R eview Article

HOST MODULATION IN PERIODONTICS

of Periodontics

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Shantipriya Reddy Professor and Head, Prasad MGS Reader, Sanjay Kaul Professor, Hrishikesh Asutkar Postgraduate student, Nirjhar Bhowmik Postgraduate student, Amudha Senior Lecturer, Department 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. Antimicrobial therapies both local and systemic administration along with mechanical debridement is one of the mainstay in periodontal treatment strategies, which answered microbial etiology of periodontal diseases, albeit critical step in a complex chain of events leading to periodontal tissue destruction. These treatment strategies however, failed to block (or) inhibit the host response mediated tissue destruction to continued bacterial challenge46. In 1985, research began to focus very closely on bacterial-host interaction, leading to host-bacterial interrelationship era 14. During this era it was recognized that although there is evidence that specific bacterial pathogens initiate pathogenesis of disease, the host response to these pathogens is equally important in mediating connective tissue breakdown and bone loss. It has become clear that it is the host derived enzymes and mediators like matrix metalloproteases (MMPS), cytokines, and other
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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 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
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FDA for clinical use. Future bodes for anticytokine drugs, bone resorption uncouplers, chemically modified tetracyclines (CMTS), anti metabolites and lipoxins. These provide operators with additional armamentarium to mechanical debridement, which could enhance and make clinical therapeutic response more predictable, in more susceptible host for the better management of periodontal disease14.

This present review highlights various host modulation therapeutic agents and ongoing development of safe and effective pharmaco therapies that specially target host response mechanism. Introduction of such pharmocotherapies as an adjunct to the traditional periodontal therapies represent a new integrated approach in long-term treatment and management of periodontitis.

Current critical pathway model of periodontal disease pathogenesis

Fig.1 Current Model of Periodontal Disease; Page and Kornman199629,41b Plaque bacteria such as porphyromonas gingivalis, bacteriodes forsythus and actinobacillus actinomycetemcomitans remain as primary causative agents. Their introduction as an exogenous infection and predominance in the pathogenic flora trigger a cascade of immune responses in the host. Once these bacteria colonizes, the tooth surface near the gingival margins, bacteria and their metabolic products and the lipopolysaccharide (LPS) initiate the host response. The bacteria and their byproducts directly challenge the cells of junctional epithelium. In response, the junctional epithelial cells release various inflammatory mediators including cytokines, PGE 2, MMPs and TNF. These mediators stimulate the immune response, recruiting neutrophils to the site of periodontal infection. If these inflammatory cells are able to contain bacterial challenge and their products (such as LPS endotoxins) by intercellular killing mechanisms, the disease limits itself to the gingiva. If the bacterial challenge is not controlled by these mechanisms and if pathogens and their products penetrate host tissues, the inflammation worsens and progress to periodontitis. However, if these mechanisms fail and if pathogens and their products penetrate host tissues, the disease becomes periodontitis. The host monocyte-lymphocytic axis is stimulated, leading to the local release of inflammatory mediators such as arachidonic acid metabolites and cytokines. These inflammatory mediators inturn directly cause the local tissue destruction, clinically perceived as periodontal pocketing and alveolar bone loss in patients. In addition, local environmental conditions secondary to these inflammatory and destructive events (such as low oxygen tension and iron availability) continue to support a pathogenic flora and perpetuate the cycle of events proposed in the model. (fig.2)

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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

Fig.2 Critical pathway model of pathogenesis; Page and Kornman 1996 The Microbial challenge consisting of antigens, lipopolysaccharide (LPS) and other virulence factors stimulates host responses, which result in disease limited to gingiva (that gingivitis) or initiation of periodontitis (Offenbacher, 1996). Protective aspects of the host response include recruitment of neutrophils, production of protective antibodies and possibly release of anti-inflammatory cytokines including transforming growth factor (TGF-), IL-4, IL-10 and IL12. Perpetuation of the host response due to persistant bacterial challenge disrupts homeostatic mechanisms and results in release of pro inflammatory cytokines (e.g.: IL-6, IL-1, TNF) proteases (e.g.: matrix metalloproteinases) and prostanoids (PGE2) which can promote extracellular matrix destruction in the gingiva and stimulate bone resorption. The determination that periodontal tissue destruction is primarily due to the host response, has directed areas of research at altering an individuals reaction to the bacterial challenge. Various host modulation therapies (HMT) have been developed and proposed to block pathways responsible for periodontal tissue breakdown14 . One of the tremendous benefits of fundamental research which seeks to elucidate key mechanism of host tissue destruction is the simultaneous identification of critical intervention with host modulating agents. So here we have given an overview of Specific aspects of disease pathogenesis for modulation: Specific aspects of disease pathogenesis for modulation a) Regulation of immune and inflammatory responses. ( Table 1) b) Regulation of excessive production of matrix metalloproteinases29,45 . (Table 2) c) Regulation of arachidonic acid metabolites32,33,37 (Table 3) d) Regulation of bone metabolism7,24,42. ( Table 4)

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Stages of host modulation Immunization methods.

Mode of interception Generation of protective antibodies to prevent Periodontitis.

Significant Contributors Ishikawa et al., 1997

Agents employed Stock vaccines such as Van Cotts vaccine, Goldenbergs vaccine (or) Inava Endocorps Vaccine. Autogenous vaccines Vaccines prepared from pure cultures of streptococci and other organisms Gingipains Agents employed Ascorbic acid, Alpha tocopherol, Keratinides

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

Stages of host modulation Regulation of reactive oxygen species3.

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. 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.

Significant Contributors Benedeck 1998, Bartold 1984, Key 1994

Regulating cytokines19.

Gortel 2004, Shapira 1992, Hendley 1995.

CYTOKINE ANALOGES, Mast cell stabilizers

Table.1 Regulation of immune and inflammatory responses

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Stages of host modulation Regulation of MMP activity at 4 gates: Transcriptional regulation of MMP genes.

Mode of interception 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-, EGF bFGF, NGF. TGF- Ablates transcription of CL & SL-1 IFN-

Significant Contributors Wahl 1979, Cury 1988

Agents employed TGF , FIBCL, SL- 1

Authors coments Insufficient data available.

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

Nagase 1997

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

Insufficient data available.

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. -macroglobulins, particularly 2-M play an important role in the regulation of MMP activity by bond cleavage region. The inhibition probably occurs as a result of binding the TIMPs at the MMP active site. However, the amino acid residues in TIMPs that are responsible for binding at the active site of MMPs are still unknown. Lipoxins regulate local acute inflammatory responses in periodontal disease by limiting neutrophil recruitment and neutrophil mediated tissue injury. Rayan and Golub 2000, Brew 2000, Kinane 2000, Lee 1995. Tetracycline, CMT Minocycline, Doxycycline ( sub antimicrobial dose of doxicycline), lipoxins, resolvins.

Insufficient data available.

MMP inhibition ( TIMPs)45,18,27.

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

Table.2 Regulation of excessive production of MMPs.

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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 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

Inhibition of arachidonic acid metabolite by blocking of the cyclooxygenase pathway.

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

Table.3 Regulation of arachidonic acid metabolites.

Quantity/Quality of bone Osteoporosis and osteopenia may be indicators for periodontal diseases. Mode of interception Inhibition of osteoclast/MMP activity through chelation of cations. Significant Contributors Howell 1991, HisMing 2004, Holzhausen 2005, Gurkan 2005, Durate 2005. Agents employed Bisphosphonates (Alendronate), Hormone replacement therapy.(HRT), OPG- Fc therapeutic agents. Authors coments 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. 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 Hartel et al 1999; Toomes et al 1999. High levels of oxidative stress have been demonstrated in Papillon-Lefevere syndrome suggesting a potential role of antioxidants (Baltino et al). Reduced glutathione serves as an antioxidant and modulator of immune function. Increasing glutathione has been shown to block reactive oxygen species mediated association of nuclear factor K and to block proinflammatory cytokine production according to Schreck et. al 1991. Many studies have demonstrated that microorganisms influence tissue damage through cytokine production by degrading glutathione or from preventing glutathione formation from cystine according to Perrson et. al 1990. Omega 3 fatty acids as dietary fish oil has been demonstrated to protect mice against infection w i t h n u m e r o us e x t r a c e l l u l a r b a c t e r i a l p a t h o g e n s , r e g u l a t e s e r um triglycerides and cholesterol levels, inhibit synthesis of lipid mediators of inflammation (PGE 2 , arachidonic acid, cyclo-oxygenase, 5-lipoxygenase), a l t e r c e l l u l a r f u n c t i o n s o f p o l ymo r p h o n u c l e a r l e u k o c y t e s , mo d u l a t e lymphocyte
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proliferation and cytokine production, and increase endogenous host anti-oxidant capacity, e.g., SOD and catalase (Alam et al., 1991; Blok et al., 1992; Fernandes and Venkataraman, 1993). These effects have been proposed to account for the potent anti-inflammatory properties of omega ()-3 fatty acids (FA) in human, non-human primate, and rodent disease models. While much of the attention over the last decades has focused on the beneficial effects of fish oil, particularly the -3 FA components, on a v a r i e t y of ch r on i c in fl a m m a t or y di sea ses (c a r d i o v a s c u l a r d i s e a s e , rheumatoid arthritis), few studies have examined its effects on the chronic 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

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.

Ishihara y, nishihara t et al (1991)16

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

Host modulating agent Indomethacin, dexamethasone

Parameters

Subjects

Results

PGE2 and IL-1 levels

Mouse PGE2 and IL-1 participate in y4 LPS induced bone resorption in vitro. Beagle dogs Significantly inhibit the development of gingival inflammation

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

Piroxicam

Gingival inflammation, plaque index Radioactive gelatin degradation and gelatin enzymography

Oxytetracycline, doxycycline and dedimethylamino tetracycline

Results showed that periodontal epithelial cells produce MMPs whose activities are inhibited by tetracycline and their non-antimicrobial analogues at concentration present in gingival crevicular fluid following tetracycline therapy.

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Author 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

Purpose To evaluate the effect on bone resorption: A retrospective study

Host modulating agent Aspirin (asp) or aspirin plus indomethcin Indomethacin 5mg / kg /day

Parameters Radiographs

Subjects Humans

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

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

Alveolar bone height

Squirrel monkeys

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

Flurbiprofen

Crevicular fluid levels of PGE2 and TXB2

Rhesus monkey

Exogenous human timp

NSAIDs

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

Humans

Taiyeb ali TB and Waite IM (1993)43 Heasman PA, Offenbac her S et al (1993)10 Shoji K, Horiuchi H and Shinoda H (1995)42 Mathur a, Michalow icz b, et al (1996)20

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

Flurbiprofen

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

Humans

Significantly greater reduction for all parameters.

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

Efficacy of risendronate to prevent alveolar bone resorption

Risendronate

To evaluate the concentration of IL-1 IL-8) and interferon- in periodontitis patients.

Gingival crevicular fluid.

Humans 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

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

To check for potency of low dose doxycycline

Host modulating agent Low dose doxycycline

Parameters

Subjects

Results

Golub LM, Lee HM et al (1997)8

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

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

Doxycycline

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 Antibacterial broth assay and diffusion assay

Beagle dogs.

Significantly lower mean rates of bone loss compared to placebo

A study to evaluate the efficacy of synthetic (hbd-2) against actinobacillus actinomycetum comitans, p.gingivalis, s.mutans and e.coli

Human beta defensin-2

Human

Antibacterial activity of hbd2 was approximately equal to that of minocycline.

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

Purpose To compare wound healing in normal and diabetic rats

Host modulating agent CMT-2

Parameters Volume of granulation tissue.

Subjects Diabetic and nondiabetic rats. Rat model

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.

Breivk T, Thrane PS et al (2000)1

To evaluate the efficacy of glucocorticoiod receptor antagonist ru486 (mitepristone)

Mitepristone

Radiographs and histologically.

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)

Indomethacin, meloxicam.

Alveolar bone level.

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.

GCF investigations

Humans 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%.

Delima AJ, Oatent ET al (2001)6

To investigate the role of il-1 and tnf in the loss of connective tissue attachment.

Proinflammatory cytokines i.e. IL-1, TNF

Histomorpho metric analysis

Macaca fascicularis

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

P u rp o s e 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. 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. 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 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. 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 .

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 C lin ica l attac h m en t lev el

S u b je cts H u m an s

R esu lts

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

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

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

B is p h o sp h o n ates

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

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 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.
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 .
R e s u lt s

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

A u th o r

P u rp o se

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

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

P a ram e ters

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 I L - 1 le v e ls

H um ans 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 . H um ans 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 . 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 .

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

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 . 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 .

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

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 .

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

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

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.

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