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)

A decade of spectacular innovation in maintenance immunosuppression drugs has resulted in dramatic reductions in acute rejection and improvement in short and long term outcome after renal transplantation. However the new drugs continue to lack specificity, many require frequent therapeutic drug monitoring and all are associated with acute and chronic toxicities. The new biologic agents, monoclonal antibodies (chimeric, humanized, and fully human) and receptor-fusion proteins, lack immunogenicity, have long half-life and prolonged biologic effects, require intermittent administration and have minimal toxicity. The specificity and selectively of the targets of the new biologic agents render them less toxic than the oral maintenance drugs and thus could possibly replace the maintenance drugs most associated with long-term toxicity such as the corticosteroids and the calcineurin inhibitors. The recently introduced anti-interleukin 2 receptor (IL-2R) monoclonal antibodies (mAbs) are the prototype of future biologic agents; selective, safe, and inducing prolonged biologic effects. The IL-2R mAbs have been used with a variety of maintenance immunosuppression regimens double therapy with cyclosporine and prednisone, triple therapy with cyclosporine, azathioprine and prednisone and with newer regimens such as cyclosporine or tacrolimus, mycophenolate mofetil (MMF) and prednisone, and most recently with sirolimus, MMF and prednisone. The major thrust of the new biologics in clinical development is to block the co-stimulatory pathway. The first attempt at blockade of the CD40-CD154 with anti-CD154 mAbs was disappointing. Anti-CD 154 therapy was associated with thromboembolic events and acute rejection. Attempts at blocking the CD28-B7s (CD80-CD86) pathway are currently underway with the receptor fusion protein, LEA29Y a second generation CTL4Aig, and humanized mAbs to CD 80 and CD86. LFA1, an adhesion molecule that also participates in the co-stimulatory pathway, has also been targeted with a mAb that binds to the CD11a chain of LFA1. Efalizumab, a humanized anti-CD11a mAb, was shown in a phase I trial to be potentially effective in renal transplantation. A humanized anti-CD45 RB mAb is currently in pre-clinical studies and will likely be tested in a phase I trial of renal transplantation within 1 year. While excellent results with anti-CD45 RB mAbs have been published in experimental transplantation, the mechanism of action of anti-CD45 RB mAbs remains to be determined. Several antibodies that are currently approved for non-transplant indications are currently used in single center clinical trials in renal transplantation including Campath 1 H, a humanized anti-CD52 mAb, Rituxamab, an anti-CD20 chimeric mAb, and Infliximab an anti-TNFa chimeric mAb. In addition, several humanized mutagenized anti-CD3 mAbs, huOKT3g1, aglycosyl CD3 and HuM291 have been used in limited trials in renal transplantation but have yet to have a formal clinical development. Humanized mAbs and receptor fusion proteins offer the potential of providing renal transplant recipients with a novel algorithm for immunosuppression that relies on chronic intermittent intravenous administration of safe, non-toxic agents replacing oral drug therapy maintenance.
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PMID:New monoclonal antibodies in renal transplantation. 1277 67

Many features of pediatric ulcerative colitis (UC) are similar to adult-onset disease, but the rate of extensive disease is doubled in children. It is, therefore, not surprising that the admission rate for severe UC is higher in childhood-onset UC, reaching 28% by the age of 16 years. Approximately 30-40% of children will fail corticosteroids and require second-line medical therapy or colectomy. A pediatric UC activity index (PUCAI) score of >65 indicates severe disease and the index can assist in determining the need and timing of second-line medical therapy or colectomy early during the admission. A PUCAI score of >45 points on day 3 identify patients likely to fail corticosteroids (negative predictive value 90-95%), and a score >70 points on day 5 identify patients who will require short-term treatment escalation (positive predicting value 95-100%). Data in children are limited, but it seems that cyclosporine, tacrolimus and infliximab achieve a similar short-term response rate, in the range of 60-80%. Infliximab has the advantage that it may be given for a prolonged period of time while calcineurin inhibitors should not be used for more than 3-4 months, bridging to a thiopurine regimen. Colectomy is indicated in toxic megacolon or in cases refractory to one salvage therapy. The choice of colectomy in other cases should carefully consider its effect on the patient's quality of life, its impact on the physical and emotional development at a critical age of personality development, and its association with a high infertility rate in females undergoing pouch procedure before childbearing age.
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PMID:Severe acute ulcerative colitis: the pediatric perspective. 1978 59