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The
Return of Thalidomide Thalidomide is a medication that is well-known for its teratogenic effects during pregnancy. It was developed during the 1950s in Germany, originally as an anticonvulsant medication. It was found to be ineffective in this area, but useful as a sedative and a hypnotic. Thalidomide was also found to be useful in treating the nausea and vomiting ("morning sickness") that women experience during pregnancy. It was first developed and sold in Germany as an over-the-counter drug starting in 1956. Shortly after, the United Kingdom started the sale of this drug, however as a prescription medication. Thalidomide was also available in Canada until 1962. Thalidomide was marketed and developed in different forms. Compound preparations were made which included thalidomide in combination with other chemicals. These compound drugs were used in the treatment of a variety of disorders including hypertension, asthma and migraine. The United States never approved the sale of Thalidomide. The drug was only in clinical trials in the US. because of concerns over reports from Europe of potential side effects including irreversible peripheral neuritis. Some of the cases that appeared in the United States resulted from medication purchased in other countries. Thalidomide was withdrawn in the early 1960s after the appearance of reports of teratogenic effects, such as phocomelia. More than 10,000 children worldwide were born with malformations that were attributed to use of thalidomide during pregnancy. More affected children were reported in Germany due to the fact that thalidomide was an over-the-counter medication there. The mechanism of teratogenicity was unknown. The greatest period of sensitivity appeared to be between 21 and 33 days post conception (4 - 6 weeks post LMP). The effects did not show a dose-related relationship. Teratogenic effects appeared in over 80% of fetuses exposed during the critical period. The malformations that have been seen with Thalidomide include a broad spectrum of defects. The most characteristic malformations are limb-reduction abnormalities. The upper extremity findings vary between missing thumbs, to absent radii, ulnas, and/or humeri, known as phocomelia or micromelia. There can also be malformations of the lower extremities. The majority of thalidomide affected individuals have normal lower limbs. A minority have defects of all the limbs. Defects of the lower limbs with normal upper limbs is rare. The spectrum of congenital defects also includes most systems of the body. Other malformations include congenital heart disease, craniofacial anomalies, facial palsies, urogenital anomalies, renal malformations, eye abnormalities such as microphthalmos, coloboma, eye muscle and lacrimal gland defects, ear abnormalities such as abnormal pinnae, rib anomalies, sacral agenesis, hemivertebrae, cleft palate/lip, bifid uvula, malocclusion, facial hemangiomata, esophageal and duodenal atresia, and other structural defects. Short stature and muscle hypoplasia were also more frequent. Neurodevelopmental problems were observed, such as mental retardation, epilepsy, dyslexia, behavior abnormalities and involuntary movements. Mortality rate was ~40% due to serious internal malformations. The use of thalidomide in recent years has been a topic of much controversy. The drug is well liked because of its broad spectrum of pharmacologic and immunologic effects. It has been found useful in the treatment of leprosy, graft-vs-host disease, aphthous ulcers in AIDS and several other disorders. Celgene Inc, the manufacturer of Thalomid believes that thalidomide has the ability to selectively inhibit a protein called tumor necrosis factor alpha and to inhibit the growth of new blood vessels, resulting in an anti-angiogenic effect. On July 16, 1998 the FDA approved the use of thalidomide in the treatment of erythema nodosum leprosum, an inflammatory manifestation of leprosy. It can potentially be used in therapeutic applications for a wide spectrum of diseases. The drug has already been approved for use in Brazil and Mexico. There has been much controversy over the re-introduction of thalidomide given its great teratogenic potential. The American Academy of Pediatrics believes that the use of thalidomide should be restricted to disorders for which it has been shown effective in clinical trials, and for which other therapies are not available or have not been successful. They also believe that it should be available only for indication through a national agency. The proposed guidelines by Celgene Inc., with assistance from the FDA, AAP and the Thalidomide Victims Association require that a person not be pregnant while using thalidomide. For premenopausal women, a blood or urine test must be done before starting treatment and a negative result must be documented. The test must be repeated every month while taking thalidomide and four weeks after the last dose. For premenopausal women and for men, two forms of birth control are recommended for at least one month before starting thalidomide and for one month after the last dose. The product is not to be shared with others. Prior to beginning use of thalidomide, patients receive written and verbal information about the medication including side effects and possible effects on the fetus should a woman become pregnant. A video is made available which reviews information about thalidomide and which also includes a statement at the end from a member of the Thalidomide Victims Association requesting that users comply with the recommended guidelines. The patient must sign a form stating they understand the risks and consequences and the actions they may have to take to avoid them. They are also included in part of a national registry of thalidomide users and they must complete a questionnaire for the registry. In the future, the use of thalidomide may be expanded to include other chronic conditions. Given the great potential for teratogenic effects in pregnancy, it is hoped that the restrictions for use of thalidomide are maintained and that people who are using the medication comply with restrictions and recommendations. REFERENCES
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