Host modulation therapy

Periodontitis is a complex infection initiated by bacteria –tissue destruction.
Host: the organism from which a parasite obtains its nourishment/ an individual who receives a graft
Modulation: the alteration of function or status of something in response to a stimulus or an altered physical or chemical environment

1. GUIDED BY: PRESENTED BY: DR DIVYA JAGGI DR ANKITA DADWAL HOST MODULATION THERAPY

2. CONTENTS INTRODUCTION PATHOGENESIS OF PERIODONTITIS AND HOST RESPONSE HOST MODULATORY THERAPY HOST MODULATING AGENTS LOCALLY ADMINISTERED HOST MODULATION THERAPY NEW AGENTS IN HOST MODULATION CONCLUSION REFRENCES 1/38

3. INTRODUCTION Periodontitis is a complex infection initiated by bacteria –tissue destruction. 2/38

4. PATHOGENESIS OF PERIODONTITIS AND HOST RESPONSE 3/38

5. HOST MODULATION THERAPY Treatment concept that aims to reduce the tissue destruction and stabilize or even regenerate the periodontium by modifying or down regulating destructive aspects of the host response and up regulating protective or regenerative responses . 1 st introduced in dentistry – William’s (1990) and Golub et al ( 1992) 4/38

6. RATIONALE 5/38

7. CLASSIFICATION 6/38

8. HOST MODULATING AGENTS INHIBITION OF ARACHADONIC ACID METABOLITE : A ) COX-1 INHIBITOR: indomethacin B) cox-2 INHIBITOR : Rofecoxi C) COX and LOX inhibitors: Triclosan , topical ketoprofen D) LOX INHIBITOR: lipoxins MODULATION OF MMPs: TETRACYCLINE B) CMT C) SDD D) BISPHOSPHONATES 7/38

9. MODULATION OF BONE REMODELLING : A) Conventional therapy B) Tumor necrosis factor – alpha C) Anticytokines drugs D) Antiresorptive therapies hormonal replacement therapy bisphosphonates disruptive of the RANKL/RANK/ OPG vitamin D statins 8/38

10. REGULATION OF IMMUNE AND INFLAMMATORY RESPONSE : A) Supressing proinflammatory cytokines: IL1 and TNF alpha antagonist B) modulation of nitric oxide activity OTHER AGENTS : A) probiotics B) nutrients LOCALLY ADMINISTERED HMT NEW EMERGING HOSTS : Azithromycin paratyroid 9/38

11. MODULATION OF ARACHIDONIC ACID METABOLITE NSAIDS 10/38

12. NSAIDs such as indomethacin ( williams RC jp 1987), flurbiprofen ( jeffcoat MK JP 1989), and naproxen (Howell TH 1993) administered daily for up to 3 years, significantly slowed the rate of alveolar bone loss compared with placebo. DISADVANTAGES OF NSAIDS AS HMT: gastrointestinal problems, hemorrhage (from decreased platelet aggregation), and renal and hepatic impairment REBOUND EFFECT 11/38

13. TOPICAL NSAIDS IN PERIODONTICS NSAIDS : KETOROLAC TRIMETHAMINE RINSE S- KETOPROFEN DENTRIFICE chronic periodontitis who received topical ketorolac mouthrinse reported that gingival crevicular fluid (GCF) levels of PGE 2  were reduced by approximately half over 6 months and that bone loss was halted (  Jeffcoat  MK et al: .   J Periodontol    1995). Ketoprofene block both CO and LO pathways. 12/38

14. LIPOXINS, RESOLVINS, PROTECTINS Biosynthesized during the resolution phase of acute inflammation. Pouliot et al ( 1999 ) , lipoxins blocked IL1 beta secretion from PMNs. LIPOXIN A4 LIPOXIN B4 13/38

15. INHIBITION OF MMPs 14/38

16. TETRACYCLINES

17. CHEMICALY MODIFIED TETRACYCLINES 16/38

18. ADVANTAGES OVER TETRACYCLINES No development of bacterial resistance that is found with the traditional tetracyclines . Less incidence of adverse effects such as GIT disturbances, superinfection. It has anticollagenase property that is very important to inhibit the periodontal tissue destruction. Substantivity of the drug, high concentration in GCF. Rifkin et al reported that CMT could also inhibit PTH induced bone resorption. 17/38

19. SUBANTI MICROBIAL DOSE DOXYCYCLINE At present SDD ( Periostat ) is the only systemically administered HMT specifically indicated for the treatment of chronic periodontitis that is approved by the US Food and Drug Administration (FDA) and accepted by the American Dental Association (ADA ). Studies conducted by Preshaw et al in J Periodontol   2008  utilizing this same modified-release SDD versus placebo with periodontitis as an adjunct to SRP resulted in significantly greater clinical benefits than SRP alone in the treatment of periodontitis. 18/38

20. Golub et al 1985  reported that a 2-week regimen of SDD reduced collagenase in GCF and in the adjacent gingival tissues surgically excised for therapeutic purposes. He found using SDD therapy adjunctive to routine scaling and prophylaxis cause 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 , 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. these reductions in collagenase levels were gains in the relative attachment levels in the SDD group(  Ashley RA 1999 ) 19/38

21. Sequencing Prescription With Periodontal Treatment Not used as monotherapy, Used as an adjunct to SRP. To be prescribed to coincide with the first episode of SRP. Taken as 20mg twice daily for 3 months and up to a maximum of 9 months of continuous dosing. After initial periodontal treatment, the patient is enrolled into an intensive maintanence program. (re evaluation of probing depths, reinforcement of oral hygiene, SRP, remotivation of the patient) . 20/38

22. INDICATIONS 21/38

23. CONTRAINDICATIONS 22/38

24. BISPHOSPHONATES The bisphosphonates are bone-seeking agents . inhibit bone resorption by disrupting osteoclast activity. interfere with osteoclastic metabolism and secretion of lysosomal enzymes ( Weinreb  M et al J Periodontal  1994 ) possess anticollagenase properties ( Nakaya  H et al J Periodontol   2000) treatment with the bisphosphonate significantly increased bone density compared with placebo ( Reddy MS et al   J Periodontol   1995 ) 23/38

25. MECHANISM OF ACTION 24/38

26. DISADVANTAGES OF BISPHOSPHONATES inhibiting bone calcification inducing changes in white blood cell counts. avascular necrosis of the jaws following bisphosphonate therapy, with the resultant risk of bone necrosis following dental extractions (Carter G, Goss AN Med J Aust    2005) As with NSAIDs, at present there are no bisphosphonate drugs that are approved and indicated for treatment of periodontal diseases BRONJ 25/38

27. MODULATION OF BONE REMODELLING TUMOR NECROSIS FACTOR – ALPHA : indirect and direct bone resorption. TNF alpha antagonist drugs – Infliximab Golimumab centrolizumab 26/38

28. ANTICYTOKINES DRUGS 27/38

29. DISRUPTIVE RANK/RANKL/OPG Expression of the RANKL gene in osteoblasts/stromal cells is enhanced by Vitamin D3 PTH IL-1, IL-6, IL- 17 TNF-α BMP-2 PGE2 RANKL inhibitor : Denosumab 28

30. CATHEPSIN K INHIBITOR It has role in degradation of type I and II collagen. So it can be viewd as a target for modulation bone resorption. VIT D has anti inflammatory and immunomodulatory properties. STATINS - SIMVASTATIN 29/38

31. NO SYNTHETASE INHIBITOR L-N G -monomethyl arginine L- arginie methyl ester Mercapto ethyle guanidine : blocks inducible NOS, scavenges peroxy nitrite & inhibits COX production. N- iminoethyl -L-lysine: reduce MMP activity in cartilage reduce production of IL-1 β 30/38

32. ANTIOXIDANT TYPES EXAMPLES 31/38 PREVENTIVE ANTIOXIDANTS RADICAL SCAVENGING ANTIOXIDANTS DNA REPAIR ENZYMES CATALASE GPX VIT A VIT E VIT C PROTEASES TRANSFERASES LIPASES

33. LOCALLY ADMINISTERD AGENTS NONSTEROIDAL ANTIINFLAMMATORY DRUGS ENAMEL MATRIX PROTEINS BONE MORPHOGENETIC PROTEINS ( BMP-2 , BMP-7), GROWTH FACTORS ( PLATELET-DERIVED GROWTH FACTOR , INSULIN LIKE GROWTH FACTOR. TETRACYCLINES 32/38

34. The initial local host modulatory agent approved by the FDA for adjunctive use during surgery to assist with clinical attachment gain and wound healing was EMDOGAIN PLATELET-DERIVED GROWTH FACTOR combined with a resorbable synthetic bone matrix (GEM 21S) to assist in regenerative procedures , wound healing, particularly in patients with diabetes rhBMP-2 (INFUSE) soaked on to an absorbable collagen sponge to assist with ridge and sinus augmentation and healing of fractures by the orthopedic community 33/38

35. PROBIOTICS 34/38 A preparation or a product containing viabale , defined microorganism in sufficient number, which can alter the microflora in a compartment of the host. Can be becteria , yeast or moulds. Eg : yougurt , cheese, lozenges

36. NEW AGENTS FOR HOST MODULATION AZITHROMYCIN , a type of macrolide antibiotic. Suppress periodontopathogens Anti inflammatory activity Healing through persistence at low levels in macrophages and fibroblasts Suppress the production of pro-inflammatory cytokines and increase the production of anti inflammatory cytokines. 35/38

37. PARATHYROID HORMONE TERIPARATIDE, a biosynthetic human parathyroid hormone, is an anabolic agent. Fibroblast growth factor 2, production is upregulated. It regulates the proliferation and differentiation of osteoblast progenitors Reduce sclerostin , a potent inhibtor of bone formation, could account for part of the anabolic response to PTH. 36/38

38. CONCLUSION Plaque bacteria are essential for periodontitis to occur but are insufficient by themselves to cause the disease. For periodontitis to develop, a susceptible host is also required. As we know the majority of periodontal destruction is caused by host immuno-inflammatory response, various advanced treatment modalities have been introduced in the recent years including HMT. Though various agents are there to modulate host response, only few have shown successful result in humans . 37/38

39. REFRENCES Carranza 12 th edition Newman M, Takei H, Klokkevold P, Carranza F. “Clinical Periodontology”,10,11 th, Edition. Saunders, Elsevier. Preshaw PM. Host response modulation in periodontics. Periodontol 2000. 2008;48:92-110. Review. D W Paquette & R C. Williams. Modulation of host inflammatory mediators as a treatment strategy for periodontal diseases. Minkle Gulati, Vishal Anand , Vivek Govila , and Nikil Jain. Host modulation therapy: An indispensable part of perioceutics . JIndian Soc Periodontol . 2014 MayJun;18(3): 282–288 38/38

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