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PubMed1994

Gender and diet interactions with simvastatin treatment.

Twelve men and thirteen women with hypercholesterolaemia participated in a 20-week controlled cross-over trial to assess the interaction between dietary fat intake, gender and an HMGCoA reductase inhibitor, simvastatin. Subjects were matched for total cholesterol, age, body mass index (BMI) and plasma triglyceride. Gender-drug interactions were noted with men demonstrating only a 27% fall in LDL cholesterol with simvastatin when consuming a high fat (40% energy) diet compared to women with a 35% fall. In men, the lowest LDL/HDL ratio was achieved with simvastatin on a low fat diet (22% energy). Gender differences in the effect of simvastatin on HDL were confined to HDL3 cholesterol, although the drug raised HDL2 in both sexes on the low fat diet. Simvastatin was responsible for an 11% increase in HDL3 cholesterol in men particularly when on a low fat diet but did not affect HDL3 in women. An important diet-drug interaction was seen in triglyceride response, with a lowering of 17%-20% only when subjects were on a low fat diet. There was a gender difference in response to dietary fat change with men demonstrating a 19% decrease in triglycerides with dietary fat reduction while on simvastatin, whereas women showed a 9% increase which did not reach significance. Men also responded more favourably to dietary fat reduction with at least two-fold greater falls in plasma cholesterol than was seen in women.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholesterol↗
PubMed1995

Long-term efficacy and tolerability of simvastatin in a large cohort of elderly hypercholesterolemic patients.

The long-term efficacy and tolerability of simvastatin, a 3-hydroxy-3-methylglutaryl-co-enzyme A (HMG-CoA) reductase inhibitor, was assessed during a 24-month follow-up period in 168 elderly hypercholesterolemic patients. After completing a 4 week double blind dose ranging study with simvastatin, 47 males and 122 females over 62 years of age with type II hyperlipidemia, a total cholesterol level above 6.5 mmol/l and clinically manifest cardiovascular disease were included in this extended study. A total of 159 patients completed the 12-month follow-up period and 141 patients were monitored over the full 24 months. All patients were started on 10 mg simvastatin once daily and the dosage was increased until the target levels of low density lipoprotein (LDL) cholesterol between 2.3 mmol/l (90 mg/dl) and 3.6 mmol/l (140 mg/dl) were reached. Fifty percent of patients reached the targeted LDL cholesterol goal of < 3.6 mmol/l (140 mg/dl) during the study. At study completion, 65 patients (39%) were taking 40 mg simvastatin per day, 56 patients (33%) 20 mg, 42 patients (25%) 10 mg and 5 patients (3%) only used 5 mg per day. Sixteen patients (9%) received concomitant lipid lowering therapy. Over 2 years, the mean decrease in LDL cholesterol ranged from 36% to 38%, the median decrease in triglycerides was 12% to 19% and the mean increase in high density lipoprotein (HDL) cholesterol ranged from 9% to 10%, respectively. Seven patients discontinued simvastatin because of adverse clinical or laboratory events, but only in two (1.1%) was this considered to be drug-related. Side-effects were mild and most frequently gastrointestinal in nature. Mean changes in asparate aminotransferase (AST) were not significantly different from zero and mean changes in alanine aminotransferase (ALT) and creatine phosphokinase (CPK) showed a small increase. We conclude that simvastatin is an efficacious and well-tolerated treatment for hypercholesterolemia in elderly individuals for extended periods.

Aged↗
PubMed1994

Effect of simvastatin treatment on plasma apolipoproteins and hepatic apolipoprotein mRNA levels in the genetically hypercholesterolemic rat (RICO).

The effects of long-term treatment with simvastatin on plasma lipoproteins, plasma apolipoproteins, and on hepatic apolipoprotein gene expression were evaluated in genetically hypercholesterolemic (RICO) rats. Simvastatin administration caused a decrease in plasma triglyceride and phospholipid concentrations. Plasma cholesterol concentration was not changed by simvastatin, but cholesterol distribution among plasma lipoproteins was altered. Plasma apo B, apo A-I, and apo A-IV concentrations were lowered by simvastatin treatment whereas plasma apo E concentration was not affected by this drug. In the liver, simvastatin treatment induced a significant decrease of apo E mRNA level but had no effect on apo B, apo A-I, and apo A-IV mRNA abundances. It appears that simvastatin may modify plasma apolipoprotein concentrations by influencing their hepatic synthesis at both pre- and posttranscriptional levels.

Animals↗
PubMedDate not supplied

Effects of simvastatin versus gemfibrozil on lipids and glucose control in patients with non-insulin-dependent diabetes mellitus. NIDDM Study Group.

The objective of this study was to compare the lipid-altering efficacy and safety of simvastatin with that of gemfibrozil in hypercholesterolemic patients with non-insulin-dependent diabetes mellitus (NIDDM). The study was a 24-week, double-blind, randomized, multicenter trial conducted at clinics and hospitals in the United States, Austria, Germany, Brazil, and New Zealand. The study population included 168 men and women aged 34 to 78 years with NIDDM and primary hypercholesterolemia (low-density lipoprotein cholesterol [LDL-C] level at screening was > or = 4.9 mmol/L with no other risk factor or > or = 4.1 mmol/L with one or more other risk factors). All patients had been under moderate-to-good diabetic control (hemoglobin A1c [HbA1c] < or = 10.0%) for at least 6 months with diet alone, oral hypoglycemic agents, or insulin therapy. Patients meeting eligibility criteria were randomized to receive either simvastatin 10 mg (titrated up to 40 mg to achieve an LDL-C level < 3.4 mmol/L) once in the evening or gemfibrozil 600 mg twice daily. There were 81 patients in the simvastatin group and 87 patients in the gemfibrozil group. After 17 weeks of treatment, simvastatin significantly reduced levels of total cholesterol, LDL-C, and very-low-density lipoprotein cholesterol (VLDL-C) by approximately 25%, 33%, and 20%, respectively (P < or = 0.001), and triglycerides by about 9% (P < or = 0.05). The drug increased high-density lipoprotein cholesterol (HDL-C) levels by about 6% (P < 0.01). Gemfibrozil significantly reduced total cholesterol, VLDL-C, and triglyceride levels by approximately 8%, 38%, and 27%, respectively (P < 0.001); it significantly increased HDL-C values by about 12% (P < 0.001). Gemfibrozil lowered LDL-C levels by 4% but not significantly. The decreases in total cholesterol and LDL-C were significantly greater (P < 0.001) in the simvastatin group, and decreases in VLDL-C and triglycerides were significantly greater in the gemfibrozil group (P < 0.01). The changes in HDL-C were not significantly different between groups. LDL-C values of < 3.4 mmol/L were achieved in 60% of the simvastatin patients and 14% of the gemfibrozil patients. There were no significant between-group differences in fasting serum glucose or HbA1c at any time point. Glycemic profiles (performed at baseline and after 17 weeks of treatment) and glucose area under the curve (at baseline and after 17 weeks of treatment) were not significantly different between treatment groups. Both drugs were generally well tolerated.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1996

Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro.

It has been shown previously that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA RIs) such as compactin and lovastatin suppress human lymphocyte functions in vitro (Cuthbert and Lipsky, 1981; Cutts and Bankhurst, 1989). Although it is not fully understood what inhibitory role the HMG-CoA RIs perform in causing this suppression, we show in this study that a certain inhibition threshold (inhibition level > 90%) of lymphocytic HMG-CoA reductase is required for the HMG-CoA RIs to attain effective inhibitory action in human lymphocyte lymphocyte functions in vitro. Thus the inhibitory activity of simvastatin, a lipophilic inhibitor, on sterol synthesis (HMG-CoA reductase activity) in lymphocytes was as much as 430 times more potent than that of pravastatin sodium, a hydrophilic inhibitor (IC50; 0.013 microM and 5.6 microM, respectively), and although pravastatin sodium and simvastatin at concentration levels of 10 and 0.016 microM respectively, inhibited the sterol synthesis in just over 50%, they failed to inhibit the lymphocyte functions. Significant inhibition (P < 0.01) of lymphocyte functions, including lymphocyte proliferative response to a variety of stimuli and activated natural killer-cell cytotoxicity, was demonstrated only when greater than 90% of the sterol synthesis in lymphocytes was inhibited by either simvastatin or simvastatin sodium salt at concentrations above 2 microM. This simvastatin-induced inhibition of lymphocyte functions was almost completely reversed by the addition of a 1 mM solution of mevalonate. Although simvastatin at a lower clinical blood concentration of 0.016 microM failed to inhibit either lymphocyte functions or HMG-CoA reductase activity sufficiently, at this level it caused a significant increase in cyclosporin A-induced suppression of T-cell response. These results infer that insufficient inhibition (in the 50% region) of HMG-CoA reductase activity by a low clinical blood concentration of HMG-CoA RIs, could still render the lymphocytes susceptible to immunosuppressive treatments. Pravastatin sodium on the other hand, is inactive in inhibiting lymphocyte functions in vitro, and such inactivity can be explained solely of the basis of its failure to inhibit HMG-CoA reductase activity in lymphocytes sufficiently.

Cyclosporine↗
PubMed2005

Simvastatin does not inhibit intimal hyperplasia and restenosis but promotes plaque regression in normocholesterolemic patients undergoing coronary stenting: a randomized study with intravascular ultrasound.

BACKGROUND: Restenosis after coronary stenting is mainly caused by intimal hyperplasia. Both experimental and clinical studies suggest that statins may be able to inhibit intimal hyperplasia and, therefore, in-stent restenosis (ISR), by mechanisms beyond lipid lowering. METHODS: In a 12-month study, we randomized 71 normocholesterolemic patients to 20 mg simvastatin or no treatment, 2 weeks before elective coronary stenting. Patients were evaluated by quantitative coronary angiography and intravascular ultrasound, immediately after the index procedure and at the 12-month catheterization. RESULTS: Binary ISR was present in 15% and in 18% of simvastatin-treated patients and controls, respectively (P = NS). Intimal hyperplasia did not differ significantly between the 2 groups (3.6 +/- 1.8 vs 3.8 +/- 2.3 mm3/mm, 34% +/- 15% vs 35% +/- 23% for simvastatin vs controls, P = NS). However, persistent plaque decreased with simvastatin but increased in controls (-4.0 +/- 4.0 vs +1.6 +/- 3.8 mm3/mm, -14% +/- 10% vs +6% +/- 12%, P < .05). The same behavior was shown by intermediate plaques at nonstented sites (-2.5 +/- 3.0 vs +1.0 +/- 3.0 mm3/mm, -10% +/- 8% vs +9% +/- 9%, P < .05). Major adverse events at 12 months were present in 11% and 24% of simvastatin-treated patients and controls, respectively (P = .20). CONCLUSIONS: In normocholesterolemic patients undergoing coronary stenting, simvastatin does not prevent intimal hyperplasia or ISR, but it promotes atherosclerotic regression both at stented and at nonstented sites.

Coronary Angiography↗
PubMed2004

Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors.

Three-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (statins) are first-line treatments for hypercholesterolemia. Although exceedingly well tolerated, treatment with statins incurs a small risk of myopathy or potentially fatal rhabdomyolysis, particularly when coadministered with medications that increase their systemic exposure. Studies compared the multiple-dose pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with 4 inhibitors of cytochrome P450-3A4 isoenzymes in healthy subjects. Compared with pravastatin alone, coadministration of verapamil, mibefradil, or itraconazole with pravastatin was associated with no significant changes in pravastatin pharmacokinetics. However, concomitant verapamil increased the simvastatin area under the concentration:time curve (AUC) approximately fourfold, the maximum serum concentration (C(max)) fivefold, and the active metabolite simvastatin acid AUC and C(max) approximately four- and threefold, respectively (all comparisons p <0.001). Similar (greater than fourfold) important increases in these parameters and a >60% increase in the serum half-life (p = 0.03) of atorvastatin were observed when coadministered with mibefradil. The half-life of atorvastatin also increased by approximately 60% (p = 0.052) when coadministered with itraconazole, which elicited a 2.4-fold increase in the C(max) of atorvastatin and a 47% increase in the AUC (p <0.001 for C(max) and AUC). Clarithromycin significantly (p <0.001) increased the AUC (and C(max)) of all 3 statins, most markedly simvastatin ( approximately 10-fold increase in AUC) and simvastatin acid (12-fold), followed by atorvastatin (greater than fourfold) and then pravastatin (almost twofold). Pravastatin has a neutral drug interaction profile relative to cytochrome P450-3A4 inhibitors, but these substrates markedly increase systemic exposure to simvastatin and atorvastatin.

Adolescent↗
PubMed2004

Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults.

PURPOSE: In our initial study of the potential effects of cholesterol-lowering interventions on cognitive functioning, treatment with lovastatin as compared with placebo caused performance decrements on several neuropsychological tests, whereas scores on other tests were unaffected. The current study was designed to confirm and extend those findings. METHODS: The study comprised 308 hypercholesterolemic adults between 35 and 70 years of age. Employing a randomized double-blind design, we assigned participants to daily treatment with placebo, 10 mg of simvastatin, or 40 mg of simvastatin for 6 months. A neuropsychological test battery was administered to assess cognitive functioning at baseline and at the end of the treatment period. RESULTS: A total of 283 subjects completed the study: 94 subjects on placebo, 96 taking 10 mg of simvastatin, and 93 taking 40 mg of simvastatin. Compared with placebo, decremental effects of simvastatin treatment were found on tests previously observed to be sensitive to statins (P = 0.008; difference in summary z scores = 0.18; 95% confidence interval [CI]: 0.07 to 0.29) and on tests not previously administered (P = 0.04; difference in summary z scores = 0.17; 95% CI: 0.05 to 0.29), but not on tests previously observed to be insensitive to statins (P = 0.84; difference in summary z scores = 0.02; 95% CI: -0.07 to 0.10). For the three tests specifically affected by simvastatin, effects on cognitive performance were small, manifest only as failure to improve during the 6 months of treatment (compared with placebo), and were confounded by baseline differences on one test. CONCLUSION: This study provides partial support for minor decrements in cognitive functioning with statins. Whether such effects have any long-term sequelae or occur with other cholesterol-lowering interventions is not known.

Adult↗
PubMed2003

Normalization of daytime triglyceridemia by simvastatin in fasting normotriglyceridemic patients with premature coronary sclerosis.

Postprandial hyperlipidemia is associated with premature coronary sclerosis in fasting normolipidemic subjects. Self-determined daytime capillary triglyceride (cTG) profiles were compared between 26 fasting normotriglyceridemic patients with premature coronary artery disease (CAD) and 26 controls matched for gender, age and BMI. Daytime triglyceridemia was calculated as total area under the cTG-curve (cTG-AUC). Total and LDL cholesterol were not different between CAD patients (5.4+/-0.8 mmol/l and 3.6+/-0.7 mmol/l, respectively) and controls (5.0+/-0.9 mmol/l and 3.3+/-0.8 mmol/l, respectively). Patients with CAD were characterized by a 44% higher cTG-AUC than matched controls (P<0.01). Using logistic regression analysis, cTG-AUC was the strongest predictor of the presence of CAD (P<0.001). Adding apo AI to the model improved the predictive power from 71 to 77%. Sixteen patients were studied after increasing doses of simvastatin up to 80 mg/day. Although the target for LDL cholesterol was reached by simvastatin 20mg/day, significant effects on cTG-AUC were found only by higher doses of simvastatin. Simvastatin 40 mg/day decreased cTG-AUC by 28% (P<0.05 versus baseline), reaching comparable values as in controls, without further improvement with simvastatin 80 mg/day (26% reduction versus baseline; P<0.05). Daytime triglyceridemia is linked to premature coronary sclerosis in fasting normotriglyceridemic patients. A higher dose of simvastatin was needed to normalize daytime triglyceridemia than was required to "normalize" LDL cholesterol.

Adult↗
PubMed2006

Combined therapy with ramipril and simvastatin has beneficial additive effects on tissue factor activity and prothrombin fragment 1+2 in patients with type 2 diabetes.

Tissue factor (TF) plays a pivotal role in thrombus formation. Statins and angiotensin converting enzyme inhibitors attenuate expression of TF by distinct mechanism. Therefore, we hypothesized that combined therapy with simvastatin and ramipril may have additive beneficial anti-atherogenic effects to lower TF activity when compared with either drug alone. This was a randomized, double-blind, placebo-controlled cross-over trial with three treatment arms (each 2 months) and two washout periods (each 2 months). Fifty patients with type 2 diabetes were given simvastatin 20 mg and placebo, simvastatin 20 mg and ramipril 10 mg, or ramipril 10 mg and placebo daily during each treatment period. Simvastatin and ramipril monotherapy tended to reduce TF activity (0.53 to 0.46 nM, P=0.056; 0.54 to 0.50 nM, P=0.167, respectively) while combined therapy had a significant effect (0.64 to 0.43 nM, P<0.001). All three therapies significantly reduced prothrombin fragment 1+2 (F1+2) levels from their respective baselines (P=0.037, P<0.001, and P=0.057, respectively). Combined therapy significantly reduced TF activity and F1+2 levels to a greater extent than either simvastatin or ramipril alone (P=0.029 and P=0.040 by ANOVA, respectively). Percent changes in TF activity and percent changes in F1+2 levels were significantly correlated. All three therapies reduced CD40 ligand levels from their respective baselines (P=0.098, P<0.001, and P=0.002, respectively) with no significant differences among these three therapies (P=0.204 by ANOVA). Ramipril combined with simvastatin significantly reduces plasma TF activity and F1+2 levels to a greater extent than monotherapy with either drug in patients with type 2 diabetes.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

Simvastatin inhibits lipopolysaccharide-induced tumor necrosis factor-alpha expression in neonatal rat cardiomyocytes: The role of reactive oxygen species.

Tumor necrosis factor-alpha (TNF-alpha) is implicated in heart failure and cardiomyocytes themselves can express TNF-alpha. Nevertheless, the mechanisms and regulations of TNF-alpha expression in cardiomyocytes remain poorly understood. The present study was to investigate the effects of simvastatin on TNF-alpha expression in cardiomyocytes and the underlying molecular mechanisms. In neonatal rat cardiomyocytes, RT-PCR and ELISA showed lipopolysaccharide (LPS)-induced TNF-alpha expression was attenuated by simvastatin pretreatment in a dose-dependent manner. The reactive oxygen species (ROS) scavenger N-acetylcysteine and the NADPH oxidase inhibitor diphenyleneiodonium also inhibited the LPS-induced expression of TNF-alpha. Dichlorofluorescein-fluorescence and cytochrome c reduction assay indicated LPS increased ROS generation and NADPH oxidase activity in cardiomyocytes, which were abrogated by simvastatin. Furthermore, similar to LPS, exogenous hydrogen peroxide also increased TNF-alpha secretion, but simvastatin did not significantly affect the hydrogen peroxide-induced TNF-alpha secretion. All the effects of simvastatin as mentioned above were completely reversed by concomitant pretreatment with mevalonate, a key intermediate during cholesterol synthesis. These results suggest that simvastatin attenuates LPS-induced TNF-alpha expression in cardiomyocytes via inhibition of activation of NADPH oxidase and subsequent ROS generation.

Acetylcysteine↗
PubMed2005

Promotion of bone formation by simvastatin in polyethylene particle-induced osteolysis.

The effects of statins on bone formation in periprosthetic osteolysis have not been determined to date. We investigated the effect of the HMG-CoA reductase inhibitor simvastatin on osteoblastic bone formation under conditions of ultra-high molecular weight polyethylene (UHMWPE) particle-induced osteolysis. The murine calvarial osteolysis model was utilized in 21 C57BL/J6 mice randomized to three groups. Group I underwent sham surgery only, group II received UHMWPE particles, and group III, particles and simvastatin treatment. After 2 weeks, calvaria were processed for histomorphometry and stained with Giemsa dye. New bone formation was measured as osteoid tissue area within the midline suture. Bone thickness was quantified as indicator of net bone growth. Statistical analysis was performed using one-way ANOVA and a Student's t-test. New bone formation and bone thickness were significantly enhanced following simvastatin treatment. New bone formation was 0.008+/-0.008 mm2 in sham controls (group I), 0.015+/-0.012 mm2 after particle implantation without further intervention (group II), compared to 0.083+/-0.021 mm2 with particle implantation and simvastatin treatment (group III) (p=0.003). The bone thickness was 0.213+/-0.007 mm in group I, 0.183+/-0.005 mm in group II, and 0.238+/-0.009 mm in group III (p=0.00008). In conclusion, simvastatin treatment markedly promoted bone formation and net bone growth in UHMWPE particle-induced osteolysis in a murine calvarial model. These new findings indicate that simvastatin may have favorable osteoanabolic effects on wear debris-mediated osteolysis after total joint arthroplasty, involving local stimulation of osteoblastic bone formation.

Animals↗
PubMed2005

Simvastatin inhibits NOR-1 expression induced by hyperlipemia by interfering with CREB activation.

OBJECTIVE: Our aim was to investigate whether neuron-derived orphan receptor-1 (NOR-1), an early gene induced by low density lipoproteins (LDL) in vascular smooth muscle cells (VSMC), is regulated by statins. METHODS: NOR-1 expression was analyzed in human VSMC in culture and in vivo in the aorta of diet-induced hyperlipemic pigs by RT-PCR and real-time PCR. [3H]Thymidine incorporation was used as an index of DNA synthesis. NOR-1 promoter activity was analyzed using a luciferase reporter system. Cyclic AMP response element binding protein (CREB) binding was assessed by EMSA and ELISA and CREB activation (phosphorylation in Ser133) by Western blotting. RESULTS: Simvastatin inhibited NOR-1 expression induced by LDL in VSMC and by hypercholesterolemia in the abdominal aorta of hyperlipemic pigs. The inhibition of the isoprenylation of geranylgeranylated proteins by simvastatin was key in both NOR-1 up-regulation and DNA synthesis induced by LDL. Inhibitors of RhoA (toxin B and exotoxin C3) and ROCK (Y-27632) mimicked the effect of simvastatin on NOR-1. Similarly both simvastatin treatment and cells transfected with a RhoA dominant-negative (RhoAT19N) showed inhibition of LDL-induced NOR-1 promoter activity. These effects were associated to the interference of the activation of CREB, a key transcription factor involved in NOR-1 induction. Finally, simvastatin prevented LDL induction of a reporter construct containing four consensus CRE and inhibited the expression of SMemb (a marker for dedifferentiated VSMC) dependent on CREB. CONCLUSIONS: NOR-1 is a target for simvastatin in the vascular wall. We identified NOR-1 and CREB as key transcription factors mediating the effect of statins on VSMC proliferation through a mechanism dependent on RhoA/ROCK.

Animals↗
PubMed2006

Simvastatin improves left ventricular function after myocardial infarction in hypercholesterolemic rabbits by anti-inflammatory effects.

OBJECTIVES: Hypercholesterolemia contributes to coronary artery disease progression but little is known about its effect on left ventricular (LV) function after myocardial infarction (MI). The aim of this study was to investigate the effects of hypercholesterolemia and statin treatment in rabbits with experimental MI. METHODS AND RESULTS: New Zealand White rabbits on a normal or cholesterol-rich diet for 4 weeks, underwent permanent coronary artery ligation. Starting on the first day post-MI rabbits were treated with either placebo or simvastatin (5 mg/kg/day) for 9 weeks. Hypercholesterolemia itself did not affect LV function in sham-operated animals but further impaired LV systolic (dP/dtmax -42%) and diastolic (dP/dtmin -47%) function in MI rabbits on placebo. Simvastatin treatment not only prevented deterioration of LV function associated with hypercholesterolemia but improved LV function (dP/dtmax +130%; dP/dtmin +144%, P < 0.05). Simvastatin also attenuated the depression of LV function in normocholesterolemic MI rabbits (dP/dtmax +46%; dP/dtmin +53%, P < 0.05). Hypercholesterolemia in MI rabbits coincided with a significant increase in C-reactive protein levels (marker of inflammation) and Rac1-GTPase activity (marker of oxidative stress), and a reduction in cardiac sarcoplasmic-reticulum calcium ATPase-2 expression and endothelial nitric oxide synthase protein phosphorylation, all of which were normalised by simvastatin treatment. Elevated serum cholesterol levels were only partially reduced by simvastatin. CONCLUSIONS: Hypercholesterolemia further impaired the depressed LV function in rabbits post-MI. Statin treatment reversed this effect, and conferred additional protection, as in normocholesterolemic animals. Our study suggests that anti-inflammatory and anti-oxidative effects of simvastatin substantially contribute to its beneficial effects on cardiac function after MI.

Animals↗
PubMed2006

Reduction of C-reactive protein by a single 80 mg of simvastatin in patients with unstable angina.

BACKGROUND: Increased concentrations of C-reactive protein (CRP) became widely accepted as a risk factor of the higher incidence of coronary events, and rapid lowering CRP by administration of drugs may produce early benefit to the coronary endothelium in patients with coronary heart disease and reduce angina and coronary events after revascularization. Limited information has been available, however, with respect to evaluating a potential effect of a single high-dose simvastatin on CRP in patients with unstable angina (UA) within 48 h. We investigated whether a rapid CRP reduction can be achieved by a single 80 mg of simvastatin therapy in patients with UA given immediately on admission. METHODS: Forty-two patients with rest chest pain were randomly assigned to a single placebo or 80 mg of simvastatin given at the time of admission plus standard therapy. Blood samples were also drawn at the time of admission, and 48 h later for measuring serum CRP concentrations. RESULTS: We found that 80 mg of simvastatin induced significant reductions in serum median CRP concentrations and in mean CRP concentrations 48 h later following administration of simvastatin (25.4% and 32.7%, p<0.001, respectively). CONCLUSIONS: A single high-dose simvastatin, given in the early time on admission, is an effective therapy for controlling inflammatory response in patients with UA, and the benefit to the vascular endothelium might occur quickly by reduction of CRP concentrations in this high-risk subgroup.

Angina, Unstable↗
PubMed2006

Simvastatin inhibits the migration and adhesion of monocytic cells and disorganizes the cytoskeleton of activated endothelial cells.

Statins are powerful agents for lowering plasma cholesterol levels, which act by inhibition of the 3-hydroxy-3-methylglutaryl-CoA reductase. Evidence suggests that some of the beneficial effects may depend on their anti-inflammatory properties, due to their ability to suppress the synthesis of isoprenoids. The present study analyzes the effects of short-term simvastatin exposure on monocyte migration, cell adhesion, and endothelial cytoskeleton. We demonstrate that simvastatin completely inhibited the migration of THP-1 monocytic cells after 24 h of incubation, being prevented by coincubation with mevalonate (MVA) and geranylgeranylpyrophosphate (GGPP), but not by farnesylpyrophosphate (FPP). Simvastatin decreased chemotaxis to 70% after one hour of incubation; surprisingly neither MVA, GGPP nor FPP were able to restore the effects of the drug. Simvastatin also significantly reduced the adhesion of monocytes to interleukin-1beta (IL-1beta)-activated endothelium to 80% after preincubation for 24 h. This effect was completely reversed by coincubation with MVA and GGPP, and partially with FPP. Unexpectedly, simvastatin increased adhesion molecules expression VCAM-1 and ICAM-1 on cytokine-stimulated endothelial cells. Examination of the actin cytoskeleton on IL-1beta-activated endothelial cells showed that both 4 and 24 h of incubation with simvastatin produced a complete disappearance of F-actin, being completely restored by MVA and partially by GGPP and FPP after 24 h of coincubation. We suggest that cytoskeleton disorganization in endothelial cells is important for inhibiting monocyte adhesion, altering the adhesion molecules function. Taken together, these results strongly support the beneficial anti-inflammatory properties of statins, contributing to the overall clinical effects.

Actins↗
PubMed2005

Simvastatin decreases myocardial tumor necrosis factor alpha content in heart transplant recipients.

BACKGROUND: Statins improve patient survival and decrease rejection episodes in heart transplant recipients. We studied the effects of simvastatin treatment on myocardial tumor necrosis factor alpha (TNF-alpha) expression; TNF-alpha is a potent pro-inflammatory cytokine associated with hypertrophy and fibrosis in heart transplant recipients. METHODS: We randomized 10 consecutive heart transplant recipients to receive either 20 mg/day simvastatin (n = 5) or placebo (n = 5) for 6 months after cardiac transplantation. Routine surveillance endomyocardial biopsy specimens were obtained from all patients. We analyzed tissues for myocardial TNF-alpha content, total collagen content, and myocyte size using semiquantitative immunohistochemistry. RESULTS: Myocyte size and total collagen content of placebo and simvastatin groups did not show a statistically significant difference at any biopsy time point. Myocardium TNF-alpha content (% tissue area stained) at 1 week after transplantation was similar in the simvastatin and placebo groups. At the 24(th) week after transplantation, when compared with Week 1 values, we found a significant decrease in myocardium TNF-alpha content in the simvastatin group (15.0% +/- 2.3% vs 5.8% +/- 2.4%, p = 0.02) that was not observed in the placebo group (15.0% +/- 1.5% vs 12.0% +/- 2.6%, p = not significant). CONCLUSION: Simvastatin treatment in heart transplant recipients decreased myocardium TNF-alpha expression. This decrease did not translate into a difference in the markers of hypertrophy. However, decreased myocardial TNF-alpha may be a marker of a general statin-mediated decrease in inflammation in the transplanted heart that leads to improved graft and patient survival.

Aged↗
PubMed2006

Simvastatin inhibits NF-kappaB signaling in intestinal epithelial cells and ameliorates acute murine colitis.

Statins, HMG-CoA reductase inhibitors exert pleiotropic anti-inflammatory properties in vitro and in vivo, and are associated with the risk reduction of colorectal cancer. It remains unknown, however, whether statin is effective for the treatment of inflammatory bowel disease (IBD). Therefore, we investigated anti-inflammatory effects of simvastatin on intestinal epithelial cells (IEC) and on an experimental murine colitis model, and elucidated its molecular mechanisms. Simvastatin (50 micro M) significantly inhibited TNF-alpha-induced IL-8 gene expression in COLO 205 cells. Simvastatin (50 micro M) blocked TNF-alpha-induced NF-kappaB transcriptional activity, IkappaB phosphorylation/degradation and DNA binding activity of NF-kappaB. Administration of simvastatin significantly reduced the severity of dextran sulfate sodium (DSS)-induced murine colitis as assessed by body weight, colon length, DAI, and histology in a dose-dependent manner. These results suggest that simvastatin inhibits proinflammatory gene expression by blocking NF-kappaB signaling in IEC, and attenuates DSS-induced acute murine colitis. Simvastatin could be a potential agent for the treatment of IBD.

Animals↗