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Pertti J. Neuvonen - One of the best experts on this subject based on the ideXlab platform.
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Plasma concentrations of active Simvastatin acid are increased by gemfibrozil.
Clinical pharmacology and therapeutics, 2000Co-Authors: Jt T Backman, Kari T. Kivistö, Jun-sheng Wang, Carl Kyrklund, Pertti J. NeuvonenAbstract:Background Concomitant treatment with Simvastatin and gemfibrozil, two lipid-lowering drugs, has been associated with occurrence of myopathy in case reports. The aim of this study was to determine whether gemfibrozil affects the pharmacokinetics of Simvastatin and whether it affects CYP3A4 activity in vitro. Methods A double-blind, randomized crossover study with two phases (placebo and gemfibrozil) was carried out. Ten healthy volunteers were given gemfibrozil (600 mg twice daily) or placebo orally for 3 days. On day 3 they ingested a single 40-mg dose of Simvastatin. Plasma concentrations of Simvastatin and Simvastatin acid were measured up to 12 hours. In addition, the effect of gemfibrozil (0 to 1200 μmol/L) on midazolam 1′-hydroxylation, a CYP3A4 model reaction, was investigated in human liver microsomes in vitro. Results Gemfibrozil increased the mean total area under the plasma concentration–time curve of Simvastatin [AUC(0-∞)] by 35% (P < .01) and the AUC(0-∞) of Simvastatin acid by 185% (P < .001). The elimination half-life of Simvastatin was increased by 74% (P < .05), and that of Simvastatin acid was increased by 51% (P < .01) by gemfibrozil. The peak concentration of Simvastatin acid was increased by 112%, from 3.20 ± 2.73 ng/mL to 6.78 ± 4.67 ng/mL (mean ± SD; P < .01). In vitro, gemfibrozil showed no inhibition of midazolam 1′-hydroxylation. Conclusions Gemfibrozil increases plasma concentrations of Simvastatin and, in particular, its active form, Simvastatin acid, suggesting that the increased risk of myopathy in combination treatment is, at least partially, of a pharmacokinetic origin. Because gemfibrozil does not inhibit CYP3A4 in vitro, the mechanism of the pharmacokinetic interaction is probably inhibition of non-CYP3A4–mediated metabolism of Simvastatin acid. Clinical Pharmacology & Therapeutics (2000) 68, 122–129; doi: 10.1067/mcp.2000.108507
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Rifampin greatly reduces plasma Simvastatin and Simvastatin acid concentrations
Clinical pharmacology and therapeutics, 2000Co-Authors: Carl Kyrklund, Janne T. Backman, Mikko Neuvonen, Kari T. Kivistö, Jouko Laitila, Pertti J. NeuvonenAbstract:Background Rifampin (rifampicin) is a potent inducer of several cytochrome P450 (CYP) enzymes, including CYP3A4. The cholesterol-lowering drug Simvastatin has an extensive first-pass metabolism, and it is partially metabolized by CYP3A4. This study was conducted to investigate the effect of rifampin on the pharmacokinetics of Simvastatin. Methods In a randomized cross-over study with two phases and a washout of 4 weeks, 10 healthy volunteers received a 5-day pretreatment with rifampin (600 mg daily) or placebo. On day 6, a single 40-mg dose of Simvastatin was administered orally. Plasma concentrations of Simvastatin and its active metabolite Simvastatin acid were measured up to 12 hours with a sensitive liquid chromatography-ion spray tandem mass spectrometry method. Results Rifampin decreased the total area under the plasma concentration-time curve of Simvastatin and Simvastatin acid by 87% (P < .001) and 93% (P < .001), respectively. Also the peak concentrations of both Simvastatin and Simvastatin acid were reduced greatly (by 90%) by rifampin (P < .001). On the other hand, rifampin had no significant effect on the elimination half-life of Simvastatin or Simvastatin acid. Conclusions Rifampin greatly decreases the plasma concentrations of Simvastatin and Simvastatin acid. Because the elimination half-life of Simvastatin was not affected by rifampin, induction of the CYP3A4-mediated first-pass metabolism of Simvastatin in the intestine and the liver probably explains this interaction. Concomitant use of potent inducers of CYP3A4 can lead to a considerably reduced cholesterollowering efficacy of Simvastatin. Clinical Pharmacology & Therapeutics (2000) 68, 592–597; doi: 10.1067/mcp.2000.111414
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grapefruit juice Simvastatin interaction effect on serum concentrations of Simvastatin Simvastatin acid and hmg coa reductase inhibitors
Clinical Pharmacology & Therapeutics, 1998Co-Authors: Jari J Lilja, Kari T. Kivistö, Pertti J. NeuvonenAbstract:Background Simvastatin is a cholesterol-lowering agent that is metabolized through CYP3A4. We studied the effect of grapefruit juice on the pharmacokinetics of orally administered Simvastatin. Methods In a randomized, 2-phase crossover study, 10 healthy volunteers took either 200 mL double-strength grapefruit juice or water 3 times a day for 2 days. On day 3, each subject ingested 60 mg Simvastatin with either 200 mL grapefruit juice or water, and an additional 200 mL was ingested ½ and 1½ hours after Simvastatin administration. Serum concentrations of Simvastatin and Simvastatin acid were measured by liquid chromatography-tandem mass spectrometry (LC-MS-MS) and those of active (naive) and total (after hydrolysis) 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors by a radioenzyme inhibition assay. Results Grapefruit juice increased the mean peak serum concentration (Cmax) of unchanged Simvastatin about 9-fold (range, 5.1-fold to 31.4-fold; P < .01 and the mean area under the serum Simvastatin concentration-time curve [AUC(0–∞)] 16-fold (range, 9.0-fold to 37.7-fold; P < .05). The mean Cmax and AUC(0–∞) of Simvastatin acid were both increased about 7-fold (P < .01). Grapefruit juice increased the mean AUC(0–∞) of active and total HMG-CoA reductase inhibitors 2.4-fold (P < .01) and 3.6-fold (P < .01), respectively. The time of the peak concentration of active and total HMG-CoA reductase inhibitors was increased by grapefruit juice (P < .05). Conclusion Grapefruit juice greatly increased serum concentrations of Simvastatin and Simvastatin acid and, to a lesser extent, those of active and total HMG-CoA reductase inhibitors. The probable mechanism of this interaction was inhibition of CYP3A4-mediated first-pass metabolism of Simvastatin by grapefruit juice in the small intestine. Concomitant use of grapefruit juice and Simvastatin, at least in large amounts, should be avoided, or the dose of Simvastatin should be greatly reduced. Clinical Pharmacology & Therapeutics (1998) 64, 477–483; doi:
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erythromycin and verapamil considerably increase serum Simvastatin and Simvastatin acid concentrations
Clinical Pharmacology & Therapeutics, 1998Co-Authors: Teemu Kantola, Kari T. Kivistö, Pertti J. NeuvonenAbstract:Objective To study the effects of erythromycin and verapamil on the pharmacokinetics of Simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Methods A randomized, double-blind crossover study was performed with three phases separated by a washout period of 3 weeks. Twelve young, healthy volunteers took orally either 1.5 gm/day erythromycin, 240 mg/day verapamil, or placebo for 2 days. On day 2, 40 mg Simvastatin was administered orally. Serum concentrations of Simvastatin, Simvastatin acid, erythromycin, verapamil, and norverapamil were measured for up to 24 hours. Results Erythromycin and verapamil increased mean peak serum concentration (Cmax) of unchanged Simvastatin 3.4-fold (p < 0.001) and 2.6-fold (p < 0.05) and the area under the serum Simvastatin concentration-time curve from time zero to 24 hours [AUC(0–24)] 6.2-fold (p < 0.001) and 4.6-fold (p < 0.01). Erythromycin increased the mean Cmax of active Simvastatin acid fivefold (p < 0.001) and the AUC(0–24) 3.9-fold (p < 0.001). Verapamil increased the Cmax of Simvastatin acid 3.4-fold (p < 0.001) and the AUC(0–24) 2.8-fold (p < 0.001). There was more than tenfold interindividual variability in the extent of Simvastatin interaction with both erythromycin and verapamil. Conclusions Both erythromycin and verapamil interact considerably with Simvastatin, probably by inhibiting its cytochrome P450 (CYP) 3A4-mediated metabolism. Concomitant administration of erythromycin, verapamil, or other potent inhibitors of CYP3A4 with Simvastatin should be avoided. As an alternative, the dosage of Simvastatin should be reduced considerably, that is, by about 50% to 80%, at least when a Simvastatin dosage higher than 20 mg/day is used. Possible adverse effects, such as elevation of creatine kinase level and muscle tenderness, should be closely monitored when such combinations are used. Clinical Pharmacology & Therapeutics (1998) 64, 177–182; doi:
Kari T. Kivistö - One of the best experts on this subject based on the ideXlab platform.
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Plasma concentrations of active Simvastatin acid are increased by gemfibrozil.
Clinical pharmacology and therapeutics, 2000Co-Authors: Jt T Backman, Kari T. Kivistö, Jun-sheng Wang, Carl Kyrklund, Pertti J. NeuvonenAbstract:Background Concomitant treatment with Simvastatin and gemfibrozil, two lipid-lowering drugs, has been associated with occurrence of myopathy in case reports. The aim of this study was to determine whether gemfibrozil affects the pharmacokinetics of Simvastatin and whether it affects CYP3A4 activity in vitro. Methods A double-blind, randomized crossover study with two phases (placebo and gemfibrozil) was carried out. Ten healthy volunteers were given gemfibrozil (600 mg twice daily) or placebo orally for 3 days. On day 3 they ingested a single 40-mg dose of Simvastatin. Plasma concentrations of Simvastatin and Simvastatin acid were measured up to 12 hours. In addition, the effect of gemfibrozil (0 to 1200 μmol/L) on midazolam 1′-hydroxylation, a CYP3A4 model reaction, was investigated in human liver microsomes in vitro. Results Gemfibrozil increased the mean total area under the plasma concentration–time curve of Simvastatin [AUC(0-∞)] by 35% (P < .01) and the AUC(0-∞) of Simvastatin acid by 185% (P < .001). The elimination half-life of Simvastatin was increased by 74% (P < .05), and that of Simvastatin acid was increased by 51% (P < .01) by gemfibrozil. The peak concentration of Simvastatin acid was increased by 112%, from 3.20 ± 2.73 ng/mL to 6.78 ± 4.67 ng/mL (mean ± SD; P < .01). In vitro, gemfibrozil showed no inhibition of midazolam 1′-hydroxylation. Conclusions Gemfibrozil increases plasma concentrations of Simvastatin and, in particular, its active form, Simvastatin acid, suggesting that the increased risk of myopathy in combination treatment is, at least partially, of a pharmacokinetic origin. Because gemfibrozil does not inhibit CYP3A4 in vitro, the mechanism of the pharmacokinetic interaction is probably inhibition of non-CYP3A4–mediated metabolism of Simvastatin acid. Clinical Pharmacology & Therapeutics (2000) 68, 122–129; doi: 10.1067/mcp.2000.108507
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Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate Simvastatin
Clinical pharmacology and therapeutics, 2000Co-Authors: Jari J Lilja, Kari T. KivistöAbstract:Background Grapefruit juice is a potent inhibitor of CYP3A4-mediated drug metabolism. We wanted to investigate how long the inhibitory effect of grapefruit juice lasts, with the CYP3A4 substrate Simvastatin used as a model drug. Methods This crossover study consisted of 5 study days, during which 10 healthy volunteers ingested 40 mg Simvastatin with water (control), with “high-dose” grapefruit juice (200 mL double-strength grapefruit juice three times a day for 3 days), or 1, 3, and 7 days after ingestion of “high-dose” grapefruit juice. For safety reasons, the study was performed in three parts to allow Simvastatin-free days between the study days. Serum concentrations of Simvastatin and Simvastatin acid were measured by liquid chromatography–tandem mass spectrometry up to 12 hours. Results When Simvastatin was taken with grapefruit juice, the mean peak serum concentration (Cmax) and the mean area under the serum concentration-time curve [AUC(0-∞)] of Simvastatin were increased 12.0-fold (P < .001) and 13.5-fold (P < .001), respectively, compared with control. When Simvastatin was administered 24 hours after ingestion of the last dose of grapefruit juice, the Cmax and AUC(0-∞) were increased 2.4-fold (P < .01) and 2.1-fold (P < .001), respectively, compared with control. When Simvastatin was given 3 days after ingestion of grapefruit juice, the Cmax and AUC(0-∞) were increased 1.5-fold (P = .12) and 1.4-fold (P = .09), respectively, compared with control. Seven days after ingestion of grapefruit juice, no differences in the Cmax or AUC(0-∞) of Simvastatin were seen. The mean Cmax and AUC(0-∞) of Simvastatin acid were increased 5.0-fold and 4.5-fold, respectively (P < .001), compared with control when Simvastatin was taken with grapefruit juice and 1.7-fold (P < .01) when it was taken 24 hours after ingestion of grapefruit juice. After an interval of 3 or 7 days between ingestion of grapefruit juice and Simvastatin, the pharmacokinetic variables of Simvastatin acid did not differ significantly from those in the control phase. Conclusions When Simvastatin is taken 24 hours after ingestion of “high-dose” grapefruit juice, the effect of grapefruit juice on the AUC of Simvastatin is only about 10% of the effect observed during concomitant intake of grapefruit juice and Simvastatin. The interaction potential of even high amounts of grapefruit juice with CYP3A4 substrates dissipates within 3 to 7 days after ingestion of the last dose of grapefruit juice. (Clin Pharmacol Ther 2000;68:384-90.) Clinical Pharmacology & Therapeutics (2000) 68, 384–390; doi: 10.1067/mcp.2000.110216
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Rifampin greatly reduces plasma Simvastatin and Simvastatin acid concentrations
Clinical pharmacology and therapeutics, 2000Co-Authors: Carl Kyrklund, Janne T. Backman, Mikko Neuvonen, Kari T. Kivistö, Jouko Laitila, Pertti J. NeuvonenAbstract:Background Rifampin (rifampicin) is a potent inducer of several cytochrome P450 (CYP) enzymes, including CYP3A4. The cholesterol-lowering drug Simvastatin has an extensive first-pass metabolism, and it is partially metabolized by CYP3A4. This study was conducted to investigate the effect of rifampin on the pharmacokinetics of Simvastatin. Methods In a randomized cross-over study with two phases and a washout of 4 weeks, 10 healthy volunteers received a 5-day pretreatment with rifampin (600 mg daily) or placebo. On day 6, a single 40-mg dose of Simvastatin was administered orally. Plasma concentrations of Simvastatin and its active metabolite Simvastatin acid were measured up to 12 hours with a sensitive liquid chromatography-ion spray tandem mass spectrometry method. Results Rifampin decreased the total area under the plasma concentration-time curve of Simvastatin and Simvastatin acid by 87% (P < .001) and 93% (P < .001), respectively. Also the peak concentrations of both Simvastatin and Simvastatin acid were reduced greatly (by 90%) by rifampin (P < .001). On the other hand, rifampin had no significant effect on the elimination half-life of Simvastatin or Simvastatin acid. Conclusions Rifampin greatly decreases the plasma concentrations of Simvastatin and Simvastatin acid. Because the elimination half-life of Simvastatin was not affected by rifampin, induction of the CYP3A4-mediated first-pass metabolism of Simvastatin in the intestine and the liver probably explains this interaction. Concomitant use of potent inducers of CYP3A4 can lead to a considerably reduced cholesterollowering efficacy of Simvastatin. Clinical Pharmacology & Therapeutics (2000) 68, 592–597; doi: 10.1067/mcp.2000.111414
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grapefruit juice Simvastatin interaction effect on serum concentrations of Simvastatin Simvastatin acid and hmg coa reductase inhibitors
Clinical Pharmacology & Therapeutics, 1998Co-Authors: Jari J Lilja, Kari T. Kivistö, Pertti J. NeuvonenAbstract:Background Simvastatin is a cholesterol-lowering agent that is metabolized through CYP3A4. We studied the effect of grapefruit juice on the pharmacokinetics of orally administered Simvastatin. Methods In a randomized, 2-phase crossover study, 10 healthy volunteers took either 200 mL double-strength grapefruit juice or water 3 times a day for 2 days. On day 3, each subject ingested 60 mg Simvastatin with either 200 mL grapefruit juice or water, and an additional 200 mL was ingested ½ and 1½ hours after Simvastatin administration. Serum concentrations of Simvastatin and Simvastatin acid were measured by liquid chromatography-tandem mass spectrometry (LC-MS-MS) and those of active (naive) and total (after hydrolysis) 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors by a radioenzyme inhibition assay. Results Grapefruit juice increased the mean peak serum concentration (Cmax) of unchanged Simvastatin about 9-fold (range, 5.1-fold to 31.4-fold; P < .01 and the mean area under the serum Simvastatin concentration-time curve [AUC(0–∞)] 16-fold (range, 9.0-fold to 37.7-fold; P < .05). The mean Cmax and AUC(0–∞) of Simvastatin acid were both increased about 7-fold (P < .01). Grapefruit juice increased the mean AUC(0–∞) of active and total HMG-CoA reductase inhibitors 2.4-fold (P < .01) and 3.6-fold (P < .01), respectively. The time of the peak concentration of active and total HMG-CoA reductase inhibitors was increased by grapefruit juice (P < .05). Conclusion Grapefruit juice greatly increased serum concentrations of Simvastatin and Simvastatin acid and, to a lesser extent, those of active and total HMG-CoA reductase inhibitors. The probable mechanism of this interaction was inhibition of CYP3A4-mediated first-pass metabolism of Simvastatin by grapefruit juice in the small intestine. Concomitant use of grapefruit juice and Simvastatin, at least in large amounts, should be avoided, or the dose of Simvastatin should be greatly reduced. Clinical Pharmacology & Therapeutics (1998) 64, 477–483; doi:
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erythromycin and verapamil considerably increase serum Simvastatin and Simvastatin acid concentrations
Clinical Pharmacology & Therapeutics, 1998Co-Authors: Teemu Kantola, Kari T. Kivistö, Pertti J. NeuvonenAbstract:Objective To study the effects of erythromycin and verapamil on the pharmacokinetics of Simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Methods A randomized, double-blind crossover study was performed with three phases separated by a washout period of 3 weeks. Twelve young, healthy volunteers took orally either 1.5 gm/day erythromycin, 240 mg/day verapamil, or placebo for 2 days. On day 2, 40 mg Simvastatin was administered orally. Serum concentrations of Simvastatin, Simvastatin acid, erythromycin, verapamil, and norverapamil were measured for up to 24 hours. Results Erythromycin and verapamil increased mean peak serum concentration (Cmax) of unchanged Simvastatin 3.4-fold (p < 0.001) and 2.6-fold (p < 0.05) and the area under the serum Simvastatin concentration-time curve from time zero to 24 hours [AUC(0–24)] 6.2-fold (p < 0.001) and 4.6-fold (p < 0.01). Erythromycin increased the mean Cmax of active Simvastatin acid fivefold (p < 0.001) and the AUC(0–24) 3.9-fold (p < 0.001). Verapamil increased the Cmax of Simvastatin acid 3.4-fold (p < 0.001) and the AUC(0–24) 2.8-fold (p < 0.001). There was more than tenfold interindividual variability in the extent of Simvastatin interaction with both erythromycin and verapamil. Conclusions Both erythromycin and verapamil interact considerably with Simvastatin, probably by inhibiting its cytochrome P450 (CYP) 3A4-mediated metabolism. Concomitant administration of erythromycin, verapamil, or other potent inhibitors of CYP3A4 with Simvastatin should be avoided. As an alternative, the dosage of Simvastatin should be reduced considerably, that is, by about 50% to 80%, at least when a Simvastatin dosage higher than 20 mg/day is used. Possible adverse effects, such as elevation of creatine kinase level and muscle tenderness, should be closely monitored when such combinations are used. Clinical Pharmacology & Therapeutics (1998) 64, 177–182; doi:
Debra Kush - One of the best experts on this subject based on the ideXlab platform.
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treatment of high risk patients with ezetimibe plus Simvastatin co administration versus Simvastatin alone to attain national cholesterol education program adult treatment panel iii low density lipoprotein cholesterol goals
American Journal of Cardiology, 2004Co-Authors: Ted Feldman, Michael J Koren, William Insull, James M Mckenney, Helmut G Schrott, Andrew Lewin, Sukrut Shah, Michelle Sidisin, Meehyung Cho, Debra KushAbstract:This study assessed whether the co-administration of ezetimibe and Simvastatin would be more effective than Simvastatin monotherapy in allowing high-risk patients to achieve a low-density lipoprotein (LDL) cholesterol goal of /=130 mg/dl and meeting National Cholesterol Education Program Adult Treatment Panel III criteria for coronary heart disease (CHD) or CHD risk equivalent were randomized to 1 of 4 daily treatments for 23 weeks: Simvastatin 20 mg (n = 253), ezetimibe 10 mg plus Simvastatin 10 mg (n = 251), ezetimibe 10 mg plus Simvastatin 20 mg (n = 109), and ezetimibe 10 mg plus Simvastatin 40 mg (n = 97). In all groups, patients not at goal had their Simvastatin doses doubled at weeks 6, 12, and/or 18, up to a maximum of 80 mg. The primary efficacy objective was LDL cholesterol goal attainment (<100 mg/dl) after 5 weeks of treatment. Ezetimibe plus any dose of Simvastatin produced greater reductions in LDL cholesterol and allowed more patients to achieve goal after 5 weeks (p <0.001) and at the end of the study (p <0.001) than Simvastatin 20 mg alone. At 5 weeks, 75%, 83%, and 87% of patients receiving ezetimibe plus Simvastatin 10, 20, and 40 mg had LDL cholesterol <100 mg/dl compared with 46% of patients receiving Simvastatin 20 mg. In patients who started on ezetimibe plus Simvastatin 10, 20 and 40 mg, 33%, 22%, and 12%, respectively, required Simvastatin titration during the study compared with 68% of patients who started on Simvastatin 20 mg. The corresponding median Simvastatin doses used were 10, 20, 40, and 40 mg, respectively. Ezetimibe plus Simvastatin was well tolerated, with an overall safety profile similar to that of Simvastatin monotherapy. Thus, through the dual inhibition of cholesterol absorption and synthesis, ezetimibe plus Simvastatin allowed more patients to reach LDL cholesterol <100 mg/dl at a lower Simvastatin dose and with fewer dose titrations than Simvastatin monotherapy.
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Treatment of High-Risk patients with ezetimibe plus Simvastatin Co-Administration versus Simvastatin alone to attain National Cholesterol Education Program Adult Treatment Panel III Low-Density lipoprotein cholesterol goals
The American journal of cardiology, 2004Co-Authors: Ted Feldman, Michael J Koren, William Insull, James M Mckenney, Helmut G Schrott, Sukrut Shah, Michelle Sidisin, Meehyung Cho, Andrew J. Lewin, Debra KushAbstract:This study assessed whether the co-administration of ezetimibe and Simvastatin would be more effective than Simvastatin monotherapy in allowing high-risk patients to achieve a low-density lipoprotein (LDL) cholesterol goal of /=130 mg/dl and meeting National Cholesterol Education Program Adult Treatment Panel III criteria for coronary heart disease (CHD) or CHD risk equivalent were randomized to 1 of 4 daily treatments for 23 weeks: Simvastatin 20 mg (n = 253), ezetimibe 10 mg plus Simvastatin 10 mg (n = 251), ezetimibe 10 mg plus Simvastatin 20 mg (n = 109), and ezetimibe 10 mg plus Simvastatin 40 mg (n = 97). In all groups, patients not at goal had their Simvastatin doses doubled at weeks 6, 12, and/or 18, up to a maximum of 80 mg. The primary efficacy objective was LDL cholesterol goal attainment (
David S Warner - One of the best experts on this subject based on the ideXlab platform.
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Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage
Stroke, 2002Co-Authors: Matthew J Mcgirt, John R Lynch, Augusto Parra, Huaxin Sheng, Robert D Pearlstein, Daniel T Laskowitz, Dale A Pelligrino, David S WarnerAbstract:Background and Purpose— Endothelial nitric oxide synthase (eNOS) activity is decreased after subarachnoid hemorrhage (SAH). Simvastatin increases eNOS activity. We hypothesized that Simvastatin would increase eNOS protein and ameliorate SAH-induced cerebral vasospasm. Methods— Mice were treated with subcutaneous Simvastatin or vehicle for 14 days and then subjected to endovascular perforation of the right anterior cerebral artery or sham surgery. Three days later, neurological deficits were scored (5 to 27; 27=normal), and middle cerebral artery diameter and eNOS protein were measured. The study was repeated, but Simvastatin treatment was started after SAH or sham surgery. Results— In SAH mice, Simvastatin pretreatment increased middle cerebral artery diameter (SAH-Simvastatin=74±22 μm, SAH-vehicle=52±18 μm, P=0.03; sham-Simvastatin=102±8 μm, sham-vehicle=105±6 μm). Pretreatment reduced neurological deficits (SAH-Simvastatin=25±2, SAH-vehicle=20±2, P=0.005; sham-Simvastatin and sham-vehicle=27±0). Simvast...
Dale A Pelligrino - One of the best experts on this subject based on the ideXlab platform.
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Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage
Stroke, 2002Co-Authors: Matthew J Mcgirt, John R Lynch, Augusto Parra, Huaxin Sheng, Robert D Pearlstein, Daniel T Laskowitz, Dale A Pelligrino, David S WarnerAbstract:Background and Purpose— Endothelial nitric oxide synthase (eNOS) activity is decreased after subarachnoid hemorrhage (SAH). Simvastatin increases eNOS activity. We hypothesized that Simvastatin would increase eNOS protein and ameliorate SAH-induced cerebral vasospasm. Methods— Mice were treated with subcutaneous Simvastatin or vehicle for 14 days and then subjected to endovascular perforation of the right anterior cerebral artery or sham surgery. Three days later, neurological deficits were scored (5 to 27; 27=normal), and middle cerebral artery diameter and eNOS protein were measured. The study was repeated, but Simvastatin treatment was started after SAH or sham surgery. Results— In SAH mice, Simvastatin pretreatment increased middle cerebral artery diameter (SAH-Simvastatin=74±22 μm, SAH-vehicle=52±18 μm, P=0.03; sham-Simvastatin=102±8 μm, sham-vehicle=105±6 μm). Pretreatment reduced neurological deficits (SAH-Simvastatin=25±2, SAH-vehicle=20±2, P=0.005; sham-Simvastatin and sham-vehicle=27±0). Simvast...
