On the Embrittlement and Toughness of High Purity Fe-30Cr-2Mo Alloy

Experiments were conducted to explain unexpected embrittlement phenomena encountered in fabricating a high purity Fe-30Cr-2Mo alloy. By means of a hydrostatic tensile test with a Bridgman-Type specimen it was found that the fracture behaviour of the alloy is highly dependent on stress state. Under conditions of low triaxial stress, the alloy displays excellent ductility. Under conditions of high triaxial stress, however, the alloy shows less strain to fracture and a transition from ductile to cleavage fracture. The toughness of the Fe-30Cr-2Mo alloy can be significantly improved by thermomechanical processing

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

Long-Term Stored Hemoglobin-Vesicles, a Cellular Type of Hemoglobin-Based Oxygen Carrier, Has Resuscitative Effects Comparable to That for Fresh Red Blood Cells in a Rat Model with Massive Hemorrhage without Post-Transfusion Lung Injury.

Hemoglobin-vesicles (HbV), encapsulating highly concentrated human hemoglobin in liposomes, were developed as a substitute for red blood cells (RBC) and their safety and efficacy in transfusion therapy has been confirmed in previous studies. Although HbV suspensions are structurally and physicochemically stabile for least 1-year at room temperature, based on in vitro experiments, the issue of whether the use of long-term stored HbV after a massive hemorrhage can be effective in resuscitations without adverse, post-transfusion effects remains to be clarified. We report herein on a comparison of the systemic response and the induction of organ injuries in hemorrhagic shock model rats resuscitated using 1-year-stored HbV, freshly packed RBC (PRBC-0) and by 28-day-stored packed RBC (PRBC-28). The six-hour mortality after resuscitation was not significantly different among the groups. Arterial blood pressure and blood gas parameters revealed that, using HbV, recovery from the shock state was comparable to that when PRBC-0 was used. Although no significant change was observed in serum parameters reflecting liver and kidney injuries at 6 hours after resuscitation among the three resuscitation groups, results based on Evans Blue and protein leakage in bronchoalveolar lavage fluid, the lung wet/dry weight ratio and histopathological findings indicated that HbV as well as PRBC-0 was less predisposed to result in a post-transfusion lung injury than PRBC-28, as evidenced by low levels of myeloperoxidase accumulation and subsequent oxidative damage in the lung. The findings reported herein indicate that 1-year-stored HbV can effectively function as a resuscitative fluid without the induction of post-transfused lung injury and that it is comparable to fresh PRBC, suggesting that HbV is a promising RBC substitute with a long shelf-life

Changes in hemodynamic and blood gas parameters during and after resuscitation with PRBC-0, PRBC-28 and HbV.

<p>(a) Mean arterial pressure (MAP), (b) heart rate (HR), (c) arterial blood oxygen tension (PaO₂), (d) arterial blood carbon dioxide tension (PaCO₂), (e) lactate, (f) glucose, (g) base excess (BE) and (h) hematocrit (Hct) during and after hemorrhagic shock and resuscitation with PRBC-0, PRBC-28 or HbV for 6 hours. (a and b) Values are the mean ± SD; <i>n</i> = 10 each group. (c-g) Values are means ± SD; <i>n</i> = 5 each group. *<i>p</i> < 0.05 and **<i>p</i> < 0.01 vs. baseline, ⁺⁺<i>p</i> < 0.01 vs. PRBC-0 group, ^#<i>p</i> < 0.05 and ^##<i>p</i> < 0.01 vs. PRBC-28 group. Rats that died during the observation period were excluded from the number. AB indicates after bleeding.</p

Immunological staining of lung sections.

<p>(a) Myeloperoxidase (MPO) staining and (b) 8-hydroxy-2’-deoxyguanosine (8-OH-dG) staining for evaluation of neutrophils accumulation in lung at 6 hours after resuscitation with PRBC-0, PRBC-28 or HbV. Immunofluorescent images indicated MPO (red), nuclei (blue, DAPI) and 8-OH-dG (green).</p

Evaluation of Pulmonary edema and lung injury after hemorrhagic shock and resuscitation with PRBC-0, PRBC-28 and HbV.

<p>(a) Percentage of Evans Blue (EBD) leakage into bronchoalveolar lavage fluid (BALF), (b) protein concentration in BALF, (c) lung wet/dry weight ratio and (d) changes in lung histopathology score at 6 hours after resuscitation with PRBC-0, PRBC-28 or HbV. Percent EBD leakage into BALF are calculated as [EBD concentration in BALF]/[EBD concentration in plasma (6 hour after transfusion)] × 100. Values are means ± SD; <i>n</i> = 5 each group. *<i>p</i> < 0.05, **<i>p</i> < 0.01 vs. PRBC-0 group, ^#<i>p</i> < 0.05, ^##<i>p</i> < 0.01 vs. PRBC-28 group. (e) Histopathology of lung at 6 hours after resuscitation with PRBC-0, PRBC-28 or HbV. Tissue sections were stained with HE. Scale bar = 100 μm.</p

Scheme showing the experimental procedure and survival observations made after hemorrhagic shock and resuscitation with PRBC-0, PRBC-28 and HbV.

<p>(a) Scheme showing the development of hemorrhagic shock and resuscitation. (b) Survival rates of sham treated rats (<i>n</i> = 10), hemorrhagic shock rats resuscitated with PRBC-0 (<i>n</i> = 12), PRBC-28 (<i>n</i> = 13) or HbV (<i>n</i> = 11). AB indicates after bleeding. RL indicates Ringer’s Lactate.</p