Thalidomide

1
Thalidomide

• The Wonder Drug Gone Wrong
• Jen McGowan, Sarah Patterson, Chip Smith

2
Drug Development

• Stolberg, Germany 1954
• Chemie Grünenthal
• Desired low-cost method production of antibiotics
  made from peptides
• Patented a-phthalimidoglutarimide (thalidomide)
• Unable to demonstrate antibiotic activity or any
  medicinal or sedative effects in mice or rats
• Extremely high doses were not fatal nor were
  other side effects detected in animal testing
• Therefore, thalidomide described as nontoxic

3
Manipulation of Thalidomide Test Results

• Early 1955, exploration of possibility of human
  sedative through distribution of free samples
• First prescribed for epileptic seizures
• Patients reported calming and sleep-inducing
  effects
• Germany required confirmation of the purported
  effect on animals
• Grünenthal researchers invented jiggle cage
• Explicit claim of safety lead to sale even
  sometimes as an OTC

4

• Racemic mixture of glutamic acid
• 11 mix of enantiomers (R,S)
• R() acts as sedative, probably mediated by sleep
  receptors in the forebrain
• S(-) potently inhibits the release of alpha
  tumor necrosis factor (THF-a)

5
TNF-a gene

• Genetic Location 6p21.3
• Encodes for synthesis of the cytokine tumor
  necrosis factor (TNF- a)

6
Biological Characteristics of Thalidomide

• TNF-a induces transcription factor NF-kB activate
  expression of genes
• Cell growth
• Suppression of apoptosis
• Metastasis
• Immune and inflammatory responses
• Thalidomide decreases TNF-a production by
  accelerating the degradation of the encoding mRNA

7
The Damage

• 10,000-12,000 thalidomide babies
• 46 affected countries
• Drawn-out legal battles
• Disrupted families

8
Symptom Pattern

• Phocomelia, flippers, or missing limbs
• Abnormal number of digits
• Missing/malformed eye(s) and ear(s)
• Anal atresia
• Brain damage/autism

9
Negative Family Dynamic

• Divorce
• Abandonment
• Suicide (rare, but occurred)
• Sibling Resentment
• Infanticide (Belgium case)

10
Victims Struggles

• Resentment
• Artificial limbs
• Schooling
• Self-sufficiency

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Thalidomide Today

• What was once the most feared drug in
  pharmaceutical armory could become one of its
  most valuable.
• Researchers look at the interactions that caused
  deformities to discover the safety of the drug in
  other uses

15
Current Uses

• Cancer treatment
• Inhibit tumors directly
• Drug will stop blood vessels from forming in and
  around tumors
• Activate immune system
• Anti-inflammatory
• Promising results seen in most intractable
  cancers

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Other Promising Uses

• Standard Treatment for leprosy (ENL)
• Drug is FDA approved for ENL
• Changes bodys immunological and inflammatory
  response to bacteria
• Used to heal lesions and skin ulcerations
• Currently used in some HIV patients
• Heal ulcers
• Diminish lean body mass loss during wasting
  stages

17
Potential Future Uses

• Autoimmune disorders
• HIV, Behcets disease, and Crohns disease
• Apthous and genital ulcers
• Chronic graft versus host diseases

18
Approval of Drug Presents Controversy

• Effective drug but still apparent fears of
  defects
• History of teratogenicity
• Difficult issue to face since 5,000 survivors are
  still alive and reaching middle age
• Thalidomiders believe licensed thalidomide will
  mean more thalidomide babies

19
Precautions and Concerns

• Required pregnancy test in most cases
• Contraceptives must be accessible
• Education of the drug required
• The drug has potential to stay in body for years
• Drug may enter semen and men could affect female
  partners

20
References

• Conover, Elizabeth A. Guarding against fetal
  toxins. (includes related articles). RN 57.
• n 7 (July 1994) 28(7). Health Reference Center
  Academic. Thomson Gale.Hamilton College. 16
  November 2005 http//find.galegroup.com/itx/infoma
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  16142628sourcegalesrcprodHRCAuserGroupNameny
  sl_ce_hamiltonversion1.0gt.
• Knightly, Phillip, Harold Evans, Elain Potter and
  Marjorie Wallace. Suffer the Children The
  Story of Thalidomide. New York Viking Press,
  1979.
• Kulkami, Kathy. Thalidomide. The Network News
  23.n1 (Jan-Feb 1998) 4 (2). Health
• Reference Center Academic. Thomsn
  Gale. Hamilton College. 16 November 2005
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• Nippert, I. 40 years later The health related
  quality of life of women affected byThalidomide.
  American Journal of Human Genetics 67.4 (Oct
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  Thomson Gale. Hamilton College. 16 November 2005.
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• Noble, Kate. Bad Drug Makes Good Thalidomide,
  once the most feared medications, is now showing
  promise as a cancer treatment. Time Europe
  2/3/2003. 16 November 2005 lthttp//www.time.com/t
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  5,901030203-411395,00.htmlgt.
• Stephens, Trent and Rock Brynner. Dark Remedy
  The Impact of Thalidomide and Its Revival as a
  Vital Medicine. Cambridge Perseus Publishing,
  2001.
• Thalidomide. Franks, Michael E., Gordon R.
  Macpherson, and Willliam D Figg. The Lancet.
  Vol 363. 29 May 2004. ltwww.thelancet.comgt.
• Thalidomide Plus 25. 60 Minutes. Producer
  Jeanne Solomon Langley. ND.
• The Schizophrenic Career of a Monster Drug.
  Pediatrics. Vol. 110. Aug. 2002.
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  /full/110/2/404gt.
• Wallace, Marjorie. On Giants Shoulders The
  Story of Terry Wiles. London Times Books,
  1976.
• www.google.com/images/thalidomide.html
• www.ingenious.org.uk/.../ 1040/6/10406363_3.jpg
• www.mcl.tulane.edu/classware/pathology/Krause/Bloo
  d/HP.html
• www.microvet.arizona.edu/Courses/MIC419/Tutorials/
  cytokines.html
• www.milligazette.com/ images2002/60thalidomide.