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Host modulation therapy

Host modulation therapy, periodontal disease interaction, factors affecting disease. methods of therapy

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Host modulation therapy

  2. 2. Introduction • In the past, the understanding of the etiology and the pathogenesis of the periodontal disease focused on the microbial aspect of the diseases and thus, the therapeutic efforts focused on the mechanical or the therapeutic removal of the bacterial flora. • Periodontitis can no longer be considered a simple bacterial infection that leads to periodontal destruction. Rather, it represents a collection of complex diseases involving iterative interactions between the host inflammatory and immune systems, subgingival microbiota and modifying environmental factors.
  3. 3. • Host response in periodontal disease acts as a dual edged sword, it is protective, but same time its over response or an altered response considered to be destructive to periodontium. • In persons who are not susceptible to periodontitis (disease resistant), these primary defense mechanisms control the infection, and chronic inflammation (i.e., chronic gingivitis) may persist indefinitely. In disease-susceptible individuals, however, inflammatory events extend apically and laterally to involve deeper connective tissues and alveolar bone. • The elevations in the proinflammatory or destructive mediators in response to bacterial challenge are counterbalanced by elevations in antiinflammatory or protective mediators such as the cytokines IL-4 and IL-10, as well as other mediators, such as IL-1ra (receptor antagonist), and tissue inhibitors of metalloproteinases (TIMPs).
  4. 4. • Under conditions of health, the antiinflammatory or protective mediators serve to control tissue destruction. • If there are adequate levels of these antiinflammatory or protective mediators to keep the host response to the bacterial challenge in check, the individual will be disease resistant. • If an imbalance occurs, with excessive levels of the proinflammatory or destructive mediators present in the host tissues, tissue destruction will ensue in the susceptible host.
  5. 5. • To modify or reduce destructive aspects of host response: so that immune- inflammatory response to plaque is less damaging; host modulation therapies has been developed. • The concept of host modulation was first introduced to dentistry by Williams (1990) and Golub et al (1992) and then expanded on by many other scholars in the dental profession. • “The organism from which a parasite obtains it nourishment,” or in the transplantation of tissue, “the individual who receives the graft.”Host • “The alteration of function or status of something in response to a stimulus or a altered chemical or physical environment”Modulation • Means of treating the host side of the host-bacteria interaction. Host modulation therapy Definitions
  6. 6. • The purpose of HMT is to restore the balance of proinflammatory or destructive mediators and antiinflammatory or protective mediators to that seen in healthy individuals. • HMTs offer the opportunity for modulating or reducing this destruction by treating aspects of the chronic inflammatory response. • HMTs do not “switch off” normal defense mechanisms or inflammation; instead, they ameliorate excessive or pathologically elevated inflammatory processes to enhance the opportunities for wound healing and periodontal stability. • HMT is key to addressing many of the risk factors that have adverse effects on the host response, which are either not easily managed (e.g., smoking, diabetes) or cannot be changed (e.g., genetic susceptibility). • In addition, host modulatory agents might be used to increase the levels of a person’s own protective or antiinflammatory mediators. • Use of systemic HMTs for treatment of a patient’s periodontal condition may also provide benefits for other inflammatory disorders such as arthritis, cardiovascular disease, dermatologic conditions, diabetes, rheumatoid arthritis, and osteoporosis.
  7. 7. • Hence, the Host Modulation Therapy offers the potential for the downregulating destructive aspects and upregulating protective aspects of the host response so that, in combinations with conventional treatments to reduce the bacterial burden, the ‘balance’ is tipped in the direction of a healing response. Host modulating agents Systemically Administered Agents •Acting against MMPs •Tetracycline analogues as HMTs •Acting against Arachidonic acid Metabolites •Acting against Lipid Inflammatory Mediators •Acting against Cytokines •Acting against Bone Resorption •Others: Probiotics, Vaccine, Nutrients Locally administered Agents •Topical NSAIDs •Enamel matrix proteins •Growth factors •Bone morphogenetic proteins
  8. 8. • HMT can be used to reduce excessive levels of enzymes, cytokines, and prostanoids and should not reduce levels below constitutive levels. • HMTs can also modulate osteoclast and osteoblast function but should not impact normal tissue turnover.
  9. 9. Systemically Administered Agents • Free arachidonic acid (AA) is produced in the hosts when phospholipase A2 acts on the phospholipids present in plasma membranes of the cells which can then be metabolized to produce prostaglandins via the cyclooxygenase (COX) pathway as well as leukotrienes via the lipoxygenase (LOX) pathway Host modulating agents acting against arachidonic acid metabolites
  10. 10. Nonsteroidal Antiinflammatory Drugs • There are 2 isoforms of COX (Cycloxygenase)  COX-1  COX-2 • COX-1 is a Primarily “Constitutive Isoform” found in Most Normal Cells & Tissues and have Anti-thrombogenic & Cytoprotective Functions  COX-1 is expressed as the Dominant, Constitutive Isoform in Gastric Epithelial Cells & is the major source of Cytoprotective PG Formation.  Inhibition of COX-1 at this site account largely for the Gastric Adverse Events (Ulceration) and impaired hemostasis. • COX-2 is Stimulated by variety of Cytokines & Pro-inflammatory Mediators, Growth Factors, LPS that accompany Inflammation & results in Production of Elevated Amounts of PGs Inhibition of COX-2 by selective COX-2 inhibitors results in reduction of inflammation.
  11. 11. • PGE2 upregulates bone resorption bv osteoclasts levels have been shown to be elevated in patients with periodontal disease inhibits fibroblast function inhibitory and modualtory effects on the immune response. • NSAIDs inhibit the formation of prostaglandins, including prostaglandin E2 (PGE2), formed in response to the presence of lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria and therefore, reduce tissue inflammation. Prostaglandins are produced by: neutrophils, macrophages, fibroblasts, and gingival epithelial cells.
  12. 12. Classification of NSAIDS • Nonselective COX inhibitors (traditional NSAIDs) • Salicylates: Aspirin. • Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen. • Fenamate: Mephenamic acid. • Enolic acid derivatives: Piroxicam, Tenoxicam. • Acetic acid derivatives: Ketorolac, Indomethacin, Nabumetone. • Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone. • Preferential COX-2 inhibitors • Nimesulide, • Diclofenac, • Aceclofenac, • Meloxicam, • Etodolac. • Selective COX-2 inhibitors • Celecoxib, • Etoricoxib, • Parecoxib. • Analgesic-antipyretics with poor antiinflammatory action • Paraaminophenol derivative: Paracetamol (Acetaminophen). • Pyrazolone derivatives: Metamizol (Dipyrone), Propiphenazone. • Benzoxazocine derivative: Nefopam.
  13. 13. • The ability of NSAIDs to block PGE2 production, thereby reducing inflammation and inhibiting osteoclast activity in the periodontal tissues, has been investigated in patients with periodontitis. • Studies have shown that systemic NSAIDs such as indomethacin (Williams RC., 1987), flurbiprofen (Williams, 1989) and naproxen (Howell TH,, 1993) administered daily for up to 3 years significantly slowed the rate of alveolar bone loss compared with placebo.
  14. 14. • However, NSAIDs have Some SERIOUS DISADVANTAGES when considered for use as a HMT for Periodontitis. 1. Daily Administration for Extended Periods is necessary for Periodontal Benefits to become apparent, & NSAIDs are associated with “Significant Side Effects”, including • GI Problems • Hemorrhage (from Decreased Platelet Aggregation) • Renal & Hepatic Impairment. 2. Research shows that the Periodontal Benefits of taking Long-term NSAIDs are LOST when patients STOP taking the DRUGS, with a Return to or Even an Acceleration of the Rate of Bone Loss seen Before NSAID Therapy, “Rebound Effect.” (Williams, Jeffcoat, Howell 1991) For these reasons, the Long-term Use of NSAIDs as an Adjunctive T/t for Periodontitis has Never Really Developed Beyond Research Studies.
  15. 15. • Lipoxins (LX) which are generated endogenously late in inflammation via cell-cell interaction when a second lipoxygenase (e.g. 5-LOX) interacts with a lipoxygenase product (e.g. hydroxyeicosatetraenoic acid) generated earlier from archidonic acid, also possess both anti-inflammatory and pro-resolving potential which have been summarized by Serhan et al.  as reduction of neutrophil infiltration and recruitment,  blocking cytokines and reactive oxygen species generation,  thereby preventing connective tissue and bone loss. • Hence, LXs can be targets for HMT against periodontitis.
  16. 16. • MMPs endopeptidases which are secreted by a variety of host cells (including neutrophils, macrophages, keratinocytes, fibroblasts, osteoclasts and endothelial cells), play key roles in the degradation of the extracellular matrix, basement membrane and modify the action of cytokines as well as activation of osteoclasts. • During active periodontal diseases, microbial attack leads to excessive production as well as activity of these MMPs (MMP 8, MMP 9) which, if not adequately controlled by the endogenous metalloproteinases inhibitors (TIMP, alfa macroglobulin), results in enormous tissue destruction. • To impede this destruction of host tissues synthetic inhibitors of MMP as host modulating agents have been developed which generally contain a chelating group, inhibiting MMPs by binding to the catalytic zinc atom at its active site. • The anti-matrix metalloproteinase properties of the tetracycline family were first identified in minocycline (Golub LM, 1983), and subsequent studies revealed that doxycycline was particularly effective for this purpose. Host modulating agents acting against MMPs
  17. 17. • SDD – sub-antimicrobial dose of doxycycline, previously known as low dose doxycycline (Doxycycline hyclate 20 mg; Periostat, CollaGenex, Pharmaceuticals Newton PA) has been approved by Food and drug administration (FDA) to be used as an adjunct to periodontal treatment. • A typical prescription for Periostat (20 mg doxycycline tablets) is for at least 3 months (180 tablets, 1 tablet twice a day until complete), up to a maximum of 9 months of continuous dosing. • The 20-mg dose exerts its therapeutic effect by enzyme, cytokine, and osteoclast inhibition rather than by any antibiotic effect. • SDD is used as an adjunct to SRP and must not be used as a stand--alone therapy (monotherapy). • As an adjunct to mechanical therapies, the goal of tetracycline therapy has been to enhance reattachment or even to stimulate new attachment of the supporting apparatus and osseous formation.
  18. 18. Mechanism of action of SDD
  19. 19. Indications • In the management of Chronic Periodontitis and Aggressive Periodontitis. • SDD can be used in patients with aggressive periodontitis who are being treated nonsurgically. • Emerging studies have supported efficacy of SDD as an adjunct to periodontal surgery (Gapski et al 2004). • SDD may also be of benefit in cases that are refractory to treatment, as well as in patients with risk factors such as smoking or diabetes, in whom the treatment response might be limited. Contr-indications • Any patient with a history of allergy or hypersensitivity to tetracyclines. • It should not be given to pregnant or lactating women • Children less than 12 years old - because potential for discoloration of the developing dentition • Doxycycline may reduce the efficacy of OCPs, and therefore alternative forms of birth control should be discussed. • There is a risk if increased sensitivity to sunlight (manifested by an exaggerated sunburn) seen with higher doses of doxycycline, although this has not been reported in the clinical trials using subantimicrobial dose. • SDD should not be used in conditions such as gingivitis and periodontal abscess or when an antibiotic is indicated. Side effects Doxycycline at antibiotic doses (≥100mg) is associated with adverse effects photosensitivity, hyper-sensitivity reactions, nausea, vomiting, esophageal irritation.
  20. 20. Various studies • Studies using SDD therapy adjunctive to routine scaling and prophylaxis indicated continued reductions in the excessive levels of collagenase in the GCF after 1 month of treatment. • After cessation of SDD administration, however, there was a rapid rebound of collagenase activity to placebo levels, suggesting that a 1-month treatment regimen with this host modulation agent was insufficient to produce a long-term benefit. (Ashley RA 1999) • In contrast, during the same study, a 3-month regimen produced a prolonged drug effect without a rebound in collagenase levels to baseline during the no-treatment phase of the study. • Golub et al. 1997 showed that a 2-month regimen of SDD significantly decreased both the level of bone-type collagen breakdown products and MMP-8 and MMP-13 enzyme levels (neutrophil and bone-type collagenase) in chronic periodontitis subjects • The clinical relevance of such findings confirms the utility of an MMP inhibitor in the management of chronic periodontitis. • More recent phase IV clinical studies have revealed success using SDD in particular populations of susceptible individuals
  21. 21. Combining with Periodontal Surgery or Local Delivery Systems Combining with Periodontal Surgery • SDD was used as an adjunct to access flap surgery in 24 patients revealed better probing depth reductions in surgically treated sites greater than 6 mm compared with surgically treated sites in patients given placebo. Combining with local Delivery Systems • Preliminary results from a 6-month, 180-patient clinical trial designed to evaluate the safety and efficacy of SDD combined with a locally applied antimicrobial (Atridox) and SRP versus SRP alone demonstrated that patients receiving the combination of treatments experienced more than a 2-mm improvement in mean attachment gains and probing depth reductions compared with SRP alone.
  22. 22. • Tetracycline with antibiotic activity consists of a tetracyclic naphthacene carboxamide ring system having a dimethylamine group at carbon 4 (C4) in ring “A” which is responsible for its antibacterial property. • Chemically Modified Tetracyclines were produced by removing the dimethylamino group from the carbon-4 position of the A ring of the four ringed (A, B, C, D) structure. • Golub et 1987 recognized that the antimicrobial and anti-collagenase properties of tetracyclines resided in different parts of four ringed structures. • They altered the structure of tetracyclines which had led to the development of CMTs. • Currently about 10 CMTs have been developed. Tetracycline analogues as host modulating agents
  23. 23. • Among them CMT-1, CMT-3 and CMT-8 have been tested for periodontal applications. • The Ca+2 and Zn+2-binding sites at the carbonyl oxygen and hydroxyl group of c-11 and c-12 positions are responsible for anti-collagenase action of CMTs. • CMT-5 is a pyrazole analog of tetracycline, formed by replacement of carbonyl oxygen at c-11 and hydroxyl group at C-12 by nitrogen atoms does not have metal-binding site and therefore it is inactive against MMPs. • CMT-3 has role in • reducing collagenolytic activity induced by Porphyromonas gingivalis and in inhibiting matrix metalloproteinase- mediated alveolar bone loss in an animal model • reduce P. gingivalis lipopolysaccharide-induced proinflammatory cytokine secretion in an ex vivo human whole-blood model
  24. 24. Mechanism of action • CMTs are used as HMT agents in the management of periodontitis by • inhibition of MMPs, • inhibition of proinflammatory cytokines, • inducible nitric oxide synthase (iNOS) and • inhibition of bone resorption, • enhancement of the attachment of fibroblasts and connective tissues to the tooth surface • The advantages of CMTs over conventional tetracyclines are • their rapid absorption, • a longer serum half life than tetracycline, • long-term systemic administration does not result in gastrointestinal toxicity, • no development of antibiotic-resistant microflora and • can be used for prolonged periods.
  25. 25. • Pro-inflammatory (e.g. IL-1α, IL-1β, IL-6, TNF-α, IFN-γ etc) and anti-inflammatory cytokines (IL-4, IL-10 etc) hold a great potential for controlling the adverse effects of the host immune response, consequently HMT against cytokines (cytokine therapy) may prove to be an effective strategy for treating periodontal diseases. • These therapies aim at: • ANTAGONISING THE PRO-INFLAMMATORY CYTOKINES VIA: • Cytokine receptor antagonist: binds to the receptor present on target cell and prevent cytokines to bind to the target cell. Eg. Interleukin-1 receptor antagonist. • Anti-cytokine antibodies: Anti TNF a antibodies, Anti IL-6 antibody, Anti IL-15 antibody, Anti IL-12 and 23 antibodies. Host modulating agents acting against cytokines
  26. 26. • Disrupting inflammatory cell-signalling pathways • To inhibit the production of pro-inflammatory cytokines and/or stimulate anti-inflammatory cytokine production. • Cell-signalling pathways like Mitogen Activated Protein Kinase (MAPK), Nuclear Factor-Kappa B (NFκB), Janus kinase/signal transducers and activators of transcription (JAK/ STAT) and Receptor activator of nuclear factor-kappa B (Rank)-Receptor activator of nuclear factor-kappa B ligand (Rankl)-Osteoprotegerin (OPG) pathways are dependent on a number of signaling-intermediate molecules for its uninterrupted functioning. • Targeting these pathways or the intermediate signaling molecules for their blockade with HMT may be more effective than targeting specific cytokines. • It has also been seen that the activity of cytokines is also controlled by the suppressors of cytokine signaling (SOCS -.SOCS-1, -2 and -3) messenger ribonucleic acid (mRNA), which when expressed, down-regulate the signal transduction and inflammatory cytokine production as a part of an inhibitory feedback loop.
  27. 27. • Based on the clinical data Souza et al., 2012 have listed some of the inhibitors targeting these signalling pathways that have been manufactured and have demonstrated anti-inflammatory activity, these are: • p38 inhibitors: SD-282, SC-409, SB (SmithKline Beecham) - 242235, AW-814141, BIRB-796 and VX-702 • c-Jun N-terminal kinases (JNK) inhibitor: SP600125 • Extracellular-Signal-Regulated Kinases (ERK) inhibitor: FR180204 • NFκB inhibitor: BMS (Bristol-Myers Squibb)-345541 • JK3 inhibitor: CP-690550 (Pfizer) • Lima et al. (2004) demonstrated the protective role of pentoxifylline (PTX), a methylxanthin derivative, in experimental periodontitis as a inhibitor of cytokine synthesis, mainly tumor necrosis factor (TNF). • Jin et al. (2007) demonstrated that systemic delivery of OPG-Fc fusion protein inhibits alveolar bone resorption in experimental periodontitis, supporting the fact that RANKL inhibition may represent an important therapeutic strategy for the prevention of progressive alveolar bone loss. • Studies to date have indicated that RANKL inhibitors, such as a fully human monoclonal antibody that specifically targets RANKL currently available as Denosumab, Amgen can lead to increased bone mineral density and decreased bone resorption. (Bartold PM et al., 2010)
  28. 28. • Recombinant anti-inflammatory cytokine administration • Martuscelli et al. demonstrated that subcutaneous injections of recombinant human IL-11 (rh IL-11: anti-inflammatory cytokine) were able to slow the progression of attachment and radiographic alveolar bone loss in a ligature-induced beagle dog model. • Bisphosphonates (BPs) are pyrophosphate analogs that can suppress osteoclastic bone resorption. • Bisphosphonates are known to bind to hydroxyapatite crystals and prevent their dissolution in addition to increasing osteoblast differentiation and inhibiting osteoclast activation. • More recent evidence has suggested that bisphosphonates also posses anticollagenase properties. Host modulating agents acting against bone resorption
  29. 29. • Giannobile WV has summarized and categorized the bone-specific actions of bisphosphonates at the • tissue level • decrease bone turnover due to inhibition of bone resorption, • decrease the number of new bone multicellular units resulting in a net positive whole body bone balance • cellular level • decrease osteoclast recruitment, • decrease osteoclast adhesion, • decrease depth of resorption site and • decrease release of cytokines by macrophages • increase in osteoclast apoptosis and osteoblast differentiation and number. • FDA has approved the use of these drugs orally or intravenously in the management of Paget’s disease, osteoporosis, and bone metastases. • Based on its bone-sparing properties there exists a possible use for bisphosphonates in the management of periodontal diseases as well. • Shoji et al. in 1995 demonstrated that systemic administration of a bisphosphonate could prevent alveolar bone resorption in rats with experimental periodontitis
  30. 30. • Unwanted side effects of Bisphosphonates:  Inhibiting Bone Calcification  Changes in WBC Counts.  Avascular Necrosis of the Jaws  Bone Necrosis following Dental Extractions. (Carter et al 2005) • The recent reports of BPs-related Osteonecrosis of the Jaw, (although primarily associated with i.v. Administration of BPs rather than Oral), has impeded the Dev. of BPs as an HMT to manage Periodontitis.  As the BPs are Potent Osteoclast Inhibitors, their Long-term use may Suppress Bone Turnover & Compromise Healing of Even Physiologic Micro-injuries within Bone (Odvina et al 2005) As with NSAIDs, at present there are No BPs Drugs that are approved & Indicated for T/t of Periodontal Diseases.
  31. 31. • Furthermore, anti-integrins can also block the initial osteoclast adhesion to the matrix and prevent bone resorption. • Based on the well demonstrated role of estrogen on excessive bone resorption as well as its lack in the post-menopausal osteoporosis affecting the remodeling of the bone tissue in such a way that, in most patients with periodontitis the amount of bone resorbed exceeds that being formed, resulting in net bone loss, • Inagaki et al. has also suggested the use of selective estrogen receptor modulators (SERM) and hormone replacement therapy (HRT) to improve the clinical outcome of periodontal disease as an adjunctive treatment to preserve periodontal bone mass. • Shu et al. in 2008 also demonstrated in human periodontal cells that estrogen may play a significant role in modulating periodontal tissue responses to lipo-polysaccharide, and may exert its bone-sparing effects on periodontal tissues via altering the expression of inflammatory cytokines. • Yet, given the potentially large number of significant side-effects associated with hormone replacement therapy, it is difficult to see this being recommended as a management strategy for periodontitis.
  32. 32. • It is recognized that resolution of acute inflammation is a highly controlled process, in which endogenous ‘pro-resolving’ mediators induce • Cessation of leukocyte infiltration, • Reduce vascular permeability and vasodilatation and • Facilitate the safe removal and disposal of leukocytes (primarily by apoptosis) and the removal by macrophages of apoptotic leukocytes, foreign matter (bacteria) and necrotic tissue • Resolution of inflammation is important to prevent chronic inflammation; however, if resolution of inflammation fails, then tissue injury may result from the perpetuated chronic inflammatory response. • Molecules which ‘switch off’ inflammation could theoretically be attractive in the treatment of inflammatory conditions, such as periodontitis, and potentially could offer advantages over anti-inflammatory therapies that have significant unwanted effects. Lipid mediators of resolution of inflammation
  33. 33. • A group of agents that have been investigated in this regard are the • lipoxins, • Resolvins • protectins. and • newly identified maresins • The lipoxins are derived from arachidonic acid, and the resolvins, protectins and maresins are derived from omega-3 fatty acids found in the diet (such as in fish oil), including eicosapentaenoic acid and docosahexaenoic acid. • The role of these endogenous chemical mediators is similar to that of lipoxins, i.e. inhibition of neutrophil recruitment etc. • These stereoselective players counter-regulate excessive acute inflammation and stimulate molecular and cellular events that define resolution. • Thus, designing pharmacological mimetics of naturally occurring pro-resolving mediators offers exciting new targets for drug design, especially for host modulation therapy.
  34. 34. • Nitric oxide is a free radical with important physiological functions of maintaining homeostasis. • Pro-inflammatory stimuli such as endotoxins lead to increased expression of the inducible NO synthase enzyme (iNOS) that produces a large amount of NO and peroxynitrite, which acts beneficially for host as cytotoxic molecule against the invading microorganism . • It may also cause deleterious effects to host such as DNA damage, lipid peroxidation, protein damage, and stimulation of imflammatory cytokine release. • Lohinai et al (1998) demonstrated the protective effects of mercaptoethylguanidine (MEG), which is a selective inhibitor of iNOS, against bon destruction in ligature induced periodontitis in rats. • Leitao et al (2005) also proved NOS inhibitors prevent alveolar bone resorption in experimental periodontitis. Modulation of nitric oxide synthase
  35. 35. • Epigenetic control of gene expression occurs via covalent modification of chromatin, including DNA methylation and histone acetylation. • These processes modify access of transcription factors to coding sections of DNA and therefore influence gene expression and protein production. • Histone acetylation is controlled by two enzymes: • histone acetyltransferase (which adds acetyl groups to lysine and arginine residues in histones, leading to exposure of DNA to transcription factors and therefore gene expression); and • histone deacetylases (which remove acetyl groups from histones, thereby inhibiting gene expression) • Studies of histone deacetylase inhibitors have identified that they have anti-inflammatory properties in a number of chronic inflammatory and malignant diseases Histone deacetylase inhibitors
  36. 36. • These agents posses potential anti-inflammatory properties, probably through inhibition of the nuclear factor-B pathway and subsequent suppression of inflammatory cytokines as well as inhibition of matrix metalloproteinase expression. • Of particular relevance in the context of periodontal pathogenesis is the finding that some histone deacetylase inhibitors appear to be able to regulate the effects of RANKL on osteoclasts and inflammatory cells, resulting in inhibition of RANKL- induced osteoclastic activity in mouse macrophages and murine cell lines. • The inhibition of RANKL-induced osteoclast formation occurred via suppression of induction of the osteoclastogenic transcription factor, c-Fos • The implication of these findings is that histone deacetylase inhibitors may hold promise as novel therapeutics in the treatment of diseases characterized by bone resorption, such as periodontitis.
  37. 37. • In the clinical studies conducted to date (in diseases other than periodontitis), they have been shown to be well tolerated and safe, with evidence of clinical efficacy. • However, unwanted effects are certainly a possibility because of the wide-ranging effects of these molecules in various tissues and cells. • Topical application could therefore be beneficial for reducing systemic exposure, and periodontitis could be a useful model for investigating this premise further. • Development of synthetic histone deacetylase inhibitors that specifically target those histone deacetylases that are involved in the disease processes of interest may also help to limit unwanted effects
  38. 38. • Drugs that combine both antibacterial and anti-inflammatory properties could be of interest in the management of periodontitis. • Such a drug is azithromycin, a synthetic erythromycin derivative with a bacteriostatic antimicrobial action, which is used to treat a variety of bacterial infections. However, azithromycin, similarly to other macrolide antibiotics, also possesses anti-inflammatory properties, resulting in inhibition of production of proinflammatory cytokines, such as • interleukin-1beta, • interleukin-6, • Tumor necrosis factor-alpha and • granulocyte–macrophage colony-stimulating factor, • as well as various chemokines Combined antibacterial and antiinflammatory approaches
  39. 39. Dosage Regime.. • “500mg Daily 3days” • Either 500mg OD 3days (Most Common Dosage Regime) • Or 250mg BD 3days • Patient Compliance is Very Good because of the Short Course & the Low Incidence of Side-Effects • Shud not be Prescribed to Pt. with Known Hypersensitivity to Macrolides (Erythromycin)
  40. 40. Immuno-modulatory Properties.. • Spectrum of Immuno-modulatory Action of Macrolides – Reduction of Inflammation – Regulation of PMN & Mφ Activity – Regulation of Production of Cytokines – Altering Fibroblast Activity & Host Immunity. • Azithromycin showed Extensive Systemic Distribution following Oral Administration  Leading to Good Penetration & Sustained Conc. in Tissues, even after the Levels in Serum had Decreased, making it a favourable Immune-modulator over other Macrolides. (Foulds et al 1990) • It is Rapidly taken up by PMNs, Mφ & Fibroblasts with a High Degree of Retention. (Gladue et al 1989, 1990; McDonald 1991 Bosnar et al 2002)
  41. 41. • Have been known to modulate cytokine secretion profiles, influence T-lymphocyte populations, protect against physiologic stress, and enhance intestinal epithelial cell function and antibody secretion. • Teughels et al (2011) explored the use of probiotics in influencing the periodontal microbiota and periodontal health and concluded that probiotics might offer opportunities to manipulate oral microbiota, and periodontal health by either direct microbiological interactions or by immunomodulatory interactions. • Nutrients, which include major extracellular antioxidants, like vitamin C, vitamin E, carotenoids, reduced glutathione and omega 3 fatty acids can also act as modulators of inflammation by scavenging free radicals as they are formed, sequestering transition metal ions and catalyzing formation of other molecules. • Studies have also demonstrated that cranberry juice contains molecules (A-type cranberry proanthocyanidins: AC-PACs) that inhibit MMPs, interleukin-6, interleukin-8, and prostaglandin E production by lipopolysaccharide-activated gingival fibroblasts and hence show potential of being used as a novel host-modulating agent to inhibit tissue destruction during periodontitis. Probiotics Nutrients
  42. 42. • Vaccination is a process that induces specific immune resistance to a bacterial or viral infection. • In the early twentieth century, three periodontal vaccines were employed, which includes; • Pure cultures of streptococcus and other organisms • Autogenous vaccines • Stock vaccines. • Example includes Vancott's vaccine and Inava endocarp vaccine • There are 3 types of periodontal immunization. This includes; • Active immunization • Whole bacterial cells • Sub unit vaccines • Synthetic peptides as antigens Periodontal vaccines
  43. 43. • Passive immunization • Murine monoclonal antibody • Plantibodies • Genetic immunization • Plasmid vaccines • Live, viral vector vaccines. • Antigens used for active immunization includes: • Bacterial whole cells • P.gingivalisfimbriae • P.gingivaliscysteine protease • Synthetic peptides • George Hajishengallis reported that toll like receptors (TLRs) may offer novel targets for host-modulation therapy in periodontitis since manipulation of TLR signalling may contribute to control of infection or regulation of inflammation and, moreover, synthetic or natural TLR agonists could serve as novel periodontal vaccine adjuvants. • Yokoyama et al. in 2007 also demonstrated that egg yolk antibody against Porphyromonas gingivalis (IgY-GP) proved to be an effective immunotherapeutic agent in the treatment of periodontitis.
  44. 44. Locally Administered Agents • In addition, a number of local host modulatory agents have been investigated in clinical trials for their potential use as adjuncts to surgical procedures, not only to improve on wound healing but also to stimulate • regeneration of lost bone, periodontal ligament, and cementum, • restoring the complete periodontal attachment apparatus. • It is believed that during development of root and attachment apparatus, there is a secretory phase in which Hertwig’s epithelial root sheaths secretes enamel-related matrix proteins. • Enamel matrix derivative is now commercially available for the treatment of periodontal defects as Emdogain which has received FDA approval. • The basic rationale behind using Emdogain is that it will act as a tissue-healing modulator that would mimic the events that occur during root development and help stimulate periodontal regeneration. • Enamel matrix proteins (EMD) initiates periodontal regeneration through recruitment of cementoblasts to the root-surface and stimulates these to form root-cementum, which will thereafter secondarily lead to regeneration of periodontal fibers and alveolar bone. • The above mentioned actions of EMD justify its role as a host modulating agent. Enamel matrix proteins
  45. 45. Locally Administered Agents • Topical NSAIDs have shown benefit in the treatment of periodontitis. • In general, topical application of NSAIDs is possible because these drugs are lipophilic and are absorbed into gingival tissues. • NSAIDs that have been evaluated for topical administration include ketorolac tromethamine rinse and S-ketoprofen dentifrice, triclosan. • One study of 55 patients with chronic periodontitis who received topical ketorolac mouth rinse reported that gingival crevicular fluid levels of PGE2 were reduced by approximately half over 6 months and that bone loss was halted. (Jeffcoat MK et. al, 1995) • In addition, locally administered ketoprofen has been investigated. Triclosan • A compound which has received interest as both an antibacterial and anti-inflammatory agent is triclosan. • Triclosan (2,4,4-trichloro-2-hydroxydiphenyl ether) is a nonionic antibacterial agent. Triclosan also inhibits COX and LOX and thus may interfere with the production of AA metabolites • To date, topically administered NSAIDs have not been approved as local HMTs for the management of periodontitis. Topical NSAIDs
  46. 46. • Bone morphogenetic protein (BMP) guides modulation and differentiation of mesenchymal cells into bone and bone marrow cells. • Absorbable collagen sponge (ACS) containing recombinant human BMP-2 has been approved for clinical use in certain oral surgery procedures, including localized alveolar ridge augmentation, under the name INFUSE® Bone Graft (Medtronic, Minneapolis, MN, USA) and InductOS™ (Wyeth, Maidenhead, UK). • These ACS release the protein over time in the location where it is implanted and provides a scaffold on which new bone can grow. • As the graft site heals, the ACS is absorbed and replaced by bone. Bone Morphogenetic Proteins
  47. 47. • FDA has approved Growth-factor Enhanced Matrix, GEM 21S® (Osteohealth, Shirley, NY) which is a combination of a bioactive highly purified recombinant human PDGF-BB with an osteoconductive bone matrix. • Platelet derived growth factor (PDGF), as a host modulating agent can increase chemotaxis of neutrophils and monocytes, stimulate fibroblasts proliferation and extracellular matrix synthesis, increase proliferation and differentiation of endothelial cells, stimulate proliferation of mesenchymal progenitor cells and differentiation of fibroblasts. • Nevins et al. (2005) demonstrated that the purified rhPDGF-BB mixed with bone allograft results in robust periodontal regeneration in both Class II furcations and interproximal intrabony defects. Platelet derived growth factor
  48. 48. • Role and action of BPs have already being discussed above. • Due to serious side-effects of systemically administered BPs leading to osteonecrosis of the jaws (ONJ) additional studies using topically administered bisphosphonates have been carried out which have reported a • significant increase in the postoperative percentage of bone-defect fill, • prevention of bone resorption as well as the boosting effect of locally delivered BPs on the osteoconductive and • regenerative potential of bone grafts used in periodontal therapy Bisphosphonate
  49. 49. • It has been reported that hypochlorous acid (HOCl) and taurine-N-monochloramine (TauCl) which are the end-products of the neutrophilic respiratory burst, modulate the host inflammatory response by inhibiting the production of interleukin-6, prostaglandins, and other proinflammatory substances. • Thus, HOCl and TauCl, playing a crucial role in the periodontal inflammatory process offer opportunities for the development of novel host-modulating therapies for the treatment of periodontitis. • Recently, Lorenz et al. (2009) assessed the influence of 2 and 3% N-chlorotaurine mouth rinse on dental plaque and demonstrated that rinsing with 10 mL of the test solution two times daily for 4 days reduced the plaque vitality. • Cimetidine is a powerful H2-(Histamine) receptor antagonist, and hence eliminates histamine’s inhibitory effects on immune response, thereby acting as a modulator of inflammation and immunity by inhibiting neutrophil chemotaxis and superoxide production, increasing cyclic adenosine monophosphate (cAMP) levels and down-regulating cytokines. • Hasturk et al. (2006) provided morphological and histological evidence to prove that topically active cimetidine is a potent inhibitor of P. gingivalis-elicited periodontal inflammation and can arrest and/or prevent tissue destruction and influence cell populations present in the inflammatory cell infiltrate. Hypochlorous Acid and Taurine-N-Monochloramine Cimitidine
  50. 50. Summary and Conclusion • The improved understanding of the host-bacterial interactions and the host immuno-inflammatory response leading to periodontal tissue destruction has led to the development of HMT. • Though the efficacy and usefulness of host modulating agents have been demonstrated by many clinical trials and have been approved by FDA for the management of periodontitis, yet the risk/benefit ratio relating to the use of these drugs has yet to be established. • Multicenter clinical trials are necessary to fully evaluate the benefits of these agents and to weigh their usefulness against the risks associated with their long-term administration. • Furthermore, continuous research in this field would also enable fabrication of individualized treatment for periodontal disease targeting inflammatory host response. • The current article emphasizes the promising potential of various host-modulating agents (the most crucial component of perioceutics) in the management of periodontal diseases.