赵辽辽，陈 晶，杜雅菊

哈尔滨医科大学附属第二医院消化内科，黑龙江 哈尔滨 150086

综述

阿司匹林及氯比格雷相关胃损伤治疗新进展

赵辽辽，陈 晶，杜雅菊

哈尔滨医科大学附属第二医院消化内科，黑龙江 哈尔滨 150086

阿司匹林及氯吡格雷相关的胃肠道毒性是一个重要的医疗和社会经济问题。为了预防阿司匹林及氯吡格雷相关的胃肠道毒性，临床常遵循以下6种治疗策略：(1)合用胃保护药物；(2)应用选择性COX-2抑制剂；(3)根除幽门螺杆菌(H.pylori)；(4)阿司匹林衍生物；(5)抗氧化剂；(6)中医中药治疗。长期合用质子泵抑制剂(PPI)降低胃肠毒性安全有效。选择性COX-2抑制剂是一类选择性抑制COX-2，但保留胃肠保护COX-1通路的抑制剂。H.pylori增加溃疡的风险，尤其在首次使用非甾体抗炎药(NSAIDs)的患者，因此，长期NSAID治疗或高危患者，建议根除H.pylori。另外，近期有研究报道一种新型阿司匹林衍生物，这种衍生物是通过含钙羟基磷灰石与阿司匹林相互作用得到Ca-阿司匹林，可显著抑制COX-2，而对COX-1没有显著影响，从而不影响前列腺素(PG)的合成。DA-9601是一种抗氧化剂，阿司匹林可能通过白细胞募集及活性氧的产生来引起胃肠道损伤，阻止活性氧的产生可减少胃肠道损伤的发生。中药通过健脾补肾、活血化瘀及疏肝理气减轻胃肠损伤。

阿司匹林；氯比格雷；幽门螺杆菌；质子泵抑制剂；H2受体抑制剂

目前我国人口老龄化趋势日益明显，冠心病的发病率逐年上升，经冠状动脉介入(percutaneous coronary intervention,PCI)治疗的患者也呈上升趋势。PCI术后抗血小板治疗成为患者预后的关键治疗之一[1]。作为抗血小板药物，阿司匹林和氯吡格雷应用最多[2]。阿司匹林与氯吡格雷联合抗血小板治疗与单一阿司匹林治疗相比，患者心脏病发作和心脏疾病死亡的风险明显下降[3]。阿司匹林致胃肠道黏膜损伤机制有局部和全身作用，阿司匹林呈弱酸性，对胃肠道黏膜表面直接损害，造成黏膜损伤。另一方面，阿司匹林等非甾体抗炎药(non-steroidal anti-inflammatory drugs,NSAIDs)通过抑制COX-1活性，降低了内源性前列腺素(prostaglandin,PG)的合成，减少黏膜血流量，减少黏液及碳酸氢盐的分泌，使黏膜防御能力下降，造成胃肠道糜烂、溃疡的发生[4]。与单用阿司匹林相比，阿司匹林联合氯比格雷双重抗血小板治疗降低急性冠脉综合征及PCI术后患者的心血管不良事件的风险[5]。然而双联抗血小板治疗获益的同时可能会出现上腹不适、恶心、呕吐甚至消化道出血等并发症[6]。因此，如何治疗成为一个关键的问题，迫切需要研究出预防和治疗胃肠道黏膜损伤的最佳方案。本文将对临床常遵循的6种治疗策略作一概述。

1 胃保护药物

1.1 米索前列醇 米索前列醇是一种合成的PG类似物，可以补充被阿司匹林等NSAIDs抑制的PG，预防阿司匹林所致的胃黏膜损伤[7]。与安慰剂相比，米索前列醇可以显著降低长期NSAIDs所致胃十二指肠损伤的发病率。其副作用主要包括：恶心、腹泻及腹痛等。但是一项比较米索前列醇与质子泵抑制剂(proton pump inhibitor,PPI)、H2受体阻断剂(H2 receptor antagonist,H2RA)研究[8]报道，虽然米索前列醇减少阿司匹林所致的胃肠道并发症与PPI及H2RA相当，但米索前列醇的依从性较低，因此很难准确评估其疗效。低剂量的米索前列醇也有减少阿司匹林所致胃黏膜损伤的风险[9]。

1.2 黏膜保护剂

1.2.1 硫糖铝：硫糖铝是一种黏膜保护剂，通过形成一个保护凝胶，减少受损上皮的酸暴露或中和胃酸起到保护胃黏膜的作用[7]。

1.2.2 瑞巴派特：瑞巴派特是一种治疗胃炎和消化性溃疡的药物，通过增加胃黏液、PG的产生、减少氧自由基来保护胃上皮细胞，加强胃防御机制[9-12]。在一项关于应用NSAIDs高危患者的随机、多中心、双盲研究中，通过与米索前列醇相比，瑞巴派特的疗效和安全性均较佳，是长期口服NSAIDs及抗凝血药患者防止胃肠道损伤的恰当选择[13]。

1.3 抑酸药 胃酸能增加NSAIDs所致的黏膜损伤，激活胃蛋白酶的水解作用，增加酸性NSAIDs在胃的吸收[14]。抑酸药包括PPI和H2RA两类，PPI和H2RA可通过抑制胃酸分泌和清除自由基来保护胃黏膜[15]。在急性冠脉综合征或PCI患者中，双重抗血小板治疗如阿司匹林和氯比格雷被用来减少不良心血管事件[16]，但它们可致严重的胃肠道出血[17]。PPI可减少此类患者胃肠道出血的风险[18]。PPI有埃索美拉唑、奥美拉唑、雷贝拉唑、泮托拉唑、兰索拉唑等，通过抑制壁细胞质子泵减少胃酸分泌。预防NSAIDs所致的上消化道并发症的国内和国际指南一致推荐使用PPI[19]。氯比格雷是一种前体药物，它通过肝脏细胞色素P450酶系统转化为其活性代谢产物[20]。然而，PPI可能抑制细胞色素氧化酶P450 2C19(CYP 2C19)阻止氯比格雷转化为活性代谢产物。一些报道[21-22]表明，氯比格雷合并PPI会显著增加冠心病患者心血管不良事件的风险。相比之下，其他试验未发现氯比格雷合并PPI用药出现其他显著不良影响[23-24]。H2RA是最早应用于预防NSAIDs所致的消化性溃疡药物，它们对胃溃疡在很大程度上是有效的。然而，对胃出血没有改善，因此，目前这些药物不再推荐[25]。

2 选择性COX-2抑制剂

选择性COX-2抑制剂即选择性抑制COX-2，保留COX-1的功能，从而保证PG的产生。因此，在理论上，COX-2抑制剂比非选择性NSAIDs出现上消化道并发症的概率更低更安全[26]。2007年的一项随机对照试验说明，与非选择性COX-2相比，选择性COX-2抑制剂包括塞来希布、罗非考昔、依托考昔、伐地考昔、罗美昔布，明显减少消化性溃疡及并发症的发生[27]。但是，由于选择性抑制COX-2导致PGI2与TXA2之间的失衡及舒张血管作用NO的减少，提高了心血管风险[28]，因此，选择性COX-2不适用于冠心病及PCI术后的患者。

3 根除幽门螺杆菌(H.pylori)

众所周知，H.pylori可导致简单和复杂的胃十二指肠溃疡，成功地根除H.pylori可改变疾病的自然史并防止溃疡复发[29]。但NSAIDs与H.pylori之间的相互作用一直存在争议，最近一项荟萃分析显示H.pylori和NSAIDs各自都可增加胃溃疡及出血的风险，口服NSAIDs并有H.pylori感染患者消化溃疡的发生率比未感染H.pylori患者要高[30]。在开始抗血小板治疗之前，建议根除H.pylori，这可以减少溃疡，但尚未明确证实可以减少消化道出血[29]。与此同时，筛选出H.pylori检测的最佳试验非常重要，黏膜活检试验及排泄物抗原检测的敏感性较低，虽然血清学检测不能证实是否存在活动性感染，但其具有较高敏感性[31]。尿素呼气试验也有较高的敏感性，但是在急性出血时却很难检测[32]。为此，最近的指南[33]倡导，在溃疡出血之后，尽快进行经验性抗H.pylori治疗。

4 阿司匹林的衍生物

阿司匹林的胃肠道损伤归因于许多因素：(1)阿司匹林抑制了COX-1，减少具有胃保护的PG的合成[34]；(2)阿司匹林游离羧基对胃黏膜表现出刺激性影响。为了克服上述副作用，阿司匹林的衍生物就产生了，一些阿司匹林的衍生物已经显示出前景，如阿司匹林-NO、阿司匹林-H2S[35]。这两种衍生物释放保护胃黏膜的NO和H2S气体，但是，很难控制NO和H2S气体的浓度，一旦超过正常范围，将对机体一些内脏产生毒性反应[36]。一种新的衍生物阿司匹林-Ca，在动物实验中能产生和相同剂量阿司匹林相似的抗血栓作用，同时，阿司匹林-Ca还能通过上调PGE2的合成，也可能是补充胃肠道Ca池的缺乏，从而减少对胃黏膜的损伤。还有一些关于金属阿司匹林衍生物的研究，但是关于它们保护胃黏膜的功能和机制目前尚不清楚。

5 抗氧化剂

DA-9601是一种抗氧化剂，具有抗氧化、抗炎作用，可预防NSAIDs所致的胃肠道并发症[37]。DA-9601的重要组成部分是异泽兰黄素，它可抑制FeSO4所致的氧化应激及减少促氧化基因的表达，从而预防胃黏膜损伤[38]。在胃上皮细胞中，DA-9601可通过调整p38激酶及NF-κB通路来抑制肿瘤坏死因子α(TNF-α)，而TNF-α是一种促炎因子，也可预防胃黏膜损伤[39]。一项关于米索前列醇与DA-9601对预防NSAIDs所致的胃肠道并发症疗效比较的研究表明，DA-9601组胃黏膜保护率与米索前列醇组相当，差异无统计学意义。但是米索前列醇组的胃肠道症状比DA-9601组更频繁，DA-9601能安全、有效地预防胃黏膜损伤。合用维生素C(VitC)的研究较少，VitC理论上可以清除自由基，还可诱导COX-1增加PG的合成，但其应用于预防抗血小板药物诱发的胃肠道并发症的研究较少，疗效不确切[7]。

6 中医中药治疗

目前中药治疗NSAIDs所致胃黏膜损伤的研究不断深入，如党参提取物、丹参提取物、复方黄芪汤、胃舒颗粒、和平散、胃痛灵汤、仓脂颗粒、和平散、平溃散等，都可益气健脾、活血化瘀，主要是通过促进胃黏膜PG的合成、改善黏膜血流及抗氧自由基等途径起作用[40]。中药云母来源于单斜晶系硅酸盐类矿物白云母，具有天然层状结构和特殊的物理性质，可吸附于黏膜表面，从而发挥黏膜保护作用。它可能通过维持胃肠道屏障功能、促进胃黏膜损伤修复和组织愈合、抑制和吸附促炎因子、抗脂质过氧化来预防NSAIDs相关胃肠病。

预防阿司匹林及氯比格雷相关胃病的最好方法是避免使用这类药物，因阿司匹林及氯比格雷的胃肠道副反应呈剂量依赖，在必须应用的前提下，应尽可能减少剂量。本文概述了治疗阿司匹林及氯比格雷相关胃病的药物进展，各种药物各有利弊，目前仍未找到既无胃肠副作用又不影响其抗血小板治疗的药物，因此，需要进一步研究针对阿司匹林及氯比格雷相关胃病的新型药物，为临床需要应用阿司匹林及氯比格雷的患者带来福音。

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(责任编辑：马 军)

New progress of Aspirin and Clopidogrel treatment related gastric lesions

ZHAO Liaoliao,CHEN Jing,DU Yaju

Department of Gastroenterology,the Second Affiliated Hospital of Harbin Medical University,Harbin 150086,China

Aspirin and Clopidogrel related gastrointestinal toxicity is an important medical and social economic problem. In order to prevent the Aspirin and Clopidogrel related gastrointestinal toxicity,6 strategies are followed in clinical routine: (1) conprescription of gastroprotective drug; (2) selective COX-2 inhibitors; (3) the eradication of Helicobacter pylori (H.pylori); (4) Aspirin derivatives; (5) Antioxidants; (6) Chinese medicine treatment. Long-term use of PPI is safe and effective. Selective COX-2 inhibitor is a kind of selective inhibition of it,but retain gastrointestinal protection COX-1 channel.H.pyloriincreases the risk of ulcer,especially in the first use of non-steroidal anti-inflammatory drugs (NSAIDs) of the patients,therefore,in the long term NSAID treatment before or in high-risk patients,eradication ofH.pyloriis suggested. In addition,recent studies have reported a new type of Aspirin derivative,the derivative is obtained by interaction between calcium hydroxyapatite and Aspirin,Ca-Aspirin can significantly inhibit COX-2,with no significant influence of COX-1,which does not affect the synthesis of prostaglandin. DA-9601 is an antioxidant that Aspirin may cause leukocyte recruitment and generation of reactive oxygen species to cause gastrointestinal damage,inhibiting the development of ROS in order to reduce the occurrence of gastrointestinal injury. Traditional Chinese medicine can remove blood stasis and soothing liver reduce gastrointestinal injury by invigorating kidney and promoting blood circulation.

Aspirin; Clopidogrel; Helicobacter pylori; Proton pump inhibitors; H2 receptor inhibitor

赵辽辽，在读硕士研究生，研究方向：胃肠疾病的诊断及治疗。E-mail：948494869@qq.com

杜雅菊，主任医师，硕士生导师，教授，研究方向：消化系统疾病。E-mail：duyaju1964@163.com

10.3969/j.issn.1006-5709.2016.04.028

R573

A

1006-5709(2016)04-0461-04

2015-04-15