R eview Article

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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 biolm and associated host responses
are involved in the pathogenesis of periodontitis. Organisms strongly implicated as etiologic agents include Gramnegative, anaerobic or microaerophilic bacteria within the biolm . 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 antiinammatory cytokines including
transforming growth factor- (TGF-), 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- [TNF-]), 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 individuals 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
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.

inflammatory mediators like PGE2 that cause the majority

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.

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 antiinflammatory 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

In 1985, research began to focus very closely on

bacterial-host interaction, leading to host-bacterial interrelationship 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
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FDA for clinical use. Future bodes for anticytokine drugs,

bone resorption uncouplers, chemically modified
tetracyclines (CMTS), 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.

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.

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.

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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Host Modulation In Periodontics

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

inflammatory

Systemic
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 IL12.
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 individuals reaction to the bacterial
challenge.

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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
metalloproteinases29,45 . (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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Prasad MGS et al

Stages of host
modulation
Immunization
methods.

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Mode of interception
Generation of protective
antibodies to prevent
Periodontitis.

Significant
Contributors
Ishikawa et al.,
1997

Agents employed

Authors coments

Stock vaccines such

as Van Cotts vaccine,
Goldenbergs vaccine
(or) Inava Endocorps
Vaccine.
Autogenous vaccines

Periodontitis is a
polymicrobial disease so
formulating a vaccine against a
particular pathogen has shown
favourable clinical results, so
further research for a
comprehensive vaccine is
warranted.
Vaccines are currently
available in companion
animals. TLR( Toll like
receptors) have been tried in
the form of vaccines presently.
Authors coments

Vaccines prepared
from pure cultures of
streptococci and
other organisms

Stages of host
modulation
Regulation of
reactive
oxygen
species3.

Regulating
cytokines19.

Mode of interception
Down regulation of reactive oxygen
species* using antioxidants
Antioxidants (AO's) are classified
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.
The pleiotropic actions of cytokines
include numerous effects on the
cells of immune system and
modulation of inflammatory
responses.

Significant
Contributors
Benedeck 1998,
Bartold 1984,

Gingipains
Agents employed
Ascorbic acid, Alpha
tocopherol,
Keratinides

Pharmacological inhibition of
iNOS with
mercaptoalkylguanidines was
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.

CYTOKINE
ANALOGES, Mast
cell stabilizers

Harsh enzymatic environment

in periodontal lesions may
destroy the soluble cytokine
antagonist prior to their peak
activity necessitating frequent
administration.

Key 1994

Gortel 2004,
Shapira 1992,
Hendley 1995.

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.
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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Host Modulation In Periodontics

Stages of host
modulation
Regulation of
MMP activity at
4 gates:

Mode of interception
Transcription of the CL and SL-1 genes (in
some cells the SL-3 and Mr 92K GL genes

Significant
Contributors
Wahl 1979,
Cury 1988

Agents
employed
TGF , FIBCL,
SL- 1

Nagase
1997

Organomercuria
l,chaotropic
agent CKI,
NaSCN &
detergents
CSDC.
Proteolytic
enzymes:
trypsin,
plasmin,
chymotrypsin,
neutrophil
elastase,
cathepsin B and
plasma
kalikrein.

Authors coments
Insufficient data
available.

as well) is induced by IL-1, TNF-,

Transcriptional
regulation of
MMP genes.

PDGF, TGF-, EGF bFGF, NGF.

TGF- Ablates transcription of CL & SL-1
IFN-

Precursor
activation.

The activator proteinase first attacks

the susceptible
'bait' region (located in the middle of
the propeptide)

Changes in the propeptide

Rendering the final activation site

readily cleaved by a second
proteolysis

Substrate
specificity

A certain level of regulation of MMP

activity is encoded at the level of the
substrate,
although
enzymes
have
somewhat
overlapping
substrate
specificities.

MMP inhibition
( TIMPs)45,18,27.

-macroglobulins, particularly 2-M play

an important role in the regulation of MMP
activity by bond cleavage region.
The inhibition probably occurs as a result
of binding the TIMPs at the MMP active
site. However, the amino acid residues in
TIMPs that are responsible for binding at
the active site of MMPs are still unknown.
Lipoxins regulate local acute inflammatory
responses in periodontal disease by limiting
neutrophil recruitment and neutrophil
mediated tissue injury.

Insufficient data
available.

Insufficient data
available.

Rayan and
Golub 2000,
Brew 2000,
Kinane
2000, Lee
1995.

Tetracycline,
CMT
Minocycline,
Doxycycline (
sub
antimicrobial
dose of
doxicycline),
lipoxins,
resolvins.

Tetracycline apart
from its antimicrobial
property has
capability of
inhibiting the
activities of
neutrophil,osteoclast,
MMP 8, thereby
working as antiinflammatory agent
that inhibits bone
destruction.

Table.2 Regulation of excessive production of MMPs.

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Prasad MGS et al

Role of
arachidonic acid
metabolites.
Prostaglandins
and other
arachidonic acid
metabolites within
the periodontal
tissues play a role
in the
pathogenesis.

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Mode of interception

Significant
Contributors

Inhibition of arachidonic acid metabolite by

blocking of the cyclooxygenase pathway.

Goldhaber
et al (1973)
Nyman et al
(1979)
WeaksDybvig et al
(1982)
Offenbacher
et al (1987)
Jeffcoat et
al (1991)

Agents
employed
Indomethacin,
Flurbiprofen,
S-Ketoprofen,
Triclosan.

Authors coments

Systemic daily
administration for
periods upto three
years of NSAIDs
showed significant
reduction in rate of
bone loss, but has a
major disadvantage of
rebound effect.

Table.3 Regulation of arachidonic acid metabolites.

Quantity/Quality of
bone
Osteoporosis and
osteopenia may be
indicators for
periodontal
diseases.

Mode of interception
Inhibition of
osteoclast/MMP activity
through chelation of
cations.

Significant
Contributors
Howell 1991, HisMing 2004,
Holzhausen 2005,
Gurkan 2005,
Durate 2005.

Agents employed

Authors coments

Bisphosphonates
(Alendronate),
Hormone
replacement
therapy.(HRT),
OPG- Fc
therapeutic agents.

Bisphosphonate
treatment improves the
clinical outcome of nonsurgical periodontal
therapy and may be an
appropriate adjunctive
treatment to preserve
periodontal bone mass.

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.

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).

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.

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 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.

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.

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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Host Modulation In Periodontics

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 immunoinflammatory 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 preAuthor

Purpose

Ishihara y,
nishihara t
et al
(1991)16

To demonstrate the
lipopolysaccharide isolated from a.
Actinomycetemcomitans strain y4
induced bone resorption

Howell th,
fiorellini i,
weber hp et
al (1991)14
Nip lh, vitto
vj et al
(1993)26

To study the effects of piroxicam in

preventing gingival inflammation
and plaque formation
To know the effects of tetracycline
on periodontal epithelial cells were
investigated by culture in cells from
porcine rests of malassez

e-Journal of Dentistry July - Sep 2011 Vol 1 Issue 3

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 preosteoclasts 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-oilsupplemented 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.

Host
modulating
agent
Indomethacin,
dexamethasone

Parameters

Subjects

PGE2 and IL-1

levels

Mouse

Piroxicam

Gingival
inflammation,
plaque index

Beagle dogs

Oxytetracycline,
doxycycline and
dedimethylamino
tetracycline

Radioactive
gelatin
degradation and
gelatin
enzymography

Results

PGE2 and IL-1

participate in y4 LPS
induced bone
resorption in vitro.
Significantly inhibit
the development of
gingival inflammation

Results showed that

periodontal epithelial
cells produce MMPs
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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Prasad MGS et al

Author

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Purpose

Roy S,
Feldman,
Szeto B et al
(1983)38
Weaks
Dybvig M,
Farshid
Sanavi et al
(1982)47
Offenbacher
S, Odle BM
et al (1989)30
Meikle MC,
Atkinson SJ
et al (1989)21
Heasman PA
and Seymour
RA (1990)11

Host modulating
agent

Parameters

Subjects

Results

To evaluate the effect on bone

resorption: A retrospective study

Aspirin (asp) or
aspirin plus
indomethcin

Radiographs

Humans

To determine if prostaglandins
play a role in loss of bone in
ligature model of periodontitis

Indomethacin
5mg / kg /day

Alveolar bone
height

Squirrel monkeys

To examine four principal

metabolites of cyclooxygenase
(co) during the progression of
experimental periodontitis
To investigate the effect of TNF-
(or) il-1 on human gingival
fibroblasts (hgfs), stimulated
collagenolysis.
Long-term efficacy of nonsteroidal anti-inflammatory drug
(nsaid) therapy.

Flurbiprofen

Crevicular fluid
levels of PGE2
and TXB2

Rhesus monkey

Plaque index,
gingival index
pocket probing
depth, loss of
attachment,
gingival
recession, and
gingival fluid
flow

Humans

Exogenous
human timp

NSAIDs

Taiyeb ali
TB and
Waite IM
(1993)43
Heasman
PA,
Offenbac
her S et al
(1993)10

To investigate the influence of

short-term ibuprofen therapy on the
early phase of the treatment of
adult chronic periodontitis.
To evaluate the efficacy of
flurbiprofen (50mg) on both
developing and established
gingivitis

Ibuprofen

Shoji K,
Horiuchi
H and
Shinoda
H
(1995)42
Mathur
a,
Michalow
icz b, et al
(1996)20

Efficacy of risendronate to prevent

alveolar bone resorption

Risendronate

To evaluate the concentration of

IL-1 IL-8) and interferon- in
periodontitis patients.

Flurbiprofen

Gingival
bleeding, color
and pocket
depth
GCF
concentration
of PGE2, TXB2
and LTB4,
Bleeding index

Humans

Bone mineral
density

Rats.

Gingival
crevicular fluid.

Humans

Percentage bone loss

for the entire
dentition was lower in
asa group
Indomethacin
treatment abolished
the significant loss of
alveolar bone height
It prevented rise in
TXB2, but did not
affect the increase in
PGE2.
TNF- (or) IL-1 in
collagen degradation
on human gingival
fibroblast.
Highly significant
differences were seen
between GCF flow in
study (16.74b28.63)
groups.

Significantly greater reduction

for all parameters.

Human
Flurbiprofen control gingival
inflammation with both
preventive and therapeutic
properties.
In preventing bone resorption
in periodontitis.

IL-8 and interferon- were

significantly correlated in
diseased sites, suggesting that
levels of these two cytokines
rise (or) fall in tandem.

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Host Modulation In Periodontics

Author

Purpose

Host
modulating
agent
Low dose
doxycycline

Crout RJ,
Lee HM,
et al
(1996)5

To check for potency of low dose

doxycycline

Golub
LM, Lee
HM et al
(1997)8

To determine whether an inhibitor

of matrix
metalloproteinases(MMPs)
administered to human subjects in
dental school research clinic, can
reduce bone type collagen
degradation in inflammatory
exudates
A study to evaluate effects of
systemic and topical administration.

Doxycycline

A study to evaluate the efficacy of

synthetic (hbd-2) against
actinobacillus actinomycetum
comitans, p.gingivalis, s.mutans and
e.coli

Paquette
DW,
Fiorellini
JP et al:
(1997)31
Mineshib
a,
Takashib
a S et al
(1998)22

Author

Purpose

Rammurt-hy
NS, Kucine AJ
et al (1998)35

To compare wound healing in

normal and diabetic rats

Breivk T,
Thrane PS et al
(2000)1

To evaluate the efficacy of

glucocorticoiod receptor antagonist
ru486 (mitepristone)

Mirna M,
Bezerra, et al
(2000)23

To investigated the effect of a non

selective cyclooxygenase (cox)
inhibitor (or) a type-2 cox inhibitor
in an experimental periodontal
disease (EPD) model (wister rats)

Raw-Linson A,
Dalati MHN et
al (2000)36

To investigate the cytokine il-1

and its receptor antagonist IL-1ra in
gingival crevicular fluid, in patients
with adult periodontitis.

Delima AJ,
Oatent ET al
(2001)6

To investigate the role of il-1 and

tnf in the loss of connective tissue
attachment.

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Parameters

Subjects

Results

Clinical
attachment
levels, probing
depth and GCF
collagenase
activity and
periodontal
ligament
degradation
Collagenase
activity

Human

LDD inhibits tissue

destruction in the absence of
antimicrobial property.
Long term LDD could be a
useful adjunct to
instrumentation

Human

Reduction of excessive
MMP activity with
concomitant reduction in
collagen degradation
products

S-ketoprofen

Bone height (or)

99mm tc-snmdp uptake
ratio

Beagle dogs.

Significantly lower mean

rates of bone loss compared
to placebo

Human beta
defensin-2

Antibacterial
broth assay and
diffusion assay

Human

Antibacterial activity of hbd2 was approximately equal to

that of minocycline.

Host modulating
agent
CMT-2

Parameters

Subjects

Volume of
granulation
tissue.

Diabetic
and nondiabetic
rats.

Mitepristone

Radiographs
and
histologically.

Rat model

Indomethacin,
meloxicam.

Alveolar bone
level.

Wister rats.

Results
Results showed in CMT-2
treated diabetic rats, the
volume of granulation tissue
was greater than that in
untreated diabetic rats
Significantly less periodontal
breakdown at both
experimental and control teeth
compared to the vehicle
treated control animals.
Both prevented alveolar bone
loss.
Provides a better risk benefit
ratio in the treatment of human
periodontitis than non-selective
cox inhibitors.

Proinflammatory
cytokines i.e. IL-1,
TNF

GCF
investigations

Humans

Histomorpho
metric
analysis

Macaca
fascicularis

IL-1 concentration was 0.11

pg/ for bleeding periodontitis
sites and 0.01 pg/ for healthy
sites. For healthy sites, a strong
inverse relationship was found
betweenIL-1 and IL-1ra
levels.
IL-1 and TNF antagonists
significantly reduced the loss of
connective tissue attachment by
approximately 51%.

59

Prasad MGS et al

A u th o r

www.ejournalofdentistry.com

P u rp o s e

H o s t m o d u latin g
ag e n t
D o x y c y clin e

P aram e te rs

S u b je cts

G o lu b L M ,
M cN a m a ra
T F et a l
(2 0 0 1 ) 9

T o id en tify c lin ic all y e ffe ctiv e d o se

reg i m en s u s in g su b an tim ic ro b ial
d o se d o x y cy clin e (S D D ) as an
ad ju n ctiv e th era p y in p atien ts w ith
ad u lt p erio d o n titis.

C a to n T G ,
C ia n cio S G
e t a l (2 0 0 1 ) 2

T o ev alu a te th e effic ac y o f su b
an tim icro b ial d o se d o x y cy lin e
(S D D 2 0 m g b id ) + scalin g an d ro o t
p lan n in g (S R P ) co m p a red to
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.

D o x y c y clin e

C lin ica l
attac h m en t
le v els

M y oung H ,
P a rk J Y et a l
(2 0 0 1 ) 2 5

T o ev alu a te th e clin ic al av ailab ility

o f b is p h o sp h o n a te in au to g en o u s
fre e b o n e g rafts

B is p h o sp h o n ates

R a ts

C lin ical ap p lica tio n o f

b isp h o sp h o n ates fo r
d ecreas in g res o rp tio n o f
g ra fte d b o n e .

R a m a m u r-th y
N S , B a in s e t
34
a l (2 0 0 1 )

T o ev alu a te th e effic ac y o f to p ica l

ad m in istratio n o f a b ip h o sp h o n a te
in p rev en tio n o f a lv e o lar b o n e lo ss
in rats w ith e x p erim en ta l
p erio d o n titis.

C lo d ro n a te

C lin ica l
m e asu re m en ts,
h isto m o rp h o lo g i
cal rev ie w
B o n e m in eral
d en sity

R a ts .

T o p ic a l a d m in istra tio n o f
c lo d ro n a te m a y b e
e ffe c tiv e in p re v e n tin g
o ste o c la stic b o n e
re so rp tio n in
p e rio d o n titis.

Z ha n g D ,
G o e tz W e t
a l (2 0 0 3 ) 48

In v estig ate th e ro le o f il- 1 an d

tu m o r n ecro sis fa cto r alp h a
(T N F ) in th e co u rs e o f
m e ch a n ically in d u ced ro o t
res o rp tio n .

TNF

R eces sio n
h eig h t, w id th .

H u m an s

T h e am o u n ts o f ro o t
reso rp tio n w as sig n ifica n tly
red u ce d , esp ecially
fo llo w in g s y ste m ic
a p p licatio n o f T N F , 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

P u rp o se

T o e v a lu a t e e f f ic a c y o f t h e
a d m in is t r a ti o n o f s u b
a n t im ic r o b ia l d o s e d o x y c y c l in e
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
a n d N S A ID s.
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 n te r l e u k in - 1 ( I L - 1 ) g e n e
p o l y m o r p h i s m s w ith c l in i c a l
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
e x p e r i m e n ta l g in g i v iti s

H o st
m o d u la ti n g
a g en t
D o x y c y c li n e ,
f lu r b ip r o f e n

C lin ica l
attac h m en t lev el

R esu lts

P a ram e ters

H u m an s
It h as s ig n ific an t p o ten tial as
a n o ral ad ju n ctiv e th er ap y in
th e lo n g te rm m an ag e m en t
o f ad u lt p erio d o n titis.
Im p ro v e m en t in
p erio d o n titis a n d clin ic al
a ttach m en t lev el in S D D
g ro u p o v e r 9 m o n th s

S u b je c ts

H o s t- d e r iv e d
n e u tra l
p r o t e in a s e s
le v e ls

H um ans

I L - 1 le v e ls

H um ans

R e s u lt s

C o m b i n a ti o n t h e r a p y
p r o d u c e d a s t a ti s ti c a l ly
s ig n if i c a n t s y n e r g is t ic
r e d u c ti o n o f c o l la g e n a s e .
A s s o c i a ti o n b e t w e e n I L - 1
p o ly m o r p h is m a n d
s u b je c t b a s e d c l in ic a l
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 .

D u r a te P M ,
G u r g el B C D e t al
(2 0 0 5 ) 7

T o e v a lu a t e w h e th e r
a le n d r o n a te ( a ld ) in fl u e n c e
b o n e h e a li n g a r o u n d tit a n iu m
i m p l a n ts i n s e r t e d i n
o v a r i e c t o m i z e d r a ts .

A le n d r o n a t e

E s tr o g e n
le v e ls

O v a r ie c t o
m i z e d r a ts .

S ek in os,
R am b erg P et al
(2 0 0 5 ) 40

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
a d m in is t r a ti o n o f i b u p r o f e n o n
g in g i v i ti s a n d p l a q u e b u i ld .

Ib u p r o fen ,
c h lo r h e x id in e
d i g l u c o n a te

P l a q u e in d e x
a n d g i n g iv a l
in d e x

H um ans

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

T o e v a lu a t e t h e e f f e c t o f
s e l e c t iv e c y c l o o x y g e n a s e - 2
( c o x - 2 ) i n h ib it o r , e t o r ic o x ib i n
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
l o s s i n e x p e r im e n ta l
p e r i o d o n ti ti s .

E to r ic o x ib

W B C coun t
a n d se ru m
le v e ls , d ig it a l
ra d io g ra p h s

W i s te r r a t s

N ovak M J,
D a w so n D R ,
M a g n usso n I, et
a l 2 0 0 8 28

T o t e s t t h e h y p o th e s is th a t a
c o m b i n a ti o n o f s y s te m i c a ll y
a d m in is t e r e d h o s t- m o d u la t in g
t h e r a p y & lo c a l ly a d m in i s te r e d
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
a d j u n c ts to s c a li n g a n d r o o t
p l a n in g ( S R P ) , w o u ld p r o v i d e
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
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 .

L o w d o se(2 0
m g)
d o x y c y c l in e
h yc la te,
d o x y c y c l in e
h yclate g el

C l in ic a l
a tt a c h m e n t
lo s s ( C A L ) ,
b le e d i n g u p o n
p ro b in g
(B O P ), an d
th e g in g i v a l
in d e x ( G I ) .

H um ans

A l e n d r o n a te m a y p r e v e n t
n e g a t iv e i n f lu e n c e o f
e s tr o g e n d e f ic i e n c y o n
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 h e s u b je c t s r in s e d w i th
s a li n e a c c u m u la t e d l a r g e
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
G r o u p s tr e a te d w it h b o t h
d o s e s o f e t o r ic o x i b h a d
s ig n if i c a n tl y l e s s a l v e o la r
b o n e lo ss co m p ared to
c o n tr o l s .

T h i s s t u d y s u p p o r ts th e
c o n c e p t th a t h o s t
m o d u la t o r s p la y a c r it ic a l
r o le in d is r u p tin g th e
p ro g re ssio n o f
p e r io d o n t a l b r e a k d o w n .

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

60

www.ejournalofdentistry.com

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.

5.

Crout RJ, Lee HM, Schroeder K, Crout H, Golub LM, et al. The cyclic regimen
of low dose doxycycline for adult periodontitis: A preliminary study. J
Periodontol 1996; 67: 506-514.

6.

Delima AJ, Oates T, Assuma R, Schwartz Z, Cochran D, Amar S. Soluble

antagonists to interleukin-1 (IL-1) and/and Graven DT: tumour necrosis
factor (TNF) inhibits loss of tissue attachment in experimental periodontitis.
J Clin Periodontol 2001; 28: 233-240.

7.

Durate PM, Gurgel BCD, Sallum AW, Filho GN, Enilson and Nociti Jr.
Alendronate therapy may be effective in the prevention of bone loss around
titanium implants inserted in estrogen deficient rats. J Periodontol 2005;
76: 107-114.

Conclusion

8.

Golub LM, Lee HM, Greenwald RA, Ryan ME , Sorsa T, Salo T. A matrix
metallo proteinase inhibitor reduces bone-type collagen degradation
fragments and specific collagenases in gingival crevicular fluid during adult
periodontitis. J Inflamm Res 1997; 46: 310-319.

9.

Golub LM, McNamara TF, Ryan ME, Kohut B, Blieden T. Adjunctive treatment
with substantimicrobial doses of doxycycline: effects on gingival fluid
collagenase activity and attachment loss in adult periodontitis. J Clin
Periodontol 2001; 28: 146-156.

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, polypharmaceutical 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-1 or
tumour necrosis factor-, 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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