服用氯吡格雷或替格瑞洛患者的血小板最大聚集率差异研究

摘 要 目的：研究经皮冠脉介入术（PCI）后服用氯吡格雷的患者与服用替格瑞洛的患者血小板最大聚集率（MAR）的差异和出血情况,为临床使用抗血小板药物提供参考。方法: 选取因急性冠状动脉综合征(ACS)入院行PCI后服用氯吡格雷或者替格瑞洛的患者,在出院前对其MAR值进行检测,随访3个月内出血事件的发生情况,并比较两组患者MAR值以及随访结果的差异。结果: 服用氯吡格雷的患者出院时MAR为（51.1±13.7）%（n=76）,服用替格瑞洛的患者MAR为（32.6±15.7）%（n=76）,两组差异有统计学意义（P<0.001）。随访结果显示氯吡格雷组出血事件低于替格瑞洛组（P<0.05）。结论: 服用替格瑞洛的患者出院后出血的倾向可能比服用氯吡格雷的患者更大。     

P2Y12基因多态性与心脑血管病患者氯吡格雷临床疗效相关性的Meta分析

摘 要 目的：采用Meta分析方法评价P2Y12基因多态性与心脑血管病患者氯吡格雷疗效及发生氯吡格雷抵抗的相关性。方法: 计算机检索MEDLINE、Embase、中国知网、中文生物医学文献数据库、万方数据库（时间为1995年1月~2016年12月）,全面收集有关血小板膜受体P2Y12基因多态性与发生氯吡格雷抵抗相关性的队列研究,纳入研究的受试者均为服用氯吡格雷的心脑血管疾病患者,排除动物实验研究,并对可纳入的研究进行严格的方法学质量评价,采用RevMan 5.1软件进行Meta分析。结果: 最终纳入10篇队列研究（英文3篇,中文7篇）,共5 223名受试者。Meta分析结果显示,使用氯吡格雷的心脑血管病患者中,C34T位点T等位基因携带者与CC型相比,发生不良心血管事件的风险的差异无统计学意义（RR=0.95,95%CI：0.82~1.09,P=0.46）;G52T位点T等位基因携带者发生不良心血管事件的风险高于GG型患者,差异有统计学意义（RR=1.99,95%CI：1.63~2.44,P<0.000 01）。C34T位点T等位基因携带者发生氯吡格雷抵抗的风险高于CC型患者,差异有统计学意义（RR=2.02,95%CI：1.37~2.96,P=0.000 4）。G52T位点T等位基因携带者发生氯吡格雷抵抗的风险高于GG型患者,差异有统计学意义（RR=1.56,95%CI：1.04~2.34,P=0.03）。i T744c位点C等位基因携带者发生氯吡格雷抵抗的危险与C等位基因非携带者相当,差异无统计学意义（RR=0.99,95%CI：0.78~1.25,P=0.92）。结论: C34T位点T等位基因可能是发生氯吡格雷抵抗的危险因素,G52T位点T等位基因可能是不良心血管事件和发生氯吡格雷抵抗的危险因素,i T744c位点C等位基因的存在不会增加发生氯吡格雷抵抗的风险。     

缺血性脑卒中患者发生氯吡格雷抵抗的危险因素分析

目的 探讨缺血性脑卒中患者服用氯吡格雷治疗后发生药物抵抗的危险因素，为促进临床个体化药物治疗提供依据。方法 选取202例诊断为缺血性脑卒中的住院患者，入中部战区总医院后均给予双抗治疗（阿司匹林+氯吡格雷），住院期间通过芯片杂交法检测CYP2C19基因型，将CYP2C19基因多态性根据药物代谢类型分为快代谢组、中代谢组和慢代谢组。患者服药7~14 d根据血栓弹力图（TEG）检测由腺苷二磷酸（ADP）诱导的血小板抑制率，将ADP<30%为氯吡格雷药物抵抗组，ADP≥30%为非抵抗组。采用Logistic回归分析研究发生氯吡格雷抵抗的危险因素。结果 202例缺血性脑卒中患者中，抵抗组87例，非抵抗组115例。氯吡格雷抵抗组合并糖尿病的患者比例和白细胞计数水平高于非抵抗组，差异均具有统计学意义（P<0.05）。CYP2C19中代谢组患者发生氯吡格雷抵抗的比例显著高于快代谢组，血小板抑制率也明显低于快代谢组，差异均具有统计学意义（P<0.05）。结论 合并糖尿病、高白细胞计数水平及CYP2C19中代谢型是缺血性脑卒中患者发生氯吡格雷抵抗的独立危险因素。     

冠心病合并糖尿病患者行经皮冠状动脉介入治疗后CD62p与氯吡格雷抵抗的相关性研究

目的 探讨冠心病合并糖尿病患者行经皮冠状动脉介入治疗后CD62p与氯吡格雷抵抗的相关性研究。方法 选择2013年8月-2016年12月在北京市昌平区医院行经皮冠状动脉介入治疗的冠心病合并糖尿病患者150例,所有患者手术前后接受氯吡格雷治疗,比较患者治疗前后血小板聚集率的变化情况,根据血小板聚集率变化的幅度是否 ≥ 10%,将患者分为氯吡格雷有效（C2）组和氯吡格雷抵抗（C1）组,分别检测两组患者CD62p以及血小板最大聚集率（PAGM）的水平,并分析其变化与血小板聚集率变化情况的相关性。结果 经治疗,患者血小板聚集率较治疗前均显著降低,差异有统计学意义（P<0.05）。根据血小板聚集率下降幅度分为C1组（57例）和C2组（93例）,其中C1组患者CD62p较治疗前显著降低,差异有统计学意义（P<0.05）;C2组患者CD62p、PAGM较治疗前均显著降低,且变化幅度显著大于C1组,差异有统计学意义（P<0.05）;C2组治疗前后CD62p的变化幅度与PAGM下降幅度的相关性（r=0.424,P=0.001）优于C1组（r=0.387,P=0.020）。结论 氯吡格雷对冠心病合并糖尿病患者行经皮冠状动脉介入治疗后血小板的活性具有一定的抑制作用,氯吡格雷抵抗可能与血小板活性状态相关。     

CYP2C19基因多态性对PCI术后患者氯吡格雷血药浓度、血小板抑制率和安全性的影响

目的 探讨CYP2C19基因多态性对氯吡格雷血药浓度、血小板抑制率和安全性的影响。方法 根据纳入和排除标准,筛选我院使用氯吡格雷的经皮冠状动脉介入治疗(PCI)术后患者,收集氯吡格雷用药后第6天的血样,采用反相高效液相色谱(RP-HPLC)法测定氯吡格雷血药浓度,非扩增免疫杂交技术检测患者CYP2C19基因型,并通过血栓弹力图来评估血小板抑制率。应用SPSS 20.0对数据进行统计分析。结果 共纳入87例患者,男性46例,女性41例;其中34例为快代谢型,38例中代谢型,15例慢代谢型;结果显示,快、中代谢型的药物浓度无显著性差异（P=0.667）,而慢代谢型与快、中代谢型药物浓度有显著性差异(P<0.05);方差分析和卡方检验显示CYP2C19基因多态性对氯吡格雷的血小板抑制率和安全性的影响有显著性差异(P<0.05）。结论 仅根据CYP2C19基因型指导氯吡格雷临床用药并不一定达到较好的治疗效果,可联合CYP2C19基因型检测与血药浓度监测来指导氯吡格雷的临床个体化给药。     

2014～2017年连云港地区部分汉族冠心病患者CYP2C19基因多态性分析

摘 要 目的：分析连云港地区部分汉族冠心病患者氯吡格雷代谢关键酶CYP2C19基因多态性分布情况,为临床实现抗血小板药物的个体化治疗提供参考依据。方法：选取2014～2017年我院冠心病患者302例,检测CYP2C19基因型,统计代谢表型分布特征,并对比不同地区汉族人群代谢表型分布差异。结果：302例患者CYP2C19*1、*2、*3、*17等位基因频率分别为62.58%,29.30%,5.46%,2.65%,CYP2C19基因型*1/*1、*1/*2、*1/*3、*1/*17、*2/*17、*3/*17、*2/*2、*2/*3频率分别为36.42%,41.06%,7.29%,3.98%,0.99%,0.33%,6.62%,3.31%,CYP2C19代谢表型分别为超快代谢型12例（3.98%）、快代谢型110例（36.42%）、中间代谢型150例（49.67%）及慢代谢型30例（9.93%）。各代谢型与国内其他地区汉族冠心病患者相比差异无统计学意义（P>0.05）。结论：连云港地区汉族冠心病患者基因型以CYP2C19*1/*2为主,代谢表型以中间代谢型为主,代谢表型分布与国内其他地区基本一致。     

CYP2C19基因多态性及患者主要临床资料与氯吡格雷药物抵抗的相关性研究

目的观察药物代谢酶系统中CYP2C19基因多态性及患者主要临床资料与服用氯吡格雷前后血小板聚集率变化(氯吡格雷药物抵抗)的相关性。方法入选拟行冠脉造影检查或支架植入治疗患者35例,根据围手术期应用氯吡格雷前后血小板聚集率变化,将患者分为氯吡格雷抵抗组和非抵抗组。检测CYP2C19基因型,并记录患者年龄、性别、烟酒史、高血压、糖尿病等主要临床资料,分析基因水平及临床水平各因素对血小板聚集及氯吡格雷药物抵抗的影响。结果检测出氯吡格雷抵抗的患者15例,CYP2C19慢代谢基因型患者4例,Logistic回归分析显示,CYP2C19基因型是氯吡格雷抵抗的危险因素(OR=1.236,95%CI:0.273~5.599,P=0.049)。结论 CYP2C19基因型在基因水平与氯吡格雷抵抗相关,临床水平资料未见明显相关性。     

血府逐瘀胶囊对重度血瘀证患者经皮冠状动脉介入治疗术后氯吡格雷抵抗的调节作用

目的 观察血府逐瘀胶囊联合氯吡格雷治疗氯吡格雷抵抗患者的效果,评价其改善氯吡格雷抵抗作用的效果。方法 经皮冠状动脉介入治疗（PCI）术后氯吡格雷抵抗患者80人,随机分组,分别给予3种药物治疗方案：A组用国产氯吡格雷（泰嘉）加用血府逐瘀胶囊;B组使用进口氯吡格雷（波立维）;C组用国产氯吡格雷（泰嘉）加用西洛他唑,连续3个月,采用血栓弹力图法检测干预后血小板抑制率。并随访患者半年,观察临床不良事件的发生率。结果 治疗3个月后,各组抑制率均有所提高,且均有显著差异（P<0.05）。A组对血小板抑制的有效率达40%,优于C组（33.33%）,与B组相当（40.74%）。对阿司匹林、氯吡格雷均不敏感的患者换用进口波立维对提高血小板抑制效果更佳;仅对氯吡格雷不敏感的患者加用血府逐瘀胶囊对血小板抑制有协同作用。随访半年后发现,联合使用血府逐瘀胶囊的时间延长可能会增强血小板抑制的效果,但并不增加出血及凝血功能异常等风险。结论 血府逐瘀胶囊对提高血小板抑制率有一定的作用,同时对出血风险影响较小。     

PCI术后患者氯吡格雷治疗后血小板高反应性的结构方程模型构建

摘 要 目的：构建经皮冠状动脉介入（PCI）术后患者发生氯吡格雷治疗后血小板高反应性（HTPR）的结构方程模型。方法: 461例PCI术后患者,予阿司匹林100 mg·d-1及氯吡格雷75 mg·d-1抗血小板治疗,连续服用5d后晨起空腹抽取静脉血,检测血栓弹力图（TEG）。将氯吡格雷治疗后血小板高反应性（HTPR）定义为二磷酸腺苷诱导的血小板抑制率<50%。应用单因素和多因素logistic回归分析HTPR的影响因素,利用受试者工作曲线（ROC curve）检验独立风险因素预测HTPR的效力,并基于AMOS软件构建HTPR的结构方程模型。结果: 461例PCI术后患者HTPR发生率为19.5%。多因素条件logistic回归分析结果示糖尿病（OR=1.804,95%CI=1.125～2.894,P=0.014）、CYP2C19*2携带（OR=1.696,95%CI=1.048～2.745,P=0.032）为HTPR的独立风险因素,而血红蛋白（OR=0.979,95%CI=0.964～0.993,P=0.004）为HTPR保护性因素。联合独立风险因素模型预测HTPR的ROC曲线下面积（AUC）为0.636（95%CI=0.571～0.700,P<0.001）。结构方程模型（Root Mean Square Error of Approximation,RMSEA=0.000; Comparative Fit Index, CFI=1.000）中,糖尿病、CYP2C19*2 携带及血红蛋白对于HTPR的路径系数分别为0.107（P=0.019）,0.096（P=0.038）和-0.140（P=0.002）,模型的可决系数为0.046。结论: 糖尿病、CYP2C19*2 携带及血红蛋白为PCI术后患者HTPR的独立危险因素,上述因素可分别解释10.7%、9.6%和14.0%的HTPR变异度,而模型整体可解释4.6%的HTPR变异度。     

临床药师参与1例氯吡格雷抵抗患者的个体化用药分析

摘 要 目的：探讨临床药师参与氯吡格雷抵抗患者的药物治疗。方法：临床药师参与1例CYP2C19未突变的氯吡格雷抵抗患者的治疗。氯吡格雷基因多态性测定与血栓弹力图（TEG）检测结果不一致,TEG示：氯吡格雷抑制率25.2%,MADP 57 mm。氯吡格雷治疗基因预测示：CYP2C19*2 GG,CYP2C19*3 GG,CYP2C19*17 CC,ABCB1 3435 TT,PON1 576 AA,结论为氯吡格雷抵抗低风险。综合分析患者病情,临床药师为患者制定个体化用药方案,调整抗血小板治疗方案,同时考虑到患者的经济情况,建议将氯吡格雷替换为替格瑞洛。结果：医师采纳临床药师建议,患者出院后随访1年,无心血管不良事件、胃肠道出血等不良反应。结论：临床药师参与氯吡格雷抵抗患者的个体化给药方案的制定,分析两种检验方法结果不一致的现象,为患者调整抗血小板治疗方案、提供用药教育,保证了临床合理用药。     

Theophylline kinetics in peripheral tissues in vivo in humans

Several biochemical and cellular effects have been described for methylxanthines under in vitro conditions. However, it is unknown, whether threshold concentrations required to exert these effects are attained in target tissues in vivo. We therefore employed the microdialysis technique for measuring theophylline concentrations in peripheral tissues under in vivo conditions.Following in vitro and in vivo calibration, microdialysis probes were inserted into the medial vastus muscle and into the periumbilical subcutaneous adipose layer of healthy volunteers. Following single oral dose administration of 300 mg or i.v. infusion of 240 mg theophylline, in vivo time courses of theophylline concentrations were monitored in tissues and plasma. Major pharmacokinetic parameters (c_max, t_max, AUC) were calculated for plasma and tissue time courses. The mean AUC_tissue /AUC_plasma-ratio was 0.56 (p.o.) and 0.55 (i.v.) for muscle and 0.55 (p.o.) and 0.72 (i.v.) for subcutaneous adipose tissue.We conclude that microdialysis provides important information on the distribution and the tissue pharmacokinetics of theophylline.Abbreviations FPIA Fluorescence polarisation immuno assay - AUC Area under the curve - t_max Time to peak concentration - c_max Peak concentration     

Interindividual variability in metabolic activation in humans in vivo

In assessing interindividual variability in metabolic activation, the toxic metabolite is often too unstable for conventional analysis. Possible alternatives include a stable product of the reactive metabolite e.g. cysteinyl derivatives of N-acetyl-4-benzoquinoneimine, the toxic metabolite of paracetamol, adducts with DNA or protein, and indirect measurement of the activity of the enzyme(s) producing the active metabolite. An example of the last approach is the use of furafylline, a highly specific inhibitor of human CYP1A2, to determine the extent of the metabolic activation of the cooked food mutagens PhIP and MeIQx. The extent of inhibition, determined from levels of unchanged amine in urine, is an indirect measure of the activity of the activation pathway. Further refinement of this approach, allied to improved measures of the biological process of interest should prove of value in evaluating interindividual variability and its role in the risk assessment process.     

休克时血中氧自由基的变化

本实验测定10名休克患者血浆和红细胞的丙二醛(MDA)、血浆总抗的氧化活性(AOA)的含量。结果表明:休克病人红细胞膜和血浆 MDA 含量(4.298±0.722;5.348±0.834)与对照组(3.235±0.682;4.356±1.081)比较明显增高(P<0.05);血浆 AOA(39.65±7.858)与对照组(48.21±10.81)比较明显降低(P<0.01)。提示:休克时,患者机体内自由基反应增强是引起组织细胞损伤的原因之一。     

Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg.kg) or i.p. (50 mg.kg) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) l.h. kg in the male rat and 10.6 (95% CI: 7.5, 15.0) l.h. kg in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p 0.001) in plasma obtained from the male (8.8 2.0%) compared with the female rat (11.7 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.     

Polymorphisms in genes involved in neurotransmission in relation to smoking

Smoking behavior is influenced by both genetic and environmental factors. The genetic contribution to smoking behavior is at least as great as its contribution to alcoholism. Much progress has been achieved in genomic research related to cigarette-smoking within recent years. Linkage studies indicate that there are several loci linked to smoking, and candidate genes that are related to neurotransmission have been examined. Possible associated genes include cytochrome P450 subfamily polypeptide 6 (CYP2A6), dopamine D₁, D₂, and D₄ receptors, dopamine transporter, and serotonin transporter genes. There are other important candidate genes but studies evaluating the link with smoking have not been reported. These include genes encoding the dopamine D₃ and D₅ receptors, serotonin receptors, tyrosine hydroxylase, trytophan 2,3-dioxygenase, opioid receptors, and cannabinoid receptors. Since smoking-related factors are extremely complex, studies of diverse populations and of many aspects of smoking behavior including initiation, maintenance, cessation, relapse, and influence of environmental factors are needed to identify smoking-associated genes. We now review genetic polymorphisms reported to be involved in neurotransmission in relation to smoking.     

Genotoxic effects of chlorophenoxy herbicide diclofop-methyl in mice in vivo and in human lymphocytes in vitro

Diclofop-methyl (DM) is a chlorophenoxy derivative used in large quantities for the control of annual grasses in grain and vegetable crops. In this study, the genotoxic effects of DM were investigated by measuring chromosomal aberrations (CAs) in mouse bone-marrow cells and CA and the comet assay in human peripheral lymphocytes. Mice were treated with 15.63, 31.25, 62.5, and 125?mg/kg body weight of DM intraperitoneally for 24 hours, and 15.63-, 31.25-, 62.5-, 125-, and 250-µg/mL concentrations were applied to human lymphocytes for both 24 and 48 hours. In in vivo treatments, DM significantly, but not dose dependently, increased the total chromosome aberrations, compared to both negative and solvent controls. Cell proliferation was significantly, but not dose dependently, affected by all doses. In in vitro treatments, DM (except 15.63 µg/mL) significantly and dose dependently increased the frequency of chromosome aberrations. Also, 250 µg/mL of 48-hour treatment was found to be toxic. Cell proliferation was significantly and dose dependently affected by DM applications, when compared to negative control. In in vitro treatments, DM significantly decreased the mitotic index only at the highest concentration for 24 hours, and 62.5- and 125-µg/mL concentrations for 48 hours. In the comet assay, a significant and dose-dependent increase in comet-tail intensity was observed at 62.5-, 125-, and 250-µg/mL concentrations. The mean comet-tail length was significantly increased in all concentrations. Our results demonstrate that DM is genotoxic in mammalian cells in vivo and in vitro.     

2010调脂治疗领域进展

2010年在调脂治疗领域针对他汀治疗心血管病的防治又进行了许多探索。本文通过综述他汀类药物的国际大规模临床试验结果,重新评价了他汀类药物在冠心病一级预防和冠心病二级预防中的地位,阐明了强化他汀治疗的意义;对他汀的心肾保护作用和安全性新证据进行了说明。     

Pradigastat disposition in humans: in vivo and in vitro investigations

1.?Pradigastat is a potent and specific diacylglycerol acyltransferase-1 (DGAT1) inhibitor effective in lowering postprandial triglycerides (TG) in healthy human subjects and fasting TG in familial chylomicronemia syndrome (FCS) patients.

2.?Here we present the results of human oral absorption, metabolism and excretion (AME), intravenous pharmacokinetic (PK), and in vitro studies which together provide an overall understanding of the disposition of pradigastat in humans.

3.?In human in vitro systems, pradigastat is metabolized slowly to a stable acyl glucuronide (M18.4), catalyzed mainly by UDP-glucuronosyltransferases (UGT) 1A1, UGT1A3 and UGT2B7. M18.4 was observed at very low levels in human plasma.

4.?In the human AME study, pradigastat was recovered in the feces as parent drug, confounding the assessment of pradigastat absorption and the important routes of elimination. However, considering pradigastat exposure after oral and intravenous dosing, this data suggests that pradigastat was completely bioavailable in the radiolabeled AME study and therefore completely absorbed.

5.?Pradigastat is eliminated very slowly into the feces, presumably via the bile. Renal excretion is negligible. Oxidative metabolism is minimal. The extent to which pradigastat is eliminated via metabolism to M18.4 could not be established from these studies due to the inherent instability of glucuronides in the gastrointestinal tract.