Monday Article #65: The Thalidomide Scandal- The Medical Negligence & ignorance that woke the World
Figure 1: Distaval Forte thalidomide tablets
Thalidomide, C13H10N2O4, first developed by the German Company, Chemie Grünenthal GmbH, was initially marketed as a sedative drug in the 50s. Then, as the drug had the ability to relieve morning sickness, it was soon prescribed to pregnant mothers suffering from morning sickness. Medicational uses for pregnant women were lenient back then as, ignorantly, the fact that the effects of the drug were able to affect the foetus through the placental barrier were still unknown to scientists in the 1950s. [1]
Figure 2: Baby born with deformities in the legs as a result of Thalidomide
Birth defects:
Defects in the limbs known as Phocomelia are the most common symptoms. Other symptoms include paralysis of facial nerves, defects of internal organs and sight and hearing loss. [2] The damage varies from the day the conception started. For example, if it was consumed on the 20th day of pregnancy it caused central brain damage, day 21 would damage the eyes, day 22 the ears and face, day 24 the arms, and leg damage would occur if taken up to day 28. [3]
Ignorance, coincidence or Negligence?
Based on the LD50 test, there was not a ‘lethal dose’ of Thalidomide that could be given to test animals. [1] In human tests, except for those who took high doses and suffered from symptoms such as sleepiness, giddiness and constipation, Thalidomide was well tolerated. [4] However, it was found out later that the tests conducted would have barely fulfilled the strict and rigorous compliance of today's drug testing: It was never tested on pregnant animals, no placebo groups were formed and there was a lack of scientific data such as the length of the treatment, the concentration of Thalidomide in the patients’ blood and tissue. Also it is evident that negligence partly contributed to this tragedy as other sedatives that were developed in the 50s, such as Meprobamate, ran through several comprehensive tests, where both female and male rats were fed, mated and had their offsprings examined for birth defects. [4]
Nonetheless, when animal tests were further examined, it was realised that test animals fed with thalidomide indeed gave birth to defected babies but it was overlooked as rats normally gave birth at night and would cannibalise malformed babies instead of healthy ones. In addition, it was later discovered that active ingredients in thalidomide would break down and become inactive in solution. Therefore, it justified why many pregnant test animals did not give birth to deformed offsprings as instead of being fed with pill form of thalidomide, it was being injected in them. [4]
Proponents argued that despite taking Thalidomide, some mothers gave birth to healthy babies whereas mothers of defective babies could not recall taking Thalidomide. [4] Then it was revealed in a later research that the embryo would only be damaged if the drug was consumed at 20 and 37 days of conception. [1]
Figure 3: Thalidomide Enantiomers
The chemistry behind the drug:
Thalidomide consists of a chiral carbon. The drug that was marketed to the public was a racemic mixture consisting of two different forms of mirror images. In 1979, it was first discovered that the (R)-enantiomer is effective as a sedative whereas the (S)-enantiomer is teratogenic. Therefore, it was thought that if a pure (R)-enantiomer was marketed instead of a racemic, the tragedy would have been prevented. [5] However, in subsequent studies the suggestion was proven futile as under aqueous forms, the isomers interconvert and epimerization occurs. Therefore, with the stereochemistry of the molecule altered, it is safe to say that the explanation that only one enantiomer displays teratogenicity is incorrect. [6]
Conclusion:
The Thalidomide tragedy is responsible for over 10,000 birth defects in babies. Despite the tragic nature of this event, it served as a catalyst to tighten controls of pharmaceutical products as well as a new era of developments in toxicity. Recently, Thalidomide has also returned to the medicinal field with renewed uses: treatment for leprosy and a targeted cancer drug to control symptoms of cancers such as myeloma. [1]
Reference(s):
[1] Science Museum. (2019, December 11). Thalidomide.
Retrieved from:
https://www.sciencemuseum.org.uk/objects-and-stories/medicine/thalidomide#:~:text=The%20th alidomide%20scandal,-The%20first%20time&text=In%20the%20few%20short%20years,the%20 effects%20of%20the%20drug.
[2] UK Teratology Information Service (UKTIS). (2022, September). Thalidomide. Retrieved from: https://www.medicinesinpregnancy.org/Medicine--pregnancy/Thalidomide/
[3] St Mary's Calne Blogs & Logs. (2021, June 30). Is re-introducing Thalidomide a risk worth taking?
Retrieved from:
https://www.stmaryscalne.org/blogs/is-re-introducing-thalidomide-a-risk-worth-taking/
[4] Wendy Jarrett. (2021, December 2). Sixty years on: the history of the thalidomide tragedy Retrieved from:
https://www.understandinganimalresearch.org.uk/news/sixty-years-on-the-history-of-the-thalidomide-tragedy
[5] Etsuko Tokunaga, Takeshi Yamamoto, Emi Ito & Norio Shibata. (2018, November 20). Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers
Retrieved from: https://www.nature.com/articles/s41598-018-35457-6
[6] Josh Bloom. (2023, June 6). The Story You Thought You Knew About Thalidomide And Birth Defects Is All Wrong
Retrieved from:
https://www.acsh.org/news/2023/06/06/story-you-thought-you-knew-about-thalidomide-and-birth -defects-all-wrong-17110
This article was prepared by Ang Kai Yue