不同质子泵抑制剂和CYP2C19失功能基因对冠心病患者的影响
摘要
双联抗血小板药物氯吡格雷联合阿司匹林已经成为ACS和PCI患者的标准治疗。但是这种治疗也增加了胃肠出血的风险。PPIs能有效的保护胃粘膜而经常与抗血小板药物同时应用。氯吡格雷和PPIs都经过CYP2C19酶代谢,因此两者会产生药物相互干涉。氯吡格雷联合应用PPIs对氯吡格雷抗血小板的影响仍在深入研究。
CYP2C19*2和CYP2C19*3被称为CYP2C19酶的失功能基因,而携带CYP2C19失功能基因的患者消弱了氯吡格雷抗血小板作用。研究发现在亚洲CYP2C19失功能基因发生率要远远高于欧美国家,而我国冠心病患者联合应用氯吡格雷和PPIs对血小板聚集产生的影响尚未深入研究。本研究首先明确CYP2C19失功能基因在中国汉族人群的发生率；再次分析冠心病患者服用氯吡格雷时,联合应用不同PPIs对血小板抑制率的影响以及对携带CYP2C19失功能基因的冠心病患者血小板聚集率的影响；进一步分析PCI患者服用氯吡格雷同时联合应用不同PPIs对PCI术后早期心肌损伤的影响以及对携带CYP2C19失功能基因的PCI患者PCI术后早期心肌损伤的影响；为冠心病患者应用氯吡格雷时选择何种PPI s提供依据。实验内容主要包括以下三部分。
第一部分CYP2C19失功能基因在中国汉族人群的分布
目的:观察CYP2C19失功能基因在中国汉族人群的发生率,为进一步探讨氯吡格雷和PPIs在冠心病患者联合应用提供依据。
方法：入选到河北医科大学二院体检中心的体检者共1108例。每一位体检者首先采集2ml静脉血以提取DNA；其次应用TaqMan荧光探针标记的real-time PCR方法对提取的DNA进行基因分型。
结果：CYP2C19*1/*1、*1/*2、*2/*2、*1/*3、*2/*3、*3/*3的发生率分别是39.53%、35.83%、8.48%、8.84%、6.32%和1%。
结论：在中国汉族人群CYP2C19*2和*3失功能基因携带者的比例接近60%。
第二部分不同PPIs和CYP2C19失功能基因对氯吡格雷抗血小板作用的影响
目的：观察不同的PPIs对冠心病患者氯吡格雷抗血小板作用的影响,以及携带失功能基因的冠心病患者应用氯吡格雷联合不同PPIs对氯毗格雷抗血小板的影响,为应用抗血小板药物的冠心病患者预防和治疗上消化道出血提供最佳的PPIs。
方法：入选164例到河北医科大学二院心血管内科住院的冠心病患者,根据应用不同的PPIs分为四组,奥美拉唑组(35例)、埃索美拉唑组(50例)、泮托拉唑组(41例和未用PPIs组(38例)。所有患者于入院时给予肠溶阿司匹林100mg每日1次,氯毗格雷首先300mg顿服,随后75mg每日1次口服。进入不同PPIs组的患者分别服用：奥美拉唑20mg,每日1次；埃索美拉唑40mg,每日1次；泮托拉唑40mg,每日1次。PPIs与氯吡格雷同时服用。所有患者在服氯毗格雷前采血以检测血小板聚集率和提取DNA；在服氯吡格雷3天后再次采集静脉血以检测血小板聚集率。血小板聚集率的检测应用电阻法(10ul ADP作为诱导剂),氯吡格雷对血小板的抑制率=(服氯吡格雷前的血小板聚集率-服氯吡格雷后的血小板聚集率)／服氯吡格雷前的血小板聚集率×100%。应用TaqMan荧光探针标记的real-time PCR方法对提取的DNA进行基因分型。结果：1.氯吡格雷对血小板的抑制率在奥美拉唑组、埃索美拉唑组、泮托拉唑组和未服用PPIs组分别是40.93%、41.24%、46.67%和47.59%,血小板抑制率有下降的趋势,但是没有统计学差异(P>0.05)。根据基因分型将所有患者再进一步分为野生型组(CYP2C19*1/*1)和失功能基因型组(CYP2C19*1/*2、2C19*1/*3、2C19*2/*2、2C19*2/*3和2C19*3/*3),野生型组和失功能基因型组氯吡格雷对血小板的抑制率在两组之间有统计学差异(41.21%vs39.33%,P<0.05)。
2.奥美拉唑组、埃索美拉唑组、泮托拉唑组和未服用PPIs组再根据野生型和失功能基因型又分为8组。在这8组间氯吡格雷对血小板的抑制率相比也没有统计学差异(P>0.05)。在不同PPIs组内野生型和失功能基因型两组间再分别比较氯毗格雷对血小板抑的制率,也没有统计学差异(P>0.05)。
结论：对于冠心病患者,CYP2C19失功能基因携带者降低了氯吡格雷对血小板的抑制率。联合应用PPIs并不影响冠心病患者氯毗格雷对血小板的抑制作用,同时也不影响携带CYP2C19失功能基因的冠心病患者对血小板的抑制率。
第三部分不同质子泵抑制剂和CYP2C19失功能基因对择期PCI患者术后心肌的影响
目的:观察服用不同PPIS的PCI患者术后早期cTnI的变化,以及氯毗格雷联合不同PPIs对携带失功能基因的PCI患者术后早期cTnI的变化,分析不同的PPIs对PCI患者术后早期心肌损伤的影响,为PCI患者在预防和治疗上消化道出血以及减少心肌损伤方面提供最佳的PPIs。
方法：陆续在河北医科大学二院心血管内科住院并接受PCI治疗的患者149例。根据应用不同的PPIs分为四组,奥美拉唑组(32例)、埃索美拉唑组(42例)、泮托拉唑组(32例)和未用PPIs组(43例)。所有患者于入院时应用肠溶阿司匹林100mg每日1次,氯毗格雷首先300mg顿服,随后75mg每日1次口服。进入不同PPIs组的患者分别服用：奥美拉唑20mg,每日1次；埃索美拉唑40mg,每日1次；泮托拉唑40mg,每日1次。PPIs与氯毗格雷同时服用。PCI术后第二天采静脉血检测cTnI和提取DNA。cTnI>Ing/ml为肌钙蛋白阳性。应用TaqMan荧光探针标记的real-time PCR方法对提取的DNA进行基因分型。
结果：PCI术后cTnI阳性率在奥美拉唑组、埃索美拉唑组、泮托拉唑组和未服用PPIs组没有统计学差异(P>0.05)。根据基因分型将所有患者再进一步分为野生型和携带失功能基因型，两组间cTnI阳性率分别是12.07%和12.09%,没有统计学差异(P>0.05)。不同的PPIs组再根据基因分型分为8组,这8组间cTnI阳性率没有统计学差异(P>0.05)。不同PPIs组内野生型和失功能基因型两组间再分别比较cTnI阳性率,还是没有统计学差异(P>0.05)
结论:服用氯吡格雷的PCI患者,与不同PPIs联合应用不会对PCI术后早期心肌损伤产生影响,也不会对携带失功能基因的PCI患者术后早期心肌损伤产生影响。对于服用氯吡格雷的冠心病患者如果联合应用PPIs,奥美拉唑、埃索美拉唑和泮托拉唑都可以选用,但最好选择泮托拉唑。
Clopidogrel co-administered with aspirin have become a corner-stone in treatment of ACS and PCI patients. Given the increased bleeding risk associated with antiplatelet therapy, PPIs are prescribed oiten.Clopidogrel and PPIs have a pharmacodynamie interaction because they are both metabolited by CYP2C19.
CYP2C19*2and*3belong to loss of function CYP2C19alleles which decrease the inhibition of clopidogrel on platelet aggregation. The prevalence of the loss of function CYP2C19alleles in Asia was higher than that in Europe and America. There has been rare research for clopidogrel co-administered with PPIs on platelet aggregation in Chinese. So the first step of this research was to study the loss of function CYP2C19alleles in Chinese Han population. Then, the effects of clopidogrel on platelet aggregation was analysised in the CHD patients who were treated clopidogrel co-administered with PPIs and those patients who carried of loss of function CYP2C19alleles. Finally, the effects on early myocardial injury were determined in the elective PCI patients who received clopidogrel co-administered with different PPIs and those patients who carried of loss of function CYP2C19alleles. Three parts are showed as below.
Part1The prevalence of the loss of function CYP2C19alleles in Chinese Han population.
Objective:To investigate the prevalence of the loss of function CYP2C19alleles in Chinese Han population.
Methods:1108consecutive volunteers were enrolled in this study, CYP2C19*2and*3genotype were performed by real-time PCR-TaqMan assay.
Results:The prevalence of CYP2C19*1/*1、*1/*2、*2/*2、*1/*3、*2/*3、 *3/*3were39.53%、35.83%、8.48%、8.84%、6.32%and1%,respectively.
Conclusions:The prevalence of loss of function CYP2C19alleles were about60%in Chinese Han population.
Part2Effects of different PPIs on the antiplatelet activity of clopidogrel in CHD patients
Objective:To examine the effects of different PPIs on the antiplatelet activity of clopidogrel in CHD patients with or without loss of function CYP2C19alleles.
Methods:A total of164CHD patients admitted to the hospital were divided into four groups by administion of different PPIs:Group Omeprazole (35patients, omeprazole20mg daily、Group Esomeprazole(50patients, esomeprazole40mg daily)、Group Pantoprazole (41patients, pantoprazole40mg daily) and Group without PPIs (38patients). All patients were administered with aspirin (100mg daily) and clopidogrel (300loading dose,75mg daily thereafter). Blood samples for examining platelet aggregation and genotype were obtained from all patients before administion of clopidogrel and three days after. ADP (10u1)-induced platelet aggregation was assessed by multiple electrode aggregometry. The inhibition rate of clopidogrel on platelet aggregation=platelet aggregation before clopidogrel admonition—platelet aggregation after clopidogrel admonition/platelet aggregation before clopidogrel administion×100%. CYP2C19*2and*3genotype were performed by real-time PCR-TaqMan assay.
Results:The inhibition rate of clopidogrel on platelet aggregation in the Group Omeprazole, Group Esomeprazole, Group Pantoprazole and Group without PPIs were40.93%,41.24%,46.67%and47.59%respectively. The inhibition rate of clopidogrel on platelet aggregation had a descending trend in the Group Omeprazole, Group Esomeprazole, Group Pantoprazole and Group without PPIs, but there were no significant difference among the four groups (P>0.05). The inhibition rate of clopidogrel on platelet aggregation had significant difference in non-carriers group and carriers of loss of function CYP2C19alleles group in all patients (41.21%vs39.33%, P<0.05). The patients of four groups were divided into non-carriers groups and carriers of loss of function CYP2C19alleles groups furthermore. The inhibition rate of clopidogrel on platelet aggregation had no significant difference among these eight groups (P>0.05), and had no significant difference in non-carriers group and carriers of loss of function CYP2C19alleles group in different PPIs groups (P>0.05)
Conclusions:The inhibition rate of clopidogrel on platelet aggregation was reduced in the CHD patients who carried of loss of function CYP2C19alleles. The inhibition rate of clopidogrel on platelet aggregation wasn't affected by co-admonition with different PPIs in CHD patients, and wasn't affected by co-admonition with different PPIs in CHD patients who carriered of loss of function CYP2C19alleles.
Part3Influence of different PPIs combined with clopidogrel on early myocardial injury in elective PCI patients
Objective:To evaluate the influence of different PPIs combined with clopidogrel on early myocardial injury in elective PCI patients with or without loss of function CYP2C19alleles.
Methods:A total of149patients with PCI were divided into four groups administered with different PPIs:Group Omeprazole (32patients, omeprazole20mg daily)、Group Esomeprazole (42patients, esomeprazole40mg daily)、 Group Pantoprazole (32patients, pantoprazole40mg daily) and Group without PPIs (43patients). All patients were administered with aspirin (100mg daily) and clopidogrel (300loading dose,75mg daily thereafter). Blood samples for examining cTnI and genotype were obtained from all patients on the next day after PCI。Positive cTnI was defined as cTnI>Ing/ml. CYP2C19*2and*3genotyping were performed by real-time PCR-TaqMan assay.
Results:The positive rate of cTnI in Group Omeprazole, Group Esomeprazole, Group Pantoprazole and Group without PPIs were12.5%,11.9%,15.6%and9.3%respectively, and showed no significant difference in the four groups (P>0.05). The positive rate of cTnI in non-carriers groups and earriers of loss of function CYP2C19alleles groups in all patients were 12.07%and12.09%and showed no significant difference in the two groups (P>0.05). The patients of the four groups were divided into non-carriers groups and carriers of loss of function CYP2C19alleles groups furthermore. The positive rate of cTnl had no significant difference in these eight groups (P>0.05), and had no significant difference in non-carriers groups and carriers of loss of function CYP2C19alleles groups in different PPIs groups (P>0.05)
Conclusions:There were no effects on early myocardial injury in the elective PCI patients co-administered with different PPIs and in the elective PCI patients who carried of loss of function CYP2C19alleles co-administered with different PPIs. Omeprazole. Esomeprazole or Pantoprazole can be selected in CHD patients co-administered with clopidogrel, but Pantoprazole may be the optimum.
CYP2C19*2和CYP2C19*3被称为CYP2C19酶的失功能基因,而携带CYP2C19失功能基因的患者消弱了氯吡格雷抗血小板作用。研究发现在亚洲CYP2C19失功能基因发生率要远远高于欧美国家,而我国冠心病患者联合应用氯吡格雷和PPIs对血小板聚集产生的影响尚未深入研究。本研究首先明确CYP2C19失功能基因在中国汉族人群的发生率；再次分析冠心病患者服用氯吡格雷时,联合应用不同PPIs对血小板抑制率的影响以及对携带CYP2C19失功能基因的冠心病患者血小板聚集率的影响；进一步分析PCI患者服用氯吡格雷同时联合应用不同PPIs对PCI术后早期心肌损伤的影响以及对携带CYP2C19失功能基因的PCI患者PCI术后早期心肌损伤的影响；为冠心病患者应用氯吡格雷时选择何种PPI s提供依据。实验内容主要包括以下三部分。
第一部分CYP2C19失功能基因在中国汉族人群的分布
目的:观察CYP2C19失功能基因在中国汉族人群的发生率,为进一步探讨氯吡格雷和PPIs在冠心病患者联合应用提供依据。
方法：入选到河北医科大学二院体检中心的体检者共1108例。每一位体检者首先采集2ml静脉血以提取DNA；其次应用TaqMan荧光探针标记的real-time PCR方法对提取的DNA进行基因分型。
结果：CYP2C19*1/*1、*1/*2、*2/*2、*1/*3、*2/*3、*3/*3的发生率分别是39.53%、35.83%、8.48%、8.84%、6.32%和1%。
结论：在中国汉族人群CYP2C19*2和*3失功能基因携带者的比例接近60%。
第二部分不同PPIs和CYP2C19失功能基因对氯吡格雷抗血小板作用的影响
目的：观察不同的PPIs对冠心病患者氯吡格雷抗血小板作用的影响,以及携带失功能基因的冠心病患者应用氯吡格雷联合不同PPIs对氯毗格雷抗血小板的影响,为应用抗血小板药物的冠心病患者预防和治疗上消化道出血提供最佳的PPIs。
方法：入选164例到河北医科大学二院心血管内科住院的冠心病患者,根据应用不同的PPIs分为四组,奥美拉唑组(35例)、埃索美拉唑组(50例)、泮托拉唑组(41例和未用PPIs组(38例)。所有患者于入院时给予肠溶阿司匹林100mg每日1次,氯毗格雷首先300mg顿服,随后75mg每日1次口服。进入不同PPIs组的患者分别服用：奥美拉唑20mg,每日1次；埃索美拉唑40mg,每日1次；泮托拉唑40mg,每日1次。PPIs与氯吡格雷同时服用。所有患者在服氯毗格雷前采血以检测血小板聚集率和提取DNA；在服氯吡格雷3天后再次采集静脉血以检测血小板聚集率。血小板聚集率的检测应用电阻法(10ul ADP作为诱导剂),氯吡格雷对血小板的抑制率=(服氯吡格雷前的血小板聚集率-服氯吡格雷后的血小板聚集率)／服氯吡格雷前的血小板聚集率×100%。应用TaqMan荧光探针标记的real-time PCR方法对提取的DNA进行基因分型。结果：1.氯吡格雷对血小板的抑制率在奥美拉唑组、埃索美拉唑组、泮托拉唑组和未服用PPIs组分别是40.93%、41.24%、46.67%和47.59%,血小板抑制率有下降的趋势,但是没有统计学差异(P>0.05)。根据基因分型将所有患者再进一步分为野生型组(CYP2C19*1/*1)和失功能基因型组(CYP2C19*1/*2、2C19*1/*3、2C19*2/*2、2C19*2/*3和2C19*3/*3),野生型组和失功能基因型组氯吡格雷对血小板的抑制率在两组之间有统计学差异(41.21%vs39.33%,P<0.05)。
2.奥美拉唑组、埃索美拉唑组、泮托拉唑组和未服用PPIs组再根据野生型和失功能基因型又分为8组。在这8组间氯吡格雷对血小板的抑制率相比也没有统计学差异(P>0.05)。在不同PPIs组内野生型和失功能基因型两组间再分别比较氯毗格雷对血小板抑的制率,也没有统计学差异(P>0.05)。
结论：对于冠心病患者,CYP2C19失功能基因携带者降低了氯吡格雷对血小板的抑制率。联合应用PPIs并不影响冠心病患者氯毗格雷对血小板的抑制作用,同时也不影响携带CYP2C19失功能基因的冠心病患者对血小板的抑制率。
第三部分不同质子泵抑制剂和CYP2C19失功能基因对择期PCI患者术后心肌的影响
目的:观察服用不同PPIS的PCI患者术后早期cTnI的变化,以及氯毗格雷联合不同PPIs对携带失功能基因的PCI患者术后早期cTnI的变化,分析不同的PPIs对PCI患者术后早期心肌损伤的影响,为PCI患者在预防和治疗上消化道出血以及减少心肌损伤方面提供最佳的PPIs。
方法：陆续在河北医科大学二院心血管内科住院并接受PCI治疗的患者149例。根据应用不同的PPIs分为四组,奥美拉唑组(32例)、埃索美拉唑组(42例)、泮托拉唑组(32例)和未用PPIs组(43例)。所有患者于入院时应用肠溶阿司匹林100mg每日1次,氯毗格雷首先300mg顿服,随后75mg每日1次口服。进入不同PPIs组的患者分别服用：奥美拉唑20mg,每日1次；埃索美拉唑40mg,每日1次；泮托拉唑40mg,每日1次。PPIs与氯毗格雷同时服用。PCI术后第二天采静脉血检测cTnI和提取DNA。cTnI>Ing/ml为肌钙蛋白阳性。应用TaqMan荧光探针标记的real-time PCR方法对提取的DNA进行基因分型。
结果：PCI术后cTnI阳性率在奥美拉唑组、埃索美拉唑组、泮托拉唑组和未服用PPIs组没有统计学差异(P>0.05)。根据基因分型将所有患者再进一步分为野生型和携带失功能基因型，两组间cTnI阳性率分别是12.07%和12.09%,没有统计学差异(P>0.05)。不同的PPIs组再根据基因分型分为8组,这8组间cTnI阳性率没有统计学差异(P>0.05)。不同PPIs组内野生型和失功能基因型两组间再分别比较cTnI阳性率,还是没有统计学差异(P>0.05)
结论:服用氯吡格雷的PCI患者,与不同PPIs联合应用不会对PCI术后早期心肌损伤产生影响,也不会对携带失功能基因的PCI患者术后早期心肌损伤产生影响。对于服用氯吡格雷的冠心病患者如果联合应用PPIs,奥美拉唑、埃索美拉唑和泮托拉唑都可以选用,但最好选择泮托拉唑。
Clopidogrel co-administered with aspirin have become a corner-stone in treatment of ACS and PCI patients. Given the increased bleeding risk associated with antiplatelet therapy, PPIs are prescribed oiten.Clopidogrel and PPIs have a pharmacodynamie interaction because they are both metabolited by CYP2C19.
CYP2C19*2and*3belong to loss of function CYP2C19alleles which decrease the inhibition of clopidogrel on platelet aggregation. The prevalence of the loss of function CYP2C19alleles in Asia was higher than that in Europe and America. There has been rare research for clopidogrel co-administered with PPIs on platelet aggregation in Chinese. So the first step of this research was to study the loss of function CYP2C19alleles in Chinese Han population. Then, the effects of clopidogrel on platelet aggregation was analysised in the CHD patients who were treated clopidogrel co-administered with PPIs and those patients who carried of loss of function CYP2C19alleles. Finally, the effects on early myocardial injury were determined in the elective PCI patients who received clopidogrel co-administered with different PPIs and those patients who carried of loss of function CYP2C19alleles. Three parts are showed as below.
Part1The prevalence of the loss of function CYP2C19alleles in Chinese Han population.
Objective:To investigate the prevalence of the loss of function CYP2C19alleles in Chinese Han population.
Methods:1108consecutive volunteers were enrolled in this study, CYP2C19*2and*3genotype were performed by real-time PCR-TaqMan assay.
Results:The prevalence of CYP2C19*1/*1、*1/*2、*2/*2、*1/*3、*2/*3、 *3/*3were39.53%、35.83%、8.48%、8.84%、6.32%and1%,respectively.
Conclusions:The prevalence of loss of function CYP2C19alleles were about60%in Chinese Han population.
Part2Effects of different PPIs on the antiplatelet activity of clopidogrel in CHD patients
Objective:To examine the effects of different PPIs on the antiplatelet activity of clopidogrel in CHD patients with or without loss of function CYP2C19alleles.
Methods:A total of164CHD patients admitted to the hospital were divided into four groups by administion of different PPIs:Group Omeprazole (35patients, omeprazole20mg daily、Group Esomeprazole(50patients, esomeprazole40mg daily)、Group Pantoprazole (41patients, pantoprazole40mg daily) and Group without PPIs (38patients). All patients were administered with aspirin (100mg daily) and clopidogrel (300loading dose,75mg daily thereafter). Blood samples for examining platelet aggregation and genotype were obtained from all patients before administion of clopidogrel and three days after. ADP (10u1)-induced platelet aggregation was assessed by multiple electrode aggregometry. The inhibition rate of clopidogrel on platelet aggregation=platelet aggregation before clopidogrel admonition—platelet aggregation after clopidogrel admonition/platelet aggregation before clopidogrel administion×100%. CYP2C19*2and*3genotype were performed by real-time PCR-TaqMan assay.
Results:The inhibition rate of clopidogrel on platelet aggregation in the Group Omeprazole, Group Esomeprazole, Group Pantoprazole and Group without PPIs were40.93%,41.24%,46.67%and47.59%respectively. The inhibition rate of clopidogrel on platelet aggregation had a descending trend in the Group Omeprazole, Group Esomeprazole, Group Pantoprazole and Group without PPIs, but there were no significant difference among the four groups (P>0.05). The inhibition rate of clopidogrel on platelet aggregation had significant difference in non-carriers group and carriers of loss of function CYP2C19alleles group in all patients (41.21%vs39.33%, P<0.05). The patients of four groups were divided into non-carriers groups and carriers of loss of function CYP2C19alleles groups furthermore. The inhibition rate of clopidogrel on platelet aggregation had no significant difference among these eight groups (P>0.05), and had no significant difference in non-carriers group and carriers of loss of function CYP2C19alleles group in different PPIs groups (P>0.05)
Conclusions:The inhibition rate of clopidogrel on platelet aggregation was reduced in the CHD patients who carried of loss of function CYP2C19alleles. The inhibition rate of clopidogrel on platelet aggregation wasn't affected by co-admonition with different PPIs in CHD patients, and wasn't affected by co-admonition with different PPIs in CHD patients who carriered of loss of function CYP2C19alleles.
Part3Influence of different PPIs combined with clopidogrel on early myocardial injury in elective PCI patients
Objective:To evaluate the influence of different PPIs combined with clopidogrel on early myocardial injury in elective PCI patients with or without loss of function CYP2C19alleles.
Methods:A total of149patients with PCI were divided into four groups administered with different PPIs:Group Omeprazole (32patients, omeprazole20mg daily)、Group Esomeprazole (42patients, esomeprazole40mg daily)、 Group Pantoprazole (32patients, pantoprazole40mg daily) and Group without PPIs (43patients). All patients were administered with aspirin (100mg daily) and clopidogrel (300loading dose,75mg daily thereafter). Blood samples for examining cTnI and genotype were obtained from all patients on the next day after PCI。Positive cTnI was defined as cTnI>Ing/ml. CYP2C19*2and*3genotyping were performed by real-time PCR-TaqMan assay.
Results:The positive rate of cTnI in Group Omeprazole, Group Esomeprazole, Group Pantoprazole and Group without PPIs were12.5%,11.9%,15.6%and9.3%respectively, and showed no significant difference in the four groups (P>0.05). The positive rate of cTnI in non-carriers groups and earriers of loss of function CYP2C19alleles groups in all patients were 12.07%and12.09%and showed no significant difference in the two groups (P>0.05). The patients of the four groups were divided into non-carriers groups and carriers of loss of function CYP2C19alleles groups furthermore. The positive rate of cTnl had no significant difference in these eight groups (P>0.05), and had no significant difference in non-carriers groups and carriers of loss of function CYP2C19alleles groups in different PPIs groups (P>0.05)
Conclusions:There were no effects on early myocardial injury in the elective PCI patients co-administered with different PPIs and in the elective PCI patients who carried of loss of function CYP2C19alleles co-administered with different PPIs. Omeprazole. Esomeprazole or Pantoprazole can be selected in CHD patients co-administered with clopidogrel, but Pantoprazole may be the optimum.
引文
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1 Chan FK, Ching JY, Hung LC, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med. 2005. 352(3): 238-244
2 Hallas J, Dall M, Andries A, et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ. 2006. 333(7571): 726-728
3 KSB, Smith SC Jr, Hirshfeld JW Jr, et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines. J Am Coll Cardiol. 2008. 51(2): 172-209
4 Santos PC, Soares RA, Santos DB, et al. CYP2C19 and ABCB1 gene polymorphisms are differently distributed according to etlmicity in the Brazilian general population. BMC Med Genet. 2011. 12: 13-19
5 Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010. 38(1): 92-99
6 Michelson AD. Antiplatelet therapies for the treatment of cardiovascular disease. Nat Rev Drug Discov. 2010.9(2): 154-169
7 Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol. 2008. 51(20): 1925-1934
8 Furuta T, Sugimoto M, Shirai N, et al.. CYP2C19 pharmacogenomics associated with therapy of Helicobacter pylori infection and gastro-esophageal reflux diseases with a proton pump inhibitor. Pharmacogenomics. 2007. 8(9): 1199-1210
9 Li XQ, Andersson TB, Ahlstrom M, et al.. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos.2004.32(8):821-827
10 Juurlink DN. Proton pump inhibitors and clopidogrel:putting the interaction in perspective. Circulation.2009.120(23):2310-2312
11 Stedman CA, Barclay ML. Review article:comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors. Aliment Pharmacol Ther.2000.14(8):963-978
12 Ogilvie BW, Yerino P, Kazmi F, et al. The proton pump inhibitor, omeprazole, but not lansoprazole or pantoprazole, is a metabolism-dependent inhibitor of CYP2C19:implications for coadministration with clopidogrel. Drug Metab Dispos.2011.39(11): 2020-2033
13 Cuisset T, Frere C, Quilici J, et al. Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose the PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective randomized study. J Am Coll Cardiol.2009.54(13): 1149-1153
14 Angiolillo DJ, Gibson CM, Cheng S, et al. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects:randomized, placebo-controlled, crossover comparison studies. Clin Pharmacol Ther. 2011.89(1):65-74
15 Collet JP, Hulot JS, Pena A, et al. Cytochrome P4502C19 polymorphism in young patients treated with clopidogrel after myocardial infarction:a cohort study. Lancet.2009.373(9660):309-317
16 de Morais SM, Wilkinson GR, Blaisdell J, et al. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem.1994.269(22):15419-15422
17 De Morais SM. Wilkinson GR. Blaisdeil J. el al. Idemification of a genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol. 1994.46(4): 594-598
18 Pirmohamed M, Park BK. Genetic susceptibility to adverse drug reactions. Trends Pharmacol Sci. 2001. 22(6): 298-305
19 Yamamoto K, Hokimoto S, Chitose T, et al. Impact of CYP2C1P polymorphism on residual platelet reactivity in patients with coronary heart disease during antiplatelet therapy. J Cardiol. 2011. 57(2): 194-201
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21 Toth PP, Armani A. Thienopyridine therapy and risk for cardiovascular events in secondary prevention. Curr Atheroscler Rep. 2009. 11(5): 364470
22 Gilard M, Arnaud B, Le GG, Abgrall JF, et al. Influence of omeprazol on the antiplatelet action of clopidogrel associated to aspirin. J Thromb Haernost. 2006. 4(11): 2508-2509
23 Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol. 2008. 51(3): 256-260
24 Kwan J, Htun WW. Huang Y. et al. Effect of proton pump inhibitors on platelet inhibition activity of clopidogrel in Chinese patients with percutaneous coronary intervention. Vasc Health Risk Manag. 2011. 7: 399-404
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33 Harmsze A, van WJW, Bouman HJ, et al. Besides CYP2C19*2, the variant allele CYP2C9*3 is associated with higher on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective coronary stent implantation. Pharmacogenet Genomics.2010.20(1):18-25
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10 Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol.2008.51(20):1925-1934
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1 Chan FK, Ching JY, Hung LC, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med. 2005. 352(3): 238-244
2 Hallas J, Dall M, Andries A, et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ. 2006. 333(7571): 726-728
3 KSB, Smith SC Jr, Hirshfeld JW Jr, et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines. J Am Coll Cardiol. 2008. 51(2): 172-209
4 Santos PC, Soares RA, Santos DB, et al. CYP2C19 and ABCB1 gene polymorphisms are differently distributed according to etlmicity in the Brazilian general population. BMC Med Genet. 2011. 12: 13-19
5 Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010. 38(1): 92-99
6 Michelson AD. Antiplatelet therapies for the treatment of cardiovascular disease. Nat Rev Drug Discov. 2010.9(2): 154-169
7 Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol. 2008. 51(20): 1925-1934
8 Furuta T, Sugimoto M, Shirai N, et al.. CYP2C19 pharmacogenomics associated with therapy of Helicobacter pylori infection and gastro-esophageal reflux diseases with a proton pump inhibitor. Pharmacogenomics. 2007. 8(9): 1199-1210
9 Li XQ, Andersson TB, Ahlstrom M, et al.. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos.2004.32(8):821-827
10 Juurlink DN. Proton pump inhibitors and clopidogrel:putting the interaction in perspective. Circulation.2009.120(23):2310-2312
11 Stedman CA, Barclay ML. Review article:comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors. Aliment Pharmacol Ther.2000.14(8):963-978
12 Ogilvie BW, Yerino P, Kazmi F, et al. The proton pump inhibitor, omeprazole, but not lansoprazole or pantoprazole, is a metabolism-dependent inhibitor of CYP2C19:implications for coadministration with clopidogrel. Drug Metab Dispos.2011.39(11): 2020-2033
13 Cuisset T, Frere C, Quilici J, et al. Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose the PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective randomized study. J Am Coll Cardiol.2009.54(13): 1149-1153
14 Angiolillo DJ, Gibson CM, Cheng S, et al. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects:randomized, placebo-controlled, crossover comparison studies. Clin Pharmacol Ther. 2011.89(1):65-74
15 Collet JP, Hulot JS, Pena A, et al. Cytochrome P4502C19 polymorphism in young patients treated with clopidogrel after myocardial infarction:a cohort study. Lancet.2009.373(9660):309-317
16 de Morais SM, Wilkinson GR, Blaisdell J, et al. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem.1994.269(22):15419-15422
17 De Morais SM. Wilkinson GR. Blaisdeil J. el al. Idemification of a genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol. 1994.46(4): 594-598
18 Pirmohamed M, Park BK. Genetic susceptibility to adverse drug reactions. Trends Pharmacol Sci. 2001. 22(6): 298-305
19 Yamamoto K, Hokimoto S, Chitose T, et al. Impact of CYP2C1P polymorphism on residual platelet reactivity in patients with coronary heart disease during antiplatelet therapy. J Cardiol. 2011. 57(2): 194-201
20 Jorgensen PW, Calleja EL, Gaso PS, Matarranz dAM, NavaiTO RAS Sanchez JM. Antiagregation and anticoagulation, relationship with upper gastrointestinal bleeding. Rev Esp Enferm Dig. 2011. 103(7): 360-365
21 Toth PP, Armani A. Thienopyridine therapy and risk for cardiovascular events in secondary prevention. Curr Atheroscler Rep. 2009. 11(5): 364470
22 Gilard M, Arnaud B, Le GG, Abgrall JF, et al. Influence of omeprazol on the antiplatelet action of clopidogrel associated to aspirin. J Thromb Haernost. 2006. 4(11): 2508-2509
23 Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol. 2008. 51(3): 256-260
24 Kwan J, Htun WW. Huang Y. et al. Effect of proton pump inhibitors on platelet inhibition activity of clopidogrel in Chinese patients with percutaneous coronary intervention. Vasc Health Risk Manag. 2011. 7: 399-404
25 Siller-Matula JM, Spiel AO, Lang IM, et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J. 2009. 157(1): 148.el-5
26 Meyer UA. Metabolic interactions of the proton-pump inhibitors lansoprazole, omeprazole and pantoprazole with other drugs. Eur J Gastroenterol Hepatol. 1996. 8 Suppl 1: S21- S25
27 Siller-Matula JM. Spiel AO. Lang IM. et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J.2009. 157(1):148.e1-5
28 Schmidt M, Johansen MB, Robertson DJ, et al. Concomitant use of clopidogrel and proton pump inhibitors is not associated with major adverse cardiovascular events following coronary stent implantation. Aliment Pharmacol Ther.2012.35(1):165-174
29 Sarafoff N, Sibbing D, Sonntag U, et al. Risk of drug-eluting stent thrombosis in patients receiving proton pump inhibitors. Thromb Haemost. 2010.104(3):626-632
30 Gremmel T, Steiner S, Seidinger D, et al. The influence of proton pump inhibitors on the antiplatelet potency of clopidogrel evaluated by 5 different platelet function tests. J Cardiovasc Pharmacol.2010.56(5): 532-539
31 Mega JL, Close SL, Wiviott SD. et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med.2009.360(4):354-362
32 Giusti B, Gori AM, Marcucci R, et al. Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10 + 12G/A and P2Y12 T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients. Pharmacogenet Genomics.2007.17(12):1057-1064
33 Harmsze A, van WJW, Bouman HJ, et al. Besides CYP2C19*2, the variant allele CYP2C9*3 is associated with higher on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective coronary stent implantation. Pharmacogenet Genomics.2010.20(1):18-25
34 Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med.2009. 360(4):363-375
35 Huang CC, Chen YC, Leu HB, et al. Risk of adverse outcomes in Taiwan associated with concomitant use of clopidogrel and proton pump inhibitors in patients who received percutaneous coronary intervention. Am J Cardiol. 2010.105(12):1705-1709
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7 Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med.2006. 354(16):1706-1717.
8 Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction:randomised placebo-controlled trial. Lancet.2005.366(9497):1607-1621
9 Lanas A, Scheiman J. Low-dose aspirin and upper gastrointestinal damage: epidemiology, prevention and treatment. Curr Med Res Opin.2007. 23(1):163-173
10 Santos PC, Soares RA, Santos DB, et al. CYP2C19 and ABCB1 gene polymorphisms are differently distributed according to ethnicity in the Brazilian general population. BMC Med Genet.2011.12:13-19
11 Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos.2010.38(1):92-99
12 Michelson AD. Antiplatelet therapies for the treatment of cardiovascular disease. Nat Rev Drug Discov.2010.9(2):154-169
13 Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P4502C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol.2008.51(20):1925-1934
14 Li XQ, Andersson TB. Ahlstrom M, et al. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos.2004.32(8):821-827.
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17 Juurlink DN. Proton pump inhibitors and clopidogrel:putting the interaction in perspective. Circulation.2009.120(23):2310-2312
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22 De Morais SM, Wilkinson GR, Blaisdell J, et al. Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol.1994.46(4):594-598.
23 Hwang SJ, Jeong YH, Kim IS, et al. The cytochrome 2C19*2 and*3 alleles attenuate response to clopidogrel similarly in East Asian patients undergoing elective percutaneous coronary intervention. Thromb Res. 2011.127(1):23-28
24 Harmsze AM, van WJW, Ten BJM; et al. CYP2C19*2 and CYP2C9*3 alleles are associated with stent thrombosis:a case-control study. Eur Heart J.2010.31(24):3046-3053
25 Yamamoto K, Hokimoto S, Chitose T, et al. Impact of CYP2C19 polymorphism on residual platelet reactivity in patients with coronary heart disease during antiplatelet therapy. J Cardiol.2011.57(2):194-201.
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31 Chan FK, Ching JY, Hung LC, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med.2005. 352(3):238-44
32 Hallas J. Dall M, Andries A, et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ.2006.333(7571):726-728
33 Jorgensen PW, Calleja EL, Gaso PS. et al. Antiagregation and anticoagulation, relationship with upper gastrointestinal bleeding. Rev Esp Enferm Dig.2011.103(7):360-365
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