The American journal of the medical sciences
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Leflunomide is a new immunomodulatory drug that is effective in experimental models of autoimmune diseases and in allo or xenotransplantation. In a phase II clinical trial, leflunomide showed high tolerability and efficacy in patients with advanced rheumatoid arthritis. The immunomodulatory activity of leflunomide is attributed to its primary metabolite A77 1726, which is a malononitrilamide. ⋯ Phase III randomized, placebo-controlled trials that use daily dosages of 10 mg or 20 mg are under way in the United States and Europe to confirm and extend the results of the phase II study. Malononitrilamide analogues of A77 1726 are being evaluated for immunosuppressive efficacy in preclinical models of transplantation. If these analogues show efficacies and therapeutic indexes that are similar to leflunomide in these models and that have shorter half-lives than A77 1726 in phase I trials, the preclinical and phase I data will be used to select the analogues for phase II trials in organ transplant recipients.