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The ever-increasing importance of cancer and neurodegenerative diseases continues to grow as populations across the world are affected by death and aging. The vitamin A (RXR) and vitamin D (VDR) receptor pathways offer promising potential to aid in treatment of cancer and Alzheimer’s disease. This thesis discusses the potential application of novel analogs of Bexarotene (RXR agonist), MeTC7 (a new potent VDR antagonist), and vitamin D as possible therapeutics for cancer and Alzheimer’s disease.
Thalidomide is a sedative drug introduced to European markets on 1 October 1957 after extensive testing on rodent embryos to ensure its safety. Early laboratory tests in rodent populations showed that pregnant rodents could safely use it, so doctors prescribed Thalidomide to treat morning sickness in pregnant women. However, in humans Thalidomide interfered with embryonic and fetal development in ways not observed in rodent tests. Pregnant women who take Thalidomide are at grater than normal risk for spontaneous abortion and for giving birth to children with developmental anomalies such as shortened, absent, or extra limbs, as well as a variety of heart, ear, and internal organ defects. The failure of rodent models to inform scientists of Thalidomide's teratogenicity in humans ignited debate about the proper use of cross-species testing during drug development.
Thalidomide, a drug capable of causing fetal abnormalities (teratogen), has caused greater than ten thousand birth defects worldwide since its introduction to the market as a pharmaceutical agent. Prior to discovering thalidomide's teratogenic effects in the early 1960s, the US Food and Drug Administration (FDA) did not place regulations on drug approval or monitoring as it later did. By 1962, approximately 20,000 patients in the US had taken thalidomide as part of an unregulated clinical trial before any actions were taken to stop thalidomide's distribution. Due to thalidomide's effects on fetuses, both nationally and abroad, the US Congress passed the 1962 Kefauver-Harris Amendments to the 1938 Food, Drug, and Cosmetic Act. These amendments imposed guidelines for the process of drug approval in the US and required that a drug be safe as well as effective before it could be approved and marketed. Thalidomide also influenced the FDA's creation of pregnancy categories; a ranking of drugs based on their effects on reproduction and pregnancy. Thalidomide motivated the laws on regulating and monitoring drugs developed in the US and by the FDA in the twentieth and twenty-first centuries.