ABCB1基因多态性与甲基化对氯吡格雷和阿司匹林抵抗影响的研究进展

氯吡格雷联合阿司匹林的双重抗血小板治疗是预防介入术后缺血事件再发生的标准药物治疗方案。然而仍有部分患者会出现氯吡格雷抵抗和阿司匹林抵抗现象。两种药物产生抵抗存在很多方面的影响因素,如患者的依从性、给药剂量、遗传因素等。遗传因素为主要因素,相关研究较多。目前,已经发布了CYP2C19基因多态性的药物剂量调整指南,但ABCB1基因对两种药物抵抗影响的研究并未达成一致的结论。本文对ABCB1基因多态性与甲基化对氯吡格雷抵抗和阿司匹林抵抗的影响进行综述,主要包括:氯吡格雷和阿司匹林抵抗的概念,ABCB1基因多态性与两药抵抗相关性,ABCB1基因启动子区域甲基化差异对药物抵抗的影响等。     

AMI患者的血小板对抗血小板药物反应性与远期预后的相关性

目的探讨AMI(acute myocardial infarction)患者经标准剂量阿司匹林与氯吡格雷治疗后的血小板反应性与远期预后的相关性。方法收集我院90例急性ST段抬高型心肌梗死患者,全部行经皮冠状动脉介入治疗,并在入院时给予300mg阿司匹林,氯吡格雷600mg负荷剂量口服,之后每天给予阿司匹林100mg,氯吡格雷75mg。使用电阻法监测抗血小板治疗的效果,根据血小板聚集曲线了解血小板聚集的程度和速度。1个月和6个月后进行复检,一年后进行电话随访。结果对两种药物都有反应的患者只有7.7%发生MACEE(major adverse cardiac and cerebrovascular events),但是,对一种药物低反应的发生MACCE有23%,对两种药物都抵抗的有44%发生MACCE(P=0.003),差异有统计学意义。结论患者对抗血小板药物的反应性与临床预后相关,与对抗血小板药物抵抗的患者相比,对抗血小板药物反应良好者发生MACCE更少。     

急性缺血性脑卒中患者抗血小板药物反应性与血小板参数及凝血功能的关系

目的 探讨急性缺血性脑卒中患者抗血小板药物反应性与血小板参数及凝血功能的关系。方法 收集在河北医科大学第三医院神经内科住院的服用阿司匹林和氯吡格雷的急性缺血性卒中患者214例，用药后测定血小板功能。根据抗血小板抵抗将其分为阿司匹林抵抗组，氯吡格雷抵抗组，阿司匹林敏感组与氯吡格雷敏感组。比较各组血小板参数与凝血指标并分析抗血小板抵抗与血小板参数[血小板数量(PLT)、平均血小板体积(MPV)、血小板分布宽度(PDW)、血小板压积(P-CT)]、凝血指标[凝血酶原时间(PT)、活化部分凝血酶原时间(APTT)、纤维蛋白原(FIB)、 D-二聚体(D-D)、凝血酶凝结时间(TT)]的相关性。结果 应用阿司匹林和氯吡格雷治疗后患者组的PT、APTT、TT均较治疗前延长，差异有统计学意义(P<0.05),FIB、D-D、PDW较治疗前降低，差异均有统计学意义(P<0.05)。阿司匹林敏感组与抵抗组FIB差异有统计学意义(P<0.05),其余各指标差异无统计学意义(P>0.05)。氯吡格雷敏感组和抵抗组在TT和PDW上差异有统计学意义(P<0.05),其余各指标差异无...     

急性冠状动脉综合症患者抗血小板治疗策略研究进展

血小板的激活在急性冠脉综合症的发生中起着重要的作用,阿司匹林联合二磷酸腺苷受体拮抗剂是目前抗血小板治疗的金标准,但临床发现不同患者对抗血小板药物的反应性存在显著的个体差异。本文主要从氯吡格雷的体内药动药效学过程出发分析其产生个体差异的影响因素,同时对目前的抗血小板治疗策略进行综述,以为临床制定安全有效的抗血小板方案提供参考。     

氯吡格雷基因多态性在东亚人群中的研究进展

氯吡格雷是临床应用最广泛的抗血小板药物之一,但其临床疗效存在明显的个体差异,除临床因素外,遗传因素为另一个导致氯吡格雷疗效个体差异性的因素。氯吡格雷血小板高反应性(HTPR)相关基因的突变频率存在显著的种族差异,东亚人群的相关基因突变频率高于西方人群。目前研究表明,东亚人群发生氯吡格雷治疗期间HTPR的比例为20%~30%,高于西方人群,且CYP2C19*2和*3为HTPR的独立风险因素。通过增加氯吡格雷剂量,三联抗血小板治疗或换用新型P2Y12受体拮抗剂等策略可改善患者HTPR,并降低心血管事件的发生风险。     

两例氯吡格雷抵抗病例的相关实验室数据分析

氯吡格雷联合阿司匹林双联抗血小板治疗是急性冠脉综合征的重要治疗手段,随着阿司匹林及氯吡格雷抵抗现象的出现,氯吡格雷抵抗的机制及相关实验室检查方法层出不穷,本文对2例氯吡格雷抵抗患者相关实验室检查进行分析,探讨氯吡格雷抵抗的正确定义及检查方法。     

基因多态性对急性脑梗死患者抗血小板聚集药物个体化用药的临床价值

目的研究阿司匹林、氯吡格雷、西洛他唑的药物基因多态性特点及其在脑梗死患者个体化给药中的临床应用价值。方法选取2018年12月-2019年6月就诊中国人民解放军联勤保障部队第九〇〇医院神经内科的139例急性脑梗死患者,所有患者入院后均口服硫酸氢氯吡格雷片75mg,1次/d,用药后均行阿司匹林、氯吡格雷、西洛他唑的药物基因检测,结合患者的一般信息对3种药物基因检测结果进行统计分析,依据基因检测结果和循证医学证据选择个体化抗血小板聚集药物治疗方案,记录患者住院期间和出院后90d使用抗血小板聚集药物出现的不良反应和临床疗效。结果在139例患者中,氯吡格雷中代谢、慢代谢的患者有83例,阿司匹林高抵抗的患者有52例,西洛他唑弱代谢型的患者有9例,其中对氯吡格雷抵抗的患者比例最高,达59.71%。合并基础疾病的患者中,糖尿病为氯吡格雷抵抗的独立危险因素之一,差异具有统计学意义(P<0.05),而对于阿司匹林、西洛他唑则无统计学差异。对于氯吡格雷抵抗的患者均按基因检测的结果调整抗血小板聚集药物治疗方案,所有患者随访90d均未出现新发的脑血管事件。结论抗血小板聚集药物基因多态性在急性脑梗死患者的治疗中具有重要的参考价值。     

阿司匹林和氯吡格雷抵抗机制及应对方略

随着 CURE,CREDO 研究结果的公布,阿司匹林和氯吡格雷双联抗血小板成为治疗冠心病和经皮冠状动脉介入（percata-neous coronary intervention,PCI）术后长期抗血小板治疗是一种重要的治疗策略。然而,这一策略最近又暴露出了很多问题,在临床上有部分患者接受上述双联抗血小板药物治疗后仍有心肌梗死,猝死等心血管恶性事件的发生。因此,正确认识和处理阿司匹林和氯吡格雷抵抗具有重要的临床意义。     

氯吡格雷联合阿司匹林用于冠状动脉粥样硬化性心脏病患者经皮冠状动脉介入术后抗血小板治疗的疗效与预后相关性分析

目的探讨氯吡格雷联合阿司匹林用于冠状动脉粥样硬化性心脏病(CAD)患者经皮冠状动脉介入术(PCI)后抗血小板的疗效与预后相关性。方法入选2019年1月至2019年8月期间某院心血管内科CAD住院患者408例,行PCI术后予以氯吡格雷联合阿司匹林双联抗血小板治疗,即规律服用阿司匹林100 mg/d联合氯吡格雷75 mg/d。用药前及用药后均采用光学比浊法(LTA)测定血小板聚集率(PA),包括阿司匹林抗血小板反应性(LTA_(AA))及氯吡格雷抗血小板反应性(LTA_(ADP))。并根据PA结果进行分组,将LTA_(AA)≥20%定义为阿司匹林抵抗(AR),LTA_(ADP)值≥70%定义为氯吡格雷抵抗(CR)。所有患者随访6~12个月,观察心血管事件发生率。结果根据LTA法测定结果,将入选患者分为CR组和非氯吡格雷抵抗(NCR)组,入选患者中无AR。其中CR组为101例,NCR组307例,CR发生率为24.8%。所有入院患者中共有46例患者发生心血管事件,其中CR组患者中心血管事件发生17例(16.8%),NCR组患者中心血管事件发生率为29例(9.4%),CR组患者发生心血管事件发生风险显著高于NCR组(OR=1.940,95%CI:1.016~3.703,P<0.05)。多因素COX回归分析提示,吸烟因素、Grace评分及CR为CAD患者PCI术后发生心血管事件的风险因素。结论氯吡格雷联合阿司匹林用于CAD患者PCI术后抗血小板治疗安全有效;CR与心血管事件发生风险相关。     

氯吡格雷抵抗

氯吡格雷抵抗包括对氯吡格雷无反应和对氯吡格雷低反应。氯吡格雷抵抗者血小板聚集率高,易发生心血管事件。氯吡格雷抵抗原因主要包括药物-药物相互作用影响CYP 3A4的活性,P2Y12受体和CYP 3A4基因的多态性。     

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.

     

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.