pitavastatin and Coronary-Disease

Our study aims to evaluate the efficacy and safety of long-term treatment of statins for coronary heart disease (CHD).. Efficacy outcomes included changes in blood lipids, risk of CHD mortality and all-cause mortality. Safety outcomes were evaluated by the risk of adverse events (AE). Bayesian network meta-analysis was used to compare the direct and indirect effects between different statins.. The systematic review showed that levels of blood lipids decreased during statin treatment. High dose of atorvastatin was the most obvious treatment for the reduction of blood lipids. Network meta-analysis showed that statins were significantly more effective than the control in reducing the risk of CHD mortality (Odds Ratio (OR) 0.69, 95% CI 0.61-0.77) and all-cause mortality (OR 0.84, 95% CI 0.80-0.87). In terms of reducing the risk of CHD morality, fluvastatin (77.3%), atorvastatin (72.3%) and lovastatin (68.4%) had higher cumulative probability than other statins, which were more effective treatments for the reduction of CHD morality. In terms of reducing all-cause mortality, atorvastatin (78.6%), fluvastatin (77.1%) and pitavastatin (74.1%) had higher cumulative probability than other statins, which were more effective treatment for reducing the all-cause mortality. Compared with placebo, statins increased the incidence risk of muscle disease (OR 1.05, 95% CI 1.00-1.10) and kidney disease (OR 1.11, 95% CI 1.05-1.72).. Statins significantly reduced levels of blood lipids, with a high dose of atorvastatin being the most effective in blood-lipid level modification. Statins reduced the risk of CHD mortality and all-cause mortality, with atorvastatin and fluvastatin being the most effective in reducing the risk of CHD mortality and all-cause mortality. Statins increased the risk of muscle disease and kidney damage.

Topics: Anticholesteremic Agents; Atorvastatin; Bayes Theorem; Coronary Disease; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Kidney Diseases; Lipids; Lovastatin; Muscles; Network Meta-Analysis; Patient Safety; Pravastatin; Quinolines; Randomized Controlled Trials as Topic; Simvastatin; Treatment Outcome

Coronary heart disease (CHD) is the leading cause of morbidity and mortality in the Western world, with hypercholesterolemia as the major risk factor. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors represent the most efficient drugsfor the treatment of hypercholesterolemia. They lower plasma cholesterol due to the inhibition of endogenous cholesterol synthesis in the liverand subsequent increased expression of low-density lipoprotein (LDL) receptors, resulting in an up-regulated catabolic rate for plasma LDL. The beneficial effect of statins on the incidence of CHD was clearly demonstrated in several large-scale clinical trials. Currently, five statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) are available, and two novel compounds (pitavastatin, rosuvastatin) are undergoing clinical investigation. To point out potential mechanisms leading to increased toxicity and to compare the novel statins with the established ones, this article summarizes their pharmacological data since the prevalence of adverse events can be explained at least in part by their pharmacokinetic differences.

Topics: Acyl Coenzyme A; Coronary Disease; Enzyme Inhibitors; Fluorobenzenes; Hypolipidemic Agents; Pyrimidines; Quinolines; Rosuvastatin Calcium; Sulfonamides

Rosuvastatin (ZD4522) and pitavastatin (NK-104) are novel HMG-CoA reductase inhibitors with a peculiar pharmacological profile. In particular, they show a high potency in decreasing LDL-C and their catabolism is not mediated by the cytochrome P-450 3A4, thus reducing the potential for drug-drug interaction and improving the management of blood cholesterol. As the magnitude of LDL-C reduction is directly associated with the decrease in the incidence of myocardial infarction and mortality for CAD, statins with increased LDL-C lowering potency may ensure the achievement of target LDL-C levels and offer a more aggressive cholesterol control, further improving CAD morbidity and mortality.

Topics: Animals; Cholesterol, LDL; Clinical Trials as Topic; Coronary Disease; Fluorobenzenes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Naphthalenes; Pyrimidines; Quinolines; Rosuvastatin Calcium; Sulfonamides

This study is a prospective multicenter study designed to investigate the effects of lipid-lowering therapy with pitavastatin on atherosclerotic plaque in patients with coronary heart disease, and to determine which factor is more closely associated with plaque regression. Participants (n = 63) were treated with pitavastatin for 12 months, and the carotid intima-media thickness (IMT) was measured by ultrasound before and after treatment. Mean IMT slightly but significantly decreased (from 0.99 ± 0.33 to 0.94 ± 0.28 mm for overall, P = 0.01) regardless of the presence of pretreatment with other statins. There were no significant relations with hs-CRP, malondialdehyde-LDL, LDL cholesterol, and smaller LDL cholesterol levels despite their decrease by pitavastatin. Decreases in mean IMT were observed significantly more frequently in subjects with high on-treatment HDL cholesterol levels than with low HDL cholesterol levels (P = 0.017). The change in mean IMT tended to be inversely correlated with increments in HDL cholesterol and apolipoprotein A-I. The IMT regression was more often observed in the absence of diabetes and metabolic syndrome. In conclusion, we demonstrated that treatment with pitavastatin attenuated atherosclerotic plaque. This effect was associated with the level of HDL cholesterol, and was stronger in the absence of diabetes and metabolic syndrome in our ischemic heart disease patients.

Topics: Aged; Biomarkers; Carotid Artery Diseases; Carotid Artery, Common; Carotid Intima-Media Thickness; Cholesterol, HDL; Comorbidity; Coronary Disease; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Japan; Male; Middle Aged; Plaque, Atherosclerotic; Predictive Value of Tests; Prospective Studies; Quinolines; Risk Factors; Time Factors; Treatment Outcome

Despite the proven efficacy of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in lowering total and low-density lipoprotein cholesterol (LDL-C), many patients do not reach recommended lipid targets. This study compared pitavastatin, a new and highly effective statin, and simvastatin in patients at high risk of coronary heart disease (CHD). The primary objective was to demonstrate noninferiority of pitavastatin to simvastatin.. The study was a phase 3, randomized, double-blind, double-dummy, parallel-group, active-controlled study conducted at 37 centers in five European countries. Following a dietary run-in period of 6-8 weeks, patients with primary hypercholesterolemia or combined dyslipidemia and at least two CHD risk factors were randomized 2:1 to receive pitavastatin 4 mg or simvastatin 40 mg once daily for 12 weeks. The primary efficacy variable was the change in LDL-C from baseline.. In total, 355 patients were randomized, 236 to pitavastatin and 119 to simvastatin; 330 patients (223 and 107, respectively) completed the study. In the pitavastatin group, mean (± SD) reduction in LDL-C concentrations from baseline was -44.0 ± 12.8% compared with -43.8 ± 14.4% in the simvastatin group. The adjusted mean treatment difference (simvastatin--pitavastatin) was 0.31% (95% confidence interval -2.47, 3.09; P = 0.829), which was within the predefined noninferiority range. More than 80% of patients in each group reached recommended LDL-C targets. Pitavastatin provided a greater increase in high-density lipoprotein cholesterol (HDL-C; 6.8% vs. 4.5%; P = 0.083) and a significantly greater decrease in triglycerides (-19.8% vs. -14.8%; P = 0.044) than simvastatin. Both treatments were well tolerated.. Pitavastatin 4 mg is as effective as simvastatin 40 mg in lowering LDL-C in dyslipidemic patients at high risk of CHD, with additional effects on HDL-C and triglycerides. Therefore, pitavastatin may be appropriate for the management of dyslipidemic patients at high cardiovascular risk.

Topics: Aged; Cholesterol, LDL; Coronary Disease; Dyslipidemias; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Quinolines; Simvastatin

Although a low level of high density lipoprotein-cholesterol (HDL-C) is an important risk factor for coronary heart disease, few available agents are capable of significantly increasing HDL-C. This multicenter study demonstrated that administration of pitavastatin, a new HMG-CoA reductase inhibitor, significantly and persistently increased HDL-C (from 36.0+/-5.9 to 40.5+/-9.1 mg/dL: p<0.001) and apolipoprotein A-I levels (from 108.4+/-18.0 to 118.7+/-19.3 mg/dL: p<0.01) in 43 hypercholesterolemic patients with low HDL-C over the course of 12 months of treatment. This suggests that pitavastatin may contribute to reduction in coronary heart disease.

Topics: Aged; Apolipoprotein A-I; Cholesterol, HDL; Coronary Disease; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Middle Aged; Quinolines

Neointimal hyperplasia plays a crucial role in restenosis after stenting. The severity of neointimal thickness correlates with inflammatory reactions in the injured vessel and statins can inhibit inflammation. Pitavastatin has favorable effects on plasma lipoproteins and inflammation. Thus, we hypothesized that pitavastatin might inhibit the early inflammatory response, resulting in prevention of neointimal hyperplasia in porcine coronary arteries after stenting. Pitavastatin (18 coronaries, 40 mg per day) or placebo (20 coronaries) was administered orally from 7 days before stenting until the time of euthanasia at 3 or 28 days after stenting. The coronary artery of the animals was injured with an oversized metallic coil stent. Inflammatory cell infiltration was evaluated by scanning electron microscopy and was significantly reduced in the treated vessels compared to controls. On Day 28, intravascular ultrasound analysis revealed the neointimal area was significantly less at the stent site in the pitavastatin group than in the placebo. Histopathologic assessment showed significantly decreased in neointimal area in the pitavastatin group compared to the placebo (2.16 +/- 0.13 mm(2) versus 2.88 +/- 0.25 mm(2), p = 0.029), whereas the mean injury score in the pitavastatin group was larger than in the placebo group. In conclusion, Pitavastatin inhibited neointimal hyperplasia after stenting through a reduction of inflammatory reactions.

Topics: Animals; Coronary Disease; Coronary Restenosis; Coronary Vessels; Disease Models, Animal; Female; Hypertrophy; Male; Microscopy, Electron, Scanning; Probability; Quinolines; Random Allocation; Reference Values; Sensitivity and Specificity; Stents; Swine; Tunica Intima; Ultrasonography, Interventional

Although statins are reported to have a cardioprotective effect, their immediate direct influence on ischemia-reperfusion injury and the underlying mechanisms remain obscure. We investigated these issues an in vivo canine model.. Dogs were subjected to coronary occlusion (90 minutes) and reperfusion (6 hours) immediately after injection of pravastatin (0.2, 2, or 10 mg/kg), pitavastatin (0.01, 0.1, or 0.5 mg/kg), or cerivastatin (0.5, 5, or 50 microg/kg). Then myocardial phosphatidylinositol 3-kinase (PI3-K) and 5'-nucleotidase activities were measured, as well as infarct size. After 15 minutes of reperfusion, pravastatin caused dose-dependent activation of Akt and ecto-5'-nucleotidase in the ischemic zone, and the effect was significant at higher doses. Pitavastatin also significantly increased these activities, and its optimal dose was within the clinical range, whereas cerivastatin caused activation at the lowest dose tested. In all cases, both Akt and ecto-5'-nucleotidase showed activation in parallel, and this activation was completely abolished by wortmannin, a PI3-K inhibitor. The magnitude of the infarct-limiting effect paralleled the increase in Akt and ecto-5'-nucleotidase activity and was blunted by administration of wortmannin, alpha,beta-methyleneadenosine-5'-diphosphate, or 8-sulfophenyltheophylline during reperfusion. Both collateral flow and the area at risk were comparable for all groups.. Activation of ecto-5'-nucleotidase after ischemia by PI3-K activation may be crucial for immediate infarct-size limitation by statins. There seems to be an optimal dose for each statin that is independent of its clinical cholesterol-lowering effect.

Topics: 5'-Nucleotidase; Adenosine Triphosphate; Androstadienes; Animals; Cardiotonic Agents; Chromones; Coronary Disease; Dogs; Dose-Response Relationship, Drug; Enzyme Activation; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Morpholines; Myocardial Infarction; Myocardial Reperfusion Injury; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Pravastatin; Pyridines; Quinolines; Signal Transduction; Theophylline; Wortmannin

NK-104 ((+)-monocalcium bis(3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy- 6-heptenoate), CAS 147526-32-7) an inhibitor of 3-hydroxy-3-metylglutaryl coenzyme A reductase, was administered in drinking water (0.5 mg/kg equivalent) to Watanabe heritable hyperlipidemic (WHHL) rabbits for 26 weeks. It lowered plasma total cholesterol (TC, 7-20%) and triglyceride (TG, 16-39%) levels throughout the experimental period due to a significant reduction of very low density lipoprotein cholesterol (VLDL-C, 61-62%, p < 0.05), intermediate density lipoprotein cholesterol (IDL-C, 49-60%, p < 0.05), VLDL-TG (40-53%, p = 0.06-0.08) and IDL-TG (29-59%, p = 0.06-0.14); low density lipoprotein cholesterol (LDL-C) was not affected. The pattern of the lipoprotein reduction along with a decrease in liver cholesteryl ester (CE, 33.1%, p < 0.01) suggests an intense reduction of VLDL secretion and a marginal induction of LDL-receptor. Enhanced expression of LDL receptor-related protein (LRP) in the liver was observed at mRNA levels (49.5% increase, P = 0.13), which might play a role in the lipoprotein reduction. Histological analyses of aorta revealed that aortic arch showed the most advanced lesions with larger lesion area (70.0 vs 41.3%) and much greater CE content (more than 2 fold) with less macrophages than thoracic aorta. NK-104 decreased the surface lesion area at the arch (23.1%, p = 0.054) and reduced the degeneration of media in the thoracic aorta (69.9% increase in medial smooth muscle cells, p < 0.01). Thus NK-104 preferentially reduced TG-rich lipoproteins (VLDL and IDL) without affecting LDL-C levels and prevented progression of atherosclerosis in WHHL rabbits.

Topics: Animals; Aorta; Arteriosclerosis; Coronary Disease; Coronary Vessels; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Lipids; Liver; Male; Quinolines; Rabbits; Receptors, LDL; RNA, Messenger