Abstract It is generally believed that bioavailability ( F ) calculated based on systemic concentration area under the curve (AUC) measurements cannot exceed 1.0, yet some published studies report this inconsistency. We teach and believe, differential equation derivations, rate of absorption has no influence measured clearance following an oral dose, i.e., determined as available dose divided by AUC. Previously, it was thought any difference in calculating from urine data versus AUC due to...

Although hyperlipidemia, high blood pressure, and diabetes increase the risk of arteriosclerosis, it is not clear whether hyperuricemia increases arteriosclerosis or not. We examined effects uric acid curative drugs for on atherosclerosis-susceptible C57BL/6J apolipoprotein E-deficient (apoE−/−) mice. Male apoE−/− mice (age: 6 weeks) were fed a normal diet (normal group) acid-enriched diet. Mice divided into three groups administered drinking vehicle (high group), allopurinol (20...

Endothelium-dependent vasodilation via protease-activated receptor 2 (PAR2) is preserved in mesenteric arteries from SHRSP.Z-<i>Lepr</i><sup><i>fa</i></sup>/IzmDmcr rats (SHRSP.ZF) with metabolic syndrome even though nitric oxide (NO)-mediated attenuated. Therefore, we examined the PAR2 mechanisms underlying syndrome-resistant SHRSP.ZF aortas ageing. In isolated aortas, agonist 2-furoyl-LIGRLO-amide (2fly) caused that was sustained male until 18 weeks of...

The selective β3-adrenoceptor agonist mirabegron, an established alternative to antimuscarinic therapy for patients with overactive bladder, induces additional effects against receptors, transporters, and hepatic enzymes. present study aimed elucidate the of mirabegron on muscarinic receptors in rat bladder using radioligand binding functional assays. Mirabegron (0.1-100 μM) inhibited specific [N-methyl-3H]scopolamine methyl chloride other tissues rats a concentration-dependent manner....

Royal jelly (RJ) is widely used as a cosmetic or dietary supplement to relieve various health disorders, such dry skin, fatigue, and menopause. RJ has been recommended improve constipation on commercial basis. However, the detailed mechanisms by which influences intestinal motility whether improves remain unclear. Therefore, we investigated effects of mouse ileum both in vitro vivo. Using myograph methods, dose-dependently induced contractions isolated ileal segments, were inhibited...

Panax notoginseng saponins (PNS) are major components of notoginseng, a herb with established clinical efficacy against vascular diseases. SHRSP.Z-Lepr(fa) /IzmDmcr (SHRSP.ZF) rats, new animal model for metabolic syndrome, display an impaired vasorelaxation response in aortas and mesenteric arteries that is mediated by nitric oxide (NO). This study investigated whether PNS its can ameliorate this dysfunction SHRSP.ZF rats. In vitro study, the presence or absence components, vasodilation to...

Protease-activated receptor 2 (PAR2) is expressed in vascular endothelium. Nitric oxide (NO) - cyclic GMP-mediated vasodilation response to 2-furoyl-LIGRLO-amide (2fLIGRLO), a PAR2-activating peptide, impaired aortas from aged SHRSP.Z-Leprfa/IzmDmcr (SHRSP.ZF) rats with metabolic syndrome. Here we investigated mechanisms linking PAR2's effects phenotypic characteristics of male SHRSP.ZF at 10, 20, and 30 weeks age. We found responses either 2fLIGRLO or enzyme-mediated PAR2 activation by...

This study evaluated the utility of combination digoxin (0.25 mg) and rosuvastatin (5 as a new transporter (P‐glycoprotein/breast cancer resistance protein/organic anion‐transporting polypeptide ( OATP )1B1/ 1B3) probe cocktail (Oita combination) for drug–drug interaction DDI ) studies by demonstrating lack on pharmacokinetics PK s) rosuvastatin, it was already known that did not affect . an open‐label, two‐period in which primary end points were geometric mean ratio GMR area under plasma...

We established a highly sensitive method for evaluating P-glycoprotein activity in Caco-2 cells. Using time-lapse confocal laser-scanning microscopy, we measured the change fluorescence of residual rhodamine 123 Horizontal images apical and central parts these cells were captured 90 min. A continuous significant decrease fluorescent intensity part occurred during measurement period, while was mild. The abolished presence 10 μM digoxin, but not. total over whole no influence digoxin observed....

Metabolic syndrome is known to increase the risk of abnormal cardiac structure and function, which are considered contribute increased incidence cardiovascular disease mortality. We previously demonstrated that ventricular hypertrophy diastolic dysfunction occur in SHRSP.Z-Lepr fa /IzmDmcr (SHRSP fatty) rats with metabolic syndrome. The aim this study was investigate possible mechanisms underlying heart function SHRSP fatty rats. amount sarcoplasmic reticulum Ca 2+ -ATPase (SERCA) 2a,...

The present study aimed to directly characterize specific binding sites of tritium ([(3)H])-labeled imidafenacin, a new radioligand for labeling muscarinic receptors, in the bladder and other peripheral or central nervous tissues rats. Muscarinic receptors rat were measured by assay using [(3)H]imidafenacin. Specific [(3)H]imidafenacin was saturable, reversible, high affinity. Estimated dissociation constants (Kd values) significantly lower submaxillary gland prostate higher heart than...

Abstract Phosphodiesterase 4 (PDE4) inhibitor is associated with a broad‐spectrum anti‐inflammatory mechanism. However, securing clinically efficacious doses sufficient safety margins remains challenging due to class specific adverse events that are often unavoidable in the clinic. ART‐648 an orally available PDE4 being developed for treatment of inflammatory diseases. According estimated clinical based on vitro whole‐blood assay, phase I study was designed. The purpose this assess safety,...

<sec> <title>BACKGROUND</title> High levels of physical activity are key to improving health outcomes, yet many people fail take action. Using pedometers target steps per day and providing financial incentives is a simple scalable approach promoting public health. However, conventional do not account for “intensity” “duration,” making it challenging efficiently increase people’s moderate-to-vigorous (MVPA), which expected improve outcomes. Based on these rationales, we developed smartphone...

Background High levels of physical activity are key to improving health outcomes, yet many people fail take action. Using pedometers target steps per day and providing financial incentives is a simple scalable approach promoting public health. However, conventional do not account for “intensity” “duration,” making it challenging efficiently increase people’s moderate-to-vigorous (MVPA), which expected improve outcomes. Based on these rationales, we developed smartphone app that sets step...

We evaluated the effects of anticholinergic drugs principally used for therapy overactive bladder (OAB) on activity P-glycoprotein, an efflux transport protein, in Caco-2 cells. The time-dependent changes fluorescence residual rhodamine 123, a P-glycoprotein marker, apical region cells were measured presence using time-lapse confocal laser scanning microscopy. effect human ATPase was also measured. 123 untreated decreased over time. gradual decrease significantly inhibited by treatment with...

The aim of this study was to use time-lapse confocal laser scanning microscopy establish a more sensitive and specific method for evaluating P-glycoprotein activity in Caco-2 cells.The change the fluorescence residual rhodamine 123 at apical central regions cells measured presence digoxin or St John's wort by using microscopy. data were compared with measurements made conventional techniques, microplate reader microscope.The percentage decrease caused 10 µm 0.1 µg/ml significantly larger...

Objective: In this study, we aimed to study the effects of ICI204,448, naloxone methiodide and levocetirizine on scratching behavior induced by intradermal injection a ?-opioid antagonist, nor-binaltorphimine (nor-BNI), into rostral back ICR mice were investigated.Materials methods: Male weighing 30?35 g used. The number episodes counted for 60 min after i.d. nor-BNI.Results: nor-BNI dose dependently increased in mice. nor-BNI-induced was inhibited not only nalfurafine but also peripherally...

Metabolic syndrome facilitates the development of cardiovascular disease due to atherosclerosis. We propose that chronic oxidative-nitrative stress is linked vascular dysfunction in response nitric oxide (NO) coronary and mesenteric arteries SHRSP.Z- Lepr fa /IzmDmcr (SHRSP.ZF) rats, an animal model metabolic syndrome. Perivascular adipose tissue (PVAT), which located outside blood vessels, has now been recognized as playing a role function. assessed PVAT observed SHRSP.ZF rats with used at...

The aim of this study was to evaluate the effects mitogen-activated protein kinase (MAPK) pathway inhibitors SB203580, CMPD-1, SB239063, SP600125, and FR180204 on activity P-glycoprotein (P-gp) assess whether MAPK affects P-gp directly. Changes in fluorescence residual rhodamine 123, a marker activity, apical region Caco-2 cells were measured presence using time-lapse confocal laser scanning microscopy at 0, 10, 20, 30, 60 min. Significant differences observed between levels control treated...

Protease-activated receptor-2 (PAR2) is activated by proteases, such as trypsin, human mast cell beta-tryptase, kallikrein isoforms, coagulation factors VIIa and Xa, etc. PAR2 believed to have an important role under inflammatory pathological conditions, but its in metabolic syndrome remains uncertain. We reported that PAR2-activating peptide, 2-furoyl-LIGRLO-amide (2fly) causes NO-mediated vasorelaxation rat aortas similar observed with acetylcholine (ACh), 2fly-induced maintained from...