Regression of carotid and femoral artery intima-media thickness in familial hypercholesterolemia: treatment with simvastatin.

Kastelein JJ.

Departments of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands. p.desauvagenolting amc.uva.nl

OBJECTIVE: To investigate whether high-dose simvastatin therapy could reduce carotid and femoral artery intima-media thickness (IMT) in patients with familial hypercholesterolemia (FH) to prevent cardiovascular disease. BACKGROUND: Imaging of arterial walls with B-mode ultrasonography is increasingly used as a noninvasive surrogate marker of cardiovascular disease. Intervention trials using this modality have shown that by reducing risk factors, progression of atherosclerosis was inhibited. METHODS: After a washout period of 6 weeks, all patients with FH started monotherapy with simvastatin, 80 mg/d, for 2 years. The primary end point was the change (in millimeters) of the mean combined far-wall IMT of predefined carotid and femoral arterial segments at 2 years. RESULTS: We included a total of 153 patients with FH. Mean +/- SD combined baseline IMT was 1.07 +/- 0.23 mm. After treatment with simvastatin for 2 years, this IMT decreased by a mean of 0.081 mm (95% confidence interval, -0.109 to -0.053; P<.001), with its largest reduction in the femoral artery (-0.283 mm; P<.001). An actual decrease of combined IMT was seen in 69.8% of all patients. CONCLUSIONS: High-dose simvastatin therapy reduces arterial wall IMT in more than two thirds of the patients, with its largest effect on the femoral artery. Furthermore, patients with FH who were treated with both statin and antihypertensive medication experienced a significantly greater benefit in terms of IMT reduction.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12912721&dopt=Abstract simvastatin, Zocor




Simvastatin induces osteoblastic differentiation and inhibits adipocytic differentiation in mouse bone marrow stromal cells.

Dang G.

Department of Orthopedics, Peking University Third Hospital, Beijing, PR China.

To clarify the mechanism of the stimulatory effect of statins on bone formation, we investigated the effect of simvastatin, a widely used statin, on osteoblastic and adipocytic differentiation in primary cultured mouse bone marrow stromal cells (BMSCs). Simvastatin treatment enhanced the expression level of mRNA for osteocalcin and protein for osteocalcin and osteopontin, and increased alkaline phosphatase activity significantly (p<0.05). After BMSCs were exposed to an adipocyte differentiation agonist, Oil Red O staining, fluorescence activated cell sorting, and decreased expression level of lipoprotein lipase mRNA showed that treatment with simvastatin significantly inhibits adipocytic differentiation compared to controls that did not receive simvastatin (p<0.05). Lastly, we found that simvastatin induces high expression of BMP(2) in BMSCs. These observations suggested that simvastatin acts on BMSCs to enhance osteoblastic differentiation and inhibits adipocytic differentiation; this effect is at least partially mediated by inducing BMP(2) expression in BMSCs.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12914771&dopt=Abstract simvastatin, Zocor




Migration, proliferation, and invasion of human glioma cells following treatment with simvastatin.

Terzis AJ.

Department of Neurosurgery, Medical University of Lubeck, Ratzeburger Allee 160, 23538 Lubeck, Germany. jan.gliemroth t-online.de

This study describes the migration, proliferation, and invasion behaviour of two human glioma cell lines, GaMg and U-87 Mg, grown as multicellular tumour spheroids after 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitor (simvastatin) therapy. Migration and proliferation studies were performed using simvastatin in concentrations of 0.2-30 microg/ml(-1). A coculture system in which tumour spheroids were confronted with foetal rat brain aggregates was used for invasion studies. A dose-dependent growth and migratory inhibitory response to simvastatin treatment was observed. Marked invasion of the glioma spheroids into the brain aggregates could be seen in both treated and nontreated groups. Simvastatin therapy inhibits tumour cell growth and migration, but the invasiveness of the remaining tumour cells seems to be unaffected.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12962298&dopt=Abstract simvastatin, Zocor




Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells.

Kao PN.

Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, Calif 94305-5236, USA.

BACKGROUND: Pulmonary vascular injury by toxins can induce neointimal formation, pulmonary arterial hypertension (PAH), right ventricular failure, and death. We showed previously that simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in pneumonectomized rats injected with the alkaloid toxin monocrotaline. The present study was undertaken to investigate the efficacy of simvastatin and its mechanism of reversing established neointimal vascular occlusion and pulmonary hypertension. METHODS AND RESULTS: Pneumonectomized rats injected with monocrotaline at 4 weeks demonstrated severe PAH at 11 weeks (mean pulmonary artery pressure [mPAP]=42 versus 17 mm Hg in normal rats) and death by 15 weeks. When rats with severe PAH received simvastatin (2 mg x kg(-1) x d(-1) by gavage) from week 11, there was 100% survival and reversal of PAH after 2 weeks (mPAP=36 mm Hg) and 6 weeks (mPAP=24 mm Hg) of therapy. Simvastatin treatment reduced right ventricular hypertrophy and reduced proliferation and increased apoptosis of pathological smooth muscle cells in the neointima and medial walls of pulmonary arteries. Longitudinal transcriptional profiling revealed that simvastatin downregulated the inflammatory genes fos, jun, and tumor necrosis factor-alpha and upregulated the cell cycle inhibitor p27Kip1, endothelial nitric oxide synthase, and bone morphogenetic protein receptor type 1a. CONCLUSIONS: Simvastatin reverses pulmonary arterial neointimal formation and PAH after toxic injury.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12963647&dopt=Abstract simvastatin, Zocor




Simvastatin attenuates renal ischemia/reperfusion injury in rats administered cyclosporine A.

Lukaszek VA.

College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA. inmans ohio.edu

BACKGROUND: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors increase renal blood flow independent of their lipid-lowering properties. In organ transplantation, the calcineurin inhibitor cyclosporine A (CyA) is the immunosuppressant of choice. However, its renal vasoconstrictor properties limit its use. This study aimed to determine the effect of an HMG-CoA reductase inhibitor, simvastatin (Zocor), on renal function in rats after ischemia/reperfusion injury (I/R) with concomitant CyA treatment. METHODS: Male Wistar rats (250 g) were anesthetized and the suprarenal aorta clamped for 40 minutes. The right kidney was removed. After recovery, the rats were divided into 5 groups: (1) control rats, no ischemia, no treatment; (2) ischemia with no treatment; (3) ischemia plus CyA only; (4) ischemia plus CyA and low-dose simvastatin; and (5) ischemia plus CyA and high-dose simvastatin. Five to 7 days after I/R injury, glomerular filtration rate (GFR) was determined using urinary iohexol clearance. RESULTS: The GFR values (mL/min) for all 5 groups were as follows: (1) 1.23 +/- 0.08; (2) 1.05 +/- 0.10; (3) 0.44 +/- 0.06 (P < 0.05 versus groups 1, 2, and 5; one-way analysis of variance); (4) 0.51 +/- 0.04 (P < 0.05 versus groups 1, 2, and 5; one-way analysis of variance); and (5) 0.85 +/- 0.11. CONCLUSIONS: After I/R injury and cyclosporine treatment, simvastatin preserved renal function compared with cyclosporine treatment alone because it may not have a direct vasoconstrictor effect on the renal microcirculation. In fact, it may exhibit vasodilator properties on the renal microcirculation mediated by nitric oxide.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14501225&dopt=Abstract simvastatin, Zocor




Cost-effectiveness analysis of simvastatin and lovastatin/extended- release niacin to achieve LDL and HDL goal using NHANES data.

Malone DC.

Department of Pharmacy Practice, Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA. armstrong pharmacy.arizona.edu

OBJECTIVE: The Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, Adult Treatment Panel III (ATP III) encouraged reduced low-density lipoprotein (LDL) cholesterol levels for a greater number of patients and reemphasized the benefits of high-density lipoprotein (HDL) cholesterol. The purpose of this study was to compare 2 regimens achieving simultaneous LDL and HDL goals. METHODS: A decision-analytic model compared the cost-effectiveness of simvastatin and lovastatin/extended-release niacin. The perspective of the analysis was that of a health system. Product labeling was used to determine changes in cholesterol concentrations and frequencies of clinically important adverse events. The Third National Health and Nutrition Examination Survey (NHANES III) adult data were used for baseline cholesterol levels. Each product was titrated to achieve LDL and HDL goals unless an adverse effect occurred. Direct medical costs were determined for each treatment to determine cost-effectiveness. RESULTS: For both the 130 mg/dL and 100 mg/dL LDL goal analyses (and HDL e40 mg/dL), lovastatin/extended-release niacin had higher success rates and lower estimated direct-medical costs than simvastatin. Simvastatin had the highest success rate in achieving LDL level <160 mg/dL and HDL e40 mg/dL; however, its estimated direct-medical cost was approximately twice that of lovastatin/extended-release niacin (665 US dollars versus 333 US dollars). CONCLUSION: For the LDL goals <130 mg/dL and <100 mg/dL (and HDL e40 mg/dL) required of the majority of U.S. residents, lovastatin/extended-release niacin was both more successful and less costly than simvastatin.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15228376&dopt=Abstract simvastatin, Zocor