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HOST MODULATION IN PERIODONTICS

Shantipriya Reddy Professor and Head, Prasad MGS Reader, Sanjay Kaul Professor, Hrishikesh
Asutkar Postgraduate student, Nirjhar Bhowmik Postgraduate student, Amudha Senior Lecturer, Department
of Periodontics
Dr. Syamala Reddy Dental College, Hospital and Research Center, Bengaluru, Karnataka, India.
Correspondence: Prasad MGS Reader, Department of Periodontics Dr. Syamala Reddy Dental College, Hospital and Research Center
Bengaluru, Karnataka India Email: prasadmgs@indiatimes.com
Received July 22, 2011 ; Revised Sep 05, 2011 ; Accepted Sep 28, 2011

ABSTRACT
Periodontitis is a polymicrobial infectious disease of multifactorial origin. Plaque bioûlm and associated host responses
are involved in the pathogenesis of periodontitis. Organisms strongly implicated as etiologic agents include Gram-
negative, anaerobic or microaerophilic bacteria within the bioûlm . The microbial challenge consisting of antigens,
lipopolysaccharide (LPS), and other virulence factors stimulates host responses which result in disease limited to the
gingiva (i.e., gingivitis) or initiation of periodontitis. Protective aspects of the host response include recruitment of
neutrophils, production of protective antibodies, and possibly the release of antiinûammatory cytokines including
transforming growth factor-β (TGF-β), interleukin-4 (IL-4), IL-10, and IL-12.Perpetuation of the host response due to a
persistent bacterial challenge disrupts homeostatic mechanisms and results in release of mediators including
proinflammatory cytokines (e.g., IL-1, IL-6, tumor necrosis factor-α [TNF-α]), proteases (e.g., matrix metalloproteinases),
and prostanoids (e.g., prostaglandin E2[PGE2]) which can promote extracellular matrix destruction in the gingiva and
stimulate bone resorption. The determination that periodontal tissue destruction is primarily due to the host response
has created areas of research directed at altering an individual’s reaction to the bacterial challenge the present paper
aims at reviewing various host modulatory therapies (HMT) have been developed or proposed to block pathways
responsible for periodontal tissue breakdown.
Keywords : Polymicrobial disease, host response, proanti-inflammatory cytokines, host modulation therapy.

INTRODUCTION inflammatory mediators like PGE2 that cause the majority

Periodontitis is multifactorial infectious disease
of the supporting structures of the teeth, characterized by
destruction of the bone and connective tissue. Specific
periodontopathic bacteria and their virulence factors are
the primary etiologic agents. However interaction of host
defense mechanisms and these etiological agents plays an
important role in the onset and progression of the disease41a.
of tissue destruction in the periodontium. This shift in
paradigm of concentration on host response has led to the
development of Host Modulatory Therapies (HMT) which
could improve therapeutic outcomes, slow the progression
of disease, allow for more predictable management of
patients, and possibly even work as preventive agents
against the development of periodontitis15,44.

Antimicrobial therapies both local and systemic
administration along with mechanical debridement is one
of the mainstay in periodontal treatment strategies, which
answered microbial etiology of periodontal diseases, albeit
critical step in a complex chain of events leading to
periodontal tissue destruction. These treatment strategies
however, failed to block (or) inhibit the host response
mediated tissue destruction to continued bacterial
challenge46.
In 1985, research began to focus very closely on
bacterial-host interaction, leading to “host-bacterial inter-
relationship era 14. During this era it was recognized that
although there is evidence that specific bacterial pathogens
initiate pathogenesis of disease, the host response to these
pathogens is equally important in mediating connective
tissue breakdown and bone loss. It has become clear that it
is the host derived enzymes and mediators like matrix
metalloproteases (MMPS), cytokines, and other
“Perioceutics” or the use of the pharmacological
agents specifically developed to manage periodontitis is
an interesting and emerging aid in the management of
periodontal diseases along with mechanical debridement39.
Host modulation therapies are being proposed and
developed to bring down excessive levels of enzymes,
cytokines, prostanoids, as well modulate osteoclast
functions.Over the last two decades periodontal scientists
have produced and investigated various host modulating
agents in both animal and early human clinical studies.
These agents include non-steroidal anti-inflammatory drugs
(NSAIDS), sub antimicrobial dose doxycycline (periostat),
systemic biphosphonates. The non-steroidal anti-
inflammatory drugs (NSAIDS) like systemic flurbiprofen
and topical ketoprofen act by inhibiting prostanoids (PGE2).
Systemic biphosphonates (alendronate) modulates the
osteoclast function and subantimicrobial dose doxycycline
(Periostat) utilizes the anticollagenase properties of
tetracycline. This is the only drug, which is approved by

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Prasad MGS et al
FDA for clinical use. Future bodes for anticytokine drugs,
bone resorption uncouplers, chemically modified
tetracyclines (CMT’S), anti metabolites and lipoxins. These
provide operators with additional armamentarium to
mechanical debridement, which could enhance and make
clinical therapeutic response more predictable, in more
susceptible host for the better management of periodontal
disease14.
Current critical pathway model of periodontal disease pathogenesis
Fig.1 Current Model of Periodontal Disease; Page and Kornman199629,41b
Plaque bacteria such as porphyromonas gingivalis,
bacteriodes forsythus and actinobacillus
actinomycetemcomitans remain as primary causative
agents. Their introduction as an exogenous infection and
predominance in the pathogenic flora trigger a cascade of
immune responses in the host. Once these bacteria
colonizes, the tooth surface near the gingival margins,
bacteria and their metabolic products and the
lipopolysaccharide (LPS) initiate the host response. The
bacteria and their byproducts directly challenge the cells
of junctional epithelium. In response, the junctional
epithelial cells release various inflammatory mediators
including cytokines, PGE 2, MMPs and TNF. These
mediators stimulate the immune response, recruiting
neutrophils to the site of periodontal infection. If these
inflammatory cells are able to contain bacterial challenge
and their products (such as LPS endotoxins) by intercellular
killing mechanisms, the disease limits itself to the gingiva.
www.ejournalofdentistry.com
This present review highlights various host
modulation therapeutic agents and ongoing development
of safe and effective pharmaco therapies that specially target
host response mechanism. Introduction of such
pharmocotherapies as an adjunct to the traditional
periodontal therapies represent a new integrated approach
in long-term treatment and management of periodontitis.
If the bacterial challenge is not controlled by these
mechanisms and if pathogens and their products penetrate
host tissues, the inflammation worsens and progress to
periodontitis. However, if these mechanisms fail and if
pathogens and their products penetrate host tissues, the
disease becomes periodontitis.
The host monocyte-lymphocytic axis is
stimulated, leading to the local release of inflammatory
mediators such as arachidonic acid metabolites and
cytokines. These inflammatory mediators inturn directly
cause the local tissue destruction, clinically perceived as
periodontal pocketing and alveolar bone loss in patients.
In addition, local environmental conditions secondary to
these inflammatory and destructive events (such as low
oxygen tension and iron availability) continue to support a
pathogenic flora and perpetuate the cycle of events
proposed in the model. (fig.2)
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Poor oral hygiene Normal Exogenous infection

Pathogenic flora Antibody response

Neutrophil clearance

Pocketing and bone loss Gingivitis

Inflammation & tissue destruction Bacterial penetration

Cytokines & Monocyte lymphocyte axis Systemic

inflammatory exposure
mediation

Fig.2 Critical pathway model of pathogenesis; Page and Kornman 1996

The Microbial challenge consisting of antigens,
lipopolysaccharide (LPS) and other virulence factors
stimulates host responses, which result in disease limited
to gingiva (that gingivitis) or initiation of periodontitis
(Offenbacher, 1996).
Protective aspects of the host response include recruitment
of neutrophils, production of protective antibodies and
possibly release of anti-inflammatory cytokines including
transforming growth factor– (TGF-), IL-4, IL-10 and IL-
12.
Perpetuation of the host response due to persistant bacterial
challenge disrupts homeostatic mechanisms and results in
release of pro inflammatory cytokines (e.g.: IL-6, IL-1, TNF-
) proteases (e.g.: matrix metalloproteinases) and
prostanoids (PGE2) which can promote extracellular matrix
destruction in the gingiva and stimulate bone resorption.
The determination that periodontal tissue destruction is
primarily due to the host response, has directed areas of
research at altering an individual’s reaction to the bacterial
challenge.
Various host modulation therapies (HMT) have been
developed and proposed to block pathways responsible
for periodontal tissue breakdown14 .
One of the tremendous benefits of fundamental research
which seeks to elucidate key mechanism of host tissue
destruction is the simultaneous identification of critical
intervention with host modulating agents. So here we have
given an overview of Specific aspects of disease
pathogenesis for modulation:
Specific aspects of disease pathogenesis for modulation
a) Regulation of immune and inflammatory responses.
( Table 1)
b) Regulation of excessive production of matrix
metalloproteinase’s29,45 . (Table 2)
c) Regulation of arachidonic acid metabolites32,33,37
(Table 3)
d) Regulation of bone metabolism7,24,42. ( Table 4)

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Stages of host Mode of interception Significant Agents employed Author’s coments

modulation
Immunization Generation of protective
methods. antibodies to prevent
Periodontitis.
Stages of host Mode of interception
modulation
Regulation of Down regulation of reactive oxygen
reactive species* using antioxidants
oxygen Antioxidants (AO's) are classified
species3. according to their mode of action.
"Scavenging AO's" prevent
oxidative stress by literally
scavenging radicals as they form.
"Preventative AO's" function
largely by sequestering transition
metal ions and preventing Fenton
reactions, they are therefore largely
proteins by nature.
"Enzyme AO's" are systems
that function by catalyzing the
oxidation of other molecules.
Regulating The pleiotropic actions of cytokines
cytokines19. include numerous effects on the
cells of immune system and
modulation of inflammatory
responses.
Suppression of eicosanoid synthesis
by INF- and IL-4 is the primary
mechanism which inhibits
macrophage MMP production.
These findings demonstrate that
IFN- and IL-4 may have potent
anti-inflammatory effects.
Contributors
Ishikawa et al., Stock vaccines such Periodontitis is a
1997 as Van Cotts vaccine, polymicrobial disease so
Goldenberg’s vaccine formulating a vaccine against a
(or) Inava Endocorps particular pathogen has shown
Vaccine. favourable clinical results, so
Autogenous vaccines further research for a
comprehensive vaccine is
Vaccines prepared warranted.
from pure cultures of Vaccines are currently
streptococci and available in companion
other organisms animals. TLR( Toll like
receptors) have been tried in
Gingipains the form of vaccines presently.
Significant Agents employed Author’s coments
Contributors
Benedeck 1998, Ascorbic acid, Alpha Pharmacological inhibition of
tocopherol, iNOS with
Bartold 1984,
Keratinides mercaptoalkylguanidines was
Key 1994 associated with decreased
inflammation, haemorrhagic
shock and arthritis scores.
Through its ability to inhibit
cox and scavenge peroxynitrite
( product of NO and
superoxide), block iNOS.
However furthur studies are
needed to substantiate its
therapeutic effects in
periodontal diseases.
Gortel 2004, CYTOKINE Harsh enzymatic environment
ANALOGES, Mast in periodontal lesions may
Shapira 1992,
cell stabilizers destroy the soluble cytokine
Hendley 1995. antagonist prior to their peak
activity necessitating frequent
administration.

Several cytokines have been

implicated in the suppression of
tissue destructive cytokines. IL-10,
IL-4 has been shown to down
regulate IL-1 and TNF- gene
expression in human monocytes.

TGF- is an anti-inflammatory
agent which induces synthesis and
secretion of IL-1 is potent
regulator of bone resorption invitro
and it may promote osteoblast
growth and matrix synthesis.

Table.1 Regulation of immune and inflammatory responses

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Stages of host Mode of interception Significant Agents Author’s coments

modulation Contributors employed
Regulation of Transcription of the CL and SL-1 genes (in Wahl 1979, TGF β, FIB- Insufficient data
MMP activity at Cury 1988 CL, available.
some cells the SL-3 and Mr 92K GL genes
‘4’ gates: SL- 1
as well) is induced by IL-1, TNF-,
Transcriptional
regulation of PDGF, TGF-, EGF bFGF, NGF.
MMP genes. TGF- Ablates transcription of CL & SL-1
IFN-

Precursor The activator proteinase first attacks Nagase Organomercuria Insufficient data
activation. the susceptible 1997 l,chaotropic available.
'bait' region (located in the middle of agent CKI,
the propeptide) NaSCN &
 detergents
Changes in the propeptide CSDC.
 Proteolytic
Rendering the final activation site enzymes:
readily cleaved by a second trypsin,
proteolysis plasmin,
chymotrypsin,
neutrophil
elastase,
cathepsin B and
plasma
kalikrein.
Substrate A certain level of regulation of MMP Insufficient data
specificity activity is encoded at the level of the available.
substrate, although enzymes have
somewhat overlapping substrate
specificities.

MMP inhibition -macroglobulins, particularly 2-M play Rayan and Tetracycline, Tetracycline apart
( TIMP’s)45,18,27. an important role in the regulation of MMP Golub 2000, CMT from its antimicrobial
activity by bond cleavage region. Brew 2000, Minocycline, property has
The inhibition probably occurs as a result Kinane Doxycycline ( capability of
of binding the TIMP’s at the MMP active 2000, Lee sub inhibiting the
site. However, the amino acid residues in 1995. antimicrobial activities of
TIMP’s that are responsible for binding at dose of neutrophil,osteoclast,
the active site of MMP’s are still unknown. doxicycline), MMP 8, thereby
lipoxins, working as anti-
Lipoxins regulate local acute inflammatory resolvins. inflammatory agent
responses in periodontal disease by limiting that inhibits bone
neutrophil recruitment and neutrophil destruction.
mediated tissue injury.

Table.2 Regulation of excessive production of MMP’s.

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Role of Mode of interception Significant Agents Author’s coments

arachidonic acid Contributors employed
metabolites.
Prostaglandins Inhibition of arachidonic acid metabolite by Goldhaber Indomethacin, Systemic daily
and other blocking of the cyclooxygenase pathway. et al (1973) Flurbiprofen, administration for
arachidonic acid Nyman et al S-Ketoprofen, periods upto three
metabolites within (1979) Triclosan. years of NSAID’s
the periodontal Weaks- showed significant
tissues play a role Dybvig et al reduction in rate of
in the (1982) bone loss, but has a
pathogenesis. Offenbacher major disadvantage of
et al (1987) rebound effect.
Jeffcoat et
al (1991)
Table.3 Regulation of arachidonic acid metabolites.

Quantity/Quality of Mode of interception Significant Agents employed Author’s coments

bone Contributors
Osteoporosis and Inhibition of Howell 1991, His-
osteopenia may be osteoclast/MMP activity Ming 2004,
indicators for through chelation of Holzhausen 2005,
periodontal cations. Gurkan 2005,
diseases. Durate 2005.
Table.4 Regulation of bone metabolism.
Nutrients as modulators of inflammation
The damage mediated by reactive oxygen species can be
mitigated by antioxidants through three separate
mechanisms namely: 1) Scavengers of free radicals as they
are formed.
2) Sequestering transition metal ions. 3) Catalyzing
formation of other molecules. Major extracellular
antioxidants include vitamin C, vitamin E, carotenoids,
reduced glutathione and omega 3 fatty acids.
Vitamin C (as corbate) is a powerful scavenger of free
radicals protects against oxidants in cigarette smoke.it also
generated tocopherol from tocopherol radicals that forms
membrane surfaces.Though the clear association between
plasma as corbate and periodontitis is not established
epidermalogical studies on the intake of vitamin C
demonstrated a positive association between low dietary
intake of vitamin C and periodontitis according to Legott
et.al 1991, Nishada et.al 2000.
Vitamin E is said to terminate the free radical chain reaction
and stabilize membrane structure, but the molecule has
limited mobility which reduces its efficacy. Studies of
gingival tissues have suggested a mitigatory effect of
vitamin E on inflammation and collagen breakdown. Also
lower gingival levels of vitamin E among those with
periodontal disease when compared with healthy controls
according to Cohen et al 1993; Offenbacher et al 1990;
Asman et al 1999.
Bisphosphonates Bisphosphonate
(Alendronate), treatment improves the
Hormone clinical outcome of non-
replacement surgical periodontal
therapy.(HRT), therapy and may be an
OPG- Fc appropriate adjunctive
therapeutic agents. treatment to preserve
periodontal bone mass.
Carotenoids function as reduced trapping antioxidants. The
role of carotenoids in periodontal disease has been limited
to Papillon-Lefevere syndrome according to Lundgren et
al. Recent genetic research has indicated that defects in
PMN Functional enzymes are responsible for the syndrome.
The defective enzyme cathepsin C is central for the
generation of reactive oxygen species according to Hartel
et al 1999; Toomes et al 1999. High levels of oxidative stress
have been demonstrated in Papillon-Lefevere syndrome
suggesting a potential role of antioxidants (Baltino et al).
Reduced glutathione serves as an antioxidant and
modulator of immune function. Increasing glutathione has
been shown to block reactive oxygen species mediated
association of nuclear factor K â and to block
proinflammatory cytokine production according to Schreck
et. al 1991. Many studies have demonstrated that
microorganisms influence tissue damage through cytokine
production by degrading glutathione or from preventing
glutathione formation from cystine according to Perrson
et. al 1990.
Omega 3 fatty acids as dietary fish oil has been
demonstrated to protect mice against infection w i t h n u
m e r o us e x t r a c e l l u l a r b a c t e r i a l p a t h o g e
n s , r e g u l a t e s e r um triglycerides and cholesterol
levels, inhibit synthesis of lipid mediators of inflammation
(PGE 2 , arachidonic acid, cyclo-oxygenase, 5-lipoxygenase),
a l t e r c e l l u l a r f u n c t i o n s o f p o l ymo r p h o
n u c l e a r l e u k o c y t e s , mo d u l a t e lymphocyte
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proliferation and cytokine production, and increase
endogenous host anti-oxidant capacity, e.g., SOD and
catalase (Alam et al., 1991; Blok et al., 1992; Fernandes and
Venkataraman, 1993). These effects have been proposed to
account for the potent anti-inflammatory properties of
omega ()-3 fatty acids (FA) in human, non-human primate,
and rodent disease models. While much of the attention
over the last decades has focused on the beneficial effects
of fish oil, particularly the -3 FA components, on a v a r i e
t y of ch r on i c in fl a m m a t or y di sea ses (c
a r d i o v a s c u l a r d i s e a s e , rheumatoid arthritis), few
studies have examined its effects on the chronic immuno-
inflammatory lesions of periodontal disease. In a recent
study, eicosapentaenoic acid (EPA) and docosahexaenoic
acid (DHA), principal - 3 polyunsaturated fatty acids (PUFA)
present in fish oil, were shown to decrease osteoclast
activation in vitro (Sun et al., 2003). Campan et al. (1996,
1997) reported that human experimental gingivitis appeared
to be modified by -3 FA, although no definitive conclusions
were provided. It has also been reported that the n-6 PUFA
levels in the serum are higher in periodontitis patients,
suggesting that an imbalance between n-6 and n-3 fatty
acids may contribute to susceptibility to oral bone loss
(Requirand et al., 2000). Topical application of n-3 or n-6
fatty acids failed to inhibit the development of experimental
gingivitis (Eberhard et al., 2002), osteoclasts and pre-
osteoclasts following pulp exposure (Indahyani et al., 2002),
significantly reduced the gingival tissue levels of lipid
inflammatory mediators in LPS-induced experimental
periodontitis (Vardar et al., 2004), and reduced osteoclastic
activity and alveolar bone resorption although Rosenstein
et al. (2003) suggested that dietary fatty acid
supplementation in adult periodontitis correlated with an
improvement in gingival inflammation. Treatment of rats
with fish oil significantly reduced osteoclasts and pre-
osteoclasts following pulp exposure (Indahyani et al., 2002),
significantly reduced the gingival tissue levels of lipid
inflammatory mediators in LPS-induced experimental
periodontitis (Vardar et al., 2004),ion, suggesting that this
model may be useful in exploring host bacterial interactions
leading to periodontitis (Iwami-Morimoto et al., 1999). The
hypothesis tested in this investigation was that a fish-oil-
supplemented diet would modulate the host response to
oral P.gingivalis determined by decreased alveolar bone
resorption in rats.
After reviewing the work of various researchers in the field
of perioceutics the following articles were selected to be
reviewed on the basis of various criteria such as size of the
study sample, validity of the material and methods and
follow up period in the study.

Author Purpose Host Parameters Subjects Results

modulating
agent
Ishihara y, To demonstrate the Indomethacin, PGE2 and IL-1 Mouse
nishihara t lipopolysaccharide isolated from a. dexamethasone levels PGE2 and IL-1
et al Actinomycetemcomitans strain y4 participate in y4 LPS
(1991)16 induced bone resorption induced bone
resorption in vitro.

Howell th, To study the effects of piroxicam in Piroxicam Gingival Beagle dogs Significantly inhibit
fiorellini i, preventing gingival inflammation inflammation, the development of
weber hp et and plaque formation plaque index gingival inflammation
al (1991)14
Nip lh, vitto To know the effects of tetracycline Oxytetracycline, Radioactive
vj et al on periodontal epithelial cells were doxycycline and gelatin Results showed that
(1993)26 investigated by culture in cells from de- degradation and periodontal epithelial
porcine rests of malassez dimethylamino gelatin cells produce MMP’s
tetracycline enzymography whose activities are
inhibited by
tetracycline and their
non-antimicrobial
analogues at
concentration present
in gingival crevicular
fluid following
tetracycline therapy.

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Author Purpose Host modulating Parameters Subjects Results

agent

Roy S, To evaluate the effect on bone Aspirin (asp) or Radiographs Humans Percentage bone loss
Feldman, resorption: A retrospective study aspirin plus for the entire
Szeto B et al indomethcin dentition was lower in
(1983)38 asa group
Weaks– To determine if prostaglandins Indomethacin Alveolar bone Squirrel monkeys Indomethacin
Dybvig M, play a role in loss of bone in 5mg / kg /day height treatment abolished
Farshid ligature model of periodontitis the significant loss of
Sanavi et al alveolar bone height
(1982)47
Offenbacher To examine four principal Flurbiprofen Crevicular fluid Rhesus monkey It prevented rise in
S, Odle BM metabolites of cyclooxygenase levels of PGE2 TXB2, but did not
et al (1989)30 (co) during the progression of and TXB2 affect the increase in
experimental periodontitis PGE2.
Meikle MC, To investigate the effect of TNF- Exogenous TNF- (or) IL-1 in
Atkinson SJ (or) il-1 on human gingival human timp collagen degradation
et al (1989)21 fibroblasts (hgf’s), stimulated on human gingival
collagenolysis. fibroblast.
Heasman PA Long-term efficacy of non- NSAID’s Plaque index, Humans Highly significant
and Seymour steroidal anti-inflammatory drug gingival index differences were seen
RA (1990)11 (nsaid) therapy. pocket probing between GCF flow in
depth, loss of study (16.74b±28.63)
attachment, groups.
gingival
recession, and
gingival fluid
flow

Taiyeb ali To investigate the influence of Ibuprofen Gingival Humans Significantly greater reduction
TB and short-term ibuprofen therapy on the bleeding, color for all parameters.
Waite IM early phase of the treatment of and pocket
(1993)43 adult chronic periodontitis. depth
Heasman To evaluate the efficacy of Flurbiprofen GCF Human
PA, flurbiprofen (50mg) on both concentration Flurbiprofen control gingival
Offenbac developing and established of PGE2, TXB2 inflammation with both
her S et al gingivitis and LTB4, preventive and therapeutic
(1993)10 Bleeding index properties.

Shoji K, Efficacy of risendronate to prevent Risendronate Bone mineral Rats. In preventing bone resorption
Horiuchi alveolar bone resorption density in periodontitis.
H and
Shinoda
H
(1995)42
Mathur To evaluate the concentration of Gingival Humans
a, IL-1 IL-8) and interferon- in crevicular fluid. IL-8 and interferon- were
Michalow periodontitis patients. significantly correlated in
icz b, et al diseased sites, suggesting that
(1996)20 levels of these two cytokines
rise (or) fall in tandem.

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Author Purpose Host Parameters Subjects Results

modulating
agent
Crout RJ, To check for potency of low dose Low dose Clinical Human LDD inhibits tissue
Lee HM, doxycycline doxycycline attachment destruction in the absence of
et al levels, probing antimicrobial property.
(1996)5 depth and GCF Long term LDD could be a
collagenase useful adjunct to
activity and instrumentation
periodontal
ligament
degradation
Golub To determine whether an inhibitor Doxycycline Collagenase Human Reduction of excessive
LM, Lee of matrix activity MMP activity with
HM et al metalloproteinases(MMP’s) concomitant reduction in
(1997)8 administered to human subjects in collagen degradation
dental school research clinic, can products
reduce bone type collagen
degradation in inflammatory
exudates
Paquette A study to evaluate effects of S-ketoprofen Bone height (or) Beagle dogs. Significantly lower mean
DW, systemic and topical administration. 99mm tc-sn- rates of bone loss compared
Fiorellini mdp uptake to placebo
JP et al: ratio
(1997)31
Mineshib A study to evaluate the efficacy of Human beta Antibacterial Human Antibacterial activity of hbd-
a, synthetic (hbd-2) against defensin-2 broth assay and 2 was approximately equal to
Takashib actinobacillus actinomycetum diffusion assay that of minocycline.
a S et al comitans, p.gingivalis, s.mutans and
(1998)22 e.coli

Author Purpose Host modulating Parameters Subjects Results

agent
Rammurt-hy To compare wound healing in CMT-2 Volume of Diabetic Results showed in CMT-2
NS, Kucine AJ normal and diabetic rats granulation and non- treated diabetic rats, the
et al (1998)35 tissue. diabetic volume of granulation tissue
rats. was greater than that in
untreated diabetic rats
Breivk T, To evaluate the efficacy of Mitepristone Radiographs Rat model Significantly less periodontal
Thrane PS et al glucocorticoiod receptor antagonist and breakdown at both
(2000)1 ru486 (mitepristone) histologically. experimental and control teeth
compared to the vehicle –
treated control animals.
Mirna M, To investigated the effect of a non Indomethacin, Alveolar bone Wister rats. Both prevented alveolar bone
Bezerra, et al selective cyclooxygenase (cox) meloxicam. level. loss.
(2000)23 inhibitor (or) a type-2 cox inhibitor
in an experimental periodontal Provides a better risk benefit
disease (EPD) model (wister rats) ratio in the treatment of human
periodontitis than non-selective
cox inhibitors.
Raw-Linson A, To investigate the cytokine il-1 GCF Humans
Dalati MHN et and its receptor antagonist IL-1ra in investigations IL-1 concentration was 0.11
al (2000)36 gingival crevicular fluid, in patients pg/ for bleeding periodontitis
with adult periodontitis. sites and 0.01 pg/ for healthy
sites. For healthy sites, a strong
inverse relationship was found
betweenIL-1 and IL-1ra
levels.
Delima AJ, To investigate the role of il-1 and Proinflammatory Histomorpho Macaca IL-1 and TNF antagonists
Oatent ET al tnf in the loss of connective tissue cytokines i.e. IL-1, metric fascicularis significantly reduced the loss of
(2001)6 attachment. TNF α analysis connective tissue attachment by
approximately 51%.

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A u th o r P u rp o s e H o s t m o d u latin g P aram e te rs S u b je cts R esu lts

ag e n t
G o lu b L M , T o id en tify c lin ic all y e ffe ctiv e d o se D o x y c y clin e C lin ica l H u m an s
M cN a m a ra reg i m en s u s in g su b an tim ic ro b ial attac h m en t lev el It h as s ig n ific an t p o ten tial as
T F et a l d o se d o x y cy clin e (S D D ) as an a n o ral ad ju n ctiv e th er ap y in
(2 0 0 1 ) 9 ad ju n ctiv e th era p y in p atien ts w ith th e lo n g te rm m an ag e m en t
ad u lt p erio d o n titis. o f ad u lt p erio d o n titis.

C a to n T G , T o ev alu a te th e effic ac y o f su b D o x y c y clin e C lin ica l Im p ro v e m en t in

C ia n cio S G an tim icro b ial d o se d o x y cy lin e attac h m en t p erio d o n titis a n d clin ic al
e t a l (2 0 0 1 ) 2 (S D D 2 0 m g b id ) + scalin g an d ro o t le v els a ttach m en t lev el in S D D
p lan n in g (S R P ) co m p a red to g ro u p o v e r 9 m o n th s
p lace b o p lu s S R P in a d o u b le b lin d ,
p lace b o – co n tro lled w ith a d u lt
p erio d o n titis.

M y oung H , T o ev alu a te th e clin ic al av ailab ility B is p h o sp h o n ates C lin ica l R a ts C lin ical ap p lica tio n o f
P a rk J Y et a l o f b is p h o sp h o n a te in au to g en o u s m e asu re m en ts, b isp h o sp h o n ates fo r
(2 0 0 1 ) 2 5 fre e b o n e g rafts h isto m o rp h o lo g i d ecreas in g res o rp tio n o f
cal rev ie w g ra fte d b o n e .
R a m a m u r-th y T o ev alu a te th e effic ac y o f to p ica l C lo d ro n a te B o n e m in eral R a ts . T o p ic a l a d m in istra tio n o f
N S , B a in s e t ad m in istratio n o f a b ip h o sp h o n a te d en sity c lo d ro n a te m a y b e
34 in p rev en tio n o f a lv e o lar b o n e lo ss
a l (2 0 0 1 ) e ffe c tiv e in p re v e n tin g
in rats w ith e x p erim en ta l o ste o c la stic b o n e
p erio d o n titis.
re so rp tio n in
p e rio d o n titis.
Z ha n g D , In v estig ate th e ro le o f il- 1 an d TNF α R eces sio n H u m an s T h e am o u n ts o f ro o t
G o e tz W e t tu m o r n ecro sis fa cto r alp h a h eig h t, w id th . reso rp tio n w as sig n ifica n tly
a l (2 0 0 3 ) 48 (T N F  ) in th e co u rs e o f red u ce d , esp ecially
m e ch a n ically in d u ced ro o t fo llo w in g s y ste m ic
res o rp tio n . a p p licatio n o f T N F α , ro o t
reso rp tio n w as co m p letely
p re v en ted .

A u th o r
H is - M i n g L e e ,
S e b a stia n G e t a l
(2 0 0 4 ) 12
C h ia r a S , T a t a k is
D N e t a l (2 0 0 5 )4
D u r a te P M ,
G u r g el B C D e t al
(2 0 0 5 ) 7
S ek in os,
R am b erg P et al
(2 0 0 5 ) 40
H o lz h a u s e n M ,
S p o li d o r i D M P e t
a l (2 0 0 5 )1 3
P u rp o se H o st P a ram e ters S u b je c ts R e s u lt s
m o d u la ti n g
a g en t
T o e v a lu a t e e f f ic a c y o f t h e D o x y c y c li n e , H o s t- d e r iv e d H um ans
a d m in is t r a ti o n o f s u b f lu r b ip r o f e n n e u tra l C o m b i n a ti o n t h e r a p y
a n t im ic r o b ia l d o s e d o x y c y c l in e p r o t e in a s e s p r o d u c e d a s t a ti s ti c a l ly
t o c h r o n ic p e r i o d o n ti ti s p a ti e n ts le v e ls s ig n if i c a n t s y n e r g is t ic
a n d N S A ID ’s. r e d u c ti o n o f c o l la g e n a s e .
T o d e t e r m in e th e a s s o c i a t io n o f I L - 1 le v e ls H um ans
i n te r l e u k in - 1 ( I L - 1 ) g e n e A s s o c i a ti o n b e t w e e n I L - 1
p o l y m o r p h i s m s w ith c l in i c a l p o ly m o r p h is m a n d
p a r a m e t e r s o f g i n g i v i ti s i n l a r g e s u b je c t b a s e d c l in ic a l
e x p e r i m e n ta l g in g i v iti s b e h a v i o u r o f g in g i v a in
r e s p o n s e to p la q u e
a c c u m u la t io n , a s w e l l a s
a p o s s ib l e a s s o c i a tio n
b e tw e e n I L - 1 
p o ly m o r p h is m a n d
g i n g iv it is s u s c e p t ib i li ty .
T o e v a lu a t e w h e th e r A le n d r o n a t e E s tr o g e n O v a r ie c t o
a le n d r o n a te ( a ld ) in fl u e n c e le v e ls m i z e d r a ts . A l e n d r o n a te m a y p r e v e n t
b o n e h e a li n g a r o u n d tit a n iu m n e g a t iv e i n f lu e n c e o f
i m p l a n ts i n s e r t e d i n e s tr o g e n d e f ic i e n c y o n
o v a r i e c t o m i z e d r a ts . b o n e h e a l in g a r o u n d
ti ta n i u m i m p l a n ts .
T o s tu d y t h e e f f e c t o f s y s t e m i c Ib u p r o fen , P l a q u e in d e x H um ans T h e s u b je c t s r in s e d w i th
a d m in is t r a ti o n o f i b u p r o f e n o n c h lo r h e x id in e a n d g i n g iv a l s a li n e a c c u m u la t e d l a r g e
g in g i v i ti s a n d p l a q u e b u i ld . d i g l u c o n a te in d e x a m o u n t s o f p la q u e a n d
d evelo p ed m arked sign o f
g i n g iv it is .
T h e p a ti e n ts p r e s e n t e d
w i th s i g n if ic a n t l y f e w e r
s it e s t h a t s c o r e d G in g i v a l
in d e x  2
T o e v a lu a t e t h e e f f e c t o f E to r ic o x ib W B C coun t W i s te r r a t s G r o u p s tr e a te d w it h b o t h
s e l e c t iv e c y c l o o x y g e n a s e - 2 a n d se ru m d o s e s o f e t o r ic o x i b h a d
( c o x - 2 ) i n h ib it o r , e t o r ic o x ib i n le v e ls , d ig it a l s ig n if i c a n tl y l e s s a l v e o la r
t h e p r e v e n t io n o f a lv e o l a r b o n e ra d io g ra p h s b o n e lo ss co m p ared to
l o s s i n e x p e r im e n ta l c o n tr o l s .
p e r i o d o n ti ti s .

N ovak M J, T o t e s t t h e h y p o th e s is th a t a L o w d o se(2 0 C l in ic a l H um ans T h i s s t u d y s u p p o r ts th e

D a w so n D R , c o m b i n a ti o n o f s y s te m i c a ll y m g) a tt a c h m e n t c o n c e p t th a t h o s t
M a g n usso n I, et a d m in is t e r e d h o s t- m o d u la t in g d o x y c y c l in e lo s s ( C A L ) , m o d u la t o r s p la y a c r it ic a l
a l 2 0 0 8 28 t h e r a p y & lo c a l ly a d m in i s te r e d h yc la te, b le e d i n g u p o n r o le in d is r u p tin g th e
t o p ic a l a n ti m ic r o b ia l t h e r a p y , a s d o x y c y c l in e p ro b in g p ro g re ssio n o f
a d j u n c ts to s c a li n g a n d r o o t h yclate g el (B O P ), an d p e r io d o n t a l b r e a k d o w n .
p l a n in g ( S R P ) , w o u ld p r o v i d e th e g in g i v a l
s i g n i f ic a n t l y im p r o v e d c l in i c a l in d e x ( G I ) .
b e n e f i ts in th e tr e a t m e n t o f
u n t r e a te d m o d e r a t e t o s e v e r e
c h r o n ic p e r io d o n ti ti s ( C P )
c o m p a r e d to S R P a lo n e .

Table.5 Review of literature with various host modulation agents.

60
Host Modulation In Periodontics
Recent research has examined the inflammatory and
resolution cascade in greater detail while looking at
endogenous and exogenous mediators that can be utilized
to achieve therapeutic end-points. The possible
introduction of “resolution indices” for drug testing
warrants a new look at pharmacologic agents that might
have been overlooked for their beneficial effects in
periodontal disease treatment.
Conclusion
Host response modulation has emerged as a valid treatment
concept for the management of periodontal disease and
represents a significant step forward for clinicians and
patients. To date, only sub antimicrobial dose doxycycline
has been approved specifically as a host response
modulator. Further research is necessary to evaluate the
efficacy of sub antimicrobial dose doxycycline in primary
care, and also to focus on very long-term outcomes, such
as prevention of tooth loss.
Given the huge and ever-expanding range of pathogenic
pathways that play a role in periodontal tissue destruction
blocking one single inflammatory pathway may not achieve
the desired outcome because receptor mediated responses
could be activated by alternate pathways. Thus, poly-
pharmaceutical approaches may be developed that modify
a number of different pathways associated with
inflammation and tissue destruction. Alternatively,
targeting of mediators that play a particularly important
role in periodontal pathogenesis, such as interleukin-1â or
tumour necrosis factor-á, may constitute a rational
therapeutic strategy.
However, it should be remembered that these pathways are
important in physiological processes and therefore their
inhibition could also result in adverse effects, such as
increased susceptibility to infection, and the development
and investigation of such agents require careful monitoring.
It is likely in the future that more effective therapeutic
approaches will include multiple, synergistic host
modulation therapies combined with treatments that target
the microbial etiology.
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