Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As a possible explanation for everolimus/cyclosporine-induced hypercholesterolemia seen in transplant recipients, we investigated the interactions of the immunosuppressants everolimus and cyclosporine on bile flow and biliary excretion of bile salts and cholesterol in a subchronic bile fistula model in rats because biliary excretion is a main elimination route of cholesterol. After 2 weeks of daily treatment, everolimus (1 mg/kg i.p.) and cyclosporine (5 mg/kg i.p) decreased bile flow (-45 and -36%) and biliary excretion of bile salts (-34 and -54%) and cholesterol (-25 and -39%) and increased serum concentrations of cholesterol (+40 and +17%) and triglycerides (+220 and +110%). Bile salt serum concentration was elevated only by cyclosporine (+100%), and not by everolimus. Everolimus/cyclosporine slightly enforced the cyclosporine-induced hyperlipidemia but not reduction of bile parameters, while the cyclosporine-induced increase in bile salts in serum was totally prevented. From these results we conclude that bile salt synthesis could be impaired by everolimus, which could be one reason for everolimus-induced hypercholesterolemia.
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PMID:Everolimus/cyclosporine interactions on bile flow and biliary excretion of bile salts and cholesterol in rats. 1499 31

Everolimus is a derivative of sirolimus, a macrocyclic lactone, originally isolated from Streptomyces hygroscopicus. Both everolimus and sirolimus have a similar mechanism of action, exerting potent inhibition of growth factor-induced proliferation of lymphocytes, as well as other hematopoietic and nonhematopoietic cells of mesenchymal origin. Each agent complexes with the FK506 binding protein 12 to inhibit cyclin dependent kinase(s), collectively termed the target of rapamycin (TOR), causing G1-S phase cell cycle arrest. Safety and efficacy have been documented in large-scale, blinded, randomized, international clinical renal and cardiac transplant trials. Everolimus is more hydrophilic, exhibits a shorter elimination half-life (approximately 30 hours), and demonstrates greater relative bioavailability compared to sirolimus. However, similar to the calcineurin inhibitors and sirolimus, everolimus is biotransformed by the cytochrome P450, 3A4 isozyme. Also similar to sirolimus, clinical experiences identified biologically relevant side effects including hyperlipidemia and exacerbation of cyclosporine (CsA)-associated nephrotoxicity. However, also similar to sirolimus, accumulating evidence suggests that the hyperlipidemia can be controlled and the CsA-associated renal effects appear reduced with a low incidence of acute rejection when everolimus is administered in combination with reduced CsA doses. The experience using everolimus in cardiac transplantation has also provided potentially important insights into the consequences of antiproliferative effects on vascular smooth muscle cells and fibroblasts where reduction in intimal expansion was identified by intravascular coronary ultrasound examination among those patients receiving everolimus. Therefore, available results suggest that the introduction of everolimus as the newest TOR inhibitor should enhance therapeutic options for immunosuppression after organ transplantation.
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PMID:The evolving experience using everolimus in clinical transplantation. 1504 95

Everolimus 1.5 or 3 mg/day was compared with mycophenolate mofetil (MMF) 2 g/day in a randomized, multicenter 36-month trial in de novo renal allograft recipients (n = 588) receiving cyclosporine microemulsion (CsA) and corticosteroids. The study was double-blind until all patients had completed 12 months, then open-label. By 36 months, graft loss occurred in 7.2, 16.7 and 10.7% of patients in the everolimus 1.5, 3 mg/day, and MMF groups, respectively (p = 0.0048 for everolimus 1.5 mg/day vs. 3 mg/day); efficacy failure (biopsy-proven acute rejection (BPAR), graft loss, death or lost to follow-up) occurred in 33.0, 38.9 and 37.2% of patients (p = 0.455 overall), respectively. Mortality and incidence of BPAR were comparable in all groups. Creatinine values were higher in everolimus groups, requiring a protocol amendment that recommended lower CsA exposure. Diarrhea, lymphocele, peripheral edema and hyperlipidemia were more common among everolimus-treated patients, whereas viral infections, particularly cytomegalovirus infection, increased in the MMF group. Overall safety and tolerability were better with MMF and everolimus 1.5 mg/day than with everolimus 3 mg/day. In conclusion, at 36 months, an immunosuppressive regimen containing everolimus 1.5 mg/day had equivalent patient, and graft survival and rejection rates compared with MMF in de novo renal transplant recipients, whereas everolimus 3 mg/day had inferior graft survival. Renal dysfunction in everolimus cohorts necessitates close monitoring.
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PMID:Three-year efficacy and safety results from a study of everolimus versus mycophenolate mofetil in de novo renal transplant patients. 1616 3

Everolimus is an orally available inhibitor of the mammalian target of rapamycin (mTOR), which has been approved in combination with exemestane for hormone receptor-positive (HR) breast cancer after failure of treatment with non-steroidal aromatase inhibitors. Everolimus is generally very well tolerated with most common side effects including stomatitis, rash, fatigue, hyperglycemia, hyperlipidemia, and myelosuppression. Most of these side effects are mild and resolve with dose interruptions or dose reductions. Symptomatic non-infectious pneumonitis is a relatively uncommon class effect of mTOR inhibitors, which can be life threatening. Given the efficacy of everolimus in HR-positive metastatic breast cancer, it is crucial for physicians to recognize toxicities related to everolimus and start timely interventions. This review will focus on the adverse events reported with everolimus in breast cancer trials and will provide practical guidelines for the management of these adverse events.
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PMID:Everolimus: side effect profile and management of toxicities in breast cancer. 2390 51

Everolimus (EVE) is now approved by many agencies for the treatment of variable neoplasms. The risk for adverse events with this agent is not adequately defined. The purpose of this review is to summarize the EVE-induced cardiotoxic effect as an antineoplastic factor on patients who received the specific drug and to evaluate any possible antiatherogenic effects due to systemic use of the drug. Articles were searched on PubMed until August 2017. Articles included an expanded-access clinical trial, as well as phase 2 or 3 clinical trials (most of them were randomized). Three experimental studies that provided evidence for the possible antiatherogenic action of EVE were also included. In addition, only studies that evaluated the systemic use of the drug were included. To be eligible for inclusion, trials should have evaluated patients with malignancy, treated by EVE, or assessed the antiatherogenic effect of the systemic use of EVE through clinical or experimental studies. Only articles written in English language were included. No direct cardiotoxic adverse effects (arrhythmia, acute coronary event, heart failure, and echocardiography pathologic findings) were reported. Patients appeared to have a risk of developing adverse events that could be associated with the risk factors of cardiovascular disease. In all clinical studies, patients suffered hyperglycemia, and in most of them, hyperlipidemia was observed. Fewer studies have reported the incidence of hypertension. Finally, there is evidence claiming that EVE has an antiatherogenic action. Three experimental studies have shown that the systemic use of EVE in mice or rabbits with atherosclerotic lesions led to the reduction in atheromatous plaque growth. However, we could not find any clinical study that showed similar results in patients with cancer. To sum up, the only reported cardiac adverse event of EVE treatment in patients with cancer is indirect. They are associated with the risk factors of cardiovascular disease (hyperglycemia, hyperlipidemia, and hypertension), which are mainly mild and easily manageable. Further research and data that support the antiatherogenic action of EVE are needed.
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PMID:Everolimus as cancer therapy: Cardiotoxic or an unexpected antiatherogenic agent? A narrative review. 2941 Jan 75

BACKGROUND Everolimus can be utilized after heart or lung transplantation to reduce calcineurin inhibitor associated nephrotoxicity, due to cell cycle inhibitor adverse effects, and as adjunct therapy for rejection, cardiac allograft vasculopathy, and bronchiolitis obliterans syndrome. MATERIAL AND METHODS A single-center, retrospective cohort study was conducted including 51 adult heart transplant patients (n=32) and lung transplant patients (n=19) started on everolimus due to immunosuppressive therapy intolerance or failure, between 2010 and 2017. Everolimus indication, response, efficacy, and tolerability were assessed. RESULTS Everolimus was most commonly initiated due to leukopenia/neutropenia (n=17, 33%) or renal dysfunction (n=13, 25%). Leukopenia/neutropenia resolved in 76% of patients (13 out of 17 patients). Renal function (GFR) increased 7.4 mL/min from baseline to 3 months after everolimus initiation (P=0.011). The most common adverse effects were edema (n=23, 45%) and hyperlipidemia (n=25, 49%). A high discontinuation rate was observed (n=21, 41%), mostly from edema. CONCLUSIONS Everolimus might be beneficial in heart and lung transplant patients with leukopenia or neutropenia and lead to modest, short-term renal function improvement. Patient selection is crucial because adverse effects frequently lead to everolimus discontinuation.
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PMID:Everolimus Use for Intolerance or Failure of Baseline Immunosuppression in Adult Heart and Lung Transplantation. 3034 35

Everolimus is a mTOR inhibitor which demonstrates clinical activity in several solid tumors, especially in kidney cancer after first line TKI anti VEGF treatment and in breast cancer in association with exemesthane after failure of aroamatase inhibitors. The purpose of this study was to analyze in clinical practice the tolerance of everolimus in patients with breast cancer and kidney cancer. We conducted a retrospective study on patients followed up for breast cancer and kidney cancer over the period January 2008 - January 2015. All patients received everolimus at a dosage of 10 mg/day alone or in association with exemesthane for breast cancer. Adverse reactions were classified according to the National Cancer Institute Common Terminology Criteria for Adverses version 4.0 (NCI-CTCAE). A total of 100 patients were enrolled in the study: 76 patients with breast cancer and 24 patients with kidney cancer. The median follow-up period was 5.7 months. Treatment was stopped in more than 70% of the cases because of intolerance. The main adverse events, with a prevalence of more than 30% for all grades were mucositis, rash, fatigue, anemia, lymphopenia, hyperglycaemia, hyperlipidemia and infections. Mucositis, noninfectious pneumopathies and infections had high incidence of toxicity grade 3-4. Treatment discontinuation rate due to intolerance is high compared to literature data. At the beginning of treatment, particular attention should be given to mucositis, the immunosuppressive effect of treatment and non-infectious pneumopathies.
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PMID:[Tolerablity of everolimus in clinical practice: a retrospective study]. 3277 3