Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Simvastatin”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 163 records · Page 9Linked to original sources
PubMed1999

Enhanced cholesterol reduction by simvastatin in diltiazem-treated patients.

AIMS: To investigate whether an interaction between diltiazem and the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin may enhance the cholesterol-lowering response to simvastatin in diltiazem-treated patients. METHODS: One hundred and thirty-five patients attending the Sheffield hypertension clinic who started consecutively on simvastatin for primary or secondary prevention of coronary heart disease (CHD) during the 2 years June, 1996-May 1998 were surveyed. From the clinic records we extracted and recorded absolute and percentage cholesterol responses to the starting dose of simvastatin and coprescription of diltiazem. RESULTS: The cholesterol reduction for the 19 patients on diltiazem was 33.3% compared with 24.7% in the remaining 116 patients (median difference 8.6%, 95% CI 1.1-12.2%, P<0.02). The interindividual variability of cholesterol response to simvastatin was greater for patients not taking diltiazem than for those patients taking diltiazem. The ratio of the variances in response for the nondiltiazem group relative to the diltiazem group was 1.34 at 10 mg simvastatin daily (not significant, 95% CI 0.16-4.11), and 3.42 at 20 mg daily (P<0.01, 95% CI 1.26-7.18). Concurrent diltiazem therapy (P<0.04), age (P=0.001) and starting dose of simvastatin (P=0.002) were found to be significant independent predictors of percentage cholesterol response. CONCLUSIONS: Patients who take both simvastatin and diltiazem may need lower doses of simvastatin to achieve the recommended reduction in cholesterol. The pharmacokinetic and pharmacodynamic aspects of this interaction need further study to confirm an enhanced effect on cholesterol reduction, and exclude an increased risk of adverse events.

Anticholesteremic Agents↗
PubMed2001

Different effects of St John's wort on the pharmacokinetics of simvastatin and pravastatin.

OBJECTIVE: St John's Wort, a widely used herbal product, is an inducer of CYP3A4 and it decreases blood concentrations of CYP3A4 substrates. The effects of St John's Wort on the pharmacokinetics of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors simvastatin (an inactive lactone pro-drug) and pravastatin were determined in this study. METHODS: Sixteen healthy male subjects (n = 8 in group 1 and n = 8 in group 2) took a St John's Wort caplet (300 mg) or matching placebo three times a day for 14 days in a double-blind, crossover study. On day 14, a single oral dose of 10 mg simvastatin and 20 mg pravastatin was given to subjects in group 1 and group 2, respectively. Blood samples were obtained during a 24-hour period after the administration of each drug. RESULTS: Repeated St John's Wort treatment tended to lower plasma simvastatin concentration and significantly (P <.05) lowered concentrations of simvastatin hydroxy acid, its active metabolite. The peak concentration in plasma (ratio, 0.72 of placebo) of simvastatin hydroxy acid tended to be decreased and its area under the plasma concentration-time curve between time zero and 24 hours after administration (ratio, 0.48 of placebo) was significantly decreased (P <.05) by St John's Wort. On the other hand, St John's Wort did not influence plasma pravastatin concentration. No significant differences were observed in the elimination half-life of simvastatin or pravastatin between the placebo and St John's Wort trials. CONCLUSIONS: This study showed that St John's Wort decreases plasma concentrations of simvastatin but not of pravastatin. Because simvastatin is extensively metabolized by CYP3A4 in the intestinal wall and liver, which are induced by St John's Wort, it is likely that this interaction is partly caused by the enhancement of the CYP3A4-mediated first-pass metabolism of simvastatin in the small intestine and liver.

Adult↗
PubMed2000

Endothelium-dependent responses in patients with hypercholesterolemic coronary artery disease under the effects of simvastatin and enalapril, either separately or combined.

BACKGROUND: Endothelial dysfunction is an early event in atherosclerotic disease that precedes clinical manifestations and complications. The noninvasive assessment of endothelial function in patients with risk factors undergoing clinical treatment is an important medical advance. In this setting, altered endothelial function in patients with coronary hypercholesterolemia and its modifications by treatment with enalapril and simvastatin, either separately or in combination, was assessed in the brachial artery in a randomized, double-blind, 2-period crossover study. METHODS: Thirty-eight patients were separated in 2 groups. Group 1 (18 patients, 3 female, mean age 63 +/- 6.0 years) received simvastatin 10 mg/d for 8 weeks and simvastatin plus enalapril 5 mg/d for another 8 weeks. Group 2 (20 patients, 3 female, mean age 64 +/- 5.8 years) received enalapril 5 mg/d for 8 weeks and enalapril plus simvastatin 10 mg/d for another 8 weeks. All subjects underwent measurements of brachial artery diameter before and after postischemic hyperemia with high-resolution ultrasound at basal conditions (control) and under the effects of the drugs at the end of 8 and 16 weeks. RESULTS: Cholesterol and LDL cholesterol levels significantly decreased with simvastatin treatment alone or with enalapril. Mean baseline arterial diameter was 5.24 +/- 1.25 mm in group 1 and 4.83 +/- 0.99 mm in group 2 (not significant). In group 1 after the first 8 weeks, endothelium-dependent vasodilation significantly increased with simvastatin treatment (control, 4.4%; 8 weeks, 7.6%; P <.001). After 16 weeks with the addition of enalapril, a further increase in vasodilation was seen (8.6%, P <.05 vs 8 weeks). In group 2, with enalapril treatment an increase in vasodilation versus control was seen (control, 4.3%; 8 weeks, 5.8%; P <.01). After 16 weeks, with the addition of simvastatin an additional increase in vasodilation was observed (9.1%, P <.001 vs 8 weeks). After nitroglycerin, vasodilation in group 1 at control, 8, and 16 weeks was 17%, 17.5%, and 18%, respectively. In group 2, nitroglycerin vasodilation at control, 8, and 16 weeks was 21%, 21%, and 22%, respectively. CONCLUSIONS: Simvastatin significantly increased the postischemic vasodilator response in patients with coronary hypercholesterolemia, either as single treatment or added to enalapril. Similarly, the response was increased by enalapril, either alone or while simvastatin was being administered. Both drugs improve vasodilation and additive effects appear to be present.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

The effects of lacidipine on the steady/state plasma concentrations of simvastatin in healthy subjects.

AIMS: Lacidipine, a long acting 2, 4-dihydropyridine calcium channel antagonist is frequently administered with cholesterol lowering agents, particularly in elderly populations. The effects of lacidipine on the pharmacokinetics of simvastatin were investigated, since they share the CYP3A4 pathway for metabolism. METHODS: The study was an open, randomised, two-way crossover design, with at least 7 days washout. Eighteen healthy subjects received simvastatin, 40 mg once daily, alone and together with lacidipine, 4 mg once daily, for 8 days. The pharmacokinetics of simvastatin were studied on the eighth day. Analysis was made of total simvastatin acid concentrations (naive simvastatin acid plus that derived from alkaline hydrolysis of the lactone). RESULTS: Lacidipine increased the maximum concentration of simvastatin (Cmax) by approximately 70% (P=0.016) and the area under the plasma concentration-time curve AUC(0,24 h) by approximately 35% (P=0.001). The mean Cmax and AUC(0,24 h) of simvastatin (95% confidence interval) when given alone were 8.76 (6.72-11.41) ng ml(-1) and 60.36 (47.15-77.28) ng ml(-1) h. During treatment with lacidipine they were, respectively, 14.89 (10.77-20.58) ng ml(-1) and 80.96 (64.62-101.44) ng ml(-1) h. No significant differences were observed in either time to peak concentration (tmax was 1.0 h for simvastatin alone and 1.5 h for the combination) or in the half-life (t1/2,z was 8.5 h in both cases). The combination was safe and well tolerated. CONCLUSIONS: The observed increased exposure to simvastatin 40 mg following coadministration of lacidipine is unlikely to be of clinical relevance.

Adult↗
PubMed2006

Simvastatin does not influence the intestinal P-glycoprotein and MPR2, and the disposition of talinolol after chronic medication in healthy subjects genotyped for the ABCB1, ABCC2 and SLCO1B1 polymorphisms.

AIMS: To evaluate whether simvastatin influences (i) the intestinal expression of P-glycoprotein (P-gp) and MRP2, and (ii) the disposition of the beta(1)-selective blocker talinolol, a substrate of these transporter proteins. METHODS: The disposition of talinolol after intravenous (30 mg) and single or repeated oral administration (100 mg daily) was monitored before and after chronic treatment with simvastatin (40 mg daily) in 18 healthy subjects (10 males, eight females, body mass index 19.0-27.0 kg m(-2)) genotyped for ABCB1, ABCC2 and SLCO1B1 polymorphisms. The steady-state pharmacokinetics of simvastatin was evaluated before and after repeated oral talinolol administration. The duodenal expression of ABCB1 and ABCC2 mRNA before and after simvastatin treatment was quantified using real-time reverse transcriptase-polymerase chain reaction (TaqMan. RESULTS: Simvastatin did not influence the expression of duodenal ABCB1 and ABCC2. There was no significant pharmacokinetic interaction between simvastatin and talinolol. Duodenal ABCB1 mRNA content was significantly correlated with the AUC(0-infinity) (r = 0.627, P = 0.039) and C(max) (r = 0.718, P = 0.013) of oral talinolol. The ABCB1 and ABCC2 gene polymorphisms did not influence simvastatin and talinolol disposition. The half-life of the latter was significantly shorter in the nine carriers with a SLCO1B1*1b allele compared with the seven subjects with the wild-type SLCO1B1*1a/*1a genotype (12.2 +/- 1.6 h vs. 14.5 +/- 1.4 h, P = 0.01). CONCLUSIONS: Simvastatin does not influence the intestinal expression of P-gp and MRP2 in man. There was no pharmacokinetic interaction between talinolol and simvastatin during their chronic co-administration to healthy subjects.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2006

Simvastatin prevents oxygen and glucose deprivation/reoxygenation-induced death of cortical neurons by reducing the production and toxicity of 4-hydroxy-2E-nonenal.

Lipid membrane peroxidation is highly associated with neuronal death in various neurodegenerative diseases including cerebral stroke. Here, we report that simvastatin decreases oxygen and glucose deprivation (OGD)/reoxygenation-evoked neuronal death by inhibiting the production and cytoxicity of 4-hydroxy-2E-nonenal (HNE), the final product of lipid peroxidation. Simvastatin markedly decreased the OGD/reoxygenation-evoked death of cortical neurons. OGD/reoxygenation increased the intracellular HNE level mostly in neuronal cells, not glial cells. Simvastatin decreased the intracellular level of HNE in neuronal cells exposed to OGD/reoxygenation. We further found that HNE induced the cytotoxicity in neuronal cells and synergistically increased the N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity. Simvastatin largely blocked the NMDA neurotoxicity potentiated by HNE. However, simvastatin did not alter the NMDA-evoked calcium influx in the absence or presence of HNE. HNE inhibited the activity of nuclear factor-kappa B (NF-kappaB), and the cytotoxicity of HNE was in good correlation with inactivation of NF-kappaB. Simvastatin reversed the inhibition of NF-kappaB activity induced by OGD/reoxygenation or HNE. The neuroprotection by simvastatin was significantly attenuated by various NF-kappaB inhibitors, implying that simvastatin inhibits the cytotoxicity of HNE at least in part by maintaining the activity of NF-kappaB. Further understanding of the neuroprotective mechanism of simvastatin may provide a therapeutic strategy for oxidative stress-related neurodegenerative diseases.

Aldehydes↗
PubMed2004

Effect of simvastatin on left ventricular mass in hypercholesterolemic rabbits.

Epidemiological studies showed that hypercholesterolemia is associated with higher left ventricular mass. Endothelin signaling is activated in hyperlipidemic animals and may contribute to progressive ventricular hypertrophy. Simvastatin has been shown to inhibit endothelin-1. However, the behavior of simvastatin on ventricular hypertrophy in hyperlipidemic animals is not well understood. In this study, we evaluated the hemodynamic, biochemical, and morphological responses to simvastatin in cholesterol-fed (1%) rabbits. The left ventricular weight increased 8 wk after cholesterol feeding compared with that in normocholesterolemic rabbits. Simvastatin at a clinical therapeutic dose (1.2 mg x kg(-1) x day(-1)) significantly decreased left ventricular weight by 14% and left ventricular myocyte sizes by 14% as isolated by enzymatic dissociation. Hypercholesterolemia upregulated ventricular preproendothelin-1 mRNA as assessed by real-time quantitative RT-PCR and elevated production of cardiac endothelin-1 concentration. The increased endothelin-1 responses can be inhibited after simvastatin administration. Left ventricular mass indexed by body weight positively correlated with tissue endothelin-1 levels (P = 0.0003). In Langendorff-perfused rabbit hearts, hyperlipidemia led to significant QT prolongation compared with normocholesterolemia, which can be reversed by administering simvastatin. In contrast, simvastatin-induced beneficial effects were reversed by the addition of mevalonate. The addition of bosentan, a nonspecific endothelin receptor blocker, improved the response in hypercholesterolemic rabbits and did not have additional beneficial effects in simvastatin-treated rabbits. The results of the present study suggest that the antihypertropic and electrocardiographic effects of simvastatin at a clinical therapeutic dose are mediated through inhibition of tissue endothelin-1 expression, which is linked to mevalonate metabolism, and result in an amelioration of cardiomyocyte hypertrophy development by an atherogenic diet.

Animals↗
PubMed2002

Simvastatin inhibits inflammatory properties of Staphylococcus aureus alpha-toxin.

BACKGROUND: Simvastatin, a 3-hydroxy-methylglutaryl coenzyme A reductase inhibitor, has been shown to lower serum cholesterol levels in clinical use. Moreover, statins exert beneficial effects in vascular diseases by inhibition of leukocyte rolling, adherence, and transmigration. The aim of this study was to determine if pretreatment with simvastatin attenuates Staphylococcus aureus alpha-toxin-induced increase in leukocyte-endothelial interactions during exotoxemia. METHODS AND RESULTS: The effects of simvastatin on leukocyte-endothelial cell interactions were observed by intravital microscopy in the rat mesenteric microcirculation. Simvastatin (50 or 100 microg/kg) was administered 18 hours before the study. Activation of microcirculation was induced by bolus administration of 40 microg/kg S aureus alpha-toxin. Exotoxemia resulted in a significant and time-dependent increase in leukocyte rolling, adherence, and transmigration of leukocytes as well as P-selectin expression on the intestinal vascular endothelium. Pretreatment with simvastatin significantly inhibited exotoxin-induced leukocyte rolling from 71+/-10 to 14+/-4.7 cells/min (P<0.01) and adherence from 14+/-3.5 to 0.4+/-0.2 cells (P<0.01). In addition, simvastatin pretreatment significantly inhibited transmigration of leukocytes from 10.5+/-1.2 to 4.2+/-0.9 (P<0.05) cells. Immunohistochemical detection of endothelial cell adhesion molecule P-selectin showed a 50% decrease in endothelial cell surface expression after simvastatin treatment. Furthermore, simvastatin treatment resulted in enhanced expression of endothelial cell NO synthase III in the intestinal microcirculation. CONCLUSIONS: These results demonstrate that simvastatin interferes with exotoxin-induced leukocyte-endothelial cell interactions, which may be relevant in various infectious diseases. Statin treatment may offer a new therapeutic strategy for these clinical conditions.

Animals↗
PubMed2001

Simvastatin exerts both anti-inflammatory and cardioprotective effects in apolipoprotein E-deficient mice.

BACKGROUND: Simvastatin attenuates ischemia and reperfusion in normocholesterolemic animals by stabilizing endothelial nitric oxide synthase activity and inhibiting neutrophil-mediated injury. Because endothelial dysfunction is a detrimental effect of hypercholesterolemia, we examined whether short-term treatment with simvastatin could inhibit leukocyte-endothelium interaction and attenuate myocardial ischemia-reperfusion injury in apoE-deficient (apoE(-/-)) mice fed a high-cholesterol diet. METHODS AND RESULTS: We studied leukocyte-endothelium interactions in apoE(-/-) mice fed a normal or a high-cholesterol diet after short-term (ie, 18 hours) simvastatin treatment. We also studied simvastatin treatment in myocardial ischemia-reperfusion injury by subjecting apoE(-/-) mice to 30 minutes of ischemia and 24 hours of reperfusion. ApoE(-/-) mice fed a high-cholesterol diet exhibited higher blood cholesterol levels, which were not affected by short-term simvastatin treatment. However, the increased leukocyte rolling and adherence that occurred in cholesterol-fed apoE(-/-) mice (P<0.001 versus control diet) were significantly attenuated by simvastatin treatment (P<0.01 versus vehicle). Cholesterol-fed apoE(-/-) mice subjected to myocardial ischemia-reperfusion also experienced increased myocardial necrosis (P<0.01 versus control diet), which was significantly attenuated by simvastatin (P<0.01 versus vehicle). Simvastatin therapy also significantly increased vascular nitric oxide production in apoE(-/-) mice. CONCLUSIONS: Simvastatin attenuates leukocyte-endothelial cell interactions and ameliorates ischemic injury in hypercholesterolemic mice independently of lipid-lowering actions.

Animals↗
PubMed2004

Simvastatin combined with ramipril treatment in hypercholesterolemic patients.

Mechanisms underlying biological effects of statin and angiotensin-converting enzyme inhibitor therapies differ. Thus, we studied vascular responses to combination therapy in hypercholesterolemic patients. A randomized, double-blind, placebo-controlled, crossover trial was conducted with 50 hypercholesterolemic patients with simvastatin and either placebo or ramipril (study I) and in 45 hypercholesterolemic diabetic patients with simvastatin or ramipril with placebo or simvastatin combined with ramipril (study II) for 2 months with 2 months washout. In study I simvastatin combined with ramipril significantly reduced blood pressure after 2 months. Simvastatin alone or combined with ramipril significantly changed lipoproteins, improved percent flow-mediated dilator response to hyperemia by 30+/-5% and 53+/-6%, respectively (P<0.001), and reduced plasma levels of malondialdehyde by 4+/-7% (P=0.026) and 25+/-4% (P<0.001), respectively. Monocyte chemoattractant protein-1 levels decreased by 3+/-3% and 12+/-2%, respectively (P=0.049 and P=0.001, respectively), C-reactive protein levels changed by 0% and 18%, respectively (P=0.036 and P<0.001, respectively), and plasminogen activator inhibitor-1 antigen levels changed by -7+/-7% and 17+/-5%, respectively (P=0.828 and P<0.001, respectively). In study II ramipril alone did not significantly change lipoproteins and C-reactive protein levels, however, simvastatin combined with ramipril significantly changed lipoproteins and C-reactive protein levels more than ramipril alone (P<0.001 and P=0.048 by ANOVA, respectively). Ramipril alone or simvastatin combined with ramipril significantly improved the percent flow-mediated dilator response to hyperemia (both P<0.001), however, simvastatin combined with ramipril showed significantly more improvement than ramipril alone (P<0.001 by ANOVA). Simvastatin combined with ramipril significantly improved endothelium-dependent vasodilation and fibrinolysis potential and reduced plasma levels of oxidant stress and inflammation markers in hypercholesterolemic patients.

Angina Pectoris↗
PubMed2005

LDL-C goal attainment with the addition of ezetimibe to ongoing simvastatin treatment in coronary heart disease patients with hypercholesterolemia.

OBJECTIVE: To evaluate the addition of ezetimibe or placebo to on-going simvastatin treatment on attaining the LDL-C treatment target of </= 2.60 mmol/L (100 mg/dL) in coronary heart disease (CHD) patients with hypercholesterolemia. METHODS: Patients with documented CHD were recruited if they were on a stable dose of simvastatin 10 mg or 20 mg for at least 6 weeks, had LDL-C > 2.60 mmol/L and </= 4.20 mmol/L (> 100 mg/dL and </= 160 mg/dL), triglycerides </= 4.00 mmol/L (355 mg/dL) and hepatic transaminases and creatine kinase </= 50% above the upper limit of normal. After a 4-week placebo and diet run-in period, eligible patients were randomized to a double-blind, placebo-controlled comparative study with ezetimibe 10mg co-administered with on-going simvastatin 10mg or 20 mg (n = 208) versus placebo to match ezetimibe co-administered with simvastatin 10mg or 20mg for 6 weeks (n = 210). RESULTS: When ezetimibe was added to on-going simvastatin therapy, a significantly greater percentage of patients attained the LDL-C target of </= 2.60 mmol/L after 6 weeks of treatment compared to placebo added to on-going simvastatin (80.4% vs. 17.4%, respectively;p </= 0.001). When co-administered with on-going simvastatin therapy, mean percentage reduction in LDL-C from baseline was significantly larger in the ezetimibe group compared to placebo (27.1% vs. 4.1%, respectively; p </= 0.001). The co-administration of ezetimibe or placebo to on-going simvastatin treatment was generally well tolerated. CONCLUSIONS: Ezetimibe co-administered with on-going simvastatin 10 mg or 20 mg treatment enabled more CHD patients with hypercholesterolemia to attain the LDL-C treatment target of </= 2.60 mmol/L.

Administration, Oral↗
PubMed2006

Simvastatin-induced decline in cognition.

OBJECTIVE: To describe a case of new-onset cognitive difficulties in an older patient after initiation of simvastatin therapy. CASE SUMMARY: A 64-year-old man developed cognitive difficulties within one week after starting simvastatin 40 mg/day. There was a 3 point decline from baseline in the Mini-Mental State Exam (MMSE) score 2 weeks after simvastatin was initiated, as well as declines in the Activities of Daily Living and Instrumental Activities of Daily Living scales. Simvastatin was discontinued, and the patient's cognition improved to baseline within 6 weeks. Rechallenge with simvastatin at half the original dose was attempted. His cognition deteriorated over a 2 week period. Simvastatin was stopped, and the patient's MMSE scores returned to baseline within 4 weeks. DISCUSSION: This patient developed new-onset problems with short-term memory, long-term memory, and item misplacement in addition to the baseline problems with names and word-finding that had been present prior to beginning statin therapy. Decreased cognition identified with neuropsychological tests has been shown in clinical trials with simvastatin; however, as of August 23, 2006, this is the first report of cognitive and functional problems that have been documented using standardized instruments. The Naranjo probability scale revealed a highly probable adverse reaction of cognitive decline associated with simvastatin therapy. CONCLUSIONS: Statins are commonly used in the older population. Simvastatin appeared to be associated with worsened cognition in our patient, an older person with preexisting memory problems. Statins should be used with caution in this vulnerable population.

Brief Psychiatric Rating Scale↗
PubMed2004

Effects of simvastatin on bone turnover and BMD: a 1-year randomized controlled trial in postmenopausal osteopenic women.

UNLABELLED: To study effects of statins on human bone, 82 postmenopausal women were randomized to 1-year treatment with simvastatin 40 mg/day or placebo. The study showed no effect of simvastatin on biochemical bone markers or on BMD at the hip or spine. Thus, our results do not support a general beneficial effect of simvastatin on bone. INTRODUCTION: Statins have been reported to cause bone anabolic as well as antiresorptive effects, and therefore statins have been suggested as potential agents in treatment of osteoporosis. MATERIALS AND METHODS: In a double-blinded design, 82 healthy postmenopausal women with osteopenia were randomized to 1-year simvastatin treatment 40 mg/day or placebo. BMD and plasma levels of cholesterol, parathyroid hormone (PTH), and biochemical bone markers were measured at baseline, after 1 year of treatment (week 52), and 26 weeks after withdrawal of treatment (week 78). Calcium supplements (400 mg/day) were administrated during the entire 1.5-year study period. RESULTS: Seventy-eight women completed the 1-year treatment. After 1 year, simvastatin but not placebo caused reduced plasma cholesterol (-27% versus +1%, p < 0.001) and low-density lipoprotein (LDL) levels (-43% versus +1%, p < 0.001). After withdrawal of treatment, cholesterol and LDL levels returned to baseline levels and no longer differed from the placebo group. However, plasma levels of PTH and biochemical bone markers did not differ between groups at week 52 or 78. Compared with placebo, simvastatin caused no changes in BMD at the lumbar spine, total hip, femoral neck, or whole body at week 52 or 78. However, a significant increase in BMD was found in response to simvastatin at the forearm. Within the simvastatin group, changes in cholesterol levels did not correlate to BMD changes at any site. CONCLUSIONS: Our results do not support a general beneficial effect of simvastatin on bone.

Aged↗
PubMed2005

Simvastatin promotes cell metabolism, proliferation, and osteoblastic differentiation in human periodontal ligament cells.

BACKGROUND: Simvastatin is one of the cholesterol lowering drugs. Recent studies demonstrated that it has a bone stimulatory effect. Periodontal ligament (PDL) cells are believed to play an important role in periodontal regeneration; that is, they may differentiate into specific cells which make cementum, bone, and attachment apparatus. It would be of interest whether simvastatin has a positive effect on PDL cells. Therefore, effects of simvastatin on cell proliferation and osteoblastic differentiation in PDL cells were analyzed. METHODS: Human PDL cells were cultured in monolayer with simvastatin for 24 and 72 hours and cell metabolism and proliferation were determined. To analyze osteoblastic differentiation, human PDL cells were cultured in organoid culture for 7, 14, and 21 days and alkaline phosphatase (ALP) activity, osteopontin (OPN), bone morphogenetic protein (BMP) -2, osteocalcin (OCN), and calcium contents were measured. They were co-treated by simvastatin and mevalonate. RESULTS: Simvastatin enhanced cell proliferation and metabolism dose-dependently after 24 hours. Simvastatin also stimulated ALP activity of human PDL cells dose-dependently, and maximum effect was obtained at the concentration of 10(8) M. In time dependent analysis, 10(8) M simvastatin stimulated ALP activity and osteopontin content after 7 days and calcium contents after 21 days. BMP-2 and OCN contents were not detected. Moreover this statin-enhanced ALP activity was abolished by mevalonate. CONCLUSION: These results suggest that at low concentration, simvastatin exhibits positive effect on proliferation and osteoblastic differentiation of human PDL cells, and these effects may be caused by the inhibition of the mevalonate pathway.

Adolescent↗
PubMed1999

Concurrent use of simvastatin and estrogen--progestin therapy compared with each therapy alone for hypercholesterolemia in postmenopausal women.

OBJECTIVE: Substantial improvements in lipoprotein-lipid profiles have previously been shown with both simvastatin and combined estrogen-progestin therapy in postmenopausal hypercholesterolemic women. Since little is known about the impact of the concomitant use of these therapies, the effects of concurrent hormone therapy and simvastatin in hypercholesterolemic postmenopausal women have been evaluated. METHODS: Twenty-three postmenopausal women with fasting serum total cholesterol levels greater than 250 mg/dl received, in a randomized cross-over design, simvastatin (10 mg daily) for 8 weeks or postmenopausal hormone therapy (up to 1.25 mg of conjugated equine estrogens plus 5 mg of medroxyprogesterone acetate daily) for 8 weeks, with an 8-week wash-out interval between the two treatment periods. In a third, non-randomized treatment period after a second wash-out interval, each woman received a combination of simvastatin and postmenopausal hormone therapy in the same dosage regimens as above. Fasting blood was sampled monthly from baseline to measure total cholesterol, high- and low-density lipoprotein (HDL and LDL) cholesterol, triglycerides and lipoprotein(a). RESULTS: For total cholesterol, the mean decreases with hormone therapy, simvastatin and combination therapy were 12% (95% confidence interval 6-17%), 26% (20-31%) and 28% (24-31%), respectively, and for LDL cholesterol 21% (14-27%), 37% (30-44%) and 46% (41-51%), respectively. Simvastatin was more effective than hormone therapy (p < 0.001), while the effect of the combined therapy was even greater (total cholesterol, p = 0.012; LDL cholesterol, p < 0.001). The level of HDL cholesterol increased similarly with each treatment: 4% (-3-11%), 6% (2-10%) and 7% (2-13%), respectively. Triglyceride levels increased with hormone therapy and decreased with simvastatin (p < 0.001), while there was little change with the combination (effect of combined therapy vs. simvastatin, p = 0.002; vs. hormone therapy, p < 0.001). Both hormone therapy and combined therapy reduced lipoprotein(a) similarly (-23% and -14%, respectively, p = 0.078). Simvastatin had no effect on lipoprotein(a) levels. CONCLUSION: For postmenopausal women with hypercholesterolemia, use of a statin in combination with continuous combined oral estrogen and progestin therapy can result in a more cardioprotective lipoprotein-lipid profile than that achieved with either therapy used alone.

Anticholesteremic Agents↗
PubMed2005

Conversion to atorvastatin in patients intolerant or refractory to simvastatin therapy: the CAPISH study.

OBJECTIVE: To examine the safety and efficacy of switching from simvastatin to atorvastatin in patients who had either an inadequate lipid-lowering response with, or an adverse reaction to, simvastatin. PATIENTS AND METHODS: The Conversion to Atorvastatin in Patients Intolerant or Refractory to Simvastatin Therapy (CAPISH) study was designed in 2 parts: a retrospective cohort study of patients (group A), identified from a large pharmacy database, who converted from simvastatin to atorvastatin at a single academic military medical center (between April 1998 and March 2002) and a prospective cohort study of patients (group B) monitored in a lipid clinic at the same institution (between April 2002 and March 2003). Group A was identified by 2 or more simvastatin prescription fills and at least 1 atorvastatin prescription fill. Group B was identified by a physician-perceived need to switch from simvastatin to atorvastatin. Clinical, pharmaceutical, and laboratory records of both cohorts were reviewed. RESULTS: Approximately 1 in 4 simvastatin-treated patients discontinued therapy during a 4-year period. The most common reason for switching to atorvastatin was inadequate low-density lipoprotein (LDL) cholesterol control, although asymptomatic creatine kinase (CK) elevation and myalgias were also common. In most cases of myositis and in nearly all cases of rhabdomyolysis, patients were taking 80 mg of simvastatin. Achievement of National Cholesterol Education Program LDL cholesterol goals increased from 25% to 63% in group A and from 13% to 78% in group B, both P<.001. Significant reductions in CK also were seen in both groups. Adherence to atorvastatin was greater than 80% in both groups after 28.1+/-13.2 months (group A, 841 patients) and 8.1+/-3.8 months (group B, 104 patients). Among patients not taking atorvastatin at follow-up, 58% were no longer taking statins. CONCLUSION: Atorvastatin was well tolerated in patients who previously were taking simvastatin. Serum lipid panels were improved substantially and CK levels were decreased without compromise to patient safety.

Aged↗
PubMed2000

Attaining United States and European guideline LDL-cholesterol levels with simvastatin in patients with coronary heart disease (the GOALLS study).

The effectiveness and safety of simvastatin in reducing low-density lipoprotein cholesterol (LDL-C) to target levels in patients with coronary heart disease (CHD) were evaluated in the GOALLS (Getting to Appropriate LDL-C Levels with Simvastatin) study. This multinational, multicentre, prospective, open-label, study consisted of a six-week diet washout period followed by a 14-week titrate-to-goal treatment period with simvastatin. One hundred and ninety-eight men and women with documented CHD and a fasting LDL-C level between 115 mg/dl (3.0 mmol/l) and 180 mg/dl (4.7 mmol/l) and triglycerides (TGs) < or = 400 mg/dl (4.5 mmol/l) were enrolled. The patients were started on 20 mg simvastatin with dose titration up to 80 mg if the LDL-C remained above 100 mg/dl at weeks 6 and 10. The key efficacy parameters were the percentage of patients achieving US and European LDL-C goals [< or = 100 mg/dl (2.6 mmol/l) and < or = 115 mg/dl (3.0 mmol/l), respectively]. Safety was evaluated by monitoring laboratory tests and recording adverse events. After 14 weeks of simvastatin (20-80 mg) treatment, approximately 90% of the patients achieved LDL-C goals according to US (87%) and European (94%) guidelines. Most patients (72-93%) achieved target LDL-C levels on 20 mg simvastatin. An estimated 14% of the patients required titration to the 80 mg dose. Treatment with simvastatin (20-80 mg) produced statistically significant improvements in all measured lipid variables by the end of the study. The mean reductions in total cholesterol and LDL-C, and the median reduction in TG, were 28%, 41% and 16%, respectively. The increase in high-density lipoprotein cholesterol and apolipoprotein A-1 were 5% and 4%, respectively. Simvastatin was well tolerated across the dosage range. In conclusion, simvastatin, 20-80 mg/day, was safe and highly effective at reducing LDL-C levels. The recommended US and European LDL-C treatment goals were achieved in approximately 90% of the patients. These goals were similarly achieved for a variety of high-risk sub-groups (hypertensives, diabetics and elderly patients).

Aged↗
PubMedDate not supplied

Effects of simvastatin on the development of osteopenia caused by ovariectomy in rats.

Simvastatin is a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-determining enzyme for cholesterol synthesis which is used in the treatment of hypercholesterolemias, particularly in type IIa and IIb hyperlipoproteinemias, frequently in postmenopausal women. Inhibition of cholesterol synthesis by simvastatin may cause disorders of bone remodelling. The aim of the present study was to investigate the effects of simvastatin (3 mg and 6 mg/kg/day per os) administered for 4 weeks on the development of ovariectomy-induced osteopenia in 3-month-old female Wistar rats. The experiments were carried out on six groups of animals: I (C)--sham operated rats, II (S-3)--sham operated rats + simvastatin 3 mg/kg/day p.o., III (S-6)--sham operated rats + simvastatin 6 mg/kg/day p.o., IV (OVX)--ovariectomized rats, V (OVX + S-3)--ovariectomized rats + simvastatin 3 mg/kg/day p.o., VI (OVX + S-6)--ovariectomized rats + simvastatin 6 mg/kg/day p.o. In all the groups, we examined body weight gain, and macrometrical, histomorphometrical and mechanical parameters. Bilateral ovariectomy induced osteopenic skeletal changes in mature female rats. In cortical bone, ovariectomy intensified resorption processes at the marrow cavity, as indicated by a decrease in endosteal transverse growth and an increase in transverse cross-section surface area of the marrow cavity in the tibia. Intensification of resorption processes was observed in cancellous bone (a statistically significant decrease in the width of trabeculae in the epiphysis and metaphysis of the femur). Structural changes in the long bones resulting from bilateral ovariectomy were manifested by deterioration of mechanical properties of the shaft and neck of the femur. The force needed to fracture the neck and shaft of the femur was significantly smaller than that in sham operated rats. Simvastatin (3 and 6 mg/kg/day p.o.) slightly influenced bone remodelling in sham operated rats. Simvastatin (3 and 6 mg/kg p.o. daily) administered to ovariectomized rats intensified bone formation processes and decreased bone resorption processes induced by bilateral ovariectomy, showing stronger activity at 6 mg/kg.

Animals↗