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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.
51
Prasad MGS et al
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52
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Normal
Exogenous infection
Pathogenic flora
Antibody response
Neutrophil clearance
Gingivitis
Bacterial penetration
Cytokines &
inflammatory
Systemic
exposure
mediation
53
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
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
Key 1994
Gortel 2004,
Shapira 1992,
Hendley 1995.
54
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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.
Precursor
activation.
Substrate
specificity
MMP inhibition
( TIMPs)45,18,27.
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.
55
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
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.
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.
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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
Host
modulating
agent
Indomethacin,
dexamethasone
Parameters
Subjects
Mouse
Piroxicam
Gingival
inflammation,
plaque index
Beagle dogs
Oxytetracycline,
doxycycline and
dedimethylamino
tetracycline
Radioactive
gelatin
degradation and
gelatin
enzymography
Results
57
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
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
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
Ibuprofen
Shoji K,
Horiuchi
H and
Shinoda
H
(1995)42
Mathur
a,
Michalow
icz b, et al
(1996)20
Risendronate
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
Human
Flurbiprofen control gingival
inflammation with both
preventive and therapeutic
properties.
In preventing bone resorption
in periodontitis.
58
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Author
Purpose
Host
modulating
agent
Low dose
doxycycline
Crout RJ,
Lee HM,
et al
(1996)5
Golub
LM, Lee
HM et al
(1997)8
Doxycycline
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
Breivk T,
Thrane PS et al
(2000)1
Mirna M,
Bezerra, et al
(2000)23
Raw-Linson A,
Dalati MHN et
al (2000)36
Delima AJ,
Oatent ET al
(2001)6
Parameters
Subjects
Results
Clinical
attachment
levels, probing
depth and GCF
collagenase
activity and
periodontal
ligament
degradation
Collagenase
activity
Human
Human
Reduction of excessive
MMP activity with
concomitant reduction in
collagen degradation
products
S-ketoprofen
Beagle dogs.
Human beta
defensin-2
Antibacterial
broth assay and
diffusion assay
Human
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
59
Prasad MGS et al
A u th o r
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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
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
B is p h o sp h o n ates
R a ts
R a m a m u r-th y
N S , B a in s e t
34
a l (2 0 0 1 )
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
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 .
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7.
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