Biochemical and behavioural characterization of EMPA,a novel high-affinity,selective antagonist for the OX2 receptor

Background and purpose:

The OX₂ receptor is a G-protein-coupled receptor that is abundantly found in the tuberomammillary nucleus, an important site for the regulation of the sleep-wake state. Herein, we describe the in vitro and in vivo properties of a selective OX₂ receptor antagonist, N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulphonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA).

Experimental approach:

The affinity of [³H]EMPA was assessed in membranes from HEK293-hOX₂-cells using saturation and binding kinetics. The antagonist properties of EMPA were determined by Schild analysis using the orexin-A-or orexin-B-induced accumulation of [³H]inositol phosphates (IP). Quantitative autoradiography was used to determine the distribution and abundance of OX₂ receptors in rat brain. The in vivo activity of EMPA was assessed by reversal of [Ala¹¹,D-Leu¹⁵]orexin-B-induced hyperlocomotion during the resting phase in mice and the reduction of spontaneous locomotor activity (LMA) during the active phase in rats.

Key results:

[³H]EMPA bound to human and rat OX₂-HEK293 membranes with K_D values of 1.1 and 1.4 nmol·L⁻¹ respectively. EMPA competitively antagonized orexin-A-and orexin-B-evoked accumulation of [³H]IP at hOX₂ receptors with pA₂ values of 8.6 and 8.8 respectively. Autoradiography of rat brain confirmed the selectivity of [³H]EMPA for OX₂ receptors. EMPA significantly reversed [Ala¹¹,D-Leu¹⁵]orexin-B-induced hyperlocomotion dose-dependently during the resting phase in mice. EMPA, injected i.p. in rats during the active phase, reduced LMA dose-dependently. EMPA did not impair performance of rats in the rotarod procedure.

Conclusions and implications:

EMPA is a high-affinity, reversible and selective OX₂ receptor antagonist, active in vivo, which should prove useful for analysis of OX₂ receptor function.     

血管紧张素转换酶抑制剂对心力衰竭患者细胞因子干预作用的研究进展

充血性心力衰竭（congestive heart failure,CHF）是多种心血管疾病所致的一种临床综合征,其病理生理机制除交感神经系统（sympathetic nervous system,SNS）和肾素-血管紧张素-醛固酮系统（rennin-angiotensin-aldosterone system,RAAS）的激活外,细胞因子的激活和失衡也参与了CHF的发生发展过程。有研究证实,血管紧张素转换酶抑制剂（angiotensin convertingenzyme inhibiter,ACEI）不但能阻断SNS及RAAS的激活,还能调整细胞因子网络的失衡,逆转心室肥厚以及防止和延缓心室重构,有助于延缓、遏止CHF进展。本文总结了ACEI对CHF患者血清炎症细胞因子的干预作用的研究现状,探讨通过此途径治疗CHF的效果。     

肠癌患者中医基本证候的临床调查分析

目的：探讨肠癌患者中医证候的临床分布规律。方法：对311例肠癌患者进行临床流行病学调查,组织专家组对其进行辨证,对患者正虚和邪实类基本证候的出现频率进行统计。结果：正虚类证候中,以脾气虚、脾胃虚弱、阴虚（火旺）、肝阴虚和肾阴虚证候为主;邪实类证候中以痰浊流注、血瘀、血热、肝气郁滞、湿（痰）浊内生、湿热内蕴、胃肠积热为主。结论：肠癌中医基本证候分布具有一定的规律性。     

肿瘤标志物在乳腺肿瘤诊断价值的探讨

目的探讨肿瘤标志物在乳腺肿瘤诊断的价值。方法对162例乳腺恶性肿瘤（A组）、34例乳腺良性肿瘤（B组）、78例健康成人（C组）进行血清CA15-3、CA19-9、CA24-2、CA125和CEA五项指标的检测,并进行对比分析。结果（1）5种肿瘤标志物在A组的阳性分布高于B组和C组（P〈0.01）;（2）5种肿瘤标志物对乳腺恶性肿瘤诊断的阳性率为：越晚期的恶性肿瘤各标志物的阳性率越高;（3）5种标志物联合检测提高诊断的阳性率;（4）乳腺恶性肿瘤术后或化疗可使各项标志物的水平降低。结论血清CA15-3、CA19-9、CA24-2、CA125和CEA五项肿瘤标志物在乳腺恶性肿瘤的阳性分布高,手术或化疗可使肿瘤标志物水平下降。     

Effect of Fire on Pools of Mercury in Forest Soil,Central Europe

In year 2006, 17.9 ha of forest was burned during a forest fire at the Bohemian Switzerland National Park found in northern part of Czech Republic (CR), central Europe. Complete combustion of organic soil (4,039 t) on the burned area caused volatilization of 1.34 ± 0.07 kg of Hg. Thus Hg emissions due to fire amounted to 75.1 g ha⁻¹. The average burned forested areas in CR for the period 2000–2006 were reported at 356 ha with estimated Hg emissions at 26.7 kg year⁻¹, while the average anthropogenic emissions in the same period amounted to 3 t year⁻¹. Thus estimated mean emissions of Hg from burned forest soil in the period 2000–2006 reached 1% of the annual anthropogenic Hg emissions.     

2005～2007年郑州市腹泻患者志贺菌监测结果分析

[目的]了解郑州市志贺菌的菌型分布,为防控菌痢流行提供可靠数据。[方法]按照《全国细菌性痢疾监测工作方案》对郑州市市辖医院20052007年腹泻患者粪便标本进行志贺菌分离培养、生化鉴定和血清学分型以及药敏试验。[结果]20052007年郑州市共检测1 321份标本,检出志贺菌116株,检出率为8.78%。志贺菌分布在福氏和宋內氏2个群,未检出A群和C群。不同年份间菌株均以B群志贺菌为主,分别为39、37和21株,分别占当年阳性菌株的92.86%、77.08%、80.77%;福氏志贺菌以F4c（47株）为主,占48.45%,其次是F1a（21株）、F2a（17株）,分别占21.65%和17.53%;志贺菌对萘啶酸和四环素100.00%耐药。[结论]各年优势菌群均为福氏志贺菌,F4c为优势菌型,多种菌型并存,临床治疗要根据耐药情况合理使用抗生素。     

Prediction of Human Bioavailability from Human Oral Administration Data and Animal Pharmacokinetic Data Without Data from Intravenous Administration of Drugs in Humans

Purpose  To predict the absolute oral bioavailabilities (BAs) of drugs in humans without using pharmacokinetic data from intravenous administration in humans. Methods  The distribution volume of the terminal phase () in humans was predicted by three methods using animal pharmacokinetic data. Then, total body clearance (CL_tot) was calculated by multiplying the elimination rate constant and , and the BA was calculated as a ratio between CL_tot and oral clearance. The predicted and observed values were compared for 67 drugs for which pharmacokinetic data after intravenous administration in humans were available. Results  For , predicted values within twice the observed value were obtained for 72.1% of drugs by both methods Ia and Ib, respectively, in which only rat pharmacokinetic data were used. The corresponding percentage was 75.0% for method II, in which pharmacokinetic data from animals other than rats were used. For BA, predicted values within 1.3 times the observed values were obtained for 66.7% and 57.4% of drugs by methods Ia and Ib, respectively, and 75.0% by method II. Conclusions  Using the present methods, it is possible to predict BA from human oral administration data combined with animal pharmacokinetic data to a certain level without using intravenous injection data. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

泌尿系感染耐药分布及穿心莲对其作用的临床研究

目的：探讨泌尿系感染耐药分布及穿心莲对其作用的临床疗效价值,为临床合理使用抗生素提供可靠的参考依据。方法：收集2008年1月～2009年2月中山市三乡医院住院的中段尿细菌培养阳性的泌尿系感染患者。回顾性分析患者的病原菌分布和药敏试验结果,采用新的中药抑菌实验方法对穿心莲提取物进行100株凝固酶阴性葡萄球菌的最低抑菌浓度MIC测定。结果：共100例泌尿系感染患者尿细菌培养阳性,男35例,女65例。培养出100株病原菌,革兰阳性菌25株,革兰阴性菌75株。绝大多数病原菌均具有多重耐药性。穿新莲提取物对57株耐甲氧西林的凝固酶阴性葡萄球菌和43株甲氧西林敏感凝固酶阴性葡萄球菌的MIC50、MCI90分别为0．072,0．072mg/ml和0．288,0．144mg／ml。结论：穿心莲是很好的抗感染中药,临床用药应合理地选择抗生素。     

社区获得性肺炎病原学分布及药物治疗概况

目的:了解社区获得性肺炎病原体分布及药物治疗情况。方法:通过查阅相关国内、外文献。结果:社区获得性肺炎病原体中非典型病原体比率不断增加。结论:治疗社区获得性肺炎应强调应用针对非典型病原体的大环内酯类药物治疗     

我国药品不良反应监测工作对开展医疗器械不良事件监测的启示

为探讨我国医疗器械不良事件监测工作开展模式,分析比较影响药品不良反应监测与医疗器械不良事件监测工作发展的关键因素。根据医疗器械不良事件监测工作的特点,从相关法律法规制订、组织机构与人员配备、技术体系建设等方面提出了医疗器械不良事件监测的工作思路。