趙遼遼，陳 晶，杜雅菊

哈爾濱醫(yī)科大學(xué)附屬第二醫(yī)院消化內(nèi)科，黑龍江 哈爾濱 150086

綜述

阿司匹林及氯比格雷相關(guān)胃損傷治療新進(jìn)展

趙遼遼，陳 晶，杜雅菊

哈爾濱醫(yī)科大學(xué)附屬第二醫(yī)院消化內(nèi)科，黑龍江 哈爾濱 150086

阿司匹林及氯吡格雷相關(guān)的胃腸道毒性是一個(gè)重要的醫(yī)療和社會(huì)經(jīng)濟(jì)問(wèn)題。為了預(yù)防阿司匹林及氯吡格雷相關(guān)的胃腸道毒性，臨床常遵循以下6種治療策略：(1)合用胃保護(hù)藥物；(2)應(yīng)用選擇性COX-2抑制劑；(3)根除幽門螺桿菌(H.pylori)；(4)阿司匹林衍生物；(5)抗氧化劑；(6)中醫(yī)中藥治療。長(zhǎng)期合用質(zhì)子泵抑制劑(PPI)降低胃腸毒性安全有效。選擇性COX-2抑制劑是一類選擇性抑制COX-2，但保留胃腸保護(hù)COX-1通路的抑制劑。H.pylori增加潰瘍的風(fēng)險(xiǎn)，尤其在首次使用非甾體抗炎藥(NSAIDs)的患者，因此，長(zhǎng)期NSAID治療或高?；颊撸ㄗh根除H.pylori。另外，近期有研究報(bào)道一種新型阿司匹林衍生物，這種衍生物是通過(guò)含鈣羥基磷灰石與阿司匹林相互作用得到Ca-阿司匹林，可顯著抑制COX-2，而對(duì)COX-1沒(méi)有顯著影響，從而不影響前列腺素(PG)的合成。DA-9601是一種抗氧化劑，阿司匹林可能通過(guò)白細(xì)胞募集及活性氧的產(chǎn)生來(lái)引起胃腸道損傷，阻止活性氧的產(chǎn)生可減少胃腸道損傷的發(fā)生。中藥通過(guò)健脾補(bǔ)腎、活血化瘀及疏肝理氣減輕胃腸損傷。

阿司匹林；氯比格雷；幽門螺桿菌；質(zhì)子泵抑制劑；H2受體抑制劑

目前我國(guó)人口老齡化趨勢(shì)日益明顯，冠心病的發(fā)病率逐年上升，經(jīng)冠狀動(dòng)脈介入(percutaneous coronary intervention,PCI)治療的患者也呈上升趨勢(shì)。PCI術(shù)后抗血小板治療成為患者預(yù)后的關(guān)鍵治療之一[1]。作為抗血小板藥物，阿司匹林和氯吡格雷應(yīng)用最多[2]。阿司匹林與氯吡格雷聯(lián)合抗血小板治療與單一阿司匹林治療相比，患者心臟病發(fā)作和心臟疾病死亡的風(fēng)險(xiǎn)明顯下降[3]。阿司匹林致胃腸道黏膜損傷機(jī)制有局部和全身作用，阿司匹林呈弱酸性，對(duì)胃腸道黏膜表面直接損害，造成黏膜損傷。另一方面，阿司匹林等非甾體抗炎藥(non-steroidal anti-inflammatory drugs,NSAIDs)通過(guò)抑制COX-1活性，降低了內(nèi)源性前列腺素(prostaglandin,PG)的合成，減少黏膜血流量，減少黏液及碳酸氫鹽的分泌，使黏膜防御能力下降，造成胃腸道糜爛、潰瘍的發(fā)生[4]。與單用阿司匹林相比，阿司匹林聯(lián)合氯比格雷雙重抗血小板治療降低急性冠脈綜合征及PCI術(shù)后患者的心血管不良事件的風(fēng)險(xiǎn)[5]。然而雙聯(lián)抗血小板治療獲益的同時(shí)可能會(huì)出現(xiàn)上腹不適、惡心、嘔吐甚至消化道出血等并發(fā)癥[6]。因此，如何治療成為一個(gè)關(guān)鍵的問(wèn)題，迫切需要研究出預(yù)防和治療胃腸道黏膜損傷的最佳方案。本文將對(duì)臨床常遵循的6種治療策略作一概述。

1 胃保護(hù)藥物

1.1 米索前列醇 米索前列醇是一種合成的PG類似物，可以補(bǔ)充被阿司匹林等NSAIDs抑制的PG，預(yù)防阿司匹林所致的胃黏膜損傷[7]。與安慰劑相比，米索前列醇可以顯著降低長(zhǎng)期NSAIDs所致胃十二指腸損傷的發(fā)病率。其副作用主要包括：惡心、腹瀉及腹痛等。但是一項(xiàng)比較米索前列醇與質(zhì)子泵抑制劑(proton pump inhibitor,PPI)、H2受體阻斷劑(H2 receptor antagonist,H2RA)研究[8]報(bào)道，雖然米索前列醇減少阿司匹林所致的胃腸道并發(fā)癥與PPI及H2RA相當(dāng)，但米索前列醇的依從性較低，因此很難準(zhǔn)確評(píng)估其療效。低劑量的米索前列醇也有減少阿司匹林所致胃黏膜損傷的風(fēng)險(xiǎn)[9]。

1.2 黏膜保護(hù)劑

1.2.1 硫糖鋁：硫糖鋁是一種黏膜保護(hù)劑，通過(guò)形成一個(gè)保護(hù)凝膠，減少受損上皮的酸暴露或中和胃酸起到保護(hù)胃黏膜的作用[7]。

1.2.2 瑞巴派特：瑞巴派特是一種治療胃炎和消化性潰瘍的藥物，通過(guò)增加胃黏液、PG的產(chǎn)生、減少氧自由基來(lái)保護(hù)胃上皮細(xì)胞，加強(qiáng)胃防御機(jī)制[9-12]。在一項(xiàng)關(guān)于應(yīng)用NSAIDs高?；颊叩碾S機(jī)、多中心、雙盲研究中，通過(guò)與米索前列醇相比，瑞巴派特的療效和安全性均較佳，是長(zhǎng)期口服NSAIDs及抗凝血藥患者防止胃腸道損傷的恰當(dāng)選擇[13]。

1.3 抑酸藥 胃酸能增加NSAIDs所致的黏膜損傷，激活胃蛋白酶的水解作用，增加酸性NSAIDs在胃的吸收[14]。抑酸藥包括PPI和H2RA兩類，PPI和H2RA可通過(guò)抑制胃酸分泌和清除自由基來(lái)保護(hù)胃黏膜[15]。在急性冠脈綜合征或PCI患者中，雙重抗血小板治療如阿司匹林和氯比格雷被用來(lái)減少不良心血管事件[16]，但它們可致嚴(yán)重的胃腸道出血[17]。PPI可減少此類患者胃腸道出血的風(fēng)險(xiǎn)[18]。PPI有埃索美拉唑、奧美拉唑、雷貝拉唑、泮托拉唑、蘭索拉唑等，通過(guò)抑制壁細(xì)胞質(zhì)子泵減少胃酸分泌。預(yù)防NSAIDs所致的上消化道并發(fā)癥的國(guó)內(nèi)和國(guó)際指南一致推薦使用PPI[19]。氯比格雷是一種前體藥物，它通過(guò)肝臟細(xì)胞色素P450酶系統(tǒng)轉(zhuǎn)化為其活性代謝產(chǎn)物[20]。然而，PPI可能抑制細(xì)胞色素氧化酶P450 2C19(CYP 2C19)阻止氯比格雷轉(zhuǎn)化為活性代謝產(chǎn)物。一些報(bào)道[21-22]表明，氯比格雷合并PPI會(huì)顯著增加冠心病患者心血管不良事件的風(fēng)險(xiǎn)。相比之下，其他試驗(yàn)未發(fā)現(xiàn)氯比格雷合并PPI用藥出現(xiàn)其他顯著不良影響[23-24]。H2RA是最早應(yīng)用于預(yù)防NSAIDs所致的消化性潰瘍藥物，它們對(duì)胃潰瘍?cè)诤艽蟪潭壬鲜怯行У?。然而，?duì)胃出血沒(méi)有改善，因此，目前這些藥物不再推薦[25]。

2 選擇性COX-2抑制劑

選擇性COX-2抑制劑即選擇性抑制COX-2，保留COX-1的功能，從而保證PG的產(chǎn)生。因此，在理論上，COX-2抑制劑比非選擇性NSAIDs出現(xiàn)上消化道并發(fā)癥的概率更低更安全[26]。2007年的一項(xiàng)隨機(jī)對(duì)照試驗(yàn)說(shuō)明，與非選擇性COX-2相比，選擇性COX-2抑制劑包括塞來(lái)希布、羅非考昔、依托考昔、伐地考昔、羅美昔布，明顯減少消化性潰瘍及并發(fā)癥的發(fā)生[27]。但是，由于選擇性抑制COX-2導(dǎo)致PGI2與TXA2之間的失衡及舒張血管作用NO的減少，提高了心血管風(fēng)險(xiǎn)[28]，因此，選擇性COX-2不適用于冠心病及PCI術(shù)后的患者。

3 根除幽門螺桿菌(H.pylori)

眾所周知，H.pylori可導(dǎo)致簡(jiǎn)單和復(fù)雜的胃十二指腸潰瘍，成功地根除H.pylori可改變疾病的自然史并防止?jié)儚?fù)發(fā)[29]。但NSAIDs與H.pylori之間的相互作用一直存在爭(zhēng)議，最近一項(xiàng)薈萃分析顯示H.pylori和NSAIDs各自都可增加胃潰瘍及出血的風(fēng)險(xiǎn)，口服NSAIDs并有H.pylori感染患者消化潰瘍的發(fā)生率比未感染H.pylori患者要高[30]。在開始抗血小板治療之前，建議根除H.pylori，這可以減少潰瘍，但尚未明確證實(shí)可以減少消化道出血[29]。與此同時(shí)，篩選出H.pylori檢測(cè)的最佳試驗(yàn)非常重要，黏膜活檢試驗(yàn)及排泄物抗原檢測(cè)的敏感性較低，雖然血清學(xué)檢測(cè)不能證實(shí)是否存在活動(dòng)性感染，但其具有較高敏感性[31]。尿素呼氣試驗(yàn)也有較高的敏感性，但是在急性出血時(shí)卻很難檢測(cè)[32]。為此，最近的指南[33]倡導(dǎo)，在潰瘍出血之后，盡快進(jìn)行經(jīng)驗(yàn)性抗H.pylori治療。

4 阿司匹林的衍生物

阿司匹林的胃腸道損傷歸因于許多因素：(1)阿司匹林抑制了COX-1，減少具有胃保護(hù)的PG的合成[34]；(2)阿司匹林游離羧基對(duì)胃黏膜表現(xiàn)出刺激性影響。為了克服上述副作用，阿司匹林的衍生物就產(chǎn)生了，一些阿司匹林的衍生物已經(jīng)顯示出前景，如阿司匹林-NO、阿司匹林-H2S[35]。這兩種衍生物釋放保護(hù)胃黏膜的NO和H2S氣體，但是，很難控制NO和H2S氣體的濃度，一旦超過(guò)正常范圍，將對(duì)機(jī)體一些內(nèi)臟產(chǎn)生毒性反應(yīng)[36]。一種新的衍生物阿司匹林-Ca，在動(dòng)物實(shí)驗(yàn)中能產(chǎn)生和相同劑量阿司匹林相似的抗血栓作用，同時(shí)，阿司匹林-Ca還能通過(guò)上調(diào)PGE2的合成，也可能是補(bǔ)充胃腸道Ca池的缺乏，從而減少對(duì)胃黏膜的損傷。還有一些關(guān)于金屬阿司匹林衍生物的研究，但是關(guān)于它們保護(hù)胃黏膜的功能和機(jī)制目前尚不清楚。

5 抗氧化劑

DA-9601是一種抗氧化劑，具有抗氧化、抗炎作用，可預(yù)防NSAIDs所致的胃腸道并發(fā)癥[37]。DA-9601的重要組成部分是異澤蘭黃素，它可抑制FeSO4所致的氧化應(yīng)激及減少促氧化基因的表達(dá)，從而預(yù)防胃黏膜損傷[38]。在胃上皮細(xì)胞中，DA-9601可通過(guò)調(diào)整p38激酶及NF-κB通路來(lái)抑制腫瘤壞死因子α(TNF-α)，而TNF-α是一種促炎因子，也可預(yù)防胃黏膜損傷[39]。一項(xiàng)關(guān)于米索前列醇與DA-9601對(duì)預(yù)防NSAIDs所致的胃腸道并發(fā)癥療效比較的研究表明，DA-9601組胃黏膜保護(hù)率與米索前列醇組相當(dāng)，差異無(wú)統(tǒng)計(jì)學(xué)意義。但是米索前列醇組的胃腸道癥狀比DA-9601組更頻繁，DA-9601能安全、有效地預(yù)防胃黏膜損傷。合用維生素C(VitC)的研究較少，VitC理論上可以清除自由基，還可誘導(dǎo)COX-1增加PG的合成，但其應(yīng)用于預(yù)防抗血小板藥物誘發(fā)的胃腸道并發(fā)癥的研究較少，療效不確切[7]。

6 中醫(yī)中藥治療

目前中藥治療NSAIDs所致胃黏膜損傷的研究不斷深入，如黨參提取物、丹參提取物、復(fù)方黃芪湯、胃舒顆粒、和平散、胃痛靈湯、倉(cāng)脂顆粒、和平散、平潰散等，都可益氣健脾、活血化瘀，主要是通過(guò)促進(jìn)胃黏膜PG的合成、改善黏膜血流及抗氧自由基等途徑起作用[40]。中藥云母來(lái)源于單斜晶系硅酸鹽類礦物白云母，具有天然層狀結(jié)構(gòu)和特殊的物理性質(zhì)，可吸附于黏膜表面，從而發(fā)揮黏膜保護(hù)作用。它可能通過(guò)維持胃腸道屏障功能、促進(jìn)胃黏膜損傷修復(fù)和組織愈合、抑制和吸附促炎因子、抗脂質(zhì)過(guò)氧化來(lái)預(yù)防NSAIDs相關(guān)胃腸病。

預(yù)防阿司匹林及氯比格雷相關(guān)胃病的最好方法是避免使用這類藥物，因阿司匹林及氯比格雷的胃腸道副反應(yīng)呈劑量依賴，在必須應(yīng)用的前提下，應(yīng)盡可能減少劑量。本文概述了治療阿司匹林及氯比格雷相關(guān)胃病的藥物進(jìn)展，各種藥物各有利弊，目前仍未找到既無(wú)胃腸副作用又不影響其抗血小板治療的藥物，因此，需要進(jìn)一步研究針對(duì)阿司匹林及氯比格雷相關(guān)胃病的新型藥物，為臨床需要應(yīng)用阿司匹林及氯比格雷的患者帶來(lái)福音。

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(責(zé)任編輯：馬 軍)

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

趙遼遼，在讀碩士研究生，研究方向：胃腸疾病的診斷及治療。E-mail：948494869@qq.com

杜雅菊，主任醫(yī)師，碩士生導(dǎo)師，教授，研究方向：消化系統(tǒng)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