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At least 1,099 records · Page 61Linked to original sources
PubMed2004

Effect of simvastatin on endothelial function in cardiac syndrome X patients.

Patients with cardiac syndrome X with mild hypercholesterolemia were randomized to placebo (n = 20) or simvastatin 20 mg/day (n = 20). In the simvastatin group, there was a significant (26%; p < 0.0001) decrease in total cholesterol, a 38% (p < 0.0001) decrease in low-density lipoprotein cholesterol levels, and 7% a (p < 0.0001) increase in high-density lipoprotein cholesterol levels, without significant changes in triglyceride levels. Brachial artery flow-mediated dilation increased significantly (52% relative increase, p < 0.0001), and the time to > 1-mm ST-segment depression during stress testing was longer by the end of the study (p < 0.0001).

Aged↗
PubMed2005

Effect of splitting simvastatin tablets for control of low-density lipoprotein cholesterol.

The efficacy, safety, and economics of a voluntary conversion from whole simvastatin tablets to split tablets in 6 Veterans Affairs medical centers were retrospectively evaluated in 3,787 patients who received a consistent daily dose (5 to 40 mg) of simvastatin in 1999. Baseline and final low-density lipoprotein cholesterol levels and average change from baseline were not significantly different between groups (p >0.05), nor were the incidence of transaminase increases (p >0.05) or measurements of patient compliance (p = 0.07). Widespread implementation of this initiative resulted in a cost avoidance of >$1.2 million in the 6 medical centers and $10.3 million across the Veterans Affairs medical system in 1999, with >$46 million avoided in 2003.

Administration, Oral↗
PubMed2004

Simvastatin potenciates PGI(2) release induced by HDL in human VSMC: effect on Cox-2 up-regulation and MAPK signalling pathways activated by HDL.

High density lipoproteins (HDL) induce prostacyclin (PGI(2)) release in vascular smooth muscle cells (VSMC) by up-regulation of cyclooxygenase-2 (Cox-2). Our goal was to analyse the mechanisms underlying this effect, and its potential modulation by HMG-CoA reductase inhibition in human VSMC. The contribution of mitogen-activated protein kinase (MAPK) signalling pathways was assessed by Western blot analysis and using specific inhibitors [PD098059 for p42/44 MAPK kinase (MEK); SB203580 for p38 MAPK or L-JNKI1 for c-Jun N-terminal kinase-1 (JNK-1)]. HDL-induced PGI(2) release was inhibited by rofecoxib (a specific Cox-2 inhibitor, 5 microM). HDL induced the early activation of p42 MAPK, p38 MAPK and JNK-1. p42/44 MAPK was the major pathway involved in both Cox-2 up-regulation and PGI(2) synthesis; p38 MAPK was also involved in both processes while JNK inhibition only affected PGI(2) synthesis. Pertussis toxin (an inhibitor of Galphai/Galphao proteins) prevented MAPK activation and inhibited both Cox-2 up-regulation and PGI(2) release. Genistein (a tyrosine kinase inhibitor) inhibited PGI(2) release without affecting MAPK activation or Cox-2 up-regulation. Simvastatin (0.1-1 microM) increased HDL-induced PGI(2) release ( approximately 45% at 1 microM) but did not significantly modify early MAPK activation or Cox-2 expression. Simvastatin alone did not significantly affect PGI(2) release. Our results suggest that mechanisms associated with G protein-coupled receptor activation, trigger Cox-2 up-regulation and PGI(2) release via multiple MAPK signalling pathways in VSMC. The mechanism is independent of tyrosine kinase receptors, although cytosolic tyrosine kinases could activate Cox-2 post-translationally. The potential contribution of HDL to vascular homeostasis, via increases in PGI(2) synthesis, could be enhanced by HMG-CoA reductase inhibitors.

Analysis of Variance↗
PubMed2006

Risk of coronary events in Japanese patients with both hypercholesterolemia and type 2 diabetes mellitus on low-dose simvastatin therapy: implication from Japan Lipid Intervention Trial (J-LIT).

Hypercholesterolemic patients with type 2 diabetes mellitus are at increased risk of coronary heart disease (CHD); however, direct evidence is very limited in Japanese patients. The J-LIT is the first nationwide study conducted to assess the relationship between serum lipid levels and development of coronary events in Japanese hypercholesterolemic patients. We analyzed the coronary events in the J-LIT study subjects by having type 2 diabetes or not. Of the total 41,801 subjects without prior CHD who received open-label simvastatin, 5mg/day, 6554 (male 40.2%, age 57.8+/-7.8) subjects had type 2 diabetes, while 35,247 (male 30.0%, age 57.8+/-7.9) did not. In this analysis, relative coronary event risks based on a 0.26 mmol/l (10mg/dl) increase in low density lipoprotein-cholesterol (LDL-C), were similar between hypercholesterolemic subjects with and without type 2 diabetes (17.3% versus 19.4%). Although all subjects were treated with simvastatin, the subjects with type 2 diabetes have significantly more coronary events compared to the subjects without type 2 diabetes (1.80/1000 and 0.76/1000 patient-years, respectively). Given the results above, to reduce the risk of coronary events in Japanese patients with both hypercholesterolemia and type 2 diabetes, careful and strict cholesterol management is needed in addition to the control of blood glucose.

Adult↗
PubMed2006

Antioxidant effect of bisphosphonates and simvastatin on chondrocyte lipid peroxidation.

The objective of this study was to evaluate the effect of bisphosphonates (BPs) and simvastatin on chondrocyte lipid peroxidation. For this purpose, a flow cytometrical method using C11-BODIPY(581/591) was developed to detect hydroperoxide-induced lipid peroxidation in chondrocytes. Tertiary butylhydroperoxide (t-BHP) induced a time and concentration dependent increase in chondrocyte lipid peroxidation. Addition of a Fe2+/EDTA complex to t-BHP or hydrogen peroxide (H2O2) clearly enhanced lipid peroxidation. The lipophilic simvastatin demonstrated a small inhibition in the chondrocyte lipid peroxidation. None of three tested BPs (clodronate, pamidronate, and risedronate) had an effect on chondrocyte lipid peroxidation induced by t-BHP. However, when Fe2+/EDTA complex was added to t-BHP or H2O2, BPs inhibited the lipid peroxidation process varying from 25% to 58%. This study demonstrates that BPs have antioxidant properties as iron chelators, thereby inhibiting the chondrocyte lipid peroxidation. These findings add evidence to the therapeutic potential of bisphosphonates and statins in rheumatoid arthritis.

Animals↗
PubMed2005

Pharmacogenetic study of apolipoprotein E, cholesteryl ester transfer protein and hepatic lipase genes and simvastatin therapy in Brazilian subjects.

BACKGROUND: In recent years, one of the focuses of genetic investigation in cardiology has been to identify the genetic factors associated with variable response to statin treatment. Polymorphisms in apolipoprotein E (APOE), cholesteryl ester transfer protein (CETP) and hepatic lipase (LIPC), proteins with major roles in lipid metabolism and homeostasis have been shown associated with lipid-lowering drugs response. METHODS: One hundred forty-six hypercholesterolemic patients of European descent were prospectively enrolled and treated with simvastatin 20 mg per day for over 6 months. Ninety-nine subjects completed the 6-month follow-up. Plasma lipids and lipoproteins were measured before and throughout the study. APOE (E*2, E*3 and E*4), LIPC-250A > G and CETP TaqIB genotypes were determined by PCR and restriction mapping. RESULTS: After a 6-month follow-up, no differences among genotypes in the percentage variation in lipid and lipoprotein concentrations for APOE and LIPC SNPs were observed. After adjustment for covariates, CETP B2B2 homozygotes showed a greater HDL-cholesterol increase compared to B1B2 and B1B1 subjects (14.1% vs. 1.7% and 1.3%, P < 0.05, respectively). CONCLUSION: Our study demonstrates that individual plasma HDL-cholesterol response to simvastatin is mediated, in part, by the CETP gene locus, with the B2 homozygotes having more benefit in HDL-C improvement than carriers of B1 allele.

Adult↗
PubMed2006

Influence of structural and interfacial properties of microemulsion eluent on chromatographic separation of simvastatin and its impurities.

In order to calculate the structural and compositional characteristics of microemulsions, used as eluents in the investigation of HPLC separation of simvastatin and its six impurities, predictive molecular thermodynamic approach is developed. For calculating fundamental interfacial properties of microemulsions, from pure component properties, the lattice fluid self-consistent field theory (SCF), in conjunction with new classical thermodynamic expressions, was applied. Calculation of predicted radii (PR), area per surfactant (ApS) and film thickness (FT), as well as is interfacial tension and bending moment enabled better understanding of separation of such a complex mixture. The microemulsion, which contained 1% (w/w) of diisopropyl ether, 2% (w/w) of sodium dodecyl sulphate (SDS), 6.6% (w/w) of co-surfactant such as n-butanol and 90.4% (w/w) of aqueous 25 mM disodium phosphate pH 7.0 enabled appropriate chromatographic separation between investigated compounds. It has been proved that this microemulsion had the smallest droplet radii and film thickness, which enabled optimal separation. Also the interfacial tension is the smallest, so the free energy change associated with dispersing the drops favoured a large number of small droplets. Hydrophobic interactions between solutes and stationary phase, as well as the microstructural characteristics of microemulsion eluents had a significant influence on chromatographic behavior of simvastatin and its six impurities.

Chromatography, High Pressure Liquid↗
PubMed2004

Quantitative analysis of simvastatin and its beta-hydroxy acid in human plasma using automated liquid-liquid extraction based on 96-well plate format and liquid chromatography-tandem mass spectrometry.

An assay based on automated liquid-liquid extraction (LLE) and liquid chromatography-tandem mass spectrometry (LC/MS/MS) has been developed and validated for the quantitative analysis of simvastatin (SV) and its beta-hydroxy acid (SVA) in human plasma. A Packard MultiProbe II workstation was used to convert human plasma samples collected following administration of simvastatin and quality control (QC) samples from individual tubes into 96-well plate format. The workstation was also used to prepare calibration standards and spike internal standards. A Tomtec Quadra 96-channel liquid handling workstation was used to perform LLE based on 96-well plates including adding solvents, separating organic from aqueous layer and reconstitution. SV and SVA were separated through a Kromasil C18 column (50 mm x 2 mm i.d., 5 microm) and detected by tandem mass spectrometry with a TurboIonspray interface. Stable isotope-labeled SV and SVA, 13CD(3)-SV and 13 CD(3)-SVA, were used as the internal standards for SV and SVA, respectively. The automated procedures reduced the overall analytical time (96 samples) to 1/3 of that of manual LLE. Most importantly, an analyst spent only a fraction of time on the 96-well LLE. A limit of quantitation of 50 pg/ml was achieved for both SV and SVA. The interconversion between SV and SVA during the 96-well LLE was found to be negligible. The assay showed very good reproducibility, with intra- and inter-assay precision (%R.S.D.) of less than 7.5%, and accuracy of 98.7-102.3% of nominal values for both analytes. By using this method, sample throughput should be enhanced at least three-fold compared to that of the manual procedure.

Chromatography, Liquid↗
PubMed2006

Effects of IFN-beta, leptin and simvastatin on LIF secretion by T lymphocytes of MS patients and healthy controls.

In multiple sclerosis (MS), oligodendrocyte injury is believed to be caused by an aberrant immune response initiated by autoreactive T cells. Increasing evidence indicates that inflammatory responses in the central nervous system are not exclusively detrimental, but may also exert protective effects. Such protective effects are potentially mediated by the local secretion of neurotrophic factors by immune cells. We previously reported that T cells and monocytes in vitro and in inflammatory MS lesions produce leukaemia inhibitory factor (LIF), a member of the neuropoietic family of neurotrophins. In the present study, we report a reduced LIF production by CD4+ T cells of relapsing remitting MS patients as compared to healthy controls. Furthermore, immunomodulatory agents such as leptin, IFN-beta and simvastatin were studied for their potential to alter LIF and secretion of other cytokines by T cells and monocytes of relapsing remitting MS patients and healthy controls. Low doses of simvastatin, but not IFN-beta or leptin enhanced LIF secretion by CD4+ T cells of RR-MS patients. We further demonstrated that LIF did not influence viability, proliferation and cytokine secretion of T cells. Together these data provide new information on the regulation of LIF secretion by immune cells. Further insights into the complex regulation of neurotrophic factors such as LIF may prove useful for treatment of MS.

Adult↗
PubMed2004

Simvastatin modulates TNFalpha-induced adhesion molecules expression in human endothelial cells.

Adhesion and transendothelial migration of leukocytes into the vascular wall is a crucial step in atherogenesis. Expression of cell adhesion molecules by endothelial cells plays a leading role in this process. We investigated the effect of simvastatin, an inhibitor of HMG-CoA reductase administered to reduce plasma levels of LDL-cholesterol, on the expression of vascular cell adhesion molecule-1 (VCAM-1) and intracellular cell adhesion molecule-1 (ICAM-1) by human umbilical vein endothelial cells (HUVEC) stimulated with tumor necrosis factor alpha (TNFalpha). We found the expression to be significantly inhibited by the drug in a time and concentration-dependent manner and to a greater extent in the case of VCAM-1 as compared with ICAM-1. In TNFalpha-stimulated HUVEC, simvastatin decreased VCAM-1 and ICAM-1 mRNA levels, inhibited TNFalpha-induced activation of nuclear factor kappaB (NF-kappaB) and enhanced expression of peroxisome proliferator-activated receptor alpha (PPARalpha). These effects were associated with reduction of adherence of monocytes and lymphocytes to HUVEC. The present findings suggest that the benefits of statins in vascular disease may include the inhibition of expression of VCAM-1 and ICAM-1 through effects on NF-kappaB.

Cell Adhesion↗
PubMed2006

The effect of high-dose simvastatin on free fatty acid metabolism in patients with type 2 diabetes mellitus.

Statins improve all major lipid fractions, reduce coronary heart disease risk, and may have a minor effect on glucose tolerance. A reduction in free fatty acid flux and concentrations could be partly responsible for these effects. We measured nocturnal and postprandial plasma palmitate concentrations and rate of appearance (R(a)) on 2 occasions in 12 obese dyslipidemic subjects with type 2 diabetes mellitus, using a single-blind, crossover format (placebo followed by simvastatin, 80 mg/d), and also on 1 occasion in 6 untreated control subjects. The diabetic subjects had increased average nocturnal (127+/-13 vs 80+/-10 micromol/L, P<.05) and 2-hour postprandial (49+/-6 vs 17+/-2 micromol/L, P<.001) palmitate concentrations, as well as increased nocturnal (31.6+/-3.7 vs 19.5+/-3.7 mmol/m(2) over 9 hours, P<.05) and postprandial (11.5+/-3.7 vs 5.5+/-3.7 mmol/m(2) every 4 hours, P<.005) integrated palmitate R(a) compared to normal controls. High-dose simvastatin reduced serum triglycerides by 35% but had no effect on plasma palmitate concentrations or R(a). These results suggest that the triglyceride-lowering effect of statins is not mediated through an effect on FFA metabolism.

Adult↗
PubMed2000

High-density lipoprotein cholesterol and triglyceride response with simvastatin versus atorvastatin in familial hypercholesterolemia.

The clinical and biochemical determinants of high-density lipoprotein (HDL) and triglyceride response to simvastatin and atorvastatin were assessed in 150 patients with severe hyperlipidemia treated in a randomized open-trial format design. Triglyceride reduction was only dependent on HDL:apolipoprotein A1, change in apolipoprotein B, and dose response, whereas an increase in HDL was dependent on initial LDL, change in LDL or dose response, and therapy with simvastatin.

Anticholesteremic Agents↗
PubMed2001

Effectiveness of high doses of simvastatin as monotherapy in mixed hyperlipidemia.

Twenty subjects with mixed hyperlipidemia participated in a 3-arm crossover trial to evaluate the effectiveness of high-dose simvastatin as monotherapy. Significant reductions were observed in atherogenic lipids and lipoproteins. The highest dose of simvastatin also resulted in significant increases in high-density lipoprotein cholesterol (21%) with a comparable increase in large, protective high-density lipoprotein particles.

Drug Administration Schedule↗
PubMed2001

Effect of simvastatin in preventing progression of carotid artery stenosis.

This study examines the effect of simvastatin on progression of carotid artery stenosis and shows that the drug substantially reversed the anticipated disease development. This finding indicates that treatment with simvastatin may reduce the risk for stroke in patients with known carotid artery disease.

Aged↗
PubMed1996

Effects of short-term reduction in serum cholesterol with simvastatin in patients with stable angina pectoris and mild to moderate hypercholesterolemia.

To evaluate the effects of short-term cholesterol-lowering treatment on myocardial effort ischemia, 22 patients with stable effort ischemia and mild to moderate hypercholesterolemia (low density lipoprotein [LDL] cholesterol 160 to 220 mg/dl) were randomly allocated at baseline (TO) in 2 groups. Group A included 12 patients treated with simvastatin 10 mg bid; group B included 10 patients treated with placebo. All patients underwent a treadmill electrocardiography (ECG) test; total cholesterol, HDL and LDL cholesterol, triglycerides, plasma, and blood viscosity were measured. All tests were repeated after 4 and 12 weeks. For 18 of the same patients (11 taking simvastatin, 7 receiving placebo), forearm strain-gouge plethysmography was performed at baseline and after 4 weeks, both at rest and during reactive hyperemia. At 4 and 12 weeks, group A showed a significant reduction in total cholesterol (p <0.05) and LDL (p <0.05), with unchanged HDL, triglycerides, blood, and plasma viscosity. Effort was unmodified, ST-segment depression at peak effort and ischemic threshold were significantly improved after 4 and 12 weeks (all p <0.05) with unchanged heart rate x systolic blood pressure product. A significant increase in the excess flow response to reactive hyperemia was detected in group A (p <0.03); group B showed no changes in hematochemical and ergometric parameters. These data suggest that cholesterol-lowering treatment is associated with an improvement in myocardial effort ischemia; this might be explained by a more pronounced increase of coronary blood flow and capacity of vasodilation in response to effort.

Analysis of Variance↗
PubMed1996

Effect of simvastatin on ejection fraction in cardiac transplant recipients.

In a prospective observational study, we looked at the effects of simvastatin on cardiac function, lipids, and blood pressure after cardiac transplantation. Our study suggests that simvastatin treatment is associated with improved ejection fraction in cardiac transplant recipients independent of effects attributable to the lipid profile.

Blood Pressure↗
PubMed1997

The clinical therapeutic implications of the Scandinavian Simvastatin Survival Study.

This analysis of the Scandinavian Simvastatin Survival Study (4S) describes how the design, implementation, and results answer most questions or concerns of practicing physicians regarding practicality and advantages of blood cholesterol-lowering drug intervention in patients who already have coronary artery disease. The results demonstrated that a drug with the safety and efficacy profile of simvastatin, utilized as it would be in a physician's office, can improve mortality and morbidity in patients with existing coronary disease without important side effects, and reduce hospitalizations for patients with coronary heart disease.

Anticholesteremic Agents↗