Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nephrotoxicity-sparing protocols, using mycophenolate mofetil (MMF) and steroids without calcineurin inhibitors (CNIs) or mammalian target rapamycin (mTOR), could be used to treat maintenance renal transplant patients. However, the risk for acute rejection seems to be high. The aim of this pharmacodynamic study was to analyze T-cell function, T-cell activation, and T-cell proliferation among patients receiving MMF and steroids (n = 15) compared with patients receiving immunosuppression with CNI-based therapy including tacrolimus, MMF, and steroids. Our data suggested that among stable maintenance patients, dual therapy with MMF and steroids might provide a similar reduction in T-cell proliferation and T-cell activation as that observed among patients on standard immunosuppressive therapy. As expected, intralymphocytic interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha) expressions were higher in patients not receiving CNIs.
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PMID:T-cell function in maintenance renal transplant patients receiving mycophenolate mofetil and steroids with or without tacrolimus. 1910 Apr 3

Renal transplant patients lose their grafts most frequently from chronic allograft nephropathy and their lives from cardiac disease, malignancy, and infection. These are thus the challenges for renal transplant programs for this decade, just as acute rejection was the challenge of the last two decades. Most immunosuppressive protocols aim to minimize acute allograft rejection through heavy induction strategies and powerful but toxic maintenance therapies, counterbalanced by powerful and expensive infection prophylaxis. However, while the short-term results have improved steadily from the 1980s, and despite all the current efforts, the long-term success rates of renal transplants have not improved. Future aims include controlling both rejection and the long-term consequences of toxicity and infection risk. The biological facts that have determined our approach to the use of immunosuppressants have required us to try to balance the conflicting need for control of the allograft response and the inevitable toxicities of our drugs. The early period after transplantation requires maximum immunosuppressive efficacy with minimal ischemia reperfusion and good surgical-related wound healing. The latter period after transplantation requires less immunosuppressive efficacy and avoidance of chronic nephrotoxicity, cardiovascular, and malignancy risk factors. This usually leads to an induction strategy using a biological agent; a calcineurin inhibitor; an antiproliferative agent; and variable use of corticosteroids. In the long term, there are a variety of strategies for dose reduction or elimination of calcineurin inhibitors, incorporation of mammalian target of rapamycin inhibitors, and variable approaches to the risks of continued low-dose corticosteroids. The multiplicity of alternative strategies available testifies to the absence of evidence for a single dominant protocol and the urgent need to determine the relevant early indicators for measuring long-term success.
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PMID:Addressing the challenges for improving long-term outcomes in renal transplantation. 1910 Sep

Recent improvements in immunosuppressive therapies have reduced the incidence of acute rejection and increased patient survival. These agents may however contribute to higher rates of mortality due to an increased risk of cardiovascular disease or malignancy. Transplant patients are immunocompromised with a reduced ability to combat the development of malignancy. The higher risk for the activity of oncoviruses may also contribute to the higher incidence and determine specific tumor types. Some immunosuppressants seem to have direct oncogenic effects. In vitro data have demonstrated that calcineurin inhibitors (CNIs) may show direct effects on tumor growth and the development of metastases. In contrast, mTOR inhibitors have demonstrated anti-tumoral properties in vitro and perhaps potent anti-angiogenic effects thereby. Recent studies and registry analyses have confirmed that mTOR inhibitors are associated with a reduced incidence of malignancies. UNOS data demonstrated that an mTOR inhibitor, with or without a CNI, is associated with a reduced incidence of tumors compared to regimens without mTOR inhibitors. The Rapamune Maintenance Regimen study demonstrated that patients receiving sirolimus-based, CNI-free therapy after CsA withdrawal at 3 months showed a reduced incidence of malignancy at 5 years posttransplant, compared with those who continued on a regimen that included CsA. In the CONVERT study, patients converted to sirolimus revealed a significantly lower malignancy rate at 24 months (3.1%) compared with those who continued CNI-based therapy (9.8%, P < .001). The elimination of CNIs and the introduction of sirolimus may, therefore, have a role to reduce the risk of cancer among posttransplant patients.
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PMID:Minimizing the risk of posttransplant malignancy. 1910 Sep 6

Liver transplant recipients are at increasingly high risk for suffering from impaired renal function and probable need of renal replacement therapy. Extended criteria organs and transplantation of patients with higher model for end-stage liver disease scores further increase this problem. Acute and chronic nephrotoxicity are the trade-off in immunosuppression with potent calcineurin inhibitors (CNIs). As a good renal function is associated with better graft and patient survival, CNI minimization protocols have been developed. Current strategies to overcome CNI toxicity include reduction or withdrawal of CNIs concurrently with switching over to mammalian target of rapamycin inhibitor or mycophenolate mofetil (MMF)-based regimens. This strategy caused an improvement in renal function in a significant number of liver transplantation patients according to several studies. However, total CNI avoidance seems to result in higher rejection rates. To prevent chronic renal dysfunction in patients prone to or with acute renal failure, CNI delay - with induction therapy for bridging - followed by low-dose CNI in combination with MMF are proven strategies without risking higher rejection rates. An individualized, tailor-made immunosuppressive regime, with a special focus on renal function is recommended. This review gave an overview on CNI minimization protocols in liver transplantation also focusing on recently analyzed studies.
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PMID:Calcineurin inhibitor minimization protocols in liver transplantation. 1912 Nov 46

Immunosuppression remains the mainstay of therapy for successful outcomes after lung transplantation. The need for optimal immunosuppression became evident to maintain long-term graft survival and to navigate the delicate balance between infection and rejection. Over the past two decades, immunosuppression for solid organ transplantation has evolved to target multiple immune pathways with the hope of decreasing both acute and chronic allograft rejection. Although current maintenance therapy after lung transplantation typically includes a calcineurin inhibitor, antimetabolite and corticosteroid therapy, newer therapies including induction therapy with biological agents, mTOR inhibitors, and salvage therapies including photopheresis and total lymphoid irradiation have emerged as alternate therapeutic options. This review will discuss both the current immunosuppressive medications that are used as well as different therapeutic combinations that are currently employed. In addition, we will discuss the current literature regarding the efficacy of these agents in lung transplantation.
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PMID:Immunosuppression for lung transplantation. 1913 30

The purpose of this study was to compare the effects of sirolimus (SRL) vs cyclosporine (CsA) concerning the cardiovascular mechanisms hypothetically contributing to hypertension development. Three rat groups were studied: control (vehicle), CsA (5 mg/kg/d), and SRL (1 mg/kg/d). The following parameters were evaluated after 7 weeks of treatment: blood pressured (BP) and heart rate (HR; tail cuff), lipid profile, hematology, plasma and platelet 5-HT and catecholamines (HPLC-ECD), and oxidative equilibrium (serum malondialdehyde [MDA] and total antioxidant status [TAS]). Systolic (SBP) and diastolic blood pressure (DBP) values were higher (P < .001) in both the CsA (146.2 +/- 4.5 and 124.9 +/- 4.5 mm Hg) and SRL (148.9 +/- 4.8 and 126.4 +/- 6.0 mm Hg) groups vs the controls (115.9 +/- 3.3 and 99.1 +/- 2.0 mm Hg). However, HR values were elevated in CsA but not SRL animals. The dyslipidemic pattern of CsA was even more enhanced in the SRL group, with significantly higher low-density lipoprotein cholesterol (LDL-c) and triglyceride (TG) levels vs CsA (P < .05); red blood cells, hematocrit, hemoglobin concentration, mean platelet volume, and platelet distribution width were significantly (P < .05) higher in the SRL vs CsA group. The pro-oxidative profile (increased MDA/TAS) in the CsA group was not reproduced in the SRL cohort. While plasma and platelet 5-HT were elevated in SRL rats, catecholamine content was higher in CsA animals. In conclusion, this study demonstrated that CsA and SRL produce identical hypertensive effects. However, while CsA promotes oxidative stress and sympathetic activation, SRL mainly interferes with lipid profile and hematological parameters. Thus, the hypertensive effects of CsA, a calcineurin inhibitor, and of SRL, an mTOR inhibitor, are associated with impairment of distinct cardiovascular pathways.
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PMID:Hypertension induced by immunosuppressive drugs: a comparative analysis between sirolimus and cyclosporine. 1937 75

A de novo calcineurin inhibitor avoidance regimen based on sirolimus has been successfully used worldwide; demonstrating improved renal function from 1 to 5 years. This includes use of an induction antibody followed by sirolimus, mycophenolate mofetil, and steroids. This combination has a somewhat different side effect profile and wider experience has revealed that the use of de novo sirolimus requires careful therapeutic drug level monitoring, especially the first 6 months posttransplant. Experience has also demonstrated that delaying the introduction of sirolimus in patients considered at high risk for early mammalian target of rapamycin associated complications will optimize these results. For such recipients, the initial use of a calcineurin inhibitor drug for 2 to 4 months is preferred, followed by conversion to sirolimus. The late withdrawal of steroids may be possible, but awaits further evaluation in randomized controlled trials.
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PMID:Sirolimus in kidney transplantation indications and practical guidelines: de novo sirolimus-based therapy without calcineurin inhibitors. 1938 79

The new class of immunosuppressants--inhibitors of the mammalian target of rapamycin--has no nephrotoxicity and the capacity to inhibit vascular smooth cell proliferation. These characteristics may afford considerable clinical advantages in the transplantation of kidneys from expanded criteria donors (ECD). Six clinical experiences of the use of sirolimus (SRL) in ECD kidneys recipients have been reported in the literature. Although the results varied somewhat, probably due to differences in the types of deceased donor and in the immunosuppressive regimens used, it seems that a calcineurin inhibitor free, SRL-based protocol can assure a good immunosuppressive effect with less nephrotoxicity and a low incidence of cytomegalovirus infection. For recipients of ECD kidneys at low immunological risk, we would recommend a regimen based on antithymocyte globulin induction and SRL, mycophenolate mofetil, and steroids for maintenance. For strongly responding recipients, we recommend SRL combined with a reduced, 76% to 87% dose of calcineurin inhibitor.
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PMID:Sirolimus-based therapy for kidney transplantation from expanded criteria donors. 1938 80

Nowadays cancer represents the second main cause of death in renal transplant patients with normal function of the graft. The incidence is 10 to 20 times higher than normal population. Calcineurin inhibitor therapy contributes to the increase in the development of neoplasia. Important evidence could bring a preventive effect of mammalian target of rapamycin in skin cancer, Kaposi's sarcoma, and renal cell carcinoma.
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PMID:Minimizing the risk of posttransplant malignancy. 1938 82

Sirolimus (SRL) is a non-nephrotoxic immunosuppressive drug blocking T-cell proliferation through mTOR inhibition. SRL can be used as (1) an early drug in a calcineurin inhibitor-free protocol in the first 3 months after transplantation, (2) in the early and late conversion protocols as suggested by the multicenter randomized CONVERT trial, and (3) in recipients from marginal donors, because calcineurin inhibitors can increase the preexisting renal damage induced by age, hypertension, and diabetes that are frequent in elderly cadaveric donors. In any case, SRL should be used in patients with a cutoff of proteinuria (<or=800 mg/24 hr) or proteinuria-to-creatinine ratio less than 0.11.
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PMID:Review of symposium. Sirolimus in kidney transplantation. 1938 85


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