Ezetimibe administration with ongoing statin therapy is an effective option for further lowering low-density lipoprotein cholesterol (LDL-C) levels. Thus, we investigated the long-term efficacy and safety of fixed-dose combination of pitavastatin/ezetimibe (K-924 LD: 2 mg/10 mg; K-924 HD: 4 mg/10 mg). We conducted a phase III, multicenter, open-label trial involving patients with hypercholesterolemia receiving pitavastatin (2 or 4 mg) who had not achieved their LDL-C management target. Patients were enrolled into the K-924 LD and HD groups based on whether they had received pitavastatin 2 and 4 mg, respectively, and treated for 52 weeks. K-924 was administered orally once daily. The primary objective was to examine the percent change in LDL-C from baseline at week 52 with last observation carried forward imputation (LOCF) in all patients. Of the 109 patients evaluated, 62 and 47 were assigned to the K-924 LD and HD groups, respectively. In all patients, LDL-C decreased by -30.3±14.3% (p＜0.001) from baseline (134.4±37.9 mg/dL). Consequently, 91.8% and 37.5% of the patients for primary and secondary prevention reached their LDL-C management target, respectively. These results were consistent in both the K-924 LD and HD groups. In the safety analysis, a single adverse drug reaction occurred in a patient in the K-924 HD group. After replacing pitavastatin monotherapy, K-924 was found to be effective and well-tolerated over 52 weeks. Thus, K-924 can contribute to intensifying LDL-C-lowering therapy without increasing the number of medications.

Idiopathic pulmonary fibrosis (IPF) is a poor prognosis disease that affects approximately 5 million people worldwide, and the detailed mechanisms underlying the pathogenesis of IPF remain unclear. Bleomycin-induced pulmonary fibrosis has been widely used as a representative animal model of IPF that induces fibrosis in lung tissue. The lungs of rodent consist of five lobes and each bronchus enters each lobe of the lung at a different bifurcation angle, path length, and diameter. The method of administration of bleomycin is considered as important thing to establish appropriate animal models. We conducted a time-dependent histopathological study to examine how pulmonary fibrosis develops in each lung lobe when bleomycin was intratracheally sprayed in ICR mice. And we then explored the suitable points for evaluation of anti-fibrotic agents in this model. As a result, we found that homogeneous fibrosis was induced in the 5 lobes of the lungs following initial inflammation. The expression of transforming growth factor (TGF)-β1 and phospho-Smad2 (pSmad2) was observed from Day 1, and their positivity increased until Day 21. In conclusion, we have observed a detailed time course of histological changes in bleomycin-induced pulmonary fibrosis in ICR mice using the aerosolization technique. We found that our protocol can induce a highly homogeneous lesion in the lung and that the most suitable time point to assess anti-fibrotic agents is 14 days after treatment in this model.

Abstract Background Pemafibrate, a selective PPARα modulator (SPPARMα), decreases plasma TG and increases HDL-C. The effects of pemafibrate on cardiovascular outcomes were examined in patients with type 2 diabetes, moderately high TG, and low HDL-C who were on statin therapy (the PROMINENT trial) [1]. Against our expectation, the intervention with pemafibrate did not reduce the outcomes. The increases in LDL-C and ApoB observed in the trial may have mitigated the beneficial effects of lowering TG and remnants. On the contrary, pemafibrate decreased LDL-C and ApoB in some of the clinical trials conducted in Japanese population [2, 3], suggesting that the effects of pemafibrate on LDL-C and ApoB may vary depending on the target patient population. Purpose To clarify the mechanisms behind the LDL-C-lowering effects of pemafibrate, we evaluated the effects of pemafibrate on serum levels of lathosterol, beta-sitosterol and campesterol, surrogate markers for cholesterol synthesis and absorption. Methods This is a post hoc analysis of a Phase 2 study comparing a once-daily extended-release formulation (ER) of pemafibrate to a twice-daily immediate-release formulation (IR). The study was a multicentre, randomized, single-blind, 3-treatment, 2-period crossover clinical trial. Patients with fasting serum TG >150 mg/dL were treated with IR 0.2 mg/day (IR0.2), ER 0.4 mg/day (ER0.4), or ER 0.8 mg/day (ER0.8) for 4 weeks in each treatment period. We measured serum levels of TG, LDL-C, ApoB, lathosterol (a cholesterol synthesis marker), and beta-sitosterol and campesterol (cholesterol absorption markers) before and after the intervention and evaluated their correlations. Results Among 63 patients randomized, 60 received the study drug. At baseline, the mean TG was 221.3 mg/dL, LDL-C was 134.5 mg/dL, and 10% of patients were concomitantly treated with a statin. The least squares mean percentage changes from baseline at 4 weeks were -43.6%, -41.1%, and -39.7% for TG, -3.5%, -7.0%, and -11.3% for LDL-C, and -9.8%, -11.9%, and -13.4% for ApoB with IR0.2, ER0.4, and ER0.8, respectively, which were significant except for LDL-C with IR0.2. Lathosterol, beta-sitosterol, and campesterol significantly decreased with each dose (see Fig.). The percentage change in LDL-C was positively correlated with those in the synthesis and absorption markers. There was a trend that the reductions in LDL-C and lathosterol increased in a dose-dependent manner. The reduction in LDL-C was larger in the subgroup with higher baseline levels than those with lower baseline levels. Conclusion Pemafibrate reduced serum levels of LDL-C and ApoB. In parallel, they reduced serum markers for cholesterol synthesis and absorption. Because the percentage changes in LDL-C were significantly correlated with those in the absorption and synthesis markers, we would propose that pemafibrate reduced LDL-C by inhibiting both synthesis and absorption of cholesterol.

We compared the efficacy and safety of pitavastatin/ezetimibe fixed-dose combination with those of pitavastatin monotherapy in patients with hypercholesterolemia. This trial was a multicenter, randomized, double-blind, active-controlled, parallel-group trial. A total of 293 patients were randomly assigned into four groups receiving 2 mg pitavastatin, 4 mg pitavastatin, 2 mg pitavastatin/10 mg ezetimibe (K-924 LD), and 4 mg pitavastatin/10 mg ezetimibe (K-924 HD) once daily for 12 weeks. The percentage changes in lo w-density lipoprotein cholesterol (LDL-C), the primary endpoint, were －39.5% for 2 mg pitavastatin, －45.2% for 4 mg pitavastatin, －51.4% for K-924 LD, and －57.8% for K-924 HD. Compared with pitavastatin monotherapy, the pitavastatin/ezetimibe fixed-dose combination significantly reduced LDL-C, total cholesterol, and non-high-density lipoprotein cholesterol. Meanwhile, the cholesterol synthesis marker, lathosterol, was significantly decreased with pitavastatin monotherapy and the pitavastatin/ezetimibe fixed-dose combination, although the decrease was attenuated in the latter. On the other hand, the cholesterol absorption markers, beta-sitosterol and campesterol, were reduced with the fixed-dose combination but not with pitavastatin monotherapy. The incidence of adverse events and adverse drug reactions was not significantly different between the two groups receiving the fixed-dose combination and monotherapy. The mean values of laboratory tests that are related to liver function and myopathy increased but remained within the reference range in all groups. The pitavastatin/ezetimibe fixed-dose combination showed an excellent LDL-C-reducing effect by the complementary pharmacological action of each component, and its safety profile was similar to that of pitavastatin monotherapy (ClinicalTrials.gov Identifier: NCT04289649).

To clinically evaluate a diffractive continuous-range-of-vision intraocular lens (IOL) that combines bifocal and extended depth-of-focus technologies in refractive lens exchange (RLE) patients. University eye clinic. Prospective interventional clinical study. Bilateral implantation of the TECNIS Synergy IOL was performed during a RLE procedure in 28 patients. At 3 months postoperatively, uncorrected (UDVA) and corrected (CDVA) distance visual acuities, uncorrected (UIVA) and distance-corrected (DCIVA) intermediate visual acuities at 80 cm, and uncorrected (UNVA) and distance-corrected (DCNVA) near visual acuities at 40 cm were assessed. Defocus curve testing and contrast sensitivity testing were also performed. Binocular UDVA and CDVA of 56 eyes (28 patients) were -0.06 ± 0.07 logMAR and -0.13 ± 0.05 logMAR, respectively. UIVA and DCIVA were -0.06 ± 0.05 logMAR and -0.08 ± 0.06 logMAR, and UNVA and DCNVA were -0.01 ± 0.07 logMAR and -0.04 ± 0.07 logMAR. The defocus curve revealed a visual acuity of 0.10 logMAR or better from +0.50 to -3.00 diopters (D). Photopic contrast sensitivity at spatial frequencies 3.0, 6.0, 12.0, and 18.0 was 1.68 ± 0.20, 1.77 ± 0.19, 1.45 ± 0.18, and 1.02 ± 0.19 log units, respectively. Mesopic contrast sensitivity at the same frequencies was 1.56 ± 0.20, 1.44 ± 0.25, 0.92 ± 0.38, and 0.44 ± 0.37, respectively. The Synergy IOL provided very good distance, intermediate, and near visual outcomes. A visual acuity of 0.10 logMAR or better was achieved from +0.50 to -3.0 D. Contrast sensitivity was within the normal range.

Installation suitability of a vertical closed loop GSHP system in the Echigo Plain of Japan was assessed considering the regional scale groundwater flow and heat transport analysis. For evaluating and understand the variation of development potential of the system, the necessary length of ground heat exchanger (GHE) was analyzed at different points, where groundwater, geology and subsurface temperature distribution varies. The computation was done for the model case of the Japanese single-family dwelling with reference to standard for energy saving in Japan. The necessary length of GHE ranged from 67 m to 101 m within the plain and found comparatively longer at the central coastal area around the Niigata City. These results showing the variation of the necessary length of GHE in the plain scale is significant and essential for the proper design and site selection of the system in the Echigo Plain, and can also be beneficial for the development of GSHP system in Japan. Influence of the existing groundwater pumping system was also evaluated to determine if the pumping system can enhance heat exchange performance for space-heating. The effect of groundwater pumping was not so significant to improve heat exchange rates due to the natural existence of groundwater flow.

The emergence and spread of antimicrobial resistant pathogens continue to threaten our ability to combat several infections. Among them, Pseudomonas aeruginosa (P. aeruginosa) poses a major threat to human health. P. aeruginosa has intrinsic resistance to many antibiotics due to the impermeability of its outer membrane and a resistance-nodulation-cell division type multidrug efflux pump system. Therefore, only limited therapeutic drugs are effective against the pathogen. To address this problem, we have recently discovered an overlooked anti- P. aeruginosa compound, 5-O-mycaminosyltylonolide (OMT) from the Ōmura Natural Compound library using an efflux pump deletion P. aeruginosa mutant strain, YM64. In this report, we aim to demonstrate the promising potential of OMT for as a novel anti- P. aeruginosa compound and performed combination assays of OMT with polymyxin B nonapeptide, an example of a permeabilizing agent, against multi-drug resistant P. aeruginosa clinical isolates.

5-Fluorouracil (5-FU) is widely used for colorectal cancer (CRC) treatment; however, continuous treatment of CRC cells with 5-FU can result in acquired resistance, and the underlying mechanism of 5-FU resistance remains unclear. We previously established an acquired 5-FU-resistant CRC cell line, HCT116RF10 , and examined its biological features and 5-FU resistance mechanisms. In this study, we evaluated the 5-FU sensitivity and cellular respiration dependency of HCT116RF10 cells and parental HCT116 cells under conditions of high- and low-glucose concentrations. Both HCT116RF10 and parental HCT116 cells were more sensitive to 5-FU under low-glucose conditions compared with high-glucose conditions. Interestingly, HCT116RF10 and parental HCT116 cells exhibited altered cellular respiration dependence for glycolysis and mitochondrial respiration under high- and low-glucose conditions. Additionally, HCT116RF10 cells showed a markedly decreased ATP production rate compared with HCT116 cells under both high- and low-glucose conditions. Importantly, glucose restriction significantly reduced the ATP production rate for both glycolysis and mitochondrial respiration in HCT116RF10 cells compared with HCT116 cells. The ATP production rates in HCT116RF10 and HCT116 cells were reduced by approximately 64% and 23%, respectively, under glucose restriction, suggesting that glucose restriction may be effective at enhancing 5-FU chemotherapy. Overall, these findings shed light on 5-FU resistance mechanisms, which may lead to improvements in anticancer treatment strategies.