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

Atopic dermatitis (AD) is a common disease in childhood that is a serious burden on patients and their families. Most AD is mild and can be managed with the use of emollients and standard therapy consisting of topical corticosteroids or topical calcineurin inhibitors. However, in a subgroup of patients with moderate to severe AD, the disease is recalcitrant to topical therapy and systemic treatments become necessary. Short courses of systemic corticosteroids are often used in clinical practice, but their use is controversial. International guidelines suggest that in the case of acute flare-ups, patients might benefit from a short course of systemic corticosteroids, but long-term use and use in children should be avoided. Ciclosporin is an immunosuppressant agent that acts directly on cells of the immune system, with an inhibitory effect on T cells. When AD cannot be controlled by standard topical therapies, ciclosporin significantly decreases symptom scores, disease extent, pruritus and sleep deprivation, and improves quality of life. The most frequent adverse effects associated with the use of ciclosporin are hypertension and renal dysfunction, but they are usually reversible after drug discontinuation. Ciclosporin has been found to be safely used, effective and well tolerated in children with severe AD. However, studies to assess the long-term effectiveness and safety of ciclosporin in AD are lacking. In patients for whom ciclosporin is not suitable, or when there is a lack of response, alternative drugs should be considered, such as azathioprine or interferon-gamma. Intravenous immunoglobulins and the monoclonal antibody infliximab only have a place in the systemic therapy of AD when other drugs have failed. Mycophenolate mofetil has recently been introduced in the treatment of recalcitrant AD. Efalizumab and omalizumab are monoclonal antibodies with a possible future role in the treatment of AD, but further studies are needed.
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PMID:Systemic therapy of atopic dermatitis in children. 1927 73

The applicability of islet transplantation as treatment for type 1 diabetes is limited by renal and islet toxicities of currently available immunosuppressants. We describe a novel immunosuppressive regimen using the antileukocyte functional antigen-1 antibody efalizumab which permits long-term islet allograft survival while reducing the need for corticosteroids and calcineurin inhibitors (CNI). Eight patients with type 1 diabetes and hypoglycemic unawareness received intraportal allogeneic islet transplants. Immunosuppression consisted of antithymocyte globulin induction followed by maintenance with efalizumab and sirolimus or mycophenolate. When efalizumab was withdrawn from the market in mid 2009, all patients were transitioned to regimens consisting of mycophenolate and sirolimus or mycophenolate and tacrolimus. All patients achieved insulin independence and four out of eight patients became independent after single-islet transplants. Insulin independent patients had no further hypoglycemic events, hemoglobin A1c levels decreased and renal function remained stable. Efalizumab was well tolerated and no serious adverse events were encountered. Although long-term follow-up is limited by discontinuation of efalizumab and transition to conventional imunnosuppression (including CNI in four cases), these results demonstrate that insulin independence after islet transplantation can be achieved with a CNI and steroid-free regimen. Such an approach may minimize renal and islet toxicity and thus further improve long-term islet allograft survival.
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PMID:Islet transplantation in type 1 diabetics using an immunosuppressive protocol based on the anti-LFA-1 antibody efalizumab. 2175 35