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Section C
Thalidomide
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Thalidomide: “Perhaps the Most Infamous Drug in Medical History”
! Produced by German company, Chemie Grünenthal
! Released to market in Germany on October 1, 1957
Source: TD Stephens et al. (2000). Biochem Pharm, 59: 1489; T Stephens and R Brynner. (2001). Dark Remedy: The Impact of Thalidomide and its Revival.
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Thalidomide: Properties and Effects
! Chemical properties: lipophilic,
insoluble, unstable
Thalidomide
! Clinical effects—humans
! Sedation/anxiolytic; antiemetic
! Effects in rats
! Sedation
! Virtually non-toxic in adult rats
! Effects on development not tested
S enantiomer—teratogen
Image source: http://www.toxipedia.org/
R enantiomer—non toxic
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Discovery of Side Effects
! Ultimate distribution to 50 countries
! Adverse health effects
! Intolerance
! Peripheral neuropathy
! Birth defects
! “Thalidomide syndrome”
! 20% embryopathy on exposure in
utero (http://www.fetalexposure.org/)
! 10,000 children recorded with
“thalidomide syndrome”
! First in 1956: born without ears
! Approximately 5,000 survived
• Amelia
• Phocomelia
• Other effects: respiratory,
cardiovascular, urogenital
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Sales of
Thalidomide and
Incidence of
Malformations
This image can not be provided
due to copyright
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Timetable of
Human
Malformations
with
Thalidomide:
Period of
Sensitivity
Defect
Duplication of thumbs
Drug administration
(days after menstruation)
34–38
Abnormal ears (anotia)
Heart and vessel anomalies
36–45
Renal defects
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Amelia, arms
38–43
Phocomelia, arms
38–47
Duodenal and gall bladder atresia
40–45
Urogenital and respiratory defects
41–43
Phocomelia, legs
42–47
Rectal stenosis
Triphalangism, thumbs
49–50
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Thalidomide in the United States
! Did not receive FDA approval in United States
! Dr. Frances Kelsey
! Kelsey received the President’s Award for
Distinguished Federal Civilian Service at a 1962
ceremony with President John F. Kennedy
Source: http://en.wikipedia.org/wiki/Thalidomide
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Current Clinical Uses of Thalidomide
! Advanced leprosy, 1964
! Serendipitous discovery by an
Israeli physician
! Two leading causes of blindness
! Diabetic retinopathy
! Macular degeneration
! Graft vs. host disease
! Certain cancers
! Multiple myeloma
! Other bone marrow failure diseases
and hematological malignancies
• For example, myelofibrosis;
myelodysplastic syndrome (MDS)
! Aphthous ulcers, wasting, and HIV
replication in AIDS
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Mechanisms of Action
! Metabolism
! Immunomodulation: reduction of TNFα—reduction in inflammation
! Inhibition of angiogenesis (blood vessel formation)
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Mechanisms of Action
! Inhibition of IGF-1 and FGF-2 (growth factors) expression and effects
! Intercalation into DNA at GGGCGC sequences (GC boxes) in promoter regions
! Specific inhibition of gene expression
! Leads to abnormal regulation of the BMP and fgf8 signaling pathways and of
developmental programs that require their normal functions
! Binds to cereblon (CRBN), a protein involved in the ubiquination of proteins destined
for degradation
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Thalidomide
Binding to
Cereblon Block
Limb
Development
! Expression of a drug binding–deficient form of CRBN
suppresses thalidomide-induced limb malformations in
chicks (below)
This image can not be provided
due to copyright
Source: (2010). Science, 327, 1345.
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