Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibition of inosine monophosphate dehydrogenase by mycophenolate compounds results in potent immunosuppression, as demonstrated by the efficacy of the marketed prodrug mycophenolate mofetil (MMF) in clinical allotransplantation. Side effects are well-known and include bone marrow depression and gastrointestinal intolerability. Mycophenolate sodium (MPS) is in clinical development as an enteric-coated formulation to alleviate this gastrointestinal adverse effect. Accompanying this development, MPS and MMF were evaluated in a tolerability study in rats and in efficacy studies in rat allo- and xenotransplantation models. The compounds were given either singly or in combination with cyclosporine A and were efficacious in the prevention of allo- or xeno-graft rejection, but with a rather narrow window between optimal immunosuppression and adverse side effects. For instance, the minimal effective dose to prevent rejection of a kidney or heart allograft or a hamster heart xenograft is a daily dose of 10-20 mg/kg MPS, at which dose the first adverse side effects can be observed: the compound at 40 mg/kg is not tolerated. This window is even narrower for MMF than for MPS, and in most models, a minimal effective MMF dose could not be established. The window between optimal immunosuppression and adverse side effects is larger when the compounds are given in combination with cyclosporine A: in all models investigated combinations were established yielding long-term survival without histologic signs of rejection and without signs of side effects. Thus, the combination of an IMPDH inhibitor (MPS, MMF) and a calcineurin inhibitor (cyclosporine A) enables fine-tuning in achieving optimal immunosuppression avoiding drug side effects.
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PMID:Mycophenolate sodium: tolerability and efficacy in transplantation in the rat. 1218 Aug 29