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Thalidomide
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- 2. Contents • Introduction • Thalidomidepharmacology • Thalidomide revival • Thalidomide today
- 3. Historic perspective • Developedby Swiss pharmaceutical company CIBA -1953 • German pharmaceutical company Chemi Grunenthal – 1956 • Contergan
- 4. Cont…. Median lethal dose •Morning sickness
- 5. Dr William McBrideDr Widukind Lenz
- 6. Cont….. • Amelia • Phocomelia •Syndactyly • Underdeveloped long bones
- 7. 10,000 infants affected 1961–THALIDOMIDE Banned
- 8. DIRECT RESULT- THALIDOMIDEINCIDENT • USA - 1962 amendment to Federal Food, drug & Cosmetic Act • UK - 1964 Yellow card scheme • WHO - 1968 Program for International Drug Monitoring
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- 12. Cont….. • Poorly solublein water and ethanol • Undergoes rapid spontaneous (nonenzymatic) degradation • Rapid chiral interconversion between the two isomers
- 13. Proposed mechanisms ofaction • Enhances the immune system effector cells • Suppresses angiogenesis • Inhibits various cytokine mediators • Interferes with the bone marrow stromal cell-malignant plasma cell interaction
- 15. Pharmacological properties • Anxiolytic •Antiemetic • Anti-inflammatory • Cytokine (TNFα, ILs, interferon) modulatory property
- 16. Pharmacokinetics • Tmax -2.9 to 5.7 hours • PPB 55% and 66%, respectively, for (+)-(R)- and (-)-(S)-thalidomide • Metabolism - Hepatic – CYP3A4 - Non enzymatic degradation - End Product - Phthalic Acid
- 17. Toxicity Teratogenicity Peripheral neuropathy Toxic epidermalnecrolysis Tremor Interstitial pneumonia
- 18. DRUG INTERACTIONS Opioids, antihistamines,antipsychotics, anti-anxiety agents, Alcohol Additive sedative effect Bortezomib, amiodarone, cisplatin, docetaxel, paclitaxel Peripheral neuropathy Additive effect Hormonal contraceptives Risk of thromboembolism
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- 20. Cont…. Dr Jacob Sheskin(1964) Erythema nodosum leprosum (ENL) Resolution(48 hours)
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- 22. Cont….. Chronic graft-versus-host disease (GVHD) 200-1600 mg per day Higher incidence of chronic GVHD and a lower overall survival
- 23. Cont…. • Thalidomide emergedas an effective drug • HIV wasting syndrome • Kaposi's sarcoma • Aphthous ulcer
- 24. Immunomodulatory derivatives Lenalidomide (Revlimid,CC-5013) Pomalidomide (CC-4047)
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- 27. Myelodysplastic syndrome (with5q- syndrome) Anticytokine immunomodulatory and anti-angiogenic properties FDA approval -2005 Lenalidomide (Revlimid)
- 28. Plasma cell myeloma May2006 – FDA Approval Newly diagnosed plasma cell myeloma Thalidomide + Dexamethasone Pomalidomide FDA – FEB 2013 Relapsed and refractory multiple myeloma
- 31. Gastrointestinal • Behcet's disease. •Recurrent aphthous oral ulceration. • HIV associated oral and esophageal ulceration. • Crohn’s disease.
- 32. Rheumatological • Rheumatoid arthritis. •Systemic lupus erythematosus. • Discoid lupus erythematosus. • Sjogren's syndrome. • Sarcoidosis.
- 33. Dermatological • Leprosy • Actinicpruritis • Pyoderma gangrenosum
- 34. Hematological malignancy • Multiplemyeloma • Myelodysplasia • Acute myeloid leukemia/chronic myeloid leukemia
- 35. Cachexia and weightloss • HIV associated wasting • Cancer cachexia • Tuberculosis associated wasting
- 36. Miscellaneous • Graft versushost disease
- 37. Summary • Phocomelia • Anxiolytic •Antiemetic • Anti-inflammatory • Cytokine (TNFα, ILs, interferon) modulatory property
- 38. Reference 1. The Rise,Fall and Subsequent Triumph of Thalidomide: Lessons Learned in Drug Development doi: 10.1177/2040620711413165 2. Goodman & Gilman's: The Pharmacological Basis of Therapeutics 3. Essentials of Medical Pharmacology KDT
- 39. No limits :The ThalidomideSaga (2016)
Editor's Notes
- #4 Nonbarbiturate hypnotic sedative able to produce deep sleep
- #7 White arrow: fusion at the elbow joint and absence of fingers; Yellow arrow: absence of radius and shortening of ulna
- #10 John F. Kennedy in 1962
- #12 The (R)-form is responsible for sedative effects and the (S)-form is responsible for immunomodulatory effects.
- #13 Off-white to white crystalline powder
- #20 Despite being banned from commercial markets, thalidomide remained available primarily in developing countries
- #21 World Health Organization published the results of a randomized trial that confirmed the efficacy of thalidomide in ENL1971