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) 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

The aims of this study were reviewing our experience regarding the pulmonary toxicity of the mammalian target of rapamycin (mTOR) inhibitor temsirolimus, discussing potential pathogenic mechanisms and proposing management strategies. Medical records and radiological reports of 22 patients treated with weekly doses of temsirolimus 25 mg were reviewed. Eight (36%) out of 22 patients developed pulmonary abnormalities compatible with drug-induced pneumonitis. Half were asymptomatic and in those with symptoms, dyspnea and dry cough were the most common. Radiologically two different patterns, ground glass opacities and lung parenchymal consolidation, were described. The management of this toxicity was variable, ranging from no intervention to discontinuation of the drug. In our experience temsirolimus may cause drug-induced pneumonitis at a higher incidence than that previously reported. The presentation and its severity are variable. The risk of developing this toxicity may be increased among subjects with abnormal pre-treatment pulmonary functions or history of lung disease.
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PMID:Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus. 1680 3

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

Enormous advancements in visceral transplantation have led to significant improvements in the quality of life of patients. However, despite these developments, the average graft half-life after transplantation has remained almost unchanged and chronic rejection is still considered a major problem. In this regard, more concerns have shifted to factors influencing long-term graft survival, patient survival, and quality of life. To achieve this goal, detrimental effects of immunosuppressive (IS) agents, which have deleterious influence on the quality of life and/or patient survival, should be reduced. In the course of recent years, the transplant community has worked on reducing these side effects by developing new ISs, employing new combination regimens, or finding and adjusting optimal dosages and blood level concentrations. Among the IS agents, the antifungal, antitumoral and IS activity of mammalian target of rapamycin (mTOR) inhibitors without nephrotoxicity, have received special attention regarding this new class of IS. Sirolimus (SRL), as the first member of mTOR inhibitors, has been utilized in many clinical trials with respect to its benefit-risk assessment. In our review, the clinical evolution of SRL, as well as the evidence-based clinical benefits of SRL in kidney and liver transplantation (KTx, LTx), are summarized. Various studies of SRL in KTx and LTx have shown that combination therapy with SRL will enrich the variety of IS modalities. It also can be regarded as a safe base therapy to which other necessary drugs can be added. In addition to the enhanced acute rejection prophylaxis, and in contrast to the calcineurin inhibitors (CNI) and steroids, this drug solely does not have common side effects such as nephrotoxicity, neurotoxicity, diabetes mellitus and hypertension. Moreover, this agent might diminish vasculopathic processes that mediate chronic allograft nephropathy (CAN). Therefore, by reducing the likelihood of CAN it can decrease the rate of long-term organ failure. One possibly desirable characteristic of SRL is its antiproliferative effect, which could provoke antitumoral or antiatherogenic activity following transplantation. Despite all promising impacts of SRL in organ transplantation, there are some concerns regarding the adverse effects of this drug, for instance dyslipidemia, pneumonitis and wound healing problems. However, the majority of these side effects can be reduced or ceased by careful dose adjustments and correct timing of use. In conclusion, after a decade of both in vivo and in vitro studies on SRL, it can be advocated that SRL is a promising, potent and effective IS agent as it reduces the rate of acute rejection episodes in de novo transplants. It could improve the quality of life, graft and patient survival rate, and achieve excellent outcomes with few adverse effects when wisely used in combination with other immunosuppressants.
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PMID:The role and value of sirolimus administration in kidney and liver transplantation. 1710 Jun 99

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

Inhibitors of mTOR (mammalian target of rapamycin) are immunosuppressants with less nephrotoxic potential than calcineurin inhibitors and antiproliferative effects, which are advantageous in the case of malignancy. However, a series of adverse events has been reported with the first-generation mTOR inhibitor sirolimus that includes hypersensitivity-like interstitial pneumonitis. To our knowledge, only one case of a pneumonitis associated with everolimus in a heart transplant patient has been reported, and it was related to elevated trough blood levels. We report herein the first case of a kidney graft recipient who developed everolimus-associated pneumonitis with normal trough blood levels that was completely reversed after drug withdrawal.
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PMID:Severe everolimus-associated pneumonitis in a renal transplant recipient. 1865 77

Sirolimus (SRL) is an mTOR inhibitor that has been shown, in contrast to calcineurin inhibitors (CNI), to inhibit cancers in experimental models. Since February 2005, we introduced SRL in liver transplant patients in group a, in whom the primary disease was hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic or autoimmune liver cirrhosis, and group b, HCC-negative patients who developed posttransplantation cancers de novo. Of 18 patients in group a, 11 received SRL ab initio (subgroup a1), starting for 10 patients at 66.1+/-29.2 days after surgical healing and after 10 days in 1 case; the remaining 7 patients (subgroup a2) received SRL at 31.2+/-24.2 months. Three patients in group b, included 1 with Kaposi's sarcoma, 1 with bladder cancer, and 1 with thyroid cancer. In this group, SRL was introduced at 80.8+/-40.4 months. In all patients but one, who received a single 5 mg loading dose, SRL was started at 2 mg/d and adjusted to 6 to 8 ng/mL blood levels. CNI drugs, present as primary therapy, were gradually tapered to low levels and eventually stopped. The following observations were drawn from this initial experience: (1) 4/21 (19.0%) patients had to discontinue SRL because of early and late side effects: thrombocytopenia (n=2) and headache with leukopenia and leg edema associated with knee joint arthralgia (n=2); (2) 14 patients (11 in group a and 3 in group b) are still on SRL monotherapy; (3) 1 HCC recurrence and 1 de novo pancreatic adenocarcinoma were observed at 14 and 16 months, respectively (at the time of transplantation, both patients were beyond the MIlan HCC criteria), and (4) 1 patient, from subgroup a1, died after 99 days due to pneumonitis and possible relation to SRL lung toxicity. In conclusion, SRL appeared to be an effective immunosuppressant that could be used as monotherapy in liver transplant patients. Any conclusion on SRL anticancer effects can only come from randomized large studies after long follow-up.
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PMID:Sirolimus therapy in liver transplant patients: an initial experience at a single center. 1867 98

Lymphangioleiomyomatosis is a rare and progressive lung cystic disease, caused by the infiltration of lung parenchyma by mesenchymal cells characterized by co-expression of contractile proteins and melanocytic markers. The pathogenesis of lymphangioleiomyomatosis is determined by mutations affecting tuberous sclerosis complex (TSC) genes, with eventual deregulation of the Rheb/mTOR/p70S6K pathway, and the potential therapeutic activity of mTOR inhibitors is currently under investigation. To better understand the molecular mechanisms involved in the pathogenesis of lymphangioleiomyomatosis, we investigated the expression of cathepsin-k (a papain-like cysteine protease with high matrix-degrading activity). The rationale of this choice was based on the recent demonstration that mTOR inhibitors can regulate major functional activities of osteoclasts, including the expression of cathepsin-k. The immunohistochemical study included 12 cases of lymphangioleiomyomatosis. Twelve angiomyolipomas and several lung diseases (sarcoidosis, organizing pneumonia, usual interstitial pneumonia, emphysema) were investigated as controls. In all lymphangioleiomyomatosis cases, strong cathepsin-k immunoreactivity was demonstrated, restricted to lymphangioleiomyomatosis cells. Similar expression levels were observed in renal angiomyolipomas. These observations extend the knowledge regarding the immunophenotypic profile of lymphangioleiomyomatosis cells, and provide a useful new marker for diagnosis in difficult cases (eg, in small transbronchial biopsies). The strong expression of such a potent papain-like cysteine protease in lymphangioleiomyomatosis cells can significantly contribute to the progressive remodelling of lung parenchyma observed in this deadly disease, with eventual formation of lung cysts. It is possible to speculate that mTOR inhibitors may exert part of their action by limiting the destructive remodelling of lung structure.
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PMID:Cathepsin-k expression in pulmonary lymphangioleiomyomatosis. 1906 Aug 45

Mammalian target of rapamycin (mTOR) has emerged as an important target for cancer therapy. Rapamycin has a distinct, well-documented toxicity profile and most of the toxicity data has been reported in patients with organ transplantation. Newer mTOR inhibitors have slightly different pharmacokinetic properties, yet they present toxicity profiles similar to rapamycin. Most of these toxicities are mild to moderate in severity and can be managed clinically by dose modification and supportive measures. Mucositis and pneumonitis are the most commonly reported toxicities, but they rarely lead to treatment discontinuation. Pathogenesis of pneumonitis is uncertain, but various hypotheses have been suggested, including cell-mediated immune response to the drug.
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PMID:The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents. 1938 54

Mammalian target of rapamycin (mTOR) inhibitors induce pneumonitis, an unusual but potentially fatal side effect of this drug group. We retrospectively collected the cases of pneumonitis induced by sirolimus or everolimus among 1471 adult cadaveric renal transplant recipients who were grafted at our institution from 1980-2008. Due to chronic transplant dysfunction or tumor, 205 patients were switched from calcineurin inhibitors to sirolimus (n = 88) or to everolimus (n = 117). Six patients (2.9%) developed pneumonitis: 1 was associated with sirolimus and 5 with everolimus (5 males and 1 female; median age, 60 years [range, 47-73 years]). Median times from conversion to pneumonitis onset were 34 days in 4 patients (range, 24-46 days) and 491 days in 2 subjects (range, 454-528 days). The mean drug trough level at presentation was 8.2 microg/L (range, 5.5-13.8 microg/L). The most common symptoms were dry cough (n = 6), fever (n = 5), and dyspnea (n = 4). Imaging tests revealed lower lobe involvement in all patients. Bronchoalveolar lavage performed in 4 patients showed lymphocytic alveolitis. All patients completely recovered after drug withdrawal. Five patients received steroids, 5 were switched to a calcineurin inhibitor, and 1 was switched to the other mTOR inhibitor. In conclusion, mTOR inhibitor-associated pneumonitis is a rare disease. Sirolimus did not cause more cases of pneumonitis than everolimus. Pneumonitis development was not dependent upon the drug blood level. Lower lobe involvement and lymphocytic alveolitis were usually present. Discontinuation of the mTOR inhibitor with steroid prescription resulted in adequate outcomes. A change to the other mTOR inhibitor should be contemplated if patient circumstances require this type of immunosuppression.
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PMID:Sirolimus and everolimus induced pneumonitis in adult renal allograft recipients: experience in a center. 1971 62


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