The promise of thalidomide: evolving indications.

Thalidomide was first used in the late 1950s but it was withdrawn from the market in the 1960s for its notorious teratogenic effects. This drug was more recently rediscovered as a powerful immunomodulatory and antiinflammatory agent and was approved by the FDA in 1998 for treatment of erythema nodosum leprosum. Thalidomide has shown great promise in advanced or refractory multiple myeloma either alone or in combination with other agents. It has also demonstrated benefits in a wide variety of disparate conditions such as aphthous and genital ulcers, cancer cachexia, HIV, tuberculosis and chronic graft versus host disease. Thalidomide is being investigated for treatment of renal cell carcinoma, and liver and thyroid cancers. Better understanding of its many mechanisms of action has provoked great interest in its potential use for treatment of various disorders. This review focuses on thalidomide's mechanisms of action, biochemistry, pharmacokinetics and its use in erythema nodosum leprosum as well as multiple myeloma, graft versus host disease, and renal cell carcinoma.

Thalidomide and its derivatives: emerging from the wilderness.

Forty years on from its worldwide withdrawal, thalidomide is currently undergoing a remarkable renaissance as a novel and powerful immunomodulatory agent. Over the last decade it has been found to be active in a wide variety of inflammatory and malignant disorders where conventional therapies have failed. Recently, considerable progress has been made in elucidating its complex mechanisms of action, which include both anticytokine and antiangiogenic properties. However, in addition to its well known teratogenic potential, it has a significant side effect profile that leads to cessation of treatment in up to 30% of subjects. In response to this, two new classes of potentially safer and non-teratogenic derivatives have recently been developed. This review summarises the biological effects, therapeutic applications, safety profile, and future potential of thalidomide and its derivatives.

Thalidomide for erythema nodosum leprosum and other applications.

Thalidomide, administered as a sedative and antiemetic decades ago, was considered responsible for numerous devastating cases of birth defects and consequently was banned from markets worldwide. However, the drug remarkably has resurfaced with promise of immunomodulatory benefit in a wide array of immunologic disorders for which available treatments were limited. It is approved by the Food and Drug Administration for erythema nodosum leprosum (ENL). Although the relative paucity of leprosy and ENL worldwide may perceivably limit interest in and knowledge about thalidomide, increasing numbers of new and potential uses expand its applicability widely beyond ENL. Thalidomide, an inhibitor of tumor necrosis factor a, is the best known agent for short-term treatment of ENL skin manifestations, as well as postremission maintenance therapy to prevent recurrence. For this indication, it is effective as monotherapy and as part of combination therapy with corticosteroids. Studies of thalidomide in chronic graft-versus-host disease showed benefit in children and adults as treatment, but not as prophylaxis. The agent has been administered successfully for treatment of cachexia related to cancer, tuberculosis, and human immunodeficiency virus infection, although evidence of efficacy is inconclusive. Thalidomide monotherapy effectively induced objective response in trials in patients with both newly diagnosed and advanced or refractory multiple myeloma. Combination therapy with thalidomide and corticosteroids was also effective in these patients, as well as in treatment of aphthous and genital ulcers. Limited evidence supports the drug's benefit in treatment of Kaposi's sarcoma. Other thalidomide applications include Crohn's disease, rheumatoid arthritis, and multiple sclerosis. Somnolence, constipation, and rash were the most frequently cited adverse effects in studies, but thalidomide-induced neuropathy and idiopathic thromboembolism were critical causes for drug discontinuation. Thalidomide is still contraindicated in pregnant women, women of childbearing age, and sexually active men not using contraception. Clinicians should be conversant with thalidomide in ENL (its primary application) in the natural course of leprosy, as well as in the agent's other applications.

Thalidomide for erythema nodosum leprosum and other applications

Thalidomide, administered as a sedative and antiemetic decades ago, was considered responsible for numerous devastating cases of birth defects and consequently was banned from markets worldwide. However, the drug remarkably has resurfaced with promise of immunomodulatory benefit in a wide array of immunologic disorders for which available treatments were limited. It is approved by the Food and Drug Administration for erythema nodosum leprosum (ENL). Although the relative paucity of leprosy and ENL worldwide may perceivably limit interest in and knowledge about thalidomide, increasing numbers of new and potential uses expand its applicability widely beyond ENL. Thalidomide, an inhibitor of tumor necrosis factor a, is the best known agent for short-term treatment of ENL skin manifestations, as well as postremission maintenance therapy to prevent recurrence. For this indication, it is effective as monotherapy and as part of combination therapy with corticosteroids. Studies of thalidomide in chronic graft-versus-host disease showed benefit in children and adults as treatment, but not as prophylaxis. The agent has been administered successfully for treatment of cachexia related to cancer, tuberculosis, and human immunodeficiency virus infection, although evidence of efficacy is inconclusive. Thalidomide monotherapy effectively induced objective response in trials in patients with both newly diagnosed and advanced or refractory multiple myeloma. Combination therapy with thalidomide and corticosteroids was also effective in these patients, as well as in treatment of aphthous and genital ulcers. Limited evidence supports the drug's benefit in treatment of Kaposi's sarcoma. Other thalidomide applications include Crohn's disease, rheumatoid arthritis, and multiple sclerosis. Somnolence, constipation, and rash were the most frequently cited adverse effects in studies, but thalidomide-induced neuropathy and idiopathic thromboembolism were critical causes for drug discontinuation. Thalidomide is still contraindicated in pregnant women, women of childbearing age, and sexually active men not using contraception. Clinicians should be conversant with thalidomide in ENL (its primary application) in the natural course of leprosy, as well as in the agent's other applications.

Potential novel uses of thalidomide: focus on palliative care.

Thalidomide, after being banned from the market in the early 1960s because of the worldwide teratogenesis disaster, is currently being rediscovered because of its multiple therapeutic effects in various serious diseases and symptoms. Original studies examined the anxiolytic, mild hypnotic, anti-emetic and adjuvant analgesic properties of this drug. Subsequently, thalidomide was found to be highly effective in managing the cutaneous manifestations of leprosy (erythema nodosum leprosum) and even to be superior to aspirin (acetylsalicylic acid) in controlling leprosy-associated fever. Recent research shows promising results with thalidomide in patients with progressive bodyweight loss related to advanced cancer and HIV infection. Thalidomide therapy of diseases such as tuberculosis, sarcoidosis, aphthous ulcers in HIV syndrome and Behcet's disease, rheumatoid arthritis, multiple myeloma, graft-versus-host disease, pyoderma gangrenosum, inflammatory bowel disease, Sjögren's syndrome, lupus erythematosus and a variety of solid tumours is currently being explored. Furthermore, in preliminary studies, thalidomide has been found to be effective in several syndromes related to advanced cancer, such as the cancer cachexia syndrome, chronic nausea, insomnia, profuse sweating and pain. Whether thalidomide has a therapeutic effect on neoplastic fever has yet to be elucidated. These intriguing features make the use of the drug potentially attractive for palliative care. In addition, by a distinct mechanism of action compared with most other drugs, thalidomide offers the possibility of combined treatment with other agents with non-overlapping toxicities. The mechanism of action of thalidomide is probably based on the suppression of tumour necrosis factor-alpha and the modulation of interleukins. However, it is not possible to identify a single dominant mechanism, since the action of cytokines and the effect of thalidomide appear to be complex. This review article discusses the original uses and teratogenic effects of thalidomide within its historical context and, linking recent research at the molecular level with clinical findings, aims to provide the reader with insight into the current understanding of its biological actions, toxicities and potential benefits.

Thalidomide: a re-look.

Thalidomide was synthesized in 1954 in erstwhile West Germany and marketed as a sedative in over 46 countries until the early 1960s. Owing to serious teratogenic effects, the drug was withdrawn from the market in 1961. A chance observation suggested the utility of thalidomide in erythema nodosum leprosum (ENL). After many controlled and uncontrolled trials were published, the World Health Organization recommended its use in ENL. The Food and Drug Administration, USA approved it for use in ENL in July 1998. Only established and well-defined studies conducted to substantiate the efficacy of thalidomide have been included in this review. Thalidomide is considered the drug of choice for the treatment of ENL, but for other conditions, it is recommended only when resistance to the currently available form of therapy is encountered. Once the anti-inflammatory, immuno-modulatory, anti-TNF-alpha and anti-angiogenic properties of thalidomide were discovered, it was also tried in AIDS and related wasting, apthous ulcers, microsporidiosis and Kaposi's sarcoma. Thalidomide has no clinical place as an immunosuppressant in solid organ transplantation. However, it has a therapeutic role in graft-verus-host-disease. Among the dermatological conditions, thalidomide has been found to be effective in systemic lupus erythematosus, discoid lupus erythematosus, actinic prurigo and prurigo nodularis. Used correctly, it is a safe and effective medicine (except for its teratogenic potential and delayed neuropathy) in a variety of disease conditions.

Thalidomide. A surprising recovery.

The epidemic of birth defects in Europe in the early 1960s attributed to thalidomide led to stringent and unprecedented drug safety requirements in many countries. No definitive mechanism of action has been determined for the biological activities associated with thalidomide. Food and Drug Administration and congressional concerns about the handling of clinical investigations of thalidomide led to sweeping new regulations for clinical trials. Thalidomide is currently being used clinically to treat such conditions as cachexia associated with HIV and cancer, mycobacterial disease, and autoimmune diseases.