Pitavastatin ameliorates myocardial damage by preventing inflammation and collagen deposition via reduced free radical generation in isoproterenol-induced cardiomyopathy

Pitavastatin inhibits 3 hydroxy 3 methyl glutaryl coenzyme A (HMGCoA) reductase enzyme, preventing cholesterol synthesis along with elevating high density apolipoprotein A1 (Apo-A1). The present study was designed to evaluate cardioprotective potential of pitavastatin at 1 mg/kg/day and 3 mg/kg/day dose for 14 days in low dose isoproterenol (ISO) (5 mg/kg/day for 7 consecutive days) induced myocardial damage. ISO administration induced significant reduction in endogenous antioxidant enzymes like reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and raised thiobarbituric acid reactive substances (TBARS) indicating activated lipid peroxidation. Along with this, a significant increase in level of cardiac injury biomarkers vie, creatine kinase (CK-MB), lactate dehydrogenase (LDH), aspartate amino transferase (AST), tumor necrosis factor (TNF-α) and transforming growth factor (TGF-β) as well as brain natriuretic peptide (BNP). Histological examination also revealed marked myocardial tissue damage in ISO treated rats. However, pretreatment with pitavastatin (3 mg/kg/day) significantly maintained nearly normal levels of cardiac biomarkers and oxidant antioxidant status as well as lipid peroxidation in ISO induced MI rats. Cardiac histological assessment and infarct size assessment also showed marked reduction in myocardial architecture alteration including infarct size as well as collagen deposition by pitavastatin that strongly supported biochemical findings. These observations strongly corroborate that pitavastatin prevents myocardial damages via up regulation of endogenous oxidants along with its hypocholesterolemic activity.     

Atherosclerosis induced by chronic inhibition of the synthesis of nitric oxide in moderately hypercholesterolaemic rabbits is suppressed by pitavastatin

Background and purpose:

It is not clear if the new 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pitavastatin prevents atherogenesis by a direct effect. Statins have a cholesterol-lowering effect, so an accessible animal model of atherosclerosis showing only moderate hypercholesterolaemia as in humans, is needed. The effects of pitavastatin were evaluated on atherosclerotic lesions accumulating foam cells derived from macrophages, produced in rabbits with moderate hypercholesterolaemia by chronic inhibition of nitric oxide synthase (NOS).

Experimental approach:

White New Zealand rabbits were fed a 0.2% cholesterol diet with the NOS inhibitor N^ω-nitro-L-arginine methyl ester (L-NAME) in the same diet. Pitavastatin (0.1 and 0.3 mg·kg⁻¹) was given orally once a day for 8 weeks. The aortic arch and thoracic aorta were analysed by histochemistry and atherosclerotic lesions were quantified. The effect of pitavastatin on adhesion of THP-1 cells to endothelial cells, and cholesterol content in RAW264.7 cells incubated with oxidized or acetylated LDL were also investigated.

Key results:

Atherosclerotic lesions containing foam cells were induced in a model of atherosclerosis in rabbits with moderate hypercholesterolaemia by chronic inhibition of NOS. The area of atherosclerotic lesions was diminished by pitavastatin administration. The adhesion of THP-1 cells and cholesteryl ester content in RAW macrophages were decreased by pitavastatin treatment.

Conclusion:

Atherosclerosis induced by chronic inhibition of NOS in moderately hypercholesterolaemic rabbits was suppressed by pitavastatin via inhibition of macrophage accumulation and macrophage foam cell formation.     

Efficacy and Tolerability of Pitavastatin Versus Pitavastatin/Fenofibrate in High-risk Korean Patients with Mixed Dyslipidemia: A Multicenter,Randomized, Double-blinded,Parallel, Therapeutic Confirmatory Clinical Trial

PurposeDyslipidemia is an important risk factor for cardiovascular disease (CVD). Statins are known to effectively reduce not only low-density lipoprotein cholesterol (LDL-C) level but also death and nonfatal myocardial infarction due to coronary heart disease. The risk for CVD from atherogenic dyslipidemia persists when elevated triglyceride (TG) and reduced high-density lipoprotein cholesterol (HDL-C) levels are not controlled with statin therapy. Therefore, statin/fenofibrate combination therapy is more effective in reducing CVD risk. Here, we assessed the efficacy and tolerability of pitavastatin/fenofibrate combination therapy in patients with mixed dyslipidemia and a high risk for CVD.MethodsThis multicenter, randomized, double-blind, parallel-group, therapeutic-confirmatory clinical trial evaluated the efficacy and tolerability of fixed-dose combination therapy with pitavastatin/fenofibrate 2/160 mg in Korean patients with a high risk for CVD and a controlled LDL-C level (<100 mg/dL) and a TG level of 150–500 mg/dL after a run-in period with pitavastatin 2 mg alone. In the 8-week main study, 347 eligible patients were randomly assigned to receive pitavastatin 2 mg with or without fenofibrate 160 mg after a run-in period. In the extension study, patients with controlled LDL-C and non–HDL-C (<130 mg/dL) levels were included after the completion of the main study. All participants in the extension study received the pitavastatin/fenofibrate combination therapy for 16 weeks for the assessment of the tolerability of long-term treatment.FindingsThe difference in the mean percentage change in non–HDL-C from baseline to week 8 between the combination therapy and monotherapy groups was −12.45% (95% CI, −17.18 to −7.72), and the combination therapy was associated with a greater reduction in non-HDL-C. The changes in lipid profile, including apolipoproteins, fibrinogen, and high-sensitivity C-reactive protein from baseline to weeks 4 and 8 were statistically significant with combination therapy compared to monotherapy at all time points. Furthermore, the rates of achievement of non–HDL-C and apolipoprotein B targets at week 8 in the combination therapy and monotherapy groups were 88.30% versus 77.98% (P = 0.0110) and 78.94% versus 68.45% (P = 0.0021), respectively. The combination therapy was well tolerated, with a safety profile similar to that of statin monotherapy.ImplicationsIn these Korean patients with mixed dyslipidemia and a high risk for CVD, combination therapy with pitavastatin/fenofibrate was associated with a greater reduction in non–HDL-C compared with that with pitavastatin monotherapy, and a significantly improvement in other lipid levels. Moreover, the combination therapy was well tolerated, with a safety profile similar to that of statin monotherapy. Therefore, pitavastatin/fenofibrate combination therapy could be effective and well tolerated in patients with mixed dyslipidemia. ClinicalTrials.gov identifier: NCT03618797.     

Radiosynthesis of novel pitavastatin derivative ([18F]PTV‐F1) as a tracer for hepatic OATP using a one‐pot synthetic procedure

Pitavastatin is an antihyperlipidemic agent, a potent inhibitor of 3‐hydroxymethyl‐glutaryl‐CoA reductase, which is selectively taken up into the liver mainly via hepatic organic anion transporting polypeptide 1B1 (OATP1B1). OATP1B1 can accept a variety of organic anions, and previous reports indicated that it is responsible for the hepatic clearance of several clinically used anionic drugs. Therefore, the pharmacokinetics and the hepatic distribution of pitavastatin provide an insight into the function of OATP1B1 in humans. For the development of the in vivo evaluation of OATP1B1 function by positron emission tomography imaging, we designed a novel [¹⁸F]pitavastatin derivative ([¹⁸F]PTV‐F1), in which a [¹⁸F]fluoroethoxy group is substituted for the [¹⁸F]fluoro group of [¹⁸F]pitavastatin, with the aim of convenient radiolabeling protocol and high radiochemical yield. In vitro studies suggested that transport activities of PTV‐F1 mediated by OATP1B1 and OATP1B3 were very similar to those of pitavastatin and PTV‐F1 was metabolically stable in human liver microsomes. In the radiosynthesis of [¹⁸F]PTV‐F1 from the tosylate precursor, nucleophilic fluorination and subsequent deprotection were performed using a one‐pot procedure. [¹⁸F]PTV‐F1 was obtained with a radiochemical yield of 45% ± 3% (n = 3), and the operating time for the radiosynthesis of [¹⁸F]PTV‐F1 is very short (30 minutes) compared with [¹⁸F]pitavastatin.     

Comparison of the Lipid-Lowering Effects of Pitavastatin 4 mg Versus Pravastatin 40 mg in Adults With Primary Hyperlipidemia or Mixed (Combined) Dyslipidemia: A Phase IV,Prospective, US,Multicenter, Randomized,Double-blind,Superiority Trial

Purpose

Results from a Phase III, European, noninferiority 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.

Methods

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.

Findings

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/m²) 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.

Implications

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.     

Pitavastatin attenuates AGEs-induced mitophagy via inhibition of ROS generation in the mitochondria of cardiomyocytes

This study aimed to investigate whether pitavastatin protected against injury induced by advanced glycation end products products (AGEs) in neonatal rat cardiomyocytes, and to examine the underlying mechanisms. Cardiomyocytes of neonatal rats were incubated for 48 hours with AGEs (100 mg/mL), receptor for advanced glycation end products (RAGE), antibody (1 mg/mL) and pitavastatin (600 ng/mL). The levels of p62 and beclin1 were determined by Western blotting. Mitochondrial membrane potential (DYm) and the generation of reactive oxygen species (ROS) were measured through the JC-1 and DCFH-DA. In the AGEs group, the expression of beclin1 was remarkably increased compared to the control group, while the expression of p62 was significantly decreased. AGEs also markedly decreased DYm and significantly increased ROS compared with the control group. After treatment with RAGE antibody or pitavastatin, the level of beclin1 was markedly decreased compared with the AGEs group, but the level of p62 was remarkably increased. In the AGEs + RAGE antibody group and AGEs + pitavastatin group, DYm was significantly increased and ROS was remarkably decreased compared with the AGEs group. In conclusion, AGEs-RAGE may induce autophagy of cardiomyocytes by generation of ROS and pitavastatin could protect against AGEs-induced injury against cardiomyocytes.     

OATP1B1 388A>G polymorphism and pharmacokinetics of pitavastatin in Chinese healthy volunteers

Purpose: To investigate the contribution of the most frequent single nucleotide polymorphism (SNPs) of the organic anion transporting polypeptide 1B1 (OATP1B1) 388A>G to the pharmacokinetics of pitavastatin in Chinese healthy volunteers. Methods: Eighteen healthy volunteers participated in this study. Group 1 consisted of nine subjects who were of 388AA wild‐type OATP1B1 genotype. Group 2 consisted of seven subjects with the 388GA genotype and two 388GG homozygotes. Two milligram of pitavastatin was administered orally to the volunteers. The plasma concentration of pitavastatin was measured for up to 48 h by liquid chromatography–mass spectrometry (LC–MS). Results: The pharmacokinetic parameters of pitavastatin were significantly different between the two genotyped groups. The concentration (C_max) value was higher in the 388GA + 388GG group than that in the 388AA group (39·22 ± 8·45 vs. 22·90 ± 4·03 ng/mL, P = 0·006). The area under the curve to the last measurable concentration (AUC_0–48) and area under the curve extrapolated to infinity (AUC_0–∞) of pitavastatin were lower in the 388AA group than in the 388GA + 388GG group (100·42 ± 21·19 vs. 182·19 ± 86·46 ng h/mL, P = 0·024; 108·12 ± 24·94 vs. 199·64 ± 98·70ng h/mL, P = 0·026) respectively. The oral clearance (Cl/F) was lower in the 388GA + 388GG group than that in the 388AA group (12·46 ± 4·79 vs. 19·21 ± 3·74/h, P = 0·012). The elimination of half‐life (t_1/2) and peak concentration times (T_max) values showed no difference between these groups. Conclusions: The OATP 388A>G polymorphism causes significant alterations in the pharmacokinetics of pitavastatin in healthy Chinese volunteers and this may well be clinically significant.