Disease relevance of Zocor

• Hormone-replacement therapy compared with simvastatin for postmenopausal women with hypercholesterolemia [1].
• Cost effectiveness of simvastatin treatment to lower cholesterol levels in patients with coronary heart disease. Scandinavian Simvastatin Survival Study Group [2].
• Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone [3].
• Indeed, Sim inhibited cardiac hypertrophy and decreased myocardial Rac1 activity and O2*- production in rats treated with AngII infusion or subjected to transaortic constriction [4].
• Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis [5].

Psychiatry related information on Zocor

• Simvastatin strongly reduces levels of Alzheimer's disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo [6].
• Over the median follow-up period of 5.4 years, one or more major coronary events (MCEs) occurred in 622 (28%) of the 2223 patients in the placebo group and 431 (19%) of the 2221 patients in the simvastatin group (34% risk reduction, P<.00001) [7].
• RESULTS: Simvastatin treatment not only reversed learning and memory deficits in the Tg2576 mice, but also enhanced learning and memory in the nontransgenic mice [8].
• During biweekly assessments, four subjects on simvastatin and one on placebo experienced depressive symptoms, as manifest by Center for Epidemiological Studies Depression scale scores greater than 16 (exact P=.36) [9].
• The study found no benefit of simvastatin therapy in preventing noncardiac events (eg, dementia, osteoporotic fractures), and no negative effects, such as an increase in cancer, respiratory disease, or suicide [10].

High impact information on Zocor

• CONCLUSIONS: Simvastatin plus niacin provides marked clinical and angiographically measurable benefits in patients with coronary disease and low HDL levels [11].
• The protective increase in HDL2 with simvastatin plus niacin was attenuated by concurrent therapy with antioxidants [11].
• For total cholesterol, the mean decrease with hormone therapy was 14 percent (95 percent confidence interval, 11 to 16 percent) and the mean decrease with simvastatin was 26 percent (95 percent confidence interval, 23 to 29 percent) [12].
• Triglyceride levels increased with hormone therapy (mean increase, 29 percent; 95 percent confidence interval, 15 to 42 percent) but decreased with simvastatin (mean decrease, 14 percent; 95 percent confidence interval, 8 to 20 percent) [12].
• Accordingly, simvastatin enhanced phosphorylation of the endogenous Akt substrate endothelial nitric oxide synthase (eNOS), inhibited apoptosis and accelerated vascular structure formation in vitro in an Akt-dependent manner [13].

Chemical compound and disease context of Zocor

• Rhabdomyolysis due to interaction of simvastatin with mibefradil [14].
• These trials include the Scandinavian Simvastatin Survival Study, the West of Scotland Coronary Prevention Study, the Air Force/Texas Coronary Atherosclerosis Prevention Study, the Cholesterol and Recurrent Events investigation, and the Long-Term Intervention with Pravastatin in Ischaemic Disease trial [15].
• Here, we show that lipophilic statins (atorvastatin, simvastatin, cerivastatin) markedly induce caspases-dependent apoptosis in various human osteosarcoma cells, independently of bone morphogenetic protein (BMP)-2 signaling and cell differentiation [16].
• In vivo simvastatin (administered daily mixed with food) and BCNU (single i.p. injection), when given separately, caused a dose-dependent inhibition of labeling index in C6 glioma homografts (ID50, 61 mg/kg/day and 8.7 mg/kg, respectively) [17].
• Inhibition of isoprenoid synthesis with the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, simvastatin (Sim, 1-10 microM), inhibited PDGF-induced SMC DNA synthesis by >95%, retinoblastoma gene product hyperphosphorylation by 90%, and cyclin-dependent kinases (cdk)-2, -4, and -6 activity by 80 +/- 5, 50 +/- 3, and 48 +/- 3%, respectively [18].

Biological context of Zocor

• Lovastatin and simvastatin increased bone formation when injected subcutaneously over the calvaria of mice and increased cancellous bone volume when orally administered to rats [19].
• The role of Akt signaling in mediating effects of statin on EPCs is suggested by the observation that simvastatin rapidly activates Akt protein kinase in EPCs, enhancing proliferative and migratory activities and cell survival [20].
• We show here, using a chemotaxis assay of bone marrow mononuclear cells in vitro and EPC culture assay of peripheral blood from simvastatin-treated animals in vivo, that the HMG-CoA reductase inhibitor, simvastatin, augments the circulating population of EPCs [20].
• RESULTS: In protocol 1, acute simvastatin did not modify the hepatic venous pressure gradient but increased the hepatic blood flow (21% +/- 13% at 30 minutes; P = 0.01) and decreased hepatic sinusoidal resistance by 14% +/- 11% (P = 0.04) [5].
• Here we show that simvastatin (2 microM) inhibits clump formation and induces apoptosis of EBV-transformed LCLs [21].

Anatomical context of Zocor

• Similar to vascular endothelial growth factor (VEGF) treatment, both simvastatin administration and enhanced Akt signaling in the endothelium promoted angiogenesis in ischemic limbs of normocholesterolemic rabbits [13].
• Direct evidence that this increased pool of circulating EPCs originates from bone marrow and may enhance neovascularization was demonstrated in simvastatin-treated mice transplanted with bone marrow from transgenic donors expressing beta-galactosidase transcriptionally regulated by the endothelial cell-specific Tie-2 promoter [20].
• Cholesterol also potentiated Akt activation in normal prostate epithelial cells, which were resistant to the apoptotic effects of simvastatin [22].
• We treated neonatal rat cardiac myocytes with angiotensin II (AngII) with and without simvastatin (Sim) and found that Sim decreased AngII-induced protein content, [3H] leucine uptake, and atrial natriuretic factor (ANF) promoter activity [4].
• To confirm this advantage, patients with heterozygous familial hypercholesterolaemia and coronary artery disease were randomised to receive LDL apheresis fortnightly (with disposable dextran sulphate/cellulose columns) plus simvastatin 40 mg daily, or colestipol 20 g plus simvastatin 40 mg daily [23].

Associations of Zocor with other chemical compounds

• The ability of simvastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, to lower lipid levels in 16 patients with primary hypercholesterolaemia was compared with that of bezafibrate in a 16-week, double-blind, parallel, placebo-controlled trial that was continued in an open crossover fashion [24].
• Inhibition of the cholesterol metabolic pathway by the hydrophobic 3-hydroxy-3-methylglutaryl CoA (HMGCoA) reductase inhibitors, simvastatin and atorvastatin, reversed the effect of lipoprotein-depleted serum and up-regulated TGFbetaRII expression, whereas the hydrophilic HMGCoA reductase inhibitor, pravastatin, had no effect [25].
• In vitro inhibition of FOS using small interfering RNA and 3-hydroxy-3-methyl-glutaryl CoA reductase inhibitor simvastatin (statin) affected monocyte activation and suggested an important role in pathogenesis [26].
• C3 exotoxin, which specifically inactivates geranylgeranylated Rho GTPases, mimicked the effect of simvastatin on PAI-1 promoter activity [25].
• METHODS AND RESULTS: Human saphenous vein endothelial cells were treated with ox-LDL (50 microg/mL thiobarbituric acid reactive substances 12 to 16 nmol/mg) in the presence of HMG CoA reductase inhibitors simvastatin and lovastatin [27].
• Treatment with simvastatin led to a significant reduction (P < .005) of total and low-density lipoprotein cholesterol [28].
• Our data suggest that simvastatin, independently of its cholesterol-lowering properties, impairs the ESC self-renewal by modulating RhoA/ROCK-dependent cell-signaling [29].
• Simvastatin directly inhibited the expression of retinoic acid-related orphan nuclear hormone receptor C, a transcription factor that controls IL-17 production in CD4(+) T cells [30].
• The observed heterogeneity in AML responsiveness could not be explained by differences in effects on cholesterol metabolism genes or extracellular signal-regulated kinase phosphorylation in response to simvastatin and tipifarnib treatment [31].

Gene context of Zocor

• These simvastatin-conditioned DCs up-regulated GATA-3 expression and down-regulated T-bet expression in cocultured CD4+ T cells in the absence of additional simvastatin added to the coculture [32].
• Expression of Dhcr7 increased in Dhcr7(T93M/Delta3-5) tissues after simvastatin therapy, consistent with the hypothesis that simvastatin therapy improves the biochemical phenotype by increasing the expression of a Dhcr7 allele with residual enzymatic activity [33].
• We found that simvastatin potentiated the apoptosis induced by TNF-alpha as indicated by intracellular esterase activity, caspase activation, TUNEL, and annexin V staining [34].
• Interference with RhoA signaling by simvastatin, toxinB, C3 toxin, and Y27632 prevented up-regulation of CTGF [35].
• Northern blot analysis demonstrated an increase in steady state IL-1-induced E-selectin mRNA levels in cells pretreated with simvastatin [36].

Analytical, diagnostic and therapeutic context of Zocor

• METHODS AND RESULTS: In a 4-year prospective randomized study with heart transplant recipients, the efficacy of primary antihypercholesterolemic therapy with simvastatin was compared with that of general dietary therapy [37].
• Seventy-two heart transplant recipients receiving standard triple immunosuppression were randomly assigned to an active-treatment group (low-cholesterol diet and simvastatin, n=35) or a control group (general dietary measures, n=37) [37].
• Simvastatin reduces graft vessel disease and mortality after heart transplantation: a four-year randomized trial [37].
• In the United States, the resulting reduction in hospitalization costs over the 5.4 years of the trial would be $3872 per patient, reducing the effective cost of simvastatin by 88% to $0.28 per day [38].
• Flow-mediated dilation of the brachial artery (by ultrasonography) improved (all P<0.001 versus baseline values) on CE (4.0+/-2.6% to 10.2+/-3.9%), simvastatin (4.3+/-2.4% to 10.0+/-3.9%), and CE combined with simvastatin (4.6+/-2.0% to 9.8+/-2.6%), but similarly among therapies (P=0.507 by ANOVA) [39].

References