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Thalidomide:
Past, Present & FuturePast, Present & FutureBy Monica DuarteBy Monica Duarte
http://mde124.tripod.comhttp://mde124.tripod.com
1. History of Thalidomide: Harmful effects that 1. History of Thalidomide: Harmful effects that
lead to the ban in 1962.lead to the ban in 1962.
2. Structure of Thalidomide: Chemical make up and 2. Structure of Thalidomide: Chemical make up and chirality/enantiomer issue that led to problems.chirality/enantiomer issue that led to problems.
3. Thalidomide makes a comeback in 1998 with the 3. Thalidomide makes a comeback in 1998 with the approval by the FDA: current uses of the drug. approval by the FDA: current uses of the drug.
4. Celgene Corporation- Manufactures of new 4. Celgene Corporation- Manufactures of new Thalidomide family, ThalomidThalidomide family, Thalomid TM TM
5. S.T.E.P.S Program developed by Celgene to 5. S.T.E.P.S Program developed by Celgene to regulate Thalomidregulate Thalomid TM TM distribution distribution
6. Future of Thalidomide 6. Future of Thalidomide
•
ThalidomideThalidomide
1953- Originally synthesized by Ciba, a Swiss pharmaceutical company
1954-Chemie Grurnrnthal, German Pharmaceutical company, assumed developed
of Thalidomide.
1957-Mass production & distribution throughout Europe by Chemie.
Thalidomide
Promoted 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.
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)
History (Continued)
Approximately 10,000 “Thalidomide Approximately 10,000 “Thalidomide Babies” were born throughout 43 countriesBabies” were born throughout 43 countries
A number of infants were born with a A number of infants were born with a severe deformity of the limbs severe deformity of the limbs
The drug restricted the growth of rapidly The drug restricted the growth of rapidly growing blood vessels in developing limbs growing blood vessels in developing limbs and organsand organs
CHEMISTRY OF
THALIDOMIDE
(Courtesy of: http://www.rlc.dcccd.edu/MATHSCI/reynolds/thalidomide/chemistry/chemistry.htm)
Problem with Thalidomide
R-complex (desired effect)R-complex (desired effect)
L-complex (created fetal abnormalities)L-complex (created fetal abnormalities)
Spontaneous interconversion Spontaneous interconversion lead to a racemic mixture (50/50).lead to a racemic mixture (50/50).
How Thalidomide Works:
1. Reduces production of TNF-1. Reduces production of TNF-α α (Tumor Necrosis Factor (Tumor Necrosis Factor --α )α )
Thalidomide works as immunomodulatoryThalidomide works as immunomodulatory
2. Inhibits growth of new blood vessels2. Inhibits growth of new blood vessels
3. Works as anti-inflammatory3. Works as anti-inflammatory
Mechanism of action not exactly understood Mechanism of action not exactly understood
Current uses under “Orphan” drug basis
HIV-Associated HIV-Associated wasting syndromewasting syndrome
Aphthous ulcersAphthous ulcers Behcets’s sydromeBehcets’s sydrome Crohn’s diseaseCrohn’s disease
Kaposi’s saracoma-Kaposi’s saracoma-AIDS related cancerAIDS related cancer
Celgene Corporation
Manufactures of new family, derivative of Manufactures of new family, derivative of Thalidomide called Thalomid.Thalidomide called Thalomid.
Same chiralitySame chirality Still racemic mixtureStill racemic mixture Same side effectsSame side effects Same chemical structureSame chemical structure
S.T.E.P.S Program
SSystem for ystem for TThalidomide halidomide EEducation and ducation and PPrescribing rescribing SSafetyafety
A program created by Celgene in A program created by Celgene in conjunction with FDAconjunction with FDA
S.T.E.P.S Guidelines
Patient RegistrationPatient Registration
Physician educationPhysician education
Patient educationPatient education
Patient counselingPatient counseling
Females: monthly Females: monthly pregnancy testing and pregnancy testing and birth control measuresbirth control measures
Patient consent formPatient consent form
Limits authorized Limits authorized prescribers and prescribers and pharmacies pharmacies
Discovery and development of new classes by Celgene Co.
IMiDs-immunomodulatory drugsIMiDs-immunomodulatory drugs
SelCIDs-Selective Cykotine Inhibitory Drugs SelCIDs-Selective Cykotine Inhibitory Drugs
Both have been found to be significantly more Both have been found to be significantly more potent in vitro inhibitors of TNF-potent in vitro inhibitors of TNF- α α than Thalomid than Thalomid
Currently being studied for future uses:
Multiple Sclerosis Multiple Sclerosis
CancerCancer
Multiple MyelomaMultiple Myeloma
Breast Breast
Prostate Prostate
Rheumatoid arthritisRheumatoid arthritis
Ankylosing Ankylosing
spondylitisspondylitis
HIV/AIDS HIV/AIDS
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)