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Thalidomide: current and potential clinical applications

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Abstract

More than three decades after its withdrawal from the world marketplace, thalidomide is attracting growing interest because of its reported immunomodulatory and anti-inflammatory properties. Current evidence indicates that thalidomide reduces the activity of the inflammatory cytokine tumor necrosis factor (TNF)-α by accelerating the degradation of its messenger RNA. Thalidomide also inhibits angiogenesis. Recently, the drug was approved for sale in the United States for the treatment of erythema nodosum leprosum, an inflammatory complication of Hansen’s disease. However, it has long been used successfully in several other dermatologic disorders, including aphthous stomatitis, Behçet’s syndrome, chronic cutaneous systemic lupus erythematosus, and graft-versus-host disease, the apparent shared characteristic of which is immune dysregulation. Many recent studies have evaluated thalidomide in patients with human immunodeficiency virus (HIV) infection; the drug is efficacious against oral aphthous ulcers, HIV-associated wasting syndrome, HIV-related diarrhea, and Kaposi’s sarcoma. To prevent teratogenicity, a comprehensive program has been established to control access to the drug, including registration of prescribing physicians, dispensing pharmacies, and patients; mandatory informed consent and education procedures; and limitation of the quantity of drug dispensed. Clinical and, in some patients, electrophysiologic monitoring for peripheral neuropathy is indicated with thalidomide therapy. Other adverse effects include sedation and constipation. With appropriate safeguards, thalidomide may benefit patients with a broad variety of disorders for which existing treatments are inadequate.

Section snippets

Immunomodulatory mechanisms of action

Thalidomide’s effects on immune function are incompletely understood; however, anti-inflammatory and immunomodulatory activities have been described (Table 1).

Thalidomide reduces phagocytosis by polymorphonuclear leukocytes. This may explain its action in inflammatory processes that involve predominantly mononuclear cell accumulation, such as chronic cutaneous lupus erythematosus (3). Thalidomide inhibits monocyte phagocytosis without any sign of cytotoxicity in monocytes or polymorphonuclear

Anti-angiogenesis activity

D’Amato and colleagues (19) first demonstrated thalidomide’s anti-angiogenic activity, which has been postulated to have clinical therapeutic applications in solid tumors and other diseases. In a rabbit model of corneal neovascularization induced by angiogenic protein basic fibroblast growth factor, thalidomide reduced the area of vascularization compared with controls. More recently, experiments have shown that a combination of thalidomide and sulindac, a nonsteroidal anti-inflammatory drug

Erythema nodosum leprosum

The rehabilitation of thalidomide began in 1965 when Sheskin (21) reported that patients with acute inflammatory lesions associated with leprosy experienced astonishingly rapid improvement after taking thalidomide for sedation. Subsequent studies, including a controlled trial conducted under the auspices of the World Health Organization, confirmed the drug’s effectiveness (22). The current approved dosage is 100 to 300 mg per day for therapy of an acute episode, with a maximum dose of 400 mg

Teratogenicity

Phocomelia is the best known congenital abnormality associated with thalidomide, but duodenal stenosis, esophageal fistulae, neural tube abnormalities, micro-ophthalmia, deformities of the ears, and mid-line hemangiomas have also been reported 85, 86. To minimize the risk of teratogenicity, Celgene Corporation (Warren, New Jersey) has developed a program (System for Thalidomide Education and Prescribing Safety [STEPS]) for controlling and monitoring access to thalidomide (87). Physicians who

Conclusion

Thalidomide may have other therapeutic applications, including the treatment of bacterial meningitis and sepsis, both of which are TNF-α related 93, 94, 95. In rabbit models of bacterial meningitis, thalidomide reduced levels of TNF-α (93) and improved survival (95). Similar results were found in a rat model of septic shock (95). Another emerging potential therapeutic target is cancer cachexia. Although the role of TNF-α in cachexia in cancer patients remains to be elucidated (96), the findings

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