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1.
《Drug metabolism and pharmacokinetics》2019,34(5):308-316
LC-MS quantification of drug metabolites is sometimes impeded by the availability of internal standards that often requires customized synthesis and/or extensive purification. Although isotopically labeled internal standards are considered ideal for LC-MS/MS based quantification, de novo synthesis using costly isotope-enriched starting materials makes it impractical for early stage of drug discovery. Therefore, quick access to these isotope-enriched compounds without chemical derivatization and purification will greatly facilitate LC-MS/MS based quantification. Herein, we report a novel 18O-labeling technique using metabolizing enzyme carboxylesterase (CES) and its potential application in metabolites quantification study. Substrates of CES typically undergo a two-step oxygen exchange with H218O in the presence of the enzyme, generating singly- and doubly-18O-labeled carboxylic acids; however, unexpected hydrolytic behavior was observed for three of the test compounds – indomethacin, piperacillin and clopidogrel. These unusual observations led to the discovery of several novel hydrolytic mechanisms. Finally, when used as internal standard for LC-MS/MS based quantification, these in situ labeled compounds generated accurate quantitation comparable to the conventional standard curve method. The preliminary results suggest that this method has potential to eliminate laborious chemical synthesis of isotope-labeled internal standards for carboxylic acid-containing compounds, and can be developed to facilitate quantitative analysis in early-stage drug discovery. 相似文献
2.
目的:探讨不同民族PON1Q192R等位基因变异频率以及PON1Q192R基因多态性与冠心病患者氯吡格雷抵抗(CR)的关联性。方法:纳入新疆医科大学第二附属医院2020年1月至2020年12月使用氯吡格雷且诊断为冠心病的患者127例,患者每日服用氯吡格雷75 mg,5 d后用血栓弹力图测定相关参数,并进行CYP2C19*2、CYP2C19*3、CYP2C19*17和PON1Q192R基因分型检测。结果:不同民族之间PON1Q192R基因突变频率差异具有统计学意义(P <0.05),患者的血栓弹力图参数结果显示,PON1Q192R基突变并不会显著降低氯吡格雷疗效。结论:PON1Q192R基因突变频率与冠心病患者氯吡格雷反应的相关性还需要进一步研究。 相似文献
3.
目的观察常规溶栓联合氯吡格雷治疗对急性ST段抬高型心肌梗死近期心脏事件的影响。方法符合入选条件的患者随机分为常规溶栓治疗组(34例)和氯吡格雷组(36例,在常规溶栓治疗的基础上即刻300mg,随后每日1次75mg,连用7d)。结果7d后氯吡格雷组复合终点(13.90%)与常规治疗组(29.41%)比较差异有统计学意义(P<0.05),而主要的副作用两组之间比较差异无统计学意义(P>0.05)。结论氯吡格雷对急性ST段抬高型心肌梗死患者的近期(7d)心脏事件是安全有效的。 相似文献
4.
Chih-Jen Yang Po-Chuan Chen Chin-Sheng Lin Chia-Lin Tsai Shih-Hung Tsai 《The American journal of emergency medicine》2017,35(5):804.e1-804.e3
Acute myocardial infarction (AMI) is uncommon in the acute phase of acute ischemic stroke (AIS) and occurs in approximately 1% of the population. Here, we report a paradoxical case of AMI during tissue plasminogen activator (t-PA) infusion for AIS. We review and analyze the previously reported cases. We found that only patients with AMI which occurred after thrombolytic therapy for AIS who received an adequate combination of anticoagulation plus percutaneous coronary intervention survived their events. Several mechanisms have been proposed for the development of AMI after thrombolytic therapy. These mechanisms include fragmented intra-cardiac thrombus, intensified platelet aggregation that may lead to an increased potential for intra-cardiac thrombus formation, and a reduction in clot-associated plasminogen that may lead to a paradoxical hypercoagulable state of the coronary arteries. Currently, there is no consensus regarding this specific scenario. We propose that the therapeutic benefit and the potential risk of hemorrhagic complications should be further investigated and individualized. In patients who receive thrombolytic therapy for AIS and who then develop post-thrombolytic AMI, we suggest that the maximum treatment for the subsequent AMI be instituted promptly to avoid short-term mortality. 相似文献
5.
Despite the demonstrated benefits of Prasugrel, a new generation thienopyridine, in the prevention of thrombotic complications after percutaneous coronary interventions (PCI) for Acute Coronary Syndromes (ACS), its use is still precluded to those many patients arriving to the cath lab pre-treated with Clopidogrel. Conclusive data on the strategy of switching from Clopidogrel to Prasugrel are still missing, therefore we aimed to perform a meta-analysis of current studies evaluating the safety and efficacy of switching from Clopidogrel to Prasugrel (PS) as compared to a standard thienopyridine therapy with Clopidogrel or Prasugrel in patients undergoing PCI. Literature archives and main scientific sessions’ abstracts were scanned for studies comparing a switching strategy from Clopidogrel to Prasugrel vs. Prasugrel or Clopidogrel. Primary efficacy endpoint was overall mortality. Secondary endpoints were: non-fatal myocardial infarction and definite/probable stent thrombosis. Safety endpoint was the rate of major bleedings according to a per-protocol definition. A total of 12 studies, involving 3956 patients, were included. Among them, 1396 patients (35.3%), received Prasugrel after a Clopidogrel treatment (PS), while 2560 (64.7%) received either Prasugrel or Clopidogrel. The switch from Clopidogrel to Prasugrel was in the majority of the studies periprocedural. The mortality was numerically lower, but not statistically significant, in the PS group as compared with patients who did not switch (1.7% vs. 3.8%, OR [95% CI]?=?0.68 [0.40,1.15], p?=?0.15, phet?=?0.61), without any relationship with patients’ risk profile (r?=??0.68 [?2.09, 0.73], p?=?0.35). Similar results were obtained for secondary efficacy endpoints and at sensitivity analysis in the majority of subgroups evaluated. Moreover, the PS strategy did not increase major bleedings as compared with standard therapy (1.4% vs. 2.5%, OR [95% CI?=?0.70 [0.39, 1.25], p?=?0.23, phet?=?0.6). The present meta-analysis confirms that, among patients undergoing PCI, switching from Clopidogrel to Prasugrel may be safely performed and therefore should be encouraged among patients eligible to Prasugrel. 相似文献
6.
目的评价低剂量氯吡格雷在冠状动脉再狭窄家猪模型中的应用效果。方法选取健康家猪6头,抽取静脉血测定ADP(Adenosine Diphosphate,二磷酸腺苷)诱导的血小板聚集率作为基础值,然后开始喂食氯吡格雷(25mg/d)和常规剂量的阿司匹林,开始给药后第4天行介入手术构建冠状动脉过度扩张再狭窄模型并行支架植入术,同时在给药后第4、8﹑14天再次抽血测定ADP诱导的血小板聚集率,评价氯吡格雷对血小板聚集率的抑制效果,记录术后压迫止血情况及术中、术后的安全性,14天时处死动物并血管取材评价支架内血栓情况。采用SPSS10.0进行统计学分析。结果家猪平均体重为(23.1±4.4)Kg,ADP诱导的血小板聚集率基础值为(43.08±5.06)%。用药后第4天,血小板聚集率值较基础值明显下降[(29.05±9.26)%:(43.08±5.06)%,P=0.008],用药后8天血小板聚集率值进一步下降,用药后14天,血小板聚集率值趋于稳定,达到并维持抗血小板聚集的效果,术中和术后24小时均未发生冠状动脉事件,14天时血管取材病理切片未见支架内血栓形成。结论在冠状动脉再狭窄家猪模型中,低剂量氯吡格雷可以达到抑制ADP诱导的血小板聚集的效果,同时低剂量氯吡格雷联合常规剂量的阿司匹林可以保证冠状动脉再狭窄家猪模型的安全性,并降低实验费用。 相似文献
7.
目的 ①评价冠状动脉支架(CS)置入患者氯吡格雷抵抗的发生情况;②观察CS术后1个月复发缺血事件与氯吡格雷抵抗的关系.方法 ①所有入选患者于服氯吡格雷前、服药后24 h及1个月分别测定ADP(25 μmol/L)诱导的血小板聚集率,计算血小板聚集抑制率(△A),△A≤10%(包括负值)时考虑存在氯吡格雷抵抗;②观察CS术后1个月内复发缺血事件的情况.结果 ①共入选患者42例,其中△A 24 h≤10%者18例(43%),△A1m≤10%者13例(31%);②在1个月的随访中,无一例患者因心血管疾病死亡或再发心肌梗死,△A1m≤10%的患者有1例发生脑梗死,1例复发心绞痛,缺血事件发生率为15.4%,△A1m>10%的患者未发现缺血事件.结论 ①一部分CS患者存在氯吡格雷抵抗,测定血小板聚集率有助于发现这部分患者;②氯吡格雷抵抗患者CS术后1个月内复发缺血事件增加. 相似文献
8.
目的 评价连续血小板计数法血小板功能检测仪PL-11监测血小板功能的价值.方法 分别应用SC-2000光学比浊法(LTA)与PL-11连续血小板计数法两种血小板功能检测仪,检测30例急性心肌梗死急诊入院患者,入院时、负荷剂量(600mg)服用氯吡格雷后的第8小时、PCI术后第三天晨起时的血小板聚集功能,分析两种仪器检测结果的相关性及PL-11在氯吡格雷抵抗(clopidogrel resistance,CR)的诊断准确性.结果 在测试人群中,LTA测得最大血小板聚集率(MAR)范围均较PL-11广;所有受试者在刚入院未服用氯吡格雷时,PL-11与LTA不相关(相关系数r=0.35,P=0.058>0.05),在术前氯吡格雷大剂量冲击后及术后第三天两次检测的MAR存在相关性(r=0.500和0.571,P<0.01);两种仪器三次检测结果均为第一次和第三次明显高于第二次,差异具有统计学意义(P <0.05);PL-11用于诊断CR的ROC曲线下面积为0.798(95% CI:0.621~0.964).结论 PL-11连续血小板计数法与“金标准”的(LTA)浊法检测血小板聚集功能具有一定的相关性,其检测结果可供临床及实验室参考. 相似文献
9.
目的比较替格瑞洛和氯吡格雷对急性冠状动脉综合征(ACS)患者血小板聚集的影响。方法 81例ACS患者被随机分为替格瑞洛组(A组,41例)和氯吡格雷组(B组,40例),比较两组服药前和服药后1、2、4、8、24h及治疗第7天的血小板最大聚集率(PMAR)、血小板聚集抑制率(IPA)及出血事件。结果两组服药前PMAR水平相近(P>0.05)。A组患者服药期间的PMAR均低于B组(P<0.01),IPA及IPA≥50%的患者比例均高于B组(P<0.01)。B组服药后2h的IPA低于服药后8h(P<0.01),而A组两个时间段IPA差异无统计学意义(P>0.05)。两组均只有轻微出血事件。结论在ACS患者,替格瑞洛较氯吡格雷更能有效地抑制血小板聚集;两药短期的安全性相仿。 相似文献
10.
Aspirin and clopidogrel resistance: an emerging clinical entity. 总被引:28,自引:0,他引:28
Antiplatelet therapy is a cornerstone of cardiovascular medicine. Aspirin and clopidogrel have emerged as critical therapies in the treatment of cardiovascular disease. Despite their efficacy, patients on these medications continue to suffer complications. Millions of patients are currently on low-dose antiplatelet therapy but it is unknown how many of these patients are under-treated or on the wrong medication. Aspirin and clopidogrel resistance are emerging clinical entities with potentially severe consequences such as recurrent myocardial infarction, stroke, or death. The mechanism of resistance remains incompletely defined, but there are specific clinical, cellular, and genetic factors that influence therapeutic failure. These factors range from physicians who fail to prescribe these medications despite appropriate indications to polymorphisms of platelet membrane glycoproteins. Rapid and accurate diagnosis of antiplatelet resistance also remains an issue as new bedside tests are developed. By understanding the mechanism of therapeutic failure and by improving the diagnosis of this clinical entity, a new era of individualized antiplatelet therapy may arise with routine measurements of platelet activity in the same way that cholesterol, blood pressure, and blood sugar are followed, thus improving the care for millions of people. 相似文献