缺血后处理及其分子机制

Murry等[1]首先提出缺血预处理(ischem ic precond ition-ing,IP)概念,即一次或多次短暂重复心肌缺血再灌注,能提高心肌对此后发生较长时间缺血的耐受性。此后,人们又发现预处理存在快速和延迟两个时相,分别称经典预处理和晚期预处理。1999年国内学者高峰等[2]在研究成年大鼠心肌细胞培养细胞的缺氧/复氧模型时发现,如果在长时间复氧之前经过3次短暂的复氧/缺氧处理会比直接长时间的复氧在细胞存活率和细胞凋亡方面均有明显的改善,从而提出了缺氧后处理(hypoxic postcond ition ing)的概念。Zhao等[3]在2003年对狗的缺血再灌注研究中发现,…     

新型抗心绞痛药物雷诺嗪的研究进展

雷诺嗪是哌嗪类衍生物，它通过改变心肌能量代谢方式而减少心肌需氧量。其作用机制不同于传统的抗心绞痛药，特点是减少脂肪酸氧化，增加葡萄糖氧化，利用葡萄糖氧化每单位氧比脂肪酸氧化产能高而使心脏做更多功，发挥抗缺血和抗心绞痛作用，同时对血流动力学无影响。本文对雷诺嗪抗心绞痛可能的作用机制及临床应用等进行综述。     

曲美他嗪治疗缺血性心脏病的临床进展

缺血性心脏病的心肌供氧和需氧不平衡导致心肌缺氧。传统治疗,包括硝酸酯类、钙拮抗剂和β-受体阻滞剂,都是通过增加心肌氧供或降低心肌氧耗而发挥抗缺血作用。虽然可以改善冠心病病人的生活质量,但这类病人的病死率仍较高。为更好地控制缺血性心脏病,降低病死率,很重要的一点就是保护心肌,限制心肌损伤。曲美他嗪（ｔｒｉｍｅｔａｚｉｄｉｎｅ）是一种新型的抗缺血药物,通过调节心肌细胞能量代谢,在细胞水平提供保护作用,用于治疗缺血性心脏病,进展迅速。１心肌缺血的生化改变人类心肌细胞对缺血非常敏感,血供减少导致离子与代谢改变,并影…     

曲美他嗪在缺血性心脏病中的应用

缺血性心脏病（IHD）其病理特点是冠状动脉内粥样斑块,管腔狭窄或阻塞,导致心肌缺血,患者出现胸痛.斑块破裂提供了血小板聚集和血栓形成的场所,导致不稳定性心绞痛或心肌梗死.稳定性心绞痛常规应用β阻滞剂、硝酸酯类和钙阻滞剂,这些药物是通过增加心肌供氧或减少心肌需氧发挥作用的.近年来,作为代谢调节剂的一组药物,已充分显示其优势.曲美他嗪是该类药物的代表药,已发现在缺血心肌中,脂肪酸氧化增强,葡萄糖氧化受抑制,曲美他嗪通过抑制缺血心肌中脂肪酸的氧化,直接发挥心肌细胞的保护作用.其他的一些研究尚在进行中,以进一步阐明在与IHD有直接或间接关系的其他疾病中曲美他嗪的作用.本综述目的是总结近年来世界范围内所做的各种临床试验研究的结果,以评价该药在IHD中的作用及其确切机制,进一步认识其在心肌保护中的真正价值.     

曲美他嗪对缺血性心肌病患者的心肌纤维化和血浆脑钠肽水平的影响

缺血性心肌病(ICM)是冠心病的一种特殊类型,冠状动脉粥样硬化造成心肌细胞持续缺血,心肌纤维化,心肌细胞功能低下,影响心肌收缩功能和心室负荷,而心室负荷过重会导致脑钠肽(BNP)过度分泌。曲美他嗪能有效优化心肌氧代谢,因而具有较好的抗心绞痛和心肌保护作用,本文现将曲美他嗪治疗缺血性心肌病的药理作用机制,及对患者心肌纤维化和血浆脑钠肽水平的影响作简要综述。     

曲美他嗪治疗心肌梗死后心绞痛疗效观察

近年来,对于冠心病的药物治疗不再局限于抗血小板、调脂、改善血液动力学等药物.临床研究表明,心肌缺血也是一种代谢病,曲美他嗪作为一种心血管病治疗的辅助药物,其特有的优化心肌能量代谢的药理机制,对缺血心肌的保护作用明显.本研究旨在探讨曲美他嗪对心肌梗死后心绞痛发作的l临床疗效.     

短刺小克银汉霉AS3.153菌株对雷诺嗪的代谢转化

目的建立能够模拟雷诺嗪在哺乳动物体内代谢的微生物模型,并应用该模型制备代谢产物。方法采用液相色谱-质谱联用法测定雷诺嗪在4种小克银汉霉转化模型中的转化产物,选择其中转化能力最强的菌株,针对雷诺嗪3种主要代谢产物进行了培养基初始pH值、底物质量浓度、转化时间等转化条件的优化。结果短刺小克银汉霉AS 3.153对雷诺嗪的转化能力最强,将其转化为9种代谢产物,采用半制备液相色谱法制备分离得到3种主要代谢产物,确证其结构分别为羟基化雷诺嗪及雷诺嗪硫酸酯结合物。结论短刺小克银汉霉AS 3.153对雷诺嗪的转化与哺乳动物代谢结果类似,可作为模拟哺乳动物体内代谢的体外模型使用。     

三甲氧苄嗪对低温保存大鼠离体心脏的保护作用

目的：研究三甲氧苄嗪（10^-6M）对离体心脏低温保存的影响,并探讨其作用机制。方法：以改良的Lamgendorff离体鼠心灌注模型,观察三甲氧苄嗪加入UW液后（三甲氧苄嗪－10^-6M）,离体鼠心在4℃保存6小时后血流动力学、冠脉流出液心肌酶漏出量、心肌含水量、心肌ATP、MDA含量、心肌超微结构的变化。结果：UW液加入三甲氧苄嗪组与示加入三甲氧苄嗪组相比,复灌后心功能恢复率明显增高（P＜0.01）;心肌含水量（P＜0.05）及丙二醛含量较低（P＜0.01）;心肌酶漏出量明显减少（P＜0.01）;心肌ATP水平得到很好地维持（P＜0.01）;心肌超微结构尤其是线粒体结构改变轻,损伤小。结论：10^-6M三甲氧苄嗪对低温保存的大鼠心脏具有明显的保护作用。     

盐酸氟桂嗪工艺改进

氟桂嗪(Flunarizine)是哌嗪的双氟化衍生物[1],具有选择性钙通道阻滞作用,能透过血脑屏障.实验研究发现,氟桂嗪不影响正常细胞的钙平衡,而对在缺血和药理刺激下开放的钙通道起阻滞作用.能抑制血管的收缩、降低脑血管阻力、增加脑的血流量和氧分压,同时不增加脑组织的氧耗[2].还可以抑制动脉粥样硬化的病理进程,对实验性脑缺血具有保护作用[3].由此可见,氟桂嗪对脑血管疾病、眩晕、偏头痛、癫痫和脑复苏的抢救具有一定疗效[4].     

雷诺嗪后处理对大鼠心肌再灌注损伤营救激酶及线粒体渗透性转换孔道的影响

目的探讨雷诺嗪后处理对大鼠离体心脏缺血/再灌注时心肌细胞凋亡与再灌注损伤营救激酶(reperfusion inju-ry salvage kinase,RISK)及其线粒体渗透性转换孔道(mito-chondrial permeability transition pore,MPTP)的影响。方法建立Langendorff离体心脏灌流模型。56只SD大鼠随机分为8组(n=7):缺血/再灌注组(I/R组)、雷诺嗪后处理组(RPostC组)、雷诺嗪+atractyloside组(RA组)、雷诺嗪+PD98059组(RP组)、雷诺嗪+wortmannin(RW组)、atrac-tyloside组(A组)、P组和W组。各组均缺血30min/再灌注15min,药物后处理时间为再灌注开始后10min。用TUNEL法检测再灌注末心肌凋亡并计算凋亡指数(apoptotic index,AI),分光光度计测MPTP开放程度,Western blot法测p-AKT和p-ERK1/2的表达水平。结果与IR组比较,RPostC组心肌细胞AI和MPTP开放程度下降(P<0.05),RPostC、RA、RP和RW组p-AKT、p-ERK1/2蛋白表达升高(P<0.05),其它组间差异无统计学意义(P>0.05);与RPostC组比较,RA、RP、RW、A、P和W组AI和MPTP开放程度升高(P<0.05),RP、RW、A、P和W组p-AKT、p-ERK1/2蛋白表达下降(P<0.05),RA组p-AKT、p-ERK1/2蛋白表达差异无统计学意义(P>0.05);与RA组比较,RP、RW、A、P和W组AI和MPTP开放程度差异无统计学意义,p-AKT、p-ERK1/2蛋白表达下降(P<0.05)。结论雷诺嗪后处理对大鼠离体缺血/再灌注心肌具有明显的抗凋亡作用,其机制可能与其激活RISK途径和抑制MPTP开放有关。     

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.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

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.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.     

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.