pitavastatin and Hyperlipidemias

Statins have proven beneficial for reducing both primary and secondary events in patients with coronary heart disease. Tight control of serum lipid parameters in these patients is recommended by the most recent clinical guidelines. Although numerous lipid-lowering treatments are available, only a small percentage of eligible patients receive therapy and fewer achieve their lipid-lowering goals. Thus it is clear that new treatment strategies to manage patients with lipid abnormalities are warranted. Pitavastatin (Lival; Kowa Pharmaceuticals America, Montgomery, AL, USA) has been recently approved for the treatment of hypercholesterolemia and combined dyslipidemia. Pitavastatin 1-4 mg/day has shown similar low-density lipoprotein-reducing activity to other commercially available statins, including simvastatin and atorvastatin. Adverse events occurred at similar rates to other statins in clinical trials with favorable effects seen in patients with dyslipidemia and metabolic syndrome. Pharmacokinetic drug-drug interactions are minimized due to the lack of significant metabolism of pitavastatin by the cytochrome P450 enzyme system, although some drugs affect its uptake into hepatocytes and should be avoided. In addition to its higher acquisition cost, pitavastatin has not been shown to improve clinical outcomes in high-risk patient populations and thus may not be the agent of choice in many patients at this time in lieu of cheaper, clinically proven alternatives.

Topics: Acute Coronary Syndrome; Comorbidity; Diabetes Mellitus; Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Quinolines; Renal Insufficiency, Chronic

Pitavastatin calcium is a new addition to the class of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") approved for use in the United States for the treatment of primary hyperlipidemia and mixed dyslipidemia.. The purpose of this review was to evaluate the literature related to the medicinal chemistry, pharmacology, pharmacokinetic properties, clinical efficacy, and tolerability of pitavastatin in the treatment of hyperlipidemia.. A search of MEDLINE, EMBASE, and the Journal Archive for English-language literature was conducted for articles published through January 2011 using the following search terms: itavastatin, Livalo, nisvastatin, NK 104, and pitavastatin. Articles were reviewed if they pertained to the clinical efficacy, pharmacology, pharmacokinetic properties, or tolerability of pitavastatin. Clinical trials were systematically included in the analysis of clinical efficacy if they used a randomized design to study the effects of the drug on hyperlipidemia, hypercholesterolemia, or heart disease. Trials were excluded if they did not signify the statin used, did not pertain to clinical efficacy, or enrolled <20 patients.. A total of 16 studies were identified and reviewed for clinical efficacy. Based on findings from pharmacokinetic studies, pitavastatin may be given at any time of the day, with or without food. The drug had a mean plasma elimination t(1/2) of 12 hours, is expected to be associated with minimal drug-drug interactions because it is not metabolized by the cytochrome P450 3A4 isozyme, and is primarily excreted unchanged in the bile with little renal elimination. Clinical trials described the effects of pitavastatin on cholesterol, high-sensitivity C-reactive protein (hs-CRP), and progression of atherosclerosis. Pitavastatin at doses of 1 to 4 mg/d was reported to be associated with reductions in LDL-C of 38% to 44% and in triglycerides of 14% to 22%, and with increases in HDL-C of 5% to 8% (all, P < 0.05). Overall, the effect of pitavastatin on cholesterol was comparable to those of atorvastatin and simvastatin at low to intermediate doses. Studies on the effects of pitavastatin on cardiovascular outcomes were lacking. The adverse-events (AE) profile of pitavastatin compared favorably with those of other available statins. AEs included gastrointestinal symptoms (0.7%-2.2%), myopathies (0.3%-1.1%), and elevated hepatic enzyme concentrations (0.0%-8.8%).. Based on the findings from previously published clinical trials, pitavastatin is an effective lipid lowering agent and is another therapeutic option of currently available statins.

Topics: Animals; Cholesterol, HDL; Cholesterol, LDL; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Quinolines; Triglycerides

Topics: Animals; Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Pain; Quinolines; Randomized Controlled Trials as Topic

Pitavastatin is a new, synthetic member of the statin class of lipid-lowering drugs. Compared with other available statins, it has a unique cyclopropyl group on its base structure that is believed to increase 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition by a factor of five and to significantly increase the transcription and activity of LDL receptors. Pitavastatin is primarily metabolized via glucuronidation and is not a substrate for the cytochrome P450 3A4 enzyme, thus avoiding the potential for cytochrome P450-mediated drug-drug interactions. Clinical trials have shown that pitavastatin is comparable to atorvastatin and simvastatin in improving lipid measures, and more potent than pravastatin. Pitavastatin is effective in reducing triglycerides and increasing HDL-cholesterol, so it will be particularly beneficial in treating patients with mixed dyslipidemia. Its safety and adverse event profile is similar to that of other available statins, and it has an established history of use in Asia indicating tolerability and safety for treatment lasting up to 7 years.

Topics: Animals; Cytochrome P-450 Enzyme System; Drug Interactions; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Quinolines; Receptors, LDL

Topics: Animals; Clinical Trials as Topic; Humans; Hyperlipidemias; Hypolipidemic Agents; Quinolines

Topics: Animals; Cholesterol, LDL; Clinical Trials as Topic; Dose-Response Relationship, Drug; Fluorobenzenes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Pyrimidines; Quinolines; Rosuvastatin Calcium; Sulfonamides

Although the role of high-intensity lipid-lowering therapy in cardiovascular protection has broadened, concerns still exist about new-onset diabetes mellitus (NODM), especially in vulnerable patients. This study aimed to compare the effect of high-dose (4 mg/d) and usual dose (2 mg/d) pitavastatin on glucose metabolism in patients with hyperlipidemia and impaired fasting glucose (IFG).. In this 12-month study, glucose tolerance and lipid-lowering efficacy of high-dose pitavastatin (4 mg [study group]) was compared with that of usual dose pitavastatin (2 mg [control group]) in patients with hyperlipidemia and IFG. The primary end point was the change of glycosylated hemoglobin (HbA. The high-dose pitavastatin therapy did not aggravate glucose metabolism compared with the usual dose therapy. Moreover, it had a better effect on cholesterol-lowering and apolipoprotein distribution in the patients with hyperlipidemia and IFG.

Topics: Aged; Apolipoprotein A-I; Apolipoproteins B; Blood Glucose; Cholesterol; Fasting; Female; Glycated Hemoglobin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hyperlipidemias; Lipids; Male; Middle Aged; Quinolines

In contrast to current guidelines in Western countries, moderate reduction of low-density lipoprotein cholesterol (LDL-C) is recommended for Japanese patients with atherosclerotic cardiovascular disease and dyslipidemia even in secondary prevention. HIJ-PROPER (Heart Institute of Japan-PRoper level of lipid lOwering with Pitavastatin and Ezetimibe in acute coRonary syndrome) is a prospective, randomized, open-label, blinded endpoint multicenter trial designed to assess whether closely controlled LDL-C lowering with a standard statin dose plus ezetimibe, targeting LDL-C of <70mg/dL, would reduce cardiovascular events more than standard statin monotherapy targeting LDL-C of <100mg/dL as per the Japan Atherosclerotic Society guideline in patients with acute coronary syndrome (ACS) and dyslipidemia.. We recruited patients with ACS and dyslipidemia who had undergone coronary angiography. Participants are randomly allocated to either intensive LDL-C lowering treatment (target LDL-C of <70mg/dL; pitavastatin plus ezetimibe) or standard LDL-C lowering treatment (target LDL-C of 90-100mg/dL; pitavastatin monotherapy). The primary endpoint is a composite of total death, non-fatal myocardial infarction (MI), non-fatal stroke, unstable angina, and any ischemia-driven revascularization. Patients will be followed for a minimum of 3 years.. Between January 2010 and April 2013, 1734 patients were enrolled from 19 hospitals in Japan with a mean age of 65.6 years; 75.5% were men and 83.3% were statin-naïve. The qualifying ACS was an acute MI in 61.5%. This study is expected to report its findings in August 2016.. HIJ-PROPER will determine whether targeting LDL-C of <70mg/dL with pitavastatin plus ezetimibe can improve cardiovascular outcomes in Japanese patients with ACS and dyslipidemia in comparison to targeting LDL-C of 90-100mg/dL with standard pitavastatin monotherapy.. UMIN000002742.

Topics: Acute Coronary Syndrome; Aged; Cholesterol, LDL; Coronary Angiography; Drug Therapy, Combination; Ezetimibe; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Japan; Male; Middle Aged; Prospective Studies; Quinolines

Remnants are partially hydrolyzed, triglyceride-rich lipoproteins that are implicated in atherosclerosis. We assessed the adequacy of pitavastatin 4 mg and pravastatin 40 mg in reducing atherogenic lipid parameters beyond LDL-C, in particular remnant lipoprotein cholesterol (RLP-C).. From the Phase IV, multicenter, randomized, double-blind PREVAIL US (A Study of Pitavastatin 4 mg Vs. Pravastatin 40 mg in Patients With Primary Hyperlipidemia or Mixed Dyslipidemia) trial, we examined lipoprotein cholesterol subfractions using Vertical Auto Profile testing and apolipoproteins B and A-I at baseline and 12 weeks. Participants with primary hyperlipidemia or mixed dyslipidemia had LDL-C levels of 130 to 220 mg/dL and triglyceride levels ≤ 400 mg/dL. In this post hoc analysis, changes in lipid parameters were compared by using ANCOVA.. Lipoprotein subfraction data were available in 312 patients (pitavastatin, n = 157; pravastatin, n = 155). Pitavastatin promoted a greater reduction in RLP-C than pravastatin (-13.6 [8.7] vs -9.3 [9.5] mg/dL). Furthermore, the pitavastatin group reported greater reductions in both components of RLP-C (both, P < 0.001): intermediate-density lipoprotein cholesterol (-9.5 [6.3] vs -6.4 [6.6] mg/dL) and very low-density lipoprotein cholesterol subfraction 3 (-4.1 [3.5] vs -2.9 [3.8] mg/dL). There were also greater reductions in the major ratios of risk (apolipoprotein B/apolipoprotein A-I and total cholesterol/HDL-C) (both, P < 0.001). There were no significant changes in HDL-C, its subfractions, or natural log lipoprotein(a)-cholesterol. The mean age was 58.8 ± 8.9 years in the pitavastatin group and 57.0 ± 10.2 years in the pravastatin group.. Compared with pravastatin 40 mg daily, pitavastatin 4 mg provided superior reductions in atherogenic lipid parameters beyond LDL-C, including RLP-C. Future studies are needed investigate the clinical implications of lowering directly measured RLP-C as the principal target. ClinicalTrials.gov identifier: NCT01256476.

Topics: Aged; Cholesterol; Cholesterol, LDL; Double-Blind Method; Dyslipidemias; Female; Humans; Hyperlipidemias; Lipids; Lipoproteins; Male; Middle Aged; Pravastatin; Quinolines

To assess the safety and efficacy of pitavastatin in children and adolescents with hyperlipidemia.. A total of 106 children and adolescents with hyperlipidemia, ages 6 to 17 years, were enrolled in a 12-week randomized, double-blind, placebo-controlled study and randomly assigned to pitavastatin 1 mg, 2 mg, 4 mg, or placebo. During a 52-week extension period, subjects were up-titrated from 1 mg pitavastatin to a maximum dose of 4 mg in an effort to achieve an optimum low-density lipoprotein cholesterol (LDL-C) treatment target of <110 mg/dL (2.8 mmol/L). Adverse events rates, including abnormal clinical laboratory variables, vital signs, and physical examination were assessed.. Compared with placebo, pitavastatin 1, 2, and 4 mg significantly reduced LDL-C from baseline by 23.5%, 30.1%, and 39.3%, respectively, and in the open-label study 20.5% of the subjects reached the LDL-C goal <110 mg/dL (2.8 mmol/L). No safety issues were evident.. Pitavastatin at doses up to 4 mg is well tolerated and efficacious in children and adolescents aged 6-17 years.. Registered with EudraCT 2011-004964-32 and EudraCT 2011-004983-32.

Topics: Adolescent; Age Factors; Apolipoproteins; Cardiovascular Diseases; Child; Cholesterol; Dose-Response Relationship, Drug; Double-Blind Method; Europe; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Male; Quinolines; Risk Factors; Treatment Outcome; Triglycerides

Results from a Phase III, European, non-inferiority trial in elderly (age ≥65 years) patients with primary hyperlipidemia or mixed (combined) dyslipidemia demonstrated significantly greater reductions in LDL-C for pitavastatin versus pravastatin across 3 pair-wise dose comparisons (1 mg vs 10 mg, 2 mg vs 20 mg, and 4 mg vs 40 mg, respectively). The present study investigated whether pitavastatin 4 mg is superior to pravastatin 40 mg in LDL-C reduction in adults (18-80 years old) with primary hyperlipidemia or mixed (combined) dyslipidemia.. This was a Phase IV, multicenter, randomized, double-blind, double-dummy, active-control superiority study conducted in the United States. Patients with baseline LDL-C levels of 130 to 220 mg/dL (inclusive) and triglyceride levels ≤400 mg/dL after a 6-week washout/dietary stabilization period were randomized to 12 weeks of once-daily treatment with either pitavastatin 4 mg or pravastatin 40 mg.. A total of 328 subjects (164 per treatment arm) were randomized (mean age, 57.9 years [76% were aged <65 years]; 49.4% women; mean body mass index, 30.2 kg/m(2)) to treatment. The median percent change in LDL-C from baseline to the week 12 endpoint was -38.1% for pitavastatin 4 mg and -26.4% for pravastatin 40 mg; the difference in median percent change between treatments was -12.5% (P < 0.001). Differences between treatments in median percent reductions from baseline for apolipoprotein B, total cholesterol, and non-HDL-C were also significant in favor of pitavastatin (P < 0.001). Both treatments significantly (P < 0.001) increased HDL-C and decreased triglycerides, but the differences between treatments were not statistically significant. The overall rate of treatment-emergent adverse events was 47.6% (78 of 164) for pitavastatin and 44.5% (73 of 164) for pravastatin. Myalgia was reported by 3 patients (1.8%) in the pitavastatin group and by 4 patients (2.4%) in the pravastatin group. There were no reports of myositis or rhabdomyolysis.. Pitavastatin 4 mg demonstrated superior LDL-C reductions compared with pravastatin 40 mg after 12 weeks of therapy in adults with primary hyperlipidemia or mixed (combined) dyslipidemia. There were no new safety findings in the trial. Clinical Trials.gov identifier: NCT01256476.

Topics: Aged; Apolipoproteins B; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Dyslipidemias; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Male; Middle Aged; Pravastatin; Prospective Studies; Quinolines; Triglycerides

The effects of a low dose of rosuvastatin (ROS) and pitavastatin (PIT) on lipid profiles and inflammation markers were assessed in subjects with type 2 diabetes mellitus.. A total of 90 Japanese type 2 diabetes patients with hyperlipidemia (low-density lipoprotein cholesterol [LDL-C] ≥140 mg/dL) were enrolled in this study. They were randomly assigned to four groups with open-label treatment with ROS (2.5 mg daily) or PIT (2 mg daily); two groups were sequentially treated with both drugs, with crossover of medication after 12 weeks, and the other two groups underwent treatment with either ROS or PIT for 24 weeks. The primary endpoints were the percentage changes in LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglyceride, and the LDL-C/HDL-C ratio.. Both ROS and PIT lowered LDL-C and triglyceride, and increased HDL-C. In particular, significantly greater reduction in LDL-C was seen with ROS (-44.1%) than with PIT (-36.9%, P<0.01) in the crossover group from ROS to PIT, and the same result was detected in the crossover group from PIT (-34.8%) to ROS (-44.7%). The ratio of LDL-C/HDL-C was significantly reduced with ROS treatment (from 3.45 to 1.85) compared with that with PIT (from 3.45 to 2.22, P<0.01). Both ROS and PIT lowered plasma levels of high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor (TNF)-alpha, and plasminogen activator inhibitor-1 (PAI-1). In addition, the hsCRP level with the administration of ROS was significantly improved compared with the administration of PIT. There was no significant correlation between changes in LDL-C and hsCRP, TNF-alpha, and PAI-1 levels. ROS and PIT did not have an adverse effect on glycemic control in type 2 diabetes patients.. Therapy with both statins improved lipid profiles and reduced proinflammatory responses; however, 2.5 mg of ROS have a potent LDL-C-lowering and hsCRP-lowering effect compared with 2 mg of PIT in patients with diabetes.

Topics: C-Reactive Protein; Cholesterol, HDL; Cholesterol, LDL; Cross-Over Studies; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Monitoring; Fluorobenzenes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Japan; Plasminogen Activator Inhibitor 1; Pyrimidines; Quinolines; Rosuvastatin Calcium; Sulfonamides; Treatment Outcome; Triglycerides; Tumor Necrosis Factor-alpha

The aim of the present study was to evaluate the factors that modulate the protective action of statins on cardiorenal function, regardless of the lipid-lowering effect. To treat abnormal serum lipid profiles, low-dose pitavastatin (1.0 mg/day) was administered to 65 hyperlipidemic patients. The exclusion criteria included left ventricular ejection fraction <40% and apparent renal disease. Age- and gender-matched patients with hyperlipidemia (n = 40) served as the controls. After 12 to 16 weeks of pitavastatin treatment, pitavastatin had decreased low-density lipoprotein cholesterol (from 143.5 ± 31.4 to 98.2 ± 19.4 mg/dl, p <0.01), triglycerides (from 157.7 ± 57.2 to 140.5 ± 60.7 mg/dl, p <0.01), E/e' (from 10.8 ± 6.2 to 9.0 ± 4.5, p <0.05), a parameter of left ventricular diastolic function, and albuminuria (from 47.6 ± 55.9 to 28.5 ± 40.0 mg/g creatinine, p <0.01). Furthermore, pitavastatin decreased serum transforming growth factor-β1 (from 709 ± 242 to 550 ± 299 pg/ml, p <0.01), urinary 8-hydroxy-2'-deoxyguanosine (from 6.6 ± 4.1 to 5.0 ± 3.1 μg/g creatinine, p <0.01), an oxidative stress marker, and increased urinary nitrate and nitrite (from 22.5 ± 14.6 to 29.4 ± 27.6 nmol/g creatinine, p <0.05). No such changes were observed in the controls. Multiple regression analysis in the pitavastatin group revealed the effect of pitavastatin on cardiorenal function was associated with suppression of oxidative stress, but not on low-density lipoprotein cholesterol reduction. In conclusion, pitavastatin decreases E/e' and albuminuria, which is associated with suppression of oxidative stress.

Topics: Aged; Albuminuria; Case-Control Studies; Cholesterol, LDL; Diastole; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Male; Middle Aged; Quinolines; Treatment Outcome; Triglycerides; Ventricular Function, Left

The present study was undertaken to compare the efficacy of pitavastatin and colestimide in patients with diabetes mellitus complicated by hyperlipidemia and metabolic syndrome. 48 diabetic patients with metabolic syndrome were randomly assigned to a pitavastatin group or colestimide group. The clinical parameters, serum lipids, fasting (FPG) and postprandial plasma glucose(PPG), HOMA-IR, hemoglobin A1c(HbA1c), hs-CRP and urinary albumin were measured before/after 24-week administration. Treatment with pitavastatin reduced LDL-C and TG, while that with colestimide significantly reduced waist circumference, BMI, LDL-C, HbA1c, FPG, PPG, HOMA-R , hs-CRP and urinary albumin. Percent improvement in LDL-C was greater in the pitavastatin group than in the colestimide group. Colestimide appeared to be useful in the management of Japanese patients with diabetes mellitus complicated by metabolic syndrome, since it alleviates obesity and insulin resistance in addition to exhibiting lipid profile-improving effects, and can thus improve markers of atherosclerosis.

Topics: Adult; Aged; Albuminuria; Atherosclerosis; Biomarkers; C-Reactive Protein; Cholesterol, LDL; Diabetes Complications; Epichlorohydrin; Female; Glycated Hemoglobin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperglycemia; Hyperlipidemias; Hypolipidemic Agents; Imidazoles; Insulin Resistance; Japan; Male; Metabolic Syndrome; Middle Aged; Obesity; Quinolines; Resins, Synthetic; Triglycerides; Weight Loss

To investigate the SLCO1B1 388A>G and 521T>C polymorphisms in hyperlipidemia patients and evaluate the effect of the two polymorphisms on the lipid-lowering efficacy of pitavastatin.. The functional polymorphisms of SLCO1B1 (388A>G and 521T>C) were genotyped in 140 Chinese patients with essential hyperlipidemia using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and one-step tetra-primers ARMS-PCR. Eighty-five patients were enrolled in the clinical trial and given 2 mg of pitavastatin daily for 8 weeks. Total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) serum levels were measured at baseline, after 4 weeks and after 8 weeks of treatment.. The allele frequencies of SLCO1B1 388A>G and 521T>C in essential hyperlipidemia patients were 71.1% and 11.1%, respectively. The 4- and 8-week treatment with pitavastatin significantly reduced TC, TG, and LDL levels, but there was no statistical difference among patients with wild type, SLCO1B1 388A>G or SLCO1B1 521T>C in the lipid-lowering efficacy of pitavastatin.. The present study found that the allele frequencies of SLCO1B1 388A>G and 521T>C in Chinese patients with essential hyperlipidemia are comparable to those in healthy Chinese population. SLCO1B1 388A>G and 521T>C do not affect the lipid-lowering efficacy of pitavastatin.

Topics: Adolescent; Adult; Aged; Asian People; Cholesterol; Enzyme Inhibitors; Female; Gene Frequency; Humans; Hyperlipidemias; Hypolipidemic Agents; Lipid Metabolism; Lipoproteins, HDL; Lipoproteins, LDL; Liver-Specific Organic Anion Transporter 1; Male; Middle Aged; Organic Anion Transporters; Polymorphism, Genetic; Quinolines; Triglycerides; Young Adult

Platelet-derived microparticles (PDMP) play an important role in the pathogenesis of diabetic vasculopathy, and statins or eicosapentaenoic acid (EPA) have been shown to have a beneficial effect on atherosclerosis in hyperlipidemic patients. However, the influence of EPA and statins on PDMP and adiponectin in atherosclerosis is poorly understood. We investigated the effect of pitavastatin and EPA on circulating levels of PDMP and adiponectin in hyperlipidemic patients with type II diabetes. A total of 191 hyperlipidemic patients with type II diabetes were divided into three groups: group A received pitavastatin 2 mg once daily (n = 64), group B received EPA 1800 mg daily (n = 55) and group C received both drugs (n = 72). PDMP and adiponectin were measured by ELISA at baseline and after 3 and 6 months of drug treatment. Thirty normolipidemic patients were recruited as healthy controls. PDMP levels prior to treatment in hyperlipidemic patients with diabetes were higher than levels in healthy controls (10.4 +/- 1.9 vs. 3.1 +/- 0.4 U/ml, p < 0.0001), and adiponectin levels were lower than controls (3.20 +/- 0.49 vs. 5.98 +/- 0.42 microg/ml, p < 0.0001). PDMP decreased significantly in group B (before vs. 6M, 10.6 +/- 2.0 vs. 8.0 +/- 1.7 U/ml, p < 0.01), but not in group A (before vs. 6M, 9.4 +/- 1.9 vs. 9.6 +/- 1.7 U/ml, not significant). In contrast, group A exhibited a significant increase in adiponectin levels after treatment (before vs. 6M, 3.29 +/- 0.51 vs. 4.16 +/- 0.60 microg/ml, p < 0.001). Furthermore, group C exhibited significant improvement in both PDMP and adiponectin levels after treatment (PDMP, before vs. 6M, 11.2 +/- 2.0 vs. 4.5 +/- 2.7 U/ml, p < 0.001; adiponectin, before vs. 6M, 3.24 +/- 0.41 vs. 4.02 +/- 0.70 microg/ml, p < 0.001). Reductions of PDMP in combined therapy were significantly greater than those observed with EPA alone (p < 0.05 by ANOVA). In addition, soluble CD40 ligand exhibited almost the same change as PDMP in all therapy groups. These results suggest that pitavastatin possesses an adiponectin-dependent antiatherosclerotic effect, and this drug is able to enhance the anti-platelet effect of EPA. The combination therapy of pitavastatin and EPA may be beneficial for the prevention of vascular complication in hyperlipidemic patients with type II diabetes.

Topics: Adiponectin; Age Factors; Aged; Blood Platelets; CD40 Ligand; Cell-Derived Microparticles; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Therapy, Combination; E-Selectin; Eicosapentaenoic Acid; Female; Glycated Hemoglobin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Male; Middle Aged; Quinolines; Sex Factors

The effects of statins on platelet activation markers, chemokines and adiponectin, were investigated in 135 patients with hyperlipidemia. Of the 135 hyperlipidemic patients, 63 were allocated to the simvastatin group, treated with simvastatin at the dose of 10 mg daily, and the remaining 72 were allocated to the pitavastatin group, treated with pitavastatin at the dose of 2 mg daily. Plasma levels of platelet-derived microparticles (PDMP), cell adhesion molecules (sCD40L and sP-selectin), chemokines [monocyte chemoattractant protein-1 (MCP-1) and regulated on activation normally T-cell expressed and secreted] and adiponectin were measured at the baseline and after 6 months of treatment in both the groups. In addition, we carried out a basic study to investigate the MCP-1-dependent induction of tissue factor expression on a histiocytic cell line (U937 cells). The plasma levels of PDMP, sCD40L, sP-selectin, regulated on activation normally T-cell expressed and secreted and MCP-1 were higher, whereas those of adiponectin were lower, in the hyperlipidemic patients than in the normolipidemic controls. Plasma PDMP and sCD40L were positively correlated, whereas plasma adiponectin was negatively correlated, with the plasma levels of MCP-1. No significant differences in the plasma levels of PDMP, sCD40L, sP-selectin, regulated on activation normally T-cell expressed and secreted and MCP-1 measured before and after treatment were observed in either the simvastatin or pitavastatin group. A significant increase of the plasma adiponectin levels was observed after 6 months of treatment with pitavastatin but not after an equal duration of treatment with simvastatin. When pitavastatin-treated patients were divided into two groups according to the adiponectin response to pitavastatin treatment, significant decreases of the plasma MCP-1, PDMP and sCD40L levels were observed after pitavastatin treatment in the responder group. In the aforementioned basic study, MCP-1 by itself did not induce the expression of tissue factor on the U937 cells. However, the recombinant sCD40L-induced expression of tissue factor on U937 was enhanced by the addition of MCP-1. These findings suggest that PDMP, sCD40L and MCP-1 may participate in the development of atherothrombosis in patients with hyperlipidemia and that pitavastatin may exert an adiponectin-dependent antiatherothrombotic effect in hyperlipidemic patients.

Topics: Adiponectin; Adult; Aged; Atherosclerosis; CD40 Ligand; Cell-Derived Microparticles; Chemokine CCL2; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Male; Middle Aged; P-Selectin; Quinolines; T-Lymphocytes; Thrombophilia; Thromboplastin; U937 Cells

The effects of treatment with pitavastatin on inflammatory and platelet activation markers and adiponectin in 117 patients with hyperlipidemia were investigated to determine whether pitavastatin may prevent the progression of atherosclerotic changes in hyperlipidemic patients. Adiponectin levels prior to pitavastatin treatment in hyperlipidemic patients with and without diabetes were lower than levels in normolipidemic controls. Both total cholesterol and the low-density lipoprotein cholesterol decreased significantly after pitavastatin administration. Additionally, hyperlipidemic patients with or without type 2 diabetes exhibited a significant increase in adiponectin levels 6 months after pitavastatin treatment (diabetes: 3.52 +/- 0.80 vs. 4.52 +/- 0.71 microg/ml, p < 0.001; no diabetes: 3.48 +/- 0.71 vs. 4.23 +/- 0.82 microg/ml, p < 0.05). However, high-sensitivity C-reactive protein, platelet-derived microparticle and soluble P-selectin did not exhibit any differences before or after pitavastatin administration. Levels of adiponectin significantly increased after pitavastatin administration in the group of lower soluble P-selectin (soluble P-selectin before pitavastatin treatment <200 ng/ml). These results suggest that pitavastatin possesses an adiponectin-increasing effect in patients with hyperlipidemia and this effect is influenced by intensive platelet activation.

Topics: Adiponectin; Aged; Atherosclerosis; C-Reactive Protein; Cholesterol; Cholesterol, LDL; Diabetes Mellitus, Type 2; Disease Progression; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Male; Middle Aged; Oxidative Stress; P-Selectin; Quinolines

Pitavastatin has a potent cholesterol-lowering action. The clinical efficacy and safety of a low dose, 1 mg, of pitavastatin were examined.. The effect of 12 weeks' treatment with pitavastatin 1 mg in an open label, non-randomized trial involving 137 patients with hypercholesterolemia as compared with treatment with atorvastatin 10 mg.. Total cholesterol, low-density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and triglyceride (TG) levels at baseline did not differ between the two groups. At follow-up, there were no significant differences in total cholesterol, LDL cholesterol and HDL cholesterol levels between the groups. The TG levels at follow-up were higher in the pitavastatin group than atorvastatin group (p < 0.01). In patients with hyperlipidemia type IIa, TG levels at follow-up were lower in the atorvastatin subgroup (p < 0.01). However, there was no significant difference in TG levels at follow-up between the two subgroups in patients with hyperlipidemia type IIb.. Pitavastatin 1 mg daily was safe and efficacious in reducing LDL cholesterol levels as compared with atorvastatin 10 mg daily. Further randomized comparative studies are needed to clarify the effect of a low dose of pitavastatin.

Topics: Aged; Atorvastatin; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hyperlipoproteinemia Type II; Male; Middle Aged; Pyrroles; Quinolines; Safety; Triglycerides

Pitavastatin (CAS 147526-32-7, NK-104), the first totally synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor discovered in Japan, was examined. Pitavastatin significantly decreased the serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) at doses of 1 mg/day or more, and significant dose-dependence of the effect of this drug was observed within the dose range from 1 mg/day to 4 mg/day. It also significantly decreased the serum levels of triglycerides (TG) within this dose range. There was no dose-dependence of the incidence of adverse reactions to pitavastatin.

Topics: Adult; Aged; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Lipids; Liver Function Tests; Male; Middle Aged; Quinolines; Triglycerides

Topics: Drug Approval; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Quinolines; United States; United States Food and Drug Administration

Very few studies conducted in Korea have investigated the relationship between statins and the incidence of diabetes. Therefore, we analyzed the progression from normal blood glucose to prediabetes and then to diabetes mellitus (DM) according to the type, intensity, and dose of statin prescribed.. Data of patients who were first prescribed statins between 2009 and 2011 were extracted from electronic medical records. Patients with normal blood glucose or prediabetes were observed for 4 years after initiation of statin therapy.. A total of 2890 patients were included in our study and analyzed on the basis of the first statin they were prescribed. The incidence rate of DM in patients with prediabetes was 1.72 times that of patients with normal glucose levels (odds ratio = 1.72, 95% confidence interval = 1.41-2.10, P < .001). Regarding progression from normal blood glucose to prediabetes, the incidence rate of prediabetes was significantly lower in patients prescribed pitavastatin (odds ratio = 0.62, 95% confidence interval = 0.40-0.96, P = .031) compared to that in patients prescribed atorvastatin. Regarding the progression from normal blood glucose or prediabetes to DM, there were no significant differences among all statins.. Lower DM incidence in patients prescribed pitavastatin appears to be primarily because of the lower rate of progression from normal blood glucose to prediabetes. These findings indicate that avoiding statins because of DM risk is unjustified and that clinicians should prescribe statins from the appropriate potency group.

Topics: Aged; Atorvastatin; Blood Glucose; Diabetes Mellitus; Disease Progression; Electronic Health Records; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Incidence; Male; Middle Aged; Prediabetic State; Quinolines; Republic of Korea; Retrospective Studies

To examine the effects of pitavastatin on atherosclerotic plaque in Watanabe heritable hyperlipidemic (WHHL) rabbits using serial in vivo tissue-characterizing intravascular ultrasound.. A total of 11 WHHL rabbits of 10-12 weeks of age were divided into two groups, control and pitavastatin-administered groups. A total of 29 atherosclerotic plaque segments from control group and 43 plaque segments from the pitavastatin group were serially imaged by 40MHz intravascular ultrasound in vivo with a tissue characterization software (iMAP™, Boston Scientific, Natick, MA, USA) at the baseline and the follow-up (16th week).. The level of low-density lipoprotein cholesterol was significantly decreased in pitavastatin group. During the follow-up period, plaque area was significantly increased in the control group, whereas it was not significantly changed in the pitavastatin group. The fibrotic, necrotic, and necrotic plus lipidic areas were significantly increased in the control group, while no significant change was revealed for tissue profile in pitavastatin group. The change in the percent areas of fibrotic and lipidic plus necrotic tissues were significantly different between the two groups especially in the superficial half portion of plaque.. These data indicate that pitavastatin could attenuate atherosclerotic plaque formation and that it could stabilize the plaque in WHHL rabbits. Considering the fact that these were observed even with a high follow-up level of cholesterol, these data might come from the pleiotropic effects of pitavastatin.

Topics: Animals; Cholesterol, LDL; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Lipids; Plaque, Atherosclerotic; Quinolines; Rabbits; Ultrasonography, Interventional

In this study, an injectable in situ-forming gel has been designed and fabricated for the controlled and prolonged release of pitavastatin calcium (Pit) for treating hyperlipidemia. By mixing phospholipids and soybean oil with ethanol, the phospholipid-based platform material (PSE) displayed in a sol state with low viscosity in vitro. After subcutaneous injection, pregel solution underwent rapid-phase separation and gelation in situ thus forming a drug release depot. Pit was loaded within PSE (PSE-P), which achieved prolonged release profiles for 15 consecutive days in vitro. Correspondingly, the pharmacokinetic study in rats demonstrated that PSE-P achieved sustained in vivo release for 15 days after 1 subcutaneous injection. The pharmacodynamic study in hyperlipidemia rats further revealed that the levels of total cholesterol, total triglyceride, and low-density lipoprotein decreased remarkably, and the in vivo therapeutic effect was well maintained for over 20 days. Additionally, PSE-P showed mild tissue inflammatory responses and excellent degradability in vivo. Thus, in situ-forming PSE-P gel represents a viable and promising drug delivery platform to achieve long-term therapeutic effects in the management of hyperlipidemia.

Topics: Animals; Cholesterol; Delayed-Action Preparations; Drug Delivery Systems; Gels; Hyperlipidemias; Injections, Subcutaneous; Lipoproteins, LDL; Male; Quinolines; Rats; Rats, Sprague-Dawley; Triglycerides; Viscosity

We investigated the effects of co-administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor and angiotensin II type 1 receptor blocker (ARB) on nitric oxide (NO) bioavailability in genetically hyperlipidemic rabbits with our newly developed NO sensor. A total of 36 myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits equally derived (n=6 per group) were treated with 1) vehicle (control), 2) hydralazine (15 mg/kg/d), 3) the HMG-CoA reductase inhibitor pitavastatin (P: 0.5 mg/kg/d), 4) the ARB valsartan (V: 5 mg/kg/d), and 5) pitavastatin+valsartan (P+V) together without or 6) with N(G)-nitro-L-arginine methyl ester (L-NAME) for 8 weeks. After treatment, acetylcholine (ACh)-induced NO production was measured as a surrogate for endothelium protective function, and vascular peroxynitrite (a product of superoxide and NO) was measured for assessing dysfunctional endothelial NO synthase activity. Plaque area was quantified by histology as well as optical coherence tomography (OCT). Intra-aortic infusion of ACh produced an increase in plasma NO concentration, which was significantly greater with all drug treatments than with the control. P+V increased ACh-induced NO by 4.1 nmol/L significantly more than either P or V singly. The vascular peroxynitrite concentration was 1.6 pmol/mg protein in the control group and significantly less than those in the P- and V-monotherapy-groups. The lowest peroxynitrite concentration was observed in the P+V group (0.4 pmol/mg protein), which was significantly lower than those in the P- and the V-monotherapy-groups. OCT and histology of the thoracic aorta revealed that the plaque area decreased significantly more with the combination than with the monotherapy. In conclusion, the combined treatment with an HMG-CoA reductase inhibitor and an ARB may have additive protective effects on endothelial function as well as atherosclerotic change.

Topics: Acetylcholine; Angiotensin II Type 1 Receptor Blockers; Animals; Atherosclerosis; Biological Availability; Drug Therapy, Combination; Echocardiography; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Myocardial Infarction; Nitric Oxide; Quinolines; Rabbits; Reactive Oxygen Species; Tetrazoles; Tyrosine; Valine; Valsartan

The aim of this study was to determine whether pitavastatin may prevent the progression of atherosclerotic changes in hyperlipidemic patients. Seventy-five hyperlipidemic patients with and without type 2 diabetes were enrolled to receive pitavastatin 2 mg daily. Cell adhesion molecules (sCD40L, sP-selectin, sE-selectin, and sL-selectin), chemokines (MCP-1 and RANTES) and adiponectin were measured at baseline and after 3 and 6 months of pitavastatin treatment. Adiponectin levels prior to pitavastatin treatment in hyperlipidemic patients with and without diabetes were lower than levels in normolipidemic controls. Both total cholesterol and the LDL-cholesterol (LDL-C) decreased significantly after pitavastatin administration. Additionally, hyperlipidemic patients with type 2 diabetes exhibited a significant increase in adiponectin levels after pitavastatin treatment (before vs. 3 months, 6 months, 2.81+/-0.95 vs. 3.84+/-0.84 microg/ml (p<0.01), 4.61+/-1.15 mug/ml (p<0.001)). Furthermore, hyperlipidemic diabetics exhibited significant decreases in sE-selectin and sL-selectin levels after 6 months of pitavastatin treatment (sE-selectin, before vs. 6 months, 74+/-21 vs. 51+/-10 ng/ml, p<0.05; sL-selectin, before vs. 6 months, 896+/-141 vs. 814+/-129 ng/ml, p<0.05). In addition, adiponectin showed significant correlation with sE-selectin and sL-selectin in diabetic hyperlipidemia. However, MCP-1, RANTES and sCD40L did not exhibit any differences before or after pitavastatin administration. These results suggest that pitavastatin possesses an adiponectin-dependent anti-atherosclerotic effect in hyperlipidemic patients with type 2 diabetes in addition to its lowering effects on total cholesterol and LDL-C.

Topics: Adiponectin; Adult; Aged; CD40 Ligand; Cell Adhesion Molecules; Chemokine CCL5; Cholesterol, LDL; Diabetes Mellitus, Type 2; E-Selectin; Female; Glycated Hemoglobin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Male; Middle Aged; P-Selectin; Quinolines; Receptors, CCR2; Reference Values; Smoking

Independent of their lipid-lowering effects, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have renal protective effects on various models of progressive renal diseases, therefore, additional therapeutic advantages have been considered. In the present study, using spontaneously hypercholesterolaemic Imai rats, we examined the protective effects of pitavastatin on renal injuries and the oxidative modification of the low-density lipoprotein (LDL) and high-density lipoprotein (HDL), since oxidized lipoproteins are speculated to be involved in the mechanism of this rat strain's renal injuries.. Male Imai rats were treated with pitavastatin (n = 11) at a dose of 100 mg/kg diet or received no specific therapy as controls (n = 11) from 10 to 22 weeks of age. Body weight, urinary protein excretion and serum constituents were evaluated every 4 weeks. At the end of the study, the effects of pitavastatin on the susceptibility of serum LDL and HDL to oxidation, and renal histology were examined.. Pitavastatin treatment did not affect hyperlipidaemia, but significantly reduced proteinuria and preserved creatinine clearance deterioration. At the end of the study, lag times for LDL and HDL oxidation were prolonged by the treatment of pitavastatin to 126 and 153%, respectively, compared with the controlled group. The glomerulosclerosis index (SI) for untreated controlled rats was significantly higher than that for the pitavastatin-treated group. An immunohistochemistry study showed significantly lower numbers of ED-1 positive macrophages in the glomeruli and interstitium in pitavastatin-treated rats compared with those controlled.. Pitavastatin treatment prevented renal injuries in Imai rats independent of lipid-lowering effects. Prevention of oxidative modification of LDL and HDL may play an important role on the beneficial effects of pitavastatin treatment.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Blood Pressure; Blood Urea Nitrogen; Deoxyguanosine; Enzyme Inhibitors; Hypercholesterolemia; Hyperlipidemias; Kidney; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Macrophages; Oxygen; Quinolines; Rats

Recent lipid-lowering trials have reported that statin therapy may retard progression or stimulate regression of human coronary plaque. In the present study volumetric intravascular ultrasound (IVUS) analyses were performed to investigate the effect of pitavastatin, a newly developed statin, on regression of human coronary plaque.. Eighty-two patients matched for age and gender from 870 consecutive patients undergoing IVUS guided percutaneous coronary intervention were retrospectively assigned to either lipid-lowering therapy (n=41; pitavastatin 2 mg/day) or control group (n=41; diet only). Serial volumetric IVUS analyses of a matched left main coronary arterial site were performed. A significant reduction in low-density lipoprotein-cholesterol (LDL-C) level of 33.2% (p<0.001) was observed in the pitavastatin group. Plaque volume index (PVI) was significantly reduced in the pitavastatin group (10.6+/-9.4% decrease) compared with the control group (8.1+/-14.0% increase, p<0.001). There were positive correlations between the percent change in the PVI and follow-up LDL-C level (r=0.500, p<0.001) and the percent change in LDL-C level (r=0.479, p<0.001).. Lipid-lowering therapy with pitavastatin induced significant coronary plaque regression, associated with a significant reduction in the LDL-C level. The percent change in the PVI showed a significant positive correlation with the percent change in LDL-C level.

Topics: Aged; Angioplasty, Balloon, Coronary; Cholesterol, LDL; Coronary Artery Disease; Coronary Vessels; Data Interpretation, Statistical; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Male; Middle Aged; Quinolines; Retrospective Studies; Triglycerides; Ultrasonography, Interventional

Statins (HMG-CoA reductase inhibitors) are one of the most widely prescribed classes of drugs throughout the world, because of their excellent cholesterol-lowering effect and overall safety profile except for rare but fatal rhabdomyolysis arising either directly or indirectly by pharmacokinetic interactions with certain other drugs. As package inserts in pharmaceuticals are the primary source of information for health care providers, we carried out a literature search to examine how crucial information was provided in package inserts of five statins approved in Japan (simvastatin, atorvastatin, fluvastatin, pravastatin and pitavastatin).. A MEDLINE search from 1996 to June 2004 was carried out to identify studies on clinical pharmacokinetic drug interactions for the five statins. We mainly collected information on area under plasma concentration (AUC) following co-administration of statins with other drugs. The current package inserts used in Japan were obtained from the website of the Pharmaceutical and Medical Device Agency whereas USA package inserts were obtained from the Food and Drug Administration website.. The majority of package inserts listed the drugs that interacted with statins with most describing the risk of rhabdomyolysis because of the possibility of increases in blood concentration. However, quantitative information such as change in AUC was provided in only a few cases. Instructions for dosage adjustment are seldom provided in the Japanese package inserts. USA package inserts list almost identical drug interactions as the Japanese package inserts, although they contain more quantitative data, especially for typical cytochrome P450 (CYP) inhibitors.. All pharmacokinetic drug interactions including relevant quantitative data for potential effectors and details on mechanisms of interaction need to be given in package inserts as soon as the information becomes available, to ensure safe and proper use of the drugs concerned. Including such information in the package insert will be an extremely valuable aid for health care providers.

Topics: Area Under Curve; Atorvastatin; Biomedical Research; Databases, Bibliographic; Drug Interactions; Fatty Acids, Monounsaturated; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Indoles; Japan; Pharmacology, Clinical; Pravastatin; Product Labeling; Pyrroles; Quinolines; Simvastatin; United States; United States Food and Drug Administration

Inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase are antilipidemic agents (statins) widely used for the prevention of cardiovascular diseases. Recent studies have suggested that the overall benefits of statin therapy cannot be accounted for solely by its antilipidemic effect. To obtain further insight into the mechanism of action of statins, we studied the effect of pitavastatin on the generation of reactive oxygen species (ROS) by peritoneal polymorphonuclear leukocytes (PMN) obtained from control and hyperlipidemic guinea pigs. Flow cytometric analysis revealed that the amount of ROS generated by PMN from the hyperlipidemic animals that had been administered a laurate-containing diet (LD) for 4 weeks was larger than that from the normal diet (ND) group (837% increase, ND; 82.17 arbitrary units, LD; 688.10 arbitrary units, P < 0.01, n = 6). Administration of pitavastatin to the LD group significantly decreased plasma levels of total cholesterol (TC) and low-density lipoprotein (LDL) with a reduction in ROS generation by PMN (19% decrease, LD control; 688.10 arbitrary units, LD + pitavastatin; 556.87 arbitrary units, P < 0.01, n = 6). Western blotting analysis revealed that the expression of protein kinase C alpha (PKC alpha) and betaI was higher in PMN from the LD group than in PMN from the ND group (PKC alpha; 74% increase, PKC betaI; 339% increase, P < 0.05, n = 4, respectively). Furthermore, expression of NADPH oxidase gp91phox in PMN from the LD group was higher than that in PMN from the ND group (18% increase, P < 0.05, n = 4). By administration of pitavastatin to the LD group, the expression of PKC alpha, betaI and gp91phox was suppressed compared with the control LD group (PKC alpha; 41% decrease, PKC beta; 28% decrease, gp91phox; 56% decrease, P < 0.05, n = 4, respectively). These results indicate that PMN from hyperlipidemic animals is associated with an accelerated respiratory burst of ROS by increasing the expression of PKC alpha, betaI and gp91phox, and pitavastatin inhibits this by suppressing the expression of those proteins.

Topics: Animals; Blotting, Western; Enzyme Inhibitors; Guinea Pigs; Hydroxymethylglutaryl CoA Reductases; Hyperlipidemias; Lipids; Male; NADPH Oxidases; Neutrophils; Oxidative Stress; Peritoneal Cavity; Protein Kinase C; Quinolines; Reactive Oxygen Species

Since the rat is an atherosclerosis-resistant species, the study of atherosclerosis using rats is limited. The present study was undertaken to develop an atherosclerotic model in rats, to investigate the effect of nitric oxide (NO) inactivation and hyperlipidemia, and to evaluate the effect of pitavastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitor, on NO inactivation and on hyperlipidemia-induced changes in the cardiovascular system. Four-month-old male spontaneously hypertensive hyperlipidemic rats (SHHR) and Sprague-Dawley (SD) rats were used to study 1) the effect of the period of treatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 100 mg/L) on high fat diet (HFD)-treated SHHR and SD rats, and 2) the effect of pitavastatin (Pit, 0.3 mg/kg/day) on the changes in the aorta of L-NAME- and HFD-treated SHHR and SD rats. L-NAME administration for 1 month then HFD feeding for 2 months markedly increased the deposition of lipids and the thickness of the endothelium in SHHR. Continuous L-NAME treatment with HFD produced severe injury and stripped of endothelium in both strains. The plasma total cholesterol of L-NAME + HFD-treated and L-NAME + HFD + Pit-treated SHHR was significantly higher than that of control SHHR. Lipid deposition, however, was comparatively less in the aorta of L-NAME + HFD + Pit-treated SHHR. The concentration of cholesterol in the aorta of control SHHR was significantly lower than that in the aorta of L-NAME + HFD-treated SHHR, whereas that of L-NAME + HFD + Pit-treated SHHR was the same as that in control SHHR. These data indicated that Pit blocked lipid deposition in the aorta of L-NAME + HFD treated SHHR without changing plasma lipid profiles. In conclusion, NO inactivation and HFD induce lipid deposition in the endothelium, and the HMG-CoA reductase inhibitor blocks the deposition in SHHR.

Topics: Animals; Aorta; Arteriosclerosis; Cholesterol; Dietary Fats; Disease Models, Animal; Drug Therapy, Combination; Endothelium, Vascular; Enzyme Inhibitors; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypertension; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Quinolines; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley

This study investigated the effect of pitavastatin, a 3-hydroxy-3-methylglutaryl coenzyme A ( HMG-CoA ) reductase inhibitor with strong cholesterol-lowering activity, on the composition of atherosclerotic plaque. Pitavastatin ( 0.5mg/kg ) was administered to Watanabe heritable hyperlipidemic ( WHHL ) rabbits for 16 weeks, with the result that plasma total cholesterol ( TC ), very low density lipoprotein ( VLDL )-C, intermediate density lipoprotein ( IDL )-C and low density lipoprotein ( LDL )-C decreased by 28.6, 60.0, 42.3 and 21.7%, respectively. In the aorta, pitavastatin reduced the area of the lesion by 38.6%. In the pitavastatin group, the macrophage-positive area in the aortic plaque was reduced by 39.4%, and the areas occupied by collagen and a-smooth muscle actin ( alpha-SMA )-positive area increased by 66.4 and 91.7%, respectively. In the aortic arch, pitavastatin increased the average thickness of alpha-SMA in the plaque by 96.7% and reduced the vulnerability index by 76.0%. Furthermore, pitavastatin reduced the positive areas of monocyte chemoattractant protein ( MCP )-1, matrix metalloproteinase ( MMP )-3 and MMP-9 by 39.1, 40.6 and 52.3%, respectively. These results indicated that pitavastatin had an excellent lipid-lowering effect in WHHL rabbits, suppressing the progression of atherosclerosis and stabilizing atherosclerotic plaque.

Topics: Animals; Aorta; Arteriosclerosis; Chemokine CCL2; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Lipid Metabolism; Lipoproteins; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Quinolines; Rabbits

The triglyceride-lowering effect of pitavastatin, a potent 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, was investigated in a rat model of postprandial lipemia. Plasma triglyceride levels started to increase 4 h after the fat load, reached the maximum at 6 h and then gradually decreased. A single dose of pitavastatin (1 mg/kg) significantly suppressed chylomicron-triglyceride secretion into the lymph by 40% and delayed the elevation of plasma triglyceride. Pitavastatin at 1 mg/kg decreased the 6-h plasma triglyceride levels by 53% and at 0.5 mg/kg decreased the 0-12 h area under the curve (AUC) of triglyceride levels by 56%. Atorvastatin also caused decreases, but to a lesser extent. Pitavastatin, and atorvastatin to a lesser extent, reduced the activity of the intestinal microsomal triglyceride transfer protein (MTP) at 6 h. These results suggested that a single dose of pitavastatin lowered postprandial triglyceride levels in rats by decreasing chylomicron-triglyceride secretion, probably through a reduction of intestinal MTP activity and triglyceride droplet formation in the endoplasmic reticulum.

Topics: Animals; Chylomicrons; Hyperlipidemias; Male; Postprandial Period; Quinolines; Rats; Rats, Wistar; Triglycerides

Although benefits of statins have been demonstrated even in normolipidemic patients at high risk, the main target of statin therapy is the hypercholesterolemic patient. The aim of this study was to examine the hypocholesterolemic effect of NK-104 ((+)-monocalcium bis((3R,5S,6S)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]- 3,5-dihydroxy-6-heptenoate), CAS 147526-32-7), a potent 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, and its mechanism of action in hypercholesterolemic animals. In guinea pigs fed a diet containing 15% (w/w) fat rich in laurate for 6 weeks, the liver cholesterol content was markedly increased and plasma total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and LDL-apoB were elevated 4.8, 5.2 and 1.7 times, respectively, compared with normal diet fed animals. These changes were maintained by reduced LDL clearance in the presence of markedly cholesterol-enriched LDL in the plasma. In this model, the LDL-C reduction rates by 0.1, 0.3 and 1 mg/kg of NK-104 orally administered for 2 weeks (from week 4 to week 6), were 11, 27 and 32%, respectively, from controls, being similar in normal guinea pigs previously examined. Those for 3 and 10 mg/kg of atorvastatin (CAS 134523-00-5) were 25 and 39%, respectively. Thus about 10 times higher doses of atorvastatin were required than of NK-104 to cause a similar cholesterol-lowering effect. This reduction of plasma cholesterol was accompanied by an improvement of LDL clearance (24 and 47% increase in fractional catabolic rate by 1 mg/kg of NK-104 and 10 mg/kg of atorvastatin, respectively) and LDL composition. In conclusion, in guinea pig hypercholesterolemia caused by high-laurate diet, NK-104 and atorvastatin lowered plasma cholesterol levels with an improvement of LDL composition and with an increase in LDL clearance, presumably through reduction of the liver cholesterol content, although hepatic cholesterol synthesis might have been markedly suppressed in this model.

Topics: Animals; Anticholesteremic Agents; Atorvastatin; Diet; Guinea Pigs; Heptanoic Acids; Hydroxymethylglutaryl CoA Reductases; Hyperlipidemias; Lauric Acids; Lipids; Lipoproteins, LDL; Liver; Male; Pyrroles; Quinolines; Triglycerides

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

The hypolipidemic effect of NK-104 and its mechanisms of action (effects on hepatic sterol synthesis, low density lipoprotein (LDL)-receptor expression and very low density lipoprotein (VLDL) secretion) were studied in guinea pigs using simvastatin as a reference substance. There was a dose-dependent and significant reduction of both plasma total cholesterol (17.4, 24.5 and 45.3% at 0.3, 1 and 3 mg/kg, respectively) and triglycerides (21.1 and 32.2% at 1 and 3 mg/kg, respectively) after 14-day administration of NK-104. Simvastatin at 30 mg/kg lowered plasma total cholesterol (25.0%) but not triglyceride levels. NK-104 (3 mg/kg) and simvastatin (30 mg/kg) inhibited hepatic sterol synthesis by approximately 80%, 3 h after dosing, and enhanced LDL receptor binding-capacity of liver membranes 1.5-fold after 14-day dosing. The former group accelerated LDL clearance somewhat more markedly than the latter, and increased fractional catabolic rate 1.8-fold (vs. 1.4-fold). Furthermore, only the NK-104 (3 mg/kg) suppressed VLDL secretion into the liver perfusate (triglyceride. 19.9%; apoB, 24.2%) with extensive reduction of hepatic sterol synthesis caused by prolonged action. These results indicate that NK-104 and simvastatin at 10 times the dosage of the former, similarly enhances hepatic LDL receptor; however, only NK-104 with prolonged action suppresses VLDL secretion to show higher cholesterol-lowering potency and triglyceride-reducing effect.

Topics: Animals; Apolipoproteins B; Cholesterol; Chromatography, High Pressure Liquid; Disease Models, Animal; Electrophoresis, Polyacrylamide Gel; Guinea Pigs; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Lipoproteins, VLDL; Liver; Male; Quinolines; Receptors, LDL; Simvastatin; Sterols; Triglycerides