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Page 1
Post Graduate Department Of Periodontics &
Oral Implantology
Host Modulation Therapy
Page 2
• Host:- defined as the “the organism from which a parasite obtains
its nourishment” or in the transplantation of t...
Page 3
• Periodontists previously believed that p. disease was an
consequence of aging and uniformly distributed.
• Though...
Page 4
• Better epidemiologic data, there has been shift about prevalence and
progression of periodontitis
• Well establis...
Page 5
• This host response to the bacterial challenge presented by subgingival
plaque is the important determinant of dis...
Page 6
• majority of the destructive events occurring in the periodontal
tissues result from activation of destructive pro...
Page 7
Page 8
to modify or reduce destructive aspects of host response: so
that immune-inflammatory response to plaque is less
da...
Page 9
– Treatment concept that aims to reduce tissue
destruction and stabilize or even regenerate the
periodontium by mod...
Page 10
• HMTs are systemically or locally delivered pharmaceuticals that are
prescribed as part of periodontal therapy an...
Page 11
• Periodontal disease and health can be seen as balance between
 Persisting bacterial burden and proinflammatory ...
Page 12
Page 13
• Poor oral hygiene Normal Exogenous infection
Pathogenic flora Antibody response
Neutrophil clearance
Pocketing a...
Page 14
The host monocyte-lymphocytic axis is stimulated,
 local release of inflammatory mediators such as arachidonic ac...
Page 15
• HMTs offer the opportunity for modulating or reducing this
destruction by treating aspects of the chronic inflam...
Page 16
Page 17
.
Systemically
Administered Agents :-
 NSAIDs
Bisphosphonates
Subantimicrobial-
Dose Doxycycline
 Locally admi...
Page 18
• NSAIDs inhibit the formation of prostaglandins, including
prostaglandin E2 (PGE2) (Grenier et al 2002).
– Produc...
Page 19
NSAIDs
Gram neg bacteria
LPS activates
# Neutrophils
# Macrophage PGE2 Osteoclast
# Fibroblast cells cells
# Gingi...
Page 20
Page 21
• Inhibits prostaglandins
• Reduce inflammation
– Used to treat pain, acute inflammation, and chronic inflammatory...
Page 22
Disadvantages when used as a HMT for periodontitis.
• Administration for extended periods is necessary for periodo...
Page 23
selective cyclooxygenase-2 (COX-2) inhibitors offers as
adjunctive treatments in the management of periodontitis.
...
Page 24
– use of selective COX-2 inhibitors reduce periodontal inflammation
without the side effects typically observed af...
Page 25
NSAIDs (including the selective COX-2 specific
inhibitors) are presently not indicated as adjunctive
HMTs in the t...
Page 26
Role of
arachidonic acid
metabolites.
Mode of
interception
Significant
Contributors
Agents
employed
Author’s comen...
Page 27
Author Purpose Host M
Agent
Parameters Subjects Results
Ishihara y,
nishihara t
et al
(1991)
demonstrate the
lipop...
Page 28
• The bisphosphonates are bone-seeking agents . inhibit bone
resorption by disrupting osteoclast activity.
• inter...
Page 29
Page 30
• Some bisphosphonates have the unwanted effects
– inhibiting bone calcification
– inducing changes in white blood...
Page 31
Page 32
Page 33
Author Purpose Host
modulating
agent
Parameters Subject
s
Results
Shoji
K,Horiuchi
H (1995)
Efficacy of
risendrona...
Page 34
» Sub-Antimicrobial-Dose Doxycycline
• Sub-antimicrobial-dose doxycycline (SDD) is a 20-mg dose of
doxycycline (Pe...
Page 35
• studies have found no detectable antimicrobial effect on the
oral flora or the bacterial flora in other regions ...
Page 36
• In addition, a modified-release SDD was recently approved by the
FDA (Oracea) for the treatment of the common sk...
Page 37
• Tetracycline's work well as host modulation agents because of their
pleiotropic effects on multiple components o...
Page 38
• doxycycline was found to be a more effective inhibitor of
collagenase than either minocycline or
tetracycline (B...
Page 39
• Each capsule contained 20 mg of doxycycline versus the commercially
available 50 mg and 100 mg, antimicrobially ...
Page 40
• doxycycline ( other members of the tetracycline
family) has the ability to downregulate MMPs,
• a family of zinc...
Page 41
• The predominant MMPs in periodontitis, particularly MMP-8 and
MMP-9, derive from PMNs (Golub LM et al J Clin Per...
Page 42
 Golub et al 1985 reported that a 2-week regimen of SDD reduced
collagenase in GCF and in the adjacent gingival t...
Page 43
 history of allergy or hypersensitivity to tetracyclines.
 pregnant or lactating women or children less than 12 ...
Page 44
 Doxycycline at antibiotic doses (≥100 mg) is associated with adverse
effects, including
 photosensitivity, hype...
Page 45
• Combining with Periodontal Surgery or Local Delivery
Systems:-
• SDD was used as an adjunct to flap surgery reve...
Page 46
• SDD can also be combined with the local delivery of antibiotics
into the periodontal pocket through sustained-de...
Page 47
Author Purpose Host
modulating
agent
Parameters Subjects Results
Crout RJ,
Lee HM,
et al
(1996)
check for potency
...
Page 48
• Nonsteroidal Antiinflammatory Drugs
– Topical NSAIDs have shown benefit in the treatment of periodontitis.
– chr...
Page 49
– Enamel Matrix Proteins, Growth Factors, and Bone
Morphogenetic Proteins:-
 local HMTs used as adjuncts to surgi...
Page 50
• The locally applied HMTs currently approved by the FDA for
adjunctive use during surgery are
– enamel matrix pro...
Page 51
• The initial local host modulatory agent approved by the FDA
for adjunctive use during surgery to assist with cli...
Page 52
• NO synthase inhibitors:-
• Lietao et al (2005) reported that nitric oxide synthase (NOS) inhibitors
have protect...
Page 53
 Although NO has an antimicrobial protective activity, its
elevated concentration in the tissues has a cytotoxic ...
Page 54
– Recombinant human interleukin-11
 According to Trepicchion et al 1995, IL-11 was shown to have anti-
inflammato...
Page 55
• Omega-3 fatty acid
• Vardar et al. in 2005 evaluated the use of omega-3 fatty acids for
blocking arachidonic aci...
Page 56
• Disruption of Cell Signaling Pathway
• preventing cell activation seek to inhibit the intracellular transduction...
Page 57
• Therapeutic strategies have been directed toward many of these
major signaling pathways, notably MAPK and NF-kB,...
Page 58
Page 59
• Disruption of the
RANKL/RANK/Osteoprotegerin Axis
• The RANKL/RANK interaction is responsible for differentiatio...
Page 60
Page 61
• Periodontal pathogens and destructive host responses are
involved in the initiation and progression of periodont...
Page 62
• adjunctive therapies such as host modulation to enhance the
efficacy of existing mechanical procedures contribut...
Page 63
• The use of HMT as an adjunct may be particularly useful in
susceptible, high-risk patients in whom a prolonged a...
Page 64
• In the future, a range of HMTs targeting different aspects of the
destructive cascade of breakdown events in the...
Page 65
• the use of HMT to better manage chronic periodontal disease have
applications to other chronic systemic diseases...
Page 66
Page 67
• The three main sub-families of MAPKs are extracellular-
regulated kinases (ERK-1/-2), c-Jun N-terminal activated...
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Transcript of "Host modulation therapy"

  1. 1. Page 1 Post Graduate Department Of Periodontics & Oral Implantology Host Modulation Therapy
  2. 2. Page 2 • Host:- defined as the “the organism from which a parasite obtains its nourishment” or in the transplantation of the tissue,’ the individual who receives graft. • Modulation is defined as “ alteration of function or status of something in response to a stimulus or an altered chemical or physical environment. • Concept of host modulation was 1st introduced by Williams (1990) and Golub et al (1992)
  3. 3. Page 3 • Periodontists previously believed that p. disease was an consequence of aging and uniformly distributed. • Thought that severity was directly correlated with plaque • Disease progression occurred in a continuous, linear manner throughout life.
  4. 4. Page 4 • Better epidemiologic data, there has been shift about prevalence and progression of periodontitis • Well established that periodontitis is not related to aging • Disease severity is not correlated with plaque  pts with abundant plaque and calculus deposits with widespread gingivitis but have minimal deep pockets,  In contrast ; despite maintaining high standard of plaque control , succumb to aggressive forms of periodontitis with deep pockets , tooth mobility and early tooth lost,  the former group of patients is periodontal disease resistant,  Whereas the latter is periodontal disease susceptible.
  5. 5. Page 5 • This host response to the bacterial challenge presented by subgingival plaque is the important determinant of disease severity. • Although plaque bacteria are capable of causing direct damage to the periodontal tissues(antigens, lipopolysaccharide (LPS), and other virulence factors stimulates like H2S, butyric acid, other enzymes ).
  6. 6. Page 6 • majority of the destructive events occurring in the periodontal tissues result from activation of destructive processes that occur as part of the host immune-inflammatory response to plaque bacteria. – Host response is essentially protective bt paradoxically can also result in tissue damage : breakdown of connective tissue fibers in the periodontal ligament and resorption of alveolar bone. • The nature of host response to the presence of plaque is modified by genetic factors( seen in aggressive periodontitis) and systemic and environmental factors( smoking , diabetes, stress).
  7. 7. Page 7
  8. 8. Page 8 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;
  9. 9. Page 9 – Treatment concept that aims to reduce tissue destruction and stabilize or even regenerate the periodontium by modifying or downregulating destructive aspects of host response and upregulating protective or regenerative responses.(CARRANZA) Definition:-
  10. 10. Page 10 • HMTs are systemically or locally delivered pharmaceuticals that are prescribed as part of periodontal therapy and are used as adjuncts to conventional periodontal treatments. • Historically , treatment has focused on reducing the bacterial challenge by the use of SRP, improved oral hygiene, and periodontal surgery. – However , the outcomes ( chronic disease) are not always predictable or stable.
  11. 11. Page 11 • Periodontal disease and health can be seen as balance between  Persisting bacterial burden and proinflammatory destructive events in the tissue. • Removal of plaque by SRP targets one aspect by reducing bacterial burden • Antigenic challenge that drives the inflammatory response in the host tissue. • Bacterial challenge is never completely eliminated after SRP and recolonization occurs.  HMTs offers the potential for downregulating destructive aspects and upregulating protective aspects of host response, • In combination with conventional treatments to reduce the bacterial burden, the balance between health ( resolution of inflammation and wound healing) and disease progression ( continued proinflammatory events) is tipped in the direction of healing.
  12. 12. Page 12
  13. 13. Page 13 • 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
  14. 14. Page 14 The host monocyte-lymphocytic axis is stimulated,  local release of inflammatory mediators such as arachidonic acid metabolites and cytokines.  intern directly cause the local tissue destruction,  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.
  15. 15. Page 15 • 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 mechanism or inflammation; instead, they ameliorate excessive of pathologically elevated inflammatory processes to enhance opportunities for wound healing. • Specific aspects of disease pathogenesis for modulation a) Regulation of immune and inflammatory responses. b) Regulation of excessive production of matrixmetalloproteinase’s c) Regulation of arachidonic acid metabolites d) Regulation of bone metabolism.
  16. 16. Page 16
  17. 17. Page 17 . Systemically Administered Agents :-  NSAIDs Bisphosphonates Subantimicrobial- Dose Doxycycline  Locally administered Agents :-  Topical NSAIDs  Enamel matrix proteins  Growth factors  Bone morphogenetic proteins Host modulating agents
  18. 18. Page 18 • NSAIDs inhibit the formation of prostaglandins, including prostaglandin E2 (PGE2) (Grenier et al 2002). – Produced by neutrophils, macrophages, fibroblasts, and gingival epithelial cells in response to lipopolysaccaride(LPS). • Upregulates bone resorption by osteoclasts;(Heasman PA and Collins j p 1993) • Levels of PGE2 are elevated in pts with periodontitis ( Plamondon and sorsa jp 2002) • It also inhibits fibroblasts function and has inhibitory effects on the immune response (Grossi and Genco Ann Periodontics 1997). Nonsteroidal antiinflammatory drugs
  19. 19. Page 19 NSAIDs Gram neg bacteria LPS activates # Neutrophils # Macrophage PGE2 Osteoclast # Fibroblast cells cells # Gingival epi. Cells BONE RESORPTION Mechanism:-
  20. 20. Page 20
  21. 21. Page 21 • Inhibits prostaglandins • Reduce inflammation – Used to treat pain, acute inflammation, and chronic inflammatory conditions. – Inhibits osteoclastic activity in periodontitis (Howell TH in oral bio med 1993). • 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. Action:-
  22. 22. Page 22 Disadvantages when used as a HMT for periodontitis. • Administration for extended periods is necessary for periodontal benefits to become apparent, and are associated with significant side effects: – gastrointestinal problems, – hemorrhage (from decreased platelet aggregation), – and renal and hepatic impairment. • 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, often referred to as a “rebound effect.”[ (William RC j dent res 1991)
  23. 23. Page 23 selective cyclooxygenase-2 (COX-2) inhibitors offers as adjunctive treatments in the management of periodontitis. • cyclooxygenase, which converts arachidonic acid to prostaglandins, exists in two functionally distinct isoforms, COX-1 and COX-2. • • COX-1 has antithrombogenic and cytoprotective functions. • inhibition of COX-1 by nonselective NSAIDs causes side effects – gastrointestinal ulceration – and impaired hemostasis. • .
  24. 24. Page 24 – use of selective COX-2 inhibitors reduce periodontal inflammation without the side effects typically observed after long-term (nonselective) NSAID therapy. – selective COX-2 inhibitors slowed alveolar bone loss in animal models(Bezerra MM jp 1993) and modified prostaglandin production in human periodontal tissues (Vardar S JPeriodontol 2003). However, the selective COX-2 inhibitors were later identified to be associated with significant and life-threatening adverse effects, resulting in some drugs being withdrawn from the market.
  25. 25. Page 25 NSAIDs (including the selective COX-2 specific inhibitors) are presently not indicated as adjunctive HMTs in the treatment of periodontal disease summary,
  26. 26. Page 26 Role of arachidonic acid metabolites. Mode of interception Significant Contributors Agents employed Author’s coments Prostaglandins and other arachidonic acid metabolites within the periodontal tissues play a role in the pathogenesis. Inhibition of arachidonic acid metabolite by blocking of the cyclooxygenase pathway Goldhaber et al (1973) Nyman et al (1979) Weaks- Dybvig et al (1982) Offenbacher et al (1987) Jeffcoat et al (1991) Indomethacin, Flurbiprofen, S-Ketoprofen, Triclosan. Systemic daily administration for periods up to three years ,showed significant reduction in rate of bone loss, major disadvantage of rebound effect
  27. 27. Page 27 Author Purpose Host M Agent Parameters Subjects Results Ishihara y, nishihara t et al (1991) demonstrate the lipopolysaccharide isolated from a.a comitans strain induced bone resorption Indomethacin dexamethasone PGE2 and IL- 1 levels Mouse PGE2 and IL-1 participate in LPS induced bone resorption in vitro. Howell th, fiorellini i, weber hp et al (1991) To study the effects of piroxicam in preventing gingival inflammation and plaque formation Piroxicam Gingival inflammation plaque index Beagle dogs Significantly inhibit the development of gingival inflammation Roy S, Feldman, Szeto B et al (1983) To evaluate the effect on bone resorption: A retrospective study Aspirin (asp) or aspirin plus indomethcin Radiographs Humans Percentage bone loss for the entire dentition was lower in asa group Offenbacher S, Odle BM et al (1989) metabolites of cyclooxygenase (co) during the progression of periodontitis Flurbiprofen Crevicular fluid levels of PGE2 and TXB2 Rhesus monkey prevented rise in TXB2, but did not affect increase in PGE2. Heasman PA, et al (1993) efficacy of flurbiprofen (50mg) on both developing and established gingivitis Flurbiprofen GCF concentration of PGE2, TXB2 and LTB4, Bleeding index Human control gingival inflammation with both preventive and therapeutic properties
  28. 28. Page 28 • 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) • In human studies, these agents resulted in enhanced alveolar bone status and density (Rocha M et al J Periodontol 2001) • The ability of bisphosphonates to modulate osteoclast activity clearly may be useful in the treatment of periodontitis, Bisphosphonates
  29. 29. Page 29
  30. 30. Page 30 • Some bisphosphonates have the unwanted effects – 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) • Bisphosphonate-related osteonecrosis of the jaw, although primarily associated with intravenous administration of bisphosphonates rather than oral administration, • has impeded the development of bisphosphonates as an HMT to manage periodontitis. • As with NSAIDs, at present there are no bisphosphonate drugs that are approved and indicated for treatment of periodontal diseases
  31. 31. Page 31
  32. 32. Page 32
  33. 33. Page 33 Author Purpose Host modulating agent Parameters Subject s Results Shoji K,Horiuchi H (1995) Efficacy of risendronate to prevent alveolar bone resorption Risendronate Bone mineral density Rats. In preventing bone resorption in periodontitis M young H , P ark JY et al (2 001 ) evaluate the clinic al availability of bisphosphonate in auto genous free bone grafts Bisphosphonates Clinical measurements, histomorphologi cal review Rats Clinical application of bisphosphonates for decreasing resorption of grafted bone Durate P M , Gurgel B C D e t a l (2 0 0 5 To evaluate whether alendronate (ald) influence Bone healing around titan ium implants Alendronate Estrogen levels rats . Alendronate may prevent negative influence of estrogen deficiency on bone healing around titanium implants Howell 1991, His- Ming 2004, Holzhausen 2005, Gurkan 2005, Durate 2005. Inhibition of osteoclast/M MP activity through chelation of cations. Bisphosphonates (Alendronate), Hormone replacement therapy.(HRT), OPG- Fc therapeutic agents Osteoporosis and osteopenia may be indicators for periodontal diseases. humans improves the clinical outcome of nonsurgical periodontal therapy and may be an appropriate adjunctive treatment to preserve periodontal bone mass.
  34. 34. Page 34 » Sub-Antimicrobial-Dose Doxycycline • Sub-antimicrobial-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. • It is taken twice daily for 3 months, up to a maximum of 9 months of continuous dosing. • therapeutic effect by enzyme, cytokine, and osteoclast inhibition rather than by any antibiotic effect. Sub-antimicrobial dose doxycycline
  35. 35. Page 35 • studies have found no detectable antimicrobial effect on the oral flora or the bacterial flora in other regions of the body. • 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).
  36. 36. Page 36 • In addition, a modified-release SDD was recently approved by the FDA (Oracea) for the treatment of the common skin disorder rosacea and is routinely prescribed within the dermatology community. • 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. • There has also been considerable off-label use of this new modified- release SDD for the treatment of periodontal diseases based on the understanding that once-a-day administration can increase the level of compliance as compared to twice-a-day oral administration.
  37. 37. Page 37 • Tetracycline's work well as host modulation agents because of their pleiotropic effects on multiple components of the host response . The only enzyme (MMP) inhibitors that have been approved for clinical use and tested for the treatment of periodontitis . • Golub et al (J Periodont Res 1985). reported that the semisynthetic compound (e.g., doxycycline) was more effective than the parent compound tetracycline in reducing excessive collagenase activity in the GCF of chronic periodontitis patients. • Mechanisms of Action
  38. 38. Page 38 • doxycycline was found to be a more effective inhibitor of collagenase than either minocycline or tetracycline (Burns FR 1989) and • because of its safety profile, pharmacokinetic properties, and ready systemic absorption. to eliminate the side effects of long-term tetracycline therapy, especially the emergence of tetracycline-resistant organisms, SDD capsules were prepared and tested( Golub LM1985)
  39. 39. Page 39 • Each capsule contained 20 mg of doxycycline versus the commercially available 50 mg and 100 mg, antimicrobially effective, capsules or tablets. • clinical studies using sub-antimicrobial doses of doxycycline have shown no difference in the composition or resistance level of the oral flora (Thomas J; jp 2000) • no appreciable differences in either fecal or vaginal microflora ( Walker C; J Clin Periodontol 2005) • no overgrowth of opportunistic pathogens, such as Candida, in the oral cavity, gastrointestinal system, or genitourinary system.
  40. 40. Page 40 • doxycycline ( other members of the tetracycline family) has the ability to downregulate MMPs, • a family of zinc-dependent enzymes that are capable of degrading extracellular matrix molecules, including collagen (Birkedal-Hansen H J Periodontol 1993 • MMPs are secreted by fibroblasts, keratinocytes, macrophages, PMNs, endothelial cells and play a key role in periodontitis. • Excessive MMPs are released in inflamed periodontal tissues, resulting in breakdown of the connective tissue matrix.
  41. 41. Page 41 • The predominant MMPs in periodontitis, particularly MMP-8 and MMP-9, derive from PMNs (Golub LM et al J Clin Periodontol 1995) and are extremely effective in degrading type I collagen, the most abundant collagen type in gingiva and periodontal ligament (Mariotti A Periodontol 2000 ) • Levels of PMN-type MMPs have been shown to increase with severity of periodontal disease and decrease after therapy (Golub LM, Ciancio et al J Periodontal Res 1990) • The rationale for using SDD as a HMT in the treatment of periodontitis is that doxycycline downregulates the activity of MMPs by a variety of synergistic mechanisms, including reductions in cytokine levels, and stimulates osteoblastic activity and new bone formation by upregulating collagen production
  42. 42. Page 42  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)
  43. 43. Page 43  history of allergy or hypersensitivity to tetracyclines.  pregnant or lactating women or children less than 12 years old (because of the potential for discoloration of the developing dentition).  reduce the efficacy of oral contraceptive.  There is a risk of increased sensitivity to sunlight (manifested by an exaggerated sunburn) seen with higher doses of doxycycline, although this has not been reported in using the sub-antimicrobial dose. Contraindications:
  44. 44. Page 44  Doxycycline at antibiotic doses (≥100 mg) is associated with adverse effects, including  photosensitivity, hypersensitivity reactions, nausea, vomiting, and esophageal irritation.  SDD (20-mg dose), it was reported that the drug was well tolerated, and the profile of unwanted effects was virtually identical in the SDD and placebo groups (Caton JG JP2000; Novak MJ J Periodontol 2002) Side Effects:-
  45. 45. Page 45 • Combining with Periodontal Surgery or Local Delivery Systems:- • SDD was used as an adjunct to flap surgery revealed better probing depth reductions in surgically treated sites greater than 6 mm compared with surgically treated sites in patients given placebo (Gapski R J Periodontol 1999) • greater reductions in ICTP (carboxy-terminal peptide, a breakdown product of collagen) than the placebo group, indicating that collagenolytic activity was reduced in the patients taking SDD.
  46. 46. Page 46 • SDD can also be combined with the local delivery of antibiotics into the periodontal pocket through sustained-delivery systems. The two treatment approaches target different aspects of the pathogenic process: – local delivery systems deliver antimicrobial concentrations of an antibacterial agent directly into the site of the pocket, whereas SDD is a systemic host response modulator. • (SRP + local antibiotics) can be combined with HMT (SDD) to maximize the clinical benefit for patients (Novak MJ J Periodontol 2008)
  47. 47. Page 47 Author Purpose Host modulating agent Parameters Subjects Results Crout RJ, Lee HM, et al (1996) check for potency of low dose doxycycline Low dose doxycycline CAL, PD and GCF Collagenase activity and Periodontal ligament degradation Human LDD inhibits tissue destruction in the absence of antimicrobial property. Long term LDD could be a useful adjunct to instrumentation Golub LM, Lee HM et al (1997) inhibitor of matrix metalloproteinases(MM P’s) administered to human , can reduce bone type collagen degradation in inflammatory exudates Doxycycline Collagenase activity Human Reduction of excessive MMP activity with concomitant reduction in collagen degradation products Golub LM , Mc Namara T F et al (2 001 ) clinically effective dose regimens using subantimicroal dose doxycycline (SDD) as an adjunctive therapy in patients with adult periodontitis Doxycycline Clinical attachment level Human s significant potential as an oral adjunctive therapy in the long term management of adult periodontitis Novak M J , Dawson D R , e t a l 2 0 0 8 combination of systemically administered host-modulating therapy & locally administered topical antimicrobialtherapy , as adjuncts to scaling and root planing(SRP),would provide significantly improved clinical benefits in the treatment of untreated moderate to severe chronic periodontitis(CP) Low dose(20mg) doxycycline hyclate , doxycycline Hyclate gel (CAL) ,(BOP), and the gingival index(GI) Humans critical role in disrupting the progression of periodontal breakdown
  48. 48. Page 48 • Nonsteroidal Antiinflammatory Drugs – Topical NSAIDs have shown benefit in the treatment of periodontitis. – chronic periodontitis who received topical ketorolac mouthrinse reported that gingival crevicular fluid (GCF) levels of PGE2 were reduced by approximately half over 6 months and that bone loss was halted ( Jeffcoat MK et al:. J Periodontol 1995.. – topically administered NSAIDs have not been approved as local HMTs for the management of periodontitis. Locally Administered Agents
  49. 49. Page 49 – Enamel Matrix Proteins, Growth Factors, and Bone Morphogenetic Proteins:-  local HMTs used as adjuncts to surgical procedures, not only to improve wound healing but also to stimulate regeneration of lost bone, periodontal ligament, and cementum, restoring the complete periodontal attachment apparatus.  These have included – enamel matrix proteins – bone morphogenetic proteins (BMP-2, BMP-7), – growth factors (platelet-derived growth factor, – Insulin like growth factor. – and tetracyclines.
  50. 50. Page 50 • The locally applied HMTs currently approved by the FDA for adjunctive use during surgery are – enamel matrix proteins (Emdogain), – recombinant human platelet-derived growth factor-BB (GEM 21S), – and BMP-2 (INFUSE).
  51. 51. Page 51 • 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; • this has been followed by 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.
  52. 52. Page 52 • NO synthase inhibitors:- • Lietao et al (2005) reported that nitric oxide synthase (NOS) inhibitors have protective effects against bone resorption and inflammatory process in periodontitis in rats. • Lappin et al. in 2000 reported that inducible NOS (iNOS) is responsible for nitric oxide (NO) production by epithelial and inflammatory cells in response to proinflammatory cytokines in some inflammatory diseases such as rheumatoid arthritis and periodontal disease. Newer Agents for Host Modulation
  53. 53. Page 53  Although NO has an antimicrobial protective activity, its elevated concentration in the tissues has a cytotoxic effect toward the host cells.  Leitao et al. in 2005 found a reduction of alveolar bone loss and gingival inflammation after the use of a selective iNOS inhibitor – mercaptoethylguanidine – confirming that NO has a deleterious role in the pathophysiology of periodontitis and that its modulation may prevent tissue destruction.
  54. 54. Page 54 – Recombinant human interleukin-11  According to Trepicchion et al 1995, IL-11 was shown to have anti- inflammatory effects by inhibition of TNF-α and other proinflammatory cytokines.  Leng et al. in 1995 observed that it indirectly minimizes tissue injury through stimulation of tissue inhibitor of metalloproteinase-1 (TIMP- 1).  Martuscelli et al. in 2000 investigated the ability of recombinant human IL-11 (rhIL-11) to reduce periodontal disease progression. – Significant reduction in the rate of clinical attachment and radiographic bone loss were observed after an 8-week period of rhIL-11 administration twice a week (Elias JA. J Immunol. 1997)
  55. 55. Page 55 • Omega-3 fatty acid • Vardar et al. in 2005 evaluated the use of omega-3 fatty acids for blocking arachidonic acid cascade in induced periodontal disease in rats. • results in the inhibition of production of not only prostaglandins derived from the COX pathway but also leukotrienes derived from the lipooxygenase pathway. The combined use of omega- 3 fatty acid with celecoxib, acts as synergism for anti- inflammatory effect. • Therapy resulted in significant superior reductions on periodontal tissue levels of prostaglandins, leukotriene B4, and platelet-activating factor
  56. 56. Page 56 • Disruption of Cell Signaling Pathway • preventing cell activation seek to inhibit the intracellular transduction of signals produced when ligands bind to their membrane receptors. • Inhibition of signal transduction pathways abolish both cell activation by cytokines or other stimuli and the production of proinflammatory cytokines. • Cytokines and bacterial components activate many signal transduction pathways . – include the mitogen-activated protein kinase (MAPK) pathway, – phosphatidylinositol-3 protein kinase (PI3) pathway, – janus kinase-signal transducer and activator of transcription (Jak-STAT), – and nuclear factor kappa B (NF-kB) .
  57. 57. Page 57 • Therapeutic strategies have been directed toward many of these major signaling pathways, notably MAPK and NF-kB, which are discussed below • MAPK inhibitors • Inhibit LPS-induced MMP, cytokine (IL-1b, TNF-α, IL-6, IL-8), and prostaglandin expression.( Lee JC, Immunopharmacology. 2000) • NF-kB family inhibitors • Inhibit NF-kB–dependent expression (IL-1, TNF-α, IL-6, IL-8), MMPs, and others (Kimura A1998)
  58. 58. Page 58
  59. 59. Page 59 • Disruption of the RANKL/RANK/Osteoprotegerin Axis • The RANKL/RANK interaction is responsible for differentiation and maturation of osteoclast precursor cells to activate osteoclasts. • Osteoprotegerin acts as a decoy receptor, expressed by osteoblastic cells, which binds to RANKL and inhibits osteoclast development (Kong YY 1999) Several studies have shown the opposite effect of RANKL and osteoprotegerin in bone modulation.
  60. 60. Page 60
  61. 61. Page 61 • Periodontal pathogens and destructive host responses are involved in the initiation and progression of periodontitis. • Therefore the successful long-term management require a treatment strategy that address both etiologic components. • Evidence for the role of MMPs, cytokines, and other mediators in the pathogenesis of periodontal disease distinguishes them as viable targets for a chemotherapeutic approach. summary
  62. 62. Page 62 • adjunctive therapies such as host modulation to enhance the efficacy of existing mechanical procedures contributes favorably to an integrated approach for the long-term, clinical management of periodontitis. • HMTs are an emerging treatment concept in the management of periodontitis.
  63. 63. Page 63 • The use of HMT as an adjunct may be particularly useful in susceptible, high-risk patients in whom a prolonged and excessive host response occurs to presence of bacteria ,promotes the activity of MMPs and osteoclasts. • SDD is the only systemically administered HMT currently approved and indicated as an adjunct to SRP for treating periodontitis. Clinical trials have demonstrated a clear treatment benefit when using SDD versus SRP alone.
  64. 64. Page 64 • In the future, a range of HMTs targeting different aspects of the destructive cascade of breakdown events in the periodontal tissues are likely to be developed as adjunctive treatments for periodontitis • The goal is to maximize the treatment response by reducing inflammation and inhibiting destructive processes in the tissues, which will result in enhanced periodontal stability after conventional periodontal treatments such as SRP and surgery.
  65. 65. Page 65 • the use of HMT to better manage chronic periodontal disease have applications to other chronic systemic diseases such as arthritis, diabetes, osteoporosis, and cardiovascular disease. • In addition, studies utilizing locally applied antimicrobials as part of an intensive periodontal therapy (IPT) regimen have shown very promising results both in periodontal disease and overall health status of high risk patients.. • The proper management of local infection and inflammation (periodontitis) will have a significant impact on general overall health of the population.
  66. 66. Page 66
  67. 67. Page 67 • The three main sub-families of MAPKs are extracellular- regulated kinases (ERK-1/-2), c-Jun N-terminal activated kinases (JNK) and p38.
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