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Thalidomide
The “Wonder Drug” Gone Wrong
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Jen McGowan, Sarah Patterson, Chip Smith
Drug Development
•Stolberg, Germany 1954
•Chemie Grünenthal
–Desired low-cost method production of antibiotics
made from peptides
–Patented α-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”
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
• Racemic mixture of
glutamic acid
– 1:1 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-α)
TNF-α gene
gene
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• Genetic Location: 6p21.3
• Encodes for synthesis of
the cytokine tumor
necrosis factor (TNF- α)
<=TNF£\
Biological Characteristics of
Thalidomide
• TNF-α induces transcription factor NF-kB
activate expression of genes
– Cell growth
– Suppression of apoptosis
– Metastasis
– Immune and inflammatory responses
• Thalidomide decreases TNF-α production by
accelerating the degradation of the encoding
mRNA
The Damage
• 10,000-12,000 thalidomide babies
• 46 affected countries
• Drawn-out legal battles
• Disrupted families
Symptom Pattern
• Phocomelia, flippers, or missing limbs
• Abnormal number of digits
• Missing/malformed eye(s) and ear(s)
• Anal atresia
• Brain damage/autism
Negative Family
Dynamic
• Divorce
• Abandonment
• Suicide (rare, but occurred)
• Sibling Resentment
• Infanticide (Belgium case)
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
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
Other Promising Uses
• Standard Treatment for leprosy (ENL)
– Drug is FDA approved for ENL
– Changes body’s 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
Potential Future Uses
• Autoimmune disorders
– HIV, Behcet’s disease, and Crohn’s
disease
• Apthous and genital ulcers
• Chronic graft versus host diseases
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
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
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/infomark.do?type=retrieve&tabID=T002&prodId=HRCA&docId=A16142628&sou
rce=gale&srcprod=HRCA&userGroupName=nysl_ce_hamilton&version=1.0>.
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
<http://find.galegroup.com/itx/infomark.do?&type=retrieve&tabID=T002& prodId=HRCA&docId=
A20842663source=gale&srcprod=HCRA&userGroupName=nysl_ce_hamilton&version=1.0>.
Nippert, I. “40 years later: The health related quality of life of women affected byThalidomide.” American Journal of
Human Genetics 67.4 (Oct 2000): 134. Health Reference Center Academic. Thomson Gale. Hamilton
College. 16 November 2005. <http://find.galegroup.com/itx/infomark.do?type=retrieve&tabID=T002&prodId
=HRCA&docId=
A66669545&source=gale&srcprod=HRCA&userGroupName=nysl_ce_hamilton&version=1.0>.
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
<http://www.time.com/time/europe/magazine/article/0,1300 5,901030203-411395,00.html>.
Stephens, Trent and Rock Brynner. Dark Remedy: The Impact of Thalidomide and It’s 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. <www.thelancet.com>.
“Thalidomide Plus 25.” 60 Minutes. Producer Jeanne Solomon Langley. ND.
“The Schizophrenic Career of a “Monster Drug.” Pediatrics. Vol. 110. Aug. 2002.
<http://pediatrics.aappublications.org/cgi/content/full/110/2/404>.
Wallace, Marjorie. On Giant’s 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/Blood/HP.html
www.microvet.arizona.edu/Courses/MIC419/Tutorials/cytokines.html
www.milligazette.com/ images2002/60thalidomide.