Thalidomide; Past and Present – Blog Post #405 by Asrar Qureshi

Thalidomide; Past and Present – Blog Post #405 by Asrar Qureshi

Dear Colleagues!  This is Pharma Veterans Blog Post #405. Pharma Veterans welcomes sharing of knowledge and wisdom by Veterans for the benefit of Community at large. Pharma Veterans Blog is published by Asrar Qureshi on WordPress, the top blog site. Please email to asrar@asrarqureshi.com for publishing your contributions here.

Thalidomide is known for its dark history. It remained off market for quite a number of years but has made appearance again as a drug for certain types of cancer and for thalassemia.

Development and Marketing

Thalidomide was probably developed by Ciba, a Swiss pharmaceutical company which later became Novartis. It was subsequently marketed by a German company Chemi Grunenthal by the brand name Contergan. 

Thalidomide first entered the German market in 1957 as an over-the-counter remedy, based on the maker’s safety claims. They advertised their product as “completely safe” for everyone, including mother and child, “even during pregnancy,” as its developers “could not find a dose high enough to kill a rat.” By 1960, thalidomide was marketed in 46 countries, with sales nearly matching those of aspirin.

Around this time, Australian obstetrician Dr. William McBride discovered that the drug also alleviated morning sickness. He started recommending this off-label use of the drug to his pregnant patients, setting a worldwide trend.

Thalidomide and Congenital Malformations

After its use became popular, multiple cases of ‘phocomelia’ or congenital limbs malformation were reported across the globe. 

In 1961, McBride began to associate this so-called harmless compound with severe birth defects in the babies he delivered. The drug interfered with the babies' normal development, causing many of them to be born with phocomelia, resulting in shortened, absent, or flipper-like limbs. 

Various types of abnormalities were reported.

• Phocomelia – a congenital deformity whereby the hands and feet are bound to the child’s trunk, or are absent, or grossly underdeveloped

• Disfigurement of ear

• Ocular abnormalities

• Facial palsies

• Internal organ damage

• Congenital heart disease

A German newspaper soon reported 161 babies were adversely affected by thalidomide, leading the makers of the drug—who had ignored reports of the birth defects associated with the it—to finally stop distribution within Germany. Other countries followed suit and, by March of 1962, the drug was banned in most countries where it was previously sold.

Discussion

The first paper describing the pharmacological actions of thalidomide was published in 1956. The drug, then designated as K17, was thought to have sedative effects superior to those of comparator drugs and was thought to be virtually nontoxic. Only 2 years after thalidomide's launch as Contergan in Germany, it's alleged lack of toxicity came into question, with reports of the drug causing numerous side effects. Shortly thereafter, thalidomide was connected with an epidemic of horrific deformities in children whose mothers had taken the drug during pregnancy. An objective examination of published papers and contemporary accounts confirms that the preclinical tests on thalidomide were superficial, and there is no doubt that it was never administered to pregnant animals prior to its use in patients. Within a short time after its withdrawal from the market due to its suspected association with fetal abnormalities, the drug was shown to produce fetal toxicity in laboratory animals. Had there been more extensive testing on laboratory animals before the drug was launched, the disaster could have been avoided.

There are numerous conflicting historical and anecdotal accounts about the origin of thalidomide. Some accounts claim that the drug was developed by Swiss pharmaceutical giant Ciba (now part of Novartis), others claim that the drug was developed by researchers working for Grünenthal.

According to data published in a report by Martin Johnson, director of The Thalidomide Trust in the United Kingdom, the drug was developed at the end of World War II in Nazi Germany, more than 10 years before Grünenthal secured a patent in 1954, as an antidote to nerve gases such as Sarin.

Martin discovered that a Heinrich Muckter, a former Nazi doctor, was paid large bonuses before thalidomide tragedy broke. According to Martin's report, following the launch of the thalidomide, Grünenthal paid Muckter nearly 22 times his annual executive salary.

Otto Ambros, who became an advisor for the British pharmaceutical company The Distillers Company (Biochemicals) Ltd, a subsidiary of Distillers Co. Ltd., was another convicted Nazis war criminal linked to Grünenthal and thalidomide. Distillers marketed thalidomide under the brand name Distavel in the United Kingdom, Australia and New Zealand.

Conflicting reports suggest that the drug was first synthesized in 1949 by British scientists at the University of Nottingham.

Thalidomide in Present Time

Since the tragedy, there’s been an increased body of research investigating the action of thalidomide. It was found that thalidomide acts through two main types of mechanisms; anti-angiogenesis and anti-inflammatory. These properties have made the drug an ideal treatment option for a range of medical conditions.

Back in 2006, thalidomide became one of the first new agents in over ten years to be approved to treat plasma cell myeloma, a type of bone marrow cancer. Due to boasting anti-angiogenic properties, thalidomide prevents the metastasis, growth, and hypervascularity of cancer tumors.

Thalidomide is also prescribed to treat a specific implication of leprosy: erythema nodosum leprosum (ENL). ENL is an immunological implication thought to occur in approximately half of those with lepromatous leprosy. It is characterized by the presence of a range of conditions including neuritis, orchitis, lymphadenitis, and eye inflammation. As ENL is an inflammatory condition, thalidomide’s anti-inflammatory properties make it a viable treatment option.

In Pakistan, India and some other countries with a higher prevalence of Thalassemia, thalidomide is being prescribed to children of various ages having a certain form of thalassemia. The drug helps to reduce or even eliminate need for blood transfusions.

Thalidomide case was a huge tragedy with implications for years to come. It highlighted the need for more rigorous and in-depth testing before putting the drug on the market. It is expected that the Pharma companies now act more responsibly in this regard.

Concluded.

https://www.news-medical.net/health/History-of-Thalidomide.aspx

https://pubmed.ncbi.nlm.nih.gov/12677202/

https://helix.northwestern.edu/article/thalidomide-tragedy-lessons-drug-safety-and-regulation