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)

Rapamycin (sirolimus) is a macrolide, related to cyclosporine with immunosuppressive properties and antiproliferative activity in various human tumor cells lines and tumor xenograft models. The cytosolic kinase mTOR which controls the initiation of the translation of messenger RNA is the main known target of rapamycin. During clinical studies, rapamycin given by oral route as immunosuppressant did not show dose-limited toxicity and only asymptomatic thrombopenia and hyperlipemia were observed. In murine models, best antitumoral activity was observed using parental routes. CCI-779, an analog formulated for intravenous use has antitumor activity without significant immunosuppressive property in mice and is currently in phase I trials in man.
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PMID:[Rapamycin and CCI-779]. 1057 30

Since the approval of cyclosporine in 1983, only 3 drugs, mycophenolate mofetil, tacrolimus, and sirolimus, have been approved for maintenance immunosuppression in renal transplant recipients. All 3 agents decrease the incidence of early acute allograft rejection. An increase in intermediate and long-term graft survival has not been shown. However, survival data from these clinical trials should be interpreted with caution because the studies were not designed for this purpose. All 3 drugs have significant, albeit different, safety profiles. It remains to be seen whether, the lower incidence of hypertension and hyperlipidemia seen in tacrolimus-treated patients will reduce the incidence and severity of the cardiovascular disease experienced by renal transplant recipients. Sirolimus causes severe hyperlipidemia, and the long-term consequences both on the pathogenesis of cardiovascular disease and on lipid-associated renal injury have yet to be determined. Tacrolimus and mycophenolate mofetil appear to increase graft survival in pancreas-kidney recipients but their efficacy in another high-risk group, African-American recipients, has not yet been clearly shown. However, the trend toward improved graft survival in African-American recipients treated with tacrolimus is encouraging. Steroid-withdrawal remains a goal in the posttransplant period. The available data from steroid-withdrawal and steroid-avoidance clinical trials are mixed. Steroid withdrawal can be achieved in about 50% of patients on a cyclosporine-based immunosuppression regimen. Steroid-withdrawal under coverage of tacrolimus, mycophenolate mofetil or Neoral (Novartis Pharmaceuticals, East Hanover, NJ) may be more successful than that achieved in patients receiving Sandimmune (Novartis Pharmaceuticals). Further studies are needed in this area.
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PMID:Maintenance immunosuppression: new agents and persistent dilemmas. 1078 29

Chronic rejection represents the most common cause of transplanted graft loss in the long term. Rapamycin (sirolimus), and it's derivate RAD, are new and potent, immunosuppressive drugs. They inhibit cell proliferation driven by various growth factors. These drugs were successfully tested in some experimental models of the chronic rejection. Results of the first clinical trials have defined rapamycin pharmacokinetics and proved immunosuppressive efficacy. Rapamycin acts synergistically with cyclosporin A. The side effects are a dose-dependent thrombocytopenia and leukopenia but the most frequent is hyperlipidemia. The question, if rapamycin and RAD inhibit development of chronic rejection in man, will be solved by the prospective clinical trials over years.
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PMID:[Rapamycin: a new immunosuppressive agent capable of inhibiting chronic rejection?]. 1124 80

Sirolimus, which has a distinctive mechanism of action that inhibits cytokine-driven cell proliferation and maturation, provides an exciting addition to the immunosuppressive regimen for organ transplantation. A significant decrease in the number and severity of rejection episodes has been noted when sirolimus is used; it also offers the potential for patients to be withdrawn from steroids, making kidney transplantation an option for many more potential recipients. Toxic conditions such as hyperlipidemia, thrombocytopenia, and leukopenia become transient and manageable with reduction of the sirolimus dose and/or countermeasure therapy.
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PMID:Use of sirolimus in kidney transplantation. 1135 54

DE NOVO DIABETES AND CARDIOVASCULAR RISK: Certain kidney transplant recipients who develop de novo diabetes have an unfavorable cardiovascular risk profile, comparable to patients with type 2 diabetes mellitus, with advanced age, dyslipidemia, obesity and high blood pressure. MYOCARDIAL INFARCTION IN THE PERIOPERATIVE PERIOD: Among kidney transplant recipients, those whose risk factors include male gender diabetes, age over 50 years and prior revascularization procedure for coronary artery disease have a higher risk for myocardial infarction in the perioperative period. The usefulness of anticoagulant or beta-blockers as preventive treatment for these high-risk patients remains to be determined. HYPERLIPIDEMIA: A retrospective analysis of 530 kidney transplant recipients demonstrated that a very significant proportion of those with dyslipidemia are not receiving appropriate care although their lipid profile is indicative of a high or very high cardiovascular risk. MASSIVE PROTEINURIA: An angiotensin II inhibitor, losartan, has been found to be effective against massive proteinuria (> 3.5 g/l) occurring after kidney transplantation. CALCINEURIN-INHIBITOR-INDUCED HEMOLYTIC UREMIA SYNDROME: Five to ten percent of patients given calcineurin inhibitors develop a hemolytic uremia syndrome. Sirolimus appears to be a very interesting alternative for immunoprophylaxys against acute rejection.
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PMID:[Complications in kidney transplantation]. 1157 77

MONOCLONAL ANTIBODIES: Monoclonal antibodies have been humanized to improve their duration of action and their tolerance. Lymphocyte-depleting humanized anti-CD3 antibodies are globally well tolerated. Coupled with an immunotoxin, Campath 1H, a humanized anti-CD3 antibody with specific anti-CD52 depleting properties which also depletes immunocompetent cells, is being tested. There is increasing interest in the use of monoclonal antibodies in combination with rapamycin. SIROLIMUS AND EVEROLIMUS: The half-life of sirolimus is twice that of everolimus. Otherwise quite similar, these compounds have dose-dependent side effects: leukopenia, thrombocytopenia, hyperlipidemia. There use allows a lower dosage for the calcineurin inhibitor. Sirolimus is particularly active in reducing intimal proliferation within the vessel walls. Precise indications at the present time include induction of tolerance, withdrawal of the calcineurin inhibitor, use of low-dose calcineurin inhibitor, and corticosteroid withdrawal. ELIMINATING THE SIDE EFFECTS OF CORTICOSTEROIDS: Complications resulting from the use of corticosteroids, particularly bone complications, are still a problem with the low doses used in long-term regimens for transplant recipients. Several means have been proposed to reduce the risk. Total withdrawal is possible, but the risk of an increased rate of acute rejection limits indications. It appears that total withdrawal then complete abstention is not compatible immunologically. IMMUNOSUPPRESSORS IN PERSPECTIVE: Three groups of compounds have immunosuppressor potential: anti-adhesion molecule antibodies, co-stimulation blockers, and molecules inhibiting T-lymphocyte activators and their signalization factors.
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PMID:[Immunosuppression, ongoing clinical trials]. 1157 87

The immunosuppressive benefits of cyclosporine and tacrolimus in short-term and medium-term renal allograft survival are well documented. It is becoming increasingly clear that the basis of this immunosuppression, the inhibition of calcineurin, may be linked with nephrotoxicity, hypertension, hyperlipidemia, and new-onset diabetes mellitus, side effects that may lead to CRAD, death due to CVD, and late renal allograft loss. This clinical picture presents a clear need for new strategies that produce adequate immunosuppression to prevent acute rejection while simultaneously reducing the side effects associated with CNI-related therapies. Sirolimus combined with cyclosporine and tacrolimus has demonstrated an ability to reduce incidences of early acute rejection and, used as base therapy, has provided protection against acute rejection equivalent to that of cyclosporine, without the consequent nephrotoxicity associated with CNIs. In preliminary results from an ongoing clinical trial, sirolimus has been used to eliminate cyclosporine during maintenance immunosuppression, with subsequent improvements in measures of blood pressure and renal function. In addition, the antiproliferative properties of sirolimus and its ability to prevent graft vascular disease in animal studies make sirolimus a promising agent to decrease incidences of CRAD and improve long-term renal allograft survival. These findings point to a clear need to further explore both the efficacy of sirolimus immunotherapy and its long-term effects.
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PMID:Exploring treatment options in renal transplantation: the problems of chronic allograft dysfunction and drug-related nephrotoxicity. 1158 88

Sirolimus (Rapammune, rapamycin, RAPA) is a potent immunosuppressive drug that reduces renal transplant rejection. Hyperlipidemia is a significant side effect of sirolimus treatment, and frequently leads to cardiovascular disease. This study was undertaken to determine the repeatability, reversibility, and dose dependence of the plasma lipid and apolipoprotein altering effects of sirolimus, and to elucidate the mechanism by which sirolimus induces hypertriglyceridemia in some renal transplant patients. Six patients with renal allografts maintained on cyclosporine A and prednisone were selected on the basis of their previous hyperlipidemic response to short term (14 days) sirolimus administration. For longer-term treatment, each patient was started on 10 mg/day sirolimus and continued as tolerated for 42 days to reinduce hyperlipidemia. Timed blood samples were analyzed for lipid, apolipoprotein, and sirolimus levels. During sirolimus administration, mean total plasma cholesterol increased from 214 mg/dl to 322 mg/dl (+50%; range 25-92%); LDL-cholesterol levels followed a similar pattern. Mean triglyceride level rose from 227 to 432 mg/dl (+95%; range 9-254%). ApoB-100 concentration rose from 124 to 160 mg/dl (+28%; P < 0.05). ApoC-III level increased from 28.9 to 55.5 mg/dl, +92%; (P < 0.013). These lipid and apolipoprotein changes were found to be repeatable, reversible, and dose dependent. [(13)C(4)]palmitate metabolic studies in four patients with hypertriglyceridemia indicated that the free fatty acid pool was expanded by sirolimus treatment (mean = 42.3%). Incorporation of [(13)C(4)]palmitate into triglycerides of VLDL, IDL, and LDL was decreased 38.3%, 42,1%, and 38.4%, respectively, by sirolimus treatment of these patients. These results suggest that sirolimus alters the insulin signaling pathway so as to increase adipose tissue lipase activity and/or decrease lipoprotein lipase activity, resulting in increased hepatic synthesis of triglyceride, increased secretion of VLDL, and increased hypertriglyceridemia.
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PMID:Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. 1217 61

There has been a necessary change in attitude to transplantation; there is much less concern with short-term outcome and more concern with long-term kidney function, overall health and quality of life. Nephrotoxicity is an invariable consequence of long-term treatment with calcineurin antagonists and it is one of the most underestimated causes of late graft loss; it has been reported as a serious threat to both patient and graft survival following heart, liver and bone marrow transplantation. Sirolimus has been shown in many recent studies to be of great value in allowing patients to be weaned from cyclosporine with excellent patient and graft survival at 24 months a significant improvement in renal function with resolution of hirsutism and gum hyperplasia. Patients maintained on the combined regime of cyclosporine and sirolimus had significantly higher blood pressure, much more cyclosporine nephrotoxicity and hyperuricaemia at 12 months. The experimental studies have found cyclosporine and sirolimus potentiate with each other's good and adverse effects. Cyclosporine therefore augments hyperlipidaemia caused by sirolimus, and sirolimus augments nephrotoxicity caused by cyclosporine. The results of these studies indicate that sirolimus is a suitable replacement for cyclosporine or tacrolimus for long-term maintenance therapy. By contrast the use of sirolimus in combination with cyclosporine results in potentiation of side effects. The principal disadvantages being increased cyclosporine associated nephrotoxicity and sirolimus associated hyperlipidaemia
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PMID:Sirolimus (Rapamune) in renal transplantation. 1239 5

(1) Sirolimus, an immunosuppressant, is chemically related to tacrolimus but has a different mechanism of action. (2) In a double-blind trial in patients also treated with ciclosporin and a steroid, sirolimus was more effective than azathioprine at preventing acute rejection during the first three months, but caused more adverse effects (especially renal). (3) An unblinded trial compared ciclosporin + steroid + sirolimus with steroid + sirolimus for maintenance treatment. Ciclosporin was withdrawn gradually from the steroid + sirolimus group. Side effects from ciclosporin were therefore reduced (mainly nephrotoxicity and arterial hypertension), but rates of acute rejection, hepatotoxicity, and thrombocytopenia went up. (4) Sirolimus has numerous adverse effects, including hyperlipidemia, thrombocytopenia, hepatic disorders and opportunistic infections. The adverse effects of long term treatment are unknown. Sirolimus is metabolised by the cytochrome P450 isoenzyme CYP3A4, so may induce drug interactions. (5) In practice, sirolimus offers no advantage over existing immunosuppressive treatments for people with renal transplants.
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PMID:Sirolimus: new preparation. No tangible advance in renal transplantation. 1246 93


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