The second life of thalidomide, a drug marked by tragedy

In 1954, the pharmaceutical market was booming and companies were looking for tranquilizers that were safer than barbiturates, which at the time were causing large numbers of deaths. It was then that the German company Chemie Grünenthal synthesized thalidomide, a sedative that did not resemble any of the existing ones. Supposedly it was less harmful.

The experiments carried out in some animal models showed little sedative activity and there were no data on its teratogenic effect, that is, the possibility of producing malformations in the fetus.

Even so, three years later it was authorized for sale to treat nausea and vomiting during pregnancy in up to 50 countries. In France and the United States, it was used for other indications, after a case of peripheral neuropathy was detected. In Spain it was registered under the trade name of Contergan®.

A box of Contergan.
Wikimedia Commons / TobiToaster, CC BY-SA

serious malformations

Unfortunately, the most shocking adverse effects were not long in coming. In all countries where this drug was marketed, children were born with severe malformations. Among the most frequent was phocomelia, the absence of bones and muscles in the upper or lower extremities, but also babies without ears, with palate defects and with esophageal and gastrointestinal malformations came into the world.

The first to warn that these teratogenic effects could be caused by thalidomide was Widukind Lenz, a German clinician and geneticist, in 1961. The evidence led to its withdrawal from the German market, although it continued to be marketed in Spain for a few more years.

The discovery of its efficacy in the treatment of leprosy made some of its different commercial presentations continue in Latin America and other latitudes, even after they were banned in 1965.

The repercussion in the scientific world and the social alarm unleashed had notable consequences. Until then, the evaluation of the efficacy and safety of drugs was not supervised by any official health authority. This misfortune prompted the creation of independent organisms for the control of medicines. For this reason, in some way, thalidomide is at the origin of clinical pharmacology and pharmacovigilance, which has been of significant benefit to later generations.

The victims, great forgotten

The WHO estimates that more than 10,000 children were born with severe malformations as a result of thalidomide, although some put this number almost twice as high. Although there are no official data on the people affected in Latin America, its consequences have been seen especially in Brazil and Peru.

In Spain it was denied for more than 30 years that the drug had been sold, with the consequent damage to the between 1,500 and 3,000 newborns with malformations. The lack of an official registry of those affected has prevented their access to any financial compensation or health care.

To help this group, almost 40 years later the Spanish Association of Victims of Thalidomide (AVITE) was created. In 2003, AVITE was concerned with creating a census that would allow social recognition and fair compensation to repair physical and moral damage. And work was done to make this aid comparable to that developed in other countries such as Germany or the United Kingdom.

After multiple interviews and negotiations with the Spanish authorities, in 2010 those affected were finally recognized and the procedure for granting aid was regulated. However, this group does not give up and continues to fight for their rights after, in 2015, the Supreme Court ruled in favor of the pharmaceutical company with the argument that the case had prescribed.

This helplessness means that the victims of thalidomide continue to be largely forgotten in our society. Its recognition, if it ever comes, may come too late.

Why does it produce malformations in the fetus?

Despite the time that has elapsed since the scandal broke, the molecular mechanisms that trigger the malformations, as well as part of their biological activities, are not exactly known. There are up to 30 hypotheses and models to explain it. However, two theories prevailed: first, those that make the production of molecules called reactive oxygen species (ROS) responsible for teratogenicity; and secondly, those that attribute these effects to antiangiogenesis, that is, its ability to inhibit the new formation of blood vessels.

The identification of the binding of thalidomide to a protein called CEREBLON (CRBN) was an invaluable help in identifying the mechanism that produces the malformations. As a consequence of this union, the destruction of other proteins is generated, among which is the transcription factor called SALL4, essential for the development of limbs.

It would be, therefore, in this transcription factor SALL4 where we would find the missing link in the teratogenic mechanism of thalidomide. In any case, these discoveries have not been confirmed in some animal models, which shows the different susceptibility of the species to the appearance of malformations.

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Lower extremities of a patient affected by phocomelia as a result of the administration of thalidomide to his mother.
Wikimedia Commons / Otis Historical Archives National Museum of Health and Medicine, CC BY-SA

The Thalidomide Resurgence

Thalidomy seemed to be condemned to the most absolute ostracism. However, in 2001, the European Commission designated it as orphan drug for the treatment of multiple myeloma. The so-called orphan drugs generally do not arouse any interest from the pharmaceutical industry. They must be intended for patients with rare diseases or a condition that lacks alternative treatment. For a new compound to be included in this group, it must provide additional benefits over available therapies.

The reuse of thalidomide arose from the thought that rapid embryonic development could resemble uncontrolled tumor growth. study data in vitro and clinical evidence suggest that the immunomodulatory, anti-inflammatory, and antineoplastic effects of thalidomide may be related to the inhibition of tumor necrosis factor (TNF-α) production and the modulation of certain intercellular adhesion molecules involved in leukocyte migration and in antiangiogenic activity.

Currently, this drug is prescribed mainly for two diseases: leprosy and multiple myeloma. In Spain, it is the treatment of choice in patients with multiple myeloma who have not been treated before, always combined with prednisone and melphalan. It is indicated from the age of 65 or in younger people who cannot receive high doses of chemotherapy.

The resurgence of thalidomide, with its promising results, should not erase its fateful history. The bad practice that led to fatal consequences for a group that has been cornered into oblivion cannot be repeated.

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