HOST MODULATION IN PERIODONTICS.pdf

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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: [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 bioûlm 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 bioûlm . The microbial challenge consisting of antigens, lipopolysaccharide (LPS), and other virulence factors stimulates host responses which result in disease limited to the gingiva (i.e., gingivitis) or initiation of periodontitis. Protective aspects of the host response include recruitment of neutrophils, production of protective antibodies, and possibly the release of antiinûammatory cytokines including transforming growth factor-β (TGF-β), interleukin-4 (IL-4), IL-10, and IL-12.Perpetuation of the host response due to a persistent bacterial challenge disrupts homeostatic mechanisms and results in release of mediators including proinflammatory cytokines (e.g., IL-1, IL-6, tumor necrosis factor-α [TNF-α]), proteases (e.g., matrix metalloproteinases), and prostanoids (e.g., prostaglandin E2[PGE2]) which can promote extracellular matrix destruction in the gingiva and stimulate bone resorption. The determination that periodontal tissue destruction is primarily due to the host response has created areas of research directed at altering an individual’s reaction to the bacterial challenge the present paper aims at reviewing various host modulatory therapies (HMT) have been developed or proposed to block pathways responsible for periodontal tissue breakdown. Keywords : Polymicrobial disease, host response, proanti-inflammatory cytokines, host modulation therapy. INTRODUCTION 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 e-Journal of Dentistry July - Sep 2011 Vol 1 Issue 3

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FDA for clinical use. Future bodes for anticytokine drugs, bone resorption uncouplers, chemically modified tetracyclines (CMT’S), anti metabolites and lipoxins. These provide operators with additional armamentarium to mechanical debridement, which could enhance and make clinical therapeutic response more predictable, in more susceptible host for the better management of periodontal disease14.

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 individual’s reaction to the bacterial challenge.

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

Various host modulation therapies (HMT) have been developed and proposed to block pathways responsible for periodontal tissue breakdown14 . One of the tremendous benefits of fundamental research which seeks to elucidate key mechanism of host tissue destruction is the simultaneous identification of critical intervention with host modulating agents. So here we have given an overview of Specific aspects of disease pathogenesis for modulation: Specific aspects of disease pathogenesis for modulation a) Regulation of immune and inflammatory responses. ( Table 1) b) Regulation of excessive production of matrix metalloproteinase’s29,45 . (Table 2) c) Regulation of arachidonic acid metabolites32,33,37 (Table 3) d) Regulation of bone metabolism7,24,42. ( Table 4)

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Stages of host modulation Immunization methods.


Mode of interception Generation of protective antibodies to prevent Periodontitis.

Significant Contributors Ishikawa et al., 1997

Agents employed

Author’s coments

Stock vaccines such as Van Cotts vaccine, Goldenberg’s 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. Author’s 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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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 β, 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.

Author’s 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 ( TIMP’s)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 TIMP’s at the MMP active site. However, the amino acid residues in TIMP’s that are responsible for binding at the active site of MMP’s 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 MMP’s.


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


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.

Author’s coments

Systemic daily administration for periods upto three years of NSAID’s 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

Author’s 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 â and to block proinflammatory cytokine production according to Schreck et. al 1991. Many studies have demonstrated that microorganisms influence tissue damage through cytokine production by degrading glutathione or from preventing glutathione formation from cystine according to Perrson et. al 1990.

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 56



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


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 MMP’s whose activities are inhibited by tetracycline and their non-antimicrobial analogues at concentration present in gingival crevicular fluid following tetracycline therapy.

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Author


Purpose

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 (hgf’s), 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

NSAID’s

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 (16.74b±28.63) 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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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(MMP’s) 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.


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 α

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%.

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A u th o r


P u rp o s e

H o s t m o d u latin g 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 α

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 α , ro o t reso rp tio n w as co m p letely p re v en ted .

A u th o r

H is - M i n g L e e , S e b a stia n G e t a l (2 0 0 4 ) 12

C h ia r a S , T a t a k is D N e t a l (2 0 0 5 )4

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



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-1â or tumour necrosis factor-á, may constitute a rational therapeutic strategy. However, it should be remembered that these pathways are important in physiological processes and therefore their inhibition could also result in adverse effects, such as increased susceptibility to infection, and the development and investigation of such agents require careful monitoring. It is likely in the future that more effective therapeutic approaches will include multiple, synergistic host modulation therapies combined with treatments that target the microbial etiology. REFERENCES

10. Heasman PA, Offenbacher S, Collins JG, Edwards G and Seymour RA. Flurbiprofen in the prevention and treatment of experimental gingivitis. J Clin Periodontol 1993; 20: 732-738. 11. Heasman PA and Seymour RA. An association between long-term nonsteroidal anti-inflammatory drug therapy and severity of periodontal disease. J Clin Periodontol 1990; 17: 654-658. 12. His-Ming Lee, Sebastian G, Ciancio, Tuter G, Maria E, Ryan, Golub LM. Subantimicrobial dose doxycycline efficacy as a matrix metalloproteinase inhibitor in chronic periodontitis patients is enhanced when combined with NSAID. J Periodontol 2004; 75: 453-463 13. Holzhausen M, Spoldori DMP, Muscara MN, Hebling J, Spolidoris. Protective effects of etoricoxib, a selective inhibitor of cyclooxygenase-2, in experimental periodontitis in rats. J Periodont Res 2005; 40: 208-211. 14. Howell TH, Fiorellini J, Weber HP, Williams RC. Effect of the NSAID piroxicam, topically administered, on the development of gingivitis in beagle dogs. J Periodont Res 1991; 26: 180-183. 15. Information Paper. The pathogenesis of periodontal diseases. J Periodontol 1999; 70: 457-470 16. Ishihara Y, Nishihara T, Maki E, Noguchi T and Koga T. Role of interleukin1 and prostaglandin in in-vitro bone resorption induced by antinobacillus actinomycetum comitans lipopolysaccharide. J. Periodont Res 1991; 26: 155-160 17. Kornman KS. Host modulation as a therapeutic strategy in the treatment of periodontal disease. Clin Infect Dis 1999; 28: 520-526 18. Kubota T, Matsuki Y, Nomura T, Hara K. In situ hybridization study on tissue inhibitors of metalloproteinases (TIMP’s) mRNA expressing cells in human inflamed gingival tissue. J Periodont Res 1997; 32: 467-472 19. Mary B, Alexander, Petros D, Damoulis. The role of cytokines in the pathogenesis of periodontal diseases. Curr opinion in periodontol 1994; 39-53 20. Mathur A, Michalowicz B, Castillo M, Aeppli D. Interleukin-1 alpha, interleukin 8 and interferon-alpha levels in gingival crevicular fluid. J Periodont Res 1996; 31: 489-495 21. Meikle MC, Atkinson SJ, Ward RV, Murthy G and Reynokin JJ. Gingival fibroblasts degrade type I collagen films when stimulated with TNF and interleukin-1: Evidence that breakdown is mediated by metalloproteinases. J Periodont Res 1989; 24: 207-213

1.

Breivik T, Thrane PS, Gjermo P, Opstad PK. Glucocorticoid receptor antagonist RU 486 treatment reduces periodontitis in Fischer 344 rats. J Periodont Res 2000; 35: 285-290.

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Caton JG, Ciancio SG, Blieden TM, Bradshaw M, Crout RJ. Subantimicrobial dose doxycycline as an adjunct to scaling and root planing post treatment effects. J Clin Periodontol 2001; 28: 782-789.

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Chapple ILC. Reactive oxygen species and antioxidants in inflammatory disease. J Clin Periodontol 1997; 24: 287-296.

23. Mirna M, Bezerra, Lima VD, Veruska BM, Alencar. Selective cyclooxygenase2 inhibition prevents alveolar bone loss in experimental periodontitis in rats. J Periodontol 2000; 71: 1009-1014.

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Chiara S, Tatakis DN, Mamolini E and Trombelli L. Modulation of clinical expression of plaque induced gingivitis: Interleukin-1 gene cluster polymorphisms. J Periodontol 2005; 76: 49-56.

24. Mitsuta T, Horiuchi H, Shinoda H. Effects of topical administration of clodronate on alveolar bone resorption in rats with experimental periodontitis. J Periodontol 2002; 73: 479-486


22. Mineshiba, Takashiba S, Mineshiba J, Kokeguchi S and Murayama Y. Antibacterial activity of synthetic human B defensin-2 against periodontal bacteria. International Academy of Periodontology 1998

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Prasad MGS et al


25. Myoung H, Park JY, Choung PH. Effects of a bisphosphonate on the expression of bone specific genes after autogenous free bone grafting in rats, J Periodont Res. 2001; 36: 244-251

47. Weaks-Dybvig M, Farshid Sanavi, Zander H, Rifkin Barry R. The effect of indomethacin on alveolar bone loss in experimental periodontitis. J Periodont Res 1982; 17: 90-100

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Source of Support : Nil, Conflict of Interest : Nil

28. Novak MJ, Dawson DR, Magnusson I, et al. Combining host modulation and topical antimicrobial therapy in the management of moderate to severe periodontitis: a randomized multicenter trial. J Periodontol 2008; 79(1): 33-41 29. Offenbacher S. Periodontal diseases: pathogenesis. Ann. Periodontol 1996; 1: 821-878 30. Offenbacher S, Odle BM, Braswell LD, Johnson HG, Hall CM, et al. changes in cyclooxygenase metabolites in experimental periodontitis in Macaca mulatta. J Periodont Res 1989; 24: 63-74 31. Paquette DW, Fiorellini JP, Matuscelli G, Oringer RJ, Howell TH. Enantio specific inhibition of ligature-induced periodontitis in beagles with topical (s) keto profen. J Clin Periodontol 1997; 24: 521-528 32. Paquette DW, and Williams RC. Modulation of host inflammatory mediators as a treatment strategy for periodontal diseases. Perio 2000; 24: 239-252 33. Philstrom BL. Overview of periodontal clinical trials utilizing anti-infective or host modulating agents. Ann. Periodontol 1997; 2: 153-165 34. Ramamurthy NS, Bain S, Liang CT, Barne S, Strachan Golub LM. A combination of subtrherapeutic doses of chemically modified doxycycline (CMT-8) and a biophosphonate (chodronate) inhibits bone loss in the overiectomized rat: A dynamic histomorphometric and gene expression study. Curr Medicinal Chemistry 2001; 8: 295-303 35. Rammurthy NS, Kucine AJ, McClain SA, McNamara TEF, Golub IM. Topicaly applied CMT-2 enhances wound healing in streptozotocin diabetic rat skin. Adv sDent Res 1998; 12: 144-148 36. Rawlinson A, Dalati MHN, Rahman S, Walsh TF and Fairclough AL. Interleukin-1 and IL-1 receptor antagonist in gingival crevicular fluid. J Clin Periodontol 2000; 27: 738-743 37. Reddy MS, Nico C, Geurs and Gunsolley. Periodontal host modulation with antiproteinase, anti-inflammatory and bone-sparing agents. A systemic review. Ann Periodontol 2003; 8 (1): 12-37 38. Roy S, Feldman, Szeto B, Chouncey HH, Goldhaber P. Non-steroidal antiinflammatory drugs in the reduction of human alveolar bone loss. J Clin Periodontol 1983; 10: 131-136 39. Ryan ME. Host modulation: conceptualization to clinical trials and integration into clinical practice J. Candian Assoc 2002; 6: 1-8 40. Sekino S, Ramberg P, Lindhe J. The effect of systemic administration of ibuprofen in experimental gingivitis model. J Clin Periodontol 2005; 32: 182-187 41. a) Seymour GJ. Importance of the host response in the periodontium. J Clin Periodontol 1991; 18: 421-426 41. b) Seymour GJ. Imporatance of the host response in the periodontium. J Clin Periodontol 1991; 18: 421-426 42. Shoji, Horiuchi H and Shinoda H. Inhibitory effects of a bisphosphonate (risedronate) on experimental periodontitis in rats. J Periodont Res 1995; 30: 277-284 43. Taiyeb Ali TB and Waite IM. The effect of systemic ibuprofen on gingival inflammation in humans. J Clin Periodontol 1993; 20: 723-728 44. Thomson RG. Modulating the host response as an adjunctive treatment for periodontitis. Periodontol 2001; 22(1): 26-34 45. Tumuluri V, Matrix metalloproteinase regulation in periodontal treatment perio 2001; 22(2): 50-57 46. Van Dyke, Lester MA, and Shapira L. The role of host response in periodontal disease progression: Implications for future treatment strategies. J Periodontol 1993; 64: 792-806

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