奥硝唑对映体对小鼠中枢抑制作用机制探究

【摘 要】 目的： 探讨右旋奥硝唑中枢抑制效应与脑内γ－氨基丁酸系统的关系。方法：经不同剂量右/左奥硝唑处理后使用Ｎ-Ｎ二甲基二吖啶硝酸盐(MQAE)荧光探针检测原代培养小鼠皮层神经元氯离子浓度， 并通过western blot方法检测GABAA受体亚基的表达。尾静脉注射给予右/左奥硝唑后测定小鼠高架十字迷宫行为。结果：右旋奥硝唑剂量依赖型激活小鼠皮层神经元的氯离子通道，经右旋奥硝唑处理后皮层神经元能增加GABAA受体α1亚基的水平且右旋奥硝唑有潜在的抗焦虑活性。结论: 右/左奥硝唑中枢作用不同，右旋奥硝唑较强的中枢抑制作用可能与激活GABA系统有关。     

几种静脉麻醉药对GABA能神经元的Phasic／Tonic抑制的影响

γ-氨基丁酸（gama-amino butyic acid ,GABA ）是广泛存在于中枢神经系统中一种重要的抑制性神经递质,参与调控睡眠和镇静等作用,主要通过作用于 GABAA 离子型亚基受体发挥生理效用。GABAA 受体属配体门控离子通道受体,通过增加神经细胞膜对氯离子和碳酸根离子的通透性,使细胞膜外高浓度的阴离子顺浓度梯度产生内向流动,从而引起突触后的超极化反应,导致神经元的兴奋性降低,这种由突触内的GABAA 型受体短暂的或“阶段性”的激活突触囊泡释放GABA ,从而产生的抑制,称为Phasic抑制,也是 GABAA 受体介导抑制性作用的经典途径。而近年来,研究者们提出了一种GABAA 受体介导的新型抑制作用即Tonic抑制［1］,它是由于轴突末梢保持一种持续少量的GA-BA释放,细胞外低浓度GABA 的环境能持续性的激活突触外的GABAA 受体引起的生理效应。本篇拟综述突触内和突触外GABAA 受体在控制神经元兴奋性的独特作用以及与全麻机制相关的最新研究进展。     

脑源性神经营养因子对大鼠海马神经元GABAA受体效应的影响

目的:观察不同浓度脑源性神经营养因子(BDNF)对大鼠海马神经元γ-氨基丁酸(GABA)A受体效应的影响。方法:原代培养海马神经元,应用BDNF(100、300及1000 ng/L)处理20 min后,施加GABA(终浓度为100μmol/L),5 min后应用流式细胞仪测定细胞内钙离子浓度。采用全细胞膜片钳记录模式,向锥体细胞施加BDNF(100、300及1000 ng/L)2 min,再施加GABA 100μmol/L并持续5 s,记录钳制电位为-60 mV时的GABAA受体电流。将神经元钳制电位从-100 mV至0 mV以10 mV递增,记录BDNF作用下GABAA受体电流的幅度和方向,并绘制电流电压曲线,计算GABAA受体电流的反转电位。结果:BDNF 100 ng/L和300 ng/L对GABA诱发的细胞内钙浓度、GABAA受体电流及反转电位均无影响,但在BDNF 1000 ng/L作用下,GABA诱发的细胞内钙浓度显著增加(P<0.05),GABAA受体电流在钳制电位-60 mV时变为外向电流,并且反转电位由对照的0 mV左移至-93 mV。结论:高浓度BDNF可使GABAA受体电流反转电位左移,导致GABA诱发锥体细胞内钙浓度增高而发挥兴奋效应。     

大鼠耳蜗螺旋神经节神经元GABA_A受体激活电流的特性

目的研究大鼠耳蜗螺旋神经节神经元GABAA受体激活电流的特性。方法采用全细胞膜片钳记录技术,观察离体培养大鼠螺旋神经节神经元上GABAA受体激活电流的特点。结果不同浓度的GABA可诱出螺旋神经节神经元的内向电流,该电流可被10μM荷包牡丹碱可逆性阻断。GABA诱导出的内向电流幅度随着浓度（10、50、100、500μM）的增大而增大。结论耳蜗螺旋神经节神经元可诱出GABAA受体电流,GABA诱导的GABAA受体电流呈浓度依赖关系。     

左奥硝唑与奥硝唑治疗急性盆腔炎疗效和经济学评价的回顾性研究

摘要：目的:对比分析左奥硝唑和奥硝唑治疗急性盆腔炎的临床有效性、安全性及经济性。方法:收集2018年1月～2019年6月武汉大学人民医院妇产科诊断为急性盆腔炎的住院患者资料进行回顾性研究,根据治疗方案分为左奥硝唑联合头孢替安组(左奥硝唑组)和奥硝唑联合头孢替安组(奥硝唑组)采用1∶1病例对照方法对两组进行匹配。比较两组患者用药后的临床有效率、细菌清除率、不良反应发生率,并结合住院时间和住院费用进行药物经济学分析。结果:共成功匹配左奥硝唑组和奥硝唑组病例各50例。左奥硝唑组和奥硝唑组的临床有效率、厌氧菌清除率比较,差异无统计学意义(P>0.05)。两组患者的白细胞恢复情况、腹痛和发热改善情况等比较差异均无统计学意义(P>0.05);不良反应发生率差异也无统计学意义(P>0.05),不良反应类型为胃肠道反应和肝功能异常,未见其他不良反应。左奥硝唑组和奥硝唑组患者平均住院时间比较差异无统计学意义(P>0.05),奥硝唑组治疗方案的成本-效果比明显低于左奥硝唑组,左奥硝唑组的增量成本-效果比为316.50。结论:左奥硝唑和奥硝唑治疗急性盆腔炎均有效、安全,但奥硝唑更具有经济性,这一结论仍需进一步临床研究证实。     

GABA受体激动剂对氧-葡萄糖剥夺诱导皮层神经元死亡的保护作用

目的:研究GABA受体激动剂对氧-葡萄糖剥夺诱导皮层神经元死亡的保护作用。方法:培养12d的皮层神经元更换为Earle's平衡盐溶液(Earle's balanced salts,EBSS)后置于37℃三气缺氧(N2:CO2:O2=94%:5%:1%)培养箱内培养,4h后恢复正常条件培养,同时在培养液内加入GABA A受体和B受体激动剂作用24h,用Hoechst33342/PI的染色方法检测其死亡情况。结果:GABA A受体激动剂(musci mol)和GABA B受体激动剂(baclofen)均分别能显著降低神经细胞死亡率49.9%和35.3%。结论:GA-BA A受体激动剂和B受体激动剂对氧-葡萄糖剥夺诱导的皮层神经元死亡均有显著的保护作用。     

γ-氨基丁酸及拮抗剂对大鼠黑质致密部神经元活动的影响

目的:研究γ-氨基丁酸(γ-Aminobutyric Acid,GABA)和GABAA受体阻断剂荷包牡丹碱(Bicuculine,Bic)对大鼠黑质致密部(pars compacta of substantia nigra,SNc)神经元自发放电活动的影响。方法:采用微电泳及细胞外记录方法观察GABA和Bic对SNc神经元自发放电活动的影响。结果:GABA使42个受试神经元自发放电活动几乎完全停止。在30个受试神经元中,Bic使22个神经元放电频率加快,6个神经元无作用,2个神经元受到抑制。在35个受试神经元中,微电泳GABA期间给予GABAA受体阻断剂Bic,其可使91.43%神经元放电频率加快。结论:GABA能投射对SNc神经元有抑制作用,GABAA受体阻断剂Bic能拮抗GABA的抑制作用。     

GABA_A受体研究现状

γ-氨基丁酸(GABA)是中枢神经系统中一种重要的抑制性氨基酸类神经介质,通过与GABA受体结合而发挥功能。根据受体对兴奋剂和拮抗剂敏感性的不同,可将GABA受体分为3个药理学亚型——GABAA、GABAB和GABA[1]C;根据配体与受体作用的方式不同,可将GABA受体分为2类——离子型受体GABAA、GABAC和代谢型受体GABAB。GABAA受体是三者中最为重要的一种,因为:①约50%的中枢突     

依托咪酯对小鼠小脑皮层浦肯野细胞自发放电活动的影响

<正>依托咪酯(etomidate,ET)是一种作用强、短效的非巴比妥类静脉麻醉药,常用于麻醉诱导和门诊手术麻醉。研究表明,ET可直接或间接作用于丘脑皮层神经元GABAA受体,产生GABA样的作用,或增强GABA与GABAA受体结合所引起的效应,减少神经元动作电位的发生频率~([1])。ET明显抑制初级感觉皮层锥体细胞电压门控Na~+通道,减小Na~+电流,提示ET可能通过抑制初级感觉皮层神经元Na~+通道,降低神经元兴奋性~([2]),而ET影响小脑皮层神经元功能的文     

口腔厌氧感染患者应用不同药物治疗效果比较分析

目的比较与分析左奥硝唑氯化钠注射液与奥硝唑氯化钠注射液治疗口腔压氧菌感染者的临床疗效及安全性。方法 86例口腔厌氧菌患者按照随机抽签法分为对照组与观察组。对照组采用奥硝唑氯化钠注射液,静脉滴注,2次/d;观察组采用左奥硝唑氯化钠注射液,静脉滴注,2次/d。比较2组临床治疗效果与治疗期间所发生不良反应,同时评价2者安全性。结果治疗后,观察组治疗有效率为93%(40/43)与对照组88%(38/43)比较差异无统计学意义(P>0.05);2组厌氧菌清除率比较差异无统计学意义(P>0.05)。左奥硝唑氯化钠注射液治疗不良反应发生率小,2组患者不良反应发生率,差异有统计学意义(P<0.05)。结论相对奥硝唑氯化钠注射液来说,左奥硝唑氯化钠注射液的临床疗效及细菌清除效果与其相当,但其临床治疗过程中所发生不良反应少,因而更具有安全性。     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

Glycofection: The Ubiquitous Roles of Sugar Bound on Glycoplexes

Glycofection (transfection by using sugar-substituted polylysine) was assessed in order to provide an alternative to viral vectors for the transfer of genes into vascular smooth muscle cells. A rabbit vascular smooth muscle cell line (Rb-1 cells) was selectively transfected by using glycoplexes (glycosylated polylysine/pSV2LUC complexes) in the presence of 10 mu M of the fusogenic peptide GALA. A sugar-specific transfection was obtained when the glycofection was conducted for 1 h with glycoplexes containing either alpha Gal, alpha -Glc, alpha -GalNAc, beta -GlcNAc, or beta -GalNAc residues. The gene expression was high after transfection, with glycoplexes bearing alpha Gal, alpha -GalNAc, or beta -GalNAc residues that were weakly internalized, and low with glycoplexes carrying Lact or Rha residues that were well taken up by cells. These results suggest that 1) glycofection can be a good approach for a selective transfer of genes intovascular smooth muscle cells, 2) an efficient uptake of the glycoplexes is not the unique limiting step for an efficient transfection, and 3) the sugar-dependent trafficking of the glycoplexes inside the cells may account for the transfection efficiency.     

直肠癌下切缘病理组织学分析

目的探讨直肠癌逆向浸润与下切缘的安全距离的关系。方法对36例直肠癌Miles手术和Dixon手术后标本的肿瘤下缘1.0cm、2.0cm、3.0cm的肠壁及对应的系膜病理组织学检查,观察直肠癌逆向浸润或转移的距离。结果36例直肠癌标本距癌肿下缘1.0 cm、2.0cm、3.0cm的肠壁及对应的系膜病理组织学检查均为阴性,结论直肠癌远恻逆向浸润或转移未见超过1.0cm,因此认为保肛手术时切除肿瘤远侧肠管(包括系膜)2.0cm是安全的。