(1/654) Involvement of tyrosine phosphorylation in HMG-CoA reductase inhibitor-induced cell death in L6 myoblasts.

Our previous studies have shown that the HMG-CoA reductase (HCR) inhibitor (HCRI), simvastatin, causes myopathy in rabbits and kills L6 myoblasts. The present study was designed to elucidate the molecular mechanism of HCRI-induced cell death. We have demonstrated that simvastatin induces the tyrosine phosphorylation of several cellular proteins within 10 min. These phosphorylations were followed by apoptosis, as evidenced by the occurrence of internucleosomal DNA fragmentation and by morphological changes detected with Nomarski optics. Simvastatin-induced cell death was prevented by tyrosine kinase inhibitors. The MTT assay revealed that the addition of mevalonic acid into the culture medium partially inhibited simvastatin-induced cell death. Thus, these results suggested that protein tyrosine phosphorylation might play an important role in the intracellular signal transduction pathway mediating the HCRI-induced death of myoblasts.  (+info)

(2/654) The effects of pravastatin on hospital admission in hypercholesterolemic middle-aged men: West of Scotland Coronary Prevention Study.

OBJECTIVES: The purpose of the study was to assess the effect of lipid reduction with pravastatin on hospital admissions in middle-aged men with hypercholesterolemia in the West of Scotland Coronary Prevention Study. BACKGROUND: A prospective, randomized controlled trial was undertaken in primary care centers in the West of Scotland. METHODS: A total of 6,595 participants randomized to receive pravastatin 40 mg or placebo daily were followed up for a mean of 4.9 years (range 3.5 to 6.1 years). Analysis of hospital admissions was undertaken according to the "intention to treat" principle both for cardiovascular diseases and noncardiovascular diseases (including malignant neoplasms, psychiatric diagnoses, trauma and other causes). A secondary analysis of hospitalization in patients who were > or = 75% compliant was performed. RESULTS: During the trial, 2,198 (33%) of the 6,595 men were admitted to hospital on 4,333 occasions, of which 1,234 (28%) were for cardiovascular causes. Pravastatin reduced the number of subjects requiring hospital admission for cardiovascular causes by 21% (95% CI [confidence interval] 9 to 31, p = 0.0008) overall, and by 27% (95% CI 15 to 38) in compliant participants. The number of admissions per 1,000 subject-years for cardiovascular disease was reduced by 10.8 (95% CI 4 to 17.4, p = 0.0013) in all subjects, and by 15.6 (95% CI 8.3 to 23, p < 0.0001) in compliant participants. Pravastatin had no significant influence on hospital admission for any noncardiovascular diagnostic category. There were 13.4 fewer admissions per 1,000 subject-years for all causes in the pravastatin-treated group (95% CI -0.4 to 27.3, p = 0.076). No significant difference in duration of hospital stay was found between the pravastatin and placebo patients in any diagnostic group. CONCLUSIONS: Pravastatin therapy reduced the burden of hospital admissions for cardiovascular disease, without any adverse effect on noncardiovascular hospitalization.  (+info)

(3/654) International economic analysis of primary prevention of cardiovascular disease with pravastatin in WOSCOPS. West of Scotland Coronary Prevention Study.

AIMS: The results of the West of Scotland Coronary Prevention Study (WOSCOPS) demonstrated the clinical benefit of using pravastatin for the primary prevention of cardiovascular disease in hypercholesterolaemic men. To inform decision makers, who must also consider costs, this study assesses the economic efficiency of such an intervention in a broad range of countries. METHODS AND RESULTS: A generalized model of cardiovascular disease prevention was used to estimate the cost-effectiveness of primary prevention with pravastatin compared to diet alone. This model follows a cohort of hypercholesterolaemic men over a given period quantifying the effect in terms of the avoidance of cardiovascular disease based on treatment-specific risks derived from WOSCOPS data and extensive record-linkage data on disease-specific survival. Country-specific costs are accounted for by expressing all such parameters in terms of the ratio of monthly treatment to that of managing a myocardial infarction. Over a broad range of inputs the cost-effectiveness ratios remain below $25,000 per life years gained, regardless of country. Subgroups with even better economic efficacy can be defined on the basis of higher baseline risk. CONCLUSIONS: In contrast to some previous reports, this analysis based on trial data demonstrates that pravastatin provides not only an effective means of primary cardiovascular disease prevention, but also an efficient one.  (+info)

(4/654) Pravastatin therapy in hyperlipidemia: effects on thrombus formation and the systemic hemostatic profile.

OBJECTIVES: The study sought to determine the effects of lipid-lowering with pravastatin on the systemic fibrinolytic profile and on thrombus formation under dynamic flow conditions. BACKGROUND: Lowering cholesterol (C) decreases clinical events in coronary artery disease (CAD) patients, but an analysis of the effects of lipid-lowering on the entire hemostatic and thrombotic profile has not been conducted. METHODS: We prospectively studied 93 stable patients with untreated low-density lipoprotein cholesterol (LDL-C) >145 mg/dl. The CAD patients received pravastatin, and non-CAD patients were randomized to pravastatin versus placebo (double-blind). Thrombus formation upon an injured vascular surface was assessed in a substudy of 40 patients with a previously validated ex vivo perfusion chamber system. Systemic hemostatic markers and thrombus formation were evaluated at baseline, three and six months. RESULTS: Placebo produced no changes in either the lipid profile, any of the hemostatic markers, or the ex vivo thrombus formation. Both pravastatin groups (CAD and non-CAD) showed decreased LDL-C by 30% within 6 weeks (188 to 126 mg/dl, p < 0.001 vs. baseline), and decreased plasminogen activator inhibitor-1 at 3- and 6-month follow-up compared to baseline (15% to 18% decrease at 3 months and 21% to 23% at 6 months). For the tissue plasminogen activator antigen, CAD and non-CAD groups showed significant decreases at 6 months compared to baseline (10% and 13%, respectively). No significant changes were observed with treatment in d-dimer, fibrinopeptide A, prothrombin fragment F1.2, factor VIIa, von Willebrand factor, or C-reactive protein. Fibrinogen levels were significantly increased at 6 months compared to baseline, though still below the upper normal limit. In the perfusion chamber substudy, there was a decrease in thrombus area in non-CAD patients treated with pravastatin at both 3 and 6 months compared to baseline (by 21% and 34%, respectively). The CAD patients showed decreases in thrombus formation by 13% at 3 months, and by 16% at 6 months. The change in LDL-C- correlated modestly with the change in thrombus formation (r = 0.49; p < 0.01). CONCLUSIONS: Pravastatin therapy significantly decreased thrombus formation and improved the fibrinolytic profile in patients with and without CAD. These early effects may, in part, explain the benefit rendered in primary and secondary prevention of CAD.  (+info)

(5/654) Inhibition by simvastatin, but not pravastatin, of glucose-induced cytosolic Ca2+ signalling and insulin secretion due to blockade of L-type Ca2+ channels in rat islet beta-cells.

1. Hypercholesterolaemia often occurs in patients with type 2 diabetes, who therefore encounter administration of HMG-CoA reductase inhibitors. Alteration of pancreatic beta-cell function leading to an impaired insulin secretory response to glucose plays a crucial role in the pathogenesis of type 2 diabetes. Therefore, it is important to examine the effects of HMG-CoA reductase inhibitors on beta-cell function. 2. Cytosolic Ca2+ concentration ([Ca2+]i) plays a central role in the regulation of beta-cell function. The present study examined the effects of HMG-CoA reductase inhibitors on the glucose-induced [Ca2+]i signalling and insulin secretion in rat islet beta-cells. 3. Simvastatin, a lipophilic HMG-CoA reductase inhibitor, at 0.1-3 microg ml(-1) concentration-dependently inhibited the first phase increase and oscillation of [Ca2+]i induced by 8.3 mM glucose in single beta-cells. The less lipophilic inhibitor, simvastatin-acid, inhibited the first phase [Ca2+]i increase but was two orders of magnitude less potent. The hydrophilic inhibitor, pravastatin (100 microg ml(-1), was without effect on [Ca2+]i. 4. Simvastatin (0.3 microg ml(-1)), more potently than simvastatin-acid (30 microg ml(-1)), inhibited glucose-induced insulin secretion from islets, whereas pravastatin (100 microg ml(-1)) had no effect. 5. Whole-cell patch clamp recordings demonstrated a reversible inhibition of the beta-cell L-type Ca2+ channels by simvastatin, but not by pravastatin. Simvastatin also inhibited the [Ca2+]i increases by L-arginine and KCl, agents that act via opening of L-type Ca2+ channels. 6. In conclusion, lipophilic HMG-CoA reductase inhibitors can inhibit glucose-induced [Ca2+]i signalling and insulin secretion by blocking L-type Ca2+ channels in beta-cells, and their inhibitory potencies parallel their lipophilicities. Precaution should be paid to these findings when HMG-CoA reductase inhibitors are used clinically, particularly in patients with type 2 diabetes.  (+info)

(6/654) Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (reduction of cholesterol in ischemia and function of the endothelium) trial.

BACKGROUND: Cholesterol lowering reduces coronary events. One mechanism could be improvement of endothelial function. In line with this hypothesis, this study investigates whether cholesterol reduction can result in rapid improvement of endothelial function after acute coronary syndromes. METHODS AND RESULTS: Patients with acute myocardial infarction or unstable angina and total cholesterol levels at admission >/=5.2 mmol/L or LDL >/=3.4 mmol/L were randomized to placebo (n=30) or pravastatin 40 mg daily (n=30) for 6 weeks. Brachial ultrasound was used to measure endothelium-dependent flow-mediated dilatation (FMD) and response to endothelium-independent nitroglycerin. Changes in the levels of markers of platelet activation, coagulation factors, and plasma endothelin levels were also assessed. Total and LDL cholesterol levels were similar at admission and before randomization in both groups. With pravastatin, but not with placebo, they decreased by 23% (P<0.05) and 33% (P<0.01), respectively. FMD was unchanged with placebo, 5.43+/-0.74% (mean+/-SEM) to 5.84+/-0.81%, but increased with pravastatin, 4.93+/-0.81% to 7.0+/-0.79% (P=0.02), representing a 42% relative increase. Responses to nitroglycerin were similar during the time course of the study in the 2 groups. Markers of platelet activity, coagulation factors, and endothelin levels were not affected by pravastatin. CONCLUSIONS: Cholesterol reduction with pravastatin initiated early after acute coronary syndromes rapidly improves endothelial function after 6 weeks of therapy.  (+info)

(7/654) Impact of therapeutic interchange from pravastatin to lovastatin in a Veterans Affairs Medical Center.

OBJECTIVE: To evaluate the impact of a therapeutic interchange from pravastatin to lovastatin on treatment outcomes, quality of life, patient satisfaction, and costs. STUDY DESIGN: A prospective cohort study of 170 patients switched from pravastatin to lovastatin from September 1997 through November 1997. PATIENTS AND METHODS: The therapeutic interchange program promoting lovastatin as the preferred agent went into effect June 2, 1997 after Merck & Co. was awarded the Veterans Health Administration national contract for 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Patients were switched to lovastatin by either their primary care physician during routine clinic visits or the pharmacist by mail. The following outcomes were measured before and after conversion to lovastatin: lipid values, liver function tests, National Cholesterol Education Program (NCEP) low-density cholesterol (LDL-C) goals achieved, quality of life (QOL) (measured by the Medical Outcomes Study 36-item short-form health survey [SF-36]), medication tolerance (measured with a global symptom survey), patient satisfaction, and cost-minimization analysis. RESULTS: Lipid values and liver function test results were similar for pravastatin and lovastatin treatment. Forty percent of patients achieved NCEP LDL-C goals before and after formulary conversion. There were no significant differences between pravastatin and lovastatin in QOL, medication tolerance, and patient satisfaction. The projected cost savings from this therapeutic interchange was approximately $211,000 annually. CONCLUSION: Therapeutic interchange from pravastatin to lovastatin resulted in substantial cost savings. QOL, patient satisfaction, and achievement of NCEP LDL-C goals were maintained.  (+info)

(8/654) Pravastatin prevents clinical events in revascularized patients with average cholesterol concentrations. Cholesterol and Recurrent Events CARE Investigators.

OBJECTIVES: This analysis was carried out to determine if revascularized patients derive benefit from the 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pravastatin. BACKGROUND: The HMG-CoA reductase inhibitors result in substantial reductions in serum cholesterol and stabilization of atherosclerotic plaques in patients with coronary artery disease. METHODS: Pravastatin was found to reduce clinical cardiovascular events in the Cholesterol and Recurrent Events (CARE) trial consisting of 4,159 patients with a documented myocardial infarction and an average cholesterol level (mean 209 mg/dl and all <240 mg/dl). A total of 2,245 patients underwent coronary revascularization before randomization including 1,154 patients with percutaneous transluminal coronary angioplasty (PTCA) alone, 876 patients with coronary artery bypass graft (CABG) alone, and 215 patients with both procedures. Clinical events in revascularized patients were compared between patients on placebo and on pravastatin. RESULTS: In the 2,245 patients who had undergone revascularization, the primary endpoint of coronary heart disease death or nonfatal myocardial infarction (MI) was reduced by 4.1% with pravastatin (relative risk [RR] reduction 36%, 95% confidence interval [CI] 17 to 51, p = 0.001). Fatal or nonfatal MI was reduced by 3.3% (RR reduction 39%, 95% CI 16 to 55, p = 0.002), postrandomization repeat revascularization was reduced by 2.6% (RR reduction 18%, 95% CI 1 to 33, p = 0.068) and stroke was reduced by 1.5% (RR reduction 39%, 95% CI 3 to 62, p = 0.037) with pravastatin. Pravastatin was beneficial in both the 1,154 PTCA patients and in the 1,091 CABG patients who had undergone revascularization before randomization. CONCLUSIONS: Pravastatin reduced clinical events in revascularized postinfarction patients with average cholesterol levels. This therapy was well tolerated and its use should be considered in most patients following coronary revascularization.  (+info)