cerivastatin and Hyperlipidemias

Cerivastatin was the most potent statin until it was withdrawn from the market due to a number of fatalities due to rhabdomyolysis, however, the dose-related magnitude of effect of cerivastatin on blood lipids is not known.. Primary objective To quantify the effects of various doses of cerivastatin on the surrogate markers: LDL cholesterol, total cholesterol, HDL cholesterol and triglycerides in children and adults with and without cardiovascular disease. The aim of this review is to examine the pharmacology of cerivastatin by characterizing the dose-related effect and variability of the effect of cerivastatin on surrogate markers. Secondary objectives To quantify the effect of various doses of cerivastatin compared to placebo on withdrawals due to adverse effects. To compare the relative potency of cerivastatin with respect to fluvastatin, atorvastatin and rosuvastatin for LDL cholesterol, total cholesterol, HDL cholesterol and triglycerides.. The Cochrane Hypertension Information Specialist searched the following databases for RCTs up to March 2019: CENTRAL (2019, Issue 3), Ovid MEDLINE, Ovid Embase, the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov.We also searched the European Patent Office, FDA.gov, and ProQuest Dissertations & Theses, and contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions.. RCTs and controlled before-and-after studies evaluating the dose response of different fixed doses of cerivastatin on blood lipids over a duration of three to 12 weeks in participants of any age with and without cardiovascular disease.. Two review authors independently assessed eligibility criteria for trials to be included and extracted data. We entered data from RCTs and controlled before-and-after studies into Review Manager 5 as continuous and generic inverse variance data respectively. We collected information on withdrawals due to adverse effects from the RCTs. We assessed all trials using the 'Risk of bias' tool under the categories of sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other potential biases.. Fifty trials (19 RCTs and 31 before-and-after studies) evaluated the dose-related efficacy of cerivastatin in 12,877 participants who had their LDL cholesterol measured. The participants were of any age with and without cardiovascular disease and the trials studied cerivastatin effects within a treatment period of three to 12 weeks. Cerivastatin 0.025 mg/day to 0.8 mg/day caused LDL cholesterol decreases of 11.0% to 40.8%, total cholesterol decreases of 8.0% to 28.8% and triglyceride decreases of 9.0% to 21.4%. We judged the certainty of evidence for these effects to be high. Log dose-response data over doses of 2.5 mg to 80 mg revealed strong linear dose-related effects on LDL cholesterol, total cholesterol and triglycerides. When compared to fluvastatin, atorvastatin and rosuvastatin, cerivastatin was about 250-fold more potent than fluvastatin, 20-fold more potent than atorvastatin and 5.5-fold more potent than rosuvastatin at reducing LDL cholesterol; 233-fold more potent than fluvastatin, 18-fold more potent than atorvastatin and six-fold more potent than rosuvastatin at reducing total cholesterol; and 125-fold more potent than fluvastatin, 11-fold more potent than atorvastatin and 13-fold more potent than rosuvastatin at reducing triglycerides. There was no dose-related effect of cerivastatin on HDL cholesterol, but overall cerivastatin increased HDL cholesterol by 5%. There was a high risk of bias for the outcome withdrawals due to adverse effects, but a low risk of bias for the lipid measurements. Withdrawals due to adverse effects were not different between cerivastatin and placebo in 11 of 19 of these short-term trials (risk ratio 1.09, 95% confidence interval 0.68 to 1.74).. The LDL cholesterol, total cholesterol, and triglyceride lowering effect of cerivastatin was linearly dependent on dose. Cerivastatin log dose-response data were linear over the commonly prescribed dose range. Based on an informal comparison with fluvastatin, atorvastatin and rosuvastatin, cerivastatin was about 250-fold more potent than fluvastatin, 20-fold more potent than atorvastatin and 5.5-fold more potent than rosuvastatin in reducing LDL cholesterol, and 233-fold greater potency than fluvastatin, 18-fold greater potency than atorvastatin and six-fold greater potency than rosuvastatin at reducing total cholesterol. This review did not provide a good estimate of the incidence of harms associated with cerivastatin because of the short duration of the trials and the lack of reporting of adverse effects in 42% of the RCTs.

Topics: Cholesterol, HDL; Cholesterol, LDL; Dose-Response Relationship, Drug; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Lipids; Pyridines; Randomized Controlled Trials as Topic; Treatment Outcome; Triglycerides

Rosuvastatin is the first statin approved by the regulatory authorities since the withdrawal of cerivastatin. Although highly efficacious, this new statin has generated considerable controversy regarding its safety. Rosuvastatin was approved for clinical use based on the largest pre-approval database for all statins prior to commercial use. In this database, rosuvastatin had a similar safety profile to other approved statins up to the highest approval dose of 40 mg. As with all statins, there is a marked increase in adverse effects when the dose is titrated from 40 to 80 mg, and rosuvastatin demonstrates a similar dose/toxicity relationship. In the pre-approval data trials on 80 mg, there was a 1.0% (n = 16) incidence of myopathy and 7 patients developed rhabdomyolysis. However the

Topics: Acute Kidney Injury; Adverse Drug Reaction Reporting Systems; Biomarkers; Cholesterol, LDL; Creatine Kinase; Creatine Kinase, MM Form; Drug Approval; Fluorobenzenes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Incidence; Isoenzymes; Kidney Tubules; Muscular Diseases; Product Surveillance, Postmarketing; Proteinuria; Pyridines; Pyrimidines; Rhabdomyolysis; Rosuvastatin Calcium; Sulfonamides

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

Combination lipid-altering regimens represent an emerging clinical paradigm to meet increasingly stringent consensus lipoprotein targets for coronary prevention. This practice, together with escalating prevalences of coronary artery disease in certain ageing (western industrial) populations, polypharmacy in the elderly and the recent voluntary market withdrawal of cerivastatin, warrants a re-examination of the safety profiles of 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors (i.e., statins). These agents are exceedingly well-tolerated in the vast majority of patients, very infrequently precipitating musculoskeletal symptoms and/or signs. Statins vary in their pharmacological profiles, leading to distinct levels of systemic exposure and capacities to penetrate skeletal myocytes. Pharmacokinetic interactions with certain agents increase the likelihood of statin-induced myopathy and, in exceedingly rare instances, potentially fatal rhabdomyolysis with myoglobinuria and renal failure. As with other medical decisions, the anticipated benefits of long-term statin therapy, with or without other lipid-altering agents, need to be weighed against the prospects of clinically significant drug interactions. In clinical trials and postmarketing surveillance, the two statins that are not metabolised by the cytochrome P450 3A4 system (fluvastatin and pravastatin) have exhibited very low propensities to elicit myopathy when combined with other agents. These agents should be considered initially when contemplating combination lipid-lowering regimens for coronary prevention.

Topics: Cytochrome P-450 Enzyme System; Drug Interactions; Drug Therapy, Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Lipids; Muscular Diseases; Practice Guidelines as Topic; Product Surveillance, Postmarketing; Pyridines; Risk Factors

In England, only 30% of patients with established coronary heart disease (CHD) and raised serum lipids, and fewer than 4% of individuals eligible for primary prevention, receive lipid-lowering therapy. Target total cholesterol concentrations are achieved in fewer than 50% of patients who do receive such treatment. Here, we review the use of statin therapy in the prevention of CHD events.

Topics: Anticholesteremic Agents; Atorvastatin; Coronary Disease; Drug Interactions; Fatty Acids, Monounsaturated; Fluvastatin; Heptanoic Acids; Humans; Hyperlipidemias; Indoles; Patient Selection; Pravastatin; Pyridines; Pyrroles; Risk Factors; Simvastatin; Treatment Outcome

Topics: Animals; Arteriosclerosis; Cardiovascular Diseases; CCAAT-Enhancer-Binding Proteins; Cholesterol; Cholesterol, LDL; Coenzyme A Ligases; Diabetes Mellitus, Type 2; DNA-Binding Proteins; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hydroxymethylglutaryl-CoA Synthase; Hyperlipidemias; Pravastatin; Pyridines; Randomized Controlled Trials as Topic; Sterol Regulatory Element Binding Protein 1; Transcription Factors

Rhabdomyolysis is a rare but potentially fatal complication associated with the use of cholesterol synthesis inhibitors (statins). The complication can develop in susceptible patients and with the concomitant use of medications that impede the biodegradation of statins, for example, biotransformation via the cytochrome P450 system. This may result in the plasma and tissue concentrations of statins, and their active metabolites, increasing to levels that are toxic for striated muscle. Myopathy is present when plasma activity levels of creatinine kinase are raised to in excess of 10 times the upper limit of the normal value. Muscular complaints which may be indicative of myotoxicity and subsequent myopathy are present in 1-7% of statin users. Albeit to varying degrees, all statins can induce myotoxicity especially at high dosages. Rhabdomyolysis was clearly more prevalent under cerivastatin users than the users of other statins and was therefore recently withdrawn from the market. Statins should be withdrawn immediately if myopathy is suspected. Prompt withdrawal may prevent rhabdomyolysis.

Topics: Creatine Kinase; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug and Narcotic Control; Drug Interactions; Drug Therapy, Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Mixed Function Oxygenases; Muscular Diseases; Netherlands; Pyridines; Rhabdomyolysis

Statins act by competitive inhibition of HMG-CoA reductase, a key enzyme regulating cholesterol synthesis. Reduction in serum LDL, the crucial biological expression dependent on this mechanism, varies in intensity as a function of the type and of the dose of statin.. Besides their lipid lowering effect, statins have also been demonstrated to have pleiotropic effects mostly directly related to HMG-CoA reductase inhibition.. Several clinical studies investigating prevention of cardiovascular disease have established that statins decrease cardiovascular morbidity and mortality. Results have been very coherent for both primary and secondary prevention with statins. The cardiovascular benefit is most likely partly related to its pleiotropic effects, particularly those inducing a stabilization of the atheromatous plaques.. Interventional studies have clearly established the role of statins in comparison with other lipid lowering agents for the prevention of cardiovascular events in most situations although a few therapeutic choices remain a subject of debate. Globally, the primary indications of statins are hypercholesterolemia and mixed hyperlipidemia with moderately elevated triglycerides. There are still some questions concerning the therapeutic goals of statin therapy.

Topics: Anticholesteremic Agents; Atorvastatin; Cardiovascular Diseases; Fatty Acids, Monounsaturated; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Indoles; Lovastatin; Pravastatin; Pyridines; Pyrroles; Simvastatin

Hyperlipidemia is recognized as one of the major risk factors for the development of coronary artery disease and progression of atherosclerotic lesions. Dietary therapy together with hypolipidemic drugs are central to the management of hyperlipidemia, which aims to prevent atherosclerotic plaque progression, induce regression, and so decrease the risk of acute coronary events in patients with pre-existing coronary or peripheral vascular disease. In patients at high risk of coronary artery disease but without evidence of atherosclerosis, treatment is designed to prevent the premature development of coronary artery disease, whereas in those with hypertriglyceridemia, treatment aims to prevent the development of hepatomegaly, splenomegaly, and pancreatitis. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are the most potent lipid-lowering agents currently available, and their use in the treatment of hyperlipidemia provides the focus for this review. Particular emphasis is given to cerivastatin, a new HMG-CoA reductase inhibitor that combines potent cholesterol-lowering properties with significant triglyceride-reducing effects. Recently completed primary and secondary intervention trials have shown that the significant reductions in low-density lipoprotein (LDL) cholesterol achieved with statins result in significant reductions in morbidity and mortality associated with coronary artery disease as well as reductions in the incidence of stroke and total mortality. Such benefits occur early in the course of statin therapy and have led to suggestions that these drugs may possess antiatherogenic effects over and above their capacity to lower atherogenic lipids and lipoproteins. Experimental studies have also shown statin-induced improvements in endothelial function, decreased platelet thrombus formation, improvements in fibrinolytic activity, and reductions in the frequency of transient myocardial ischemia.

Topics: Coronary Disease; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Lovastatin; Pyridines; Safety; Simvastatin; Treatment Outcome

Cerivastatin, a novel, synthetic, and enantiomerically pure 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been administered, in clinical trials, to >2,700 patients with primary hypercholesterolemia, of whom > 1,000 received treatment for periods of up to 1 year. A global, pooled analysis of the efficacy, safety, and tolerability of cerivastatin was performed on data obtained from all randomized, double-blind studies in which cerivastatin at doses of 0.025-0.4 mg/day was compared with either placebo or active comparator. All studies had a 10-week, diet-controlled run-in period, the last 6 weeks of which included administration of single-blind placebo. Efficacy analysis of the pooled data at 8 weeks postrandomization showed that in comparison with placebo, cerivastatin achieved significant dose-dependent reductions in low-density lipoprotein (LDL) cholesterol, the primary efficacy parameter, of 14.2-36.1 %. Reductions in LDL cholesterol were accompanied by significant reductions in total cholesterol and triglycerides, together with increases in high-density lipoprotein (HDL) cholesterol. The magnitude of the reduction in plasma triglycerides was strongly related to baseline triglyceride levels. In patients with baseline plasma triglycerides of >250 mg/dL, treatment with 0.4 mg/day cerivastatin decreased these levels by 37%. Cerivastatin was well tolerated, with the type and incidence of clinical adverse effects comparable to that of placebo and comparator drugs. The incidence of biochemical adverse effects was also similar to that seen with either placebo or comparator drugs and was independent of the dose of cerivastatin. Less than 1% of patients treated with cerivastatin at doses of 0.025-0.4 mg/day experienced clinically significant increases in either hepatic transaminases (>3x the upper limit of normal) or creatine phosphokinase (>5x the upper limit of normal). The good tolerability of cerivastatin was reflected in a low rate of premature withdrawal from treatment, below or comparable to that of placebo-treatment. The pooled efficacy and safety analyses have shown that at doses equal to 1-3% of the doses of other statins, cerivastatin is a safe, well-tolerated, and highly effective HMG-CoA reductase inhibitor for the treatment of type IIa (triglycerides <250 mg/dL) and IIb (triglycerides >250 mg/dL) hypercholesterolemia.

Topics: Cholesterol; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Multicenter Studies as Topic; Pyridines; Randomized Controlled Trials as Topic; Safety; Treatment Outcome; Triglycerides

Cerivastatin, a novel, synthetic, and enantiomerically pure 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been administered, in clinical trials, to over 2700 patients with primary hypercholesterolemia, of whom over 1000 received treatment for periods of up to 1 year. A global, pooled analysis of the efficacy, safety, and tolerability of cerivastatin was performed on data obtained from all randomized, double-blind studies in which cerivastatin at doses of 0.025-0.4 mg/day were compared with either placebo or active comparators. All studies had a 10-week, diet-controlled run-in period, the last 6 weeks of which included administration of single-blind placebo. Efficacy analysis of the pooled data at 8 weeks post-randomization showed that in comparison with placebo, cerivastatin achieved significant dose-dependent reductions in low-density lipoprotein cholesterol (LDL-C), the primary efficacy parameter, of between 14.2 and 36.1%. Reductions in LDL-C were accompanied by significant reductions in total cholesterol and triglycerides, together with increases in high-density lipoprotein cholesterol (HDL-C). The magnitude of the reduction in plasma triglycerides was strongly related to baseline triglyceride levels. In patients with baseline plasma triglycerides of >250 mg/dl, treatment with 0.4 mg/day cerivastatin decreased these levels by 37%. Cerivastatin was well tolerated, with the type and incidence of clinical adverse effects comparable to that of placebo and comparator drugs. The incidence of biochemical adverse effects was also similar to that seen with either placebo or comparator drugs and was independent of the dose of cerivastatin. Less than 1% of patients treated with cerivastatin at doses of 0.025-0.4 mg/day experienced clinically significant increases in either hepatic transaminases (> 3 x the upper limit of normal) or creatine phosphokinase (CPK) (> 5 x the upper limit of normal). The good tolerability of cerivastatin was reflected in a low rate of premature withdrawal from treatment, below or comparable to that of placebo-treatment. The pooled efficacy and safety analyses have shown that at 1% of the doses of other statins, cerivastatin is a safe, well-tolerated, and highly effective HMG-CoA reductase inhibitor for the treatment of type IIa and IIb hypercholesterolemia.

Topics: Adult; Aged; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Male; Middle Aged; Multicenter Studies as Topic; Pyridines; Randomized Controlled Trials as Topic; Treatment Outcome

The objective of the study was to evaluate potential benefits of docosahexaenoic acid (DHA) rich fish oil supplementation as an adjunct to statin therapy for hyperlipidaemia. A total of 45 hyperlipidaemic patients on stable statin therapy with persistent elevation of plasma triglycerides (averaging 2.2 mmol/L) were randomised to take 4 g/day (n = 15) or 8 g/day (n = 15) of tuna oil or olive oil (placebo, n = 15) for 6 months. Plasma lipids, blood pressure and arterial compliance were assessed initially and after 3 and 6 months in 40 subjects who completed the trial. Plasma triglycerides were reduced 27% by 8 g/day DHA-rich fish oil (P < 0.05) but not by 4 g/day when compared with the placebo and this reduction was achieved by 3 months and was sustained at 6 months. Even though total cholesterol was already well controlled by the statin treatment (mean initial level 4.5 mmol/L), there was a further dose-dependent reduction with fish oil supplementation (r = -0.344, P < 0.05). The extent of total cholesterol reduction correlated (r = -0.44) with the initial total cholesterol levels (P < 0.005). In the subset with initial plasma cholesterol above 3.8 mmol/L, plasma very low density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL) were isolated and assayed for cholesterol and apolipoprotein B (apoB) at the commencement of the trial and at 3 months of intervention. Fish oil tended to lower cholesterol and apoB in VLDL and raise both in LDL. There were no changes in IDL cholesterol, IDL apoB and high-density lipoprotein cholesterol. The results demonstrate that DHA-rich fish oil supplementation (2.16 g DHA/day) can improve plasma lipids in a dose-dependent manner in patients taking statins and these changes were achieved by 3 months. Fish oil in addition to statin therapy may be preferable to drug combinations for the treatment of combined hyperlipidaemia.

Topics: Animals; Apolipoproteins B; Atorvastatin; Cholesterol, LDL; Dietary Fats; Dietary Fats, Unsaturated; Dietary Supplements; Docosahexaenoic Acids; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Female; Fish Oils; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Indoles; Lipid Metabolism; Lipids; Lipoproteins, IDL; Lipoproteins, VLDL; Male; Middle Aged; Pyridines; Pyrroles; Simvastatin; Treatment Outcome; Triglycerides

The objective of the study was to investigate the effects of cerivastatin therapy on forearm endothelial dependent acetylcholine (ACH) and independent (nitroprusside) vasodilator responses, blood pressure (BP) responses to intravenous infusions of angiotensin II (AII) and noradrenaline (NA) and on 24-h ambulatory BP recordings in type 2 diabetic men.. Eleven type 2 diabetic men aged 59 +/- 9 years with total cholesterol levels of 5.0 +/- 1.26 mmol/l, triglycerides of 2.23 mmol/l and high-density lipoprotein cholesterol levels of 1.24 mmol/l completed a double-blind, randomized, crossover trial comparing 8 weeks of cerivastatin therapy (800 microg of nocte) with placebo. Forearm vascular resistance (FVR) responses to intrabrachial-arterial infusions of ACH (3-24 microg/min), nitroprusside (2-16 microg/min), the nitric oxide(NO) synthase inhibitor l-nitro-mono-methyl arginine (l-nmma) (8 micromol/min), ACH during l-NMMA infusion and BP responses to intravenous infusions of AII (12.5-50 ng/min) and NA (20-400 ng/min) were measured at the end of each treatment period. Twenty-four-hour ambulatory BP recordings were also performed.. FVR responses to ACH during l-NMMA infusion were significantly (p = 0.026) greater during cerivastatin than during placebo therapy. In contrast, FVR responses to ACH in the absence of NO synthase inhibition did not differ significantly between cerivastatin and placebo therapies (p = 0.81). FVR increased by 31.4 +/- 57.3% in response to l-NMMA infusion during cerivastatin therapy compared with 6.1 +/- 41.2% during placebo therapy (p = 0.20). FVR responses to nitroprusside did not differ between cerivastatin and placebo therapies (p = 0.28), nor did BP responses to AII (systolic BP, p = 0.99; diastolic BP, p = 0.98) or NA (systolic BP, p = 0.21; diastolic BP, p = 0.48). Mean 24-h BP was similar during cerivastatin (123 +/- 10 or 70 +/- 7 mmHg) and placebo therapies (129 +/- 11 or 74 +/- 7 mmHg) (systolic BP, p = 0.26; diastolic BP, p = 0.41).. Cerivastatin increases FVR responses to ACH in type 2 diabetic men with mild dyslipidaemia but only following NO synthase inhibition. This may indicate an improvement in endothelium-derived hyperpolarizing factor-mediated responses.

Topics: Acetylcholine; Aged; Analysis of Variance; Angiotensin II; Blood Pressure Monitoring, Ambulatory; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Endothelium, Vascular; Forearm; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypertension; Infusions, Intravenous; Male; Middle Aged; Nitric Oxide Synthase; Nitroprusside; Norepinephrine; omega-N-Methylarginine; Pyridines; Vascular Resistance; Vasodilator Agents

Currently, there are various types of statins used in the treatment of hyperlipidemia and coronary artery disease. The purpose of this study was to compare the effects of a lipophilic statin (cerivastatin) with those of a hydrophilic statin (pravastatin) on the carotid arterial media using integrated backscatter (IB) ultrasound. Cerivastatin (C) has a strong anti-proliferative effect (APE) on smooth muscle cells (SMCs), whereas pravastatin (P) has a weak effect.. The IB values in the media of 72 segments of carotid arteries were measured in 36 patients with hyperlipidemia before and after statin therapy or diet for 6 months (C, n=13: P, n=12: diet, n=11). In addition, IB values of 34 segments of carotid arteries were measured in 34 patients without coronary risk factors. Intima - media thickness (IMT) and arterial stiffness (stiffness beta) were measured by conventional echo at the same time. IB values did not significantly change in the P group (12.8+/-3.5 vs 12.7+/-2.7 dB), but decreased in the C group (12.1 +/-2.9 vs 10.0+/-2.7 dB, p<0.01). Also, stiffness beta did not significantly change in the P group (8.3+/-3.1 vs 7.6+/-2.5), but decreased in the C group (10.1+/-4.3 vs 7.9+/-3.3, p<0.05). IB values correlated with age (r=0.70, p<0.01) and stiffness beta (r=0.67, p<0.01) in the 34 patients without coronary risk factors.. Statin therapy with cerivastatin, but not pravastatin, decreased the IB values of the carotid media and arterial stiffness. The difference between these 2 statins may be related to their effective dose range.

Topics: Aged; Body Mass Index; Carotid Arteries; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Lipids; Male; Middle Aged; Pravastatin; Pyridines; Tunica Media; Ultrasonography

The effects of cerivastatin and fenofibrate on proteins involved in haemostasis and on markers of inflammation were investigated in otherwise healthy middle-aged males with combined hyperlipidemia. Besides classical risk factors, other so-called novel risk factors for coronary artery disease are seen to be playing an increasingly important role in the development and progression of atherosclerosis. Thirty-eight males, aged 49 +/-5 years were randomised to 12 weeks treatment either with cerivastatin at a daily dose of 0.2 mg to 0.4 mg to achieve the LDL cholesterol goal of <3.0 mM, or with fenofibrate 250 mg daily. Fasting serum lipids, homocysteine, total and free tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor (PAI-1) and tissue plasminogen activator (t-PA) antigen and activity, C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were measured. No change in homocysteine level was observed in the cerivastatin group, while after fenofibrate administration it increased (p <0.0001). Total TFPI decreased significantly after cerivastatin (p = 0.002), but not after fenofibrate. Free TFPI did not decrease after either drug. Neither drug affected (t-PA) antigen and activity, while fenofibrate increased PAI-1 antigen (p <0.05) and activity (p <0.05). Cerivastatin decreased serum CRP values by 49.5% (p = 0.001), and fenofibrate by 29.8% (p = 0.03). The decreases of CRP in the two groups differed significantly (p = 0.04). IL-6 levels decreased significantly in the fenofibrate group (39%; p <0.0001), but not in the cerivastatin group (15%; p = 0.24) No significant decreases were observed for TNF-alpha. Cerivastatin had neutral effects on fibrinolysis, homocysteine or coagulation. On the other hand, fenofibrate increased PAI-1 antigen and activity and homocysteine, and did not affect coagulation. Both cerivastatin and fenofibrate reduced CRP levels, the decrease being significantly greater after cerivastatin. Fenofibrate also significantly decreased IL-6.

Topics: Adult; Arteriosclerosis; Blood Coagulation; Blood Coagulation Factors; Body Weight; C-Reactive Protein; Cholesterol, LDL; Clofibric Acid; Cytokines; Fenofibrate; Homocysteine; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Lipids; Male; Middle Aged; Pyridines; Risk Factors

Platelet activation, impairment of fibrinolysis, activation of the coagulation pathway, and dyslipidemia are important factors in the pathogenesis and progression of ischemic heart disease, and patients generally need to use an antiplatelet agent. Lipid-lowering cerivastatin, a novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, was administered to 20 patients with primary mixed hyperlipidemia for the assessment of the effect of cerivastatin on lipid levels, plasma fibrinogen concentration, factor VII, VIII, and X levels, plasminogen and antiplasmin concentrations, platelet count, and aggregation (adenosine diphosphate [ADP], collagen, and epinephrine induced). Assessments were made immediately after 2 months of a standard lipid-lowering diet, 4 weeks of placebo administration, and 4 weeks of cerivastatin treatment. Cerivastatin achieved significant reductions in triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels. The significant improvement of the lipid profile was associated with platelet aggregation reduction in vitro stimulated by ADP, collagen, and epinephrine (P < .05, P = .05, P < .005, respectively). Significantly lower levels of factor VII and fibrinogen were observed (P = .001, P < .0001) immediately after cerivastatin treatment. No significant differences were detected in factor VIII level, plasminogen and antiplasmin concentrations, and platelet count after cerivastatin treatment. It was concluded that cerivastatin in mixed hyperlipidemia can exert beneficial changes on specific hemostatic variables and platelet aggregation in addition to its positive effects on plasma lipid values.

Topics: Administration, Oral; Blood Coagulation; Blood Coagulation Factors; Collagen; Female; Fibrinogen; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Lipids; Male; Middle Aged; Myocardial Ischemia; Platelet Aggregation; Platelet Count; Pyridines; Treatment Outcome

The aim of this study was to compare the effects of cerivastatin and fenofibrate on endothelium dependent and independent arterial dilation.. In a prospective, double blind study, 38 overweight, nonsmoking, males aged between 40 and 60 years with combined hyperlipidaemia were randomized and, after 6 weeks run-in phase with American Heart Association step I diet treatment, submitted to 12 weeks' treatment either with fenofibrate (250 mg daily) or cerivastatin. Cerivastatin was given in a daily dose of 0.2 mg for 6 weeks and was increased to 0.4 mg daily, if the LDL-C did not decrease below 3.0 mmol x L(-1). Flow-mediated (endothelium-dependent) dilation (FMD) and nitroglycerin-induced (endothelium-independent) [gliceryltrinitrate (GTN)] dilation of brachial artery were measured using high resolution ultrasound.. The FMD increased from 3.4 +/- 3.3 to 9.3 +/- 2.4% (P < 0.001) in the cerivastatin group, and from 3.3 +/- 2.8 to 6.5 +/- 3.1% (P < 0.001) in the fenofibrate group, the improvement being significantly better after cerivastatin (P=0.006). GTN increased from 11.5 +/- 4.1 to 16.2 +/- 3.5% (P < 0.01) and from 11.1 +/- 2.5 to 16.0 +/- 2.9% (P < 0.01), respectively, with no difference between the groups. Cerivastatin reduced total cholesterol by 24%, LDL-cholesterol by 31%, triglycerides by 24%, ox-LDL by 29% and increased HDL-cholesterol by 5%, whilst, after fenofibrate, these changes were -15, -13, -41, -17 and 18%, respectively. Only the decrease of LDL-C turned out to be an independent predictor the FMD improvement. The improvement in GTN-induced dilation did not correlate with the changes in blood lipids.. Both cerivastatin and fenofibrate lead to an improvement of endothelium-dependent and endothelium-independent dilation of brachial artery in overweight patients with combined hyperlipidaemia and no other atherosclerotic risk factors. The effects on FMD were greater in subjects receiving cerivastatin than in subjects receiving fenofibrate, but the effects on GTN were equal in both groups.

Topics: Adult; Brachial Artery; Double-Blind Method; Fenofibrate; Hemodynamics; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Male; Middle Aged; Prospective Studies; Pyridines; Statistics, Nonparametric; Treatment Outcome; Vasodilation

Topics: Cardiovascular Diseases; Cholesterol; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Lipids; Lipoproteins; Male; Postoperative Complications; Pyridines; Risk Factors; Time Factors

Hyperlipidaemia is an important risk factor for cardiovascular disease in renal transplant recipients. The aim of this study was to test the efficacy and possible drug-drug interactions of the new HMG-CoA reductase inhibitors (statins) atorvastatin and cerivastatin in cyclosporin A (CsA)-treated renal transplant patients. Subjects and methods. Thirty patients with stable graft function and LDL cholesterol of 130 mg/dl were randomly assigned to active treatment groups (10 mg atorvastatin or 0.2 mg cerivastatin), or a control group. CsA blood trough levels were controlled on a weekly basis and adapted if they changed more than 25% from baseline values (100-150 ng/ml). Lipid levels and routine laboratory parameters before and after a treatment period of 3 months were compared.. In the group treated with cerivastatin no significant changes in CsA blood trough levels occurred (CsA 116+/-21 ng/ml vs 110+/-20 ng/ml). In contrast, in the group treated with atorvastatin, four of 10 patients had a rise in CsA blood trough levels of more than 25% within 7-14 days of starting therapy. In the remaining patients no significant changes in CsA drug levels occurred. After therapy with atorvastatin or cerivastatin, total cholesterol, LDL cholesterol, and triglycerides were significantly lower compared with baseline conditions. No changes of CsA or lipoprotein levels were present in the control group.. In our study population both statins were very effective in lowering elevated LDL cholesterol levels. Cerivastatin did not influence CsA blood trough levels, whereas atorvastatin increased CsA levels in four of 10 patients. Further research in a larger study is necessary in order to confirm these results and to investigate the possible reasons for this drug interaction.

Topics: Adult; Aged; Atorvastatin; Cardiovascular Diseases; Cyclosporine; Drug Interactions; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Pyridines; Pyrroles; Safety

The effects of cerivastatin on antiatherogenic properties of high-density lipoproteins were studied in patients with coronary heart disease and hyperlipidemia. Apart from hypolipidemic effects, cerivastatin changed the phospholipid composition of high-density lipoproteins and improved their cholesterol-acceptor properties. This effect was most pronounced in the serum from patients with low content of high-density lipoprotein cholesterol. These data indicate that cerivastatin modulates antiatherogenic properties of high-density lipoproteins.

Topics: Adult; Aged; Arteriosclerosis; Cholesterol; Coronary Disease; Double-Blind Method; Humans; Hyperlipidemias; Lipoproteins, HDL; Male; Middle Aged; Phospholipids; Pyridines

To elucidate efficacy, safety and tolerance of lipobay (cerivastatin), a new HMG-CoA-reductase inhibitor (0.2 mg/day) in patients with primary hyperlipidemia (PHL).. The trial enrolled 15 men aged 21-64 years with PHL of type 2a and 2b. After 1 and 3 months of treatment all the patients underwent a general clinical examination with measurements of blood lipids (total cholesterol, triglycerides, high density lipoprotein cholesterol--HDL-C), apolipoproteins (apo A-1 and apo B).. After 3 months of treatment total cholesterol, LDL-C and apolipoprotein B decreased by 24.94 +/- 2.87%, 28.94 +/- 3.08%, 19.32 +/- 2.43% (p = 0.0001), respectively, while LDL-C levels were < 3.4 mmol/l in 4 patients. Triglycerides dropped by 17.84 +/- 6.41%, while HDL-C rose by 5.01 +/- 4.47%, but the changes were not significant. Lipobay in doses 0.2 mg/day was well tolerated. One patient stopped taking the drug because of severe abdominal pain.. Lipobay is a novel, effective and well-tolerated drug for treatment of patients with primary hyperlipidemia of type 2a and 2b.

Topics: Adult; Apolipoproteins B; Cholesterol, HDL; Cholesterol, LDL; Drug Evaluation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Male; Middle Aged; Pyridines; Safety; Stereoisomerism; Treatment Outcome; Triglycerides

A mutation of the CD36 gene that encodes a fatty acid transporter has been reported to play a role in insulin resistance in spontaneously hypertensive rat (SHR). Statins reduce circulating cholesterol and triglyceride concentrations. The objective of this study was to determine the role of CD36 and the significance of statin therapy in insulin-resistance syndromes. We determined the isometric relaxation induced by acetylcholine or lecithinized superoxide dismutase (SOD) in aortas obtained from Otsuka Long Evans Tokushima Fatty (OLETF) rats, a model of insulin resistance and dyslipidemia, and normal control (Long Evans Tokushima Otsuka; LETO) rats with or without cerivastatin treatment. We also determined the effect of cerivastatin on aortic expression of CD36 and PPARgamma. The CD36 genotype and microsatellite markers on chromosome 4 were also determined. The relaxation induced by acetylcholine and lecithinized SOD were attenuated in OLETF rats but restored by a low dose of cerivastatin without significant changes in serum cholesterol. These relaxations were also restored by a high dose of cerivastatin with significant reductions in serum cholesterol and triglyceride. Cerivastatin increased the aortic expression of CD36 and PPARgamma mRNA in both LETO and OLETF rats. However, the basal level of CD36 mRNA and the increase in CD36 mRNA in response to cerivastatin were significantly lower in OLETF rats than in LETO rats. Although the abnormal CD36 genotype reported in SHR was not found in OLETF rats, the microsatellite markers of D4Rat151 and D4Rat115 differed between OLETF and LETO rats. In conclusion, insulin resistance in OLETF rats may be partially due to an altered expression of CD36. Increased aortic expression of CD36 in response to cerivastatin could explain the reduction in serum triglyceride concentrations with statin therapy and may have pronounced beneficial effects in insulin-resistance syndromes.

Topics: Animals; Aorta; CD36 Antigens; Diabetes Mellitus; Disease Models, Animal; Endothelium, Vascular; Genotype; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Insulin Resistance; Male; Microsatellite Repeats; PPAR gamma; Pyridines; Rats; Rats, Inbred OLETF; RNA, Messenger

Topics: Clinical Trials as Topic; Drug and Narcotic Control; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Myocardial Infarction; Myocardial Ischemia; Practice Guidelines as Topic; Pyridines; Research Design

We report a patient with renal insufficiency who developed rhabdomyolysis 1 month after initiating cerivastatin and gemfibrozil for hyperlipidemia. Myopathy caused by HMG-CoA reductase inhibitors (statins) alone is rare, but occurs more frequently when a statin is used with gemfibrozil, a medication that likely has a direct toxic effect on muscles. Predisposing factors to the development of myopathy from the combination include use of medications affecting statin metabolism, higher doses of statins, renal insufficiency, diuretics, and hypothyroidism. It has been proposed that alternate-day therapy with a statin and fibrate, spacing of doses in a single day, or use of lower doses of statins may prevent the development of myopathy. Currently, no predictable method to determine who is at risk for myopathy exists, nor is there a reliable screening test. Therefore, patients should be advised to watch for generalized muscle pain or weakness, and if it occurs, stop medications and report symptoms immediately.

Topics: Drug Therapy, Combination; Female; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Middle Aged; Pyridines; Rhabdomyolysis

Statins inhibit HMG-CoA reductase to reduce the synthesis of cholesterol and isoprenoids that modulate diverse cell functions. We investigated the effect of the statins cerivastatin and atorvastatin on angiogenesis in vitro and in vivo.. Endothelial cell proliferation, migration, and differentiation were enhanced at low concentrations (0.005 to 0.01 micromol/L) but significantly inhibited at high statin concentrations (0.05 to 1 micromol/L). Antiangiogenic effects at high concentrations were associated with decreased endothelial release of vascular endothelial growth factor and increased endothelial apoptosis and were reversed by geranylgeranyl pyrophosphate. In murine models, inflammation-induced angiogenesis was enhanced with low-dose statin therapy (0.5 mg x kg(-1) x d(-1)) but significantly inhibited with high concentrations of cerivastatin or atorvastatin (2.5 mg x kg(-1) x d(-1)). Despite the fact that high-dose statin treatment was effective at reducing lipid levels in hyperlipidemic apolipoprotein E-deficient mice, it impaired rather than enhanced angiogenesis. Finally, high-dose cerivastatin decreased tumor growth and tumor vascularization in a murine Lewis lung cancer model.. HMG-CoA reductase inhibition has a biphasic dose-dependent effect on angiogenesis that is lipid independent and associated with alterations in endothelial apoptosis and vascular endothelial growth factor signaling. Statins have proangiogenic effects at low therapeutic concentrations but angiostatic effects at high concentrations that are reversed by geranylgeranyl pyrophosphate. At clinically relevant doses, statins may modulate angiogenesis in humans via effects on geranylated proteins.

Topics: Animals; Apolipoproteins E; Apoptosis; Atorvastatin; Carcinoma, Lewis Lung; Cell Differentiation; Cell Division; Cell Movement; Cells, Cultured; Dose-Response Relationship, Drug; Endothelial Growth Factors; Endothelium, Vascular; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Lymphokines; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Pathologic; Neovascularization, Physiologic; Polyisoprenyl Phosphates; Pyridines; Pyrroles; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

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

Topics: Endothelium, Vascular; Fenofibrate; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Pyridines; Vasodilation

Topics: beta 2-Microglobulin; Biomarkers; Drug Therapy, Combination; Gemfibrozil; Humans; Hyperlipidemias; Kidney Diseases; Kidney Tubules; Magnetic Resonance Spectroscopy; Male; Membrane Glycoproteins; Pyridines; Rhabdomyolysis; Trypsin Inhibitor, Kunitz Soybean

Topics: Acute Kidney Injury; Drug Therapy, Combination; Gemfibrozil; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Hypolipidemic Agents; Male; Middle Aged; Pyridines; Rhabdomyolysis

Topics: Bezafibrate; Cholesterol, HDL; Cholesterol, LDL; Drug Therapy, Combination; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Pyridines; Treatment Outcome; Triglycerides

HMG-CoA reductase inhibitors ("statins") have become the drug class of choice for the treatment of hyperlipidemia. Six product brands encompassing 20 dosage strengths have been available during the past two years. The objective of this review is to describe dosing trends for the six statin brands and to determine if and how these trends vary among managed care plans as a function of product market share.. Utilization of HMG-CoA reductase inhibitors was examined using the NDC Health Information Services (Phoenix, Ariz.) database for the two-year period ending December 2000. This database contains unit dispensing data at the dosage-strength level for 1,079 managed care plans. Trends in market share, mean daily dose, and dosage distribution of the six current statin brands were examined. The relationship of market share to mean dose was also examined for each brand.. Market share decreased for all statin brands during the two-year period, except for the two newest entries, atorvastatin (up 9.7 share points) and cerivastatin (up 4.6 share points). The mean dose of all statins increased during the two-year period. A statistically significant negative correlation between market share and mean dose was found for atorvastatin and a positive correlation was found for fluvastatin (P < 0.01). Furthermore, atorvastatin share was significantly correlated to lower mean doses of all other statin brands. That is, higher use of atorvastatin was associated with lower doses of all statin products.. In developing a cost-management strategy, managed care organizations should take historical and anticipated market-share changes and dose-mix changes into account along with the product's clinical efficacy and total cost of care.

Topics: Anticholesteremic Agents; Atorvastatin; Databases, Factual; Drug Costs; Drug Utilization Review; Fatty Acids, Monounsaturated; Fluvastatin; Health Care Sector; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Indoles; Lovastatin; Managed Care Programs; Pravastatin; Pyridines; Pyrroles; Simvastatin; United States

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

Gemfibrozil-statin combination therapy is a well-known risk factor for myopathy and rhabdomyolysis. Cerivastatin is a currently available statin with dual elimination; it is therefore expected to cause less drug-drug interaction. This case is the second reported case with severe rhabdomyolysis caused by cerivastatin-gemfibrozil combination. Moreover, in this case, the rhabdomyolysis was more severe and caused severe renal failure and death. The authors discuss how these drugs cause rhabdomyolysis and how rhabdomyolysis can cause renal failure.

Topics: Diabetes Mellitus; Drug Interactions; Drug Therapy, Combination; Electrocardiography; Fatal Outcome; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Male; Middle Aged; Myocardial Ischemia; Pyridines; Renal Dialysis; Renal Insufficiency; Rhabdomyolysis

Topics: Aged; Drug Therapy, Combination; Female; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Pyridines; Rhabdomyolysis

Topics: Aged; Drug Synergism; Drug Therapy, Combination; Female; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Liver; Pyridines; Rhabdomyolysis; Stereoisomerism

Topics: Humans; Hyperlipidemias; Hypolipidemic Agents; Pyridines

Cerivastatin is a third generation pure enantiomeric HMG-CoA reductase inhibitor. It reduces low density lipoprotein (LDL)-cholesterol by 22 to 44% at doses of 0.1 to 0.8 mg/day. The drug has been extensively evaluated for more than 5 years in clinical trials and is currently marketed in a number of countries at doses of 0.1 to 0.3 mg/day. Cerivastatin has been tested in more than 4000 patients during extensive phase II and III studies. About 40% of patients in these trials were women, and many participants were aged between 65 and 75 years. The trial populations had moderate to severe hypercholesterolaemia, with mean baseline LDL-cholesterol levels of approximately 5.2 mmol/L (200 mg/dl). In large phase III trials, cerivastatin, over the dosage range of 0.1 to 0.4 mg/day, reduced LDL-cholesterol by 22.4 to 36.1% from baseline. As with other HMG-CoA reductase inhibitors, the log-linear dose-response curve of cerivastatin showed a 6% additional decrease in mean LDL-cholesterol levels for each doubling of the daily dose, with no plateau effect noted at the highest dosage yet tested (0.8 mg/day). High density lipoprotein cholesterol levels increased by 4 to 10% during cerivastatin therapy. This effect, which was consistent with that of other HMG-CoA reductase inhibitors, was not dose related. As has been found with other statins, the triglyceride-lowering effects of cerivastatin are dependent on baseline triglyceride levels, with very small reductions occurring in patients with low initial levels [< 1.7 mmol/L (150 mg/dl)], and larger dose-dependent reductions of up to 36% with the 0.4 mg/day dose observed in patients with baseline triglyceride levels >2.8 mmol/L (250 mg/dl). Cerivastatin was well tolerated in all studies. Cerivastatin recipients and recipients of other HMG-CoA reductase inhibitors experienced a similar incidence of adverse events (including hepatic transaminase elevations) in comparative studies. Cerivastatin is an effective and safe lipid-lowering agent for most patients with hypercholesterolaemia.

Topics: Anticholesteremic Agents; Cholesterol, LDL; Clinical Trials as Topic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Pyridines

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

1. The aim of this study was to determine whether BAYw6228 (BAYw), a newly developed 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor, could suppress an atherogenic process such as intimal thickening by a mechanism other than lowering the level of serum cholesterol. 2. First, we evaluated the in vitro effect of BAYw on the proliferation of vascular smooth muscle cells (SMC) from various species: Sprague-Dawley (SD) rats. New Zealand (NZ) white rabbits, intimal cells from Watanabe hereditary hyperlipidemic (WHHL) rabbit and SMC from the new-born human aorta. The increasing rate of total protein content of these cells was inhibited by the addition of BAYw in a dose-dependent fashion. In the presence of 2% foetal calf serum (FCS), the value of IC50 was 1.0 microM in SD rats, 2.1 microM in NZ white rabbits, and 0.3 microM in WHHL rabbits. With human SMC, the value was 0.02 microM in the presence of 10% FCS and 0.2 microM with a mixture of growth factors. 3. Based on these above in vitro findings, we next examined the in vivo effect of the agent to determine whether it could suppress rabbit intimal thickening induced by balloon catheterization. A balloon catheter was inserted from a peripheral branch of the left external carotid artery to the aorta to denude the endothelium of the left common carotid artery in Japanese white rabbits. After 12 days they were divided into control and BAYw groups. The former were subcutaneously injected with saline and the latter with BAYw 1 mg kg-1 day-1. Two days after the beginning of treatment, a second balloon injury was performed to the previously injured left common carotid artery in both groups. After another two weeks, the left common carotid artery was removed and variously stained. Although the total serum cholesterol in the BAYw group was significantly lower than in the control (P < 0.05), the difference was not enough to affect intimal thickening. In addition, the BAYw group had a smaller intima/media ratio than the control group, decreasing to 45% of control (P < 0.05). By anti-alpha smooth muscle actin antibody staining, these intimal thickening areas were entirely occupied by SMCs, and their amount was attenuated by BAYw. By anti-rabbit macrophage antibody (RAM 11) staining, the number of positive cells in the intimal thickening was markedly decreased in the BAYw group compared to control (P < 0.01). 4. These results indicate that BAYw has an inhibitory effect on intimal thickening by attenuating intim

Topics: Animals; Arteriosclerosis; Carotid Arteries; Catheterization; Cell Division; Cells, Cultured; DNA; Enzyme Inhibitors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Muscle, Smooth, Vascular; Pyridines; Rabbits; Rats; Rats, Sprague-Dawley; Stereoisomerism