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Diacerein

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  • 1. Osteoarthritis The need for innovative therapeutic options?
  • 2. OA – current status
    • OA  decreased mobility and decreased quality of life
      • Treatment is towards treating OA symptoms only
      • Significant unmet medical & society need exists for disease modifying OA drugs (DMOADs) that lead to clinically relevant functional improvement
  • 3. OA – multiple spheres of influence
  • 4. OA – multiple influences Injury Obesity Biomechanics Genetics Age / Sex Metabolic abnormalities Subchondral bone changes
  • 5. OA - approaches
    • Painkillers, NSAIDs or anticytokines?
    • SYSADOA - Slow-acting symptomatic drugs for OSTEOARTHRITIS
      • called slow action as opposed to traditional analgesics, whose onset is immediate, because the clinical effect occurs several weeks after starting treatment and are temporarily after removal.
      • used as symptomatic treatment of osteoarthritis, for reducing pain and improving function, and are postulated as possible disease-modifying or chondroprotective, because delay progression of articular cartilage deterioration.
      • diacerein is a drug synthesis inhibitory activity of interleukin-1, substance involved in inflammation and cartilage degradation
  • 6. DMOADs DMOADs What they need to do How they need to do Delay structural progression Prevent the OA Effect on Radiographic Joint Space Narrowing (JSN) Effect on progression to control JSN and pain / function relation Halting progression (improving the x-ray) Reversing progression (normalizing the x-ray)
  • 7. Diacerein
    • Diacerein is distinct from all other painkillers & joints treatments due to its ability to reduce joint inflammation and pain, without having negative side effects on the stomach, blood pressure or heart.
    • Diacerein inhibits the production of ‘Interleukin – 1 beta’, the protein in the human body, which causes osteoarthritis and joint inflammation.
  • 8. Role of IL-1
  • 9. Role of different therapies
  • 10. Role of different therapies Diacerein Steroids NSAIDs
  • 11. DMOAD clinical targets
  • 12. DMOAD clinical targets
  • 13. DMOAD clinical trials
  • 14. DMOAD clinical trials
  • 15. What did we learn
    • Chronic administration = must for response;
    • Subjects with less-advanced disease before the development of marked aberrant mechanics give maximum response;
    • Typically select knees with moderate to severe OA (KLG3) so that progression can be measured
    • Disease too advanced: too late for pharmacological interventions
  • 16. What did we learn
    • OA is a disease of the whole joint not just articular cartilage and meniscus
      • Subchondral bone, synovium, ligaments, capsule…
    • Therapies likely to affect cartilage/meniscus prevent whole joint damage
    • JSW -> meniscal lesions /extrusions + cartilage degenerative changes
    • It is a weight-bearing measurement -> mechanical properties, whose quantitative measurements = Min JSW, Mean JSW, JSW at fixed locations.
  • 17. Diacerein as a DMOAD
    • A systematic meta-analysis on randomized controlled trials with diacerein was performed to provide an evidence-based assessment of its symptomatic efficacy in the treatment of osteoarthritis.
    • A total of 23 studies were identified, 19 of which were included
    Arch Intern Med. 2006;166:1899-1906
  • 18. Diacerein as a DMOAD
    • Diacerein was significantly superior to placebo during the active treatment phase (Glass score, 1.50 [95% confidence interval, 0.80-2.20]).
      • Both diacerein and nonsteroidal anti--nflammatory drugs (NSAIDs) were similarly efficacious during the treatment period;
      • however, diacerein, but not NSAIDs, showed a carryover effect, persisting up to 3 months after treatment, with a significant analgesic-sparing effect during the follow-up period.
    Arch Intern Med. 2006;166:1899-1906
  • 19. Case study 1 – before & after therapy with diacerein Before treatment After treatment
  • 20. Case study 2 – before & after therapy with diacerein Before treatment After treatment
  • 21. Case study 3 – before & after therapy with diacerein Before treatment After treatment
  • 22. Study1 Arch Intern Med. 2006;166:1899-1906
  • 23. Study2 Arch Intern Med. 2006;166:1899-1906
  • 24. Study3 Arch Intern Med. 2006;166:1899-1906
  • 25. Study4 Arch Intern Med. 2006;166:1899-1906
  • 26. Study5 Arch Intern Med. 2006;166:1899-1906
  • 27. Study6 Arch Intern Med. 2006;166:1899-1906
  • 28. Study7
    • In a study (ECHODIAH) conducted to evaluate the effect of diacerein in a patient of hip Osteoarthritis over a 3 year period using progression of joint space narrowing as assessment criteria, it has been found that mean progression of narrowing was significantly less in patients treated with diacerein from 0.18 per year to 0.13 per year at the end of third year.
  • 29. Summary of the studies
    • For diacerein, this meta-analysis provides evidence for a superiority over placebo and an equality with NSAIDs with respect to improvement in pain and function during the active treatment period in patients with osteoarthritis of the hip and/or knee.
    • Moreover, diacerein was superior to placebo and NSAIDs during the follow-up period with an NSAID-sparing effect, indicating that the drug has a carryover effect.
  • 30. Summary of the studies
  • 31. Diacerein - pharmacology
    • Diacerein has efficacy on functional manifestations of osteoarthritis and on structural component.
    • Diacerien is a prodrug and acts by getting converted to its active metabolite - rhein before reaching systemic circulation & then exerts its pharmacologic action.
      • Rhein later gets eliminated by renal route (20%) or conjugated in liver to rhein glucronide (60%) and rhein sulphate (20%)
      • Metabolites mainly eliminated by renal route
  • 32. Diacerein - pharmacokinetics
    • Oral diacerein undergoes complete de-acetylation to its active metabolite rhein
    • Cmax of rhein : 3.2mg/L
    • Tmax : 2.2 hrs after single oral dose of 50mg
    • Elimination half life : 4.3 hrs
    • Time to Cmax & AUC increase by concomitant food, indicating slower absorption & greater bioavailability
  • 33. Diacerein – anabolic effects
    • Diacerein has beneficial effects on the anabolic processes that occur in the cartilage.
    • It increases the production of transforming growth factor-β (TGF-β) that triggers chondrocyte proliferation and stimulates the production of collagen & proteoglycan.
  • 34. Diacerein - tolerability
    • Diacerein is well tolerated with the only prominent side-effect being a mild and transient laxative effect. This is due to the chemical nature of the product and is an expected side-effect.
    • Excellent gastro-duodenal tolerability as it does not inhibit the synthesis of PGs, and hence no gastric irritation.
  • 35. Diacerein - precautions
    • Adverse effects – Diarrhea, discoloration of urine, gastralgia, dyspepsia, allergic skin reactions.
    • Dosage of diacerein should be reduced by 50% in patients with severe renal failure
    • Dosage adjustment is not required for hepatic impaired patients
    • AUC values of diacerein increase by 40-58% in elderly (>60 years) patients.
  • 36. Diacerein - MOA
    • Diacerein directly inhibits IL-1 synthesis and release in vitro &down modulate IL-1 induced activities.
      • IL-1 plays a fundamental role in OA patho-physiology and cartilage destruction & also promotes expression of inducible nitric oxide synthase [iNOS], increases release of prostaglandin E2, IL-6,IL-8 in human OA chondrocytes, which promote joint degradation.
  • 37. Diacerein - MOA
    • Diacerein directly inhibits IL-1 synthesis and release in vitro &down modulate IL-1 induced activities.
      • Diacerein also inhibits IL-1 induced expression of cartilage degrading enzymes.
      • It also inhibits superoxide production, chemotaxis and phagocytic activity of neutrophils in addition to effect on macrophage migration and phagocytosis.
      • In contrast to NSAIDS diacerein does not inhibit synthsis of prostaglandins.
  • 38. Diacerein - MOA
    • Hence, by inhibiting IL-1 diacerein retards all pathological prepossess initiated in OA.
    • Drugs like diacerein have gradual onset of action (4-6 weeks) but maintain their symptomatic effect for a period of 4-8 weeks after cessation of treatment.
  • 39. Diacerein - dosage
    • The optimal daily dosage of diacerein for patients with knee OA is 100 mg/day (50 mg twice daily).
    • To reduce the incidences of diarrhea, begin with 50mg once a day for one week, then 50mg twice a day from the second week.

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