Pravastatin and simvastatin differently inhibit cholesterol biosynthesis in human lens.

Cohen LH.

TNO Institute of Ageing and Vascular Research (IVVO-TNO), Gaubius Laboratory, Leiden, The Netherlands.

PURPOSE. In the current study, the hypocholesterolemic drugs pravastatin and simvastatin were compared for their influence on cholesterol biosynthesis in the human lens. METHODS. For measurements of cholesterol and fatty acid synthesis rates, human lenses were incubated for 20 hr in the presence of [14C]-acetate, and pravastatin or simvastatin. Radiolabeled [14C]-cholesterol and [14C]-fatty acids were determined. To avoid the influence of individual differences, one lens from each donor was incubated without drug (control) and the other lens was incubated in the presence of drug. For each lens pair, the percentage inhibition of the cholesterol synthesis caused by the drug was calculated. Fatty acid synthesis was not influenced by the drugs. By comparing the fatty acid synthesis rate of the drug-incubated with the control lens of a pair, a predefined exclusion criterion was used to eliminate lens pairs in which the lenses had no comparable biosynthetic capacities. RESULTS. Using various concentrations of the drugs, a dose-response curve was constructed for the inhibition of the cholesterol synthesis. The IC50 values (drug concentration give 50% inhibition) were 0.5 mumol/l and 0.004 mumol/l for pravastatin and simvastatin, respectively. 3-Hydroxy-3-methylglutaryl coenzyme A reductase activity in microsomal membranes from human lens cortex was inhibited by simvastatin and pravastatin to the same extent. CONCLUSIONS. Under the conditions used in this study, cholesterol synthesis in human lenses is inhibited by simvastatin 100-fold more effectively than by pravastatin. This difference was likely due to differences in the intracellular exposure of the reductase to the drugs in intact human lenses.

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Treatment with simvastatin suppresses the development of experimental abdominal aortic aneurysms in normal and hypercholesterolemic mice.

Thompson RW.

Department of Surgery (Section of Vascular Surgery), Washington University School of Medicine, St. Louis, Missouri 63110, USA.

OBJECTIVE: To determine if treatment with hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) can influence the development of experimental abdominal aortic aneurysms (AAAs). SUMMARY BACKGROUND DATA: AAAs are associated with atherosclerosis, chronic inflammation, and matrix metalloproteinase (MMP)-mediated connective tissue destruction. Because statins exert antiinflammatory activities independent of their lipid-lowering effects, these agents may help suppress aneurysmal degeneration. METHODS: C57Bl/6 wild-type and hypercholesterolemic apoE-deficient mice underwent transient perfusion of the aorta with elastase followed by subcutaneous treatment with either 2 mg/kg simvastatin per day or vehicle. Aortic diameter (AD) was measured before and 14 days after elastase perfusion. The extent of aortic dilatation (DeltaAD) was determined with AAAs defined as DeltaAD >100%. RESULTS: Wild-type mice treated with simvastatin exhibited a 21% reduction in DeltaAD and a 33% reduction in AAAs compared with vehicle-treated controls. Suppression of AAAs in simvastatin-treated mice was associated with preservation of medial elastin and vascular smooth muscle cells, as well as a relative reduction in aortic wall expression of MMP-9 and a relative increase in expression of TIMP-1. In hypercholesterolemic apoE-deficient mice, treatment with simvastatin was associated with a 26% reduction in DeltaAD and a 30% reduction in AAAs. Treatment with simvastatin had no effect on serum cholesterol levels in either normal or hypercholesterolemic mice. CONCLUSIONS: Treatment with simvastatin suppresses the development of experimental AAAs in both normal and hypercholesterolemic mice. The mechanisms of this effect are independent of lipid-lowering and include preservation of medial elastin and smooth muscle cells, as well as altered aortic wall expression of MMPs and their inhibitors.

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Influence of specific mutations at the LDL-receptor gene locus on the response to simvastatin therapy in Afrikaner patients with heterozygous familial hypercholesterolaemia.

Marais D.

MRC Research Unit for the Cell Biology of Atherosclerosis, Dept. of Medical Biochemistry, University of Cape Town, South Africa.

Simvastatin, an inhibitor of HMG CoA reductase, lowers the plasma total cholesterol and LDL-cholesterol concentration in familial hypercholesterolemic patients. The efficacy of the drug shows considerable inter-individual variation, however. In this study we have assessed the influence of certain LDL-receptor gene mutations on this variation. A group of 20 male and female heterozygotic familial hypercholesterolemic patients, all Afrikaners and each bearing one of two different LDL receptor gene mutations, FH Afrikaner-1 (FH1) and FH Afrikaner-2 (FH2), was treated with simvastatin (40 mg once daily) for 18 months. The average reduction in total plasma cholesterol was 35.3% in the case of the FH2 men but only 23.2% in that of the FH1 men (P = 0.005); the reduction in LDL cholesterol concentrations was also greater in the FH2 group (39% as opposed to 27.1%, P = 0.02). The better response of the FH2 group was also evident when men and women were considered together. Female FH1 patients responded better to simvastatin treatment, however, than did males with the same gene defect. Mutations at the LDL-receptor locus may thus play a significant role in the variable efficacy of the drug. The particular mutations in the males of this group may have contributed up to 35% of the variance in total cholesterol response and 29% of the variance in LDL-cholesterol response to simvastatin treatment.

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Cholesterol content of the rat lens is lowered by administration of simvastatin, but not by pravastatin.

Cohen LH.

TNO Institute of Ageing and Vascular Research (IVVO-TNO), Gaubius Laboratory, Leiden, The Netherlands.

The influence of the 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors pravastatin and simvastatin on lens cholesterol metabolism was investigated in the rat. Short-term organ culture experiments with explanted lenses from 21-day-old Wistar rats showed that simvastatin was at least 35 times more effective than pravastatin in inhibiting cholesterol synthesis. In vivo the cholesterol content of the rat lens increased linearly with age. Experiments were designed to answer the question whether simvastatin and pravastatin inhibit lens cholesterol synthesis in vivo, which would result in a reduced cholesterol accumulation in the lens with age. Young Wistar rats were weaned at an age of 21 days and had ad libitum access to a chow supplemented with 10-100 mg vastatin kg-1 (drug consumption: 1.5-15 mg vastatin kg-1 body weight day-1, respectively) or no additions for 3 weeks. Both drugs induced the HMG-CoA reductase activity in rat liver microsomes (isolated after 1, 2 and 3 weeks of treatment) to a similar extent. This indicates that the two drugs inhibited hepatic cholesterol synthesis to a comparable extent. During the whole treatment period no significant differences between control and drug-treated animals could be observed when the wet weight and protein content of the lenses were considered. However, a striking difference between the control group and pravastatin group (50 mg drug kg-1 diet) on the one hand and the simvastatin group (50 mg drug kg-1 diet) on the other was observed when the cholesterol content of the lenses were compared as a function of age.(ABSTRACT TRUNCATED AT 250 WORDS)

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Simvastatin-induced decrease in the transfer of cholesterol esters from high density lipoproteins to very low and low density lipoproteins in normolipidemic subjects.

Ponsin G.

Laboratoire de Metabolisme des Lipides, INSERM U. 63, Hopital de l'Antiquaille, Lyon, France.

Hyperlipidemic patients often have an accelerated esterified cholesterol transfer (ECT) from high density lipoproteins (HDL) to very low (VLDL) and low density lipoproteins (LDL). We investigated the effect of simvastatin on ECT in twelve normolipidemic subjects. After 6 weeks of simvastatin administration, ECT was decreased by 23%. To determine the mechanism of action of simvastatin, we measured ECT in different recombination experiments, using an isotopic assay in which the transfer of labelled EC from HDL to VLDL/LDL was determined. When HDL of the treated subjects were incubated with VLDL/LDL and CETP fractions isolated from control plasma, no effect of simvastatin was observed, indicating that the drug did not alter the HDL-dependent ECT. This might be expected since simvastatin induced only minor modifications of HDL structure. When HDL and VLDL/LDL of control plasma were incubated with CETP fractions of the treated subjects, a clear reduction of ECT occurred after simvastatin administration. The decrease of plasma transfer activity was correlated to that of CETP concentration and accounted for the simvastatin-induced lowering of ECT. The diminution of plasma CETP was correlated to that of the apo B-containing lipoproteins concentration. This finding confirms previous reports suggesting a relationship between LDL level and CETP activity. In conclusion, our work shows that simvastatin administration results in a decrease of ECT and that this effect occurs through a lowering of plasma CETP activity.

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[Effectiveness and tolerability of simvastatin in patients with moderate-to-severe hypercholesterolemia. Results of a 12-month study]

[Article in Italian]

Gardini A.

Divisione di Cardiologia, Ospedale S. Orsola Fatebenefratelli di Brescia.

Several epidemiological and clinical studies have underlined the close relationship between hypercholesterolemia and risk of coronary heart disease suggesting the opportunity of treating hypercholesterolemic patients according to their associated risk factors. Simvastatin, a drug for the treatment of hypercholesterolemia, is a competitive inhibitor of 3-Hydroxy-Methyl-Glutaryl-CoA reductase, the rate limiting enzyme in cholesterol biosynthesis. In the present study we have assessed the efficacy, safety and tolerability of simvastatin (10-20 mg) administered once daily for a period of 12 months to 50 patients with coronary heart disease (CHD) or at high risk for CHD according to the National Cholesterol Education Program. All patients underwent complete physical examination and laboratory safety tests (including blood cell count, liver function tests, creatine kinase and lipid profile) at baseline and every 6 weeks during treatment. Simvastatin was highly effective in reducing total and LDL cholesterol (-25% and -35% respectively). No significant effect on HDL cholesterol or triglycerides was obtained. Two patients were excluded after 6 weeks of treatment because of a serum creatine kinase increase (more than twice normal values). This was the only drug related side effect. In conclusion our data show that: a) simvastatin treatment is well accepted and compliance is good; b) the effect of simvastatin is evident after the first 6 weeks of treatment and is maintained during the whole treatment time; c) simvastatin is highly effective in lowering total and LDL cholesterol. When considering a patient who has had an atherosclerotic event the best deterrent to the occurrence of a subsequent event (secondary prevention) could be reduction of serum total and LDL cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)

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