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
Pravastatin prevents miscarriages in antiphospholipid antibody-treated mice.
J Reprod Immunol. 2009 Jun 23;
Girardi G
Miscarriages in patients with antiphospholipid (aPL) antibodies have been attributed to thrombosis of placental vessels. However, we have shown that inflammation plays a crucial role in fetal injury. We identified tissue factor (TF), the major cellular activator of the coagulation cascade, as a key mediator in inflammation and fetal injury in aPL antibody-treated mice. We found that TF in maternal neutrophils was associated with fetal injury. TF expression in neutrophils contributes to the respiratory burst and subsequent trophoblast oxidative injury and pregnancy loss induced by aPL antibodies. We also analysed how TF contributes to neutrophil activation and trophoblast injury in this model. We showed that neutrophils from aPL antibody-treated mice express protease activated receptor 2 (PAR-2) and that stimulation of this receptor leads to neutrophil activation, trophoblast injury and fetal death. Mice deficient in PAR-2 and treated with aPL antibodies exhibited reduced neutrophil activation and normal pregnancies, indicating that PAR-2 plays an important role in the pathogenesis of aPL antibody-induced fetal injury. In addition, we demonstrated that the statins simvastatin and pravastatin downregulate TF and PAR-2 expression in neutrophils and thus prevent pregnancy loss. In summary, this study shows that TF signaling through PAR-2 mediates neutrophil activation and fetal death in antiphospholipid syndrome, and that statins may be an appropriate treatment for women with aPL antibody-induced pregnancy complications.
Nutr Res. 2009 May; 29(5): 291-7
Schulze F, Glos S, Petruschka D, Altenburg C, Maas R, Benndorf R, Schwedhelm E, Beil U, Böger RH
We recently noticed a possible triglyceride-lowering effect during dietary supplementation with L-arginine. The major limitation of prior studies on L-arginine, however, was that triglyceride levels were not the primary end point, and patients were not necessarily hypertriglyceridemic. Therefore, we conducted a 2-arm, randomized, double-blind study in 33 hypertriglyceridemic patients to investigate the hypothesis that oral L-arginine may lower serum triglyceride levels in hypertriglyceridemic patients on and off statins. The study consisted of a 6-week run-in phase, 6 weeks of treatment with L-arginine (n = 22, 1.5 g bid) or placebo (n = 11), and a 6-week extension period where simvastatin (20 mg qd) was added. All patients received dietary advice during each study visit. Routine and lipid laboratory parameters were determined in the local routine clinical laboratory. Treatment with L-arginine alone had no effects on serum lipids compared to placebo. The combination of L-arginine with simvastatin led to a significantly stronger reduction in triglycerides compared to placebo plus simvastatin (-140.5 +/- 149.2 mg/dL vs -56.1 +/- 85.0 mg/dL; P = .048). In addition, we found simvastatin-induced increases in aspartate transaminase and fibrinogen to be attenuated by L-arginine as compared to placebo. We conclude from our data that L-arginine enhances the effects of simvastatin on lipid metabolism, but it has no triglyceride-lowering effects when given alone.
Synergistic effects of telmisartan and simvastatin on endothelial progenitor cells.
J Cell Mol Med. 2009 Jun 23;
Steinmetz M, Brouwers C, Nickenig G, Wassmann S
Background: Circulating endothelial progenitor cells (EPC) contribute to endothelial replenishment. Telmisartan is an angiotensin receptor blocker with PPARgamma-agonistic properties. PPARgamma-agonists and HMG-CoA reductase inhibitors have been shown to enhance EPC number and function. We focused on the effects of telmisartan alone or in combination with simvastatin on EPC. Methods and Results: EPC were isolated from healthy human volunteers, cultured and stimulated with telmisartan, simvastatin, or the combination of telmisartan and simvastatin. Telmisartan significantly increased the number of acLDL/lectin double-positive early outgrowth EPC, the number of colony forming units (EC-CFU) as well as EPC migratory capacity, inhibited TNFalpha-induced EPC apoptosis and reduced glucose-induced oxidative stress. The telmisartan effect was dose-dependent and could be inhibited by GW9662, indicating a PPARgamma-dependent mechanism. The combination of telmisartan and simvastatin led to a significant additive increase in EPC count and function. In wild-type mice, systemic treatment with either telmisartan or simvastatin elevated the number of sca-1/flk-1-positive EPC in bone marrow and peripheral blood, spleen-derived acLDL/lectin double-positive EPC, EPC migration and EC-CFU. Consistent with the in vitro findings, the combination of telmisartan and simvastatin resulted in a further enhancement of EPC counts. Reendothelialisation after carotid injury was significantly enhanced by telmisartan, simvastatin and the combination. Conclusions: Telmisartan increases EPC number and function mediated by a PPARgamma-dependent mechanism. This effect is further enhanced by combination with simvastatin, suggesting a synergistic activation of potentially diverse intracellular pathways.
Fundam Clin Pharmacol. 2009 Jun 25;
Cicero AF, Veronesi M, Prandin MG, Di Gregori V, Ambrosioni E, Borghi C
Recent evidences suggest a relationship between angiotensin 1 (AT1) receptor gene expression and low density lipoprotein cholesterol (LDL-C) plasma level. We enrolled 16 untreated hypertensive hypercholesterolemic patients (57.4 +/- 7 years old) in a randomized, single-blind, cross-over design. All the patients were allocated to treatment with simvastatin 20 mg/day for 2 weeks, then randomly assigned to telmisartan (40-80 mg/day) or bisoprolol (5-10 mg/day). After 4 weeks the antihypertensive drugs have been withdrawn for a wash-out period of 2 weeks when they were treated with simvastatin alone, then they have been allocated to the alternative antihypertensive treatment for four additional weeks. We measured: systolic (SBP) and diastolic BP (DBP), 24-h mean BP (MBP), Baseline and post-ischemia forearm blood flow (FBF) and vascular resistance (FVR), and Lipid profile. After 2 weeks of treatment with Simvastatin, baseline and post-ischemic FBF increased (both P < 0.05), while baseline and post-ischemic FVR decreased (both P < 0.05). Standing DBP and MBP were reduced more after treatment with telmisartan than with bisoprolol (P < 0.05). Basal and post-ischemic FBF were significantly increased (P < 0.05 and P < 0.005, respectively) and basal and post-ischemic FVR significantly decreased (both P < 0.005) only after treatment with telmisartan, as well as plasma triglycerides (TG) (P < 0.05). From this preliminary study carried out on hypercholesterolemic hypertensive patients it appears that the association of telmisartan and simvastatin (but not of bisoprolol and simvastatin) could exert positive effects on a large quantity of vascular functionality parameters, just after a short treatment.
Curr Med Res Opin. 2009 Jun 25;
Derosa G, Maffioli P, Salvadeo SA, Ferrari I, Gravina A, Mereu R, Palumbo I, D'Angelo A, Cicero AF
ABSTRACT Objective: To evaluate the efficacy of fenofibrate, simvastatin or their combination in type 2 diabetic patients with combined dyslipidaemia. Research design and methods: 241 patients, who had never previously taken lipid-lowering medications, received fenofibrate 145 mg/day, or simvastatin 40 mg/day, or fenofibrate 145 mg/day + simvastatin 40 mg/day combination for 12 months. We evaluated lipids, glycaemic, haemostatic, and inflammatory variables at baseline, and after 6 and 12 months. Results: After 12 months total cholesterol (TC), LDL cholesterol (LDL-C) and triglycerides (Tg) decreased while HDL cholesterol (HDL-C) increased in all groups, even if the values obtained with fenofibrate + simvastatin were the best. At the end of the study apolipoprotein A-1 (Apo A-1) increased with fenofibrate + simvastatin, while apolipoprotein B (Apo B) decreased in all groups compared to baseline. Plasminogen activator inhibitor-1 (PAI-1) and high-sensitivity C reactive protein (hs-CRP) decreased after 12 months compared to baseline with simvastatin, and with fenofibrate + simvastatin even if the value obtained with fenofibrate-simvastatin was the lowest. After 12 months, fibrinogen (Fg) decreased compared to baseline with fenofibrate + simvastatin. Limitations: This study has some limitations. The first one is the relatively small sample of studied patients. The second one is the lack of an advanced lipid proteins evaluation, such as lipoprotein subfraction changes in the different treatment regimen. Finally, we have not selected patients that could show the best response to fibrate (i.e.: hypertriglyceridemics) or statins (i.e.: hypercholesterolemics) monotherapy, so the effect of these drugs administered alone may have been partly attenuated. Conclusions: Fenofibrate + simvastatin association improved lipid parameters, prothrombotic and inflammatory factors, and appeared to have a good tolerability profile over 12 months of therapy.
Concurrent use of statins and amiodarone.
Consult Pharm. 2009 May; 24(5): 372-9
Vicky BH
OBJECTIVE: To estimate the concurrent use between statins and amiodarone in context with published case reports of drug-interaction-induced rhabdomyolysis. DESIGN: Retrospective analysis of a longitudinal prescription claims database for concurrent prescriptions of statins and amiodarone dispensed during 2006. PATIENTS, PARTICIPANTS: The study population includes an unprojected annual number of patients who filled a prescription for an HMG CoA reductase inhibitor or simvastatin-containing products or lovastatin-containing products or Lipitor (atorvastatin) or Caduet (amlodipine/atorvastatin) concurrently with brand and generic forms of amiodarone during 2006. The concurrency analysis was used to provide context for published case reports of rhabdomyolysis/myopathy related to simvastatin and amiodarone concurrent use. MAIN OUTCOME MEASURE: Episodes of concurrent use between statins and amiodarone. RESULTS: Findings from this analysis indicate noteworthy amiodarone and statin concurrency (44%) when based on amiodarone patient volume. Atorvastatin had the greatest level of concurrency (23.5%) with amiodarone followed by simvastatin (13.3%). Proportionality based on amiodarone patient volume shows a greater level of concurrency with 20 mg (6%) and 40 mg (5.5%) simvastatin strengths compared with other simvastatin strengths. CONCLUSION: Clinicians should be vigilant in monitoring the regimens of patients prescribed a statin with drugs that may increase the risk of myopathy. In particular, since nearly half of the patients prescribed amiodarone may also be prescribed a statin, then addition of amiodarone or changes in statin dose should trigger a drug regimen review and patient level monitoring. Clinicians should avoid simvastatin doses greater than 20 mg per day in patients taking amiodarone.
Br J Clin Pharmacol. 2009 May; 67(5): 520-6
Krishna R, Garg A, Jin B, Keshavarz SS, Bieberdorf FA, Chodakewitz J, Wagner JA
AIMS: Anacetrapib is an orally active, potent inhibitor of cholesteryl ester transfer protein (CETP), which is in development for the treatment of dyslipidaemia. Because of the likely use of anacetrapib with hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, we aimed to evaluate the potential for a pharmacokinetic interaction with simvastatin. METHODS: A randomized, two-period, two-treatment, balanced, open-label, crossover study in 12 healthy subjects was performed. Subjects received simvastatin 40 mg alone or anacetrapib 150 mg co-administered with simvastatin 40 mg, once daily. Both treatments were administered following a low-fat breakfast for 14 days, separated by a wash-out period of at least 14 days. Safety and tolerability, simvastatin and simvastatin acid concentrations, and lipoproteins, were assessed. RESULTS: Both treatments were well tolerated. The pharmacokinetics of simvastatin and simvastatin acid were similar with and without anacetrapib administration {AUC(0-24 h) geometric mean ratio [90% confidence interval (CI)] for simvastatin acid and simvastatin were 1.36 [1.17, 1.57] and 1.30 [1.14, 1.47], respectively} based on the prespecified comparability bounds of (0.50, 2.00). Treatment with simvastatin alone led to a mean (95% CI) % reduction from baseline in low-density lipoprotein-cholesterol (LDL-C) of -36% (-27, -46) compared with a reduction of -54% (-44, -63) for anacetrapib co-administered with simvastatin. CONCLUSIONS: There appears to be no clinically meaningful effect of anacetrapib on the pharmacokinetic parameters of simvastatin. When co-administered with simvastatin, anacetrapib appeared to exhibit incremental LDL-C-lowering efficacy, due to CETP inhibition. Co-administration of anacetrapib and simvastatin was well tolerated.
J Intern Med. 2009 Jun 22;
Malmström RE, Ostergren J, Jørgensen L, Hjemdahl P,
Objectives. Possible interactions between clopidogrel and atorvastatin, simvastatin or rosuvastatin (a 'non-CYP3A4' metabolized statin) were investigated in a randomized prospective study using sensitive and specific ex vivo platelet function tests. Methods. Patients with coronary artery disease participating in a double-blind study comparing lipid-lowering effects of atorvastatin (20-80 mg OD; n = 22) and rosuvastatin (10-40 mg OD; n = 24) were studied before and after 2 weeks treatment with clopidogrel 75 mg OD after completed statin dose titration. In addition, 23 patients were randomized to open-label simvastatin 40 mg OD. Results. Clopidogrel inhibited 10 mumol L(-1) ADP-induced platelet aggregation by 40 +/- 27%, 57 +/- 28% and 51 +/- 29%, respectively, in patients on rosuvastatin, atorvastatin and simvastatin treatment. The other platelet tests yielded similar results. No dose-dependent effects of rosuvastatin or atorvastatin co-treatment on clopidogrel efficacy were observed. Conclusions. Treatment with CYP3A4 metabolized statins, atorvastatin or simvastatin, did not attenuate the platelet inhibitory effect of clopidogrel maintenance treatment compared with the non-CYP3A4 metabolized, rosuvastatin.
The expression of efflux and uptake transporters are regulated by statins in Caco-2 and HepG2 cells.
Acta Pharmacol Sin. 2009 Jun 22;
Rodrigues AC, Curi R, Genvigir FD, Hirata MH, Hirata RD
AbstractAim:Statin disposition and response are greatly determined by the activities of drug metabolizing enzymes and efflux/ uptake transporters. There is little information on the regulation of these proteins in human cells after statin therapy. In this study, the effects of atorvastatin and simvastatin on mRNA expression of efflux (ABCB1, ABCG2 and ABCC2) and uptake (SLCO1B1, SLCO2B1 and SLC22A1) drug transporters in Caco-2 and HepG2 cells were investigated.Methods:Quantitative real-time PCR was used to measure mRNA levels after exposure of HepG2 and Caco-2 cells to statins.Results:Differences in mRNA basal levels of the transporters were as follows: ABCC2>ABCG2>ABCB1>SLCO1B1>>>SLC22A1>SLC O2B1 for HepG2 cells, and SLCO2B1>>ABCC2>ABCB1>ABCG2>>>SLC22A1 for Caco-2 cells. While for HepG2 cells, ABCC2, ABCG2 and SLCO2B1 mRNA levels were significantly up-regulated at 1, 10 and 20 mumol/L after 12 or 24 h treatment, in Caco-2 cells, only the efflux transporter ABCB1 was significantly down-regulated by two-fold following a 12 h treatment with atorvastatin. Interestingly, whereas treatment with simvastatin had no effect on mRNA levels of the transporters in HepG2 cells, in Caco-2 cells the statin significantly down-regulated ABCB1, ABCC2, SLC22A1, and SLCO2B1 mRNA levels after 12 or 24 h treatment.Conclusion:These findings reveal that statins exhibits differential effects on mRNA expression of drug transporters, and this effect depends on the cell type. Furthermore, alterations in the expression levels of drug transporters in the liver and/or intestine may contribute to the variability in oral disposition of statins.Acta Pharmacologica Sinica advance online publication, 22 June 2009; doi: 10.1038/aps.2009.85.
J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Jun 17;
Nováková L, Vlčková H, Satínský D, Sadílek P, Solichová D, Bláha M, Bláha V, Solich P
Simvastatin and atorvastatin belong to the group of hypolipidemic drugs, more exactly to the second generation of inhibitors of microsomal 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. They induce a significant reduction in total cholesterol, low-density lipoprotein cholesterol and plasma triglycerides, therefore they are widely used in the treatment of hypercholesterolemia even of its severe form-familiar hypercholesterolemia. Simvastatin and atorvastatin as the most widely used statins in clinical treatment and their hydroxy-acid/lactone forms were determined by means of UPLC in connection with triple quadrupole mass spectrometer. Deuterium labeled reference standard compounds were used as internal standards for the quantitation. Separation was performed on Acquity BEH C18 (100mmx2.1mm, 1.7mum) using gradient elution by mobile phase containing acetonitrile and ammonium acetate pH 4.0, which is convenient in order to prevent interconversion of analytes. ESI in positive mode was used for the ionization of all compounds. Two SRM (selected reaction monitoring) transitions were carefully optimized for each analyte in order to get high sensitivity and selectivity. SPE on Discovery DSC-18 was used as a sample preparation step. Intra-day precision was generally within 10% RSD, while inter-day precision within 15% RSD. Method accuracy expressed as recovery ranged from 75 to 100%. The method was validated with the sensitivity reaching LOQ 0.08-5.46nmol/l and LOD 0.01-1.80nmol/l in biological samples. Atorvastatin, simvastatin, its metabolites and hydroxy-acid/lactone forms were monitored in human serum and in lipoprotein fractions (LDL, HDL and VLDL) at patients with end stage renal diseases.