Thalidomide:

1. Thalidomide: Past, Present & Future By Monica Duarte http://mde124.tripod.com

2. 1.   History of Thalidomide: Harmful effects that lead to the ban in 1962. 2. Structure of Thalidomide: Chemical make up and chirality/enantiomer issue that led to problems. 3.   Thalidomide makes a comeback in 1998 with the approval by the FDA: current uses of the drug. 4.   Celgene Corporation- Manufactures of new Thalidomide family, Thalomid TM 5.   S.T.E.P.S Program developed by Celgene to regulate Thalomid TM distribution 6.   Future of Thalidomide

3. PAST (Photo Courtesy of: http://pubs.acs.org/hotartcl/mdd/00/jun/mddkling.html)

4. Thalidomide1953- Originally synthesized by Ciba, a Swiss pharmaceutical company1954-Chemie Grurnrnthal, German Pharmaceutical company, assumed developed of Thalidomide.1957-Mass production & distribution throughout Europe by Chemie.

5. ThalidomidePromoted by maker as being nontoxic, with no side effects and completely safe for pregnant women.1960-Distributed throughout Australia, Asia, Africa, Canada (total of 43 nations)1957-1962 given to pregnant women primarily as a sedative, a sleeping pill, aid with morning sickness.

6. US FDA did not approve Thalidomide for use in America.Dr. Frances Kelsey (Photo courteous: http://www.tlchm.bris.ac.uk/motm/thalidomide/effects.html)

7. (Courtesy of: http://teratology.org/jfs/ThalidomidePics.html)

8. (Photo Courtesy of: http://www.tlchm.bris.ac.uk/motm/thalidomide/first.html)

9. History (Continued) • Approximately 10,000 “Thalidomide Babies” were born throughout 43 countries • A number of infants were born with a severe deformity of the limbs • The drug restricted the growth of rapidly growing blood vessels in developing limbs and organs

10. (Courtesy of: http://www.thehistorychannel.co.uk/photos/24hour2.htm)

11. (Photo courtesy of: http://colossus.chem.umass.edu/genchem/chem102/Articles/thalid.htm)

12. Worldwide Ban 1962

13. CHEMISTRY OF THALIDOMIDE (Courtesy of: http://www.rlc.dcccd.edu/MATHSCI/reynolds/thalidomide/chemistry/chemistry.htm)

14. Problem with ThalidomideChirality & Enantiomer issues

15. (Courtesy of http//www.ric.dccd.edu/mathsci/reynolds/thalidomide/chemistry/chemistry.htm)

16. Problem with Thalidomide • R-complex (desired effect) • L-complex (created fetal abnormalities) • Spontaneous interconversion lead to a racemic mixture (50/50).

17. 1998 The Comeback of Thalidomide as ThalomidTM

18. FDA approves use of Thalidomideto treat Erythema Nodosum Leprosum (ENL) July 1998

19. How Thalidomide Works: 1. Reduces production of TNF-α (Tumor Necrosis Factor -α ) Thalidomide works as immunomodulatory 2. Inhibits growth of new blood vessels 3. Works as anti-inflammatory Mechanism of action not exactly understood

20. PRESENT

21. HIV-Associated wasting syndrome Aphthous ulcers Behcets’s sydrome Crohn’s disease Kaposi’s saracoma-AIDS related cancer Current uses under “Orphan” drug basis

22. Celgene Corporation • Manufactures of new family, derivative of Thalidomide called Thalomid. • Same chirality • Still racemic mixture • Same side effects • Same chemical structure

23. ThalomidTM (Courtesy of http://www.studentbmj.com/back_issues/1099/education/368.html)

24. S.T.E.P.S Program • System for Thalidomide Education and Prescribing Safety • A program created by Celgene in conjunction with FDA

25. Patient Registration Physician education Patient education Patient counseling Females: monthly pregnancy testing and birth control measures Patient consent form Limits authorized prescribers and pharmacies S.T.E.P.S Guidelines

26. FUTURE

27. Discovery and development of new classes by Celgene Co. • IMiDs-immunomodulatory drugs • SelCIDs-Selective Cykotine Inhibitory Drugs • Both have been found to be significantly more potent in vitro inhibitors of TNF- α than Thalomid

28. Multiple Sclerosis Cancer Multiple Myeloma Breast Prostate Rheumatoid arthritis Ankylosing spondylitis HIV/AIDS Currently being studied for future uses:

29. THE END (Courtesy of: http://pubs.acs.org/hotartcl/mdd/00/jun/mddkling.html)

30. Bibliography Agarwal, M.B. Thalidomide: An old wine in new bottle. JAPI, vol.51, p.597-604, 2003 Author unknown. Thalidomide Pros and Cons. American Journal of Nursing, vol.98(4),p.63,1998. Dally, A. Thalidomide: was the tragedy preventable? Lancet, vol. 351, p.1197-1199, 1998. Hamuryudan, V. Thalidomide in the treatment of the mucocutaneous lesions of the Behcet syndrome: a randomized, double-bind, placebo-controlled trial. The Journal of the American Medical Association, vol. 279(18), p. 1422G(1),1998. Jacobson, J., Greenspan, J., & Spritzler, J. Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. The New England Journal of Medicine, vol.336(21), p.1487(7). Kling, Jim. Redeeming Thalidomide. Modern Drug Discovery, vol.3(5), p.35-39,2000 Marwick, C. Thalidomide back-under strict control. The Journal of the American Medical Association, vol.278(14),p.1135(3),1197. Patil, C.R. & Bhise, S.B. Indian Jornal of Pharmacology, vol. 35, p. 204-212, 2003. Stambe, C. & Wicks, I. TNFa and response of treatment-resistant adult-onset Still disease to thalidomide. Lancet, vol.352(28), p.544. Photos from the web (Photo courteous: http://www.tlchm.bris.ac.uk/motm/thalidomide/effects.html) (Photo courteous: http://www.tlchm.bris.ac.uk/motm/thalidomide/effects.html)