Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The last several decades have seen a substantial decrease in the prevalence of acute allograft rejection in kidney transplant recipients, while equivalent improvements in long-term graft function have not been realized. As a result, the primary focus of new immunosuppressive drug development has expanded to include ease of use, improved side effect profiles, and reduced nephrotoxicity in addition to the more traditional goal of improved short-term outcomes. A number of novel drugs are currently under investigation in Phase I, II, or III clinical trials primarily to replace the nephrotoxic but highly effective calcineurin inhibitors. ISA247 (voclosporine) is a cyclosporine (CsA) analog with reduced nephrotoxicity in Phase III study. AEB071 (sotrastaurin), a protein kinase C inhibitor, and CP-690550, a JAK3 inhibitor, are small molecules in Phase II studies. Everolimus is derived from the mTOR inhibitor sirolimus and is in Phase III study. Belatacept is a humanized antibody that inhibits T-cell costimulation and has shown encouraging results in multiple Phase II and III trials. Alefacept and Efaluzimab are humanized antibodies that inhibit T-cell adhesion and are in Phase I and II clinical trials. This article reviews the mechanisms of action as well as published and preliminary results of the Phase I-III clinical trials involving these novel immunosuppressive agents.
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PMID:Novel immunosuppressive agents in kidney transplantation. 2042 Jul 93

Medium- and long-term renal graft survival depends on 4 main factors: the quality of the harvested graft, ischemia-reperfusion injury during harvesting and re-implantation, rejection, and the nephrotoxicity of certain drugs (especially immunosuppressants) used in this setting. The most nephrotoxic immunosuppressive drugs are the anticalcineurins (cyclosporine A and tacrolimus), a class discovered in the late 1970s and currently representing a basic component of all immunosuppressive protocols for solid organ graft recipients. The renal tubular and vascular toxicity of anticalcineurins is due to their immunosuppressive mechanism: they block the calcineurin pathway and thereby prevent transmission of the first signal from the T cell receptor to the nucleus, which normally triggers cytokine synthesis, New non-nephrotoxic immunosuppressants are therefore needed, especially for grafts of poor quality or subject to severe ischemia-reperfusion injury. Attention is turning to "old " molecules such as anti-thymocyte globulins, but exciting new immunosuppressants are now appearing. Alefacept is a fusion protein that binds to the immunological synapse-associated molecule CD2, which normally interacts with LFA-3. Belatacept, another fusion protein, blocks the T cell second signal CD 28-B7.1/B7.2. Finally, new chemical agents are being developed, such as sautrasporine, a tyrosine kinase inhibitor, and tofacitinib, a Jak inhibitor.
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PMID:[Use of new non-nephrotoxic immunosuppressive drugs in kidney transplantation, especially after ischemia-reperfusion injury]. 2237 59