A novel plant nuclear gene encoding chloroplast ribosomal protein S9 has a transit peptide related to that of rice chloroplast ribosomal protein L12

AbstractWe have cloned a novel nuclear gene for a ribosomal protein of rice and Arabidopsis that is like the bacterial ribosomal protein S9. To determine the subcellular localization of the gene product, we fused the N-terminal region and green fluorescent protein and expressed it transiently in rice seedlings. Localized fluorescence was detectable only in chloroplasts, indicating that this nuclear gene encodes chloroplast ribosomal protein S9. The N-terminal region of rice ribosomal protein S9 was found to have a high sequence similarity to the transit peptide region of the rice chloroplast ribosomal protein L12, suggesting that these transit peptides have a common lineage

Pharmacokinetics of Mirabegron, a β3-Adrenoceptor Agonist for Treatment of Overactive Bladder, in Healthy East Asian Subjects

AbstractPurposeThe objective of these studies was to evaluate the pharmacokinetic profile, safety, and tolerability of mirabegron, a β3-adrenoceptor agonist for the treatment of overactive bladder, including food effects (low- or high-fat meals) and sex, in healthy East Asian subjects.MethodsIn total, 5 pharmacokinetic studies of mirabegron were conducted in healthy East Asian subjects. Food effects were assessed in 3 randomized, single-dose studies in young Japanese male subjects (study 1), male and female subjects (study 2), and young Taiwanese male and female subjects (study 3). In the other 2 single- and multiple-dose studies in young Chinese male and female subjects (study 4 and study 5), mirabegron was administered as a single dose under fasted conditions. After the washout period, mirabegron was administered once daily under fed conditions for 8 days. Pharmacokinetic parameters were determined using noncompartmental methods. Safety and tolerability assessments included physical examinations, vital signs, 12-lead ECG, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse event monitoring.FindingsAfter administration of single oral doses of mirabegron, exposure under fed conditions was lower than under fasted conditions in Japanese and Taiwanese subjects. In Japanese subjects, a greater reduction in mirabegron Cmax and AUC0–∞ was observed after a low-fat meal compared with a high-fat meal. In Chinese subjects, Cmax was reached at approximately 4.0 hours after single oral doses. Mirabegron accumulated 2- to 3-fold on once-daily dosing of multiple-dose relative to single-dose data. Steady state was reached within 7 days. After administration of mirabegron, mean values for Cmax and AUC in female subjects were higher than those in male subjects. Mirabegron was well tolerated in Japanese, Taiwanese, and Chinese subjects.ImplicationsOur studies confirm the higher exposure levels of mirabegron in female compared with male East Asian subjects as found earlier in Western subjects. Furthermore, the effects of food on the pharmacokinetic profiles appeared to be similar among the 3 populations tested in our studies. The findings suggest that there are no significant pharmacokinetic differences among the Japanese, Taiwanese, and Chinese populations

Pharmacokinetics of Mirabegron, a β3-Adrenoceptor Agonist for Treatment of Overactive Bladder, in Healthy Japanese Male Subjects: Results from Single- and Multiple-Dose Studies

BACKGROUND: Mirabegron is a human β(3)-adrenoceptor agonist for the treatment of overactive bladder. The pharmacokinetic profile of mirabegron has been extensively characterized in healthy Caucasian subjects. OBJECTIVE: The objective of this study was to evaluate the pharmacokinetics, dose-proportionality, and tolerability of mirabegron following single and multiple oral doses in healthy Japanese male subjects. The results were compared with those reported in non-Japanese (primarily Caucasian) subjects. METHODS: Two studies were conducted. In a single-blind, randomized, placebo-controlled, parallel-group, single- and multiple-ascending dose study (Study 1), mirabegron oral controlled absorption system (OCAS) tablets were administered at single doses of 50, 100, 200, 300, and 400 mg, with eight subjects (six active, two placebo) per dose group (Part I), and once daily for 7 days at 100 and 200 mg with 12 subjects (eight active, four placebo) per group (Part II). In an open-label, three-period, single-ascending dose study (Study 2), mirabegron OCAS was administered to 12 subjects at 25, 50, and 100 mg in an intra-subject dose-escalation design. Plasma and/or urine samples were collected up to 72 h after the first and last dose and analyzed for mirabegron. Pharmacokinetic parameters were determined using non-compartmental methods. Tolerability assessments included physical examinations, vital signs, 12-lead electrocardiogram, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse event (AE) monitoring. RESULTS: Forty and 24 young male subjects completed Part I and II, respectively, of Study 1. Twelve young males completed Study 2. After single oral doses (25–400 mg), maximum plasma concentrations (C(max)) were reached at approximately 2.8–4.0 h postdose. Plasma exposure (C(max) and area under the plasma concentration–time curve) of mirabegron increased more than dose proportionally at single doses of 25–100 mg and approximately dose proportionally at high doses of 300 and 400 mg. A more than dose proportional increase in plasma exposure was noted in the body of the same individual. Mirabegron accumulated twofold upon once-daily dosing relative to single-dose data. Steady state was reached within 7 days. Mirabegron was generally well-tolerated at single doses up to 400 mg and multiple doses up to 200 mg. The AE with the highest incidence was increased pulse rate at 400 mg in Study 1. CONCLUSIONS: Mirabegron OCAS exhibits similar single- and multiple-dose pharmacokinetic characteristics and deviations from dose proportionality in healthy Japanese male subjects compared with those observed in non-Japanese (primarily Caucasian) subjects in previous studies

Intestinal Absorption Mechanism of Mirabegron, a Potent and Selective β₃‑Adrenoceptor Agonist: Involvement of Human Efflux and/or Influx Transport Systems

Mirabegron, a weak-basic compound, is a potent and selective β₃-adrenoceptor agonist for the treatment of overactive bladder. Mirabegron extended release formulation shows dose-dependent oral bioavailability in humans, which is likely attributable to saturation of intestinal efflux abilities leading to higher absorption with higher doses. This study evaluated the membrane permeability of mirabegron and investigated the involvement of human intestinal transport proteins in the membrane permeation of mirabegron. Transcellular transport and cellular/vesicular uptake assays were performed using Caco-2 cells and/or human intestinal efflux (P-glycoprotein [P-gp], breast cancer resistance protein [BCRP], and multidrug resistance associated protein 2 [MRP2]) and influx (peptide transporter 1 [PEPT1], OATP1A2, and OATP2B1) transporter-expressing cells, vesicles, or <i>Xenopus laevis</i> oocytes. The absorptive permeability coefficients of mirabegron in Caco-2 cells (1.68–1.83 × 10^–6 cm/s) at the apical and basal pH of 6.5 and 7.4, respectively, were slightly higher than those of nadolol (0.97–1.41 × 10^–6 cm/s), a low permeability reference standard, but lower than those of metoprolol and propranolol (both ranged from 8.49 to 11.6 × 10^–6 cm/s), low/high permeability boundary reference standards. Increasing buffer pH at the apical side from 5.5 to 8.0 gradually increased the absorptive permeation of mirabegron from 0.226 to 1.66 × 10^–6 cm/s, but was still less than the value in the opposite direction (11.0–14.2 × 10^–6 cm/s). The time- and concentration-dependent transport of mirabegron was observed in P-gp-expressing cells and OATP1A2-expressing oocytes with apparent <i>K</i>_m values of 294 and 8.59 μM, respectively. In contrast, no clear BCRP-, MRP2-, PEPT1-, or OATP2B1-mediated uptake of mirabegron was observed in their expressing vesicles or cells. These findings suggest that mirabegron has low-to-moderate membrane permeability and P-gp is likely to be involved in its efflux into the lumen in the intestinal absorption process. The results also suggest that mirabegron could possibly be transported by intestinal influx transporters as well as simple diffusion

Diagnostic Abilities of the Optical Microangiography Parameters of the 3x3mm and 6x6mm Macular Scans in Glaucoma

Purpose:To evaluate the diagnostic abilities of macular vessel length and perfusion densities measured with optical microangiography (OMAG) over a 3x3mm and a 6x6mm region, and to compare these with macular ganglion cell-inner plexiform layer (GCIPL) thickness in eyes with primary open-angle glaucoma (POAG).Methods:In a cross-sectional study, 96 eyes of 57 control subjects and 88 eyes of 57 POAG patients underwent macular imaging with optical coherence tomography. Area under receiver operating characteristic curves (AUC) and sensitivities at 90% specificity of OMAG and GCIPL parameters were evaluated.Results:Most OMAG parameters of the 3x3mm macular scan and all inner sector parameters of the 6x6mm scan were similar (P&gt;0.05) in the POAG and control eyes. All outer sector OMAG parameters of the 6x6mm scan were significantly less (P&lt;0.05) in the POAG eyes. AUC and sensitivity at 90% specificity of the best parameter of the 3x3mm OMAG scan (inner temporal vessel length density; 0.65% and 26%, respectively) were statistically similar (P&gt;0.05) to that of the 6x6mm scan (outer inferior vessel length density; 0.72% and 30%, respectively). AUC and sensitivity of the best GCIPL thickness parameter (inferotemporal GCIPL thickness, 0.84% and 67%) were significantly better (P&lt;0.05) than that of the vessel length densities.Conclusions:The outer sector measurements of the 6x6mm macular OMAG scans seem to be better than the inner sector measurements in diagnosing glaucoma. The GCIPL thickness measurements were significantly better than all macular OMAG parameters in diagnosing glaucoma