Thalidomide The “Wonder Drug” Gone Wrong Jen McGowan, Sarah Patterson, Chip Smith.

ThalidomideThe “Wonder Drug” Gone Wrong

Jen McGowan, Sarah Patterson, Chip Smith

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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)

• Genetic Location: 6p21.3

• Encodes for synthesis of the cytokine tumor necrosis factor (TNF- α)

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<=TNF£\

gene TNF-α gene

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

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