“Dark Remedy: The Impact of Thalidomide and its Revival as a Vital Medicine,” by Trent Stephens and Rock Brynner, Perseus Publishing, Cambridge, MA, 2001. This 228-page hardback is the story of thalidomide, the drug that produced serious birth defects in the 1960s.
Thalidomide was discovered by Chemie Gruenthal in Germany. They began to market it as a non-toxic tranquillizer and sleeping pill in 1957. Its major selling point was low toxicity. No dose was found that killed test animals. At the time, barbituates were commonly prescribed and they were often used for suicide. Little testing was required. The marketing program consisted of a large sampling program to physicians. Who got the samples was rarely recorded.
In UK, Distillers began investigation and distribution throughout the British Empire as Distoval. In the US, it was Merrill-Richardson, the former Vick Chemical Company, maker of Vicks Vaporub, under the name Kevadon. They filed an application with FDA in 1960. Astra had distribution in Scandinavia.
The first sign of trouble came in 1956 when a baby girl was born without ears. Numbness and tingling in feet was the most common complaint. The neuritis did not stop when the medication was stopped. Reports of peripheral neuritis began to accumulate in 1960.
Tetra-phocomelia–babies born with hands and feet attached directly to the body–was extremely rare but began to appear in Germany in 1959. Birth defects were first suspected at Hamburg University in Germany and in Australia in 1961. A search of Hamburg city records found only one case of phocomelia in 212,000 births before 1955, but 8 in the last 12 months out of 6420 births. Studies found that women who took one tablet between 20 and 36 days after conception were at risk of birth defects. Newspapers got the story in November, 1961; Distillers removed Distoval from the market in UK on December 2. In the end, 40,000 patients got nephritis; 8000 to 12000 deformed babies were born; 5000 survived past childhood.
A chapter describes the fight to get FDA approval in the US. It was Dr. Frances Kelsey who stuck to her guns in spite of considerable pressure and refused to approve Kevadon. In February, 1961, the application was delayed based on published reports of nerve damage. The application was withdrawn in March, 1962.
After six years investigation, the West German Ministry of Justice opened a criminal case against nine executives of Chemie Gruenthal in 1968. The defense were able to disallow testimony of key witnesses. Gruenthal offered to put up $27MM for the children if the criminal charge was dropped. The 2866 German children shared $31MM from the company and $13MM from the German government. In UK, Distillers created a $7.8MM trust fund with interest to be shared by 430 victims.
After thalidomide Congress passed the Kefaufer-Harris amendments to the FDA act in August, 1962. New drugs must be shown to be safe and effective. The FDA must be advised of new drug trials and records are required of those participating.
Efforts to develop suitable prosthetics for the children is described. The devices available then were heavy, clumsy, and not very suitable.
That thalidomide has unique properties was discovered in the case of leprosy. Its most serious form known as ENL results in numerous painful boils all over the body. In 1964, a patient treated with two tablets had significant improvement. Trials in Venezuela (1965) and later by WHO confirmed major improvement. Thalidomide is still the drug of choice for treatment of ENL. Studies found that thalidomide controls inflammation by reducing TNF-alpha levels.
Chemie Gruenthal stopped production of thalidomide. Availability was limited. Celgene, the drug company spun off from Celanese Chemical, began manufacture. Thalidomide was effective in treating some effects of AIDs. Word of mouth on the internet caused widespread use of illegal thalidomide in the AIDs community. Better drugs are now available. Use to treat AIDs is now rare.
Antiangiogenisis, the ability to block enhanced blood supply, was of interest as a way to control tumor growth and other diseases such as diabetic retinopathy or macular degeneration. A screen for existing drugs turned up thalidomide. The drug itself was ineffective in lab tests; it requires activation suggesting that the liver metabolizes the drug into active agents.
In 1998, FDA approved Celgene’s thalidomide under the name Thalomid for treatment of ENL. To guard against birth defects, physicians must register with Celgene before writing the prescription and patients must agree to use of two methods of birth control.
Studies on additional uses of thalidomide continue. Treatment for multiple myeloma is promising as is possible treatment for Crohn’s disease.
This is a thorough telling of the thalidomide story. References. Index.