cerivastatin and Hypercholesterolemia

Hypertension and hypercholesterolemia are frequently associated, and their treatment is proven to reduce cardiovascular risk. Current guidelines on cardiovascular prevention strongly recommend treating both disorders. Unfortunately, the low treatment and control rates, combined with the high prevalence of both conditions, still contribute to the high burden of cardiovascular disease in Western countries. In the past 5 years, many studies evaluating the benefit of combined antihypertensive and lipid-lowering treatment on endothelial dysfunction, coronary atherosclerosis, hypertension control, and on primary and secondary prevention of cardiovascular events have been published. In this article, we discuss and critically evaluate the available evidence on the potential benefits of combined antihypertensive and lipid-lowering treatment.

Topics: Anticholesteremic Agents; Antihypertensive Agents; Arteriosclerosis; Cardiovascular Diseases; Comorbidity; Drug Therapy, Combination; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypertension; Nifedipine; Pyridines; Simvastatin

The 'statin story' began in 1987 when the first-generation, fungal HMG-CoA reductase inhibitor lovastatin received FDA approval in the USA. Ten years later, the sixth compound of this class came onto the world market--the fully synthetic statin cerivastatin. A number of clinical studies had confirmed its high pharmacological efficacy, its excellent pharmacokinetic properties with fast and nearly complete absorption after oral uptake, a linear kinetic over a broad concentration range, and its favorable safety profile. The greatest advantages, of cerivastatin, however, are its lipophilicity, its high bioavailability of about 60% after oral application and its potency at 100-fold lower doses compared to other lipophilic statins. Nevertheless, the most exciting findings are certainly its non-lipid-related, pleiotropic effects at the cellular and molecular level. Statin therapy was also found to reduce mortality in cases where cholesterol levels or atherosclerotic plaque formation remained unaltered. However, cerivastatin improves endothelial dysfunction, possesses anti-inflammatory, antioxidant, anticoagulant, antithrombotic, antiproliferative, plaque-stabilizing, immunmodulatory, and angiogenic effects, and may even prevent tumor growth, Alzheimer's disease, and osteoporosis. Most of these effects seem to be based on the inhibition of isoprenoid synthesis. Although cerivastatin is no longer on the market because of some problematic side effects, it could be one of the most potent cellular and molecular drugs for the future.

Topics: Angiotensin II; Animals; Anticholesteremic Agents; Arteriosclerosis; Endothelium, Vascular; Epoprostenol; Extracellular Matrix; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hyperlipidemias; Hypolipidemic Agents; Monocytes; Muscle, Smooth, Vascular; Neovascularization, Physiologic; Pyridines; Receptors, Angiotensin; Thrombosis

Statins alter lipid concentrations. This systematic review determined the efficacy of particular statins, in terms of their ability to alter cholesterol.. PubMed, the Cochrane Library, references lists of reports, and reviews were searched (September 2001) for randomised, double blind trials of statins for cholesterol in trials of 12 weeks or longer. Mean change in total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides was calculated using pooled data for particular statins, and for particular doses of a statin. Pre-planned sensitivity analyses were used to determine the effects of initial concentration of total cholesterol, study duration, the effects of major trials, and effects in placebo versus active controlled trials. Information was not collected on adverse events.. Different statins at a range of doses reduced total cholesterol by 17-35% and LDL-cholesterol by 24-49% from baseline. Lower doses of statins generally produced less cholesterol lowering, though for most statins in trials of 12 weeks or longer there was at best only a weak relationship between dose and cholesterol reduction. Duration of treatment and baseline total cholesterol concentration did not alter the amount of the benefit attained.. Statins are effective medicines and confer benefit to patients in terms of primary and secondary prevention of coronary heart disease. Reductions in total cholesterol of 25% or more and LDL cholesterol of more than 30% were recorded for fixed doses of simvastatin 40 mg, atorvastatin 10 mg, and rosuvastatin 5 mg and 10 mg.

Topics: Atorvastatin; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Female; Fluorobenzenes; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Lovastatin; Male; Pravastatin; Pyridines; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Rosuvastatin Calcium; Simvastatin; Sulfonamides; Triglycerides

Children have been tested and treated for hypercholesterolemia for more than 30 years. Although most treatment regimens have been limited to dietary intervention, statin use is increasing. Statins have been used in children since 1987, but published sources have only reported on small numbers of children with severe hypercholesterolemia. The available data indicates that statins can be useful and well tolerated. New data will be available in the next few years that will lead to the wider use of these drugs. Although statin drugs have proven to be safe in the adult population, physicians will be obliged to follow pediatric patients closely when these agents are widely used in the first few years. The use of highly effective safe drugs such as statins will allow for the assessment of the best time to initiate therapy in younger populations and what benefits may be found over the long term.

Topics: Atorvastatin; Bezafibrate; Child; Child Welfare; Cost-Benefit Analysis; Drug Approval; Gemfibrozil; Heptanoic Acids; Humans; Hypercholesterolemia; Hypolipidemic Agents; Lovastatin; Pyridines; Pyrroles; Simvastatin

Topics: Arteriosclerosis; Coronary Disease; Diabetes Complications; Diabetes Mellitus; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipids; Pyridines; Randomized Controlled Trials as Topic

Topics: Animals; Arteriosclerosis; Cholesterol, LDL; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Pyridines; Receptors, LDL

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)-reductase inhibitors (statins) are mainly considered for long-term use and often constitute part of a multiple-drug regime. Besides common adverse drug effects, such as nausea, abdominal discomfort and headaches, all statins harbour the risk of myopathy and fatal rhabdomyolysis. Usually, the frequency of myopathy is low but the incidence increases during concomitant drug therapy. Statins do not differ in their pharmacodynamic property. Therefore, the differences in their pharmacokinetic profiles, i.e. affinity for metabolising enzymes, constitute the rationale for choosing a specific statin especially for combination therapy. In order to point out harmful combinations of therapeutics, this review summarises the pharmacokinetic data of six clinically used statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin and simvastatin) with special regard to metabolism and drug interactions. In summary, statins that lack a significant hepatic metabolism, i.e. pravastatin, or that are metabolised by more than one cytochrome P450 isoenzyme, i.e. fluvastatin, or whose metabolism is taken over by other cytochrome P450 isoenzymes in case of blockage of the main metabolising enzyme, i.e. cerivastatin, are the least prone to drug interactions. Nevertheless, in case of a specific concomitant drug therapy known to be associated with a higher risk of adverse events, i.e. cyclosporin A and statin, clinical symptoms of myopathy and biochemical data, such as increasing serum creatine phosphokinase, should be monitored carefully.

Topics: Atorvastatin; Drug Interactions; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Lovastatin; Pravastatin; Pyridines; Pyrroles; Simvastatin

Cerivastatin sodium, a novel statin, is a synthetic, enantiomerically pure, pyridine derivative that effectively reduces serum cholesterol levels at microgram doses. Cerivastatin is readily and completely absorbed from the gastrointestinal tract, with plasma concentrations reaching a peak 2 to 3 hours postadministration followed by a monoexponential decay with an elimination half-life (t1/2beta) of 2 to 3 hours. Cerivastatin pharmacokinetics are linear: maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) are proportional to the dose over the range of 0.05 to 0.8 mg. No accumulation is observed on repeated administration. Cerivastatin interindividual variability is described by coefficients of variation of approximately 30 to 40% for its primary pharmacokinetic parameters AUC, Cmax and t1/2beta. The mean absolute oral bioavailability of cerivastatin is 60% because of presystemic first-pass effects. Its pharmacokinetics are not influenced by concomitant administration of food nor by the time of day at which the dose is given. Age, gender, ethnicity and concurrent disease also have no clinically significant effects. Cerivastatin is highly bound to plasma proteins (>99%). The volume of distribution at steady state of about 0.3 L/kg indicates that the drug penetrates only moderately into tissue; conversely, preclinical studies have shown a high affinity for liver tissue, the target site of action. Cerivastatin is exclusively cleared via metabolism. No unchanged drug is excreted. Cerivastatin is subject to 2 main oxidative biotransformation reactions: demethylation of the benzylic methyl ether moiety leading to the metabolite M-1 [catalysed by cytochrome P450 (CYP) 2C8 and CYP3A4] and stereoselective hydroxylation of one methyl group of the 6-isopropyl substituent leading to the metabolite M-23 (catalysed by CYP2C8). The product of the combined biotransformation reactions is a secondary minor metabolite, M-24, not detectable in plasma. All 3 metabolites are active inhibitors of hydroxymethylglutaryl-coenzyme A reductase with a similar potency to the parent drug. Approximately 70% of the administered dose is excreted as metabolites in the faeces, and 30% in the urine. Metabolism by 2 distinct CYP isoforms renders cerivastatin relatively resistant to interactions arising from inhibition of CYP. If one of the pathways is blocked, cerivastatin can be effectively metabolised by the alternative route. In addition, on the basis of in

Topics: Animals; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Mixed Function Oxygenases; Pyridines

Cerivastatin is an HMG-CoA reductase inhibitor used for the treatment of patients with hypercholesterolaemia. The lipid-lowering efficacy of cerivastatin has been demonstrated in a number of large multicentre, randomised clinical trials. Earlier studies used cerivastatin at relatively low dosages of < or =0.3mg orally once daily, but more recent studies have focused on dosages of 0.4 or 0.8 mg/day currently recommended by the US Food and Drug Administration (FDA). Along with modest improvements in serum levels of triglycerides and high density lipoprotein (HDL)-cholesterol, cerivastatin 0.4 to 0.8 mg/day achieved marked reductions in serum levels of low density lipoprotein (LDL)-cholesterol (33.4 to 44.0%) and total cholesterol (23.0 to 30.8%). These ranges included results of a pivotal North American trial in almost 1000 patients with hypercholesterolaemia. In this 8-week study, US National Cholesterol Education Program (Adult Treatment Panel II) [NCEP] target levels for LDL-cholesterol were achieved in 84% of patients randomised to receive cerivastatin 0.8 mg/day, 73% of those treated with cerivastatin 0.4 mg/day and <10% of placebo recipients. Among patients with baseline serum LDL-cholesterol levels meeting NCEP guidelines for starting pharmacotherapy, 75% achieved target LDL-cholesterol levels with cerivastatin 0.8 mg/day. In 90% of all patients receiving cerivastatin 0.8 mg/day, LDL-cholesterol levels were reduced by 23.9 to 58.4% (6th to 95th percentile). Various subanalyses of clinical trials with cerivastatin indicate that the greatest lipid-lowering response can be expected in women and elderly patients. Cerivastatin is generally well tolerated and adverse events have usually been mild and transient. The overall incidence and nature of adverse events reported with cerivastatin in clinical trials was similar to that of placebo. The most frequent adverse events associated with cerivastatin were headache, GI disturbances, asthenia, pharyngitis and rhinitis. In the large pivotal trial, significant elevations in serum levels of creatine kinase and transaminases were reported in a small proportion of patients receiving cerivastatin but not in placebo recipients. As with other HMG-CoA reductase inhibitors, rare reports of myopathy and rhabdomyolysis have occurred with cerivastatin, although gemfibrozil or cyclosporin were administered concomitantly in most cases. Postmarketing surveillance studies in the US have been performed. In 3 mandated formulary. Cerivastatin is a well tolerated and effective lipid-lowering agent for patients with hypercholesterolaemia. When given at dosages currently recommended by the FDA in the US, cerivastatin achieves marked reductions in serum levels of LDL-cholesterol, reaching NCEP target levels in the vast majority of patients. Thus, cerivastatin provides a useful (and potentially cost effective) alternative to other currently available HMG-CoA reductase inhibitors as a first-line agent for hypercholesterolaemia.

Topics: Administration, Oral; Adult; Aged; Arteriosclerosis; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Endothelium; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipid Metabolism; Male; Middle Aged; Pyridines

To compare cerivastatin with simvastatin in their long term safety and efficacy in reducing low density lipoprotein cholesterol (LDL-C).. Multicentre, randomized, double-blind, parallel group study.. Thirteen Canadian centres.. A total of 387 patients with primary hypercholesterolemia received treatment with either cerivastatin (0. 05 to 0.3 mg/day) or simvastatin (5 to 40 mg/day) to achieve plasma LDL-C levels below 3.36 mmol/L (130 mg/dL) for an initial 32-week dose-titration phase and a subsequent 72-week extension phase.. Cerivastatin and simvastatin produced clinically significant reductions in LDL-C of 28.4% and 35.4%, respectively, at the end point for the 32-week study, and reductions of 32.8% and 35. 0%, respectively, at the end of the extension phase of the study. Response rates (a greater than 15% drop in LDL-C) were comparable for the two treatments (88.9% cerivastatin versus 93.2% simvastatin) at the 32-week end point. Response rates were 100% for both treatments at the end of the 72-week extension phase. Both treatments also reduced total cholesterol, apolipoprotein B and very low density lipoprotein cholesterol levels. Cerivastatin and simvastatin increased HDL-C levels significantly by 8.8% and 11.0%, respectively, at the end point for the 32-week study, and by 8.6% and 12.1%, respectively, at the end of the extension phase of the study. Treatments were well tolerated, and the incidence of adverse effects was similar in both groups.. This forced titration study demonstrates that cerivastatin, given once daily at doses up to 0.3 mg/day, is effective and well tolerated. The results of this study support further investigation of higher doses of cerivastatin given the excellent safety profile at doses up to 0.3 mg.

Topics: Anticholesteremic Agents; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Pyridines; Simvastatin; Titrimetry

Experimental evidence suggests a lipid-independent effect of statins on endothelial function and nitric oxide (NO) availability in humans. We investigated whether improvement in NO availability in hypercholesterolemia can be achieved rapidly with statins before lipid-lowering therapy is complete.. We studied 41 patients (52 +/- 11 years) with low-density lipoprotein (LDL) cholesterol > or = 130 mg/dL (179 +/- 45 mg/dL) randomly assigned to treatment either with atorvastatin (20 mg/day) or cerivastatin (0.4 mg/day). Endothelium-dependent vasodilation of the forearm vasculature was measured by plethysmography and intra-arterial infusion of acetylcholine (ACh) after 3 days (n = 18) and 14 days (n = 39) of treatment. NO availability and oxidative stress were assessed by coinfusion of l-NMMA and vitamin C.. After 3 days of treatment, LDL-cholesterol decreased by 11.9% with a further decrease to 29.6% after 14 days ( P < .001). Endothelium-dependent vasodilation improved by +46.7% after 3 days of statin therapy compared with before therapy (ACh 48 microg/min: +15.7 +/- 10.6 vs +10.7 +/- 10.8 mL/min per 100 mL, P < .05). No further improvement in endothelium-dependent vasodilation (+42.7% compared with before therapy) could be demonstrated after 14 days of treatment (ACh 48 microg/min: +17.7 +/- 10.3 vs +12.4 +/- 9.3 mL/min per 100 mL before therapy, P < .001). Coinfusion of ACh plus vitamin C was able to improve endothelium-dependent vasodilation before but not after 3 or 14 days of statin therapy either. The improvement in endothelium-dependent vasodilation after therapy was no longer observed when the NO-synthase inhibitor l-NMMA was coinfused together with ACh.. Short-term lipid-lowering therapy with statins is able to improve endothelial function and NO availability almost completely after 3 days in hypercholesterolemic patients probably by decreasing oxidative stress. This improvement seems to be more rapid than the accompanying decline in LDL-cholesterol and not related to these lipid changes. This finding can support the concept of lipid-independent effects of statins in humans.

Topics: Acetylcholine; Adult; Aged; Ascorbic Acid; Atorvastatin; Biological Availability; C-Reactive Protein; Dose-Response Relationship, Drug; Double-Blind Method; Endothelium, Vascular; Female; Forearm; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipid Metabolism; Male; Middle Aged; Nitric Oxide; Nitroprusside; omega-N-Methylarginine; Pyridines; Pyrroles; Regional Blood Flow; Vasodilation

Disturbances in nitric oxide (NO) metabolism resulting in endothelial dysfunction play a central role in the pathogenesis of atherosclerosis in hypercholesterolemia and in individuals with type 2 diabetes. It is unclear whether lipid lowering therapy with HMG-CoA-reductase inhibitors might improve endothelial function in subjects with type 2 diabetes as it is demonstrated in non-diabetic subjects with hypercholesterolemia. We examined the influence of 0.2 mg and 0.8 mg cerivastatin on endothelial function in a multicenter, randomised, double-blind, and three-arm placebo-controlled clinical trial. Endothelial function was assessed by nitric oxide-dependent flow mediated vasodilatation (FMD) of the brachial artery. A total of 103 patients with type 2 diabetes were enrolled in the study. Bayer Company undertook a voluntary action to withdraw cerivastatin from market, therefore the study was terminated earlier. At this point 77 patients were randomised, of which 58 completed the study (mean age 60 +/- 8 years, HbA1c 7.4 +/- 0.9 %). At baseline mean FMD was disturbed in all three therapy arms (5.18 +/- 2.31 % in the placebo group, 3.88 +/- 1.68 in the 0.2-mg cerivastation group, and 4.86 +/- 2.25 in the 0.8-mg cerivastatin group). Despite a significant reduction in cholesterol and LDL-cholesterol-levels after 12 weeks of treatment (decrease in LDL-cholesterol - 26.8 +/- 13.9 % in the 0.2-mg group and - 40.3 +/- 16.0 % in the 0.8-mg group, p = 0.0001, ANCOVA) there was no difference in flow mediated vasodilatation (p = 0.52 and p = 0.56 vs. placebo, respectively, ANCOVA). HbA1c, CRP, and HDL-cholesterol did not change during the study. Furthermore no difference in safety profile between cerivastatin and placebo was found. Despite a significant improvement in lipid profile under statin therapy, no improvement of endothelial dysfunction in terms of nitric oxide bioavailability could be detected.

Topics: Blood Glucose; Blood Pressure; Brachial Artery; C-Reactive Protein; Cholesterol; Diabetes Mellitus, Type 2; Double-Blind Method; Endothelium, Vascular; Female; Fibrinogen; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Middle Aged; Nitric Oxide; Pyridines; Triglycerides; Ultrasonography; Vasodilation

It is unclear whether there are temporal differences for the pleiotropic effects for different members of the statin class. The present study investigated differences in the short- and intermediate-term pleiotropic effects of statins in hypercholesterolemic patients.. Thirty-five hypercholesterolemic patients were randomly treated with either atorvastatin or cerivastatin for 3 months. We measured fasting lipid concentrations, thiobarbituric acid reactive substances (TBARS), fibrinolytic parameters, and flow-mediated dilation of the brachial artery (FMD) at baseline and after 2 weeks and 3 months of therapy.. After 2 weeks of therapy, atorvastatin decreased the low density lipoprotein (LDL) cholesterol, small, dense LDL cholesterol (34+/-22 vs. 18+/-20%, P<0.01), remnant-like particles (RLP) cholesterol (8.8+/-6.0 vs. 5.1+/-2.6 mg/ml, P<0.01), and TBARS (3.3+/-1.0 vs. 3.1+/-0.9 nmol/ml, P<0.05), and cerivastatin decreased LDL cholesterol. After 3 months of therapy, atorvastatin decreased small dense LDL cholesterol (8+/-13%, P<0.0001) additionally, and cerivastatin decreased small, dense LDL cholesterol (51+/-11 vs. 12+/-22%, P<0.0001) and plasminogen activator inhibitor type 1 (68+/-32 vs. 51+/-21 ng/ml, P<0.05). FMD increased significantly in both groups after 2 weeks, although the relative change in FMD was greater with cerivastatin therapy after 2 weeks than atorvastatin therapy (60+/-78 vs. 23+/-26%, P<0.05). However, FMD was the same for both groups after 3 months (58+/-65 vs. 66+/-61%, NS), because atorvastatin additionally increased FMD. There was no correlation between these pleiotropic effects and the improvement in the lipid profile for either group.. These findings suggest that the degree of pleiotropic effect as well as the time course for the effect are different among members of the statin class of drugs.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Anticholesteremic Agents; Atorvastatin; Female; Heptanoic Acids; Humans; Hypercholesterolemia; Lipoproteins; Male; Middle Aged; Mutation; Phenotype; Pyridines; Pyrroles; Time Factors

Angiotensin II type 1 (AT(1)) receptors are well known to mediate angiotensin II (Ang II)-induced pro-atherosclerotic effects. It has been found that hypercholesterolemia influences the expression of AT(1) receptors on vascular smooth muscle cells and that increased density of AT(1) receptors exaggerates the hemodynamic response to Ang II. We analyzed to what extent statins and AT(1) receptor antagonists diminish the vasoconstrictive response to Ang II infusion in hypercholesterolemic patients.. A total of 24 male patients with LDL cholesterol levels >130 mg/dL were enrolled in a randomized, cross-over study. After baseline evaluation, 12 patients received first cerivastatin (0.3 mg/day) and the other 12 patients initially received candesartan (8 mg/day) for 3 weeks, with subsequent cross-over of the medication for the second 3-week drug period. The vascular response was analyzed by the increase in mean arterial pressure (MAP) and total peripheral resistance (TPR) during infusion of increasing doses of Ang II at baseline and the end of each treatment period. Hemodynamic changes were also compared with those in 24 normocholesterolemic subjects without any therapy.. At baseline, Ang II provoked a similar increase of MAP and TPR in patients and control subjects. Treatment with cerivastatin did not affect the response to Ang II compared with baseline. By contrast, treatment with candesartan attenuated significantly the response to Ang II compared with baseline and cerivastatin.. Our hemodynamic data indicate the hypothesis that statins do not reduce the responsiveness to Ang II in resistance arteries of young, mildly hypercholesterolemic patients.

Topics: Adolescent; Adult; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Biomarkers; Biphenyl Compounds; Blood Pressure; Cholesterol, HDL; Cholesterol, LDL; Cross-Over Studies; Dose-Response Relationship, Drug; Heart Rate; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Middle Aged; Pyridines; Severity of Illness Index; Tetrazoles; Triglycerides; Vascular Resistance; Vasoconstrictor Agents

Endothelin blocking drugs have vasodilator effects mediated at least in part via the nitric oxide system. Hypercholesterolaemia is associated with vascular dysfunction manifest as impaired nitric oxide-mediated vasodilatation and arterial stiffness. Treatment with HMG CoA reductase inhibitors (statins) has proven mortality benefits in a range of patient populations. Subjects (n = 5) received either placebo or 800 mug cerivastatin for an 8-week period in a double-blind, placebo-controlled, cross-over study. Cerivastatin reduced the total plasma cholesterol compared with baseline by 27% (5.4 +/- 0.4 mmol/L versus 7.3 +/- 0.4 mmol/L, P = 0.04). Selective endothelin-A receptor blockade caused an increase in forearm blood flow (FBF) (18.0 +/- 7.2%, P = 0.04). Compared with placebo, cerivastatin therapy caused a trend towards a further increase in FBF (18.0 +/- 7.2% versus 52.0 +/- 19.0%, P = 0.06). Selective endothelin-B receptor blockade reduced FBF (-11.0 +/- 3.9%, P = 0.02) with no difference between placebo and cerivastatin therapy (-11.0 +/- 3.9% versus -13.0 +/- 3.6%, P = 0.9). Combined endothelin-A/endothelin-B receptor blockade increased FBF (39.8 +/- 13.4%, P < 0.01) with no difference between placebo and cerivastatin therapy (39.8 +/- 13.4% versus 42.4 +/- 19.0%, P = 0.7). There was a trend towards a reduction in the augmentation index between cerivastatin and placebo (6.2 +/- 2.7 versus 9.1 +/- 2.4, n = 5, P = 0.4) compared with baseline (7.2 +/- 1.0). In conclusion, statin therapy may decrease large artery stiffness and increase the vasodilating effects of endothelin-A receptor blockade.

Topics: Cholesterol, LDL; Compliance; Cross-Over Studies; Double-Blind Method; Down-Regulation; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Forearm; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Oligopeptides; Peptides, Cyclic; Piperidines; Pyridines; Receptor, Endothelin A; Receptor, Endothelin B; Time Factors; Treatment Outcome; Vasodilation; Vasodilator Agents

Hydroxymethyl-glutaryl-CoA-reductase inhibitors (statins) reduce cardiovascular events by cholesterol lowering as well as by non-lipid related actions. Among them, the modulation of platelet activity could play a relevant role in vascular protection. Furthermore withdrawal of statins has been associated with increased cardiovascular event rate. The aim of our study was to evaluate platelet activity after cerivastatin discontinuation in eighteen subjects that did not accept other drugs and in sixteen subjects continuing treatment with simvastatin. Fourteen subjects at the end of the discontinuation period decided to receive other drugs (simvastatin) and they were evaluted six weeks later. We measured complete lipid profile by the chromogenic method (LDL-C was calculated); oxidized-LDL (ox-LDL; ELISA), platelet P-selectin (P-sel) expression (flow cytometry detection), platelet aggregation (% change of transmitted light), intracellular citrullin production (iCit; HPLC) as an indicator of intracellular NO synthase activity at baseline and 7, 14, 28, 60 days after statin discontinuation. P-sel expression and platelet aggregation were increased at 14 days (p < 0.001 and p < 0.05) in association with raised ox-LDL (r = 0.30, p < 0.05) and decreased iCit (r = 0.53, p < 0.01). Increased LDL-C was related to P-sel and platelet aggregation at 28 days (r = 0.30, p < 0.05). Subjects continuing statin treatment had no significant changes of P-sel at 28 (p = 0.221) and 60 days (p = 0.238). Subjects treated with simvastatin after 60 days of diet showed a significant reduction of P-sel and platelet aggregation after six weeks of treatment (p < 0.01). Our data suggest a platelet hyperactivation state in the second week after statin discontinuation which is partially related to raised LDL-C. Such a finding could participate in the increased cardiovascular event rate after statin discontinuation.

Topics: Adult; Blood Platelets; Citrulline; Diet; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipids; Lipoproteins, LDL; Male; Middle Aged; Nitric Oxide Synthase; P-Selectin; Platelet Activation; Platelet Aggregation; Pyridines; Substance Withdrawal Syndrome

The efficacy and safety of the new statin, cerivastatin, in the Chinese patients with primary hypercholesterolemia remains to be determined.. In this prospective, double-blind, parallel-group study, patients with primary hypercholesterolemia were randomized to treatment with cerivastatin, 0.3 mg (n = 21) or lovastatin, 20 mg (n = 22), for 8 weeks. The primary efficacy variable was percentage change of low-density lipoprotein (LDL) cholesterol from baseline. The secondary efficacy variables were percentage change of total cholesterol, triglycerides and high-density lipoprotein (HDL) cholesterol. RESULTS.:Both cerivastatin and lovastatin effectively reduced LDL cholesterol (-33.2% vs. -29.3%, p = 0.63), total cholesterol (-25% vs. -20%, p = 0.10), and triglycerides (-21% vs. -14%,p = 0.27) (all p < 0.0001 for comparison with baseline), and slight increased HDL cholesterol (+2% vs. +8%, p = 0.008) over the 8-week treatment period. The LDL cholesterol responsive rates according to the recommendations from the National Cholesterol Educational Panel (NCEP) were 43% and 32% for cerivastatin and lovastatin, respectively. The adverse event profiles of cerivastatin and lovastatin were similar.. Cerivastatin 0.3 mg once daily is as effective and safe as lovastatin 20 mg once daily in lowering LDL and total cholesterol in Chinese patients with primary hypercholesterolemia.

Topics: Adult; Aged; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lovastatin; Male; Middle Aged; Prospective Studies; Pyridines; Triglycerides

The objective of this study was to evaluate whether plant sterol-ester margarine has an additive or interactive effect on low-density lipoprotein (LDL) cholesterol reduction when ingested in combination with a statin drug. This was a multicenter, randomized, double-blind study with 4 parallel treatment arms in a balanced 2 x 2 factorial design. The 4 daily treatment options were: (1) placebo plus regular margarine 25 g (n = 38); (2) placebo plus sterol-ester margarine 25 g (2 g of plant sterol) (n = 39); (3) cerivastatin 400 microg plus regular margarine 25 g (n = 38); and (4) cerivastatin 400 microg plus sterol-ester margarine 25 g (n = 37). The study was conducted in men and women with primary hypercholesterolemia with baseline LDL cholesterol >/=97 mg/dl (mean 206). The primary efficacy parameter was the percent change in LDL cholesterol between baseline and at the end of 4 weeks' treatment. Cerivastatin (vs placebo) reduced LDL cholesterol by 32% (95% confidence intervals 28% to 36%, p <0.0001) and sterol-ester margarine (vs regular margarine) by 8% (95% confidence interval 4% to 12%, p <0.0001). The effect of sterol-ester margarine and cerivastatin together was additive (39% reduction in LDL cholesterol), but there was no significant interactive effect between sterol-ester margarine and cerivastatin (p = 0.29). The treatments were generally well tolerated with no major differences in adverse events between groups. In subjects with primary hypercholesterolemia, statin and sterol-ester margarine used together produce a purely additive effect on LDL cholesterol reduction. The addition of sterol-ester margarine to statin therapy offers LDL cholesterol reduction equivalent to doubling the dose of statin.

Topics: Apolipoproteins; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diet, Fat-Restricted; Dietary Fats; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Margarine; Middle Aged; New South Wales; Phytosterols; Pyridines; Queensland; Treatment Outcome; Triglycerides

We previously reported urinary podocytes to be a marker of glomerular injury. The aim of the present study was to determine whether cerivastatin, a newly developed, potent synthetic statin, affects proteinuria and urinary podocyte excretion in patients with chronic glomerulonephritis (CGN).. We randomly assigned 40 normotensive hypercholesterolemic patients with CGN to receive either cerivastatin 0.15 mg/day (n=20) or placebo (n=20). Subjects comprised 24 men and 16 women, with a mean age of 40.8+/-14.4 years; 27 had IgA nephropathy and 13 had non-IgA proliferative glomerulonephritis. Treatment was continued for 6 months. Plasma total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides, urinary protein excretion and the number of podocytes were measured before treatment and at 3 and 6 months after treatment.. After 6 months, a significant reduction in total cholesterol (P<0.001), LDL-cholesterol (P<0.001) and triglycerides (P<0.05), and a significant increase in HDL-cholesterol (P<0.001) were observed in the group treated with cerivastatin. Urinary protein excretion decreased from 1.8+/-0.6 to 0.8+/-0.4 g/day, (P<0.01) in this group, and urinary podocyte excretion decreased from 1.6+/-0.6 to 0.9+/-0.4 cells/ml (P<0.01). However, placebo showed little effect on these lipid levels, urinary protein excretion and urinary podocyte excretion. The differences between the cerivastatin group and the placebo group were significant (cholesterol, P<0.001; LDL-cholesterol, P<0.001; triglycerides, P<0.05; HDL-cholesterol, P<0.001; urinary protein, P<0.01; and urinary podocytes, P<0.01).. Statins such as cerivastatin may be beneficial for restoration of injured podocytes in patients with CGN and hypercholesterolaemia.

Topics: Adult; Cholesterol, HDL; Cholesterol, LDL; Chronic Disease; Female; Glomerulonephritis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Middle Aged; Proteinuria; Pyridines; Sialoglycoproteins; Triglycerides; Urine

Most studies on the topic have shown that statin therapy decreases plasma LDL levels but not those of lipoprotein(a) [Lp(a)]. This specificity of action, although previously noted, has not been systematically investigated. In the current study we approached this problem by monitoring LDL- and Lp(a) cholesterol in 80 hypercholesterolemic subjects with high Lp(a) levels, at entry and 8 mon after initiation of statin therapy. We found that commonly used direct and indirect LDL cholesterol assays gave an LDL cholesterol value that comprised both true LDL- and Lp(a) cholesterol. We estimated these two analytes from the values of Lp(a) protein determined by ELISA and from knowledge of the Lp(a) chemical composition, complemented by data from immunochemical and ultracentrifugal analyses. Statin therapy, while not affecting plasma Lp(a) protein levels (21.7+/-10.4, before, and 22.0+/-10.1 mg/dL, after), caused a decrease in the estimated or true LDL cholesterol (P < 0.0001) to values in some cases as low as 10 mg/dL. This drop in true LDL was validated by the decrease in the LDL band in the ultracentrifugation profiles, and its magnitude was proportional to the degree of total cholesterol lowering and to the pretreatment true LDL/Lp(a) cholesterol weight ratio. We conclude that true LDL but not Lp(a) cholesterol is affected by statin therapy and that this specific response cannot be monitored by current LDL cholesterol assays and must, rather, rely on estimates of these two analytes.

Topics: Adult; Aged; Anticholesteremic Agents; Atorvastatin; Enzyme-Linked Immunosorbent Assay; Female; Heptanoic Acids; Humans; Hypercholesterolemia; Lipoprotein(a); Lipoproteins, LDL; Male; Middle Aged; Pravastatin; Pyridines; Pyrroles; Simvastatin

Long-term therapy with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) has been shown to reduce levels of C-reactive protein (CRP). However, the generalizability, speed of onset, and dose-response characteristics of this effect are uncertain.. We measured CRP, LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C) levels among 785 patients with primary hypercholesterolemia at baseline and after 8 weeks of therapy with either 0.4 or 0.8 mg of cerivastatin. Overall, cerivastatin resulted in a 13.3% reduction in median CRP levels (P:<0.001) and a 24.5% reduction in mean CRP levels (P:<0.001). Although LDL-C promptly decreased in a dose-dependent manner (mean LDL-C reduction, 37.3% for 0.4 mg and 42.2% for 0.8 mg of cerivastatin), no clear dose-response effect of cerivastatin on CRP was observed, nor was there any substantive correlation between the magnitude of change in CRP and the magnitude of change in LDL-C (r=-0.08) or the magnitude of change in HDL-C (r=-0.04). Thus, <2% of the variance in the percent change in CRP over 8 weeks could be attributed to the percent change in either of these lipid parameters. Further, there was no evidence of correlation between baseline CRP levels and baseline lipid levels or between end-of-study CRP levels and end-of-study lipid levels.. Among 785 patients with primary hypercholesterolemia, CRP levels were significantly reduced within 8 weeks of initiating cerivastatin therapy in a lipid-independent manner.

Topics: Administration, Oral; Adult; Aged; C-Reactive Protein; Cholesterol, HDL; Cholesterol, LDL; Cohort Studies; Dose-Response Relationship, Drug; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Middle Aged; Pyridines; Treatment Outcome

We investigated whether improvement of endothelial dysfunction in hypercholesterolemia can be achieved with short-term lipid-lowering therapy.. Impaired endothelium-dependent vasodilation plays a pivotal role in the pathogenesis of atherosclerosis and acute coronary syndromes.. In a randomized, double-blind, placebo-controlled trial, we studied 37 patients (52 +/- 11 yrs) with low density lipoprotein cholesterol > or = 160 mg/dl (196 +/- 44 mg/dl) randomly assigned to either cerivastatin (0.4 mg/d) or placebo. Endothelium-dependent vasodilation of the forearm vasculature was measured by plethysmography and intra-arterial infusion of acetylcholine (ACh 12, 48 microg/min) and endothelium-independent vasodilation by intra-arterial infusion of nitroprusside (3.2, 12.8 microg/min).. Low density lipoprotein cholesterol decreased after two weeks of treatment (cerivastatin -33 +/- 4% vs. placebo + 2 +/- 4%, x +/- SEM, p < 0.001). Endothelium-dependent vasodilation improved after two weeks of therapy with cerivastatin compared with baseline (ACh 12 microg/min: + 22.3 +/- 5.2 vs. + 11.2 +/- 1.9 ml/min/100 ml, p < 0.01; ACh 48 microg/min: +31.2 +/- 6.3 vs. +19.1 +/- 3.1 ml/min/100 ml, p < 0.05). In contrast, changes in forearm blood flow to ACh were similar before and after therapy in the placebo group (ACh 12 microg/min: + 12.9 +/- 3.6 vs. + 9.0 +/- 1.9 ml/min/100 ml, NS; ACh 48 microg/min: +20.7 +/- 3.7 vs. 19.4 +/- 2.9 ml/min/100 ml, NS). Endothelium-dependent vasodilation improved in comparison with placebo (ACh 48 microg/min: +203 +/- 85% [cerivastatin] vs. -26 +/- 71% [placebo], p < 0.05). This improvement in endothelium-dependent vasodilation was no longer observed when the nitric oxide-synthase inhibitor N(G)-monomethyl-L-arginine was coinfused (ACh 48 microg/min + N(G)-monomethyl-L-arginine 4 micromol/min -48 +/- 85% [cerivastatin]).. Short-term lipid-lowering therapy with cerivastatin can improve endothelial function and NO bioavailability after two weeks in patients with hypercholesterolemia.

Topics: Adult; Anticholesteremic Agents; Biological Availability; Blood Flow Velocity; Cholesterol, LDL; Double-Blind Method; Endothelium, Vascular; Female; Forearm; Humans; Hypercholesterolemia; Male; Middle Aged; Nitric Oxide; Plethysmography; Pyridines; Vasodilation

The short-term effects of hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) on endothelial function at doses that do not affect plasma lipid levels are not known.. We investigated the short-term effects of cerivastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, on endothelial function and endothelium-related products in elderly diabetic patients. Twenty-seven elderly diabetic patients (aged 69.3+/-3.4 years), with or without mild hypercholesterolemia, were enrolled in this study, which tested cerivastatin treatment (0.15 mg/d) for 3 days. Endothelium-dependent flow-mediated dilatation, endothelium-independent dilatation by nitroglycerin in the brachial artery, nitric oxide-related products (nitrite/nitrate and cGMP), endothelium-related products (von Willebrand Factor, soluble vascular cell adhesion molecule-1, and soluble intercellular adhesion molecule-1), and a marker of oxidant stress (8-isoprostane) were assessed. Levels of plasma lipids were not changed before and after treatment with cerivastatin. Flow-mediated dilatation was significantly increased by cerivastatin treatment, as were plasma nitrite/nitrate levels (from 16.9+/-3.4 to 22.0+/-3.7 micromol/L, P<0.05) and cGMP values. The percent of nitroglycerin-induced dilatation was not changed. Plasma concentrations of 8-isoprostane decreased, and levels of soluble vascular cell adhesion molecule also tended to decrease with cerivastatin.. Improvement of endothelial function was in line with antiatherosclerotic effects. Cerivastatin improved impaired endothelial function in the short-term without affecting lipid profiles in elderly diabetic patients. This effect may be partly due to upregulation of endothelial nitric oxide synthase.

Topics: Aged; Brachial Artery; Cyclic GMP; Diabetes Complications; Diabetes Mellitus; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipids; Male; Nitrates; Nitrites; Pyridines; Time Factors; Treatment Outcome; Vasodilation

This 6-week Prospective, Randomized, Open-label Blinded End point (PROBE) study conducted at 12 sites in the United States compared the efficacy and safety of atorvastatin with cerivastatin. In all, 215 hypercholesterolemic patients (low-density lipoprotein [LDL] cholesterol > or = 160 mg/dl [4.14 mmol/L]; triglycerides < or = 400 mg/dl [4.52 mmol/L]) were randomized to receive either atorvastatin 10 mg once daily (n = 108) or cerivastatin 0.3 mg once daily (n = 107). Efficacy was assessed by measuring changes from baseline in LDL cholesterol, total cholesterol, high-density lipoprotein cholesterol, apolipoprotein B, and triglycerides. Atorvastatin produced significantly greater (p < 0.0001) reductions from baseline to week 6 in LDL cholesterol (37.7% vs 30.2%), total cholesterol (27.5% vs 22.2%), and apolipoprotein B (28.6% vs 21.2%), and a significantly greater (p < 0.05) increase from baseline to week 6 in high-density lipoprotein cholesterol (6.8% vs 4.3%) than cerivastatin. Atorvastatin treatment was also associated with a greater percent decrease from baseline to week 6 in triglycerides, with a trend toward statistical significance (p = 0.0982). The percentage of patients that achieved the National Cholesterol Education Program LDL cholesterol goal was greater for those receiving atorvastatin (73%) than for those receiving cerivastatin (66%). The proportion of patients experiencing drug-attributable adverse events, which were mostly mild to moderate and related to the digestive system, was significantly less (p < 0.05) with atorvastatin (5%) than with cerivastatin (14%) treatment. In conclusion, atorvastatin (10 mg/day) is more effective at lowering LDL cholesterol in hypercholesterolemic patients than cerivastatin (0.3 mg/day). Both atorvastatin and cerivastatin are well tolerated, with safety profiles similar to other members of the statin class.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticholesteremic Agents; Apolipoproteins B; Atorvastatin; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Drug Administration Schedule; Female; Heptanoic Acids; Humans; Hypercholesterolemia; Male; Middle Aged; Prospective Studies; Pyridines; Pyrroles; Treatment Outcome; Triglycerides; United States

Potential cost differences between statins are driven primarily by drug costs, differential lowering effects on low-density lipoprotein cholesterol (LDL-C) levels, and adverse drug interactions and reactions.. The purpose of this study was to compare the efficacy, safety, and direct treatment costs of cerivastatin and branded pravastatin in adult patients with primary hypercholesterolemia over a 1-year period.. This was a multicenter (48 sites), randomized, open-label, parallel-group, optional dose-titration study conducted in Canada. Patients aged 18 to 75 years with documented primary hypercholesterolemia (mean LDL-C > or = 160 mg/dL [> or = 4.5 mmol/L] and at least 1 fasting triglyceride measurement < or = 400 mg/dL [< or = 4.5 mmol/L]) that did not respond adequately to dietary intervention were enrolled. Patients who were on a diet at study entry were instructed to continue that diet for the duration of the study. Patients not following a diet were also entered into the study provided they had received previous dietary counseling and were unwilling or unable to comply with this dietary advice. Before randomization, treating physicians were required to record a target lipid level for each patient and then instructed to randomize patients to treatment with any dose and any titration schedule of cerivastatin or branded pravastatin according to their normal practice. Physicians were not required to titrate the study drug dose if the patient did not achieve the predefined target goal. Lipid analyses were conducted at baseline/randomization and at months 3, 6, 9, and 12. All samples drawn for lipid analyses were collected after a fast of > or = 10 hours. A cost-minimization approach was used to compare the direct treatment costs between cerivastatin and branded pravastatin. Since the analysis was from the perspective of the third-party payer (Ministries of Health), only costs attributed to the third-party payer were included.. A total of 417 patients were randomized to once-daily treatment with cerivastatin 0.1 mg to 0.4 mg (n = 209) or branded pravastatin 10 mg to 40 mg (n = 208); 39 (9.4%) of patients discontinued prematurely, 19 (4.6%) because of an adverse event. The incidence of adverse events was similar for cerivastatin (73.6%) and branded pravastatin (74.9%). The majority of adverse events were mild or moderate and included headache, nausea, pain, and dizziness. Both cerivastatin and pravastatin were effective in lowering LDL-C to target levels (mean reduction 29.8% and 27.5%, respectively, P = 0.35). An LDL-C decrease of > or = 20% from baseline to end point was achieved in 74.2% of cerivastatin patients and 74.0% of pravastatin patients. The annualized direct hyperlipidemia treatment cost was 19% higher in the branded pravastatin group compared with the cerivastatin group. A sensitivity analysis designed to examine the impact of generic pricing on the cost-minimization analysis indicated that the cost difference between cerivastatin and generic pravastatin was not significant.. Both cerivastatin and branded pravastatin were well tolerated and effective in lowering LDL-C by > or = 20% versus baseline. A cost savings in favor of cerivastatin was a reflection of the lower drug acquisition cost of cerivastatin compared with branded pravastatin.

Topics: Adolescent; Adult; Aged; Anticholesteremic Agents; Cholesterol, LDL; Female; Health Care Costs; Humans; Hypercholesterolemia; Male; Middle Aged; Pravastatin; Pyridines; Treatment Outcome

Statins are the agents of choice in reducing elevated plasma low-density lipoprotein cholesterol (LDL-C).. Cerivastatin 0.8 mg has greater long-term efficacy in reducing LDL-C than pravastatin 40 mg in primary hypercholesterolemia.. In this double-blind, parallel-group, 52-week study, patients (n = 1,170) were randomized (4:1:1) to cerivastatin 0.8 mg, cerivastatin 0.4 mg, or placebo daily. After 8 weeks, placebo was switched to pravastatin 40 mg. Patients with insufficient LDL-C lowering after 24 weeks were allowed open-labeled resin therapy.. Cerivastatin 0.8 mg reduced LDL-C versus cerivastatin 0.4 mg (40.8 vs. 33.6%, p <0.0001) or pravastatin 40 mg (31.5%, p<0.0001), and brought 81.8% of all patients, and 54.1% of patients with atherosclerotic disease, to National Cholesterol Education Program (NCEP) goals. Cerivastatin 0.8 mg improved mean total C (-29.0%), triglycerides (-18.3%), and high-density lipoprotein cholesterol (HDL-C) (+9.7%) (all p < or = 0.013 vs. pravastatin 40 mg). Higher baseline triglycerides were associated with greater reductions in triglycerides and elevations in HDL-C with cerivastatin. Cerivastatin was well tolerated; the most commonly reported adverse events were arthralgia, headache, pharyngitis, and rhinitis. Symptomatic creatine kinase > 10x the upper limit of normal (ULN) occurred in 1, 1.5, and 0% of patients receiving cerivastatin 0.8 mg, cerivastatin 0.4 mg, and pravastatin 40 mg, respectively. Repeat hepatic transaminases >3 x ULN occurred in 0.3-0.5, 0.5, and 0% of patients, respectively.. In long-term use, cerivastatin 0.8 mg effectively and safely brings the majority of patients to NCEP goal.

Topics: Adolescent; Aged; Anticholesteremic Agents; Double-Blind Method; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Middle Aged; Pravastatin; Prospective Studies; Pyridines

Hypercholesterolemia, a risk factor for cardiovascular disease, is associated with inflammation and hypercoagulability. Both can be mediated by the CD40 system. This study investigated whether the CD40 system is upregulated in patients with moderate hypercholesterolemia and whether it is influenced by therapy with a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor.. Fifteen patients with moderate hypercholesterolemia and 15 healthy control subjects were investigated. CD154 and P-selectin were analyzed on platelets and CD40 was analyzed on monocytes before and under therapy with the statin cerivastatin by double-label flow cytometry. Blood concentrations of soluble CD154 and monocyte chemoattractant protein-1 (MCP-1) were evaluated. Our main findings were as follows. Patients with moderate hypercholesterolemia showed a significant increase of CD154 and P-selectin on platelets and CD40 on monocytes compared with healthy subjects. Soluble CD154 showed a nonsignificant trend for higher plasma levels in patients. A positive correlation was found for total or LDL cholesterol and CD154, but not for CD40 on monocytes. The latter was upregulated in vitro by C-reactive protein, which was found to be significantly elevated in patients with moderate hypercholesterolemia. CD154 on platelets proved to be biologically active because it enhanced the release of MCP-1, which was markedly elevated in an in vitro platelet-endothelial cell coculture model and in the serum of patients. Short-term therapy with a HMG-CoA reductase inhibitor significantly downregulated CD40 on monocytes and serum levels of MCP-1.. Patients with moderate hypercholesterolemia show upregulation of the CD40 system, which may contribute to the known proinflammatory, proatherogenic, and prothrombotic milieu found in these patients.

Topics: Adult; Arteriosclerosis; Blood Platelets; CD40 Antigens; CD40 Ligand; Cells, Cultured; Chemokine CCL2; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Inflammation; Male; Monocytes; P-Selectin; Pyridines; Thrombosis; Up-Regulation

Platelets are strictly involved in arterial thrombosis and their hyperactivity has been shown in hypercholesterolemia. It has been reported that drugs affecting cholesterol metabolism (statins) decrease cardiovascular events by lowering lipid levels or by means of non-lipidic actions such as the direct inhibition of platelet function. The aim of this study was to detect the effect on platelet-dependent thrombin generation (PDTG) of a reduction in cholesterol obtained by means of a lipid-lowering diet or treatment with statins.. We compared PDTG (T0) in 144 hypercholesterolemic subjects (94 males and 50 females of child-bearing age, mean age 48.2 +/- 13.8, plasma total cholesterol 6.93 +/- 0.64, high density lipoprotein cholesterol 1.25 +/- 0.14, triglycerides 1.15 +/- 0.19 mmol/L) and 70 normolipidemic controls (37 males and 33 females, mean age 43.1 +/- 12.6. After six weeks on an appropriate diet, the patients were randomised to receive different statin therapies if there was no reduction in their lipid profile and/or PDTG (T1). They were re-evaluated six weeks later, and the drug doses were maintained or increased on the basis of the variables (T2). A final evaluation was made after a further six weeks (T3). All of the data were evaluated using ANOVA and Spearman's correlation coefficent. The results showed increased PDTG in hypercholesterolemic subjects (418.2 +/- 29.2 mIU/mL, p < 0.001 vs controls). Diet alone did not reduce PDTG (380.2 +/- 28.5 mIU/mL, p = 0.226 vs controls). At T2, simvastatin and atorvastatin significantly decreased PDTG (P < 0.001 vs T0-1) and low-density lipoprotein cholesterol (LDL-C). No correlation was found between the two variables in the simvastatin group (r = 0.16). Cerivastatin reduced PDTG without significantly decreasing LDL-C (p < 0.001 and p = 0.476, r = 0.14). Pravastatin and fluvastatin significantly reduced thrombin generation only at T3 (40 mg/day); pravastatin was also associated with a decrease in LDL-C (p < 0.01, r = 0.66).. Our results confirm an increased PDTG in patients with type IIa hyperlipoproteinemia, which is not reduced by diet. Statins at different doses significantly decrease PDTG but do not correlate with a reduction in LDL-C.

Topics: Adult; Anticholesteremic Agents; Atorvastatin; Blood Platelets; Cholesterol; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heptanoic Acids; Humans; Hypercholesterolemia; Indoles; Male; Middle Aged; Pravastatin; Pyridines; Pyrroles; Simvastatin; Thrombin; Treatment Outcome

We previously reported the results of a multicentre, randomised, double-blind, parallel-group study comparing the efficacy and safety of cerivastatin 0.4 mg/day and cerivastatin 0.2 mg/day in patients with primary hypercholesterolaemia. Exploratory analysis in this study suggested a gender difference in the 0.4 mg group: mean low-density lipoprotein cholesterol (LDL-C) decreased by 44.4 +/- 8.9% in women, compared with a mean decrease of 37.0 +/- 0.9% in men (p < 0.046). This paper reports the results of further sub-analyses from this study. Overall in the per-protocol (PP) population, 71.5% (n = 73) of women taking cerivastatin 0.4 mg had an LDL-C decrease of > 40%, compared with 38.0% (n = 76) of men taking the same dose. In the cerivastatin 0.2 mg PP population, 34% (n = 17) of women had an LDL-C decrease of > 40%, compared with 19% (n = 18) of men. Mean LDL-C/HDL-C ratio decreased by 43% from baseline to the end of the study in the cerivastatin 0.4 mg PP group: -41.3% in males vs. -48.3% in females. In the cerivastatin 0.2 mg group, the decrease in LDL-C/HDL-C ratio from baseline to endpoint did not markedly differ between genders: -37.0% for males vs. -37.3% for females. Categorial analysis of the LDL-C/HDL-C ratio found that 90% of PP patients taking cerivastatin 0.4 mg, and 84% of PP patients taking cerivastatin 0.2 mg, had a low CHD risk (defined as a LDL-C/HDL-C ratio < or = 3) after 8 weeks of treatment. The 6th and 95th percentiles of the distribution of LDL-C reduction from baseline revealed that 90% of PP patients taking cerivastatin 0.4 mg had an LDL-C reduction of between 22% and 56%. The mean LDL-C reduction for this 90% subset of patients was 40.1%. The same analysis for PP patients taking cerivastatin 0.2 mg found that 90% had an LDL-C reduction of between 13% and 49%. The mean LDL-C reduction in this 90% subset of patients was 31.5%. Of the patients taking cerivastatin 0.4 mg and valid for treatment according to National Cholesterol Education Program (NCEP) criteria, 71% (149/211) achieved NCEP targets for LDL-C at Week 16.

Topics: Adult; Aged; Analysis of Variance; Anticholesteremic Agents; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Female; Finland; Humans; Hypercholesterolemia; Male; Middle Aged; Pyridines; Risk Factors; Scandinavian and Nordic Countries; Sex Factors; United Kingdom

In this randomized, double-blind, parallel group study, the efficacy and safety of cerivastatin (0.3 mg) and pravastatin (20 mg) were compared in 402 patients with primary hypercholesterolemia with and without documented coronary heart disease or peripheral vascular disease. After 8 weeks of treatment, cerivastatin provided significantly greater reductions than pravastatin in low-density lipoprotein (LDL)-cholesterol (31.1% vs. 26.0%; p < 0.0001) and total cholesterol (21.1% vs. 17.8%; p < 0.0001). A greater proportion of patients treated with cerivastatin than pravastatin achieved > 30% and > 40% reductions from baseline in LDL-cholesterol. Both agents also increased high density lipoprotein-cholesterol and reduced triglycerides. Overall, 65.1% of patients treated with cerivastatin and 63.3% of patients with pravastatin achieved LDL-cholesterol goals defined by the National Cholesterol Education Program. Both drugs were well tolerated, with most adverse events being mild. These results demonstrate that cerivastatin (0.3 mg) is a highly effective 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, which enables a large proportion of patients to achieve clinically meaningful reductions in LDL-cholesterol.

Topics: Adolescent; Adult; Aged; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Middle Aged; Pravastatin; Pyridines; Safety; Stereoisomerism; Treatment Outcome; Triglycerides

To determine the relative efficacy and safety of cerivastatin and pravastatin in patients with type II hypercholesterolemia.. In this prospective, double-blind, parallel-group study, hypercholesterolemic patients were randomized to treatment with cerivastatin, 0.3 mg (n=250) or 0.4 mg (n=258), or pravastatin, 20 mg (n=266) or 40 mg (n=256), for 8 weeks.. Cerivastatin, 0.3 mg, was significantly more effective than pravastatin, 20 mg, in reducing low-density lipoprotein (LDL) cholesterol from baseline (-29.6% vs -26.8%; P=.008). Cerivastatin, 0.4 mg, was significantly more effective than pravastatin, 40 mg, in reducing LDL cholesterol (-34.2% vs -30.3%; P<.001). A larger proportion of cerivastatin-treated patients had greater than 40% reductions in LDL cholesterol than those receiving pravastatin (11.1% vs 6.0%). The percentage of patients who achieved the National Cholesterol Education Program (NCEP) target was 71.3% with cerivastatin, 0.3 mg, compared with 67.5% with pravastatin, 20 mg, and 74.0% with cerivastatin, 0.4 mg, compared with 71.1% with pravastatin, 40 mg (no significant difference). Cerivastatin, 0.3 mg, reduced total cholesterol to a greater extent than did pravastatin, 20 mg (P<.03). Both agents reduced triglycerides and increased high-density lipoprotein cholesterol to a similar degree (no significant differences). Cerivastatin and pravastatin were well tolerated.. Cerivastatin, 0.3 mg and 0.4 mg, showed greater efficacy than pravastatin, 20 mg and 40 mg, respectively, in lowering LDL cholesterol. Cerivastatin is safe and effective for patients with hypercholesterolemia who require aggressive LDL cholesterol lowering to achieve NCEP-recommended targets.

Topics: Adolescent; Adult; Aged; Cholesterol, HDL; Cholesterol, LDL; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents; Male; Middle Aged; Pravastatin; Prospective Studies; Pyridines; Treatment Outcome; Triglycerides

Topics: Apolipoproteins; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cyclosporine; Drug Therapy, Combination; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Immunosuppressive Agents; Kidney Transplantation; Lipids; Male; Middle Aged; Postoperative Complications; Pyridines; Triglycerides

Cerivastatin is a third generation hydroxy-methyl-glutaryl-Co-enzyme A (HMG-CoA) reductase inhibitor proven to lower low-density lipoprotein (LDL) cholesterol 28% to 31% in patients with primary hypercholesterolemia when given at 0.3 mg/day. This study evaluates the safety, tolerability, pharmacodynamics, and pharmacokinetics of cerivastatin 0.8 mg once daily for 4 weeks. In this randomized, double-blind, placebo-controlled parallel group trial conducted at 2 study centers, 41 patients (63% women) with primary hypercholesterolemia were placed on an American Heart Association Step 1 diet for 4 weeks. Single-blind placebo was administered for the final 2 weeks, before randomization. Patients received cerivastatin 0.8 mg (n = 28) or placebo (n = 13) once each evening for 28 days. Cerivastatin at 0.8 mg daily was well tolerated. No discontinuations occurred during the study. Adverse events were mild and transient. One cerivastatin-treated patient experienced asymptomatic creatinine kinase, 8x the upper limit of normal (ULN) elevation on the last day of the study, which resolved 6 days after the completion of the study. Cerivastatin 0.8 mg daily significantly reduced LDL cholesterol compared with placebo (-44.0 +/- 2.0% vs 2.2 +/- 2.8%, p <0.0001); total cholesterol (-30.8 +/- 1.4% vs 2.6 +/- 2.1%, p <0.0001), triglycerides (-11.2 +/- 5.9% vs 15.9 +/- 8.6%, p <0.02), but did not significantly alter high-density lipoprotein (HDL) cholesterol (3.2 +/- 2.1% vs -1.2 +/- 3.1%, p = NS). The pharmacokinetics of the 0.8-mg dose revealed dose proportional elevations in the 24-hour area under the curve and maximum plasma concentration relative to 0.3- and 0.4-mg doses with no change in time to maximum concentration or the elimination half-life in plasma. The increased efficacy and lack of clinically significant laboratory abnormalities or adverse events demonstrates a need for a large long-term study to confirm the safety and efficacy of this dose of cerivastatin.

Topics: Cholesterol, LDL; Double-Blind Method; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Pyridines

To compare cerivastatin with simvastatin in their long term safety and efficacy in reducing low density lipoprotein cholesterol (LDL-C).. Multicentre, randomized, double-blind, parallel group study.. Thirteen Canadian centres.. A total of 387 patients with primary hypercholesterolemia received treatment with either cerivastatin (0. 05 to 0.3 mg/day) or simvastatin (5 to 40 mg/day) to achieve plasma LDL-C levels below 3.36 mmol/L (130 mg/dL) for an initial 32-week dose-titration phase and a subsequent 72-week extension phase.. Cerivastatin and simvastatin produced clinically significant reductions in LDL-C of 28.4% and 35.4%, respectively, at the end point for the 32-week study, and reductions of 32.8% and 35. 0%, respectively, at the end of the extension phase of the study. Response rates (a greater than 15% drop in LDL-C) were comparable for the two treatments (88.9% cerivastatin versus 93.2% simvastatin) at the 32-week end point. Response rates were 100% for both treatments at the end of the 72-week extension phase. Both treatments also reduced total cholesterol, apolipoprotein B and very low density lipoprotein cholesterol levels. Cerivastatin and simvastatin increased HDL-C levels significantly by 8.8% and 11.0%, respectively, at the end point for the 32-week study, and by 8.6% and 12.1%, respectively, at the end of the extension phase of the study. Treatments were well tolerated, and the incidence of adverse effects was similar in both groups.. This forced titration study demonstrates that cerivastatin, given once daily at doses up to 0.3 mg/day, is effective and well tolerated. The results of this study support further investigation of higher doses of cerivastatin given the excellent safety profile at doses up to 0.3 mg.

Topics: Anticholesteremic Agents; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Pyridines; Simvastatin; Titrimetry

Cerivastatin sodium a synthetic and pure enantiomeric 3-hydroxy-3-methylglutaril-coenzyme A (HMG-CoA) reductase inhibitor, is considered effective in the treatment of mild-to-moderate primary hypercholesterolemia (total cholesterol < or = 220-259 mg/dL) at a daily dose of 0.15 mg. We compared the efficacy and tolerability of a dosage of 0.3 mg/d with those of a dosage of 0.15 mg/d in patients with severe primary hypercholesterolemia (serum total cholesterol > or = 260 mg/dL). After a minimum of 4 week's lead-in with placebo, 73 patients with severe primary hypercholesterolemia were randomly assigned to receive either 0.15 or 0.3 mg of cerivastatin sodium once daily after the evening meal for 12 weeks. In 58 patients, the same drug was continued at a flexible dosage for an additional 36 weeks or longer to assess the long-term efficacy and tolerability of cerivastatin sodium. During the 12-week treatment period, serum total cholesterol levels decreased significantly from baseline in both dosage groups, but the percentage reduction was significantly greater in the 0.3-mg group (range, 24.4% to 25.6%) than in the 0.15-mg group (range, 19.4% to 21.6%). The percentage reduction in levels of low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B and the percentage increase in levels of high-density lipoprotein cholesterol were significantly greater in the 0.3-mg group than in the 0.15-mg group. When the results for the 0.3- and 0.15-mg groups were combined, the percentage of change in serum lipid levels at 48 weeks remained as stable as at 12 weeks. No serious adverse reactions were observed. We concluded that the higher dose of cerivastatin sodium was more effective than the lower dose, with comparable tolerability, in the treatment of patients with severe primary hypercholesterolemia.

Topics: Adult; Anticholesteremic Agents; Apolipoproteins B; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Longitudinal Studies; Male; Middle Aged; Placebos; Pyridines; Stereoisomerism; Triglycerides

An international multicentre double-blind randomised trial compared the efficacy and safety of cerivastatin (0.025, 0.05, 0.1 and 0.2 mg once daily) with placebo and simvastatin (20 mg) over a period of 12 weeks, with study extensions to 52 and 100 weeks. The primary efficacy parameter was the percentage change in low density lipoprotein cholesterol (LDL-C). This was reduced from the baseline by 12.5% (0.025 mg) to 30.6% (0.2 mg) compared with falls of 2.0% on placebo and 40.3% on simvastatin. All four cerivastatin doses and simvastatin (20 mg) produced significantly greater falls than placebo (p < 0.0001) and the decrease in LDL-C was dose-dependent for cerivastatin. Simvastatin produced significantly greater falls than any cerivastatin dose or placebo (p < 0.0001). The effect was maintained at 1 year but somewhat attenuated at 100 weeks. Significant falls were also seen in serum total cholesterol and triglycerides. High density lipoprotein cholesterol (HDL-C) levels were significantly increased by cerivastatin (0.1 and 0.2 mg) and simvastatin (20 mg) at 12 weeks and increased further by 100 weeks. Mean fasting apolipoprotein A1 and lipoprotein A1 were increased and apolipoprotein B decreased by cerivastatin and simvastatin therapy. All doses of cerivastatin produced significant falls in the total cholesterol/HDL-C ratio at 12 weeks (0.5-1.6) compared with a fall of 2.1 for simvastatin (20 mg). Cerivastatin was well tolerated. Elevations in creatine phosphokinase, aspartate aminotransferase and alanine aminotransferase were mostly minor and transitory. Vital signs, electrocardiogram determinations, urinalysis and ophthalmic assessment showed similar results for both drugs. Cerivastatin, at doses of 0.1 mg and 0.2 mg daily, is considered to be of therapeutic value in the treatment of patients with primary hypercholesterolaemia, with 0.2 mg cerivastatin achieving reductions of LDL-C and total cholesterol similar to those achieved in the WOSCOP and CARE studies.

Topics: Anticholesteremic Agents; Double-Blind Method; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Middle Aged; Pyridines; Simvastatin; Treatment Outcome

Elevated serum cholesterol level is a key risk factor for cardiovascular morbidity and mortality. Cerivastatin is a highly effective lipid-lowering agent currently licensed at doses of 0.1, 0.2, 0.3 and 0.4 mg. This was a multicentre, randomised, double-blind, parallel-group study comparing the efficacy and safety of cerivastatin 0.4 mg/day with that of cerivastatin 0.2 mg/day in patients with primary hypercholesterolaemia. There was a six-week placebo run-in phase followed by a 24-week active treatment phase. A total of 494 patients were randomised to receive cerivastatin 0.4 mg (n = 332) or 0.2 mg (n = 162). Per-protocol (PP) analysis revealed that mean low-density lipoprotein cholesterol (LDL-C) level decreased by 38.4 +/- 0.7% from baseline in the 0.4 mg group, compared with a decrease of 31.5 +/- 0.9% in the 0.2 mg group (p < 0.0001). There was a significant gender difference in the 0.4 mg group: LDL-C decreased by 44.4 +/- 8.9% in women, compared with a decrease of 37.0 +/- 0.9% in men (p < 0.046). In the PP group as a whole, total cholesterol decreased by 26.0 +/- 0.5% from baseline in the 0.4 mg group, compared with a decrease of 21.6 +/- 0.7% in the 0.2 mg group (p < 0.0001). Both doses were well tolerated; only eight (2.4%) patients in the 0.4 mg group and five (3.1%) patients in the 0.2 mg group withdrew owing to adverse events. Cerivastatin 0.2 mg/day and 0.4 mg/day was found to lower low-density lipoprotein cholesterol and total cholesterol levels in a dose-dependent manner, with both doses exhibiting a good safety profile.

Topics: Adult; Aged; Analysis of Variance; Cholesterol; Cholesterol, LDL; Consumer Product Safety; Diet; Dose-Response Relationship, Drug; Double-Blind Method; Exercise; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Least-Squares Analysis; Male; Middle Aged; Pyridines; Triglycerides

The prevalence of coronary heart disease (CHD) is markedly increased in diabetic patients compared with non-diabetic individuals, and its prognosis is less good. Serum total and low-density lipoprotein (LDL) cholesterol concentrations have been shown to be powerful predictors of CHD morbidity and mortality in patients with type 2 diabetes. The available data suggest that the target cholesterol concentration in patients with diabetes should be similar to that in non-diabetic individuals with a previous myocardial infarction. This led us to investigate the efficacy, tolerability and safety of a new, highly potent statin, cerivastatin, in diabetic hyperlipidaemia.. This was a multinational, multicentre, double-blind, randomized study in type 2 diabetic patients with hypercholesterolaemia (LDL cholesterol >3.35 mmol/l; triglycerides <4.56 mmol/l). Eligible patients were randomly assigned to groups to receive cerivastatin 0.1 mg or 0.3 mg or placebo in a ratio of 2:2:1 for 12 weeks. They were monitored in the clinic every 4 weeks.. Of the 453 patients screened, 265 were allocated to the study groups. Fifty-one received placebo and 107 patients were assigned to each active treatment group (0.1 mg and 0.3 mg cerivastatin). At the close of the study, total cholesterol had decreased by 13.7% and 23.5%, LDL cholesterol decreased by 20.2% and 33.8%, and triglyceride concentrations decreased by 3.9% and 12.3% in the cerivastatin 0.1 mg and 0.3 mg groups, respectively. There was no significant difference between the groups in haemoglobin A1c, adverse events or increases in liver and muscle enzymes during the study period.. Hypercholesterolaemic patients with type 2 diabetes had a significant reduction in LDL cholesterol and total cholesterol concentrations after cerivastatin treatment once daily. The dose of 0.3 mg cerivastatin is effective in diabetic hypercholesterolaemia, with co-reduction of triglyceride concentrations. The effect of cerivastatin on coronary morbidity and mortality is currently being investigated in clinical trials.

Topics: Adult; Aged; Aged, 80 and over; Chi-Square Distribution; Coronary Disease; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypertriglyceridemia; Male; Middle Aged; Pyridines; Risk Factors

Phase IIa clinical studies with cerivastatin--including 2 pilot US and European dose-ranging studies, and 1 US dose-scheduling study--were conducted to establish a dosage regimen and effective therapeutic doses of cerivastatin in the treatment of hypercholesterolemia. Both dose-ranging studies included a 10-week dietary run-in, to which placebo was added in the last 6 weeks, before patients (n = 385) were randomized to 1 of 6 4-week treatment groups: cerivastatin (0.025, 0.05, 0.1, and 0.2 mg/day), 40 mg/day lovastatin (US), 20 mg/day simvastatin (Europe), or placebo. The dose-scheduling study also included a 10-week dietary run-in and 6-week single-blind placebo run-in phase, before patients (n = 319) were randomized to 4 weeks of treatment with either 0.1 mg cerivastatin twice daily, 0.2 mg cerivastatin with the evening meal, 0.2 mg cerivastatin at bedtime, or placebo in a 2:2:2:1 ratio. The 4-week dose-ranging studies showed that all 4 doses of cerivastatin produced significantly greater reductions in low-density lipoprotein (LDL) cholesterol than placebo. Cerivastatin 0.2 mg decreased LDL cholesterol by 30.5%. Cerivastatin also significantly decreased total cholesterol, triglycerides, and apolipoprotein B, and significantly increased high-density lipoprotein (HDL) cholesterol. Similar reductions in LDL cholesterol and total cholesterol occurred with 0.2 mg/day cerivastatin in the dose-scheduling study, although the reductions were significantly greater when cerivastatin was administered once daily with either the evening meal or at bedtime compared with 2 divided doses. LDL cholesterol reductions were similar when cerivastatin was taken with the evening meal and at bedtime. Cerivastatin was well tolerated, with the incidence of adverse events comparable to that of placebo treatment. No clinically significant increases in either hepatic isoenzymes or creatine phosphokinase were observed after treatment with cerivastatin.

Topics: Apolipoproteins B; Cholesterol, HDL; Cholesterol, LDL; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lovastatin; Male; Middle Aged; Pyridines; Safety; Simvastatin; Treatment Outcome; Triglycerides

Cerivastatin is a new, third-generation 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor ("statin"), which is administered to hypercholesterolemic patients at doses equivalent to 1-3% of the doses of other statins. This report reviews the pivotal Phase IIb/III clinical trials in which the efficacy and safety of cerivastatin was compared with placebo and active comparator statins (lovastatin, simvastatin, and pravastatin) after both short- and long-term administration. Overall, the studies showed that at doses of 0.025-0.4 mg/day, cerivastatin produced dose-dependent reductions in low-density lipoprotein (LDL) cholesterol and total cholesterol, which were significantly greater than placebo. The greatest reductions were achieved with 0.4 mg/day cerivastatin. On this dose, >40% of patients achieved reductions in LDL cholesterol >40% and in a further 9% of patients, LDL cholesterol was decreased by >50%. At higher doses, cerivastatin also demonstrated potent triglyceride-lowering effects in a subgroup of patients with raised plasma triglycerides. Reductions in atherogenic lipids and lipoproteins were accompanied by significant increases in high-density lipoprotein (HDL) cholesterol, apolipoprotein A-I, and antiatherogenic lipoprotein A-I. Long-term administration of cerivastatin for periods of up to 2 years was associated with persistent reductions in LDL cholesterol, total cholesterol, triglycerides, and apolipoprotein B as well as increases in HDL cholesterol similar to those observed after initial administration. Long-term cerivastatin treatment was also well tolerated. There was no significant difference between the incidence of adverse effects with cerivastatin and comparator statins or between cerivastatin and other statins with respect to clinically significant increases in either hepatic enzymes or creatine phosphokinase. In conclusion, these studies indicate that cerivastatin is a safe and effective long-term treatment for patients with primary hypercholesterolemia and also suggest that higher doses should be investigated.

Topics: Adolescent; Adult; Aged; Apolipoprotein A-I; Cholesterol, HDL; Cholesterol, LDL; Dose-Response Relationship, Drug; Double-Blind Method; Drug Evaluation; Female; Follow-Up Studies; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lovastatin; Male; Middle Aged; Pravastatin; Pyridines; Safety; Simvastatin; Treatment Outcome

In light of accumulating evidence that aggressive LDL-lowering therapy may offer increased protection against coronary heart disease, we undertook the design and synthesis of a novel series of HMG-CoA reductase inhibitors based upon a substituted pyrazole template. Optimizing this series using both structure-based design and molecular property considerations afforded a class of highly efficacious and hepatoselective inhibitors resulting in the identification of (3 R,5 R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2 H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic (PF-3052334) as a candidate for the treatment of hypercholesterolemia.

Topics: Animals; Cholesterol, LDL; Cricetinae; Guinea Pigs; Hepatocytes; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; In Vitro Techniques; Liver; Male; Mesocricetus; Muscle Cells; Pyrazoles; Rats; Stereoisomerism; Structure-Activity Relationship

Topics: Aged; Alleles; Creatine Kinase; DNA; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Metabolic Diseases; Middle Aged; Muscular Diseases; Mutation; Neurologic Examination; Pravastatin; Protein Prenylation; Pyridines

It has been suggested that the apolipoprotein E (APOE) genotype modifies the effect of dietary and pharmacological interventions for lowering lipid levels. We wanted to determine whether APOE genotyping information would be useful in making lipid-lowering treatment decisions in clinical practice. We included 981 patients with coronary heart disease (CHD) enrolled in an inpatient 3-week standardized rehabilitation program. Of these, 555 (57%) patients received continued statin therapy and 232 (24%) patients received newly initiated statin therapy. Dietary intervention was part of the program only for 194 (20%) patients. Total cholesterol (TC) and low-density lipoprotein cholesterol (LDLC) levels decreased in all the groups of patients during rehabilitation. The decreases were less pronounced among the APOE E2 carriers. However, the observed variation among the groups with respect to reduction of lipid levels was accounted for mainly by the initial lipid levels (30-47%) and only marginally on the APOE genotype (1%) . We therefore found no evidence that APOE genotyping will be useful in guiding dietary or pharmacological lipid-lowering treatment decisions.

Topics: Adult; Aged; Alleles; Apolipoprotein E2; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Atorvastatin; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Decision Making; Fatty Acids, Monounsaturated; Female; Fluvastatin; Genotype; Germany; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Inpatients; Linear Models; Lovastatin; Male; Middle Aged; Multivariate Analysis; Pravastatin; Predictive Value of Tests; Pyridines; Pyrroles; Simvastatin; Triglycerides

The preventive effect of statins on coronary events is not only associated with the cholesterol-lowering effect of these drugs, but also various direct effects on the vascular wall, which include improvement of endothelial function, antioxidant activity, and anti-inflammatory activity. We investigated whether short-term statin therapy could improve arterial stiffness and assessed its mechanism of action in patients with hypercholesterolemia. We assessed arterial stiffness in 10 patients (mean age: 62.9 +/- 9.0 years) with hypercholesterolemia (total cholesterol > or =220 mg/dl). The patients were treated with cerivastatin (0.15 mg/day) for 4 weeks. Before and after 4 weeks of treatment, we determined arterial stiffness from brachial-ankle pulse wave velocity and the ankle-brachial blood pressure index (ABI) using a FORM apparatus (Colin, Komaki, Japan). We also measured the blood levels of high-sensitivity C-reactive protein (hsCRP) and malondialdehyde low-density lipoprotein (MDA-LDL) as markers of inflammation and oxidation, respectively. After statin therapy, both the right and left abPWV were significantly decreased from 1544.6 +/- 157.1 to 1349.0 +/- 223.9 cm/s and from 1592.1 +/- 164.8 to 1424.8 +/- 245.2 cm/s, respectively (P < 0.05). However, the ABI was unchanged after 4 weeks of cerivastatin therapy. MDA-LDL decreased significantly (from 161.2 +/- 42.4 to 119.4 +/- 33.5 U/l, P < 0.05) and hsCRP also decreased. Total cholesterol and LDL-cholesterol decreased, while triglycerides and high-density lipoprotein-cholesterol were unchanged. Blood pressure was not significantly altered from the baseline value by statin therapy. These results suggest that the preventive effect of statins on coronary events is partly associated with the various actions of these drugs on the vascular wall, and that statins are not only cholesterol-lowering agents but also antiatherosclerotic agents.

Topics: Administration, Oral; Aged; Antioxidants; Arteries; Dose-Response Relationship, Drug; Drug Administration Schedule; Endothelium, Vascular; Female; Follow-Up Studies; Humans; Hypercholesterolemia; Male; Middle Aged; Probability; Prospective Studies; Pyridines; Risk Assessment; Severity of Illness Index; Treatment Outcome; Vascular Resistance; Vasodilation

We report on a patient who developed acute rhabdomyolysis after taking cerivastatin. A 74-year-old hypercholestrerolaemic woman taking cerivastatin (0.15 mg/day) for 22 days complained of general muscle weakness and muscle pain. Her serum creatinine phosphokinase level was 19,190 IU/L. Serum myoglobin was over 3000 ng/mL. Serum concentration of cerivastatin at 6 h after taking the last dose (0.15 mg) was 8062.5 ng/L, which was almost 5.7 times higher than that of normal persons. The serum concentration of cerivastatin showed that the half-life of cerivastatin in this patient was 22.4 h, compared with 2.4 h for normal controls. Cerivastatin is catabolized by cytochrome P450, 3A4 and 2C8 to M-1, and by 2C8 to M-23. The ratio of M-23 to M-1 in her serum was much lower than that of control persons (0.64 vs. 2.08). She had previously taken simvastatin which is metabolized by CYP3A4, without any sign and symptoms of rhabdomyolysis. These results suggest that the slowed clearance of cerivastatin in this patient might have been compounded by cytochrome P450, 2C8 dysfunction.

Topics: Acute Disease; Aged; Aryl Hydrocarbon Hydroxylases; Creatinine; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Administration Schedule; Female; Half-Life; Humans; Hypercholesterolemia; Metabolic Clearance Rate; Myoglobin; Myoglobinuria; Pyridines; Rhabdomyolysis; Simvastatin; Time Factors

3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, or statins, are widely prescribed to lower cholesterol. Recent reports suggest that statins may promote angiogenesis in ischemic tissues. It remains to be elucidated whether statins potentially enhance unfavorable angiogenesis associated with tumor and atherosclerosis. Here, we induced hind limb ischemia in wild-type mice by resecting the right femoral artery and subsequently inoculated cancer cells in the same animal. Cerivastatin enhanced blood flow recovery in the ischemic hind limb as determined by laser Doppler imaging, whereas tumor growth was significantly retarded. Cerivastatin did not affect capillary density in tumors. Cerivastatin, pitavastatin, and fluvastatin inhibited atherosclerotic lesion progression in apolipoprotein E-deficient mice, whereas they augmented blood flow recovery and capillary formation in ischemic hind limb. Low-dose statins were more effective than high-dose statins in both augmentation of collateral flow recovery and inhibition of atherosclerosis. These results suggest that statins may not promote the development of cancer and atherosclerosis at the doses that augment collateral flow growth in ischemic tissues.

Topics: Animals; Apolipoproteins E; Arteriosclerosis; Fatty Acids, Monounsaturated; Femoral Artery; Fluvastatin; Hindlimb; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Ischemia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Pathologic; Neovascularization, Physiologic; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Pyridines; Quinolines

In August 2001, cerivastatin was removed from European and USA markets because of a higher risk of rhabdomyolysis associated with its use in comparison with other statins. The objective of this study was to compare cholesterol-lowering drug use in Italy before and after the withdrawal of cerivastatin from the market, and to evaluate if the withdrawal influenced patients compliance and physicians prescribing habits. After August 2001, 48% of cerivastatin users discontinued any statin treatment. The major risk factor for discontinuation was a concomitant use of fibrate during the first 7 months of 2001 (OR = 2.3; 95% CI = -2.9). Comparing the discontinuation of statin therapy between 2001 and 2000 we can estimate that there was a 5% increase, corresponding to about 200,000 patients, who discontinued statin therapy during autumn 2001 because of cerivastatin emergency.

Topics: Aged; Drug Utilization; Female; Health Services Research; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Italy; Male; Middle Aged; Patient Compliance; Pyridines; Rhabdomyolysis; Risk Assessment

Cerivastatine was administered as a reversible HMG-CoA reductase inhibitor (statine) to treat hypercholesterolemia until its withdrawal from the market following 52 reports of death due to drug-related rhabdomyolysis and acute renal failure. In most cases, cerivastatine was applied in combination with drugs which influenced the liver metabolism of cerivastatine via cytochromeoxidase P 450 isoenzymes. We report a well-documented case of acute rhabdomyolysis following cerivastatine monotherapy. The diagnosis was confirmed additionally by muscle biopsy.Finally,we give an overview of the current knowledge concerning therapy with HMG-CoA reductase inhibitors,1 year after the withdrawal of cerivastatine from the market.

Topics: Acute Disease; Anticholesteremic Agents; Aryl Hydrocarbon Hydroxylases; Biopsy; Coenzymes; Comorbidity; Creatine Kinase; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Diagnosis, Differential; Drug Interactions; Electromyography; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Liver Cirrhosis, Alcoholic; Liver Function Tests; Middle Aged; Muscle, Skeletal; Neurologic Examination; Pancreatic Diseases; Pyridines; Rhabdomyolysis; Stomach Neoplasms; Ubiquinone

Topics: Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Pyridines

There is little information on how target lipid levels can be achieved in end stage renal disease (ESRD) patients in a systematic, multidisciplinary fashion.. We retrospectively reviewed a pharmacist-directed hyperlipidemia management program for chronic hemodialysis (HD) patients. All 26 adult patients on chronic HD at a tertiary care medical facility were entered into the program. A clinical pharmacist was responsible for laboratory monitoring, patient counseling, and the initiation and dosage adjustment of an appropriate 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) using a dosing algorithm and monitoring guidelines. The low-density lipoprotein (LDL) cholesterol goal was leq; 100 mg/dl. A renal dietitian provided nutrition counseling and the nephrologist was notified of potential or existing drug interactions or adverse drug reactions (ADRs). Patients received a flyer containing lipid panel results to encourage compliance. Data was collected at program initiation and for 6 months thereafter.. At the start of the program, 58% of patients were at target LDL cholesterol. At 6 months, 88% had achieved target LDL (p = 0.015). Mean LDL cholesterol decreased from 96 +/- 5 to 80 +/- 3 mg/dl (p < 0.01), and mean total cholesterol decreased from 170 +/- 7 to 151 +/- 4 mg/dl (p < 0.01). Fifteen adjustments in drug therapy were made. Eight adverse drug reactions were identified; 2 required drug discontinuation or an alternative agent. Physicians were alerted to 8 potential drug-drug interactions, and appropriate monitoring was performed.. Our findings demonstrate both feasibility and efficacy of a multidisciplinary approach in management of hyperlipidemia in HD patients.

Topics: Algorithms; Drug Interactions; Feasibility Studies; Female; Guidelines as Topic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Kidney Failure, Chronic; Lipoproteins, LDL; Male; Middle Aged; Patient Care Team; Pharmacy Service, Hospital; Pyridines; Reference Values; Renal Dialysis; Retrospective Studies; Simvastatin; Statistics as Topic

Inhibitors of the key enzyme of cholesterol biosynthesis beta-hydroxy-beta-methylglutaryl-coenzyme A reductase (statins) decrease cholesterol content in atherogenic low-density lipoproteins in patients with coronary heart disease and hypercholesterolemia, but inhibited biosynthesis of ubiquinone Q10 protecting low-density lipoproteins from free radical oxidation. Cerivastatin in a daily dose of 0.4 mg markedly increased the content of lipid peroxides in low-density lipoproteins. However, complex therapy with cerivastatin and antioxidant probucol (250 mg/day) was accompanied by a sharp decrease in the content of lipid peroxides in low-density lipoproteins in patients with coronary heart disease in vivo. These data indicate that antioxidant agents should be used in combination with inhibitors of beta-hydroxy-beta-methylglutaryl-coenzyme A reductase (hypolipidemic preparations) for the therapy of patients with coronary heart disease.

Topics: Antioxidants; Cholesterol; Cholesterol, LDL; Coenzymes; Double-Blind Method; Enzyme Inhibitors; Free Radicals; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipid Metabolism; Lipoproteins, LDL; Male; Middle Aged; Myocardial Ischemia; Oxygen; Peroxides; Placebos; Probucol; Pyridines; Random Allocation; Time Factors; Ubiquinone

Topics: Aged; Arteriosclerosis; Diabetes Mellitus; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Kinetics; Nitroglycerin; Pyridines; Reproducibility of Results; Ultrasonography; Vasodilation; Vasodilator Agents

Topics: Aged; Brachial Artery; Diabetes Mellitus; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Nitroglycerin; Pyridines; Vasodilation; Vasodilator Agents

Topics: Dose-Response Relationship, Drug; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Muscle, Skeletal; Muscular Diseases; Pyridines

Topics: Aged; Antipsychotic Agents; Drug Interactions; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Pyridines; Rhabdomyolysis; Risk Factors; Risperidone

Topics: Alleles; Apolipoproteins E; Genotype; Graft Survival; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hyperlipidemias; Kidney Transplantation; Polymorphism, Genetic; Postoperative Complications; Pyridines

Rosuvastatin (formerly ZD4522) is a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) with distinct pharmacologic properties. Compared with most other statins, it is relatively hydrophilic, similar in this respect to pravastatin. Rosuvastatin has been shown to be a comparatively potent inhibitor of HMG-CoA reductase activity in a purified preparation of the catalytic domain of the human enzyme, as well as in rat and human hepatic microsomes. In rat hepatocytes, rosuvastatin was found to have significantly higher potency as an inhibitor of cholesterol synthesis than 5 other statins. Rosuvastatin was approximately 1,000-fold more potent in rat hepatocytes than in rat fibroblasts. Further studies in rat hepatocytes demonstrated that rosuvastatin is taken up into these cells by a high-affinity active uptake process. Rosuvastatin was also taken up selectively into the liver after intravenous administration in rats. Potent and prolonged HMG-CoA reductase inhibitory activity has been demonstrated after oral administration to rats and dogs. Pharmacokinetic studies in humans using oral doses of 5 to 80 mg showed that maximum plasma concentrations and areas under the concentration-time curve are approximately linear with dose. The terminal half-life is approximately 20 hours. Studies with human hepatic microsomes and human hepatocytes have suggested little or no metabolism via the cytochrome P-450 3A4 isoenzyme. On the basis of these observations, it is suggested that rosuvastatin has the potential to exert a profound effect on atherogenic lipoproteins.

Topics: Animals; Arteriosclerosis; Cholesterol, LDL; Clinical Trials as Topic; Drug Evaluation, Preclinical; Fluorobenzenes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Molecular Structure; Pyrimidines; Rosuvastatin Calcium; Sulfonamides

Topics: Aged; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Pyridines; Rhabdomyolysis

Topics: Aged; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypothyroidism; Pyridines; Rhabdomyolysis

Topics: Drug Industry; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Pyridines; Rhabdomyolysis; United States

We recently obtained evidence demonstrating that cultured bovine endothelial cells contain cytosolic proteins that form complexes with the 3'-untranslated region of endothelial nitric oxide synthase (eNOS) mRNA and are associated with its destabilization. The aim of this study was to determine the presence of such proteins and eNOS expression in hypercholesterolemic rabbits as an in vivo model of endothelial dysfunction.. Endothelium-dependent relaxation to acetylcholine and the calcium ionophore A23187 was reduced in aortic segments from hypercholesterolemic rabbits compared with controls. Treatment of hypercholesterolemic rabbits with cerivastatin (0.1 mg. kg body wt(-1). d(-1)) restored endothelium-dependent relaxation. Aortic eNOS expression was reduced in hypercholesterolemic rabbits and was accompanied by enhanced binding activity of a 60-kDa cytosolic protein and reduced stability of eNOS mRNA. Cerivastatin treatment upregulated eNOS expression and reduced the interaction of the cytosolic protein with the 3'-untranslated region of eNOS mRNA. Mononuclear cells from hypercholesterolemic rabbits also showed a marked reduction of eNOS expression and eNOS mRNA stability and an increase in binding activity of the cytosolic protein, which were also prevented by cerivastatin treatment.. These results demonstrate the presence of a 60-kDa protein that binds to eNOS mRNA and reductions in eNOS expression in both vascular wall and mononuclear cells that are prevented by cerivastatin.

Topics: 3' Untranslated Regions; Animals; Aorta; Cytosol; Disease Models, Animal; Endothelium, Vascular; Gene Expression Regulation; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; In Vitro Techniques; Ionophores; Leukocytes, Mononuclear; Macromolecular Substances; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Protein Binding; Pyridines; Rabbits; RNA Stability; RNA, Messenger; Substrate Specificity; Vasodilation; Vasodilator Agents

Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Pyridines; Rhabdomyolysis

Topics: Acute Disease; Aged; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Pyridines; Rhabdomyolysis

Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Pyridines; Rhabdomyolysis

Topics: Anticholesteremic Agents; Anuria; Clopidogrel; Coronary Artery Bypass; Humans; Hypercholesterolemia; Intracranial Thrombosis; Male; Middle Aged; Muscle Weakness; Myocardial Infarction; Platelet Aggregation Inhibitors; Postoperative Complications; Pyridines; Rhabdomyolysis; Ticlopidine

Cerivastatin, commercialized under the trade names of Lipobay by Bayer and Cholstat by Fournier Pharma, is a new synthetic statin. Because of its high affinity for HMG-CoA reductase enzyme that it specifically and selectively inhibited in the hepatocytes, cerivastatin exerts its cholesterol-lowering effect at very low doses, between 0.1 and 0.3 mg/day. Cerivastatin is indicated, after diet failure, in the treatment of primary forms of isolated hypercholesterolaemia or combined hyperlipidaemia. It is presented by the two pharmaceutical companies as 0.1, 0.2 and 0.3 mg filmed tablets. Usual dose is 0.3 mg, once daily, to be reduced in presence of renal failure. Cerivastatin is metabolised within the liver by two different families of cytochrome P450, which limits the risk of drug interferences. Besides this potential advantage as compared with some other statins, its pharmacodynamic activity and safety profile seem to be similar to those of other agents of the same pharmacological family.

Topics: Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hyperlipidemias; Pyridines

Topics: Budgets; Cost-Benefit Analysis; Germany; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypertriglyceridemia; Pyridines

Low density lipoprotein (LDL) with low sialic acid content has been reported to cause intracellular cholesterol accumulation, and therefore desialylation has been proposed to be an atherogenic modification of LDL. However, it is not known whether hypolipidemic treatment has any effect on LDL sialylation. Accordingly, we investigated the sialic acid/apolipoprotein (apo) B ratio of total LDL and its subfractions in 26 moderately hypercholesterolemic patients at baseline and after treatment with statins for 2-3 months. Cholesterol and triglyceride levels were reduced in all apo B-containing lipoproteins, including all LDL subfractions, while the sialic acid ratio was increased in total LDL and in all its subfractions. Cholesterol concentrations and sialic acid ratios were inversely correlated in light and dense LDL subfractions both before and during statin treatment, and the greater the decrease in cholesterol and apo B contents of dense LDL, the higher was the increase in its sialic acid ratio. Furthermore, the lower the baseline sialic acid ratio of dense LDL, the greater was the reduction in its lipid and apo B concentrations. In conclusion, inhibition of cholesterol synthesis by statin treatment increased sialic acid/apo B ratio in LDL proportionately to the decrease of LDL apo B and cholesterol.

Topics: Adult; Aged; Anticholesteremic Agents; Apolipoproteins B; Cholesterol; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hypercholesterolemia; Indoles; Lipoproteins, LDL; Male; Middle Aged; N-Acetylneuraminic Acid; Pyridines; Simvastatin

The incidence of coronary heart disease (CHD) is greatly increased in overweight diabetic patients. Modification of dietary intake and weight loss improve hypercholesterolaemia. However, cholesterol goal levels are not achieved in several patients under this treatment. The aim of our study was to evaluate the effect of Cerivastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, in patients with type 2 diabetes mellitus. A population of 40 diabetic type 2 outpatients were analyzed in a prospective way. The mean+/-SD age was 60.7+/-11.6 years, with a diabetes duration of 8.5+/-6.6 years. All patients were treated with cerivastatin (0.2 mg once a day) for 6 months. Weight HbAlc fasting blood glucose, urine microalbuminuria, total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides were measured at the beginning of the study and again after 3 and 6 months of treatment with cerivastatin. An improvement in lipid levels was achieved, with a significant decrease in LDL-cholesterol (27.7%), total cholesterol (21.4%), triglycerides levels (10.4%) and a significant increase in HDL-cholesterol levels (8.3%) (P<0.05). Cardiovascular risk ratios such as; total cholesterol/HDL-cholesterol and LDL-cholesterol/HDL-cholesterol improved during treatment, decreasing 11.3% and 30%, respectively (P<0.05). Low incidence of side effects was demonstrated. In summary, cerivastatin improved lipid control in patients with type 2 diabetes, with a low incidence of side effects.

Topics: Aged; Cholesterol; Coronary Disease; Diabetes Mellitus, Type 2; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Incidence; Male; Middle Aged; Prospective Studies; Pyridines; Treatment Outcome

Thrombosis is a complication of atherosclerosis and monocytes play a determinant role either in the progression of atherosclerotic plaque or in blood coagulation by way of tissue factor expression. Platelets play a direct role in thrombosis and a hyperfunctional state has been described in hypercholesterolemic subjects. Moreover, platelets seem to be able to enhance monocyte activity. Cholesterol-lowering molecules (statins) are reported to reduce cardiovascular risk, either by decreasing the circulating level of cholesterol or by non-lipidic actions such as the reduction of monocyte and platelet activity. The aim of our study was to investigate the influence of platelets on the expression of tissue factor by monocytes and the effect induced by cerivastatin. We measured tissue factor levels by ELISA and the procoagulant activity of stimulated monocytes by a clotting assay on cellular preparations and whole blood in 40 hypercholesterolemic subjects (22 male, 18 female, mean age 52.7 +/- 12 years, total cholesterol 251.6 +/- 19.9 mg/dl) before and after cerivastatin addition. Tissue factor expression was enhanced in hypercholesterolemic subjects compared with normal subjects (31.6 +/- 7.6 vs. 23 +/- 5.8 pg/cells, P < 0.01). The presence of platelets increased the amount of tissue factor (55.3 +/- 7.3 pg/cells, P < 0.001) and cerivastatin reduced the expression of tissue factor in isolated monocytes, in the mixed cellular system, and in whole blood (19.6 +/- 4.1 pg/cells, P < 0.001). In conclusion, tissue factor expression by monocytes is enhanced in hypercholesterolemic subjects compared with normal controls. Platelets enhance monocyte production of tissue factor, and cerivastatin is able to counteract this prothrombotic mechanism.

Topics: Adult; Blood Platelets; Cholesterol; Cholesterol, HDL; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; In Vitro Techniques; Lipopolysaccharides; Male; Middle Aged; Monocytes; Pyridines; Thromboplastin; Triglycerides

Topics: Clinical Trials as Topic; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Hypercholesterolemia; Pyridines; Transaminases

Topics: Coronary Disease; Humans; Hypercholesterolemia; Hyperlipidemias; Hypolipidemic Agents; Lipoproteins, HDL; Lipoproteins, LDL; Lovastatin; Pyridines; Risk Factors

Topics: Drug Approval; Enzyme Inhibitors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Pyridines; United States; United States Food and Drug Administration