J. Vet. Pharmacol. Therap. 36, 105--115. doi: 10.1111/jvp.12041.

REVIEW ARTICLE

Veterinary pharmacology: history, current status and future prospects1

P. LEES* Lees, P., Fink-Gremmels, J., Toutain, P. L. Veterinary pharmacology: history,

J. FINK-GREMMELS & † current status and future prospects. J. vet. Pharmacol. Therap. 36, 105–115.
P. L. TOUTAIN ‡
*The Royal Veterinary College, Hawkshead
Campus, Hatfield, Herts, UK; †Faculty of
Veterinary Medicine, Veterinary Pharmaco-
logy, Pharmacotherapy and Toxicology, Utr-
echt University, Utrecht, Holland; ‡Ecole
Nationale Veterinaire de Toulouse, Toulouse,
France
Veterinary therapeutics, based on the art of Materia Medica, has been
practised for countless centuries, but the science of veterinary pharmacology
is of very recent origin. This review traces the contribution of Materia
Medica to veterinary therapeutics from the Egyptian period through to the
Age of Enlightenment. The first tentative steps in the development of the
science of veterinary pharmacology were taken in the 18th century, but it
was not until the mid 20th century that the science replaced the art of
Materia Medica. This review traces the 20th century developments in
veterinary pharmacology, with emphasis on the explosion of knowledge in
the 35 year period to 2010. The range of factors which have influenced the
current status of the discipline are reviewed. Future developments are
considered from the perspectives of what might be regarded as desirable and
those innovations that might be anticipated. We end with words of
encouragement for young colleagues intent upon pursuing a career in
veterinary pharmacology.
(Paper received 17 January 2013; accepted for publication 17 January 2013)
Peter Lees, D Sc, The Royal Veterinary College, Hawkshead Campus, Hatfield,
Herts., AL9 7TA, UK. E-mail: plees@rvc.ac.uk

INTRODUCTION
THE DOMINANCE OF THERAPEUTICS BY MATERIA
MEDICA
This manuscript is dedicated to those many colleagues from
previous generations, who laid the foundations of veterinary
We should remind ourselves that, based on the art/science of
pharmacology and toxicology, the twin disciplines served by
Materia Medica, veterinary therapeutics is an old discipline,
EAVPT, ECVPT, AAVPT and ACVCP. The manuscript is direc-
whereas the discipline of veterinary pharmacology is a new
ted especially to those young colleagues in many countries
science - <100 years old; indeed, it has emerged and devel-
who will carry forward these disciplines, notably those ECVPT
oped almost entirely in our working lifetimes, that is to say
Residents, who have recently achieved or who aspire to mem-
post 1960. When in 1968 Frank Alexander, a pioneer of vet-
bership of the European College. We trust that they, like their
erinary pharmacology, was elected to a personal chair in vet-
forbears, will devote their working lives to the pursuit of
erinary pharmacology at Edinburgh University, he delivered
excellence in our disciplines, as teachers, researchers and regu-
an inaugural lecture entitled: ‘Materia Medica to veterinary
lators in academia, industry or regulatory affairs. Between
pharmacology: a transition’ (Alexander, 1969) to explain why
them, the three co-authors of this lecture have devoted
and how the teaching of Materia Medica that persisted up to
upwards of 130 years of effort to this cause, which therefore
1952 at the ‘Dick vet’ school was replaced by veterinary phar-
clearly implies that the baton must soon be passed on to our
macology, a discipline having its own legitimacy. At least
younger colleagues. We encourage our successors to note
97%, perhaps 99%, of drugs currently licensed for veterinary
that the intellectual rewards of a career in veterinary phar-
use have been introduced in the last 50–60 years. This has
macology and toxicology are there for the taking. As the
been a monumental achievement (transforming animal health
early English chemist Humphrey Davey remarked, ‘there has
and welfare for the better), to which individuals in academia
never been a higher source of satisfaction than the pursuit of
and regulatory affairs have made major contributions. How-
science’.
ever, most of all, it stands to the credit of colleagues in the
pharmaceutical industry – they have made this transformation
possible.
1 Over at least 30 centuries prior to the 19th century, human
Presented by Peter Lees as a plenary lecture during the 12th
International Congress of the European Association for and animal diseases were treated with a range of botanical,
Veterinary Pharmacology and Toxicology, held in mineral and other natural substances, described (often in great
Noordwijkerhout, The Netherlands, 8–12th of July, 2012. detail) in various Materia Medica texts. These have been dis-

© 2013 Blackwell Publishing Ltd 105

106 P. Lees et al.
cussed in several excellent 20th century reviews (Alexander,
1969; Davis, 1984; Van Miert, 2000; Appelgren, 2009; Cun-
ningham et al., 2010). The latter author has traced these early
beginnings through the Egyptian, Greek, Latin and European
medieval periods, to the Age of Enlightenment and on into the
19th and 20th centuries. In the Egyptian period, the plants
used therapeutically were described in various papyri, the con-
tents of which became known with the translation of the
Rosetta stone in 1822. The Ebers papyrus (1150 B.C.) covering
15 prior centuries contained more than 800 prescriptions for
plasters, pills, suppositories and other dosage forms for specific
conditions. In India, Buddha not only prohibited the vivisec-
tion of animals, but established animal hospitals throughout
the country. Later, Arrian, a Greek historian, described the
conditions and medications in such animal hospitals (Pinjra-
poles) at the time of the invasion of Alexander the Great. The
Greek period, however, was dominated by the writings of
Hippocrates (430 BC) and later those of Galen (94 AD). The
former used extracts of the bark of the willow tree to ease the
pain of childbirth. Interest in Salix alba revived in 1792 when
an English clergyman, Edward Stone, described its antipyretic
properties. However, domination of the views of Hippocrates
and Galen persisted for some 1400 years up to the Age of
Enlightenment.
In the early 16th century, the Swiss physician, Paracelsus,
introduced into human medicine laudanum (opium) and a
range of extracts of various plants. He has achieved everlast-
ing fame through his dictum that ‘all substances are poisons;
there is none which is not a poison. The proper dose sets a
poison from a remedy’. As Appelgren (2009) points out, con-
cern was expressed at this time, relating to the use of plant
extracts therapeutically in animals on the basis of human
experience. The great Swedish botanist and doctor Carolus
Linnaeus voiced this concern, in stating: ‘human medicines
are used for animals without knowledge if they work, which
is devastating barbarism’ - a prescient thought for those of us
interested in the 21st century in refining dosage schedules to
optimize efficacy and minimize side effects through the appli-
cation of pharmacodynamic (PD) and pharmacokinetic (PK)
principles and data.
EARLY DEVELOPMENTS IN PHARMACOLOGY
INCLUDING VETERINARY ASPECTS
The 16th and 17th centuries marked the beginning of the
experimental paradigm in biology and medicine, including
early pharmacological studies. Jesuit priests brought to Europe
the bark of the Cinchona tree from South America and applied
its antipyretic properties as the first antimalarial drug. In
1656, Sir Christopher Wren observed the effects of intravenous
opium in the dog, and in 1783, William Withering described
the use of extracts of foxglove in patients with congestive heart
failure.
Many of the experiments conducted, and therefore, much of
the data generated from the early 19th century on were
necessarily obtained from animal studies. By modern stan-
dards, these were often barbaric, being conducted in the
absence of anaesthetics. Nevertheless, in the early 19th
century, the French physiologists/pharmacologists Magendie
and Pelletier introduced a new period of drug discovery by
experimentation, injecting plant extracts of Papaver somniferum
(containing opium alkaloids) and Nux vomica (containing
strychnine) intravenously. Magendie further showed that
drugs can be absorbed into the circulation after oral dosing to
exert systemic effects. From these investigations, Magendie
and Pelletier developed a formulary prescribing dosages for
administration to animals. In the mid-19th century, Claude
Bernard, a student of Magendie, commenced the process of
extraction of active principles from plants, such as the skeletal
muscle relaxant, d-tubocurarine from curare, previously
known as a South American arrow poison. He demonstrated
its action in paralysing skeletal muscle without affecting CNS
functions.
Through the work of these and other early pioneers, the
science of pharmacology was starting to emerge in the early-
mid 19th century. By mid century, further advances were
facilitated by the rapid progress achieved in methods for
extracting and purifying drugs from plants, combined with
advances in analytical and synthetic organic chemistries.
These led, for example, to the recognition of the glycoside sali-
genin as the active principle in the bark and leaves of the wil-
low. By 1875, there followed the introduction of first sodium
salicylate, then phenacetin and then aspirin, as first genera-
tion analgesic/nonsteroidal anti-inflammatory drugs. However,
the sequence of events leading to the introduction of aspirin
in 1895 commenced several centuries BC, with use of the
willow bark and leaves by Hippocrates followed by a descrip-
tion of its properties in the first century AD by Dioscorides in
the first true pharmacopoeia. The antipyretic properties of the
willow were rediscovered in the 17th century by the Reverend
Edward Stone of Chipping Norton, UK. There was, however,
only limited veterinary therapeutic use of aspirin prior to
1972. In this year, Lloyd Davis and colleagues published what
was perhaps the most game changing publication in veteri-
nary pharmacology to that date (and even now) on ‘species
differences in transformation and excretion of salicylate’. Davis
and Westfall (1972) reported on salicylate half-life values in
the goat (0.8 h), horse (1 h), pig (5.9 h), dog (8.6 h) and cat
(37.6 h). They thus revealed the utter futility of extrapolating
dose regimens from one species to another, a common prac-
tice prior to that time. PK differences were and remain the
cornerstone of veterinary pharmacology, but pre-1970, they
were largely unknown; this was principally due to the
unavailability of analytical techniques for establishing plasma
concentration–time relationships, with the exception of a few
drugs of low potency, such as salicylate and drugs of the
sulphonamide group.
Three other great achievements in chemical and biological
sciences had been made by the mid-late 19th and early 20th
centuries. First, an increasing understanding of the chemistry
and physiology of the body led to the emergence of biochemis-
© 2013 Blackwell Publishing Ltd

try and to recognition that hormones and neurotransmitters
interact either with enzymes or ‘receptive sites’ on cell mem-
branes or intracellular organelles to trigger chain reactions
leading to physiological responses. From this knowledge, it was
only a short step to recognize that both older and new drugs
were acting on these same sites to elicit their responses, both
beneficial and harmful. Secondly, the researches of Charles
Darwin led first to slow and then widespread acceptance that
evolution of all biological forms occurred through a process of
natural selection, the so-called survival of the fittest hypothesis.
This simple concept laid the foundations for all biological sci-
ences and emphasized the basis for animal species, breed and
gender similarities and differences. Darwin further used an
astonishing range of drugs and chemicals in his detailed stud-
ies on insectivorous plants. In the 20th and 21st centuries, the
most exciting advances, based on Darwinian concepts, relate to
the sciences of pharmacogenetics and pharmacogenomics; their
veterinary applications are destined to transform veterinary
therapeutics in the medium-term future. Thirdly, the discover-
ies of Louis Pasteur on several fronts were truly monumental.
For the purposes of this review, we cite two of these: (i) the
discovery of bacteria and recognition of their supremely impor-
tant role in the causation of infectious diseases, and (ii) his
work on chirality, recognizing the right- and left-handedness of
the salts of lactic acid and further recognizing that the differ-
ences between isomers extend from the crystal structure level
to the molecular level. The latter discovery carries great impli-
cations for the now widely recognized PD and PK differences
between enantiomeric drug pairs.
During the first four to five decades of the 20th century,
pharmacology emerged as a new discipline, but the scale and
application to therapeutics were limited. In the first decade,
Paul Ehrlich, the father of chemotherapy, introduced the con-
cept of selective toxicity of drugs against microbial cells, with
relative safety for mammalian cells, through the selective
uptake of dyes such as Trypan Red. His work led directly to
the introduction of the organo-arsenical group of synthetic
chemotherapeutics. Arsphenamine became available in 1910
as the first anti-syphilitic drug.
In 1935, Gerhard Domagk introduced the first systemically
effective and safe antimicrobial drug, Prontosil rubrum. It was
quickly realized that this dye was converted in vivo into the
active form, sulphanilamide. By chemical substitutions in the
sulphonamido grouping, there emerged the sulphonamide
group of broad-spectrum antibacterial drugs. The PD properties
of sulphanilamide were first reported in ruminants in 1939 by
Stableforth (1939), and the first articles on the veterinary PK
were then published on this drug class. Maclay and Slavin
(1947) reported the excretion profile in dairy cows of several
sulphonamides.
Several sulphonamides were specially developed for use in
veterinary therapeutics, after being modified by our colleague
Franco Faustini (Italy), who was moreover one of the founding
fathers of EAVPT. He held many patents on veterinary sulph-
onamides. We also note the pioneering work of Clarence
Stowe, in introducing sulphonamides into farm animal medi-
© 2013 Blackwell Publishing Ltd
Veterinary pharmacology 107
cine, and Folke Rasmussen in conducting classical studies on
sulphonamide PK in farm animal species. Meanwhile, although
penicillin had been discovered by Fleming in 1929, it was not
the Scot but a multidisciplinary team led by the Australian Flo-
rey who recognized its potential, thus opening up the new era
of antibiotics for human and animal use. The first penicillin
administration in man was in 1941, and a few years later,
when penicillin was produced on an industrial scale, Doll and
Dimock reported on the blood concentrations of penicillin in
horses (Doll & Dimock, 1946). Shortly thereafter, Doll and
Wallace (1948) described the serum concentration profile of
streptomycin in the horse.
The ‘modern area’ of veterinary antimicrobial therapy was
initiated with the regulatory approval of the first veterinary flu-
oroquinolone (enrofloxacin) in 1987, and the first third-gener-
ation cephalosporin (ceftiofur) in 1988. These two classes of
antimicrobial drugs are currently the most challenged in terms
of public health, emphasizing that veterinary medicine needs
urgently to review its antimicrobial drug armentarium, to meet
public health expectations in the 21st century. Thus, there is
now a need to develop new compounds having minimal impact
on gut flora and on environmental bacterial ecosystems. These
requirements might be met either by developing new anti-
microbial drugs or new local formulations of already available
drugs to guarantee an appropriate PK profile and/or PD selec-
tivity for target pathogens. This challenge for industry is not
unattainable. In this regard, we recall that florfenicol was
approved for food animal use in 1991 as an alternative to chl-
oramphenicol, which was banned for food safety reasons.
By 1960, drugs had become available, which could, at that
time, be described as ‘modern’. Some of these had been used in
previous decades and centuries, in the form of plant extracts or
were present in the environment, notably in soil-dwelling
micro-organisms. Others were simple chemicals produced syn-
thetically. They included digitalis glycosides, phenothiazine,
atropine, d-tubocurarine, morphine, halothane, aspirin, thi-
opentone, the sulphonamides, benzylpenicillin, streptomycin
and oxytetracycline. There were others of more dubious prove-
nance, including the flukicide and hepatotoxin carbon tetra-
chloride, which killed the flukes and sometimes the sheep as
well. Another memorable, if dubious, drug combination, com-
prising chloral hydrate, pentobarbitone and magnesium
sulphate, was guaranteed to anaesthetize any horse when
given intravenously.
The case of digitalis glycosides further illustrates major pro-
gress in clinical veterinary pharmacology and toxicology; in
the early 20th century, a major advance in human medicine
was the development of accurate radioimmunoassay methods
for determining serum concentrations of digitalis glycosides.
This enabled drug monitoring in treated patients and the corre-
lation between concentration and therapeutic and toxic effects
(as we would now describe it as a PK/PD relationship). Deitwe-
iler (1977) reported that therapeutic serum concentrations of
digoxin should not exceed 2.5 ng/mL in dogs.
Another major landmark was development of the avermec-
tins. This derived from the isolation in Japan of a soil-dwelling
108 P. Lees et al.
bacterium (S. avermitilis) and its evaluation in 1974 in the
laboratories of Merck & Co., Inc. At Merck, this organism was
shown to produce potent anthelmintic substances, leading to
the introduction of ivermectin commercially in 1981, as the
first endectocide for use in livestock. Subsequently, ivermectin
was introduced into human medicine for the treatment of
onchocerciasis (River Blindness). Ivermectin offers a unique
example of a veterinary drug subsequently developed for
human medicine, as recently reviewed by Campbell (2012).
The contribution of veterinary pharmacology to human medi-
cine is another facet of our discipline, although most veterinary
drugs derive from either the human pharmaceutical industry
(antibiotics, functional drugs) or the agrochemical industry
(insecticides, parasiticides, etc.). Our contributions derive pri-
marily from animal research studies and from innovative prac-
tices. As examples, in the 19th century, veterinarians
developed the first syringes, administered the first parenteral
medications, introduced the technique of spinal anaesthesia
and reported that diseases can be transmitted by arthropods,
as discussed by Quimby (1998).
FACTORS DETERMINING OR INFLUENCING PAST,
PRESENT AND FUTURE DEVELOPMENTS
As well as advances in biological and chemical sciences, the
emergence and continuing development of veterinary
pharmacology has depended on changes in the structures and
attitudes of global societies (Zengler and Palsson, 2012). In the
20th century, transportation and wars were transformed by the
replacement of horses by automobiles and tanks. However, with
increasing affluence, equine activities relating to competitive
sports and leisure activities have guaranteed a continuing role
for the horse in society. Dogs retain only a minor role as working
animals but now, with cats and other species, have both diversi-
fied and expanded their role as pets. Dogs and cats in particular
are now widely accepted as integral family members. For food-
producing species, the introduction of novel anthelmintics and
antimicrobial drugs to control and prevent infectious diseases
has combined with changes in husbandry practices to provide a
greatly expanded availability and affordability of meat and dairy
products, first in industrialized and more recently in developing
countries. At the same time, societies now place major and
sometimes unrealistic demands on ensuring the safety and effi-
cacy of drugs used in animals, as well as the safety of foodstuffs
derived from food-producing species. These demands add consid-
erably to development and marketing costs; the danger for the
future is that they could act as a brake on new product develop-
ment. Safety demands can also lead to the banning of drugs that
were formerly used for decades in veterinary medicine and are
still in use in human medicine. An example is metronidazole
(Flagyl©), an antiprotozoal and antibacterial agent that was
shown to be genotoxic and possibly carcinogenic in man. The
ban on this drug left the poultry industry without an effective
treatment for histomoniasis and the disease re-emerged with up
to 100% mortality in turkey flocks.
The development of more companion animal products, at
the expense of therapeutics for farm animals, has been dri-
ven, in part, by financial imperatives. The antiparasitic mar-
ket for dogs and cats has grown to a value of several billion
dollars, driven by the development of highly efficacious agents
for treating ectoparasites, with the introduction of fipronil
(1994) and imidacloprid (1996), as discussed by Woods and
Knauer (2010). Currently, fipronil is the leading drug in
respect of veterinary sales. The global extension of the
human–animal bond has further favoured the companion ani-
mal therapeutics market. An additional driving factor, in the
new ascendancy of companion animal medicines, has been
the similarities between dogs and cats and humans, both
physiologically and in disease states, such as the arthritides
and cancers. Angiotensin-converting enzyme Inhibitors, such
as benazepril, enalapril and ramipril, are now extensively
used for treating heart and kidney diseases in both canines
and felines. Relative to the time courses of development in
humans, animal diseases are often accelerated. Hence, their
study over relatively short time scales assists advances in
understanding human disease mechanisms. This facilitates the
development of new products for both human and non-
human animals. This synergy is further promoted by major
recent advances in our understanding of the molecular basis
of disease processes and drug actions.
Also significant for future advances in therapeutics is the
impact of economic factors on medicine in general and
veterinary pharmacology in particular. At the present time, the
elephant in the European room is the Great Recession. Its full
consequences and duration remain unknown at this time.
However, advances in veterinary therapeutics are necessarily
driven by commercial considerations. If the market declines
and/or if development and registration costs increase, innova-
tions may stall or even cease. Without a fair profit, there can
be few if any new products. Nevertheless, societal demands for
improvement in animal health and welfare programmes will
stimulate research into existing and new clinical circumstances
and conditions, requiring pharmacological intervention.
As well as food safety considerations, arising from drug, drug
metabolite and pesticide residues in foodstuffs (Reeves, 2010;
Lees & Toutain, 2012), advanced and developing societies are
increasingly concerned with the impact of veterinary medicines
on the environment (Boxall, 2010). Environmental conse-
quences of treating cattle with ivermectin relate to the effects
of excreted drug on the cow pat fauna, associated with the
absence of dung-degrading insects (Wall & Strong, 1987). This
discovery was very influential in directing focus on the envi-
ronmental impact assessment for veterinary medicinal prod-
ucts, leading to the release of VICH harmonized guidance in
2000. Also of great concern is the transfer of antimicrobial
resistance factors (zoonotic pathogens or genes of resistance)
between species, including the theoretical and much hyped risk
of possible inability to treat life-threatening human as well as
animal diseases, arising from the use of antimicrobial drugs in
animals. For a scientifically based review of this topic, see Mar-
tinez and Silley (2010).
© 2013 Blackwell Publishing Ltd

All of the foregoing factors have led to extensive consider-
ation of the desirability of establishing global harmonization of
regulatory policies and guidelines to govern the licensing of
veterinary drugs. Progress here is urgently needed. This is
especially true for antimicrobial drugs. According to Shryock
(2004), the discovery, development and marketing of anti-
infective products are at an important cross-roads. The current
uncertainties regarding the regulatory acceptance of new anti-
microbial drugs have led to a very regrettable reorientation of
research, away from traditional antimicrobial drugs and
towards other products, having an increased probability of
acceptance in the market place and with better financial
returns.
VETERINARY PHARMACOLOGY: THE LAST 35 YEARS
From a range of online citation indices, it is possible to derive
useful quantitative information on the development of our dis-
cipline. For the period 1975–2010, the Web of Science (WOS)
has been explored. The initial input was the word ‘drugs’,
which was then further refined under either veterinary sci-
ences or pharmacology, the latter providing a comparator for
the veterinary component of all citations in pharmacology. Of
814 631 publications for ‘drugs’, 205 684 were classified as
‘pharmacology’ and 11 115 were selected in ‘veterinary
sciences’.
Divided into successive 4-year periods, the ‘total’, ‘pharma-
cology’ and ‘veterinary science’ publications are illustrated in
Fig. 1. This demonstrates parallel trends for the three curves
(note the logarithmic scale for the ordinate). The accelerated
increase in publications in the late 1980s–early 1990s was not
a specific veterinary event but conformed, rather, to the gen-
eral trend. Table 1 presents the ‘total’ number of articles
retrieved over nine periods between 1975 and 2010 for
1 000 000
100 000
Number of publicaƟons
10 000
1000
100
1975 1980 1985 1990 1995
Years
Fig. 1. Numbers of publications on ‘drugs’ over nine 4 year periods
between 1975 and 2010 in three categories; ‘total’ (upper curve),
“pharmacology” (middle curve) and ‘veterinary science’ (lower curve).
Note that the ordinate is a logarithmic scale (data from Web of
Science).
© 2013 Blackwell Publishing Ltd
Veterinary pharmacology 109
‘drugs’, with the subclasses ‘pharmacology’ and ‘veterinary sci-
ences’ (and veterinary drug articles as a percentage of pharma-
cology articles) together with numbers of veterinary citations,
average veterinary citations per articles and the H-index (for
definition see below). There was a more than tenfold increase
in the number of ‘veterinary science’ article from 219 in 1975
–1979 to 2506 in 2007–2010. Corresponding figures for
‘pharmacology (nonveterinary)’ articles were 4833 in 1975–
1979 and 54 292 in 2007–2010. The number of veterinary
science (drug) articles has been within the range 4.53–6.23,
as a percentage of articles in pharmacology during the whole
period. There was an increased number of citations from 1068
to 7899 for veterinary pharmacology articles. The average
number of citations per article increased from 4.88 in the per-
iod 1975–1979 to plateau at 9–10 from the early 1990s to
2000 (Fig. 2).
Further analysis was undertaken using the search queries,
‘authors, countries, languages, source titles and subject area’.
For countries/continents, veterinary pharmacology publications
in the USA, EU and rest of the world have been approximately
equal, each contributing approximately one-third of the total
over each 4-year period (Table 2). Of the 11 115 veterinary
pharmacology publications identified for the period 1975–
2010, the language was overwhelmingly English (85.8%), fol-
lowed by German (5.6%) and French (2.5%). Regarding subject
area, the top five, in descending order for the 11 115 records,
were pharmacology (6.70%), parasitology (3.89), zoology
(3.85), toxicology (3.84) and agriculture (1.64%). For sources
(journal titles), it is pleasing to note that Journal of Veterinary
Pharmacology and Therapeutics leads with 6.70%, followed by
Journal of the American Veterinary Medical Association
(5.41%), with Veterinary Clinics of North America Small Ani-
mal Practice (1.66%) in tenth position.
Data for the 50 most cited veterinary pharmacology publica-
tions for the periods 1975–1979 and 1980–1989 and the 100
most cited publications for the periods 1990–1999 and 2000–
2010 can be supplied on request to PLT. In summary, the total
citation numbers for the most cited articles for these four peri-
ods were, respectively, 74, 102, 207 and 540. For the 1990–
1999 and 2000–2010 periods, even the publications in
position 100 had healthy citation numbers of 55 and 47,
respectively. Inspection of these tables reveals an initial pre-
dominance of interest in functional pharmacology (1975–
1989) involving analgesic, anti-inflammatory, anti-arthritic,
cardiovascular, respiratory and anti-epileptic drugs, but with
anthelmintic, antimicrobial and anticoccidial agents also well
represented. Over the last 20 years (1990–2010), the emphasis
has shifted overwhelmingly to anthelmintic, antifungal and
antimicrobial drugs. For example, for the period 2000–2010,
2000 2005 2010 17 of the 25 most cited articles concerned antifungal, anthel-
mintic, antimicrobial or anticoccidial drugs. Of particular
interest is the emphasis on the development of resistance to
these drug classes. The numbers of articles with the word resis-
tance in the title for the 10, 25, 50 and 100 most cited arti-
cles, over the four successive periods, were 5, 8, 12 and 21,
respectively. Publications on analgesic and anti-inflammatory
110 P. Lees et al.

Table 1. Analysis of publications and citations on ‘drugs’ over nine 4-year periods, 1975–2010*

Veterinary Vet Sci Average Vet %vet

Range of years Total drugs Pharmacol. Sciences Citations Sci Citations H-index* pharmacol

1975–1979 15 048 4833 219 1068 4.88 17 4.53

1979–1982 17 743 5346 306 1617 5.28 20 5.72
1983–1986 21 429 6211 366 2124 5.8 23 5.89
1987–1990 23 029 6619 413 2501 6.06 25 6.23
1991–1994 90 595 25 618 1550 16 424 10.6 49 6.05
1995–1998 110 620 29 110 1738 19 266 11.09 53 5.97
1999–2002 130 204 32 321 1872 21 505 11.49 58 5.79
2003–2006 170 804 41 334 2145 18 238 8.5 43 5.18
2007–2010 235 159 54 292 2506 7899 3.15 25 4.61
Total 814 631 205 684 11 115 90 642 Mean 5.55
SD 0.63

*Data from Web of Science.

100 ings and many textbooks. This source indicates that veterinary
Average number of citaƟons or H-index

pharmacology became ‘visible’ in terms of published research

output only in the mid-sixties. From 1964 to 1995, the num-
ber of publications increased slowly and progressively; then in
the late 1990s and beyond, there was a surge with a sixfold
10
increase from 1997 to 2007 (358 versus 2291 publications
Fig. 3). This was due to both a general increase in the number
of pharmacology publications and a specific increase in our
field with a percentage of veterinary publications that has
1
increased from 1995. The WOK database indicates that there
1975 1980 1985 1990 1995 2000 2005 2010 were three periods of interest for veterinary pharmacology:
Years 1950–1965, when there was a very low level of relative activ-
ity (<0.2% of all pharmacology publications); followed by the
Fig. 2. Average number of citations (lower curve) and H-index (upper
next 25 years (1970–1995) when the ratio was of the order of
curve) over nine 4 year periods between 1975 and 2010 in veterinary
0.5–0.7% of all publications in pharmacology; and a third per-
pharmacology (data from Web of Science).
iod 1995–2010 when the ratio was in the range 3–4%
(Table 3).
Figure 4 presents the H-index of publications in veterinary
pharmacology, obtained from the WOK database. This index
Table 2. Countries of publication for articles on veterinary drugs attempts to measure both the productivity and impact of pub-
between 1975 and 2010 (total number and percentage of total)* lished work. For example, in 1988, the H-index was 25, indi-
USA 3897 35.06% cating that for articles published in veterinary pharmacology
Germany 651 5.86% in that year, there were 25 articles that each received at least
England 644 5.79% 25 citations; beyond 2004, the H-index decreased, because
France 529 4.76%
these articles were recent; the H-index increases as citations
Canada 528 4.75%
accumulate, and thus, it depends on the ‘academic age’ of each
Japan 440 3.96%
Australia 336 3.02% publication. The general trend of the curve is increasing, at
India 274 2.47% least until 2000. It is concluded that veterinary pharmacology
Netherlands 270 2.43% articles have steadily become not only more numerous but also
Spain 249 2.24% more cited, at least until 2000.
*Data from Web of Science.
KNOWLEDGE DISSEMINATION THROUGH JOURNALS
drugs continue to be well represented in the latest 10-year AND LEARNED SOCIETIES
period (2000–2010), comprising 9 of the top 50 and 20 of the
top 100. Of very special note was the launching of Journal of Veterinary
Further information on the rapid development of veterinary Pharmacology and Therapeutics in 1978, under the editorship
pharmacology has been gleaned from another database, the of Charles Short and Andrew Yoxall. As well as our own jour-
Web of Knowledge (WOK). This gives coverage of 23 000 nal, the dissemination of knowledge in veterinary pharmacol-
academic and science journals, 110 000 conference proceed- ogy has depended on monographs, such as Veterinary Clinics

© 2013 Blackwell Publishing Ltd

 Veterinary pharmacology 111

4000 60

3500
50
3000
40
PublicaƟons

2500

H-index
2000 30

1500
20
1000
10
500

0 0
1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 2010 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 2010

Years Years

Fig. 3. Number of publications per year in veterinary pharmacology as Fig. 4. H-index of publications in veterinary pharmacology (data from
reported in the Web of Knowledge between 1960 and 2010. Web of Knowledge).

Table 3. Total number of publications in veterinary pharmacology, total The outset of this 35-year period, 1975–2010, also wit-
number of publications in pharmacology and percentage of veterinary nessed the pivotal formation of learned societies, devoted to the
publications over the total number of publications in pharmacology* advancement of and dissemination of knowledge within our
discipline: The American Academy of Veterinary Pharmacology
Vet. pharmacology
and Therapeutics (AAVPT), 1977; The European Association
as% of total
Vet. Pharmacology pharmacology for Veterinary Pharmacology and Toxicology (EAVPT), 1978;
Years publications publications publications and the Association for Veterinary Clinical Pharmacology and
Therapeutics in the UK also 1978. The European College of
1950 0 167 0
Veterinary Pharmacology and Therapeutics was formed in
1960 11 9022 0.122
1965 30 15 028 0.200
1997, as part of the programme for veterinary specialization in
1970 152 24 773 0.614 Europe, which had been encouraged by the Advisory Commit-
1975 221 40 109 0.551 tee for Veterinary Training (ACVT). More recently, the disci-
1980 282 44 426 0.635 pline has benefitted by the creation of further bodies, including
1985 310 50 090 0.619 the American College of Veterinary Clinical Pharmacology and
1990 358 62 474 0.573 the Chapter of Veterinary Pharmacology of the Australian Col-
1995 484 68 442 0.707
lege of Veterinary Scientists. These organisations hold major
2000 2041 69 777 2.925
2005 2709 77 573 3.492
congresses on 2–3 year cycles and regularly run educational
2010 3630 90 931 3.992 workshops in the intervening years.

*Data from Web of Knowledge.

of North America, and we note particularly the first edition of
the textbook, Veterinary Pharmacology and Therapeutics,
under the editorship of L. Meyer Jones in 1954. This was a
landmark publication, because, as pointed out by Dunlop and
Williams (1996), ‘veterinary medicine with few exceptions did
not follow the human field in adopting pharmacology as an
experimental science until after the Second World War and the
first scientifically based textbook authored by L. Meyer Jones’.
This magnum opus continues to function as the veterinary
pharmacologist’s bible, now in its ninth edition (2009) under
the editorship of Jim Riviere and Mark Papich (2009).
As Dunlop and Williams (1996) explained, the slowness of
veterinarians to take up the new science of pharmacology
related to the fact that they, more than their human physician
colleagues, were primarily concerned with treating microbial
infectious diseases. On the other hand, veterinary anaesthetists
were quick to take up the newly introduced local and general
anaesthetics soon after their introduction; cocaine, ether and
chloroform in the 19th and halothane, barbiturates, procaine
and lignocaine, in 3rd to 5th decades of the 20th century.
THE NEXT 35 YEARS: PREDICTED AND DESIRABLE
ADVANCES
As discussed by Jim Riviere (2007) ‘the field of veterinary ther-
apeutics is in a state of tremendous flux, being at the vortex of
strong currents arising from rapid technological advances,
altered consumer perceptions on food safety and bioengineer-
ing, and changing public attitudes towards the value of pet
ownership; all occurring in an economic maelstrom, which is
changing corporate structure and forcing extreme cost efficien-
cies on the development, production and marketing of products
targeted towards veterinary species’.
Developments over the next 35 years (2013–2048) might be
considered from two perspectives, those that are ‘anticipated’
and those that are ‘desirable’, with inevitable overlap between
these categories. The desirable developments are relatively easy
to state, whilst accurate prediction of developments is necessarily
highly speculative. We asked several prominent leaders in veteri-
nary pharmacology for their thoughts. The results are presented
in Table 4. Many of these thoughts of the great and the good
need no further elaboration, and some developments are antici-

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112 P. Lees et al.

Table 4. The most important single advance in veterinary pharmacology/therapeutics over the next 35 years.

Colleague Advance

D. Church The use of species-specific whole genome scans to determine subpopulations based on differing sensitivities to
specific pharmacological compounds, thereby facilitating more appropriate ‘dosing’ regimens.
P. De Backer Innovation and development of new veterinary drugs, especially for large animals, are highly desirable, but there are
constraints due to increased legislation and the strong tendency for consolidation of companies in the pharmaceutical market.
F.M. Cunningham Ensuring the training and development of future generations of dedicated researchers and teachers in veterinary pharmacology.
J. Elliott Transcriptomics to identify new drug targets; genomics to predict which members of the patient population will respond to
recommended therapeutic dose; and proteomics to devise biomarkers of disease.
J.Fink-Gremmels Refinement of drug use (new application forms and devices), Reduction of the use of anti-infectives by preventive
measures (innovative vaccinations, modulation of the innate immunocompetence, bacteriophage therapy, etc.)
Replacement of general dose and application recommendations by individual therapeutic approaches.
J.N.King Use of modelling and other techniques to provide dosage recommendations for minor uses and minor species
M.F.Landoni Nanotechnology for drug delivery to ensure that drugs reach target sites in high concentrations, thereby reducing
systemic effects and for antimicrobial drugs avoiding drug resistance.
P. Lees Physiologically based pharmacokinetics (PB-PK), PK-PD modelling and population PK to optimize dosage schedules for
clinical use in animal subgroups, including individualization of dosage.
A.Livingston A switch from studying drugs acting on enzymes and receptors to investigating drugs acting on genes.
J. Maddison Antimicrobial drugs that are resistance proof.
M. Martinez Increased focus on mechanisms for manipulating transcriptional and translational processes, with implications for
treatment of physiological diseases, behavioural modification and cancer, immune modulation, as well as genetic testing
and applying novel delivery methods, including nanotechnology.
Q. McKellar An effective trypanocide with no toxicity to humans
C.Nebbia Gaining insights into interspecies differences in the expression of drug transporters to better explain species differences in
drug PK unrelated to phase I and phase II mechanisms.
M.Papich Improving the method by which regulatory agencies approve veterinary medications for animals, so that sponsors will be
encouraged to bring more compounds forward to meet the needs of animals and the veterinarians who treat them.
P.Reeves Advances in nanotechnologies with novel and beneficial applications in veterinary medicine.
J.Riviere Individualized and targeted drug therapy across all species, using miniature sensing and delivery devices, some with
embedded PK-PD algorithms or using nanodelivery platforms that provide local feedback on delivery mechanisms.
S. Soback Improvement of PK/PD-based dosing protocols to maximize efficacy and to justify scientifically extra label use of drugs.
P.-L.Toutain Pharmacodynamics will be the most important factor to prospectively develop new drugs having the appropriate selectivity;
as ‘omics’ sciences mature they will allow a comprehensive analysis of biological systems of many different species that
in turn will allow individualization. ‘omics’ will also impact on diagnostic and prognostics, and in toto, these factors
with those outlined by J.Riviere and P Reeves will change the face of veterinary therapeutics, provided that (a)
companies consider research and innovation as their pivotal role; and (b) regulatory authorities do not apply the brake
of the precautionary principle but rather seek to understand and facilitate innovations.

pated by several respondents. A common theme is the require-
ment to expand not only the range of veterinary medicines, but
also the adoption of novel means of delivering them, a theme fur-
ther discussed in the next section of this review.
Physiologically based PK (PB-PK) models lend themselves to
extrapolation of data between species and breeds, as they
incorporate physiological and metabolic variables, such as
organ blood flow and hepatic biotransformation enzymes
(Rowland et al., 2011). Recent veterinary examples include
prediction of: (i) withdrawal times for oxytetracyclin in sheep
(Craigmill, 2003), (ii) tulathromycin in goats (Leavens et al.,
2011), and (iii) extrapolation of data on valnemulin in rats
to pigs (Yuan et al., 2010). PB-PK will create systems biology
approaches, incorporating genomic and proteomic data,
which will describe drug actions based on models from recep-
tor to the whole animal. When validated, these models will
allow in silico trials to reduce the number of whole animal
studies.
These developments will introduce an era of drug and dos-
age selection to meet the requirements of within species, breed,
gender, age, weight and disease status differences. Models to
integrate population PK data with statistical models defining
covariates, which identify the source of population variability,
were described by Martin-Jimenez and Riviere (1998) and have
been applied in several recent studies. Prominently expected
also is the impact of the ‘omics’ as disease markers, prediction
of response in individual animals and individualization of dos-
age (Hindre et al., 2012; Sutton, 2012). Even if not fully real-
ized, these developments will provide drug manufacturers with
major challenges, so that constructive inter-relationships
between regulators and regulated will be vital.
THE NEXT 35 YEARS: TECHNOLOGY-DRIVEN
ADVANCES
An international leader in the discipline of veterinary pharma-
cology recently predicted advances in veterinary therapeutics,
based on six new transforming technologies (Riviere, 2007,
2010). These are summarized in Table 5. Riviere emphasized
the expectation of major breakthroughs through a combination
of two or more of these areas to enable development strategies

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 Veterinary pharmacology 113

Table 5. Impact of technological advances on future developments in veterinary pharmacology and therapeutics*
Technological advance Description and impact on veterinary pharmacology and therapeutics.

Computer technology
Microfluidics and miniaturisation
of devices
Nanotechnology
High-throughput screening
Controlled and targeted drug
delivery
Increased knowledge of
pharmacogenomics
Increased speed and quantity of data processing and integration of separate systems to facilitate (a)
dealing with large genomic data sets and (b) PK, population PK and PBPK models.
Development of devices providing (a) complete analytical chemistry platforms on the size of a postage
stamp, that is, ‘lab on a chip’, also described as micro-total analysis systems and (b) micro-electromechanical
systems for controlled drug delivery.
Manufactured materials <100 nm diameter, possessing properties, providing targeted drug delivery systems
and microscale biological sensors.
Combinatorial chemistry, involving libraries of hundreds (even thousands) of compounds, with a common
chemical motif are screened ‘en mass’ to identify (a) desirable PK properties or (b) compounds with the
greatest in vitro potency and/or efficacy and/or least toxicity.
Controlled release and targeted drug delivery is already well advanced in veterinary therapeutics and will be
further refined.
Establishment of the genetic code of more animal species and breeds and of micro-organisms will enable the
specific targeting of drugs to animal and microbial species and the achievement of more specific endpoints.

*Adapted from Riviere (2007).

and yield novel products. The potential computer technology
advances have been discussed earlier.
Microfluidics will lead to the introduction of micro-total
analysis systems (TAS), which reduce sample sizes and
reagent volumes for quantitation and minimize hazardous
waste. Also, micro-electromechanical systems (MEMS) can be
expected to lead to the introduction of implantable feedback-
controlled delivery devices on a much smaller scale than cur-
rently possible. Such devices may be powered by absorbing
ionic substances from the animal to charge internal batteries.
Microfluidic or miniaturized devices might be used to: (i) deter-
mine biomarkers of disease and facilitate individualization of
therapeutics, (ii) detect specific genetic determinants of drug
resistance and thereby target drugs for the individual animal.
The latter might be coupled to microcomputers containing PK
algorithms to optimize dosage regimens, being especially appli-
cable to drugs with narrow safety margins. When used in
combination, TAS and MEMS devices might be used for insu-
lin delivery with an on-board glucose sensor. All aspects of
individualization of dosages will require the introduction of
new regulatory guidelines.
The occurrence of chemical reactions on the surface of a
nanofibre will provide biological sensors linked, for example, to
specific antibodies, providing early warning of disease onset.
Nanomaterials may also be developed to contain tissue target-
ing molecules for treatment of organ-based cancers. Their high
surface reactivity on a weight basis may provide for scavenging
applications, for example of toxins or oxygen free radicals. The
PK of nanomaterials will require further study, however, as tis-
sue uptake seems to be related more to mechanisms of cellular
uptake, for example by vesicular transport, than to blood flow.
Their poor elimination from the body will also need to be
addressed from a toxicological perspective. Their particulate
and hydrophobic character may lead to clearance primarily by
the lymphatic system.
High-throughput screening to identify desirable PK or PD
properties is already used extensively in the initial stages
of human drug development programmes. The approach
combines rapid exclusion of drugs with undesirable properties
with consequently reduced development costs. These methods
will be extended to the selection of veterinary drugs for next
stage development in more complex in vivo systems. It is
expected that the potential for screening large numbers of
agents will be enhanced by the use of microfluidic and minia-
turised devices and possibly with nanotechnology and in silico
approaches. Rapid screening will also be extended to the field
of drug–drug interactions and has already been applied to the
field of genomics. The sequencing of a gene with 10 000 base
pairs can now be accomplished in a few days, compared to
1 year 20 years ago.
An excellent recent account of the many varieties of drug deliv-
ery systems currently applied in veterinary therapeutics has been
provided by Brayden et al. (2010). These range from osmotically
driven minipump devices and reservoir-based polyethylene glycol/
drug systems for the intraruminal delivery of anthelmintics to
depot/sustained release formulations of antimicrobial drugs admin-
istered intramuscularly or subcutaneously. Of particular future
interest is the role of ABC efflux transporters in drug transport
mechanisms. Increased understanding of these pathways will facil-
itate the introduction of safer, more efficacious drugs and enable a
better understanding of drug–drug interactions. Riviere (2007)
points out that a commercial application of microneedles, which
puncture the skin without the chance of contamination or produc-
tion of any sensation, may provide a novel means of transdermal
drug delivery.
Riviere (2010) and Mosher and Court (2010) have reviewed
recent advances in comparative and veterinary pharmacoge-
nomics. It is clear that further advances in genomics, proteomics
and metabolomics will be fundamental to development of the
next generation of more efficacious, selective, safer and targeted
veterinary drugs. As Riviere (2007) points out, all of these devel-
opments will depend not only on scientific advances, commercial
potential and acceptance by societies, but also on an enlightened
approach of national regulatory authorities. Moreover, without
greater international harmonization of regulatory guidelines,
the development costs alone will prevent the introduction of

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114 P. Lees et al.
many potentially useful novel agents and delivery mechanisms.
As Riviere (2007) states ‘the global harmonisation of animal
drug regulations would, at a stroke, remove impediments to
rapid drug approval and subsequent marketing’.
CONCLUDING RECOMMENDATIONS AND GUIDELINES
FOR OUR YOUNG COLLEAGUES FOR A SUCCESSFUL
CAREER IN VETERINARY PHARMACOLOGY
On history, we note the comment of Winston Churchill that
‘the further backward you can look, the further forward you
are likely to see’. We refer our young colleagues to the pioneer-
ing work and writings of those greatest of all biologists, Charles
Darwin and Louis Pasteur, as the individuals who laid the
foundations for all modern biological disciplines.
On serendipity, we emphasize that the most exciting results
are often the most unexpected; the experiment that fails to
confirm the hypothesis may offer the best prospects for new
advances.
On data, we ask our younger colleagues to reflect carefully
on the nature of data, on how to generate, observe, interpret
and use it. For example, when using the excellent available
programmes for analysis of PK and PD data, remember the
adage ‘rubbish in ……. rubbish out’. In 1871, the physicist
Lord Kelvin (who gave his name to the °K absolute tempera-
ture scale) told us to forget the ‘eureka moment’ of scientific
discovery. It did not happen like that for us or Darwin or Pas-
teur or Bernard or Kelvin himself. Kelvin stated, ‘accurate and
minute measurement seems to the non-scientific imagination a
less lofty and dignified work than looking for something new.
But nearly, all the grandest discoveries of science have been
but the rewards of accurate measurement and patient, long
continued labour on the minute sifting of numerical results’.
Never a truer word.
On publishing, there is the need to reflect on how to achieve
maximal impact and benefit for the individual author and the
discipline. The pressures are to publish in high-impact journals.
Yet, the golden rule must be, reserve your best articles for sub-
mission to Journal of Veterinary Pharmacology and Therapeu-
tics! Always remember the words of the referee who rejects the
article you have spent years of your life producing, ‘this paper
is full of excellent and original ideas; unfortunately, the excel-
lent ideas are not original and the original ideas are not excel-
lent’. Take this as a challenge to do better next time; it
happens to all of us.
On antimicrobial resistance, we recognize that many of you
will be engaged on untangling this knot. You will note the
literature-dominating contributions of microbiologists and
molecular biologists, whilst observing that (at present) limited
recognition is given to the huge contributions we pharmacolo-
gists have made and will continue to make, through rational
dosage schedule design, to minimizing its emergence and
spread.
On reading outside the box, that is outside each individual’s
immediate research area, note that this is not only a broaden-
ing experience but a necessary one. For example, if the interest
is pain control or antimicrobial therapy, the researcher will be
well advised to improve his/her knowledge of pain mechanisms
and pathways and those aspects of the biochemical and molec-
ular processes in micro-organisms, which provide potential tar-
gets for drug action, respectively. Moreover, such knowledge, if
not always acquired at the deepest level, will be necessary to
facilitate collaboration with colleagues from related disciplines.
Relevant here is the ‘one-health concept’; this is likely to
increase the interest of colleagues outside our fields in veteri-
nary pharmacology and toxicology, as disciplines governing
the multifaceted interactions and links between animals and
man, animals and the environment and acceptable and safe
food supplies.
In summary, the major task of veterinary pharmacologists is
to tackle the continuing challenge in improving our under-
standing of inter- and intra-species differences and the task will
be to signal individual variability (including the variability
within and across animal populations) in PK and PD to our
clinical colleagues, and thereby to translate fundamental
insights into drug action and fate into clinical therapy.
And finally, we note the advice of the 17th century philoso-
pher of science, Francis Bacon, ‘if a man will begin with cer-
tainties, he will end in doubt; if a man will begin with doubt,
he will end in certainties’.
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