Map Kinases

FIGURE 10.9 Inhibition of the NHE3 Na+/H+ exchanger by squalamine. 2.5.2. Thalidomide and its analogs

Thalidomide was introduced in the 1950s as a sedative that was prescribed for nausea and insomnia in pregnant women. However, it was found to be the cause of severe birth defects in children whose mothers had taken the drug in their first trimester of pregnancy. In 1965, it was serendipitiously discovered that thalidomide was effective at improving the symptoms of patients with erythema nodo-sum leprosum (ENL), and was approved for this use in 1998. In 1994, thalidomide was found to inhibit angiogenesis through a complex mechanism that includes inhibition of the synthesis by activated monocytes of TNF-a, which seems to have a role in angiogenesis by upregulation of the expression of the endothelial integrin and VEGF, among others. It has been demonstrated that inhibition of angiogen-esis by thalidomide requires prior metabolic activation,38 which has prompted the synthesis and evaluation of a large number of potential metabolites of this lead compound.

Thalidomide is being used, in association with dexamethasone39 and cytotoxic agents such as cyclophosphamide,40 for the treatment of multiple myeloma.41 Its mechanism of antitumor action is complex and, besides the inhibition of angiogenesis, also involves induction of apoptosis and other mechanisms.42

Thalidomide has been used as the lead compound in the development of a class of drugs known as immunomodulatory drugs (ImiDsĀ®),43 which have shown activity in multiple myeloma and other hematological and solid malignancies. The most advanced one is lenalidomide (CC-5013), which has recently been approved by the FDA, in combination with dexamethasone, for the treatment of multiple myeloma patients who have received at least one prior therapy.44 It has also shown efficacy in the hematological disorders known as the myelodysplastic syndromes (MDS). CC-4047 is another thalidomide analog that is in Phase II trials to determine its potential safety and efficacy as a treatment for multiple myeloma and prostate cancer.45 The S-isomer of CC-4047 has been reported to be its more potent enantiomer, but it has been shown to undergo rapid racemization in human plasma, a finding that supports the development of the drug in its racemate form.46

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