Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal transplant patients are inherently predisposed to cardiovascular disease (CVD) as a result of prolonged exposure to multiple cardiovascular risk factors. Approximately one half of all late graft losses are due to death with a functioning graft, and CVD is the most frequent cause of death with a functioning graft among these patients. Immunosuppressive therapies associated with a reduced burden of risk for CVD would therefore greatly decrease post-transplantation morbidity and mortality. The nephrotoxic effects observed with the use of calcineurin inhibitors (CNIs), such as cyclosporine (CsA), run counter to the goal of renal transplant therapy. Sirolimus, a more recent immunosuppressive agent with a unique mechanism of action, offers an alternative to CsA. Recent data from a 4-year study investigating early CsA withdrawal from a sirolimus-CsA-steroid (SRL-CsA-ST) combination demonstrated significantly better renal function, lower blood pressure, and improved graft survival after CsA withdrawal. During that trial, the increase in serum lipids induced by sirolimus was generally manageable with lipid-lowering therapy. Further investigation is warranted to evaluate the value of CNI-free therapy compared with CNI-based regimens in reducing cardiovascular risk factors and improving patient and graft survival.
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PMID:Cardiovascular risk profile in patients treated with sirolimus after renal transplantation. 1561 72

We conducted a phase II trial in 19 chronic graft-versus-host disease (cGVHD) patients with rapamycin, calcineurin inhibitors, and prednisone with the goals of controlling cGVHD, reducing prednisone use, and defining the safety of this regimen. Rapamycin was begun as second-line (n = 9) or more than second-line (n = 10) therapy. With a median follow-up of 42 months, 16 patients were evaluable for response. Nine patients discontinued rapamycin because of poor compliance/patient request (n = 2) or an adverse event (n = 7), 3 of whom were not evaluable because of withdrawal at < or =1 month or noncompliance. The adverse events included serum creatinine > or =2.4 mg/dL (n = 4), hemolytic uremic syndrome (n = 2), and relapse of malignancy (n = 1). Fifteen of 16 evaluable patients had a clinical response. Five of the 16 discontinued the drug, and 1 died of relapsed leukemia. Of the 10 patients who continued rapamycin, 2 discontinued and 1 successfully tapered all systemic immunosuppression. Three of the 10 developed progressive cGVHD with tapering immunosuppression; all responded to resumption of prior medications. Four of the 10 patients required alternate therapy for persistent or progressive cGVHD while receiving rapamycin; prednisone was discontinued (n = 2) or tapered at the time of progressive disease (n = 2). Seventeen of 19 original patients were alive. One death was due to relapsed malignancy, and 1 was due to congestive heart failure. In this report of rapamycin as cGVHD therapy, there is evidence of rapamycin's efficacy. Given the significant toxicities described, investigation of altered administration of rapamycin and calcineurin inhibitors should be pursued in future cGVHD trials.
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PMID:Rapamycin (sirolimus) for treatment of chronic graft-versus-host disease. 1604 15

Pancreas transplantation is considered the optimal therapy for patients with diabetes mellitus who reach end-stage renal disease. Despite achievement of euglycaemia after this procedure, the progression to impaired pancreatic function and metabolic exhaustion still represents one of the major concerns that increase the risk of graft loss. This paper reviews the possible mechanisms that can induce post-transplant hyperglycaemia, including those related to immunosuppression and those non-related, and the new strategies available for minimising or preventing this complication. Different aetiologies can induce pancreatic dysfunction. Technical complications, acute pancreatitis and delayed graft function, mostly related to impaired insulin secretion, are considered the early causes for abnormal glucose control. In general, acute rejection does not affect the endocrine portion of the pancreas graft because islet destruction occurs later than the inflammation of the exocrine components. Hyperinsulinaemia and insulin resistance represent the main concern for the progression of blood glucose intolerance. The anastomotic techniques of the exocrine portion of the pancreas and the immunosuppressive regimens are of critical importance for the development of impaired glucose metabolism. Hyperinsulinaemia, as a result of the fact that systemic-enteric or systemic-bladder drainages reducing the hepatic clearance of insulin, has led to the introduction of more physiological techniques using portal drainage of the endocrine secretions. Experimental and clinical data have shown that many of the current immunosuppressants account, to a large degree, for the increased risk of the development of post-transplant hyperglycaemia. The most common maintenance regimen in pancreatic transplantation still consists of triple therapy with a combination of corticosteroids, calcineurin inhibitors (either ciclosporin [cyclosporine] or tacrolimus), and mycophenolate mofetil (MMF).The diabetogenic effects of corticosteroids and calcineurin inhibitors have resulted in the need for protocols able to minimise their use. Recent studies have shown the safety and efficacy of steroid-sparing or -free regimens. Sirolimus has shown powerful immunosuppressive potency in absence of nephrotoxicity and diabetogenicity. Multicentre and single-centre reports have demonstrated that both calcineurin inhibitor withdrawal and avoidance were possible when sirolimus was used in a concentration-controlled fashion, with low-dose corticosteroids and MMF. Although the experience with sirolimus in pancreatic transplantation is still limited, the results are promising. Patients affected by diabetic gastroparesis seem to better tolerate a regimen with sirolimus and low-dose tacrolimus than one with tacrolimus in combination with MMF.For successful, long-term results of pancreatic transplantation, it is crucial to combine donor selection, technical aspects, modified anastomotic techniques and new therapeutic approaches designed to minimise the metabolic and non-metabolic adverse effects of the immunosuppressive regimens.
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PMID:Management of hyperglycaemia after pancreas transplantation: are new immunosuppressants the answer? 1563 39

Sirolimus (rapamycin) is a macrocyclic lactone isolated from a strain of Streptomyces hygroscopicus that inhibits the mammalian target of rapamycin (mTOR)-mediated signal-transduction pathways, resulting in the arrest of cell cycle of various cell types, including T- and B-lymphocytes. Sirolimus has been demonstrated to prolong graft survival in various animal models of transplantation, ranging from rodents to primates for both heterotopic, as well as orthotopic organ grafting, bone marrow transplantation and islet cell grafting. In human clinical renal transplantation, sirolimus in combination with ciclosporin (cyclosporine) efficiently reduces the incidence of acute allograft rejection. Because of the synergistic effect of sirolimus on ciclosporin-induced nephrotoxicity, a prolonged combination of the two drugs inevitably leads to progressive irreversible renal allograft damage. Early elimination of calcineurin inhibitor therapy or complete avoidance of the latter by using sirolimus therapy is the optimal strategy for this drug. Prospective randomised phase II and III clinical studies have confirmed this approach, at least for recipients with a low to moderate immunological risk. For patients with a high immunological risk or recipients exposed to delayed graft function, sirolimus might not constitute the best therapeutic choice--despite its ability to enable calcineurin inhibitor sparing in the latter situation--because of its anti-proliferative effects on recovering renal tubular cells. Whether lower doses of sirolimus or a combination with a reduced dose of tacrolimus would be advantageous in these high risk situations remains to be determined. Clinically relevant adverse effects of sirolimus that require a specific therapeutic response or can potentially influence short- and long-term patient morbidity and mortality as well as graft survival include hypercholesterolaemia, hypertriglyceridaemia, infectious and non-infectious pneumonia, anaemia, lymphocele formation and impaired wound healing. These drug-related adverse effects are important determinants in the choice of a tailor-made immunosuppressive drug regimen that complies with the individual patient risk profile. Equally important in the latter decision is the lack of severe intrinsic nephrotoxicity associated with sirolimus and its advantageous effects on arterial hypertension, post-transplantation diabetes mellitus and esthetic changes induced by calcineurin inhibitors. Mild and transient thrombocytopenia, leukopenia, gastrointestinal adverse effects and mucosal ulcerations are all minor complications of sirolimus therapy that have less impact on the decision for choosing this drug as the basis for tailor-made immunosuppressive therapy. It is clear that sirolimus has gained a proper place in the present-day immunosuppressive armament used in renal transplantation and will contribute to the development of a tailor-made immunosuppressive therapy aimed at fulfilling the requirements outlined by the individual patient profile.
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PMID:Benefit-risk assessment of sirolimus in renal transplantation. 1569 Dec 25

Sirolimus (SRL) is a substrate for cytochromes P-450 3A and P-glycoprotein, the product of the MDR1 gene. We postulated that single nucleotide polymorphisms (SNPs) of these genes could be associated with inter-individual variations in SRL requirements. We then evaluated in 149 renal transplant recipients the effect of polymorphisms CYP3A4*1/*1B, CYP3A5*1/*3 and MDR1 SNPs in exon 12, 21 and 26 on SRL concentration/dose (C/D) ratio 3 months after sirolimus introduction. SRL C/D ratio was significantly higher in patients treated with calcineurin inhibitors. The CYP3A4*1B and CYP3A5*1 alleles were present in 17% and 21% of patients, respectively. When treated with a SRL-based therapy and low-dose steroids, patients carrying the CYP3A4*1B or the CYP3A5*1 alleles required significantly more SRL to achieve adequate blood trough concentrations (p < 0.01 and p < 0.02, respectively). None of the MDR1 SNPs was associated with the SRL concentration/dose ratio. These findings suggest that the variations in SRL requirements are secondary to both genetic and non-genetic factors including pharmacokinetic interactions. In patients with SRL-based therapy, genotyping of the CYP3As genes may help to optimize the SRL management in transplant recipients.
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PMID:Consequences of genetic polymorphisms for sirolimus requirements after renal transplant in patients on primary sirolimus therapy. 1570 15

Alternative to nephrotoxic calcineurin inhibitors regimens are feasible in renal transplantation. Sirolimus is an effective immunosuppressive drug with less drug-induced nephrotoxicity. Enteric-coated mycophenolate sodium provides a safety and efficacy alternative to mycophenolate mofetil. In peritoneal effluent, cancer antigen 125 (Ca 125) is a mesothelial cell marker and of in vivo biocompatibility of the new dialysis solutions. Longterm PD and peritoneal sclerosis are associated with a low number of mesothelial cells and a low concentration of dialysate Ca 125. Exposure to glucose and degradation products (GDPs) is important in the genesis of mesothelial damage. Short results of the more biocompatible solutions are promising (increasing of Ca 125). In the future, exposure to glucose can be reduced by using combinations of various osmotic agents, each in a low concentration (glycerol and amino acid solution).
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PMID:[Nephrology]. 1577 97

Graft failure and mortality among heart transplant recipients remains higher than in populations receiving renal transplants. A major cause of graft loss is cardiac allograft vasculopathy (CAV), a condition characterized by diffuse thickening of coronary blood vessels. CAV often progresses silently, with major cardiac events (eg, ventricular arrhythmia) being the first presentation. Better diagnosis and monitoring of CAV is now possible with intravascular ultrasonography, a sensitive technique for measuring intimal thickness. To date, immunosuppressants have shown little efficacy for preventing CAV. However, a new class of agents, proliferation signal inhibitors (sirolimus and everolimus), have shown considerable efficacy in this regard and for preventing rejection. In an open-label trial, sirolimus therapy was associated with less intimal and medial proliferation than azathioprine. More robust evidence is available from a larger-scale, double-blind trial involving everolimus. At 12-month follow-up the incidence of CAV was significantly lower in patients receiving everolimus (35.7% and 30.4% for everolimus 1.5 and 3.0 mg/d vs 52.8% for azathioprine; P < .05). Sirolimus and everolimus were also associated with a lower rate of cytomegalovirus infection. As with other immunosuppressants, these agents are associated with adverse events (eg, hyperlipidemia), but they can be managed. Coadministration with calcineurin inhibitors (CNIs) can exacerbate CNI-related nephrotoxicity, but evidence suggests that everolimus administered with reduced-exposure cyclosporine in the maintenance phase preserves renal function without loss of immunosuppressive efficacy. Reduced CNI dosing in de novo patients is also a potential future benefit. Proliferation signal inhibitors have considerable potential for improving outcomes in heart transplantation.
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PMID:Improving outcomes in heart transplantation: the potential of proliferation signal inhibitors. 1580 2

Side effects of calcineurin inhibitors (CNIs) include nephrotoxicity and hypertension. Moreover, children have a higher risk of infections and posttransplantation lymphoproliferative disorders. We retrospectively evaluated the efficacy and safety of Sirolimus (SRL) in 18 patients, who were 10.52 +/- 5.03 years at time of transplantation and received a CNI as the core immunosuppression. The most common indications for starting SRL therapy were chronic allograft nephropathy, Epstein-Barr virus-associated neoplasia, and thrombotic microangiopathy. The patients were converted to SRL at 49.14 +/- 45.9 months posttransplantation. Mean follow-up after the switch to SRL was 13.83 +/- 7.24 months. All patients who began SRL therapy remained on that medication. We observed a significant improvement (P < .05) in glomerular filtration rate assessed using the Schwartz formula at 3 months, which was sustained thereafter. There were no changes in proteinuria, plasma lipids, and platelet number. Although the prevalence of hypertensive patients decreased during follow-up, it was not significant. There was one steroid-sensitive, acute rejection episode. Serious adverse events included 1 death due to a relapse of B lymphoma, 1 sepsis, and 1 pancreatic pseudo-cyst. Adverse events were present in 17% of patients: 3 Herpes Simplex infections, and 1 dose-related lymphedema. Further studies are necessary to assess the impact of adverse events in the pediatric transplant population receiving SRL as immunosuppression.
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PMID:Sirolimus in pediatric renal transplantation. 1584

Sirolimus, a macrocyclic lactone that displays a novel mechanism of immunosuppressive action, is a critical-dose drug requiring therapeutic drug monitoring for optimal outcomes. The compound was documented in two multicenter, blinded clinical trials to reduce the incidence of acute rejection episodes when used in combination with cyclosporine and steroids vs. azathioprine or placebo comparators. Furthermore, studies utilizing cyclosporine withdrawal documented a long-term benefit on renal function of chronic sirolimus therapy, albeit with a modestly enhanced incidence of acute rejection episodes. Although this application may be useful in selected cases, we believe that minimal initial cyclosporine exposures de novo mitigate the need for eventual withdrawal for chronic nephropathy, while preserving the immunosuppressive synergy during the maintenance phase. Recipients treated de novo with a sirolimus-cyclosporine combination tolerate steroid withdrawal at 1 month after living-donor or at 3 to 6 months after cadaveric kidney transplantation with only a 5% risk of acute rejection episodes and 6% incidence of chronic reactions within 3 years. However, sirolimus exacerbates the hypertriglyceridemic and hypercholesterolemic proclivities of transplant recipients, as well as exerts myelosuppressive effects, which are augmented by concomitant therapy with azathioprine or, particularly, with mycophenolate mofetil. Due to its apparent lack of nephrotoxicity, sirolimus has been employed for induction therapy in a calcineurin antagonist-free regimen in combination with either basiliximab or rabbit antilymphocyte sera for weak or strong immune responders, respectively, followed by introduction of a calcineurin antagonist upon resolution of the ischemia-reperfusion injury. Therefore, sirolimus proffers a potent and unique platform for new immunosuppressive strategies in organ transplantation.
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PMID:Sirolimus: a current perspective. 1585 2

Thrombotic microangiopathy (TMA) may occur after allogeneic hematopoietic stem cell transplantation (HSCT) and is related in part to calcineurin inhibitor toxicity. We observed a higher-than-expected rate of TMA when calcineurin inhibitors were combined with sirolimus. To determine the incidence of and risk factors for TMA after HSCT, we performed a retrospective cohort analysis of myeloablative allogeneic HSCT recipients between 1997 and 2003. TMA diagnosis required the simultaneous occurrence of (1) creatinine increase >2 mg/dL or >50% above baseline, (2) schistocytosis, (3) increased lactate dehydrogenase, and (4) no evidence of disseminated intravascular coagulopathy. A total of 111 sirolimus-exposed subjects were compared with 216 nonexposed subjects after HSCT. TMA occurred in 10.8% of the sirolimus group and 4.2% in the nonsirolimus group (odds ratio, 2.79; P=.03). Sirolimus exposure was associated with TMA earlier than in nonsirolimus patients (25 versus 58 days; P=.04). Only the use of sirolimus (exact odds ratio, 3.49; P=.02) and grade II to IV acute graft-versus-host disease (exact odds ratio, 6.60; P=.0002) were associated with TMA in regression analyses. Treatment of TMA varied among affected individuals. Renal recovery was complete in 92% of sirolimus-treated patients. Overall survival after TMA diagnosis was better for sirolimus subjects than for nonsirolimus subjects (58.3% versus 11.1%; P=.02). Sirolimus seems to potentiate the effects of calcineurin inhibitors on TMA after HSCT. TMA associated with sirolimus seems reversible and has a favorable prognosis when compared with TMA associated with calcineurin inhibitors alone. A careful monitoring strategy for TMA should be used with a sirolimus-containing graft-versus-host disease prophylaxis regimen.
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PMID:Sirolimus and thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. 1598 55


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