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Thalidomide

Thalidomide. The “Wonder Drug” Gone Wrong 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)

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Thalidomide

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  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 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”

  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 • 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)

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

  6. 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

  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

  11. 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

  12. 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

  13. 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

  14. Potential Future Uses • Autoimmune disorders • HIV, Behcet’s disease, and Crohn’s disease • Apthous and genital ulcers • Chronic graft versus host diseases

  15. 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

  16. 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

  17. 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&source=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.

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