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

PASTPAST

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

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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)

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

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

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

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

Worldwide Ban 1962

                    

CHEMISTRY OF

THALIDOMIDE

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

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Problem with Thalidomide

Chirality & Enantiomer issues

(Courtesy of http//www.ric.dccd.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).

1998

The Comeback of ThalidomideThe Comeback of Thalidomide

as Thalomidas ThalomidTMTM

FDA approves use of Thalidomideto treat Erythema Nodosum Leprosum

(ENL) July 1998

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

PRESENT

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

ThalomidTM

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

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

FUTURE

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

THE END

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

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)