Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

More than $100 billion is spent in the United States each year on cardiovascular disease, primarily for hospitalizations and revascularization procedures. This is more than for any other disease state. As the clinical practice of medicine shifts from the paradigm of private practice to the managed care environment, cost-effectiveness is becoming increasingly important. A primary measure in analyzing cost-effectiveness is the cost-effectiveness ratio, or the dollar cost per unit of improvement for a given expenditure. This measure allows healthcare planners to compare completely different interventions. With approximately 52 million adult U.S. citizens having elevated low-density lipoprotein (LDL) cholesterol levels, lipid-lowering therapy---with diet or 3-hydroxy-3methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors---is an important consideration for primary care physicians and managed care providers. The National Health and Nutrition Examination Survey (NHANES) III indicates that 75-88% of adults who have coronary artery disease (CAD) risk factors or CAD require only a moderate (20--30%) reduction in LDL cholesterol levels to reach National Cholesterol Education Program goals. The clinical literature shows that all 4 of the currently available HMG-CoA reductase inhibitors can provide appropriate, moderate LDL cholesterol reductions within their recommended dosage ranges. For the majority of patients who need a 20--30% reduction in LDL cholesterol, fluvastatin 20 or 40 mg once daily provides the most cost-effective HMG-CoA therapy, expressed as cost of therapy per 1% LDL cholesterol reduction. For patients who need a >30% LDL cholesterol reduction, a high-dose HMG-CoA reductase inhibitor (e.g., simvastatin 20 or 40 mg/day) or a combination of a lower-dose HMG-CoA reductase inhibitor and a bile acid resin is the preferred initial therapy. Although a true cost-effectiveness analysis would incorporate morbidity and mortality data from clinical trials, analysis using intermediate endpoints, such as LDL cholesterol reduction, suggests that fluvastatin is the preferred initial HMG-CoA reductase inhibitor for the treatment of moderate hyperlipidemia.
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PMID:Cost-effectiveness of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor therapy in the managed care era. 887 73

This study was designed to determine the frequency of hyperlipidemia after orthotopic liver transplantation and whether treatment with a hydroxy-methylglutaryl coenzyme A reductase inhibitor was safe and efficacious. Cholesterol levels were assessed in 45 consecutive adult liver transplants (mean +/- SE). Four of 22 patients on cyclosporine (CsA) (18%) and three of 23 patients on FK506 (13%) had levels >225 mg/dl at 12 months (cholesterol levels for patients on CsA [total n=22]: pre-Tx = 140+/-11, 1 month = 183+/-36,3 months = 221+/-12, 6 months = 211+/-11, 12 months = 202+/-14 [P<0.01 vs. pre-Tx]; FK506 [total n=23]: Pre-Tx = 151+/-13, 1 month = 187+/-22, 3 months = 188+/-10, 6 months = 184+/-13, 12 months = 164+/-9 [P=0.02 vs. CsA]). A separate cohort of patients with stable graft function, cholesterol >225 mg/dl, and two additional risk factors for coronary artery disease were started on pravastatin. Ninety-eight patients were enrolled. Sixteen patients (16%) discontinued the drug because of subjective complaints. No episodes of rhabdomyolysis or hepatotoxicity occurred (cholesterol levels for patients on CsA [total n=65]: pretreatment = 251+/-7, 6 months = 220+/-7 [P=0.01 vs. pretreatment], 12 months = 224+/-8 [P=0.01 vs. pretreatment]; FK506 [total n=17]: pretreatment = 251+/-17, 6 months = 219+/-17, 12 months = 208+/-17 [P=0.08 vs. pretreatment]). Natural killer cells isolated from normal volunteers (n=14) exhibited 27+/-9% specific lysis. Patients on FK506 or cyclosporine-based immunosuppression alone (n=11) exhibited 20+/-4% specific lysis. Standard immunosuppression plus pravastatin (n=10) decreased lysis to 0.2+/-10% (P<0.02 vs. controls and standard immunosuppression). We conclude: (1) posttransplant hyperlipidemia occurs less frequently in liver transplant patients than in renal or cardiac transplants; (2) pravastatin is safe and efficacious for cholesterol reduction in liver transplant patients; and (3) pravastatin coadministered with standard immunosuppression reduces natural killer cell-specific lysis in these recipients.
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PMID:Hyperlipidemia after liver transplantation: natural history and treatment with the hydroxy-methylglutaryl-coenzyme A reductase inhibitor pravastatin. 887 87

Occlusive atherosclerosis is a major cause of morbidity and mortality in renal transplant recipients. Hyperlipidemia associated with the transplanted state may be at least partially responsible for this complication and is therefore an important target of therapy. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are powerful cholesterol-lowering drugs, but their broad use in transplant recipients has been hindered by concerns about interactions with cyclosporine. Cyclosporine interferes with the elimination of these agents, increasing their plasma and tissue levels and predisposing the patient to rhabdomyolysis. Fluvastatin, the first entirely synthetic HMG-CoA reductase inhibitor, possesses a distinct pharmacologic profile, including a shorter half-life and virtually no active circulating metabolites. Therefore, it may interact differently with cyclosporine. The pharmacokinetics and safety of fluvastatin, 20 mg/day, were evaluated in 20 hypercholesterolemic renal transplant recipients also receiving cyclosporine, usually in combination with azathioprine and methylprednisolone, during the 14-week study. Fluvastatin area under the curve, maximum plasma concentration, and time to maximum plasma concentration were minimally increased in these patients, unlike findings reported for lovastatin, pravastatin, and simvastatin. This suggests that metabolism of fluvastatin may be less affected by cyclosporine than that of other reductase inhibitors. Fluvastatin was well tolerated, with no evidence of myopathy, rhabdomyolysis, or ophthalmologic abnormalities. These findings and the significant reductions in total cholesterol and low-density lipoprotein cholesterol levels and the ratio of low-density to high-density lipoproteins achieved in these patients support the broader use of fluvastatin to treat hypercholesterolemia in renal transplant recipients.
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PMID:Evaluation of fluvastatin in the treatment of hypercholesterolemia in renal transplant recipients taking cyclosporine. 897 Jun 7

The efficacy and safety of hydroxymethylglutaric coenzyme A reductase inhibitor (statins) in the treatment of hyperlipidemia were evaluated in 12 infants and children with steroid-resistant nephrotic syndrome followed prospectively for 1 to 5 years. All patients experienced a hypolipidemic response with a marked reduction in their total cholesterol (40%), low-density lipoprotein cholesterol (44%), and triglyceride levels (33%), but no appreciable change in high-density lipoprotein cholesterol. Statin therapy was well tolerated without clinical or laboratory adverse effects. In spite of a significant hypolipidemic response to statin therapy there were no changes observed in the degree of proteinuria, hypoalbuminemia, or in the rate of progression to chronic renal failure. Long-term controlled studies with statin therapy are needed to further document or negate their renoprotective role in refractory nephrotic syndrome.
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PMID:Management of hyperlipidemia in children with refractory nephrotic syndrome: the effect of statin therapy. 906 27

Preclinical and clinical data on atorvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, indicate that it has superior activity in treating a variety of dyslipidemic disorders characterized by elevations in low-density lipoprotein cholesterol (LDL-C) and/or triglycerides. Results for patients randomized in early efficacy and safety studies were combined in one database and analyzed. This analysis included a total of 231 atorvastatin-treated patients (131 with hypercholesterolemia (HC), 63 with combined hyperlipidemia (CH), 36 with hypertriglyceridemia (HTG), and 1 with hyperchylomicronemia (Fredrickson Type V)). Patients were treated with a cholesterol-lowering diet (National Institutes of Health National Cholesterol Education Program Step 1 diet or a more rigorous diet) and either 2.5, 5, 10, 20, 40, or 80 mg/day of atorvastatin or placebo. Efficacy was based on percent change from baseline in total cholesterol, total triglycerides, LDL-C, very low-density lipoprotein cholesterol (VLDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (apo B), and non-HDL-C/HDL-C. Safety was assessed in all randomized patients. Atorvastatin seemed to preferentially lower those lipid and lipoprotein component(s) most elevated within each dyslipidemic state: LDL-C in patients with HC, triglycerides and VLDL-C in patients with HTG, or all 3 in patients with CH. Atorvastatin was well-tolerated with a safety profile similar to other drugs in its class.
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PMID:A brief review paper of the efficacy and safety of atorvastatin in early clinical trials. 918 Feb 40

We have previously demonstrated that monatepil maleate, AJ-2615, a new calcium antagonist endowed with alpha1-adrenoceptor blocking property, has antiatherosclerotic and plasma lipid-lowering effects in Japanese monkeys fed on a cholesterol-rich diet. To clarify the mechanisms on plasma lipid-lowering action, we investigated the effect of monatepil maleate in these monkeys on hepatic acyl-CoA:cholesterol acyltransferase (ACAT) activity. Both ACAT activity and esterified cholesterol content in the livers of monkeys fed on a cholesterol-rich diet for 6 months significantly increased about 7- and 16-fold, respectively, as compared with those in monkeys fed on a standard diet. Monatepil maleate (30 mg/kg/day for 6 months, orally) inhibited the increases of ACAT activity and esterified cholesterol content by 51% and 71%, respectively. In in vitro experiments, monatepil maleate inhibited ACAT activity in a concentration-dependent manner, whereas it did not affect 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity. A kinetic analysis revealed that monatepil maleate was a noncompetitive type inhibitor of ACAT. Hepatic ACAT activity was significantly correlated to hepatic esterified cholesterol content (r = 0.775, P < .0001), to plasma very low density lipoprotein (VLDL) content (r = 0.765, P < .0001) and to plasma total cholesterol content (r = 0.573, P < .005) in the monkeys. These results suggest that ACAT-inhibiting effect of monatepil maleate plays an important role in the reduction of hyperlipidemia.
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PMID:Inhibitory effect of monatepil maleate on acyl-CoA:cholesterol acyltransferase activity in the liver of cholesterol-fed Japanese monkeys. 923 33

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors reduces serum cholesterol in patients with high cholesterol blood levels including organ transplant recipients. HMG-CoA reductase inhibitor also inhibits a series of immune responses and thus have the potential of exerting immunosuppressive effect in patients with organ allografts. Experimentally, HMG-CoA reductase inhibitors reduces transplant arteriosclerosis. Whether this is linked to an immunosuppressive effect or not is unknown. There is little evidence that post-transplant hyperlipidemia directly increases the risk of cardiovascular diseases. Lipid lowering with HMG-CoA reductase inhibitor is not indicated for all allograft recipients but should be used if other cardiovascular risk factors are present.
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PMID:HMG-CoA reductase inhibitors in organ transplantation. 923 13

Cardiac allograft vasculopathy (CAV) remains a troublesome long-term complication of heart transplantation. It is manifested by a unique and unusually accelerated form of coronary disease affecting both intramural and epicardial coronary arteries and veins.CAV is characterized by vascular injury induced by a variety of noxious stimuli, including the immune system response to the allograft, ischemia-reperfusion injury, viral infection, immunosuppressive drugs, and classic risk factors such as hyperlipidemia, insulin resistance, and hypertension. The obstructive vascular lesions are thought to progress through repetitive endothelial injury followed by repair response. The role of major histocompatibility complex donor-recipient differences in the pathogenesis of CAV has not yet been completely elucidated. Intracoronary ultrasound studies reveal a dual morphology with donor-transmitted or de novo focal, noncircumferential plaques in proximal segments and/or a diffuse, concentric pattern observed in distal segments. A lack of correlation between microvascular and epicardial vessel disease suggests discordant manifestations and progression of CAV. Apoptosis and loss of functional vascular remodeling have to be considered as important mediators of clinically relevant CAV. Strategies for blocking T-cell costimulation and expression of adhesion molecules may help prevent chronic rejection in clinical transplantation. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and antiproliferative drugs may slow progression of CAV by various effects. Methods to augment endogenous nitric oxide bioavailability as well as newer immunosuppressive regimens may be protective. Balloon angioplasty has a limited role in the treatment of focal lesions. Experiences with coronary stenting, coronary artery bypass grafting, and transmyocardial laser revascularization are limited. Retransplantation has a worse outcome than initial transplantation.
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PMID:Cardiac allograft vasculopathy: a review. 932

There has been much debate over the past three decades concerning the role of hyperlipidaemia in coronary heart disease (CHD) and the efficacy of reducing plasma lipids levels. Although reduction in plasma cholesterol has been associated with a favourable effect on both primary and secondary CHD, there is a growing feeling that cholesterol may not be the only significant lipoprotein risk factor to be involved. Only relatively recently has the true role of triglycerides become apparent. Studies have indicated that the greatest reduction in CHD with some treatments has been found in those patients in whom high triglyceride levels accompany hypercholesterolaemia. In particular, in younger patients who have suffered a myocardial infarction, hypertriglyceridaemia is more common than hypercholesterolaemia. Nevertheless, recent large studies have shown that reduction of low-density lipoprotein (LDL) is beneficial, even in post-infarction patients with a relatively normal total cholesterol level. Furthermore, studies with fibrates and with HMG Co-A reductase inhibitors have indicated that progression of atheromatous lesions can be halted and in may cases there is evidence of regression. Continuing research on the pathophysiology of atherosclerosis, including the role of macrophages and thrombotic involvement, will further define the role of hypolipidaemics in the prevention and management of coronary heart disease.
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PMID:Is cholesterol the major lipoprotein risk factor in coronary heart disease?--a Franco-Scottish overview. 932 95

Both glucocorticoids and cyclosporine are used to prevent rejection in organ transplant recipients. However, long-term treatment with these drugs is known to induce hyperlipidemia and premature development of atherosclerosis. In previous studies, we have shown that the immunosuppressive drug cyclosporine inhibits catabolism of low-density lipoproteins (LDL) mainly by reducing the expression of LDL-receptor messenger RNA (mRNA), thus explaining the increased plasma levels of LDL cholesterol observed in patients treated with cyclosporine. In the present study, our objective was to investigate the mechanism by which glucocorticoids increase plasma levels of LDL cholesterol. We studied the catabolism of LDL in the human hepatoma cell line HepG2. Our results show that hydrocortisone at physiologically relevant concentrations inhibits LDL binding, uptake, and degradation in a dose-dependent way. Moreover, hydrocortisone also reduces the expression of LDL-receptor mRNA in a dose-dependent way. Cyclosporine also has an additive inhibitory effect on hydrocortisone in the catabolism of LDL. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor fluvastatin reverses the inhibitory effect of both hydrocortisone and cyclosporine. We conclude that treatment with hydrocortisone and/or cyclosporine induces increased plasma levels of LDL cholesterol because of reduced hepatic LDL receptor activity. HMG-CoA reductase inhibitors reverse this undesirable effect and thus reduce the risk of the development of atherosclerosis in patients subjected to immunosuppressive treatment.
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PMID:Additive inhibitory effect of hydrocortisone and cyclosporine on low-density lipoprotein receptor activity in cultured HepG2 cells. 932 21


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