Sustained reduction of serum cholesterol in low-dose 6-year simvastatin treatment with minimum side effects in 51,321 Japanese hypercholesterolemic patients.

J-LIT Study Group.

Osaka University Graduate School of Medicine, Japan.

The Japan Lipid Intervention Trial (J-LIT) study, a nationwide cohort study utilizing the clinical practice of general physicians, was designed to clarify the relationship between the incidence of coronary heart disease and serum lipid concentrations during simvastatin therapy, as well as the safety of the therapy, in a large number of Japanese hypercholesterolemic patients. All the enrolled patients were treated with simvastatin. The current study analyzed the lipid lowering effect and safety of the low-dose simvastatin therapy used in the J-LIT study. Open-labeled simvastatin was given to 51,321 patients at an initial dose of mostly 5 mg/day. After 6 months of the treatment, the average serum total cholesterol (TC) and low density lipoprotein-cholesterol concentrations in all the patients followed up were reduced by 18.3% and 26.0%, respectively, and that of high density lipoprotein-cholesterol increased 2.3% on average. These concentrations were well maintained throughout the 6-year treatment period. A minority of patients (1.4%) unexpectedly had a remarkable reduction in TC concentration by more than 40%. Hyper-responders, even to low-dose statin, were found for the first time in this large-scale and long-term investigation. Overall adverse drug reactions occurred in 3.3% of subjects during the 6-year treatment, the major events being hepatic and musculoskeletal disorders, of which the incidence was less than 1%. Low-dose simvastatin therapy of 5 mg/day effectively controlled the serum TC concentration by reducing it by approximately 20% on average in hypercholesterolemic Japanese patients, a reduction that corresponds to the effect of simvastatin 20 mg/day in Western studies. In addition, the low incidence of drug-related adverse events in this study may be also related to the low dosage of simvastatin.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12655157&dopt=Abstract simvastatin, Zocor




Effect of simvastatin treatment on bone mineral density and bone turnover in hypercholesterolemic postmenopausal women: a 1-year longitudinal study.

Gennari C.

Department of Internal Medicine, University of Siena, Italy. amontagnani unisi.it

Although several studies have reported a lower risk of osteoporotic fracture in hypercholesterolemic patients treated with statins, so far longitudinal studies on the effects of statins on bone are lacking. The aim of the present study was to evaluate bone mineral density (BMD) and bone turnover changes induced by 1-year simvastatin treatment on postmenopausal women. Thirty consecutive postmenopausal hypercholesterolemic women (61.2 +/- 4.9 years) were treated for 12 months with 40 mg/day simvastatin and 30 normocholesterolemic age-matched postmenopausal women provided control data. In all subjects, at baseline and at 3-month intervals, serum lipids, calcium, phosphate, total and bone alkaline phosphatase (Bone-ALP), and carboxy-terminal fragment of type I collagen (CTx) were measured in a fasting blood sample. At baseline and after 6 and 12 months BMD was measured at lumbar spine (BMD-LS) and at femur (BMD-Ftot) and at femoral neck (BMD-Fn) by DXA. In the simvastatin-treated group Bone-ALP showed a significant increase (P < 0.05) with respect to baseline from the sixth month, whereas serum CTx showed a weak and nonsignificant increase over the study period. In treated women BMD-LS, BMD-Fn, and BMD-Ftot increased respectively by 1.1, 0.9, and 0.4% at Month 6; and by 2.8, 1.0, and 0.8% at Month 12. In controls BMD-LS, BMD-Fn, and BMD-Ftot at the end of the study period decreased by 1.6, 1.4, and 1.2%, respectively. The difference between controls and simvastatin-treated patients was significant (P < 0.05) for both BMD-LS and BMD-Fn only at Month 12. In conclusion our results, although obtained from a small sample of postmenopausal hypercholesterolemic women, suggest a probable positive effect of simvastatin on bone formation and BMD.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12689687&dopt=Abstract simvastatin, Zocor




Simvastatin normalizes autonomic neural control in experimental heart failure.

Zucker IH.

Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, NE 68198-4575, USA.

BACKGROUND: HMG-CoA reductase inhibitors (statins) have been shown to beneficially affect outcomes in chronic heart failure (CHF). We hypothesized that statins exert effects on autonomic function, as assessed by plasma norepinephrine levels, direct recordings of renal sympathetic nerve activity (RSNA), and baroreflex function. METHODS AND RESULTS: Normolipidemic CHF rabbits were treated with simvastatin or vehicle. CHF was induced by continuous ventricular pacing at 320 to 340 bpm for 3 weeks. Two to 3 days after instrumentation of the rabbits with renal nerve electrodes and arterial and venous catheters, blood samples and RSNA recordings were obtained in the conscious state. Baroreflex function was assessed after administration of sodium nitroprusside and phenylephrine. Mean baseline RSNA (+/-SEM) in normal rabbits was 19.3+/-3.8%; in CHF rabbits, 39.4+/-2.9% (P<0.05); in CHF rabbits on low-dose (0.3 mg x kg(-1) x d(-1)) simvastatin, 39.8+/-8.3% (P<0.05); and in CHF rabbits on high-dose simvastatin (3 mg x kg(-1) x d(-1)), 21.1+/-4.5% (P=NS). Similar data were observed for plasma norepinephrine. In CHF rabbits treated with 3 mg x kg(-1) x d(-1) simvastatin, baroreflex regulation of heart rate to transient hypotension with sodium nitroprusside was normalized by 66% compared with CHF controls. CONCLUSIONS: These are the first data showing that non-lipid-lowering statin effects include a normalization of sympathetic outflow and reflex regulation in CHF. The precise neural and cellular pathways involved in these responses need further clarification. This finding may have important implications for the treatment of CHF and progression of the disease process.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12695293&dopt=Abstract simvastatin, Zocor




Effect of HMG-CoA reductase inhibitors on proliferation and protein synthesis by rat hepatic stellate cells.

Geerts A.

Laboratory for Molecular Liver Cell Biology, Faculty of Medicine and Pharmacy, Free University of Brussels (VUB), Laarbeeklaan 103, 1090 Brussels-Jette, Belgium. krom cyto.vub.ac.be

BACKGROUND/AIMS: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors called statins, have besides their cholesterol-lowering function, therapeutic value in conditions such as neo-angiogenesis and atherosclerosis. We investigated the effect of two statins on the proliferation rate and protein steady state levels of hepatic stellate cells (HSC). METHODS: Cellular DNA synthesis under the influence of statins and/or platelet derived growth factor (PDGF) and mevalonate was evaluated by measuring BrdU incorporation. Synthesis of collagens type I, III, IV and fibronectin was quantified by ELISA. Additionally, we examined the influence of simvastatin on isoprenylation of Ras and RhoA proteins. RESULTS: Lovastatin and simvastatin induced a dose-dependent inhibition of the proliferation rate of HSC. Subsequent addition of PDGF and/or mevalonate, after long-term exposure of simvastatin to HSC, did not reverse simvastatins' antiproliferative effect. Lovastatin and simvastatin reduced the protein steady state level of collagens type I (-40%), III (-45%) and IV (-27%). Membrane bound Ras steady state levels decreased under the influence of simvastatin. Membrane bound RhoA remained unaltered, whereas, cytosolic RhoA protein level was strongly reduced. CONCLUSIONS: Our data showed that lovastatin and simvastatin inhibited HSC proliferation and collagen steady state levels by mechanisms independent of their lipid reducing activities.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12713866&dopt=Abstract simvastatin, Zocor




Attenuation of chronic hypoxic pulmonary hypertension by simvastatin.

Johns RA.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, 1830 E. Monument, 5th Floor, Baltimore, MD 21205, USA. rgirgis jhmi.edu

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to improve multiple normal endothelial cell functions and inhibit vascular wall cell proliferation. We hypothesized that one such agent, simvastatin, would attenuate chronic hypoxic pulmonary hypertension. Male adult Sprague-Dawley rats were exposed (14 days) to normoxia (N), normoxia plus once-a-day administered simvastatin (20 mg/kg ip) (NS), hypoxia (10% inspired O2 fraction) (H), or hypoxia plus simvastatin (HS). Mean pulmonary artery pressure, measured in anesthetized, ventilated rats with an open-chest method, was reduced from 25 +/- 2 mmHg in H to 18 +/- 1 in HS (P < 0.001) but did not reach normoxic values (12 +/- 1 mmHg). Similarly, right ventricular/left ventricular plus interventricular septal weight was reduced from 0.53 +/- 0.02 in the H group to 0.36 +/- 0.02 in the HS group (P < 0.001). The increased hematocrit in H (0.65 +/- 0.02) was prevented by simvastatin treatment (0.51 +/- 0.01, P < 0.001). Hematocrit was similar in N versus NS. Alveolar vessel muscularization and medial thickening of vessels 50-200 microM in diameter induced by hypoxia were also significantly attenuated in the HS animals. Lung endothelial nitric oxide synthase (eNOS) protein expression in the HS group was less than H (P < 0.01) but was similar in N versus NS. We conclude that simvastatin treatment potently attenuates chronic hypoxic pulmonary hypertension and polycythemia in rats and inhibits vascular remodeling. Enhancement of lung eNOS expression does not appear to be involved in mediating this effect.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12750068&dopt=Abstract simvastatin, Zocor




Simvastatin suppresses tissue factor expression and increases fibrinolytic activity in tumor necrosis factor-alpha-activated human peritoneal mesothelial cells.

Kooistra T.

Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands.

BACKGROUND: Patients treated with peritoneal dialysis frequently suffer from recurrent peritonitis episodes. During peritonitis, inflammatory mediators are released and a serofibrinous exudate is formed in the peritoneal cavity, which promotes fibrosis and abdominal adhesion development. Human peritoneal mesothelial cells (HMC) play a critical role in maintaining the intraperitoneal balance between fibrinolysis and coagulation by expressing the fibrinolytic enzyme tissue-type plasminogen activator (t-PA) and its specific inhibitor, plasminogen activator inhibitor-1 (PAI-1) as well as the procoagulant protein, tissue factor. METHODS: Cultured HMC were used to examine the effect of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, on the expression of t-PA, PAI-1 and tissue factor after activation of the cells with tumor necrosis factor-alpha (TNF-alpha). Antigen concentrations in the cell supernatants were measured by enzyme-linked immunosorbent assay (ELISA). Northern blot analysis was conducted for mRNA expression. Luciferase reporter gene assays and Western blot analysis in human fibrosarcoma HT1080 cells and HMC were performed to analyze the effect of simvastatin on the transcription factors nuclear factor kappa B (NF-kappa B) and activator protein-1 (AP-1), which regulate tissue factor gene expression. RESULTS: Incubation of HMC with TNF-alpha resulted in significantly decreased t-PA and increased PAI-1 synthesis. In the presence of simvastatin t-PA synthesis in control and TNF-alpha-treated cells dose-dependently increased, reaching 5.8-fold and 7.7-fold higher t-PA levels, respectively, at 5 micromol/L simvastatin after 48 hours. Simvastatin dose-dependently suppressed PAI-1 production in both control and TNF-alpha-treated cells. At 5 micromol/L, simvastatin lowered PAI-1 synthesis 3.4-fold and 4.0-fold, respectively, thereby also completely suppressing the TNF-alpha effect itself. Similarly, simvastatin down-regulated the expression of tissue factor and also completely opposed the TNF-alpha-induced tissue factor expression. The effects of simvastatin on t-PA, PAI-1 and tissue factor expression were prevented by mevalonate and geranylgeraniol (GG), suggesting the involvement of geranylgeranyl-modified intermediates in simvastatin's mode of action. Also, simvastatin reduced NF-kappa B- and AP-1-dependent reporter gene activity in TNF-alpha-treated HT-1080 fibrosarcoma cells and reduced the nuclear levels of p50-NF-kappa B, p65-NF-kappa B, and the AP-1 components c-fos and c-jun in HMC. CONCLUSION: The HMG-CoA reductase inhibitor simvastatin is an effective stimulator of the mesothelial fibrinolytic capacity and suppresses the procoagulant activity both under normal and inflammatory conditions. Our findings provide a molecular explanation for the anti-inflammatory properties of statins in HMC and a rationale for the use of these drugs to protect peritoneal dialysis patients from peritoneal fibrosis and adhesion development during bacterial peritonitis.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12753293&dopt=Abstract simvastatin, Zocor