Side effects thalidomide

Professor Gerhard Zbinden stated that The point at which maximum vigilance is required typically comes when the drug has been on the market for 2-3 years after its sales curve has had time to rise and when effects (good and bad) have had time to show themselves (1). There has been a great deal of controversy over drugs that have been kept on the market despite considerable evidence of worrisome side effects Thalidomide being just one example. 

The glutarimide best known to the lay public, thalidomide (40), owes its reputation not to efficacy, but to the wholly unanticipated and tragic teratogenic effects elicited by this compound. It might be noted that the very efficacy and lack of the usual barbiturate side effects shown by this drug led to its prescription as a hypnotic for expectant mothers. Condensation of the phthalimide of glutamic acid (39) with ammonia at elevated... 

Lenalidomide was approved recently for the indication of myelodysplastic syndrome where the 5q deletion is present. Since lenalidomide is an analog of thalidomide, all the same precautions must be taken to prevent phocomelia. The time to maximum lenalidomide concentrations occurs 0.5 to 4 hours after the dose. The terminal half-life ranges from 3 to 9 hours. Approximately 65% of lenalidomide is eliminated unchanged in the urine, with clearance exceeding the glomerular filtration rate. To date, no pharmacokinetic studies have been done in patients with renal dysfunction. Lenalidomide is used in the treatment of myelodysplastic syndrome and multiple myeloma. Other side effects are neutropenia, thrombocytopenia, deep vein thrombosis, and pulmonary embolus. 

Lenalidomide is an immunomodulating agent related to thalidomide that was recently approved for the treatment of patients with multiple myeloma and myelodysplastic syndrome (MDS). Lenalidomide lacks the common side effects of thalidomide, such as constipation and peripheral neuropathy. Interim analyses of two phase III trials show that lenalidomide in combination with dexamethasone produces higher response rates than dexamethasone alone in relapsed and refractory myeloma. Adverse effects of lenalidomide include diarrhea, nausea, muscle cramps, hematologic side effects and deep vein thrombosis.42... 

Thalidomide was in 2006 approved by the FDA for the treatment, in combination with dexametha-sone, of newly diagnosed multiple myeloma patients. Thalidomide was sold in the late fifties as an hypnotic, with the infamous epidemic of birth defects as a result. Thalidomide is racemic and the S enantiomer is teratogenic. However the enantiomers interconvert in vivo, so giving only the R enantiomer cannot be a solution. After oral administration peak levels are reached in 2-A hours. It is eliminated mainly by biotransformation with a halfiife of about 6 hours. The most common side effects observed with use of thalidomide in myeloma include drowsiness or fatigue, constipation, dizziness, dry skin or rash, low white blood cell counts, and peripheral neuropathy. 

Lenalidomide, a derivative of thalidomide, was introduced in 2004. Patients with multiple myeloma stage II/III, who have undergone at least one previous treatment can be treated with bortezomib or with lenalidomide in combination with dexamethasone. There is good oral absorptin with peak plasma levels at 0.5-4 hours. Lenalidomide is maily eliminated by the kidneys with a half-life of circa 3-9 hours. Teratogenicity cannot be excluded. Side effects include thrombosis, pulmonary embolus, and hepato-toxicity, as well as bone marrow toxicity resulting in neutropenia and thrombocytopenia. 

Other side effects of thalidomide may include sedation (in fact, thalidomide was originally marketed in Europe as a sleeping aid), constipation, and peripheral neuropathy, which may be permanent. 

Tseng S et al. Rediscovering thalidomide A review of its mechanism of action, side effects, and potential uses. J Am Acad Dermatol 1996 35 969-979. 

Thalidomide the S isomer is a sedative and has teratogenic side effects. The R isomer is also a sedative but has no teratogenic activity. 

The existence of chirality in nature is of particular importance in numerous recognition processes, often illustrated by examples detectable by non-spectroscopic methods such as the different orange and lemon odors of R-(+)- and S-(-)-limonene, respectively (Fig. 3) [8]. As such, chiral discrimination is also of considerable consequence in the medical sciences, as often one enantiomer is pharmaceutically active whereas the other may show adverse side effects. A historic example is the anti-emetic activity of one of the enantiomers of thalidomide, while the other can cause fetal damage [9,10]. These considerations highlight the importance of chiral discrimination in the production of biologically active materials, whereas on the other hand, the design of routes to asymmetric synthesis presents an active challenge to synthetic chemists worldwide. 

Side effects that arise as a consequence of a known mechanism of action are plausible and the connection with drug ingestion is simple to recognize. It is more dif cult to detect unwanted effects that arise from an unknown action. Some compelling examples of these include fetal damage after intake of a hypnotic (thalidomide), pulmonary hypertension after appetite depressants, and fibrosis after antimigraine drugs. 

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