LEFLUNOMIDE AND MALONONITRILAMIDES

Leflunomide is a new immunomodulatory drug that is effective in experi mental models of autoimmune diseases and in allo or xenotransplantatio n. In a phase II clinical trial, leflunomide showed high tolerability and efficacy in patients with advanced rheumatoid arthritis. The immun omodulatory activity of leflunomide is attributed to its primary metab olite A77 1726, which is a malonon-itrilamide. The in vitro and in viv o mechanisms of action of this class of compounds are not defined comp letely. Several malononitrilamide analogues and A77 1726 inhibit T- an d B-cell proliferation, suppress immunoglobulin production, and interf ere with cell adhesion. Although no central molecular mechanism of act ion has been proposed to explain all the effects of the malononitrilam ides, the inhibition of de novo pyrimidine biosynthesis and of cytokin e- and growth factor receptor-associated tyrosine kinase activity are leading hypotheses for the effects of A77 1726 on T- and B-cell prolif eration and function. Leflunomide is effective when administered in da ily dosages of 10 mg and 25 mg to patients with active rheumatoid arth ritis. The improved efficacy of a 25 mg dose is associated with a high er incidence of adverse effects (gastrointestinal symptoms, weight los s, allergic reactions, skin rash, and reversible alopecia). Because of the long plasma half-life of A77 1726 (11 to 16 days), loading doses are necessary to achieve steady state concentrations. Phase III random ized, 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 preclinica l models of transplantation. If these analogues show efficacies and th erapeutic indexes that are similar to leflunomide in these models and that have shorter half-lives than A77 1726 II phase I trials, the prec linical and phase I data will be used to select the analogues for phas e II trials in organ transplant recipients.