Thalidomide: The Tragedy of Birth Defects and the Effective Treatment of Disease
Thalidomide, a name etched in medical history for its tragic consequences, yet hailed for its therapeutic potential. A paradoxical tale of despair and hope, exploring the devastating birth defects it caused and its unexpected efficacy in treating certain diseases.
Thalidomide was first marketed in the late 1950s as a sedative and was used in the treatment of nausea in pregnant women
Within a few years of its widespread use in Europe, Australia, and Japan, approximately 10,000 children were born with phocomelia, leading to the ban of the drug in most countries in 1961.
- In the United States, the drug was held up for approval by Dr Frances Kelsey because of concerns about peripheral neuropathy in the patient and the potential effects a biologically active drug could have after treatment of pregnant women, a development that led to the development of segment I (fertility and general reproduction), II (teratogenicity), and III (perinatal) testing protocols.
Drug-induced vascular injury (DIVI) is observed in rat mesenteric arterioles in response to treatment with phosphodiesterase-4 inhibitors (PDE4i)
However, the mechanisms responsible for causing the characteristic vascular lesions are unclear.
- Nitrotyrosine (NT) adducts, markers of local nitric oxide (NO) production, have been observed in close proximity to the arterial lesions and in the inflammatory cells associated with DIVI.
Current and Future Challenges
Recent studies have investigated the association of thalidomide-associated peripheral neuropathy with single nucleotide polymorphisms in 1495 multiple myeloma patients.
- In these studies, it was found that the risk of developing peripheral neuropathy was mediated by polymorphisms of genes involved in repair and inflammation of the peripheral nervous system.
- More research is needed to understand the mechanistic differences between the two compounds
Challenges
Prevention of inadvertent exposure of pregnant women to this drug is a continuing challenge, particularly in parts of the world where access to the drug is less restricted than in the United States.
- The development of thalidomide analogs that retain the therapeutic benefits of the drug without its teratogenic liability is a second challenge.
- Research into mechanisms of action remains a priority for a better understanding of whether and how safer alternatives can be developed
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