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)

Daclizumab and basiliximab, engineered human IgG monoclonal antibodies to the interleukin-2 (IL-2) receptor alpha-subunit, were approved to prevent acute rejection after renal transplantation. Daclizumab was studied in adult and pediatric renal allograft recipients, liver allograft recipients, and calcineurin-sparing protocols in renal transplant recipients. Basiliximab was studied in renal allograft recipients and subgroups of recipients of living-related and cadaveric transplants, and in patients with diabetes mellitus. Both agents reduced acute rejection and were associated with few adverse effects. However, information regarding their long-term effects on infection, malignancy, chronic rejection, and patient survival must be available before a final decision is made regarding their proper administration. We propose that a likely role the drugs will play in the field of solid organ transplantation is in new protocols that allow sparing of other more toxic immunosuppressive agents.
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PMID:A review of interleukin-2 receptor antagonists in solid organ transplantation. 1051 62

Orthotopic liver transplantation (OLT) is effective therapy for end-stage liver disease but immunosuppression with calcineurin inhibitors (CNI) leads to significant nephrotoxicity, resulting in either a reduction of dosage to below the therapeutic level or omission of the drug altogether. Basiliximab (Bx) is a human/mouse chimeric monoclonal antibody that inhibits binding of interleukin-2 (IL-2) to IL-2 receptors and thus prevents proliferation of T cells, which is the main step in the development of acute cellular rejection. The aim of this study was to identify the role of Bx in the prevention of acute cellular rejection and in the reduction of nephrotoxicity in children post-liver transplantation. We evaluated three children (19 months, 22 months, and 11 yr of age; one male, two female) who were treated with Bx post-OLT on compassionate grounds. The indications were: nephrotoxicity in two children, requiring re-transplantation for hepatic artery thrombosis and recurrent giant cell hepatitis, respectively; and nephrotoxicity secondary to chemotherapy for hepatoblastoma in the third child. All patients received 10 mg of Bx, at OLT and on Day 4. Tacrolimus (0.15 mg/kg/day) was started at 48 h (n = 2) and cyclosporin (5 mg/kg/day) at 2 weeks (n = 1). Trough levels of tacrolimus were maintained at 5-8 ng/mL and trough levels of cyclosporin at 100-150 mg/L for the first 3 months. All patients received methylprednisolone (2 mg/kg) with azathioprine (1.5 mg/kg) (n = 2) and/or mycophenolate mofetil (20 mg/kg) (n = 1). The glomerular filtration rate (cGFR) was calculated using the Schwartz formula before and 10 weeks after transplant. Bx was found to be easy to administer and no major side-effects were reported. One child had two episodes of mild acute rejection at 5 and 9 weeks post-OLT and one developed chronic rejection requiring re-transplantation at 9 weeks post-OLT. One child did not develop rejection. The mean pretransplant cGFR was 58.1 (54.6-64.1) mL/min/m2. Within 10 weeks of transplantation, the cGFR had improved by 69% to a mean of 116 (88-157.6) mL/min/m2. To conclude, Bx was well tolerated in all children and had a renal sparing effect. It was effective in preventing early acute rejection, but the combination of Bx and low-dose CNI drugs did not prevent late acute or chronic rejection. Further studies to evaluate the appropriate levels of CNI immunosuppression with Bx are required.
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PMID:Concomitant basiliximab with low-dose calcineurin inhibitors in children post-liver transplantation. 1210 May 5

The risk of acute rejection is at its highest early post-transplant. The use of various antibodies early after transplant achieves potent immunosuppression to prevent acute rejection, allowing the clinician the opportunity to optimise baseline immunosuppressive management and to delay the use of nephrotoxic agents (calcineurin inhibitors), while the graft reaches a baseline function. Basiliximab (Simulect trade mark, Novartis) is a monoclonal antibody that binds specifically to the alpha-subunit of the human high-affinity interleukin-2 receptor (IL-2r) complex, consequently inhibiting interleukin-2 (IL-2) binding. IL-2 receptors are selectively expressed on the surface of the activated lymphocytes. Administration of basiliximab inhibits IL-2 mediated activation of lymphocytes, a critical pathway involved in allograft rejection. Several clinical studies have shown that basiliximab administration as an induction agent significantly reduces the incidence of acute rejection, even in high risk patients. In addition, basiliximab is well-tolerated with minimal side effects.
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PMID:The use of basiliximab in solid organ transplantation. 1243 98

Interleukin-2 (IL-2) and its receptor (IL-2R) play a central role in T lymphocyte activation and immune response after transplantation. Research on the biology of IL-2R allowed the identification of key signal transduction pathways involved in the generation of proliferative and antiapoptotic signals in T cells. The alpha-chain of the IL-2R is a specific peptide against which monoclonal antibodies have been raised, with the aim of blunting the immune response by means of inhibiting proliferation and inducing apoptosis in primed lymphocytes. Indeed, basiliximab, one of such antibodies, has proved to be effective in reducing the episodes of acute rejection after kidney and pancreas transplantation. The use of basiliximab was associated with a significant reduction in the incidence of any treated rejection episodes after kidney transplantation in the two major randomised studies (placebo 52.2% vs basiliximab 34.2% at 6 months, European study; placebo 54.9% vs basiliximab 37.6% at 1 year, US trial). Basiliximab and equine antithymocyte globulin (ATG) administration resulted in a similar rate of biopsy-proven acute rejection at 6 months (19% for both) and at 12 months (19% and 20%, respectively). The use of basiliximab appears not to be associated with an increased incidence of adverse events as compared with placebo in immunosuppressive regimens, including calcineurin inhibitors, mycophenolate mofetil or azathioprine and corticosteroids, and its safety profile is superior to ATG. Moreover, a similar occurrence of infections is noted in selected studies (65.5% after basiliximab vs 65.7% of controls), including cytomegalovirus infection (17.3% vs 14.5%), and cytokine-release syndrome is not observed. Finally, economic analysis demonstrated lower costs of overall treatment in patients treated with basiliximab. Therefore, the use of basiliximab entails a very low risk, allows safe reduction of corticosteroid dosage and reduces the short- and mid-term rejection rates. However, the improvement in the long-term survival of kidney grafts in patients treated according to modern immunosuppressive protocols is still to be demonstrated. These conclusions are based on a systematic review of the scientific literature, indexed on Medline database, concerning the mechanism of action, therapeutic activity, safety and pharmacoeconomic evaluation of basiliximab in renal transplantation.
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PMID:A benefit-risk assessment of basiliximab in renal transplantation. 1471 21

Basiliximab is a chimeric monoclonal antibody that selectively binds to the alpha-subunit (CD25) of IL-2 receptors on the surface of activated T lymphocytes, and is a highly effective prophylaxis agent against rejection in organ transplant recipients. Its pharmacokinetic profile is characterized by a biphasic and slow clearance with long terminal half-life and a volume of distribution within the central compartment and outside the circulatory system. Basiliximab induction demonstrated an excellent safety profile, with no increase in the incidence of malignancy, infections or death. It has also been used effectively in high-risk recipients, steroid-sparing and steroid-minimization protocols, and in post-transplant patients with renal dysfunction who would benefit from delayed introduction of calcineurin inhibitors. Basiliximab induction therapy given at days 0 and 4 after transplantation appears to be safe and cost-effective for immunoprophylaxis in solid organ transplant recipients, specifically in kidney and liver transplantation, when given in conjunction with dual or triple immunosuppressive therapy.
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PMID:The role of basiliximab induction therapy in organ transplantation. 1715 25

Vascular disease and chronic allograft nephropathy have prompted re-evaluation of steroids and calcineurin inhibitors (CNIs) in renal transplantation. Sirolimus (SRL) can facilitate early CNI withdrawal. We report on the Early CNI and Steroid Elimination in Leeds (ECSEL) study, which was terminated early due to poor tolerability of SRL. Basiliximab/methylprednisolone induction was used, then 2 months of tacrolimus (TAC) and mycophenolate mofetil (MMF) treatment. A total of 51 patients were randomized to continue TAC/MMF or switch to SRL/MMF. In ECSEL1, patients were switched at 2 months (n=10). In ECSEL2, SRL was introduced at months 4-6 and TAC was tapered (n=13). Median overall follow up was 701 days. All 10 ECSEL1 and 10 of 13 (77%) ECSEL2 patients discontinued SRL due to adverse events, including leucopenia, rash, mucosal ulceration, arthralgia, and possible pneumonitis. Mean end-of-study creatinine was comparable in all groups. Sirolimus should be used with caution in complete CNI and steroid withdrawal, due to the resultant intolerable adverse event profile.
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PMID:Poor tolerance of sirolimus in a steroid avoidance regimen for renal transplantation. 1834 44

Basiliximab is a chimeric mouse-human monoclonal antibody directed against the alpha chain of the interleukin-2 (IL-2) receptor on activated T lymphocytes. It was shown in phase III trials to reduce the number and severity of acute rejection episodes in the first year following renal transplantation in adults and children, with a reasonable cost-benefit ratio. The drug does not increase the incidence of opportunistic infections or malignancies above baseline in patients treated with conventional calcineurin inhibitor-based immunosuppression. In the field of renal transplantation, basiliximab does not increase kidney or patient survival, despite the reduction in the number of rejection episodes. Basiliximab may reduce the incidence of delayed graft function. In comparison with lymphocyte-depleting antibodies basiliximab appears to have equal efficacy in standard immunological risk patients. Recently, IL-2 receptor monoclonal antibodies have been used with the objective of reducing or eliminating the more toxic elements of the standard immunosuppression protocol. Several trials have incorporated basiliximab in protocols designed to avoid or withdraw rapidly corticosteroids, as well as protocols which substitute target-of-rapamycin (TOR) inhibitors for calcineurin inhibitors.
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PMID:The role of basiliximab in the evolving renal transplantation immunosuppression protocol. 1970 52

Basiliximab (Simulect) is a recombinant chimeric murine/human IgG1 monoclonal anti-interleukin-2 receptor antibody that is indicated for the prevention of acute organ rejection in adult and pediatric renal transplant recipients in combination with other immunosuppressive agents. Induction therapy with two doses (day 0 and day 4) of intravenous basiliximab as part of double- or triple-immunotherapy regimens in adult renal transplant recipients reduces acute rejection episodes without increasing the incidence of adverse events. Compared with rabbit-derived antithymocyte globulin (RATG), basiliximab is generally associated with similar efficacy in standard-risk patients, but reduced efficacy in high-risk patients. Initial results indicate that induction with basiliximab is associated with a higher rate of biopsy-proven acute rejection than alemtuzumab induction. Basiliximab is generally associated with a tolerability profile that is similar to that reported with placebo, and better than that reported with RATG. As with other induction agents, basiliximab has not demonstrated improved graft or patient survival over the long term (periods of up to 7 years). Basiliximab induction allows for reduced dosage of corticosteroids or calcineurin inhibitors, while maintaining adequate immunosuppression, thereby reducing the potential for adverse effects associated with these coadministered agents. Thus, basiliximab provides an effective, well tolerated option for the prophylaxis of acute renal transplant rejection.
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PMID:Basiliximab: a review of its use as induction therapy in renal transplantation. 2005 33

Antibody therapy for induction is seldom used in liver transplantation in the United States, but continues to be used in approximately 10% of patients. The most commonly used antibody at the current time is basiliximab (Simulect, Novartis) and is used in adults with renal dysfunction at the time of liver transplantation with the intention of delaying introduction of calcineurin-inhibitors. In children, the same antibody is commonly used in order to reduce rates of acute rejection. Most patients, adult and pediatric, are treated with initially higher levels of tacrolimus rather than antibody induction.
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PMID:Induction immunosuppression in liver transplantation: a review. 2365 Oct 83