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e-Journal of Dentistry July - Sep 2011 Vol 1 Issue 3 51

R eview Article www.ejournalofdentistry.com

HOST MODULATION IN PERIODONTICSShantipriya Reddy Professor and Head, Prasad MGS Reader, Sanjay Kaul Professor, Hrishikesh

Asutkar Postgraduate student, Nirjhar Bhowmik Postgraduate student, Amudha Senior Lecturer, Departmentof 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: [email protected]

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 responsesare involved in the pathogenesis of periodontitis. Organisms strongly implicated as etiologic agents include Gram-

negative, 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 chal lenge disrupts homeostatic mechan isms 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 andstimulate 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 pathwaysresponsible 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.

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

challenge

46

.

In 1985, research began to focus very closely on

bacterial-host interaction, leading to host-bacterial inter-

relationship era14.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

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.

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 modulatingagents 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 MGSet al www.ejournalofdentistry.com

FDA for clinical use. Future bodes for anticytokine drugs,

bon e resorpti on uncoup ler s, ch emical ly modi fied

tetracyclines (CMTS), anti metabolites and lipoxins. These

provide operators with additional armamentar ium to

mechanical debridement, which could enhance and make

clinical therapeutic response more predictable, in more

susceptible host for the better management of periodontaldisease14

.

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,

bact er iodes forsyth us and act in obaci llu s

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,

bact er ia and thei r met abolic produc ts and the

lipopolysaccharide (LPS) initiate the host response. The

bacteria and their byproducts directly challenge the cells

of junctional epithelium. In response, the junctionalepithelial cells release various inflammatory mediators

including cytokines, PGE2, 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 directlycause 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 flor a and perpetuate the cycle of events

proposed in the model. (fig.2)

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

pharmocotherapi es as an adjunct to the tradit ional

periodontal therapies represent a new integrated approach

in long-term treatment and management of periodontitis.


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

Poor oral hygiene Normal Exogenous infection

Pathogenic flora Antibody response

Neutrophil clearance

Pocketing and bone loss Gingivitis

Inflammation & tissue destruction Bacterial penetration

Cytokines &

inflammatory

mediation

Monocyte lymphocyte axis Systemic

exposure

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 recruitmentof 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) andprostanoids (PGE

2) 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 ofresearch at altering an individuals 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 criticalintervention 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)

Host Modulation In Periodontics


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Stages of hostmodulation

Mode of interception SignificantContributors

Agents employed Authors coments

Immunization

methods.

Generation of protective

antibodies to prevent

Periodontitis.

Ishikawa et al.,

1997

Stock vaccines such

as Van Cotts vaccine,

Goldenbergs vaccine(or) Inava Endocorps

Vaccine.

Autogenous vaccines

Vaccines prepared

from pure cultures of

streptococci andother organisms

Gingipains

Periodontitis is a

polymicrobial disease so

formulating a vaccine against aparticular pathogen has shown

favourable clinical results, so

further research for acomprehensive vaccine is

warranted.

Vaccines are currently

available in companionanimals. TLR( Toll like

receptors) have been tried in

the form of vaccines presently.

Stages of host

modulation

Mode of interception Significant

Contributors


Regulation of

reactiveoxygen

species3.

Down regulation of reactive oxygen

species* using antioxidantsAntioxidants (AO's) are classified

according to their mode of action.

"Scavenging AO's"preventoxidative stress by literally

scavenging radicals as they form.

"Preventative AO's"function

largely by sequestering transitionmetal ions and preventing Fenton

reactions, they are therefore largelyproteins by nature.

"Enzyme AO's" are systems

that function by catalyzing the

oxidation of other molecules.

Benedeck 1998,

Bartold 1984,

Key 1994

Ascorbic acid, Alpha

tocopherol,Keratinides

Pharmacological inhibition of

iNOS withmercaptoalkylguanidines was

associated with decreased

inflammation, haemorrhagicshock and arthritis scores.

Through its ability to inhibit

cox and scavenge peroxynitrite

( product of NO andsuperoxide), block iNOS.

However furthur studies areneeded to substantiate its

therapeutic effects in

periodontal diseases.

Regulating

cytokines19.

The pleiotropic actions of cytokines

include numerous effects on the

cells of immune system andmodulation of inflammatory

responses.

Suppression of eicosanoid synthesisby INF- and IL-4 is the primarymechanism which inhibitsmacrophage MMP production.

These findings demonstrate that

IFN- and IL-4 may have potentanti-inflammatory effects.

Several cytokines have beenimplicated in the suppression of

tissue destructive cytokines. IL-10,

IL-4 has been shown to down

regulate IL-1 and TNF-geneexpression in human monocytes.

TGF- is an anti-inflammatoryagent which induces synthesis and

secretion of IL-1 is potentregulator of bone resorption invitro

and it may promote osteoblastgrowth and matrix synthesis.

Gortel 2004,

Shapira 1992,

Hendley 1995.

CYTOKINE

ANALOGES, Mast

cell stabilizers

Harsh enzymatic environment

in periodontal lesions may

destroy the soluble cytokineantagonist prior to their peak

activity necessitating frequent

administration.

Table.1 Regulation of immune and inflammatory responses


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Stages of hostmodulation


Agentsemployed

Authors coments

Regulation ofMMP activity at

4 gates:

Transcriptional

regulation ofMMP genes.

Transcription of the CL and SL-1 genes (in

some cells the SL-3 and Mr 92K GL genes

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

PDGF, TGF-, EGFbFGF, NGF.TGF-

IFN-

Wahl 1979,Cury 1988

TGF , FIB-CL,

SL- 1

Insufficient dataavailable.

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 sitereadily cleaved by a second

proteolysis

Nagase

1997

Organomercuria

l,chaotropicagent CKI,

NaSCN&

detergentsCSDC.Proteolytic

enzymes:trypsin,

plasmin,chymotrypsin,

neutrophilelastase,

cathepsin B andplasmakalikrein.

Insufficient data

available.

Substratespecificity

A certain level of regulation of MMPactivity is encoded at the level of thesubstrate, although enzymes havesomewhat overlapping substrate

specificities.

Insufficient dataavailable.

MMP inhibition( TIMPs)45,18,27.

-macroglobulins, particularly 2-M playan important role in the regulation of MMPactivity by bond cleavage region.

The inhibition probably occurs as a resultof binding the TIMPs at the MMP activesite. However, the amino acid residues inTIMPs that are responsible for binding at

the active site of MMPs are still unknown.

Lipoxins regulate local acute inflammatoryresponses in periodontal disease by limitingneutrophil recruitment and neutrophil

mediated tissue injury.

Rayan andGolub 2000,

Brew 2000,Kinane2000, Lee1995.

Tetracycline,CMT

Minocycline,Doxycycline (subantimicrobial

dose ofdoxicycline),lipoxins,

resolvins.

Tetracycline apartfrom its antimicrobial

property hascapability ofinhibiting theactivities of

neutrophil,osteoclast,MMP 8, therebyworking as anti-

inflammatory agent

that inhibits bonedestruction.

Ablates transcription of CL & SL-1

Table.2 Regulation of excessive production of MMPs.

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Role ofarachidonic acid

metabolites.


Agentsemployed

Authors coments

Prostaglandins

and other

arachidonic acid

metabolites within

the periodontaltissues play a role

in the

pathogenesis.

Inhibition of arachidonic acid metabolite by

blocking of the cyclooxygenase pathway.

Goldhaber

et al (1973)

Nyman et al

(1979)

Weaks-Dybvig et al

(1982)

Offenbacher

et al (1987)Jeffcoat et

al (1991)

Indomethacin,

Flurbiprofen,

S-Ketoprofen,

Triclosan.

Systemic daily

administration for

periods upto three

years of NSAIDs

showed significantreduction in rate of

bone loss, but has a

major disadvantage of

rebound effect.

Table.3 Regulation of arachidonic acid metabolites.

Quantity/Quality of

bone

Mode of interception Significant

Contributors


Osteoporosis and

osteopenia may beindicators for

periodontaldiseases.

Inhibition of

osteoclast/MMP activitythrough chelation of

cations.

Howell 1991, His-

Ming 2004,Holzhausen 2005,

Gurkan 2005,Durate 2005.

Bisphosphonates

(Alendronate),Hormone

replacementtherapy.(HRT),

OPG- Fctherapeutic agents.

Bisphosphonate

treatment improves theclinical outcome of non-

surgical periodontaltherapy and may be an

appropriate adjunctivetreatment 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.

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.

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 Hartelet 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 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 Perrsonet. 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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proli ferat ion 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 attentionover the last decades has focused on the beneficial effects

of fish oil, particular ly the -3 FA components, on a v a r i e

t y o f c h r o n i c i n f l a m m a t o r y d i s e a s e s ( 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 PUFAlevels 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 animprovement 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

modulatingagent

Parameters Subjects Results

Ishihara y,

nishihara t

et al(1991)16

To demonstrate the

lipopolysaccharide isolated from a.

Actinomycetemcomitans strain y4induced bone resorption

Indomethacin,

dexamethasone

PGE2 and IL-1

levels

Mouse

PGE2 and IL-1

participate in y4 LPSinduced bone

resorption in vitro.

Howell th,

fiorellini i,

weber hp etal (1991)14

To study the effects of piroxicam in

preventing gingival inflammation

and plaque formation

Piroxicam Gingival

inflammation,

plaque index

Beagle dogs Significantly inhibit

the development of

gingival inflammation

Nip lh, vittovj et al

(1993)26

To know the effects of tetracyclineon periodontal epithelial cells were

investigated by culture in cells from

porcine rests of malassez

Oxytetracycline,doxycycline and

de-

dimethylaminotetracycline

Radioactivegelatin

degradation and

gelatinenzymography

Results showed thatperiodontal epithelial

cells produce MMPswhose activities are

inhibited bytetracycline and their

non-antimicrobial

analogues atconcentration present

in gingival crevicular

fluid followingtetracycline therapy.



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Author Purpose Host modulating

agent


Roy S,

Feldman,

Szeto B et al

(1983)38

To evaluate the effect on bone

resorption: A retrospective study

Aspirin (asp) or

aspirin plus

indomethcin

Radiographs Humans Percentage bone loss

for the entire

dentition was lower in

asa group

Weaks

Dybvig M,

Farshid

Sanavi et al

(1982)47

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 Indomethacin

treatment abolished

the significant loss of

alveolar bone height

Offenbacher

S, Odle BM

et al (1989)30

To examine four principal

metabolites of cyclooxygenase

(co) during the progression of

experimental periodontitis

Flurbiprofen Crevicular fluid

levels of PGE2

and TXB2

Rhesus monkey It prevented rise in

TXB2, but did not

affect the increase in

PGE2.

Meikle MC,Atkinson SJ

et al (1989)21

To investigate the effect of TNF-(or) il-1 on human gingival

fibroblasts (hgfs), stimulated

collagenolysis.

Exogenoushuman timp

TNF-(or) IL-1 incollagen degradation

on human gingival

fibroblast.

Heasman PAand Seymour

RA (1990)11

Long-term efficacy of non-steroidal anti-inflammatory drug

(nsaid) therapy.

NSAIDs Plaque index,gingival index

pocket probing

depth, loss of

attachment,

gingival

recession, and

gingival fluidflow

Humans Highly significantdifferences were seen

between GCF flow in

study (16.74b28.63)

groups.

Taiyeb ali

TB and

Waite IM

(1993)43

To investigate the influence of

short-term ibuprofen therapy on theearly phase of the treatment of

adult chronic periodontitis.

Ibuprofen Gingival

bleeding, colorand pocket

depth

Humans Significantly greater reduction

for all parameters.

HeasmanPA,

Offenbacher S et al(1993)10

To evaluate the efficacy offlurbiprofen (50mg) on both

developing and establishedgingivitis

Flurbiprofen GCFconcentration

of PGE2, TXB2and LTB4,

Bleeding index

Human

Flurbiprofen control gingival

inflammation with bothpreventive and therapeutic

properties.

Shoji K,

HoriuchiH and

ShinodaH

(1995)42

Efficacy of risendronate to preventalveolar bone resorption

Risendronate Bone mineraldensity

Rats. In preventing bone resorptionin periodontitis.

Mathura,

Michalowicz b, et al

(1996)20

To evaluate the concentration of

IL-1IL-8) and interferon-inperiodontitis patients.

Gingivalcrevicular fluid.

Humans

IL-8 and interferon-weresignificantly correlated indiseased sites, suggesting that

levels of these two cytokines

rise (or) fall in tandem.

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Author Purpose Host

modulatingagent


Crout RJ,

Lee HM,et al

(1996)5

To check for potency of low dose

doxycycline

Low dose

doxycycline

Clinical

attachmentlevels, probing

depth and GCF

collagenaseactivity andperiodontal

ligament

degradation

Human LDD inhibits tissue

destruction in the absence ofantimicrobial property.

Long term LDD could be a

useful adjunct toinstrumentation

GolubLM, Lee

HM et al

(1997)8

To determine whether an inhibitorof matrix

metalloproteinases(MMPs)administered to human subjects in

dental school research clinic, canreduce bone type collagen

degradation in inflammatoryexudates

Doxycycline Collagenaseactivity

Human Reduction of excessiveMMP activity with

concomitant reduction incollagen degradation

products

PaquetteDW,

Fiorellini

JP et al:(1997)31

A study to evaluate effects of

systemic and topical administration.

S-ketoprofen Bone height (or)

99mm tc-sn-mdp uptake

ratio

Beagle dogs. Significantly lower mean

rates of bone loss comparedto placebo

Mineshiba,

Takashiba S et al

(1998)22

A study to evaluate the efficacy of

synthetic (hbd-2) against

actinobacillus actinomycetumcomitans, p.gingivalis, s.mutans and

e.coli

Human beta

defensin-2

Antibacterial

broth assay and

diffusion assay

Human Antibacterial activity of hbd-

2 was approximately equal to

that of minocycline.

Author Purpose Host modulatingagent


Rammurt-hy

NS, Kucine AJet al (1998)35

To compare wound healing innormal and diabetic rats

CMT-2 Volume ofgranulation

tissue.

Diabeticand non-

diabeticrats.

Results showed in CMT-2treated diabetic rats, the

volume of granulation tissuewas greater than that in

untreated diabetic rats

Breivk T,Thrane PS et al

(2000)1

To evaluate the efficacy ofglucocorticoiod receptor antagonist

ru486 (mitepristone)

Mitepristone Radiographsand

histologically.

Rat model Significantly less periodontalbreakdown at both

experimental and control teethcompared to the vehicle

treated control animals.

Mirna M,

Bezerra, et al(2000)23

To investigated the effect of a nonselective cyclooxygenase (cox)

inhibitor (or) a type-2 cox inhibitor

in an experimental periodontaldisease (EPD) model (wister rats)

Indomethacin,meloxicam.

Alveolar bonelevel.

Wister rats. Both prevented alveolar boneloss.

Provides a better risk benefitratio in the treatment of human

periodontitis than non-selective

cox inhibitors.

Raw-Linson A,

Dalati MHN etal (2000)

36

To investigate the cytokine il-1and its receptor antagonist IL-1ra ingingival crevicular fluid, in patientswith adult periodontitis.

GCF

investigations

Humans

IL-1concentration was 0.11pg/for bleeding periodontitissites and 0.01 pg/for healthysites. For healthy sites, a strong

inverse relationship was found

betweenIL-1and IL-1ralevels.

Delima AJ,

Oatent ET al

(2001)6

To investigate the role of il-1 and

tnf in the loss of connective tissueattachment.

Proinflammatory

cytokines i.e. IL-1,TNF

Histomorpho

metricanalysis

Macaca

fascicularis

IL-1 and TNF antagonists

significantly reduced the loss ofconnective tissue attachment byapproximately 51%.



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Author Purpose Host modu lat ingagent

Param eters Subjects Resul t s

G o l u b L M ,M c N a m a r aTF et al

( 2001)9

To ident i fy c l in ical ly effect ive doseregimens using subant imicrobia l

dose doxycycl ine (SDD) as an

adjunct ive therapy in pat ien ts w i thadult periodontitis.

Doxycycl ine Cl in icala t tachm ent level

H u man s

It has significant potential as

an ora l ad junct ive therapy in

the long term managementof adult periodontitis.

Cat on TG,Cian c io S G

et al (2001)2

To evaluate the efficacy of sub

ant imicrobia l dose doxycyl ine(SDD 20mg bid) + scal ing and root

pl an ni n g (S RP ) co m pa re d topl ac ebo pl u s S RP in a do ub le bl in d,pl ac ebo co nt ro ll ed w ith adu lt

pe r io do nt iti s.

Doxycycl ine Cl in ical

a t tachmentlevels

Imp ro v emen t i n

p er io do n ti tis and cl in ic ala t tachment level in SDD

g ro u p o v e r 9 m o n t h s

Myou n g H,Park JY e t a l

( 2001)25

To evaluate the clinical availabili tyof b isphosphonate in au togenous

free bone graft s

Bisphosphonates Cl in icalmeasurements ,

h is tomorphological rev iew

Ra t s Cl in ical appl icat ion o f

b is ph os p ho n at es fo r

decreasing resorp t ion ofgrafted bone.

R a m a m u r - t h y

NS, Bains et

al (2001)34

To evaluate the efficacy of topicaladminist ra t ion of a b iphosphonate

in prevent ion of a lveolar bone lossin ra ts wi th experimen tal

pe r io do nt iti s.

Clodronate Bone mineraldensity

Rats . Top ical adminis tra t ion ofc lodronate may be

effect ive in prevent ingosteoclas t ic bo neresorpt ion in

p eri o don ti ti s.

Zh an g D,Goet z W et

al (2003)

48

Invest igate the ro le of i l -1 and

tumor n ecrosis fac tor a lpha

(TN F ) in the course ofmechanical ly induced rootresorp t ion .

T N F Recession

height , wid th .

H u man s Th e amo u n t s o f ro o t

resorp t ion was s igni ficant lyreduced, especia l ly

fo l lowing systemicappl icat ion of TNF , root

resorp t ion was com plete ly

p re ve nt ed .

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

60

A u t h o r P u r p o s e H o s tm o d u l a t i n g

a g e n t

P a r a m e t e r s S u b j e c t s R e s u l t s

H i s - M i n g L e e ,

S e b a s t i a n G e t a l( 2 0 0 4 ) 12

T o e v a l u a t e e f f ic a c y o f t h e

a d m i n i s tr a t io n o f s u b

a n t i m i c r o b i a l d o s e d o x y c y c l i n e

t o c h r o n i c p e r i o d o n t i t is p a t i e n t s

a n d N S A I D s .

D o x y c y c l i n e ,

f l u r b i p r o f e n

H o s t - d e r i v e d

n e u t r a l

p ro te in a s e s

l e v e l s

H u m a n s

C o m b i n a t i o n t h e r a p yp ro d u c e d a s ta ti s ti c a l ly

s i g n i f i c a n t s y n e r g i s t i c

r e d u c t i o n o f c o l l a g e n a s e .

C h i a r a S , T a t a k i sD N e t a l ( 2 0 0 5 ) 4

T o d e t e r m i n e t h e a s s o c i a t i o n o f

i n t e r le u k i n - 1 ( I L - 1 ) g e n e

p o l y m o r p h i s m s w it h c l in i c a lp a ra m e t e rs o f g i n g i v it i s i n l a rg e

e x p e r i m e n t a l g i n g i v i t is

I L - 1 l e v e l s H u m a n s

A s s o c i a t i o n b e t w e e n I L - 1

p o ly m o rp h is m an d

s u b j e c t b a s e d c l i n ic a l

b e h a v i o u r o f g in g iv a in

r e s p o n s e t o p l a q u ea c c u m u l a t io n , a s w e l l a s

a p o s s i b l e a s s o c i a t i o nb e tw e e n IL -1 p o ly m o rp h is m an d

g i n g i v i t i s s u s c e p t i b i l i t y .

D u r a t e P M ,

G u r g e l B C D e t a l

( 2 0 0 5 ) 7

T o e v a l u a t e w h e t h e r

a l e n d r o n a t e ( a l d ) i n f l u e n c eb o n e h e a li n g a ro u n d ti t a n iu m

i m p l a n t s 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 t s .

A l e n d r o n a t e E s t r o g e n

l e v e l s

O v a r i e c t o

m i z e d r a t s . A l e n d r o n a t e m a y p r e v e n t

n e g a t i v e i n f lu e n c e o f

e s t ro g e n d e f i c i e n c y o n

b o n e h e a l in g a r o u n d

t i ta n i u m i m p l a n t s .

S e k i n o s ,

R a m b e r g P e t a l

( 2 0 0 5 ) 40

T o s t u d y t h e e f f e ct o f s y s t e m i c

a d m i n i s tr a t io n o f i b u p r o f e n o n

g i n g i v i ti s a n d p l a q u e b u i l d .

I b u p r o f e n ,

c h l o r h e x i d i n e

d i g l u c o n a t e

P l a q u e i n d e x

a n d g i n g i v a l

i n d e x

H u m a n s T h e s u b j e c t s r i n s e d w i t h

s a l i n e a c c u m u l a t e d l a r g e

a m o u n t s o f p l a q u e a n dd e v e l o p e d m a r k e d s i g n o f

g i n g i v i t i s .

T h e p a t i en t s p r e s e n t e dw i t h s i g n i f i c a n t ly f e w e r

s i te s t h a t s c o r e d G i n g i v a l

i n d e x 2H o l z h a u s e n M ,

S p o l id o r i D M P e t

a l ( 2 0 0 5 ) 1 3

T o e v a l u 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 i b i t o r , e t o r i c o x i b i n

t h e p r e v e n t i o n o f a l v e o l a r b o n el o s s i n e x p e r i m e n t a l

p e ri o d o n ti ti s .

E t o r ic o x i b W B C c o u n t

a n d s e r u ml e v e l s , d i g i t a l

r a d i o g r a p h s

W i s te r r a t s G r o u p s t r e a te d w i t h b o t h

d o s e s o f e t o r i c o x i b h a ds i g n i f i c a n t l y l e s s a l v e o l a r

b o n e l o s s c o m p a r e d t oc o n t r o l s .

N o v a k M J ,D a w s o n D R ,

M a g n u s s o n I , e ta l 2 0 0 8 28

T o t e s t t h e h y p o t h e s i s th a t a

c o m b i n a t i o n o f sy s t e m i c a l l y

a d m i n i s te r e d h o s t - m o d u l a t i n g

t h e r a p y & l o c a l l y a d m i n i s te r e d

t o p i c a l a n t i m i c r o b i a l t h e r a p y , a s

a d j u n c t s t o s c a l i n g a n d r o o tp l a n in g ( S R P ), w o u ld p r o v i d e

s i g n i fi c a n t l y i m p r o v e d c l i n i c a lb e n e fi ts in th e tr e a t m e n t o f

u n t r e a t e d m o d e r a t e t o s e v e rec h r o n i c p e r i o d o n t i t i s ( C P )

c o m p a r e d t o S R P a l o n e .

L o w d o s e ( 2 0

m g )

d o x y c y c l i n e

h y c l a t e ,

d o x y c y c l i n e

h y c l a t e g e l

C l i n i c a l

a t t a c h m e n t

l o s s ( C A L ) ,

b le e d i n g u p o n

p ro b in g

( B O P ) , a n dt h e g i n g i v a l

i n d e x ( G I ) .

H u m a n s T h i s s t u d y s u p p o r t s t h e

c o n c e p t t h a t h o s t

m o d u l a t o r s p l a y a c r i t ic a l

r o l e i n d i s r u p t i n g t h e

p ro g re s s i o n o f

p e ri o d o n ta l b re a k d o w n .


11/12

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 inperiodontal 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-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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