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PubMedDate not supplied

Rhabdomyolysis induced by simvastatin and ketoconazole treatment.

Rhabdomyolysis is described as an adverse event of simvastatin therapy either by itself or in combination with other medications. It is unclear whether this phenomenon is specific to simvastatin or to all cholesterol-lowering agents as single-dose therapy or caused by the association of special coadministered medications. We describe two cases in which rhabdomyolysis developed after coadministration of simvastatin (20 mg/d) and the antifungal ketoconazole. The clinical features, blood examination results, and positive outcome were very similar in both cases. We concluded that ketoconazole, an antifungal sterol synthetic inhibitor of the azol group, may induce rhabdomyolysis in patients undergoing treatment with simvastatin, a lipid lowering agent, and increase the possibility of muscle-damaging adverse events of the agents.

Aged↗
PubMed2000

[Unaltered homocysteine levels during simvastatin therapy].

Homocysteinemia is regarded as a risk factor for vascular disease. Several risk factors and diseases, but also various drugs, amongst them some lipid lowering medications, have been shown to increase plasma homocysteine concentrations. We therefore assessed the influence of simvastatin on plasma homocysteine levels in 57 patients suffering from severe familial heterozygous hypercholesterolemia. After 1, 3 and 6 months of simvastatin therapy plasma homocysteine levels did not show any change compared to the levels before therapy. Males had typically higher homocysteine levels than females and concentrations in smokers were in most subgroups significantly higher than in non-smokers. No difference in patients taking either 20 or 40 mg simvastatin was apparent and no correlation to the lipid lowering action was found. These findings indicate that in contrast to a number of other lipid lowering agents, simvastatin does not affect plasma homocysteine levels.

Adult↗
PubMed2000

Simvastatin does not affect CYP3A activity, quantified by the erythromycin breath test and oral midazolam pharmacokinetics, in healthy male subjects.

Potential for inhibition of CYP3A activity by simvastatin, an HMG-CoA reductase inhibitor, was evaluated in 12 healthy male subjects who received placebo or 80 mg of simvastatin, the maximal recommended dose, once daily for 7 consecutive days. On day 7, an intravenous injection of 3 microCi [14C N-methyl]erythromycin for the erythromycin breath test (EBT) was coadministered with a 2 mg oral solution of midazolam. The values for percent 14C exhaled during the first hour (for EBT) and the pharmacokinetic parameters of midazolam (AUC, Cmax, t1/2) were not affected following multiple once-daily oral doses of simvastatin 80 mg. The 95% confidence interval was 0.97 to 1.18 for EBT and 0.99 to 1.23 for midazolam AUC. In addition, the total urinary recoveries of midazolam and its 1'-hydroxy metabolites (free plus conjugate) obtained from both treatments were not statistically different (p > 0.200). These data demonstrate that multiple dosing of simvastatin, at the highest recommended clinical dose, does not significantly alter the in vivo hepatic or intestinal CYP3A4/5 activity as measured by the commonly used EBT and oral midazolam probes.

Administration, Oral↗
PubMed2001

[Inhibition of proliferation and induction of apoptosis by simvastatin in K562 leukemic cell line].

OBJECTIVE: To investigate the anti-apoptotic mechanism and explore approach to inhibiting proliferation and inducing apoptosis of chronic myclogenous leukemia (CML) cells. METHODS: K562 cell line was used to evaluate the effects of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, and the combination of simvastatin with chemotherapeutic agents on the proliferation and apoptosis of CML cells. RESULTS: Simvastatin could significantly inhibit proliferation and induce apoptosis of K562 cells, and could increase the sensitivity of K562 cells to chemotherapeutic agents. Addition of mevalonate, the immediate product of HMG-CoA, could completely reverse this effect. CONCLUSION: Simvastatin inhibited proliferation and induced apoptosis of K562 cells through inhibiting the metabolic pathway of mevalonate. It is promising that HMG-CoA reductase inhibitors may be an effective chemotherapeutic approach to the treatment of CML.

Antineoplastic Agents↗
PubMed2002

Rapid spectrophotometric method for quantitative determination of simvastatin and fluvastatin in human serum and pharmaceutical formulations.

A spectrophotometric method has been developed and applied to the determination of simvastatin and fluvastatin in human serum and in tablets. Simvastatine and fluvastatin were determined by measurement of their first derivative signals at 241.6, 245.9, 249.1 nm (for simvastatin) and 259.6 nm (for fluvastatin), respectively. Calibration curves were linear and the ranges of quantification were 12.0-28.0 micrograms.ml-1 for simvastatin and 10.0-28.0 micrograms.ml-1 for fluvastatin. The procedure was successfully applied to the determination of these compounds in pharmaceutical formulations as well as in human serum with a high percentage of recovery, good accuracy and precision, and without measurable interference by the excipients.

Anticholesteremic Agents↗
PubMed2002

Simvastatin and pravastatin equally improve flow-mediated dilation in males with hypercholesterolemia.

BACKGROUND: Both simvastatin and pravastatin have been shown to improve endothelial function in patients with hypercholesterolemia. To our knowledge there has been no comparative study of these two HMG-CoA reductase inhibitors on endothelial dysfunction measured by flow-mediated dilation of the brachial artery in patients with hypercholesterolemia. METHODS: Fourteen middle-aged males with hypercholesterolemia (means +/- SD: total cholesterol 7.03 +/- 0.88 mmol/l, LDL cholesterol 5.02 +/- 0.63 mmol/l, HDL cholesterol 1.3 +/- 0.38 mmol/l and triglycerides 1.47 +/- 0.26 mmol/l) were randomised, after a 6 weeks' run-in phase with AHA step I diet treatment, to 12 weeks' treatment either with simvastatin or pravastatin. Both statins were given in a daily dose of 10 mg for 6 weeks, which was increased to 20 mg daily in patients who did not achieve an LDL-cholesterol goal of < 3.4 mmol/l. Endothelial dysfunction was measured as flow-mediated brachial artery dilation (FMD) using high resolution ultrasound. RESULTS: There were no significant differences between the drugs in reduction of total cholesterol, LDL cholesterol and triglycerides, or elevation of HDL cholesterol. FMD increased in the simvastatin group from 6.8 +/- 3.2 to 12.3 +/- 2.9% (p < 0.03) and in the pravastatin group from 6.3 +/- 4.8 to 13.3 +/- 4.7% (p = 0.001). The improvement in FMD was the same in both groups (p = 0.64) and did not correlate with changes of the lipid parameters measured. CONCLUSIONS: Both simvastatin and pravastatin reduce endothelial dysfunction to the same degree in patients with hypercholesterolemia, independently of changes in lipid parameters.

Anticholesteremic Agents↗
PubMed2002

Simvastatin and markers of endothelial function in patients undergoing continuous ambulatory peritoneal dialysis.

Patients undergoing continuous ambulatory peritoneal dialysis (CAPD) are prone to dyslipidemia and have a high risk of cardiovascular death. The aim of this study was to assess the effects of a 6-month treatment with simvastatin (10 mg at bedtime) on markers of endothelial cell injury in 12 hypercholesterolemic CAPD patients. Cholesterol and low-density lipoprotein cholesterol fell significantly after 1 month of therapy. Simvastatin treatment significantly decreased concentrations of vascular cell adhesion molecule and intracellular adhesion molecule after 3 and 6 months of the therapy, respectively. Thrombomodulin decreased significantly after 6 months of the treatment, whereas von Willebrand's factor, P-selectin and E-selectin remained unaltered during simvastatin therapy. Simvastatin, an effective hypolipemic agent, favorably affects endothelial function and may potentially slow the progression of atherosclerosis and confer protection from thrombotic complications in patients with hypercholesterolemia undergoing CAPD.

Biomarkers↗
PubMed2003

Oral simvastatin as an antilipemic therapy: effect on creatine kinase in hypercholesterolemic subjects.

UNLABELLED: This study was aimed at evaluating the short-term efficacy and effect on serum creatine kinase of simvastatin, a recently available antilipemic drug, as a monotherapy for hypercholesterolemic patients. This prospective study was performed at the Outpatient Division, King Chulalongkorn Memorial Hospital. All 45 Thai hypercholesterolemic subjects (aged 30 to 60 years) who were unable to normalize cholesterol by dietary means were recruited in this study. All subjects were assigned to receive oral simvastatin therapy (dose 10 mg/day) for a 2-month study. Before initiation of therapy, monitoring of lipid profile and serum creatine kinase levels was performed. Lipid profile and serum creatine kinase enzyme determinations were also performed 4 weeks after initial treatment and at the the end. After 8 weeks of therapy, total cholesterol had significantly declined from 267 +/- 33 mg/dL to 192 +/- 32 mg/dL, while no significant change in the levels of the serum creatine kinase (p > 0.05) was observed. Clinical follow-up and blood chemistry profile did not indicate any muscle side effects from oral simvastatin therapy. CONCLUSION: simvastatin is an effective oral antilipemic agent for treating Thai patients with hypercholesterolemia. Adverse effects presenting as elevation of the serum creatine kinase were not experienced by this group of patients.

Administration, Oral↗
PubMed2003

Effect of simvastatin on trioleylglycerol hydrolysis and transacylation with cholesterol in serum of outpatients with coronary heart disease.

At present, the most effective drugs in treating hypercholesterolemia and atherosclerosis are the statins, which are potent inhibitors of the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Serum triacylglycerol (TAG) levels associate positively with the risk for coronary heart disease (CHD). Triacylglycerols are mainly hydrolyzed by the enzyme lipase (glycerol ester hydrolase [GEH], EC 3.1.1.3) but can also be transformed by transacylation with cholesterol (glycerol ester:cholesterol acyltransferase [GECAT], EC 2.3.1.43). We evaluated the effect of a 3-month treatment with simvastatin (10 mg/day) on GEH and GECAT activity in the serum of 26 outpatients with CHD. The activity of both GEH and GECAT was reduced in the CHD group compared with that in the control group: 5.9 +/- 0.9 mU/mg vs. 7.5 +/- 1.8 mU/mg and 11.1 +/- 1.4 mU/mg vs. 19.3 +/- 3.3 mU/mg, respectively (p < or = 0.05). In addition to the well known effect of reducing total cholesterol and low-density lipoprotein cholesterol in patients with CHD, we observed two other results of simvastatin treatment. First, GEH activity increased to values similar to those found in healthy subjects and, simultaneously, GECAT activity decreased. Trioleylglycerol transacylation with cholesterol amounted to 72% and hydrolysis to 28% in the control group and to 65% and 35% in the CHD group, respectively. After simvastatin treatment, transacylation with cholesterol and hydrolysis amounted to 51% and 49%, respectively. In conclusion, by increasing GEH and reducing GECAT, simvastatin seems not only to affect cholesterol synthesis but also to alter triacylglycerol metabolism. Further studies are needed to determine the physiological significance of these changes and their relationship with the development of atherosclerosis.

Acylation↗
PubMed1992

Efficacy and tolerability of medium-term treatment with simvastatin in primary hypercholesterolaemia.

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, a new class of hypolipidaemic agents, have been recently shown to be effective in lowering both total and low-density lipoprotein (LDL)-cholesterol. In the present study 20 patients were treated with simvastatin for six months. Various dosing regimens of 10, 20, and 40 mg/day were employed. Administration of simvastatin 10 to 40 mg/day resulted in a 24.7 to 35.8% reduction in LDL-cholesterol levels and in a 19.5 to 26.9% decrease of total cholesterol levels. Moreover, simvastatin increased high-density lipoprotein-cholesterol and induced a decrease in plasma triglycerides. The side-effect profile was similar to other observations and included reversible transaminase elevations, myalgia and gastrointestinal complaints. From the present study simvastatin seems to be well tolerated in the short- to medium-term and to be effective; however, its long-term tolerability needs to be confirmed.

Adult↗
PubMed2003

[Studies on the simvastatin effect on the artery of atherosclerotic rabbit using proteomics approaches].

AIM: To evaluate the inhibitory effect of simvastatin via investigating the overall expression level of proteins in the artery of atherosclerotic rabbit. METHODS: Experimental model was established by feeding the rabbits a high fat diet (cholesterol 0.5 g.kg-1.d-1, lard 0.5 mL.kg-1.d-1) for 8 weeks. Then simvastatin (5 mg.kg-1) were fed for 4 weeks to the rabbits. The overall protein levels were measured using two-dimensional gel electrophoresis and a PDQUEST data processing. RESULTS: Twenty nine protein spots showed significant quantitative changes in comparison with the normal and the diseased rabbits. Furthermore, after the diseased rabbit having taken simvastatin, an obvious decay of symptom of fatty liver was observed, and the intensity of most spots has not been back-regulated. CONCLUSION: Simvastatin facilitates the metabolism of fat in the blood, but the lesion of the internal wall of the atherosclerotic artery cannot be restored.

Animals↗
PubMedDate not supplied

Evaluation of simvastatin antioxidant effects.

3-Hydroxy-3-methyl-coenzyme A reductase (HMG-CoA reductase) which transforms 3-hydroxy-3-methylglutaril-coenzyme A (HMG-CoA) in mevalonate, is the rate limiting enzyme in cholesterol biosynthesis. In our study, from HMG-CoA reductase's known inhibitors, we used simvastatin (ZOCOR), which is a semi synthetic derivative of the second generation. The study was performed on 25 subjects (12 men and 12 women) aged 33-67 yo, with hypercholesterolemia, which have received simvastatin, 10 mg daily for 8 months. Under treatment with simvastatin we obtained a significant decrease of total cholesterol (p < 0.0001) and an improvement of enzymatic antioxidant parameters: superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT). In conclusion, simvastatin therapy determines a significant decrease in SOD, GPx, CAT, and an increase in CAT/SOD and GPx/SOD ratios.

Adult↗
PubMed1992

[Dyslipidemia in the uremic patient: the therapeutic role played by simvastatin].

Simvastatin is a pharmacological molecule belonging to the family of HMG-CoA reductase inhibitors, recently included in plasma cholesterol lowering therapy. The authors carried out a study on the possible triglyceride lowering activity of simvastatin in dialyzed patients with chronic uremia considering its particular mechanism of action. The subjects selected for the study were suffering from uremia either complied with dosage prescribed or not. The obtained data showed the substance's triglyceride lowering effect, but no simvastatin-related side effect in the dialysed patients with uremia. For these reasons and for the substance's well-known cholesterol-lowering effect, simvastatin seems to deserve the definition of choice drug in the treatment of altered lipidemia in patients with uremia.

Aged↗
PubMedDate not supplied

Simvastatin decreases concentration of interleukin-2 in hypercholesterolemic patients after treatment for 12 weeks.

UNLABELLED: Statins, HMG-CoA reductase inhibitors are drugs with a potent lipid-lowering effect. They are also able to inhibit proliferation of smooth muscle cells, T-lymphocytes, to restore endothelial activity and to inhibit inflammatory responses. These effects have been called the pleiotropic effect of statins. Statins have demonstrated contrast to the inflammatory activity of macrophages. The aim of the study was to assess the influence of simvastatin on serum levels of proinflammatory cytokines such as IL-2 and TNFalpha in hypercholesterolemic patients. METHODS: In 58 non-smoking men with total cholesterol (TC) >7.8 mmol/L, LDL-cholesterol>5.5 mmol/L and fasting triglycerides<4.6 mmol/L serum IL-2 and TNFalpha were determined at the beginning of the study, after 3 months diet and after 3 months of simvastatin therapy (20 mg/day). The control group was composed of 10 healthy volunteers with correct lipid values: TC<5.2 mmol/L, LDL-cholesterol <2.3 mmol/L, HDL-cholesterol >1.5 mmol/L and triglycerides<2.3 mmol/L. RESULTS: There were significant reductions in IL-2 concentration after 3 months diet (p=0.0059) and significant (p=0.0003) decrease of IL-2 after 3 months of simvastatin therapy. Meanwhile we observed a significant decrease of TNFalpha concentration after 3 months diet (p=0.0001) and no significant decrease after 3 months of simvastatin therapy.

Adult↗
PubMed2005

Concentration and distribution of ubiquinone (coenzyme Q), the endogenous lipid antioxidant, in the rat lens: effect of treatment with simvastatin.

PURPOSE: Ubiquinone (Ub) is the only known endogenously synthesized lipid soluble antioxidant. It is synthesized from intermediates in the cholesterol metabolic pathway. Our goal was to identify the Ubs and determine the concentration and distribution of Ubs in the rat lens and the effect of treatment with simvastatin, a cholesterol synthesis inhibitor, on lens levels. METHODS: Intact lenses and separated lens fractions from young rats were homogenized in organic solvents, the Ubs recovered, and identified by HPLC analysis. Rats were fed Ub-10 to determine effects of supplementation on tissue levels. Sprague-Dawley (SD) and Chbb:Thom (CT) rats were treated with simvastatin, an inducer of cataracts in CT rats, to determine its effects on lens Ubs. RESULTS: Ubiquinone-9 (9 isoprenes in its hydrocarbon tail) was the main Ub in the rat lens. The intact lens contained about 3.0 microg Ub/g lens wet weight of which 80-90% was Ub-9 and the remainder Ub-10. No reduced Ubs were detected. Although the epithelial fraction contained the highest Ub concentration (about 8 microg/g), the cortex and nucleus combined accounted for about 90% of the lens' total content. Dietary supplementation with Ub-10 markedly increased the Ub-10 concentration in liver but not lens. Treatment with simvastatin decreased lens Ubs of both SD and CT rats by about 20%. CONCLUSIONS: The abundance of mitochondria in lens epithelium likely accounted for its high level of Ubs; but, finding most of the lens' total Ub in the cortex plus nucleus also suggests roles in maintaining the fiber cell membrane. The decrease in lens Ubs caused by simvastatin is interpreted to reflect a response to drug induced cellular stress rather than to inhibition of the cholesterol synthesis pathway.

Adolescent↗
PubMed2005

[The comparison of simvastatin and atorvastatin effects on hemostatic parameters in patients with hyperlipidemia type II].

The studies results of statin influence on hemostasis are various. The aim of our study was to evaluate the effects of simvastatin and atorvastatin on hemostatic parameters, such as activity of factor X, antithrombin III, fibrinogen concentration and Lp(a). 72 patients (pts) aged 40-65 were involved in the study; 49 of them suffered from hyperlipidemia II (hlp II) with the initial concentration of total cholesterol (TC) >200 mg/dL, cholesterol LDL (LDL-C) >145 mg/dL, triglycerides (TG) <400 mg/dL. The control group consisted of 20 healthy persons. The pts with hlp II who underwent 4 weeks long lipid lowering diet were randomized into two groups: I--27 pts treated with simvastatin (20 mg/d), II--22 pts treated with atorvastatin (10 mg/d). The active statin therapy lasted 8 weeks. The activity of factor X and antithrombin III (AT III) was estimated by amidolytic methods, fibrinogen concentration (Fb) by the Clauss method, Lp(a)-immunoenzymatic method. The mean values of factor X activity and Fb serum concentration were higher in pts with hip II than in the control group, the AT III activity was lower. The Lp(a) concentration didn't differ between groups. Statin treatment was associated with significant reduction of factor X activity. Both simvastatin and atorvastatin markedly increased AT III (87%, 98%) in comparison to the initial values. No changes of Lp(a) concentration were observed during statin therapy. Atorvastatin therapy significantly increased the Fb concentration (12.3%). Simvastatin treatment didn't influence Fb concentration.

Aged↗
PubMed1992

[Simvastatin in the treatment of hypercholesterolemia in the aged. An epidemiological and clinical study].

The paper review the literature on the subject and underlines the importance of hypercholesterolemia. It also reports the findings of the large trials, works and consensus studies, including the results of the Framingham Study, the Lipidic Research Clinics Program and the main international conferences. On the basis of these findings, it assesses the hypocholesterolemic effect of simvastatin in a sample group of 51 mainly geriatric outpatients following a standard period of preliminary dietary therapy. Subjects were treated with 20 mh/day simvastatin for not less than one month, after which lipidic parameters were evaluated and revealed significant variations: circulating cholesterin was reduced from 322 mg% +/- 49.4 to 225 mg% +/- 37.6 (p less than 0.001), the LDL-lipoprotein level fell from 229 mg% +/- 6.6 to 152 mg% +/- 36.3; HDL-lipoproteins showed no significant variation, nor did other tests to ascertain possible hepatic involvement or other parenchymas secondary to the use of simvastatin. Overall cholesterol levels decreased from 16423 mg% to 11511 mg%, equivalent to 29.9%. Lastly, simvastatin also proved to be clinical efficacious, and was easy to manage and well tolerated by elderly patients. All subjects responded equally well to treatment independent of their general condition and sex. Basal cholesterolemia in elderly subjects decreased from 320 mg% +/- 46.3 to 226 mg% +/- 33.2 (p less than 0.001) and in adults from 325 mg% +/- 56.6 to 224 mg% +/- 46.5 (p less than 0.001); LDL-cholesterol decreased from 232 mg% +/- 46.5 to 153 mg% +/- 35.6 (p less than 0.001) and from 224 mg% +/- 46.6 to 147 mg% +/- 38.7 (p less than 0.001) respectively.

Adult↗
PubMed2005

[Changes of elastic properties of magistral arteries in patients with ischemic heart disease during treatment with atorvastatin and simvastatin].

AIM: To elucidate effect of atorvastatin and simvastatin on elastic properties and reactivity of large arteries in patients with ischemic heart disease. MATERIAL: Patients (n=38) with ischemic heart disease receiving atorvastatin (10 mg/day, n=20) and simvastatin (20 mg/day, n=18). METHODS: Elasticity of arteries was assessed by pulse wave propagation velocity measured by Coloson computer system. Test with reactive hyperemia was used for assessment of large muscular type vessels reactivity in response to blood flow augmentation was assessed by. RESULTS: Treatment with statins for 6 months was associated with positive changes of elasticity of arteries of elastic type (-10.05% and -4.66% in atorvastatin and simvastatin treated patients, respectively) and endothelium dependent reactivity of arteries of muscular type (-16.01%, p<0.001 and -11.1% p<0.001 compared with initial values in atorvastatin and simvastatin treated patients, respectively). CONCLUSION: Therapy with statins positively affects parameters of elasticity and reactivity of large arteries.

Anticholesteremic Agents↗