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PubMed2004

Impaired myocardial vasodilatation during hyperaemic stress is improved by simvastatin but not by pravastatin in patients with hypercholesterolaemia.

AIMS: Impaired myocardial vasodilatation during hyperaemic stress with dipyridamole has been documented in hypercholesterolaemics without evidence of ischaemia. This study investigated whether two commonly used hydroxymethylglutaryl coenzyme A reductase inhibitors, simvastatin and pravastatin, are equally effective in restoring myocardial vasodilatation. METHODS AND RESULTS: Forty-four hypercholesterolaemics with a low probability of coronary artery disease and 22 controls were studied. Before and after lipid-lowering therapy with simvastatin (n = 22) or pravastatin (n = 22), myocardial blood flow at rest and during dipyridamole loading was measured using positron emission tomography with [(13)N]ammonia, and myocardial vasodilatation was assessed. Treatments with simvastatin and pravastatin similarly reduced plasma total cholesterol and plasma low-density lipoprotein cholesterol. Resting myocardial blood flow was comparable in the controls, simvastatin group, and pravastatin group and unchanged after therapy. Myocardial blood flow during dipyridamole loading and myocardial vasodilatation was lower in the two therapy groups before treatment than in the controls. These parameters improved significantly after therapy with simvastatin, whereas no improvement was observed after pravastatin therapy. The per cent change in myocardial vasodilatation after simvastatin therapy was significantly and inversely correlated with per cent changes in plasma lipid fractions. CONCLUSION: Diminished myocardial vasodilatation in hypercholesterolaemics is improved by simvastatin but not by pravastatin, suggesting differences in vascular effects among statins.

Anticholesteremic Agents↗
PubMed2006

Short- and long-term influence of diet and simvastatin on brachial artery endothelial function.

BACKGROUND: Endothelium-dependent dilation (EDD) has often been studied in patients with hypercholesterolemia without overt coronary atherosclerosis where an improvement after statin treatment has been documented within few weeks. The aim of the study was to assess the short-term effect of diet as well as short- and long-term effect of simvastatin on EDD in patients with hypercholesterolemia and ischemic heart disease. METHODS: In 43 male patients with hypercholesterolemia and ischemic heart disease, EDD of the brachial artery was measured at baseline, after 3 months on a lipid-lowering diet, and after another 1, 3 and 12 months on simvastatin at 40 mg/day. RESULTS: Three months changes in EDD were neither influenced by diet nor short-term simvastatin therapy (4.9% vs. 4.9% vs. 4.8%, p=ns). Twelve months simvastatin treatment, however, significantly improved EDD by 32.7% (4.9% vs. 6.5%, p=0.007). By regression analysis an individual adjusted increase in EDD during the simvastatin treatment period was seen (coefficient 0.132 a month, p=0.002). A significant reduction in total cholesterol of 31.0% (6.1+/-0.8 vs. 4.2+/-0.7, p<0.001) and LDL cholesterol of 42.6% (4.0+/-0.8 vs. 2.2+/-0.6, p<0.001) was observed. CONCLUSION: EDD is improved after long-term simvastatin therapy; however, neither did 3 months diet or 3 months simvastatin therapy has influence on the EDD.

Aged↗
PubMed2006

Simvastatin does not exhibit therapeutic anti-inflammatory effects in asthma.

BACKGROUND: Statins lower cholesterol and also exhibit anti-inflammatory properties. In vitro and animal studies have suggested they may be useful for the treatment of a number of inflammatory conditions. OBJECTIVE: To evaluate the in vivo therapeutic potential of simvastatin as an anti-inflammatory agent in patients with asthma. METHODS: Potential signal from treatment effect was optimized by withdrawing all anti-inflammatory treatment for the duration of the study. Participants received 1 month of daily simvastatin and 1 month of daily placebo in a randomized, double-blind crossover trial. A total of 16 patients completed per protocol. Asthmatic inflammation was evaluated by measuring exhaled tidal nitric oxide, alveolar nitric oxide, sputum and peripheral eosinophil count, methacholine hyperresponsiveness, salivary eosinophilic cationic protein, and C-reactive protein. Measurements of dynamic and static lung volumes and of cholesterol were also made. RESULTS: After initial withdrawal of usual asthma medication, there was a 1.43 geometric mean fold increase (ie, 43% difference) in fraction of exhaled nitric oxide (95% CI, 1.15 to 1.78; P = .004). Compared with placebo, simvastatin led to a 0.86 geometric mean fold decrease (95% CI, 0.7 to 1.04; P = .15) in exhaled nitric oxide (ie, a 14% difference), and a -0.18 doubling dilution shift (95% CI, -1.90 to 1.55; P = 1.0) in methacholine hyperresponsiveness. There were no significant differences in other inflammatory outcomes, lung volumes, or airway resistance between simvastatin and placebo. Treatment with simvastatin led to a significant reduction (P < .005) of total and low-density lipoprotein cholesterol. CONCLUSION: There is no evidence to suggest simvastatin has anti-inflammatory activity in patients with asthma. CLINICAL IMPLICATIONS: Simvastatin is not useful for the treatment of asthma.

Adult↗
PubMed2005

Effects of raloxifene and low-dose simvastatin coadministration on plasma lipids in postmenopausal women with primary hypercholesterolemia.

Abstract Raloxifene and low-dose simvastatin can each reduce low-density lipoprotein (LDL) cholesterol without affecting high-density lipoprotein (HDL) cholesterol and triglycerides. The objective of this double-blind, 12-week study is to determine whether raloxifene and simvastatin coadministration gives added benefit beyond either monotherapy in affecting fasting lipoproteins and apolipoproteins. Ninety-five postmenopausal women with moderately elevated LDL cholesterol (mean, 146 mg/dL) were randomized to placebo, raloxifene 60 mg/d, simvastatin 10 mg/d, or raloxifene 60 mg/d coadministered with simvastatin 10 mg/d. Raloxifene, simvastatin, and coadministration therapy reduced mean LDL cholesterol by 10.5%, 23.3%, and 31.0% from baseline, respectively ( P < .003 vs baseline; P < .02 vs placebo), and mean apolipoprotein B by 10.4%, 24.2%, and 30.0% from baseline, respectively ( P < .003 vs baseline; P < .02 vs placebo). Each active treatment decreased non-HDL cholesterol compared with placebo ( P < .01). Coadministration treatment was more effective than either monotherapy in reducing LDL cholesterol ( P < .05). Coadministration treatment reduced mean apolipoprotein B ( P < .001) and non-HDL cholesterol ( P < .001) when compared with raloxifene, but was not significantly different when compared with simvastatin. Coadministration therapy increased HDL cholesterol and apolipoprotein A1 levels compared with placebo ( P < .02). No significant effect on triglycerides, very low density lipoprotein cholesterol, and lipoprotein (a) occurred with any active treatment. Raloxifene, simvastatin, and the coadministration therapy were generally well tolerated with clinical adverse effects similar to placebo. No woman had clinically significant elevated liver function tests requiring drug discontinuation. Further data on safety and lipid-lowering effects are needed before raloxifene and statin coadministration may be considered as therapeutic interventions for treating postmenopausal women to achieve National Cholesterol Education Program-Adult Treatment Panel III treatment guidelines.

Adult↗
PubMed2006

Effects of high dose of simvastatin on levels of dopamine and its reuptake in prefrontal cortex and striatum among SD rats.

Statins are increasingly being used for the treatment of a variety of conditions beyond their original indication for cholesterol lowering. We previously reported that simvastatin increased dopamine receptors in the rat prefrontal cortex [Q. Wang, W.L. Ting, H. Yang, P.T. Wong, High doses of simvastatin upregulate dopamine D(1) and D(2) receptor expression in the rat prefrontal cortex: possible involvement of endothelial nitric oxide synthase, Br. J. Pharmacol. 144 (2005) 933-939] and restored its downregulation in a model of Parkinson's disease (PD) [Q. Wang, P.H. Wang, C. McLachlan, P.T. Wong, Simvastatin reverses the downregulation of dopamine D1 and D2 receptor expression in the prefrontal cortex of 6-hydroxydopamine-induced Parkinsonian rats, Brain Res. 1045 (2005) 229-233]. Here we explore the effects of simvastatin treatment on tissue dopamine content and reuptake. Sprague-Dawley rats were given simvastatin (1 and 10 mg kg(-1)day(-1), p.o.) for 4 weeks. Brain tissue from prefrontal cortex and striatum were taken out for dopamine content and its reuptake. Using high-performance liquid chromatographic-mass spectrometer (HPLC-MS), simvastatin (10 mg kg(-1)day(-1)) was found to increase dopamine content by 110% in the striatum but decreased by 76% in the prefrontal cortex compared with the saline treated group. Dopamine (DA) reuptake was unchanged in both brain regions. These results suggest that chronic treatment with high dose of simvastatin may affect DA tissue level in prefrontal cortex and striatum without changing on DA reuptake. This may have important clinical implications in psychiatric and striatal dopaminergic disorders.

Analysis of Variance↗
PubMed2005

Neuroprotective effect of simvastatin in stroke: a comparison between adult and neonatal rat models of cerebral ischemia.

Statins, the most widely used lipid lowering drugs, have been demonstrated to play a protective role in stroke. Animal studies confirmed the observations obtained in clinical trials and provided additional data on the putative mechanism/s of action underlying this beneficial effect. We have shown that simvastatin reduced the size of the infarct to a different extend, according to the animal model used. Indeed, in the rat neonatal model of hypoxia/ischemia simvastatin affords protection only when is administered before the ischemic insult. In contrast, in adult rats bearing middle cerebral artery occlusion, simvastatin exerted its beneficial effect on brain injury when injected for 3 days either before or after induction of ischemia. Studies carried out to determine the therapeutic window of simvastatin demonstrated that the protective effect is observed after a single dose and when the drug is administered within 3-6 hours after ischemia. Simvastatin-dependent activation of eNOS has been claimed to be one of the main mechanisms responsible for neuroprotection. This hypothesis is confirmed in the adult animal model where eNOS is activated by either pre- or post- simvastatin treatment but is not supported by the data obtained in the neonate where eNOS activity is not affected by drug treatment. These observations suggest that the protective effect of simvastatin on stroke may be mediated by multiple mechanisms as can be expected by its pleiotropic effects.

Aging↗
PubMed2006

Beneficial effect of simvastatin treatment on LDL oxidation and antioxidant protection is more pronounced in combined hyperlipidemia than in hypercholesterolemia.

AIMS: Beneficial effects of statin treatment on cardiovascular morbidity and mortality has been not entirely explained by the reduction in LDL-cholesterol level. We hypothesised that antioxidant activity of statins may contribute to their salutary cardiovascular effects. The aim of the present study was to examine effect of simvastatin treatment on some parameters of LDL oxidation and antioxidant protection in patients with hypercholesterolemia and combined hyperlipidemia. Furthermore, we were interested, whether the effect of treatment is related to the type of hyperlipidemia. PATIENTS AND METHODS: Fourty-two patients (12 males, 30 females, mean age 60+/-10 years) were included in the present study. Fourteen patients had hypercholesterolemia defined as total cholesterol>5.0 mmol/l. Twenty-eight patients had combined hyperlipidemia defined by total cholesterol>5.0 mmol/l and triglycerides>1.7 mmol/l. Simvastatin was administered to patients during 8-week period in a daily dose of 20mg. Oxidation of LDL was measured by assessment of circulating conjugated diene (CD) and malondialdehyde (MDA) level. Antioxidant properties of blood were assessed based on measurement of total antioxidant status (TAS) and glutathione peroxidase (GPx) activity. RESULTS: Besides expected significant decrease in total cholesterol, LDL-cholesterol, apolipoprotein B and triglyceride levels, simvastatin treatment also reduced significantly circulating CD by 41% (p<0.0001) and MDA level non-significantly by 6% (p=0.078). Simvastatin treatment resulted in an increase of GPx activity by 38% (p<0.0001), but did not have a significant effect on TAS. Patients with combined hyperlipidemia had significantly higher baseline CD (p<0.01) and consequently significantly greater absolute and relative decrease (46% versus 23%) in circulating CD (DeltaCD), when compared with patients with hypercholesterolemia. The increase in GPx activity was significant only in patients with combined hyperlipidemia (p<0.0001). In the multiple stepwise linear regression analysis, both baseline triglyceride (r(2)=0.32; p=0.004) and LDL cholesterol (r(2)=0.08; p=0.05) levels were significant independent predictors of DeltaCD after simvastatin treatment. CONCLUSION: Simvastatin treatment significantly reduced circulating conjugated diene level and led to an increase in glutathione peroxidase activity. These effects were more pronounced in patients with combined hyperlipidemia than in hypercholesterolemia. The results suggest that simvastatin possesses certain antioxidant properties, which may contribute to its beneficial cardiovascular effect.

Aged↗
PubMedDate not supplied

The use of simvastatin in rabbit posterolateral lumbar intertransverse process spine fusion.

BACKGROUND CONTEXT: There has been recent enthusiasm regarding the potential positive effects of statins on bone. Statins vary in their ability to influence bone activity. Simvastatin has been shown in experimental models to stimulate bone acting growth factors and enhance bone formation. PURPOSE: The potential efficacy of Simvastatin in enhancing spinal fusion was evaluated in a rabbit posterolateral intertransverse process fusion model. STUDY DESIGN/SETTING: Posterior lumbar intertransverse process spinal fusion performed on New Zealand White rabbits. PATIENT/STUDY SAMPLE: 44 New Zealand White rabbits. OUTCOME MEASURES: Spinal fusion as determined by manual palpation testing and fine detail radiography. Bone fusion mass volume and density as determined by CT scan imaging. METHODS: Forty-four New Zealand White rabbits underwent posterolateral intertransverse process spine fusion using autogenous iliac crest bone graft. Simvastatin was administered orally in 20 animals and the serum lipid profile quantified in test and control animals. The animals were euthanized 9 weeks following index surgery and the lumbar spine was harvested. Spinal fusion was determined by manual palpation testing and fine detail radiography. The volume and density of the bone fusion mass was quantified by computed tomography. RESULTS: Drug treatment for 9 weeks caused a reduction in serum lipid biochemical markers when compared with controls. The spinal fusion rate, as judged by manual palpation testing (13.0% control group, 16.6% Simvastatin group) and fine detail radiography, was not significantly different comparing treatment with control animals. Accordant with the assessment of spinal fusion, there was no statistically significant effect on the volume of the fusion mass (1,224.7+/-98.7 mm(3) in the control group and 1,075.9+/-66.3 mm(3) in the Simvastatin group), the density of bone in the lumbar spine or that in the formed fusion mass. CONCLUSIONS: Systemic use of Simvastatin caused a reduction in lipid biochemical parameters in treated animals. Successful spinal fusion as judged by manual palpation testing and fine detail radiography was not significantly different in treated versus untreated animals. The bone volume density of the formed fusion mass was not significantly different in treated versus untreated animals. There did not appear to be a significant advantage or disadvantage to the use of Simvastatin rabbit posterolateral spinal fusion. The potential positive effects of statins on bone require further study.

Animals↗
PubMedDate not supplied

The manifold actions of statins. Comment on "Effects of systemic administration of simvastatin on retinal circulation, by T. Nagaoka, A. Takahashi, E. Sato, et al. Arch Ophthalmol 124:665-70, 2006.

OBJECTIVE: To investigate the effect of systemic administration of simvastatin on the retinal circulation. METHODS: The effects of systemic administration of simvastatin on the retinal circulation after 90 minutes and after 7 days were studied in a placebo-controlled, double-masked, clinical trial among 12 healthy men. We used laser Doppler velocimetry to measure vessel diameter and blood velocity and calculated the blood flow in retinal arteries and veins. We also measured the intraocular pressure and the plasma nitrite/nitrate levels, the stable end products of nitric oxide metabolism. RESULTS: There were no significant changes in any retinal circulatory parameters at 90 minutes after administration of simvastatin. Daily administration of simvastatin for 7 days significantly increased blood velocity and blood flow in retinal arteries and veins but did not significantly change vessel diameter. The intraocular pressure significantly decreased at 90 minutes and at 7 days after administration of simvastatin. Simvastatin also significantly increased the plasma nitrite/nitrate levels. CONCLUSION: Simvastatin induced an increase in blood velocity and blood flow in retinal arteries and veins, increased the plasma nitrite/nitrate levels, and decreased the intraocular pressure, probably through the increase in nitric oxide.

Administration, Oral↗
PubMed2002

Effects of simvastatin on C-reactive protein in mixed hyperlipidemic and hypertriglyceridemic patients.

This study examined the effects of simvastatin on C-reactive protein (CRP) and other inflammatory markers in study subjects with significant elevations in triglyceride (TG) blood levels. CRP, vascular cellular adhesion molecule (VCAM), serum amyloid A (SAA), and interleukin 6 (IL-6) were measured in archived plasma samples from 2 multicenter, randomized, double-blind, placebo-controlled studies designed to examine the lipid-altering efficacy of simvastatin in study subjects with elevated TGs. In the first study, 130 study subjects with mixed hyperlipidemia (low-density lipoprotein [LDL] cholesterol > or =130 mg/dl; TGs 300 to 700 mg/dl) received placebo or simvastatin 40 or 80 mg once daily for three 6-week periods in a complete-block crossover design. In the second study, 195 study subjects with hypertriglyceridemia (TGs 300 to 900 mg/dl) received daily doses of placebo or simvastatin 20, 40, or 80 mg for 6 weeks. Significant but weak correlations were observed between baseline CRP values and baseline levels of LDL cholesterol and high-density lipoprotein (HDL) cholesterol, but not with TGs. CRP was also correlated with body mass index and fasting levels of glucose and insulin. Treatment with simvastatin 20, 40, and 80 mg led to significant reductions in CRP plasma levels versus placebo (p <0.05). Although CRP change was weakly correlated with changes in LDL cholesterol, TGs, and HDL cholesterol, results of regression analyses showed that only baseline CRP and treatment allocation were significant predictors of CRP response after 6 weeks of study drug administration. Simvastatin had no effect on VCAM, SAA, or IL-6. In summary, simvastatin significantly reduced CRP in patients with mixed hyperlipidemia and hypertriglyceridemia.

Anticholesteremic Agents↗
PubMed2003

Comparison of the effects of atorvastatin versus simvastatin on subclinical atherosclerosis in primary preventionas determined by electronbeam tomography.

This study was designed to evaluate the effects of lipid-lowering therapy by atorvastatin versus simvastatin on calcified plaque progression, as determined by serial electron beam tomography (EBT), in primary prevention patients. In this observational study, serial EBT was performed before and after 1.2 years of atorvastatin (n = 103) and simavastatin therapy (n = 46); approximately 50% of each group was on niacin as well, in similar doses. There were no differences in demographic parameters between the groups. Total, low-density lipoprotein (LDL), and non-high-density lipoprotein (HDL) cholesterol were significantly higher in the atorvastatin group before treatment. Before treatment, EBT calcium score and volume scores were 469 and 378, respectively, in the atorvastatin patients, and 388 and 307, respectively, in the simvastatin patients (p = NS, atorvastatin vs simvastatin). After treatment, there were no differences in any lipid or EBT values between the groups. Post-treatment total cholesterol and LDL cholesterol were 156 and 79 mg/dl, respectively, in the atorvastatin cohort and 154 and 76 mg/dl, respectively, in the simvastatin group (p = NS). Calcium score and volume progressed 10.8%/year and 8.5%/year, respectively, in the atorvastatin group, and 7.5%/year and 7.8%/year in the simvastatin group (p = NS, atorvastatin vs simvastatin). We conclude that aggressive treatment with atorvastatin and simvastatin in the primary prevention population, to similar lipid levels, is associated with equal progression of EBT-determined calcified plaque. This suggests that these hydroxymethylglutaryl coenzyme A reductase inhibitors exhibit a "class effect" with respect to progression of subclinical atherosclerosis.

Analysis of Variance↗
PubMed2001

Simvastatin reduces reperfusion injury by modulating nitric oxide synthase expression: an ex vivo study in isolated working rat hearts.

OBJECTIVE: We tested the hypothesis of beneficial effects of the 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA)-reductase inhibitor simvastatin in a model of ischemia-reperfusion, and investigated potential mechanisms. METHODS: Isolated working rat hearts were subjected to 15 min global ischemia and 22-180 min reperfusion in the presence or absence of simvastatin (10-100 microM). We evaluated creatinephosphokinase and nitrite levels in coronary effluent, heart weight changes, microvascular permeability (extravasation of fluoresceine-labeled albumin), ultrastructural alterations, and the expression of endothelial (e) and inducible (i) nitric oxide synthase (NOS) (by reverse-transcribed polymerase chain reaction and Western blotting) in the presence or absence of the transcriptional inhibitor actinomycin-D. RESULTS: Simvastatin (25 microM) significantly reduced myocardial damage and vascular hyperpermeability, concomitant with a reduction in endothelial and cardiomyocyte lesions. Protection became less evident at 50 microM and reverted to increased damage at 100 microM. At 25 microM, simvastatin significantly increased eNOS mRNA and protein compared with untreated hearts, probably due to a post-transcriptional regulation since unaltered by animal pretreatment with actinomycin D. Simvastatin also significantly decreased iNOS mRNA and protein, as well as nitrite production after ischemia-reperfusion. The addition of the NOS inhibitor N(pi)-nitro-L-arginine methylester (L-NAME, 30 microM) to 25 microM simvastatin-treated hearts significantly reduced cardioprotection against ischemia-reperfusion. CONCLUSIONS: In this model, in the absence of perfusing granulocytes, the acute administration of a pharmacologically relevant simvastatin concentration reduces ischemia-reperfusion injury and prevents coronary endothelial cell and cardiomyocyte damage by cholesterol-independent, NO-dependent mechanisms.

Analysis of Variance↗
PubMed2003

Simvastatin reduces NF-kappaB activity in peripheral mononuclear and in plaque cells of rabbit atheroma more markedly than lipid lowering diet.

OBJECTIVE: To study whether simvastatin reduces inflammation in atherosclerosis beyond its hypolipidemic effects. METHODS: Twenty-four rabbits with induced femoral injury and on an atherogenic diet were randomized to normolipidemic diet (n=9), or to continue the atherogenic diet while receiving simvastatin 5 mg/kg/day (n=9) or no treatment (n=6) for 4 weeks. RESULTS: As compared with no treatment, the normolipidemic diet significantly reduced lipid levels, while simvastatin produced nonsignificant reductions. In spite of this, NF-kappaB binding activity in peripheral mononuclear cells was reduced in the simvastatin group [2,958+/-5,123 arbitrary units (a.u.)] as compared with no treatment (49,267+/-20,084 a.u.; P<0.05) and normolipidemic groups (41,492+/-15,876 a.u.; P<0.05) (electrophoretic mobility shift assay). NF-kappaB activity in the atherosclerotic lesions was also reduced by simvastatin as compared to nontreated animals (4,108+/-3,264 vs. 8,696+/-2,305 nuclei/mm(2); P<0.05), while the normolipidemic diet induced only a nonsignificant diminution (P>0.05) (Southwestern histochemistry). Similarly, simvastatin decreased macrophage infiltration (4.6+/-12 vs. 19+/-12% of area staining positive; P<0.05) and the expression of interleukin-8 (24+/-12 vs. 63+/-21%; P<0.05) and metalloproteinase-3 (16+/-3 vs. 42+/-28%; P<0.05) (immunohistochemistry), while the reduction achieved by normolipidemic diet in all these parameters was again nonsignificant (P>0.05). CONCLUSIONS: These findings suggest that simvastatin reduces inflammation in atherosclerotic plaques and in blood mononuclear cells more than expected for the lipid reduction achieved.

Animals↗
PubMed2001

Effect of simvastatin on vascular smooth muscle responsiveness: involvement of Ca(2+) homeostasis.

This report is focused on the study of simvastatin-induced relaxation of rat aorta through its effects on vascular smooth muscle and Ca(2+) signalling. The presence of endothelium affected only the simvastatin-induced relaxation of aortic rings precontracted with noradrenaline, but not by depolarization with KCl 80 mM. Blockade of Ca(2+) entry through voltage-operated Ca(2+) channels (VOCCs) by diltiazem abolished the endothelium-dependent and direct relaxation, whereas Ca(2+)-ATPase inhibition by cyclopiazonic acid (3 x 10(-5) M) only affected the endothelium-dependent relaxation. In KCl-depolarised arteries concentration-response curves for CaCl(2) were shifted to the right in the presence of simvastatin (3 x 10(-6) and 3 x 10(-5) M) or diltiazem (10(-6) and 10(-7) M). The transient contraction caused by noradrenaline in Ca(2+)-free medium, which is mainly due to intracellular Ca(2+) release, was inhibited by simvastatin (3 x 10(-5) M) or cyclopiazonic acid (3 x 10(-5) M) and the contraction induced by CaCl(2) (2 x 10(-3) M) added after noradrenaline was inhibited by diltiazem and simvastatin. All the reported effects of simvastatin were inhibited by the product of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, mevalonate (10(-3) M). These findings demonstrate that the vascular effects of simvastatin may involve both Ca(2+) release from intracellular stores, which could promote activation of endothelial factors, and blockade of extracellular Ca(2+) entry, which promote relaxations independent of the presence of endothelium. This action on Ca(2+) could be related to the inhibition of isoprenoid synthesis, which subsequently affects the function of G-proteins involved in communication among intracellular Ca(2+) pools and capacitative Ca(2+) entry.

Animals↗
PubMed2003

Efficacy of fenofibrate and simvastatin on endothelial function and inflammatory markers in patients with combined hyperlipidemia: relations with baseline lipid profiles.

Given that combination therapy with statin plus fibrate confers a risk of myopathy, it is worthwhile to determine whether statin or fibrate monotherapy is associated with greater clinical benefit in individuals with combined hyperlipidemia. In this randomized double-blind study, we compared the efficacy of simvastatin and fenofibrate on indexes of endothelial function (flow-mediated dilation (FMD) of the brachial artery) and inflammatory markers (plasma high-sensitivity C-reactive protein (CRP), interleukin-1 beta (IL-1 beta), soluble CD40, and soluble CD40 ligand (sCD40L) levels), as surrogate indicators of future coronary heart disease (CHD), in patients with combined hyperlipidemia. A total of 70 patients with plasma triglyceride levels between 200 and 500 mg/dl and total cholesterol levels of >200 mg/dl were randomly assigned to receive either simvastatin (20 mg/day) (n=35) or micronized fenofibrate (200 mg/day) (n=35) for 8 weeks. Treatment with simvastatin was associated with significantly greater reduction of total cholesterol and low-density lipoprotein cholesterol (LDL-C), while the decrease in triglycerides was significantly greater in patients receiving fenofibrate. Both fenofibrate and simvastatin markedly reduced plasma levels of high-sensitivity CRP, IL-1 beta, and sCD40L, and improved endothelium-dependent FMD without mutual differences. The changes in plasma inflammatory markers did not correlate with baseline clinical characteristics in both groups. However, the improvement in FMD with fenofibrate treatment correlated inversely with baseline high-density lipoprotein cholesterol (HDL-C) levels, whereas the improvement in FMD with simvastatin treatment was positively related to HDL-C levels. Accordingly, in the subgroup with a baseline HDL-C of < or =40 mg/dl, only fenofibrate significantly improved the endothelium-dependent FMD. On the other hand, in the subgroup with HDL-C >40 mg/dl, only treatment with simvastatin achieved significant improvement in FMD. The data here indicate that in patients with combined hyperlipidemia, both fenofibrate and simvastatin have comparative beneficial effects on various inflammatory markers and differential beneficial effects on endothelial function according to baseline HDL-C levels. These findings should be validated by additional prospective studies, in which patients are stratified by baseline HDL-C prior to randomization.

C-Reactive Protein↗
PubMed1997

A comparative study of the efficacy of simvastatin and gemfibrozil in combined hyperlipoproteinemia: prediction of response by baseline lipids, apo E genotype, lipoprotein(a) and insulin.

Combined hyperlipoproteinemia (CHL) can be difficult to treat because of the heterogeneous nature of the lipoprotein abnormalities. We compared the relative efficacies of simvastatin and gemfibrozil and sought predictors of responsiveness in terms of the baseline lipids and other potential metabolic determinants (plasma insulin, Lp(a) and apo E genotype). Sixty-six subjects entered a cross-over, randomized trial involving 12 weeks on each drug. Efficacy was assessed after 6 and 12 weeks on each treatment. Simvastatin lowered total cholesterol 24%, triglycerides 12%, LDL cholesterol 33%, raised HDL cholesterol 13% and substantially reduced the cholesterol:triglyceride ratio in VLDL and IDL. Gemfibrozil lowered total cholesterol 5%, triglycerides 44%, raised HDL 26% and reduced VLDL and IDL lipids more than simvastatin did. LDL size increased with both treatments and HDL size increased with simvastatin. Responsiveness (25% fall in cholesterol or 40% fall in triglycerides) was shown by 31/61 subjects when taking simvastatin (cholesterol-lowering) and by 44/60 taking gemfibrozil (triglyceride-lowering). Responsiveness was greatest in those with apo E2 genotype with both drugs (P < 0.05). Unexpectedly, responders to simvastatin tended to have lower baseline total cholesterol but higher triglyceride levels than those whose cholesterol or triglyceride was lowered by gemfibrozil. Nevertheless, more hypercholesterolemic subjects responded to simvastatin and more hypertriglyceridemic subjects to gemfibrozil. Lp(a) (P = 0.04) and plasma insulin concentrations (P = 0.03) were negative predictors of percentage triglyceride-lowering with gemfibrozil. The difference between the two drugs in triglyceride-lowering lessened with rising insulin and falling HDL cholesterol. Thus, the responsiveness to the two major classes of lipid lowering drugs can be partly predicted from baseline lipids and related metabolic parameters.

Anticholesteremic Agents↗
PubMed1998

Effects of atorvastatin monotherapy and simvastatin plus cholestyramine on arterial endothelial function in patients with severe primary hypercholesterolaemia.

Endothelial dysfunction is an important early event in atherogenesis. Changes in arterial endothelial physiology were studied in patients with severe primary hypercholesterolaemia participating in an ongoing clinical trial evaluating atorvastatin and simvastatin. Endothelial function was assessed non-invasively using brachial ultrasound and the primary outcome measure was flow-mediated endothelium-dependent dilatation (FMD) in response to reactive hyperaemia. Patients were studied upon entry while still using simvastatin 40 mg daily and again after a 10-week washout (baseline). Over the next 30 weeks, 20 patients received atorvastatin titrated up to 80 mg daily and 12 patients received simvastatin titrated up to 40 mg daily (plus cholestyramine 4 g daily in 10/12), followed by a final ultrasound study. During simvastatin washout, total and low density lipoprotein (LDL) cholesterol rose by a median 23-29% and 30-34%, respectively. During atorvastatin therapy, total and LDL cholesterol fell by a median of 41 and 46%, respectively, triglycerides fell by 45%, and high density lipoprotein (HDL) cholesterol rose by 10%. During simvastatin plus cholestyramine therapy, the respective median changes were - 32, - 39, - 44 and + 11%. Patients at baseline showed evidence of impaired FMD and this improved significantly on either treatment, from a median + 2.2 to + 5.5% on atorvastatin and from + 1.8 to + 4.5% on simvastatin plus cholestyramine (P < 0.01 for both treatments). Typical response in healthy subjects would be from + 8 to + 9%. FMD at baseline was correlated with HDL cholesterol (r=0.49, P < 0.01). Change in FMD was inversely correlated with baseline FMD (r=-0.54, P < 0.001). Endothelial dysfunction in primary hypercholesterolaemia was improved by treatment with atorvastatin or simvastatin plus cholestyramine and this effect may result in the prevention of future coronary events.

Adult↗
PubMed2000

Inhibition of tissue-factor-mediated thrombin generation by simvastatin.

A previous study has shown that simvastatin reduces in vivo clotting activation and monocyte tissue factor (TF) expression. This effect, however, was only in part attributable to the reduction of serum cholesterol, suggesting that more than one mechanism may be involved. Furthermore, it was not investigated if the inhibition of clotting activation was dependent upon the reduced expression of monocyte TF. In order to assess if simvastatin directly affects clotting activation, we developed an in vitro method in which clotting system is activated by monocytes stimulated with LPS. Monocytes were prepared from blood taken from healthy volunteers or patients with hypercholesterolemia and incubated with heparinized plasma plus either simvastatin (0.01-10 microM) or medium as control. Samples were then stimulated with LPS (4 microg/ml) and after 6 h the rate of thrombin generation, assessed by prothrombin fragment (F) 1+2, was measured. In separate experiments, we measured the expression of TF by monocytes which were incubated with simvastatin and then stimulated with LPS. The study showed that compared to control, LPS-stimulated monocytes induced abundant formation of F1+2, which was inhibited by simvastatin in a dose-dependent manner. Simvastatin also inhibited dose dependently the monocyte expression of TF. This study suggests that simvastatin inhibits the rate of thrombin generation by directly interfering with the monocyte expression of TF.

Cells, Cultured↗