Effects of increasing doses of simvastatin on fasting lipoprotein subfractions, and the effect of high-dose simvastatin on postprandial chylomicron remnant clearance in normotriglyceridemic patients with premature coronary sclerosis.

Castro Cabezas M.

Department of Vascular Medicine, University Medical Center Utrecht, The Netherlands.

Postprandial hyperlipidemia has been linked to premature coronary artery disease (CAD) in fasting normotriglyceridemic patients. We investigated the effects of increasing doses of simvastatin up to 80 mg/day on fasting and postprandial lipoprotein metabolism in 18 normotriglyceridemic patients with premature CAD. Fasting lipoprotein subfractions and cholesteryl ester transfer protein (CETP) activity were determined after each 5-week dose titration (0, 20, 40 and 80 mg/day). At baseline and after treatment with simvastatin 80 mg/day, standardised Vitamin A oral fat loading tests (50 g/m2; 10 h) were carried out. Ten normolipidemic healthy control subjects matched for gender, age and BMI underwent tests without medication. Treatment with simvastatin resulted in dose-dependent reductions of fasting LDL-cholesterol, without changing cholesterol levels in the VLDL-1, VLDL-2 and IDL fractions. In addition, simvastatin decreased CETP activity dose-dependently, although HDL-cholesterol remained unchanged. Simvastatin 80 mg/day decreased fasting plasma triglycerides (TG) by 26% (P < 0.05), but did not decrease significantly TG levels in any of the subfractions. The TG/cholesterol ratio increased in all subfractions. The plasma TG response to the oral fat loading test, estimated as area under the curve (TG-AUC), improved by 30% (from 21.5 +/- 2.5 to 15.1 +/- 1.9 mmol h/L; P < 0.01). Treatment with simvastatin 80 mg/day improved chylomicron remnant clearance (RE-AUC) by 36% from 30.0 +/- 2.6 to 19.2 +/- 3.3 mg h/L (P < 0.01). After therapy, remnant clearance in patients was similar to controls (19.2 +/- 3.3 and 20.3 +/- 2.7 mg h/L, respectively), suggesting a normalization of this potentially atherogenic process. In conclusion, high-dose simvastatin has beneficial effects in normotriglyceridemic patients with premature CAD, due to improved chylomicron remnant clearance, besides effective lowering of LDL-cholesterol. In addition, the lipoprotein subfractions became more cholesterol-poor, as reflected by the increased TG/cholesterol ratio, which potentially makes them less atherogenic.

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[Preventive effect of simvastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on coronary atherosclerosis in cholesterol-fed rabbits]

[Article in Japanese]

Oogushi K.

Department of Internal Medicine, Faculty of Medicine, Saga Medical School, Japan.

A study was made on the effect of simvastatin (the generic name of MK-733), a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on coronary atherosclerosis in cholesterol-fed rabbits with focus on the serum lipids and morphology. Twenty-seven Japanese white rabbits were divided according to dosage of simvastatin into four groups as follows, group P (placebo, 5 rabbits), group MK 1 (simvastatin 1mg/kg, 5 rabbits), group MK 3 (simvastatin 3mg/kg, 6 rabbits) and group MK 5 (simvastatin 5mg/kg, 5 rabbits). They were placed on a 0.5% cholesterol atherogenic diet for 16 weeks and measurements were made of the concentration of serum lipids weekly. After sacrifice, the degree of surface involvement (SI) of aorta stained with Sudan III and the degree of coronary stenosis (CS) of the left circumflex artery were measured using an image-processing system. Serum total cholesterol (TC) level and beta-lipoprotein level decreased dose-dependently in MK groups compared with group P. High density lipoprotein cholesterol level increased in groups MK 3 and MK 5 slightly. Triglyceride level decreased in groups MK 3 and MK 5. The progressions of SI and CS were suppressed in MK groups dose-dependently. Integrated TC, that is, sum of the serum TC values obtained at each week multiplied by 7 corresponded more closely to CS than SI. Intimal thickening constructed from large foam cells originated from macrophages and proliferating smooth muscle cells included lipid droplets in MK groups was almost similar in group P. But it was likely that lipid droplets in each smooth muscle cell in MK groups were less than in group P. In conclusion, the development of coronary atherosclerosis in cholesterol-fed rabbits was suppressed dose-dependently by simvastatin and it was suggested that this preventive effect was due to reducing the integrated TC and local action to vessel walls by simvastatin. (Fukuoka Acta Med.)

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The HMG-CoA reductase inhibitor simvastatin suppresses human testicular testosterone synthesis in vitro by a selective inhibitory effect on 17-ketosteroid-oxidoreductase enzyme activity.

Kloppenborg PW.

Department of Medicine, University of Nijmegen, The Netherlands.

In concentrations probably exceeding those achieved in vivo, the cholesterol lowering compound simvastatin was found to suppress the synthesis of the androgens androstenediol and testosterone in vitro by human testicular homogenates. It was demonstrated that simvastatin in addition to its known inhibitory effect on HMG-CoA reductase activity, also affects the later steps of testicular steroidogenesis by selectively inhibiting the 17-ketosteroid-oxidoreductase catalyzed conversion of dehydroepiandrosterone and androstenedione to androstenediol and testosterone respectively. There was no effect of simvastatin on the Cytochrome P-450-dependent microsomal enzymes. Although in doses conventionally used in the treatment of hypercholesterolemia, simvastatin does not affect testicular steroidogenesis, at higher doses--especially when inadvertently administered during early pregnancy--adverse effects on normal testosterone biosynthesis and thereby fetal development should be considered.

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[Effects of simvastatin on blood levels of lipoprotein (a)]

[Article in Italian]

Bionda A.

Istituto di Clinica Medica II, Universita degli Studi, Pisa.

The efficacy of Simvastatin to reduce plasma cholesterol is well documented. Other molecule within the lipo-lipoprotein family, such as, particularly, lipoprotein (a) -Lp(a)-, have been recently found to have a predictive and/or causative role in atherosclerosis. Based on the above consideration, we studied 20 patients (7 females and 13 males), mean age 52.4 +/- 14.2 years, affected by primary hypercholesterolemia to evaluate the effect of simvastatin on Lp(a), in addition to the classic lipidic parameters. Five weeks after suspension of lipid-lowering drugs and on a normal caloric-fat diet, were given 20 mg simvastatin/day for 12 months. Clinical and laboratory parameters, cholesterol (CH), triglycerides (TG), high density and low density lipoprotein cholesterol (HDL-CH and LDH-CH) measured enzymatically, apoproteins A1, B measured radial immunodiffusion technique and Lp(a) measured as apoprotein(a) with immunoradiometric assay and were evaluated before therapy and after 12 months of therapy. Simvastatin determined a significant reduction in total cholesterol and cholesterol-LDL (CH 327.7 +/- 44.4 vs 255.5 +/- 37.3, p < 0.0001; LDL-CH 257.1 +/- 60.9 vs 183.8 +/- 46.9, p < 0.0001) and a significant increase in HDL-CH (36.7 +/- 5.9 vs 40.2 +/- 5.7, p < 0.005); no variation was observed in triglycerides (TG) levels. Simvastatin therapy further determined a significant increase in Lp(a) plasma levels (43.8 +/- 25.6 vs 50.5 +/- 28.0, p < 0.02). The our data, in agreement with those documenting the beneficial effect of Simvastatin in greatly decreasing CH and LDL-CH, but point out the need for further studies concerning the long-ter effect of simvastatin on Lp(a), in order to fully establish its role in the secondary prevention of atherosclerosis.

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Influences of pravastatin and simvastatin, HMG-CoA reductase inhibitors, on myocardial stunning in dogs.

Abiko Y.

Department of Pharmacology, Hokkaido College of Pharmacy, Otaru, Japan.

We examined the effects of pravastatin and simvastatin, HMG-CoA reductase inhibitors, on stunned myocardium in vivo. Pravastatin and simvastatin were given orally 2 mg/kg for 3 weeks. After 3 weeks of administration, pentobarbital-anesthetized dogs were subjected to 15-min left anterior descending (LAD) coronary artery occlusion followed by 2-h reperfusion. Myocardial segment function was determined by sonomicrometry. The tissue energy and carbohydrate metabolites were determined in the 2-h-reperfused hearts. Administration of pravastatin and simvastatin for 3 weeks decreased serum cholesterol level and blood pressure (BP). Simvastatin resulted in a worsening of segment shortening in the reperfused myocardium as compared with control and pravastatin groups. The level of ATP in the simvastatin group was significantly lower as compared with that in the control group. The other metabolite levels were not significantly altered by either pravastatin or simvastatin. These results suggest that simvastatin enhances stunning of the myocardium in association with ATP reduction after reperfusion subsequent to ischemia.

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Effects of an HMG-CoA reductase inhibitor on cytokine production by human monocytes/macrophages.

Ikejima T.

Second Department of Internal Medicine, Nippon Medical School.

It has been reported that the HMG-CoA reductase inhibitor simvastatin does not always effectively lower plasma LDL. This drug acts to monocytes/macrophages directly and inhibits cholesterol ester accumulation in these cells. However cytokine production in macrophages when simvastatin was administrated has not been described. In this study, we examined whether simvastatin affects cytokine production in human monocyte-derived macrophages. Simvastatin at doses ranging from 10(-9) to 10(-5) M did not affect the synthesis of proinflammatory cytokines (IL-1 beta, IL-6, IL-8) from human peripheral mononuclear cells. In addition, any changes in cytokine-induced cytokine production (IL-1-induced IL-8 synthesis) were not detected after the addition of simvastatin. The present results suggest that simvastatin suppresses foam cell formation in monocyte/macrophage, without affecting the immunological or inflammatory functions of these cells.

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