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PubMed1993

[Comparison of 2 cholesterol synthesis inhibitors (simvastatin and pravastatin)].

Inhibitors of cholesterol synthesis (HMG-CoA reductase) are the most effective cholesterol-lowering drugs. Comparison of several studies in the literature suggests that simvastatin is approximately twice as effective as pravastatin on a milligram basis. These results are confirmed by the present study, which compares treatment with simvastatin (10 mg/d) with pravastatin (20 mg/d) in the same hypercholesterolemic patients (n = 17). The reduction in LDL cholesterol is the same with twice the dose of pravastatin as with simvastatin (26 +/- 3% vs 27 +/- 2% respectively). The reductions in atherogenic ratios, total cholesterol, HDL cholesterol and ApoB/ApoA1 are similar. Undesirable effects are rare and comparable. The differences between the two inhibitors appear to be on the molecular level, in tissue selectively and regarding in vivo efficacy.

Anticholesteremic Agents↗
PubMed1993

Dislipemia in patients undergoing continuous ambulatory peritoneal dialysis: pharmacological therapy (simvastatin) versus hemodialysis.

Peritoneal dialysis can worsen dislipemia, which is frequent in chronically uremic patients. In order to verify the therapeutic possibilities, we retrospectively studied 20 chronically uremic patients who had been previously treated with continuous ambulatory peritoneal dialysis (CAPD) and who had developed an IV-type dislipemia. Twelve have continued CAPD treatment and have been simultaneously treated with simvastatin; 8 have withdrawn from CAPD and have begun HD, without any antidislipemic pharmacological support. The results, after 3, 6, 12, and 18 months of treatment, showed the following: in patients treated with CAPD and simvastatin, highly significant decreases were noted in total cholesterol (T-cho) and triglycerides (TG) (p < 0.001), and highly significant increases were noted in HDL-cholesterol (HDL-cho) (p < 0.005) and apolipoprotein-A1 (Apo-A1) (p < 0.01). In patients treated with HD, only slightly significant decreases were noted in T-cho (p < 0.01) and TG (p < 0.02), a slightly significant increase in Apo-A1 (p < 0.05), and no significant change in HDL-cho. Apolipoprotein-B showed no change in the two groups. Therefore, patients undergoing CAPD, with dislipemia only, can continue the treatment, because simvastatin is capable of correcting dislipemia, while those patients who have displemia as well as other complications strictly due to CAPD must abandon treatment and must be transferred to extracorporeal methods.

Female↗
PubMed1996

[Clinically manifest liver lesions during use of simvastatin].

Symptomatic hepatic damage was diagnosed in six patients, three males and three females, during treatment with simvastatin. All patients recovered after discontinuation of the drug. One patient used the drug again, which led to another increase of serum liver enzyme activity. The period between the start of the treatment with simvastatin and the first symptoms of hepatic damage varied between 1 month and 3 years. If serum liver enzyme activities increase in patients using simvastatin, a causative relation should be considered.

Aged↗
PubMed1996

[Effect of the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme-A reductase, pravastatin and simvastatin, on colony formation by hematopoietic progenitor cells].

The inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase, pravastatin and simvastatin, are widely used clinically as anti-hypercholesterolemic drugs. To determine whether these drugs affect hematopoiesis, we examined the effect of the drugs on colony formation by human bone marrow cells. Simvastatin strongly inhibited both erythroid and granulocyte-macrophage colony formation by total or CD34-positive bone marrow cells at the concentration of 10 microM, which is about 100-1,000 fold higher than the pharmacologically effective level. On the other hand, the inhibitory effect of pravastatin was much weaker than that of simvastatin. These findings show that these drugs, especially pravastatin have little effect on hematopoiesis.

Bone Marrow Cells↗
PubMed1997

The additional effects of acipimox to simvastatin in the treatment of combined hyperlipidaemia.

OBJECTIVES: Nicotinic acid, an effective drug for treatment of combined hyperlipidaemia, is often not tolerated because of side-effects. Acipimox is a nicotinic acid like lipid lowering drug with less side-effects. We studied whether the addition of acipimox to simvastatin improves the lipid profile in patients with a combined hyperlipidaemia. DESIGN: Randomized double-blind placebo controlled crossover trial. SETTING: Outpatient lipid clinic of a tertiary referral centre. SUBJECTS: Eighteen patients with combined hyperlipidaemia treated with diet and 20-40 mg simvastatin for at least 3 months. INTERVENTION: Acipimox in a daily dose of 3 x 250 mg for 12 weeks. MAIN OUTCOME MEASURES: Effects on the concentration of LDLc, TG, HDLc, Lp(a) and Apolipoprotein B, as well as on LDL-size and LDL-resistance to oxidative modification. RESULTS: Acipimox reduced Lp(a) levels by 8% (P < 0.05). A substantial but not statistically significant change in TG (-32%) and HDLc (+6%) levels was seen. All patients were found to have small dense LDL, with a size of 229 +/- 4 A. LDL size and the resistance to oxidation, reflected in the lag phase during in vitro oxidation, were not affected by the addition of acipimox. In a subgroup of 8 patients with the most severe hypertriglyceridaemia (baseline TG < 4 mmol L- [1]), acipimox induced a significant increase in HDLc (+15%, P < 0.01). The effects on TG (-41%), LDLc (-10%) and lag phase (+17%) were also more pronounced than in the group with a lower baseline TG, but non of these changes reached the level of significance. CONCLUSIONS: Adding acipimox to simvastatin reduced Lp(a) and substantially but not significantly lowered TG. However, in patients with the highest TG levels, HDLc was also significantly improved.

Adult↗
PubMed1998

The additional effects of acipimox to simvastatin in the treatment of combined hyperlipidaemia.

OBJECTIVES: Nicotinic acid, an effective drug for treatment of combined hyperlipidaemia, is often not tolerated because of side-effects. Acipimox is a nicotinic acid like lipid lowering drug with less side-effects. We studied whether the addition of acipimox to simvastatin improves the lipid profile in patients with a combined hyperlipidaemia. DESIGN: Randomized double-blind placebo controlled crossover trial. SETTING: Outpatient lipid clinic of a tertiary referral centre. SUBJECTS: Eighteen patients with combined hyperlipidaemia treated with diet and 20-40 mg simvastatin for at least 3 months. INTERVENTION: Acipimox in a daily dose of 3 X 250 mg for 12 weeks. MAIN OUTCOME MEASURES: Effects on the concentration of LDLc, TG, HDLc, Lp(a) and Apolipoprotein B, as well as on LDL-size and LDL-resistance to oxidative modification. RESULTS: Acipimox reduced Lp(a) levels by 8% (P < 0.05). A substantial but not statistically significant change in TG (-32%) and HDLc (+6%) levels was seen. All patients were found to have small dense LDL, with a size of 229 +/- 4 A. LDL size and the resistance to oxidation, reflected in the lag phase during in vitro oxidation, were not affected by the addition of acipimox. In a subgroup of 8 patients with the most severe hypertriglyceridaemia (baseline TG > 4 mmol L- [1]), acipimox induced a significant increase in HDLc (+ 15%, P < 0.01). The effects on TG (-41%), LDLc (-10%) and lag phase (+17%) were also more pronounced than in the group with a lower baseline TG, but none of these changes reached the level of significance. CONCLUSIONS: Adding acipimox to simvastatin reduced Lp(a) and substantially but not significantly lowered TG. However, in patients with the highest TG levels. HDLc was also significantly improved.

Adult↗
PubMed2002

Effect of simvastatin on bone markers in osteopenic women: a placebo-controlled, dose-ranging trial [ISRCTN85429598].

BACKGROUND: Hydroxymethylglutaryl coenzyme A reductase inhibitors increase new bone formation in vitro and in rodents. Results of epidemiologic analyses evaluating the association between use of these cholesterol-lowering drugs, bone mineral density and fracture have been mixed. METHODS: Women (n = 24) with osteopenia, assessed by broad band ultrasound attenuation, were randomized to simvastatin 20 mg, 40 mg or identical-appearing placebo for 12 weeks. Fasting lipid profiles and biochemical markers of bone formation (bone-specific alkaline phosphatase) and resorption (N-telopeptides and C-terminal propeptide of type 1 collagen) were measured at baseline, 6 and 12 weeks. RESULTS: Plasma low density lipoprotein-cholesterol concentration fell 7%, 39% (p < 0.01 vs baseline) and 47% (p < 0.01 vs baseline) after 12 weeks of treatment with placebo, simvastatin 20 mg and 40 mg, respectively. At baseline, bone marker concentrations were similar in the three treatment groups. At 6 and 12 weeks, bone marker concentrations were not different from baseline, and no significant differences in bone marker concentrations were observed between treatment groups at either 6 or 12 weeks. CONCLUSION: Among osteopenic women, treatment with simvastatin for 12 weeks did not affect markers of bone formation or resorption.

Clinical Trial↗
PubMed1993

[Reductions in lipid fraction plasma levels induced by simvastatin and bezafibrate. Brazilian multicenter study].

PURPOSE: To compare the effects of simvastatin and bezafibrate on the lipid profile to attain the objectives proposed by National Cholesterol Education Program (NCEP). METHODS: One hundred twenty six hypercholesterolemic patients (69 females and 57 men, 56.0 +/- 10.0 years old), after selection and placebo period (4 weeks) were maintained on lipid-lowering diet and were randomly assigned in a double-blind fashion to receive for 12 weeks, bezafibrate (B, 200mg t.i.d. - BG(n = 66)) or simvastatin (S, 10-40mg q.p.m. - SG(n = 60)). During the study, 28 patients (SG0) received S 10mg; in 14 patients (SG1) dosage was titrated to 20mg and in 18 cases (SG2) to 40mg. Clinical examination, lipid profile and safety determinations, and adverse effects were assessed in different periods of the study. RESULTS: Mean profile analysis showed different behaviour of BG, SG0, SG1 and SG2 through time for TC, TG, LDL-C and VLDL-C. Mean reductions of TC and LDL-C were more marked in SG (30.3 and 40.9%) than in BG (18.8 and 24.8%). BG showed greater increase of TG (33.7%) and HDL-C (25.9%) than did SG (16.3 and 7.7% respectively). Reduction greater than 30% (optimal responses) and between 20 and 29% (good responses) were more frequent in SG and LDL-C. BG showed greater frequency of good and optimal responses for TG reduction and HDL-C increase. NCEP goals were achieved in 75.4% of SG and 46.9% of BG (p = 0.001). No clinical or laboratorial adverse experiences were reported in any treatment groups. CONCLUSION: Simvastatin was more effective in the reduction of plasma levels of atherogenic lipid fractions (TC and LDL-C) and this treatment allowed earlier achievement of the goals proposed by NCEP in a greater number of patients.

Bezafibrate↗
PubMed2004

Ezetimibe + simvastatin (Merck/Schering-Plough).

Merck/Schering-Plough Pharmaceuticals has developed and launched ezetimibe + simvastatin (Vytorin), a fixed combination tablet of Schering-Plough's cholesterol absorption inhibitor ezetimebe (Zetia), and Merck's HMG CoA reductase inhibitor simvastatin (Zocor), for the treatment of hypercholesterolemia. The drug had been launched in Germany and Mexico by April 2004, and, in July 2004, was approved in the US, with expected launch late in 2004.

Animals↗
PubMed2003

Pharmacokinetics and bioequivalence evaluation of two simvastatin 40 mg tablets (Simvast and Zocor) in healthy human volunteers.

The pharmacokinetics of two brands of simvastatin 40 mg tablets were compared in 24 healthy human volunteers after a single oral dose in a randomized cross-over study, conducted at IPRC, Amman, Jordan. Reference (Zocor, MSD, Netherlands) and test (Simvast, Julphar, UAE) products were administered to fasted volunteers; blood samples were collected at specified time intervals, plasma separated and analyzed for simvastatin and its active metabolite (beta-hydoxy acid) using a validated LC-MS/MS method at Cartesius Analytical Unit, Institute of Biomedical Sciences - USP, Sao Paulo, Brazil. The pharmacokinetic parameters AUC(0-t), AUC(0-variant), C(MAX), T(MAX), T(1/2) and elimination rate constant were determined from plasma concentration-time profile for both formulations and were compared statistically to evaluate bioequivalence between the two brands, using the statistical modules recommended by FDA. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals fell within the acceptable range for bioequivalence. Based on these statistical inferences it was concluded that the two brands exhibited comparable pharmacokinetic profiles and that Julphar's Simvast is bioequivalent to Zocor of MSD, Netherlands.

Administration, Oral↗
PubMed2006

Analysis of five HMG-CoA reductase inhibitors-- atorvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin: pharmacological, pharmacokinetic and analytical overview and development of a new method for use in pharmaceutical formulations analysis and in vitro metabolism studies.

A specific, accurate, precise and reproducible high-performance liquid chromatographic (HPLC) method was developed and validated for the simultaneous quantitation of five 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors, viz. atorvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin, in pharmaceutical formulations and extended the application to in vitro metabolism studies of these statins. Ternary gradient elution at a flow rate of 1 mL/min was employed on an Intertisl ODS 3V column (4.6 x 250 mm, 5 microm) at ambient temperature. The mobile phase consisted of 0.01 m ammonium acetate (pH 5.0), acetonitrile and methanol. Theophylline was used as an internal standard (IS). The HMG-CoA reductase inhibitors and their metabolites were monitored at a wavelength of 237 nm. Drugs were found to be 89.6-105.6% of their label's claim in the pharmaceutical formulations. For in vitro metabolism studies the reaction mixtures were extracted with simple liquid-liquid extraction using ethyl acetate. Baseline separation of statins and their metabolites along with IS free from endogenous interferences was achieved. Nominal retention times of IS, atorvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin were 7.5, 17.2, 21.6, 28.5, 33.5 and 35.5 min, respectively. The proposed method is simple, selective and could be applicable for routine analysis of HMG-CoA reductase inhibitors in pharmaceutical preparations as well as in vitro metabolism studies.

Animals↗
PubMed1993

Determination of the HMG-CoA reductase inhibitors simvastatin, lovastatin, and pravastatin in plasma by gas chromatography/chemical ionization mass spectrometry.

A general method for the assay of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors lovastatin, pravastatin, and simvastatin in plasma has been developed and validated. The analytes are isolated from plasma by a solid-phase extraction procedure which separates the lactone and acid forms of the drugs. The lactone is converted to the acid form, which is subsequently derivatized by pentafluorobenzylation of the carboxyl group, and trimethylsilylation of the hydroxyl functions. Derivatized samples of intrinsic and converted acid are assayed by gas chromatography/mass spectrometry using negative chemical ionization mass spectrometry. The method has sufficient sensitivity, precision, accuracy, and selectivity for the analysis of clinical samples containing the drugs administered at therapeutic doses. The method thus permits determination of both the lactone and hydroxy acid forms of lovastatin and simvastatin, and is also applicable to the assay of pravastatin.

Anticholesteremic Agents↗
PubMed1993

Simvastatin in severe primary hypercholesterolemia: efficacy, safety, and tolerability in 595 patients over 18 weeks. The Principal Investigators.

We report the results of an open multicenter study which evaluated the efficacy, safety, and tolerability of simvastatin in a large cohort of patients with primary hypercholesterolemia. Against a background of standard dietary advice, the study enrolled 595 patients with total cholesterol > or = 6.5 mmol/l and triglycerides < 6.0 mmol/l across 20 centers. After 4 weeks on placebo, treatment began with simvastatin 10 mg each night, titrating to 20 mg after 6 weeks, and then to 40 mg after 12 weeks if cholesterol levels still exceeded 5.5 mmol/l. By Week 18, 70% of patients were using 40 mg/day. After 18 weeks of treatment, the mean reductions (95% confidence interval) in total and low density lipoprotein (LDL) cholesterol were 30% (29-31%) and 38% (37-39%), respectively. There was a mean increase in high density lipoprotein (HDL) cholesterol of 12% (10-13%), while triglycerides were reduced by a median 19% (16-23%). From a mean entry total cholesterol of 9.31 +/- 2.15 mmol/l, 52% of patients achieved cholesterol levels < or = 6.2 mmol/l on treatment. The changes noted were essentially independent of gender, age, or lipid phenotype (IIa vs. IIb). Compliance with prescribed medication was very good and the drug was well tolerated; only 3% of patients manifested a clinical adverse experience requiring discontinuation or a clinical adverse experience described as serious (associated with hospitalization or serious disability). Isolated laboratory adverse experience required discontinuation in 0.2% of patients. One in 3 patients manifested a clinical adverse experience and 1 in 10 a laboratory adverse experience.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Comparative pharmacokinetics of lovastatin, simvastatin and pravastatin in humans.

Twelve healthy male volunteers received single market-image 40-mg oral doses of lovastatin and simvastatin (both lactone prodrugs), or pravastatin (a beta-hydroxyacid) at 1 week intervals in a three-way crossover study to quantify HMG-CoA reductase inhibitors in plasma. Multiple plasma samples were collected up to 24 hours after the dose and assayed for active and total HMG-CoA reductase inhibitors. After equal oral doses, higher plasma concentrations of HMG-CoA reductase inhibitory activity after pravastatin than after either lovastatin of simvastatin (2-3 fold greater area under the concentration-time curve) suggest a greater potential availability of pravastatin-related inhibitory activity to peripheral tissues.

Administration, Oral↗
PubMed2003

Collision-induced dissociation of the negative ions of simvastatin hydroxy acid and related species.

Simvastatin hydroxy acid (1) is a well-known, potent HMG-CoA reductase inhibitor for the treatment of hypercholesterolemia. Its lactone, simvastatin (commercial name Zocor) (a prodrug of 1), has been widely prescribed in the USA and throughout the world. In this work, collision-induced dissociation (CID) of the negative ion of 1 (m/z 435), a carboxylic anion, was analyzed in detail. The major fragmentation pathway of this ion is a novel de-esterification to form the negative product ions at m/z 319 and 115. The ion at m/z 319 undergoes further collision-induced rearrangements to form the negative ions at m/z 215, 159 and 85. Possible mechanisms of the de-esterification are discussed in terms of both charge-initiated and charge-remote fragmentations. The de-esterification of the negative ion of 1 and the rearrangements of the ion at m/z 319 are rationalized by charge transfer and negative-charge initiated fragmentation. This study deepens our understanding of collision-induced fragmentations of carboxylic anions with multi-functional groups. A comparison of the CID data for the negative ions of 1 and 5 (a major oxidation degradate of 1) indicates that the analysis of the CID data for 1 can serve as a basis for identification of oxidation degradation products or metabolites of 1. The analysis of the CID data for the negative ion of 1 also reveals the fundamental characteristics of the CID data for the negative ions of other statin hydroxy acids such as lovastatin (3) and pravastatin (4).

Hydroxymethylglutaryl-CoA Reductase Inhibitors↗
PubMed2004

Retention modelling in liquid chromatographic separation of simvastatin and six impurities using a microemulsion as eluent.

A novel and unique approach was used for retention modelling in the separation of simvastatin and six impurities by liquid chromatographic using a microemulsion as mobile phase. A microemulsion is a modification of a micellar system where a lipophilic organic solvent is dissolved in the micelles; for that reason, microemulsions are usually treated as solvent-modified micellar solutions. When microemulsions are used as eluents in HPLC separations, solutes partition between the charged oil droplets and the aqueous buffer phase. The complexity of the composition of the microemulsion permits extensive manipulations to be made during method development in order to achieve acceptable resolution of such a complex mixture of substances. In order to avoid a laborious "trial and error" procedure, a 2(3) full factorial design was applied for choosing an optimal microemulsion composition to obtain good separation in a reasonable run time. Organic solvent, sodium dodecyl sulphate, and n-butanol content were varied within defined experimental domain. Optimal conditions for the separation of simvastatin and its six impurities were obtained using an X Terra 50 x 4.6 mm, 3.5 microm particle size column at 30 degrees C. The mobile phase consisted of 0.9% w/w of diisopropyl ether, 2.2% w/w of sodium dodecylsulphate (SDS), 7.0% w/w of co-surfactant such as n-butanol, and 89.9% w/w of aqueous 25 mM disodium phosphate pH 7.0.

Chromatography, High Pressure Liquid↗
PubMed2006

Sporadic rippling muscle disease unmasked by simvastatin.

We report a 53-year-old-man who developed rippling muscle disease (RMD) 2 months after starting simvastatin therapy for hypercholesterolemia. He experienced stiffness, myalgias, and classic rippling, which was confirmed on clinical examination. Discontinuation of the statin improved his symptoms. Simvastatin therapy was resumed and resulted in a prompt and severe return of his symptoms. Approximately 1 year after symptom onset he developed mild seropositive oculobulbar myasthenia gravis, which spontaneously remitted after 5 months. We postulate that an immune-mediated disruption of caveolar function was exacerbated by statin exposure. We are unaware of any previous cases of statin-mediated unmasking of RMD.

Anticholesteremic Agents↗
PubMed2007

The impact of over-the-counter simvastatin on the number of statin prescriptions in the United Kingdom: a view from the General Practice Research Database.

PURPOSE: The United Kingdom (UK) government changed the prescription policy of statins, making low-dose simvastatin (10 mg) available as an over-the-counter (OTC) drug in August 2004. We assessed the impact of this policy change on statin prescribing. METHODS: We examined all statin prescriptions in the General Practice Research Database (GPRD), a well-validated database of approximately 3.5 million patients, from the first quarter of 2001 to the second quarter of 2005. RESULTS: From 2001, the number of statin prescriptions written for GPRD patients was increasing by approximately 437 prescriptions per 100,000 people per quarter until the time of the policy change. Over the four quarters post-policy implementation, however, this trend changed abruptly (p < 0.0001) with a decrease of 281 prescriptions per 100,000 people per quarter. This decrease was not restricted to prescriptions of 10 mg statins but was also observed for statin prescriptions of >or=20 mg. Several other cardiovascular medications displayed a similar trend as that observed in the number of statin prescriptions. This trend was not observed among non-cardiovascular control medications. CONCLUSIONS: Our study suggests that the policy allowing the OTC sale of 10 mg simvastatin has had a significant impact on statin prescriptions by general practitioners. However, this new policy may also be leading to less aggressive statin therapy. An alternative explanation for the observed decrease in statin prescriptions may be related to the unknown factors responsible for the overall decrease observed with other cardiovascular prescription drugs.

Databases, Factual↗