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PubMedDate not supplied

[Effects of simvastatin on blood levels of lipoprotein (a)].

The efficacy of Simvastatin to reduce plasma cholesterol is well documented. Other molecule within the lipo-lipoprotein family, such as, particularly, lipoprotein (a) -Lp(a)-, have been recently found to have a predictive and/or causative role in atherosclerosis. Based on the above consideration, we studied 20 patients (7 females and 13 males), mean age 52.4 +/- 14.2 years, affected by primary hypercholesterolemia to evaluate the effect of simvastatin on Lp(a), in addition to the classic lipidic parameters. Five weeks after suspension of lipid-lowering drugs and on a normal caloric-fat diet, were given 20 mg simvastatin/day for 12 months. Clinical and laboratory parameters, cholesterol (CH), triglycerides (TG), high density and low density lipoprotein cholesterol (HDL-CH and LDH-CH) measured enzymatically, apoproteins A1, B measured radial immunodiffusion technique and Lp(a) measured as apoprotein(a) with immunoradiometric assay and were evaluated before therapy and after 12 months of therapy. Simvastatin determined a significant reduction in total cholesterol and cholesterol-LDL (CH 327.7 +/- 44.4 vs 255.5 +/- 37.3, p < 0.0001; LDL-CH 257.1 +/- 60.9 vs 183.8 +/- 46.9, p < 0.0001) and a significant increase in HDL-CH (36.7 +/- 5.9 vs 40.2 +/- 5.7, p < 0.005); no variation was observed in triglycerides (TG) levels. Simvastatin therapy further determined a significant increase in Lp(a) plasma levels (43.8 +/- 25.6 vs 50.5 +/- 28.0, p < 0.02). The our data, in agreement with those documenting the beneficial effect of Simvastatin in greatly decreasing CH and LDL-CH, but point out the need for further studies concerning the long-ter effect of simvastatin on Lp(a), in order to fully establish its role in the secondary prevention of atherosclerosis.

Adult↗
PubMed1994

Safety and efficacy of low dose simvastatin in cardiac transplant recipients treated with cyclosporine.

Hyperlipidemia is common in heart transplant patients. Lipid-lowering therapy poses special problems, yet may be important because accelerated graft atherosclerosis is the major factor limiting long-term survival. Simvastatin 5 mg/day was started > 6 months after surgery in 26 consecutive cardiac transplant recipients with a total serum cholesterol level of > 250 mg/dl. The dose of simvastatin was increased in 5-mg increments until total serum cholesterol fell below 220 mg/dl or until side effects developed or up to a maximal dose of 20 mg/day. The final average daily dose was 10 mg. Changes in serum lipid levels after 6 months of therapy were compared with data from a matched and concurrent control group of heart transplant patients not taking simvastatin. Immunosuppression for both groups consisted of CsA, AZA, and corticosteroids. In the simvastatin-treated group, the serum level of total cholesterol decreased by 27% from 315 +/- 53 to 230 +/- 38 mg/dl (P < 0.0001), low density lipoprotein cholesterol decreased by 40% from 205 +/- 30 to 123 +/- 32 mg/dl (P < 0.0001), and triglycerides decreased by 21% from 177 +/- 89 to 140 +/- 49 mg/dl (P < 0.01). There was no significant change in high density lipoprotein cholesterol level. Body weight and CsA blood levels remained stable. Steroid intake decreased during the study period to a similar extent in both the treated and the control groups. In the control group, no significant changes in serum lipid levels were observed. Two patients experienced a mild form of myotoxicity. In one other patient simvastatin treatment was stopped after an acute pancreatitis of uncertain etiology developed. Low dose simvastatin effectively lowers total serum cholesterol, low density lipoprotein cholesterol, and triglycerides in heart transplant patients. With due precautions, the safety profile of the drug in this patient population seems reasonable.

Anticholesteremic Agents↗
PubMed1994

Short-term effects of simvastatin on bile acid synthesis and bile lipid secretion in human subjects.

To test whether de novo synthesis of cholesterol is a limiting factor for bile acid synthesis, we studied the acute effect of simvastatin, an inhibitor of HMG-coenzyme A reductase (the limiting step of cholesterol synthesis) on bile acid synthesis and biliary lipid secretion in subjects with interrupted enterohepatic circulation. In these conditions bile acid synthesis is derepressed and is assumed to equal biliary bile acid secretion. Five cholecystectomized patients fitted with T-tubes were studied. All subjects were administered simvastatin (80 mg as a single dose) 5 days after surgery. Bile was collected in 3-hr intervals for 15 hr before and 30 hr after the administration of the drug. During the experiment we kept the enterohepatic circulation of bile acid interrupted by inflating an occludable balloon inserted, during cholecystectomy, in the common bile duct. Simvastatin induced significant decreases of plasma total and low density lipoprotein cholesterol concentrations, from 163 +/- 29 mg/dl and 97 +/- 24 mg/dl of the pretreatment value to 144 +/- 30 mg/dl and 82 +/- 22 mg/dl 18 hr after simvastatin administration, respectively. Bile flow tended to increase after simvastatin, and the mean values from the third to the 15th hour after simvastatin administration (22.1 +/- 1.9 ml/hr) were significantly greater than the mean values of the pretreatment period (19.9 +/- 2.8 ml/hr). Concomitantly biliary bile acid, cholesterol and phospholipid concentrations fell from basal values of 15.9 +/- 5.1, 2.3 +/- 0.3 and 5.5 +/- 0.3 mmol/L to mean values, after treatment, of 9.0 +/- 3.5, 1.9 +/- 0.5 and 3.0 +/- 0.9 mmol/L, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

[Efficacy and tolerability of simvastatin and omega-3 fatty acid combination in patients with coronary disease, hypercholesterolemia and hypertriglyceridemia].

Patients with ischemic heart disease are often affected by a mixed hyperlipoproteinemia, where a hypercholesterolemia of various severity is accompanied by slight or moderate hypertriglyceridemia (type IIb dyslipidemia). Current epidemiologic evidence suggests that hypertriglyceridemia has not to be disregarded, particularly in certain subgroups of patients. We evaluated the effect of the association of simvastatin 10 mg/day [an hydroxymethyl-glutaryl-CoA (HMG-CoA) reductase inhibitor] and omega-3 polyunsaturated fatty acids (n3-PUFA) in comparison with simvastatin 10 mg/day alone. The subjects undergoing the study were affected by coronary artery disease and showed hypercholesterolemia (LDL-cholesterol > 160 mg/dl) and moderate hypertriglyceridemia (serum triglycerides 200-400 mg/dl) after 2 months of moderate dietary therapy for hyperlipidemia (Step 1 of the National Cholesterol Education Program [NCEP]). Thirty-nine patients were randomized to have 1 of 2 scheduled treatments. At the same time the patients underwent severe dietary therapy for hyperlipidemia (Step 2 of the NCEP). After 3 months of treatment, total-cholesterol, LDL-cholesterol, and triglycerides were significantly lower than basal values in both groups (p < 0.05). Total-cholesterol, LDL-cholesterol, and triglycerides were lower in the group treated with n3-PUFA and simvastatin compared to simvastatin alone. However, only for triglycerides was the difference significant (-39.99% in patients treated with n3-PUFA and simvastatin versus -25.65% in patients treated with simvastatin alone, particularly in the first group of 35.85%; p < 0.05). With regard to HDL-cholesterol, the differences between the basal values and the 2 groups of treatments were non significant. Remarkable side effects were not observed in the 2 groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Low-dose simvastatin is safe in hyperlipidaemic renal transplant patients.

Hyperlipidaemia is common after renal transplantation, and because of its association with atherosclerosis, interest has increased in the use of lipid-lowering drugs in transplant patients. Dietary approaches have not been consistently successful, and multiple pharmacotherapy and drug interactions have led to difficulties in establishing lipid-lowering drug regimes. The statins reduce plasma cholesterol by inhibiting the rate-limiting step in cholesterol synthesis, and although some side-effects have been reported in their use after transplantation, the efficacy and safety of low doses has not been formally established. A randomized single-blind placebo crossover study designed to determine the safety and effectiveness of simvastatin in a single daily 5-mg evening dose was therefore conducted in 26 stable renal transplant patients, 14 of whom were receiving cyclosporin A. The results demonstrated no difference between total cholesterol levels in the baseline simvastatin and placebo periods: 7.97 +/- 1.2 and 7.59 +/- 1.5 mmol/l respectively. After 8 weeks of simvastatin, the total cholesterol declined significantly to 6.72 +/- 0.87 mmol/l (P < 0.001). A significant difference was found when the placebo and simvastatin cholesterol levels were compared at 4 and 8 weeks (P < 0.01). LDL cholesterol decreased from 4.74 +/- 0.87 to 3.78 +/- 0.78 mmol/l after 8 weeks on simvastatin (P < 0.001), and apo B fell from 142 +/- 31 to 112 +/- 22 mg/dl (P < 0.001). The difference in LDL cholesterol and apo B after 8 weeks of simvastatin when compared with the corresponding values on placebo was also significant (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

[Effectiveness and tolerability of simvastatin in patients with moderate-to-severe hypercholesterolemia. Results of a 12-month study].

Several epidemiological and clinical studies have underlined the close relationship between hypercholesterolemia and risk of coronary heart disease suggesting the opportunity of treating hypercholesterolemic patients according to their associated risk factors. Simvastatin, a drug for the treatment of hypercholesterolemia, is a competitive inhibitor of 3-Hydroxy-Methyl-Glutaryl-CoA reductase, the rate limiting enzyme in cholesterol biosynthesis. In the present study we have assessed the efficacy, safety and tolerability of simvastatin (10-20 mg) administered once daily for a period of 12 months to 50 patients with coronary heart disease (CHD) or at high risk for CHD according to the National Cholesterol Education Program. All patients underwent complete physical examination and laboratory safety tests (including blood cell count, liver function tests, creatine kinase and lipid profile) at baseline and every 6 weeks during treatment. Simvastatin was highly effective in reducing total and LDL cholesterol (-25% and -35% respectively). No significant effect on HDL cholesterol or triglycerides was obtained. Two patients were excluded after 6 weeks of treatment because of a serum creatine kinase increase (more than twice normal values). This was the only drug related side effect. In conclusion our data show that: a) simvastatin treatment is well accepted and compliance is good; b) the effect of simvastatin is evident after the first 6 weeks of treatment and is maintained during the whole treatment time; c) simvastatin is highly effective in lowering total and LDL cholesterol. When considering a patient who has had an atherosclerotic event the best deterrent to the occurrence of a subsequent event (secondary prevention) could be reduction of serum total and LDL cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Anticholesteremic Agents↗
PubMed1995

Potential risk of myopathy by HMG-CoA reductase inhibitors: a comparison of pravastatin and simvastatin effects on membrane electrical properties of rat skeletal muscle fibers.

To get insight into the potential risk of myopathy associated with therapy involving 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, we evaluated in vivo and in vitro the effects of a daily 2 to 3-month treatment with pravastatin (100 mg/kg) and with simvastatin (5, 10 and 50 mg/kg) on the electrical properties of rat skeletal muscle fibers. The electromyographic activity revealed no sign of myopathy during treatment with pravastatin and with simvastatin. At the end of the treatment, the passive and active membrane electrical parameters of the extensor digitorum longus muscles were measured in vitro by computerized two-intracellular-microelectrode technique. A dose-dependent reduction of membrane chloride conductance was recorded in extensor digitorum longus fibers of simvastatin-treated groups, and at 50 mg/kg the reduction of chloride conductance was significant in 6 out of the 7 treated rats. By contrast, none of the pravastatin-treated rats showed significant alteration of chloride conductance. Consequently, the excitability parameters were modified by simvastatin but not by pravastatin treatment, whereas the resting membrane potential was not affected. An increase in potassium conductance, reduced by in vitro application of glybenclamide, was recorded in 30% of the simvastatin-treated rats (50 mg/kg) and in only 15% of the pravastatin-treated rats. Our results suggest that the risk of myopathy is much higher with the lipophilic simvastatin than with the hydrophilic pravastatin and support the hypothesis that the muscle toxicity of HMG-CoA reductase inhibitors is due to an intracellular action mediated by the inhibition of muscle cholesterol synthesis.

Animals↗
PubMed1996

Lipid-lowering effects of simvastatin and gemfibrozil in CAPD patients: a prospective cross-over study.

We compared the lipid-lowering effects of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, and gemfibrozil, a fibric acid derivative, in 22 continuous ambulatory peritoneal dialysis patients whose serum total cholesterol and/or triglyceride levels were > or = 220 mg/dL after a standard diet for six months. The study group was first treated with gemfibrozil (600 mg/b.i.d.) for three months (stage 1). After a wash-out period of two months, during which no treatment was given, all of the patients became hyperlipidemic again and, therefore, were given simvastatin (10 mg/day) for three months (stage 2), which was followed by another two-month wash-out period. A control group, which served to evaluate the natural progression of pharmacologically untreated dyslipidemia, was followed during the same period. Blood determinations of triglyceride, total cholesterol, and high-density lipoprotein (HDL) cholesterol were performed after each step. Low-density lipoprotein (LDL) cholesterol and HDL ratio were calculated from the measured values. Both gemfibrozil and simvastatin improved all parameters of the lipid profile, but the effect of simvastatin was better than that of gemfibrozil (-69 vs -39 mg/dL for triglyceride and -95 vs -64 mg/dL for cholesterol), while their actions on LDL and HDL cholesterol were of equal magnitude. Two months after discontinuation of simvastatin, significant decreases of total cholesterol (-46 mg/dL) and triglyceride (-60 mg/dL) were still present, while these values had returned to pretreatment levels after stopping gemfibrozil. The HDL ratio remained markedlyhigher (p < 0.05) during the wash-out period after simvastatin, while it decreased to pretreatment values after gemfibrozil was stopped. The lipid profile of the control group did not change during the follow-up. Both drugs were well tolerated, and no serious side effects occurred.

Adult↗
PubMed1997

Effects of simvastatin on the metabolism of polyunsaturated fatty acids and on glycerolipid, cholesterol, and de novo lipid synthesis in THP-1 cells.

In the monocytic THP-1 cells, the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor simvastatin (5 microM) enhances the conversion of exogenous linoleic (18:2 n-6) and eicosapentaenoic (20:5 n-3) acids to their long-chain polyunsaturated fatty acid (LC-PUFA) derivatives, and this effect is associated with changes in the desaturation steps. In addition, formation of monounsaturated fatty acids from endogenously synthesized precursors is increased. These metabolic changes lead to elevated LC-PUFA and fatty acid (FA) unsaturation in cells. The effects of simvastatin on FA metabolism are associated with increased synthesis of triglycerides from glycerol. The dose-effect relationships for the activity of simvastatin on total linoleic acid (LA) conversion and cholesterol synthesis reveal that enhancement of PUFA metabolism is already maximal at 0.5 microM simvastatin, whereas cholesterol synthesis is further inhibited by concentrations of simvastatin up to 5 microM. The effects of 5 microM simvastatin on PUFA metabolism are partially prevented by mevalonate (1 mM) and geranylgeraniol (5 microM) but not by farnesol (10 microM). These data indicate that HMG-CoA inhibitors have profound effects on PUFA metabolism, and that the pathways for cholesterol and PUFA synthesis are mutually modulated.

Acetates↗
PubMed1996

Effects of simvastatin on plasma lipids and apolipoproteins in familial hypercholesterolemic swine.

Familial hypercholesterolemia (FHC) in swine, which resembles human familial combined hyperlipidemia, is a complex lipid and lipoprotein disorder associated with the development of severe coronary lesions similar to those occurring in advanced human coronary disease. The disorder is characterized by elevated plasma total cholesterol (TC), triglycerides (TG), LDL-cholesterol (LDL-C), apolipoproteins (apo) B, C-III, and E, and by decreased levels of HDL-cholesterol (HDL-C), apoA-I, and lecithin:cholesterol acyltransferase (LCAT) activity. A dose-response study with simvastatin, a specific inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, was conducted in four treatment groups of FHC animals, exhibiting TC > or = 250 mg/dL. The animals were fed 0, 80, 200, or 400 mg simvastatin daily for 3 weeks. The measured serum parameters included the levels of TC, VLDL-C, LDL-C, HDL-C, TG, lathosterol, apoA-I, B, C-III, and E, as well as LCAT activity. Simvastatin at 200 mg/d significantly decreased the levels of TC (-25%), LDL-C (-27%), lathosterol (-40%), apoB (-22%), apoC-III (-37%), and apoE (-24%) and modestly decreased the levels of HDL-C (-12%) and apoA-I (-11%) (percent relative to the average pretreatment and posttreatment baseline values) but did not affect the levels of TG, VLDL-C, the lathosterol/TC ratio, or LCAT activity. The levels of TC, LDL-C, apoB, and E were also lowered by simvastatin at 80 or 400 mg/d, but to a lesser extent than at 200 mg/d, while the other parameters were not influenced at these doses. The simvastatin-induced decreases of LDL-C, HDL-C, and apoA-I, B, C-III, and E were significantly correlated among each other. These results show that the trend of responses in TC, LDL-C, apoB, apoC-III, and apoE to simvastatin in the FHC swine is similar to that observed in humans, although the drugs is less potent and efficacious in swine, while the results are different from those in humans with regard to the remaining parameters.

Animals↗
PubMed2005

High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial.

CONTEXT: Evidence suggests that more intensive lowering of low-density lipoprotein cholesterol (LDL-C) than is commonly applied clinically will provide further benefit in stable coronary artery disease. OBJECTIVE: To compare the effects of 2 strategies of lipid lowering on the risk of cardiovascular disease among patients with a previous myocardial infarction (MI). DESIGN, SETTING, AND PARTICIPANTS: The IDEAL study, a prospective, randomized, open-label, blinded end-point evaluation trial conducted at 190 ambulatory cardiology care and specialist practices in northern Europe between March 1999 and March 2005 with a median follow-up of 4.8 years, which enrolled 8888 patients aged 80 years or younger with a history of acute MI. INTERVENTIONS: Patients were randomly assigned to receive a high dose of atorvastatin (80 mg/d; n = 4439), or usual-dose simvastatin (20 mg/d; n = 4449). MAIN OUTCOME MEASURE: Occurrence of a major coronary event, defined as coronary death, confirmed nonfatal acute MI, or cardiac arrest with resuscitation. RESULTS: During treatment, mean LDL-C levels were 104 (SE, 0.3) mg/dL in the simvastatin group and 81 (SE, 0.3) mg/dL in the atorvastatin group. A major coronary event occurred in 463 simvastatin patients (10.4%) and in 411 atorvastatin patients (9.3%) (hazard ratio [HR], 0.89; 95% CI, 0.78-1.01; P = .07). Nonfatal acute MI occurred in 321 (7.2%) and 267 (6.0%) in the 2 groups (HR, 0.83; 95% CI, 0.71-0.98; P = .02), but no differences were seen in the 2 other components of the primary end point. Major cardiovascular events occurred in 608 and 533 in the 2 groups, respectively (HR, 0.87; 95% CI, 0.77-0.98; P = .02). Occurrence of any coronary event was reported in 1059 simvastatin and 898 atorvastatin patients (HR, 0.84; 95% CI, 0.76-0.91; P<.001). Noncardiovascular death occurred in 156 (3.5%) and 143 (3.2%) in the 2 groups (HR, 0.92; 95% CI, 0.73-1.15; P = .47). Death from any cause occurred in 374 (8.4%) in the simvastatin group and 366 (8.2%) in the atorvastatin group (HR, 0.98; 95% CI, 0.85-1.13; P = .81). Patients in the atorvastatin group had higher rates of drug discontinuation due to nonserious adverse events; transaminase elevation resulted in 43 (1.0%) vs 5 (0.1%) withdrawals (P<.001). Serious myopathy and rhabdomyolysis were rare in both groups. CONCLUSIONS: In this study of patients with previous MI, intensive lowering of LDL-C did not result in a significant reduction in the primary outcome of major coronary events, but did reduce the risk of other composite secondary end points and nonfatal acute MI. There were no differences in cardiovascular or all-cause mortality. Patients with MI may benefit from intensive lowering of LDL-C without an increase in noncardiovascular mortality or other serious adverse reactions.Trial Registration ClinicalTrials.gov Identifier: NCT00159835.

Aged↗
PubMed1997

Comparison of bezafibrate and simvastatin in the treatment of dyslipidaemia in patients with NIDDM.

Fibrates and HMG CoA reductase inhibitors are commonly used in the treatment of diabetic dyslipidaemia. However, these two groups of drugs have not been compared in diabetic patients in a randomized controlled trial. Therefore, a multicentre study was performed in 73 subjects with non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) and combined hyperlipidaemia (serum cholesterol 6.2-10.0 mmol l(-1), serum triglycerides 2.3-10.0 mmol l(-1)), comparing the efficacy of 400 mg bezafibrate with 10 mg simvastatin in a double-blind fashion. Treatment with bezafibrate during 12 weeks reduced serum triglycerides significantly more than simvastatin (-41% vs -22%, p < 0.001) and increased HDL cholesterol more (bezafibrate: + 17% vs simvastatin: + 9%, p < 0.05). LDL cholesterol levels decreased by 14% (p < 0.001) during simvastatin and increased by 21% (p < 0.01) during bezafibrate. This increase in LDL cholesterol was positively correlated with fasting serum triglycerides (p < 0.001) and was associated with a reduction of the serum apolipoprotein B concentration, suggesting an increase in LDL particle size. Metabolic control of diabetes (fasting glycaemia; HbA1c) and insulin secretion (C-peptide levels) were unaffected by both treatments. The incidence of side-effects during treatment was similar for both drugs. Thus, 400 mg bezafibrate mainly increases HDL cholesterol and lowers serum triglycerides but at the expense of an increase in LDL cholesterol; 10 mg simvastatin lowers LDL cholesterin more effectively but has a smaller effect on HDL cholesterol and triglycerides.

Aged↗
PubMed2006

Inhibition of systemic sclerosis dermal fibroblast type I collagen production and gene expression by simvastatin.

OBJECTIVE: To examine whether statins are capable of modulating collagen gene expression in cultured systemic sclerosis dermal fibroblasts. METHODS: Cultured dermal fibroblasts from 3 patients with diffuse systemic sclerosis of recent onset were treated with 5 microM and 10 microM of simvastatin for 3 or 4 days. Morphologic features, cytotoxicity, and type I collagen production and messenger RNA (mRNA) levels in the fibroblasts were examined. The effects of mevalonate, geranylgeranyl pyrophosphate (GGPP), and farnesyl pyrophosphate (FPP), which are lipids downstream from the hydroxymethylglutaryl-coenzyme A block, were also examined. Transient transfections with COL1A1 promoter-reporter constructs and electrophoretic gel mobility shift assays were utilized to examine COL1A1 transcription and Sp1 and CCAAT-box binding factor (CBF) binding. RESULTS: Simvastatin did not cause morphologic changes or cytotoxicity in the fibroblasts, even after 4 days of treatment. Type I collagen production and mRNA levels showed a potent and dose-related inhibition following 3 and 4 days of treatment. The inhibition of collagen gene expression by simvastatin was completely reversed by mevalonate and GGPP, but not by FPP. The statin effects occurred at the transcriptional level and involved the proximal COL1A1 promoter region encompassing -174 bp. A significant reduction in Sp1 and CBF binding activity was also found in simvastatin-treated cells. CONCLUSION: Simvastatin is a powerful inhibitor of type I collagen gene expression in normal and systemic sclerosis fibroblasts. The pleiotropic protective effects of statins on various endothelial and immune cell functions in conjunction with their potent inhibitory effects on type I collagen gene expression suggest that statins may be effective therapeutic agents in systemic sclerosis.

Cells, Cultured↗
PubMedDate not supplied

Effects of simvastatin treatment on oxidant/antioxidant state and ultrastructure of streptozotocin-diabetic rat lung.

In the present study, we investigated the effects of simvastatin, a 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor, on lipid metabolism, lipid peroxidation, antioxidant enzyme activities and ultrastructure of diabetic rat lung. Diabetes was induced by a single injection of streptozotocin (45 mg kg(-1), i.p.). After 8 weeks induction of diabetes, some control and diabetic rats were treated with simvastatin (10 mg kg(-1) rat day(-1); orally) for 4 weeks. Diabetes resulted in significantly high levels of blood glucose and plasma lipids. Malondialdehyde levels were unchanged after 12-week-old diabetic rats, whereas catalase activity significantly decreased in the lung. Glutathione peroxidase activity and nitric oxide level were significantly elevated in the diabetic lung. Histological analysis of the diabetic lung revealed some deterioration in the structure. Simvastatin treatment reduced plasma lipid levels and partially decreased the severity of hyperglycaemia. Catalase, glutathione peroxidase activities and nitric oxide levels were partially restored and accompanied by improved structure in diabetic lung by the simvastatin treatment. These results suggest that structural disturbances and alteration of antioxidative enzyme activities occurred in diabetic lung. Simvastatin treatment may provide some benefits in the maintenance of antioxidant status and structural organization of diabetes-induced injury of lung.

Animals↗
PubMed2003

Effects of simvastatin, an HMG-CoA reductase inhibitor, in patients with hypertriglyceridemia.

BACKGROUND: Patients with elevated levels of serum triglycerides (TG) often have other associated lipid abnormalities (e.g., low levels of high-density lipoprotein cholesterol [HDL-C]) and are at increased risk of developing coronary heart disease. Although the therapeutic benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in hypercholesterolemic patients have been well established, less is known about the effects of statins in patient populations with hypertriglyceridemia. HYPOTHESIS: The purpose of this study was to evaluate the lipoprotein-altering efficacy of simvastatin in hypertriglyceridemic patients. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study. In all, 195 patients with fasting serum triglyceride levels between 300 and 900 mg/dl received once daily doses of placebo or simvastatin 20, 40, or 80 mg for 6 weeks. RESULTS: Compared with placebo, simvastatin treatment across all doses resulted in significant reductions (p < 0.05 - < 0.001) in serum levels of triglycerides (-20 to -31% decrease) and TG-rich lipoprotein particles. Significant (p < 0.001) reductions were also seen in low-density lipoprotein cholesterol (-25 to -35%) and non-HDL-C (-26 to -40%). Levels of HDL-C were increased (7-11%) in the simvastatin groups compared with placebo (p < 0.05 - < 0.001). CONCLUSION: The results of this study demonstrate the beneficial effects of simvastatin in patients with hypertriglyceridemia.

Adult↗
PubMed2007

Simvastatin regulates oligodendroglial process dynamics and survival.

Simvastatin, a lipophilic statin that crosses the blood-brain barrier, is being evaluated as a potential therapy for multiple sclerosis (MS) due to its anti-inflammatory properties. We assessed the effects of simvastatin on cultures of rat newborn and human fetal oligodendrocyte progenitor cells (OPCs) and human adult mature oligodendrocytes (OLGs) with respect to cellular events pertaining to myelin maintenance and repair. Short-term simvastatin treatment of OPCs (1 day) induced robust process extension, enhanced differentiation to a mature phenotype, and decreased spontaneous migration. These effects were reversed by isoprenoid products and mimicked with an inhibitor of Rho kinase (ROCK), the downstream effector of the isoprenylated protein RhoA GTPase. Prolonged treatment (2 days) caused process retraction that was rescued by cholesterol, and increased cell death (4 days) partially rescued by either cholesterol or isoprenoid co-treatment. In comparison, simvastatin treatment of human mature OLGs required a longer initial time course (2 days) to induce significant process outgrowth, mimicked by inhibiting ROCK. Prolonged treatment of mature OLGs was associated with process retraction (6 days) and increased cell death (8 days). Human-derived OPCs and mature OLGs demonstrated an increased sensitivity to simvastatin relative to the rodent cells, responding to nanomolar versus micromolar concentrations. Our findings indicate the importance of considering the short- and long-term effects of systemic immunomodulatory therapies on neural cells affected by the MS disease process. (c) 2006 Wiley-Liss, Inc.

Animals↗
PubMed1994

Effect of simvastatin, an inhibitor of hydroxy-methylglutaryl coenzyme A reductase, on the growth of human Ito cells.

During hepatic fibrogenesis, Ito cells proliferate, acquire a myofibroblastlike phenotype and synthesize increased amounts of extracellular matrix components. In this study, we have assessed the effects of simvastatin, an inhibitor of hydroxy-methylglutaryl-coenzyme A reductase, on the growth of human myofibroblastlike Ito cells. Cells were grown from explants of normal human liver and characterized by a positive staining for desmin and smooth muscle alpha-actin. Simvastatin (0.1 to 10 mumol/L) induced a marked dose-dependent decrease of [3H]thymidine incorporation in human Ito cells, whether stimulated by human serum or by purified growth factors. Simvastatin-induced inhibition of DNA synthesis was confirmed by nuclear autoradiography and was not explained by a cytotoxic effect. The growth inhibitory effect of simvastatin was specifically due to inhibition of hydroxy-methylglutaryl-coenzyme A reductase because it was overcome by addition of mevalonic acid, the product of the enzymatic reaction. The reduction in [3H]thymidine incorporation was not affected by supplementation of culture medium with purified cholesterol-low-density lipoprotein or isopentenyl adenine. It was partially reversed by addition of farnesol. These results show that simvastatin decreases the growth of human Ito cells, independently of its effect on cholesterol synthesis. This decrease may be due in part either to reduced farnesylation of proteins involved in growth factor signaling pathway or to inhibition of N-linked protein glycosylation. Whether this effect exists in vivo and could thus lead to a parallel decrease of fibrosis deposition within the liver requires further study.

Actins↗
PubMed1994

PKC activity in rat C6 glioma cells: changes associated with cell cycle and simvastatin treatment.

The parallel effects of simvastatin on cell cycle and PKC activity in rat C6 glioma cells were investigated. Simvastatin, 2.5 microM, for 24 h resulted in cell growth arrest in early G1 phase of the cell cycle and in a significant increase of total PKC activity (283 +/- 42 vs 470 +/- 61 pmoles/min/mg protein p = 0.002 for control cells and simvastatin-treated cells, respectively). The effect of simvastatin was fully prevented by mevalonate. A time dependent increase of PKC activity was observed in control exponentially free-growing C6 cells approaching confluency: a highly significant negative correlation (r = -0.91 p < 0.0001) between PKC activity and growth rate was calculated. PKC activity was high in cells arrested in G0 by serum starvation (0.4%). Following addition of complete medium (17.5% serum) the PKC activity progressively decreased and reached a minimum when cells traversed the G2/M phase, as determined by DNA analysis distribution. PKC activity dropped 30% in simvastatin-arrested early G1 cells; 44% in hydroxyurea-arrested cells at the G1/S boundary; and 73% in Colcemid mitosis-blocked cells. The results show that C6 glioma cell PKC activity is maximal in a G0 quiescent state and varies at different points of the cell cycle.

Animals↗