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Discovering effective anti-cancer agents poses a formidable challenge given the limited efficacy of current therapeutic modalities against various cancer types due to intrinsic resistance mechanisms. Cancer immunochemotherapy is an alternative strategy for breast cancer treatment and overcoming cancer resistance. Human Indoleamine 2,3-dioxygenase (hIDO1) and human Tryptophan 2,3-dioxygenase 2 (hTDO2) play pivotal roles in tryptophan metabolism, leading to the generation of kynurenine and other bioactive metabolites. This process facilitates the de novo synthesis of Nicotinamide Dinucleotide (NAD), promoting cancer resistance. This study identified a new dual hIDO1/hTDO2 inhibitor using a drug repurposing strategy of FDA-approved drugs. Herein, we delineate the development of a ligand-based pharmacophore model based on a training set of 12 compounds with reported hIDO1/hTDO2 inhibitory activity. We conducted a pharmacophore search followed by high-throughput virtual screening of 2568 FDA-approved drugs against both enzymes, resulting in ten hits, four of them with high potential of dual inhibitory activity. For further in silico and in vitro biological investigation, the anti-hypercholesterolemic drug Pitavastatin deemed the drug of choice in this study. Molecular dynamics (MD) simulations demonstrated that Pitavastatin forms stable complexes with both hIDO1 and hTDO2 receptors, providing a structural basis for its potential therapeutic efficacy. At nanomolar (nM) concentration, it exhibited remarkable in vitro enzyme inhibitory activity against both examined enzymes. Additionally, Pitavastatin demonstrated potent cytotoxic activity against BT-549, MCF-7, and HepG2 cell lines (IC50 = 16.82, 9.52, and 1.84 µM, respectively). Its anticancer activity was primarily due to the induction of G1/S phase arrest as discovered through cell cycle analysis of HepG2 cancer cells. Ultimately, treating HepG2 cancer cells with Pitavastatin affected significant activation of caspase-3 accompanied by down-regulation of cellular apoptotic biomarkers such as IDO, TDO, STAT3, P21, P27, IL-6, and AhR. [ABSTRACT FROM AUTHOR]

Background: The use of statins as a prophylactic drug for ischemic damage in flap surgery has been suggested in recent years, due to their pleiotropic effects. Among the statins, pitavastatin has greater activity and fewer side effects than other forms. In this study, we have analyzed the effect of pitavastatin on the distal ischemic damage of the flaps in a rat flap model. Methods: An experimental study was carried out with 2 groups of 12 Wistar rats. A dorsal McFarlane flap was used in both groups. The first group was given a placebo for 7 days after the intervention while the second group was given the placebo mixed with pitavastatin at a dose of 5 mg/kg per day. At the end of these 7 days, the rats were sacrificed and the necrotic area of each flap was evaluated, as well as the degree of histological damage under microscopy. Results: All 24 rats survived to the end of the study. The control group presented an average necrosis area of 22.77 cm2, compared to 8.14 cm2 in the treatment group. Regarding histological damage, the control group presented an average score of 23.91 points, compared to 15.08 points in the treatment group. We found statistically significant differences in favor of the treatment group for both variables. Conclusions: Our study shows a significant prophylactic effect of pitavastatin over distal ischemia damage on a rat flap model. Therefore, said drug may be useful in planning large flaps. Despite this, new studies in humans are necessary. Level of evidence: Not ratable [ABSTRACT FROM AUTHOR]

Pitavastatin, a potent 3-hydroxymethylglutaryl coenzyme A reductase inhibitor, is indicated for the treatment of hypercholesterolemia and mixed dyslipidemia. Hepatic uptake of pitavastatin is predominantly occupied by the organic anion transporting polypeptide 1B1 (OATP1B1) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene, which is a polymorphic gene that encodes OATP1B1. SLCO1B1 genetic polymorphism significantly alters the pharmacokinetics of pitavastatin. This study aimed to establish the physiologically based pharmacokinetic (PBPK) model to predict pitavastatin pharmacokinetics according to SLCO1B1 genetic polymorphism. PK-Sim® version 10.0 was used to establish the whole-body PBPK model of pitavastatin. Our pharmacogenomic data and a total of 27 clinical pharmacokinetic data with different dose administration and demographic properties were used to develop and validate the model, respectively. Physicochemical properties and disposition characteristics of pitavastatin were acquired from previously reported data or optimized to capture the plasma concentration–time profiles in different SLCO1B1 diplotypes. Model evaluation was performed by comparing the predicted pharmacokinetic parameters and profiles to the observed data. Predicted plasma concentration–time profiles were visually similar to the observed profiles in the non-genotyped populations and different SLCO1B1 diplotypes. All fold error values for AUC and Cmax were included in the two fold range of observed values. Thus, the PBPK model of pitavastatin in different SLCO1B1 diplotypes was properly established. The present study can be useful to individualize the dose administration strategy of pitavastatin in individuals with various ages, races, and SLCO1B1 diplotypes. [ABSTRACT FROM AUTHOR]

Lung cancer is the most common cause of cancer-related deaths worldwide and is caused by multiple factors, including high-fat diet (HFD). CD36, a fatty acid receptor, is closely associated with metabolism-related diseases, including cardiovascular disease and cancer. However, the role of CD36 in HFD-accelerated non-small-cell lung cancer (NSCLC) is unclear. In vivo, we fed C57BL/6J wild-type (WT) and CD36 knockout (CD36−/−) mice normal chow or HFD in the presence or absence of pitavastatin 2 weeks before subcutaneous injection of LLC1 cells. In vitro, A549 and NCI-H520 cells were treated with free fatty acids (FFAs) to mimic HFD situation for exploration the underlying mechanisms. We found that HFD promoted LLC1 tumor growth in vivo and that FFAs increased cell proliferation and migration in A549 and NCI-H520 cells. The enhanced cell or tumor growth was inhibited by the lipid-lowering agent pitavastatin, which reduced lipid accumulation. More importantly, we found that plasma soluble CD36 (sCD36) levels were higher in NSCLC patients than those in healthy ones. Compared to that in WT mice, the proliferation of LLC1 cells in CD36−/− mice was largely suppressed, which was further repressed by pitavastatin in HFD group. At the molecular level, we found that CD36 inhibition, either with pitavastatin or plasmid, reduced proliferation- and migration-related protein expression through the AKT/mTOR pathway. Taken together, we demonstrate that inhibition of CD36 expression by pitavastatin or other inhibitors may be a viable strategy for NSCLC treatment. 1) Pitavastatin reduces NSCLC progression by inhibiting CD36. 2) Inhibition of CD36 can improve HFD- or FFA-induced NSCLC. 3) AKT/mTOR pathway is involved in CD36-regulated NSCLC. 4) Inhibition of CD36 by pitavastatin or other inhibitors may be a strategy for NSCLC treatment. [ABSTRACT FROM AUTHOR]

To select a drug candidate for clinical development, accurately and promptly predicting human pharmacokinetic (PK) profiles, assessing drug-drug interactions (DDIs), and anticipating potential PK variations in disease populations are crucial steps in drug discovery. The complexity of predicting human PK significantly increases when hepatic transporters are involved in drug clearance (CL) and volume of distribution (Vss). A strategic framework is developed here, utilizing pitavastatin as an example. The framework includes the construction of a monkey physiologically-based PK (PBPK) model, model calibration to obtain scaling factors (SF) of in vitro-in vivo extrapolation (IVIVE) for various clearance parameters, human model development and validation, and assessment of DDIs and PK variations in disease populations. Through incorporating in vitro human parameters and calibrated SFs from the monkey model of 3.45, 0.14, and 1.17 for CLint,active, CLint,passive, and CLint,bile, respectively, and together with the relative fraction transported by individual transporters obtained from in vitro studies and the optimized Ki values for OATP inhibition, the model reasonably captured observed pitavastatin PK profiles, DDIs and PK variations in human subjects carrying genetic polymorphisms, i.e., AUC within 20%. Lastly, when applying the functional reduction based on measured OATP1B biomarkers, the model adequately predicted PK changes in the hepatic impairment population. The present study presents a strategic framework for early-stage drug development, enabling the prediction of PK profiles and assessment of PK variations in scenarios like DDIs, genetic polymorphism, and hepatic impairment-related disease states, specifically focusing on OATP substrates. [ABSTRACT FROM AUTHOR]

The interaction between α casein (α-CN) and two drugs, fluvastatin (FLU) and pitavastatin (PIT) was investigated using fluorescence, UV absorption and FTIR. In addition, the binding site was established by applying molecular modeling technique. Fluorescence data suggested that FLU and PIT quench the intrinsic fluorescence of α-CN. The binding constants for the interaction of FLU and PIT with α-CN were found to be (8.18±0.08)·104 M–1 and (9.04±0.07)·104 M–1, respectively, indicating that the binding affinity of PIT to α-CN was higher than that for FLU. The number of binding site FLU and PIT per α-CN were 1.06 and 1.04 respectively. Docking calculation showed the probable binding sites of FLU and PIT are located in the hydrophobic core of α-CN where the FLU and PIT are lined by hydrophobic residues and make three and four hydrogen bonds with FLU and PIT respectively. Simulation, molecular docking and experimental data reciprocally supported each other. Therefore, it can be concluded that α-CN can act as a carrier of FLU and PIT drugs. [ABSTRACT FROM AUTHOR]

Stains remain the first therapeutic approach in patients with dyslipidemia to control plasma lipids levels and cardiovascular risk. Multiple clinical trials have demonstrated the benefits of statins in reducing major cardiovascular adverse events in primary and secondary prevention. Moreover, in patients with coronary artery disease, statins decrease coronary atherosclerotic plaque volume and composition, inducing atheroma stabilization. Pitavastatin, is a new-generation lipophilic statin, indicated for the treatment of dyslipidemia and prevention of cardiovascular diseases. The purpose of this review, the first at our knowledge on this topic, is to summarize and examine the current knowledge about the effectiveness of pitavastatin in patients with coronary artery disease. The available data suggest that pitavastatin significantly, lowers the rate of adverse cardiovascular events, in patients at a high risk of atherosclerotic disease, with stable angina pectoris or with acute coronary syndrome. Moreover intravascular ultrasound have shown that pitavastatin induces favorable changes in plaque morphology, increasing the fibrous cap thickness, and decreasing both plaque and lipid volume indexes. Globally the efficacy of pitavastatin is greater or similar to other statins. [ABSTRACT FROM AUTHOR]

Statins play a major role in reducing circulating cholesterol levels and are widely used to prevent coronary artery disease. Although they are recently confirmed to up-regulate mitophagy, little is known about the molecular mechanisms and its effect on endothelial progenitor cell (EPC). Here, we explore the role and mechanism underlying statin (pitavastatin, PTV)-activated mitophagy in EPC proliferation. ApoE−/− mice are fed a high-fat diet for 8 weeks to induce atherosclerosis. In these mice, EPC proliferation decreases and is accompanied by mitochondrial dysfunction and mitophagy impairment via the PINK1-PARK2 pathway. PTV reverses mitophagy and reduction in proliferation. Pink1 knockout or silencing Atg7 blocks PTV-induced proliferation improvement, suggesting that mitophagy contributes to the EPC proliferation increase. PTV elicits mitochondrial calcium release into the cytoplasm and further phosphorylates CAMK1. Phosphorylated CAMK1 contributes to PINK1 phosphorylation as well as mitophagy and mitochondrial function recover in EPCs. Together, our findings describe a molecular mechanism of mitophagy activation, where mitochondrial calcium release promotes CAMK1 phosphorylation of threonine177 before phosphorylation of PINK1 at serine228, which recruits PARK2 and phosphorylates its serine65 to activate mitophagy. Our results further account for the pleiotropic effects of statins on the cardiovascular system and provide a promising and potential therapeutic target for atherosclerosis. Endothelial progenitor cell (EPCs) proliferation decreased, accompanied by mitochondrial dysfunction and mitophagy impairment via the PINK1-PARK2 pathway in atherosclerosis. Statins induce mitophagy to protect EPCs by mitochondrial calcium release and CAMK1-mediated PINK1 phosphorylation. [ABSTRACT FROM AUTHOR]

We developed a simple, rapid, ecological RP-HPLC method for the estimation of Pitavastatin (PIT), Fenofibrate (FEN), and their impurities in a novel fixed dose combination. We achieved an efficient chromatographic separation in gradient elution mode using Hypersil BDS C18 (100 × 4.6 mm, 3.0 μm) column. The mobile phase A consisted of 0.1% glacial acetic acid buffer and mobile phase B consisted of ethanol and the flow rate was 1.7 mL per minute. We monitored the chromatogram at 250 nm detection wavelength and the column thermostat at 35 °C. The observed resolution for PIT, FEN, and 12 impurities is more than 1.5 for any pair of compounds. The proposed method was validated as per the ICH guidelines for precision, specificity, accuracy, linearity, robustness, ruggedness and it is efficient in estimating PIT, FEN, and their impurities in the same run. The drug product was subjected to various stress degradation conditions and observed a significant amount of degradation in hydrolytic and thermal degradation study. We estimated the method greenness using different Green Analytical Chemistry (GAC) metrics such as Analytical Eco-scale, scoring of hazardous values, Analytical Method Volume Intensity (AMVI), Environmental Assessment Tool (EAT), solvent selection guide approach, and Eco-solvent approach. [ABSTRACT FROM AUTHOR]

Background: Excessive angiogenesis of the retina is a key component of irreversible causes of blindness in many ocular diseases. Pitavastatin is a cholesterol-lowering drug used to reduce the risk of cardiovascular diseases. Various studies have shown the effects of pitavastatin on angiogenesis but the conclusions are contradictory. The effects of pitavastatin on retinal angiogenesis have not been revealed. This study investigated the effects of pitavastatin at clinically relevant concentrations on retinal angiogenesis and its underlying mechanisms using retinal microvascular endothelial cells (RMECs). Methods: The effects of pitavastatin on retinal angiogenesis were determined using in vitro model of retinal angiogenesis, endothelial cell migration, adhesion, proliferation, and apoptosis assays. The mechanism studies were conducted using immunoblotting and stress fiber staining. Results: Pitavastatin stimulated capillary network formation of RMECs in a similar manner as vascular endothelial growth factor (VEGF) and lipopolysaccharide (LPS). Pitavastatin also increased RMEC migration, adhesion to Matrigel, growth, and survival. The combination of pitavastatin with VEGF or LPS was more effective than VEGF or LPS alone in stimulating biological activities of RMECs, suggesting that pitavastatin can enhance the stimulatory effects of VEGF and LPS on retinal angiogenesis. Pitavastatin acted on RMECs in a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase-independent manner. In contrast, pitavastatin activated pro-angiogenic microenvironment via promoting the secretion of VEGF and stimulated retinal angiogenesis via multiple mechanisms including activation of RhoA-mediated pathways, induction of focal adhesion complex formation, and activation of ERK pathway. Conclusion: Our work provides a preclinical evidence on the pro-angiogenic effect of pitavastatin in retina via multiple mechanisms that are irrelevant to mevalonate pathway. [ABSTRACT FROM AUTHOR]

Background: Many people infected with hepatitis C virus have comorbidities, including hypercholesterolemia, that are treated with statins. In this study, we evaluated the drug–drug interaction potential of the hepatitis C virus inhibitors elbasvir (EBR) and grazoprevir (GZR) with statins. Pitavastatin, rosuvastatin, pravastatin, and atorvastatin are substrates of organic anion-transporting polypeptide 1B, whereas rosuvastatin and atorvastatin are also breast cancer resistance protein substrates. Methods: Three open-label, phase I clinical trials in healthy adults were conducted with multiple daily doses of oral GZR or EBR/GZR and single oral doses of statins. Trial 1: GZR 200 mg plus pitavastatin 10 mg. Trial 2: Part 1, GZR 200 mg plus rosuvastatin 10 mg, then EBR 50 mg/GZR 200 mg plus rosuvastatin 10 mg; Part 2, EBR 50 mg/GZR 200 mg plus pravastatin 40 mg. Trial 3: EBR 50 mg/GZR 200 mg plus atorvastatin 10 mg. Results: Neither GZR nor EBR pharmacokinetics were meaningfully affected by statins. Coadministration of EBR/GZR did not result in clinically relevant changes in the exposure of pitavastatin or pravastatin. However, EBR/GZR increased exposure to rosuvastatin (126%) and atorvastatin (94%). Coadministration of statins plus GZR or EBR/GZR was generally well tolerated. Conclusions: Although statins do not appreciably affect EBR or GZR pharmacokinetics, EBR/GZR can impact the pharmacokinetics of certain statins, likely via inhibition of breast cancer resistance protein but not organic anion-transporting polypeptide 1B. Coadministration of EBR/GZR with pitavastatin or pravastatin does not require adjustment of either dose of statin, whereas the dose of rosuvastatin and atorvastatin should be decreased when coadministered with EBR/GZR. [ABSTRACT FROM AUTHOR]

The limited number of antifungals and the rising frequency of azole-resistant Candida species are growing challenges to human medicine. Drug repurposing signifies an appealing approach to enhance the activity of current antifungal drugs. Here, we evaluated the ability of Pharmakon 1600 drug library to sensitize an azole-resistant Candida albicans to the effect of fluconazole. The primary screen revealed 44 non-antifungal hits were able to act synergistically with fluconazole against the test strain. Of note, 21 compounds, showed aptness for systemic administration and limited toxic effects, were considered as potential fluconazole adjuvants and thus were termed as "repositionable hits". A follow-up analysis revealed pitavastatin displaying the most potent fluconazole chemosensitizing activity against the test strain (ΣFICI 0.05) and thus was further evaluated against 18 isolates of C. albicans (n = 9), C. glabrata (n = 4), and C. auris (n = 5). Pitavastatin displayed broad-spectrum synergistic interactions with both fluconazole and voriconazole against ~89% of the tested strains (ΣFICI 0.05–0.5). Additionally, the pitavastatin-fluconazole combination significantly reduced the biofilm-forming abilities of the tested Candida species by up to 73%, and successfully reduced the fungal burdens in a Caenorhabditis elegans infection model by up to 96%. This study presents pitavastatin as a potent azole chemosensitizing agent that warrant further investigation. [ABSTRACT FROM AUTHOR]

This document is a retraction note from the journal Acta Neurochirurgica. The article in question, titled "Preconditioning with pitavastatin, an HMG-CoA reductase inhibitor, attenuates C-Jun N-terminal kinase activation in experimental subarachnoid hemorrhage-induced apoptosis," has been retracted by the Editor-in-Chief due to concerns about the data presented in the figures. The retraction note outlines specific similarities and inconsistencies in the figures and data, and states that the Editor-in-Chief no longer has confidence in the presented data. The authors have not responded to any correspondence from the publisher regarding this retraction. [Extracted from the article]

Current ACC/AHA guidelines recommend high-dose statin therapy after coronary stenting, especially in diabetic patients; however, pitavastatin 4 mg or pitavastatin 1 mg are frequently used after coronary stenting in Asia, even in patients with acute coronary syndrome. We compared the effects of highest-dose and lowest-dose pitavastatin therapy on coronary neointimal hyperplasia at 12-month follow-up in diabetic patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) using optical coherence tomography. A total of 72 diabetic patients with NSTE-ACS were randomized to lowest-dose pitavastatin [1 mg (n = 36)] or highest-dose pitavastatin [4 mg (n = 36)] after everolimus-eluting stent implantation. The primary endpoint was to compare the normalized neointimal volume at 12-month follow-up. Normalized neointimal volume was significantly lower in the pitavastatin 4 mg group (4.00 ± 2.80 vs. 8.24 ± 2.83 mm3/mm, p < 0.01) at 12-month follow-up. There was also significant difference in neointimal area between the pitavastatin 4 mg group and pitavastatin 1 mg group (0.41 ± 0.28 vs. 0.74 ± 0.23 mm2, p < 0.01). Improvement of brachial artery flow-mediated dilation (baFMD) was significantly higher in the pitavastatin 4 mg group than in pitavastatin 1 mg group (0.15 ± 0.15 vs. − 0.03 ± 0.19 mm, p < 0.001). In addition, the improvement of adiponectin levels was significantly greater in the pitavastatin 4 mg group than in the pitavastatin 1 mg group (2.97 ± 3.98 vs. 0.59 ± 2.80 μg/mL, p < 0.05). Pitavastatin 4 mg significantly improved inflammatory cytokines and lipid profiles compared to pitavastatin 1 mg during the 12-month follow-up, contributing to the reduction of neointimal hyperplasia and to the improvement of baFMD in diabetic patients with NSTE-ACS requiring coronary stenting. Thus, the administration of pitavastatin 4 mg can be safely and effectively used in high-risk patients requiring coronary stenting. Trial registration NCT02545231 (Clinical Trial registration information: https://clinicaltrials.gov/ct2/show/NCT02545231) [ABSTRACT FROM AUTHOR]

Background: Hypertension and dyslipidemia are major risk factors for cardiovascular disease (CVD). In 2012, over 270 million patients (25.2%) in China were hypertensive and 40.4% was dyslipidemic. The majority of these patients rely on statins for the prevention of cardiovascular disease. However, certain types of statins (e.g., atorvastatin), compared to others (e.g., pitavastatin), may be associated with unfavorable effects on glucose metabolism. This leads to concerns when prescribing statins to patients who also have a predisposition to glucose metabolic disorders (i.e., prediabetes). Thus, this study aims to investigate the effect of pitavastatin, compared to atorvastatin, on glucose metabolism, as measured by hemoglobin A1c (HbA1c), in Chinese prediabetics with hypertension and dyslipidemias.Methods: The China hemoglobin A1c Metabolism Protection Union Study (CAMPUS) is a multi-center, prospective, open-label, 12-month, two-arm parallel group, and non-inferiority randomized controlled trial (RCT). A total of 396 prediabetics with hypertension and dyslipidemias will be randomly assigned 1:1 to either pitavastatin 2 mg/day or atorvastatin 20 mg/day, and followed for 12 months (follow-up visits at 1, 3, 6, and 12 months) for HbA1c levels, as well as other measures of glucose metabolism, serum lipid levels, blood pressure control, measures of inflammation, vascular endothelial function, carotid atherosclerosis, and hypertension-related left ventricular hypertrophy. If the results of low-density lipoprotein cholesterol (LDL-C) levels in month 3 after treatment initiation do not meet individual target, drug dose for the participant would be doubled.Discussion: CAMPUS will be the first RCT to investigate the effect of pitavastatin, compared to atorvastatin, on glucose metabolism in Chinese prediabetics with hypertension and dyslipidemias. Further, this study might eventually provide information to design a clinical strategy, and facilitate the improvement of primary prevention in patients at risk for diabetes and CVD.Trial Registration: ClinicalTrials.gov number: NCT03532620. Registered 22 May 2018 [ABSTRACT FROM AUTHOR]

Objectives: Medical therapy for patients with uncomplicated acute type B aortic dissection (ABAD) is essentially accepted for its excellent early outcome; however, long-term outcomes have not been satisfactory due to aorta-related complications. This trial was performed to investigate the efficacy of a statin as an additive that may enhance the effectiveness of conventional medical treatment in patients with ABAD.Methods: This was a multi-center, prospective, and randomized comparative investigation of patients with uncomplicated ABAD. Fifty patients with ABAD compatible with inclusion criteria were randomly assigned to two groups and then received administration of pitavastatin (group P) or not (group C). We followed up the patients for 1 year from study onset.Results: Two patients demised during the follow-up period (both were in group C). In addition, aorta-related interventions were performed in two patients (entry closure for aortic dissection by endovascular repair in one patient in each group). Aortic arch diameters at 1 year in group P tended to be smaller than in group C (P = 0.17), and the rate of change of the aortic arch diameters from onset to 1 year was significantly lower in group P (P = 0.046). Multivariate analysis identified patency of the false lumen was detected as a risk factor for aortic arch dilatation (P = 0.02), and pitavastatin intake was a negative risk factor (P = 0.03).Conclusions: Pitavastatin treatment, in addition to the standard antihypertensive therapy, may have a suppressive effect on aortic arch dilatation in patients with ABAD. [ABSTRACT FROM AUTHOR]

Background: Accumulating results have disclosed that early brain injury (EBI) may play a major role in the determination of the outcome of aneurysmal subarachnoid hemorrhage (SAH) patients. This study is of interest to examine the efficacy of pitavastatin, a 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) inhibitor, on SAH-induced apoptosis. Methods: A rodent double SAH model was employed. Pitavastatin was administered orally. CSF IL-1β, IL-6, IL-8 and TNF-α were measured (rt-PCR). Basilar arteries were harvested for C-Jun N-terminal kinase p46/p55 (cJNK (p46/p55)), matrix metallopeptidase-9 (MMP-9) (Western blot), caspase and Bcl-2 (rt-PCR) evaluation. Results: Pitavastatin reduced the bioexpression of cJNK p55 compared with the SAH groups. Cleaved caspase-9a was significantly reduced in the pitavastatin-preconditioned group compared with the SAH group ( p > 0.05). IL-1β and TNF-α levels were reduced in the pitavastatin-preconditioned group. Pretreatment with pitavastatin significantly reduced activated MMP-9, capsase-9a and B-cell lymphoma 2(Bcl) mRNA. Conclusion: Preconditioning with pitavastatin exerts its neuroprotective effect through the dual action of inhibiting cJNK(p46/p55) activation and reducing cleaved caspase-9a expression. Besides, the bioinhibition of MMP-9 may partially contribute to the neuroprotective effect. This study lends credence to the theory that statins, especially in the preconditioning status, may attenuate SAH-induced neuron apoptosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This study aimed to clarify the relationships between arterial remodeling patterns and plaque volume regression or stabilization. The TOGETHAR trial is a prospective open-label trial designed to assess coronary plaque regression and stabilization with multiple plaque imaging modalities following 52 weeks of pitavastatin treatment (2 mg/day). Coronary plaques were observed in 46 patients with both angioscopy and intravascular ultrasound at baseline and after 52 weeks of drug treatment. We divided these patients into three groups according to their remodeling indices (RI). Group P consisted of patients with a baseline RI >1.05, Group M of patients with a baseline RI of 0.95-1.05, and Group N of patients with a baseline RI <0.95 and then evaluated differences in coronary plaque volume changes and yellow grade among the three groups. In the positive remodeling group, whose remodeling index (RI) exceeded 1.05 at baseline, RI and percent atheroma volume (PAV) were significantly reduced (RI 1.14 ± 0.07 to 1.05 ± 0.10, p = 0.010, PAV 47.3 ± 8.3 to 45.3 ± 7.3 mm, p = 0.048). There was no relationship between baseline RI and the change in yellow grade of plaque. RI increased without significant change of PAV or a decrease in lumen volume in group N, with RI below 0.95 at baseline. Plaques with positive remodeling were more likely to have plaque volume regression by pitavastatin than those without in patients with coronary artery disease. Moreover, plaques with positive and negative remodeling were changed into those with intermediate remodeling by pitavastatin. Pitavastatin might induce not only plaque regression or stabilization, but also conformational normalization of vessel structure. [ABSTRACT FROM AUTHOR]

Purpose: Periprocedural ischemic stroke is one problem associated with carotid artery stenting (CAS). This study was designed to assess whether preoperative statin therapy reduces the risk of periprocedural ischemic complications with CAS. Methods: In this prospective study at 11 centers, patients with carotid artery stenosis (symptomatic ≥50 %, asymptomatic ≥80 %) and a high risk of carotid endarterectomy but without previous statin treatments were divided into two groups by low-density lipoprotein cholesterol (LDL-C) levels. With LDL-C ≥120 mg/dl, the pitavastatin-treated (PS) group received pitavastatin at 4 mg/day. With LDL-C <120 mg/dl, the non-PS group received no statin therapy. After 4 weeks, both groups underwent CAS. Frequencies of new ipsilateral ischemic lesions on diffusion-weighted imaging within 72 h after CAS and cerebrovascular events (transient ischemic attack, stroke, or death) within 30 days were assessed. Results: Among the 80 patients enrolled, 61 patients (PS group, n = 31; non-PS group, n = 30) fulfilled the inclusion criteria. New ipsilateral ischemic lesions were identified in 8 of 31 patients (25.8 %) in the PS group and 16 of 30 patients (53.3 %) in the non-PS group ( P = 0.028). Cerebrovascular events occurred in 0 patients in the PS group and in 3 of 30 patients (10.0 %) in the non-PS group ( P = 0.071). Multivariate analyses demonstrated the pitavastatin treatment ( β = 0.74, 95 % confidence interval 0.070-1.48, P = 0.042) to be an independent factor for decreasing post-CAS ischemic lesions. Conclusion: Pretreatment with pitavastatin significantly reduced the frequency of periprocedural ischemic complications with CAS. [ABSTRACT FROM AUTHOR]

Purpose: As an inhibitor of HMG-CoA reductase that catalyses the first step of cholesterol synthesis, pitavastatin undergoes little hepatic metabolism; however, it is a substrate of uptake and efflux transporters. Since pitavastatin is potentially co-administered with agents that affect transporter activities, the pharmacokinetics of pitavastatin was investigated on the effects of a single-dose rifampin in healthy volunteers. Methods: Twelve Chinese healthy male volunteers took 4 mg pitavastatin orally with 150 ml water or with a single dose of 600 mg rifampin on separate occasions and the plasma concentrations of pitavastatin were measured over 48 h by HPLC-MS/MS. Results: A single dose of rifampin significantly increased the mean area under the plasma concentration-time curve(AUC) and C of pitavastatin by 573.5 %(95%CI, 373.3-773.7 %, p < 0.001) and 819.2 %(95 % CI, 515.4-1123.0 %, p < 0.001) respectively, while significantly decreased the t and CL/F of pitavastatin by 38.8 % (95 % CI, 18.2-59.4 %, p < 0.001) and 81.4 % (95 % CI, 75.0-87.7 %, p < 0.001) respectively. Conclusions: Co-administration of pitavastatin with a single dose of rifampin resulted in a significant increase in plasma levels of pitavastatin in Chinese healthy subjects. [ABSTRACT FROM AUTHOR]

The Rho/Rho-kinase pathway is considered important in the pathogenesis of sustained smooth muscle cell contraction during cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). The aims of this study were to investigate whether combination treatment, with pitavastatin as an inhibitor of RhoA and fasudil as an inhibitor of Rho-kinase, prevents the cerebral vasospasm. SAH was simulated using the double-hemorrhage rabbit model, and pitavastatin, or fasudil, or both (combination treatment) were administrated. The basilar artery (BA) cross-sectional area only in the combination treatment group was statistically larger than in the SAH group ( p < 0.05). BA Rho-kinase, as measured by ELISA, was statistically reduced only in the combination treatment group compared with the SAH group ( p < 0.05). In the other two treatment groups, pitavastatin or fasudil treatment group showed larger BA cross-sectional areas and lower value for BA Rho-kinase, but there were no statistically significant differences compared with the SAH group. The expression of endothelial nitric oxide synthase (eNOS), evaluated by immunohistochemistry in the pitavastatin group and the combination group, was higher than in the SAH group. Results indicate that combination treatment could extensively prevent cerebral vasospasm due to the synergic effect of combining pitavastatin and fasudil on the Rho/Rho-kinase pathway and on eNOS. [ABSTRACT FROM AUTHOR]

Background: Chronic kidney disease (CKD) is a serious health problem worldwide. Therapies that can halt the progression of CKD are limited, and the identification of new strategies for CKD treatment is therefore important. Pitavastatin, one of the newest statins introduced to the market, has been shown to exhibit some beneficial effects on renal and endothelial function. Method: We enrolled 12 healthy volunteers for our study. With or without pitavastatin administration, creatinine clearance (Ccr), urinary albumin excretion, lipid status, and oxidative stress markers were evaluated in acute and early phases after administration of the drug. Results: A single pitavastatin administration increased Ccr and reduced oxidative stress parameters, such as 8-OHdG levels and isoprostane production, within 6 h, without altering lipid status in healthy participants. A two-week treatment with pitavastatin lowered total and LDL cholesterol and triglycerides but not HDL cholesterol at 7 and 14 days. This change in lipid profile is associated with enhanced Ccr and the suppression of oxidative stress parameters. Urinary albumin excretion was reduced after either acute or chronic administration of pitavastatin, although this effect was not yet significant. Conclusion: We found that pitavastatin augmented Ccr and reduced oxidative stress parameters in healthy subjects. These data suggest that pitavastatin affects renal outcomes in both lipid status-dependent and -independent manners. These observations suggest that pitavastatin treatment could be beneficial for CKD patients. [ABSTRACT FROM AUTHOR]

This study reports the results of an investigation of the phototoxicity mechanism induced by pitavastatin and its photoproducts, namely 6-cyclopropyl-10-fluoro-7,8-dihydrobenzo[ k]phenanthridine (PP3) and 6-cyclopropyl-10-fluorobenzo[ k]phenanthridine (PP4). The phototoxicity was tested in human keratinocytes cell lines NCTC-2544, and the results proved that under the same conditions, all three compounds exhibited phototoxic effects in the model tested. The reduction in cell viability was found to be both concentration- and UVA dose-dependent. A point of note is that both the photoproducts produced a dramatic decrease in cell viability with GI values one order of magnitude lower compared to the parent compound. In particular, the fully aromatic derivative (PP4) showed the highest antiproliferative activity. Flow cytometric analysis indicated that pitavastatin and the photoproduct PP4 principally induced necrosis, as revealed by the large appearance of propidium iodide-positive cells and also confirmed by the rapid drop in cellular ATP levels. Further studies committed to better understanding of photoinduced cell death mechanism(s) revealed that neither pitavastatin nor PP4 induced mitochondrial depolarization or lysosomal damage, but, interestingly, extensive cell lipid membrane peroxidation along with a significant oxidation of model proteins occurred, suggesting that pitavastatin and PP4 exert their phototoxic effect mainly in the cellular membranes. The present results suggest that the phototoxicity of pitavastatin may be mediated by the formation of benzophenanthridine-like photoproducts that appear to have high potential as photosensitizers. [ABSTRACT FROM AUTHOR]

Introduction: Pitavastatin is a novel, potent, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. This study compared the long-term efficacy of pitavastatin and simvastatin in dyslipidemic patients at high risk of coronary heart disease. Methods: A 44-week blinded extension study was conducted at 24 centers in five European countries for patients who had previously completed a 12-week randomized, double-blind core study in which they received pitavastatin 4 mg or simvastatin 40 mg once daily. Patients originally randomized to pitavastatin 4 mg continued at the same dose throughout the extension study ( n=121). In simvastatin-treated patients ( n=57), the dose was increased to 80 mg in five patients who had not attained the National Cholesterol Education Program (NCEP) target for low-density lipoprotein cholesterol (LDL-C) during the core study. Primary endpoints were the proportion of patients attaining the NCEP and European Atherosclerosis Society (EAS) LDL-C targets, and the NCEP target for non-high-density lipoprotein cholesterol (non-HDL-C) at weeks 16 and 44. Results: Of the 178 patients who entered the extension study, 156 patients (109 in the pitavastatin group, 47 in the simvastatin groups) completed the 44-week treatment period. At week 44, NCEP and EAS targets were attained by 81.7% and 84.2%, respectively, of pitavastatin-treated patients, and 75.4% and 73.7%, respectively, of simvastatin-treated patients. NCEP targets for non-HDL-C were achieved by 79.2% of pitavastatin-treated patients and 70.2% of simvastatin-treated patients. Both treatments were generally well tolerated, but pitavastatin 4 mg was associated with a numerically lower incidence of discontinuations due to treatment-emergent adverse events (5.8% vs. 10.5% of patients) and a lower rate of myalgia (4.1% vs. 12.3%) compared with simvastatin 40-80 mg. Conclusion: Pitavastatin 4 mg provides long-term efficacy similar to that of simvastatin 40-80 mg. Further studies should ascertain whether trends suggesting that pitavastatin may exhibit a more favorable long-term tolerability profile are statistically significant. [ABSTRACT FROM AUTHOR]

Introduction: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Obesity is a well-established risk factor for the development and progression of coronary heart disease. Moreover, endothelial dysfunction is an early event in atherosclerosis and is known to be associated with postprandial hypertriglyceridemia. The purpose of this study was to determine whether a statin might have an effect on postprandial hypertriglyceridemia, and thereby on endothelial function in obese subjects. Twenty-four obese male subjects were recruited for this study. They were randomly assigned to receive pitavastatin (2 mg/day) or placebo for 2 weeks. The oral fat loading test using OFTT cream was performed pre- and post-treatment, in which the lipid profile and flow-mediated dilation (FMD) were assessed before and 4 h after an oral fat load. In the oral fat loading test conducted pretreatment, the oral fat load induced a marked increase of the serum triglyceride (TG) level and decrease in FMD in the pitavastatin and placebo group. In the test conducted post-treatment, the increase in postprandial TG was attenuated (+183 vs. +81 mg/dL, P < 0.001) and decrease in postprandial FMD was completely abolished (−1.1 vs. +0.1%, P < 0.01) by pitavastatin treatment. Moreover, there was a good correlation between the change in postprandial TG and the change in postprandial FMD after the 2 weeks of treatment ( r = −0.737, P < 0.001). Pitavastatin might prevent endothelial dysfunction caused by postprandial hypertriglyceridemia within 2 weeks of therapy in obese subjects. [ABSTRACT FROM AUTHOR]

Introduction: 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. Methods: 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. Results: 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 highsensitivity 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Statins have a neuroprotective effect in neurological diseases, a pleiotropic effect possibly related to blood–brain barrier (BBB) function. We investigated the effect of pitavastatin on barrier functions of an in vitro BBB model with primary cultures of rat brain capillary endothelial cells (RBEC). Pitavastatin increased the transendothelial electrical resistance (TEER), an index of barrier tightness of interendothelial tight junctions (TJs), at a concentration of 10−8 M, and decreased the endothelial permeability for sodium fluorescein through the RBEC monolayer. The increase in TEER was significantly reduced in the presence of isoprenoid geranylgeranyl pyrophosphate, whereas farnesyl pyrophosphate had no effect on TEER. Our immunocytochemical and Western blot analyses revealed that treatment with pitavastatin enhanced the expression of claudin-5, a main functional protein of TJs. Our data indicate that pitavastatin strengthens the barrier integrity in primary cultures of RBEC. The BBB-stabilizing effect of pitavastatin may be mediated partly through inhibition of the mevalonate pathway and subsequent up-regulation of claudin-5 expression. [ABSTRACT FROM AUTHOR]

AbstractAim: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.Methods: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.Results: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.Conclusion: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. [ABSTRACT FROM AUTHOR]