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PubMed2000

The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction : a substudy of the Scandinavian simvastatin survival study.

BACKGROUND: Carriers of the epsilon4 allele of the apolipoprotein E gene are at a higher risk of coronary heart disease than individuals with other genotypes. We examined whether the risk of death or a major coronary event in survivors of myocardial infarction depended on apolipoprotein E genotype and whether the benefits of treatment with simvastatin differed between genotypes. METHODS AND RESULTS: Cox proportional hazards models were used to analyze 5.5 years of follow-up data from 966 Danish and Finnish myocardial infarction survivors enrolled in the Scandinavian Simvastatin Survival Study. A total of 16% of the 166 epsilon4 carriers in the placebo group died compared with 9% of the 312 patients without the allele, which corresponds to a mortality risk ratio of 1.8 (95% confidence interval, 1.1 to 3.1). The risk ratio was unaffected by considerations of sex, age, concurrent angina, diabetes, smoking, and serum lipids in multivariate analyses. Simvastatin treatment reduced the mortality risk to 0.33 (95% confidence interval, 0.16 to 0.69) in epsilon4 carriers and to 0.66 (95% confidence interval, 0. 35 to 1.24) in other patients (P=0.23 for treatment by genotype interaction). Apolipoprotein E genotype did not predict the risk of a major coronary event. Baseline serum levels of lipoprotein(a) also predicted mortality risk and could be combined with epsilon4-carrier status to define 3 groups of patients with different prognoses and benefits from treatment. CONCLUSIONS: Myocardial infarction survivors with the epsilon4 allele have a nearly 2-fold increased risk of dying compared with other patients, and the excess mortality can be abolished by treatment with simvastatin.

Adult↗
PubMedDate not supplied

Comparative effects of simvastatin and lovastatin in patients with hypercholesterolemia. The Simvastatin and Lovastatin Multicenter Study Participants.

The efficacy, safety profile, and tolerability of the HMG-CoA reductase inhibitors simvastatin and lovastatin were compared in a multicenter, randomized, double-blind study in patients with moderate hypercholesterolemia. Commonly prescribed doses of these two drugs were used by 544 men and women, who followed an American Heart Association phase I diet during a 6-week baseline period and for the 24 weeks of active treatment. Simvastatin 10 mg and lovastatin 20 mg produced statistically significant reductions in total and low-density lipoprotein cholesterol (LDL-C). Patients receiving simvastatin 10 mg once daily and lovastatin 20 mg once daily experienced similar reductions in LDL-C and total cholesterol; however, simvastatin 20 mg was statistically superior to lovastatin 40 mg in decreasing these lipid fractions. For all treatment groups, increases in high-density lipoprotein cholesterol were inversely related to baseline levels. Moderate decreases in triglycerides occurred with all doses. Lipoprotein(a) levels, measured in a subset of patients, were similar before and after treatment. Both drugs were well tolerated.

Adult↗
PubMedDate not supplied

Use of simvastatin treatment in patients with combined hyperlipidemia in clinical practice. For the Simvastatin Combined Hyperlipidemia Registry Group.

OBJECTIVE: To describe and understand current care of simvastatin-treated patients with combined hyperlipidemia in routine clinical practice. DESIGN: A 6-month prospective observational study. Demographics, simvastatin dosage, cardiac risk factors, and lipid profile were collected from August 1997 to December 1998 at 20 sites (230 patients) across the United States. RESULTS: Overall mean percentage of reduction in total cholesterol levels was 27% (P<.001), low-density lipoprotein cholesterol (LDL-C) was 35% (P<.001), and triglyceride values was 28% (P<.001). Among those patients with low baseline high-density lipoprotein cholesterol (HDL-C) values (<0.91 mmol/L [<35 mg/dL]) (N = 49), there was a 17% increase in HDL-C (P< or =.001); 35% of these patients achieved National Cholesterol Education Program HDL-C goal (ie, < or =0.91 mmol/L [> or =35 mg/dL]). Coronary heart disease (CHD) patients were given significantly higher initial doses (mean, 15.1 mg) compared with non-CHD patients (mean, 11.5 mg) (P< or =.001). Overall, 74% of patients achieved LDL-C goal (52% on starting dose, 22% after 1 titration). Among those patients who were not at goal and had a follow-up lipid profile result available, only 1 patient (2%) was at the maximum dose (80 mg); 69% were receiving 20 mg or less. Approximately 63% of patients with CHD, 80% of patients with 2 or more risk factors, and 91% of patients with fewer than 2 risk factors achieved LDL-C goal. CONCLUSIONS: Multiple factors contribute to LDL-C goal achievement in a usual care setting. A significant opportunity exists to increase the number of patients who achieve LDL-C goal by appropriate dose titration and/or give patients a higher initial dose of simvastatin.

Adult↗
PubMed1998

Effect of simvastatin on ischemic signs and symptoms in the Scandinavian simvastatin survival study (4S).

In patients participating in the Scandinavian Simvastatin Survival Study, cholesterol lowering with simvastatin reduced the incidence of carotid bruits and cerebrovascular events as well as new-onset or worsening of angina pectoris and intermittent claudication. These effects suggest that simvastatin may have a general antiatherosclerotic effect not limited to the coronary bed.

Adult↗
PubMed2002

LDL-cholesterol lowering effect of a generic product of simvastatin compared to simvastatin (Zocor) in Thai hypercholesterolemic subjects -- a randomized crossover study, the first report from Thailand.

BACKGROUND: It is commonly agreed that people with a high blood LDL-cholesterol will have a higher risk of coronary artery disease (CAD) than people with low blood LDL-cholesterol. Due to the increasingly high costs of medication in Thailand, the government has set up several measures to combat the problem. One of such strategies is to promote the utilization of locally manufactured drug products, especially those contained in the National Drug List. Simvastatin, an HMG-CoA reductase inhibitor, is listed as an essential drug for the treatment of hypercholesterolemia. Here, we reported the study on the LDL-cholesterol-lowering effect of a generic simvastatin product in comparison with the Zocor, in 43 healthy thai volunteers. METHOD: The generic product tested was Eucor, locally manufactured by Greater Pharma Ltd., Part, Thailand, and the reference product was Zocor (Merck Sharp & Dohme, USA). The two products were administered as 10-mg single oral doses in a two-period crossover design. After drug administration, serial blood samples were collected every 4 weeks for 16 weeks. The major parameter monitored in this study was blood LDL-cholesterol. RESULT: After taking the drugs for the first 8 weeks, no statistically significant difference was detected in blood LDL-cholesterol between the first (Zocor-treated) and the second (Eucor-treated) groups. After crossover and taking drugs for further 8 weeks, a similar result was obtained, i.e., no significant difference in blood LDL-cholesterol between the first (Eucor-treated) and the second (Zocor-treated) groups was observed. Upon completion of the 16-week study, there was also no statistically significant difference in the changes of all tested blood parameters between the two products (randomized block ANOVA, N = 37). Only minor side effects, mainly dizziness and nausea, were observed in both products. CONCLUSION: Our study demonstrated no significant differences in the therapeutic effect and safety between the generic and original simvastatin products.

Adult↗
PubMed1989

[Swiss simvastatin multicenter study: 1. Efficacy of 10 mg simvastatin daily in patients with primary hypercholesterolemia].

In a Swiss multicenter study with determination of lipid and lipoprotein parameters in a central laboratory, the efficacy of simvastatin, MSD, was evaluated in patients with primary hypercholesterolemia. Lipid and lipoprotein values were determined in 109 patients before and after 6 weeks' therapy with 10 mg simvastatin per day. A significant decrease in total cholesterol, LDL-cholesterol and apo B, of 21.1, 25.8 and 24.1% respectively, was observed. No influence of simvastatin on apo A-II was found, but HDL-cholesterol and apo A-I were slightly increased (+6.1 and 4.4% respectively). The data show that HMG-CoA reductase inhibitors constitute a new class of effective drugs for the treatment of hypercholesterolemia.

Adult↗
PubMedDate not supplied

A one-year multicentre study of simvastatin in the treatment of hypercholesterolaemia. UK and Eire Simvastatin Study Group.

A 1-year prospective study was conducted in 475 hypercholesterolaemic men and women who received simvastatin monotherapy 10-40 mg daily for 3 months followed by additional lipid-lowering medication after this period, if necessary, to reach a target of plasma cholesterol < 5.3 mmol/l. Of these, 403 subjects completed 1 year of follow-up. By the end of the 3-month monotherapy period, the following percentage mean changes were seen (with 95% confidence intervals): total cholesterol (TC) -31% (-30 to -32%), low-density lipoprotein cholesterol -39% (-38 to -40%), triglycerides -14% (-11 to -17%) and high-density lipoprotein cholesterol +12% (+11 to +14%). These levels were maintained for the remainder of the study. When subjects with a baseline TC of 6.5-7.8 mmol/l were considered (n = 89), 42.7% achieved the target TC levels on simvastatin monotherapy alone. Additional hypolipidaemic medication had no significant impact on plasma lipid and lipoprotein levels. Simvastatin was well tolerated both as monotherapy and in combination.

Adolescent↗
PubMed1998

Simvastatin-tacrolimus and simvastatin-cyclosporin interactions in rats.

The effect of simvastatin (SV)-tacrolimus (TL) and simvastatin-cyclosporin (CyA) interactions on creatine phosphokinase levels and renal and hepatic function were investigated in rats. Animals were divided into seven groups; (1) SV (150 mg kg-1 oral) alone, (2) SV + TL (150 mg kg-1 oral + 0.5 mg kg-1 intraperitoneal (i.p.)), (3) TL (0.5 mg kg-1 i.p.) alone, (4) SV + CyA (150 mg kg-1 oral + 10 mg kg-1 oral), (5) CyA (10 mg kg-1 oral) alone, (6) control vehicle for oral administration, and (7) control vehicle for i.p. administration. A marked reduction in body weight and mortality was observed in the (SV + CyA) and (SV + TL) groups. Plasma creatine kinase levels in the (SV), (TL), (SV + CyA) and (SV + TL) groups, 7 days postadministration, were significantly higher compared with those before administration (p < 0.05). The plasma urea nitrogen levels in the (TL), (SV + CyA) and (SV + TL) groups after 7 days of administration were significantly higher than those of the controls. In addition, a marked increase in the plasma levels of alanine and aspartate amino transferases were observed in the (SV + CyA) groups.

Animals↗
PubMed2005

Application of a novel ultra-low elution volume 96-well solid-phase extraction method to the LC/MS/MS determination of simvastatin and simvastatin acid in human plasma.

A novel extraction method has been utilized in the LC/MS/MS determination of simvastatin and simvastatin acid in human plasma. In this method, 300 microl of plasma sample was loaded onto a Waters Oasis 96-well HLB microElution plate, the stationary phase was washed using 2 x 400 microl of 5% methanol in water, and the analytes were eluted using 35 microl of 95/5 acetonitrile/H(2)O twice. The sample extracts were diluted with 40 microl of methyl ammonium acetate (1mM, pH 4.5). Chromatography was performed on a Phenomenex Synergi Max-RP column (2.0 mm x 50 mm, 4 microm). A PE Sciex API 3000 tandem mass spectrometer interfaced with a turbo ionspray source was used for mass detection. Compared to solid-phase extraction, liquid-liquid extraction and solid-supported liquid-liquid extraction methods that were developed and previously used in our laboratory, this method reduced the labor cost and was less time consuming in sample preparation, due to the fact that post-extraction solvent evaporation and reconstitution steps were avoided using this microElution solid-phase extraction plate. The method has been proved to be fast, reliable and reproducible.

Chromatography, Liquid↗
PubMed2005

Validated HPLC-MS/MS method for simultaneous determination of simvastatin and simvastatin hydroxy acid in human plasma.

Cholesterol lowering statin drugs are the most frequently prescribed agents for reducing morbidity and mortality related to coronary heart disease. This publication presents a validated, highly sensitive and selective isocratic HPLC method for the quantitative determination of the major statin drug simvastatin (SIM) and its metabolite simvastatin hydroxy acid (SIMA). Detection was performed on an electrospray ionization triple quadrupole mass spectrometer equipped with an ESI interface operated in positive and negative ionization mode. The multiple reaction-monitoring mode (MRM) was used to provide MS/MS detection. The linearity for the calibration curve in the concentration range of 0.10-16.00 ng/mL for SIM and 0.10-16.00 ng/mL for SIMA is presented. Inter- and intra-day precision and accuracy of the proposed method were characterized by relative standard deviation (R.S.D.) and percentage deviation, respectively; with both lower than 7% for all analytes. The limit of quantitation was 0.03 ng/mL for SIM and 0.02 ng/mL for SIMA. The devised method was employed in the pharmacokinetic study of SIM and the pharmacokinetic parameters of all analytes are also presented.

Chromatography, High Pressure Liquid↗
PubMed2004

Interactions of human P-glycoprotein with simvastatin, simvastatin acid, and atorvastatin.

PURPOSE: In this study, P-glycoprotein (P-gp) mediated efflux of simvastatin (SV), simvastatin acid (SVA), and atorvastatin (AVA) and inhibition of P-gp by SV, SVA, and AVA were evaluated to assess the role of P-gp in drug interactions. METHODS: P-gp mediated efflux of SV, SVA, and AVA was determined by directional transport across monolayers of LLC-PK1 cells and LLC-PK1 cells transfected with human MDR1. Inhibition of P-gp was evaluated by studying the vinblastine efflux in Caco-2 cells and in P-gp overexpressing KBV1 cells at concentrations of SV, SVA, and AVA up to 50 microM. RESULTS: Directional transport studies showed insignificant P-gp mediated efflux of SV, and moderate P-gp transport [2.4-3.8 and 3.0-6.4 higher Basolateral (B) to Apical (A) than A to B transport] for SVA and AVA, respectively. Inhibition studies did not show the same trend as the transport studies with SV and AVA inhibiting P-gp (IC50 -25-50 microM) but SVA not showing any inhibition of P-gp. CONCLUSIONS: The moderate level of P-gp mediated transport and low affinity of SV, SVA, and AVA for P-gp inhibition compared to systemic drug levels suggest that drug interactions due to competition for P-gp transport is unlikely to be a significant factor in adverse drug interactions. Moreover, the inconsistencies between P-gp inhibition studies and P-gp transport of SV, SVA, and AVA indicate that the inhibition studies are not a valid means to identify statins as Pgp substrates.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Fenofibrate plus simvastatin therapy versus simvastatin plus cholestyramine therapy for familial hypercholesterolaemia.

Combination therapy is routinely used to achieve improved cholesterol reduction in familial hypercholesterolaemia. We compared the standard simvastatin plus bile-acid sequestrant (cholestyramine) therapy with simvastatin plus fenofibrate in 29 patients with severe familial hypercholesterolaemia. The fibrate regimen resulted in an 35.1 +/- 10.7% reduction in total cholesterol, a 40.6 +/- 20.5% in LDL cholesterol, 17.2 +/- 56.5% reduction in triglycerides and a 20.3 +/- 52.0% increase in HDL cholesterol. The cholestyramine regimen produced reductions of 29.3 +/- 13.2% in cholesterol, 37.1 +/- 21.9% in LDL cholesterol, and 12.5 +/- 48.9% in triglycerides, and a 5.0 +/- 25.4% rise in HDL cholesterol. The fibrate regimen was significantly more effective in reducing total cholesterol (p < 0.001) and LDL-cholesterol (p = 0.004), and also reduced triglycerides significantly (p = 0.05), compared to the cholestyramine regimen. There were significant improvements in the LDL:HDL cholesterol ratio (3.62 +/- 1.54 vs. 4.00 +/- 1.36; p = 0.05) and in the apolipoprotein B:A1 ratio (1.13 +/- 0.036 vs. 1.20 +/- 0.34; p = 0.05). Gastrointestinal side-effects occurred in 10 patients on cholestyramine therapy, and four patients on fibrate therapy had myalgia. There were no cases of rhabdomyolysis with either regime. No significant differences in liver biochemistry or creatine kinase were seen with either regimen.

Adolescent↗
PubMed1992

[The hypotriglyceridemic action of the combination of L-carnitine + simvastatin vs. L-carnitine and vs. simvastatin].

Previous studies had determined the role played by L-carnitine and simvastatin in the treatment of altered lipidemia in dialyzed patients with chronic uremia. The authors carried out a study on the above substances either singly or together administered to the same patients with chronic uremia in hemodialysis. This study was aimed at demonstrating the possible synergic normolipidemic action of both substances in comparison with their single administration, because their different mechanism of action could be metabolically enhanced. The obtained results demonstrated that the therapeutic association proposed is preferable to the use of the single substances. Moreover, a higher and more rapid normolipidemic effect was obtained after using L-carnitina associated with simvastatin with respect to the separated substances.

Aged↗
PubMed1991

Lecithin: cholesterol acyltransferase activity in familial hypercholesterolemia treated with simvastatin and simvastatin plus low-dose colestipol.

In 19 patients with heterozygous familial hypercholesterolemia (FH), the effects of simvastatin (S) 20 mg/d, 40 mg/d, and 40 mg/d plus low-dose colestipol (10 g/d) on plasma lipids, plasma lipoproteins, and plasma lecithin: cholesterol acyltransferase (LCAT) activity were investigated after an original dose-range escalation/descalation design. The drug regimen was changed every 8 weeks. A significant reduction in total cholesterol and LDL-cholesterol was observed, reaching 39% and 54% for the drug combination (week 28), and total apoprotein B and LDL-apoprotein B were reduced by 39% and 50%, respectively. Triglycerides were significantly lowered by S alone (up to 29% with 40 mg/d). HDL-cholesterol increased during therapy but the cholesterol content in HDL2-HDL3 fractions (isolated by ultracentrifugation) did not change significantly during the different steps. The ratio LDL-C/HDL-C fell by 57% at week 28. Plasma LCAT activity expressed as FER was significantly enhanced by S alone (+33%), and a further increase on drug combination regimen (+58%) was observed. This effect could be considered as a consequence of the increased fractional clearance of LDL-C. It tended to be sustained during the descalation part of the study. Biochemical adverse effects were scarce and transient. In conclusion, the combination therapy increased the plasma LCAT/FER activity without a preferential enhancement in HDL2-C concentration. This original design allowed to define the most appropriate individual cholesterol-lowering drug dosage in FH patients.

Adolescent↗
PubMed1991

Bioconversion of the sodium salt of simvastatin (MK-733) to 6-desmethyl-6-alpha-hydroxymethyl simvastatin.

An actinomycete (MA 6474, ATCC 53828) isolated from a soil sample (Mutare, Zimbabwe) was found to biotransform the sodium salt of Simvastatin (MK-733) to 6-alpha-hydroxymethyl MK-733, 6-beta-hydroxymethyl MK-733, and 6-ring-hydroxy MK-733. The bioconversion efficiency to the desired compound, 6-alpha-hydroxymethyl MK-733, was enhanced by optimizing the physico-chemical parameters of the process. In shake flask cultures, addition of magnesium (0.125 mg/l Mg SO4.7H2O) to the medium resulted in a five-fold increase in the rate of bioconversion to the alpha diastereomer. The ratio of bioconversion products (6-alpha-hydroxymethyl,6-beta-hydroxymethyl, and 6-ring-hydroxy MK-733) was regulated by pH. Process improvements and scale up in 23-1 fermentors, which consisted of a controlled addition of substrate (MK-733), resulted in a 2-fold increase in alpha diastereomer production (42 vs. 79 U/ml) and a 23-fold rate increase in the formation of alpha-diastereomer. A high diastereomeric ratio (alpha: beta = 9:1) facilitated downstream processing.

Actinomycetales↗
PubMed1993

Comparison of the short term efficacy and tolerability of lovastatin and simvastatin in the management of primary hypercholesterolemia.

OBJECTIVES: To compare the safety and efficacy of lovastatin and simvastatin in patients with primary hypercholesterolemia. METHODS: Fourteen Canadian centres participated in this double-blind, randomized, parallel-design study with a six-week screening period, a four-week placebo baseline period and an 18-week active treatment period. Patients were included in the study if their total cholesterol (TC) was at least 6.2 mmol/L and total triglycerides (TG) were 4.0 mmol/L or less at baseline. Half of the patients were in stratum I (TC 6.2 to 7.8 mmol/L at baseline and placebo period) and half in stratum II (TC greater than 7.8 mmol/L). The initial dose of lovastatin or simvastatin (20 and 10 mg/day, respectively) was doubled if the patient's cholesterol was greater than 5.2 mmol/L after six and/or 12 weeks, to a maximum of 80 mg/day lovastatin or 40 mg/day simvastatin. Of 298 randomized patients, two had baseline data only (and were excluded from the efficacy analysis), while 77 were treated with lovastatin and 74 with simvastatin in stratum I, and 72 were on lovastatin and 75 on simvastatin in stratum II. RESULTS: In stratum I, both lovastatin and simvastatin lowered TC (-26.0% in both the lovastatin and simvastatin groups), low density lipoprotein (LDL) cholesterol (-33.4% in lovastatin and -34.4% in simvastatin), TG (-11.4% in lovastatin and -16.2% in simvastatin), apolipoprotein (apo)-B (-24.8% in lovastatin and -26.3% in simvastatin) and the TC:high density lipoprotein (HDL) cholesterol ratio (from 6.65 to 4.73 in lovastatin and from 6.45 to 4.46 in simvastatin), and increased HDL cholesterol (+3.6% in lovastatin and +7.8% in simvastatin) and apo-A1 (+6.3% in lovastatin and +9.0% in simvastatin) with P < 0.001 in all within-group tests except for HDL cholesterol (P < 0.05). Similar results were obtained in stratum II for TC (-30.7% in lovastatin and -30.3% in simvastatin), LDL cholesterol (-37.6% in lovastatin and -36.8% in simvastatin), TG (-21.9% in lovastatin and -16.9% in simvastatin), apo-B (-32.0% in lovastatin and -31.7% in simvastatin), TC:HDL cholesterol ratio (from 8.62 to 5.47 in lovastatin and from 8.96 to 5.77 in simvastatin), HDL cholesterol (+9.7% in lovastatin and +7.5% in simvastatin) and apo-A1 (+7.2% in lovastatin and +8.8% in simvastatin), with P < 0.001 in all within-group tests. Serious adverse events (clinical and laboratory) were reported in four patients in the lovastatin group and three in the simvastatin group. The most reported nonserious adverse effects were gastrointestinal tract (15 patients in the lovastatin group and 16 in the simvastatin group) and musculoskeletal (14 patients in the lovastatin group and 11 in the simvastatin group). Medication was withdrawn in eight patients. CONCLUSIONS: Both lovastatin and simvastatin were found to be effective and well tolerated in each stratum. However, there were no significant differences between lovastatin and simvastatin in the treatment of moderate or severe primary hypercholesterolemia.

Anticholesteremic Agents↗