Weeks Of Simvastatin Treatment Research Articles

PHOSPHO1 Gene DNA Methylations are Associated with a Change in HDL-C Response to Simvastatin Treatment.

Our aim was to detect the effects of DNA methylations in the phosphoethanolamine/ phosphocholine phosphatase (PHOSPHO1) gene on the therapeutic efficacy of simvastatin. We used an extreme sampling approach by selecting 211 individuals from approximately the top and bottom 15% of adjusted lipid-lowering response residuals to simvastatin (n=104 for the high response group and n=107 for the low response group) from a total of 734 subjects with hyperlipidemia. They received a daily oral dose of 20 mg simvastatin for eight consecutive weeks. DNA methylation loci at the PHOSPHO1 gene were measured using high-throughput next-generation sequencing-based sequencing technology. Fasting serum lipids were measured at baseline and after eight weeks of simvastatin treatment. Mean PHOSPHO1 DNA methylation had a significant negative correlation with high-density lipoprotein cholesterol (HDL-C) variation (β=-0.014, P=0.045) in the high response group. After stratifying by body mass index (BMI), the associations between the PHOSPHO1 DNA methylations and the change in HDL-C in response to simvastatin were more significant in obese subjects with a BMI of 25 kg/m2 or higher (β=-0.027, P=0.002). Mean PHOSPHO1 methylation and traditional predictors could explain up to 24.7% (adjusted R2) of the change in HDL-C response in obese patients. There was a statistically significant additive interaction term (P=0.028) between BMI and mean PHOSPHO1 methylation in the model of the change in HDL-C in response to simvastatin. Our findings suggest that PHOSPHO1 DNA methylations are associated with a change in HDL-C in response to simvastatin treatment, and this association is especially dependent on the extent of patient obesity.

Validation of a pharmacological model for mitochondrial dysfunction in healthy subjects using simvastatin: A randomized placebo-controlled proof-of-pharmacology study

Proof-of-pharmacology models to study compounds in healthy subjects offer multiple advantages. Simvastatin is known to induce mitochondrial dysfunction at least partly by depletion of co-enzyme Q10. The goal of this study was to evaluate a model of simvastatin-induced mitochondrial dysfunction in healthy subjects and to determine whether mitochondrial dysfunction could be pharmacologically reversed by treatment with co-enzyme Q10 (ubiquinol).Subjects received simvastatin 40mg/day for 8 weeks. After 4 weeks, subjects were randomized to receive ubiquinol 300mg/day or placebo in a double-blinded fashion. Mitochondrial function was assessed by measuring the phosphocreatine recovery time (τ-PCr) using phosphorous Magnetic Resonance Spectroscopy (31P-MRS) after in-magnet exercise.After 4 weeks of simvastatin treatment, τ-PCr prolonged with 15.2% compared to baseline, (95%CI, 2.5–29.4%; P = 0.018, Fig. 3). After 8 weeks, τ-PCr further prolonged to 37.27s in the placebo group (prolongation of 18.5% compared to baseline, still significantly prolonged, 95%CI, 1.1–38.9%; P = 0.037), but shortened to 33.81s in the ubiquinol group (prolongation of 9.1% compared to baseline, no longer significantly prolonged, 95%CI, −7.9 to 29.2%; P = 0.31). At 8 weeks, there was no significant difference between groups (difference of 8.2%, 95%CI, −14.5 to 37.0%; P = 0.51).Simvastatin induces subclinical mitochondrial dysfunction in healthy subjects, which can be partly reversed by treatment with ubiquinol. This model of pharmacologically induced and reversed mitochondrial dysfunction can be used to study the effects of compounds that enhance mitochondrial function in healthy subjects.

Pharmacometabolomic signature links simvastatin therapy and insulin resistance.

Statins, widely prescribed drugs for treatment of cardiovascular disease, inhibit the biosynthesis of low density lipoprotein cholesterol (LDL-C). Despite providing major benefits, sub populations of patients experience adverse effects, including muscle myopathy and development of type II diabetes mellitus (T2DM) that may result in premature discontinuation of treatment. There are no reliable biomarkers for predicting clinical side effects in vulnerable individuals. Pharmacometabolomics provides powerful tools for identifying global biochemical changes induced by statin treatment, providing insights about drug mechanism of action, development of side effects and basis of variation of response. To determine whether statin-induced changes in intermediary metabolism correlated with statin-induced hyperglycemia and insulin resistance; to identify pre-drug treatment metabolites predictive of post-drug treatment increased diabetic risk. Drug-naïve patients were treated with 40 mg/day simvastatin for 6 weeks in the Cholesterol and Pharmacogenetics (CAP) study; metabolomics by gas chromatography-time-of-flight mass-spectrometry (GC-TOF-MS) was performed on plasma pre and post treatment on 148 of the 944 participants. Six weeks of simvastatin treatment resulted in 6.9% of patients developing hyperglycemia and 25% developing changes consistent with development of pre-diabetes. Altered beta cell function was observed in 53% of patients following simvastatin therapy and insulin resistance was observed in 54% of patients. We identified initial signature of simvastatin-induced insulin resistance, including ethanolamine, hydroxylamine, hydroxycarbamate and isoleucine which, upon further replication and expansion, could be predictive biomarkers of individual susceptibility to simvastatin-induced new onset pre-type II diabetes mellitus. No patients were clinically diagnosed with T2DM. Within this short 6 weeks study, some patients became hyperglycemic and/or insulin resistant. Diabetic markers were associated with decarboxylated small aminated metabolites as well as a branched chain amino acid directly linked to glucose metabolism and fatty acid biosynthesis. Pharmacometabolomics provides powerful tools for precision medicine by predicting development of drug adverse effects in sub populations of patients. Metabolic profiling prior to start of drug therapy may empower physicians with critical information when prescribing medication and determining prognosis.

Influence of simvastatin on dopaminergic neurons of lipopolysaccharide-induced rat model of Parkinson's disease.

To investigate the neuroprotective effects of simvastatin on lipopolysaccharide (LPS)-induced rat model of Parkinson's disease (PD) and the mechanisms involved. Hemiparkinsonian rat models were induced by stereotaxieal injection of LPS in the right substantia nigra compacta. After 2 weeks of simvastatin treatment, rotational behavior test was performed after the intraperitoneal injection of apomorphine. Expression of tyroxine hydroxylase (TH) and glial fibrillary acidic protein were analyzed through immunohistochemical staining of substantia nigra and striatum, and the level of TNF- α was evaluated using enzyme-linked immunosorbent assay. Comparing with untreated group, behavioral symptoms of the rats were significantly less in the rats that received simvastatin treatment. The TH positive cell count in substantia nigra and striatum were significantly increased (P<0.05) and TNF- α expression was significantly decreased (P<0.05) in simvastatin group compared to untreated group. Simvastatin could effectively inhibit the activation of astrocytes, reduce TNF- α expression, and exert anti-inflammatory effects, and thus protect the dopaminergic neurons in substantia nigra and striatum of the rat model of PD.

The effects of improved metabolic risk factors on bone turnover markers after 12 weeks of simvastatin treatment with or without exercise

ObjectiveEmerging evidence supports an association between metabolic risk factors and bone turnover. Statins and exercise independently improve metabolic risk factors; however whether improvements in metabolic risk factor affects bone turnover is unknown. The purpose of the present study was to: 1) evaluate the relationship between metabolic risk factors and bone turnover; and 2) determine if improvements in metabolic risk factors after 12weeks of statin treatment, exercise or the combination affect bone turnover. MethodsFifty participants with ≥2 metabolic syndrome defining characteristics were randomly assigned to one of three groups: statin (STAT: simvastatin, 40mg/day), exercise (EX: brisk walking and/or slow jogging, 45minutes/day, 5days/week), or the combination (STAT+EX). Body composition and whole body bone mineral density were measured with dual energy X-ray absorptiometry. Serum markers of bone formation (bone specific alkaline phosphatase, BAP; osteocalcin, OC), resorption (C-terminal peptide of type I collagen, CTX) and metabolic risk factors were determined. Two-factor (time, group) repeated-measures ANCOVA was used to examine changes of metabolic risk factors and bone turnover. General linear models were used to determine the effect of pre-treatment metabolic risk factors on post-treatment bone turnover marker outcomes. ResultsParticipants with ≥4 metabolic syndrome defining characteristics had lower pre-treatment OC than those with 3 or fewer. OC was negatively correlated with glucose, and CTX was positively correlated with cholesterol. STAT or STAT+EX lowered total and LDL cholesterol. The OC to CTX ratio decreased in all groups with no other significant changes in bone turnover. Higher pre-treatment insulin or body fat predicted a greater CTX reduction and a greater BAP/CTX increase. ConclusionMetabolic risk factors were negatively associated with bone turnover markers. Short-term statin treatment with or without exercise lowered cholesterol and all treatments had a small effect on bone turnover.

Hemostatic effects of simvastatin in subjects with impaired fasting glucose

The aim of our study was to compare the effect of simvastatin on a range of hemostatic variables in subjects with impaired fasting glucose (IFG) and isolated hypercholesterolemia. We enrolled 28 subjects with IFG, 25 primary hypercholesterolemic patients and 24 age-, sex- and weight-matched control subjects with normal lipid profile and glucose metabolism. The tested parameters (lipid profile, fasting and 2-h post-glucose load plasma glucose levels, the homeostasis model assessment (HOMA) ratio, glycated hemoglobin, the prothrombin and partial thromboplastin time, plasma fibrinogen, PAI-1 levels and factor VII coagulant activity) were determined at baseline and after 4 and 12 weeks of simvastatin treatment (20mg/daily). Compared to the control subjects, hypercholesterolemic and IFG patients exhibited increased plasma levels of fibrinogen and PAI-1 and increased factor VII activity. PAI-1 was higher in hypercholesterolemic than in IFG patients. Simvastatin improved lipid profile in both groups of patients, but it did not influence glucose metabolism. In both IFG and hypercholesterolemic patients, simvastatin reduced fibrinogen and PAI-1 levels and factor VII activity, and it prolonged the prothrombin and partial thromboplastin time in a lipid- and glucose-independent manner. The main conclusion of our study is that early glucose metabolism abnormalities are associated with disturbed coagulation and fibrinolysis, which contribute to the development and progression of atherosclerosis. Treatment with a lipid lowering agent may bring multidirectional beneficial effects on hemostasis in IFG patients.

Effects of Simvastatin on Proinflammatory Cytokines and Matrix Metalloproteinases in Hypercholesterolemic Individuals

Statins are potent lipid-lowering drugs but anti-inflammatory effects have also been suggested. Our aim was to investigate the effects of simvastatin on proinflammatory cytokines and matrix metalloproteinases (MMPs). Eighty hypercholesterolemic men were randomized to simvastatin 40 mg or placebo for 6 weeks. Simvastatin treatment significantly reduced C-reactive protein (CRP) levels while interleukin (IL)-6 levels remained unchanged. The ex vivo release of IL-1β and IL-6 was not altered by simvastatin, whereas the release of TNF-α and IL-8 increased after 6 weeks of simvastatin treatment. Similarly, the circulating levels of MMP-3 and TIMP-1 remained unaffected by simvastatin while MMP-9 increased. However, none of the effects except for the CRP reduction within the simvastatin group reached statistical significance when compared to the placebo group. Our findings are in contrast to previous in vitro and animal data and question the in vivo relevance of some of the pleiotropic effects of simvastatin.

The role of dysfunctional HDL in atherosclerosis

This review focuses on HDL function in modulating LDL oxidation and LDL-induced inflammation. Dysfunctional HDL has been identified in animal models and humans with chronic inflammatory diseases including atherosclerosis. The loss of antiinflammatory function correlated with a loss of function in reverse cholesterol transport. In animal models and perhaps in humans, dysfunctional HDL can be improved by apoA-I mimetic peptides that bind oxidized lipids with high affinity.

Intradiscal injection of simvastatin retards progression of intervertebral disc degeneration induced by stab injury

IntroductionEarlier work indicates that the cholesterol-lowering drug, simvastatin, is anabolic to chondrogenic expression of rat intervertebral disc (IVD) cells, which suggests a potential role for simvastatin in IVD regeneration. In this study, we expand on our earlier work to test the effectiveness of simvastatin on disc degeneration utilizing a rat tail disc degeneration model.Methods30 rats that underwent 21 G needle-puncture at rat tail discs were injected with simvastatin-loaded poly(ethylene glycol)-poly(lactic acid-co-glycolic acid)-poly(ethylene glycol) (PEG-PLGA-PEG) gel (5 mg/ml) or vehicle control at 4 weeks after needle injury. All animals were sacrificed 2 weeks after simvastatin injection. Bone morphogenetic protein-2 (BMP-2), aggrecan, collagen type II, and collagen type I messenger ribonucleic acid (mRNA) expression in the rat nucleus pulposus (NP) were measured by real-time polymerase chain reaction (PCR). In vivo magnetic resonance imaging (MRI) was performed to monitor changes in disc degeneration. Rat discs were also assessed by histology using hematoxylin and eosin (H&E) and safranin O staining. In addition, the NP weight, glycosaminoglycan (sGAG) and DNA content were also measured.ResultsA single dose of simvastatin loaded in thermo-sensitive PEG-PLGA-PEG gel injected into the NP had the trend to increase aggrecan expression and sGAG content, and significantly increased mRNA levels of BMP-2, collagen type II, and the differentiation index (the ratio of collagen type II to collagen type I). The decreased NP weight, T2 intensity, as well as MRI index in the rat tail discs induced by needle puncture were significantly reversed after 2 weeks of simvastatin treatment. In addition, simvastatin treatment also improved histological changes induced by needle puncture.ConclusionsA single injection of simvastatin loaded in PEG-PLGA-PEG gel into rat tail discs had the potential to retard or regenerate the degenerative disc.

Macrophage Infiltration, Lectin-Like Oxidized-LDL Receptor-1, and Monocyte Chemoattractant Protein-1 are reduced by Chronic HMG-CoA Reductase Inhibition

Statin reduces cerebrovascular events independent of its cholesterol lowering effect. We hypothesized that statin inhibits early atherosclerotic change in common carotid artery (CCA), and investigated its effect on lectin-like oxidized-LDL receptor-1 (LOX-1) and monocyte chemoattractant protein-1 (MCP-1) expression, both of which are early atherosclerotic markers. Stroke-prone spontaneous hypertensive rats (SHR-SP) of 8 weeks old were orally treated with vehicle or simvastatin (20mg/kg) daily. After 4 weeks of simvastatin or vehicle treatment, or 2 weeks of vehicle and 2 weeks of simvastatin treatment, CCA was removed. LOX-1 and MCP-1 expression as well as macrophage infiltration were histologically investigated. Lipid deposition was also investigated by Sudan III staining. Simvastatin groups showed significantly smaller amount of lipid deposition and LOX-1 and MCP-1 expression, independent of serum lipid levels. Macrophage infiltration was also decreased. Reduction of cerebrovascular events by statins may be brought by the direct inhibition of atherosclerotic change.

Proteomic Study of Plasma from Moderate Hypercholesterolemic Patients

Proteomics is a technology to detect and identify several proteins and their isoforms in a single sample. We used proteomics to analyze modifications in the protein map of plasma after simvastatin treatment of moderate hypercholesterolemic patients. Plasma from hypercholesterolemic patients (n = 9) was compared before and after 12 weeks of simvastatin treatment (40 mg/day). Patients with similar cardiovascular risk factors were used as controls (CR group). By using two-dimensional electrophoresis and mass spectrometry, we identified the different protein isoforms. The plasma expression of three fibrinogen gamma chain isoforms (FGG) was enhanced, whereas the expression of two isoforms of the fibrinogen beta chain (FGB) was reduced in the hypercholesterolemic patients compared with the CR group. The expression of apolipoprotein A-IV and three haptoglobin isoforms was higher in hypercholesterolemic patients. Simvastatin treatment modified the plasma expression of FGG chain isoform 1, FGB chain isoforms 1 and 2, vitamin D binding protein isoform 3, apo A-IV, and haptoglobin isoform 2. The modification of FGG chain isoform 1 and FGB chain isoforms 1 and 2 was positively correlated with total plasma cholesterol level. Proteomic analysis of plasma may help to know more in depth the molecular mechanism modified by simvastatin treatment.

Simvastatin Versus Ezetimibe

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. 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. 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.

Impact of simvastatin on hemostatic and fibrinolytic regulators in Type 2 diabetes mellitus

Simvastatin, a widely used 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor, effectively reduced cardiac death and ischemic events in patients with coronary heart disease (CHD) and diabetes mellitus (DM). The mechanism of cardiovascular benefits of statins in DM remains unclear. We examined how simvastatin influences the levels of several in vivo markers for coagulation and fibrinolysis in 26 Type 2 DM patients. The diabetic patients received 20 mg/day of simvastatin up to 12 months. The levels of total cholesterol (TC), low density lipoprotein–cholesterol (LDL-c) and triglycerides in peripheral circulation of patients were significantly reduced after ≥6 weeks of simvastatin treatment. Levels of prothrombin fragment 1 + 2 (F1 + 2), factor VII, plasminogen activator inhibitor-1 (PAI-1) and tissue factor pathway inhibitor (TFPI) antigens, but not tissue plasminogen activator (tPA) antigen, in the pre-simvastatin plasmas of the diabetic patients were significantly higher than the levels found in plasmas of healthy subjects. Significant reductions in F1 + 2 and PAI-1 levels were evident ≥6 weeks after the diabetic patients received simvastatin. Levels of total tPA, TFPI, FVII, hemoglobin A1c, fasting blood glucose, and insulin in the diabetic patients’ plasma were not significantly altered by simvastatin treatment. Positive correlations were found between PAI-1 versus TC, PAI-1 versus LDL-c, and FVII versus triglycerides in the plasmas of simvastatin-treated patients. The results suggest that simvastatin reduces in vivo prothrombinase activity and PAI-1 levels in type 2 DM patients. These actions may contribute to the protective properties of simvastatin against ischemic events in diabetic patients.

Efficacy and safety of simvastatin in Asian and non-Asian coronary heart disease patients: a comparison of the GOALLS and STATT studies

SUMMARYBackground: Asians are thought to be more responsive to the lipid-lowering effects of statins than non-Asians although there are no head-to-head trials that examine this perception.Objective: To compare the results of the GOALLS and STATT studies that used similar titrate-to-goal protocols with 20 mg up to 80 mg simvastatin in Asian and non-Asian coronary heart disease (CHD) patients.Methods: GOALLS (N = 198; included non-Asians and Asians) and STATT (N = 133; included Asians only) were both multi-center, open-label 14-week studies in CHD patients with serum low density lipoprotein cholesterol (LDL-C) levels 115 mg/dL–180 mg/dL and triglycerides (TG) levels ≤ 400 mg/dL. Simvastatin was titrated from 20 mg/day up to 80 mg/day in order to achieve the National Cholesterol Education Program (NCEP) LDL-C target ≤ 100 mg/dL. The primary efficacy variable was the percentage of patients attaining the NCEP LDL-C target at Week 14. Secondary endpoints included proportion of patients achieving the European Society of Cardiology/European Atherosclerosis Society/European Society of Hypertension (European) LDL-C target ≤ 115 mg/dL at Week 14 and percentage change in lipid parameters. Safety and tolerability were assessed by monitoring adverse experiences and safety laboratory tests. Fifteen Asian patients were part of the GOALLS cohort and their data were compared separately with results of non-Asians from GOALLS and Asians from the STATT study.Results: After 14 weeks of simvastatin treatment, 87.1% of GOALLS non-Asians, 85.7% of GOALLS Asians, and 78.2% of STATT patients attained the NCEP LDL-C target. At Week 14, 94.4%, 92.9%, and 91.7% of the GOALLS non-Asians, GOALLS Asians, and STATT patients achieved the European LDL-C target, respectively. The average treatment doses to attain NCEP and European targets were comparable among groups. The percentage reductions in lipid parameters from baseline to week 14 were similar among groups except, changes in high density lipoprotein cholesterol and apolipoprotein A-I favored Asian subjects. There was also a greater reduction in TG in the STATT study, but this was not consistent with TG reductions experienced by Asians in the GOALLS study. In both studies, simvastatin was generally well tolerated by all patients across the dosage range of 20 mg–80 mg. No cases of rhabdomyolysis or myopathy were reported in either study.Conclusions: A great majority of CHD patients is able to achieve LDL-C treatment goals (up to 90%) on simvastatin regardless of racial background. Simvastatin treatment at doses of 20 mg–80 mg is well-tolerated in Asian and non-Asian CHD patients. This side-by-side comparison provides evidence that Asian and non-Asian CHD populations respond similarly to comparable doses of simvastatin.

Simvastatin inhibits expression of tissue factor in advanced atherosclerotic lesions of apolipoprotein E deficient mice independently of lipid lowering: potential role of simvastatin-mediated inhibition of Egr-1 expression and activation

Recent studies suggest that the beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) in reducing cardiovascular events may in part, be independent of their capacity to lower plasma lipids. To test this hypothesis, simvastatin (50 mg/kg/d) was administered to 30-week-old apolipoprotein E deficient mice (apo E−/−) for 12, 18 and 24 weeks. In contrast to other experimental models and humans, simvastatin treatment increases plasma cholesterol levels in apo E−/− mice. Quantitative real-time polymerase chain reaction was used to quantify expression of tissue factor (TF) and monocyte chemoattractant protein-1 (MCP-1) in the aorta of each mouse. Expression of TF was reduced to 34, 24, and 13% of control levels at 12, 18 and 24 weeks, respectively, of simvastatin administration. Advanced lesions in the innominate arteries of the simvastatin treated mice had reduced levels of TF, fewer macrophages and reduced expression of early growth response-1 (Egr-1). In vitro studies in mouse macrophages demonstrated decreased lipopolysaccharide induced binding of nuclear proteins to the Egr-1 consensus DNA sequence following pretreatment with simvastatin. RNA levels for MCP-1 were reduced to 30% of control values following 24 weeks of simvastatin treatment. In conclusion, these data suggest that chronic administration of simvastatin to older apo E−/− mice can inhibit the expression of pro-thrombotic/pro-inflammatory genes within established atherosclerotic lesions via mechanisms that are independent of reductions in plasma lipids.

The Change of Cholesterol Level and IL-6, CRP in Unstable Angina Patients with Hypercholesterolemia after Low Dose Simvastatin Therapy

Background and Objectives：Cardiovascular mortality in patients with atherosclerosis can be reduced by treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase inhibitors. This proven effect is probably due, not only to the cholesterol lowering effect, but also to the non-lipid-lowering mechanisms elicited by the action of statins. These results, however, were achieved with high or usual doses of statin therapy, whereas similar results with low dose statins are rare. The aims of this study wereas to investigate the changes ofin cholesterol level and the inflammatory markers, Interleukin-6 (IL-6, and C-Reactive protein (CRP, in unstable angina patients with hypercholesterolemia, using low dose simvastatin therapy. Subjects and Methods：Eighteen unstable angina patients (55±6 years, M：F＝10：8, Baunwald class IIIb with hypercholesterolemia (a LDL-cholesterol level over 100 mg/dLwere evaluated. A Llow dose of simvastatin (5 mg was administrated for 4 weeks. The changes of total cholesterol, LDL-cholesterol, triglyceride, HDL-cholesterol and the inflammatory markers, IL-6, and CRP, were all elevated from the baseline following 4 weeks of treatment. Results：The baseline mean values of total cholesterol, LDL-cholesterol, triglyceride, and HDL-cholesterol were 237.1±56.9 mg/dL, 131.9±39.0 mg/dL, 168.3±20.4 mg/dL, and 50.0±3.8 mg/dL, respectively. The baseline mean values of IL-6 and hs CRP were 6.842±6.661 pg/mL, and 0.866±1.083 mg/dL, respectively. Following the 4 weeks of simvastatin treatment, the levels of total cholesterol, LDL- cholesterol, triglyceride, and HDL-cholesterol were 200.8±47.5 mg/dL, 101.6±35.4 mg/dlL, 155.8±18.6 mg/dL, and 47.0±2.3 mg/dL, respectively, giving percentage changes of -17.6% (p 0.05, and -2.1% (p>0.05, respectively. Following the 4 weeks of treatment, the levels of IL-6 and hs CRP were 6.955±5.555 pg/mL, and 0.753±0.571 mg/dL, respectively, giving percentage changes of 51.8 (p>0.05, and 36.5% (p>0.05, respectively. There was no significant correlation between the level of LDL-cholesterol and the levels of IL-6, or hs CRP at the baseline, or post-treatment. There was also no significant correlation between the change of LDL-cholesterol and the changes of IL-6 or hs CRP levels during the simvastatin therapy. There was no significant correlation between the levels of IL-6 and hs CRP at the baseline or ost-treatment. Conclusion：Our data showed that in patients with unstable

The effect of Simvastatin on the plasma antioxidant concentrations in patients with hypercholesterolaemia

The aim of the study was to monitor the antioxidant status of patients with hypercholesterolaemia during treatment with Simvastatin. Forty-seven patients, of whom 25 had confirmed familial hypercholesterolaemia (FH), were treated with 10 or 20 mg of Simvastatin per day for 14 weeks. As expected, total cholesterol and LDL cholesterol concentrations decreased considerably, while HDL cholesterol concentrations increased during drug treatment. In neither FH nor non-FH patients were any significant changes observed for retinol status, while plasma vitamin C concentrations were also not adversely affected by the drug therapy. In both patient groups Simvastatin therapy led to a significant decrease in plasma α-tocopherol ( P<0.05) concentrations, however, the α-tocopherol/total cholesterol ratio increased by 9.1 ( P<0.01) and 12.1% ( P<0.01) in FH and non-FH patients, respectively, during the 14-week treatment period. The coenzyme Q 10/total cholesterol ratio did not change significantly in non-FH patients, but was significantly lower ( P<0.05) than the baseline ratio after 4 and 14 weeks of Simvastatin treatment in FH patients. The α-tocopherol/total cholesterol ratio of FH patients remained consistently and significantly lower ( P<0.01) compared with non-FH patients, indicating that LDL from the former group may be more vulnerable to free radical-mediated damage and lipid peroxidation. Our results suggest that the significant decline in circulating α-tocopherol and coenzyme Q 10 concentrations was mainly a function of the decrease in serum total cholesterol concentrations.

Decreases in serum ubiquinone concentrations do not result in reduced levels in muscle tissue during short-term simvastatin treatment in humans*

Statins, which are commonly used drugs for hypercholesterolemia, inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. Important nonsterol compounds, such as ubiquinone, are also derived from the same synthetic pathway. Therefore it has been hypothesized that statin treatment causes ubiquinone deficiency in muscle cells, which could interfere with cellular respiration causing severe adverse effects. In this study we observed decreased serum levels but an enhancement in muscle tissue ubiquinone levels in patients with hypercholesterolemia after 4 weeks of simvastatin treatment. These results indicate that ubiquinone supply is not reduced during short-term statin treatment in the muscle tissue of subjects in whom myopathy did not develop.

Plasma lipoproteins in familial dysbetalipoproteinemia associated with apolipoproteins E2(Arg158--&gt;Cys), E3-Leiden, and E2(Lys146--&gt;Gln), and effects of treatment with simvastatin.

Using a density-gradient ultracentrifugation technique, we analyzed in detail the plasma lipoprotein profiles of 18 patients with familial dysbetalipoproteinemia (FD) who had apolipoprotein (apo) E2(Arg158-->Cys) homozygosity (the E2-158 variant, n = 6), apoE3-Leiden heterozygosity (the E3-Leiden variant, n = 6), or apoE2(Lys146-->Gln) heterozygosity (the E2-146 variant, n = 6), with average plasma cholesterol concentrations of 8.99 +/- 1.34 mmol/L, 9.29 +/- 1.55 mmol/L, and 8.46 +/- 1.10 mmol/L, respectively. No significant differences in sex, age, body mass index, dietary habits, and standard laboratory tests between the three groups were observed. The lipoprotein profiles of all FD patients were characterized by higher concentrations of very-low-density lipoprotein (VLDL) 1, VLDL2, and intermediate-density lipoprotein (IDL) and a higher cholesteryl ester content of VLDL1 and VLDL2 than in 6 normolipidemic control subjects with an average plasma cholesterol concentration of 5.90 +/- 0.53 mmol/L. Major differences between the plasma lipoprotein profiles of patients with the E2-158 variant, the E3-Leiden variant, and the E2-146 variant and the normolipidemic control subjects were in IDL cholesterol concentration (1.70 +/- 0.26, 1.50 +/- 0.26, 1.05 +/- 0.36, and 0.47 +/- 0.14 mmol/L, respectively), LDL cholesterol concentration (1.83 +/- 0.50, 3.09 +/- 0.32, 3.79 +/- 0.76, and 3.77 +/- 0.56 mmol/L, respectively), and the molar ratio of IDL cholesterol to LDL cholesterol (0.98 +/- 0.28, 0.48 +/- 0.04, 0.28 +/- 0.09, and 0.12 +/- 0.03, respectively). After 10 weeks of simvastatin treatment the concentrations of plasma cholesterol, VLDL2 cholesterol, IDL cholesterol, and LDL cholesterol in 3 patients with the E2-158 variant fell significantly, by 46%, 56%, 53%, and 48%, respectively; they also fell in 3 patients with the E3-Leiden variant, by 48%, 54%, 57%, and 52%, respectively, and in 3 patients with the E2-146 variant, by 38%, 55%, 46%, and 35%, respectively. Simvastatin therapy lowered plasma activity of cholesteryl ester transfer protein but had no significant effect on plasma activity of lecithin:cholesterol acyltransferase. It is concluded that patients with FD due to various apoE variants have different lipoprotein profiles, mainly with regard to IDL and LDL levels, although they have a number of similar features of dysbetalipoproteinemia. Simvastatin therapy effectively reduced the plasma concentrations of total cholesterol, VLDL2 cholesterol, IDL cholesterol, and LDL cholesterol in the three groups of patients studied. It is proposed that apoE-dependent defects of the conversion of IDL to LDL may be an important mechanism in the pathophysiology of FD.

Long-term treatment with simvastatin in hypercholesterolemic non-insulin-dependent diabetic patients

Patients with non-insulin-dependent diabetes mellitus (NIDDM) show a high risk for coronary heart disease and frequently exhibit lipid and lipoprotein abnormalities. The efficacy and safety of simvastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, were evaluated in 13 NIDDM patients (10 women and 3 men, aged 54 to 70 years, 11 on diet and 2 on oral hypoglycemic agents) with high plasma cholesterol levels (297 ± 27 mg/dl, mean ± SD) and normal triglyceride levels (181 ± 62 mg/dl). The patients received placebo for 6 weeks and simvastatin (up to 23 ± 10 mg/day) over 24 weeks. Nine patients continued the simvastatin treatment for 48 weeks with 13 ± 5 mg/day. Cholesterol and triglyceride levels in plasma and in lipoprotein fractions, isolated by preparative ultracentrifugation at density = 1.006 gm/ml, were measured before and after placebo, and after 6, 12, 18, 24, and 48 weeks of simvastatin treatment. Apoprotein (apo) AI and B determinations were also performed in plasma. Body mass index, fasting plasma glucose, C peptide before and after glucagon, and HbA 1c did not change during the study period. Simvastatin reduced plasma cholesterol (31% after 24 weeks and 22% after 48 weeks), low-density lipoprotein cholesterol (37% after 24 weeks and 26% after 48 weeks), and apo B levels (39% after 24 weeks and 27% after 48 weeks). Verylow-density lipoprotein, high-density lipoprotein, and apo AI levels were not affected by treatment. No side effects were reported. Simvastatin appears to be an effective and safe hypocholesterolemic drug in patients with NIDDM.