Host Modulation.pptx
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The document discusses host modulation therapy for treating periodontal disease. It explains that periodontal disease is caused by an imbalance between proinflammatory and anti-inflammatory host responses to bacterial pathogens. Host modulation therapy aims to restore this balance by reducing destructive aspects of the host response and enhancing protective responses. The document outlines the role of mediators like cytokines, prostaglandins, and matrix metalloproteinases in periodontal tissue destruction. It discusses currently used host modulation therapies like non-steroidal anti-inflammatories and sub-antimicrobial dose doxycycline, which is the only systemically administered therapy approved as an adjunct to scaling and root planing.
Host Modulation.pptx
- 2. • Host :the organism from which a parasite obtains its nourishment or in the transplantation of tissue ,the individual who receives the graft • Modulation : the alteration of function or status of something in response to a stimuli or an altered chemical or physical environment
- 3. • The concept of host modulation is used for the management of chronic progressive disorders such as arthritis and osteopetrosis • Introduced in dentistry by William & Golub et al
- 4. • Periodontal disease appear as an opportunistic infection. • There is no way to eliminate bacteria from the oral cavity, so bacteria are always present in the periodontal milieu • When more virulent species exist in an environment that allows for their presence in greater proportion, there is the opportunity for periodontal destruction to occur.
- 5. • Bacterial pathogens initiate the periodontal inflammation, the host response to these pathogens,is equally important in mediating connective tissue breakdown, including bone loss. • Host derived enzymes known as the matrix metallo-proteinases (mmps), changes in osteoclast activity driven by cytokines and prostanoids, cause most of the tissue destruction in the periodontium.
- 6. • This shift in paradigms, with a focus on the host response, led to the development of host modulatory therapies to improve : • therapeutic outcomes, • Slow the progression of disease, • Allow for more predictable management of patients
- 8. ROLE OF THE HOST RESPONSE IN PERIODONTAL PATHOGENESIS After the accumulation of subgingival plaque bacteria, a variety of microbial substances, (including chemotactic factors such as lipopolysaccharide (LPS), microbial peptides, and other bacterial antigens,) diffuse across the junctional epithelium into the gingival connective tissues. Epithelial and connective tissue cells stimulated to produce inflammatory mediators that result in an inflammatory response in the tissues. The gingival vasculature dilates (vasodilation) increasingly permeable to fluid and cells.
- 9. Fluid accumulates in the tissues, Defense cells migrate from the circulation toward the chemotactic stimulus in the gingival crevice Neutrophils, or polymorphonuclear leukocytes (PMNS), predominate in the early stages These cells phagocytose and kill plaque bacteria. Bacterial killing by PMNS involves both intra-cellular mechanisms (after phagocytosis of bacteria within membrane-bound structures inside the cell) extracellular mechanisms (by release of PMN enzymes and oxygen radicals outside the cell). As bacterial products enter the circulation, Committed lymphocytes return to the site of infection, lymphocytes are transformed to plasma cells produce antibodies against specific bacterial antigens. Antibodies are released in the gingival tissues In the presence of complement, enhance PMN phagocytosis and bacterial killing. v
- 10. • Thus a host immune inflammatory response is established in the gingival tissues • The clinical signs of gingivitis develop. • This response is essentially protective to combat the bacterial infection and prevent ingress of bacteria into the tissues. • (Disease resistant), these primary defense mechanisms control the infection, and chronic inflammation (i.e., Chronic gingivitis) may persist
- 11. In disease-susceptible individuals, Inflammatory events extend apically and laterally Involve deeper connective tissues and alveolar bone. Proliferation of the junctional epithelium, which becomes increasingly permeable and ulcerated, Thus accelerating the ingress of bacterial products, inflammation worsens. Defense cells are recruited to the area, including macrophages and lymphocytes
- 12. Large numbers of PMNs migrate into the tissues, secreting destructive enzymes and inflammatory mediators. MMPs, such as collagenases, which break down collagen fibers in the gingival and periodontal tissues. The infiltrating inflammatory and immune cells are accommodated by the breakdown of structural components of the periodontium. Pharmacologic agents or chemotherapeutics can be administered to suppress excessive levels of MMPs. MMPs are a primary target for host modulation.
- 13. Macrophages are recruited to the area activated (by binding to LPS) to produce prostaglandins (e.g., prostaglandin E2, PGE2), interleukins (e.g., IL-α, IL-lβ, IL-6), tumor necrosis factor alpha (TNF-α), and MMPs. The cytokines (interleukins and TNF-α) and prostanoids are additional targets for host modulatory therapeutics. Interleukins and TNF-a bind to fibroblasts, which are stimulated to produce additional quantities of PGE2, interleukins, TNF-a, and MMPs in positive-feedback cycles. The concentration of these enzymes and inflammatory mediators becomes pathologically high in the periodontal tissues. Host modulatory therapy can be used to reduce the excessive levels of cytokines, prostanoids, and enzymes.
- 14. MMPs break down collagen fibers disrupting the normal anatomy of the gingival tissues and resulting in destruction of the periodontal ligament. The inflammation extends apically, and osteoclasts are stimulated to resorb alveolar bone by the high levels of prostaglandins, interleukins, and TNF-a in the tissues. The osteoclasts themselves are targets for host modulation. Drugs can be administered to downregulate osteoclastic activity and ultimately to inhibit bone resorption by these cells.
- 15. • The elevations in the proinflammatory or destructive mediators in response bacterial challenge are counterbalanced • by elevations in antiinflammatory or protective mediators • such as • cytokines IL-4 and IL-10, • ILl ra (receptor antagonist) • tissue inhibitors of matrix metalloproteinase (TIMPs)
- 16. • Under conditions of health, the antiinflammatory or protective mediators serve to control tissue destruction. • If there are adequate levels of these anti-inflammatory 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 • Another potential target for .host modulation could entail the use pharmacologic agents, which either mimic or result in elevations of endogenous antiinflammatory or protective mediators.
- 17. • The purpose of host modulation therapy is to restore the balance of proinflammatory or destructive mediators and antiinflammatory or protective mediators to that seen in healthy individuals
- 18. HOST MODULATORY THERAPY • Adjunctive treatment options. The term adjunctive is meant to imply "in addition to conventional therapies"
- 19. • HOST MODULATORY THERAPY is a treatment concept that aims to reduce tissue destruction and stabilize or even regenerate the production by modifying or downregulating destructive aspects of the host response and upregulating protective or regenerative response
- 20. • HMT’s are locally delivered pharmaceuticals that are prescribed as part of periodontal therapy and are used as adjuncts to conventional periodontal treatment such as scaling and root planing • HMT means treating host side of host bacteria interaction
- 21. • HMT’s do not switch off normal defense mechanism or inflammation instead they ameliorate excessive or pathologically elevated inflammatory process to enhance the opportunities for wound healing and periodontal stability
- 22. Systemically administrated agents Locally adminstrated agents NSAIDS NSAIDS Bisphosphanates Enamel matrix protein Sub antimicrobial dose Doxycycline Growth factors Bone morphogenic protein
- 23. NSAIDS • Inhibit formation of prostaglandin including PGE2 • PGE2 Upregulates bone resorption by osteoclast . Inhibit fibroblast function. Inhibitory and modulatory effect on immune response.
- 24. • NSAIDS used to treat pain ,acute inflammation • Chronic inflammatory condition Include salicylates Ibuprofen Naproxen NSAIDS Block PGE2 Reduce inflammation Inhibit osteoclast action
- 25. Side effects • Gastrointestinal problems • Hemorrhage • Renal and hepatic involvement • Once drug is stopped return or acceleration the rate of bone loss seen before NSAIDS therapy “Rebound effect”
- 26. Selective COX 2 inhibitor • COX-1 and COX-2. • COX-1 has antithrombogenic and cytoprotective functions. Therefore, inhibition of COX-1 by nonselective NSAIDs causes side effects such as gastrointestinal ulceration and impaired homeostasis. • COX-2 is induced after stimulation by various cytokines, growth factors, and LPS, • Results elevated quantities of prostaglandins. • Inhibition of COX-2 by selective COX-2 inhibitors results in reduction of inflammation • Life-threatening adverse effects • Not indicated as adjunctive HMTS in the treatment of periodontal disease
- 27. Bisphosphonates • The bisphosphonates are bone-seeking agents that inhibit bone resorption by disrupting osteoclast activity • The ability of bisphosphonates to modulate osteoclast activity clearly may be useful in the treatment of periodontitis. • Unwanted effects Include inhibiting bone calcification and inducing changes in white blood cell counts
- 28. Subantimicrobial-Dose Doxycycline • Subantimicrobial-dose doxycycline(SDD) is a 20-mg dose of doxycycline (Periostat that is approved and indicated as an adjunct to SRP in the treatment of chronic periodontitis. • Daily for 3 months, up to a maximum of 9 months of continuous dosing. The 20-mg dose exerts its therapeutic effect by enzyme, cytokine, and osteoclast inhibition
- 29. Locally Administered Agents Nonsteroidal Anti-inflammatory Drugs • Topical NSAIDs have shown benefit in the treatment of periodontitis • Topical ketorolac mouth rinse • Gingival crevicular fluid levels of PGE2 were reduced
- 30. Enamel Matrix Proteins, Growth Factors, and Bone Morphogenetic Proteins • Improve wound healing ,stimulate regeneration of lost bone, periodontal ligament, and cementum, restoring the complete periodontal attachment apparatus. • The only local host modulation agent currently approved by the PDA for adjunctive use during surgery is Emdogain
- 31. SUBANTIMICROBIAL-DOSE DOXYCYCLINE • SDD is the only PDA-approved, systemically administered HMT • Indicated specifically in the treatment of Periodontitis. • SDD is used as an adjunct to SRP • Must not be used as a stand alone therapy (monotherapy). • Marketed as periostat, is based on subantimicrobial dosage of doxycycline, a member of the tetracycline family • Therapy versus mechanical therapy alone resulted in significantly greater mean probing depth reductions in pockets
- 32. Mechanism of action • Downregulate MMP ,a family of zinc dependent enzyme capable of degrading extracellular matrix molecules including collagen. • Secreted by fibroblast keratinocytes,macrophages. • Play a key role in periodontitis • MMP 8 ,9 derived from PMNS are extremely effective in degrading type 1 collagen
- 33. • Rationale for using SDD as an HMT is that it regulates the activity of MMPS by a variety of synergistic mechanism including reduction in cytokine level ,stimulates Osteoblastic activity and new bone formation
- 34. Candidate Patients • Consider the patient's, motivation toward periodontal care, the medical history, and the patient's willingness to take a systemic drug treatment. • The rationale for using SDD must be clearly explained to the patient • Patients who show little enthusiasm for complying with the treatment plan or with oral hygiene practices are less likely to be good candidates for systemic drug therapy.
- 35. Treatable Periodontal Conditions Chronic periodontitis, Aggressive forms of periodontitis who are being treated nonsurgically Adjunct to periodontal surgery. Refractory to treatment, patients with risk factors such as smoking or diabetes
- 36. CONTRAINDICATED • History of allergy or hypersensitivity to tetracyclines. • Pregnant or lactating women • children less than 12 years old (because of the potential for discoloration of the developing dentition) • Reduce the efficacy of oral contraceptives, • Should not used gingivitis periodontal abscess when an antibiotic is indicated
- 37. • Side Effects • antibiotic doses (>100 mg) is associated with a photosensitivity, • hyper-sensitivity reactions, • nausea, vomiting.
- 38. Sequencing Prescription with Periodontal Treatment SDD is indicated as an adjunct to mechanical periodontal therapy and should not be used as a stand alone therapy. • SDD should be prescribed to coincide with the first episode of SRP and is prescribed for 3 months, up to a maximum of 9 months of continuous dosing • After initial periodontal treatment, the patient is enrolled into an intensive periodontal maintenance program
- 39. • For patients demonstrating a good treatment response with significant reduction in probing depth further SDD may not necessary • If progressive pocket SDD extended for 3 month
- 40. EMERGING HOST MODULATORY THERAPIES Chemically modified tetracylines (cmts) • Nonantibiotic tetracycline • Inhibit osteoclastic bone resorption and promote bone formation,enhance wound healing, and inhibit proteinases produced by periodontal pathogens. Anticytokine drugs • Targeted against cytokines such as TNF α • Increase the levels of antiinflammatory or protective mediators • Eg:infliximab,etanercept
- 41. CONCLUSION
- 42. CONCLUSION • The use of HMTs such as SDD offers the opportunity to improve the treatment outcomes that can be anticipated following SRP alone. • Subantimicrobial-dose doxycyline (SDD) is the only HMT currently approved and indicated as an adjunct to SRP for treating periodontitis