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)

The proliferation signal inhibitors [PSIs; mammalian target of rapamycin (mTOR) inhibitors] are widely used for immunosuppression in transplant recipients. Alongside their immunosuppressive properties, PSIs also have substantial anti-neoplastic activity, as a result of their inhibition of cellular signalling pathways involved in critical functions such as cell division, T-cell activation, invasion and growth factor production. In vitro and in vivo studies have shown that PSIs can prevent the growth of experimentally transformed cells and tumour-derived cell lines, and can also increase the sensitivity of cells to apoptosis-inducing agents. The mechanisms of anti-tumour activities of PSIs identified in pre-clinical studies include up-regulation of adhesion molecules with reversion to less invasive phenotypes, and inhibition of angiogenesis resulting from both decreased vascular endothelial growth factor production and decreased endothelial sensitivity to such growth factors. In clinical trials of PSIs in transplant recipients, results show that the incidence of malignancies is substantially lower in patients receiving PSIs than in those receiving calcineurin inhibitor (CNI)-based immunosuppression, with significantly longer times to the development of malignancy. This protective effect of the PSIs is also present in patients receiving combination therapy with a CNI and a PSI. There is also evidence to suggest a role for PSIs in the management of post-transplantation malignancy, with reports of complete resolution of primary and metastatic tumours after conversion from a CNI to a PSI. These beneficial effects have led to the investigation of everolimus and an analogue of sirolimus as a treatment for patients with advanced solid tumours.
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PMID:The role of proliferation signal inhibitors in post-transplant malignancies. 1736 Jul 68

New immunosuppressive agents are being actively researched to avoid complications of chronic allograft nephropathy (CAN), calcineurin inhibitor (CNI) nephrotoxicity, and posttransplantation cancer. The family of mTOR inhibitors offers a unique immunosuppressive opportunity to avoid CNI toxicity and reduce the incidence of malignancy. Nevertheless, increasing data have demonstrated that sirolimus (SRL), the first mTOR introduced in the treatment of solid organ transplant recipients, induces proteinuria, an adverse event that could produce deterioration of long-term renal function. In this short-term study of patients followed for 1 to 16 months, we examined changes in renal function and proteinuria among renal transplant recipients converted from a CNI-based regimen to an everolimus (EVL)-based one, a recently introduced mTOR inhibitor. Our data showed that renal function can be optimized after conversion to EVL by up to 42% in recipients showing CAN grade 1 or 2, or CNI nephrotoxicity. Importantly, patients who improved their creatinine clearance did not show increased proteinuria measured in a voided specimen as the ratio of urinary protein and creatinine concentration (P/C). These results, if confirmed with long-term follow-up and a larger number of patients, would allow us to consider EVL as a promising agent for maintenance immunosuppressive regimens in kidney transplantation.
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PMID:Conversion from a calcineurin inhibitor-based immunosuppressive regimen to everolimus in renal transplant recipients: effect on renal function and proteinuria. 1744 51

Many kidney transplant patients experience an increase in proteinuria when converted from a calcineurin inhibitor-based regimen to one based on a mammalian target of rapamycin (mTOR) inhibitor, and preexisting proteinuria and poor renal function have been identified as risk factors for this increase. Our aim was to evaluate the effect of sirolimus, an mTOR inhibitor, on renal function and histology in a proteinuric model of reduced renal mass. Sirolimus-treated animals had approximately half as much proteinuria as vehicle-treated animals (P < 0.05), and had less glomerulosclerosis, tubular atrophy, interstitial fibrosis, and inflammation. Immunohistochemistry showed that sirolimus attenuated the increased expression of renal vascular endothelial growth factor (VEGF), as well as the expression of VEGF receptors 1 and 2. In conclusion, sirolimus halted the progression of proteinuria and structural damage in a rat model of reduced renal mass, possibly through a reduction in renal VEGF activity.
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PMID:Mammalian target of rapamycin inhibition halts the progression of proteinuria in a rat model of reduced renal mass. 1780 74

Acute rejection episodes are now as low as 5-20% in the first year after renal transplantation; however, graft half-life has remained almost unchanged in the last decade. This statistic is mainly attributable to the side effects of immunosuppression, with loss of allografts due to the chronic allograft nephropathy that is a consequence of calcineurin inhibitor toxicity or hypertension. Patient death due to cardiovascular events, infections and malignancy also contribute to allograft loss. The introduction of the inhibitors of the mammalian target of rapamycin sirolimus and everolimus in renal transplantation has increased the repertoire of immunosuppressive protocols substantially. They have a different mode of action and a different side effect profile (i.e. lower nephrotoxicity, less hypertension and less neoplastic potential) than the calcineurin inhibitors. The inhibitors of the mammalian target of rapamycin therefore provide an especially promising alternative for the maintenance immunosuppression after renal transplantation. This overview provides a summary of the current literature on inhibitors of the mammalian target of rapamycin, with a special focus on sirolimus.
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PMID:Sirolimus in renal transplantation. 1789 Feb 66

In two separate pharmacokinetic studies, the drug interaction between immunosuppressive agents was examined in a total of 12 cardiac transplant recipients by conversion of the concomitant immunosuppressant. In six patients under continuous tacrolimus therapy, the concomitant drug azathioprine was converted to everolimus (PK-TAC study). No significant effect on tacrolimus pharmacokinetic parameters was observed. In the second study in which the patients were converted from cyclosporine to tacrolimus under continuous everolimus therapy (PK-EVL study), a significant decrease in everolimus predose concentration (from 4.2 to 2.3 microg/L), maximum concentration (from 9.1 to 5.9 microg/L), and area under the concentration time curve (mean values decreased from 64.2 to 33.7 microg*h/L) was found, indicating a lower everolimus exposure. A pharmacokinetic interaction between cyclosporine and everolimus has been described previously for healthy volunteers after single-dose application and presumably originates from a comparatively greater inhibition of hepatic CYP3A4 or P-glycoprotein efflux transporter with a low-dose cyclosporine regimen. Our results confirm this interaction under clinical conditions and suggest close drug monitoring when converting the calcineurin inhibitor under concomitant mammalian target of rapamycin-inhibitor therapy.
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PMID:Everolimus exposure in cardiac transplant recipients is influenced by concomitant calcineurin inhibitor. 1822 73

Cardiovascular disease is the major cause of death in renal transplant recipients. Renal transplant recipients share the same cardiovascular risk factors as the general population, including hypertension, hyperlipidemia, diabetes mellitus, smoking, and positive family history. However, renal transplant recipients are also exposed to transplant-specific risk factors such as chronic immunosuppression. Most renal transplant recipients receive combinations or permutations of immunosuppressive drugs including a calcineurin inhibitor (cyclosporine or tacrolimus), a mammalian target of rapamycin (mTOR) inhibitor (sirolimus), an antiproliferative drug (mycophenolate mofetil and azathioprine), and corticosteroids. Cyclosporine and tacrolimus can induce glucose intolerance, hypertension, and hyperlipidemia. Sirolimus can induce hyperlipidemia. Corticosteroids can induce glucose intolerance, hypertension, hyperlipidemia, and weight gain. Central to the development of metabolic complications in renal transplant recipients is insulin resistance induced by immunosuppressive drugs. Insulin resistance is considered to be the central pathophysiological feature of metabolic syndrome, which is linked to increased risk of cardiovascular disease and to chronic renal failure. Therefore, metabolic syndrome likely contributes to cardiovascular disease and chronic renal allograft dysfunction in renal transplant recipients. Treatment of metabolic complications in renal transplant recipients is difficult, as conversion to an alternate immunosuppressive drug may lead to introduction of new metabolic complications, and as discontinuation of immunosuppressive therapy may lead to rejection. Future research should focus on designing immunosuppressive regimens that have minimal effects on insulin resistance and metabolic complications but that are effective in preventing acute rejection and in prolonging both allograft and patient survival.
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PMID:Immunosuppression and metabolic syndrome in renal transplant recipients. 1837 Jun 95

A nonquantitative summary of the current evidence suggests that calcineurin inhibitor (CNI) minimization and also CNI-free protocols are safe and efficient when used after the initial 3 months post-transplantation. In fact, the largest study so far showed that low-dose CNI in combination with mycophenolate mofetil (MMF) and steroids performed better than standard dose cyclosporine A (CsA). If CsA is used in combination with a mammalian target of rapamycin-Inhibitor (mTOR-I) considerable dose reduction of both drugs is required. A better choice than using both drug groups in lower doses together may be the withdrawal of CsA from this combination after 3-12 months. Later withdrawals or conversions to an mTOR-I failed to show additional benefit in terms of graft function or survival but caused less post-transplant malignancies. With improved short- and medium-term outcomes, this entity will become more of an issue. In fact, in some areas of the world, nowadays malignancies are the leading cause of death.
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PMID:Calcineurin inhibitor minimization, withdrawal and avoidance protocols after kidney transplantation. 1876 37

Newer immunosuppressive strategies have resulted in a marked reduction in graft rejection after transplantation, with the price being an increase of infectious complications, such as BK-related nephropathy. The targeting of new immunosuppressive pathways, such as interleukin-2-mammalian target of rapamycin inhibition, may have unexpected consequences for the immune response. Cell-depleting agents have long-lasting effects on cellular recovery and function, with the activation of latent viral infections and late viral and fungal infections. The multitude of different induction and maintenance protocols renders the detection of small increases of often rare infections very difficult. At the same time, preemptive and prophylactic strategies have gained widespread acceptance and may further offset small changes in infection rates. Other factors related to an increase or shift of infections may be of equal importance, such as increased use of marginal donors, older age at transplantation, or more patients receiving a second transplant. Not all the changes observed result in an increased immunosuppression. Steroid- and calcineurin inhibitor-sparing protocols may have a beneficial impact on infectious complications. Antimycotic or antiviral activity has been described for specific immunosuppressive agents, although the in vivo effect of these activities is uncertain. The possible role of specific drugs in the occurrence of infections is discussed, with emphasis on the antibodies and fusion proteins. The unequivocal attribution of a given infection to a specific drug is often impossible, as the risk of infection is dependent on the entirety of immunosuppression and the epidemiological pressure ('net immunosuppression'). It is important to remain vigilant for unexpected infections, not only in the context of clinical studies with selected patients, but also in the routine follow-up of our transplant patients.
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PMID:New immunosuppressive strategies and the risk of infection. 1881 28

The most serious complication of peritoneal dialysis is encapsulating peritoneal sclerosis (EPS). The prolonged inflammatory stimuli, fibrogenic cytokine overexpression, and angiogenesis that underlie EPS ultimately result in increased production of fibrous tissue, encapsulating the bowel loops. In recent years, inhibitors of mammalian target of rapamycin (mTOR) as an alternative agent for calcineurin inhibitor toxicity have been widely used in organ transplantation. These agents have also been used since the 1990s in endovascular medicine for drug-eluting stents because of antiproliferative effects on vascular smooth muscle cells and potent anti-inflammatory properties by direct action on human immune cells. Because of the shared characteristics of EPS and other fibrotic processes, we hypothesized that everolimus, an mTOR inhibitor can reverse the process responsible for the eventual development of EPS. We allocated 32 non-uremic albino Wistar rats to 4 groups: control group, 2 mL isotonic saline injected intraperitoneally (IP) daily for 3 weeks; CG group, 2 mL/200 g (0.1%) chlorhexidine gluconate (CG) injected IP daily and ethanol (15%) dissolved in saline, for 3 weeks; resting group, CG (weeks 0 - 3), plus peritoneal rest (weeks 3 - 6); and Evo-R, CG (weeks 0 - 3), plus 0.3 mg/L everolimus in drinking water (weeks 3 - 6). At the end of the study, we performed a 1-hour peritoneal equilibration test with 25 mL 3.86% PD solution, and examined the dialysate-to-plasma ratio of urea (D/P urea), dialysate white blood cell count, ultrafiltration (UF) volume, and morphologic change in the parietal peritoneum. Exposure to CG for 3 weeks resulted in alterations in peritoneal transport (increased D/P urea, decreased UF volume, p < 0.05) and morphology (increased inflammation, neovascularization, fibrosis, and peritoneal thickness, p < 0.05). Peritoneal rest has some beneficial effect only on UF failure and dialysate cell count (p < 0.05). However; everolimus was more effective than peritoneal rest with regard to vascularity and peritoneal thickness (p < 0.05). Everolimus has beneficial effects on UF failure, inflammation, and fibrosis. Everolimus may have therapeutic value in the management of EPS.
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PMID:Effects of everolimus as an antiproliferative agent on regression of encapsulating peritoneal sclerosis in a rat model. 1898 12

The clinical use of the immunosuppressant calcineurin inhibitor cyclosporine is limited by its nephrotoxicity. This is enhanced when combined with the immunosuppressive mTOR inhibitor sirolimus. Nephrotoxicity of both drugs is not yet fully understood. The goal was to gain more detailed mechanistic insights into the time-dependent effects of cyclosporine and sirolimus on the rat kidney by using a comprehensive approach including metabolic profiling in urine ((1)H NMR spectroscopy), kidney histology, kidney function parameters in plasma, measurement of glomerular filtration rates, the oxidative stress marker 15-F(2t)-isoprostane in urine, and immunosuppressant concentrations in blood and kidney. Male Wistar rats were treated with vehicle (controls), cyclosporine (10/25 mg/kg/day), and/or sirolimus (1 mg/kg/day) by oral gavage once daily for 6 and 28 days. Twenty-eight day treatment led to a decrease of glomerular filtration rates (cyclosporine, -59%; sirolimus, -25%). These were further decreased when both drugs were combined (-86%). Histology revealed tubular damage after treatment with cyclosporine, which was enhanced when sirolimus was added. No other part of the kidney was affected. (1)H NMR spectroscopy analysis of urine (day 6) revealed time-dependent changes of 2-oxoglutarate, citrate, and succinate concentrations. In combination with increased urine isoprostane concentrations, these changes indicated oxidative stress. After 28 days of cyclosporine treatment, urine metabonomics shifted to patterns typical for proximal tubular damage with reduction of Krebs cycle intermediates and trimethylamine-N-oxide concentrations, whereas acetate, lactate, trimethylamine, and glucose concentrations increased. Again, sirolimus enhanced these negative effects. Our results indicate that cyclosporine and/or sirolimus induce damage of the renal tubular system. This is reflected by urine metabolite patterns, which seem to be more sensitive than currently used clinical kidney function markers such as creatinine concentrations in serum. Metabolic profiling in urine may provide the basis for the development of toxicodynamic monitoring strategies for immunosuppressant nephrotoxicity.
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PMID:Urine metabolites reflect time-dependent effects of cyclosporine and sirolimus on rat kidney function. 1909


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