替格瑞洛与氯吡格雷对急性心肌梗死患者介入治疗后的心功能和炎症反应的影响

目的:探讨替格瑞洛与氯吡格雷对急性心肌梗死患者介入治疗后的心功能和炎症反应的影响。方法:选取2015年1月-2018年1月期间我院收治的行介入治疗的急性心肌梗死患者300例为研究对象。根据随机数字表法将患者分为替格瑞洛组(n=150)和氯吡格雷组(n=150),其中替格瑞洛组给予阿司匹林、替格瑞洛治疗,氯吡格雷组给予阿司匹林、氯吡格雷治疗。比较两组患者治疗前后的左心室射血分数(LVEF)、左心室舒张末期内径(LVEDd)及白介素-6(IL-6)、C反应蛋白(CRP)、可溶性CD40配体(s CD40L)、肿瘤坏死因子-α(TNF-α)水平,随访3个月,观察两组患者随访期间心血管不良事件的发生情况。结果:两组患者治疗后LVEF较治疗前升高,且替格瑞洛组高于氯吡格雷组,LVEDd较治疗前降低,且替格瑞洛组低于氯吡格雷组(P0.05)。两组患者治疗后IL-6、CRP、s CD40L、TNF-α均较治疗前升高,但替格瑞洛组低于氯吡格雷组(P0.05)。替格瑞洛组随访期间心血管不良事件总发生率为10.00%(15/150),显著低于氯吡格雷组患者的31.33%(47/150),组间比较差异有统计学意义(P0.05)。结论:相较于氯吡格雷而言,替格瑞洛治疗行介入治疗的急性心肌梗死患者效果满意,可显著改善心功能,降低炎症因子水平及心血管不良事件发生率。     

Stereoselective synthesis of the key intermediate of ticagrelor and its diverse analogs using a new alcohol dehydrogenase from Rhodococcus kyotonensis

Bioreduction catalyzed by alcohol dehydrogenase/reductase is one of the most valuable biotransformation processes widely used in industry. The (S)-2-Chloro-1-(3, 4-difluorophenyl) ethanol is a key chiral synthon for synthesizing the antithrombotic agent ticagrelor. Herein, a new alcohol dehydrogenase (named Rhky-ADH) identified from Rhodococcus kyotonensis by an enzyme promiscuity-based genome mining method was successfully cloned and functionally expressed in Escherichia coli. The whole cell biocatalyst harboring Rhky-ADH was biochemically characterized and was shown to be able to convert 2-Chloro-1-(3, 4-difluorophenyl) ethanone to (S)-2-Chloro-1-(3, 4-difluorophenyl) ethanol with more than 99 % enantiomeric excess (ee) and 99 % conversion. Our data showed that the optimum temperature and pH for Rhky-ADH were 25 °C and pH 8.0, respectively. The addition of NADH and an appropriate concentration of isopropanol enhanced the activity of Rhky-ADH, and 1 mM Mn²⁺ increased the enzyme activity by about 8 %. Substrate specificity experiments showed that Rhky-ADH had notable enzyme promiscuity and could reduce several ketones with high stereoselectivity. Our investigation on this novel enzyme adds another rare biocatalyst to the toolbox for producing chiral alcohols, which are widely used in the pharmaceutical industry.     

葛兰心宁软胶囊联合替格瑞洛片对冠心病心绞痛患者心功能和血管内皮功能的影响

摘要 目的：观察葛兰心宁软胶囊联合替格瑞洛片治疗冠心病心绞痛的疗效及对心功能和血管内皮功能的影响。方法：选择我院心内科收治的150例冠心病心绞痛患者,按门诊号单双数分为对照组和研究组,各为75例。对照组给予替格瑞洛片治疗,研究组给予葛兰心宁软胶囊联合替格瑞洛片治疗,对比两组疗效、血管内皮功能、心功能、心绞痛发作次数和持续时间以及不良反应发生率。结果：治疗1个月后,研究组的临床总有效率85.33%（64/75）高于对照组的69.33%（52/75）,差异有统计学意义（P<0.05）。治疗1个月后,研究组左心室射血分数（LVEF）、心输出量（CO）、每搏输出量（SV）高于对照组（P<0.05）。治疗1个月后,与对照组比较,研究组的心绞痛发作次数更少,持续时间更短（P<0.05）。治疗1个月后,研究组一氧化氮（NO）、血流介导的舒张功能（FMD）高于对照组,内皮素-1（ET-1）、胞间黏附分子-1（ICAM-1）、血管紧张素Ⅱ（Ang Ⅱ）低于对照组（P<0.05）。两组不良反应发生率组间对比无明显差异（P>0.05）。结论：冠心病心绞痛患者经葛兰心宁软胶囊联合替格瑞洛片治疗后,疗效明确,可缓解患者临床症状,促进心功能和血管内皮功能恢复。     

参麦注射液联合西药对急性心肌梗死患者疗效及机制研究

目的:研究参麦注射液联合西药对急性心肌梗死患者的疗效及机制。方法:选择我院2016年3月~2019年12月收治的101例急性心肌梗死患者,根据随机数字表法分为对照组和观察组。对照组口服替格瑞洛治疗,观察组联用参麦注射液治疗,观察两组治疗的疗效及治疗前后血浆乳酸、脑钠肽(Brain natriuretic peptide,BNP)和血清降钙素原(Procalcitonin,PCT)、超敏C反应蛋白(Hypersensitive C-reactive protein,hs-CRP)水平及心功能指标变化。结果:观察组的有效率明显高于对照组(P<0.05);两组治疗前的血浆乳酸、BNP和PCT、hs-CRP水平无明显差异(P>0.05),治疗后,两组的上述指标明显降低(P<0.05),且观察组低于对照组(P<0.05);两组治疗前的左心室射血分数(Left ventricular ejection fraction,LVEF)、左心室舒张期末内径(End diastolic diameter of left ventricle,LVEDd)、CO和左心室收缩末期直径(leftventricular end systolic diameter,LVESd)无明显差异(P>0.05),治疗后,两组的上述指标明显改善(P<0.05),且观察组优于对照组(P<0.05);观察组的药物不良反应率为14.00%(7/50),与对照组的11.76%(6/51)相比无明显差异(P>0.05)。结论:参麦注射液联合替格瑞洛能减轻急性心肌梗死患者体内的炎症反应,改善心功能,可能与其机制有关。     

Effets secondaires d’un stress par Régadénoson en scintigraphie myocardique chez les patients traités par Ticagrélor

IntroductionAs an anti-aggregant that has demonstrated its superiority in the management of acute coronary syndrome, Ticagrelor is an inhibitor of adenosine recapture by red blood cells. Regadenoson, an adenosine agonist, is a preferred cardiac pharmacological stress in patients with a history of spastic bronchopathy. A synergistic effect of both drugs is therefore theoretically expected if they are combined during myocardial scintigraphy. In 2015, European Association of Nuclear Medicine did not rule on the use of Regadenoson in patients previously treated with Ticagrelor. The objective of this work is to study the frequency of adverse events in these patients during Regadenoson stress.Materials and methodsWe retrospectively included patients who underwent a myocardial scintigraphy with pharmacological stress by Regadenoson between February 2016 and February 2019. We compared the frequency of expected side effects of Regadenoson in patients treated with Ticagrelor and not treated with Ticagrelor. The data were analysed using a logistic regression model including patient characteristics and side effects.ResultsSeventeen treated patients were included for 49 untreated patients. There was no significant difference in the frequency of each adverse event between treated and untreated patients. However, a higher number of side effects have been reported in treated patients than in untreated patients. No major adverse event was reported.ConclusionIn order to rule about the use of Regadenoson in patients treated with Ticagrelor, a larger study is needed to support the hypothesis of more noted minor side effects and which of them should be more encountered.     

替格瑞洛在急性冠脉综合征患者经皮冠状动脉介入治疗术后的应用价值

目的:评价替格瑞洛在急性冠脉综合征(acute coronary syndrome,ACS)患者经皮冠状动脉介入治疗(percutaneous coronary intervention,PCI)术后的应用价值。方法:将我院收治的565例成功行PCI的急性冠脉综合征(acute coronary syndrome,ACS)患者随机分为2组:氯吡格雷组253例,术后口服氯吡格雷75 mg、QD;替格瑞洛组312例,术后口服替格瑞洛首剂180 mg,维持量90mg、BID。两组患者术后常规口服阿司匹林100 mg、QD。研究主要终点为主要不良心血管事件(major adverse cardiovascular events,MACE),包括全因死亡、靶血管血运重建和脑梗塞;次要终点为TIMI主要出血(定义为血红蛋白下降50 g/L或颅内出血有关的临床显著出血事件)。结果:565例患者平均随访12个月,替格瑞洛组MACE发生率低于氯吡格雷组(3.8%vs.8.7%,P0.05),两组TIMI主要出血事件发生率比较,差异无统计学意义(2.9%vs.3.2%,P0.05)。结论:替格瑞洛能明显减少PCI术后主要不良心血管事件,并不增加主要出血。     

Comparative study of ticagrelor and clopidogrel in therapeutic effect of acute myocardial infarction patients undergoing percutaneous coronary intervention

ObjectivesComparison of Ticagrelor vs clopidogrel in antiplatelet therapeutic effect of acute myocardial infarction patients undergoing percutaneous coronary intervention.MethodsThe study focused on 2000 acute myocardial infarction patients undergoing percutaneous coronary intervention (PCI) in our hospital from January 2013 to December 2015. To reduce the formation of acute stent thrombosis caused by clopidogrel resistance, we had two options, one was to double the dosage of clopidogrel, and the other was to substitute ticagrelor for clopidogrel. Based on random number table method, the 2000 patients were divided into experimental group and control group, each containing 1,000 patients. The patients in experimental group took 180 mg ticagrelor before PCI and 90 mg ticagrelor twice a day after PCI (Gu, 2016). In contrast, the patients control group took 600 mg clopidogrel before PCI and 150 mg clopidogrel once a day after PCI. Both groups were drawn 2.7 ml of fasting venous blood for platelet aggregation rate test before PCI and 2 h, 24 h, 7 days after PCI respectively. Turbidimetric method was used to measure the ADP-induced platelet aggregation rate and observe change of platelet aggregation rate and success rate. Incidence of liver and kidney malfunction and adverse actions were monitored. All patients accepted a 6-month of follow-up examination to record and compare incidences of major adverse cardiac and cerebrovascular events. The statistical results of both groups are analyzed and compared.ResultsThe platelet aggregation rate of experimental group before PCI and 2 h, 24 h, 7 days after PCI was 59.71% ± 7.24%, 59.20% ± 7.70%, 48.66% ± 7.80% and 43.39% ± 8.28%; The control group was 58.04% ± 5.61%, 56.25% ± 6.02%, 55.68% ± 3.14%, 53.94% ± 5.30%; Comparing the platelet aggregation rate of different time, P was less than 0.05. The success rate of platelet aggregation of experimental group and control group was 80.56% and 46.86% respectively. There were significant differences between the two groups and the P was less than .05. The postoperative serum creatinine level of experimental group was higher than that in the control group (P < .05). The incidence of adverse reactions in the experimental group was significantly lower than that of the control group. There were significant differences between the two groups and the difference was of statistical significance (P < .05). According to the 5-month follow-up examination: the incidence of major adverse cardiac and cerebrovascular events in experimental group was 2.60% (52/2000) ,while the control group was 13.00% (260/2000) . There were significant differences between the two groups and the difference was of statistical significance (P < .05).ConclusionsCompared with clopidogrel, ticagrelor can achieve better n antiplatelet effect for patients with acute myocardial infarction undergoing percutaneous coronary intervention (PCI). It can effectively reduce the incidence of postoperative adverse cardiac and cerebrovascular events and control the rate of adverse reactions within the acceptable range.     

Determination of ticagrelor and two metabolites in plasma samples by liquid chromatography and mass spectrometry

Rapid and sensitive analytical methods using liquid chromatography with tandem mass spectrometry (LC/MS/MS) were developed for the determination of ticagrelor, the first reversible oral platelet P2Y₁₂ receptor inhibitor, and its metabolites AR-C124910XX and AR-C133913XX in human plasma. Ticagrelor and its metabolites were extracted using protein precipitation with acetonitrile. Chromatographic separations were performed on reversed phase columns and detection using atmospheric pressure chemical ionization (APCI). Ticagrelor and AR-C124910XX were analyzed in the same assay, with the internal standard, d7-ZD6140, on a C18 column using negative ionization; AR-C133913XX analyzed separately on a phenyl column using positive ionization. Full validation of the methods was performed including selectivity, lower limit of quantification, accuracy, precision stability and incurred sample reproducibility and incurred sample stability. Total analytical run time was short (2 min). Calibration curves were established in the range 5–5000 ng/mL for ticagrelor, 2.5–2500 ng/mL for AR-C124910XX and 2–1000 ng/mL for AR-C133913XX. Lower limits of quantification for ticagrelor, AR-C124910XX and AR-C133913XX were determined to be 5, 2.5 and 2.0 ng/mL, respectively from 100 μL of human plasma. For ticagrelor, AR-C124910XX and AR-C133913XX, mean intra-batch accuracy was 91.9–109.0%, 86.8–109.2% and 100.5–112.0%, respectively; intra-batch precision was 4.0–8.4%, 5.2–16.9% and 3.9–12.3%, respectively. The methods were also applied to quantification of ticagrelor, AR-C124910XX and AR-C133913XX in rabbit, rat, mouse and marmoset, using 25 μL of animal plasma. A modified methodology was developed to quantify ticagrelor and AR-C124910XX in plasma from dog and cynomolgus monkey. Human incurred samples were found to generate consistent reproducibility and stability results. This method was successfully applied to determine plasma concentrations following administration of ticagrelor in human volunteers and patients, and animal safety evaluation studies. This validated methods has the advantages of being straightforward, robust and allows a fast throughput of samples.     

替格瑞洛联合瑞舒伐他汀钙片对冠心病患者心功能、凝血功能及基质金属蛋白酶的影响

目的:探究替格瑞洛联合瑞舒伐他汀钙片及阿司匹林对冠心病患者心功能、凝血功能及基质金属蛋白酶的影响。方法:选择2015年7月～2018年12月于我院心内科接受治疗的77例冠心病患者,按患者是否服用替格瑞洛将其分为替格瑞洛组和对照组。对照组在常规西药治疗方法上服用阿司匹林和瑞舒伐他汀钙片,替格瑞洛组在对照组的治疗方法上联合替格瑞洛。检测和比较两组治疗前及治疗4周后心功能指标[肌酸激酶同工酶(CK-MB)、心肌肌钙蛋白Ⅰ(cTnⅠ)],炎症反应指标[肿瘤坏死因子(TNF-α)、单核细胞趋化蛋白-l(MCP-1)、C反应蛋白(CRP)],凝血功能指标[活化部分凝血酶原时间(APTT)、凝血酶时间(TT)、凝血酶原时间(PT)、纤维蛋白原(FIB)]及基质金属蛋白酶9(MMP-9)和基质金属蛋白酶12(MMP-12)水平的变化。结果:治疗4周后,两组患者血清CK-MB、cTnⅠ水平、TNF-α、MCP-1、CRP、MMP-9、MMP-12及FIB水平均显著低于治疗前(P0.05),且替格瑞洛组患者以上指标均显著低于对照组(P0.05);两组APTT、PT、TT均显著高于治疗前,且替格瑞洛组以上指标均明显高于对照组(P0.05)。结论:替格瑞洛联合联合阿司匹林及瑞舒伐他汀钙片可有效改善冠心病患者的心功能和凝血功能,可能与其有效减轻炎症反应及减少基质金属蛋白酶的含量有关。     

替格瑞洛对行PCI术后患者心肌酶影响及一年随访事件相关性分析

摘要 目的：研究替格瑞洛对行PCI术后患者心肌酶影响及一年随访事件相关性分析。方法：选取2019年5月至2019年12月的133例急性心肌梗死患者。按照随机数表法分为观察组（n=68）和对照组（n=65）,两组均采用PCI术治疗,术后对照组采用氯吡格雷治疗,观察组采用替格瑞洛治疗。对比两组治疗效果,心肌血流灌注指标,心肌酶变化,不良反应发生率。结果：治疗后,观察组总有效率显著高于对照组[95.58%（65/68）vs75.38％（49/65）]（P＜0.05）;TIMI3级、TMPG3级及无复流/满血流均显著低于对照组[17.64%（12/68）vs40.00%（26/65）,26.47%（18/68）vs46.15%（30/65）,7.35%（5/68）vs27.69%（18/65）]（P<0.05）; LDH、CK、CK-MB均显著低于对照组[（207.38±21.90）U/L vs（253.75±26.37）U/L,（166.38±19.32）U/L vs（389.75±52.03）U/L,（121.58±15.86）U/L vs（162.60±18.75）U/L]（P<0.05）;一年随访事件发生率显著低于对照组［11.76％（8/68）vs36.92％（24/65）］（P<0.05）。结论：替格瑞洛对可有效改善行PCI术后患者血流灌注,保护心肌细胞,改善心肌功能,提高治疗疗效。