Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This randomized, double-blind, placebo-controlled trial was conducted in 52 centers in North America to compare the effects of the new, highly effective statin, rosuvastatin, with atorvastatin and placebo in hypercholesterolemic patients. After a 6-week dietary run-in, 516 patients with low-density lipoprotein (LDL) cholesterol > or =4.14 mmol/L (160 mg/dl) and < 6.47 mmol/L (250 mg/dl) and triglycerides < or =4.52 mmol/L (400 mg/dl) were randomized to 12 weeks of once-daily placebo (n = 132), rosuvastatin 5 mg (n = 128), rosuvastatin 10 mg (n = 129), or atorvastatin 10 mg (n = 127). The primary efficacy end point was percent change in LDL cholesterol. Secondary efficacy variables were achievement of National Cholesterol Education Program (NCEP) Adult Treatment Panel II (ATP II), ATP III, and European Atherosclerosis Society LDL cholesterol goals and percent change from baseline in high-density lipoprotein (HDL) cholesterol, total cholesterol, triglycerides, non-HDL cholesterol, apolipoprotein B, and apolipoprotein A-I. Rosuvastatin 5 and 10 mg compared with atorvastatin 10 mg were associated with greater LDL cholesterol reductions (-40% and -43% vs 35%; p <0.01 and p <0.001, respectively) and HDL cholesterol increases (13% and 12% vs 8%, p <0.01 and p <0.05, respectively). Total cholesterol and apolipoprotein B reductions and apolipoprotein A-I increases were also greater with rosuvastatin; triglyceride reductions were similar. Rosuvastatin 5 and 10 mg were associated with improved achievement in ATP II (84% in both rosuvastatin groups vs 73%) and ATP III (84% and 82% vs 72%) LDL cholesterol goals, and rosuvastatin 10 mg was more effective than atorvastatin in achieving European Atherosclerosis Society LDL cholesterol goals. Both treatments were well tolerated.
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PMID:Comparison of effects on low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia. 1180 27

Cardiovascular disease (CVD) remains a major cause of death in industrialised societies, and elevated serum lipids are a significant, highly prevalent and undertreated risk factor for this condition. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have revolutionised the treatment of hyperlipidaemia, and results from large-scale, long-term clinical trials have shown that the substantial reductions in low-density lipoprotein cholesterol (LDL-C) achieved with these drugs are associated with dramatic decreases in cardiovascular risk. Results from recent comparative clinical trials that have included a new drug in this class, rosuvastatin (Crestor), have demonstrated that it is significantly superior to atorvastatin, pravastatin and simvastatin in reducing total cholesterol, LDL-C and apolipoprotein B (Apo B). It is also significantly more effective than atorvastatin in increasing high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (Apo A-I). Rosuvastatin was also superior to all these agents in helping patients meet European Atherosclerosis Society (EAS) and National Cholesterol Education Programme (NCEP) goals for LDL-C. The results of an increasing number of studies indicate that statins have a wide range of pleiotropic properties that almost certainly contribute to their ability to decrease cardiovascular risk and may also make them valuable for treatment of other diseases. These actions include plaque stabilisation, improvement of endothelial function, inhibition of smooth muscle cell proliferation and migration, reduction of expression of adhesion molecules, prevention of cholesterol esterification and accumulation, reduction of secretion of matrix metalloproteinases by macrophages, reduction of platelet activity, reduction of formation of thrombogenic factors, chemoprotection and induction of bone morphogenic protein-2 (BMP-2). Further exploration of these actions will provide key information about class effects and properties of specific members of this highly useful group of drugs.
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PMID:Statin therapy: rationale for a new agent, rosuvastatin. 1213 48

Rosuvastatin, a new statin, has been shown to possess a number of advantageous pharmacological properties, including enhanced HMG-CoA reductase binding characteristics, relative hydrophilicity, and selective uptake into/activity in hepatic cells. Cytochrome p450 (CYP) metabolism of rosuvastatin appears to be minimal and is principally mediated by the 2C9 enzyme, with little involvement of 3A4; this finding is consistent with the absence of clinically significant pharmacokinetic drug-drug interactions between rosuvastatin and other drugs known to inhibit CYP enzymes. Dose-ranging studies in hypercholesterolemic patients demonstrated dose-dependent effects in reducing low-density lipoprotein cholesterol (LDL-C) (up to 63%), total cholesterol, and apolipoprotein (apo) B across a 1- to 40-mg dose range and a significant 8.4% additional reduction in LDL-C, compared with atorvastatin, across the dose ranges of the two agents. Rosuvastatin has also been shown to be highly effective in reducing LDL-C, increasing high-density lipoprotein cholesterol (HDL-C), and producing favorable modifications of other elements of the atherogenic lipid profile in a wide range of dyslipidemic patients. In patients with mild to moderate hypercholesterolemia, rosuvastatin has been shown to produce large decreases in LDL-C at starting doses, thus reducing the need for subsequent dose titration, and to allow greater percentages of patients to attain lipid goals, compared with available statins. The substantial LDL-C reductions and improvements in other lipid measures with rosuvastatin treatment should facilitate achievement of lipid goals and reduce the requirement for combination therapy in patients with severe hypercholesterolemia. In addition, rosuvastatin's effects in reducing triglycerides, triglyceride-containing lipoproteins, non-HDL-C, and LDL-C and increasing HDL-C in patients with mixed dyslipidemia or elevated triglycerides should be of considerable value in enabling achievement of LDL-C and non-HDL-C goals in the numerous patients with combined dyslipidemias or metabolic syndrome who require lipid-lowering therapy. Rosuvastatin is well tolerated alone, and in combination with fenofibrate, extended-release niacin, and cholestyramine, and has a safety profile similar to that of currently marketed statins. A large, long-term clinical trials program is under way to investigate the effects of rosuvastatin on atherosclerosis and cardiovascular morbidity and mortality.
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PMID:Rosuvastatin: a highly effective new HMG-CoA reductase inhibitor. 1248 Dec 2

Newer, more effective statins are powerful agents for reducing elevated levels of low-density lipoprotein (LDL) cholesterol and thereby lowering the risk of coronary heart disease (CHD) and related adverse events. Although LDL remains the primary target of therapy for reducing CHD risk, increased interest is focusing on apolipoprotein B (apoB)-containing lipoprotein subfractions--particularly very-low-density lipoprotein (VLDL). VLDL remnants, and intermediate-density lipoproteins (IDL)--as secondary targets of therapy. Elevated apoB is known to be an important risk factor for CHD, and dysregulation of the metabolism of apoB-containing lipoproteins is involved in the progression of atherosclerosis. Statins reduce circulating concentrations of atherogenic apoB-containing lipoproteins by decreasing the production of VLDL in the liver and, thus, the production of VLDL remnants and LDL. Statins also increase the clearance of these particles through upregulation of LDL receptors in the liver. Efforts to develop statins with enhanced lipid-modifying properties are ongoing. The optimal statin would offer a high degree of inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a prolonged duration of action, hepatic selectivity for maximal upregulation of LDL receptors, and a low potential for drug-drug interactions. Recent studies have shown that rosuvastatin, a new agent in this class, demonstrates these qualities. Rosuvastatin is a highly effective inhibitor of HMG-CoA reductase, is relatively nonlipophilic, has a half-life of approximately 20 h, exhibits hepatic selectivity, has little systemic availability, and has a low potential for drug-drug interactions because of its limited degree of metabolism by the cytochrome P450 system. A recent double-blind, crossover study revealed that treatment with rosuvastatin resulted in marked reductions in apoB-containing lipoproteins in patients with type IIa or IIb dyslipidemia. By reducing the number of atherogenic lipoprotein particles, rosuvastatin decreases the atherosclerotic burden in hyperlipidemic patients at high risk for CHD and related adverse outcomes.
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PMID:New dimension of statin action on ApoB atherogenicity. 1253 16

A total of 5 randomized, double-blind trials in patients with hypercholesterolemia were prospectively designed to allow pooling of plasma lipid data after 12 weeks of treatment. The purpose was (1) to compare rosuvastatin 5 and 10 mg with atorvastatin 10 mg (data from 3 of the 5 trials); (2) to compare rosuvastatin 5 and 10 mg with simvastatin 20 mg and pravastatin 20 mg (data from 2 of the 5 trials); and (3) to summarize overall efficacy and subset analyses of rosuvastatin data from all 5 trials. Rosuvastatin 5 mg (n = 390) and 10 mg (n = 389) reduced low-density lipoprotein (LDL) cholesterol significantly more than did atorvastatin 10 mg (n = 393) (41.9% and 46.7% vs 36.4%, both p <0.001). Treatment with rosuvastatin 5 mg (n = 240) and 10 mg (n = 226) also resulted in significantly greater reductions in LDL cholesterol compared with both simvastatin 20 mg (n = 249) and pravastatin 20 mg (n = 252) (40.6% and 48.1% vs 27.1% and 35.7%, all p <0.001). Significant differences favoring rosuvastatin 10 mg were also observed for total cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol, apolipoprotein (apo) B, and apo A-I versus atorvastatin 10 mg, and for total cholesterol, HDL cholesterol, triglycerides, non-HDL cholesterol, and apo B versus simvastatin 20 mg and pravastatin 20 mg. Analyses of all the rosuvastatin 10 mg data (n = 615) from the 5 trials in subgroups defined by age > or =65 years, female sex, postmenopausal status, hypertension, atherosclerosis, type 2 diabetes, and obesity showed that rosuvastatin had consistent efficacy across patient subgroups.
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PMID:Efficacy of rosuvastatin compared with other statins at selected starting doses in hypercholesterolemic patients and in special population groups. 1264 36

Carotid artery intima-media thickness (IMT) measured by ultrasound has been shown to be correlated with existing cardiovascular disease (CVD) and predictive of CVD in individuals without clinically evident disease. Carotid IMT is now widely used as a surrogate marker for atherosclerotic disease. A number of studies have shown that lipid-lowering therapy with a statin can reduce or reverse carotid IMT progression. The METEOR trial (Measuring Effects on Intima-Media Thickness: an Evaluation Of Rosuvastatin) will examine the effects of aggressive lipid-lowering treatment with rosuvastatin on IMT in mildly hypercholesterolemic low-risk subjects with relatively high IMT values. The results will provide important information on the ability to achieve regression of abnormal IMT with robust reductions in low-density lipoprotein (LDL) cholesterol levels to below current target levels. Another study will examine the effects of potent LDL cholesterol reduction with rosuvastatin in young patients with heterozygous familial hypercholesterolemia (FH). Patients with FH are at increased risk of premature coronary heart disease in association with marked LDL cholesterol elevations, exhibiting a rate of progression of IMT 5x greater than that of low-risk controls without the disorder and early intervention may be the optimal approach to modifying atherosclerosis progression in these patients.
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PMID:Surrogate markers of atherosclerosis: impact of statins. 1271 35

The National Cholesterol Education Program Adult Treatment Panel III guidelines and the results of the Heart Protection Study have provided a stronger rationale to more aggressively treat high-risk patients to a low-density (LDL) cholesterol goal of less than 100 mL/dL. Two new therapies, ezetimibe and rosuvastatin, have recently been added to the lipid-lowering armamentarium to improve guideline adherence. Ezetimibe, a novel cholesterol absorption inhibitor, lowers LDL by 18% to 20% and can be used safely in combination with statins. Adding ezetimibe to a statin is comparable with the LDL-lowering efficacy of tripling the dose of the statin. Rosuvastatin is a highly efficacious statin providing 8% greater LDL reduction than equivalent doses of atorvastatin, and the starting dose of 10 mg/d provides nearly a 50% reduction in LDL cholesterol. There are several investigational drugs in development for the prevention and treatment of atherosclerosis. Of these investigational drugs, the most promising are the cholesterol ester transfer protein inhibitors, which have the potential to significantly raise high-density lipoprotein cholesterol and acetyl-coenzyme A: cholesterol acyltransferase inhibitors, which may directly inhibit the progression of atherosclerosis.
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PMID:Newer pharmaceutical agents to treat lipid disorders. 1455 88

This randomised, double-blind, placebo-controlled crossover study evaluated the effects of rosuvastatin (40 mg/day for 8 weeks) on atherogenic apolipoprotein B-containing lipoprotein subfractions. Subjects, recruited based on raised plasma triglyceride (TG) or low-density lipoprotein cholesterol (LDL-C), were divided into normotriglyceridaemic (NTG, n = 13; TG < 2.0 mmol/l) and hypertriglyceridaemic (HTG, n = 16; TG > or = 2.0 mmol/l) groups. Similar reductions on rosuvastatin were observed for both groups in LDL-C (NTG -60%; HTG -56%), apoB (both -49%), intermediate-density lipoprotein (NTG -57%; HTG -54%) and LDL circulating mass (NTG -52%, HTG -58%) (all P < 0.001 versus placebo), i.e., these changes were phenotype independent. Phenotype dependency in response was observed in HTG relative to NTG in concentration of small dense LDL (LDL-III) (NTG -44%, P = NS; HTG -69%, P < 0.001), very-low-density lipoprotein1 (NTG -18%, P = NS; HTG 46%, P < 0.01), and remnant-like particle cholesterol (NTG -31%, P = NS; HTG -48%, P < 0.05). Rosuvastatin reduced cholesteryl ester transfer protein (CETP) by 33% in NTG and 37% in HTG (both P < 0.001); a reduction in cholesteryl ester transfer activity (-59%, P < 0.001) was observed in HTG only. Rosuvastatin therefore, in addition to lowering LDL and apoB-concentrations, largely corrected the TG and LDL abnormalities in subjects who had the propensity to develop the atherogenic lipoprotein phenotype.
Atherosclerosis 2003 Dec
PMID:Phenotype-dependent and -independent actions of rosuvastatin on atherogenic lipoprotein subfractions in hyperlipidaemia. 1464 93

Rosuvastatin is a new statin with a great number of pharmacological benefits related to the capacity of modifying favorably the lipid profile but also for the selective binding with 3-hydroxy-3-methylglutaryl coenzyme A reductase, relative hydrophilic properties and selectivity for hepatic cells. Rosuvastatin demonstrated to be more efficacious in reducing LDL cholesterol levels than other statins and to be capable of increasing HDL cholesterol levels. It is well tolerated in a wide range of dosages maintaining its effectiveness. Many trials are ongoing with the aim to evaluate not only the efficacy of rosuvastatin in terms of surrogate endpoints but also in terms of cardiovascular morbidity and mortality. The usefulness of rosuvastatin will be evaluated also in selective patient populations affected by advanced renal disease or chronic heart failure. Two relevant research projects have been started recently, the GALAXY Programme, designed for evaluating the efficacy of rosuvastatin in atherosclerosis and ischemic heart disease and the GISSI-HF trial planned with the aim of testing the efficacy of this statin on morbidity and mortality in chronic heart failure and investigating the pharmacological effects on the pathophysiological mechanisms of heart failure.
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PMID:[Ongoing trials and future prospects]. 1498 47

Rosuvastatin (Crestor) has been recently launched in Belgium by AstraZeneca. This new statin is indicated for the treatment of primary hypercholesterolaemia or combined dyslipidaemia, when changes in dietary habits are insufficient. Direct comparative randomised clinical trials with other statins demonstrated that rosuvastatin exerts a more favourable impact on lipid profile. When compared on a mg basis to other statins, rosuvastatin is associated with a greater reduction in total and LDL cholesterol levels and a greater increase of HDL cholesterol concentration, with a similar decrease in triglyceride levels. At the usual dosage of 10 mg, rosuvastatin allowed to reduce LDL cholesterol below recommended target levels for at risk patients among almost 80% of treated individuals in phase III clinical trials. If necessary, the daily dosage may be increased to 20 mg, or up to 40 mg (maximal dose), mostly in case of severe familial hypercholesterolaemia. Safety profile is good and similar to that of other commercialised statins. Rosuvastatin is currently evaluated in an extensive programme of randomised clinical trials (Galaxy programme) in order to demonstrate its efficacy in both prevention of atherosclerosis and reduction of cardiovascular morbidity and mortality.
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PMID:[Drug of the month. Rosuvastatin (Crestor)]. 1503 45


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