Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new zocor research articles will be listed here shortly after becoming available to us.
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Medical research on zocor
Fixed-dose combination of extended-release niacin plus simvastatin for lipid disorders.
Expert Rev Cardiovasc Ther. 2008 Nov; 6(10): 1303-1310
Vo AN, Kashyap ML
Coronary heart disease (CHD) carries significant morbidity and mortality worldwide. Elevated LDL-cholesterol and reduced HDL-cholesterol levels are well-recognized CHD risk factors. Despite guideline recommendations for intensive therapy among patients at high risk for CHD to lower LDL-cholesterol, such lowering has failed to prevent approximately two-thirds of cardiovascular events. As a result of new data, guidelines have begun to focus on non-HDL-cholesterol, HDL-cholesterol and triglycerides as treatment targets, with the end result being a recommendation for combination therapy, such as niacin plus statin for the treatment of dyslipidemia. Compared with statin monotherapy, a combination of niacin and statin therapy provides beneficial effects on a broad range of lipid particles and some evidence suggests a further reduction in CHD risk. Recent studies have shown that the combination of a fixed dose of extended-release niacin plus simvastatin reduces non-HDL-cholesterol, LDL-cholesterol, triglycerides and total cholesterol:HDL-cholesterol ratio by approximately 50% while increasing HDL-cholesterol by 25%. The safety of this combination is consistent with the safety profiles of each individual component and is well tolerated. A long-term study is currently being conducted to evaluate whether this combination therapy confers an additive impact on clinical end points.
Cardiology. 2008 Nov 15; 113(2): 89-97
Brudi P, Reckless JP, Henry DP, Pomykaj T, Lim ST, Massaad R, Vandormael K, Johnson-Levonas AO
Objective: The aim of the study was to compare the efficacy/safety of doubling the dose of low-, medium- and high-potency statins on lipids/lipoproteins versus ezetimibe/simvastatin (EZE/SIMVA) 10/40 mg in patients with a recent coronary event. Methods: In this open-label study, patients were stratified by baseline statin therapy (low, medium and high potency) and randomized equally to statin dose doubling or EZE/SIMVA 10/40 mg for 12 weeks. Primary analysis concerned change in low-density lipoprotein cholesterol for the whole population. Treatment-by-stratum interaction evaluated the consistency of treatment effect across statin potency strata. Post hoc analysis of between-group efficacy within strata was performed using ANCOVA. Results: Within each stratum, EZE/SIMVA produced significantly greater reductions in low-density lipoprotein cholesterol, total cholesterol, apolipoprotein B and non-high-density lipoprotein cholesterol (HDL-C) compared to statin doubling. Numerical trends toward smaller between-group reductions were observed with higher-potency statins and reached statistical significance for apolipoprotein B and non-HDL-C. No significant between-group differences in HDL-C and C-reactive protein were observed within each stratum. EZE/SIMVA produced larger reductions in triglycerides versus low-potency statin, whereas it was similarly effective compared with intermediate-/high-potency statins. The safety/tolerability profiles of the treatments were similar across the strata. Conclusions: EZE/SIMVA 10/40 mg produced greater improvements in lipids with a similar safety profile compared to doubling the dose of low-, medium- and high-potency statins.
Berberine, a natural lipid-lowering drug, exerts prothrombotic effects on vascular cells.
J Mol Cell Cardiol. 2008 Oct 30;
Holy EW, Akhmedov A, Lüscher TF, Tanner FC
Berberine (BBR) is a novel natural hypolipidemic agent. This study investigates whether BBR, similar to statins, exerts pleiotropic effects on endothelial tissue factor (TF) expression. BBR enhanced tumor necrosis factor-alpha (TNF-alpha) and thrombin induced TF expression in human endothelial cells by 3.5-fold. These effects were paralleled by an enhanced TF surface activity. In contrast, expression of TF pathway inhibitor was impaired. BBR enhanced TNF-alpha induced TF mRNA expression; however, TF promoter activity was inhibited. Activation ERK and p38 remained unaffected, while c-Jun terminal NH(2) kinase was inhibited. BBR reduced TF mRNA degradation rates, prolonging its half-life from 1.1 to 4.3 h. The HMG-CoA reductase inhibitor simvastatin impaired thrombin induced TF expression, and BBR blunted this inhibition. Simvastatin did not affect TNF-alpha induced TF expression, and BBR enhanced TF under these conditions. Administration of BBR (100 mg/kg/d) increased TF activity and impaired TFPI expression in carotid artery of ApoE(-/-) mice. BBR enhances TF via mRNA stabilization at clinically relevant concentrations. Clinical application of BBR, either as an alternative to or in combination with statins, should be considered with caution.
Clin Ther. 2008 Oct; 30(10): 1782-93
Rump LC, Baranova E, Okopien B, Weisskopf M, Kandra A, Ferber P
Background: Together, high blood pressure (BP) and high cholesterol levels constitute a cumulative risk for coronary heart disease (CHD). Elevations in cholesterol increase BP through upregulation of angiotensin type 1 receptors, with a corresponding increase in cholesterol oxidation due to elevations in BP. Hence, control of low-density lipoprotein cholesterol (LDL-C) and BP through coadministration of an antihypertensive and a statin have potential benefit in the management of CHD. Objectives: This study examined the dose response to simvastatin 20 and 40 mg in reducing LDL-C and the efficacy and tolerability of a high dose of valsartan (320 mg) when administered with simvastatin. Methods: In this multicenter, 12-week, double-blind, double-dummy, parallel-group superiority study, patients with hypertension and hypercholesterolemia were randomized to receive valsartan 160 mg along with simvastatin 20 or 40 mg. At week 6, valsartan was titrated upward to 320 mg in both groups. The primary efficacy variable was the change in LDL-C, calculated using the Friedewald formula or measured directly (depending on triglyceride levels) and analyzed for superiority. Secondary efficacy variables were the change in LDL-C and the proportion of patients achieving LDL-C and BP control. Safety assessments included the occurrence of adverse events (AEs) and serious AEs, and changes in hematology and biochemistry variables, vital signs, and findings on physical examinations. Results: Eight hundred seventy-two patients were randomized to receive double-blind treatment, and the intent-to-treat population included 838 patients. The combination of valsartan 160 mg + simvastatin 40 mg was statistically superior to that of valsartan 160 mg + simvastatin 20 mg in reducing LDL-C at week 6 (least squares mean percent change from baseline: -38.5% vs -33.6%, respectively; P < 0.001); at week 12, the corresponding values were -36.8% in the valsartan 320 mg + simvastatin 40 mg group and -32.7% in the valsartan 320 mg + simvastatin 20 mg group (P = 0.002). Rates of combined LDL-C and BP control at week 6 were 35.1% (146/416) in the valsartan 160 mg + simvastatin 20 mg group and 37.4% (154/412) in the valsartan 160 mg + simvastatin 40 mg group; at week 12, rates of combined control were 50.7% (212/418) in the valsartan 320 mg + simvastatin 20 mg group and 50.0% (206/412) in the valsartan 320 mg + simvastatin 40 mg group. AEs occurred in 24.3% (102/420) of the valsartan 160/320 mg + simvastatin 20 mg group and 22.2% (93/419) of the valsartan 160/320 mg + simvastatin 40 mg group. Conclusions: In these patients with hypertension and hypercholesterolemia, coadministration of valsartan and simvastatin was well tolerated and was associated with significant reductions from baseline in BP and LDL-C. Coadministered with valsartan 160/320 mg in the evening, simvastatin 40 mg had superior LDL-C-lowering efficacy to simvastatin 20 mg. Clinical Trials Identification Number: NCT00254475.
Shock. 2008 Nov 11;
Fraunberger P, Gröne E, Gröne HJ, Walli AK
Statins which are effective lipid lowering drugs also possess anti-inflammatory potential. However circulating lipoproteins may also play a protective role during acute inflammatory diseases due to their ability to bind bacterial toxins. Low cholesterol levels have been reported in inflammatory conditions and plasma cholesterol concentrations inversely correlate with severity and clinical outcome in septic patients. It is thus paradoxical that statins which drastically reduce circulating cholesterol levels should be beneficial in patients with inflammatory disease who are already hypocholesteremic. We investigated the effect of simvastatin on LPS induced NF-kappaB activation, TNF release and mortality in guinea pigs, an animal model with a lipoprotein profile and pattern similar to humans. In the present study simvastatin reduced circulating total and LDL cholesterol levels by 68 % and 76 %, respectively and LPS induced mortality from 73 % to 20 %. This reduction was accompanied by a significant reduction of NF-kappaB activation in the liver tissue, splenocytes and plasma TNF levels by about 80 %, 50 % and 77 %, respectively. Our data suggest that simvastatin despite lowering circulating LDL-cholesterol, decreased LPS toxicity by reduction of NF-kappaB activation and subsequent release of TNF by modulating HMG-CoA reductase activity and therefore deserves consideration as a possible adjuvant therapy in acute inflammatory disease.
Efficacy of statins in familial hypercholesterolaemia: a long term cohort study.
BMJ. 2008; 337: a2423
Versmissen J, Oosterveer DM, Yazdanpanah M, Defesche JC, Basart DC, Liem AH, Heeringa J, Witteman JC, Lansberg PJ, Kastelein JJ, Sijbrands EJ
OBJECTIVE: To determine the efficacy of statin treatment on risk of coronary heart disease in patients with familial hypercholesterolaemia. DESIGN: Cohort study with a mean follow-up of 8.5 years. SETTING: 27 outpatient lipid clinics. SUBJECTS: 2146 patients with familial hypercholesterolaemia without prevalent coronary heart disease before 1 January 1990. MAIN OUTCOME MEASURES: Risk of coronary heart disease in treated and "untreated" (delay in starting statin treatment) patients compared with a Cox regression model in which statin use was a time dependent variable. RESULTS: In January 1990, 413 (21%) of the patients had started statin treatment, and during follow-up another 1294 patients (66%) started after a mean delay of 4.3 years. Most patients received simvastatin (n=1167, 33 mg daily) or atorvastatin (n=211, 49 mg daily). We observed an overall risk reduction of 76% (hazard ratio 0.24 (95% confidence interval 0.18 to 0.30), P
J Physiol. 2008 Nov 10;
Mallinson J, Constantin-Teodosiu D, Sidaway J, Westwood FR, Greenhaff P
Statins are used clinically for cholesterol reduction, but statin therapy is associated with myopathic changes through a poorly defined mechanism. We used an in vivo model of statin myopathy to determine whether statins upregulate genes associated with proteasome and lysosomal mediated proteolysis and whether PDK gene expression is simultaneously upregulated leading to the impairment of muscle carbohydrate oxidation. Animals were dosed daily with 80mg(.)kg(-1.)d(-1) simvastatin for 4 (n=6) and 12 days (n=5), 88mg(.)kg(-1.)d(-1) simvastatin for 12 days (n=4), or vehicle (0.5% w/v hydroxypropyl-methylcellulose and 0.1% w/v polysorbate 80; Control, n=6) for 12 days by oral gavage. We found, in biceps femoris muscle, decreased Akt(Ser473), FOXO1(Ser253) and FOXO3a(Ser253) phosphorylation in the cytosol (p
Apparent seizure and atrial fibrillation associated with paliperidone.
Am J Health Syst Pharm. 2008 Nov 15; 65(22): 2122-5
Schneider RA, Lizer MH
PURPOSE: A case of apparent seizure and atrial fibrillation associated with paliperidone is reported. SUMMARY: A 46-year-old man arrived at the emergency room (ER) via ambulance. Earlier that morning, his wife observed him awakening in a panic, drifting back to sleep, and then subsequently awakening in a panic with an apparent seizure lasting one to two minutes. The episode included tongue biting and urinary incontinence. His medical history included bipolar disorder, diabetes mellitus, hyperlipidemia, and hypertension. The patient's medications included metformin, insulin glargine, insulin lispro, simvastatin, enalapril, escitalopram, lamotrigine, and clonazepam and had not changed for many months except for the recent addition of paliperidone four days before his arrival at the ER. Electrocardiography revealed atrial fibrillation, a ventricular rate of 151 beats/min, a Q-Tc interval of 461 msec, and no significant changes in the ST segment or T wave. He had no chest pain, and all other laboratory test results and vital signs were normal. The patient was admitted for evaluation and given a single oral dose of potassium chloride. Diltiazem i.v. was administered with resultant conversion to normal sinus rhythm, after which the patient's heart rate and Q-Tc interval normalized. The patient was discharged after one day. CONCLUSION: A man taking paliperidone and multiple other drugs experienced atrial fibrillation and a possible seizure. Although these are known adverse effects of atypical antipsychotics, it is unusual to have both events occur concurrently and with low-to-average dosages, and these events have not been associated with paliperidone in published case reports.
Role for protein geranylgeranylation in adult T-cell leukemia cell survival.
Exp Cell Res. 2008 Nov 1;
Nonaka M, Uota S, Saitoh Y, Takahashi M, Sugimoto H, Amet T, Arai A, Miura O, Yamamoto N, Yamaoka S
Adult T-cell leukemia (ATL) is a fatal lymphoproliferative disease that develops in human T-cell leukemia virus type I (HTLV-I)-infected individuals. Despite the accumulating knowledge of the molecular biology of HTLV-I-infected cells, effective therapeutic strategies remain to be established. Recent reports showed that the hydroxyl-3-methylglutaryl (HMG)-CoA reductase inhibitor statins have anti-proliferative and apoptotic effects on certain tumor cells through inhibition of protein prenylation. Here, we report that statins hinder the survival of ATL cells and induce apoptotic cell death. Inhibition of protein geranylgeranylation is responsible for these effects, since simultaneous treatment with isoprenoid precursors, geranylgeranyl pyrophosphate or farnesyl pyrophosphate, but not a cholesterol precursor squalene, restored the viability of ATL cells. Simvastatin inhibited geranylgeranylation of small GTPases Rab5B and Rac1 in ATL cells, and a geranylgeranyl transferase inhibitor GGTI-298 reduced ATL cell viability more efficiently than a farnesyl transferase inhibitor FTI-277. These results not only unveil an important role for protein geranylgeranylation in ATL cell survival, but also implicate therapeutic potentials of statins in the treatment of ATL.
Biotechnol Bioeng. 2008 Jun 18;
Xie X, Pashkov I, Gao X, Guerrero JL, Yeates TO, Tang Y
Simvastatin is the active pharmaceutical ingredient of the blockbuster cholesterol lowering drug Zocor. We have previously developed an Escherichia coli based whole-cell biocatalytic platform towards the synthesis of simvastatin sodium salt (SS) starting from the precursor monacolin J sodium salt (MJSS). The centerpiece of the biocatalytic approach is the simvastatin synthase LovD, which is highly prone to misfolding and aggregation when overexpressed from E. coli. Increasing the solubility of LovD without decreasing its catalytic activity can therefore elevate the performance of the whole-cell biocatalyst. Using a combination of homology structural prediction and site-directed mutagenesis, we identified two cysteine residues in LovD that are responsible for nonspecific intermolecular crosslinking, which leads to oligomer formation and protein aggregation. Replacement of Cys40 and Cys60 with alanine residues resulted in marked gain in both protein solubility and whole-cell biocatalytic activities. Further mutagenesis experiments converting these two residues to small or polar natural amino acids showed that C40A and C60N are the most beneficial, affording 27% and 26% increase in whole cell activities, respectively. The double mutant C40A/C60N combines the individual improvements and displayed approximately 50% increase in protein solubility and whole-cell activity. Optimized fed-batch high-cell-density fermentation of the double mutant in an E. coli strain engineered for simvastatin production quantitatively (>99%) converted 45 mM MJSS to SS within 18 h, which represents a significant improvement over the performance of wild-type LovD under identical conditions. The high efficiency of the improved whole-cell platform renders the biocatalytic synthesis of SS an attractive substitute over the existing semisynthetic routes. (c) 2008 Wiley Periodicals, Inc.