Thalidomide factors

We must inteiject an interesting historical sidelight at this point. Despite its reputation, thalidomide made a bit of a comeback in the 1990s (Blakeslee, 1994). Among other properties, thalidomide has been shown to have good anti-inflammatory properties, because it apparently decreases the synthesis and/or release of tissue necrosis factor. 

Thalidomide (Thalomid) is a derivative of glutamic acid that is chemically related to glutethimide. It exerts a number of biological effects as an immunosuppressive, antiinflammatory, and antiangiogenic agent, yet its mechanisms of action have not been fuUy elucidated. Thalidomide potently inhibits production of tumor necrosis factor (TNF) a and interleukin (IL) 12, and its effect on these and other cytokines may account for some of its clinical effects. 

The importance of chiral factors in disposition and toxicity has been fully recognized only relatively recently, although important examples have been known for some time. For instance the S(—) enantiomer of thalidomide is known to have greater embryotoxicity than the R(+) enantiomer (see chap. 7). Another example in which a particular isomer of a metabolite is responsible for a carcinogenic effect is the exo-oxide of aflatoxin Bi, discussed later in this chapter (Fig 5.14). 

More recent studies have indicated a probable mechanism, which relies on the interaction of thalidomide with DNA. The phthalimide double-ring structure of S-thalidomide can intercalate with DNA and binds to the polyG sites in the promoter regions coding for growth factors and integrins. 

Drugs known to be teratogenic include cytotoxics, warfarin, alcohol, lithium, methotrexate, phenytoin, valproate, ACE inhibitors and isotretinoin. Selective interference can produce characteristic anatomical abnormalities, and the phocomelia (flipper-Uke) limb defect was one factor that caused thalidomide to be so readily recognised. (For an account of thalidomide see p. 81.)... 

The risk of thrombosis from thalidomide may be increased in certain conditions, such as malignancies, cicatricial pemphigoid (29), and systemic lupus erythematosus. Four episodes of thrombosis (two arterial, two venous) occurred in three patients with systemic lupus erythematosus and one with severe atopic dermatitis within 10 weeks of starting treatment with thahdomide 50-100 mg/day (30). All four had at least one risk factor for thrombosis, but none had thrombosis before or after treatment with thahdomide. 

A 28-year-old woman took thalidomide 100 mg/day for Behget s disease and after 3 months developed amenorrhea (89). She took an oral contraceptive for 8 months, but then had a deep vein thrombosis in association with a factor V Leiden mutation the oral contraceptive was withdrawn and she was given warfarin. She remained amenorrheic. She had a raised serum concentration of follicle-stimulating hormone but all other laboratory tests were normal. Ultrasonography showed a normal uterus and an endometrial lining of 4 mm. The amenorrhea was attributed to thahdomide, which she decided to continue taking she remained amenorrheic. 

Moreira AL, Sampaio EP, Zmuidzinas A, Frindt P, Smith KA, Kaplan G. Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. J Exp Med 1993 177(6) 1675-80. 

Zangari M, Barlogie B, Thertulien R, Jacobson J, Eddleman P, Fink L, Fassas A, Van Rhee F, Talamo G, Lee CK, Tricot G. Thalidomide and deep vein thrombosis in multiple myeloma risk factors and effect on survival. Qin Lymphoma 2003 4(l) 32-5. 

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