiness
and performance are limited to H 1-antagonist enantiomers with a high affinity
for CNS histamine H 1-receptors. For example, (⫹)-chlorpheniramine (chlorphen-
amine) and (⫺)-dimethindene enantiomers produce sleepiness, decrease daytime
sleep latency, and impair digit–symbol substitution tests, whereas the enantio-
mers (⫺)-chlorpheniramine and (⫹)-dimethindene, both of which have low af-
finity for the H 1-receptor, do not differ from placebo in their subjective or objec-
tive CNS effects (28). Other mechanisms may play a role in the central effects
of some H 1-antagonists, such as their known ability to inhibit the metabolism of
histamine by N-methyltransferase, and the additional ability of some to block
cholinergic, alpha-adrenergic, and serotonin receptors in the brain.
The idea that peripheral and central H 1-receptors differ (29) is no longer
accepted; however, H 1-receptor subtypes possibly exist (30). Also, in contrast to
earlier views (31), it is now believed the H 1-antagonists probably have similar
affinity for peripheral H 1-receptors and for central H 1-receptors (32). The precise
structural requirements for receptor selectivity and affinity are still being eluci-
dated (33).
Most of the second-generation H 1-antagonists penetrate poorly into the
CNS, which accounts for their relative nonsedating properties. The proportional
contribution of factors such as large molecular size, electrostatic charge, lipo-
philicity, binding to serum albumin, and small volume of distribution to this phe-
nomenon is either unknown or is still being elucidated (34, 35). The addition of
a chemical group that is ionized at physiological pH will convert a potentially
sedating H 1-antagonist into a less sedating one. For example, the oxidation of
the terminal alcohol group of hydroxyzine to a carboxylic acid group results in
cetirizine, which is less sedating than its parent compound. The second-genera-
tion H 1-antagonists also have much less affinity for muscarinic cholinergic and
342 Welch et al.
serotoninergic receptors than their predecessors do, and this, too, contributes to
their relative lack of adverse CNS effects (31, 36–38).
IV. ASSESSMENT OF CNS EFFECTS
CNS effects after oral H 1-antagonist administration have been assessed subjec-
tively (self-reported impairment) and objectively (investigator-measured impair-
ment) (12, 39) (Table 3). One common source of subjective assessment is from
clinical trials of H 1-antagonists in large numbers of patients with chronic allergic
rhinitis or urticaria (15, 40). Adverse CNS effects in these trials are usually unso-
licited: patients are asked to simply state if they had any problems while taking
the medication being studied. The data obtained in these multiple-dose studies
reflect ‘‘real-life’’ conditions (the disorder being treated, as well as the treatment
itself ) and are thus helpful. Subjective information is also obtained in a more
direct and quantifiable way by having patients self-rate CNS symptoms such as
somnolence, impairment of concentration, or fatigue, using a simple scoring sys-
tem, a standardized score such as Stanford Sleepiness Scale, Leeds sleep evalua-
tion score, Epworth Scale, the Profile-of-Moods Questionnaire, or a linear or
visual analog rating scale.
In objective studies (Table 3), usually performed in healthy volunteers,
performance tests and several electroencephalographic (EEG) tests are used to
assess CNS function. Drowsiness can be objectively measured through the use
of the EEG, such as with continuous 24-hour EEG monitoring. The multiple sleep
latency test measures the time needed to induce EEG signs of stage 1 sleep in
individuals given repeated opportunities to fall asleep. The EEG, in particular
the P300 (or P3), a positive auditory EEG response, can also be used as an objec-
tive and sensitive measure of sustained attention and cerebral processing speed.
Its latency depends on the amount of time required for evaluation of the stimulus.
Medications that cause cognitive impairment can prolong P300 latency. Objective
EEG tests are useful in that they are not influenced by subjects’ motivation, per-
formance strategy, task familiarity, boredom, memory, or amount of practice.
Objective assessment of the effects of H 1-antagonists on performance
and learned tasks involves sensorimotor coordination, memory, CNS arousal/
information processing, and psychomotor tests. Most investigators use a battery
of standardized tests which, although influenced by a number of patient variables
that are difficult to control fully, are believed to be representative of real-life
functions. The relative sensitivity of the various performance tests in identifying
persons susceptible to CNS dysfunction from H 1-antagonists is not well docu-
mented. The critical flicker fusion (CFF) test, a task of cognitive capacity, and
the choice reaction time (CRT) test, a measure of sensorimotor performance, are
both thought to be sensitive indicators of impairment with H 1-antagonists.
Effects on CNS 343
Table 3 Tests Used to Assess CNS Function After H 1-Antihistamine Treatment
Subjective
Adverse event reporting in clinical trials (unsolicited; multiple-dose, real-life condi-
tions)
Scoring systems (volunteers asked specifically about somnolence or impairment)
Stanford Sleepiness Scale (SSS)
Leed’s sleep evaluation score
Profile-of-moods status questionnaire
Linear analog rating scale (LARS)
Visual analog rating scale (VARS)
Objective
Electroencephalogram (EEG) tests
Continuous EEG monitoring
Multiple sleep latency (time to stage 1 EEG sleep when subjects are given re-
peated opportunities to sleep under standardized daytime conditions)
P3 or P300 event-related potential (time-locked electrical field potential reflecting
active cognitive processing of information)
Performance Tests
Sensorimotor coordination
Critical tracking test (using a control stick to keep an oscillating vertical line in
the center of a television screen)
Adaptive tracking
Pursuit meter or rotor
Trials B maze
Visuomotor coordination
Reaction time
Simple
Choice
Auditory
Memory
Waking
Visual
Short-term, long-term
Sensory
Attention task
Auditory vigilance
Continuous performance task
Spatial perception
Dynamic visual acuity (determining the orientation of gaps in rings as the images
sweep by)
CNS arousal information processing
Mental arithmetic
Visual screening
Digit-symbol substitution (filling in blank spaces with the appropriate symbol indi-
cated by a code)
344 Welch et al.
Table 3 Continued
Color test
Stroop test
Critical flicker fusion (defining the frequency at which a group of flickering lights
appears steady)
Motor ability
Glass bead picking test
Dexterity tests
Psychomotor
Computerized simulated car driving
Computerized flight simulator
Actual car-driving tests (steering, weaving and gap acceptance; usually computer
monitored)
The Digit Symbol Substitution Test, a simple pencil and paper test, believed to
measure integration, speed, and accuracy of visual and fine motor skills, is also
employed in a large number of studies and appears to be a reliable indicator
of sedation (41). Actigraphy, the process in which one continuously measures
movement (the motor component of behavior throughout the day) has been used
to detect impairments in performance and to overcome the problems associated
with testing at fixed time intervals. Tests involving complex sensorimotor activi-
ties (e.g., application of learned strategy, car tracking, simulated driving or flying
tests, or, where permitted by law, computer-monitored on-the-road driving tests)
have also been utilized, and are believed to be more representative than simple
tests of reaction time or memory (41). In a few performance studies, a school
environment (42, 43) or a work environment (44–46) has been simulated.
Most of the objective performance and EEG studies have been conducted
following a single H 1-antagonist dose in healthy volunteers, using a double-blind,
crossover study design. Multiple-dose studies, studies in patients with allergic
disorders such as rhinitis or urticaria, and dose–response studies are less common.
In an ideal situation, a new H 1-antagonist is compared not only with placebo but
also with an H 1-antagonist known to be sedating, so that the sensitivity of the tests
being used to identify CNS dysfunction can be assessed. If an old H 1-antagonist
comparator either is not given or is given but does not produce impairment of
CNS function, it cannot be ascertained if the tests being used have the required
sensitivity. Tests are usually performed at baseline and at one or more additional
preselected intervals, almost always including tests 2–3 h postdose, at the time
of anticipated peak serum concentrations, and presumably peak CNS effects. In
some studies, attempts have been made to relate CNS effects to peripheral H 1-
blockade and/or to serum H 1-antagonist concentrations (47–58). This is helpful
Effects on CNS 345
in the interpretation of test results and prevents the problem of mistakenly identi-
fying an H 1-antagonist as being nonsedating when, in fact, the dose administered
was too low to produce adequate peripheral H 1-blockade and was, therefore, clini-
cally irrelevant.
In EEG and performance studies, after H 1-antagonist administration there
is generally good correlation among the objective tests (56, 59–65). The relation-
ship between performance and subjective feelings of somnolence, however,
seems to be more complex and less well understood. Sleepiness/alertness level
provides a basic capacity (or incapacity) for performance. Performance, therefore,
should be lowest when alertness is lowest and sleepiness is highest; however, it
can be modified by factors such as motivation and task familiarity. In most studies
in which subjective and objective measures are used, patients who report somno-
lence or show EEG evidence of decreased sleep latency also have performance
impairment on psychomotor tests or driving tests. Various researchers, however,
have reported an inconsistent correlation between the symptoms and measures
of drowsiness and H 1-antagonist-induced mental impairment. The most common
type of discrepancy between subjective and objective measures of sedation occurs
when the patient shows impairment on psychomotor tests but does not report a
Figure 1 Effects of cetirizine 10 mg, hydroxyzine 50 mg, diphenhydramine 50 mg, and

placebo on objective testing of CNS function. Percentage difference from baseline in the
latency of the P300 event-related potential 2.5 h after drug ingestion. EEG recordings
made at the PZ electrode. Double-blind, placebo-controlled, single-dose four-way cross-
over design in 20 healthy subjects. *p ⬍ 0.05 from pre-dose; **p ⬍ 0.05 from cetirizine;
†p ⬍ 0.005 from placebo. (From Ref. 56.)
346 Welch et al.
subjective feeling of impairment or sleepiness (66–68). In a few studies, the

opposite phenomenon has been observed: although patients were able to achieve
good results on performance tests, they reported somnolence (69–71).
The results obtained in the single- and multiple-dose studies in healthy
volunteers generally correlate well with results obtained in studies of patients
with allergic disorders. An interesting, unexplained exception is that in many
objective EEG and performance studies cetirizine has been documented to be
free from objective CNS adverse effects (48, 52–54, 56, 57, 67, 72, 73) (Fig. 1),
yet it has been reported to produce more subjective somnolence than placebo in
patients with allergic rhinoconjunctivitis being evaluated in clinical trials for ef-
ficacy and safety (74–76) (Fig. 2).
A number of theories have been proposed for the more than occasional
observation of a lack of correlation between subjective and objective findings.
One hypothesis is that sleepiness and psychomotor performance may be caused
by different mechanisms (77). Another theory is that thresholds for objective
and subjective CNS effects of H 1-antagonists differ (i.e., the slope of the plasma
concentration vs. time curve may be steeper for impairment of performance than
Figure 2 Reports of somnolence in a clinical trial evaluation of cetirizine in 3 doses

compared with placebo in patients with seasonal allergic rhinoconjunctivitis. 10 mg and
20 mg doses of cetirizine were significantly different from placebo (*p ⬍ 0.05). (From
Ref. 75.)
Effects on CNS 347
for somnolence) (12, 49). It has also been postulated that the time course and
pattern for induction of sleepiness and performance impairment in the day do
not coincide, resulting in a potential poor correlation between the two types of
CNS effects (41). Finally, it has been suggested that self-assessments of perfor-
mance and sleepiness are basically unreliable and easily influenced by a multitude
of factors, while performance-based and objective measures are superior to sub-
jective ones, although also affected by changing performance strategies and/or
motivation levels (41). Whatever the mechanism, both subjective and objective
tests should be conducted in order to determine the potential for CNS impairment,
because either one alone may underestimate the CNS effects of an H 1-antagonist.
V. FIRST-GENERATION H 1-ANTIHISTAMINES
The true prevalence of CNS dysfunction after ingestion of first-generation H 1-

antagonists in recommended dosages is unknown. While some individuals seem
more prone than others to develop CNS dysfunction, the problems are surpris-
ingly common. For example, chlorpheniramine is not generally considered to be
a very sedating first-generation H 1-antagonist, yet approximately 45% of healthy
volunteers ingesting chlorpheniramine (4 mg) will have some objective impair-
ment of CNS function (70, 78, 79). Approximately 50% of healthy volunteers
ingesting diphenhydramine (50 mg) and 80% of volunteers ingesting hydroxyzine
(50 mg) will have some objective impairment of CNS function (56, 78). Impair-
ment of cognitive function, diminished alertness, and slow reaction times may
be documented even in the absence of complaints of somnolence. O’Hanlon de-
vised a specially instrumented automobile to evaluate ‘‘real-world’’ driving per-
formance by measuring lane weaving on the open road and in traffic (80). Triprol-
idine (10 mg) and two second-generation antihistamines, terfenadine (60 mg) and
loratadine (10 mg), were studied. The weaving tendency produced by triprolidine
was comparable to that seen in drivers with blood alcohol concentrations of
0.05%; terfenadine and loratadine had no undesirable effect on the weaving in-
dex. Although this effect of triprolidine persisted for up to 4 h, most drivers
reported sedative effects and impairment performance at 1–2 h but not at 3 and
4 h after drug ingestion. This suggests that the drivers had adapted to the sensation
of sedation, but not to the objective adverse effects of sedation on driving.
It has been hypothesized that patients with delayed elimination of first-
generation H 1-receptor antagonists, such as the elderly or those with hepatic dys-
function, may be particularly prone to CNS adverse effects that correlate with
peak serum and presumably peak CNS drug concentrations (21, 58, 81–83).
First-generation H 1-antagonists vary in their proclivity to cause CNS dys-
function, but significant impairment is well documented to occur after single
doses of diphenhydramine (25–50 mg), hydroxyzine (20–50 mg), triprolidine
348 Welch et al.
(1.25–10 mg), chlorpheniramine (4–8 mg), and clemastine (1–3 mg) (42, 44–
50, 52, 53, 55–57, 59, 61, 64, 65, 67, 69–73, 79, 81, 84–118). Impairment has
also been documented to occur after ingestion of azatadine, brompheniramine,
dimethindene, mequitazine, promethazine, trimeprazine, and tripelennamine (66,
70, 90, 96, 100, 108, 119–130).
First-generation H 1-antagonists are still commonly used for treatment of
symptoms of allergic disorders in children, since some of the newer nonsedating
H 1-antagonists are not available in pediatric formulations in many countries, and
because of the former’s low-cost nonprescription availability. Few objective eval-
uations of their adverse CNS effects have been performed in young subjects (42,
55, 131, 132). When diphenhydramine and hydroxyzine were studied in children
ages 6–12 years using objective (P300 latency test) and subjective (visual analog
scale) measures, CNS impairment was seen in much the same manner demon-
strated in adults with these measures of sedation (132). The elderly population
as a special group has also been studied in a limited fashion in terms of sensitivity
to H 1-antagonists. Results showed that first-generation H 1-antagonists such as
chlorpheniramine and diphenhydramine impair cognitive processing and cause
subjective somnolence in a way similar to young adults (58). (See Chapters 14 and
15 for more details regarding effects of H 1-antagonists in the young and elderly).
Diphenhydramine and other older H 1-antagonists were used in the past
for induction of sleep EEGs, and are still commonly used as a remedy by self-
medicating insomniacs (133–136). Six hours postdose, diphenhydramine (50 mg)
has a sedative effect comparable to that of alcohol and triazolam (137). Hydroxy-
zine continues to be used as a preoperative sedative and anxiolytic (138, 139).
VI. ATTEMPTS TO AVOID SEDATION FROM

FIRST-GENERATION H 1-ANTIHISTAMINES
Several strategies have been suggested for minimizing the sedative effects of H 1-
antagonists when used for the treatment of allergic rhinitis, allergic conjunctivitis,
or chronic urticaria. One strategy is to use a first-generation H 1-antagonist in a
single large dose at bedtime. Since the patient will be sleeping during the night,
sedation or impairment of CNS function might not cause any problems. This
strategy is based on the assumption that the sedative effects are limited to the
hours of sleep and that symptom relief from peripheral H 1-blockade lasts through-
out the next day. Goetz (69) studied this idea prospectively and found that patients
given hydroxyzine (50 mg) at bedtime maintained peripheral H 1-blockade for up
to 24 h, based on suppression of histamine-induced wheals and flares, but subjec-
tive drowsiness was also increased significantly the morning after the nighttime
dose. In another study using the Multiple Sleep Latency Test and the Stanford
Sleepiness Scale, the sedating effects of pm dosing with chlorpheniramine and am
Effects on CNS 349
dosing with terfenadine were investigated. Results demonstrated that the CNS-
depressant effects of evening administration of a sedating H 1-antagonist persisted
throughout the following day (140) (Fig. 3). Similar findings of daytime sleepi-
ness following evening dosing with chlorpheniramine were obtained using the
new technique of functional magnetic resonance imaging as a tool to assess levels
of brain activation (141). Carryover effects are most likely a result of the long
elimination half-lives of sedating antihistamines, which for hydroxyzine, brom-
pheniramine, and chlorpheniramine are 20–24 h (13) (Chap. 5).
Some physicians advise regular daily use of a first-generation H 1-antagonist
with the expectation that tolerance to the CNS adverse effects will occur after a
few days. It is known that tolerance to the peripheral H 1-blockade effects of
H 1-antagonists (e.g., skin test suppression) does not develop (52, 68, 89, 142).
Tolerance to H 1-antagonist-induced drowsiness and sedation has been reported
by some, but not all, investigators. Volkerts (65) treated volunteers with triproli-
dine 5 mg twice daily or placebo for 4 consecutive days and conducted testing
on the first and fourth treatment day. Triprolidine significantly reduced scores
Figure 3 Carryover sedative effects of PM dosing with a sedating H 1-antihistamine. A.

Daytime alertness was objectively measured using the multiple sleep latency test (MSLT)
in 29 volunteers on the day after (i.e., day 2) receiving a PM dose of chlorpheniramine
(8 mg or 12 mg), or placebo. The MSLT is an objective physiological measure of alertness
used to quantify daytime sleepiness; lower values indicate sleepiness. B. Subjective sleepi-
ness was measured using the Stanford Sleepiness Scale. P, placebo; C8, chlorpheniramine
8 mg; C12, chlorpheniramine 12 mg. Note reduced alertness (i.e., decreased sleep latency)
and increased subjective sleepiness on the day after PM dosing with chlorpheniramine.
(From Ref. 140.)
350 Welch et al.
on the various tests done on the first day, including self-assessment rating, objec-
tive sleep latency test, cognitive performance test, and an actual driving test. By
the fourth day, the subjective (self-rating) and objective (sleep latency) measures
of drowsiness, as well as the speed performance in the driving test, were no
longer statistically different between the triprolidine-treated and placebo groups.
In contrast to this evidence for the development of tolerance, some of the cogni-
tive studies and the lateral weaving part of the driving test continued to show
statistically significant differences between groups, perhaps implying partial tol-
erance. Schweitzer (114) treated subjects with diphenhydramine (50 mg three
times daily) for 3 days and measured multiple sleep latency, a simulated assem-
bly-line task, and sleepiness ratings by visual analog scale on day 1 and day 3.
Diphenhydramine produced marked impairment and drowsiness only on the first
day of treatment; no difference between diphenhydramine and placebo was noted
on the third day, suggesting that tolerance occurred. Manning (142) using diphen-
hydramine, and Bye (89) using triprolidine, also reported tolerance to the CNS
effects of these first-generation H 1-antagonists; however, the development of tol-
erance is not universal or predictable. Volunteers given hydroxyzine 25 mg twice
daily for 5 days did not develop tolerance to the CNS effects, as evidenced by
continued drowsiness and prolongation of reaction time (95). Similarly, Brook-
huis (143) gave volunteers triprolidine 10 mg/day for 5 days and tolerance to its
adverse effects on a car-driving test was not observed. Kay (98) tested various
measures of sedation after dosing with diphenhydramine 50 mg on day 1, and
then on days 3 and 5 after continual dosing with 25 mg four times daily. Fatigue
and sleepiness were reported, and scores were reduced on the measures of divided
attention, working memory, and vigilance on day 1. On days 3 and 5, the amount
of fatigue had decreased but was still significantly greater than it was for subjects
receiving loratadine 10 mg daily or placebo. Furthermore, subjects on day 5 re-
ceiving diphenhydramine continued to have significantly greater psychomotor
impairment than those receiving placebo or loratadine. Given these conflicting
findings, using a first-generation H 1-antagonist and hoping the patient develops
tolerance to the adverse CNS effects appears to be unwise, as tolerance is an
inconsistent and unpredictable phenomenon.
The two aforementioned strategies to avoid the sedating effects of first-
generation H 1-antagonists are not currently recommended. Physicians should be
aware of the recommendations made by the Joint Task Force on Practice Parame-
ters in Allergy, Asthma, and Immunology (1998):
Sedation and performance impairment are undesirable and potentially dan-
gerous side effects of first-generation antihistamines. Consequently, second-
generation antihistamines that are associated with less risk or no risk for
these side effects should usually be considered before sedating antihistamines
for the treatment of allergic rhinitis, and are even mandated in some segments
of the transportation industry. Studies have demonstrated that many patients
Effects on CNS 351
may not perceive performance impairment that is associated with first-gener-

ation (classical) antihistamines. In the majority of states, patients taking se-
dating antihistamines are legally considered ‘‘under the influence’’ of drugs
(144).
Furthermore, physicians advocating any use of first-generation H 1-antagonists

should be aware of the epidemiological data implicating these medications as a
cause of traffic fatalities (145–148).
VII. SEDATIVE EFFECTS OF ALLERGIC DISEASE
Research on the sedative effects of H 1-antagonists is often conducted in individu-

als not experiencing allergic disease symptoms. Although this has the advantage
that the CNS effects of allergic disorders (of varying severity) do not interfere
with the results, findings from these studies may be misleading since the allergic
disease itself can cause performance and learning impairment. There has been
found to be significant impairment in patients with allergic rhinitis in many of
the dimensions of the SF-36, a widely used quality-of-life questionnaire, some
of which reflect central nervous system functioning (149). Treatment of allergic
rhinitis with the second-generation H 1-antagonist cetirizine 10 mg daily, actually
improves overall SF-36 scores, further indicating that allergic disease alone may
have an impact on CNS function which can be reversed with treatment (150).
Marshall and Colon (151) studied depressed individuals with allergic rhinitis in
and out of their ‘‘allergy season’’ and demonstrated effects of the season on
mood and cognitive functions. Atopic and control subjects were given tests to
assess mood, psychomotor speed, and cognitive functioning. Atopic subjects ex-
hibited declines in verbal learning, slower decision-making, and psychomotor
speed on both simple and choice reaction times, and lower positive affect during
their ‘‘allergy season’’ compared to out of their ‘‘allergy season.’’ Vuurman (42)
found similar adverse effects of seasonal allergic rhinitis alone in children. Chil-
dren with seasonal allergic rhinitis and healthy matched controls were instructed
on a computer assignment and tested 2 weeks later on their knowledge of the
material. The atopic children received different treatments just before their in-
struction: diphenhydramine (first-generation), loratadine (second-generation), or
placebo. Both the placebo- and diphenhydramine-treated groups learned signifi-
cantly less than the nonallergic untreated controls. The loratadine-treated group’s
learning performance was superior to either of the other atopic groups but still
inferior to that of the healthy children. These findings suggest that allergic rhinitis
alone reduces learning ability in children, that this effect is partially counteracted
by treatment with loratadine, and can be aggravated by a first-generation H 1-
antagonist such as diphenhydramine. A similar study in young adults revealed
352 Welch et al.
the same findings (43). Spaeth used a visual analog scale to measure vigilance
in patients with untreated symptomatic seasonal allergic rhinitis (152). Their
baseline scores were below normal, but improved after treatment with either a
second-generation oral or topical H 1-antagonist. The exact mechanisms by which
CNS impairment occurs with symptomatic allergic disease are not known. Sleep
disturbance may be playing a role (153), as patients with allergic rhinoconjunctiv-
itis often report difficulty initiating or maintaining sleep (154) and sleep
disruption/deprivation is known to cause excessive daytime sleepiness, cognitive
difficulties, and poor school academic performance (155). Whatever the mecha-
nisms, the above studies point out the importance of controlling for the presence
or absence of allergic symptoms when conducting research on the effects of new
H 1-antagonists on mental function.
VIII. SECOND-GENERATION H 1-ANTIHISTAMINES
Information regarding CNS effects can be obtained from results of clinical trials
conducted primarily to evaluate the efficacy and safety of the second-generation
H 1-antagonists in patients who have symptomatic allergic disease (e.g., allergic
rhinitis, urticaria), or from results of studies specifically performed with objective
tools to measure sedation and/or impairment, usually carried out in healthy volun-
teers. Clinical trials almost always involve multiple dosing over days to weeks,
with adverse effects such as somnolence being self-reported and unsolicited by
the investigator. Conclusions from these studies may be difficult since some lack
a placebo group, the percentage of patients reporting any adverse events is some-
times low, and/or statistical analysis of the difference between groups may not
be performed with regards to adverse effects. Nevertheless, results of these clini-
cal trials have shown, in general, that patients taking loratadine and fexofenadine
and the now unavailable terfenadine and astemizole, report somnolence at a rate
not significantly different than patients treated with placebo (see US package
inserts for each agent). However, findings from clinical trials evaluating acrivas-
tine, ketotifen, ebastine, mizolastine, cetirizine, and topical azelastine are more
variable, with one or more studies showing self-reported somnolence with use
of these agents to be higher than with placebo, even at the usual recommended
therapeutic dosage (14, 18, 75, 156–159).
In objective, single-dose studies in healthy volunteers, the incidence of
somnolence and impairment of CNS function associated with manufacturers’ rec-
ommended daily dosages of many of the second-generation H 1-antagonists is
similar to that produced by placebo and significantly lower than that produced
by first-generation H 1-antagonists such as triprolidine, diphenhydramine, chlor-
pheniramine, clemastine, or hydroxyzine. The first of the second-generation H 1-
Effects on CNS 353
antagonists, terfenadine, has been studied most extensively (47, 53, 55, 57, 59,
60–62, 65, 69, 71, 85, 90, 94, 95, 99, 101–106, 111, 112, 120, 160, 161). Another
early second-generation H 1-antagonist, astemizole, has also been well studied
with similar findings to terfenadine (51, 57, 79, 104, 105, 123, 162–165). As
noted previously, both terfenadine and astemizole have been removed from the
market in many countries throughout the world because of adverse cardiac ef-
fects; however, they remain historically important because they were the first H 1-
antagonist agents to demonstrate an absence of sedation and performance impair-
ment properties.
Other well-studied second-generation H 1-antagonists that are widely avail-
able include cetirizine (46–48, 50, 52–54, 56, 57, 63, 65, 67, 72, 73, 93, 114,
160, 166, 167) (Table 4), loratadine (42, 44, 45, 54, 57, 63, 64, 86, 93, 98, 106,
111, 120, 168) (Table 5), and fexofenadine (41, 73, 115, 150, 169–171, 178)
(Table 6). These second-generation agents produce significantly less somnolence
and mental impairment than their first-generation predecessors (Fig. 4).
Less well-studied and less widely available oral second-generation H 1-an-
tagonists include ebastine (97, 116, 143, 172, 173) (Table 7) and mizolastine (99,
107, 117, 174, 175) (Table 8). Information from studies so far show that both of
these H 1-antagonists, when used at their usual therapeutic dosage, have objective
sedative profiles similar to placebo.
There are few studies of acrivastine (91, 92, 110) and ketotifen (68, 70,
176–178), both of which have been considered second-generation H 1-antago-
nists. Unlike the other agents in the second-generation category, acrivastine and
ketotifen have been shown to cause more somnolence and impaired performance
than placebo (Table 9), although not consistently in all tests.
IX. TOPICAL H 1-ANTIHISTAMINES
Local administration of H 1-antagonists is intended to confine the activity of the

drug to the site of application while reducing possible adverse effects from sys-
temic exposure. Azelastine can be sedating when administered orally (179), and
has therefore been developed for nasal mucosal topical use. Self-reported somno-
lence, despite intranasal use, can still result from use of azelastine compared with
placebo (158, 180, 181) but is less than that seen with ebastine (182) or cetirizine
(183) when studied in a comparative fashion. Other studies with intranasal azelas-
tine, especially more long-term ones, have shown no increased incidence of som-
nolence (184, 185). One trial using a visual analog scale to assess vigilance
showed an actual improvement in vigilance during a 2-week treatment period
(152).
Levocabastine, like azelastine, can cause sedation when given systemically,
354
Table 4 Objective CNS Studies of Cetirizine

No. of
Reference volunteers Design Drug/dose (mg) Tests Time postdose (h) Results
Gengo et al. (48) 12 db, pc, co C 10, 20 CFF; Stroop; VAS; PHB 0.5, 1, 2, 4, 6, 8, 12, H, but not C, ↓ CNS function
H 25 24, 36
P
Doms et al. (166) 36 db, pc, co C 10 Psychomotor; learning, mem- Not stated Results for C ⫽ P; Alc im-
P ory, attention; concentration; paired all tests except one
Alc 0.6g/kg (positive coordination; VAS; anxiety
control)
Pechadre et al. (53) 9 db, pc, co C 10 EEG spectrum analysis; VAS; 3, 6 C did not affect EEG; T inhib-
T 60 PHB ited EEG at 6h; C, T or P
P did not cause subjective feel-
ings of impairment; no posi-
tive control
Alford et al. (47) 14 db, pc, co C 10, 20 qd EEG; LARS; PHB 1.5 (LARS) continuous C 10 & 20, T 60 and P pro-
T 60 bid (EEG) duced ⬍20% total EEG seda-
Ch 4 tid tion; Ch & Tr produced
Tr 5 tid ⬎40% EEG sedation. Sig-
P nificant subjective sedation
seen only with Tr
De Roeck (93) 16 db, pc C 20 DSS; MSLT; SSS Every 2 hrs ⫻ 5 D ↓ sleep latency in 1h and
L 20 this effect differed signifi-
D 50 ⫻ 2 cantly from L and P, but not
P C; similar trends were seen
in performance and subjec-
tive data
Gengo et al. (50) 15 db, pc, co C 5, 10, 20 DSS; Trails B maze; driving 2, 4, 6, 8, 24 D, but not C, ↑ reaction time
D 50 simulator and produced significant
Welch et al.
P drowsiness
Seidel et al. (67) 60 db, pc, pa C 5, 10, 20 MSLT; EEG ⫹ eye move- 2, 4, 6, 8, 10 (MSLT, H, but not C, affected MSLT,
H 25 ments; RT; SSS; POMS SSS); 2.5, 8.5 (RT); EEG and eye movement
P 4.5 (POMS) tests, but no subjective im-
pairment was reported in any
group
Betts et al. (160) Not stated pc T 120, 240 Actual slow driving; EEG vi- Not stated C 20, but not C 10, T 120, T
C 10, 20 sual evoked potential 240, produced impairment
Effects on CNS
P
Levander et al. (52) 12 db, pc, co C 10 ⫻ 7d Psychological tests; VAS; PHB 4 (after AM dose on d1 H, but not C, ↓ CNS function
H 20 ⫻ 7 d and d7) after single dose; no differ-
P⫻7d ence between C and H at
steady-state
Pechadre et al. (54) 10 db, pc, co C 10 Quantified EEG; VAS; PHB 2, 6 C and P did not affect EEG; L
L 10, 40 10 and 40 produced slight
P EEG changes at 2 h; no posi-
tive control
Ramaekers et al. 16 db, pc, co C 10 Actual driving; EEG; 0.5–5 C alone and L, C, or P ⫹ Alc
(63) L 10 subjective affected EEG, driving (weav-
P ing, speed), and subjective
⫾ Alc drowsiness. Alc had a
greater effect than C. L had
no effect on any of measures
Volkerts et al. (65) 27 db, pc, co C 10 daily ⫻ 4d Actual driving; computerized 1, 2, 2.5, 3.5, 6 C 10 mg, T 120 mg, and P did
T 60 bid ⫻ 4d memory tasks; sleep latency not affect any tests. Tr ↓
T 120 qd ⫻ 4d driving and psychometric
Tr 5 bid ⫻ 4d tests and reduced sleep la-
P tency; tolerance to Tr by day
4; T 60mg bid ↓ psychomet-
ric performance after sub-
chronic treatment
Walsh et al. (46) 12 db, pc, co C 10 Simulated assembly line task 0.5, 1.5, 2.5, 3.5, 5.5, Pretrained to minimum correct
H 25 with seven variables; 8 ⫻ 50 6.5, 7.5, 8.5 response rate; H, but not C,
P min tasks; subjective ↓ performance and ↑ sleepi-
ness; H & C did not differ
subjectively
355
356
Table 4 Objective CNS Studies of Cetirizine—Continued

No. of
Schweitzer et al. 12 db, pc, co C 10 qd ⫻ 3d MSLT; simulated assembly line 1, 3, 5, 7, 9 (MSLT); D, not C, adversely affected all
(114) D 50 tid ⫻ 3d task; actigraphy; subjective VAS 1.5, 3.5, 5.5, 7.5 objective tests and increased
P (VAS) (assembly line task) subjective sleepiness by day
on days 1 and 3 1. No effect by D seen at
day 3.
Simons et al. (56) 20 db, pc, co C 10 P300; VAS; PHB 3 H and D but not C or P ↑
H 50 P300 latency
D 50
P
Patat et al. (175) 18 db, pc, co C 10 qd ⫻ 7d 1) Driving (actual and simu- 1) 4, 7.3 (actual); 3.2, M and C had no effect on driv-
M 10 qd ⫻ 7d lated) 6.5 (simulated) ing or CFF; both did cause
P 2) CFF, adaptive tracking, di- 2) 1.5, 2.6, 4.5, 6, 7.8 minimal but significant
Alc or P, single vided attention changes in tracking and di-
dose, d 5 or 7, 2h vided attention tasks at cer-
post dose of M, C, tain time points post-dose.
or P Alc caused significant detri-
mental effects in all psycho-
motor and driving tests
Welch et al.
Sannita et al. (72) 8 db, pc, co C 10 Short-term Retention Test; 1, 2, 3, 4, 6 C 20 and Ch affected EEG, but
C 20 Backward Digit Span Test; not C 10. No effect on any
Ch 4 Immediate Retention Test; performance tests by C or
P quantitative EEG Ch.
Simons et al. (57) 15 db, pc, co C 10 P300; subjective somnolence 2–2.5 C had no effect on P300 la-
L 10 (SSS) tency, but did ↑ subjective
A 10 somnolence compared to
Effects on CNS
T 60 baseline and P. D affected

K2 P300 and ↑ somnolence.
D 50
P
Nicholson and 6 db, pc, co C5 EEG sleep latency; DSS; 0.5, 1.5, 2.5, 3.5, 5.5, C at various doses reduced
Turner (167) C 10 tracking task; visual vigi- 7.5 sleep latency, impaired
C 15 lance; subjective tracking, and increased sub-
Pr 10 jective sleepiness at certain
P time points but not all. No
dose-response relationship
seen with these effects. Pr de-
creased vigilance, impaired
tracking and increased subjec-
tive sleepiness.
A, astemizole; Alc, alcohol; C, cetirizine; CFF, critical flicker fusion; Ch, chlorpheniramine (chlorphenamine); co, crossover; d, days; D, diphenhydramine;
db, double-blind; DSS, digit-symbol substitution; EEG, electroencephalogram; h, hours; H, hydroxyzine; K, ketotifen; L, loratadine; LARS, line analog
rating scale (subjective sedation); MSLT, multiple sleep latency test; P, placebo; P300, P300 event-related potential; pa, parallel group; pc, placebo-controlled;
PHB, peripheral H 1-blockade; POMS, Profile of Mood States questionnaire; RT, reaction time; SSS, Stanford Sleepiness Scale; T, terfenadine; Tr, triprolidine;
VAS, visual analog scale; ↑, enhance/increase; ↓, impair/decrease; m, mizolastine; Pr, promethazine; qd, once daily; bid, twice daily; tid, three times daily.
357
358
Table 5 Objective CNS Studies of Loratadine

No. of
Bradley and Nichol- 6 db, pc, co L 10, 20, 40 VMC; DVA; short-term mem- 0.3, 1.5, 3.5, 5.5 L 40, but not L 20 or L 10, ↓
son (86) Tr 10 ory; DSS; subjective DSS (5.5h) and DVA, sug-
P gesting sedation; Tr ↓ all
tests
Riedel et al. (111) 20 db, pc, co L 10, 20 Actual driving (weaving index); 4 Tr, but not T or L, caused weav-
T 60 self-reported sedation ing comparable to that seen
Tr 10 with blood Alc of 0.05%
⫾Alc
P
Roth et al. (64) 16 db, pc, co L 10 ⫻ 2d MSLT; SRT; CRT; auditory vig- MSLT 1, 3, 5, 7, 9; D, but not L 10 or L 40, ↓
L 40 ⫻ 2d ilance; DSS; symbol copying; performance sleep latency, affected perfor-
D 50 tid ⫻ 2d SSS (i.e., everything mance tests and ↑ sleepiness
P else) 1.5, 5.5
Gaillard et al. (120) 1) 12 db, pc 1) L 10 Reaction time; tracking; mem- 6 1) L & T no effect; Cl ↓ perfor-
2) 16 T 60 ory; subjective (VAS) mance on tracking test, ↑ sub-
Cl 1 jective drowsiness
P 2) Diaz no effect with any drug
2) ⫹ Diaz 5 or with placebo.
O’Hanlon (106) 1) 20 db, pc 1) L 10 Car driving (high-speed, open 1, 3 Tr impaired driving; T and L
2) 16 T 60 road, 10 km); highway cir- did not; T and L did not po-
Tr 10 cuit, weaving index tentiate Alc
P
2) L 10 qd ⫻ 4d
T 60 mg bid ⫻ 4d
P
Welch et al.
⫾ Alc
Adelsberg and 69 pc, co L, D, P 12 performance tests relating to 1.5, 6 L did not ↓ performance; D sig-
D’Amico-Beadon office skills nificantly impaired 8/12 tests
(44)
De Roeck (93) 16 db, pc L 20 DSS; MSLT; SSS Every 2 h ⫻ 5 D ↓ sleep latency and this ef-
C 20 fect differed significantly
D 50 ⫻ 2 from L and P but not C; simi-
P lar trends were seen in perfor-
Effects on CNS
mance and subjective data

Pechadre et al. (54) 10 db, pc, co L 10, 40 Quantified EEG; VAS; PHB 2, 6 C and P did not affect EEG; L
C 10 10 and 40 produced slight
P EEG changes at 2h; no posi-
tive control
Neves-Pinto et al. 40 db, pc L 10 Flight simulation; subjective 2 L did not ↓ performance or sub-
(168) P jective somnolence
Ramaekers et al. (63) 16 db, pc, co L 10 Actual driving; EEG; subjective 0.5–5 L had no effect on driving,
C 10 EEG, subjective drowsiness;
P C and Alc did
⫾Alc
Vuurman et al. (42) 52 (included children db, pc, pa L 10 Factual and conceptual knowl- ?8 Allergic rhinitis alone ↓ learn-
with allergy) D 25 bid ⫻ 2 doses edge, application of learned ing ability in children; this ef-
P strategy (computer simula- fect was partially counter-
tion) acted by treatment with L but
aggravated by D
Simons et al. (57) 15 db, pc, co L 10 P300; subjective somnolence 2–2.5 L had no effect on P300 latency
A 10 or subjective somnolence; D
C 10 did
T 60
K2
D 50
P
359
360
Table 5 Objective CNS Studies of Loratadine—Continued

No. of
Kay et al. (98) 98 db, pc, co L 10 qd ⫻ 5d VAS; SSS; Mood Scale; numer- 1.5 on days 1, 3, 5 L caused no deficits at anytime;
D 50 first dose, ous cognitive and psychomo- D caused deficits in measures
then 25 qid ⫻ 5d tor performance measures of sleepiness, fatigue, mood,
divided attention, speed,
working memory, and vigi-
lance on day 1; some deficits
with D present at day 3; all
deficits with D gone by day 5
Hindmarch et al. 24 db, pc, co L 10 CFF; CRT; subjective (LARS); 1.5, 3, 6, 9, 12, 24 L and F at all doses caused no
(169) F 80 actigraphy significant impairment on any
F 120 of the tests while Pr nega-
F 180 tively affected CFF, recogni-
Pr 10 tion reaction time, and acti-
graphy
Valk et al. (45) 18 db, pc, co L 10 Vig Track; MAT (objective); 1, 2, 3, 5, 6 No significant difference in alert-
Tr 5 SSS (subjective); in a hypo- ness and performance results
P baric chamber simulating an between L and P. Tr caused
altitude of 8,000 ft. significant detrimental effects
on subjective and objective
measures
A, astemizole; bid, twice daily; C, cetirizine; CFF, critical flicker fusion; CRT, choice reaction time; d, days; D, diphenhydramine; db, double-blind; DSS,
digit–symbol substitution; DVA, dynamic visual acuity; F, fexofenadine; h, hours; K, ketotifen; L, loratadine; LARS, line analog rating scale; MAT, Multi-
Attribute Task Battery; MSLT, multiple sleep latency test; P, placebo; P300, P300 event-related potential; pa, parallel group; pc, placebo-controlled; PHB,
peripheral H 1-blockade; qd, once daily; SRT, simple reaction time; SSS, Stanford Sleepiness Scale; T, terfenadine; tid, 3 times daily; Tr, triprolidine; VAS,
visual analog scale; Vig Track, Vigilance and Tracking test; VMC, visuomotor coordination; ↑, enhance/increase; ↓, impair/decrease; Pr, promethazine;
Alc, ethanol; EEG, electroencephalogram; qid, four times daily; co, crossover.
Welch et al.
Table 6 Objective CNS Studies of Fexofenadine
No. of
Vermeeren and 24 db, pc, co F 120 qd ⫻ 5d Critical tracking; 1.5–2.5 except driv- F at any dosage did
O’Hanlon (115) F 240 qd ⫻ 5d CRT; sustained at- ing (3–4), on days not impair driving
Effects on CNS
F 60 bid ⫻ 5d tention; actual driv- 1, 4, and 5 performance

F 120 bid ⫻ 5d ing test whereas Cl did. F
Cl 2 bid ⫻ 5d 120 and F 240 and
P Cl, after AM sin-
gle dose, ad-
versely affected
critical tracking on
day 1 but not on
days 4, 5.
Hindmarch et al. 24 db, pc, co F 80 CFF; CRT; subjec- 1.5, 3, 6, 9, 12, 24 F at all doses and L
(169) F 120 tive assessment were same as P
F 180 (LARS); acti- with all tests. Pr ↓
L 10 graphy CFF, CRT, LARS,
Pr 30 actigraphy
P
Nicholson et al. 6 db, pc, co F 120 DSS; tracking; vigi- 0.5, 1.5, 2.5, 3.5, 5, F both doses same as
(170) F 180 lance; MSLT; sub- 6.5, 8 P. Pr impaired
Pr 10 jective DSS, tracking and
P vigilance; also ↑
objective and sub-
jective sleepiness
bid, twice daily; CFF, critical flicker fusion; Cl, clemastine; co, crossover; CRT, choice reaction time; d, days; db, double-blind; F, fexofenadine; h, hours;
LARS, linear analog rating scale; P, placebo; pc, placebo-controlled; Pr, promethazine; qd, once daily; DSS, digit-symbol substitution; MSLT, multiple
361
sleep latency test; ↑, enhance/increase; ↓, impair/decrease; L, loratadine.

362 Welch et al.
Figure 4 Effects of a single dose of loratadine, triprolidine, and placebo on tests of

pilot simulated aircraft flying. A. Objective; results of Vigilance and Tracking test (Vig-
Track), mean and standard error of percentage on omissions (i.e., errors). B. Subjective;
results of Stanford Sleepiness Scale (SSS), mean and standard error of subjective ratings.
Arrow indicates time of drug administration. Note that triprolidine showed significant
detrimental effects on both objective and subjective measures; loratadine had no effect
(i.e., same as placebo). (From Ref. 45.)
Table 7 Objective CNS Studies of Ebastine
No. of Time
Reference volunteers Design Drug/dose (mg) Tests postdose (h) Results
Vincent et al. (116) 9 sb E 10, 50 CFF; CRT; VAS 1, 2, 4, 6, 8, 24 E 10 and 50 did not ↓
P CFF performance but
Effects on CNS
did mildly ↓ CRT;

E50 but not E 10
caused some drowsi-
ness on VAS
Hopes et al. (97) 16 db, pc, co E 10 EEG vigilance (relative 2.5, 4.5, 6.5 Cl, not E, ↓ vigilance, ↓
E 20 delta power), matching tracking, ↑ subjective
Cl 2 paradigm, pursuit ro- drowsiness; maximum
tor, pursuit tracking, effect at 4.5–5.5 h
subjective ratings
Mattila et al. (172) 12 db, pc, co E 20 qd ⫻ 6 d DSS, CFF, Madox; body 2, 4, 6 E did not affect perfor-
P balance; nystagmus, mance or cause subjec-
simulated driving, tive changes
VAS
Mattila et al. (173) 12 db, pc, co E 20 qd ⫻ 6d DSS, CFF, Madox; body 1.5, 3, 4.5, 6 E did not affect perfor-
P balance, simulated driv- mance, borderline sub-
ing, VAS jective drowsiness
noted at 3 h
Brookhuis et al. (143) 15 db, pc, co E 10, 20, 30 qd ⫻ Actual driving perfor- 2, 6 E did not ↓ driving per-
5d mance; subjective formance; Tr did. Tr
Tr 10 SR ⫻ 5d also affected subjective
P ratings; E did not
CFF, critical flicker fusion; Cl, clemastine; co, crossover; CRT, choice reaction time; DSS, digit–symbol substitution; d, days; db, double-blind; E, ebastine;
EEG, electroencephalogram; h, hours; P, placebo; pc, placebo-controlled; qd, once daily; sb, single-blind; SR, sustained-released; Tr, triprolidine; VAS,
visual analog scale; ↑, enhance/increase; ↓, impair/decrease.
363
364
Table 8 Objective CNS Studies of Mizolastine

No. of Time
Kerr et al. (99) 18 db, pc, co M5 CFF, CRT, tracking, mem- 1, 3, 5, 8, 24 M 5, 15 did not affect per-
M 15 ory tests (Stroop, Stern- formance tests or subjec-
M 45 berg), subjective tive ratings whereas M
T 60 (LARS) 45 and Tr did ↓ perfor-
Tr 10 mance in various psy-
P chomotor measures. T
negatively affected CFF
only
Vuurman et al. 24 db, pc, co M5 CFF, tracking, divided at- 2–3, 3.45–4.45 (driving M 5, M 10 had no effect
(117) M 10 tention, memory search, only), 5.30–6.30 (other on psychomotor tests,
M 20 CRT, vigilance studies; tests) driving and subjective
M 40 actual driving; subjec- ratings. M 40 ↓ driving
Cl 2 tive (VAS) and performance tests
and ↑ subjective drowsi-
ness similar to Cl; M 20
had effects intermediate
Welch et al.
to M 5, 10 and M 40
Patat et al. (107) 15 (elderly females, db, pc, co M 10 CFF, CRT, DSS, free re- 4, 8 M produced no effects on
ages 66–77) Cl 2 call memory (immediate performance, memory,
P and delayed), VAS or subjective ratings of
drowsiness whereas Cl
significantly ↓ perfor-
mance (CFF, CRT)
Patat et al. (174) 16 db, pc, co M 10 qd ⫻ 8d 1) CFF, CRT, tapping, 1) 2, 4, 6, 8 M 10 at steady state de-
Effects on CNS
P arithmetic calcula- 2) 3 void of effects on mea-

Loraz 2 or P on d 6 tion, body sway, sures of performance
or 8 only, with VAS and memory, and subjec-
M 2) Short-term, long-term tive ratings; Loraz
memory caused marked ↓ of al-
most all objective and
subjective tests
Patat et al. (175) 18 db, pc, co M 10 qd ⫻ 7d 1) Driving (actual and 1) 4, 7.3 (actual), 3.2, 6.5 M and C had no effect on
C 10 qd ⫻ 7d simulated) (simulated) driving or CFF; both
P 2) CFF, adaptive tracking, 2) 1.5, 2.6, 4.5, 6, 7.8 did cause minimal but
Alc or P, single divided attention significant changes in
dose, d 5 or 7, tracking and divided at-
2h post-dose of tention tasks at certain
M, C, or P time points post-dose.
Alc caused significant ↓
in all psychomotor and
driving tests
Alc, alcohol; C, cetirizine; CFF, critical flicker fusion; Cl, clemastine; co, crossover; CRT, choice reaction time; db, double-blind; DSS, digit–symbol
substitution; LARS, linear analog rating scale; Loraz, lorazepam; M, mizolastine; P, placebo; pc, placebo-controlled; qd, once daily; VAS, visual analog
scale; d, days; ↑, enhance/increase; ↓, impair/decrease; h, hours.
365
Table 9 Objective CNS Studies of Acrivastine, Ketotifen, and Levocabastine (Topical Ophthalmic)
No. of Drug/dose Time

366
Reference volunteers Design (mg) Tests postdose (h) Results
Acrivastine
Cohen et al. (91) 12 db, pc, co Ac 4, 8, 16 Adaptive tracking per- 1.5, 3 Ac did not ↓ adaptive
Tr 2, 5 formance; reaction tracking or reaction
P time; VAS time; both doses of
Tr ↓ adaptive
tracking and ↑ reac-
tion time, and also
caused subjective
effects
Ramaekers and 18 db, pc, co Ac 8 Driving tests 1.5–2.75 Ac ↓ driving perfor-
O’Hanlon (110) Ac 16 3.25–4.50 mance in a dose-
Ac 24 related fashion. D
Ac/Ps 8/60 also significantly ↓.
T 60 T at all doses and
T 120 Ac/Ps did not
T 180 cause any effect on
D 50 driving
P
Ketotifen
Hindmarch and Par- 50 db, pc K 1 bid CRT; CFF; sleep eva- K did not ↓ psycho-
rott (70) Ch 4 tid luation motor behavior but
Meb 50 tid did ↑ ease of get-
Cl 1 bid ting to sleep; Ch ↓
Pr 25 od CFF; Ch and Pr af-
fected sleep and
produced early
Welch et al.
morning ‘‘hang-
over’’
Vollmer et al. (68) 7 sb, pc K 1 bid ⫻ 3 wks EEG ⫻ 15 min pre- 3, 6 Peak sedation effect
P dose, 3 and 6 h on day 3 gradually
postdose on 8 study ↓ thereafter; no pos-
days itive control
Simons et al. (57) 15 db, pc, co K2 P300; subjective som- 2–2.5 No effect on P300 la-
T 60 nolence (SSS) tency, like D did,
Effects on CNS
L 10 but did ↑ subjec-

A 10 tive somnolence
C 10 compared to base-
D 50 line and P
P
Levocabastine (topical
ophthalmic)
Arriaga and Rombaut 12 db, pc, co Le (0.5 mg/ml) CFF; CRT; VAS 5 Le did not affect any
(186) 2 drops/eye tests (but no posi-
qid ⫻ 1 wk tive control)
P
Rombaut et al. (113) 12 db, pc, co Le (0.5 or 2.0 CFF; CRT; simulated 5 Tr but not Le im-
mg/ml) car tracking; Stem- paired CFF, mem-
2 drops/eye berg memory scan- ory task, caused
and nostril ning; word recogni- subjective somno-
Tr 10 tion; subjective lence
P LARS
A, astemizole; Ac, acrivastine; bid, twice daily; C, cetirizine; CFF, critical flicker fusion; Ch, chlorpheniramine (chlorphenamine); Cl, clemastine; co,
crossover; CRT, choice reaction time; d, days; db, double-blind; EEG, electroencephalogram; h, hours; K, ketotifen (oral); L, loratadine; Le, levocabastine;
Meb, mebhydrolin; P, placebo; P300, P300 event-related potential; pc, placebo-controlled; Pr, promethazine; Ps, pseudoephedrine; qid, four times daily;
sb, single-blind; SSS, Stanford Sleepiness Scale; tid, three times daily; Tr, triprolidine; VAS, visual analog scale; wks, weeks; ↑, enhance/increase; ↓,
impair/decrease; T, terfenadine; D, diphenhydramine; LARS, linear analog rating scale.
367
368 Welch et al.
so topical ophthalmic and nasal formulations have been developed. Levocabas-

tine does not cause somnolence or impair performance when given via these
routes to healthy volunteers (113, 186, 187) (Table 9).
X. HIGHER THAN USUAL DOSAGES OF

SECOND-GENERATION H 1-ANTIHISTAMINES
Some second-generation H 1-antagonists, when given at dosages higher than those

recommended by the manufacturer, may cause some CNS dysfunction. This was
first noted by Bhatti and Hindmarch (161) when studying the CNS effects of
terfenadine, at a dosage of 240 mg instead of the usual 60–120 mg/day. The
finding of impairment with higher than usual dosages of terfenadine was not seen
in all studies (65, 160). Dose-related effects have been found for other second-
generation H 1-antagonists including loratadine (40 mg) (54, 86), cetirizine (20
mg) (72, 160, 188), ebastine (50 mg) (116), and mizolastine (20 mg, 40 mg, and
45 mg) (99, 117, 189, 190). A series of studies of actual driving performance
using a weaving index as an indicator of sedation found significant driving im-
pairment after two- to three-times higher than currently recommended dosages
of various newer H 1-antagonists (loratadine, terfenadine, cetirizine, acrivastine,
mizolastine, and ebastine) (191). In contrast, higher than usual dosages of fexo-
fenadine (i.e, up to 240 mg) have not been reported to cause any CNS impairment
(41, 115, 170, 171). The observation that CNS effects can be seen as the dosage
of most second-generation H 1-antagonists is increased points out how CNS pene-
tration of this category of H 1-antagonists is still possible at high enough dosages.
Nevertheless, at recommended dosages the therapeutic benefit/risk ratio for seda-
tion by these new H 1-antagonists is vastly superior to that of the older compounds.
XI. COMPARISON AMONG H 1-ANTIHISTAMINES
Before second-generation antihistamines were available, investigators tried to de-

termine if certain first-generation H 1-antagonists were less sedating than others.
Clemastine is one H 1-antagonist that was claimed to induce less sedation than
other first-generation H 1-antagonists; however, the results of a placebo-controlled
comparison study with hydroxyzine and azatadine refuted this contention (100).
Other comparison studies with first-generation H 1-antagonists have been done
(70, 192), but the information gleaned from them is limited since the studies
were never repeated, and the findings only pertain to the specific H 1-antagonists
studied. Clearly, there can be differences among older H 1-antagonists in terms
of their CNS effects, but these are usually not consistent or predictable, and are
Effects on CNS 369
more likely a function of the individual variation from patient to patient in their
sensitivity to have, perceive, or report these adverse effects. Traditional clinical
practice advised that if sedation was occurring from an H 1-antagonist in one of
the six classes of first-generation H 1-antagonists, the patient should be given a
trial of an agent from another class because of the possibility that the sedation
would be less; however, no scientific basis for this recommendation can be found
in the literature. The availability of the second-generation H 1-antagonists with
an absent or much reduced tendency to cause sedation has made this kind of
practice both inappropriate and unnecessary.
There is also only limited comparative information among the second-
generation H 1-antagonists regarding objective CNS effects. Most studies of these
agents have been designed using the single second-generation H 1-antagonist of
interest, a positive control (a first-generation H 1-antagonist known to cause CNS
impairment) and negative (placebo) control, with no additional second-generation
H 1-antagonist comparator. Because the battery of objective tests used to study
these medications varies greatly from one study to another, it is difficult to draw
conclusions about relative CNS effects by comparing the results from these vari-
ous single-agent studies. Studies of many of the second-generation H 1-antagonists
reveal limited or no sedative effects, so one would not expect comparison studies
to be very informative. Indeed, most of the comparative studies that have been
reported, usually just studying two of the second-generation H 1-antagonists at a
time, have not revealed significant differences between agents (47, 78, 99, 104,
105, 175). Most of the rare exceptions were studies that found either a small
difference, or a difference with only one of the many objective tests done (53,
54, 65), or used a second-generation H 1-antagonist comparator (e.g., ketotifen,
acrivastine, cetirizine) known to be more sedating than the others in this class
(e.g., terfenadine, astemizole, loratadine) (110, 156, 164). Simons et al. evaluated
six different H 1-antagonists (five second-generation agents, with diphenhydra-
mine as the positive control) at one time in a single-dose, placebo-controlled,
crossover study using an objective EEG test for somnolence and a visual analog
scale (VAS) for subjective rating in 15 healthy subjects. No significant differ-
ences were found in the change in the P300 event-related potential and in the
VAS score among the five second-generation H 1-antagonists studied (loratadine,
cetirizine, astemizole, terfenadine, and ketotifen) (Fig. 5) although patients taking
cetirizine and ketotifen, similarly to patients taking diphenhydramine, had a sig-
nificant change in VAS relative to placebo (178). Hindmarch and Shamsi (41)
reviewed the extensive literature on sedating effects of H 1-antagonists and catego-
rized the tests for CNS impairment in the various studies of first- and second-
generation H 1-antagonists as ones that demonstrated impairment vs. no impair-
ment. They calculated a ratio of the number of tests in which significant impair-
ment was found over the number of tests in which no impairment was detected,
370 Welch et al.
Figure 5 Percentage change from baseline in the P300 event-related potential 2.5 h
after terfenadine 60 mg, cetirizine 10 mg, loratadine 10 mg, astemizole 10 mg, ketotifen
2 mg, diphenhydramine 50 mg, and placebo. Note that no significant differences were
found among the second-generation H 1-antihistamines, while diphenhydramine demon-
strated significant changes suggestive of sedation. *p ⬍ 0.05 compared to baseline and
placebo. (From Ref. 57.)
representing the likelihood that a given antihistamine would cause sedative ef-
fects. Fexofenadine and ebastine had the best ratio in favor of not inducing CNS
effects; triprolidine and diphenhydramine had the worst.
XII. CNS EFFECTS OF COMBINATION

H 1-ANTIHISTAMINES/DECONGESTANTS
Decongestants, used to relieve the symptoms of upper respiratory tract congestion

and obstruction, are commonly used in combination with H 1-antagonists. These
sympathomimetic agents promote vasoconstriction and improve nasal patency,
thereby complementing the effects of H 1-antagonists in allergic rhinitis, which are
predominantly to decrease the symptoms of nasal itch, sneezing, and rhinorrhea.
Decongestants are pharmacologically related to epinephrine and amphetamine,
and therefore can cause CNS stimulation, resulting in restlessness, insomnia, ap-
Effects on CNS 371
prehension, and tremor in certain sensitive patients. It has been theorized that
the use of a decongestant in combination with a first-generation H 1-antagonist
could potentially cancel out the sedative effects of the H 1-antagonist, an expecta-
tion commonly held by physicians using combination preparations in the pre-
second-generation H 1-antagonists era. However, when this was tested with tri-
prolidine-d (triprolidine 2.5 mg plus pseudoephedrine 60 mg three times daily)
using EEG monitoring, it could not be documented; the combination product
caused significantly more patient-reported daytime sedation and drowsiness than
either placebo or astemizole-d (193). The finding that sedation usually predomi-
nates has been reported for years by patients using either an over-the-counter or
a prescription agent that contains both an H 1-antagonist of the first-generation
type and a decongestant. With the advent of second-generation H 1-antagonists
with reduced sedating properties, the fixed-dose combination of a second-genera-
tion H 1-antagonist with a decongestant, not surprisingly, is associated with a high
incidence of patient reports of CNS stimulation (1,194–196). The impact of these
combination agents on objective measures of CNS function has not been studied
optimally, but a limited number of investigations have shown either no effect or
actual improvement of objective performance (193, 195). Given the above, the
convenience of having a single tablet or capsule of a fixed H 1-antagonist/decon-
gestant combination has to be weighed against the increased potential of adverse
subjective CNS stimulation effects due to the decongestant component.
XIII. COADMINISTRATION OF H 1-ANTIHISTAMINES

AND ALCOHOL OR CNS-ACTIVE SUBSTANCES
Objective psychomotor testing and tests of actual driving performance have con-
firmed that alcohol (0.50–0.75 g/kg) or diazepam 10 mg, administered concur-
rently with a first-generation H 1-antagonist such as clemastine, chlorpheniramine,
cyproheptadine, or diphenhydramine, potentiates the CNS dysfunction produced
by the H 1-antagonist (79, 87, 92, 102, 120, 197, 198). It is presumed that other
CNS-active medications, including antidepressants and hypnotics, also potentiate
CNS dysfunction produced by older H 1-antagonists, although this has not been
well documented objectively.
In contrast, in most studies, second-generation H 1-antagonists have not po-
tentiated the adverse CNS effects of alcohol or the benzodiazepines (diazepam,
lorazepam) (63, 79, 80, 102, 106, 111, 115, 120, 161, 162, 166, 172–175) (Table
10) (Fig.6). The degree of somnolence and impairment of CNS function associ-
ated with recommended daily doses of most second-generation H 1-antagonists
in combination with alcohol or benzodiazepines is similar to that produced by
alcohol or benzodiazepines alone.
Table 10 Objective CNS Studies of H 1-Antihistamines Administered with Alcohol or Diazepam/Lorazepam 372
No. of Time
Moser et al. (102) 20 db, pc, co T 60, 120, 240 Psychomotor skills, includ- 4 D ↓ subjective, not objec-
D 100 ing reaction time; CFF; tive, scores. T did not at
P subjective any dose. D potentiated
Diaz 10 adverse effects of Diaz
Alc 0.75 g/kg and D. T 120 did not
Bateman et al. (162) 7 db, pc, co A 10 qd ⫻ 7 d Psychomotor reaction 6 Alc ↓ performance; no ↑
P⫻7d time; pursuit rotor; vi- effect with A; A did not
Vodka 100ml on 7th d sual discrimination; alter Alc kinetics
VAS
Cohen et al. (92) 1) 12 db, pc, co 1) Ac 8 ⫾ Alc Adaptive tracking; reac- 1, 2.5, 5.5, 7.5 1) Ac 8 alone did not ↓
2) 12 D 50 ⫾ Alc tion time; eye move- CNS performance; Ac
P⫹P ment; body sway; VAS ⫹ Alc ↓ performance
2) Ac 4 ⫹ Alc but less than D ⫹ Alc
Ac 8 ⫹ Alc 2) Effects of Ac (4 and
T 60 ⫹ Alc 8) ⫹ Alc and T ⫹
T 120 ⫹ Alc Alc did not differ
P suggesting Ac effect
in combination with
Alc is small
Hindmarch and Bhatti (79) 18 db, pc, co A 30 CFF; CRT; car tracking 6 Ch, but not A, affected
Ch 12 (simulated); VAS; sub- tests; Alc potentiated
P jective Ch but not A
Alc 0.5 g/kg
Riedel et al. (111) 20 db, pc, co T 60 Actual driving (weaving in- 4 Tr, but not T or L, caused
L 10, 20 dex); self-reported seda- weaving comparable to
Tr 10 tion that seen with blood
⫾Alc Alc of 0.05%
P
Doms et al. (166) 36 db, pc, co C 10 Psychomotor; learning; Not stated C ⫽ P, no ↓ of perfor-
P memory; attention; mance; no interaction
⫾Alc 0.6 g/kg conc.; coordination; with Alc; C did not
VAS; subjective health; change Alc kinetics or
Welch et al.
anxiety vice versa

Gaillard et al. (120) 1) 12 db, pc 1) L 10 Reaction time; tracking; 6 1) L & T no effect; Cl ↓
2) 16 T 60 memory; subjective performance on
Cl 1 (VAS) tracking test, ↑ sub-
2) ⫹Diaz 5 jective drowsiness
2) Diaz no effect with any
drug or with placebo
O’Hanlon (80) 1) 20 1) db, pc 2) T 60 Car driving (high speed, 1, 3 Tr impaired driving; T and
2) 16 2) db, pc L 10 open road, 10 km); high- L did not ↓ driving; T
Effects on CNS
Tr 10 way circuit, weaving did not potentiate Alc

P index
3) T 60 bid ⫻ 4d
P
Alc
Bhatti and Hindmarch 12 db, pc, co T 60, 120, 240 Car driving (simulated); 1.5, 3 In contrast to T 60 or 120,
(161) P CFF; CRT; LARS T 240 alone ↓ driving;
⫾Alc 0.5 g/kg (subjective) T 60, 120 did not po-
tentiate Alc effects. T
240 ⫹ Alc same as T
240
Mattila et al. (172) 12 db, pc, co E 20 qd ⫻ 7d DSS; CFF; Maddox; nys- E alone at day 6; E did not ↓ performance
P tagmus; simulated driv- E ⫹ Alc on day 7; on day 6 but Alc did on
Alc 0.8 g/kg on day 7 ing; body balance; VAS 2, 4, 6 day 7; E did not potenti-
ate the effect of Alc
Ramaekers et al. (63) 16 db, pc, co L 10 Actual driving perfor- 0.5–5 C alone and L, C or P ⫹
C 10 mance; EEG; subjective Alc affected the EEG
P and ↑ weaving motion,
⫾Alc 0.72 g/kg speed, and subjective
drowsiness; L did po-
tentiate effects of Alc.
Effects of Alc and C
were additive. Alc had
a greater effect than C
Mattila et al. (173) 12 db, pc, co E 30 qd ⫻ 7d DSS; CFF; Maddox; nys- E alone at day 6, E did not ↓ performance
P tagmus; simulated driv- E ⫹ Diaz on day objectively or subjec-
Diaz 15 (day 7 only) ing; body balance; VAS 7; 1.5, 3, 4.5, 6 tively on day 6; on day
7 Diaz ↓ performance
in objective and subjec-
373
tive tests; E did not en-

hance effects of Diaz
374
Table 10 Objective CNS Studies of H 1-Antihistamines Administered with Alcohol or Diazepam/Lorazepam—Continued

No. of Time
Patat et al. (174) 16 db, pc, co M 10 qd ⫻ 8 d 1) CFF; CRT; tapping; 1) 2, 4, 6, 8 M 10 devoid of any ef-
P arithmetic calcula- 2) 3 fects on performance,
Loraz 2 or P on d 6 or 8 tion; body sway; memory, subjective rat-
with M VAS ings. Loraz caused
2) short-term, long-term marked ↓ of almost all
memory tests. M did not potenti-
ate effects of Loraz.
Patat et al. (175) 18 db, pc, co M 10 qd ⫻ 7 d 1) Driving (actual and sim- 1) 4, 7.3 (actual), 3.2, M and C had no effect on
C10 qd ⫻ 7 d ulated) 6.5 (simulated) driving or CFF. Alc
P 2) CFF; adaptive tracking; 2) 1.5, 2.6, 4.5, 6, 7.8 caused significant ↓ of
Alc or P, d 5 or d 7 divided attention all psychomotor and
2 h post dose of M, C, driving tests. M and C
or P did not potentiate ad-
verse effects of Alc.
Vermeeren and O’Hanlon 24 db, pc, co F 120 qd ⫻ 5 d Critical tracking; CRT; sus- 1.5–2.5 except driv- F did not impair driving
(115) F 240 qd ⫻ 5 d tained attention; actual ing (3–4) on days performance or most
F 60 bid ⫻ 5 d driving test 1, 4, and 5 psychomotor tests at
F 120 bid ⫻ 5 d any dose, nor did it po-
Cl 2 bid ⫻ 5 d tentiate the effects of
P Alc; F actually attenu-
Alc on day 5 ated alcohol’s adverse
effect on driving.
A, astemizole; Ac, acrivastine; Alc, alcohol; bid, twice daily; C, cetirizine; CFF, critical flicker fusion; Ch, chlorpheniramine (chlorphenamine); Cl, clemastine;
co, crossover; CRT, choice reaction time; CTT, critical tracking test; d, days; D, diphenhydramine; db, double-blind; Diaz, diazepam; DSS, digit-symbol
substitution; E, ebastine; EEG, electroencephalogram; F, fexofenadine; h, hours; H, hydroxyzine; K, ketotifen; L, loratadine; LARS, linear analog rating
scale (subjective sedation); Loraz, lorazepam; M, mizolastine; P, placebo; pc, placebo-controlled; qd, once daily; T, terfenadine; Tr, triprolidine; VAS, visual
analog scale; ↑, enhance/increase; ↓, impair/decrease.
Welch et al.
Effects on CNS 375
Figure 6 Mean degree of weaving in a standardized actual driving test undertaken 1.5–
4 h after administration of a morning dose of drug on days 1, 4, and 5. On day 5, subjects
were given a moderate alcohol dose along with study drug. Drugs used: clemastine 4 mg
bid, placebo, fexofenadine 120 mg qd, fexofenadine 60 mg bid, fexofenadine 240 mg qd,
fexofenadine 120 mg bid. Asterisks over bars indicate level of significance for drug–
placebo differences. *p ⬍ 0.05; **p ⬍ 0.01. Note that clemastine significantly impaired
driving performance on days 1 and 4; fexofenadine did not affect driving on day 1, and
appeared actually to improve driving (i.e., less weaving compared to placebo) on day 4.
Alcohol given on day 5 impaired driving but it was not potentiated by clemastine or by
fexofenadine. Fexofenadine 120 mg bid appeared to attenuate the effect of alcohol on
driving. (From Ref. 115.)
XIV. SUMMARY
An extensive body of research exists on CNS effects of H 1-antagonists. There

is great interest in this area due to the well-known adverse CNS effects associ-
ated with first-generation H 1-antagonists, and the many new second-generation
agents claiming to have nonsedative properties. Because the CNS effects of H 1-
antagonists are complex and cannot be reflected in one measurement, a variety of
assessments of CNS function are required. These range from the subjective (e.g.,
self-rating of drowsiness) to the objective (e.g. 24 h EEG sleep latency, P300),
and from the simple (e.g., critical flicker fusion) to the complex (e.g., actual
driving). When these tests are applied to the evaluation of the H 1-antagonists
currently available, it is clear that there is a real distinction between the older first-
376 Welch et al.
generation H 1-antagonists and the newer second-generation ones. At the recom-

mended dosages, all the second-generation H 1-antagonists are clearly less sedat-
ing in more patients than their predecessors. These newer medications do not
cross the blood–brain barrier readily; are highly specific for H 1-receptors; have
little to no anticholinergic, antiserotoninergic, or anti-alpha-adrenergic effects;
and do not enhance the adverse CNS effects of alcohol or other CNS-active sub-
stances such as the benzodiazepines. Since most second-generation H 1-antago-
nists are found to be relatively nonsedating, their benefit/risk ratios will be deter-
mined more by their other properties such as non-CNS adverse effects (e.g.,
potential to cause cardiac arrhythmias), potency, onset of action, duration of ac-
tion, ease of administration, and cost. The future role and usefulness of the older
sedating H 1-antagonists, given the availability of the safer second-generation
agents, are unclear at the present time. When H 1-antagonist treatment is indicated,
physicians should recommend an effective H 1-antagonist with a favorable clinical
pharmacology profile and a wide margin of safety in patients of all ages. The
common, often subclinical, adverse CNS effects produced by the old H 1-antago-
nists remain a major concern and, therefore, these compounds are no longer medi-
cations of choice in the treatment of allergic rhinitis, allergic conjunctivitis, or
urticaria.
REFERENCES
1. Storms W, Meltzer E, Nathan R, Selner J. The economic impact of allergic rhinitis.

J Allergy Clin Immunol 1997; 99:S820–S824.
2. Watemberg NM, Roth KS, Alehan FK, Epstein CE. Central anticholinergic
syndrome on therapeutic doses of cyproheptadine. Pediatrics 1999; 103:158–
160.
3. Arisaka O, Shimura N, Nakayama Y, Yabuta K. Cyproheptadine and growth. Am
J Dis Child 1988; 142:914–915.
4. Strayhorn JM. Case study: cyproheptadine and aggression in a five-year old boy.
J Am Acad Child Adolesc Psychiatry 1998; 37:668–670.
5. Dollberg S, Hurvitz H, Kerem E, Navon P, Branski D. Hallucinations and hyper-
thermia after promethazine ingestion. Acta Paediatr Scand 1989; 78:131–132.
6. Jones J, Dougherty J, Cannon L. Diphenhydramine-induced toxic psychosis. Am
J Emerg Med 1986; 4:369–371.
7. Köppel C, Ibe K, Tenczer J. Clinical symptomatology of diphenhydramine over-
dose: an evaluation of 136 cases in 1982 to 1985. J Toxicol Clin Toxicol 1987;
25:53–70.
8. Meltzer EO. Antihistamine- and decongestant-induced performance decrements. J
Occup Med 1990; 32:327–334.
Effects on CNS 377
9. Meltzer EO. Comparative safety of H 1 antihistamines. Ann Allergy 1991; 67:625–

633.
10. Rihoux JP and Donnelly F. CNS effects of histamine H 1-antagonists. Clin Exp
Allergy 1999; 29(suppl. 3):143–146.
11. Simons FER. New H 1-receptor antagonists: worth the price? Ann Allergy 1992;
69:163–165.
12. Simons FER. H 1-receptor antagonists—comparative tolerability and safety. Drug
Safety 1994; 10:350–380.
13. Simons FER. Antihistamines. In: Middleton E, Jr., Reed CE, Ellis EF, Adkinson
NF, Jr., Yunginger JW, Busse WW, eds. Allergy Principles and Practice. Vol. 1.
5th ed. St Louis: Mosby-Year Book Inc., 1998:612–637.
14. Simons FER. H 1-receptor antagonists: safety issues. Ann Allergy Asthma Immunol
1999; 83:481–488.
15. Simons FER, Simons KJ. The pharmacology and use of H 1-receptor antagonist
drugs. N Engl J Med 1994; 330:1663–1670.
16. Brion N, Beaumont D, Advenier C. Evaluation of the antimuscarinic activity of
atropine, terfenadine and mequitazine in healthy volunteers. Br J Clin Pharmacol
1988; 25:27–32.
17. Ryan JR, McMahon FG, Vargas R, Gotzkowsky S. Antimuscarinic activity of ter-
fenadine, chlorpheniramine, atropine and placebo in normal volunteers. J Allergy
Clin Immunol 1987; 79:190.
18. Grant SM, Goa KL, Fitton A, Sorkin EM. Ketotifen. A review of its pharmacody-
namic and pharmacokinetic properties, and therapeutic use in asthma and allergic
disorders. Drugs 1990; 40:412–448.
19. Janssens MM-L. Astemizole. A nonsedating antihistamine with fast and sustained
activity. Clin Rev Allergy 1993; 11:35–63.
20. Ramlakhan N, Altman J. Breaching the blood-brain barrier. New Scientist 1990;
128:52–55.
21. Goldberg MJ, Spector R. Chiang C-K. Transport of diphenhydramine in the central
nervous system. J Pharmacol Exp Ther 1987; 240:717–722.
22. Sangalli BC. Role of the central histaminergic neuronal system in the CNS toxicity
of the first generation H 1-antagonists. Prog Neurobiol 1997; 52:145–157.
23. Nicholson AN, Pascoe PA, Stone BM. Histaminergic systems and sleep. Studies
in man with H 1- and H 2-antagonists. Neuropharmacology 1985; 24:245–250.
24. Panula P, Rinne J, Kuokkanen K, Eriksson KS, Sallmen T, Kalimo H, and Relja
M. Neuronal histamine deficit in Alzheimer’s disease. Neuroscience 1998; 82:993–
997.
25. Prell GD, Green JP, Kaufmann CA, Khandelwal JK, Morrishow AM, Kirch DG,
Linnoila M, Wyatt RJ. Histamine metabolites in cerebrospinal fluid of patients with
chronic schizophrenia: their relationships to levels of other aminergic transmitters
and ratings of symptoms. Schizophr Res 1995; 14:93–104.
26. Schneider C, Risser D, Kirchner L, Kitzmuller E, Cairns N, Prast H, Singewald
N, Lubec G. Similar deficits of central histaminergic system in patients with Down
syndrome and Alzheimer disease. Neurosci Lett 1997; 222:183–186.
27. Yanai K, Ryu JH, Watanabe T, Iwata R, Ido T, Sawai Y, Ito K, Itoh M. Histamine
H 1-receptor occupancy in human brains after single oral doses of histamine H 1-
378 Welch et al.
antagonists measured by positron emission tomography. Br J Pharmacol 1995; 116:

1649–1655.
28. Nicholson AN, Pascoe PA, Turner C, Ganellin CR, Greengrass PM, Casy AF, Mer-
cer AD. Sedation and histamine H 1-receptor antagonism: studies in man with the
enantiomers of chlorpheniramine and dimethindene. Br J Pharmacol 1991; 104:
270–276.
29. Barbe J, et al. Individualisation des supports structuraux des actions sedatives et
anti-H 1. Eur J Med Chem 1983; 18:531–534.
30. Ruat M, Bouthenet ML, Schwartz J-C, Ganellin CR. Histamine H 1-receptor in
heart: unique electrophoretic mobility and autoradiographic localization. J Neuro-
chem 1990; 55:379–385.
31. Ahn H-S, Barnett A. Selective displacement of [3H] mepyramine from peripheral
vs central nervous system receptors by loratadine, a nonsedating antihistamine. Eur
J Pharmacol 1986; 127:153–155.
32. ter Laak AM, Donné-Op den Kelder GM, Bast A, Timmerman H. Is there a differ-
ence in the affinity of histamine H 1-receptor antagonists for CNS and peripheral
receptors? An in vitro study. Eur J Pharmacol 1993; 232:199–205.
33. Zhang MQ, ter Laak AM, Timmerman H. Structure-activity relationships within a
series of analogues of the histamine H 1-antagonist terfenadine. Eur J Med Chem
1993; 28:165–173.
34. ter Laak AM, Tsai RS, Donné-Op den Kelder GM, Carrupt PA, Testa B, Timmer-
man H. Lipophilicity and hydrogen-bonding capacity of H 1-antihistaminic agents
in relation to their central sedative side-effects. Eur J Pharm Sci 1994; 2:373–384.
35. Timmerman H. Why are non-sedating antihistamines non-sedating? Clin Exp Al-
lergy 1999; 29(Suppl. 3):13–18.
36. Laduron PM, Janssen PFM, Gommeren W, Leysen JE. In vitro and in vivo binding
characteristics of a new long-acting histamine H 1-antagonist, astemizole. Mol Phar-
macol 1982; 21:294–300.
37. Snyder SH, Snowman AM. Receptor effects of cetirizine. Ann Allergy 1987; 59:
4–8.
38. Timmerman H. Factors involved in the incidence of central nervous system effects
of H 1-blockers. In: Church MK, Rihoux J-P, eds. Therapeutic Index of Antihista-
mines. Lewiston: Hogrefe & Huber Publishers. 1992:19–31.
39. Nolen T. Sedative effects of antihistamines: safety, performance, learning, and
quality of life. Clinical Therapeutics 1997; 19(1):39–55.
40. Simons FER, Simons KJ. Antihistamines. In: Middleton E Jr., Reed CE, Ellis EF,
Adkinson NF Jr., Yunginger JW, Busse WW, eds. Allergy Principles and Practice.
Vol. 1. 4 th ed. St. Louis: Mosby–Year Book, Inc., 1993:856–892.
41. Hindmarch I, Shamsi Z. Antihistamines: models to assess sedative properties,
assessment of sedation, safety and other side-effects. Clin Exp Allergy 1999;
29(Suppl. 3):133–142.
42. Vuurman EFPM, van Veggel LMA, Uiterwijk MMC, Leutner D, O’Hanlon JF.
Seasonal allergic rhinitis and antihistamine effects on children’s learning. Ann Al-
lergy 1993; 71:121–126.
43. Vuurman EFPM, van Veggel LMA, Sanders RL, Muntjewerff ND, O’Hanlon JF.
Effects on CNS 379
Effects of Semprex-D and diphenhydramine on learning in young adults with sea-

sonal allergic rhinitis. Ann Allergy Asthma Immunol 1996; 76:247–252.
44. Adelsberg BR, D’Amico-Beadon A. The effects of loratadine, diphenhydramine
and placebo on worker productivity: results of a double blind trial. J Allergy Clin
Immunol 1990; 85:296.
45. Valk PJ, Simons RM, Struyvenberg PA, Kruit H, van Berge Henegouwen MT.
Effects of a single dose of loratadine on flying ability under conditions of simulated
cabin pressure. Am J Rhinol 1997; 11:27–33.
46. Walsh JK, Muehlbach MJ, Schweitzer PK. Simulated assembly line performance
following ingestion of cetirizine or hydroxyzine. Ann Allergy 1992; 69:195–200.
47. Alford C, Bhatti JZ, Rombaut NEI, Curran S. Hindmarch I. A comparison of anti-
histamines using EEG and questionnaire-based assessments. Med Sci Res 1989;
17:421–423.
48. Gengo FM, Dabronzo J, Yurchak A, Love S, Miller JK. The relative antihistaminic
and psychomotor effects of hydroxyzine and cetirizine. Clin Pharmacol Ther 1987;
42:265–272.
49. Gengo F, Gabos C, Miller JK. The pharmacodynamics of diphenhydramine-
induced drowsiness and changes in mental performance. Clin Pharmacol Ther
1989; 45:15–21.
50. Gengo FM, Gabos C, Mechtler L. Quantitative effects of cetirizine and diphenhy-
dramine on mental performance measured using an automobile driving simulator.
Ann Allergy 1990; 64:520–526.
51. Kohl RL, Homick JL, Cintron N, Calkins DS. Lack of effects of astemizole on
vestibular ocular reflex, motion sickness, and cognitive performance in man. Aviat
Space Environ Med 1987; 58:1171–1174.
52. Levander S, Stahle-Bäckdahl M, Hägermark O. Peripheral antihistamine and cen-
tral sedative effects of single and continuous oral doses of cetirizine and hydroxy-
zine. Eur J Clin Pharmacol 1991; 41:435–439.
53. Pechadre JC, Vernay D, Trolese JF, Bloom M, Dupont P, Rihoux J-P. Comparison
of the central and peripheral effects of cetirizine and terfenadine. Eur J Clin Pharma-
col 1988; 35:255–259.
54. Pechadre JC, Beudin P, Eschalier A, Trolese JF, Rihoux J-P. A comparison of
central and peripheral effects of cetirizine and loratadine. J Int Med Res 1991; 19:
289–295.
55. Simons FER, Reggin JD, Roberts JR, Simons KJ. Benefit/risk ratio of the antihis-
tamines (H 1-receptor antagonists) terfenadine and chlorpheniramine in children. J
Pediatr 1994; 124:979–983.
56. Simons FER, Fraser TG, Reggin JD, Simons KJ. Individual differences in central
nervous response to antihistamines (H 1-receptor antagonists). Ann Allergy Asthma
Immunol 1995; 75:507–514.
57. Simons FER, Fraser TG, Reggin JD, Simons KJ. Comparison of the central nervous
system effects produced by six H 1-receptor antagonists. Clin Exp Allergy 1996;
26:1092–1097.
58. Simons FER, Fraser TG, Maher J, Pillay N, Simons KJ. Central nervous system
effects of H 1-receptor antagonists in the elderly. Ann Allergy Asthma Immunol
1999; 82:157–160.
380 Welch et al.
59. Aso T, Sakai Y. Effect of terfenadine, a novel antihistamine, on actual driving

performance. Ann Allergy 1989; 62:250.
60. Murri L, Massetani R, Krause M, Dragonetti C, Iudice A. Evaluation of antihista-
mine-related daytime sleepiness. A double-blind, placebo-controlled study with ter-
fenadine. Allergy 1992; 47:532–534.
61. Nicholson AN, Stone BM. Antihistamines: impaired performance and the tendency
to sleep. Eur J Clin Pharmacol 1986; 30:27–32.
62. Offenloch K, Zahner G. Rated performance, cardiovascular and quantitative
EEG parameters during simulated instrument flight under the effect of terfenadine.
Arzneim-Forsch/Drug Res 1992; 42:864–868.
63. Ramaekers JG, Uiterwijk MMC, O’Hanlon JF. Effects of loratadine and cetirizine
on actual driving and psychometric test performance, and EEG during driving. Eur
64. Roth T, Roehrs T, Koshorek G, Sicklesteel J, Zorick F. Sedative effects of antihista-
mines. J Allergy Clin Immunol 1987; 80:94–98.
65. Volkerts ER, van Willigenburg APP, van Laar MW, Maes RAA. Does cetirizine
belong to the new generation of antihistamines? An investigation into its acute and
subchronic effects on highway driving, psychometric test performance and daytime
sleepiness. Hum Psychopharmacol Clin Exp 1992; 7:227–238.
66. Nicholson AN. Effect of the antihistamines, brompheniramine maleate and triproli-
dine hydrochloride, on performance in man. Br J Clin Pharmacol 1979; 8:321–
324.
67. Seidel WF, Cohen S, Bliwise NG, Dement WC. Direct measurement of daytime
sleepiness after administration of cetirizine and hydroxyzine with a standardized
electroencephalographic assessment. J Allergy Clin Immunol 1990; 86:1029–1033.
68. Vollmer R, Matejcek M, Greenwood C, Grisold W, Jellinger K. Correlation be-
tween EEG changes indicative of sedation and subjective responses. Neuropsy-
chobiol 1983; 10:249–253.
69. Goetz DW, Jacobson JM, Apaliski SJ, Repperger DW, Martin ME. Objective anti-
histamine side effects are mitigated by evening dosing of hydroxyzine. Ann Allergy
1991; 67:448–454.
70. Hindmarch I, Parrott AC. A repeated dose comparison of the side effects of five
antihistamines on objective assessments of psychomotor performance, central ner-
vous system arousal and subjective appraisals of sleep and early morning behaviour.
Arzneim-Forsch/Drug Res 1978; 28:483–486.
71. Kulshrestha VK, Gupta PP, Turner P, Wadsworth J. Some clinical pharmacological
studies with terfenadine, a new antihistamine drug. Br J Clin Pharmacol 1978; 6:
25–29.
72. Sannita WG, Crimi E, Riela S, Rosadini G, Brusasco V. Cutaneous antihistaminic
action of cetirizine and dose-related EEG concomitants of sedation in man. Eur J
Pharmacol 1996; 300:33–41.
73. Shamsi Z, Hindmarch I. Sedation and antihistamines: a review of inter-drug differ-
ences using proportional impairment ratios. Hum Psychopharmacol Clin Exp 2000;
15 (Suppl 1):S3–S30.
74. Breneman DL. Cetirizine versus hydroxyzine and placebo in chronic idiopathic
urticaria. Ann Pharmacother 1996; 30:1075–1079.
Effects on CNS 381
lergy 1991; 66:257–262.
76. Monroe EW. Chronic urticaria: review of nonsedating H 1-antihistamines in treat-
ment. J Am Acad Dermatol 1988; 19:842–849.
77. Aaronson DW. Effects of terfenadine on psychomotor performance: an overview.
Drug Saf 1993; 8:321–329.
78. Hindmarch I. Psychometric aspects of antihistamines. Allergy 1995; 50:48–54.
79. Hindmarch I, Bhatti JZ. Psychomotor effects of astemizole and chlorpheniramine,
alone and in combination with alcohol. Int Clin Psychopharmacol 1987; 2:117–
119.
80. O’Hanlon JF. Antihistamines and driving performance: the Netherlands. J Resp
Dis 1988; 9:S12–S17.
81. Carruthers SG, Shoeman DW, Hignite CE, Azarnoff DL. Correlation between
plasma diphenhydramine level and sedative and antihistamine effects. Clin Pharma-
col Ther 1978; 23:375–382.
82. Simons FER, Watson WTA, Chen XY, Minuk GY, Simons KJ. The pharmacokinet-
ics and pharmacodynamics of hydroxyzine in patients with primary biliary cirrho-
sis. J Clin Pharmacol 1989; 29:809–815.
83. Simons KJ, Watson WTA, Chen XY, Simons FER. Pharmacokinetic and pharma-
codynamic studies of the H 1-receptor antagonist hydroxyzine in the elderly. Clin
84. Alford C, Rombaut N, Jones J, Foley S, Idzikowski C, Hindmarch I. Acute effects
of hydroxyzine on nocturnal sleep and sleep tendency the following day: a C-EEG
study. Hum Psychopharmacol Clin Exp 1992; 7:25–35.
85. Betts T, Markman D, Debenham S, Mortiboy D, McKevitt T. Effects of two antihis-
tamine drugs on actual driving performance. Br Med J 1984; 288:281–282.
86. Bradley CM, Nicholson AN. Studies on the central effects of the H 1-antagonist,
loratadine. Eur J Clin Pharmacol 1987; 32:419–421.
87. Burns M, Moskowitz H. Effects of diphenhydramine and alcohol on skills perfor-
88. Bye C, Dewsbury D, Peck AW. Effects on the human central nervous system of
two isomers of ephedrine and triprolidine, and their interaction. Br J Clin Pharmacol
1974; 1:71–78.
89. Bye CE, Claridge R, Peck AW, Plowman F. Evidence for tolerance to the central
nervous effects of the histamine antagonist, triprolidine, in man. Eur J Clin Pharma-
col 1977; 12:181–186.
90. Clarke CH, Nicholson AN. Performance studies with antihistamines. Br J Clin
Pharmacol 1978; 6:31–35.
91. Cohen AF, Hamilton M, Philipson R, Peck AW. The acute effects of acrivastine
(BW 825C), a new antihistamine, compared with triprolidine on measures of central
nervous system performance and subjective effects. Clin Pharmacol Ther 1985; 38:
381–386.
382 Welch et al.

93. De Roeck J, Cluydts R, Herman P. Effects of antihistamines on daytime alertness.
J Allergy Clin Immunol 1990; 85:179.
94. Fink M, Irwin P. CNS effects of the antihistamines diphenhydramine and terfena-
dine (RMI 9918). Pharmakopsychiatr Neuropsychopharmakol 1979; 12:35–44.
95. Goetz DW, Jacobson JM, Murnane JE, Reid MJ, Repperger DW, Goodyear C,
Martin ME. Prolongation of simple and choice reaction times in a double-blind
comparison of twice-daily hydroxyzine versus terfenadine. J Allergy Clin Immunol
1989; 84:316–322.
96. Hägermark O, Levander S, Stahle M. A comparison of antihistaminic and sedative
effects of some H 1-receptor antagonists. Acta Derm Venereol 1985; 114:155–156.
97. Hopes H, Meuret GH, Ungethum W, Leopold G, Wiemann H. Placebo controlled
comparison of acute effects of ebastine and clemastine on performance and EEG.
Eur J Clin Pharmacol 1992; 42:55–59.
98. Kay GG, Berman B, Mockoviak SH, Morris CE, Reeves D, Starbuck V, Sukenik
E, Harris AG. Initial and steady-state effects of diphenhydramine and loratadine
on sedation, cognition, mood, and psychomotor performance. Arch Intern Med
1997; 157:2350–2356.
99. Kerr JS, Dunmore C, Hindmarch I. The psychomotor and cognitive effects of a
new antihistamine, mizolastine, compared to terfenadine, triprolidine and placebo
in healthy volunteers. Eur J Clin Pharmacol 1994; 47:331–335.
100. Levander S, Hagermark O, Stahle M. Peripheral antihistamine and central sedative
effects of three H 1-receptor antagonists. Eur J Clin Pharmacol 1985; 28:523–
529.
101. Meador KJ, Loring DW, Thompson EE, Thompson WO. Differential cognitive
effects of terfenadine and chlorpheniramine. J Allergy Clin Immunol 1989; 84:
322–325.
102. Moser L, Huther KJ, Koch-Weser J, Lundt PV. Effects of terfenadine and diphenhy-
dramine alone or in combination with diazepam or alcohol on psychomotor perfor-
mance and subjective feelings. Eur J Clin Pharmacol 1978; 14:417–423.
103. Moskowitz H, Burns M. Effects of terfenadine, diphenhydramine, and placebo on
skills performance. Cutis 1988; 42:14–18.
104. Nicholson AN, Stone BM. Performance studies with the H 1-histamine receptor an-
tagonists, astemizole and terfenadine. Br J Clin Pharmacol 1982; 13:199–202.
105. Nicholson AN, Smith PA, Spencer MB. Antihistamines and visual function: studies
on dynamic acuity and the pupillary response to light. Br J Clin Pharmacol 1982;
14:683–690.
106. O’Hanlon JF. Antihistamines and driving safety. Cutis 1988; 42:10–13.
107. Patat A, Gram LF, Dubruc C, Brohier S, Cabanis MJ, Rosenzweig P. Effects of
mizolastine, a new antihistamine, on psychomotor performance and memory in
elderly subjects. Int Clin Psychopharmacol 1994; 9:101–108.
108. Pishkin V, Sengel RA, Lovallo WR, Shurley JT. Cognitive and psychomotor evalu-
ation of clemastine fumarate, diphenhydramine HCl and hydroxyzine HCl: double
blind study. Curr Ther Res 1983; 33:230–237.
109. Preston KL, Wolf B, Guarino JJ, Griffiths RR. Subjective and behavioral effects
Effects on CNS 383
of diphenhydramine, lorazepam and methocarbamol: evaluation of abuse liability.

J Pharmacol Exp Ther 1992; 262:707–720.
110. Ramaekers JG, O’Hanlon JF. Acrivastine, terfenadine and diphenhydramine effects
on driving performance as a function of dose and time after dosing. Eur J Clin
Pharmacol 1994; 47:261–266.
111. Riedel WJ, Schoenmakers EAJM, O’Hanlon JF. The effects of loratadine alone and
in combination with alcohol on actual driving performance. In: Technical Report,
Institute for Drugs, Safety and Behaviour, University of Limburg, Maastricht, The
Netherlands, 1987:87–101.
112. Roehrs TA, Tietz EI, Zorick FJ, Roth T. Daytime sleepiness and antihistamines.
Sleep 1984; 7:137–141.
113. Rombaut N, Bhatti JZ, Curran S, Hindmarch I. Effects of topical administration
of levocabastine on psychomotor and cognitive function. Ann Allergy 1991; 67:
75–79.
114. Schweitzer PK, Muelbach MJ, Walsh JK. Sleepiness and performance during three-
day administration of cetirizine or diphenhydramine. J Allergy Clin Immunol 1994;
94:716–724.
306–311.
116. Vincent J, Sumner DJ, Reid JL. Ebastine: the effect of a new antihistamine on
psychomotor performance and autonomic responses in healthy subjects. Br J Clin
Pharmacol 1988; 26:503–508.
117. Vuurman EFPM, Uiterwijk MMC, Rosenzweig P, O’Hanlon JF. Effects of mizolas-
tine and clemastine on actual driving and psychomotor performance in healthy vol-
unteers. Eur J Clin Pharmacol 1994; 47:253–259.
118. Diaz-Guerrero R, Feinstein R, Gottlieb JS. EEG findings following intravenous
injection of diphenhydramine hydrochloride (Benadryl). EEG Clin Neurophysiol
1956; 8:299–306.
119. Biehl B. Effects of azatadine maleate on subjective appraisal and psychomotor
functions relevant to driving performance. Curr Med Res Opin 1979; 6:62–69.
120. Gaillard AWK, Gruisen A, de Jong R. The influence of antihistamines on human
performance. Eur J Clin Pharmacol 1988; 35:249–253.
121. Goldstein L, Murphree HB, Pfeiffer CC. Comparative study of EEG effects of
antihistamines in normal volunteers. J Clin Pharmacol 1968; 8:42–53.
122. Higgins EA, Chiles WD, McKenzie JM, Jennings AE, Funkhouser GE, Mullen SR.
Effects of altitude and two decongestant-antihistamine preparations on physiologi-
cal functions and performance. Aviat Space Environ Med 1979; 50:154–158.
123. Hindmarch I, Easton JC. A placebo-controlled assessment of mequitazine and as-
temizole in tests of psychomotor ability. Int J Clin Pharm Res 1986; 6:457–
464.
124. Hughes FW, Forney RB. Comparative effect of three antihistamines and ethanol
on mental and motor performance. Clin Pharmacol Ther 1964; 5:414–421.
125. Kayed K, Hansen T. Godtlibsen OB. Controlled clinical investigation of trimepra-
zine as a sleep-inducer in normal subjects. Eur J Clin Pharmacol 1977; 11:163–
167.
384 Welch et al.
126. Millar K, Standen PJ. Differences in performance impairment due to bromphenira-

mine maleate as a function of the sustained-release system. Br J Clin Pharmacol
1982; 14:49–55.
127. Molson GR, Mackey JA, Smart JV, Turner P. Effect of promethazine hydrochloride
on hand-eye coordination. Nature 1966; 209:516.
128. Peck AW, Fowle ASE, Bye C. A comparison of triprolidine and clemastine on
histamine antagonism and performance tests in man: implications for the mecha-
nism of drug-induced drowsiness. Eur J Clin Pharmacol 1975; 8:455–463.
129. Seppala T, Nuotto, E, Korttila K. Single and repeated dose comparison of three
antihistamines and phenylpropanolamine: psychomotor performance and subjective
appraisals of sleep. Br J Clin Pharmacol 1981; 12:179–188.
130. Witek TJ Jr, Canestrari DA, Miller RD, Yang JY, Riker DK. The effects of phenin-
damine tartrate on sleepiness and psychomotor performance. J Allergy Clin Immu-
nol 1992; 90:953–961.
131. Feldman W, Shanon A, Leiken L, Ham-Pong A, Peterson R. Central nervous sys-
tem side-effects of antihistamines in schoolchildren. Rhinology 1992; 13(suppl.):
13–19.
132. Simons FER, Fraser TG, Reggin JD, Roberts JR, Simons KJ. Adverse central ner-
vous system effects of older antihistamines in children. Pediatr Allergy Immunol
1996; 7:22–27.
133. Adam K, Oswald I. The hypnotic effects of an antihistamine: promethazine. Br J
134. Kudo Y, Kurihara M. Clinical evaluation of diphenhydramine hydrochloride for
the treatment of insomnia in psychiatric patients: a double-blind study. J Clin Phar-
macol 1990; 30:1041–1048.
135. Rickels K, Morris RJ, Newman H, Rosenfeld H, Schiller H, Weinstock R. Diphen-
hydramine in insomniac family practice patients: a double-blind study. J Clin Phar-
macol 1983; 23:234–242.
136. Russo RM, Gururaj VJ, Allen JE. The effectiveness of diphenhydramine HCl in
pediatric sleep disorders. J Clin Pharmacol 1976; 16:284–288.
137. Roehrs T, Zwyghuizen-Doorenbos A, Roth T. Sedative effects and plasma concen-
trations following single doses of triazolam, diphenhydramine, ethanol and placebo.
Sleep 1993; 16:301–305.
138. Franssen C, Hans P, Brichant JF, Noirot D, Lamy M. Comparison between alprazo-
lam and hydroxyzine for oral premedication. Can J Anaesth 1993; 40:13–17.
139. Kapetansky D, Warren R, Hawtof D. Cleft lip repair using intramuscular hydroxy-
zine sedation and local anesthesia. Cleft Palate Craniofac J 1992; 29:481–484.
140. Kay GG, Plotkin KE, Quig MB, Starbuck VN, Yasuda S. Sedating effects of AM/
PM antihistamine dosing with evening chlorpheniramine and morning terfenadine.
Am J Man Care 1997; 3:1843–1848.
141. Starbuck VN, Kay GG, Platenberg RC. Functional magnetic resonance imaging
shows evidence of daytime sleepiness following evening dosing with chlorphenira-
mine. J Allergy Clin Immunol 1998; 101:S97.
142. Manning C, Scandale L, Manning EJ, Gengo FM. Central nervous system effects
of meclizine and dimenhydrinate: evidence of acute tolerance to antihistamines. J
Clin Pharmacol 1992; 32:996–1002.
Effects on CNS 385
143. Brookhuis KA, De Vries G, De Waard D. Acute and subchronic effects of the H 1-
histamine receptor antagonist ebastine in 10,20 and 30 mg dose, and triprolidine
10 mg on car driving performance. Br J Clin Pharmacol 1993; 36:67–70.
144. Dykewicz MS, Fineman S, editors. Diagnosis and Management of Rhinitis: Param-
eter Documents of the Joint Task Force on Practice Parameters in Allergy, Asthma,
and Immunology. Ann Allergy Asthma Immunol 1998; 81:463–518.
145. Cimbura G, Lucas DM, Bennett RC, Warren RA, Simpson HM. Incidence and
toxicological aspects of drugs detected in 484 fatally injured drivers and pedestrians
in Ontario. J Forensic Sci 1982; 27:855–867.
146. Starmer G. Antihistamines and highway safety. Accid Anal Prev 1985; 17:311–
317.
147. Warren R, Simpson H, Hilchie J, Cimbura G, Lucas D, Bennett R. Drugs detected
in fatally injured drivers in the province of Ontario. In: Goldberg L, ed. Alcohol,
Drugs, and Traffic Safety. Vol. 1. Stockholm: Almquist & Wiksell International,
1981:203–217.
148. Gilmore TM, Alexander BH, Mueller BA, Rivara FP. Occupational injuries and
medication use. Am Industr Med 1996; 30:234–239.
149. Bousquet J, Bullinger M, Fayol C, Marquis P, Valentin B, Burtin B. Assessment
of quality of life in patients with perennial allergic rhinitis with the French version
of the SF-36 Health Status Questionnaire. J Allergy Clin Immunol 1994; 94:182–
188.
151. Marshall PS, Colon EA. Effects of allergy season on mood and cognitive function.
Ann Allergy 1993; 71:251–258.
152. Spaeth J, Klimek L, Mosges R. Sedation in allergic rhinitis is caused by the condi-
tion and not by antihistamine treatment. Allergy 1996; 51:893–906.
153. Craig TJ, Teets S, Lehman EB, Chinchilli VM, Zwillich C. Nasal congestion sec-
ondary to allergic rhinitis as a cause of sleep disturbance and daytime fatigue and
the response to topical nasal corticosteroids. J Allergy Clin Immunol 1998; 101:
633–637.
154. Juniper EF, Guyatt GH, Dolovich J. Assessment of quality of life in adolescents
with allergic rhinoconjunctivitis: development and testing of a questionnaire for
clinical trials. J Allergy Clin Immunol 1994; 93:413–423.
155. Gozal D. Sleep-disordered breathing and school performance in children. Pediatrics
1998; 102:616–620.
156. Howarth PH, Stern MA, Roi L, Reynolds R, Bousquet J. Double-blind, placebo-
Clin Immunol 1999; 104:927–933.
157. Leynadier F, Bousquet J, Murrieta M, Attali P, the Rhinitis Study Group. Efficacy
and safety of mizolastine in seasonal allergic rhinitis. Ann Allergy Asthma Immu-
nol 1996; 76:163–168.
158. Weiler JM, Meltzer EO, Benson PM, Weiler K, Widlitz MD, Freitag J. Dose rang-
ing study of the efficacy and safety of azelastine nasal spray in the treatment of
386 Welch et al.
seasonal allergic rhinitis with an acute model. J Allergy Clin Immunol 1994; 94:
972–980.
159. Wiseman LR, Faulds D. Ebastine: a review of its pharmacological properties and
clinical efficacy in the treatment of allergic disorders. Drugs 1996; 51:260–277.
160. Betts TA, Edson AE, Furlong PL. The effect of single doses of 120 mg and 240
mg of terfenadine on driving and other measures of psychomotor performance in-
cluding visual evoked responses. Ann Allergy 1991; 66:98.
162. Bateman DN, Chapman PH, Rawlins MD. Lack of effect of astemizole on ethanol
dynamics or kinetics. Eur J Clin Pharmacol 1983; 25:567–568.
163. Dhorranintra B, Limsuvan S, Bunnag C. Effect of astemizole on psychomotor per-
formance in healthy Thais. Drug Develop Res 1986; 7:285–290.
164. Moser VL, Gerdes H, Buckmann M, Hopmann G. Antihistaminika und Reaktions-
fahigkeit (Antihistamines and reactivity). Arzneim-Forsch/Drug Res 1983; 33(I):
262–265.
165. Rice VJ, Snyder HL. The effects of Benadryl and Hismanal on mood, physiological
measures, antihistamine detection and subjective symptoms. Aviat Space Environ
Med 1993; 64:717–725.
166. Doms M, Vanhulle G, Baelde Y, Coulie P, Dupont P, Rihoux J-P. Lack of potentia-
tion by cetirizine of alcohol-induced psychomotor disturbances. Eur J Clin Pharma-
col 1988; 34:619–623.
167. Nicholson AN, Turner C. Central effects of the H 1-antihistamine, cetirizine. Aviat
Space Environ Med 1998; 69:166–171.
168. Neves-Pinto RM, Moreira Lima G, da Mota Teixeira R. A double-blind study of
the effects of loratadine versus placebo on the performance of pilots. Am J Rhinol
1992; 6:23–27.
169. Hindmarch I, Shamsi Z, Stanley N, Fairweather DB. A double-blind, placebo-
controlled investigation of the effects of fexofenadine, loratadine, and promethazine
on cognitive and psychomotor function. Br J Clin Pharmacol 1999; 48:200–206.
170. Nicholson AN, Stone BM, Turner C, Mills SL. Antihistamines and aircrew: use-
fulness of fexofenadine. Aviat Space Environ Med 2000; 71:2–6.
171. Nathan RA, Mason J, Bernstein DI, Howland WC, Kaiser HB, Meltzer EO, Segall
N. Long-term tolerability of fexofenadine in healthy volunteers. Clin Drug Invest
1999; 18:317–328.
172. Mattila MJ, Kuitunen T, Pletan Y. Lack of pharmacodynamic and pharmacokinetic
interactions of the antihistamine ebastine with ethanol in healthy subjects. Eur J
173. Mattila MJ, Aranko K, Kuitunen T. Diazepam effects on the performance of healthy
subjects are not enhanced by treatment with the antihistamine ebastine. Br J Clin
Pharmacol 1993; 35:272–277.
174. Patat A, Perault MC, Vandel B, Ulliac N, Zieleniuk I, Rosenzweig P. Lack of
interaction between a new antihistamine, mizolastine, and lorazepam on psychomo-
tor performance and memory in healthy volunteers. Br J Clin Pharmacol 1995; 39:
31–38.
175. Patat A, Stubbs D, Dunmore C, Ulliac N, Sexton B, Zieleniuk I, Irving A, Jones
Effects on CNS 387
W. Lack of interaction between two antihistamines, mizolastine and cetirizine, and

ethanol in psychomotor and driving performance in healthy subjects. Eur J Clin
Pharmacol 1995; 48:143–150.
176. Coulie PJ, Ghys L, Rihoux J-P. Cetirizine, oxatomide, ketotifen and placebo. Phar-
macological evaluation of their respective anti -H 1-histamine, antipruritic and sedat-
ing effects. Drug Invest 1991; 3:324–327.
177. Le Blaye I, Donatini B, Hall M, Krupp P. Acute ketotifen overdosage. A review
of present clinical experience. Drug Safety 1992; 7:387–392.
178. Mann RD, Pearce GL, Dunn N, Shakir S. Sedation with “non-sedating” antihista-
mines: four prescription-event monitoring studies in general practice. Br Med J
2000; 320:1184–1187.
179. McTavish D, Sorkin EM. Azelastine. A review of its pharmacodynamic and phar-
180. LaForce C, Dockhorn RJ, Prenner BM, Chu TJ, Kraemer MJ, Widlitz MD, D’Eletto
TA, Freitag JJ. Safety and efficacy of azelastine nasal spray (Astelin NS) for sea-
sonal allergic rhinitis: a 4-week comparative multicenter trial. Ann Allergy Asthma
Immunol 1996; 76:181–188.
181. Meltzer EO, Weiler JM, Dockhorn RJ, Widlitz MD, Freitag JJ. Azelastine nasal spray
in the management of seasonal allergic rhinitis. Ann Allergy 1994; 72:354–359.
182. Conde Hernandez DJ, Palma Aquilar JL, Delgada Romero J. Comparison of azelas-
tine nasal spray and oral ebastine in treating seasonal allergic rhinitis. Curr Med
Res Opin 1995; 13(6):299–304.
183. Passali D, Piragine F. A comparison of azelastine nasal spray and cetirizine tablets
in the treatment of allergic rhinitis. J Int Med Res 1994; 22:17–23.
184. Newson-Smith G, Powell M, Baehre M, Garnham SP, MacMahon MT. A placebo
controlled study comparing the efficacy of intranasal azelastine and beclometha-
sone in the treatment of seasonal allergic rhinitis. Eur Arch Otorhinolaryngol 1997;
254:236–241.
185. Lassig W, Wober W, Hoflich C, Bahre M, Roloff A. Topical therapy of allergic
rhinitis in childhood: Allergodil nasal spray-non-sedating in children. Curr Med
Res Opin 1996; 13:391–395.
186. Arriaga F, Rombaut N. Absence of central effects with levocabastine eye drops.
Allergy 1990; 45:552–554.
vitis. Drugs 1991; 41:202–224.
188. Riedel WJ, Van Veggel L, O’Hanlon JF. Cetirizine 10 and 20 mg impair psychomo-
tor performance. Clin Exp Allergy 1990; 20:97.
189. Danjou G, Dunmore C, Curson VH, Rosenzweig P, Hindmarch I, Morselli PL. A
double-blind placebo-controlled study of the psychometric effects of the SL
85.0324, a new H 1-antagonist drug, compared to terfenadine and triprolidine in
healthy subjects. Eur J Pharmacol 1990; 183:534.
190. Schaffler K, Wauschkuhn CH, Zander KJ, Bianchetti G, Kyrein HJ, Eich FX,
Kauert G, Danjou PH, Rosenzweig P. CNS-pharmacodynamics and pharmacoki-
netics of the new non-sedative H 1-antagonist SL 85.0324 vs placebo and dimetinden
in volunteers. Eur J Pharmacol 1990; 183:593–594.
388 Welch et al.
191. O’Hanlon JF, Ramaekers JG. Antihistamine effects on actual driving performance
in a standard test: a summary of Dutch experience, 1989–94. Allergy 1995; 50:
234–242.
192. Witek TJ Jr, Canestrari DA, Miller RD, Yang JY, Riker DK. Characterization of
daytime sleepiness and psychomotor performance following H 1 receptor antago-
nists. Ann Allergy Asthma Immunol 1995; 74:419–426.
193. Stanley N, Alford CA, Rombaut NEI, Hindmarch I. Comparison of the effects of
astemizole/pseudoephedrine and triprolidine/pseudoephedrine on CNS activity and
psychomotor function. Int Clin Psychopharmacology 1996; 11:31–36.
194. Grossman J, Bronsky EA, Lanier BQ, Linzmayer, MI, Moss BA, Schenkel EJ,
Selner JC. Loratadine-pseudoephedrine combination versus placebo in patients
with seasonal allergic rhinitis. Ann Allergy 1989; 63:317–321.
195. Sussman GL, Mason J, Compton D, Stewart J, Ricard N. The efficacy and safety
of fexofenadine HCl and pseudoephedrine, alone and in combination, in seasonal
196. Storms WW, Bodman SF, Nathan RA, Chervinsky P, Banov CH, Dockhorn RJ,
Jarmoszuk I, Zeitz HJ, McGeady SJ, Pinnas JL. SCH 434: A new antihistamine/
decongestant for seasonal allergic rhinitis. J Allergy Clin Immunol 1989; 83:1083–
1090.
197. Landauer AA, Milner G. Antihistamines, alone and together with alcohol, in rela-
tion to driving safety. J Forensic Med 1971; 18:127–139.
198. Linnoila M. Effects of antihistamines, chlormezanone and alcohol on psychomotor
skills related to driving. Eur J Clin Pharmacol 1973; 5:247–254.
12
Potential Cardiac Toxicity
of H 1-Antihistamines
Yee Guan Yap and A. John Camm

St. George’s Hospital Medical School, London, England
I. INTRODUCTION
Antihistamines are among the most frequently prescribed drugs worldwide for
the treatment of allergic disorders, particularly in developed countries (1). The
use of first-generation antihistamines, such as diphenhydramine, hydroxyzine,
chlorpheniramine, brompheniramine, and cyproheptadine, is limited by their sed-
ative and anticholinergic properties. The second-generation, nonsedating antihis-
tamines (e.g., terfenadine, astemizole, loratadine, cetirizine, acrivastine, mizolas-
tine) are relatively free of these side effects; however, since the 1990s there have
been some reports of syncope, torsade de pointes (TdP), and sudden death in
patients taking the nonsedating antihistamines terfenadine and astemizole. As a
result of these reports, regulatory approval for terfenadine and astemizole has
since been suspended in many countries. The cardiac safety profile of the H 1-
antihistamines is now being monitored by regulatory agencies in many countries.
Although the occurrence of cardiotoxic effects in some patients taking terfenadine
and astemizole (1–12) has led to the speculation that other nonsedating antihista-
mines may induce similar cardiotoxic effects, these potential adverse effects are
not a class property of antihistamines, as will be discussed below.
389
390 Yap and Camm
II. HISTORICAL PERSPECTIVE
In a few cases, proarrhythmia from terfenadine and astemizole was due to over-
dose: the drugs were taken at doses considerably in excess of that recommended
by the manufacturer (1–6). In many cases, the cardiotoxicity of terfenadine or
astemizole was noted at usual doses of the drugs, but involved concurrent use of
other drugs that inhibit cytochrome P-450 CYP 3A4 drug metabolism (imidazole
antifungals and macrolide antibiotics) or patients with impaired liver function or
congenital long QT syndrome (7, 9, 10, 12). The reports are exemplified by that
of Simons et al., who described a case of ventricular tachyarrhythmia after a 10
mg dose of astemizole (8). Monahan et al. reported an episode of TdP with the
recommended therapeutic dose of terfenadine in association with ketoconazole
and cefaclor (10). Broadhurst et al. described QT prolongation and TdP with
astemizole in a patient with Romano-Ward congenital long QT syndrome (9).
Others reported a case of Mobitz-type 2 heart block with TdP after astemizole
overdose and QT prolongation and ventricular ectopics with a therapeutic dose
of terfenadine in a patient with liver cirrhosis (7). Furthermore, coadministration
of these nonsedating antihistamines with drugs that prolong the QT interval by
the same or other mechanisms (e.g., antiarrhythmics, antipsychotics, tricyclic an-
tidepressants) also increases their adverse effect on cardiac repolarization (11,
12).
III. MECHANISM OF DRUG-INDUCED QT PROLONGATION

AND TdP
A. Normal Ionic and Molecular Basis of the Cardiac
Action Potential
The cardiac action potential is generated by the transmembrane movement of
several ions, including Na ⫹, Ca 2⫹, and K ⫹. Like all living cells, the inside of
cardiac cells is negatively charged compared to the outside (resting transmem-
brane potential ⫽ ⫺80 mV to ⫺90 mV); however, cardiac cells are excitable
and, when appropriately stimulated, the ionic channels in the cell membrane open
and close sequentially. Depending on their voltages and time dependencies, the
movement of ions back and forth leads to changes in the transmembrane potential,
and hence a generation of action potential. The initial depolarization (phase 0)
is triggered by a rapid influx of sodium ions (I Na), which changes the cell potential
from ⫺90 mV to ⫹30 mV (13, 14). The transient outward (I to) potassium current
subsequently is responsible for the slight repolarization immediately after the
overshoot (phase 1). During the following plateau phase (phase 2), the cell poten-
tial is maintained by the influx of calcium ions (I Ca). The inflow of sodium and
calcium ions into cells where their concentrations are low elicits and maintains
the depolarization, resulting in the P wave (atrial level) and QRS complex (ven-
Potential Cardiac Toxicity 391
Figure 1 Cardiac ionic currents and their relationship with the action potential. (Modi-
fied from Ref. 12.)
tricular level) on the surface electrocardiogram (ECG). The repolarization phase

(phase 3) of the myocytes is driven predominantly by outward movement of the
potassium currents, carried by the rapid (I Kr) and slow (I Ks) components of the
delayed rectifier potassium channel. This ionic movement gives rise to the T
wave on the ECG, as the cellular potentials return in sequence to their resting
states. The diastolic depolarization (phase 4) results from a combination of the
decay of the outward delayed rectifier IKr and IKs currents, which maintains the
resting potential at approximately ⫺90 mV, and the activation of a specific in-
ward pacemaker current (I f ) and the inward sodium background leak current (I Na-
B). A variety of other different potassium channel subtypes are also present in
the heart (15) (Fig. 1) and blockade of each of these potassium channels has a
different effect on the action potential (Fig. 2).
B. Mechanism of Acquired QT Prolongation and TdP

Disturbances in any of these ionic movements, in particular of the potassium
ions, may cause arrhythmias. There are at least eight different potassium channel
subtypes in the heart (16). They differ in their voltage-, rate-, and time-dependent
opening and closing characteristics and by their regulation and response to drugs.
Each of them may be a target for drug effect. Furthermore, each potassium chan-
nel has a different effect on the action potential (Figs. 1, 2) and various potassium
channels may not be equally expressed in all species, individuals, or tissues. The
principal K ⫹ currents participating in the repolarization of the action potential in
392 Yap and Camm
Figure 2 Alteration in the action potential with individual blockade of some potassium
channels.
the human ventricular myocardium under normal conditions are the delayed recti-
fier K ⫹ current (I Kr and I Ks) (17), the inward rectifier I Ki (18), and the transient
outward K ⫹ current I TO (19). I Kr seems to play the most important role in determin-
ing the duration of action potential.
The drug-induced proarrhythmias are mostly mediated by drugs that sup-
press the I Ki and I Kr channels that govern the rapid repolarization phase (17). I Ki
is a time-independent but voltage-dependent outward current. I Ki determines and
stabilizes the resting membrane potential near the equilibrium potential for potas-
sium and also contributes to the final phase of repolarization of the action poten-
tial. I Ki is also termed the inward rectifying current, as it allows current to flow
more easily in the inward direction (18).
Initial evidence suggested that the blockade of I Ki might be responsible for
antihistamine-induced TdP (20). The inhibition of I Ki prolongs the rapid repolar-
ization phase of the action potential, and an increase in the vulnerable period,
enhancing the chances of aberrant excitation and arrhythmia in the presence of
these drugs (20). Suppression of I Ki by nonsedating antihistamines is particularly
marked when the plasma concentration of potassium is already abnormal (e.g.,

hypokalemia, ischemia); however, subsequent evidence showed that the magni-
tude of the block of I Ki by antihistamines such as terfenadine, astemizole, and
ebastine is less than 30% at a supratherapeutic concentration of 0.3–1.0 µM,
much less than their effect on I Kr (21, 22). The blockage of I Ki by an antihistamine
will only provoke arrhythmias under conditions in which the QT interval has
already been prolonged by other pharmacological, ionic, or pathological condi-
tions (20, 21) or after overdose (20). Therefore, the major cardiac adverse effects
of antihistamines are more likely to be mediated by the strong blockade of I Kr
channel (21, 22), which is also most susceptible to influence from underlying
heart disease, sex, saturated metabolism, and coadministration of other QT-pro-
longing drugs.
Figure 3 Arrhythmogenic mechanism of torsade de pointes.

394 Yap and Camm
Blockade of the I Kr current results in the prolongation of action potential

duration and slowing of the repolarization. It manifests clinically as a prolonged
QT interval and a lower-amplitude T wave on the surface ECG. The prolongation
of repolarization may result in bifid T wave and also lead to activation of an
inward depolarization current, known as an early after-depolarization (23), which
is responsible for the increased amplitude of U wave on the ECG and may pro-
mote repetitive triggered activity. When accompanied by markedly increased dis-
persion of repolarization, often induced by the same drug, this may induce re-
entry and provoke TdP, which is then sustained by further re-entry or spiral wave
activity (24) (Fig. 3). Such phenomena are more readily induced in the His-Pur-
kinje network and also from M cells, a subset of myocardial cells from the mid-
ventricular myocardium (25). One reason for this may be that resting membrane
potential in Purkinje fibers is more positive than that in the ventricles and the
blockade of I Kr channel is voltage-dependent, with greater block in depolarized
tissue (26). This may then lead to dispersion of refractoriness between the two
tissue types, which is potentially arrhythmogenic. The M cells are located deep
in the subepicardium and are electrophysiologically different from those of epi-
cardium and endocardium but intermediate between those of muscles and Pur-
kinje fibers. Compared to subendocardial or subepicardial cells, M cells show
much more pronounced action potential prolongation, easier induction of early
after-depolarization, and development of triggered activity more readily in re-
sponse to I Kr blockade (24, 25). This property results in a marked dispersion of
repolarization (i.e., heterogeneous recovery of excitability), creating a zone of
functional refractoriness in the mid-myocardial layer, which is probably the basis
of the re-entry that sustains TdP.
IV. MEASUREMENT OF QT INTERVAL
When measuring the QT interval, the ECG is best recorded at a paper speed of
50 mm/s and an amplitude of 0.5 mV/cm using a multichannel recorder capable
of simultaneous recording of all 12 leads. A tangent line to the steepest part of
the descending portion of the T wave is then drawn. The intercept between the
tangent line and the isoelectric line is defined as the end of T wave. The QT
interval is measured from the beginning of the QRS complex to the end of the
T wave on a standard ECG. Traditionally, lead II has been used for QT interval
measurement because the vectors of repolarization in this lead usually result in
a long single wave rather than discrete T and U waves.
The QT interval is influenced by heart rate. At least three or four RR in-
tervals preceding the QT interval should be measured for rate correction. Sev-
eral formulas may be used to correct the QT interval for the biophysical effect
of heart rate (QTc). The most commonly used are Fridericia’s cube-root for-
mula (QTc ⫽ QT/RR 1/3) and Bazett’s square-root formula (QTc ⫽ QT/RR 1/2).
Between the two, Bazett’s formula is more popular, but Fridericia’s correction
is preferred because it is more accurate at the extremes of physiological heart
rate.
Newer repolarization parameters such as QT dispersion (maximum ⫺ mini-
mum QT intervals) on the 12-lead surface ECG, which is considered to be an
indirect measure of spatial heterogeneity of repolarization, may be useful in as-
sessing drug efficacy and safety. In one important study, patients who received
a class 1A antiarrhythmic drug who developed QT prolongation and suffered
TdP had significantly increased precordial QT interval dispersion (27). In con-
trast, patients receiving amiodarone or class 1A antiarrhythmics without devel-
oping TdP did not have increased QT dispersion, although the QT interval was
similarly prolonged (27). Thus, spatial heterogeneity/dispersion of the ventricular
repolarization process may be required in addition to QT prolongation for the
genesis of TdP. Although the use of QT dispersion in the assessment of drugs
that prolong the QT interval needs further confirmation, it may provide informa-
tion about the clinical significance of QT prolongation.
V. DRUG-INDUCED QT PROLONGATION AND TdP
The blockade of the potassium channels prolongs the ventricular repolarization,

which manifests clinically as a prolonged QT interval and other T- or U-wave
abnormalities on surface electrocardiogram. Although these abnormalities of re-
polarization predispose to the development of TdP, there is no linear relation-
ship between the degree of QT interval prolongation and the likelihood of devel-
opment of TdP. Furthermore, TdP can occur without a prolonged QT interval,
and it does not develop in all patients with long QT intervals (28). For instance,
both quinidine and amiodarone are known to prolong the QT interval. While
quinidine is a well-recognized cause of TdP, amiodarone is rarely associated
with TdP.
QT prolongation is generally considered when the QTc interval is greater
than 440 milliseconds (ms) (men) and 460 ms (women) (29), using Bazett’s for-
mula (Table 1). The suggested upper limit of normal QTc interval for adult males
is 450 ms and for adult females is 470 ms. The severity of proarrhythmia at a
given QT interval varies from drug to drug and from patient to patient. Although
the QT interval is widely viewed as a surrogate marker of the arrhythmogenic
potential of a drug, the extent of QT prolongation and risk of TdP with a given
drug may not be linearly related to the dose or plasma level of the drug because
patient factors (e.g., gender) and metabolic factors (e.g., electrolyte levels) are
also important (see below). Apart from congenital long QT syndrome, there have
been very few data available to quantify the magnitude of arrhythmic risk assess-
396 Yap and Camm
Table 1 Normal Values of QTc Interval (corrected by Bazett’s formula) a
Study QTc interval (Bazett’s)
Moss (29) Normal Borderline Prolonged (top 1%)

Adult men ⬍430 430–450 ⬎450
Adult women ⬍450 450–470 ⬎470
Children (1–15 yr) ⬍440 440–460 ⬎460
CPMP (98) QTc interval (Bazett’s)
Adult men 450 (upper limit)
Adult women 470 (upper limit)
Concern about drug effect 500
a
Values given in milliseconds.
CPMP, Committee for Proprietary Medicinal Products.
ment with particular values of QT prolongation, especially with drug-induced QT

prolongation. Data from the Long QT Syndrome Registry showed that the risk
of malignant ventricular arrhythmias is exponentially related to the length of QTc
interval (29) (Fig. 4). In drug-induced QT prolongation, although no such relation-
ship is known, a MEDLINE search of the English-language literature for 1980–
1992 on proarrhythmia (TdP, polymorphic ventricular tachycardia, atypical ven-
tricular tachycardia, and drug-induced ventricular tachycardia) by cardiac drugs
Figure 4 ECG from a 24-year-old woman who presented with TdP while taking an
H 1-antihistamine. After discontinuation of the drug, the QT interval remained prolonged
(QTc ⫽ 573 ms), due to congenital long-QT syndrome.
(a)
(b)
Figure 5 (a) ECG of a 63-year-old female patient with thioridazine-induced ventricular

fibrillation cardiac arrest while in hospital. She was successfully resuscitated and this is
the ECG performed immediately after the cardiac arrest. Note the QTc interval was 619
ms and her serum potassium level at this time was 3.3 mmol/L. (b) ECG of the same
performed 2 days after the cardiac arrest when the offending drug thioridazine has been
removed for 2 days and her serum potassium level corrected to 4.4 mmol/L. Note that
the QT interval has returned to normal (QTc ⫽ 399 ms).
398 Yap and Camm
Figure 6 Rhythm strip in a patient with drug-induced TdP. Note the typical short–
long–short initiating ventricular cycle before the onset of TdP and the classical ‘‘twisting
of a point’’ of the cardiac axis during TdP.
known to prolong QT interval showed that among the 332 patients with proar-
rhythmia, only 25% had baseline QTc ⱖ470 ms, while 90% had QTc ⱖ500 ms
when they developed arrhythmias (30). Thus, a maximal QTc value over 500 ms
(Fig. 5) should cause concern about the potential for drug-induced TdP (Table 1).
There is a characteristic initiating sequence prior to the onset of TdP, partic-
ularly in acquired TdP. The first ventricular complex of the sequence is usually
a ventricular ectopic beat or the last beat of a salvo of ventricular premature beats
(Fig. 6). This is then followed by a pause terminated by a sinus beat. The sinus
beat frequently has a very prolonged QT interval and an exaggerated U wave.
A premature ventricular beat then falls on, or is generated by, the exaggerated
U wave of the sinus beat and precipitates TdP. It has been suggested that, in
some patients, postpause accentuation of the U wave, if present, may be a better
predictor of TdP than the duration of the QTc interval (31), particularly with
drug-associated TdP. When an ectopic beat or brief tachycardia is followed by
a pause, it is therefore important to examine the QT interval and morphology of
T/U waves in the postextrasystolic sinus beat (31).
VI. PROPERTIES OF H 1-ANTIHISTAMINES DETERMINING

PROARRHYTHMIC TOXICITY
The association of nonsedating antihistamines and TdP has been reported mainly
with terfenadine and astemizole. These H 1-antihistamines potentially exhibit their
cardiac effects at therapeutic histamine receptor-blocking concentration, whereas

others have only caused cardiac effects at supratherapeutic concentrations or have
not caused any significant cardiac effects at all. Several factors that may be re-
sponsible for the varying cardiac action of antihistamines are reviewed below.
A. Potassium Ion Channel Blockade

Like class III antiarrhythmics, terfenadine and astemizole were found to prolong
the monophasic action potential and QT interval, which led to the development
of early after-depolarization and TdP through an inhibition of the I Kr channel (13,
32, 33). Not all nonsedating antihistamines block the I Kr channels to the same
degree. Among the antihistamines evaluated, astemizole, terfenadine, and ebas-
tine have shown blocking effects in I Kr channels expressed in Xenopus oocytes
(22, 34, 35). Mizolastine also blocks I Kr channels expressed in Chinese hamster
ovary cells, although in a reversible manner and at concentrations significantly
higher than those corresponding to therapeutic free plasma levels (unpublished
observations). Terfenadine and ebastine (22) but not mizolastine (36) can also
block the slow delayed rectifier I Ks channel in guinea pig dissociated ventricular
myocytes. Loratadine does not block cloned I Kr channels expressed in Xenopus
oocytes (up to 10 µM), nor does it block I Kr channels in guinea pig ventricular
myocytes (up to 3 µM). At higher concentrations, however, it can block both
heterogeneously and constitutively expressed I Kr channels (37–39).
In contrast, ceterizine, despite having similar antihistaminic potency in vivo
with respect to other antihistamines, does not block the I Kr channel in heteroge-
neously expressed Xenopus oocytes (up to 30 µM) or prolong ventricular repolar-
ization at the highest therapeutic level in a canine model of long QT syndrome
(38, 39). Fexofenadine, the carboxylate metabolite of terfenadine, likewise had
no IKr-blocking effect, even at a concentration 30 times greater than the concentra-
tion of terfenadine producing half-maximal effect (12, 32).
Thus, there are significant differences in the ability of H 1-antihistamines
to block the different members of the cardiac potassium channel family. It appears
as if antihistamines such as terfenadine, which simultaneously suppress more
than one channel involved in the lengthening of the action potential (i.e., IKr and
I Ks) or which block I Kr at low concentration, possess a higher propensity to induce
arrhythmias. Those that do not block the I Kr channels (e.g., fexofenadine) or block
the channel with lower potency (e.g., loratadine) are less likely to be cardiotoxic.
B. Physicochemical Properties
Other drug-related factors such as the physicochemical properties of the antihista-
mines (e.g., diarylalkylamine moiety, quaternization of diphenhydramine, lipo-
philicity of the side chain) and their metabolic profile (e.g., tissue distribution)
may also contribute to the cardiac toxicity of antihistamines. Like class III antiar-
400 Yap and Camm
Table 2 Physicochemical Properties Related to

Pharmacokinetic Parameters of Nonsedating H 1-Antihistamines
Lipophilicity Estimated volume

(log P) of distribution (L/kg)
Mizolastine 2.9 1.4

Cetirizine 3.5 0.5
Fexofenadine 5.3 9.0
Loratadine 5.7 18.0
Astemizole 5.8 45.0
Terfenadine 6.9 27.0
Ebastine 7.2
Source: Modified from Ref. 41.
rhythmic agents, certain antihistamines possess a diarylalkylamine moiety that

is believed to inhibit the potassium channels (13). Quaternization of diphenhydra-
mine can result in a potent class I antiarrhythmic agent with long duration of
action and notable tachycardia (13). Lipophilicity of the side chain (nitrogen sub-
stitution) is also important in the potassium channel-blocking activities of antihis-
tamines (13). In this aspect, mizolastine and cetirizine are less lipophilic than
loratadine, astemizole, ebastine, and terfenadine (41, 42) (Table 2) and do not
contain either diarylalylamine or diphenhydramine moieties.
There are also major differences in tissue distribution and myocardial fixa-
tion among H 1-antihistamines. In animal models, a low apparent volume of distri-
bution seems to be associated with low tissue fixation (i.e., heart tissue levels
lower than blood levels). For instance, heart/plasma ratios in animals are 4 in
rats for terfenadine (43), 400 in dogs for astemizole (44), but only 0.5 for mizolas-
tine in guinea pigs (unpublished data); however, for cetirizine, the tissue drug
level is not necessarily lower than that of the serum level, at least in the skin. After
ingestion of a single dose of 10 mg of cetirizine in humans, the concentration of
cetirizine in the skin has been shown to be lower than the serum level from 1
to 9 hours but higher at 24 hours and equivalent at 168 hours (steady state) (45).
Of note is that diphenhydramine overdose can lead to an abnormal repolarization
including moderate QT prolongation, lower T-wave amplitude, as well as tachy-
cardia (46, 47). Furthermore, diphenhydramine overdose has also been reported
to cause death, seizures, pulmonary edema, and neuroleptic malignant syndrome
(48–53).
It is therefore important to note that the ability to cause QT prolongation
and proclivity for producing TdP is seen only with some antihistamines and is
not a class effect.
C. Hepatic Metabolism
Cytochrome P-450 enzymes, a superfamily of heme-containing proteins present
within the endoplasmic reticulum, have low substrate specificity and are responsi-
ble for the oxidation of a wide variety of lipophilic substrates. Cytochrome P-
450 families 1, 2, and 3 (CYP1, CYP2, and CYP3) are involved in drug metabo-
lism, with isoenzymes of CYP2B, CYP2C, CYP2D, and CYP3A being responsi-
ble for most drug oxidation. Most, but not all, of the nonsedating antihistamines
are metabolized via the hepatic cytochrome P-450 CYP3A4 system (Table 3a);
therefore, administration of these antihistamines to patients with compromised
liver function or concomitant administration of drugs (e.g., imidazole antifungals,
macrolide antibiotics) (Table 3b) or food (e.g., grapefruit juice) that inhibit the
hepatic cytochrome P-450 CYP3A4 may result in the accumulation of the parent
drug and the development of cardiotoxicity (11). For instance, terfenadine under-
goes rapid first-pass metabolism by cytochrome P-450 hepatic enzymes (CYP
3A4) and is transformed into its active metabolite terfenadine carboxylate. Ter-
fenadine carboxylate had no effect on the I Kr potassium channel, even at high
concentrations (12); however, inhibition of the hepatic oxidative metabolism of
terfenadine by imidazole antifungals (e.g., ketoconazole, itraconazole) or macro-
lide antibiotics (erythromycin, clarithromycin) will result in an accumulation and
increased bioavailability of the cardiotoxic prodrug (13, 54). In addition, drugs
such as erythromycin and ketoconazole can themselves prolong the QT interval as
well as inhibit the metabolic activity of hepatic cytochrome P-450. Concomitant
administration of terfenadine and any of these antimicrobial therapies will pro-
duce marked QT prolongation that correlates with plasma concentration of unme-
tabolized terfenadine and increases the risk of arrhythmia (55). Concomitant ad-
ministration of terfenadine with drugs that can inhibit metabolic activity of
hepatic cytochrome P-450 or those that prolong the QT interval must be avoided.
With regard to astemizole, the P-450 isoenzyme CYP3A4 metabolizes the
drug into two active metabolites, desmethylastemizole and norastemizole. The
QT prolongation is caused by astemizole and desmethylastemizole (13). Ebastine,
a highly lipophilic compound, is a prodrug, which is metabolized to a large extent
through the cytochrome P-450 CYP3A4 and its effect on QT prolongation is
enhanced after oral dosage by pretreatment with ketoconazole (56). Mizolastine
is less dependent on cytochrome P-450 hepatic metabolism than astemizole, ter-
fenadine, and ebastine. It has relatively little (1.5–50%) pharmacokinetic interac-
tion with ketoconazole and erythromycin compared with the drugs mentioned
above; the increase in mizolastine plasma concentrations observed with systemic
ketoconazole led to plasma concentrations equivalent to those obtained with a
15–20 mg dose of mizolastine alone. The QT interval prolongation observed did
not seem greater than that anticipated for ketoconazole alone.
Cetirizine and fexofenadine differ from the other currently used nonsedat-
Table 3 Metabolism of Nonsedating H 1-Antihistamines
Nonsedating antihistamines and their major metabolic pathways
Terfenadine Hepatic P-450 CYP3A4
Astemizole Hepatic P-450 CYP3A4
Ebastine Hepatic P-450 CYP3A4 and CYP2D6
Loratadine Hepatic P-450 CYP3A4 and CYP2D6
Mizolastine Mainly via glucuronidation (65%), less
via hydroxylation (hepatic P-450 CYP
3A4 and 2A6)
Fexofenadine 80% via the fecal route and 10% via the
renal route
Cetirizine 60% renal, 40% hepatic
Drugs and foods that can inhibit hepatic cytochrome P-450 CYP3A4 enzymatic ac-
tivity
Imidazole antifungals Ketoconazole
Itraconazole
Fluconazole
Metronidazole
Macrolide antibiotics Erythromycin
Clarithromycin
Troleandomycin
Josamycin
Flurythromycin
Ponsinomycin
Antidepressants Fluvoxamine
Fluoxetine
Paroxetine
Sertraline
Nefazodone
HIV protease inhibitors or non-nucleoside Amprenavir
reverse transcriptase inhibitors Indinavir
(NNRTI) Nelfinavir
Ritonavir
Saquinavir
Delavirdine (NNRTI)
Anti-ulcer drugs Ranitidine
Cimetidine
Omeprazole
Ethinyl estradiol Estrogen
Oral contraceptives
Calcium antagonists Diltiazem
Verapamil
Nifedipine
Tetracyclines Tetracycline
Doxycycline
Anti-tuberculosis drug Isoniazid
Antimalarial Primaquine
Antibiotic Quinupristin/dalfopristin
Antiarrhythmic drug Amiodarone
Antihypertensive drug Hydralazine
Food Grapefruit juice
ing antihistamines because they are not metabolized to the same extent (57). In
adults, cetirizine is eliminated 60% unchanged via the renal route and 40% via
the hepatic route. Patients with renal and hepatic impairment are advised to de-
crease the dosage. Fexofenadine is eliminated primarily by the fecal route (80%)
and only 10% by the renal route (58). Consequently, the potential drug interac-
tions are less relevant. Although renal disease rather than liver disease could
result in elevated plasma concentrations, both cetirizine and fexofenadine are
devoid of QT-prolonging effect.
Grapefruit juice contains furanocoumarins (e.g., 6′, 7′-dihydroxybergamot-
tin and its dimers), which are potent inhibitors of CYP3A4, and cause a rapid
loss of enzyme activity of intestinal but not hepatic cytochrome CYP3A4 (57).
In one study of six healthy subjects, when 60 mg terfenadine was given simulta-
neously with double-strength grapefruit juice for 7 days, all subjects had in-
creased and quantifiable levels of unmetabolized terfenadine, accompanied by an
increase in the QTc interval from 420 to 434 ms ( p ⬍ 0.05) (59). Although in
most studies of drug–grapefruit interactions, double-strength grapefruit juice was
given twice daily for a week, significant interaction between terfenadine and regu-
lar-strength grapefruit juice (60) or freshly squeezed juice (61) was also demon-
strated. Thus, grapefruit juice can inhibit the metabolism of some nonsedating
antihistamines by enzymes of the cytochrome P-450 CYP3A4 located in the gut
wall and should therefore be avoided by patients taking these drugs.
VII. EFFECTS OF NONSEDATING H 1-ANTIHISTAMINES

ON QT INTERVALS
The potential effects of any new H 1-antihistamine on human cardiac repolariza-

tion are carefully examined during its clinical development, mainly through the
assessment of its potential to prolong the QT interval and the monitoring of poten-
tial cardiac events.
Terfenadine increases the QT interval in a dose-dependent manner and QT
interval prolongation has been shown to correlate with terfenadine concentration
(62–64). This effect is significantly more marked in patients with cardiovascular
disease (64). Compared to baseline, terfenadine 60 mg twice daily is associated
with a QTc increase of 6 ms in normal subjects and a 12 ms increase in patients
with cardiovascular disease (64). Astemizole and its metabolite desmethylastemi-
zole prolong the QT interval but there is a lack of correlation among dosage,
plasma concentration, and QT prolongation (13, 55).
There has been no report of QT prolongation or ventricular arrhythmias
with ebastine administered at therapeutic dosages or at a dosage three times the
recommended level (60 mg/day) (55, 65). At a dosage five times the recom-
mended level (100 mg/day), ebastine causes a small QT prolongation (10.3 ms
404 Yap and Camm
and ⬍10%) that is not clinically meaningful, although it was statistically signifi-
cant compared with placebo (65). A detailed study, however, showed that the
minor QT prolongation with ebastine (and possibly with other drugs) is critically
dependent on the precision of the rate correction formulas and influenced by the
natural variability of the QTc interval. For instance, while all generalized heart
rate correction formulas showed consistent QT prolongation with terfenadine,
results were inconsistent with ebastine. Correction using Bazett’s formula sug-
gested significant QT interval increase with ebastine, but correction using the
Lecocq formula suggested a significant QT interval decrease. Even with an opti-
mized heart rate correction formula (QTc ⫽ QT/RR 0.314) from pooled QT/RR
regression during the drug-free state, the minor QT prolongation with ebastine
was not consistent. The QTc changes in a four-way crossover study after a 7 day
course of placebo, 60 mg ebastine, 100 mg ebastine, and 100 mg terfenadine
were ⫺1.95 ⫾ 6.87 ms, p ⫽ N.S.; ⫺3.91 ⫾ 9.38 ms, p ⫽ 0.053; 0.75 ⫾ 8.23
ms, p ⫽ N.S.; 12.95 ⫾ 14.64 ms, p ⫽ 0.0003, respectively (M. Malik, personal
communication). Thus, measurement imprecision and natural diurnal variability
of the QTc interval can lead to a QTc variation of at least 4–5 ms, which can
be critical when assessing minor drug-induced QT prolongation.
In contrast, loratadine does not cause a significant QT prolongation even
at supratherapeutic doses (66, 67). In one study, no patient had a QTc interval
of more than 440 ms when given loratadine 40 mg (four times the recommended
dosage) for 3 months (66). The clinical experience with mizolastine, particularly
in potentially high-risk patients, is still limited. An overview of the QT interval
monitoring performed during the clinical development of mizolastine showed
that this second-generation H 1-antihistamine has no significant effect on cardiac
repolarization in humans (68). Mizolastine was administered orally to healthy
volunteers in single doses of up to 75 mg and in a repeated dosage of 40 mg
daily (i.e., 7.5 and 4 times the recommended daily dosage, respectively) and at
a dose of 10 or 15 mg in patients. In healthy volunteers, there was no increased
incidence of QTc value ⬎440 ms or ∆QTc ⱖ40 ms compared with placebo. No
dose-related increase in QTc interval was observed. In patients, the mean QTc
interval changes from baseline were not significantly different between mizolas-
tine and placebo. In volunteers or patients receiving mizolastine, there was little
or no idiosyncratic QT interval prolongation and it did not induce changes in the
T/U wave morphology.
Cetirizine is the metabolite of hydroxyzine, a first-generation antihista-
mine, which at high dosages has been reported to be associated with T-wave
changes (55). In studies conducted in healthy subjects, however, and even in
supratherapeutic dosages of 20 or 60 mg daily, cetirizine was devoid of an effect
on QT interval (69). There was likewise no dose-related increase in QT interval
or significant increase in mean QT interval with fexofenadine, the carboxylate
metabolite of terfenadine, in a dosage up to 240 mg twice a day for 12 months,

compared with placebo (70). Extensive ECG data from more than 2100 patients
receiving fexofenadine or placebo in controlled clinical trials recently demon-
strated that fexofenadine does not increase the QT interval, even when adminis-
tered chronically in doses 10 times higher than that recommended by the manu-
facturer (71). Pratt et al. reported that fexofenadine in dosages up to 800 mg
once daily or 690 mg twice daily (recommended dosage: 60 mg twice daily) for
28 days resulted in no dose-related increases in QT interval. Longer-term studies
indicated no statistically significant QTc increases compared with placebo in pa-
tients receiving fexofenadine 80 mg twice daily for 3 months, 60 mg twice daily
for 6 months, or 240 mg once daily for 12 months. Clinical trials in patients with
seasonal allergic rhinitis (n ⫽ 1160) treated with 40, 60, 120, or 240 mg twice-
daily fexofenadine or placebo indicated no dose-related increases in QTc and no
statistically significant increases in mean QTc compared with placebo. In con-
trolled trials with approximately 6000 persons, no case of fexofenadine-associ-
ated TdP was observed (71). This is probably not surprising, given that fexofena-
dine does not block the I Kr potassium channel. Concerns were raised over a case
report of fexofenadine-induced QT prolongation and ventricular arrhythmia (72).
In this report, a 67-year-old man with hypertension and mild left ventricular hy-
pertrophy had his carvedilol stopped due to itching. He was subsequently pre-
scribed fexofenadine 180 mg daily and experienced QT prolongation and ventric-
ular dysrrhythmia after 2 months of treatment (72). Although there was a
temporal correlation between ECG-documented QT prolongation and institution
of fexofenadine, the patient’s age, hypertension, ventricular hypertrophy, and
sudden cessation of carvedilol themselves constitute risk factors for QT prolon-
gation and ventricular arrhythmia. Thus, this single case report contrasts with
the extensive clinical and experimental evidence that TdP is not a risk during
exposure to fexofenadine.
Azelastine has no electrocardiographic effects when administered at several
times the recommended dosage or concomitantly with agents that inhibit its me-
tabolism and elimination in human volunteers (73). The data in the public domain
on azelastine and acrivastine are currently sparse, however, and further informa-
tion on the cardiac safety of these drugs is needed.
The effect of nonsedating antihistamines that are metabolized by cyto-
chrome P-450 CYP3A4 on the QT interval is markedly increased when they are
coadministered with an enzyme inhibitor. For instance, a mean of 82 ms increase
in QTc interval at 12 h after dosing (i.e., at or near trough) was reported when
terfenadine was coadministered with ketoconazole (54). When ebastine (20 mg/
day) was coadministered with ketoconazole (400 mg/day) in healthy subjects in
multiple doses, there was a small but statistically significant increase in the QTc
interval by 10 ms compared to that produced by ketoconazole alone (65). The
406 Yap and Camm
majority of subjects receiving this combination exhibited ⬍5% increase in the

mean QTc interval relative to baseline, and approximately 30% of subjects exhib-
ited a 5–10% increase in the QTc interval (70). When ebastine (20 mg/day) was
coadministered with erythromycin (2000 mg/day) to the same subjects in multi-
ple doses in the same study, the QTc interval was likewise significantly increased
by 10 ms compared with the QTc interval during administration of erythromycin
alone (65).
Three different studies have been carried out to assess the interaction be-
tween loratadine and the cytochrome P-450 CYP3A4 inhibitors ketoconazole,
erythromycin, and cimetidine (74–76). Although ketoconazole was the most po-
tent inhibitor of loratadine metabolism, followed by cimetidine and then erythro-
mycin, no significant changes in QTc interval profile from baseline (approxi-
mately 400 ms) were demonstrated when any of the three drugs were tested in
combination with loratadine (74–76).
With mizolastine, the ECG parameters were not modified during coadmin-
istration with erythromycin compared to the effect of each coadministered drug
alone. The minor QT interval prolongation observed during coadministration of
ketoconazole with mizolastine (⬇ ⫹7 ms) might be attributable to the ketocona-
zole itself (77). The same explanation probably applied when ketoconazole (400
mg) was coadministered with cetirizine (20 mg, twice the recommended dose),
producing a minor QT prolongation of 17.4 ms compared with 9.1 ms with cetiri-
zine alone (78)
Interaction studies showed no significant increases in QTc when fexofena-
dine 120 mg twice daily was administered in combination with erythromycin
(500 mg three times daily) or ketoconazole (400 mg once daily) after dosing to
steady-state (6.5 days) (72).
VIII. INCIDENCE OF CARDIAC EVENTS WITH COMMONLY

PRESCRIBED NONSEDATING H 1-ANTIHISTAMINES
The World Health Organization’s (WHO) adverse drug reaction database pro-
vides a source of data on spontaneous adverse drug reactions from 17 countries
where nonsedating antihistamines are available. Data reported include total rate
and rhythm disorders, selected reactions (QT prolongation, TdP, ventricular
tachyarrhythmias, cardiac arrest, and supraventricular tachycardia), cardiac and
sudden deaths. From 1986 to 1996 the following data were reported: 106 cases
of selected reactions, 13 cardiac and sudden deaths for loratadine; 19 cases of
selected reactions, 2 cardiac and sudden deaths for cetirizine; and 1 case of se-
lected reaction and no incidence of cardiac and sudden death for acrivastine (79).
When calculated as reports per million defined daily doses (DDD) sold, all three
antihistamines have a very low reporting rate. Specifically, the reporting rates
for cardiac and sudden deaths were approximately 0.005 for loratadine and
0.0008 for cetirizine and none for acrivastine compared with 0.038 for terfena-
dine. Although the reported incidences of deaths were themselves very low com-
pared with terfenadine, the type of report and its analysis have attracted some
criticism because of potential flaws and biases (80, 81). For instance, the report
does not take into account the spontaneous rate of background cardiac events
in the untreated population or the inclusion of a wide variety of undefined and
unsubstantiated cardiac events in a composite numerator, rather than specific ven-
tricular events of relevance to nonsedating antihistamines. This makes the analy-
sis questionable (81). The Food and Drug Administration (FDA), which monitors,
analyzes, and reviews individual reports and follow-up of cases of adverse drug
reactions with antihistamines, did not find any definitive causal association be-
tween loratadine, cetirizine, or acrivastine and ventricular tachyarrhythmia up
to 1997. It should be emphasized that apart from the specific contraindications
described, the incidence of cardiotoxicity with antihistamines is extremely low
in view of the widespread use of the drugs. Nevertheless, as antihistamines are
prescribed for non-fatal disorders such as allergic rhinitis and chronic urticaria,
the attributable risk must be assessed very critically. It will be very difficult to
conduct a large controlled clinical study to examine the causal association be-
tween nonsedating antihistamines and ventricular arrhythmias. Any crude adverse
event report must be put in perspective and used to detect trends and generate
hypotheses that may guide surveillance and help plan future studies. The Euro-
pean Association of Allergology and Clinical Immunology (EAACI) published
a guideline on the use of nonsedating antihistamines to avoid any unwanted ar-
rhythmogenic effect associated with their use (82). It includes: avoidance of ex-
cessive dosage of antihistamines beyond that recommended by the manufacturer;
avoidance of coadministration of drugs known to interfere with the hepatic metab-
olism of antihistamines; careful use of antihistamines in patients with liver im-
pairment or at risk of cardiac arrhythmias (e.g., congenital long QT syndrome
or atrioventricular block); selection of antihistamines that do not have quinidine-
like actions and are not metabolized by hepatic cytochrome P-450 in patients at
risk of cardiac arrhythmia.
Nonsedating antihistamines are widely prescribed for the treatment of aller-
gic disorders; however, the nonsedating antihistamines such as terfenadine and
astemizole that block I Kr channels are now known to cause QT prolongation and
TdP, particularly when given in overdosage, with concomitant ingestion of imid-
azole antifungals or macrolide antibiotics, or to at-risk patients including those
with congenital long QT syndrome, cardiac disease, liver disease, or electrolyte
408 Yap and Camm
disturbance. Many questions still need to be answered, such as the roles of other
potassium channels (I Ks , I To , and I Ped ) and the relative expression of various potas-
sium channels in different individuals, which may be important in the pathogene-
sis of TdP.
IX. OTHER FACTORS THAT MAY PROLONG

VENTRICULAR REPOLARIZATION OR PREDICT TdP
There are many causes of QT interval prolongation; however, by far the most
common cause of QT prolongation is a drug. The drugs that can cause QT prolon-
gation and TdP are listed in Table 4. Apart from drugs, other conditions likely
to cause QT prolongation, some of which have already been discussed above,
include:
Organic heart disease (e.g., congenital long QT syndrome, ischemic heart

disease, congestive heart failure, dilated cardiomyopathy, hypertrophic
cardiomyopathy, myocarditis, and Kawasaki syndrome) (83–87)
Metabolic abnormalities (e.g., hypokalemia and, much less commonly, hy-
pocalcemia and hypomagnesemia) (88–90)
Bradycardia, atrioventricular and sinoatrial blocks (89, 92)
Drug-related factors (e.g., narrow therapeutic window, multiple pharmaco-
logical actions including inhibition and induction of cytochrome P-450
enzymes, polypharmacy) (13, 33, 93)
Female preponderance, which may be due to sex differences in specific
cardiac ion densities (94, 95)
Hepatic impairment (12)
X. PREVENTION AND TREATMENT OF DRUG-INDUCED

QT PROLONGATION
In clinical practice, adverse proarrhythmic effects of nonsedating antihistamines

or the effects of any QT-prolonging drugs can be prevented by not exceeding
the recommended dosage, and by avoiding their use in patients with pre-existing
heart disease or risk factors as mentioned above, previous ventricular arrhythmias
and/or electrolyte imbalance such as hypokalemia. Concomitant administration
of drugs that inhibit cytochrome P-450 (e.g., imidazole antifungals, macrolide
antibiotics) or those that can prolong the QT interval or cause electrolyte distur-
Table 4 Drugs That Can Prolong QT Interval and Lead to TdP (not a comprehensive list)
Antiarrhythmic drugs Type 1A (TdP reported in all)

Quinidine (TdP reported)
Procainamide (TdP reported)
Disopyramide (TdP reported)
Ajmaline (TdP reported)
Aprindine
Type 1C (increase QT by prolonging
QRS interval)
Encainide
Flecainide
Propafenone
Moricizine
Type 3 (TdP reported in all)
Amiodarone
Dronedarone
Sotalol
d-sotalol
Bretylium
Ibutilide
Dofetilide
Semantilide
Trecetilide
Ersentilide
Azimilide
Tedisamil
Almokalant
Calcium channel blockers Prenylamine (TdP reported, withdrawn)
Bepridil (TdP reported, withdrawn)
Terodiline (TdP reported, withdrawn)
Psychiatric drugs Thioridazine (TdP reported)
Chlorpromazine (TdP reported)
Haloperidol (TdP reported)
Droperidol (TdP reported)
Amitriptyline
Nortriptyline
Imipramine (TdP reported)
Desipramine (TdP reported)
Clomipramine
Maprotiline (TdP reported)
Doxepin (TdP reported)
Lithium (TdP reported)
Chloral hydrate
Sertindole (TdP reported, withdrawn)
Pimozide (TdP reported)
Ziprasidone
410 Yap and Camm
Table 4 Continued
Antihistamines Terfenadine (TdP reported, withdrawn)

Astemizole (TdP reported, withdrawn)
Diphenhydramine (TdP reported)
Hydroxyzine
Ebastine
Mizolastine
Antimicrobial and antimalarial drugs Erythromycin (TdP reported)
Clarithromycin (TdP reported)
Ketoconazole
Pentamidine (TdP reported)
Quinine
Chloroquine (TdP reported)
Halofantrine (TdP reported)
Amantadine (TdP reported)
Sparfloxacin
Grepafloxacin (TdP reported, withdrawn)
Pentavalent antimonial meglumine
Serotonin agonists/antagonists Ketanserin (TdP reported)
Cisapride (TdP reported, withdrawn)
Immunosuppressants Tacrolimus (TdP reported)
Antidiuretic hormones Vasopressin (TdP reported)
Other agents Adenosine
Organophosphates
Probucol (TdP reported)
Papaverine (TdP reported)
Cocaine
bance should be avoided. The serum potassium level should be checked regularly
when the patient is taking potassium-depleting diuretics. Drugs that can prolong
the QT interval should ideally be listed and regularly updated in a national drug
formulary. Any adverse event suggestive of cardiac arrhythmias should be re-
ported urgently to drug regulatory authorities and/or drug manufacturers. In our
institution, we routinely give out an advice leaflet regarding the risk of QT prolon-
gation and TdP to at-risk groups such as patients who are prescribed QT-pro-
longing drugs and those with congenital long QT syndrome (Fig. 7). Several
websites provide information about the risk of QT prolongation with a particular
drug, although none is comprehensive (Fig. 7).
TdP is often self-limiting and associated with recurrent dizziness and syn-
cope; however, it may progress to ventricular fibrillation and sudden death. The
management of patients with drug-induced TdP includes identifying and with-
drawing the offending drug(s), and identifying and correcting any electrolyte ab-
Figure 7 Contents in St. George’s Hospital advice leaflet on long-QT syndrome and
websites for checking QT-prolonging drugs.
normalities. The potassium level should be replenished to 4.5–5 mmol/L. The

treatment of choice is intravenous infusion of magnesium sulfate (1–2 g). Magne-
sium, which has no direct effect on the QT interval, reduces the I Ca-L current and
acts on the sodium/potassium-activated adenosine triphosphate system, which
facilitates potassium influx into the cardiac cell and corrects the abnormal repolar-
ization (96). In resistant cases, isoproterenol or temporary rapid atrial or ventricu-
lar cardiac pacing may be needed to increase the heart rate and shorten the QT
interval (97). Temporary pacing works by decreasing the QT interval.
XI. REGULATORY PERSPECTIVE

IN DRUG DEVELOPMENT
Apart from antiarrhythmics, many drugs capable of inducing TdP are prescribed
for noncardiac indications and are used for the treatment of relatively benign
conditions. Regulatory authorities in the European Union (EU) are now con-
cerned that the risk of cardiotoxicity should be identified and if possible quantified
during the preclinical and clinical development of a drug. There are currently no
contemporary guidelines from other regulatory authorities to address this issue;
however, in 1997, the Committee for Proprietary Medicinal Products (CPMP)
adopted a document entitled ‘‘Points to Consider: The Assessment of the Poten-
tial for QT Interval Prolongation by Non-Cardiovascular Medicinal Products’’
(96). This document should be viewed as a strong signal from the public health
Figure 8 The preclinical and clinical stages for testing the safety of new active substances (NAS) proposed in the CPMP document. (Summary
from Ref. 98.)
authorities that the problem of QT prolongation, especially caused by noncardiac

drugs, is now thought to be extremely important, and to require careful scrutiny.
Additional research and development are needed for any compound with the po-
tential to prolong the QT interval. The CPMP document details the necessary
preclinical and clinical stages required for testing the safety of new active sub-
stances (Fig. 8).
XII. SUMMARY
Nonsedating H 1-antihistamines are widely prescribed for the treatment of allergic

disorders because of their lack of sedative and anticholinergic effects; however,
certain nonsedating antihistamines such as terfenadine and astemizole are now
known to cause QT prolongation and TdP, particularly in overdosage or with
concomitant ingestion of imidazole antifungals or macrolide antibiotics. Mecha-
nistic studies showed that the cardiotoxic effects of some nonsedating antihista-
mines are due to the inhibition of repolarization potassium channels, particularly
I Kr, which leads to prolongation of the action potential and QT interval, and the
development of early after-depolarization, which triggers TdP. Patients at risk of
developing TdP, such as those with congenital long QT syndrome, cardiac dis-
ease, liver disease, electrolyte disturbance, or those taking drugs that can prolong
QT interval, should avoid nonsedating antihistamines that are also capable of
prolonging the QT interval. Many questions still need to be answered, such as
the role of other potassium channels (I Ks , I To , and I ped ) and the relative expression
of various potassium channels in different individuals, which may be important
in the pathogenesis of TdP with nonsedating antihistamines. There is also a lack
of information on the cardiac actions of newer nonsedating antihistamines. The
evidence so far indicates that the potential to cause ventricular arrhythmias is not
a class effect and that loratadine, cetirizine, and fexofenadine are not associated
with QT prolongation, TdP, or other ventricular arrhythmias. It is hoped that
with a better understanding of the arrhythmogenic mechanism of nonsedating
antihistamines, we will be able to identify patients at risk and prevent any cardiac
toxicity associated with H 1-antihistamines, and ultimately, death.
REFERENCES
1. Craft TM. Torsade de pointes after astemizole overdose. Br Med J 1986; 292:660.
2. Hoppu K, Tikanoja T, Tapanainen P, Remes M, Saarenpaa-Heikkila O, Kouvalainen
K. Accidental astemizole overdose in young children. Lancet 1991; 338:538–540.
3. Clark A, Love H. Astemizole-induced ventricular arrhythmias: an unexpected cause
of convulsions. Int J Cardiol 1991; 33:165–167.
414 Yap and Camm
4. Wiley II JF, Gelber ML, Henretig FM, Wiley CC, Sandhu S, Loiselle J. Cardiotoxic
effects of astemizole overdose in children. J Pediatr 1992; 120:799–802.
5. Davies AJ, Harindra V, McEwan A, Ghose RR. Cardiotoxic effect with convulsions
in terfenadine overdose. Br Med J 1989; 298:325.
6. MacConnell TJ, Stanners AJ. Torsades de pointes complicating treatment with ter-
fenadine. Br Med J 1991; 302:1469.
7. Venturini E, Borghi E, Maurini V, Vecce R, Carnicelli A. Prolongation of the Q-T
interval and hyperkinetic ventricular arrhythmias probably induced by terfenadine
use in liver cirrhosis patients. Recenti Prog Med 1992; 83:21–22.
induced torsade de pointes. Lancet 1988; 2:624.
9. Broadhurst P, Nathan AW. Cardiac arrest in a young woman with the long QT syn-
drome and concomitant astemizole ingestion. Br Heart J 1993; 70:469–470.
10. Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, Cantilena LR. Torsades
de pointes occurring in association with terfenadine use. JAMA 1990; 264:2788–
2790.
11. Zechnich AD, Hedges JR, Eiselt-Proteau D, Haxby D. Possible interactions with
terfenadine or astemizole. West J Med 1994; 160:321–325.
12. Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions
of terfenadine. JAMA 1993; 269:1532–1536.
13. Zhang M-Q. Chemistry underlying the cardiotoxicity of antihistamines. Curr Med
Chem 1997; 4:171–184.
14. Tan HL, Hou CJ, Lauer MR, Sung RJ. Electrophysiologic mechanism of the long
QT interval syndromes and torsade de pointes. Ann Intern Med 1995; 122:701–714.
15. Priori SG, Barhanin J, Hauer RN, Haverkamp W, Jongsma HJ, Kleber AG, McKenna
WJ, Roden DM, Rudy Y, Schwartz K, Schwartz PJ, Towbin JA, Wilde AM. Genetic
and molecular basis of cardiac arrhythmias: impact on clinical management part III.
Circulation 1999; 99:674–681.
16. Colatsky TJ. Potassium channel modulators. Weston AH and Hamilton TC (eds).
Oxford: Blackwell Scientific Publications, 304–340.
17. Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K ⫹
current: differential sensitivity to block by class III antiarrhythmic agents. J Gen
Physiol 1990; 96:195–215.
18. Sakmann B, Trube G. Conductance properties of single inwardly rectifying potas-
sium channels in ventricular cells from guinea pig heart. J Physiol 1984; 347:641–
657.
19. Rees S, Curtis MJ. Which cardiac potassium channel subtype is the preferable tar-
get for suppression of ventricular arrhythmias? Pharmacol Ther 1996; 69:199–
217.
20. Berul CI, Morad M. Regulation of potassium channels by nonsedating antihista-
mines. Circulation 1995; 91:2220–2225.
21. Cleemann L, Morad M. Cardiovascular safety of H 1-antihistamines: a roundtable
discussion. Schering-Plough Pharmaceuticals, Kenilworth, USA 1996, pp 22–31.
22. Ko CM, Ducic I, Fan J, Shuba YM, Morad M. Suppression of mammalian K ⫹ chan-
nel family by ebastine. J Pharmacol Exp Ther 1997; 281:233–244.
23. Antzelevitch C, Sicouri S. Clinical relevance of cardiac arrhythmias generated by
afterdepolarizations: role of M cells in the generation of U waves, triggered activity,

and torsade de pointes. J Am Coll Cardiol 1994; 23:259–277.
24. El-Sherif N, Chinushi M, Caref EB, Restivo M. Electrophysiological mechanism of
the characteristic electrocardiographic morphology of torsade de pointes tachyar-
rhythmias in the long-QT syndrome: detailed analysis of ventricular tridimensional
activation patterns. Circulation 1997; 96:4392–4399.
25. Liu DW, Antzelevitch C. Characteristics of the delayed rectifier current (I Kr and I Ks)
in canine ventricular epicardial, midmyocardial, and endocardial myocytes. A
weaker I Ks contributes to the longer action potential of the M cell. Circ Res 1995;
76:351–365.
26. Antzelevitch C, Davidenko JM, Sicouri S et al. Quinidine-induced early afterdepo-
larisation and triggered activity. J Electrophysiol 1989; 3:323–338.
27. Hii JTY, Wyse DG, Gillis AM, Duff HJ, Solylo MA, Mitchell LB. Precordial QT
interval dispersion as a marker of torsade de pointes. Disparate effects of class Ia
antiarrhythmic drugs and amiodarone. Circulation 1992; 86:1376–1382.
28. Morganroth J. Relations of QTc prolongation on the electrocardiogram to torsades
de pointes: definitions and mechanisms. Am J Cardiol 1993; 72:10B–13B.
29. Moss AJ. Measurement of the QT interval and the risk associated with QTc interval
prolongation: a review. Am J Cardiol 1993; 72:23B–25B.
30. Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. Female gender
as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA
1993; 270:2590–2597.
31. Roden DM. Torsade de pointes. Clin Cardiol 1993; 16:683–686.
32. Roy ML, Dumaine R, Brown AM. HERG, a primary human ventricular target of
the nonsedating antihistamine terfenadine. Circ Res 1996; 94:817–823.
33. Surawicz B. Electrophysiologic substrate of torsade de pointes: dispersion of
repolarization or early afterdepolarizations. J Am Coll Cardiol 1989; 14:172–
184.
34. Ducic I, Ko CM, Shuba Y, Morad M. Comparative effects of loratadine and terfena-
dine on cardiac K⫹ channels. J Cardiovasc Pharmacol 1997; 30:42–54.
35. Suessbrich H, Waldegger S, Lang F, Busch AE. Blockade of HERG channels ex-
pressed in Xenopus oocytes by the histamine receptor antagonists terfenadine and
astemizole. FEBS Lett 1996; 385:77–80.
36. Biton B, Maitre S, Godet D, Depoortere H, Arbilla S, O’Connor SE, Avenet P,
Scatton B. Effect of the novel non-sedative histamine H 1-receptor antagonist
mizolastine on cardiac potassium and sodium currents. Allergy 1998; 53(Suppl. 43):
160.
37. Haria M, Fitton A, Peters DH. Loratadine. A reappraisal of its pharmacodynamic
properties and therapeutic use in allergic disorders. Drugs 1994; 48:617–637.
38. Taglialatela M, Pannaccione A, Castaldo P, Giorgio G, Zhou Z, January CT, Geno-
vese A, Marone G, Annunziato L. Molecular basis for the lack of HERG K ⫹ channel
block-related cardiotoxicity by the H 1-receptor blocker cetirizine compared with
other second-generation antihistamines. Mol Pharmacol 1998; 54:113–121.
39. Lacerda AE, Roy M-L, Lewis EW, Rampe D. Interactions of the non-sedating anti-
histamine loratadine with a Kv1.5-type potassium channel cloned from human heart.
Mol Pharmacol 1997; 52:314–322.
416 Yap and Camm
40. Weissenburger J, Noyer M, Cheymol G, Jaillon P. Electrophysiological effects of

cetirizine, astemizole and D-sotalol in a canine model of long QT syndrome. Clin
Exp Allergy 1999; 29(Suppl. 3):190–196.
41. Yap YG, Camm AJ. The current cardiac safety situation with antihistamines. Clin
Exp Allergy 1999; 29(Suppl. 1):15–24.
42. Tillement JP. A low distribution volume as a determinant of efficacy and safety for
histamine (H 1)-antagonists. Allergy 1995; 50(Suppl. 24):12–16.
43. Leeson GA, Chan KY, Knapp WC, Biedenbach SA, Wright GJ, Okerholm RA.
Metabolic disposition of terfenadine in laboratory animals. Arzneim-Forsch/Drug
Res 1982; 32:1173–1178.
44. Michiels M, Van Peer A, Woestenborghs R, Heykants J. Pharmacokinetics and tissue
distribution of astemizole in the dog. Drug Dev Res 1986; 8:53–62.
45. Simons FER, Murray HE, Simons KJ. Quantitation of H 1-receptor antagonists in
skin and serum. J Allergy Clin Immunol 1995; 95:759–764.
46. Wang WX, Ebert SN, Liu XK, Chen YW, Drici MD, Woosley RL. ‘‘Conventional’’
antihistamines slow cardiac repolarization in isolated perfused (Langendorff) feline
hearts. J Cardiovasc Pharmacol 1998; 32:123–128.
47. Zareba W, Moss AJ, Rosero SZ, Hajj-Ali R, Konecki J, Andrews M. Electrocardio-
graphic findings in patients with diphenhydramine overdose. Am J Cardiol 1997;
80:1168–1173.
48. Krenzelok EP, Anderson GM, Mirick M. Massive diphenhydramine overdose re-
sulting in death. Ann Emerg Med 1982; 11:212–213.
49. Goetz CM, Lopez G, Dean BS, Krenzelok EP. Accidental childhood death from
diphenhydramine overdosage. Am J Emerg Med 1990; 8:321–322.
50. Olson KR, Kearney TE, Dyer JE, Benowitz NL, Blanc PD. Seizures associated with
poisoning and drug overdose. Am J Emerg Med 1994; 12:392–395.
51. Hausmann E, Wewer H, Wellhoner HH, Weller JP. Lethal intoxication with diphen-
hydramine. Report of a case with analytical follow-up. Arch Toxicol 1983; 53:33–
39.
52. Karch SB. Diphenhydramine toxicity: comparisons of postmortem findings in di-
phenhydramine-, cocaine-, and heroin-related deaths. Am J Forensic Med Pathol
1998; 19:143–147.
53. Park-Matsumoto YC, Tazawa T. Neuroleptic malignant syndrome associated with
diphenhydramine and diprophyllin overdose in a depressed patient. J Neurol Sci
1999; 162:108–109.
54. Honig PK, Wortham DC, Zamani K, Connor DP, Mullin JC, Cantilena LR. Terfena-
dine-ketoconazole interaction. Pharmacokinetic and electrocardiographic conse-
quences. JAMA 1993; 269:1513–1518.
55. Woosley RL. Cardiac actions of antihistamines. Annu Rev Pharmacol Toxicol 1996;
36:233–252.
56. Hey JA, del Prado M, Kreutner W, Egan RW. Cardiotoxic and drug interaction
profile of the second generation antihistamines ebastine and terfenadine in an experi-
mental animal model of torsade de pointes. Arzneim-Forsch/Drug Res 1996; 46:
159–163.
cytochrome P450 enzymes. Clin Exp Allergy 1999; 29(Suppl 3):116–124.
58. Simons FER, Simons KJ. Clinical pharmacology of new histamine H 1-receptor an-
tagonists. Clin Pharmacokinet 1999; 36:329–352.
59. Benton RE, Honig PK, Zamani K, Cantilena LR, Woosley RL. Grapefruit juice alters
terfenadine pharmacokinetics, resulting in prolongation of repolarization on the elec-
trocardiogram. Clin Pharmacol Ther 1996; 59:383–388.
60. Rau SE, Bend JR, Arnold MO, Tran LT, Spence JD, Bailey DG. Grapefruit juice-
terfenadine single-dose interaction: magnitude, mechanism, and relevance. Clin
61. Clifford CP, Adams DA, Murray S, Taylor GW, Wilkins MR, Boobis AR, Davies
DS. The cardiac effects of terfenadine after inhibition of its metabolism by grapefruit
juice. Eur J Clin Pharmacol 1997; 52:311–315.
62. Honig PK, Woosley RL, Zamani K, Conner DP, Cantilena LR Jr. Changes in the
pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with
concomitant administration of erythromycin. Clin Pharmacol Ther 1992; 52:231–
238.
63. Honig PK, Wortham DC, Zamani K, Mullin JC, Conner DP, Cantilena LR. The
effect of fluconazole on the steady-state pharmacokinetics and electrocardiographic
pharmacodynamics of terfenadine in humans. Clin Pharmacol Ther 1993; 53:630–
636.
64. Pratt CM, Ruberg S, Morganroth J, McNutt B, Woodward J, Harris S, Ruskin J,
Moye L. Dose-response relation between terfenadine (Seldane) and the QTc interval
on the scalar electrocardiogram: distinguishing a drug effect from spontaneous vari-
ability. Am Heart J 1996; 131:472–480.
65. Moss AJ, Chaikin P, Garcia JD, Gillen M, Roberts DJ, Morganroth J. A review of
the cardiac systemic side-effects of antihistamines: ebastine. Clin Exp Allergy 1999;
29(Suppl 3):200–205.
66. Lorber R, Danzig M, Brannan M. Loratadine (L) does not affect QTc interval nor
produce torsades de pointes type arrhythmias. Allergy 1997; 37:207.
67. Affrime MB, Lorber R, Danzig M, Cuss F, Brannan MD. Three month evaluation of
electrocardiographic effects of loratadine in humans. Allergy 1993; 48(Suppl 16):29.
A. QT interval monitoring during clinical studies with mizolastine, a new H 1-antihis-
tamine. Clin Exp Allergy 1999; 29(Suppl 3):206–211.
69. Sale ME, Barbey JT, Woosley RL, Edwards D, Yeh J, Thakker K, Chung M. The
electrocardiographic effects of cetirizine in normal subjects. Clin Pharmacol Ther
1994; 56:295–301.
70. Pratt C, Brown AM, Rampe D, Mason J, Russell T, Reynolds R, Ahlbrandt R. Car-
diovascular safety of fexofenadine HCl. Clin Exp All 1999; 29(Suppl 3):212–216.
71. Pratt CM, Mason J, Russell T, Reynolds R, Ahlbrandt R. Cardiovascular safety of
fexofenadine HCl. Am J Cardiol 1999; 83:1451–1454.
72. Pinto YM, van Gelder IC, Heeringa M, Crijns HJ. QT lengthening and life-threaten-
ing arrhythmias associated with fexofenadine. Lancet 1999; 353:980.
73. DuBuske LM. Second-generation antihistamines: the risk of ventricular arrhythmias.
Clin Ther 1999; 21:281–295.
74. Brannan MD, Reidenberg P, Radwanski E, Shneyer L, Lin CC, Affrime MB. Evalua-
tion of pharmacokinetic and electrocardiographic parameters following 10 days of
418 Yap and Camm
concomitant administration of loratadine with ketoconazole. J Clin Pharmacol 1994;

34:1016.
75. Brannan MD, Reidenberg P, Radwanski E, Shneyer L, Lin CC, Cayen MN, Affrime
MB. Loratadine administered concomitantly with erythromycin: pharmacokinetic
and electrocardiographic evaluations. Clin Pharmacol Ther 1995; 58:269–278.
76. Brannan MD, Affrime MB, Reidenberg P, Radwanski E, Lin CC. Evaluation of
the pharmacokinetics and electrocardiographic pharmacokinetics of loratadine with
concomitant administration of cimetidine. Pharmacother 1994; 14:347.
77. Paserchia LA, Hewett J, Woosley RL. Effects of ketoconazole on QTc. Clin Pharma-
col Ther 1994; 55(abstr):146.
78. Cetirizine prescribing information. Physician’s Desk Reference , 52nd ed., Mont-
vale, NJ: Medical Economics Co., 1998; 2234–2236.
79. Lindquist M, Edwards IR. Risks of non-sedating antihistamines. Lancet 1997; 349:
1322.
80. Cohen AT. Dangers of non-sedating antihistamines. Lancet 1997; 350:69–70.
81. Himmel MH, Honig PK, Worobec AS. Dangers of non-sedating antihistamines. Lan-
cet 1997; 350:69–70.
82. Passalacqua G, Bousquet J, Bachert C, Church MK, Bindslev-Jensen C, Nagy L,
Szemere P, Davies RJ, Durham SR, Horak F, Kontou-Fili K, Malling H-J, van
Cauwenberge P, Canonica GW. The clinical safety of H 1-receptor antagonists. An
EAACI position paper. Allergy 1996; 51:666–675.
83. Ahnve S. QT interval prolongation in acute myocardial infarction. Eur Heart J 1985;
6:D85–95.
84. Gottlieb SS, Cines M, Marshall J. Torsades de pointes with administration of high-
dose intravenous d-sotalol to a patient with congestive heart failure. Pharmacother-
apy 1997; 17:830–831.
85. Martin AB, Garson A Jr, Perry JC. Prolonged QT interval in hypertrophic and dilated
cardiomyopathy in children. Am Heart J 1994; 127:64–70.
86. Ramamurthy S, Talwar KK, Goswami KC, Shrivastava S, Chopra P, Broor S, Mal-
hotra A. Clinical profile of biopsy proven idiopathic myocarditis. Int J Cardiol 1993;
41:225–232.
87. Ichida F, Fatica NS, O’Loughlin JE, Snyder MS, Ehlers KH, Engle MA. Correlation
of electrocardiographic and echocardiographic changes in Kawasaki syndrome. Am
Heart J 1988; 116:812–819.
88. Akiyama T, Batchelder J, Worsman J, Moses HW, Jedlinski M. Hypocalcemic tor-
sades de pointes. J Electrocardiol 1989; 22:89–92.
89. Kay GN, Plumb VJ, Arciniegas JG, Henthorn RW, Waldo AL. Torsade de pointes:
the long-short initiating sequence and other clinical features; observations in 32 pa-
tients. J Am Coll Cardiol 1983; 2:806–817.
90. Curry P, Fitchett D, Stubbs W, Krikler D. Ventricular arrhythmias and hypokalae-
mia. Lancet 1976; 2:231–233.
91. Brachmann J, Scherlag BJ, Rosenshtraukh LV, Lazzara R. Bradycardia-dependent
triggered activity: relevance to drug-induced multiform ventricular tachycardia. Cir-
culation 1983; 68:846–856.
92. Kurita T, Ohe T, Marui N, Aihara N, Takaki H, Kamakura S, Matsuhisa M, Shimo-
mura K. Bradycardia-induced abnormal QT prolongation in patients with complete

atrioventricular block with torsades de pointes. Am J Cardiol 1992; 69:628–633.
93. Zimmermann M, Duruz H, Guinand O, Broccard O, Levy P, Lacatis D, Bloch A.
Torsades de pointes after treatment with terfenadine and ketoconazole. Eur Heart J
1992; 13:1002–1003.
94. Lehmann MH, Hardy S, Archibald D, Quart B, MacNeil DJ. Sex difference in risk
of torsade de pointes with d,l-sotalol. Circulation 1996; 94:2535–2541.
95. Ebert SN, Liu XK, Woosley RL. Female gender as a risk for drug-induced cardiac
arrhythmias: evaluation of clinical and experimental evidence. J Womens Health
1998; 7:547–557.
96. Smith SJ. Cardiovascular toxicity of antihistamines. Otolaryngol Head Neck Surg
1994; 111:348–354.
97. Vukmir RB. Torsades de pointes: a review. Am J Emerg Med 1991; 9:250–255.
98. European Agency for the Evaluation of Medicinal Products. Human Medicines Eval-
uation Unit. Committee for Proprietary Medicinal Products (CPMP). Points to con-
sider: The assessment of the potential for QT interval prolongation by non-cardiovas-
cular medicinal products. March 1997 (CPMP/986/96).
13
H 1-Antihistamines in
Pregnancy and Lactation
Michael Schatz
Kaiser-Permanente Medical Center, San Diego, California
I. INTRODUCTION
H 1-receptor antagonists are frequently used during pregnancy and lactation (1).
A major reason for this is that two of the diseases for which these antihistamines
are often used, allergic rhinitis and upper respiratory infections, are common in
women of child-bearing age. In addition, urticaria and atopic dermatitis, two other
indications for H 1-antihistamines, are not uncommon in this age group. Less
commonly, antihistamines may be necessary as part of adjunctive therapy for
life-threatening anaphylaxis during pregnancy. Therefore, the selection of antihis-
tamines during pregnancy and lactation is an important clinical issue. In this
chapter, we will first review general information and concepts regarding the use
of medications during pregnancy. Next, the data available regarding the safety
of specific antihistamines during pregnancy and lactation will be reviewed. Fi-
nally, based on this information, recommendations will be presented regarding
the choice and clinical use of H 1-receptor antagonists in the pregnant or lactating
patient.
II. GENERAL CONSIDERATIONS

A. Drug Effects on the Fetus
Drug effects on the fetus appear to occur by means of dose-dependent drug–
receptor interactions that lead to cell death or altered cell function (2). The respon-
sible chemical may be the drug itself or a more active or toxic metabolite.
421
422 Schatz
A number of general principles apply to drug teratogenicity. The develop-

mental insult will be dependent on the dose, route of delivery, duration of expo-
sure, and precise gestational age at the time of exposure to the drug. The ulti-
mate effect on the conceptus will also depend on the genetic make-up of the
mother and the conceptus, and on the potential interaction with other environmen-
tal agents.
The conceptus is most susceptible to major organ malformations during
the period of embryogenesis, from 4 to 10 completed weeks after the onset of the
last menstrual period. When considering birth defects, it is important to be aware
of the background risk factor. In the general population, major congenital malfor-
mations are identified in approximately 2–4% of all newborns. Another 2% may
become apparent by the age of 1 year. Minor malformations occur in an additional
10–20% of children. Genetic and chromosomal abnormalities probably account
for about 25% of congenital defects. Common environmental teratogenic agents,
including radiation, maternal infection, industrial and agricultural chemicals, and
pharmacological agents, probably account for about 10% of birth defects. Ap-
proximately 1% of all birth defects are attributable specifically to medications (3).
Thus, the cause of approximately 65% of congenital anomalies remains unknown.
Although the number of anomalies attributable to drugs is relatively quite low,
these birth defects may be the most preventable of all.
After 10 weeks of gestation, fully formed fetal organs continue to be sus-
ceptible to other effects of drugs taken by the mother. For example, tetracycline
may cause bone and tooth abnormalities, aminoglycosides may cause hearing
damage, iodides may cause fetal goiter, and corticosteroids may impair fetal
growth. The potential long-term effects of drugs administered during the second
and third trimesters on the developing central nervous system (CNS) also need
to be considered, but there is generally little information available regarding the
potential CNS effects of maternal medication.
B. Sources of Information
Information regarding the effects of drugs administered during pregnancy comes
from several sources. Appropriately performed animal studies that do not reveal
teratogenicity of an agent are reassuring, although animal studies showing ad-
verse effects are harder to interpret due to species variability and dose consider-
ations (4). Human case reports of malformations must be considered, although
the coincidental occurrence of a sporadic birth defect or a birth defect caused by
another environmental teratogen cannot be excluded. Most prospective cohort
studies of asthma medications during pregnancy suffer from low statistical power,
and case–control studies may be biased by retrospective design.
Several large prospective studies have addressed the relationship between
medications (including antihistamines) prescribed during early pregnancy and
Pregnancy and Lactation 423
subsequent congenital malformations. The Collaborative Perinatal Project (CPP)

was initially undertaken to identify factors during pregnancy or delivery that
could be related to the risk of infant cerebral palsy or other adverse neurological
outcomes. The data were subsequently reorganized and reanalyzed to investigate
the possible teratogenic role of drugs used in the first 4 lunar months of pregnancy
(5). The final cohort included 50,282 women seen in 12 United States centers
between 1959 and 1965 whose pregnancies lasted longer than 20 weeks of gesta-
tion. Data from the study were presented as relative risks, the ratio of the malfor-
mation rate in exposed versus unexposed mother–child pairs, and statistical sig-
nificance was tested. However, because of the complexities involved in such
analyses, the authors warn that ‘‘none of the associations presented in this book
should be regarded as anything more than hypothesis requiring independent con-
firmation’’ (5). Conversely, lack of an association between a specific drug and
congenital malformations cannot be taken as proof of safety because of sample
size considerations.
Subsequently, data from the Group Health Cooperative Study have been
reported (6, 7). This study analyzed computerized pharmacy records of 6837
pregnant women who delivered between July, 1977, and December, 1979 (6),
and then 6509 women who delivered between January 1, 1980, and June 30,
1982 (7). In this study, women were assumed to have ingested a medication
during pregnancy if prescriptions for that drug were filled within 1 year of deliv-
ery, which likely overestimates actual gestational drug exposure. The incidence
of ‘‘major disorders’’ diagnosed at birth was then assessed in subjects presumed
to have been exposed to various drugs during their first trimester compared to
unexposed subjects.
Recently, Briggs et al. (8) have described the results of a surveillance study
of Michigan Medicaid recipients conducted between 1985 and 1992 involving
229,101 completed pregnancies. The data were not considered to ‘‘support an
association between the drug and congenital defects’’ in subjects receiving a
number of antihistamines (see below). It is important to point out that these data
have not been published in a peer-reviewed journal.
In 1979, the Food and Drug Administration (FDA) in the United States
established five categories to describe a drug’s potential to cause adverse effects
during pregnancy (Table 1) and mandated that newly approved drugs introduced
into this country after November 1, 1980, be classified into one of these categories
in the package insert (9). These categories are based on the results of animal
studies, human data, and a consideration as to whether the benefit of the drug’s
use during pregnancy outweighs the risk. Unfortunately, no antihistamines la-
beled to date meet the requirement for category A: ‘‘Adequate and well-con-
trolled studies in pregnant women have failed to demonstrate a risk to the fetus
in the first trimester of pregnancy, and there is no evidence of a risk in later
trimesters.’’
424 Schatz
Table 1 Food and Drug Administration Pregnancy Categories
Benefit may
Category Animal studies Human data outweigh risk
A Negative a Studies b negative Yes

B Negative Studies not done Yes
B Positive c Studies negative Yes
C Positive Studies not done Yes
C Not done Studies not done Yes
D Positive or negative Studies or reports positive Yes
Xd Positive Studies or reports positive No
a
No teratogenicity demonstrated.
b
Adequate and well-controlled studies in pregnant women (9).
c
Teratogenicity demonstrated.
d
Drug is contraindicated in pregnancy.
Source: Ref. 37.
C. Risks of Uncontrolled Disease

The risks of drug use during pregnancy must be balanced against the risks of
uncontrolled disease. The only life-threatening disease for which antihistamines
are utilized (as adjunctive treatment to epinephrine) is anaphylaxis, which itself
has been associated with spontaneous abortion, perinatal death, and multicystic
fetal or infantile encephalomalacia (10–12); however, other diseases for which
antihistamines are used may have indirect adverse consequences on pregnancy
outcome.
First, increasing data support the hypothesis that treatment of rhinitis in
patients with coexistent asthma improves the asthma (see Chap. 7). Since uncon-
trolled asthma may increase perinatal complications (13), uncontrolled rhinitis
may indirectly adversely affect pregnancy by making asthma worse. Second, in-
creased stress has been associated with an increased risk of adverse pregnancy
outcomes (14). Since uncontrolled rhinitis or urticaria or other pruritic skin dis-
ease may cause substantial stress by interfering with the quality of life and sleep,
these illnesses could indirectly adversely affect pregnancy through this mecha-
nism. Thus, the risks of the treatment of anaphylaxis, rhinitis, or skin diseases
with antihistamines during pregnancy may be less than the risks of the illnesses,
which include direct and indirect adverse fetal effects, as well as maternal discom-
fort (and in the case of anaphylaxis, mortality).
D. Lactation
Almost all drugs pass into breast milk, usually in amounts less than 2% of the
maternal dose (15). The amount of drug passing into milk varies with its dose,
duration of therapy, water and lipid solubility, protein-binding characteristics,

degree of ionization and pKa, and excretory characteristics, as well as mammary
gland blood flow and the pH of plasma and milk (15).
The pharmacokinetics of breast milk transfer have not been studied for most
drugs. For drugs that the mother has already taken during pregnancy, the infant
will receive much less of the drug during breast feeding than was received during
pregnancy (2). Poorly absorbed topical medication should provide less drug to
the infant through breast milk than systemically absorbed medication (16).
Some compounds are more toxic to the neonate than the adult because the
neonate has greater blood–brain barrier permeability, relatively poor liver en-
zyme-conjugating capacity, diminished protein-binding capacity, and/or a mark-
edly decreased glomerular filtration rate. These differences are compounded if
the baby is premature (15). For systemically administered drugs, exposure of the
nursing infant may be minimized by having the mother take the medication just
after she has breast-fed the infant and/or just before the infant is due to have a
lengthy sleep period (17).
III. DATA ON THE USE OF H 1-ANTIHISTAMINES DURING

PREGNANCY AND LACTATION
A. H 1-Antihistamines as a Class
In 1971 Nelson and Forfar (18) published a case–control study investigating asso-
ciations between drugs administered during pregnancy and congenital abnormali-
ties of the fetus. Cases were 458 mothers who gave birth to an infant with a
major (n ⫽ 175) or minor (n ⫽ 283) congenital abnormality. Controls were 500
mothers of the next normal baby born after the congenitally abnormal one in the
same maternity unit and another 411 mothers of normal babies matched in respect
to maternal age, parity, and baby’s gender with the cases (total control n ⫽ 911).
No significant associations were found between antihistamine use during the en-
tire pregnancy or during the first trimester and an increased occurrence of total,
major, or minor congenital malformations in this study. Seven percent of subjects
in this study used H 1-antihistamines during the whole of pregnancy, and approxi-
mately 2% used them during the first trimester.
In the CPP 5,401 women were exposed to ‘‘antihistamines and antinause-
ants’’ (15). In this group as a whole, the hospital standardized relative risk of
any malformation was not increased (1.10). Moreover, there was no association
with specific malformations and this class of drugs after accounting for confound-
ing variables (standardized relative risk for any malformation ⫽ 1.08).
In a recent prospective study of asthma during pregnancy, 493 subjects
were exposed to antihistamines, 321 in the first trimester (19). No significant
associations were found in this study between maternal H 1-antihistamine expo-
426 Schatz
sure and adverse perinatal outcomes, including pre-eclampsia, preterm birth, low-
birth weight infants, small-for-gestational age infants, or congenital malforma-
tions.
Seto et al. (20) recently reported a meta-analysis of pregnancy outcome
following first-trimester exposure to H 1-antihistamines. Twenty-four controlled
studies published between 1960 and 1991 involving more than 200,000 women
were included. The summary odds ratio of major malformations associated with
H 1-antihistamines taken during pregnancy was 0.76, suggesting that the maternal
use of antihistamines during pregnancy does not increase the teratogenic risk.
There is a report in the literature (21) that associates H 1-antihistamine use
within 2 weeks of delivery with a twofold increased risk of retrolental fibroplasia
in very-low-birthweight (⬍1750 g) premature infants. The mechanism of this
association is unclear, but the authors suggest that histamine antagonism in the
immature retinal vasculature could initiate or promote the physiological process
leading to retrolental fibroplasia.
None of the available information suggests that the maternal use of H 1-
antihistamines during lactation is associated with serious adverse reactions in the
nursing infant (17). Moreover, no data show that the use of antihistamines by
the lactating mother interferes with lactation (3). There are a few reports associat-
ing the use of first-generation antihistamines during nursing with infant drowsi-
ness or irritability (22, 23).
B. Specific Drugs
1. First-Generation Antihistamines
Information regarding the duration of availability and the results of animal terato-
genicity studies for currently available oral first-generation antihistamines is sum-
marized in Table 2. However, only first-generation drugs for which human data
are available (Table 3) will be discussed below.
Brompheniramine. Brompheniramine is an old antihistamine for which
animal reproduction data have not demonstrated adverse effects; however, a sta-
tistically significant relationship between brompheniramine use and total congen-
ital malformations was reported in 65 exposed women in the CPP (5). The data
in 206 exposed women in two other studies were more reassuring (Table 3).
Chlorpheniramine. Chlorpheniramine is one of the oldest available anti-
histamines, and animal data have been reassuring. Gestational exposure to chlor-
pheniramine has not been associated with a significantly increased risk of congen-
ital malformations in a relatively large number of women (Table 3). No adverse
effects were reported in five nursing infants whose mothers were receiving chlor-
pheniramine (22).
Table 2 Year Introduced, Results of Animal Reproduction Studies, and FDA

Pregnancy Classification for Specific Antihistamines
Year introduced
Drug (USA) Animal studies a FDA class b
First-Generation
Azatadine 1977 Positive C
Brompheniramine 1957 Negative —c
Clemastine 1977 Negative B
Chlorpheniramine 1949 Negative —
Dexchlorpheniramine 1982 Negative B
Diphenhydramine 1946 Negative B
Hydroxyzine 1956 Positive —
Pheniramine 1948 None —
Tripelennamine 1946 Negative —
Triprolidine 1958 Negative —
Second-Generation
Astemizole d 1988 Positive C
Cetirizine 1995 Negative B
Fexofenadine 1996 Positive C
Loratadine 1993 Negative B
Terfenadine d 1985 Positive C
Topical
Azelastine 1996 Positive C
Levocabastine 1993 Positive C
Olopatadine 1996 Positive C
Pheniramine 1948 None —
a
Positive, adverse effects demonstrated; negative, adverse effects not demonstrated; none, no animal
studies reported (33).
b
See Table 1 (33).
c
Drugs for which no FDA class is listed were introduced and labeled before classification was man-
dated (1979).
d
These drugs are no longer marketed in most countries.
Dexchlorpheniramine. Dexchlorpheniramine has been introduced more

recently, but as with chlorpheniramine, animal studies have not demonstrated
adverse effects, and one human study of more than 1000 exposed subjects has
been reassuring (8).
Diphenhydramine. Diphenhydramine has been available for over 50
years, and nearly twice as many gestational exposures have been reported to
diphenhydramine than to any other antihistamine. Odds ratios for the risk of total,
selected, or major malformations have been reassuring, ranging from 0.3 to 1.3
in the published prospective studies (Table 3); however, a case control study of
428 Schatz
Table 3 Human Data on the Relationships Between the Use of Specific

Antihistamines During Pregnancy and Congenital Malformations (CM)
Ref/CM Exposed Controls Relative risk a
Drug type (n/% CM) (n/% CM) (95% CI)
First-Generation
Brompheniramine 38/Major 34/2.9 34/5.9 0.5 (⫺0.4–1.0)
5/Any 65/15.4 50,217/6.4 2.2 (1.1–4.3)
7/Selected 172/2.9 6337/1.6 1.8 (0.7–4.5)
Total b 271
Chlorpheniramine 5/Any 1070/8.4 49,212/6.4 1.2 (1.0–1.5)
7/Selected 257/1.6 6252/1.6 0.9 (0.4–2.6)
8/Major c 61/3.3 228,940/4.9 0.7 (0.6–2.7)
Total b 1388
Dexchlorpheniramine 8/Major c 1080/4.6 228,021/4.0 1.2 (0.9–1.6)
Diphenhydramine 5/Any 1080/8.2 49,687/6.4 1.3 (1.0–1.7)
6/Selected 361/0.3 6476/1.2 0.3 (0.1–1.2)
7/Selected 270/1.5 6239/ /1.6 0.9 (0.3–2.5)
8/Major c 1461/5.5 227,640/4.2 1.3 (1.0–1.6)
Total 2687
Hydroxyzine 5/Any 50/10 50,232/6.5 1.6 (0.6–4.1)
39/Any 74/0.0 34/0.0 —
8/Major c 828/5.8 228,273/5.1 1.2 (0.9–1.6)
28/Major 43/4.7 44/0.0 —
28/Minor 43/9.3 44/4.5 2.1 (0.4–12.4)
28/Any 43/13.9 44/4.5 3.4 (0.6–17.9)
Total b 995
Pheniramine 5/Any 831/8.2 49,451/6.4 1.2 (1.0–1.6)
Tripelennamine 5/Any 100/6.0 50,182/6.5 0.9 (0.4–2.1)
Triprolidine 6/Selected 384/1.6 6453/1.1 1.3 (0.6–3.1)
7/Selected 244/1.2 6265/1.6 0.8 (0.2–2.4)
Total 628
Second-Generation
Astemizole d 30/Major 114/1.8 114/1.8 1.0 (0.1–7.5)
Cetirizine 28/Major 33/0.0 38/0.0 —
28/Minor 33/6.1 38/5.3 1.2 (0.1–11.7)
28/Any 33/6.1 38/5.3 1.2 (0.1–11.7)
Terfenadine d 8/Major d 1034/4.9 228,067/4.3 1.2 (0.9–1.6)
32/Major 65/0.0 118/1.8 0.6 (0.1–5.4)
Total 1099
a
In the Collaborative Perinatal Project (5), the Hospital Standardized Relative Risk is reported.
b
Data from Jick et al. (6) are omitted because the exact number of subjects exposed (100–199) was
not reported.
c
In the Michigan Medicaid study (8), the number of unexposed subjects was calculated from the
total number studied minus the number exposed to the indicated drug, and the incidence of malforma-
tions in the unexposed subjects was calculated from the expected number of malformations divided
by the number of exposed subjects.
d
These drugs are no longer marketed in most countries.
Source: Modified from Refs. 35 and 40.
599 children with oral clefts and 599 controls found a 3.3-fold increased fre-
quency of exposure to diphenhydramine in the mothers of cases vs. controls
(p ⬍ 0.01) (24).
Diphenhydramine has been associated with several other adverse events
during pregnancy or lactation. Withdrawal manifestations (generalized tremu-
lousness and diarrhea) have been reported in the newborn of a woman receiving
150 mg diphenhydramine daily during pregnancy (25). A case of diphenhydra-
mine overdose during pregnancy has also been reported, associated with disorien-
tation and painful uterine contractions (26). The latter was attributed to the oxyto-
cin-like effects of diphenhydramine, which had been previously reported (27).
Finally, 1 of 12 nursing infants whose lactating mothers were receiving diphenhy-
dramine manifested drowsiness (22).
Hydroxyzine. Hydroxyzine, which has been available since 1956, appears
to cause adverse effects in animal studies. No statistically significant increases
in congenital malformations have been reported in nearly 1000 exposed human
pregnancies (Table 3), although somewhat increased odds ratios (1.6 and 3.4 for
any malformations) have been reported in two studies (5, 28). There is a report
of a neonatal withdrawal syndrome (jitteriness, clonic movements of the upper
extremities, and poor feeding) in the infant of a mother who ingested 600 mg
hydrozyzine daily throughout pregnancy (29).
Pheniramine. Pheniramine has been available orally and topically since
1948. No animal reproduction studies have been reported. Data from the CPP
were reassuring in 831 subjects (5).
Tripelennamine. Along with diphenhydramine, tripelennamine is the old-
est available antihistamine. Animal and human studies during pregnancy have
been reassuring, but only 100 exposed human subjects have been reported (5).
Triprolidine. Animal studies have been reassuring for triprolidine. Hu-
man data have also not suggested an increased risk of selected malformations,
although fewer exposed patients have been reported than for older antihistamines
such as chlorpheniramine or diphenhydramine (Table 3).
2. Second-Generation Antihistamines
Information regarding the duration of availability and results of animal reproduc-
tion studies for second-generation antihistamines is summarized in Table 2, and
published human studies are summarized in Table 3.
Astemizole. Animal studies with astemizole have produced adverse fetal
effects. A small human study has been reassuring, but this study does not exclude
as much as a sevenfold increased risk of congenital malformations with 95%
certainty (30). A report describing apparent reactions in nursing infants to mater-
430 Schatz
nal medications received through breast milk reported irritability in 2 of 10 infants

whose lactating mothers were taking astemizole (22). Astemizole is no longer
marketed in most countries due to its potential cardiac toxicity.
Cetirizine. Cetirizine has not produced adverse effects in animals, although
the published human experience is limited to 33 subjects in one report (28).
Fexofenadine. Animal studies with fexofenadine have not been reassur-
ing, and there are currently no published human data regarding its use during
human pregnancy.
Loratadine. Animal studies with loratadine have not demonstrated ad-
verse fetal effects, but no published human gestational data are available. Excre-
tion of loratadine into breast milk has been studied in six lactating volunteers (31).
The results suggested that a 4 kg nursing infant would ingest a dose equivalent to
0.46% of the dose received by the mother on a mg/kg basis, an amount unlikely
to present a hazard to a nursing infant.
Terfenadine. Animal reproduction studies with terfenadine have demon-
strated adverse effects, but one human study involving more than 1000 exposed
subjects has not demonstrated an increased risk (8). Loebstein et al. (32) have
recently reported pregnancy outcomes in 118 women exposed to terfenadine (65
in the first trimester) compared to 118 controls. There was no significant increase
in the rate of congenital malformations in infants of women exposed during the
first trimester, although the statistical power of the study only excluded a sixfold
or greater increased incidence of major congenital malformations with 95% cer-
tainty. The mean birthweight in the terfenadine-exposed newborns was signifi-
cantly lower than that in their matched control subjects (3335 ⫾ 582 g vs. 3499
⫾ 617 g, p ⫽ 0.04). Although the mechanism and clinical significance of this
observation are unclear, animal reproduction studies in rats have also reported
decreased weight gain in exposed pups (33).
Terfenadine pharmacokinetics in breast milk have been studied in four lac-
tating mothers (34). Newborn dosage estimates based on the highest measured
concentration of terfenadine metabolite in milk suggest that the maximum level
of newborn exposure would not exceed 0.45% of the recommended weight-cor-
rected dose, an amount not likely to produce substantial untoward effects; how-
ever, infant irritability has been reported by 3 of 25 lactating mothers who were
taking terfenadine while breast-feeding (22). Like astemizole, terfenadine is no
longer marketed in most countries due to potential cardiac toxicity.
3. Topical Antihistamines
Animal studies for azelastine, levocabastine, and olopatadine have reported ad-
verse fetal effects, but no human gestational data have been published. Phenira-
mine, which is available in both oral and topical preparations, has been discussed
above.
IV. USE OF H 1-ANTIHISTAMINES DURING PREGNANCY

AND LACTATION
A. Choice of Drugs
1. Pregnancy
Based on a review of the information available before 1993, the Working Group
on Asthma and Pregnancy recommended chlorpheniramine and tripelennamine
as the antihistamines of choice for use during pregnancy (3). More recently, we
have recommended chlorpheniramine, based on duration of availability, animal
study results, and the quantity and quality of reassuring human data (35). If chlor-
pheniramine is not effective or well tolerated, tripelennamine was suggested as
an alternative. First-generation drugs such as diphenhydramine and hydroxyzine,
for which human experience during pregnancy is large but for which animal and/
or human data have raised some concerns regarding congenital malformations,
could be considered after the first trimester. Diphenhydramine should be used at
any time in the pregnancy if injectable antihistamine therapy is indicated, since
there is no equally effective parenteral substitute.
Second-generation antihistamines present a unique situation with regard
to their use during pregnancy. The medical–legal literature recommends older
medications rather than newer ones for use during pregnancy, if equally effective
(36) and indeed, the second-generation antihistamines are not generally more
effective than their first-generation counterparts. However, as reviewed exten-
sively elsewhere (see Chap. 11), the side effects of first-generation antihistamines
(sedation and performance impairment) are increasingly well-documented and
the patient may not be aware of them. Thus, the issue is the use of older, better-
studied, and equally effective medications with more potentially important yet
imperceptible side effects vs. newer, less well-studied medications that do not
cause demonstrable adverse effects on mental functioning.
This conflict must be resolved on an individual basis. For patients with
rhinitis, the problem can often be obviated by the use of topical medication (cro-
molyn or an intranasal corticosteroid) instead of an oral antihistamine. This, of
course, would not be a solution for patients receiving H 1-receptor antagonists for
urticaria. A second option is to use chlorpheniramine or tripelennamine but to
make patients aware of their potential for sedation or peformance impairment,
even in the absence of perceptible drowsiness, so that they can adjust their activi-
ties accordingly. The third option is to choose a second-generation antihistamine.
432 Schatz
If one is to prescribe a second-generation antihistamine during pregnancy,

which one should be selected? There is a reasonable amount of reassuring human
data available for terfenadine, but terfenadine is no longer available in most coun-
tries. As discussed above, the amount of human data available for the other sec-
ond-generation antihistamines is too small to provide substantial reassurance.
Thus, if a second-generation antihistamine is to be used during pregnancy, either
cetirizine or loratadine could be recommended because of reassuring animal stud-
ies with each one. It should be noted that use of a second-generation antihistamine
after the first trimester is less problematic, because the occurrence of even a
coincidental birth defect cannot be attributed to the use of the drug after organo-
genesis is complete.
All things being equal, topical medications would be preferred to systemic
medications (2); however, the relatively frequent sedation associated with topical
azelastine suggests that there is substantial systemic absorption (33). This, in
addition to the adverse effects in animal studies and the lack of available human
pregnancy data, argues against the use of topical azelastine during pregnancy.
Of the available topical ophthalmological antihistamines, pheniramine would be
the best choice based on duration of availability, animal studies, and human gesta-
tional data.
As described above, high-dose use of hydroxyzine and diphenhydramine
during pregnancy and at term has been associated with withdrawal phenomena
in the neonate. This potential effect would presumably not be limited to these
specific drugs. Thus, a high index of suspicion should be maintained for with-
drawal phenomena in infants of mothers using high doses of any antihistamine
at term. The data regarding antihistamine use and retrolental fibroplasia described
above likewise suggest that all antihistamines should be avoided, if possible, in
women at risk of delivering very-low-birth-weight infants.
2. Lactation
As described above, there are no data suggesting that the maternal use of antihis-
tamines causes serious adverse reactions in the nursing infant. Drowsiness has
been occasionally reported with first-generation antihistamines. Although lacta-
tion pharmacokinetic data have been reassuring with terfenadine and loratadine,
irritability has been reported in some nursing infants whose mothers were taking
terfenadine or astemizole. My recommendation would be to use whatever antihis-
tamine seems best for the lactating mother, watching for drowsiness in the infant
if first-generation antihistamines are being utilized and for irritability with sec-
ond-generation antihistamines. As mentioned above, in patients with rhinitis, top-
ical (cromolyn or intranasal corticosteroid) therapy may be preferred to minimize
further infant drug exposure through breast milk.
B. Informed Consent
Although the patient’s informed consent to the therapeutic approach recommended
during pregnancy should be obtained as part of good medical care and in order to
optimize compliance, it also has important medical–legal implications. The thalido-
mide tragedy raised public awareness of the adverse effects of drugs on the fetus.
Moreover, in today’s litigious environment, the lay public and legal profession have
often related the occurrence of an adverse pregnancy outcome to malpractice.
The following approach to obtaining a woman’s informed consent during
pregnancy has been recommended (36, 37). First, state what is known and not
known regarding the effect of the particular drug(s) on pregnancy and the devel-
oping infant. These risks should be presented in relationship to the background
risk in the general population discussed in Section II.A of this chapter. It should
be emphasized that, although relatively few medications have been proved to be
harmful during pregnancy, no asthma or allergy medication can be considered
to be proven absolutely safe. Second, discuss with the patient the potential conse-
quences for the mother and for the baby of the inadequately controlled allergic
disorders. Third, discuss the medication options available for the patient’s partic-
ular situation and the rationale for the specific treatment plan recommended. Em-
phasize that this recommended treatment program is considered to entail less risk
than the uncontrolled illness that could result if it was not used. Fourth, continu-
ally address any questions the parents may have. Fifth, obtain the patient’s con-
currence with the therapeutic decisions. Finally, document the informed consent
discussion(s) on the patient’s chart. I suggest including a statement such as the
following: ‘‘The benefits, risks, and alternatives of (the specific pharmacological
approach) have been discussed with the patient and her informed consent to that
approach has been obtained.’’ A formal written consent form is not considered
to be necessary (36).
V. SUMMARY
Antihistamines may be used for the treatment of allergic rhinitis, upper respira-
tory infections, urticaria/angioedema, atopic dermatitis, and, rarely, as adjunctive
treatment for anaphylaxis, during pregnancy. Because these illnesses may affect
maternal comfort and safety as well as threaten the fetus directly (anaphylaxis) or
indirectly, they often require therapy during pregnancy. Based on the information
available to date, in this chapter we have attempted to provide rational guidelines
for the gestational use of H 1-receptor antagonists in a manner that will lead to
the optimal well-being of both the mother and her infant. As more information
becomes available, the recommendations herein may require modification.
434 Schatz
Although this chapter has dealt specifically with gestational management,

a case can be made for considering this information when making therapeutic
decisions in all women of childbearing potential. First, most pregnancies are un-
planned, and the peak period of fetal vulnerability to drug-induced teratogenesis
begins the day a woman’s period is due. Second, during gestation, substantial
alterations in a previously successful but not optimal-for-pregnancy chronic ther-
apeutic regimen may be psychologically threatening to the patient and may lead
to either uncontrolled disease or unanticipated side effects. Thus, pregnancy-ap-
propriate regimens should ideally be discussed with all women of childbearing
age as part of the informed therapeutic decision-making process.
REFERENCES
1. Buitendijk S, Bracken MB. Medication in early pregnancy: Prevalence of use and

relationship to maternal characteristics. Am J Obstet Gynecol 1991; 165:33–40.
2. Abrams RS, Hoffman CP. Use of medication during pregnancy and lactation: general
considerations. In Schatz M, Zeiger RS, Claman HN, eds. Asthma and Immunologi-
cal Diseases in Pregnancy and Early Infancy. New York: Marcel Dekker, 1998:137–
156.
3. National Asthma Education Program Report of the Working Group on Asthma and
Pregnancy: Management of asthma during pregnancy. NIH Publication number 93-
3279A, Sept. 1993.
4. Scialli AR, Lione A. Pregnancy effects of specific medications used to treat asthma
and immunological diseases. In Schatz M, Zeiger RS, Claman HN, eds. Asthma and
Immunological Diseases in Pregnancy and Early Infancy. New York: Marcel Dek-
ker, 1998:157–227.
5. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton,
MA: PSG Publishing, 1977.
6. Jick J, Holmes LB, Hunter JR, Madsen S, Stergachis A. First trimester drug use and
congenital disorders. JAMA 1981; 246:343–346.
7. Aselton P, Jick H, Milunsky A, Hunter JR, Stergachis A. First trimester drug use
and congenital disorders. Obstet Gynecol 1985; 65:451–455.
8. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation, 5th ed. Balti-
more: Williams & Wilkins, 1998.
9. Content and format for labeling for human prescription drugs: clarification of effec-
tive date. Fed Reg 1980; 45:32550.
10. Francis N. Abortion after grass pollen injection. J Allergy 1941; 12:559–563.
11. Erasmus C, Blackwood W, Wilson J. Infantile multicystic encephalomalacia after
maternal bee sting anaphylaxis during pregnancy. Arch Dis Child 1982; 57:785–
787.
12. Entman SS, Moise KJ. Anaphylaxis in pregnancy. South Med J 1984; 77:402.
13. Schatz M: Interrelationships between asthma and pregnancy: a literature review. J

Allergy Clin Immunol 1999; 103:S330–S336.
14. Copper RL, Goldenberg RL, Das A, Elder N, Swain M, Norman G, Ramsey R,
Cotroneo P, Collins BA, Johnson F, Jones P, Meier AM. The preterm prediction
study: maternal stress is associated with spontaneous preterm birth at less than thirty-
five weeks’ gestation. National Institute of Child Health and Human Development
Maternal–Fetal Medicine Units Network. Am J Obstet Gynecol 1996; 175:1286–
1292.
15. Anderson PO. Drug use during breast feeding. Clin Pharm 1991; 10:594–624.
16. Ellsworth A. Pharmacotherapy of asthma while breastfeeding. J Hum Lact 1994;
10:39–41.
17. American Academy of Pediatrics Committee on Drugs. The transfer of drugs and
other chemicals into human milk. Pediatrics 1994; 93:127.
18. Nelson MM, Forfar JO. Associations between drugs administered during pregnancy
and congenital abnormalities of the fetus. Br Med J 1971; 1:523–527.
19. Schatz M, Zeiger RS, Harden K, Hoffman CC, Chilingar L, Petitti D. The safety
of asthma and allergy medications during pregnancy. J Allergy Clin Immunol 1997;
100:301–306.
20. Seto A, Einarson T, Koren G. Pregnancy outcome following first trimester exposure
to antihistamines: meta-analysis. Am J Perinatol 1997; 14:119–124.
21. Zierler S, Purohit D. Prenatal antihistamine exposure and retrolental fibroplasia. Am
J Epidemiol 1986; 123:192–196.
22. Ito S, Blajchman A, Stephenson M, Eliopoulos C, Koren G. Prospective follow-up
of adverse reactions in breast-fed infants exposed to maternal medication. Am J
Obstet Gynecol 1993; 168:1393–1399.
23. Kok TH, Taitz LS, Bennett MJ, Holt DW. Drowsiness due to clemastine transmitted
in breast milk. Lancet 1982; 1:914–915.
24. Saxen I. Cleft palate and maternal diphenhydramine intake (letter). Lancet 1974; 1:
407–408.
25. Parkin DE. Probable Benadryl withdrawal manifestations in a newborn infant. J Ped-
iatr 1974; 85:580.
26. Brost BC, Scardo JA, Newman RB. Diphenhydramine overdose during pregnancy:
lessons from the past. Am J Obstet Gynecol 1996; 175:1376–1377.
27. Hara GS, Carter RP, Krantz KE. Dramamine in labor: potential boon or a possible
bomb? J Kans Med Soc 1980; 81:134–136, 155.
28. Einarson A, Bailey B, Jung G, Spizzirri D, Baillie M, Koren G. Prospective con-
trolled study of hydroxyzine and cetirizine in pregnancy. Ann Allergy Asthma Im-
munol 1997; 78:183–186.
29. Prenner B: Neonatal withdrawal syndrome associated with hydroxyzine hydrochlo-
ride. Am J Dis Child 1977; 131:529–530.
30. Pastuszak A, Schick B, D’Alimonte D, Donnenfeld A, Koren G. The safety of astem-
izole in pregnancy. J Allergy Clin Immunol 1996; 98:748–750.
31. Hilbert J, Radwanski E, Affrime MB, Perentesis G, Symchowicz S, Zampaglione N.
Excretion of loratadine in human breast milk. J Clin Pharmacol 1988; 28:234–
239.
32. Loebstein R, Lalkin A, Addis A, Costa A, Lalkin I, Bonati M, Koren G. Pregnancy
436 Schatz
outcome after gestational exposure to terfenadine: A multicenter, prospective con-

trolled study. J Allergy Clin Immunol 1999; 104:953–956.
33. Physicians’ Desk Reference. Montvale, NJ: Medical Economics, 1999.
34. Lucas BD, Purdy CY, Scarim SK, Benjamin S, Abel SR, Hilleman DE. Terfenadine
pharmacokinetics in breast milk in lactating women. Clin Pharmacol Ther 1995; 57:
398–402.
35. Schatz M, Petitti D. Antihistamines and pregnancy. Ann Allergy Asthma Immunol
1997; 78:157–159.
36. Fern FH, Orlando CP, Hobart JA. Medical–legal aspects of prescribing during preg-
nancy. In Schatz M, Zeiger RS, Claman HN, eds. Asthma and Immunological Dis-
eases in Pregnancy and Early Infancy. New York: Marcel Dekker, 1998:229–260.
37. Schatz M, Hoffman CP, Zeiger RS, et al. The course and management of asthma
and allergic diseases during pregnancy. In Middleton E, Reed CE, Ellis EP, et al,
eds. Allergy: Principles and Practice, 5th edition. St. Louis: CV Mosby, 1998:938.
38. Seto A, Einarson T, Koren G: Evaluation of brompheniramine safety in pregnancy.
Reprod Toxicol 1993; 7:393–395.
39. Erez S, Schifrin BS, Dirim O. Double-blind evaluation of hydroxyzine as an anti-
emetic in pregnancy. J Reprod Med 1971; 7:35–37.
40. Mazzotta P, Loebstein R, Koren G. Treating allergic rhinitis in pregnancy. Safety
considerations. Drug Saf 1999; 20:361–375.
14
H 1-Antihistamines in Children
I. INTRODUCTION
H 1-receptor antagonists are widely used in the treatment of allergic disorders in

children. The evidence base for their use is strongest in allergic rhinoconjunctiv-
itis (1) (Table 1). Most of the old, sedating first-generation H 1-antagonists, al-
though still commonly given to infants and children in many countries, have
never been adequately studied in the pediatric population. In contrast, some of
the new, relatively nonsedating second-generation H 1-antagonists have been well-
studied in children, and are now available in pediatric dosage formulations. In
this chapter, we review the clinical pharmacology, efficacy, and safety of H 1-
antagonists in children, with special emphasis on the second-generation medica-
tions cetirizine, fexofenadine, and loratadine, and on the studies that have ap-
peared since the first edition of this book was published (2).
II. CLINICAL PHARMACOLOGY OF H 1-ANTIHISTAMINES

IN CHILDREN
Pharmacokinetic and pharmacodynamic studies, which are inherently somewhat

invasive (3), present unique challenges in children. The pharmacokinetics and
pharmacodynamics of some first-generation H 1-antagonists (chlorpheniramine,
brompheniramine, diphenhydramine, and hydroxyzine (4–7), ketotifen (8) [Table
2A]) and some second-generation H 1-antagonists (cetirizine, fexofenadine, ebas-
tine, and loratadine) (Fig. 1, Table 2B), have been documented in children age
6–11 years (9–15). The clinical pharmacology of other second-generation H 1-
437
438 Simons
Table 1 Levels of Evidence Supporting H 1-Antihistamine Use

Based on Clinical Trials in Children
Evidence Level
Allergic rhinoconjunctivitis 1A
Urticaria 1A
Atopic dermatitis 1B
Upper respiratory tract infections (colds) 3D
Otitis media 3D
Asthma 1C
Other (mosquito bites, eosinophilic cellulitis, etc.) 1B
Level 1; randomized, controlled, clinical trial; level 2; case–control cohort

study; level 3; consensus of expert groups; A; good evidence for use; B;
some evidence for use; C; evidence neither for nor against use; D; some
evidence against use; E; strong evidence against use.
antagonists such as acrivastine, azelastine, levocabastine, and mizolastine has not

yet been optimally studied in children. With the exception of cetirizine (10) and
loratadine (15), there are no published studies of H 1-antagonist pharmacokinetics
and pharmacodynamics in children age 2–5 years and, to date, only cetirizine
has been studied in infants (11).
A. Pharmacokinetic Studies
H 1-antagonists are well-absorbed after oral administration as liquid or solid for-
mulations, with peak plasma concentrations usually being reached within 2 hours
(4–15). The old H 1-antagonists and the new H 1-antagonists loratadine and ebas-
tine are metabolized by the hepatic microsomal mixed-function oxygenase sys-
tems; plasma concentrations of these H 1-antagonists are low after single oral
doses, indicating considerable first-pass hepatic extraction.
Cetirizine, the active carboxylic acid metabolite of hydroxyzine, is elimi-
nated 40% unchanged in the urine within the first 24 hours of a single dose in
children (9, 10), compared to being eliminated 60% unchanged in the urine in
adults (3). Fexofenadine elimination (3), in contrast to fexofenadine pharmacoki-
netics (13) (Fig. 1), has not been studied directly in children; in adults, the drug
is eliminated largely unchanged in the feces.
Concomitant administration of H 1-antagonists with cytochrome P-450 in-
hibitors and other potential pharmacokinetic medication interactions has not been
studied directly in young subjects, with the exception of a novel study of the
effect of chlorpheniramine on the pharmacokinetics of chloroquine in children
with chloroquine-resistant falciparum malaria (16).
Table 2 Pharmacokinetics and Pharmacodynamics of H 1-Antihistamines in Children
Dosage
Drug (active (mg) or No. of Cp max ↓ Wheal/
metabolite) (mg/kg)* pts. (么) Age (yr) Weight (kg) (ng/mL) t max (h) t1/2β(h) flare (h) Reference
First-Generation
Use in Children
Brompheniramine 4 14 (8) 9.5 ⫾ 0.4 31.9 ⫾ 1.7 7.7 ⫾ 0.7 3.2 ⫾ 0.3 12.4 ⫾ 1.1 0.5–36 (30) 4
Chlorpheniramine 0.12* 11 (7) 11 ⫾ 3.0 39.6 ⫾ 9.2 13.5 ⫾ 3.5 2.5 ⫾ 1.5 13.1 ⫾ 6.3 1–24 a 5
Diphenhydramine 1.25* 7 8.9 ⫾ 1.7 31.6 ⫾ 6.8 81.8 ⫾ 30.2 1.3 ⫾ 0.5 5.4 ⫾ 1.8 1–8/1–12 6
Hydroxyzine 0.7* 12 (6) 6.1 ⫾ 4.6 22.0 ⫾ 12.0 47.4 ⫾ 17.3 2.0 ⫾ 0.9 7.1 ⫾ 2.3 n/a 7
Ketotifen b 1 bid 6 2–4 3.25 1.33 n/a n/a 8
Second-Generation
Cetirizine 5 10 (7) 8.0 ⫾ 0.6 30.5 ⫾ 2.7 427.6 ⫾ 144.2 1.4 ⫾ 1.1 7.1 ⫾ 1.6 c 1–24 9
10 9 (8) 8.0 ⫾ 0.6 25.4 ⫾ 1.9 978.4 ⫾ 340.6 0.8 ⫾ 0.4 6.9 ⫾ 1.6 0.5–24
5 8 (5) 2.7⫾ 15.0⫾ 560 ⫾ 200 1.44 ⫾ 1.1 4.9 ⫾ 0.6 c n/a 10
0.25 15/10 12.3 ⫾ 5.5 9.0 ⫾ 1.1 (est.) 2 3.1 ⫾ 1.8 90%/87% 11
months 390 ⫾ 135 2.0 ⫾ 1.3 at 12 hr
Ebastine (carebastine) 5 10 (6) 7.3 ⫾ 0.4 26.4 ⫾ 1.7 (108.6 ⫾ 11.8) (2.8 ⫾ 0.3) (11.4 ⫾ 0.7) 0.5–28 12
10 10 (6) 7.8 ⫾ 0.4 26.1 ⫾ 1.0 (209.6 ⫾ 24.2) (3.4 ⫾ 0.4) (10.1 ⫾ 1.1) 0.5–28
Fexofenadine 30/60 14 (13) 9.8 ⫾ 1.8 32.1 ⫾ 9.3 178 ⫾ 22/286 ⫾ 34 2.4 ⫾ 0.2 18.3 ⫾ 1.2/17.6 ⫾ 1.0 1–24 13
Loratadine (descarbo- 10 13 10.6 4.38 (3.79) 1.0 (1.69) n/a (13.79) 1–12 e 14
ethoxy-loratadine) 5 18 (11) 3.8 ⫾ 1.1 17.4 ⫾ 4.4 7.8 (5.1) 1.2 (2.3) n/a n/a 15
There are no published studies in children to date of acrivastine, azelastine, desloratadine, levocabastine, levocetirizine, mizolastine, or tecastemizole
pharmacokinetics/pharmacodynamics. Medications were administered as liquid formulations, except for fexofenadine and cetirizine (8-year-olds).
n/a, data not available; Cp max (ng/ml), maximum plasma concentration; t max (h), time of maximum plasma concentration; t1/2β, plasma elimination half-
life; ↓ wheal/flare (h), suppression of wheal and flare vs. baseline and vs. placebo treatment (p ⬍ 0.05).
a
Also clinical score for allergic rhinitis.
b
Sometimes classified as a second-generation H 1-receptor antagonist but is, in fact, sedating.
c
Urinary excretion of unchanged cetirizine ⫽ 40 ⫾ 15% and 33 ⫾ 14%.
d
37.8 ⫾ 5.2%.
e
Duration of study limited to 12 h.
439
440 Simons
Figure 1 In a prospective, randomized, double-blind study, plasma concentrations of

orally administered fexofenadine were monitored concomitantly with their ability to sup-
press wheals and flares produced by epicutaneous histamine phosphate, 1 mg/ml. After
administration of fexofenadine 30 mg (not shown) or 60 mg (shown), plasma fexofenadine
concentrations were monitored for 24 hours and wheal and flare suppression was moni-
tored for 28 hours. Peak wheal and flare suppression followed peak plasma H 1-antagonist
concentrations and was maintained after the H 1-antagonist concentrations became negligi-
ble. The temporal relationships between the pharmacokinetics and the pharmacodynamics
of H 1-antagonists in children are characteristic of most medications in this class in all
populations studied to date using this model. (From Ref. 13.)
B. Pharmacodynamic Studies
In children, as in adults, suppression of the histamine-induced wheal and flare
in the skin is used as an objective test of the magnitude, onset, time to peak, and
duration of peripheral H 1-blockade (3). The amount of wheal and flare suppres-
sion varies from one H 1-antagonist to another and with the H 1-antagonist dose
administered. In studies in the pediatric population, a single oral dose of the old
H 1-antagonists brompheniramine, chlorpheniramine, diphenhydramine, hydrox-
yzine, or ketotifen and the new H 1-antagonists cetirizine, ebastine, fexofenadine,
or loratadine has a prompt onset of action (3–6, 9, 11–13, 17) (Fig. 1). During
regular daily administration over weeks or months, no tachyphylaxis or resistance
to their effects occurs (9).
The residual action of H 1-antagonists (the length of time required for their
effect to wear off after the last dose of a short course of treatment) has not been
studied directly in children; however, in young patients, as in adults, it is recom-
Use in Children 441
mended that H 1-antagonists be discontinued for at least 3–4 days before allergen
skin testing.
Although the clinical pharmacology of H 1-antagonists, as objectively mea-
sured in pharmacokinetic and pharmacodynamic studies, differs to some extent
in children and adults, once- or twice-daily dosing is still possible for most H 1-
antagonists in children age 6–11 years (Table 3).
III. EFFICACY OF H 1-ANTIHISTAMINES

IN CHILDREN
The challenges involved in performing clinical trials for development of the evi-
dence base for the efficacy and safety of each H 1-antagonist in children should not
be underestimated (18) (Table 4). Here, we review the evidence for H 1-antagonist
efficacy in allergic rhinoconjunctivitis, upper respiratory tract infections, otitis
media, asthma, urticaria, atopic dermatitis, and other disorders.
A. Allergic Rhinoconjunctivitis
Allergic rhinitis affects up to 42% of children worldwide (19, 20) and is an impor-
tant cause of morbidity and impaired quality-of-life in the pediatric population
(21). The indoor and outdoor airborne allergens and other provoking factors for
allergic rhinitis are similar in children and adults, as is the pathophysiology of
the disorder. Diagnosis is based on symptoms and physical signs. Children are
more likely than adults to present with non-nasal symptoms and signs that are
indirectly related to the allergic inflammation in the nasal mucosa. For example,
they may develop tics or facial grimacing secondary to itching of the nose and
eyes, or behavioral or learning problems due to nocturnal sleep disturbance and
subsequent daytime fatigue, sometimes exacerbated by treatment with old sedat-
ing H 1-antagonists (22). Diagnosis is supported by the presence of eosinophils
in nasal secretions, and by one or more positive epicutaneous tests to airborne
allergens. Although other objective measurements such as documentation of ele-
vated histamine concentrations in nasal secretions, and of nasal blockage, can be
made, these tests are better suited to research than to office use (23, 24).
In children with allergic rhinitis challenged intranasally with allergens to
which they have been naturally sensitized, H 1-antagonists prevent sneezing, itch-
ing, and rhinorrhea during the early response, but are less effective in preventing
or relieving the nasal blockage characteristic of the late response. In children
with allergic conjunctivitis who receive an ocular challenge with allergen, H 1-
antagonists effectively prevent itching, tearing, and conjunctival erythema during
the early response, and decrease the nonspecific conjunctival hyperreactivity re-
lated to allergic inflammation.
442 Simons
Table 3 Formulations and Dosages of Representative H 1-Antihistamines

Recommended
H 1-antihistamine Formulation pediatric dosage
First-Generation
Chlorpheniramine (Chlor- Tablets 4 mg, 8 a mg, 12 a 0.35 mg/kg/24 h; for par-
Trimeton) mg enteral use as an adjunct
Syrup 2.5 mg/5 ml to epinephrine treatment
Parenteral solution 10 mg/ in anaphylaxis (severe
ml acute allergic reactions)
Diphenhydramine (Bena- Capsules 25 or 50 mg 5 mg/kg/24 h; for paren-
dryl) Elixir 12.5 mg/5 ml teral use as an adjunct
Syrup 6.25 mg/5 ml to epinephrine treatment
Parenteral solution 50 mg/ in anaphylaxis
ml
Hydroxyzine (Atarax) Capsules 10, 25, 50 mg 2 mg/kg/24 h; for paren-
Syrup 10 mg/5 ml teral use as an adjunct
Parenteral solution IM 50 to epinephrine treatment
mg/ml in anaphylaxis; oral for
itching unresponsive
to other H 1-antagonists
Second-Generation
Acrivastine (Semprex)b Tablets 8 mg d ⱖ12 yrs: 8 mg tid
Azelastine (Astelin) Nasal solution 0.1% e Topical 1–2 sprays/nostril
0.137 mg/spray 2⫻ daily
Cetirizine (Reactine) Tablets 5, 10 mg ⱖ12 yrs: 5–10 mg/day
Syrup 1 mg/ml 6–11 yrs: 5–10 mg/day
2–5 yrs: 2.5 mg od or bid,
or 5 mg od
Ebastine (Ebastel) c Tablets 10 mg c ⱖ12 yrs: 10 mg od
Fexofenadine (Allegra) Tablets 30, 60 mg ⱖ12 yrs: 60 mg bid, 180
mg od
6–11 yrs: 30 mg bid
Ketotifen (Zaditen) e Tablets 1 mg; 2 mgc ⬎3 yrs: 1 mg bid
Syrup 1 mg/5 ml c 1 drop q8–12 h
Ophthalmic solution (each eye)
0.025%
Levocabastine (Livostin) Microsuspension Topical: 2 sprays/nostril
Nasal spray c 0.50 mg/ml 2–4x daily
or eye drops 0.5 mg/ml 1 drop in each eye 2–4x
daily
Loratadine (Claritin) Tablets 10 mg 2–12 yrs: 5 mg/day
Reditabs (rapidly disinte- ⬎12 yrs and ⬎30 kg: 10
grating): 10 mg mg/day
Syrup 1 mg/ml
Mizolastine (Mizollen)c Tablets 10 mg c ⱖ12 yrs: 10 mg/day
a
Sustained-release.
b
Not approved for use in children under age 12 years in the United States.
c
Medication or formulation not available in the United States.
d
Available only as Semprex-D in combination with pseudoephedrine 60 mg.
e
Available only as ophthalmic solution in the United States.
od, once daily; bid, twice daily; tid, three times daily.
Use in Children 443
Table 4 Clinical Research in Children: Unique Challenges
Recruitment to the Study

Difficulty in obtaining truly informed consent from parent/caregiver
Difficulty in obtaining assent from the child
Parent/caregiver concerns regarding:
Potential side effects of medications
Lack of symptom relief if child is given placebo
Time missed from school for study participation
Procedures (venipunctures, skin tests, etc.)
During the Study
Parent/caregiver reports and interprets subjective symptoms
Presence or absence
Severity
Beginning and end
Specific staff expertise required for working with children
Awareness of growth and developmental issues
Understanding of family dynamics
Technical expertise (for venipunctures, skin tests, ECGs, etc.)
Withdrawal of consent from parent/caregiver
Withdrawal of assent from child (e.g., cries or refuses blood test)
ECG, electrocardiogram.
The efficacy of H 1-antagonists in children with allergic rhinitis, as in adults,

is attributed mainly to H 1-receptor blockade. In addition, the antiallergic and anti-
inflammatory effects of these medications have been documented in children with
this disorder; for example, an H 1-antagonist has been shown to decrease leuko-
triene production in vitro (25), and to decrease nasal nitric oxide levels (26),
inflammatory cell infiltrates, intercellular adhesion molecule (ICAM)-1 expression
in epithelial cells, and soluble ICAM-1 in nasal lavage fluid in vivo (27–29).
The quality of H 1-antagonist studies in children with allergic rhinitis has
improved considerably during the past decade. Although there have never been,
and probably never will be, optimal pediatric clinical trials of the old first-genera-
tion, sedating H 1-antagonists, well-designed, prospective, randomized, blinded
clinical studies of some of the new non-sedating H 1-antagonists in 4–11-year-olds
now provide level 1 evidence for the efficacy of these medications in seasonal and
perennial allergic rhinitis (30–42, 45) (Fig. 2). Evidence for the efficacy of H 1-
antagonists, like other medications, in adolescents (ⱖ12 years of age) generally
comes from clinical trials in which they have been included along with adults.
Regardless of the age of the participants enrolled in allergic rhinitis studies,
a strong placebo response is noted, and dose–response relationships cannot be
readily demonstrated using subjective measurements of efficacy such as symp-
tom-free days or symptom scores for sneezing, nasal itching, discharge, and con-
444 Simons
Figure 2 In a 4-week, randomized, double-blind, placebo-controlled, parallel-group

study in 209 children ages 6–11 years with seasonal allergic rhinitis, cetirizine syrup once
daily 10 mg significantly improved symptoms of itchy nose, eyes, and mouth, and also
significantly reduced the mean total symptom severity score (p ⬍ 0.05) over the treatment
period. Cetirizine 5 mg did not reduce the total severity score any more than placebo did.
Adverse effects did not differ among the three treatment regimens. (From Ref. 33.)
gestion as the primary outcome. In many pediatric studies, a significant difference

from placebo is obtained only with relatively high H 1-antagonist doses, similar
to those recommended for adolescents and adults. Objective measurements such
as nasal cytology and nasal peak inspiratory flows are underutilized in the pediat-
ric studies, as they are in studies in adults (23, 24).
H 1-antagonists are significantly more effective than placebo for relief of
sneezing, pruritus, and rhinorrhea and for improving quality of life in seasonal
and perennial allergic rhinitis (30–42). Old and new H 1-antagonists generally
appear to have similar efficacy; however, one of the new well-studied medications
with a superior safety profile, such as cetirizine, fexofenadine, or loratadine,
should be recommended.
In order to provide increased relief of nasal blockage, H 1-antagonists are
sold in fixed-dose combinations with the α-adrenergic agonist (decongestant)
pseudoephedrine (43), which itself has been infrequently studied in children (44,
45). Some effective, safe, second-generation H 1-antagonist/decongestant liquid
formulations are now available (45) (Fig. 3). Prospective, randomized, double-
Use in Children 445
Figure 3 In a randomized, double-blind, crossover study, loratadine and pseudoephed-

rine (0.2 mg/kg/2.4 mg/kg), or placebo, were given for 14 days to 40 children age 3–15
years with seasonal allergic rhinitis. When nasal symptoms (sneezing, itching, congestion,
and dripping) and signs (turbinate swelling, postnasal drainage) were scored together
(mean total symptom score), loratadine and pseudoephedrine were significantly more ef-
fective than placebo. For symptoms only, both loratadine/pseudoephedrine and placebo
treatments were better than baseline. (From Ref. 45.)
blind, comparative studies of H 1-antagonists vs. intranasal glucocorticoids are

needed in children.
B. Upper Respiratory Tract Infections

Loratadine downregulates the expression of ICAM-1 on epithelial cells. It has
been investigated for its ability to prevent upper respiratory tract infections in
very young children in the Preventia Study, a randomized, double-blind, placebo-
controlled, parallel-group study in 400 at-risk children age 20–30 months at entry
(46).
H 1-antagonists are ubiquitously used for symptom relief in viral upper re-
spiratory tract infections, although the scientific rationale for this practice is not
strong (47–49). Histamine concentrations are not increased in nasal secretions
in subjects with symptomatic rhinovirus-induced ‘‘colds,’’ in contrast to the in-
creased levels of kinins, N-α-p-tosyl-l-arginine methyl ester (TAME)-esterase
activity, and albumin which are found. In most studies of H 1-antagonists in chil-
446 Simons
dren with ‘‘colds’’, an H 1-antagonist with or without a decongestant resulted in

the same rate of improvement as found after placebo treatment or after no treat-
ment at all. In adults with experimentally-induced rhinovirus infections, however,
administration of the old H 1-antagonists brompheniramine or clemastine has been
found to reduce the severity and duration of the ‘‘cold’’ symptoms produced (50,
51).
C. Otitis Media
Histamine concentrations are elevated in the middle ear effusions in otitis media
(52, 53). The eustachian tube response to intranasal histamine and other chemical
mediators of inflammation is increased in subjects with allergic rhinitis compared
to healthy subjects. Allergic inflammation may be a contributing factor in the
development of otitis media with effusion.
Acute otitis media and otitis media with effusion have high spontaneous
remission rates. H 1-antagonists, often in combination with an α-adrenergic ago-
nist decongestant, are frequently prescribed for infants and young children with
otitis media; however, placebo-controlled, double-blind studies incorporating re-
peated objective assessment of tympanic membrane compliance do not support
beneficial effects of H 1-antagonists on eustachian tube function in these disorders
(54).
Additional insight into the relationship between allergic inflammation and
otitis media may eventually be obtained from clinical trials of H 1-antagonists in
the prevention or treatment of otitis media in atopic children.
D. Asthma
Histamine is one of many chemical mediators of inflammation contributing to
the pathophysiology of asthma. The early and late bronchoconstrictor responses
produced by inhalation of allergen are associated with increased plasma concen-
trations of histamine. Increased circulating histamine has also been reported dur-
ing naturally occurring acute asthma episodes. Relatively high doses of H 1-antag-
onists seem to be required for H 1-blockade in the lower airways, in comparison
to those required for H 1-blockade in the nasal mucosa or skin (55–58). In addition
to production of H 1-blockade, the antiallergic and anti-inflammatory effects of
cetirizine, fexofenadine, ketotifen, loratadine, and other H 1-antagonists may be
relevant in asthma. These effects include prevention of mediator release from
mast cells and decreased retention and activation of inflammatory cells in the
airways (59, 60).
H 1-antagonists such as cetirizine, loratadine, and ketotifen have been found
to prevent histamine- and exercise-induced asthma, and to relieve allergic cough
and other mild persistent asthma symptoms in children (59, 60). Previous con-
cerns about their adverse effects in asthma, including specific concerns about
Use in Children 447
potential drying of the secretions and bronchoconstriction, have not been substan-
tiated.
Allergic rhinitis and asthma are linked epidemiologically. They are also
linked histologically by the respiratory epithelium lining the upper and lower
airways, physiologically by the nasobronchial reflex, and pathologically by simi-
lar early- and late-phase allergic responses throughout the airways and by the
systemic immunological response to airborne allergens (61). In adults, H 1-antago-
nists in doses ordinarily used for seasonal allergic rhinitis have been reported to
improve coexisting mild seasonal asthma symptoms and to improve pulmonary
function (62).
As a potential strategy in combatting the global epidemic of asthma, there
is currently considerable interest in preventing or delaying the onset of asthma
in high-risk children by using H 1-antagonists. Ketotifen, widely used as an oral
antiasthmatic medication in some countries, was reported to prevent or delay
asthma development in infants who, at study onset, were asthma-free but had
atopic dermatitis and elevated total serum IgE concentrations (63, 64).
In the Early Treatment of the Atopic Child (ETAC) study, cetirizine 0.25
mg/kg twice daily (total daily dose, 5–11 mg) prevented asthma development
in children sensitized to house dust mite or grass pollen at study entry (65)
(Fig. 4). This randomized, double-blind, placebo-controlled, parallel-group, 18-
month study was conducted in 800 children who, at enrollment, were age 12–
24 months and asthma-free, but had atopic dermatitis and a family history of
atopic disease. After treatment with cetirizine was discontinued, its ability to
prevent asthma was still evident during 18 months of double-blind follow-up
evaluation.
In the Preventia Study described previously, loratadine 2.5 or 5 mg reduced
the average number of wheezing episodes significantly, from 1.2 per child to 0.8
per child during 12 months of treatment (46).
E. Urticaria, Mastocytosis, and Anaphylaxis

H 1-antagonists are the most important medications available for relief of urticaria.
Histamine, acting through its H 1-receptor, can mediate all the pathological fea-
tures of urticaria: vasodilation, increased vascular permeability, whealing, flaring,
and sensory nerve stimulation leading to pruritus (66). When urticarial lesions
are induced by heat, cold, or cholinergic stimuli, plasma histamine levels are
transiently elevated in the veins draining the urticated area. In clinical trials in
adults with urticaria, H 1-antagonists have proven to be significantly more effec-
tive than placebo in relieving itching and in reducing the number, size, and dura-
tion of urticarial lesions (66).
In children, acute urticaria associated with viral infections or food ingestion
or contact is more common than chronic urticaria (67). Until recently, no satisfac-
tory prospective, randomized, controlled, double-blind studies of H 1-antagonists
448 Simons
Figure 4 In the randomized, double-blind, parallel-group, 18-month-long ETAC

study, 817 children with atopic dermatitis aged 12–24 months at entry were randomized
to receive cetirizine 0.25 mg/kg (5–11 mg total daily dose) or placebo twice daily. Pla-
cebo-treated children had a relative risk (rr) of developing asthma of 1.4–1.7. Cetirizine
significantly reduced the relative risk for children sensitized to grass pollen (rr ⫽ 0.5) or
to house dust mite (rr ⫽ 0.6) by the end of the 18 months of active treatment. The reduction
persisted during 18 months of follow-up (not shown; rr ⫽ 0.7 for grass pollen, and rr ⫽
0.8 for house dust mite). (From Ref. 65.)
have been performed in pediatric patients with urticaria. One of the most interest-
ing and important outcomes of the ETAC study was that acute urticarial epi-
sodes were significantly reduced in the infants and toddlers treated with cetirizine
5–11 mg/day, compared to those receiving placebo (68) (Fig. 5). The protective
effect occurred only during the 18-month active treatment period, and disap-
peared during double-blind follow-up after the cetirizine was discontinued.
In most children with pediatric mastocytosis syndrome, plasma histamine
concentrations are elevated. H 1-antagonists are effective in the treatment of this
disorder (69,70).
In anaphylaxis (71), H 1-antagonists are a helpful adjunctive treatment for
controlling pruritus and urticaria (Table 3A), however, they are not a substitute
for epinephrine injected intramuscularly, and reliance on H 1-antagonists alone
may contribute to a fatal outcome.
Use in Children 449
Figure 5 In the ETAC study, the children treated with cetirizine 5–11 mg daily had
fewer episodes of urticaria than those treated with placebo (p ⬍ 0.001). The protection
provided by cetirizine occurred throughout the 18-month double-blind treatment period,
but did not persist after the medication was discontinued. (From Ref. 68.)
F. Atopic Dermatitis
Children with atopic dermatitis have increased numbers of mast cells in the papil-
lary and reticular dermis of affected areas of skin. A report that H 1-antagonist
treatment reduces the number of these cells (72) remains to be confirmed. Hista-
mine is an important pruritogen in atopic dermatitis and H 1-antagonists are often
given to infants and children with this disorder, primarily to decrease itching and
scratching (73–75). Some physicians are convinced that there is a role for first-
generation H 1-antagonists such as hydroxyzine in the treatment of severe atopic
dermatitis, when the itching is so intense that the nocturnal sleep of the infant
or child (and of the parents!) is disturbed. The sedation produced by the old H 1-
antagonist is perceived as being a beneficial effect rather than an adverse effect
in this situation (Table 3A).
A recent meta-analysis of the efficacy of H 1-antagonists in atopic dermatitis
did not provide strong support for their use in this disorder (76); however, no
large, randomized, double-blind, placebo-controlled clinical trial was available
for inclusion in the analysis. In the subsequently published 18-month ETAC
study, the young children with the most severe atopic dermatitis (SCORAD index
ⱖ 25 on a scale of 0–50) at enrollment who were treated with cetirizine were
reported to have significantly reduced requirements for application of high-po-
tency (class II, III, and IV) topical glucocorticoids to the skin (77).
G. Other Disorders
H 1-antagonists have been reported to be effective in a variety of other disorders
in children, including itching during varicella (78), mosquito bite reactions (79),
450 Simons
eosinophilic cellulitis (80), and ulcerative colitis (81). They are used as antiemet-
ics and sedatives (82–84) and in the treatment of cluster headache (85). They are
also given as an adjunctive treatment to chloroquine in uncomplicated falciparum
malaria (86).
When an H 1-antagonist is recommended for an off-label (nonapproved)
use, the evidence base for such use should be examined critically, since the rec-
ommendation may not be substantiated in a prospective, randomized, double-
blind, placebo-controlled clinical trial (87).
IV. SAFETY ISSUES

A. Adverse Effects of First-Generation
H 1-Antihistamines
First-generation H 1-antagonists are still advertised widely to physicians and to
parents for use in infants and young children. Although most health care profes-
sionals and parents assume that the safety of these medications has been tested
in prospective, randomized, placebo-controlled, double-blind trials in infants and
children, this is not so, because the agents were introduced before government
regulatory agencies required such investigations. The true incidence of adverse
effects following manufacturers’ recommended doses of first-generation H 1-an-
tagonists in the pediatric population is unknown. Adverse effects may occur after
ingestion of ordinary doses (88–102), as well as after overdose (103–107). Un-
derreporting probably occurs, because somnolence and other signs and symptoms
of toxicity may be attributed to the illness for which the H 1-antagonist is being
given.
First-generation H 1-antagonists cross the blood–brain barrier. Diphenhy-
dramine, promethazine, and hydroxyzine, formerly used to induce sleep for elec-
troencephalograms in children, are still recommended by some physicians for
sedation, pain relief, and emesis prophylaxis in infants and children undergoing
surgical procedures, although the safety of this practice is doubtful (82–84).
Old H 1-antagonists cause objective impairment of cognitive functioning
and school performance in children, even when administered in usual doses (22,
88–93) (Figs. 6, 7). In infants and young children, they may also have paradoxical
stimulatory effects on the central nervous system (CNS) and cause irritability,
nervousness, hyperactivity, and seizures (94, 95). Adolescents may intentionally
abuse H 1-antagonists in search of a ‘‘high.’’
In addition to adverse CNS effects, H 1-antagonists may produce blurred
vision, dry mouth, and other anticholinergic effects (1,2,96–100). Some of them
cause adverse gastrointestinal effects. The H 1-antagonist cyproheptadine is also
a 5-hydroxytryptamine (serotonin) antagonist and may cause appetite stimulation
and weight gain. Trimeprazine or methdilazine may cause jaundice. Diphenhy-
Use in Children 451
Figure 6 Fifteen children (8.9 ⫾ SD 1.3 yrs) with allergic rhinitis were tested before
and 2–2.5 hours after administration of diphenhydramine 37.5 mg or hydroxyzine 10 mg,
or placebo, in a randomized, double-blind, single-dose, three-way crossover study. Impair-
ment of cognitive processing was assessed objectively by using the latency of the P300
event-related potential (P300). Somnolence was assessed subjectively using a visual ana-
log scale (shown). Peripheral H 1-blockade was assessed by suppression of the histamine-
induced wheals and flares (not shown). At the central (Cz) and frontal (Fz) electrodes,
diphenhydramine and hydroxyzine increased the P300 latency ( p ⬍ 0.05) compared to
baseline. Both H 1-antihistamines increased subjective somnolence and decreased the
wheals and flares (not shown). (From Ref. 90.)
dramine, dimenhydrinate, and hydroxyzine may cause fixed-drug eruptions (101).

Rarely, cytopenias occur.
First-generation H 1-antagonists such as promethazine have been associated
with apnea and sudden death in infants, although no cause and effect relationship
has been established (102).
In infants and children with severe atopic dermatitis, varicella, or other
disorders in which there is epidermal breakdown due to scratching, toxic encepha-
lopathy may occur after topical application of first-generation H 1-antagonists such
as diphenhydramine or promethazine (103).
B. Overdose: First-Generation H 1-Antihistamines

More than 14,000 accidental exposures to first-generation H 1-antagonists occur
annually in children under the age of 6 years in the United States. Case reports
452 Simons
Figure 7 Seasonal allergic rhinitis adversely affected learning in children age 10–12
years who were given computer-assisted instruction in the form of a didactic simulation.
Factual knowledge, conceptual knowledge, and knowledge application were tested. Aller-
gic children treated with diphenhydramine retained significantly less factual knowledge
than healthy controls did ( p ⫽ 0.012). The adverse effect of the allergic rhinitis on learning
was partially ameliorated by loratadine 10 mg, but exacerbated by diphenhydramine 25
mg. (From Ref. 22.)
of severe toxic reactions and fatalities following overdose of these old medica-
tions in infants and children continue to appear in the medical literature (104–
107). Most overdoses are accidental, but suicide attempts and deliberate poison-
ing of very young children using these agents have also been reported (106). All
old H 1-antagonists, including cyproheptadine, diphenhydramine, dimenhydrinate,
doxylamine, hydroxyzine, pheniramines, promethazine, and tripelennamine, are
potentially lethal after overdose. Infants and young children do not necessarily
manifest lethargy, drowsiness, or coma, but may develop excitation, irritability,
hyperactivity, visual hallucinations, and seizures, as well as anticholinergic ef-
fects such as dryness of the mucous membranes, fever, flushed facies, pupillary
dilation, urinary retention, and decreased gastrointestinal motility. Hypotension
secondary to α-adrenergic blockade and sinus tachycardia secondary to the anti-
cholinergic effects of the first-generation medications have been reported.
Treatment of infants and children who have had an overdose of a first-
generation H 1-antagonist should include supportive measures such as use of anti-
convulsants or hemodialysis, if indicated. Centrally-acting emetics such as ipecac
are no longer recommended in poisonings and, in any case, are likely to be inef-
Use in Children 453
fective in infants or children who have received an overdose of H 1-antagonists

such as diphenhydramine, dimenhydrinate, or promethazine, which have an anti-
emetic effect. Unless activated charcoal is administered within 30 min after the
overdose, it is useless in preventing H 1-antagonist absorption. There are no spe-
cific antidotes for H 1-antagonist poisoning.
C. Second-Generation H 1-Antihistamines: Lack of Adverse

Effects
The second-generation H 1-antagonists appear to be relatively free from adverse
CNS effects in children, as is evident from subjective information collected in
thousands of children in allergic rhinoconjunctivitis studies lasting up to 4 weeks
(30–42), and in the long-term ETAC (108) and Preventia (46) studies. In objec-
tive studies, lack of adverse CNS effects has been documented using electro-
encephalographic (EEG) or psychomotor performance tests (22, 88–93). New
H 1-antagonists such as loratadine have even been reported to improve school
performance in children with symptoms of allergic rhinitis studied during the
pollen season, in contrast to old H 1-antagonists such as diphenhydramine which
exacerbate the performance impairment produced by the allergic rhinitis itself
(22). Long-term cetirizine treatment does not affect the achievement of develop-
mental milestones, or behavior assessed using the Behavioural Screening Ques-
tionnaire, or psychomotor ability assessed using the McCarthy Scales of Chil-
dren’s Ability (109). Also, cetirizine does not increase the frequency of apnea
episodes in infants (110).
D. Second-Generation H 1-Antihistamines: Potential

Cardiac Toxicity
Astemizole and terfenadine, which are no longer available in most countries,
provide important lessons about the potential cardiac toxicity of H 1-antagonists.
The children and adolescents who developed torsade de pointes and other cardiac
dysrhythmias after ingestion of these medications presented with symptoms such
as syncope at rest or with exercise, loss of consciousness, or palpitations (111–
114). Patients with hepatic dysfunction or pre-existing cardiac problems such as
long QT syndrome, or those taking any medication that potentially prolongs the
QT interval, (e.g., erythromycin, clarithromycin, ketoconazole, or itraconazole)
were at increased risk for H 1-antagonist-induced cardiac toxicity.
The cardiac toxicity of H 1-antagonists results from blockade of potassium
channels involved in action potential repolarization, in particular from blockade
of the I Kr component of the cardiac repolarizing current (115) (Fig. 8). Blockade
of I Kr channels leads to prolongation of the monophasic action potential (QT
interval on surface electrocardiogram), which may then induce the development
of early after-depolarizations and dispersion of repolarization, leading to torsade
454 Simons
Figure 8 Dose–response relationship for the effects of four second-generation H 1-re-

ceptor antagonists on the human HERG K ⫹ channels expressed in Xenopus oocytes. The
ability of H 1-antagonists to block HERG K ⫹ channels and to prolong the cardiac action
potential duration is heterogeneous; hence the importance of studies in in vitro expression
systems during the early development phases of new H 1-antagonists. In this system, and
in prospective studies in children in which the QTc interval has been monitored, cetirizine,
loratadine, and fexofenadine (not shown) appear to be free from potential cardiotoxicity,
in contrast to astemizole and terfenadine. (From Ref. 115.)
de pointes through re-entry mechanisms. Other potassium channels, I KS , I TO , and

I PED , which are expressed to different degrees in different individuals, may also
be involved.
Before being administered to humans, new H 1-antagonists are now
screened in vitro for cardiotoxic potential, based on their ability to block the
potassium channel encoded by the human ether-a-go-go-related gene (HERG),
which represents the molecular basis of the I Kr channel. The cardiotoxic effects
of H 1-antagonists are not a class effect, since there is no correlation between
HERG blockade/cardiotoxic potential and H 1-antagonist activity. The potential
cardiac toxicity of H 1-antagonists such as cetirizine, fexofenadine, and loratadine
has been thoroughly studied prospectively in hundreds of children with allergic
rhinitis or atopic dermatitis, in whom they do not prolong the QTc interval (116–
119) (Fig. 8, Table 5). There are no reports of arrhythmias after overdose of these
medications in children and adolescents.
Other H 1-antagonists such as acrivastine, azelastine, ebastine, ketotifen, and
levocabastine, and the newest H 1-antagonists desloratadine, levocetirizine, mizo-
Table 5 Cardiac Safety of Selected New H 1-Antihistamines in Children
H 1-receptor No. of No. of Age

Use in Children
antagonist Dose (mg) days treated children (yr) Comparator(s) Results Reference
Cetirizine (C) 5 or 10 od 28 C5, 35 6–11 P 12-lead, Hodge’s 116

C10, 44 correction; no
P, 40 prolongation of
QTc interval
Cetirizine 0.25 mg/kg bid 18 months C, 399 1–3.5 P Bazett’s correction; 108
(2.5–5.5 mg bid) P, 396 no ↑ QTc in-
terval
Fexofenadine (F) 15/30/60 bid 14 F15, 224 6–11 P QTc outliers: 6/6/3 117
F30, 209 (F) vs 7 (P);
F60, 213 mean change
P, 229 from baseline in
any ECG param-
eter ⬇F vs P
Loratadine (L) 5/10 od 14 L5, 95 6–12 P, CH post 嗱 QTc (msec) 118
L10, 232 401/395 vs 402
CH, 243 (P) and 403
P, 332 (CH)
P, placebo; CH, chlorpheniramine; od, once daily; bid, twice daily; Rx, treatment; ECG, electrocardiogram.
455
456 Simons
lastine, and tecastemizole also appear to have a negligible potential for cardiac
toxicity. Desloratadine, levocetirizine, mizolastine, and tecastemizole have not
yet been studied optimally in children.
E. Overdose: Second-Generation H 1-Antihistamines

There are few published reports of overdoses of the second-generation H 1-antag-
onists in infants and children. In the ETAC study, an 18-month-old boy who
ingested 180 mg cetirizine remained asymptomatic with normal findings on an
electrocardiogram (120). Despite this encouraging report, after significant over-
dose of any H 1-antagonist, continuous electrocardiographic monitoring should
be performed for 24 hours, even if symptoms are absent and the electrocardio-
gram is normal at the time of presentation. If indicated, antiarrhythmic treat-
ment should be instituted using cardioversion, pacing, and carefully selected
antiarrhythmic medications. Most of the second-generation H 1-antagonists are
not dialyzable (3).
V. SUMMARY
In children, as in adults, H 1-antagonists are useful in the treatment of allergic

rhinoconjunctivitis. Level 1 evidence for their efficacy in this disorder has been
obtained in many well-designed pediatric studies. The widespread use of H 1-
antagonists in upper respiratory tract infections or otitis media in children is not
supported by a strong scientific rationale. H 1-antagonists are not harmful in chil-
dren with asthma and, indeed, may have some beneficial effects in children with
mild asthma. Their role in delaying or preventing asthma from developing in
high-risk infants and toddlers is currently an important area of clinical investiga-
tion. The evidence base for their use in children with urticaria or atopic dermatitis
still contains large gaps.
First-generation H 1-antagonists are presumed to be safe for use in infants
and children. While they have undoubtedly been administered without apparent
harm to millions in this age group, they impair CNS function far more commonly
than is generally realized. Their use should be restricted to two uncommon situa-
tions: children with urticaria or atopic dermatitis whose pruritus is so severe that
the sedation produced by an old H 1-antagonist, such as hydroxyzine, is a benefit
rather than a risk; and children with anaphylaxis who require intravenous diphen-
hydramine as adjunctive treatment to epinephrine and other modalities. Apart
from these exceptions, in patients of all ages, second-generation H 1-antagonists
free from CNS adverse effects are clearly the medications of choice. Pediatric
formulations of the new H 1-antagonists cetirizine, fexofenadine, and loratadine
are now available for use.
Use in Children 457
REFERENCES
1. Simons FER, Simons KJ. The pharmacology and use of H 1-receptor antagonist
drugs. N Engl J Med 1994; 330:1663–1670.
2. Simons FER. H 1-receptor antagonists in children. In: Simons FER, ed. Histamine
and H 1-Receptor Antagonists in Allergic Disease. New York, N.Y.: Marcel Dekker,
Inc., 1996:329–356.
3. Simons FER, Simons KJ. Clinical pharmacology of new histamine H 1-receptor an-
tagonists. Clin Pharmacokinet 1999; 36:329–352.
4. Simons FER, Roberts JR, Gu X, Kapur S, Simons KJ. The clinical pharmacology
of brompheniramine in children. J Allergy Clin Immunol 1999; 103:223–226.
5. Simons FER, Luciuk GH, Simons KJ. Pharmacokinetics and efficacy of chlorphe-
niramine in children. J Allergy Clin Immunol 1982; 69:376–381.
7. Simons FER, Simons KJ, Becker AB, Haydey RP. Pharmacokinetics and antipru-
ritic effects of hydroxyzine in children with atopic dermatitis. J Pediatr 1984; 104:
123–127.
8. Schmidt-Redemann B, Brenneisen P, Schmidt-Redemann W, Gonda S. The deter-
mination of pharmacokinetic parameters of ketotifen in steady state in young chil-
dren. Int J Clin Pharmacol Ther Toxicol 1986; 24:496–498.
9. Watson WTA, Simons KJ, Chen XY, Simons FER. Cetirizine: a pharmacokinetic
and pharmacodynamic evaluation in children with seasonal allergic rhinitis. J Al-
10. Desager JP, Dab I, Horsmans Y, Harvengt C. A pharmacokinetic evaluation of the
second-generation H 1-receptor antagonist cetirizine in very young children. Clin
11. Spicak V, Dab I, Hulhoven R, Desager J-P, Klanova M, de Longueville M, Har-
vengt C. Pharmacokinetics and pharmacodynamics of cetirizine in infants and tod-
dlers. Clin Pharmacol Ther 1997; 61:325–330.
14. Lin CC, Radwanski E, Affrime MB, Cayen MN. Pharmacokinetics of loratadine
in pediatric subjects. Am J Ther 1995; 2:504–508.
15. Salmun LM, Herron JM, Banfield C, Padhi D, Lorber R, Affrime MB. The pharma-
cokinetics, electrocardiographic effects, and tolerability of loratadine syrup in chil-
dren aged 2 to 5 years. Clin Ther 2000; 22:613–621.
16. Okonkwo CA, Coker HAB, Agomo PU, Ogunbanwo JA, Mafe AG, Agomo CO,
Afolabi BM. Effect of chlorpheniramine on the pharmacokinetics of and response
to chloroquine of Nigerian children with falciparum malaria. Transactions of the
Royal Society of Tropical Medicine and Hygiene 1999; 93:306–311.
17. Simons FER, Johnston L, Simons KJ. Clinical pharmacology of the H 1-receptor
458 Simons
antagonists cetirizine and loratadine in children. Pediatr Allergy Immunol 2000;

11:116–119.
18. Harth SC, Thong YH. Parental perceptions and attitudes about informed consent
in clinical research involving children. Soc Sci Med 1995; 41:1647–1651.
19. Wright AL, Holberg CJ, Martinez FD, Halonen M, Morgan W, Taussig LM. Epide-
miology of physician-diagnosed allergic rhinitis in childhood. Pediatrics 1994; 94:
895–901.
20. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering
Committee. Worldwide variation in prevalence of symptoms of asthma, allergic
rhinoconjunctivitis, and atopic eczema: ISAAC. Lancet 1998; 351:1225–1232.
21. Juniper EF, Howland WC, Roberts NB, Thompson AK, King DR. Measuring qual-
ity of life in children with rhinoconjunctivitis. J Allergy Clin Immunol 1998; 101:
163–170.
22. Vuurman EFPM, van Veggel LMA, Uiterwijk MMC, Leutner D, O’Hanlon JF.
Seasonal allergic rhinitis and antihistamine effects on children’s learning. Ann Al-
lergy 1993; 71:121–126.
23. Meltzer EO, Orgel HA, Jalowayski AA. Histamine levels and nasal cytology in
children with chronic otitis media and rhinitis. Ann Allergy Asthma Immunol 1995;
74:406–410.
24. Watson WTA, Roberts JR, Becker AB, Gendreau-Reid LF, Simons FER. Nasal
patency in children with allergic rhinitis: correlation of objective and subjective
assessments. Ann Allergy Asthma Immunol 1995; 74:237–240.
25. Kalayci O, Saraclar Y, Adalioglu G, Sekerel B, Tuncer A. The effect of cetirizine on
sulfidoleukotriene production by blood leukocytes in children with allergic rhinitis.
Allergy 1995; 50:964–969.
26. Lanz MJ, Liu AH, Buchmeier AD, Nelson HS. Nasal nitric oxide decreases in
children with grass pollen allergy with oral cetirizine syrup. J Allergy Clin Immunol
1998; 101:S244.
Immunol 1996; 109:272–276.
28. Ciprandi G, Tosca M, Ricca A, Passalacqua G, Riccio AM, Bagnasco M, Canonica
29. Tosca M, Ciprandi G, Passalacqua G, Canonica GW. Cetirizine reduces conjuncti-
val nonspecific hyperreactivity in children with mite allergy. Invest Allergol Clin
Immunol 1998; 8:23–26.
30. Baelde Y, Dupont P. Cetirizine in children with chronic allergic rhinitis. A multi-
centre double-blind study of two doses of cetirizine and placebo. Drug Invest 1992;
4:466–472.
31. Masi M, Candiani R, van de Venne H. A placebo-controlled trial of cetirizine in
seasonal allergic rhino-conjunctivitis in children aged 6 to 12 years. Pediatr Allergy
Immunol 1993; 4:47–52.
32. Allegra L, Paupe J, Wieseman HG, Baelde Y. Cetirizine for seasonal allergic rhini-
Use in Children 459
tis in children aged 2–6 years. A double-blind comparison with placebo. Pediatr
Allergy Immunol 1993; 4:157–161.
33. Pearlman DS, Lumry WR, Winder JA, Noonan MJ. Once-daily cetirizine effective
in the treatment of seasonal allergic rhinitis in children aged 6 to 11 years: a ran-
domized, double-blind, placebo-controlled study. Clin Pediatr 1997; 36:209–215.
34. Storms WW, Garcia JD, Tobey RE, et al. Once-a-day ebastine is effective therapy
for seasonal allergic rhinitis in children. J Allergy Clin Immunol 1993; 91:197.
35. Ostrom N, Welch M, Morris R, Rosen J, Wanderer A, Dockhorn R, Tinkelman D,
Vandewalker M, Ziering W. Evaluation of ebastine, a new non-sedating antihista-
mine, in children with seasonal allergic rhinitis. J Allergy Clin Immunol 1994; 93:
163.
36. Falconieri P, Monteleone AM, Mancuso T, Arcese G, Businco L. Double-blind
placebo-controlled study with levocabastine eye drops in children with allergic con-
junctivitis. J Allergy Clin Immunol 1994; 93:272.
37. Watson WTA, Roberts JR, Knight A, Becker AB, Gendreau-Reid LF, Drouin MA,
Yang WA, Simons FER. Levocabastine-D nasal spray in the management of pediat-
ric patients with seasonal allergic rhinitis. J Allergy Clin Immunol 1994; 93:296.
38. Herman D, Garay R, Le Gal M. A randomized double-blind placebo-controlled
39. Sabbah A, Marzetto M. Azelastine eye drops in the treatment of seasonal allergic
conjunctivitis or rhinoconjunctivitis in young children. Curr Med Res Opin 1998;
14:161–170.
40. Lassig W, Wober W, Höflich C, Bähre M, Roloff A. Topical therapy of allergic
rhinitis in childhood: Allergodil nasal spray—non-sedating in children. Curr Med
Res Opin 1996; 13:391–395.
41. Tinkelman DG, Kemp J, Mitchell DQ, Galant SP. Treatment of seasonal allergic
rhinitis in children with cetirizine or chlorpheniramine: a multicenter study. Pediatr
Asthma Allergy Immunol 1996; 10:9–17.
42. Sienra-Monge JJL, Gazca-Aguilar A, Del Rio-Navarro B. Double-blind compari-
son of cetirizine and loratadine in children ages 2 to 6 years with perennial allergic
rhinitis. Am J Therapeutics 1999; 6:149–155.
43. Möller C, Mygind N. Nasal blockage in children with non-infectious rhinitis: conse-
quences and treatment. Allergy 1997; 52(Suppl. 40):45–51.
44. Simons FER, Gu X, Watson WTA, Simons KJ. Pharmacokinetics of the orally
administered decongestants pseudoephedrine and phenylpropanolamine in children.
J Pediatr 1996; 129:729–734.
45. Serra HA, Alves O, Rizzo LF, Devoto FM, Ascierto H. Loratadine-pseudoephed-
rine in children with allergic rhinitis, a controlled double-blind trial. Br J Clin Phar-
macol 1998; 45:147–150.
46. Grimfeld A, Holgate ST, Adam D, Bonini S, Borres M, Canonica GW, Gonzalez
CC, Lobaton PM, Patel P, Szczeklik A, Danzig M, Harris A, Czarlewski W. Pre-
ventia study phase I results: loratadine treatment reduces wheezing episodes in chil-
dren at risk for recurrent upper respiratory infections. Allergy 2000; 55(Suppl. 63):
242.
460 Simons
47. Hutton N, Wilson MH, Mellits ED, Baumgardner R, Wissow LS, Bonuccelli C,
Holtzman NA, DeAngelis C. Effectiveness of an antihistamine-decongestant com-
bination for young children with the common cold: A randomized, controlled clini-
cal trial. J Pediatr 1991; 118:125–130.
48. Smith MBH, Feldman W. Over-the-counter cold medications. A critical review of
clinical trials between 1950 and 1991. JAMA 1993; 269:2258–2263.
49. Mossad SB. Treatment of the common cold. Br Med J 1998; 317:33–36.
50. Gwaltney JM Jr, Druce HM. Efficacy of brompheniramine maleate for the treatment
of rhinovirus colds. CID 1997; 25:1188–1194.
51. Gwaltney JM Jr, Park J, Paul RA, Edelman DA, O’Connor RR, Turner RB. Ran-
domized controlled trial of clemastine fumarate for treatment of experimental rhino-
virus colds. CID 1996; 22:656–662.
52. Skoner DP. Control of allergic rhinitis with antihistamines may prevent the onset
or recurrence of otitis media. Pediatr Asthma Allergy Immunol 1997; 11:193–205.
53. Chonmaitree T, Patel JA, Lett-Brown MA, Uchida T, Garofalo R, Owen MJ, Howie
VM. Virus and bacteria enhance histamine production in middle ear fluids of chil-
dren with acute otitis media. J Infect Dis 1994; 169:1265–1270.
54. The Otitis Media Guideline Panel. Managing otitis media with effusion in young
children. Pediatrics 1994; 94:766–773.
55. Simons FER. Is antihistamine (H 1-receptor antagonist) therapy useful in clinical
asthma? Clin Exp Allergy 1999; 29(Suppl. 3):98–104.
56. Kjellman N-IM. Is there a place for antihistamines in the treatment of perennial
asthma? Pediatr Allergy Immunol 1993; 4:38–43.
57. Menardo JL, Clavel R, Couturier P, Peiffer G, Robert J, Wessel F, Cougnard J,
Czarlewski W. Evaluation of prophylactic treatment with loratadine (L) vs sodium
cromoglycate (SC) in allergic children with mild to moderate bronchial asthma.
Allergy 1993; 48:31.
58. Rosario NA, Kantor O Jr. Acute bronchodilator effect of loratadine in asthmatic
children. Allergy 1993; 48:36.
60. Ciprandi G, Tosca M, Ricca V, Passalacqua G, Fregonese L, Fasce L, Canonica
GW. Cetirizine treatment of allergic cough in children with pollen allergy. Allergy
1997; 52:752–754.
61. Simons FER. Allergic rhinobronchitis. The asthma/allergic rhinitis link. J Allergy
Clin Immunol 1999; 104:534–540.
62. Corren J, Harris AG, Aaronson D, Beaucher W, Berkowitz R, Bronsky E, Chen
R, Chervinsky P, Cohen R, Fourre J, Grossman J, Meltzer E, Pedinoff A, Stricker
W, Wanderer A. Efficacy and safety of loratadine plus pseudoephedrine in patients
with seasonal allergic rhinitis and mild asthma. J Allergy Clin Immunol 1997; 100:
781–788.
63. Iikura Y, Naspitz CK, Mikawa H, Talaricoficho S, Baba M, Sole D, Nishima S.
Prevention of asthma by ketotifen in infants with atopic dermatitis. Ann Allergy
1992; 68:233–236.
64. Bustos GJ, Bustos D, Bustos GJ, Romero O. Prevention of asthma with ketotifen
Use in Children 461
in preasthmatic children: a three-year follow-up study. Clin Exp Allergy 1995; 25:
568–573.
65. Wahn U, for the ETAC Study Group. Allergic factors associated with the devel-
opment of asthma and the influence of cetirizine in a double-blind, randomised,
placebo-controlled trial: first results of ETAC. Pediatr Allergy Immunol 1998;
9:116–124.
66. Greaves MW. Chronic urticaria in childhood. Allergy 2000; 55:309–320.
67. Mortureux P, Léauté-Labrèze C, Legrain-Lifermann V, Lamireau T, Sarlangue J,
Taı̈eb A. Acute urticaria in infancy and early childhood. Arch Dermatol 1998; 134:
319–323.
68. Simons FER, on behalf of the ETAC Study Group. Prevention of acute urticaria
in young children with atopic dermatitis. J Allergy Clin Immunol 2001; 107:703–
706.
69. Kettelhut BV, Metcalfe DD. Pediatric mastocytosis. J Invest Dermatol 1991; 96:
15S–18S.
70. Friedman BS, Santiago ML, Berkebile C, Metcalfe DD. Comparison of azelastine
and chlorpheniramine in the treatment of mastocytosis. J Allergy Clin Immunol
1993; 92:520–526.
71. Ditto AM, Krasnick J, Greenberger PA, Kelly KJ, McGrath K, Patterson R. Pediat-
ric idiopathic anaphylaxis: experience with 22 patients. J Allergy Clin Immunol
1997; 100:320–326.
72. Junior GG, de Luca IMS, Leonardo MB, Vilela MMS. Mast cell quantification in
the skin of children with atopic dermatitis: its value in diagnosis and in assessing
the effectiveness of therapy. Allergol Immunopathol (Madr) 1995; 23:160–163.
73. Leung DY. Atopic dermatitis: new insights and opportunities for therapeutic inter-
vention. J Allergy Clin Immunol 2000; 105:860–876.
74. Lutsky BN, Schuller JL, Cerio R, deLourdes Chieira M, Giannetti A, Goncalves
HM, deGroot LJ, Vareltzides A, Guillot B, Lynde CW, Marcoux D, Saxonis-Papa-
georgiou P, Garvin P. Comparative study of the efficacy and safety of loratadine
syrup and terfenadine suspension in the treatment of chronic allergic skin diseases
in a pediatric population. Arzneim-Forsch/Drug Res 1993; 43:1196–1199.
75. La Rosa M, Ranno C, Musarra I, Guglielmo F, Corrias A, Bellanti JA. Double-
blind study of cetirizine in atopic eczema in children. Ann Allergy 1994; 73:117–
122.
76. Klein PA, Clark RAF. An evidence-based review of the efficacy of antihistamines
in relieving pruritus in atopic dermatitis. Arch Dermatol 1999; 135:1522–1525.
77. Diepgen TL, on behalf of the ETAC Study Group. Long term treatment with
cetirizine of infants with atopic dermatitis: a multi-country, double-blind, random-
ized, placebo-controlled trial (the ETAC trial) over 18 months. Pediatr Allergy
Immunol 2002; 13 (in press).
78. English W, Bauer C-P. Dimethindene maleate in the treatment of pruritus caused
by varicella zoster virus infection in children. Arzneim-Forsch/Drug Res 1997; 47:
1233–1235.
79. Karppinen A, Kautiainen H, Reunala T, Petman L, Reunala T, Brummer-Korven-
kontio H. Loratadine in the treatment of mosquito-bite sensitive children. Allergy
2000; 55:668–671.
462 Simons
80. Aroni K, Aivaliotis M, Liossi A, Davaris P. Eosinophilic cellulitis in a child suc-

cessfully treated with cetirizine. Acta Derm Venereol (Stockh) 1999; 79:332.
81. Jones NL, Roifman CM, Griffiths AM, Sherman P. Ketotifen therapy for acute
ulcerative colitis in children. A pilot study. Digestive Diseases and Sciences 1998;
43:609–615.
82. Köseoglu V, Kürekci AE, Sorici U, Atay AA, Ozcan O. Comparison of the efficacy
and side-effects of ondansetron and metoclopramide-diphenhydramine adminis-
tered to control nausea and vomiting in children treated with antineoplastic chemo-
therapy: a prospective randomized study. Eur J Pediatr 1998; 157:806–810.
83. Ragg P, Davidson A. Comparison of the efficacy of paracetamol versus paraceta-
mol, codeine and promethazine (Painstop) for premedication and analgesia for myr-
ingotomy in children. Anaesth Intens Care 1997; 25:29–32.
84. Downs AT, Dembo J, Ferretti G, Lyons TD, Pelphery A. A comparative study of
midazolam to meperidine/promethazine as an IM sedative technique for the pediat-
ric dental patient. J Dent Child 1997; 64:197–200.
85. Neubauer D, Kuhar M, Ravnik IM. Antihistamine responsive cluster headache in
a teenaged girl. Headache 1997; 37:296–298.
86. Sowunmi A, Oduola AMJ, Ogundahunsi OAT, Falade CO, Gbotosho GO, Salako
LA. Enhanced efficacy of chloroquine-chlorpheniramine combination in acute un-
complicated falciparum malaria in children. Trans R Soc Tropical Med Hyg 1997;
91:63–67.
87. Fan HW, Marcopito LF, Cardoso JLC, Franca FOS, Malaque CMS, Ferrari RA,
Theakston RDG, Warrell DA. Sequential randomised and double-blind trial of pro-
methazine prophylaxis against early anaphylactic reactions to antivenom for
bothrops snake bites. Br Med J 1999; 318:1451–1452.
88. Simons FER. Non-cardiac adverse effects of antihistamines (H 1-receptor antago-
nists). Clin Exp Allergy 1999; 29(Suppl. 3):125–132.
29(Suppl. 3):133–142.
90. Simons FER, Fraser TG, Reggin JD, Roberts JR, Simons KJ. Adverse central ner-
vous system effects of older antihistamines in children. Pediatr Allergy Immunol
1996; 7:22–27.
91. Feldman W, Shanon A, Leiken L, Ham-pong A, Peterson R. Central nervous system
side-effects of antihistamines in schoolchildren. Rhinology 1992; 13:13–19.
92. Simons FER, Reggin JD, Roberts JR, Simons KJ. Benefit/risk ratio of the antihista-
mines (H 1-receptor antagonists) terfenadine and chlorpheniramine in children. J
Pediatr 1994; 124:979–983.
93. Simons FER. Learning impairment and allergic rhinitis. Allergy and Asthma Proc
1996; 17:185–189.
94. Yasuhara A, Ochi A, Harada Y, Kobayashi Y. Infantile spasms associated with a
histamine H 1-antagonist. Neuropediatrics 1998; 29:320–321.
95. Yokoyama H, Iinuma K, Yanai K, Watanabe T, Sakurai E, Onodera K. Proconvul-
sant effect of ketotifen, a histamine H 1-antagonist, confirmed by the use of d-chlor-
pheniramine with monitoring electroencephalography. Meth Find Exp Clin Phar-
macol 1993; 15:183–188.
Use in Children 463
96. Rusakow LS, Splaingard ML. What’s CIPRO? Pediatrics 1998; 101:1096.
97. Strayhorn JM Jr. Case Study: Cyproheptadine and aggression in a five-year-old
boy. J Am Acad Child Adolesc Psychiatry 1998; 37:668–670.
98. Lindsay CA, Williams GD, Levin DL. Fatal adult respiratory distress syndrome
after diphenhydramine toxicity in a child: A case report. Crit Care Med 1995; 23:
777–781.
99. Dinndorf PA, McCabe MA, Frierdich S. Risk of abuse of diphenhydramine in chil-
dren and adolescents with chronic illnesses. J Pediatr 1998; 133:293–295.
100. Watemberg NA, Roth KS, Alehan FK, Epstein CE. Central anticholinergic syn-
drome on therapeutic doses of cyproheptadine. Pediatrics 1999; 103:158–160.
101. Cohen HA, Barzilai A, Matalon A, Harel L, Gross S. Fixed drug eruption of
the penis due to hydroxyzine hydrochloride. Ann Pharmacother 1997; 31:327–
329.
102. Hickson GB, Altemeier WA, Clayton EW. Should promethazine in liquid form be
available without prescription? Pediatrics 1990; 86:221–225.
103. Reilly JF Jr, Weisse ME. Topically induced diphenhydramine toxicity. J Emerg
Med 1990; 8:59–61.
104. Jumbelic MI, Hanzlick R, Cohle S. Alkylamine antihistamine toxicity and review
of pediatric toxicology registry of the National Association of Medical Examiners.
Am J Forensic Med Pathol 1997; 18:65–69.
105. Garza MB, Osterhoudt KC, Rutstein R. Central anticholinergic syndrome from or-
phenadrine in a 3-year-old. Ped Emerg Care 2000; 16:97–98.
106. Goetz CM, Lopez G, Dean BS, Krenzelok EP. Accidental childhood death from
diphenhydramine overdosage. Am J Emerg Med 1990; 8:321–322.
107. Le Blaye I, Donatini B, Hall M, Krupp P. Acute ketotifen overdosage. A review
of present clinical experience. Drug Saf 1992; 7:387–392.
108. Simons FER, on behalf of the ETAC Study Group. Prospective, long-term safety
evaluation of the H 1-receptor antagonist cetirizine in very young children with
atopic dermatitis. J Allergy Clin Immunol 1999; 104:433–440.
109. Stevenson J on behalf of the ETAC Study Group. Long-term evaluation of the
impact of the H 1-receptor antagonist cetirizine on the behaviour, cognitive and psy-
chomotor development of very young children with atopic dermatitis. Pediatr Res
2002; 51 (in press).
110. Groswasser J, Brusquet Y, Cornus A, Saké J-K, de Longueville M, Kahn A. Effects
of cetirizine in night polygraphic recording in infants. Pediatr Allergy Immunol
1995; 6(Suppl 8):96.
111. Tobin JR, Doyle TP, Ackerman AD, Brenner JI. Astemizole-induced cardiac con-
duction disturbances in a child. JAMA 1991; 266:2737–2740.
112. Hoppu K, Tikanoja T, Tapanainen P, Remes M, Saarenpää-Heikkilä O, Kouva-
lainen K. Accidental astemizole overdose in young children. Lancet 1991; 338:
538–540.
113. Wiley II JF, Gelber ML, Henretig FM, Wiley CC, Sandhu S, Loiselle J. Cardiotoxic
effects of astemizole overdose in children. J Pediatr 1992; 120:799–802.
induced torsade de pointes. Lancet 1988; 2:624.
464 Simons

cardiotoxicity. Clin Exp Allergy 1999; 29(Suppl. 3):182–189.
116. Winder J, Noonan MJ. A randomized, placebo-controlled study to evaluate the
electrocardiographic effects of cetirizine in children aged 6 to 11. J Allergy Clin
Immunol 1996; 97:342.
117. Graft DF, Bernstein DL, Goldsobel A, Meltzer EO, Portnoy J, Long J. Safety of
fexofenadine in children treated for seasonal allergic rhinitis. Ann Allergy Asthma
Immunol 2001; 87:22–26.
118. Harrison JE, Danzig MR, Lorber RR. The electrocardiographic effects of loratadine
syrup in pediatric patients. J Allergy Clin Immunol 1996; 97:437.
119. Delgado LF, Pferferman A, Solé D, Naspitz CK. Evaluation of the potential cardio-
toxicity of the antihistamines terfenadine, astemizole, loratadine, and cetirizine in
atopic children. Ann Allergy Asthma Immunol 1998; 80:333–337.
120. Ridout SM, Tariq SM. Cetirizine overdose in a young child. J Allergy Clin Immu-
nol 1997; 99:860–861.
15
H 1-Antihistamines in the Elderly
Michael A. Kaliner
Institute for Allergy and Asthma, Wheaton and Chevy Chase, Maryland
I. INTRODUCTION
For many patients 65 years of age or older, polypharmacotherapy regimens are

more the rule than the exception. It is essential for physicians to consider existing
therapeutics and comorbid diseases and to coordinate therapy. Lack of attention
to polypharmacy in elderly patients may lead to serious side effects, including
cardiac arrhythmias, memory loss, lethargy, ambulation instability, blurred or
impaired vision, tinnitus, and possibly even fatal adverse events.
Allergic diseases are among the common problems encountered in the el-
derly. The mechanism involves activation of mast cells, usually through the inter-
action of allergens with mast cell-bound IgE antibodies. In humans, the mast cell
is found in the loose connective tissue of all organs, located near the blood ves-
sels, nerves, and lymphatics. Mast cells are found in abundance in the shock
organs involved in allergic diseases, namely skin, the mucosa of the upper and
lower respiratory tract, and the gastrointestinal tract (1). A related cell type, the
basophil, is found in the circulation, and also participates actively in allergic and
inflammatory responses.
IgE-mediated allergic responses occur in two phases, the early-phase re-
sponse and the late-phase response. The ‘‘immediate’’ or early-phase response
induces clinical signs within 30 min of a sensitized individual’s exposure to the
allergen(s). The late-phase response leads to clinical signs from 6 to 48 hours
following exposure (2).
Histamine is released from mast cells and basophils during the allergic
response. Mast cell–derived histamine is the major vasoactive mediator in imme-
465
466 Kaliner
diate-phase allergic reactions (3, 4). Histamine can elicit many, if not most, of
the pathological processes involved in allergic rhinitis, conjunctivitis, urticaria,
and anaphylaxis, as well as three of the four cardinal signs of asthma. Acting
through H 1-receptors in peripheral tissues, histamine initiates increased vascular
permeability, pruritus, contraction of smooth muscles of the respiratory and gas-
trointestinal tracts, and mucus secretion, and stimulates the biosynthesis and se-
cretion of additional inflammatory mediators and the recruitment of pro-inflam-
matory cells (2). Through the H 1-receptor, histamine acts as a neurotransmitter
in the central nervous system (CNS).
II. ALLERGIC RESPONSE: MECHANISMS OF ACTION

A. Histamine
Histamine is formed by decarboxylation of the amino acid, histidine, by the pyri-
doxal phosphate-dependent enzyme 1-histidine decarboxylase. The highest con-
centrations of histamine are found in the lungs and mucus membranes, preformed
in mast cells and basophils. Release of mast cell granule contents may be induced
by many heterologous stimuli (2). Most inflammatory cells produce or contain
histamine-releasing factors, which act to recruit mast cell degranulation in diverse
inflammatory events, in addition to the classic allergic response. These heteroge-
neous factors represent only one of many mechanisms by which histamine release
can be achieved (2).
The inflammatory response following allergic activation of mast cells is
complex, involving a series of intracellular events leading up to exocytosis of
the histamine-containing granule (5). Once released, histamine diffuses rapidly
into the surrounding tissues, appears in blood within 2.5 min, peaks at 5 min,
and returns to baseline by 15–30 min post-release (2). Histamine is metabolized
to N-methylhistamine by N-methyltransferase (4–8% of histamine byproducts in
urine), and further by monoamine oxidase (MAO) to N-methylimidazole acetic
acid (42–47% of byproducts in urine), after which it is excreted into the urine.
Only a small percentage (⬍3%) of histamine is excreted unchanged in the urine.
The remaining histamine (30–50%) is metabolized by diamine oxidase to imidaz-
ole acetic acid (9–11%) and further as a conjugate with ribose to form imidazole
acetic acid riboside (16–23%) (2, 6).
In humans, mast cells are found in the loose connective tissue of all organs,
especially around blood vessels, nerves, and lymphatics. Mast cells in lung tissue
form up to 2% of alveolar cells and reside below the airway basement membrane
near the submucosal blood vessels and glands, in muscle bundles, in the interalve-
olar septa, and in the bronchial lumina (2). Mast cells make up 0.1–0.5% of all
cells in the airway mucosa.
Use in the Elderly 467
B. Histamine Receptors
H 1-receptors have been identified in brain, retina, adrenal medulla, liver, endothe-
lial cells, cerebral microvasculature, lymphocytes, and smooth muscle in the air-
way, intestinal, genitourinary, and vascular tissue (2, 7). H 2-receptors are found
in the gastrointestinal tract and within the heart (8), but identifying them in pe-
ripheral tissues has been difficult since no H 2-radioligand of sufficient specificity
that exclusively differentiates the presence of H 2-receptors in those tissues has
as yet been developed. H 3-receptors are found in brain (cortical) tissue and in
some peripheral tissues, including human bronchial smooth muscles, where the
receptors mediate inhibition of cholinergic transmission.
The H 1-receptor is a G-protein-coupled receptor and as such induces inter-
nal mobilization of Ca 2⫹ and mobilization of Ca 2⫹ associated with hydrolysis of
membrane inositide phospholipids by phospholipase C (8, 9). Histamine acting
through H 1-receptors and inositol phospholipid hydrolysis causes smooth muscle
contraction in the respiratory and gastrointestinal tracts and, through sensory-
nerve stimulation, can cause pruritus. Histamine H 1-receptors acting alone at or
in combination with H 2-receptors induce the following reactions (2):
Skin wheal: increased vascular permeability (H 1-receptor-mediated endo-

thelial cell contraction)
Skin flare: vasodilation (primarily H 1-receptor-mediated axonal reflex)
Pruritus: sensory nerve activation (H 1-receptor-mediated nerve activation)
Mucosal edema: vasodilatory increase in mucosal blood flow and increased
vascular permeability (both H 1-receptor-mediated vascular responses)
Rhinorrhea or bronchorrhea: increased secretion from goblet cells and sub-
mucous glands, and increased vascular permeability (primarily an H 1-
response, although H 2-receptors are also involved)
H 2-receptor activation is associated with modulation of adenylate cyclase

(8). Activation through the H 2-receptor can result in gastric hyperactivity and
increased gastric acid secretion. Concurrent activation through H 1- and H 2-recep-
tors induces hypotension, tachycardia, flushing, and headache (10). The role(s)
of the H 2-receptor in the pathogenesis of allergic disease is (are) less well-defined
than the H 1-receptor; nevertheless, the combination of H 1- and H 2-receptor antag-
onist therapy is effective in treating chronic urticaria, in prevention of some ana-
phylactic and anaphylactoid reactions, and in modification of mucus secretion (2).
A recently described histamine receptor subtype, the H 3-receptor, is hy-
pothesized to be an autoreceptor for autonomic neurotransmission in the airways,
at the level of the autonomic ganglia (2,8,10). H 3-receptors act as modulators of
histamine synthesis and release in central nervous system neurons and may de-
crease histamine release from mast cells and inhibit the release of proinflamma-
468 Kaliner
tory tachykinins from unmyelinated C-fibers in the airway. Pharmacological

modulation of the action of histamine at H 3-receptors may have some role in
treating allergic disease, particularly allergic airway disease (2). H 3-receptor stim-
ulation may exhibit negative regulatory control of the pharmacologic activities
associated with activation of H 1-receptors (10).
In summary, H 1-receptor-related symptoms are important in allergic rhini-
tis, conjunctivitis, pruritus, anaphylaxis, asthma, urticaria, food allergy, and other
allergic disorders. H 2-receptor activation, in combination with H 1-receptor activa-
tion, is important in anaphylaxis, in part through exaggerated vasodilation causing
hypotension. H 2-receptor activation alone is responsible for increased gastric hy-
peractivity and hyperacidity. H 3-receptor activation leads to an inhibition in sym-
Table 1 Histamine Receptor-Mediated Activities and Correlating Symptoms
Receptor Actions Symptoms
H1 ↑ Vascular permeability Itching/pruritus

↓ A-V node conduction time Flushing
↑ Smooth muscle contraction Bronchoconstriction
Activation of airway vagal afferent Edema
nerves Nasal congestion
Vasodilation Hypotension
Sensory nerve stimulation Tachycardia
H2 ↑ Gastric acid secretion Acid or sour stomach
↑ Airway mucus secretion Heartburn/esophagitis
↑ cAMP Burning sensation in throat, midline
↑ Esophageal contraction chest area, or stomach
Inhibition of basophil histamine re- ↑ Airway secretions
lease ↑ Mucus production
Inhibition of neutrophil chemotaxis
and enzyme release
↑ Activation of suppressor T cells
H1 ⫹ H2 Vasodilation Hypotension
Flushing
Headache
H3 Sympathetic neurotransmission in- May decrease symptoms due to H 1-
hibition receptor stimulation (see above)
↓ Histamine synthesis
↓ Proinflammatory tachykinins (un-
myelinated C-fibers in the air-
way)
Source: From Refs. 2, 8, 10.

cAMP, cyclic 3′,5′-adenosine monophosphate.
pathetic neurotransmission and decreased histamine biosynthesis. Table 1 (2, 8,

10) presents a summary comparison of histamine receptor activity and corre-
sponding symptoms.
III. H 1-ANTIHISTAMINES
Antihistamines are among the top four categories of pharmaceutical products sold
(combining sales of both prescription and over-the-counter brands). Billions of
dollars are spent annually on these medications (11).
A. First-Generation H 1-Antihistamines
First-generation H 1-receptor antagonists contain aromatic rings and alkyl substi-
tutions that create lipophilic characteristics, explaining their ability to cross the
blood–brain barrier readily (2, 8, 12). These products bind to the H 1-receptor
and prevent histamine interactions with the receptor, thereby reducing histamine-
mediated allergic symptoms; however, the ability to cross the blood–brain barrier
gives rise to myriad CNS side effects (12–14) (Table 2). Of concern in providing
antihistamine therapy for the elderly are the classic antihistamine CNS side ef-
fects of dyskinesia, activation of epileptogenic foci, tachycardia, anxiety, confu-
sion, sedation, dilation of the pupils, blurred or diplopic vision, dizziness, sleepi-
ness, and reduced mental alertness. Moreover, first-generation H 1-receptor
antagonists lack specificity for H 1-receptors and, as a result, interact with a variety
of dopaminergic, serotoninergic, muscarinic, and cholinergic receptors, produc-
ing additional side effects (Table 2). Of concern, also, with the use of first-genera-
tion agents for the elderly are the muscarinic/cholinergic side effects of urinary
hesitancy, urinary retention, constipation, sedation, impaired coordination, and
memory dysfunction. Additionally, the α-adrenergic blockade side effects of su-
praventricular arrhythmias, peripheral vasodilation, postural hypotension, reflex
tachycardia, and dizziness are important since cardiac/cardiovascular disease is
common in the elderly, and prevention of falls is of paramount importance. In
addition to the direct and indirect cardiac effects, postural hypotension, dizziness,
and sedation can contribute to falls and put the elderly patient’s safety in jeopardy.
Concomitant diseases may be aggravated or enhanced by the lack of receptor
specificity of first-generation antihistamines, which, for example, can cause my-
driasis and worsen glaucoma.
Elderly persons medicated with first-generation H 1-antagonists may have
a heightened risk of the side effects mentioned above and in Table 2, especially
if they are taking MAO inhibitors, antidepressants, or other psychotropic medica-
tions concomitantly. All first-generation H 1-antagonists have a warning on the
470 Kaliner
Table 2 Adverse Effects Associated with the Use of First-Generation

H 1-Antihistamines
Muscarinic/cholinergic α-adrenergic receptor

CNS effects blockade effects blockade effects
Stimulatory Dry mouth Supraventricular arrhyth-

Dyskinesia a with spasms Dry eyes a mias a
of facial, tongue, neck Sinus tachycardia a Prolonged atrial refractive
and/or hand muscles Constipation a period a
Activation of epilepto- Urinary retention a Peripheral vasodilation
genic foci a Urinary hesitancy a Postural hypotension a
Euphoria, hyperreflexia, Memory dysfunction a Dizziness a
hypertension, headaches Mydriasis a Reflex tachycardia a
Anticholinergic-like ef-
fects: insomnia, irritabil-
ity, nervousness, tachy-
cardia, a and/or tremor a
Neuropsychiatric
Anxiety, confusion, depres-
sion a, hallucinations,
and/or psychosis
Peripheral
Paresthesias, a paralysis, a
and with cholinergic
blockade, dilated pu-
pils, a impairment of ac-
commodation, blurred
vision a, and/or diplopia a
Depressive a or Suppres-
sive a
Sedation a , drowsiness, a fa-
tigue, a lassitude, dizzi-
ness, reduced mental
alertness a
a
Side effects of particular concern in treatment of the elderly.
Source: From Refs. 12–14.
prescribing information regarding contraindication in conjunction with MAO in-

hibitors (13).
B. Second-Generation H 1-Antihistamines
The principal characteristics that differentiate second-generation H 1-antagonists
from their first-generation counterparts are their decreased ability to cross the
blood–brain barrier and their increased selectivity/specificity for the H 1-receptor.
Increased selectivity/specificity results in fewer adverse side effects resulting

from stimulation at muscarinic, α-adrenergic, or other physiological receptor
pathways. Second-generation H 1-antagonists have lower lipid solubility charac-
teristics than do the first-generation H 1-antagonists and therefore are less likely
to cross the blood–brain barrier, and thus have a decreased potential to cause
CNS-related side effects such as sleepiness. Some, but not all, second-generation
H 1-receptor antagonists are extensively metabolized, predominantly by cyto-
chrome P-450 (CYP) 3A4, in their first hepatic pass (96–99%) (13).
The initial second-generation H 1-antagonists approved were terfenadine and
astemizole. Although these antihistamines exhibited almost none of the CNS-re-
lated side effects associated with first-generation H 1-antagonists, patients medicated
with astemizole or terfenadine were at risk of drug–drug interactions involving
hepatic cytochrome P-450 metabolism. Both these products have to be metabolized
by the cytochrome P-450 system into active metabolites, and the parent molecules
of both cause cardiotoxicity related to prolongation of the QT interval. Thus, inter-
ference with the cytochrome P-450 enzyme that metabolizes both terfenadine and
astemizole (the C3A4 enzyme) could lead to increased concentration of the poten-
tially toxic parent molecule. Astemizole and terfenadine were subsequently re-
moved from most markets because of rare, but occasionally fatal, cardiotoxicity.
By contrast, loratadine, approved in the late 1980s, has not exhibited any
significant cardiotoxicity. Loratadine is structurally related to the antihistamine,
azatadine; however, unlike azatadine, it is a 10-fold more potent peripheral than
central H 1-receptor antagonist and is nonsedating at the recommended dose. Lora-
tadine does not exhibit the cardiac side effect profile observed with astemizole
and terfenadine, since several enzymes are involved in its metabolism and it does
not accumulate in the body.
Acrivastine, a side-chain-reduced metabolite, is derived from the first-gen-
eration antihistamine triprolidine. It has a relatively short half-life, requiring more
frequent dosing (three times daily) than do other second-generation antihista-
mines. There are relatively few published studies of acrivastine. Available only
in combination with pseudoephedrine, it is less sedating than first-generation H 1-
antagonists. There appear to be no published reports of cardiac arrhythmias.
Two additional second-generation H 1-receptor antagonists are the principal
active metabolites of first-generation antihistamines: cetirizine, the carboxylic
acid metabolite of the first-generation antihistamine hydroxyzine; and fexofena-
dine, the carboxylic acid metabolite of the second-generation antihistamine ter-
fenadine.
Cetirizine has reduced CNS-related side effects compared with its parent
antihistamine and is a relatively low-sedating compound compared with first-
generation antihistamines. Its sedative side effects are dose-related (6% with pla-
cebo, 11% with 5 mg dose, and 14% with 10 mg dose) (15). There are no reports
of cardiac arrhythmias associated with cetirizine. Cetirizine is a potent antihista-
mine and is given once a day.
472
Table 3 Comparison of H 1-Antihistamines’ Pharmacokinetic Profiles
Time to Mean terminal

Category/agent Onset of action peak action elimination half-life Dose and treatment schedule
First-Generation
Chlorpheniramine Not listed Not listed 27.9 ⫾ 8.7 h Many carry warnings against use in patients with uri-
Hydroxyzine 15–30 min Not listed 29 h (⬍65 yr) nary retention, renal obstruction, narrow angle glau-
Triprolidine Not listed 1.8 ⫾ 0.7 h 4 ⫾ 2.2 h coma, and in conjunction with MAO inhibitor ther-
Diphenhydramine Not listed 1 h* 14 h (⬎65 yr) apy. Caution is urged in patients with severe
Brompheniramine Not listed 5 h* hypertension and/or severe coronary artery disease.
Clemastine Not listed 5–7 h 12 ⫹ h
Azatadine Not listed Not listed 12 h
Second-Generation
Loratadine 60–180 min 1–1.5 h 18.2 h (⬎65 yr) 10 mg/d; renal or liver failure: 10 mg every other day
Cetirizine 30–90 min 30–90 min 8.3 ⫾ 1.8 h Usual dose 10 mg/day; decrease by 50% in renal and
(⫹50% ⬎65 yr) hepatic failure
Fexofenadine 60 min 120–180 min 14.4 h Dose is 60 mg bid or 180 mg qd. 60 mg/day in renal
failure
Topical Spray
Azelastine 60–180 min 5.3 h ⫾ 1.6 h 22 ⫾ 2 h
Source: From Refs. 2, 13, 15, 19–21.

* For four of the H1-antihistamines, data were obtained in the elderly; for the others, data were obtained in young adults.
qd, once daily; bid, twice daily; h, hour(s); d, days; ⬎ greater than; ⬍ less than; MAO, monoamine oxidase.
Kaliner
Fexofenadine has the same nonsedating antihistaminic activity as its parent

compound, terfenadine; however, in contrast to terfenadine, it is completely de-
void of cardiac toxicity. In most countries it is used once daily in a dose of 180
mg.
Recent studies in patients with renal disease (16), or hepatic dysfunction
(17) have shown that these conditions do not affect the pharmacokinetics of fexo-
fenadine; thus, there is no need to adjust the dosage. The dosage of cetirizine
should be reduced by 50% for patients who have liver or renal disease. Loratadine
should be used every other day by patients with renal or hepatic dysfunction.
Table 3 provides pharmacokinetic profiles of various first- and second-gen-
eration H 1-receptor antagonists in the elderly (2, 13, 15, 19–21).
IV. H 1-ANTIHISTAMINE TREATMENT FOR ALLERGIC

DISORDERS IN THE ELDERLY
A. Allergic Rhinitis and Rhinoconjunctivitis
Allergic inflammation of the nasal mucosa is due to contact of the sensitized
individual with allergens and may be perennial (persistent, year-round) or sea-
sonal (intermittent) in nature. Physiological connective tissue and vasculature
changes in the nose related to the aging process may predispose or contribute to
chronic rhinitis in the elderly. Allergic rhinitis is characterized by pruritus, nasal
congestion, sneezing and rhinorrhea, all of which are directly attributable to hista-
mine stimulation of the H 1-receptor as well as to other allergic response media-
tors, including kinins, leukotrienes, prostaglandins, and the late-phase reactants.
Histamine contributes to most of the symptoms of allergic rhinitis, and patients
generally show significant improvement in symptoms with use of H 1-receptor
antagonists (2, 22). The late-phase reaction leads to congestion (vasodilation)
and airway hyperirritability, due to the actions of inflammatory mediators and
cytokines.
When symptoms of rhinitis occur in response to environmental irritants
such as cold air, changes in humidity, strong smells, or stress, and infection and
allergy have been excluded as causes, the condition is termed vasomotor rhinitis
(VMR). Thus, the diagnosis of nonallergic rhinitis is both a diagnosis of exclusion
and one of recognition of the hyperirritable state of the nasal mucosa (18, 22).
Age-related changes to autonomic–sympathetic and parasympathetic function
may put the elderly at greater risk for vasomotor rhinitis. This is especially true
in women. Although data are incomplete, it is estimated that more than 10 million
women over age 40 experience VMR (22).
In the elderly, it is important to consider anticholinergic side effects of
concomitant medications (CNS drugs, some cardiac drugs, etc.) since excessive
and chronic drying of the nasal mucosa may be a complicating factor in treating
Table 4 Potential H 1-Antihistamine Drug–Drug Interactions in the Elderly
Drug use H 1-antagonist
474
category potential interactions Pertinent age-related changes Comments
Cardiovascular May exacerbate effects of CV Changes in autonomic–sympathetic Concomitant diseases (congestive
drugs and parasympathetic function heart failure, thyroid disease, can-
↓ Cardiac output cer, etc.) affect drug uptake, distri-
Arteriosclerotic/atherosclerotic dis- bution, and elimination, often re-
ease sulting in extended drug half-life
↓ Total body water values
↓ Total body protein
↓ Renal function
Orthostatic decompensation (↑ pulse
rate, ↑ cardiac output, ↓ ejection
time)
Antihypertensive Hypotension Changes in autonomic–sympathetic Orthostatic hypotension is common
Hyperkalemia and parasympathetic function in the elderly, making antihyperten-
Urinary retention ↓ Renal function sive–antihistamine therapy precari-
↓ Total body water ous to titrate
↓ Total body protein Anticholinergic effects of first-genera-
Arteriosclerotic/atherosclerotic dis- tion H 1-antagonists (urinary reten-
ease tion) may counteract actions of
Orthostatic decompensation (↑ pulse some diuretics
rate, ↑ cardiac output, ↓ ejection
time)
Antidiabetic Hyperglycemia ↑ Glucose intolerance First-generation antihistamines have
Changes in lean mass/fat ratio anticholinergic effects that may en-
Gastrointestinal absorption changes hance glucose intolerance by im-
Changes in autonomic–sympathetic peding hydrolysis and carbohy-
and parasympathetic function drate metabolism
Antimicrobial Gastrointestinal absorption changes ↑
gastric pH, ↓ motility and absorptive
surface
Kaliner
↓ Hepatic blood flow

↓ Total body protein
↓ Renal function
Respiratory Agent Theophylline slows clearance ↓ Hepatic blood flow First-generation antihistamines can
Bronchodilator of cetirizine, ↑ jittery/ ↓ Lung elasticity cause some drying effects, which
Anti-inflammatory jumpy symptoms in combi- ↓ Musculoskeletal strength might make mucus clearance more
Antileukotriene nation with systemic bron- ↓ Renal function difficult
Lung surfactant chodilators ↓ Total body protein
Antitussive ↓ Vascular wall elasticity
Antineoplastic Most H 1-receptor antagonists Gastrointestinal absorption changes:
(esp. first-generation) are ↑ gastric pH, ↓ motility and ab-
highly (⬎60%) protein- sorptive surface
Use in the Elderly
bound, primarily to plasma ↓ Hepatic blood flow

albumin. Lower albumin ↓ Total body protein
levels are common in pa- ↓ Gastric reserve leads to ↑ sensitiv-
tients with cancer, increas- ity to minor insults and decompen-
ing the amount of ‘‘free’’ sation can occur rapidly.
H 1-receptor antagonist in
the bloodstream
Central Nervous Most first-generation H 1-an- Gastrointestinal absorption changes: First-generation H 1-antagonists have
System tagonists are contraindi- ↑ gastric pH, ↓ motility and ab- sedative and anticholinergic side ef-
cated with MAO inhibitors. sorptive surface fects that could compound or be
Antihistamines may com- ↓ Hepatic blood flow confused with CNS drug effects/
pound or intensify effects ↓ Total body protein (↓ protein side effects
of CNS depressants, includ- binding)
ing tranquilizers, anti-Par- ↓ Cerebral blood flow (arterioscle-
kinson’s agents, narcotic rotic dis.) ↑ sensitivity to CNS
and non-narcotic analge- drug side effects (sedation, anticho-
sics, alcohol, among others. linergic effects, hypotension)
Gastrointestinal Gastrointestinal absorption changes ↓ Gastric reserve leads to ↑ sensitiv-
Function Modifier (↑ gastric pH, ↓ motility and ab- ity to minor insults
sorptive surface) Decompensation can occur rapidly
H 1-antagonists caution against use
with stenosing peptic ulcer disease
Source: From Refs. 13, 23–25.

CV, cardiovascular; ↑, increase; ↓, decrease; MAO, monoamine oxidase; CNS, control nervous system.
475
476 Kaliner
rhinitis. To avoid excessive drying of the nasal mucosa, antihistamines of choice

include loratadine, cetirizine, or fexofenadine. These agents possess no anticho-
linergic activity, nor do they have alpha-adrenergic-blocking activity. First-gener-
ation antihistamines are not suitable for the elderly because of the risk of the
side effects associated with this class of drugs (13, 23–25) (Table 4).
For patients with rhinoconjunctivitis, systemic antihistamine therapy may
be combined with a topical ophthalmic medication, such as olopatadine (Patanol)
or cromolyn (Crolom); however, many patients experience satisfactory relief of
eye symptoms from antihistamines alone. Some ophthalmic medications com-
monly used by the elderly have drug–drug interactions or drug–disease interac-
tions of special relevance to allergic/asthmatic patients. For example, nonselec-
tive β-adrenergic-blocking agents, including those such as timolol, used for
lowering intraocular pressure, can produce side effects of hypotension, irritabil-
ity, arrhythmias, headache, dizziness, depression, confusion, or anxiety. Further,
these medications are contraindicated in patients with asthma, and, if combined
with first-generation antihistamines, CNS and cardiac side effects may be signifi-
cantly intensified. For patients with rhinoconjunctivitis who are taking a medica-
tion such as timolol, the antihistamines of choice would be loratadine, cetirizine,
and fexofenadine. Alternatives to antihistamines might include topical ipra-
tropium.
B. Chronic and Acute Urticaria

The principal symptoms of urticaria are pruritic, erythematous hives that blanch
with pressure. Hives are the product of increased vascular permeability, venous
dilation, and edema formation. Angioedema is a similar process occurring in the
deep dermis or subcutaneous tissue, leading to ill-defined areas of swelling typi-
cally found around the eyes, mouth, and lips. The swelling found in urticaria and
angioedema is in great measure mediated by histamine acting at the endothelial
H 1-receptor; the surrounding erythema is due to H 1-induced vasodilation. The
itch is from histamine stimulation of sensory nerves. Other mediators involved
in the acute and chronic urticaria response come from both the immediate- and
the late-phase allergic response and include prostaglandins, leukotrienes, kinins,
eicosanoids, chemotactic factors, and cytokines (2, 26). The origin or causative
allergen of acute urticaria is more easily detected than the cause(s) of chronic
urticaria, which may be difficult to determine. Elderly patients with chronic urti-
caria often have idiopathic disease (26). Current research suggests that 30 to 60%
of idiopathic urticaria may be caused by a circulating IgG autoantibody against
the IgE receptor or against IgE itself.
Treatment for urticaria is based empirically on blocking the effects of hista-
mine in the skin. H 1-antihistamine therapy alone usually controls symptoms suc-
cessfully; however, for conditions in which an underlying inflammatory disorder
predominates, it may be necessary to prescribe a brief course of systemic cortico-
steroid therapy during the introduction of antihistamine therapy (26). If long-

term use of an antihistamine is required in the elderly, the physician must evaluate
its potential benefits and risks, keeping the age of the patient in mind (Table 4).
For many reasons, the agents of choice are second-generation antihistamines that
do not have cardiac or CNS side effects. Cetirizine is especially effective and
many specialists prefer this agent for the treatment of chronic urticaria; however,
because of the possible sedative properties of cetirizine, either loratadine or fexo-
fenadine (especially the once-a-day, 180 mg tablet) are the alternatives of choice.
It has been the author’s experience that many patients with urticaria or angi-
oedema do not experience significant sedation with cetirizine.
For some patients who do not respond adequately to H 1-antihistamines
alone, adding an H 2-antihistamine has provided significant additional relief.
C. Pruritus
Pruritus has many different triggers but results primarily from stimulation of
H 1-receptors in the skin, although prostaglandins may also contribute. Current
opinion is that there are only a few types of pruritus: itching provoked by immu-
nological or nonimmunological stimuli, with subsequent release of inflammatory
mediators (primarily histamine); intrinsically itchy skin, often a result of dry skin
associated with the aging process; and itching secondary to deposition of salts
in the skin, such as occurs in obstructive jaundice and renal failure. Occasionally,
patients with Hodgkin’s disease or other lymphomas may present with pruritus
unaccompanied by a rash.
Topically applied local anesthetics or antihistamines are moderately effec-
tive in relieving localized pruritus, and are useful for short-term treatment. Topi-
cal doxepin (Zonolon cream), a first-generation antihistamine, may be useful,
although systemic absorption and sedation do occur and skin sensitization has
been reported. Systemic antihistamine therapy is helpful for some patients with
pruritus. Cetirizine is often the agent of choice (15, 21, 27, 28), although both
loratadine and fexofenadine are effective alternatives. Emollients and other non-
pharmacological measures should be used to improve skin hydration in patients
with skin dryness and itchiness.
D. Atopic Dermatitis and/or Eczema

The subacute or chronic skin lesions of eczema are characterized by erythema,
scaling, lichenification, dryness, and pruritus. Eczema is defined as a pruritic
papulovesicular dermatitis occurring in reaction to exogenous or endogenous
agents. The acute lesions of eczema are characterized by erythema, edema associ-
ated with epidermal intercellular serous exudate, inflammatory infiltrates, oozing,
vesiculation, crusting, and scaling (29). The general goals of therapy for atopic
eczema are to hydrate the skin, decrease pruritus, suppress inflammation, and
478 Kaliner
lubricate the skin. Recommendations regarding mechanical, thermal, and chemi-

cal aspects of skin care are applicable (29). Decreasing pruritus can often be
accomplished with use of H 1-receptor antagonists: cetirizine, loratadine, or fexo-
fenadine.
E. Prophylaxis of Anaphylactoid Reactions

Reactions to intravenous contrast agents are anaphylactoid (nonimmunologically
mediated) in nature rather than anaphylactic (IgE-mediated, as in allergic reac-
tions). About 1000–2000 people per year die from these reactions (1 :10,000–
50,000 exposures), with severe reactions occurring in 1:1000–10,000 exposures.
Elderly patients are disproportionately highly exposed to radiocontrast media due
to their needs for diagnostic procedures. Adverse reactions to contrast media also
occur with greater frequency in older patients than in younger patients (30). Thus,
prophylaxis for contrast media exposure is an important consideration in the el-
derly.
Characteristic H 1-receptor-mediated anaphylactoid reactions associated
with injection of radiocontrast media include flushing, wheezing, urticaria, laryn-
geal edema, angioedema, pruritus, cough, tachycardia, hypotension, syncope, and
death (30, 31). Pretreatment with antihistamines has been used to reduce adverse
reactions in patients known to be at risk for reactions to radiocontrast media (32).
H 1-receptor antagonists have been used successfully to treat mild anaphylactoid
reactions (33). Prophylactic treatment with H 1-receptor antagonists for reactions
to radiocontrast media is usually supplemented with H 2-antihistamines and corti-
costeroids to achieve maximal protection (30, 34, 35). Although pretreatment is
used successfully in most patients, some patients may still have reactions, includ-
ing reactions to non-ionic agents (35). Some pretreatment regimens call for ad-
ministration of the antihistamine and corticosteroid combination as much as 12
hours prior to injection of the contrast media. One regimen recommended for
routine use in patients who are at no increased risk for reactions is the following:
fexofenadine 60 mg at 12 hours and at 1 hour before the procedure, plus ranitidine
150 mg at 12 hours and 1 hour before the procedure (36). For patients with prior
histories of contrast media reactions, we give three doses of fexofenadine and
ranitidine during the 24 hours before the procedure, plus prednisone 30 mg at
18 hours, 12 hours, and 6 hours before the procedure (36).
V. DRUG–DRUG INTERACTIONS
Potential drug–drug interactions with H 1-antagonists are presented in Table 4.

This information is only representative and is not intended to be exhaustive. The
reader is urged to evaluate each patient individually, assessing both the patient’s
medical condition and medication requirements, in reaching an optimal prescrib-

ing decision for H 1-receptor antagonist therapy.
VI. SUMMARY
In the elderly, H 1-antihistamine therapy is commonly prescribed for treatment of

rhinitis, conjunctivitis, pruritus, eczema, urticaria, and for prophylaxis of anaphy-
lactoid reactions. Second-generation H 1-receptor antagonists provide excellent,
safe, and effective alternatives to first-generation antihistamines in this popula-
tion, as in younger patients. As with all medications, the choice of which agent
to use must be tailored to the needs of the individual. Treatment should be planned
with consideration of concomitant medications and potential drug–drug interac-
tions and drug–disease interactions. First-generation antihistamines should not
be used for treatment of allergic rhinitis or urticaria in the elderly. Age-related
physiological changes can enhance or complicate the actions of H 1-receptor an-
tagonists, especially when these drugs are taken concurrently with other medica-
tions and/or in the presence of comorbid disease. Adjustments in dosages are
necessary when some agents are used in patients with renal and/or hepatic dis-
ease; however, overall, the use of the newer nonsedating antihistamines is safe,
effective, and gratifying in the elderly.
REFERENCES
1. Metcalfe DD. Effector cell heterogeneity in immediate hypersensitivity reactions.

Clin Rev Allergy. 1983;1:311–325.
2. White MV, Kaliner MA. Histamine in allergic diseases. In: Simons FER, ed. Hista-
mine and H 1-Receptor Antagonists in Allergic Disease. New York: Marcel Dekker:
1996:61–90.
3. Petersen LJ, Brasso K, Pryds M, Skov PS. Histamine release in intact human skin
by monocyte chemoattractant factor-1, RANTES, macrophage inflammatory protein
1α, stem cell factor, anti-IgE, and codeine as determined by an ex vivo skin microdi-
alysis technique. J Allergy Clin Immunol 1996;98:790–796.
4. Chowdhury BA, Kaliner MA. Molecular identification of the histamine H 1-receptor
in humans. In: Simons FER, ed. Histamine and H 1-Receptor Antagonists in Allergic
Disease. New York: Marcel Dekker, 1996:33–60.
5. Siraganian RP. Mast cells and basophils. In: Kaliner MA, ed. Current Review of
Allergic Disease, 2nd ed. Philadelphia: Blackwell Scientific, 1999:11–25.
6. White MV, Slater JE, Kaliner MA. Histamine and asthma. Am Rev Respir Dis 1987;
135:1165–1176.
7. Hill SJ. Distribution, properties, and functional characteristics of three classes of
histamine receptor. Pharmacol Rev 1990;42:45–83.
480 Kaliner
8. Leurs R, Smit MJ, Timmerman H. Histamine receptors: specific ligands, receptor

biochemistry, and signal transduction. In: Simons FER, ed. Histamine and H 1-Recep-
tor Antagonists in Allergic Disease. New York: Marcel Dekker, 1996:1–32.
9. Michel RH. Inositol phospholipids and cell surface receptor function. Biochim Bio-
phys Acta 1975; 41:81–147.
10. Simons FE, Simons KJ. The pharmocology and use of H 1-receptor-antagonist drugs.
N Engl J Med 1994;330:1663–1670.
11. Nonprescription Drug Manufacturers Association. Report on OTC Drug Retail Sales
1995. Washington DC: NDMA, 1996.
12. Bousquet J, Campbell AM, Canonica GW. H 1-receptor antagonists: structure and
classification. In: Simons FER, ed. Histamine and H 1-Receptor Antagonists in Aller-
gic Disease. New York: Marcel Dekker, 1996:91–116.
13. Physicians Desk Reference, 53rd ed. Montvale NJ: Medical Economics, 1999.
14. Meltzer EO, Welch MJ. Adverse effects of H 1-receptor antagonists in the central
nervous system. In: Simons FER, ed. Histamine and H 1-Receptor Antagonists in
Allergic Disease. New York: Marcel Dekker, 1996:357–381.
15. Cetirizine. Prescribing information. Pfizer Inc, December 1995.
16. Horton MW, Swan SK, Halstenson CE, et al. Pharmacokinetics of fexofenadine in
patients with varying degrees of renal impairment. Pharm Res 1996;13(suppl):S431.
17. Lippert CL, Rao N, Eller MG, Weir SJ. Pharmacokinetics of fexofenadine in liver
diseased patients. Pharm Res 1996;13(suppl):S431.
18. Andersson M, Greiff L, Svensson, Wollmer P, Persson CGA. Allergic and nonaller-
gic rhinitis. In: Busse W, Holgate S, eds. Asthma and Rhinitis. Cambridge, MA:
Blackwell Scientific Publications, 1995: 145–155.
19. Simons KJ, Simons FER. H 1-receptor antagonists: pharmacokinetics and clinical
pharmacology. In: Simons FER, ed. Histamine and H 1-Receptor Antagonists in Al-
lergic Disease. New York: Marcel Dekker, 1996: 175–213.
20. Fexofenadine. Prescribing Information. Kansas City, MO: Hoechst Marion Roussel,
July, 1996.
21. Nathan RA. The new antihistamines. In: Kaliner MA, ed. Current Review of Allergic
Disease, 2nd ed. Philadelphia: Blackwell Scientific, 1999: 87–101.
22. Economides A, Kaliner MA. Allergic rhinitis. In: Kaliner MA, ed. Current Review
of Allergic Disease, 2nd ed. Philadelphia: Blackwell Scientific, 1999: 225–238.
23. Jinks MJ, Fuerst RH. Geriatric therapy. In: Koda-Kimble MA, Young LL, eds. Ap-
plied Therapeutics: The Clinical Use of Drugs, 5th ed. Vancouver, WA: Applied
Therapeutics, 1992: 79:1–19.
24. McCue JD. Safety of antihistamines in the treatment of allergic rhinitis in elderly
patients. Arch Fam Med 1996;5:464–468.
25. Chabner BA, Allegra CJ, Curt GA, Calabresi P. Antineoplastic agents. In: Hardman
JG, Limbird LE, eds. Goodman & Gilman’s The Pharmacological Basis of Thera-
peutics, 9th ed. New York: McGraw-Hill, 1996: 1233–1288.
26. Finn AF. Urticaria and angioedema. In: Kaliner MA, ed. Current Review of Allergic
Disease, 2nd ed. Philadelphia: Scientific, 1999: 145–57.
27. Quercia RA, Brosman L. Focus on cetirizine. Hosp Formul 1994;29:560–566.
28. Sheffer AL, Samuels LL. Cetirizine: antiallergic therapy beyond traditional H 1-anti-
histamines. J Allergy Clin Immunol 1990;86:1040–1046.
29. Beltrani VS. Allergic dermatosis. In: Kaliner MA, ed, Current Review of Allergic
Disease, 2nd ed. Philadelphia: Scientific, 1999: 157–172.
30. Bielory L, Kaliner MA. Anaphylactoid reactions to radiocontrast materials. Int An-
esthesiol Clin 1985;23:97–118.
31. Winbery SL, Lieberman PL. Anaphylaxis and histamine antagonists. In: Simons
FER, ed. Histamine and H 1-Receptor Antagonists in Allergic Disease. New York:
Marcel Dekker, 1996: 297–327.
32. Bertrand PR, Soyer PM, Rouleau PJ, Alison DP, Billardon MJ. Comparative ran-
domized double-blind study of hydroxyzine versus placebo as premedication before
injection of iodinated contrast media. Radiology 1992;184:383–384.
33. Stovsky MD, Seftel AD, Resnick MI. Delayed hypersensitivity reaction after infu-
sion of nonionic intravenous contrast material for an excretory urogram: a case report
and review of the literature. J Urol 1995;153:1641–1643.
34. Cohan RH, Ellis JH, Dunnick NR. Use of low-osmolar agents and premedication
to reduce the frequency of adverse reactions to radiographic contrast media: a survey
of the Society of Uroradiology. Radiology 1995;194:357–364.
35. Roberts M, Fisher M. Anaphylactoid reaction to iopamiro (after pretreatment). Aus-
tralas Radiol 1992;36:144–146.
36. Kaliner MA, Anaphylaxis and serum sickness. In: Rakel RE, ed. Conn’s Current
Therapy. Philadelphia. WB Saunders Company, 1999: 756–760.
Index
Acrivastine, 77 Allergic rhinitis (see Allergic rhinocon-

adult dose, 156 junctivitis)
allergic rhinoconjunctivitis, 196, 204 Allergic rhinoconjunctivitis, 179–220
antiallergic effects, 108 adverse effects of H1-antihistamines,
assay for, 146 202, 203
cardiac study, 406, 407 antiallergic activities of H1-antihista-
CNS studies, 366, 372 mines in, 188–190
chemical structure, 142 antihistamines and experimental aller-
chronic urticaria, 274, 277 gic rhinoconjunctivitis, 185–188
pediatric dose, 442 children with, 441–445
pharmacokinetics, 148, 158 comparison of H1-antihistamines and
pharmacokinetics in special popula- intranasal corticosteroids in, 197,
tions, 150, 158 198, 328–330
pharmacodynamics, 155, 158–159 comparative studies of H1-antihista-
specific properties of, 77 mines in, 196, 197, 199
Adhesion molecules, 103, 104, 114–117 cost-effective management of, 326–
Adverse effects of antihistamines, 232– 328
234 development of, 102
see also Cardiac toxicity; central ner- direct and indirect costs of, 324–
vous system (CNS toxicity) 326
Alcohol economic impact of, 324–326
interaction with first-generation H1- elderly with, 473, 476
antihistamines, 371–375 experimental, 185
Alkylamine H1-antihistamines, 75, 338 H1-antihistamine/decongestant combi-
Allergen, 105, 106 nation therapy, 203, 204
Allergen immunotherapy (vaccinations) human allergen challenge model for
cost-effectiveness of, 330, 331 study of, 104–108
Allergic diseases links between allergic rhinitis and
sedative effects of, 351, 352 asthma, 237–240
Allergic inflammation medical expenditures attributable to,
pathophysiology of, 101–104 326
483
484 Index
[Allergic rhinoconjunctivitis] [Anaphylaxis and anaphylactoid reac-

medical management of, 190–202, tions]
327, 328 gastrointestinal system in, 298
mucosal inflammation and histamine heart and coronary arteries in, 297,
release in, 181, 182, 298
oral H1-antihistamines in, 190–200, histamine and, 294–299
327–330 histamine levels in, 299
perennial, 198–200 histamine receptors in, 295–296, 298
pregnancy and, 424 iatrogenic, 288–290, 302–307
quality-of-life questionnaire in, 323 idiopathic, 304
role of histamine and receptor speci- incidence of, 290
ficity in, 182–185 late-phase anaphylactic response in,
seasonal, 190–198 291
topical H1-antihistamines in, 200– latex and, 305
202, 327, 328 mediators in, 289, 291–294
Alpha-adrenergic effects of first- morphine and, 306
generation H1-antihistamines, N-acetylcysteine and, 307
72, 469, 470 plasma exchange and, 304
Amthamine, 29, 30 prevention of, with H1-antihistamines,
Analgesic effect of first-generation H1- 301–307
antihistamines, 72 protamine and, 306, 307
Anaphylactoid reactions (see Anaphy- radiocontrast media and, 302–304,
laxis and Anaphylactoid reactions) 478
Anaphylaxis and anaphylactoid reac- respiratory system in, 298
tions, 287–317 second-generation H1-antihistamines
adjunctive role of H1-antihistamines in, 299
in, 300, 301, 448 vancomycin and, 306
adverse effects of H1- and H2-antihis- vascular system in, 296
tamines in, 301 volume expanders and, 304
amplification of anaphylactic response Angioedema (see Urticaria)
in, 291–293 Angioedema without urticaria, 279, 280
anesthesia-related, 288, 290, 305, 306 Animal reproduction studies of H1-anti-
antiallergic properties of H1-antihista- histamines, 427
mines in, 300 Antiallergic effects of H1-antihistamines,
children with, 448 70, 71
chymopapain and, 307 acrivastine, 108
classification of, 288, 289 azatadine, 108–109, 126
combination H1- and H2-antihistamine azelastine, 109–112, 126
therapy in, 300–308 cetirizine, 68, 112–116, 123, 126,
definition of, 287, 289 127
drug-related, 288, 290, 291, 305, ebastine, 116–117, 127
306 fexofenadine, 117
elderly with, 478 human models for study of, 104–108
exercise-induced, 305 in allergic rhinoconjunctivitis, 188–
experimental models of, 307, 308 190
fluorescein and, 304 ketotifen, 117, 118, 127
Index 485
[Antiallergic effects of H1-antihistamines] [Asthma]

levocabastine, 118–120, 127 H1-antihistamine effects on bron-
loratadine, 119–125, 127, 128 choconstriction responses in, 224–
mizolastine, 125 226
oxatomide, 125, 128, 129 H1-antihistamines in, 232–237
terfenadine, 68, 129 H1-antihistamines in patients with al-
Anticholinergic effects of first-genera- lergic rhinitis and, 237–240
tion H1-antihistamines, 71, 469, H1-antihistamines in prevention of,
470, 473–476 240
Antidepressants, tricyclic, 69 histamine in, 227–228
Antidote histamine-induced bronchoconstric-
lack of, for H1-antihistamine over- tion, 224–227
dose, 452, 453 historical background, 221, 222, 232,
Antigen-presenting cells, 101, 102 233
Antihistamines (see First-generation H1- inflammatory cell recruitment in, 230,
antihistamines; Second-generation 232
H1-antihistamines) ketotifen in, 233–237
Apoptosis, 232 links between upper and lower air-
Assays for measuring H1-antihistamines ways in, 238
in plasma, 146 loratadine in, 237
Astemizole, 68, 77, 78 mast cells in, 222, 223
cardiac toxicity, 73, 340, 390, mechanism of action of H1-antihista-
407 mines in, 17, 227–232
CNS effects, 357, 359, 367, 370, mediator release in, 229, 230
372 meta-analysis of H1-antihistamines in,
Asthma, 179, 180, 221–248 233–234
anti-inflammatory action of antihista- seasonal, H1-antihistamine effects in,
mines in, 228–232 237–240
antihistamines and antileukotrienes in, Atopic dermatitis
226, 227 children with, 449
azelastine in, 233–236 cost-effectiveness of H1-antihista-
basophils in, 222, 223 mines in, 331
bronchoconstrictor responses in, 224– elderly patients with, 477, 478
227 pregnancy and, 421
cellular localization of histamine in, steroid-sparing effect of cetirizine in,
222–223 449
cetirizine in, 234, 236 Azatadine
children with, 446–447 antiallergic effects of, 108, 109,
corticosteroid-sparing effects of, 234, 126
235 effect on response to nasal challenge,
cost-effectiveness of H1-antihista- 109, 126
mines in, 332 Azelastine, 80
H1-antihistamine effect, 232–234 adult dose, 156
H1-antihistamine effect on inflam- allergic rhinoconjunctivitis, 183, 189,
matory cell recruitment in, 230– 200, 201
232 antiallergic effects, 109–112
486 Index
[Azelastine] [Cardiac toxicity of H1-antihistamines]

assay for, 146 azelastine, 405
asthma, 234–236 cetirizine, 404
chemical structure, 142 ebastine, 404
pediatric dose, 442 effects of nonsedating H1-antihista-
pharmacodynamics, 153, 155, 160 mines on QT interval, 403–406
pharmacokinetics, 148, 159, 160 factors that prolong ventricular repo-
pharmacokinetics in special popula- larization or predict torsade de
tions, 150 pointes, 408–410
pregnancy and, 427, 430 fexofenadine, 404, 405
QT interval, 405 historical perspective, 390
specific properties of, 80 hydroxyzine, 404
incidence of cardiac events with non-
Bacteria sedating H1-antihistamines, 406–
histamine production by, 8, 9 408
Basophils infants, children and, 453–456
allergic rhinoconjunctivitis and, 181, loratadine, 404
182 measurement of QT interval, 394,
asthma and, 221–223 395
monoclonal antibody (BB1) to, mechanism of acquired QT prolonga-
223 tion and torsade de pointes, 391–
Blood-brain barrier, 340–342 394
Brompheniramine prevention and treatment of drug-
adverse effects, 338, 347–348 induced QT prolongation, 408,
elimination half-life in adults, 141 410, 411
pharmacokinetic/pharmacodynamic properties of H1-antihistamines de-
map, 143 termining proarrhythmic toxicity,
pharmacokinetics and pharmaco- 398–403
dynamics in children, 439 QT prolongation and torsade de
pregnancy and, 426–428 pointes, 395–398
Bronchoconstriction regulatory perspective in drug devel-
histamine-induced, 224–225 opment, 411, 412
allergen-induced, 226–227 terfenadine, 403, 407
effects of H1-antihistamines on, 224– Carebastine (see Ebastine)
226 Central nervous system (CNS) effects of
Burimamide, 30 H1-antihistamines,
acrivastine, 366, 372
Carcinogenic effects of H1-antihista- assessment (tests) for, 342–347
mines (see Tumor-promoting ef- astemizole, 357, 359, 367, 370, 372
fects) cetirizine, 345, 346, 354–357, 359,
Cardiac action potential 365, 367, 372, 373, 374
ionic and molecular basis for, 390, children, 450, 451
391 chlorpheniramine, 338, 347, 348, 354,
Cardiac toxicity of H1-antihistamines, 357, 366, 372
389–419 clemastine, 338, 347, 348, 358, 361,
astemizole, 407 363–366, 373, 374
Index 487
[Central nervous system (CNS) effects [Cetirizine]

of H1-antihistamines] pharmacokinetics, 148, 160, 161
coadministration of alcohol and, 371– pharmacokinetics in special popula-
375 tions, 150, 439
diphenhydramine, 338, 345, 347, 348, pregnancy and, 427, 428, 430
354, 356–360, 366, 367, 370, 372 QT interval, no effect on, 404
ebastine, 363, 373 safety in the elderly, 471–473
fexofenadine, 360, 361, 374, 375 specific properties of, 78
hydroxyzine, 338, 347, 348, 354–356 Chemistry of H1-antihistamines, 66–69,
ketotifen, 357, 359, 366, 367 77–81
lack of tolerance to, 348–351 Children
levocabastine, 367 clinical research in, 443
loratadine, 354, 355, 357–361, 367, Children, H1-antihistamines and, 437–464
368, 372, 373 allergic rhinoconjunctivitis, 441–445
mechanisms of, 340–342 anaphylaxis, 448
mizolastine, 356, 364, 365, 368, 374 asthma, 446, 447
promethazine, 357, 360, 361, 366 asthma prevention, 447, 448
terfenadine, 354, 355, 357–359, 364, atopic dermatitis, 449
366, 367, 368, 372, 373 cardiac toxicity, potential, 453–456
topical H1-antihistamines, 353, 366– clinical pharmacology, 437–441
368 efficacy, 441–450
triprolidine, 347, 348, 354, 355, 358, first-generation sedating, 442, 450–453
360, 362, 363, 364, 366, 367, 372, formulation and dosage, 442
373 levels of evidence for use in, 438
Cetirizine mastocytosis, 448
acute urticaria, 448, 449 other disorders, 449, 450
adult dose, 156 otitis media, 446
allergic rhinoconjunctivitis, 183, 186, overdose of first-generation, 451–453
188–192, 199, 204, 444 overdose of second-generation, 456
antiallergic effects, 113–116 pharmacodynamics, 440–441
assay for, 146 pharmacokinetics, 438–440
asthma, 234, 236, 239 safety issues, 450–456
asthma prevention, 447, 448 second-generation nonsedating, 452,
atopic dermatitis, 449 453
cardiac safety in children, 454, 455 upper respiratory tract infections,
CNS studies, 345, 346, 354–357, 445, 446
359, 365, 367, 370, 372–374 urticaria, 447–449
chemical structure, 142 Chlorpheniramine, 338
chronic urticaria, 261, 262, 264, 274, asthma, 225
275 CNS adverse effects, 347, 348, 349,
early treatment of the atopic child 354, 357, 366, 371
(ETAC), 447–449, 455, 456 chronic urticaria, 260, 268, 269, 273
pediatric dose, 442 elimination half-life in adults, 141
pharmacodynamics, 152, 153, 155, 161 pharmacokinetics and pharmacody-
pharmacokinetic/pharmacodynamic namics in children, 439
map, 143, 144 pregnancy and, 426–428
488 Index
Cholinergic urticaria (see Urticaria) Cost utility, 320–322

Chronic idiopathic urticaria (see Urti- Cyproheptadine
caria) adverse effects, 338, 339
Chymopapain CNS effects of, 371
anaphylactoid reactions to, 307 urticaria, 268, 273, 275, 277
Cimetidine Cytochrome P-450 3A4,
anaphylaxis, 301–304, 306, 308 inhibition by drugs and foods, 401–
chemical structure, 30 403
urticaria, 268, 269, 273 Cytokines, 102–104, 109, 110, 116,
Cinnarizine, 275, 277 117, 121, 127, 251, 252
Clearance of H1-antihistamines from
body (see Pharmacokinetics) Decongestants
Clemastine CNS effects of, 370, 371
adverse effects, 338, 348, 361, 363– combination of H1-antihistamines and,
366, 374 203, 204, 445
allergic rhinoconjunctivitis, 199 Delayed-pressure urticaria, 252, 278, 279
asthma, 225 (see also Urticaria)
CNS adverse effects of, 375 Demographism
pregnancy and, 427 H1-antihistamines in, 272–274, 276,
Clinical pharmacology, 141–178 278, 279 (see also Urticaria)
Clinical research in children, 443 Desloratadine
Clobenpropit, 31 adult dose, 156,
Cognitive and psychomotor performance allergic rhinoconjunctivitis, 191–193
impairment tests, 342–347 assay for, 146
Cold-induced urticaria, 275, 277, 278 chemical structure, 142
Cold urticaria (see Urticaria) lack of cardiac toxicity and, 454,
Common cold (see Upper respiratory 456
tract infections), pharmacodynamics, 155, 162
Congenital anomalies, 421, 422 pharmacokinetics, 148, 162
Conjunctivitis (see Allergic rhinocon- pharmacokinetics in special popula-
junctivitis) tions, 150
Coronary arteries, anaphylaxis-related Dexchlorpheniramine
effects of histamine on, 297, adverse effects, 338, 347, 348
298 pregnancy and, 427, 428
Corticosteroids, intranasal, 328–330 Diazepam
Corticosteroids CNS effects when co-administered
sparing effect of H1-antihistamines in with H1-antihistamines, 371, 373
asthma, 234, 235 Dimaprit, 32
Cost-benefit, 320, 321 Dimethindene,
Cost-effectiveness, 320–322 in allergic rhinoconjunctivitis, 200
Cost-effectiveness of H1-antihistamines, Diphenhydramine, 338
324–331 CNS adverse effects in children,
Cost identification, 320, 321 451–453
Cost per day of H1-antihistamines, 327 CNS adverse effects of, 338, 345, 347,
Cost per day of intranasal corticoste- 348, 354, 356–360, 366, 367, 370
roids, 329 elimination half-life in adults, 141
Index 489
[Diphenhydramine] [Ebastine]
pharmacokinetic/pharmacodynamic assay for, 146
map, 143 CNS effects, lack of, 363, 373
pharmacokinetics and pharmacody- chemical structure, 142
namics in children, 439 pediatric dose, 442
pregnancy and, 427, 428 pharmacodynamics, 152, 155, 163
Doxepin pharmacokinetic/pharmacodynamic
CNS adverse effects of, 261 map, 143, 144
in chronic urticaria, 260, 261, 275 pharmacokinetics, 148, 162, 163
Drowsiness tests (assessment of H1- pharmacokinetics in special popula-
antihistamine effects on CNS), tions, 150, 439
342–347 QT interval, 403, 404
CNS arousal, 342, 343 specific properties of, 78
digit-symbol substitution, 343–344 Economic evaluations in health care,
electroencephalogram (EEG), 342– 319–322
343, 345 Elderly
Leed’s Sleep Evaluation Score, 342, 343 adverse effects of first-generation H1-
memory, 342, 343 antihistamines in, 469, 470, 472
performance tests, 342, 343 allergic rhinitis and allergic rhinocon-
reaction time, 342, 343 junctivitis in, 473, 476
sensory, 343 anaphylactoid reactions in, 478
sleep latency, 342, 343, 345, 349 atopic dermatitis in, 477, 478
Stanford Sleepiness Scale, 342, 343 drug-drug interactions in, 150, 474,
subjective tests/self-rating, 342, 343 475, 478, 479
Drug-drug interactions, 150, 474–475, pharmacokinetic profiles of H1-antihis-
478, 479 tamines in, 150, 472
Drugs polypharmacy in, 465
anaphylaxis and, 288, 290, 291, 305– prophylaxis of anaphylactoid reac-
307 tions in, 478
associated with torsade de pointes, pruritus in, 477
409, 410 safety of second-generation H1-antihis-
Duration of action of H1-antihistamines, tamines in, 470–473
155 urticaria in, 476–477
Dyskinesias, from first-generation H1- Emedastine, 77, 196
antihistamines, 470 Emesis, first-generation H1-antihista-
mines in treatment of, 72
Endothelial cells, histamine effect on,
Early allergic response to allergen, 102, 10
111–113, 117–119, 121 Eosinophilic chemotactic protein (ECP),
Early Treatment of the Atopic Child 104, 114, 115, 117, 118, 121, 123,
(ETAC) Study, 447–449, 453 126–128
Ebastine, 78 Epinastine, 77, 152, 196
adult dose, 156 Erythromycin, interactions of H1-antihis-
allergic rhinoconjunctivitis, 195, 196, tamines and, 149, 401, 402
199 Ethanolamine H1-antihistamines, 74, 75,
antiallergic effects, 116, 117 338
490 Index
Ethylenediamine H1-antihistamines, 74, [First-generation H1-antihistamines]

338 CNS adverse effects and, 72, 73, 338,
Exercise-induced anaphylaxis, 305 347, 348
dyskinesia from, 470
emesis and, 72
Fexofenadine, 78, 79 gastrointestinal adverse effects, 74, 75
adult dose, 156 memory loss from, 470
allergic rhinoconjunctivitis, 193, 194, motion sickness and, 72
197, 205 postural hypotension from, 470
antiallergic effects, 117 reactions following overdose, 268,
assay for, 146 451–453
cardiac safety in children, 454, 455 urinary retention, hesitancy from,
CNS effects, lack of, 361, 375 470
chemical structure, 142 Fluorescein, reaction to, 304
chronic urticaria, 263–267 Food and Drug Administration preg-
pediatric dose, 442 nancy categories, 423, 424
pharmacodynamics, 152, 154, 155,
164
G proteins, 35–40, 43, 45–48
pharmacokinetic/pharmacodynamic
Gastrointestinal system
map, 440
anaphylaxis-related actions of hista-
pharmacokinetics, 148, 163, 164
mine on, 298
pharmacokinetics in special popula-
disturbances due to H1-antihistamines,
tions, 150, 439, 440
74
pregnancy and, 427, 430
Grapefruit juice, interaction of H1-anti-
QT interval, no effect on, 404, 405
histamines and, 402, 403
safety in elderly, 471–473
GT-2331/(Perceptin), 31
skin concentrations of, 154
specific properties of, 78, 79
First-generation H1-antihistamines (see H1-antihistamines
also names of first-generation H1- adverse effects unrelated to H1-recep-
antihistamines) tor, 71, 72
activation of epileptogenic foci from, anaphylaxis and, 300–308
470 antiallergic activity, 70, 71, 101–139,
adverse effects in children, 450–453 188–190, 300
adverse effects in the elderly, 469, cardiac side effects, 73, 74, 389–419
470, 472 chemical structure, 67, 68, 142
alpha-adrenergic blockade from, 72 chemistry, 66–69
analgesic effects of, 72 clinical pharmacology of, 141–178
anticholinergic adverse effects of, 71, CNS effects, 72, 73, 337–388
470 combined with H2-antihistamines in
assessment of CNS effects of, 342– anaphylaxis, 301–308
347 duration of action in allergic rhinocon-
attempts to avoid sedation from, junctivitis, 187, 188
348–351 effects on QT interval, 394, 395
chronic urticaria and, 268, 269 effects related to H1-receptor-medi-
classification, 74, 75 ated responses, 69, 70
Index 491
[H1-antihistamines] [H2-receptor]
gastrointestinal disturbances, 74 mRNA in nasal mucosa, 7
mechanism of action, 228, 229 selective ligands for, 29, 30
onset of action in allergic rhinocon- signal transduction of, 45–47
junctivitis, 185, 186 H3-receptor
tumor-promoting effects, 74 biochemistry, 36, 37
H1-receptor chemical structure of agonists and an-
biochemistry, 32, 33 tagonists, 31
calcium signaling and, 40, 41 cloning of gene for, 37
chemical structure of agonist and an- heterologous expression of, 36, 37
tagonists, 29 molecular biology, 37
chromosomal localization of gene for, selective ligands for, 30–32
33 signal transduction of, 47
cloning of gene for, 33, 34 H4-receptor
constitutive signaling of, 43–44 cloning of gene for, 37, 38
cyclic AMP and, 43 protein, 37, 38
knockout mice, 35 selective ligands for, 32
molecular biology, 33–35 signal transduction of, 48
molecular model, 34 Half-life of H1-antihistamines (see Phar-
mRNA in nasal mucosa, 7 macokinetics)
nitric oxide synthase, 41, 42 Hay fever (see Allergic rhinoconjunctiv-
phospholipase A2 activation and, itis)
42 Heart
phospholipase C signaling, 38, 39 anaphylaxis-related action of hista-
phospholipase D stimulation and, mine on, 297, 298
42, 43 Heparin, as a mediator of anaphylaxis,
selective ligands for, 28, 29 292
signal transduction of, 38–45 Hepatic dysfunction, H1-elimination,
H2-antihistamines 149–151
allergic rhinitis and, 184, 185 Hepatic metabolism of drugs, 401–403
anaphylaxis and, 307, 308 HERG K⫹ channel, 454
chronic urticaria and, 266–271 Histamine
effect on elimination of H1-antihista- allergic rhinoconjunctivitis and, 13–
mines and, 270 15, 181–185
prevention of anaphylactic and ana- anaphylaxis and anaphylactoid
phylactoid reactions, 301–307 reactions, 16, 19, 292, 294–
H2-receptor 299
adenylcyclase stimulation, 45 asthma and, 12, 13, 224–228
biochemistry, 35, 36 atrioventricular node conduction
chemical structure of agonists and an- and, 7
tagonists, 30 bacteria and, 8, 9
chromosomal localization of gene for, bronchial smooth muscle and, 7
35, 36 cell recruitment and, 10, 11
cloning of gene for, 36 cellular localization of, 1, 2, 9
constitutive signaling, 47 chemical structure of, 67
molecular biology, 36 common cold and, 17, 18
492 Index
[Histamine] Idiopathic anaphylaxis, 304

early and late allergic reaction and, Imetit, 31
9–12, 102, 112, 114–117 Immepip, 31
effects on inflammatory cell recruit- Immunoglobulin E, 102, 104
ment, 10, 11, 230–232 Informed consent, 433, 443
effects on mediator release, 229, Insect stings, 288
230 Intercellular adhesion molecule-1
effects, overview of, 1–25 (ICAM)-1, 103, 104, 110, 111,
endothelial cells and, 10 114–117, 123, 126, 184, 189, 190,
glands and, 7 201
heart and, 7, 297, 298 Intranasal corticosteroids, 193, 198
levels, 182, 299 Itraconazole
metabolism of, 3, 466 interaction of H1-antihistamines and,
molecular model of, 34 149, 150, 401, 402
nasal polyps and, 13
Ketoconazole, interaction of, H1-antihis-
neurons and, 7
tamines and, 149, 150, 401, 402,
otitis media and, 15, 16
405, 406
plasma concentrations of, 299
Ketotifen, 80, 81
release, 4, 5, 466
antiallergic effects of, 117, 118, 127
sinusitis and, 13
asthma and, 233–237
structure, 29, 76
asthma prevention in young children,
synthesis, 1, 466
447
urticaria and, 17
chronic urticaria and, 261, 273
vascular permeability and, 7, 9, 10
CNS adverse effects of, 357, 359,
vasodilation and, 7, 9, 10
366, 367, 370
vernal conjunctivitis and, 15
effect on histamine and prostaglandin
Histamine receptors, 6–8, 467–469
D2 release, 117
activities mediated through histamine
effect on response to nasal challenge,
receptors, 7
117, 118, 127
in anaphylaxis, 295, 296
specific properties of, 80, 81
(see also H1-receptor; H2-receptor;
H3-receptor; H4-receptor) Lactation, H1-antihistamine use during,
Histaprodifen, 29 424–425, 432
Hydroxyzine Late-phase response after allergen chal-
cardiac toxicity of, 404 lenge, 102, 103, 110, 111, 119, 121
CNS adverse effects in children, Latex-induced anaphylaxis, 305
451–453 Leukotrienes (LTC4, LTD4) as mediators
CNS adverse effects of, 345, 354– of anaphylaxis
356 allergic response, 102, 109, 113, 116,
elimination half-life in adults, 141 117, 119–121, 125–128
in atopic dermatitis, 449 allergic rhinoconjunctivitis, 181, 188
in urticaria, 260, 264, 265, 268, 273, asthma, 226
274 in anaphylaxis, 292
pharmacokinetics and pharmacody- Leukotriene modifiers
namics in children, 439 combined with H1-antihistamines in
pregnancy and, 427, 428 asthma, 226, 227
Index 493
Levocabastine, 68, 79 Lower airways linked with upper air-

adult dosage, 156 way, 237–240
allergic rhinoconjunctivitis, 118–120,
186–189, 200–202 Major basic protein, 118, 127
antiallergic effects, 118, 119, 127 Mast cells
assay for, 146 in conjunctiva in allergic rhinitis,
CNS adverse effects, 367 182
chemical structure, 142 in nasal mucosa in allergic rhinitis,
pediatric dose, 442 181
pharmacodynamics, 155, 165, 166 in the airways, 222, 223
pharmacokinetics, 148, 165 subtypes, 2
pharmacokinetics in special popula- Mastocytosis, H1-antihistamines in chil-
tions, 150 dren with, 447, 448
pregnancy and, 427, 430 Mepyramine (pyrilamine), 29, 66, 67,
specific properties of, 79 232
Levocetirizine, 77, 180, 196 Meta-analysis
low potential for cardiac toxicity, H1-antihistamines in allergic rhinitis,
454, 456 330
Long QT syndrome, 408, 411 H1-antihistamines in asthma, 233,
Loratadine, 234
acute urticaria, 255 Mizolastine, 79, 80
adult dose, 156 adult dose, 156
allergic rhinoconjunctivitis, 186, allergic rhinoconjunctivitis, 194, 195,
188–190, 193, 197, 198, 199, 199
205, 445 antiallergic effects, 125
antiallergic effects, 119–125 assay for, 146
assay for, 146 CNS effects, lack of, 356, 364, 365,
cardiac safety in children, 454, 455 374
CNS effects, lack of, 354, 355, 357– chemical structure, 142
362, 367, 370, 372, 373, 453 chronic urticaria, 263, 265
chemical structure, 142 pediatric dose, 442
chronic urticaria, 262–265 pharmacodynamics, 155, 157, 168
HERG K⫹ channel and, 454 pharmacokinetics, 148, 167, 168
pediatric dose, 442 pharmacokinetics in special popula-
pharmacodynamics, 152, 155, 166, tions, 150
167 population pharmacokinetics, 147
pharmacokinetics, 148, 166 QT interval, 406
pharmacokinetics in special popula- specific properties of, 79, 80
tions, 150, 439 tachyphylaxis, absence of, 157
pregnancy and, 427, 430 Monoamine oxidase (MAO) inhibitors
QT interval, 404 and H1-antihistamines, 469, 475
safety in the elderly, 471–473 Morphine, anaphylactoid reactions to,
specific properties of, 79 306
Lorazepam, CNS effects of coadminis- Mosquito bite reactions, 449
tration of Motion sickness, effect of first-genera-
H1-antihistamines with, 371–374 tion H1-antihistamines in, 72
494 Index
Mucosal inflammation and histamine re- Pharmacoeconomics, overview of, 319–

lease 323
conjunctivitis, 182 Pharmacokinetics and pharmacodynam-
rhinitis, 181, 182 ics of
acrivastine, 148, 150, 155, 158, 159
N-acetylcysteine azelastine, 148, 150, 153, 155, 159,
anaphylactoid reactions to, 307 160
Nasal airway cetirizine, 143, 144, 148, 150, 152,
hyperreactivity to methacholine, 104, 153, 155, 160, 161, 439
105, 114, 121, 122 desloratadine, 148, 150, 155, 162
inspiratory peak flow, 107 ebastine, 143, 144, 148, 150, 152,
resistance, 106, 107 155, 162, 163, 439
secretions, 107 fexofenadine, 148, 150, 152, 154,
volume, 107 155, 163, 164, 439, 440
Neurons levocabastine, 148, 150, 155, 165,
see also Central nervous system 166
[CNS] loratadine, 148, 150, 152, 155, 166,
histamine and, 7 167, 439
Neuropsychiatric reactions to H1-antihis- mizolastine, 147, 148, 150, 155, 157,
tamines, 470 167, 168
Nitric oxide synthase, 41 second-generation H1-antihistamines,
Nonallergic rhinitis 141–178
H1-antihistamine therapy in, 206 Pharmacokinetics and pharmacodynam-
Nonallergic rhinitis with eosinophils ics of H1-antihistamines in chil-
(NARES), 206 dren, 438–441
Norastemizole (see Tecastemizole) Pheniramine
pregnancy and, 429
Phenothiazine H1-antihistamines, 75
Off-label H1-antihistamine use, 449, 450 Phenylpropanolamine, 203
Olopatadine Physical urticarias (see Urticaria)
allergic rhinitis and, 200 Piperazine H1-antihistamines, 75, 338
pregnancy and, 427 Piperidine H1-antihistamines, 75, 338
Onset of action of H1-antihistamines, Plasma exchange, anaphylaxis to, 304
155 Pollen chamber, 186
Otitis media, H1-antihistamines in chil- Polypharmacy in the elderly, 465
dren with, 446 Population pharmacokinetics of H1-anti-
Overdose, of H1-antihistamines, 451– histamines, 145, 147, 149
453, 456 Potassium ion channel blockade, 408–
Oxatomide, 81, 125, 129 410
antiallergic effects of, 125, 128, 129 Pregnancy, H1-antihistamine use during,
421–436
Perennial allergic rhinitis, oral H1-anti- azelastine, 430
histamines and, 198–200 brompheniramine, 426–428
Pharmacodynamics cetirizine, 427, 428, 430
of H1-antihistamines, 151–155, 157– chlorpheniramine, 426–428
168 dexchlorpheniramine, 427, 428
Index 495
[Pregnancy, H1-antihistamine use during] QT interval

diphenhydramine, 427–429 effect of H1-antihistamines on, 403–
fexofenadine, 427, 430 406
hydroxyzine, 427–429 measurement of, 394, 395
levocabastine, 427, 430 prevention and treatment of H1-antihis-
loratadine, 427, 430 tamine drug-induced prolongation
olopatadine, 427, 430 of, 410, 411
pheniramine, 427–431 prolongation by disease and other bio-
tripelennamine, 427–429 logical factors, 408, 410
triprolidine, 427–429 prolongation by drugs, 395–397, 408,
Pregnancy, informed consent for H1-anti- 409
histamine use during, 433
Pregnancy categories, Food and Drug R-(⬀)-Methylhistamine, 31
Administration, 424 Radiocontrast materials (RCM), 302–
Prevention of asthma in young children 304
cetirizine, 447, 448 Ranitidine
ketotifen, 447 chemical structure, 30
loratadine, 447 in anaphylaxis, 301, 303
Promethazine in urticaria, 269, 274
adverse effects, 339, 347, 348 Renal dysfunction
antiemetic effect of, 453 H1-antihistamine elimination in, 149–
CNS adverse effects of, 452 151
urticaria, 273 Residual action (after stopping) of H1-
Prostaglandin (PGD2) antihistamines, 155
as mediators of anaphylaxis, 292 Respiratory system
in allergic rhinitis, 181, 185, 189 anaphylaxis-related actions of hista-
in the allergic response, 102, 109, mine on, 298
113, 116, 119, 120, 121, 126– Rhinitis
128 see also Allergic rhinoconjunctivitis
Protamine, anaphylaxis to, 306, 307 nonallergic, 206
Pruritus in the elderly, H1-antihistamines vasomotor, 473
and, 477 Rupatadine
Pseudoephedrine, 151, 445, 203–205 allergic rhinitis, 196
Psychomotor impairment from H1-anti-
histamines, 342–347 Seasonal allergic rhinitis, oral H1-antihis-
Pyrilamine (mepyramine), 29, 66, 67, tamines and, 190–198
232 Second-generation H1-antihistamines
see also individual second-generation
Quality-of-life, health-related, 322, H1-antihistamines
323 adverse effects in elderly, 470–473
desloratadine and, 193 assays for, 145, 146
fexofenadine and, 197 assessment of CNS effects of, 342–
H1-antihistamines and, 327–330 347
in rhinoconjunctivitis, 322, 323 chemical structure, 68, 142
loratadine and, 197 chronic urticaria and, 261–266
questionnaires, 323 classification of, 339
496 Index
[Second-generation H1-antihistamines] [Structure and classifications of H1-anti-

CNS effects, lack of, 339, 352–353 histamines]
comparison of CNS effects, 368– ketotifen, 80, 81
370 oxatomide, 81
duration of action, 155 six major groups of, 67
general properties of, 76 structural formulas of second-genera-
high doses and CNS effects, 368 tion H1-antihistamines, 68, 142
onset of action of, 155 tumor-promoting effects, 74
overdose of, 456
pediatric adverse effects, 453–456 Tachyphylaxis, lack of, to second-gener-
pharmacokinetics and clinical pharma- ation H1-antihistamines, 155
cology of, 141–178 (TAME)-esterase, 109, 113, 118, 121,
residual effect after stopping, 155 122, 126–128
tachyphylaxis, lack of, 155 Tecastemizole (norastemizole), 77, 180
Sedative effects of H1-antihistamines, Terfenadine, 68, 80
353, 368–370 cardiac toxicity, 340, 407, 453, 454
coadministration of alcohol or CNS- CNS effects, 354, 355, 357–359, 364,
active medications and H1-antihista- 366, 367, 370, 372, 373
mines, 371–375 Teratogenicity, 423, 424
H1-antihistamines, 353, 368–370 Thioperamide, 31
Side effects of H1-antihistamines Tiotidine, 30
adverse effects (see Cardiac toxicity; Topical application of H1-antihistamines
CNS toxicity) CNS effects, lack of, 353, 366–368
Signal transduction, conjunctivitis, 77, 202
of the H1-receptor, 38–45 rhinitis, 77, 200–202
of the H2-receptor, 45–47 skin, 451, 477
of the H3-receptor, 47 Torsade de pointes
of the H4-receptor, 48 biological factors predicting, 408, 410
Skin drug-induced, 395–398
H1-antihistamine concentrations in, drugs that may lead to, 408, 409
154, 164 mechanisms in, 390–394
Solar urticaria (see Urticaria) physicochemical properties of H1-anti-
Stimulatory effects of H1-antihistamines histamines leading to, 400
in CNS, 452, 470 potassium channel blockade by H1-an-
Structure and classifications of H1-anti- tihistamines and other drugs, 399
histamines rhythm strip in, 398
antiallergic activities, 70, 71 Tranquilizers
azelastine, 80 interactions with first-generation H1-
cardiac adverse effects, 73, 74 antihistamines, 371–374
central nervous system adverse ef- Transmembrane signaling, 38–47
fects, 72, 73 signal transduction of the H1-receptor,
chemistry, 66–69 38–45
effects related to H1-mediated re- signal transduction of the H2-receptor,
sponses, 69, 70 45–47
effects unrelated to H1-activity, 71, 72 signal transduction of the H3-receptor,
gastrointestinal disturbances, 74 47
Index 497
Trimeprazine [Urticaria]
urticaria, 273 guidelines for use of H1-antihista-
Tripelennamine mines in treatment of, 258–280
pregnancy and, 427, 428, 429 H1-antihistamines in children with,
Triprolidine 447–449
CNS adverse effects of, 347, 348, H2-antihistamines in, 266–271
354, 355, 358, 360, 362, 363, 364, histamine and urticaria, 251, 252
366, 367 hydroxyzine in, 260, 264, 265, 268,
elimination half-life in adults, 141 273, 274
pregnancy and, 429 in the elderly, 476–477
Tryptase in allergic response, 112, 119, ketotifen in, 261
121, 127, 128, 185 loratadine in, 255, 262–265
Tumor-promoting effects of H1-antihista- mizolastine in, 263, 265
mines, lack of, 74 pathophysiology of, 251, 252, 256,
257
Uncontrolled allergic disease during physical urticarias, 272–279
pregnancy, risks of, 424 prognosis, 252
Upper airway, links with lower airway, second-generation H1-antihistamines
237–240 in, 261–266
Upper respiratory tract infection (see solar, 275, 278
Common cold), treatment of chronic idiopathic, 258–
H1-antihistamines in, 205 271
in children with, 445, 446 urticarial vasculitis, 252, 279
Urine, histamine in, 2 Urticaria and angioedema (see Urticaria)
Urticaria Urticarial vasculitis, 252, 279 (see also
acute, 255, 447, 448, 449 Urticaria)
cetirizine in, 262, 264, 274, 275
chlorpheniramine in, 260, 268, 269, Vancomycin, anaphylactoid reactions to,
273 306
cholinergic, 276, 277 Vasculature
chronic idiopathic, 255–257 anaphylaxis-related actions of hista-
cinnarizine, 275 mine on, 296, 297
classification of, 250 histamine effect on permeability of,
cold, 275, 277, 278 6, 7, 10, 14, 17, 251, 294, 296,
cost-effectiveness of H1-antihista- 297, 467, 468
mines in, 331–332 Vasodilation, histamine effect on, 7, 13,
cyproheptadine in, 268, 273, 275 14, 17, 251, 294, 296, 297, 467,
delayed pressure, 252, 278, 279 468
dermographism, 272–274, 276, 278, Vasomotor rhinitis, 473
279 Volume expanders
diagnosis of, 257 anaphylaxis from, 304
doxepin in, 260, 261, 275 Volume of distribution of H1-antihista-
fexofenadine in, 264–267 mines (see Pharmacokinetics)
first-generation H1-antihistamines in,
259–261 Wheal and flare, 151–155, 157–158,
general management of, 252–254 160–161, 163, 164, 166–168
About the Editor
F. ESTELLE R. SIMONS, M.D., is Professor and Head of the Section of Allergy

and Clinical Immunology at the University of Manitoba, Winnipeg, Canada. Dr.
Simons is an elected member of the Board of Directors of the World Allergy
Organization and of the Collegium Internationale Allergologicum. She currently
serves as Secretary-Treasurer of the American Academy of Allergy, Asthma, and
Immunology (AAAAI) and as an AAAAI Board of Directors member. She is
past Chair of the AAAAI Postgraduate Education Committee, the AAAAI Com-
mittee on Drugs, and the AAAAI Asthma, Rhinitis, and Other Respiratory Disor-
ders Interest Section. She is also a past President of the Canadian Society of
Allergy & Clinical Immunology and past Chair of the Allergy Section of the
Canadian Pediatric Society, the Royal College of Physicians and Surgeons of
Canada Specialty Committee in Clinical Immunology and Allergy, and the Royal
College Examining Board in Clinical Immunology and Allergy. Dr. Simons is
the author or coauthor of over 300 peer-reviewed publications in allergy and
clinical immunology and serves on the editorial board of The Medical Letter and
several other journals. A Fellow of the Royal College of Physicians and Surgeons
of Canada and a Diplomate of the American Board of Pediatrics and the American
Board of Allergy and Clinical Immunology, she received the B.Sc. (1965) and
M.D. (1969) degrees from the University of Manitoba, Winnipeg, Canada.

Histamine and H1-Antihistamines in Allergic Disease PDF

Загружено:

Сведения о документе

Оригинальное название

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Histamine and H1-Antihistamines in Allergic Disease PDF

Загружено:

Авторское право:

Доступные форматы

Histamine and H1-Antihistamines

Marcel Dekker, Inc. New York • Basel

Copyright © 2002 by Marcel Dekker, Inc. All Rights Reserved.

This book is printed on acid-free paper.

Eastern Hemisphere Distribution

World Wide Web

Copyright  2002 by Marcel Dekker, Inc. All Rights Reserved.

Current printing (last digit):

PRINTED IN THE UNITED STATES OF AMERICA

Michael A. Kaliner, M.D.

‘‘Yet all experience is an arch wherethro’

Part I. Histamine and Histamine Receptors

1. Histamine in Health and Disease 1

2. Histamine Receptors: Speciﬁc Ligands, Receptor Biochemistry,

Part II. H1-Antihistamines: Basic Science

3. Structure and Classiﬁcation of H1-Antihistamines and Overview

4. Antiallergic Anti-Inﬂammatory Effects of H1-Antihistamines

5. Clinical Pharmacology of H1-Antihistamines 141

Part III. H1-Antihistamines: Clinical Science

6. Antihistamines in Rhinoconjunctivitis 179

7. H1-Antihistamines in Asthma 221

8. Antihistamines in Urticaria and Angioedema 249

9. Histamine and Antihistamines in Anaphylaxis 287

10. Cost-Effectiveness of H1-Antihistamines 319

Part IV. H1-Antihistamines: Potential Adverse Effects

11. H1-Antihistamines and the Central Nervous System 337

12. Potential Cardiac Toxicity of H1-Antihistamines 389

Part V. H1-Antihistamines: Special Populations

13. H1-Antihistamines in Pregnancy and Lactation 421

14. H1-Antihistamines in Children 437

15. H1-Antihistamines in the Elderly 465

Paraya Assanasen, M.D. University of Chicago, Chicago, Illinois

Remko A. Bakker, M.Sc. Leiden/Amsterdam Center for Drug Research, Vrije

James N. Baraniuk, M.D. Georgetown University, Washington, D.C.

Jean Bousquet, M.D. Montpellier University, Montpellier, France

A. John Camm, M.D., F.R.C.P., F.A.C.S., F.E.S.C. St. George’s Hospital

G. Walter Canonica, M.D. Genoa University, Genova, Italy

Malcolm W. Greaves, M.D., Ph.D., F.R.C.P. National University of Malay-

Stephen T. Holgate, B.Sc., M.D., D.Sc., F.R.C.P., F.R.C.Path., F.I. Biol.,

Peter Howarth, B.Sc. (Hons.), D.M., F.R.C.P. University of Southampton,

Philip L. Lieberman, M.D. University of Tennessee College of Medicine,

James L. Lordan, M.B., M.R.C.P.I., B.Sc., D.C.H., D.M.E., D.Obs. Univer-

Robert M. Naclerio, M.D. University of Chicago, Chicago, Illinois

Giovanni Passalacqua, M.D. Genoa University, Genoa, Italy

M. Susana Repka-Ramirez, M.D. Georgetown University, Washington, D.C.

Michael Schatz, M.D., M.S. Kaiser-Permanente Medical Center, San Diego,

F. Estelle R. Simons, M.D., F.R.C.P. University of Manitoba, Winnipeg, Man-

Keith J. Simons, M.Sc., Ph.D. University of Manitoba, Winnipeg, Manitoba,

Hendrik Timmerman, Ph.D. Leiden/Amsterdam Center for Drug Research,

Stephen L. Winbery, M.D., Ph.D. Methodist Central Hospital Teaching Prac-

Histamine and H1-Antihistamines in Allergic Disease, Second Edition, Revised

clinically relevant, others, such as down-regulation of transcription by nuclear

firms that it no longer suffices to assess a medication’s clinical efficacy. It is also

formulations, the old sedating H1-antihistamines, which are still an important

M. Susana Repka-Ramirez and James N. Baraniuk

Table 1 Distribution of Human Mast Cell Subtypes

Human mast cell

Source: Data from Ref. 5.

histidine decarboxylase (3). It is stored preformed in cytoplasmic granules of

B. Central Nervous System

C. IgE-Mediated Histamine Release

(FCεRIαβγ) by multivalent antigens is necessary. IgE binds to the α subunit,

D. Non-IgE-Mediated Histamine Release