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)

ASTEROID is a prospective, open-label blinded end-points trial aiming to assess whether very intensive statin therapy with rosuvastatin 40 mg/day could regress coronary atherosclerosis as determined by intravascular ultrasound (IVUS). This multinational study included 507 patients, among whom 349 had evaluable serial IVUS examinations at 24 months. Rosuvastatin decreased LDL cholesterol level from 130 mg/dl to 61 mg/dl (- 53.2%) and increased HDL cholesterol from 43 to 49 mg/dl (+ 14.7%). The three prespecified IVUS efficacy parameters were positively altered by rosuvastatin, demonstrating regression of coronary atherosclerosis : the mean change in percent atheroma volume (- 0.98%), the change in atheroma volume in the most diseased 10-mm subsegment me (- 6.1 mm3) and the change in total atheroma volume (- 6.8%) were all significant (p < 0,001). Adverse events were infrequent and similar to other statin trials. The present study demonstrates that a 2-year treatment with a high dose of rosuvastatin 40 mg/day is able to induce significant regression of coronary atherosclerosis as determined by IVU imaging. Further ongoing studies in the GALAXY clinical investigation programme should now demonstrate that rosuvastatin, the most potent statin to reduce LDL and increase HDL cholesterol, is also able to diminish the incidence of clinical outcomes, cardiovascular events in general and major coronary events in particular.
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PMID:[Clinical study of the month: ASTEROID: regression of coronary atherosclerosis with rosuvastatin at a maximal daily dose of 40 mg]. 1678 16

To evaluate the potential dose effect of rosuvastatin on triglyceride (TG) levels in Japanese hypertriglyceridemic patients, we randomized 154 patients with TG levels of >or=200 and <800 mg/dL to 8 weeks of treatment with rosuvastatin 5, 10 or 20mg once daily; bezafibrate 200mg twice daily; or placebo. Compared with placebo, TG was reduced by 30.1% with rosuvastatin 5mg, 30.1% with 10mg and 32.3% with 20mg (all p<or=0.0001), with no evidence of a dose effect. Changes in TG were evident after 2 weeks of treatment and maintained thereafter. In a benchmark comparison, rosuvastatin across its dose range reduced TG by 29.1-31.1% from baseline versus 45.4% for bezafibrate. Compared with bezafibrate, rosuvastatin was superior with respect to changes in non-high-density lipoprotein cholesterol (non-HDL-C, -36.8 to -44.3% for rosuvastatin versus -2.0% for bezafibrate), low-density lipoprotein cholesterol (-31.9 to -41.0% versus +29.3%), total cholesterol (-27.1 to -33.3% versus +2.1%), although smaller improvements in HDL-C (12.4-16.7% versus 19.6%) were observed. Rosuvastatin also produced superior dose-related decreases in median high-sensitivity C-reactive protein (22.9-38.5%). Treatment was well tolerated in both rosuvastatin and bezafibrate patients, with clinically important increases in alanine aminotransferase being rare, no adverse effect on renal function being observed and no cases of myopathy or rhabdomyolysis being reported. The current study does not suggest a dose-related effect of rosuvastatin in lowering TG in hypertriglyceridemic Japanese patients, although dose-related improvements in other elements of the atherogenic lipid profile were observed.
Atherosclerosis 2007 Oct
PMID:Effect of rosuvastatin 5-20mg on triglycerides and other lipid parameters in Japanese patients with hypertriglyceridemia. 1722 12

POLARIS investigated the efficacy and safety of rosuvastatin 40 mg and atorvastatin 80 mg in high-risk patients with hypercholesterolemia. Patients (n=871) were randomized to rosuvastatin 40 mg/day or atorvastatin 80 mg/day for 26 weeks. The primary endpoint was percentage change in LDL-C levels at 8 weeks. Secondary assessments included safety and tolerability, NCEP ATP III LDL-C goal achievement, change in other lipids and lipoproteins at 8 and 26 weeks, and health economics. Mean LDL-C levels were reduced significantly more with rosuvastatin 40 mg than with atorvastatin 80 mg at 8 weeks (-56% versus -52%, p<0.001). The proportion of patients achieving the NCEP ATP III LDL-C goal at 8 weeks was significantly higher in the rosuvastatin 40 mg group (80% versus 72%, p<0.01). Significant differences in the change from baseline in high-density lipoprotein cholesterol (HDL-C) (+9.6% versus +4.4%) and apolipoprotein (Apo)A-I levels (+4.2 versus -0.5) were observed between rosuvastatin and atorvastatin (all p<0.05). Both treatments were well tolerated. Based on a US analysis, rosuvastatin used fewer resources and delivered greater efficacy. Intensive lipid-lowering therapy with rosuvastatin 40 mg/day provided greater LDL-C-lowering efficacy than atorvastatin 80 mg/day, enabling more patients to achieve LDL-C goals. Rosuvastatin may therefore improve LDL-C goal achievement in high-risk patients with hypercholesterolemia.
Atherosclerosis 2007 Oct
PMID:Efficacy and safety of rosuvastatin 40 mg versus atorvastatin 80 mg in high-risk patients with hypercholesterolemia: results of the POLARIS study. 1722 26

Given the limitations of current risk assessment strategies, adjunctive markers are needed to improve the prediction of a first coronary event. Research into the inflammatory nature of atherosclerosis suggests that inflammatory-response proteins may serve as potential predictors of clinical events. One in particular, C-reactive protein, has been the focus of much attention. Epidemiologic studies have shown a fairly consistent independent association between high-sensitivity C-reactive protein (hs-CRP) elevations and coronary risk, although a causal relation has not yet been established. Given this association, current guidelines recommend the optional use of hs-CRP to predict enhanced absolute risk in selected patients. The use of a marker in general clinical practice should be based on statistical measures that show incremental benefit over established risk factors and on randomized clinical trials in which therapy initiated as a result of marker screening improves patient outcomes. Thus far, statistical evidence concerning the incremental benefit of hs-CRP is not conclusive. Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) is now being conducted to compare the efficacy of statin therapy versus placebo in subjects considered to be at increased risk on the basis of hs-CRP elevations, despite low to normal levels of low-density lipoprotein cholesterol. In conclusion, although epidemiologic studies suggest that low-grade C-reactive protein elevations are independently associated with coronary risk, more complete evidence is needed to validate the use of hs-CRP as a risk assessment tool in general practice and as a target for therapy in individual patients.
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PMID:Role of C-reactive protein in coronary risk reduction: focus on primary prevention. 1731 80

Since the identification of a fungal metabolite that inhibits HMG-CoA reductase in 1976, statins have emerged rapidly as the global leader in pharmacotherapeutics designed to lower low-density lipoprotein cholesterol (LDL-C). In conjunction, practice guidelines have recommended increasingly aggressive measures to improve coronary heart disease (CHD) outcomes by lowering LDL-C. By virtue of unique chemical characteristics, enhanced binding thermodynamics and limited cytochrome P450 3A4 metabolism, rosuvastatin calcium has a safety profile in line with currently marketed statins, but a different efficacy profile. Mirroring this chemical profile, the GALAXY program represents a comprehensive evaluation of the efficacy, safety and cost-effectiveness of rosuvastatin in individuals representing various clinical diagnoses, pathophysiological states and ethnicities. Also results from the Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study could provide further evidence for the use of rosuvastatin in individuals with traditional and emerging CHD risk factors, such as an elevated high sensitivity C-reactive protein level. This review will provide a comprehensive evaluation of the chemistry, clinical efficacy, safety and tolerability of rosuvastatin, and discuss the future role in the management of CHD and atherosclerosis.
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PMID:Rosuvastatin: a highly potent statin for the prevention and management of coronary artery disease. 1733 62

Dyslipidaemia is an important risk factor for the development of chronic kidney disease (CKD) and cardiovascular disease (CVD). CKD generates an atherogenic lipid profile, characterised by high triglycerides, low high-density lipoprotein (HDL) cholesterol and accumulation of small dense low-density lipoprotein (LDL) particles, comparable to that in the metabolic syndrome. These changes are due specifically to the effects of CKD on key enzymes, transfer proteins and receptors involved in lipid metabolism. Dyslipidaemia is further compounded by dialysis, immunosuppressive drugs, and concomitant diseases such as diabetes mellitus. Post hoc analyses from large intervention trials suggest the benefit of statins in patients with early CKD, but prospective clinical trials in haemodialysis (HD) and renal transplant recipients have not conclusively shown improvements in hard cardiovascular end-points. The lack of efficacy of statins in late-stage CKD could be a consequence of other disease processes, such as calcific arteriopathy and insulin resistance, which are not modified by lipid-lowering agents. Despite uncertainty and pending the results of ongoing statin trials such as Study of Heart and Renal Protection (SHARP) and AURORA (A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis: an Assessment of survival and cardiovascular events), major international guidelines continue to support statin therapy in CKD and renal transplant patients to reduce cardiovascular risk burden. Because of increased risk of toxicity, particularly myopathy, statins and other lipid-regulating agents should be used cautiously in CKD and renal transplant recipients.
Atherosclerosis 2008 Feb
PMID:Dyslipidaemia and cardiorenal disease: mechanisms, therapeutic opportunities and clinical trials. 1734 61

In a randomized, double-blind, crossover trial of 5-week treatment period with placebo or rosuvastatin (10 or 40 mg/day) with 2-week placebo wash-outs between treatments, the dose-dependent effect of rosuvastatin on apolipoprotein (apo) B-100 kinetics in metabolic syndrome subjects were studied. Compared with placebo, there was a significant dose-dependent decrease with rosuvastatin in plasma cholesterol, triglycerides, LDL cholesterol, apoB and apoC-III concentrations and in the apoB/apoA-I ratio, lathosterol:cholesterol ratio, HDL cholesterol concentration and campesterol:cholesterol ratio also increased significantly. Rosuvastatin significantly increased the fractional catabolic rates (FCR) of very-low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and LDL-apoB and decreased the corresponding pool sizes, with evidence of a dose-related effect. LDL apoB production rate (PR) fell significantly with rosuvastatin 40 mg/day with no change in VLDL and IDL-apoB PR. Changes in triglycerides were significantly correlated with changes in VLDL apoB FCR and apoC-III concentration, and changes in lathosterol:cholesterol ratio were correlated with changes in LDL apoB FCR, the associations being more significant with the higher dose of rosuvastatin. In the metabolic syndrome, rosuvastatin decreases the plasma concentration of apoB-containing lipoproteins by a dose-dependent mechanism that increases their rates of catabolism. Higher dose rosuvastatin may also decrease LDL apoB production. The findings provide a dose-related mechanism for the benefits of rosuvastatin on cardiovascular disease in the metabolic syndrome.
Atherosclerosis 2008 Mar
PMID:Dose-dependent effect of rosuvastatin on apolipoprotein B-100 kinetics in the metabolic syndrome. 1741 70

Human preadipocytes and adipocytes are known to produce the proatherogenic factor PAI-1 and proinflammatory cytokines, and obesity was found to be state of increased adipose production of these factors. In the present study, we investigated the effect of rosuvastatin on the regulation of PAI-1 gene expression in human adipocytes. Human preadipocytes, adipocytes in primary culture and the SGBS cell line were used as cell models. Cells were transfected using various constructs and promoter activity was measured as luciferase activity. PAI-1 expression was measured by quantitative RT-PCR and ELISA. Rosuvastatin inhibited PAI-1 mRNA expression and secretion of the protein in a concentration-dependent manner. This effect was reversed by isoprenoids. Addition of MEK-inhibitors and NFkappaB inhibitors also reduced PAI-1 expression and PAI-1 promoter luciferase activity. Further experiments revealed that rosuvastatin down-regulated the MEKK-1 mediated activation of the PAI-1 promoter. In conclusion our data suggest that rosuvastatin inhibits PAI-1 expression and release from human adipocytes via a MEKK-1-dependent but not a NFkappaB-dependent mechanism.
Atherosclerosis 2008 Feb
PMID:The HMG-CoA reductase inhibitor rosuvastatin inhibits plasminogen activator inhibitor-1 expression and secretion in human adipocytes. 1769 20

This study assessed the efficacy of rosuvastatin for reducing plasma low-density lipoprotein (LDL) cholesterol after 18 weeks of open-label, forced titration in patients with homozygous familial hypercholesterolaemia (hoFH) and compared the efficacy of rosuvastatin 80 mg and atorvastatin 80 mg. Forty-four patients aged 8-63 years (body mass >or=32 kg) entered the study; 4 had portacaval shunts and 11 were receiving plasmapheresis. Patients sequentially received rosuvastatin 20, 40 and 80 mg/day for 6 weeks. Patients remaining in the trial after 18 weeks received double-blind, randomised crossover treatment with rosuvastatin 80 mg/day and atorvastatin 80 mg/day for 6 weeks each. After 18 weeks, mean (S.D.)% reduction from baseline in LDL cholesterol was 22 (21)% overall and by 26 (15)% in 29 patients who neither had a portacaval shunt nor were receiving plasmapheresis. Seventy-two percent of the patients had >or=15% reductions in LDL cholesterol and were considered responders and included patients who had portacaval shunts or were receiving plasmapheresis. Mean LDL reductions from baseline after crossover treatment (n=21) with rosuvastatin 80 mg and atorvastatin 80 mg were 19 and 18%, respectively. All treatments were well tolerated. Rosuvastatin may have therapeutic value in the management of hoFH.
Atherosclerosis 2008 Mar
PMID:A dose-titration and comparative study of rosuvastatin and atorvastatin in patients with homozygous familial hypercholesterolaemia. 1772 60

Endothelial dysfunction and atherosclerosis are associated with an inflammation-induced decrease in endothelial nitric oxide synthase (eNOS) expression. Based on the differences between hydrophobic and hydrophilic statins in their reduction of cardiac events, we analyzed the effects of rosuvastatin and cerivastatin on eNOS and inducible NO synthase (iNOS) expression and NOS activity in TNF-alpha-stimulated human umbilical vein endothelial cells (HUVEC). Both statins reversed down-regulation of eNOS mRNA and protein expression by inhibiting HMG-CoA reductase and isoprenoid synthesis. Cerivastatin tended to a more pronounced effect on eNOS expression compared to rosuvastatin. NOS activity - measured by conversion of [(3)H]-L-arginine to [(3)H]-L-citrulline - was enhanced under treatment with both drugs due to inhibition of HMG-CoA reductase. Statin-treatment reduced iNOS mRNA expression under normal conditions, but had no relevant effects on iNOS mRNA expression in cytokine-treated cells. Rosuvastatin and cerivastatin reverse the detrimental effects of TNF-alpha-induced down-regulation in eNOS protein expression and increase NO synthase activity by inhibiting HMG-CoA reductase and subsequent blocking of isoprenoid synthesis. These results provide evidence that statins have beneficial effects by increasing eNOS expression and activity during the atherosclerotic process.
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PMID:Isoprenoid depletion by statins antagonizes cytokine-induced down-regulation of endothelial nitric oxide expression and increases NO synthase activity in human umbilical vein endothelial cells. 1792 46


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