Thalidomide The Wonder Drug Gone Wrong Jen Mc

Thalidomide The “Wonder Drug” Gone Wrong Jen Mc. Gowan, 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 • Genetic Location: 6 p 21. 3 • Encodes for synthesis of the cytokine tumor necrosis factor (TNF- α)

Biological Characteristics of Thalidomide • TNF-α induces transcription factor NF-k. B 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 m. RNA

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

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

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