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 (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models. At 3 mo +/- 2 wk after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis. Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model. Malignancy-free survival rates for nonskin malignancies were compared using Kaplan-Meier estimates and the log-rank test. At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126 d; log-rank test, P = 0.007), and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST 0.346; 95% confidence interval 0.227 to 0.526; P < 0.001, intention-to-treat analysis). The relative risks for both basal and squamous cell carcinomas were significantly reduced. Kaplan-Meier estimates of nonskin cancer were 9.6 versus 4.0% (SRL-CsA-ST versus SRL-ST; P = 0.032, intention-to-treat analysis). Nonskin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi's sarcoma. Patients who received SRL-based, calcineurin inhibitor-free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA. Longer follow-up and additional trials are needed to confirm these promising results.
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PMID:Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. 1643 6

lmmunosuppressive therapy aims to protect transplanted organs from host responses. The success achieved during the last two decades in patient and graft survival is mainly related to the development and clinical use of efficacious immnosuppressive drugs. Nevertheless, the challenge of achieving a balance of adequate graft protection while minimizing the adverse consequences of excessive immunosuppression in the long-term continues. Current maintenance immunosuppression for renal transplant recipients generally consists of a calcineurin inhibitor plus an adjunctive antiproliferative agent, and steroids. The addition of induction therapy with a variety of monoclonal or polyclonal antibodies provides a more potent immunosuppression and its use is more relevant in patients with a high immunological risk. More recently, mammalian target of rapamycin inhibitors have been incorporated in different schemes proven its efficacy in a number of protocols. The incidence of acute rejection is now in its lower historical percentage and excellent results are reported from many transplant centers all over the world due mainly to a judicious combination of these drugs evaluated through many clinical studies. However, long-term use of immunosuppressive drugs convey inherent risks which translate in an increase of cancers and infections, among others. Ongoing investigations and clinical protocols involving new immunosuppressive drugs and biological agents are yielding important information on how to obtain tolerance or the nearest to this goal. Furthermore, there should be a continuous improvement in patient and graft survival, as the use of different immunosuppressive agents for induction and maintenance are individualized (adapted to each patient).
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PMID:[Immunosuppression for kidney transplant recipients: current strategies]. 1652 61

Everolimus is a proliferation signal inhibitor (PSI)/mammalian target of rapamycin inhibitor that is structurally similar to sirolimus, but with a number of important pharmacokinetic differences, including a shorter half-life and time to steady state. In clinical trials, the efficacy of everolimus 1.5 mg/day and 3.0 mg/day combined with ciclosporin (CsA) and steroids in de novo renal transplant recipients is similar to that of mycophenolate mofetil, with one study showing a significantly lower risk of antibody-treated acute rejection with everolimus. When combined with reduced-dose CsA, everolimus is associated with improved renal function compared with full-dose CsA, with no decrease in efficacy. Thus, everolimus may play an important role in calcineurin inhibitor (CNI)-sparing regimens for renal transplant recipients. Studies with sirolimus have shown that CNI withdrawal is associated with a significant improvement in renal function, although there may be an increase in the risk of acute rejection. however, patient and graft survival are not adversely affected by CNI withdrawal. Notably, proteinuria <800 mg/day before conversion is a strong predictor of successful response to sirolimus treatment, and hypertensive therapy and serum lactate dehydrogenase levels may also predict response. Adverse events commonly associated with the PSIs include dyslipidaemia, proteinuria and anaemia, although these can usually be managed without difficulty. Data are also available to suggest that the PSIs are associated with a lower risk of malignancy than other immunosuppressive agents. In conclusion, everolimus may permit reduced exposure to CNIs in renal transplant recipients, with the potential to improve tolerability and renal function.
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PMID:Everolimus in clinical practice--renal transplantation. 1681 52

Calcineurin inhibitors (CNIs) are associated with important side effects, such as nephrotoxicity, and thus there is an interest in developing CNI-sparing protocols using agents such as the proliferation signal inhibitor/mammalian target of rapamycin inhibitor everolimus. In a 3-month pilot study using an abrupt conversion protocol, ciclosporin (CsA) treatment was stopped after the morning dose and everolimus was started at 3.0 mg/day. Mycophenolic acid (MPA)-based therapy was continued, or prednisolone increased to 10 mg/day until target everolimus trough blood levels (3-8 ng/ml) were achieved. To date, seven patients have been enrolled, with three having completed at least 3 months of follow-up. Overall, conversion was effective and well-tolerated. Patients consistently achieved everolimus trough blood levels >3 ng/ml, and no episodes of acute rejection or proteinuria were reported after 3 months. In patients who completed the study, there were no major changes in the leucocyte or platelet counts during everolimus treatment. Serum creatinine levels were maintained or decreased slightly. One patient experienced a transient increase in serum creatinine during an episode of pneumonia, but levels decreased again after resolution of infection and temporary everolimus dose reduction. Serum cholesterol and triglyceride levels increased, but remained within acceptable limits. One patient receiving enteric-coated mycophenolate sodium 1440 mg/day experienced increasing everolimus trough blood levels and anaemia after conversion, and was therefore likely to have been over-immunosuppressed. Abrupt conversion to everolimus from CsA was effective and well-tolerated in renal transplant recipients. A reduction in MPA dosage at the time of conversion may be necessary to prevent over-immunosuppression.
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PMID:Conversion to everolimus in maintenance patients--current clinical strategies. 1681 53

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

Calcineurin inhibitors (CNIs) are frequently associated with side effects such as nephrotoxicity and hypertension, so CNI withdrawal from immunosuppressive regimens is desirable in certain cases. The proliferation signal inhibitors/mammalian target of rapamycin inhibitors everolimus and sirolimus may play an important role in achieving CNI withdrawal. Studies on sirolimus have shown that conversion from CNIs is associated with improvements in renal function and hypertension. A case report is presented of a renal transplant recipient who experienced hypertension and recurrent cutaneous neoplasia while receiving a ciclosporin (CsA)-based immunosuppressive regimen. After transplantation, the patient received full-dose CsA and prednisolone. After 7 years, the patient's serum creatinine increased from 1.9 mg/dl to 2.5 mg/dl, and mycophenolate mofetil (MMF, 1000 mg/day) was introduced, enabling the CsA dose to be reduced to 100 mg b.i.d. The patient also required resection of five cutaneous neoplastic lesions; this led to the decision to stop CsA and start treatment with everolimus 1.5 mg/day, which was increased to 3.0 mg/day to achieve target trough blood levels of 3 ng/ml. To avoid over-immunosuppression, the MMF dose was reduced to 500 mg/day. After conversion, the patient experienced a substantial improvement in blood pressure, from 175/85 mmHg to 155/70 mmHg. Serum creatinine levels decreased to 1.6 mg/dl, and there has been no recurrence of cutaneous neoplasia in 9 months of follow-up. Therefore, conversion to everolimus from CsA in a renal transplant recipient led to improvements in blood pressure and resolution of recurrent cutaneous neoplasia, with no evidence of rejection or changes in renal function.
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PMID:Conversion to everolimus in a patient with arterial hypertension and recurrent cutaneous neoplasia--a case report. 1681 57

Thyroid hormone (TH) action is mediated principally through binding of the hormone ligand, 3,3,5-triiodothyronine (T3), to TH receptors (TRs). This hormone-receptor interaction recruits other proteins to form complexes that regulate gene expression by binding to DNA sequences in the promoter of target genes. We recently described an extranuclear mechanism of TH action that consists of the association of TH-liganded TRbeta with p85alpha [regulatory subunit of phosphatidylinositol 3-kinase (PI3K)] in the cytosol and subsequent activation of the PI3K, generating phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3]. This initiates the activation of a signaling cascade by phosphorylation of Akt, mammalian target of rapamycin (mTOR) and its substrate p70(S6K), leading to the stimulation of ZAKI-4alpha synthesis, a calcineurin inhibitor. Furthermore, we found that this same mechanism leads to induction of the transcription factor hypoxia-inducible factor (HIF-1alpha), and its target genes, glucose transporter (GLUT)1, platelet-type phosphofructokinase (PFKP), and monocarboxylate transporter (MCT) 4. These genes are of special interest, because their products have important roles in cellular glucose metabolism, from glucose uptake (GLUT1) to glycolysis (PFKP) and lactate export (MCT4). These results demonstrate that the TH-TRbeta complex can exert a non-genomic action in the cytosol leading to changes in gene expression by direct (HIF-1alpha) and indirect (ZAKI-4alpha, GLUT1, PFKP) means.
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PMID:Thyroid hormone mediated changes in gene expression can be initiated by cytosolic action of the thyroid hormone receptor beta through the phosphatidylinositol 3-kinase pathway. 1686 26

Successful grafting of tissues or cells from mismatched donors requires systemic immunosuppression. It is yet to be determined whether immunosuppressive manipulations perturb transplanted cell engraftment or proliferation. We used syngeneic and allogeneic cell transplantation assays based on F344 recipient rats lacking dipeptidyl peptidase IV enzyme activity to identify transplanted hepatocytes. Immunosuppressive drugs used were tacrolimus (a calcineurin inhibitor) and its synergistic partners, rapamycin (a regulator of the mammalian target of rapamycin [mTOR]) and mycophenolate mofetil (an inosine monophosphate dehydrogenase inhibitor). First, suitable drug doses capable of inducing long-term survival of allografted hepatocytes were identified. In pharmacologically effective doses, rapamycin enhanced cell engraftment by downregulating hepatic expression of selected inflammatory cytokines but profoundly impaired proliferation of transplanted cells, which was necessary for liver repopulation. In contrast, tacrolimus and/or mycophenolate mofetil perturbed neither transplanted cell engraftment nor their proliferation. Therefore, mTOR-dependent extracellular and intracellular mechanisms affected liver replacement with transplanted cells. In conclusion, insights into the biological effects of specific drugs on transplanted cells are critical in identifying suitable immunosuppressive strategies for cell therapy.
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PMID:Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells. 1687 90

Sirolimus is a novel immunosuppressant with potent antiproliferative actions through its ability to inhibit the raptor-containing mammalian target of rapamycin protein kinase. Sirolimus represents a major therapeutic advance in the prevention of acute renal allograft rejection and chronic allograft nephropathy. Its role in the therapy of glomerulonephritis, autoimmunity, cystic renal diseases and renal cancer is under investigation. Because sirolimus does not share the vasomotor renal adverse effects exhibited by calcineurin inhibitors, it has been designated a 'non-nephrotoxic drug'. However, clinical reports suggest that, under some circumstances, sirolimus is associated with proteinuria and acute renal dysfunction. A common risk factor appears to be presence of pre-existing chronic renal damage. The mechanisms of sirolimus-associated proteinuria are multifactorial and may be due to an increase in glomerular capillary pressure following calcineurin inhibitor withdrawal. It has also been suggested that sirolimus directly causes increased glomerular permeability/injury, but evidence for this mechanism is currently inconclusive. The acute renal dysfunction associated with sirolimus (such as in delayed graft function) may be due to suppression of compensatory renal cell proliferation and survival/repair processes. Although these adverse effects occur in some patients, their occurrence could be minimised by knowledge of the molecular effects of sirolimus on the kidney, the use of sirolimus in appropriate patient populations, close monitoring of proteinuria and renal function, use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers if proteinuria occurs and withdrawal if needed. Further long-term analysis of renal allograft studies using sirolimus as de novo immunosuppression along with clinical and laboratory studies will refine these issues in the future.
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PMID:Sirolimus-associated proteinuria and renal dysfunction. 1714 61

Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor that inhibits cell cycle progression and has proven to be a potent immunosuppressive agent for use in solid organ transplant recipients. The drug was initially studied as an adjunct to ciclosporin (cyclosporine) to prevent acute rejection in kidney transplant recipients. Subsequent studies have shown efficacy when combined with a variety of other immunosuppressive agents. The most common adverse effects of sirolimus are hyperlipidaemia and myelosuppression. The drug has unique antiatherogenic and antineoplastic properties, and may promote immunological tolerance and reduce the incidence of chronic allograft nephropathy. Although sirolimus is relatively non-nephrotoxic when administered as monotherapy, it pharmacodynamically enhances the toxicity of calcineurin inhibitors. Ironically, the drug has been used to facilitate calcineurin inhibitor-free protocols designed to preserve renal function after solid organ transplantation. Whether sirolimus can be used safely over the long term with low doses of calcineurin inhibitors requires further study. The use of sirolimus as a corticosteroid-sparing agent also remains to be proven in controlled trials. Postmarketing studies have revealed a number of unforeseen adverse effects including impaired wound healing and possibly proteinuria, oedema, pneumonitis and thrombotic microangiopathy. Overall, sirolimus is a powerful agent when used judiciously with other available immunosuppressants. As is true for all immunosuppressive drugs available for treatment of solid organ transplant recipients, the efficacy of the drug must be balanced against its considerable adverse effects.
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PMID:Use of sirolimus in solid organ transplantation. 1733 96


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