Thalidomide: development to prescription
Thalidomide is a sedative that was synthesized in 1956 by a German company named Chemie Grünental. Commercially released as the brand Contergan, this drug was initially administered as an anti-convulsant, but was soon after was also used to treat morning sickness and nausea in pregnant women. The drug was also administered for individuals in need of a sleeping aid. By 1960, approximately 48 countries around the world recognized the use of this drug for treating ailments during pregnancy, as well as hypertension and headache. By 1960, the first reports were issued regarding birth defects and neuropathies related to the administration of thalidomide to pregnant women, and one year later, a shocking twelve thousand births showed physical abnormalities in different parts of the body. Such devastating news had lead to the withdrawal of thalidomide from the global market in 1963.
This drug has said to be controversial because its massive side effects were observed at a time when health policies regarding the rights of a patient and well as drug safety were still unrefined. During the 1960’s, assays for teratogenicity were not commonly conducted for every drug and drug safety was simply based on the immediate effects that a patient would feel upon the intake of a particular drug. Little has been known then that the direct effect of thalidomide was on the developing fetus and that the actual effects would only be observed months later upon birth of a child. It was also during this same period that patient rights were not yet well established and the concept of a patient’s right to terminate a pregnancy did not actually exist then. The topic of abortion was not an option in the 1960’s and the idea was even considered as taboo. The status of prenatal testing was also in its infancy then, hence there were no methods, such as amniocentesis or ultrasonography, which were available to determine whether a certain pregnancy carried gross deformities.
The massive deformities in children that were associated with the administration of thalidomide could have been prevented if comprehensive drug toxicity tests were conducted before the release of the drug to the market. At that time, ethical review boards were not fully established and any testing for effects on the human body were mainly based on actual administration of drugs to a particular population to check for any adverse effects. It should be understood that “testing” then were very brutal because it cost the lives of a significant number of people. In addition, toxicity assays have not been designed at that time that could pinpoint the exact mechanism of action as to which thalidomide may have taken in order to result in such gross deformities of the hands and feet of fetuses.
Thalidomide (C13H10N2)4 is chemically derived from glutamic acid and its structure is similar to two other sedatives, bemegride and glutethimide. The main distinguishing feature of thalidomide is its ability to trigger the immune system to generate antibodies as well as react to the presence of tumors in the body. The molecular structure of thalidomide is composed of two rings that are isomeric in configuration, with the R-isomer accountable for the sedative response in patients, while the L-isomer is responsible for the teratogenic effects that have been observed in deformed infants. The concept of isomericity has made the drug thalidomide are very elusive molecule to study because it has been observed that one isomer can switch to its homologous isomer based on a simple change in the pH level of its immediate environment. To date, the exact cause of the abnormalities that were observed in thousands of babies remains unknown. Research efforts have suggested that thalidomide may have played a role in a number of physiological pathways in the human body, resulting in gross defects during fetal development. Among such biological pathways are cell interactions, cell movements, generation of blood vessels and secretion of cytokines. Regardless of its vague mechanism of action, thalidomide is still regarded as a unique drug that is still effective in treating particular disease conditions.
Thalidomide has returned to the limelight since the 1990’s due to the increase in the information that has been reported with respect to its positive clinical effects. It has thus been possible that 40 years ago, the total effect of thalidomide was not examined, thus resulting in major damages in thousands in births. After thorough studies of this drug for almost three decades, thalidomide was again released to the market for administration to the specific disease of erythema nodosum leprosum, or as was earlier known as the skin disease, leprosy (Villahermosa et al., 2005). However, based on the history of thalidomide, the United States Food and Drug Administration (US FDA) issued of drug policy on the use of thalidomide. The policy requires that a registration database be constructed, listing both physicians who are prescribing the drug, as well as the patients who are taking the medication. In addition, the patients are educated in terms of contraceptive behavior during their treatment with thalidomide, including the confirmation that a female patient shows a negative pregnancy test result before initiation of administration of thalidomide.
Monitoring of the female patients for the subsequent months in terms of pregnancy status is also checked in order to prevent any births with possible defects. The packaging of the drug has also been modified, with the inclusion of a picture of a deformed baby in order to warn any users that the drug is indeed teratogenic. The drug policy also requires that the patient and his or her attending physician sign a document that certifies that both parties are aware of the risks of using thalidomide and that the patient will actively participate in measures for contraception during the period of treatment with the drug. The new drug policy on the use of thalidomide may prevent any additional toxicities and side-effects among patients, as current research efforts continue to determine the exact mechanism of action and potential benefits of the drug.
Villahermosa, L.G., Fajardo, Jr. T.T., Abalos, R.M., Balagon, M.V., Tan, E.V., Cellona, R.V., Palmer, J.P., Wittes, J., Thomas, S.D., Kook, K.A., Walsh, G.P., and Walsh, D.S. (2005). A randomized, double-blind, double-dummy, controlled dose comparison of thalidomide for treatment of erythema nodosum leprosum. American Journal of Tropical Medicine and Hygienics, 72(5), 518–526