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)

Sirolimus (Rapamycin, Wyeth Pharmaceuticals Australia Pty Ltd, Baulkham Hills, NSW, Australia) (SRL) has received increasing attention as an immunosuppressant in renal and other solid organ transplantation. Sirolimus is the first marketed agent in a new class of drugs with a novel mechanism of action. Sirolimus binds, like tacrolimus, to a member of the FK binding protein (FKBP) family. The SRL/FKBP complex binds to the protein kinase mTOR. Binding to mTOR blocks activation of signal transduction pathways causing arrest of the cell cycle in the G1 phase. It is now known that mTOR is a central regulator of cell growth and proliferation. The immunosuppressive properties of SRL are due primarily to blockade of interleukin-2 (IL-2)-induced proliferation of T cells. There is still much to be learnt about how best to use the drug. The key advantage over the current choice of immunosuppressive agents is the ability to preserve renal function and pathology while producing excellent rejection-free, graft survival rates. Thus, SRL may find its pivotal role as a calcineurin inhibitors replacement in patients whose grafts are affected by chronic allograft nephropathy. A second major driver for use may prove to be the impact of SRL on cancer incidence and prognosis. Studies still need to be performed to evaluate the best timing for commencement of SRL and the optimal dosage to minimize side-effects.
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PMID:Sirolimus: its role in nephrology. 1635 46

The present study has aimed to verify the influence of calcineurin and mTOR pathways in skeletal muscle longitudinal growth induced by stretching. Male Wistar rats were treated with cyclosporin-A or rapamycin for 10 days. To promote muscle stretching, casts were positioned so as completely to dorsiflex the plantar-flexor muscles at the ankle in one hind limb during the last 4 days of treatment with either cyclosporin-A or rapamycin. Thereafter, we determined soleus length, weight, protein content, and phenotype. In addition, NFATc1, Raptor, S6K1, 4E-BP1, iNOS, and nNOS gene expression in the soleus were determined by real-time polymerase chain reaction. Soleus length, weight, and protein content were significantly reduced by rapamycin treatment in animals submitted to stretching (P<0.05). In contrast, cyclosporin-A treatment did not alter these parameters. In all cyclosporin-A treated groups, there was a significant reduction in NFATc1 expression (P<0.001). Similarly, a significant reduction was noted in Raptor (P<0.001) and S6K1 (P<0.01) expression in all rapamycin-treated groups. No alteration was observed in 4E-BP1 gene expression among rapamycin-treated groups. Stretching increased gene expression of both NOS isoforms in skeletal muscle. Rapamycin treatment did not interfere with NOS gene expression (P<0.05). Cyclosporin-A treatment did not impair muscle growth induced by stretching but instead caused a marked slow-to-fast fiber shift in the soleus; this was attenuated by stretching. The data presented herein indicate that mTOR pathway is involved in skeletal muscle longitudinal growth.
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PMID:mTOR pathway inhibition attenuates skeletal muscle growth induced by stretching. 1640 96

The mTOR inhibitor sirolimus improves renal transplant function compared with the nephrotoxic calcineurin inhibitors. We evaluated retrospectively the adverse events in 119 of 134 patients getting sirolimus which seemed to be caused by sirolimus. Patients were converted to sirolimus because of malignancies (n = 47), a creeping creatinine (n = 33), or hypertension (n = 26). One cohort had started sirolimus from the time of transplantation (n = 28). A rise in serum lipids and a decrease in hemoglobin were seen relatively regularly, while arthralgia, peripheral edema, gastrointestinal complaints, skin disorders, electrolyte disturbances, and infections occurred only occasionally. Interestingly, 31% of patients developed doubling or more proteinuria. Among renal biopsies, 9/13 showed a glomerulopathy which in 6 cases was de novo and in 3 cases, a presumed recurrence of the primary kidney disease. Thus, we think that caution is required, particularly in connection with preexisting glomerular disease.
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PMID:Side effects of sirolimus. 1664 52

Over the last decade, there has been a decrease in acute graft rejection rates following renal transplantation; however, this has not corresponded with an improvement in long-term outcomes of transplantation. One of the major causes of long-term morbidity and mortality in renal transplant recipients is cardiovascular disease. Immunosuppressive regimens, especially those including steroids and calcineurin inhibitors, have a negative role in the induction of cardiovascular risk factors. The proliferation signal inhibitors (PSIs)/mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus have shown considerable promise in reducing acute rejection in renal transplant recipients. Although PSIs are associated with an increase in hyperlipidaemia (hypercholesterolaemia and hypertriglyceridaemia), which is a major risk factor for atherosclerosis and associated cardiovascular disease, recent studies with sirolimus have demonstrated protection from atheroma progression in hyperlipidaemic apolipoprotein E-deficient mice. Here, we summarize the results of pre-clinical and clinical studies with sirolimus and everolimus, with particular emphasis on the beneficial and adverse effects that these drugs exert on the cardiovascular system, and the underlying molecular mechanisms.
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PMID:Potential role of proliferation signal inhibitors on atherosclerosis in renal transplant patients. 1681 51

The calcineurin inhibitors (CNIs) ciclosporin (CsA) and tacrolimus are currently an important part of immunosuppressive regimens, but are associated with increased cardiovascular risk factors, including hyperlipidaemia, hypertension and diabetes mellitus. Conversion from CNI-based regimens to proliferation signal inhibitors or mammalian target of rapamycin inhibitors, such as everolimus and sirolimus, has been associated with an improvement in cardiovascular risk. This case study describes a 59-year-old renal transplant recipient who presented with angina pectoris while receiving immunosuppression with CsA, azathioprine and steroids. The patient developed angina pectoris 5 years after receiving a cadaveric renal transplant. At the time, the patient was obese, with hypertension controlled with diuretics and calcium channel blockers, and hyperlipidaemia controlled with statins. A scintigram revealed plurisegmental myocardial ischaemia, and a coronary angiogram showed the presence of occlusions in the left anterior descending artery and circumflex coronary artery. The patient also had 70% stenosis of the right coronary artery, which was corrected by angioplastic percutaneous intervention. The patient was converted from azathioprine to sirolimus 2 mg/day (trough blood level, 6-10 ng/ml), while the CsA dose was tapered and withdrawn. The angina pectoris subsequently resolved, no progression of coronary artery disease (CAD) has been observed during follow-up and stable renal function has been maintained throughout. Conversion to an immunosuppressive regimen of sirolimus with CsA withdrawal, along with angioplastic percutaneous correction of right coronary artery stenosis, therefore led to the complete resolution of angina pectoris and no progression of the CAD was noticed in this obese renal transplant patient with drug-controlled hypertension and hyperlipidaemia.
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PMID:Conversion to a proliferation signal inhibitor in a patient with coronary artery disease--a case report. 1681 56

Although short-term kidney allograft survival has improved significantly since the introduction of the calcineurin inhibitors (CNI) cyclosporine A (CsA) and tacrolimus, long-term transplant survival remains a major concern, chronic allograft nephropathy (CAN) being the principal reason for graft loss after the first post-transplant year. This is particularly major for pediatric renal transplant recipients because of their higher life expectancy compared with adults. The mechanisms leading to CAN are multiple, including acute and chronic alloimmune responses and nephrotoxicity of CNIs. CNI-induced nephrotoxicity is also a long-term concern in other pediatric solid organ transplant recipients, such as liver and heart. Prevention of allograft nephropathy requires a balance of maintaining adequate immunosuppression, while avoiding the toxic effects of CNIs. Regimens that are based on mycophenolate mofetil (MMF) alone or in combination with newer agents may allow for reduced reliance on CNIs and thus may represent an effective treatment paradigm for long-term maintenance of a renal allograft. From the available data it appears that the currently safest treatment strategy in pediatric renal and heart transplant recipients with CNI toxicity is an MMF-based therapy with low-dose CNIs +/- low-dose steroids, while in pediatric liver transplant recipients, CNI-free MMF-based immunosuppressive therapy with or without steroids appears feasible in a significant subset of patients. In renal transplant recipients, the benefit of a CNI-free MMF/steroid therapy on renal function is gained at the cost of increased rejection in a subset of patients, although the relative importance of rejection vs. overall renal function requires further clinical investigation. The introduction of mammalian target of rapamycin (mTOR) inhibitors provides an opportunity for unique CNI-sparing regimens that combine two antiproliferative agents (MMF and TOR inhibitors). It is possible that a sirolimus-based CNI-free immunosuppressive regimen in terms of renal transplant survival is superior to CNI minimization, where the detrimental effects of CNIs on allograft function and structure are still operative, albeit to a lesser degree. Substitution of CNIs by mTOR inhibitors is therefore promising, but requires validation in long-term studies in large cohorts.
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PMID:Treatment strategies in pediatric solid organ transplant recipients with calcineurin inhibitor-induced nephrotoxicity. 1691 97

Renewal of nongermative epithelia is poorly understood. The novel mitogen "lacritin" is apically secreted by several nongermative epithelia. We tested 17 different cell types and discovered that lacritin is preferentially mitogenic or prosecretory for those types that normally contact lacritin during its glandular outward flow. Mitogenesis is dependent on lacritin's C-terminal domain, which can form an alpha-helix with a hydrophobic face, as per VEGF's and PTHLP's respective dimerization or receptor-binding domain. Lacritin targets downstream NFATC1 and mTOR. The use of inhibitors or siRNA suggests that lacritin mitogenic signaling involves Galpha(i) or Galpha(o)-PKCalpha-PLC-Ca2+-calcineurin-NFATC1 and Galpha(i) or Galpha(o)-PKCalpha-PLC-phospholipase D (PLD)-mTOR in a bell-shaped, dose-dependent manner requiring the Ca2+ sensor STIM1, but not TRPC1. This pathway suggests the placement of transiently dephosphorylated and perinuclear Golgi-translocated PKCalpha upstream of both Ca2+ mobilization and PLD activation in a complex with PLCgamma2. Outward flow of lacritin from secretory cells through ducts may generate a proliferative/secretory field as a different unit of cellular renewal in nongermative epithelia where luminal structures predominate.
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PMID:Restricted epithelial proliferation by lacritin via PKCalpha-dependent NFAT and mTOR pathways. 1692 31

Mycophenolate mofetil (MMF) and sirolimus (SRL) are potent non-nephrotoxic xenobiotic immunosuppressants. Their complementary properties may provide the rationale for their combination in induction and maintenance regimens. MMF, a reversible inhibitor of inosin monophosphate dehydrogenase (IMPDH) acts as an antiproliferative drug; and SRL, an mTOR (mammalian target of rapamycin) inhibitor, inhibits cell proliferation driven by growth factors. Early experiences with the use of the SRL, MMF and steroid combination yielded insufficient prophylaxis of acute rejection. However, the introduction of induction therapy with mono- or polyclonal antilymphocyte antibodies to the SRL-MMF and steroid combination brings an efficient acute rejection prophylaxis, while improving renal function and/or reducing of chronic allograft nephropathy (CAN). However, adverse events related to the use of this drug combination (mainly haematological and surgery-related) result in a high rate of discontinuations in some trials, which may hamper the potential benefits of this calcineurin-inhibitor (CNI)-free strategy. Also, currently under investigation is whether in long-term immunosuppression, in MMF-treated patients, CNIs can be replaced by SRL to avoid and/or halt progression of chronic nephropathy and to improve graft survival. However, some authors reported a high proportion of patients with oral ulcers and proteinuria after switching to SRL. In short, refining the use of MMF and SRL may provide a better risk/benefit ratio to pave the way towards non-nephrotoxic immunosuppression.
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PMID:Mycophenolate mofetil and sirolimus combination in renal transplantation. 1693 Mar 95

Two forms of post-transplant thrombotic microangiopathy (TMA) may be recognized: recurrent TMA and de novo TMA. Recurrent TMA may occur in patients who developed a nondiarrhoeal form of haemolytic uraemic syndrome (HUS) being particularly frequent in patients with autosomal recessive or dominant HUS. The recurrence is almost the rule in patients with mutation in complement factor H gene. Most patients eventually lose the graft. Treatment with plasma infusions or plasmapheresis is often disappointing, but few cases may be rescued. Intravenous immunoglobulins and rituximab have also been successful in anedoctic cases. De novo TMA is rarer. A number of factors including viral infection may be responsible of de novo TMA, but in most cases TMA is triggered by calcineurin inhibitors or mTOR inhibitors. The clinical presentation of de novo TMA may be variable with some patients showing clinical and laboratory features of HUS while others showing only a progressive renal failure. The prognosis is less severe than with recurrent TMA. Complete withdrawal of the offending drug may lead to improvement in many cases. The addition of plasma exchange may result in graft salvage in about 80% of cases.
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PMID:Thrombotic microangiopathy after kidney transplantation. 1696 69

Mycophenolate mofetil (MMF) was introduced in pediatric renal transplantation almost 10 years ago. In several pediatric studies, MMF has been associated with improved graft survival and improved renal function with standard immunosuppression of steroids and calcineurin inhibitors (CNI). Both drugs are associated with significant negative effects including influence on growth, blood pressure, glucose metabolism, and also cosmetic side effects. Reduction of CNI was possible with MMF without increased rejection, improving blood pressure and renal function. Information is accumulating that steroid-sparing protocols including CNI are also associated with clinical improvement. Recent reports are positive in the pediatric population using the combination of induction with interleukin-2-receptor antagonists and mTOR inhibitors to spare steroids and CNI. Therefore MMF remains a mainstay of immunosuppressive protocols in the pediatric renal transplantation.
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PMID:Mycophenolate mofetil (Cellcept) in pediatric renal transplantation. 1697 92


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