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PubMed1999

Safety of low-density lipoprotein cholestrol reduction with atorvastatin versus simvastatin in a coronary heart disease population (the TARGET TANGIBLE trial).

Reduction in plasma lipids has been recognized as one of the primary cardiovascular risk reduction strategies in the secondary prevention of coronary heart disease (CHD). The primary end points of TARGET TANGIBLE were the safety (adverse events and laboratory measurements) and efficacy (responder rates) of therapy with atorvastatin versus simvastatin with the aim of achieving low-density lipoprotein (LDL) cholesterol lowering to < or =100 mg/dl (2.6 mmol/L). A total of 3,748 CHD patients with LDL cholesterol levels > or =130 mg/dl (3.4 mmol/L) entered a run-in diet phase of 6 weeks without any lipid-lowering drug therapy. At the end of the diet phase, 2,856 patients met the lipid criteria and were randomized to active treatment for 14 weeks. Patients received 10 to 40 mg of either drug in an optional titration design at 2:1 randomization for atorvastatin versus simvastatin. Adverse event rates were statistically equivalent (p<0.01) for simvastatin (35.7%) and for atorvastatin patients (36.3%). Both drugs were well tolerated; <5% of patients in both groups were withdrawn due to adverse events. In all, 37 atorvastatin patients (2%) and 27 simvastatin patients (3%) had serious adverse events. Drug-related side effects (elevations in creatine kinase, liver enzymes) occurred in both groups at similar rates with 10 atorvastatin patients (0.5%) and 5 simvastatin patients (0.5%) presenting confirmed transaminase elevations >3 x the upper limit of the normal range. Significantly fewer patients in the atorvastatin group (n = 724) required titration to 40 mg compared with the simvastatin group (n = 514) (38% vs. 54%, respectively; p<0.001). Atorvastatin resulted in a significantly greater number of patients reaching the LDL cholesterol goal than those treated with simvastatin, with 67% of atorvastatin patients and 53% of simvastatin patients reaching the target LDL cholesterol level of < or =100 mg/dl (2.6 mmol/L) (p<0.001). Both atorvastatin and simvastatin are safe for use by patients in the secondary prevention of CHD, with patients in both drug groups having similar adverse event rates. Despite the use of concomitant medications there was no drug-induced rhabdomyolysis with either atorvastatin or simvastatin.

Anticholesteremic Agents↗
PubMedDate not supplied

Conversion from fluvastatin to simvastatin therapy at a dose ratio of 8 to 1: effect on serum lipid levels and cost.

The objective of this study was to assess the effect on serum lipid levels of the substitution of simvastatin for fluvastatin at a dose ratio of 8:1 (fluvastatin to simvastatin). A secondary objective was to determine the number of patients at goal lipid levels before and after this substitution. The study included 60 outpatients with hyperlipidemia who had received a constant dose of fluvastatin for at least 6 weeks. After a baseline 12-hour lipid profile (total cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein [LDL]) was obtained, patients were switched from fluvastatin to simvastatin at an 8:1 dose ratio. Patients were instructed to split the simvastatin tablets in half with a pill splitter and to take one half-tablet at bedtime. A repeat lipid profile and liver function testing were performed after 6 to 8 weeks of simvastatin therapy. Lipid components were compared before and during simvastatin therapy using a paired t test. Target LDL levels were based on guidelines issued by the National Cholesterol Education Program. Fifty-six patients completed the study. No change in lipid components was observed, except for a statistically significant decrease in LDL. The majority of patients had a decrease in LDL levels, rather than an increase, after the conversion to simvastatin. Six patients required a dose increase of simvastatin in response to increased LDL levels. Forty-one percent of patients achieved goal LDL levels with simvastatin, compared with 30% with fluvastatin. Four patients withdrew from the study, two because of troublesome side effects and two for failure to complete the protocol. The results show that simvastatin can be substituted for fluvastatin at a dose ratio of 8:1 without loss of lipid control in the majority of patients and that by using this ratio and splitting tablets, significant cost savings can be realized.

Aged↗
PubMed1999

Effect of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on alpha-fetoprotein gene expression through interaction with the ras-mediated pathway.

BACKGROUND/AIMS: The ras proto-oncogene encodes a small GTP-binding protein (Ras) which regulates cell growth and differentiation by relaying signals from the cell surface to the nucleus. In the present study, the role of Ras signal transduction pathway in alpha-fetoprotein (AFP) gene expression was evaluated in HuH-7 human hepatoma cells using simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, which blocks Ras function through inhibition of farnesylation, and the ras(val-12) expression vector. METHODS: The HuH-7 cells were treated with simvastatin (10 micromol/l), or both simvastatin and mevalonate (300 micromol/l), and numbers of viable cells were counted after treatment. To elucidate the effects of simvastatin on AFP gene expression and the interactive effect of simvastatin on Ras signal transduction pathway, Northern blotting and transient chloramphenicol acetyltransferase plasmid transfection assays were performed. RESULTS: Cell growth was inhibited by simvastatin, and this growth inhibition was restored by addition of mevalonate. Levels of AFP mRNA but not albumin mRNA were elevated by simvastatin in a dose-dependent manner (1-10 micromol/l). AFP promoter and enhancer activities were stimulated by simvastatin. In contrast, both activities were repressed by transfection with the ras(val-12) expression vector. The ras(val-12)-mediated repression was restored by simvastatin and returned to the repressed level by simvastatin plus mevalonate. CONCLUSIONS: These results indicate that the Ras signal transduction pathway functions to down-regulate the AFP gene transcription in human hepatoma cells.

Carcinoma, Hepatocellular↗
PubMed2003

Apoptosis induced by simvastatin in rat vascular smooth muscle cell through Ca2+-calpain and caspase-3 dependent pathway.

Several studies have shown that simvastatin induces apoptosis in a variety of cell lines including vascular smooth muscle cells (VSMCs), but the exactly mechanisms involved in it is not very clear. The aim of this study was to investigate the mechanisms and signal pathways involved in apoptosis induced by simvastatin. When exposed to 30 microM simvastatin, [Ca2+]i in VSMCs increased with time and reached to 336 +/- 52 nM at 6 h, more than four-fold of control (P<0.01, n=5). Verapamil (80 microM), a membrane voltage-dependent Ca2+ channel blocker, attenuated simvastatin-induced augmentation of free calcium concentration from 336 +/- 52 nM to 144 +/- 34 nM (P<0.01). After being exposed to 30 microM simvastatin for 8 h, calpain activity markedly increased (P<0.05, n=4) and reached to more than three-fold of control at 12 h (P<0.01). Caspase-3 was also activated by simvastatin after 12 h. Verapamil and PD150606, a cell-permeable selective calpain inhibitor, significantly inhibited simvastatin-induced augmentation of calpain activity and blocked caspase-3 activation, respectively. Furthermore, 80 microM verapamil and 100 microM PD150606 decreased simvastatin-induced apoptosis rate from 24.2 +/- 1.7% to 7.9 +/- 0.6% (P<0.01, n=4) and 9.5 +/- 1.9% (P<0.01), respectively and also prevented simvastatin-induced DNA laddering. In conclusion, we indicated that simvastatin increases cytosolic free calcium concentration mainly through calcium influx from extracellular solution and then induces apoptosis by activating caspase-3 via calcium-dependent protease calpain.

Acrylates↗
PubMed2002

Simvastatin increases fibrinolytic activity in human peritoneal mesothelial cells independent of cholesterol lowering.

BACKGROUND: The continuous physical and chemical irritation of the peritoneum in peritoneal dialysis patients can result in a nonbacterial serositis with increased fibrin deposition, thus promoting peritoneal fibrosis and adhesion development. By expressing the fibrinolytic enzyme tissue-type plasminogen activator (t-PA) and its specific inhibitor, plasminogen activator inhibitor-1 (PAI-1), human peritoneal mesothelial cells (HMC) play an important role in regulating peritoneal fibrinolysis. METHODS: Cultured HMC were used to examine the effect of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, simvastatin, on the expression of t-PA and PAI-1. Antigen concentrations in the cell supernatants were measured by ELISA and Northern blot analysis was conducted for mRNA expression. RESULTS: Simvastatin time- and concentration-dependently increased t-PA and decreased PAI-1 synthesis, reaching maximal effects after 48 hours, when simvastatin (1 micromol/L) increased t-PA levels 5.1 +/- 0.1-fold and suppressed PAI-1 levels 2.6 +/- 0.2-fold. This was accompanied by a twofold increase in mesothelial cell-associated t-PA activity. Qualitatively similar results were obtained in cultured human endothelial cells, but the effects were less pronounced and required higher simvastatin concentrations. Northern blot analysis revealed that the action of simvastatin on t-PA and PAI-1 expression in HMC can be explained by parallel changes in t-PA and PAI-1 mRNA. The effects of simvastatin were prevented in the presence of mevalonate and geranylgeraniol, suggesting that the effect of simvastatin on t-PA and PAI-1 synthesis is mediated through geranylgeranyl-modified intermediates. Experiments using specific inhibitors of geranylgeranylated Rho GTPases excluded a role of members of this family of small GTP-binding proteins in simvastatin action in HMC. The effects of simvastatin on t-PA and PAI-1 expression as well as on cell shape were completely mimicked by cytochalasin D, a disrupter of cellular actin filaments, but not by colchicine, a disrupter of microtubules. CONCLUSIONS: In conclusion, the cholesterol-lowering drug simvastatin is an effective stimulator of local peritoneal fibrinolytic activity, as it increases t-PA and decreases PAI-1 production in mesothelial cells by a mechanism involving geranylgeranyl-modified intermediates and actin skeleton perturbation. These results provide a new rationale to prevent peritoneal fibrin deposition and adhesion development in peritoneal dialysis patients.

Cells, Cultured↗
PubMed2000

Effects of high-dose simvastatin on adrenal and gonadal steroidogenesis in men with hypercholesterolemia.

In view of the role of both the de novo biosynthesis and receptor-mediated uptake of cholesterol for normal steroidogenesis, we evaluated whether extending the therapeutic dose of the hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, to 80 mg/d would affect adrenal and gonadal steroid synthesis in men with hypercholesterolemia. To evaluate this question, we enrolled men into a multicenter randomized, placebo-controlled study lasting 12 weeks. Men with serum low-density lipoprotein cholesterol (LDL-C) more than 145 mg/dL after 6 weeks of a lipid-lowering diet were randomized to 80 mg simvastatin or placebo. Half of the subjects were asked to undergo a 6-hour infusion of corticotropin (ACTH) to evaluate cortisol synthesis, and the entire cohort received a human chorionic gonadotropin (hCG) stimulation test to assess gonadal hormone secretion using pooled serum samples taken 15 minutes apart. A total of 81 men (age, 45 +/- 11 years; 93% Caucasian) with baseline serum LDL-C of 197 mg/dL (placebo, n = 39) and 184 mg/dL (simvastatin 80 mg, n = 42) completed the study. After 12 weeks, serum LDL-C, triglycerides, and high-density lipoprotein cholesterol (HDL-C) in the simvastatin group changed by -43%, -25%, and 8%, respectively (all P < .001). The basal cortisol level and the peak serum cortisol and area under the curve response to the 6-hour ACTH infusion were comparable between the two treatment groups at baseline and after 12 weeks. The pooled total testosterone level at baseline was 541 and 513 ng/dL in the placebo and simvastatin-treated groups, respectively, which declined to 536 +/- 20.5 ng/dL (-1.5%) and 474 +/- 30.4 ng/dL (-13.6%, P = .09) after treatment (mean +/- SD). The pooled free testosterone declined by 6.3% in the simvastatin group, versus a 4.9% increase in the placebo group (P = .588), while pooled bioavailable testosterone declined 10.2% in the simvastatin group and increased 1.4% in the placebo group (P = .035). There were no changes in serum gonadotropin levels or sex hormone-binding globulin (SHBG). After administration of hCG, there were no differences in the peak total pooled testosterone level before or after 12 weeks of treatment. Simvastatin 80 mg was well tolerated compared with placebo. In conclusion, basal and stimulated cortisol production was unaffected by the use of simvastatin 80 mg versus placebo. As reported with other statins and cholestyramine, there were small declines in the simvastatin-treated group for pooled total, free, and bioavailable testosterone after 12 weeks, although there was no compensatory increase in serum follicle-stimulating hormone (FSH) or luteinizing hormone (LH) levels.

Adrenal Cortex↗
PubMed2001

Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.

BACKGROUND: Both lipid-modifying therapy and antioxidant vitamins are thought to have benefit in patients with coronary disease. We studied simvastatin-niacin and antioxidant-vitamin therapy, alone and together, for cardiovascular protection in patients with coronary disease and low plasma levels of HDL. METHODS: In a three-year, double-blind trial, 160 patients with coronary disease, low HDL cholesterol levels and normal LDL cholesterol levels were randomly assigned to receive one of four regimens: simvastatin plus niacin, vitamins, simvastatin-niacin plus antioxidants; or placebos. The end points were arteriographic evidence of a change in coronary stenosis and the occurrence of a first cardiovascular event (death, myocardial infarction, stroke, or revascularization). RESULTS: The mean levels of LDL and HDL cholesterol were unaltered in the antioxidant group and the placebo group; these levels changed substantially (by -42 percent and +26 percent, respectively) in the simvastatin-niacin group. The protective increase in HDL2 with simvastatin plus niacin was attenuated by concurrent therapy with antioxidants. The average stenosis progressed by 3.9 percent with placebos, 1.8 percent with antioxidants (P=0.16 for the comparison with the placebo group), and 0.7 percent with simvastatin-niacin plus antioxidants (P=0.004) and regressed by 0.4 percent with simvastatin-niacin alone (P<0.001). The frequency of the clinical end point was 24 percent with placebos; 3 percent with simvastatin-niacin alone; 21 percent in the antioxidant-therapy group; and 14 percent in the simvastatin-niacin-plus-antioxidants group. CONCLUSIONS: Simvastatin plus niacin provides marked clinical and angiographically measurable benefits in patients with coronary disease and low HDL levels. The use of antioxidant vitamins in this setting must be questioned.

Antioxidants↗
PubMed2004

Calcyclin, a Ca2+ ion-binding protein, contributes to the anabolic effects of simvastatin on bone.

In vitro treatment with a pharmacological dose of simvastatin, a potent pro-drug of a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, stimulates bone formation. In our study, simvastatin stimulated differentiation of osteoblasts remarkably in a dose-dependent manner, with minimal effect on proliferation. To identify the mediators of the anabolic effects of simvastatin on osteoblasts, we tried to identify and characterize simvastatin-induced proteins by using proteomic analysis. Calcyclin was significantly up-regulated by more than 10 times, and annexin I was also up-regulated by simvastatin. However, annexin III, vimentin, and tropomyosin were down-regulated. Up-regulated calcyclin mRNA by simvastatin was validated by reverse transcription in mouse calvarial cells. In confocal microscope analysis, green fluorescence protein-calcyclin fusion protein was ubiquitously observed in the of MC3T3-E1 cells transfected with green fluorescence protein-calcyclin cDNA containing plasmid and was quickly concentrated in the nucleus 20 min after simvastatin treatment. Overexpression of calcyclin cDNA stimulated both the proliferation and expression of alkaline phosphatase mRNA significantly, without exposure to simvastatin in MC3T3-E1 cells. However, both the rate of proliferation of the osteoblasts and the expression of alkaline phosphatase mRNA were suppressed significantly 1 day after treatment with the calcyclin-specific small interference RNA, and furthermore, simvastatin did not overcome this suppression in the small interference RNA-pretreated MC3T3-E1 cells. In conclusion, calcyclin is one of the candidate proteins that plays a role in osteoblastogenesis in response to simvastatin, although the precise functions of calcyclin in osteoblast remain to be verified.

Animals↗
PubMed1997

Crossover trial of simvastatin versus pravastatin in patients with primary hypercholesterolemia.

The effects of simvastatin and pravastatin administered alone at initial doses of 5 and 10 mg/day, respectively, on normalization of abnormal lipid metabolism in patients with hypercholesterolemia were evaluated by a crossover method. Patients whose serum levels of total cholesterol (TC) were > or = 220 mg/dl were randomly divided into two groups, and one of the groups (group S-P: 17 patients) was treated with simvastatin first and then with pravastatin whereas the other group (group P-S: 19 patients) was treated with pravastatin first and then with simvastatin. Simvastatin or pravastatin was replaced with the other drug after 8-week administration in each group. These drugs were administered for 8 weeks each. Simvastatin and pravastatin significantly reduced the following serum lipids as compared with the levels in the observation period: TC by 23.2 +/- 8.1% and 18.1 +/- 10.9%, triglyceride (TG) by 13.0 +/- 24.7% and 5.8 +/- 47.1%, and low-density lipoprotein cholesterol (LDL-C) by 31.3 +/- 10.1% and 23.1 +/- 14.3%, respectively. TC and LDL-C levels were significantly (p < 0.001) lower and decreased to significantly (p < 0.001) greater degrees after simvastatin treatment than after pravastatin treatment. TC was normalized in 77.8% of the patients (28 of 36) after simvastatin treatment and in 68.9% of the patients (23 of 36) after pravastatin treatment. LDL-C was normalized in 63.9% of the patients (23 of 36) after simvastatin treatment and in 44.4% of the patients (16 of 36) after pravastatin treatment. The percentage of patients whose LDL-C was normalized by simvastatin was significantly (p < 0.05) higher as compared with pravastatin. Results of this trial, which was conducted by a crossover method, show that the initial dose of simvastatin reduces serum cholesterol and LDL-C more potently than the initial dose of pravastatin in patients with hypercholesterolemia.

Adult↗
PubMed2005

Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans.

BACKGROUND: Statins may exert important pleiotropic effects, ie, improve endothelial function, independently of their impact on LDL cholesterol. In humans, however, pleiotropic effects of statins have never been unequivocally demonstrated because prolonged statin treatment always results in reduced LDL cholesterol levels. We therefore tested the hypothesis that similar reductions in LDL cholesterol with simvastatin and ezetimibe, a novel cholesterol absorption inhibitor, result in different effects on endothelial function. METHODS AND RESULTS: Twenty patients with chronic heart failure were randomized to 4 weeks of simvastatin (10 mg/d) or ezetimibe (10 mg/d) treatment. Flow-dependent dilation (FDD) of the radial artery was determined by high-resolution ultrasound before and after intra-arterial vitamin C to determine the portion of FDD inhibited by radicals (DeltaFDD-VC). Activity of extracellular superoxide dismutase, a major vascular antioxidant enzyme system, was determined after release from the endothelium by a heparin bolus injection. Endothelial progenitor cells were analyzed with an in vitro assay. Simvastatin and ezetimibe treatment reduced LDL cholesterol to a similar extent (15.6% versus 15.4%; P=NS), whereas changes in mevalonate, the product of HMG-CoA-reductase, differed between groups (Deltamevalonate-simvastatin, -1.04+/-0.62 versus Deltamevalonate-ezetimibe, 1.79+/-0.94 ng/mL; P<0.05 between groups). Importantly, FDD was markedly improved after simvastatin (10.5+/-0.6% versus 5.1+/-0.7%; P<0.01) but not after ezetimibe treatment (5.6+/-0.5% versus 5.8+/-0.6%; P=NS). DeltaFDD-VC was substantially reduced after simvastatin but not after ezetimibe treatment. Extracellular superoxide dismutase activity was increased by >100% (P<0.05) after simvastatin but not ezetimibe treatment. Simvastatin treatment increased the number of functionally active endothelial progenitor cells, whereas ezetimibe had no effect. CONCLUSIONS: Four weeks of simvastatin treatment improves endothelial function independently of LDL cholesterol lowering, at least in part by reducing oxidant stress. Simvastatin may thereby exert important pleiotropic effects in humans.

Anticholesteremic Agents↗
PubMed2001

Pretreatment with simvastatin attenuates myocardial dysfunction after ischemia and chronic reperfusion.

We have previously demonstrated that simvastatin attenuates myocardial cell necrosis after acute myocardial ischemia and reperfusion via induction of endothelial cell NO synthase. However, it remains unknown whether the cardioprotective effects of statins can persist after extended periods of reperfusion. Furthermore, it is unknown whether simvastatin therapy can attenuate postischemic cardiac dysfunction. Pretreatment with simvastatin attenuated myocardial injury after 30 minutes of myocardial ischemia and 24 hours of reperfusion. However, the protective effects are not recognized unless simvastatin is given at least 3 hours before myocardial ischemia. Subsequently, we pretreated mice with vehicle or simvastatin and subjected the mice to 30 minutes of myocardial ischemia and 6 months of reperfusion. Myocardial infarct size (percentage of left ventricle) was significantly reduced by 51% in the simvastatin-treated group compared with the vehicle-treated group. Left ventricular diastolic and systolic dilatation was significantly (P<0.05) reduced in simvastatin-treated mice compared with vehicle-treated mice. Additionally, the decrement in fractional shortening after 6 months of reperfusion was minimized in simvastatin-treated mice (P=NS versus baseline) compared with vehicle-treated mice (P<0.05 versus baseline). Left ventricular end-diastolic pressure was significantly (P<0.01) elevated in vehicle-treated mice (21+/-4 mm Hg) but not simvastatin-treated mice (5+/-2 mm Hg) compared with baseline values. These data demonstrate that simvastatin treatment before myocardial ischemia attenuates infarct size and preserves myocardial function after chronic reperfusion in mice.

Animals↗
PubMed2006

The effect of simvastatin on triglyceride-rich lipoproteins in patients with type 2 diabetic dyslipidemia: a SILHOUETTE trial sub-study.

OBJECTIVE: To determine if simvastatin effectively decreases the elevated levels of triglyceride (TG), TG-rich lipoproteins, and small, dense LDL particles, which are characteristic of diabetic dyslipidemia. RESEARCH DESIGN AND METHODS: We conducted a prespecified analysis from a double-blind, placebo-controlled, randomized, 6-week crossover trial in patients with type 2 diabetes and low HDL-C (< 40 mg/dL). Each patient was randomized to 1 of 6 possible treatment arms; each patient received simvastatin 80 mg, simvastatin 40 mg, and placebo over 3 periods. We used the validated vertical auto profile (VAP) method to directly assess TG-rich lipoproteins and LDL subclasses. We assessed the efficacy of simvastatin to improve the lipoprotein profile in adult men (71%) and women (29%) (n = 151) with stable type 2 diabetes (HbA1C < 9%), LDL-C > 100 mg/dL, HDL-C < 40 mg/dL, and fasting TG level > 150 and < 700 mg/dL (median = 273 mg/dL). MAIN OUTCOME MEASURES: Percentage change from baseline in IDL and VLDL (TG-rich lipoproteins), LDL subclasses, and additional lipoproteins at the end of each 6-week treatment interval; percentage of patients who reached NCEP ATP III non-HDL goal of < 130 mg/dL by the end of each 6-week period. RESULTS: Both simvastatin 80 mg and 40 mg significantly reduced VLDL-C, VLDL3, and IDL, as well as the four LDL subclasses measured with VAP, compared with placebo. Simvastatin 80 mg, compared with simvastatin 40 mg, provided additional efficacy. With simvastatin 80 mg, 77.2% of patients not at their non-HDL-C goal of < 130 mg/dL at study baseline reached goal, compared with 65.7% following simvastatin 40 mg treatment, and 2.2% following placebo. CONCLUSIONS: Treatment with simvastatin effectively reduced the elevated levels of TG-rich lipoproteins and improved LDL composition in patients with type 2 diabetes. A large percentage of these patients attained the NCEP ATP III non-HDL-C goal of < 130 mg/dL, which demonstrates the improvement of the atherogenic profile in these patients.

Aged↗
PubMed2004

Comparison of intermittent with continuous simvastatin treatment in hypercholesterolemic patients with end stage renal failure.

Coronary artery disease is the most important cause of morbidity and mortality in patients with end-stage renal failure (RF). Hypercholesterolemia is an important risk factor for coronary heart disease. Patients with chronic renal failure (CRF) have difficulties in compliance with their care and treatment. Intermittent simvastatin treatment may help to increase compliance and can be a treatment alternative in patients with CRF at risk of coronary artery disease. We investigated the effects of simvastatin and compared intermittent with continuous simvastatin treatment in hypercholesterolamic patients with CRF. The study group included 40 of 422 CRF patients on dialysis in our clinic. The inclusion criterion was low density lipoprotein cholesterol (LDL-C) of 130 mg/dL or more. Twenty patients received simvastatin 10 mg/day (continuous group) and 20 patients received simvastatin 20 mg three times a week (only dialysis days- intermittent group) for four months. Nineteen patients served as controls and they were given a prescribed diet only. Total cholesterol (TC) and LDL-C decreased markedly in patients receiving intermittent and continuous simvastatin compared to controls. Continuous simvastatin decreased TC by 23% (P < 0.001) and LDL-C by 39% (P < 0.001). Intermittent simvastatin decreased TC by 26% (P < 0.001) and LDL-C by 40% (P < 0.001). The atherogenic index ratios in both the continuous and intermittent groups (TC/High density lipoprotein-cholesterol (HDL-C) and LDL-C/HDL-C) decreased significantly. There was no significant difference in patient compliance between the two groups. Intermittent simvastatin is as effective and reliable as continuous simvastatin treatment and can be an alternative treatment in hypercholesterolemic patients on dialysis.

Aged↗
PubMed2005

Local simvastatin effects on mandibular bone growth and inflammation.

BACKGROUND: Simvastatin has been shown to increase bone growth when applied topically to murine bone; however, it causes considerable soft tissue inflammation at high doses (2.2 mg), making future clinical use problematic. This study evaluated the effect of lower simvastatin doses and cyclooxygenase (COX) synthase inhibitors on tissue inflammation and bone growth in rats and gene expression in mice. METHODS: Adult female rats were untreated or treated with a single dose of 0.1, 0.5, 1.0, 1.5, or 2.2 mg simvastatin in methylcellulose gel in a polylactic acid membrane (SIM) on the lateral aspect of the mandible. The contralateral mandible side was implanted with methylcellulose gel/polylactic acid membrane alone (GEL), and five rats in each dose pairing were evaluated histomorphometrically after 3, 7, and 24 days. Subsequent rats were similarly treated with 0.5 mg simvastatin (optimal dose) and daily intraperitoneal injections of COX-2 inhibitor (NS-398; 1 mg/kg x 7 days; N = 16), general COX inhibitor (indomethacin; 1 mg/kg x 7 days; N = 16), or no inhibitor (N = 10) and evaluated histomorphometrically after 7 or 24 days by analysis of variance (ANOVA). Gene arrays were also used to evaluate osteogenic gene expression from 0.5 mg simvastatin in murine calvaria (N = 12). RESULTS: There was a 45% increase in bone area with 0.5 mg simvastatin versus gel control (P <0.001; similar to the 2.2-mg dose), and clinical swelling was reduced compared to the high simvastatin dose (P <0.05). The 0.1-mg simvastatin dose failed to stimulate significant bone growth. NS-398 and indomethacin reduced inflammation and bone growth. Simvastatin significantly upregulated procollagen, fibronectin, and matrix metalloproteinase-13 genes. CONCLUSION: Reducing the simvastatin dose from 2.2 to 0.5 mg reduced inflammation to a more clinically acceptable level without sacrificing bone-growth potential, but COX-associated inflammation appears to be necessary for in vivo bone growth.

Animals↗
PubMed1990

Simvastatin. A review of its pharmacological properties and therapeutic potential in hypercholesterolaemia.

Simvastatin (epistatin; synvinolin; MK 733), an HMG-CoA reductase inhibitor, acts by decreasing cholesterol synthesis and by increasing low density lipoprotein (LDL) catabolism via increased LDL receptor activity. In patients with heterozygous familial and nonfamilial hypercholesterolaemia, orally administered simvastatin 10 to 40mg once daily reduces plasma total and LDL-cholesterol concentrations by about 30 to 45%. It also produces a beneficial moderate decrease in plasma triglycerides and a small, although significant, increase in high density lipoprotein (HDL)-cholesterol. Like many other hypocholesterolaemic agents simvastatin does not appear useful in patients with homozygous familial hypercholesterolaemia who lack LDL receptors. The hypocholesterolaemic activity of simvastatin is greater than that of the bile acid sequestrants, probucol and the fibrates. Combined administration of simvastatin with bile acid sequestrants results in further reductions in plasma cholesterol levels beyond those seen with either drug alone. Simvastatin appears well tolerated in the short to medium term, but its long term tolerability needs to be confirmed. No comparisons of simvastatin and other HMG-CoA reductase inhibitors have been reported. As yet there have been few investigations to determine the impact of simvastatin or other HMG-CoA reductase inhibitors on cardiovascular events relative to their hypocholesterolaemic effects, but at least one such trial is ongoing. Simvastatin, like other HMG-CoA reductase inhibitors, has considerable potential advantages over other classes of hypocholesterolaemic agents, i.e. the magnitude of its cholesterol-lowering effect and convenience of administration. If further study confirms long term tolerability and an impact on cardiac mortality and morbidity, then simvastatin and others of its class should offer a significant new approach to the treatment of hypercholesterolaemia.

Animals↗
PubMed2001

The inhibitory effect of simvastatin on growth in malignant gliomas--with special reference to its local application with fibrin glue spray in vivo.

Simvastatin is one of the competitive inhibitors of HMG-CoA reductase. During clinical trials, it has shown the ability to lower serum cholesterol. We investigated the effect of simvastatin on the growth of malignant gliomas in vitro, semi-in vivo, and in vivo. An in-vitro MTT assay revealed that human malignant glioma cell lines: U-251MG, U-373MG, and U-87MG, and rat malignant glioma cell line C6 were well inhibited in growth in a dose-dependent fashion. An anchorage-independent growth assay showed that the number of colonies (more than 100 microM in size) of human (U-373MG) and rat malignant gliomas (C6) was markedly reduced in a dose-dependent fashion. A flow cytometry analysis revealed that simvastatin treatment led U-251MG cells to accumulate in sub G0-G1. Immunostaining by TUNEL method showed that most glioma cells treated by 10 microM simvastatin had nuclear immunostaining, suggesting apoptotic changes of the treated cells. The human umbilical vein endothelial cells and human lung fibroblasts were inhibited in growth by no more than 20% of controls even with a high dose (10 microM) of simvastatin. In the semi-in vivo model, using newborn rat brain slice cultures, the rhodamine-labeled glioma cells were abolished after 7 days of local simvastatin treatment with fibrin glue probably suggesting that simvastatin led the cells to apoptosis. In rat models using subcutaneously inoculated C6, the local application of simvastatin combined with fibrin glue (spray method) was quite effective in inhibiting the growth of the tumor. These data suggest that simvastatin may be a novel anti-glioma drug, and the local application of simvastatin combined with fibrin glue (by spray method) may be a crucial new clinical strategy against glioma growth.

Animals↗
PubMed2004

Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To compare the efficacy and safety of 10 mg of ezetimibe coadministered with simvastatin with the safety and efficacy of simvastatin monotherapy for patients with hypercholesterolemia. PATIENTS AND METHODS: This multicenter double-blind, placebo-controlled, factorial study enrolled 887 patients with hypercholesterolemia (low-density lipoprotein cholesterol [LDL-C], 145-250 mg/dL; triglycerides, < or = 350 mg/dL). Patients were randomized to 1 of 10 treatments--placebo, ezetimibe at 10 mg/d, simvastatin at 10, 20, 40, or 80 mg/d, or simvastatin at 10, 20, 40, or 80 mg/d plus ezetimibe at 10 mg/d for 12 weeks. The study began March 13, 2001, and ended January 8, 2002. The primary efficacy end point was the mean percent change in LDL-C levels from baseline to study end point (last available postbaseline LDL-C measurement) for the pooled ezetimibe/simvastatin group vs the pooled simvastatin monotherapy group. RESULTS: Coadministration of ezetimibe/simvastatin was significantly (P<.001) more effective than simvastatin alone in reducing LDL-C levels for the pooled ezetimibe/simvastatin vs pooled simvastatin analysis and at each specific dose comparison. The decrease in LDL-C levels with coadministration of ezetimibe and the lowest dose of simvastatin, 10 mg, was similar to the decrease with the maximum dose of simvastatin, 80 mg. A significantly (P<.001) greater proportion of patients in the ezetimibe/simvastatin group achieved target LDL-C levels compared with those in the monotherapy group. Treatment with ezetimibe/simvastatin also led to greater reductions in total cholesterol, triglyceride, non-high-density lipoprotein cholesterol, and apolipoprotein B levels compared with simvastatin alone; both treatments increased high-density lipoprotein cholesterol levels similarly. The safety and tolerability profiles for the ezetimibe/simvastatin and monotherapy groups were similar. CONCLUSION: Through dual inhibition of cholesterol absorption and synthesis, coadministration of ezetimibe/simvastatin offers a highly efficacious and well-tolerated lipid-lowering strategy for treating patients with primary hypercholesterolemia.

Adult↗
PubMed2000

A pilot study with simvastatin and folic acid/vitamin B12 in preparation for the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH).

BACKGROUND AND AIM: This study was conducted in preparation for the Study Evaluating Additional Reduction in Cholesterol and Homocysteine (SEARCH). SEARCH is a 12,000 patient 2X2 factorial study in post-myocardial infarction patients that will compare simvastatin 20 mg with simvastatin 80 mg to evaluate whether greater LDL-C reductions with simvastatin provide greater coronary event reductions. SEARCH will also test the hypothesis that lowering plasma homocysteine with folic acid and vitamin B12 will reduce coronary events. This pilot study was performed to determine whether any clinically meaningful interaction between simvastatin and folic acid/vitamin B12 exists. METHODS AND RESULTS: Following a 2-week diet/placebo run-in period, 141 patients with primary hypercholesterolaemia were randomised to one of three treatments for 6 weeks: 80 mg/day simvastatin and 2 mg folic acid/0.8 mg vitamin B12 daily (combination group); or 80 mg/day simvastatin and placebo vitamins (simvastatin alone group); or 2 mg folic acid/0.8 mg vitamin B12 daily and placebo simvastatin (vitamins alone group). The combination group and simvastatin alone group experienced similar serum lipid changes with reductions in LDL-cholesterol of 55.2% and 51.5% respectively. The combination group and vitamins alone group experienced similar homocysteine lowering with reductions in homocysteine of 25.3% and 23.1% respectively. All therapies were well tolerated. CONCLUSIONS: There was no detectable antagonistic effect when simvastatin and folic acid/vitamin B12 were administered concomitantly.

Cholesterol↗