Identification of a DBA/2 Mouse Sub-strain as a Model for Pseudoxanthoma Elasticum-Like Tissue Calcification.

Ectopic calcification in the cardiovascular system adversely affects life prognosis. DBA/2 mice experience calcification owing to low expression of Abcc6 as observed in pseudoxanthoma elasticum (PXE) patients; however, little is known about its characteristics as a calcification model. In this study, we explore the suitability of a DBA/2 sub-strain as a PXE-like tissue calcification model, and the effect of a bisphosphonate which prevents calcification of soft tissues in hypercalcemic models was evaluated.

Uricosuric Agents Affect Plasma and Kidney Concentration of Adefovir via Inhibition of Oat1 and Mrp2 in Rats.

Uricosuric agents lower serum uric acid levels by increasing urinary excretion via inhibition of urate transporter 1 (URAT1), urate reabsorption transporter in the renal proximal tubules. Probenecid and benzbromarone have been used as uricosurics, but these drugs inhibit organic anion transporters (OATs) in addition to URAT1. In this study, we investigated whether uricosuric agents interacted with adefovir, known as a substrate for OAT1, using Sprague-Dawley (SD) rats.

Visceral Fat Area Measured by Abdominal Bioelectrical Impedance Analysis in School-Aged Japanese Children.

Abdominal bioelectrical impedance analysis (aBIA) has been in use to measure visceral fat area (VFA) in adults. Accurately measuring visceral fat using aBIA in children is challenging. Forty-six school-aged Japanese children aged 6-17 years (25 boys and 21 girls) were included in this study.

Dotinurad: a novel selective urate reabsorption inhibitor for the treatment of hyperuricemia and gout.

Introduction: Gout is an inflammatory disease triggered by deposition of urate crystals secondary to longstanding hyperuricemia, and its management implies both the treatment of flares and management of hyperuricemia. Dotinurad is a selective urate reabsorption inhibitor (SURI), potently inhibits urate transporter 1 in the apical surface of renal proximal tubular cells, and has been approved for the treatment of gout and hyperuricemia in Japan.

Areas Covered: This overview of dotinurad covers nonclinical and clinical pharmacology studies in special populations and its efficacy and safety in Japanese hyperuricemic patients with and without gout.

Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists.

Although several potent bile acid Farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1) dual agonists such as INT-767 have been reported, no non-bile acid FXR/TGR5 dual agonist has been investigated to date. Therefore, we attempted to discover potent non-bile acid FXR/TGR5 dual agonists and identified some non-bile acid FXR/TGR5 dual agonists, such as isonicotinamide derivatives in vitro assay. Compound 20p was evaluated in C57BL/6J mice, that were administered a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) consisting of 60 kcal% fat and 0.

Hypouricemic agents reduce indoxyl sulfate excretion by inhibiting the renal transporters OAT1/3 and ABCG2.

Indoxyl sulfate (IS) accumulates in the body in chronic kidney disease (CKD). In the renal proximal tubules, IS excretion is mediated by OAT1/3 and ABCG2. These transporters are inhibited by some hypouricemic agents; OATs by probenecid and benzbromarone, ABCG2 by febuxostat and benzbromarone.

Successful de-escalation antibiotic therapy using cephamycins for sepsis caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae bacteremia: A sequential 25-case series.

Carbapenems are frequently used to treat infections caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E), but carbapenem-resistant Enterobacteriaceae bacteria are a clinical concern. Although cephamycins (cefmetazole; CMZ) have been shown to be effective against mild cases of ESBL-E infection, data on their use for severe ESBL-E infections with sepsis or septic shock remain scarce. Herein, we discuss a de-escalation therapy to CMZ that could be used after empiric antibiotic therapy in ICU patients with sepsis or septic shock caused by ESBL-E bacteremia.

[Pharmacological properties and clinical efficacy of dotinurad (URECE tablets), a novel hypouricemic agent].

In Jan 2020, dotinurad (URECE tablets) was approved for gout and hyperuricemia therapy in Japan. We developed a novel hypouricemic agent because benzbromarone, a commercially available uricosuric agent, has several problems, such as drug-induced liver injury or drug-drug interaction caused by CYP2C9 inhibition. In transporter-overexpressing cells, dotinurad potently inhibited URAT1 which is localized in the renal proximal tubules and functions as a urate reabsorption.

Pharmacological Evaluation of Dotinurad, a Selective Urate Reabsorption Inhibitor.

The effect of dotinurad [(3,5-dichloro-4-hydroxyphenyl)(1,1-dioxo-1,2-dihydro-3H-1 -1,3-benzothiazol-3-yl)methanone] was compared with that of commercially available uricosuric agents-namely, benzbromarone, lesinurad, and probenecid. Its effect on urate secretion transporters was evaluated using probe substrates for respective transporters. Dotinurad, benzbromarone, lesinurad, and probenecid inhibited urate transporter 1 (URAT1) with IC values of 0.

Seasonal changes in sleep duration and sleep problems: A prospective study in Japanese community residents.

Background: A scientific understanding of the effects of seasonal changes on sleep duration and sleep problems such as insomnia and hypersomnia has yet to be elucidated; however, such an understanding could aid the establishment of an optimal sleep hygiene program to treat such problems.

Methods: We investigated the effects of seasonal changes on sleep duration and sleep problems in Japanese community residents. Data on 1,388 individuals aged 15-89 years who participated in the Survey of Seasonal Variations in Food Intakes conducted by the National Institute of Health and Nutrition of Japan (2004-2007) were analyzed.

Enhancement of pharmacological effects of uricosuric agents by concomitant treatment with pyrazinamide in rats.

Our goal was to establish a model for the evaluation of the effects of uricosuric agents and to clarify the underlying mechanism(s). The effects of a uricosuric agent co-treated with pyrazinamide, an anti-tubercular agent, on urate handling were examined in rats. Furthermore, the effects of uricosuric agents on urate uptake were evaluated using the vesicles of rat renal brush-border membrane.

Uricosuric agents decrease the plasma urate level in rats by concomitant treatment with topiroxostat, a novel xanthine oxidoreductase inhibitor.

Objectives: The aim of this study was to establish the rat model for evaluating hypouricemic effects by some uricosuric agents.

Methods: Rats were made hyperuricemic by subcutaneous administration of potassium oxonate, a uricase inhibitor, or made hypouricemic by oral administration of topiroxostat, a xanthine oxidoreductase inhibitor. Furthermore, rats were co-treated with topiroxostat and inosine, a urate precursor.

Establishment of simultaneous treatment model with citrate for preventing nephropathy induced by FYX-051, a xanthine oxidoreductase inhibitor, in rats.

As a precedent study for elucidating the mechanism of possible urinary bladder carcinogenesis due to xanthine crystals induced by FYX-051, a xanthine oxidoreductase inhibitor, we have determined the experimental conditions suitable for the 52-week simultaneous treatment with citrate in F344 rats. Simultaneous treatment with citrate and FYX-051 produced both increased urinary citrate excretion and suppression of urinary xanthine deposition at around 4 hours after a single dosing, but these effects disappeared 2 hours later, indicating a lack of the durability of citrate effects. Next, we carried out a 7-day simultaneous treatment study by two daily treatments, that is, FYX-051 (6 mg/kg) and citrate (2,000 mg/kg), followed by citrate-alone treatment, under the conditions of selected dosing intervals, the second dose of citrate, and dosing volume.

Alanine scanning analyses of the three major loops in domain II of Bacillus thuringiensis mosquitocidal toxin Cry4Aa.

Cry4Aa produced by Bacillus thuringiensis is a dipteran-specific toxin and is of great interest for developing a bioinsecticide to control mosquitoes. Therefore, it is very important to characterize the functional motif of Cry4Aa that is responsible for its mosquitocidal activity. In this study, to characterize a potential receptor binding site, namely, loops 1, 2, and 3 in domain II, we constructed a series of Cry4Aa mutants in which a residue in these three loops was replaced with alanine.

Elevated production of Legionella-specific immunoglobulin A in A/J mice is accompanied by T-helper 1-type polarization.

Legionella pneumophila (Lpn) is a Gram-negative bacterium and an intracellular parasite that causes Legionnaires' disease. Secretion of immunoglobulin A (IgA) against Lpn on the mucosal surface of the upper respiratory tract may be important as a self-defense mechanism. A/J mice have been demonstrated to be permissive as to Lpn replication in macrophages due to a natural mutation in neuronal apoptosis inhibitory protein 5.