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)

Although immunosuppressive treatments and therapeutic drug monitoring (TDM) have significantly contributed to the increased success of thoracic transplantation, there is currently no consensus on the best immunosuppressive strategies. Maintenance therapy typically consists of a triple-drug regimen including corticosteroids, a calcineurin inhibitor (ciclosporin or tacrolimus) and either a purine synthesis antagonist (mycophenolate mofetil or azathioprine) or a mammalian target of rapamycin inhibitor (sirolimus or everolimus). The incidence of acute and chronic rejection and of mortality after thoracic transplantation is still high compared with other types of solid organ transplantation. The high allogenicity and immunogenicity of the lungs justify the use of higher doses of immunosuppressants, putting lung transplant recipients at a higher risk of drug-induced toxicities. All immunosuppressants are characterized by large intra- and interindividual variability of their pharmacokinetics and by a narrow therapeutic index. It is essential to know their pharmacokinetic properties and to use them for treatment individualization through TDM in order to improve the treatment outcome. Unlike the kidneys and the liver, the heart and the lungs are not directly involved in drug metabolism and elimination, which may be the cause of pharmacokinetic differences between patients from all of these transplant groups. TDM is mandatory for most immunosuppressants and has become an integral part of immunosuppressive drug therapy. It is usually based on trough concentration (C(0)) monitoring, but other TDM tools include the area under the concentration-time curve (AUC) over the (12-hour) dosage interval or the AUC over the first 4 hours post-dose, as well as other single concentration-time points such as the concentration at 2 hours. Given the peculiarities of thoracic transplantation, a review of the pharmacokinetics and TDM of the main immunosuppressants used in thoracic transplantation is presented in this article. Even more so than in other solid organ transplant populations, their pharmacokinetics are characterized by wide intra- and interindividual variability in thoracic transplant recipients. The pharmacokinetics of ciclosporin in heart and lung transplant recipients have been explored in a number of studies, but less is known about the pharmacokinetics of mycophenolate mofetil and tacrolimus in these populations, and there are hardly any studies on the pharmacokinetics of sirolimus and everolimus. Given the increased use of these molecules in thoracic transplant recipients, their pharmacokinetics deserve to be explored in depth. There are very few data, some of which are conflicting, on the practices and outcomes of TDM of immunosuppressants after thoracic transplantation. The development of sophisticated TDM tools dedicated to thoracic transplantation are awaited in order to accurately evaluate the patients' exposure to drugs in general and, in particular, to immunosuppressants. Finally, large cohort TDM studies need to be conducted in thoracic transplant patients in order to identify the most predictive exposure indices and their target values, and to validate the clinical usefulness of improved TDM in these conditions. In part I of the article, we review the pharmacokinetics and TDM of calcineurin inhibitors. In part II, we will review the pharmacokinetics and TDM of mycophenolate and mammalian target of rapamycin inhibitors, and provide an overall discussion along with perspectives.
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PMID:Pharmacokinetic optimization of immunosuppressive therapy in thoracic transplantation: part I. 1969 67

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

Sirolimus, a macrolide with immunosuppressive properties, was introduced into clinical practice a decade ago. The optimal use of this drug remains controversial: It displays a wide range of organ and tissue toxicities owing to the critical role of its therapeutic site- the kinase mammalian target of rapamycin-in the signal transduction pathways of numerous cytokines, growth factors, hormones, and nutrients. However, it displays unique, recognized benefits for renal transplant recipients: synergistic interactions with cyclosporine and possibly tacrolimus, allowing marked reduction in exposure to the calcineurin inhibitor; reduction in the frequency of posttransplant malignancies, particularly lymphomas, Kaposi sarcomas, and hypernephromas; and modest nephrotoxicity in comparison with calcineurin inhibitors. Because of its inhibitory effects on endothelial and smooth muscle cell proliferation, sirolimus may be a useful tool to dampen chronic vasculo-obliterative processes that attenuate graft survival. With increasing experience with the drug, the true potential of sirolimus will be realized to be a critical element in the immunosuppressive matrix.
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PMID:Current approaches to the use of sirolimus in renal transplantation. 1985 64

The choice of immunosuppression treatment in the kidney transplant patient depends on many factors: a history of cutaneous tumor; immunological, vascular, and primary cytomegalovirus infection risks; delay in the graft resuming function; patient knowledge of the side effects of immunosuppressant treatments, etc. Starting from a case study, this article describes the indications and contraindications of mTOR inhibitor use in the long-term immunosuppression strategy in the kidney transplantation patient. It also discusses the delay after grafting when the mTOR inhibitors can be introduced, immediately or at a later time, and points out some advantages of mycophenolate or calcineurin inhibitor substitution with mTOR inhibitors.
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PMID:[The use of mTOR inhibitors in kidney transplantation: who are the best patients and how should these inhibitors be used?]. 2012 51

All immunosuppressive medications require a learning curve that enables clinicians to improve the therapeutic index of agents. Mammalian target of rapamycin (mTOR) inhibitors are potentially a less nephrotoxic form of immunosuppression than calcineurin inhibitors (CNIs) that has been used in kidney transplant recipients for more than two decades. This drug class has a novel immunosuppressive action, probably mediated in part through inhibition of growth receptor signaling mechanisms. In addition, it has a unique drug toxicity, which is partially dose-related. This medication class also possesses antiproliferative activity, which may be useful in-post-transplant patients with increased atherosclerotic and malignancy risks. mTOR inhibitors have been utilized for de novo immunosuppression with CNIs, corticosteroids, and antimetabolites. mTOR inhibitors also have been used as CNI-sparing agents both early and late post-transplant. Much debate remains over how to best utilize mTOR inhibition in kidney transplantation.
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PMID:mTOR inhibition: the learning curve in kidney transplantation. 2013 84

Coadministration of the calcineurin inhibitor cyclosporine (CsA) and the mTOR inhibitors sirolimus (SRL) or everolimus (RAD) increases the efficacy of immunosuppression after organ transplantation. Neurotoxicity of CsA is a major clinical problem. Our goal was to assess the effects of CsA, SRL, and RAD on brain cell metabolism. The studies included the comparison of immunosuppressant-mediated effects on glucose metabolism, energy production, and reactive oxygen species (ROS) formation in perfused rat brain slices, primary rat astrocytes, and C6 glioma cells. In brain slices and astrocytes, CsA inhibited Krebs cycle metabolism, while activating anaerobic glycolysis, most likely to compensate for the inhibition of mitochondrial energy production. SRL and RAD inhibited cytosolic glycolysis but did not cause changes in mitochondrial energy production. CsA + SRL inhibited Krebs cycle and glycolysis, thus reducing the ability of the cell to compensate for the negative effects of CsA on mitochondrial nucleoside triphosphate synthesis. In contrast to SRL at the concentrations tested, RAD reduced the CsA-induced ROS formation and antagonized CsA-induced effects on glucose and energy metabolism. Surprisingly, in C6 cells, SRL and RAD exposure resulted in high ROS concentrations without significant impairment of cell metabolism. Our results suggested that SRL enhances CsA-induced ROS formation and negative metabolic effects in brain cells, while RAD seems to antagonize the CsA effects. However, the three models showed different metabolic responses when challenged with the study drugs. In contrast to SRL, RAD enhances ROS formation in C6 glioma cells but has only minor effects on normal rat brain tissue.
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PMID:Immunosuppressant neurotoxicity in rat brain models: oxidative stress and cellular metabolism. 2014 32

A significant increase of potent immunosuppressive agents over the last two decades has contributed to improved patient and graft survival after liver transplantation (LT). Numerous ongoing studies aim to determine the most effective immunosuppressive protocols while minimizing drug-related side effects. These protocols often combine several drugs with different mechanisms of action and toxicities allowing dosage adjustment. There is also a trend towards tailored immunosuppressive regimens according to the etiology of liver disease and comorbidities such as renal dysfunction and cardiovascular disease. The introduction of antibody induction therapies and antimetabolites resulted in an increasing number of studies with steroid minimization and calcineurin inhibitor (CNI) reduction protocols. Combined mycophenolate mofetil and minimal dose CNI therapy has shown to be safe and to improve kidney function and cardiovascular risk profile in the majority of studies. Sirolimus (SRL) and everolimus constitute a new class of compounds designated as the mammalian target of rapamycin (mTOR) inhibitors, which exhibit immunosuppressive and antiproliferative effects. There are conflicting results with respect to renal improvement upon switch to mTOR inhibitor therapy with concomitant reduction/elimination of CNI. Further trials will determine whether earlier conversion to mTOR inhibitors enable prevention of CNI-related renal dysfunction. Future results from randomized controlled studies will also show whether SRL can improve recurrence-free survival in patients transplanted for hepatocellular carcinoma.
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PMID:Current immunosuppressive approaches in liver transplantation. 2019 32

The mammalian target of rapamycin (mTOR) inhibitor drugs rapamycin (sirolimus) and everolimus have undergone extensive clinical trials for a variety of organ grafts and have been licensed for use in human transplantation. Uniquely, they block the function of a master chemical switch, the protein kinase mTOR, which integrates the multiple biochemical pathways that are necessary for growth factors to induce cell proliferation. Many of these pathways are abnormal in tumorigenesis, and the role of mTOR and its inhibitors in cancer treatment is undergoing intense investigation. There are pharmacokinetic differences between the rapamycins, however, in all major respects, their actions are the same. They show synergy with the calcineurin inhibitors in antirejection effects but also augment the nephrotoxicity of both cyclosporine and tacrolimus. They allow marked reduction in calcineurin inhibitor drug doses, which also reduces the nephrotoxicity of the combinations. In clinical trials in kidney, heart, lung, small bowel, pancreas, islet and liver transplantation in combination with cyclosporine and tacrolimus, rejection rates are equivalent or superior to those achieved with mycophenolate mofetil combinations. Despite this, its clinical usage remains limited. The side-effect profile, especially elevations in serum lipids and nephrotoxicity when administered in combination with calcineurin inhibitors, are the major factors. However, these drugs are finding an increasing place in other areas of medicine, including incorporation into endovascular coronary artery and peripheral arterial stents and in cancer therapy. Their ability to reduce fibrosis and neovascularization suggests other areas of potential use.
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PMID:Use of mTOR inhibitors in human organ transplantation. 2047 84

Mammalian target of rapamycin (mTOR) is the core component of two complexes, mTORC1 and mTORC2. mTORC1 is inhibited by rapamycin and analogues. mTORC2 is impeded only in some cell types by prolonged exposure to these compounds. mTOR activation is linked to tubular cell proliferation in animal models and human autosomal dominant polycystic kidney disease (ADPKD). mTOR inhibitors impede cell proliferation and cyst growth in polycystic kidney disease (PKD) models. After renal transplantation, two small retrospective studies suggested that mTOR was more effective than calcineurin inhibitor-based immunosuppression in limiting kidney and/or liver enlargement. By inhibiting vascular remodeling, angiogenesis, and fibrogenesis, mTOR inhibitors may attenuate nephroangiosclerosis, cyst growth, and interstitial fibrosis. Thus, they may benefit ADPKD at multiple levels. However, mTOR inhibition is not without risks and side effects, mostly dose-dependent. Under certain conditions, mTOR inhibition interferes with adaptive increases in renal proliferation necessary for recovery from injury. They restrict Akt activation, nitric oxide synthesis, and endothelial cell survival (downstream from mTORC2) and potentially increase the risk for glomerular and peritubular capillary loss, vasospasm, and hypertension. They impair podocyte integrity pathways and may predispose to glomerular injury. Administration of mTOR inhibitors is discontinued because of side effects in up to 40% of transplant recipients. Currently, treatment with mTOR inhibitors should not be recommended to treat ADPKD. Results of ongoing studies must be awaited and patients informed accordingly. If effective, lower dosages than those used to prevent rejection would minimize side effects. Combination therapy with other effective drugs could improve tolerability and results.
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PMID:Prospects for mTOR inhibitor use in patients with polycystic kidney disease and hamartomatous diseases. 2049 48

The high incidence of cancer and its aggressive progression is a common and major problem in patients receiving immunosuppressive therapy. The calcineurin inhibitors (CNIs) may have protumorigenic effects and can promote the overexpression of several molecules inducing tumor growth. We have recently demonstrated that CNIs can mediate the transcriptional activation of the angiogenic cytokine vascular endothelial growth factor (VEGF) and promote a rapid progression of human renal cancer. Here, we investigated whether the CNI cyclosporine (CsA) and the mTOR inhibitor rapamycin (RAPA) could alter the mRNA stability of VEGF in 786-0 and Caki-1 renal cancer cells. Following actinomycin D treatment, we observed that CsA increased, whereas RAPA decreased the VEGF mRNA stability as observed by real time PCR. It is established that the mRNA-binding protein HuR may play a critical role in VEGF mRNA stability. By using HuR-siRNA, we found that the knockdown of HuR significantly decreased the CNI-induced VEGF mRNA stability. By Western blot analysis, it has been observed that CNI treatment induced the translocation of HuR from the nucleus to the cytoplasm; CNIs also induced the association between HuR and PKC-delta and promoted the phosphorylation of HuR. Finally, we found that the inhibition of PKC-delta using a dominant negative plasmid significantly decreased the CsA-induced cytoplasmic translocation of HuR and VEGF mRNA stability. Together, targeting the pathways that promote CNI-induced transcription as well as the mRNA stability of VEGF might serve as novel therapeutics for the prevention and treatment of cancer in immunosuppressed patients.
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PMID:Altered VEGF mRNA stability following treatments with immunosuppressive agents: implications for cancer development. 2055 20


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