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Background: Benzodiazepines, such as flunitrazepam, may be at risk of disinhibition, leading to aggressiveness, impulsivity, self-harm, and possibly suicide attempts, whereas ramelteon may be far from disinhibition., Case Presentation: In a 43-year-old female with primary insomnia, flunitrazepam alone did not induce any type of disinhibition, but the addition of ramelteon to flunitrazepam brought about disinhibition, leading to aggressiveness and finally to her suicide attempt. Her disinhibition rapidly subsided as soon as ramelteon alone was discontinued., Conclusion: These findings suggest that a suicide attempt may occur during ramelteon and flunitrazepam combination in a susceptible patient., Competing Interests: The author declares no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Psychiatry and Clinical Neurosciences Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Levocetirizine is classified as a second-generation antihistamine. Levocetirizine is available for the treatment of allergic disorders such as allergic rhinitis and chronic idiopathic urticaria. This was a single-center, single-dose, open-label, randomized, 2-way crossover study in healthy Japanese male subjects consisting of 2 parts. Part 1 compared the bioavailability of levocetirizine oral disintegrating tablet (ODT) and levocetirizine immediate-release tablet (IRT) taken with water in the fasted state in 24 subjects; all subjects completed this part of the trial. In part 2, the bioavailability of levocetirizine ODT without water was compared with that of levocetirizine IRT with water in the fasted state in 48 subjects; 47 subjects completed this part of the trial. Bioequivalence was demonstrated between levocetirizine IRT 5 mg and ODT 5 mg. The safety profiles were generally similar between levocetirizine ODT and levocetirizine IRT, with no serious adverse events, deaths, or adverse events leading to withdrawal reported during the study., (© 2020 GlaxoSmithKline. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

The aim of the study was to assess the safety, tolerability, and pharmacokinetics of single and repeat doses of nemiralisib administered via a dry powder inhaler to healthy Japanese subjects. This was a single-center, double-blind, randomized, placebo-controlled, parallel, single- and repeat-ascending-dose study. Thirty-six healthy Japanese male subjects were randomized to receive either 1 dose strength of nemiralisib or placebo. The study consisted of a screening period, a single-dose session (session 1), a repeat-dose session (session 2), a 10-day washout period between the sessions, and then a follow-up visit 10 ± 1 days after the last dose of session 2. No serious adverse events were reported. No clinically significant abnormalities were found in clinical laboratory results, vital signs, or spirometry results. Generally, exposure (maximum observed plasma concentration [C max ] and area under the concentration-time curve [AUC]) increased with dose in an approximately proportional manner. Plasma T max was achieved rapidly at approximately 0.08 hours, and the terminal elimination half-life (T 1/2 ) was approximately 40 hours. T max and T 1/2 did not change between days or doses in the single- and repeat-dose sessions. Following 10 daily doses of 200, 500, and 700 μg nemiralisib, accumulation was observed, and the ratios (session 2, day 10:session 1) for Ro(AUC 0-24 ) and R(C max ) were 2.4-3.0 and 1.5-1.7, respectively. Steady state was achieved by 6-7 days, based on trough observed plasma drug concentration (C trough ) values., (© 2018, The American College of Clinical Pharmacology.)

This phase 1 study characterized the safety, tolerability, pharmacokinetics, and pharmacodynamics of losmapimod and its metabolite GSK198602 following single and repeat doses of oral losmapimod in healthy Japanese volunteers. Subjects (n = 41) received single oral doses of losmapimod (2.5, 7.5, 20 mg) or matching placebo on 3 separate days (n = 20) or losmapimod 7.5 mg or matching placebo twice daily for 14 days (n = 21). Assessments included maximum observed plasma concentration (Cmax ), time to Cmax (Tmax ), apparent terminal-phase half-life (t1/ )2 , area under the curve (AUC), and change in C-reactive protein and phosphorylated heat shock protein 27 levels. No serious adverse events occurred during the study, and there were no safety concerns regarding clinical laboratory parameters, 12-lead electrocardiogram, or vital signs. The losmapimod Tmax was 3-4 hours, and the mean t1/2 was approximately 7.9-9.0 hours, with no appreciable difference in Tmax and apparent clearance following oral dosing between dosing regimens. Single and repeat oral doses of losmapimod were well tolerated in healthy Japanese volunteers. The Tmax of GSK198602 was similar to and t1/2 was slightly longer than those of losmapimod. Approximate dose-proportional increases in exposure to losmapimod and GSK198602 were observed in AUC with single-dose administration. Repeat-dose trough concentrations reached steady state within 2 days, with an observed accumulation ratio of 1.56 and 1.91 for losmapimod and GSK198602, respectively., (© 2015, The American College of Clinical Pharmacology.)

Wear performance and debris-size distribution of vitamin E (DL-alpha tocopherol, VE)-added ultrahigh molecular weight polyethylene (UHMWPE) was evaluated using a knee-simulator test. VE was mixed with GUR 1050 UHMWPE powder at 0.3 wt%, and the tibial components of the knee joint were made by direct compression molding. The VE-added UHMWPE showed consistently lower wear volume throughout the test., ((c) 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Background: Bikunin, a Kunitz-type protease inhibitor, specifically inhibits tumor invasion and metastasis., Methods: The authors initially evaluated the therapeutic efficacy of once-daily oral administration of different doses of bikunin against human ovarian carcinoma HRA cells growing in the peritonea of nude mice. For the in vivo studies, female 7-week-old nude mice were randomized to 1 of 4 groups: bikunin-treated groups (n = 9 in each group) received 3, 10, or 30 microg/g body weight per day bikunin for 7 days via gastrointestinal gavage, and a control group (n = 9) received the vehicle solution (phosphate-buffered saline) via gastrointestinal gavage. On Day 9, the abdominal cavity was examined by two observers who were blinded to treatment., Results: After oral administration, intact bikunin was detectable in mouse serum specimens at 3 and 6 hours. This was followed by a decline at 12 hours. The mice given bikunin at the highest dose level had a 40% decrease in tumor load. The highest uptake in the tumor was obtained with [125I]bikunin 12 hours postadministration. No effect on either food intake or body weight was observed in the treated versus sham groups. The current study was the first to report the potent activity of once-daily oral administration of bikunin against ovarian carcinoma. Next, the authors performed a Phase I trial to determine the maximum-tolerated dose (MTD) and safety of a once-daily oral administration schedule. The indication was locally advanced uterine cervical carcinoma after definitive treatment. An escalating dose (3, 10, and 30 mg/kg per day) of bikunin was administered orally to nine patients for 7 days. There were no dose-limiting toxicities and the MTD of the bikunin schedule was not defined. The authors also obtained preliminary data on its effect on urokinase-type plasminogen activator expression at the highest dose level., Conclusions: Once-daily oral administration of bikunin was found to be safe in humans and exhibited signs of biologic activity., (Copyright 2004 American Cancer Society.)

Plasma cells play a pivotal role in the immune system and are responsible for the synthesis and release of immunoglobulins. Numerous in vitro culture experiments on the yolk sac demonstrated the generation of mature cells of the myeloid and lymphoid lineages under appropriate culture conditions. However, there are no reports describing the development of mature lymphoid cells in the yolk sac so far. For this reason, we undertook this study to investigate the development of antibody-containing plasma cells during early yolk sac haematopoiesis. Immunohistochemistry and immunoelectron microscopy were employed in the study. Results of this work demonstrated very weak immune staining for the intracytoplasmic IgA, IgG, and IgM at days 10 and 11 of embryonic life, while dark staining was obtained at 12 days. Positive staining was localized to the endodermal cell layer. Electron microscopic examinations revealed the existence of cells with the typical characteristics of plasma cells inside the endodermal cell layer, which may suggest their endodermal origin. To further verify the nature of these cells, intracytoplasmic immunoglobulins were demonstrated by immunoelectron microscopy. The present study demonstrated emergence of mature functioning plasma cells in early rat yolk sac. In a previous work we hypothesized the possibility of endodermal origin of yolk sac macrophages. This study adds additional evidence to support that hypothesis. The possible role of plasma cells in the yolk sac is discussed.

Background: In previous studies, the authors showed that various types of cultured tumor cells treated with exogenous bikunin protein or ovarian carcinoma cells transfected with bikunin cDNA have low invasiveness and diminished metastatic potential. This study was carried out to clarify the relation between the expression of individual bikunin mRNA and tumor progression., Methods: Forty-one newly diagnosed ovarian carcinomas were investigated using a semiquantitative reverse transcriptase-polymerase chain reaction., Results: The authors found that 24 patients had tumors that overexpressed bikunin and that gene expression was reduced in the tumors of the remaining 17 individuals. Bikunin mRNA expression was independent of age, surgical stage, tumor size, degree of differentiation, histologic subtype, and serum CA 125 levels. There was a significant correlation between low expression of bikunin mRNA and lymph node status (P=0.035) or peritoneal status (P=0.042). Multivariate analysis indicated that bikunin was an independent prognostic marker (P=0.013; hazard ratio, 2.30; 95 % confidence interval, 1.13-4.19), even after controlling for lymph node metastasis and the degree of peritoneal dissemination. In addition, low expression was a significant predictor for poor prognosis compared with high expression (2-year survival rate; 75.0 % vs. 47.1 %, respectively; P<0.05)., Conclusions: The data suggest that low bikunin mRNA expression by ovarian carcinoma cells may be associated with poor prognosis. It is conceivable that testing for bikunin mRNA may identify patients with ovarian carcinoma who are at high risk for early disease recurrence and a poor prognosis., (Copyright 2003 American Cancer Society.)

Background: Interleukin-8 (IL-8) has an essential role in the mechanism of parturition. IL-8 induces its effect through specific cell binding receptors. The main purpose of this research was to elucidate the presence of IL-8 receptors in the gestational tissues and their relation to parturition., Materials and Methods: Fetal membranes, placenta, umbilical cord and myometrial samples were collected before the initiation of labor during elective Cesarean sections (n = 15). Similar biopsies (except myometrial samples) were also gathered after normal vaginal delivery (n = 15). Immunohistochemical staining for IL-8 receptors type I and II was carried out for the fresh frozen sections of all samples. Immunoreactive score (IRS) was calculated for the stained sections., Results: IL-8 Receptors type I and II were recognized in the fetal membranes, placenta, umbilical cord and myometrial samples collected from patients before the initiation of labor. The staining of amnion and placentas were found to be more intensified in the samples collected after vaginal delivery compared to those from elective cesarean sections and before initiation of labor., Conclusions: Increased expression of IL-8 receptors after initiation of labor may indicate that IL-8 receptors might have a role during parturition.

Background: This research was aimed to study the biochemical changes in cervical mucus after application of laminaria tent., Material and Methods: Cervical mucus was collected before and after insertion of laminaria tent from 20 normal pregnant women in the first and second trimesters. Interleukin-1 beta, IL-8, collagenase activity, elastase activity, PGE2 and PGF2 alpha were measured in the collected samples. Laminaria tent was also inserted in one vaginal cervix of five non-pregnant rabbits and the clinical and histological changes were compared with five non-treated rabbits. Collagen contents were assessed histologically and Leukocyte number was counted., Results: IL-1 beta and IL-8 and elastase activity were significantly increased after insertion of laminaria (p<0.0001 and 0.001 respectively). Collagenase activity was not significantly changed. Whereas concentration of PGE2 and PGF2 alpha in the mucus were markedly increased (p<0.0001 and 0.001 respectively). Collagen contents were significantly decreased in laminaria and opposite side cervices (p<0.0001). No significant changes in leukocyte count could be observed in treated and non treated cervices., Conclusions: Insertion of laminaria leads to increase concentration of IL-1 beta, IL-8, PGE2, PGF2 alpha and elastase activity. Mechanical stretching of the cervix and biochemical changes in cervical mucus may explain the mechanism of cervical ripening induced by laminaria.

Urinary trypsin inhibitor is a glycoprotein which has an inhibitory effect on many enzymes, especially neutrophil elastase. The concentration of urinary trypsin inhibitor in serum (maternal and fetal), urine and amniotic fluid was measured in 20 cases of preeclampsia and compared with levels in normal pregnancy. Urinary trypsin inhibitor levels were significantly increased in the maternal and fetal serum of preeclamptic patients compared to normal pregnancy (p < 0.0001), as well as in urine and amniotic fluid of the same patients. Relative fluorescence release of a calcium chelating agent (fura-2) from human umbilical vein endothelial cell cultures was significantly increased by preeclamptic serum compared to serum of normal pregnant women (p < 0.03). After incubation of urinary trypsin inhibitor with the cultures, significant decrease of fura-2 release was observed (p < 0.03). Urinary trypsin inhibitor has an effect on suppression of activated neutrophils, elastase production and may have a protective effect on endothelial cells.

The effects of amphiphilic excipients on the inactivation of lactate dehydrogenase (LDH) during freeze-thawing and freeze-drying were studied. Some amphiphilic excipients such as hydroxypropyl-beta-cyclodextrin (HP-beta-CD), CHAPS, polyethylene glycol (PEG) 3350, and sucrose fatty acid monoester prevented LDH inactivation during freeze-thawing and freeze-drying at a lower concentration than sugars and amino acids. Polyoxyethylene 9 lauryl ether and PEG 400 protected LDH during freeze-thawing but not during freeze-drying. The buffer concentration of the solution to be freeze-dried (10, 50, and 200 mM) affected the stabilizing effect of trehalose, but not that of HP-beta-CD. (c) 1994 John Wiley & Sons, Inc.

The present study was undertaken to determine whether monoclonal antibodies (moABs TKH-2, MA54, MA61, B72.3, and CC49) directed toward O-linked mucin-type glycoprotein detect the NeuAc alpha 2-6GalNAc (sialyl Tn) epitope in meconium- and amniotic fluid-derived mucin. Fetal colonic mucosal cells express the sialyl Tn antigen, particularly in goblet cell mucin. The reactivities of these moABs with a perchloric acid extract of meconium (meconium extract) and different native and neuraminidase treated glycoproteins were examined by solid-phase enzyme-linked immunosorbent assay (ELISA). All the moABs react with the meconium supernatant and meconium extract. The reactivities of TKH-2, MA54, and MA61 are neuraminidase sensitive, and the reactivity of TKH-2 with meconium extract was specifically inhibited by ovine submaxillary mucin (OSM). A NeuAc alpha 2-6GalNAc epitope is the characteristic component in meconium. Mucin released from the fetal respiratory tract could, in part, provide an alternative source in the amniotic fluid. TKH-2 is the most sensitive antibody directed to sialyl Tn antigen in meconium supernatant. The likelihood of TKH-2 serving as the basis for a sensitive assay to detect sialyl Tn in meconium- and amniotic fluid-derived mucin is provided.

A highly sensitive and simple method for the determination of prostaglandins (PGs) by HPLC with fluorescence detection is described. PGs are converted to the corresponding fluorescence derivatives by the reaction with 4-(N,N-dimethylaminosulphonyl)-7-(1-piperazinyl)-2,1,3-benzoxadiaz ole (DBD-PZ) in the presence of 2,2'-dipyridyl disulphide and triphenyl phosphine in acetonitrile. The reaction is completed at room temperature after 30 min. The DBD derivatives of nine PGs are separated within a single 45 min chromatographic run on a reversed phase ODS column with a linear gradient elution using water and acetonitrile. The detection limits (signal-to-noise ratio of 3) calculated from the standard mixture of PGs (6-keto-F1 alpha, F1 alpha, F2 alpha, E1, E2, D2, limaprost, A1 and B1) are in the range 1.7-5.0 fmol. The applicability of the proposed procedure is evaluated to the detection of PGs added to rat plasma.

Granulocyte elastase (elastase)-like activity in 119 samples of cervical mucus from pregnant women was measured. Though elastase-like activity in normal pregnant women was low in 2nd and 3rd trimesters (less than 20 units), it increased during labor (1st stage of labor: 70 +/- 50 U/l; 2nd stage: 72 +/- 56). Elastase-like activity in pregnant women with imminent premature delivery (24-30 gestational weeks) was also high (78 +/- 57). Elastase-like activity of cervical mucus correlated with Bishop score in both normal term and preterm labor. Elastase-containing granulocytes were identified by immunohistochemistry in ripened cervix in normal and preterm labor. Some granulocytes degranulate and release elastase into the cervical stroma. Others migrate through the basement membrane of the endocervix to reach the cervical canal. Elastase could not be demonstrated in immature cervix as assessed by Bishop score. The staining intensity of elastase in the cervix correlated closely with elastase-like activity in cervical mucus. Thus elastase-like activity in cervical mucus reflects the degree of cervical maturation. These results lead one to speculate that elastase is one of the neutral proteases which depolymerize and degrade collagen in the ripening cervix.