摘要
非甾体类抗炎药(nonsteroidal anti-inflammatory drugs,NSAIDs)在临床应用中常见胃肠道不良反应,其中NSAIDs引起的小肠损伤(NSAIDs-induced small intestinal injuries,NSIs)表现为出现空肠及回肠黏膜红斑、糜烂、溃疡、出血、肠壁穿孔、梗阻等。NSIs的病理机制复杂,且缺乏针对NSIs的有效预防或治疗手段。就近5年关于NSIs病理机制和米索前列醇、黏膜保护剂、抗生素及益生菌、中药及其活性成分、营养补充剂等药物防治NSIs的研究进展进行综述,以期为NSIs的新药研发提供参考和依据。
非甾体类抗炎药(nonsteroidal anti-inflammatory drugs,NSAIDs)是目前全世界临床应用最广泛的药物之一,除了镇痛、抗炎和解热功效外,NSAIDs还被进一步证明可以预防各种危重疾病,包括肿瘤和心脏病发作,但其使用会引起涉及胃肠道、心血管、肝、肾、脑和肺部多种不良反
NSIs是多因素影响的结果,其病理机制与上消化道损伤不
前列腺素(prostaglandin,PG)在调节胃肠道黏膜血流量、刺激黏膜防御中起重要作用,NSAIDs抑制环氧合酶导致PG耗竭引起小肠损伤。以前认为黏膜损伤只与环氧合酶-1(cyclooxygenase-1,COX-1)的抑制有关,使用选择性环氧合酶-2(cyclooxygenase-2,COX-2)抑制剂则可以降低小肠损伤。然而,内源性PG主要来源于COX-1,COX-2则在炎症中起到助于黏膜防御的作用,COX-1和COX-2都参与小肠损伤的愈合过
NSAIDs可通过与肠黏膜的直接接触产生局部刺激作用引起肠道损伤,即“三击假说”。首先,NSAIDs溶解黏膜表面细胞膜中的磷脂,直接抑制上皮细胞内线粒体氧化磷酸化解偶联,减少ATP的合
肝肠循环在NSIs中起着重要作用。含有羧基结构的NSAIDs在口服后通过门静脉进入肝脏,并在尿苷二磷酸葡萄糖醛酸转移酶(uridine diphosphate glucuronyltransferase,UGT) 的作用下通过肝小管膜排泄到胆汁中,随后被小肠肠腔中的细菌β-葡萄糖醛酸酶进行酶切,促进NSAIDs在回肠中的重吸收。肠肝循环导致小肠黏膜反复暴露于NSAIDs,这种局部作用进一步诱导了肠道损
胆汁酸在肝肠循环加剧NSIs的发展中十分关键。 初级胆汁酸在肝脏中合成,与甘氨酸或牛磺酸结合后被分泌到胆汁中并保留在胆囊中,约95%的胆汁酸会在回肠中被重吸收进入肠肝循环。初级胆汁酸在小肠中由胆盐水解酶催化形成游离的次级胆汁酸,而NSAIDs可能导致肠道微生物群紊乱并增加疏水性次级胆汁酸的产
肠道细菌在NSIs中尤为重要,对无菌大鼠给予NSAIDs不会引起肠道损伤。NSAIDs导致肠道细菌总量增加,而放线菌和厚壁菌等革兰氏阳性菌的比例下降、变形杆菌和拟杆菌等革兰氏阴性菌的比例上升,进一步加剧肠道损
高脂饮食显著减少双歧杆菌的相对丰度,致使肠道微生物群生态失调,肠道通透性增加,加剧吲哚美辛引起的小鼠小肠损
前列腺素E1(prostaglandin E1,PGE1)衍生物米索前列醇是第1个被批准用于预防NSAIDs相关溃疡的药物,可显著降低胃溃疡和十二指肠溃疡的发生率。最近一项Ⅲ期临床报告显示米索前列醇可有效治疗NSAIDs引起的小肠溃疡,溃疡愈合率为54
尽管米索前列醇在治疗非甾体抗炎药诱发的肠道损伤方面是有效的,但米索前列醇仍会引起许多胃肠道不良反应,如恶心、消化不良、腹痛和腹泻,这些不良反应可能限制其临床使用。
黏膜保护(mucoprotective,MP)药物可以预防和减少NSAIDs引起的小肠黏膜病变。预给药MP药物减少可黏膜糜烂的数量,并且治疗后发生黏膜断裂的概率显著降低(OR = 0.38,95% CI = 0.16 ~ 0.93),MP治疗与黏膜断裂完全愈合率相关(OR = 5.39,95% CI = 2.79 ~ 10.42
瑞巴派特是一种通过增加黏液和刺激PG合成来促进胃肠道黏膜保护的药物。
瑞巴派特(300 mg/kg,7 d)可逆转PPI导致的小鼠小肠拟杆菌的减少,增加厚壁菌/拟杆菌比值,调节小肠微生物群,改善吲哚美辛诱导的小肠损伤及PPI对于损伤的加
其他MP药物也已被证明具有治疗NSAIDs和LDA引起的小肠损伤的可能。多项临床试验表明替普瑞酮可有效预防阿司匹林引起的胃肠道黏膜损
研究表明NSAIDs可引起肠道中革兰氏阴性菌增加从而进一步加重肠道溃
益生菌也可用于改善肠道炎症。乳杆菌CR147 可降低小鼠肠道通透性以及TNF-α和IL-8水平,改善小鼠肠道微生物群失调,抑制炎症反应的发
由黄连、黄芩、槐花、侧柏叶、荆芥、枳壳、蒲黄、五灵脂、石榴皮组成的中药复方可有效治疗NSAIDs所致小肠黏膜损伤,降低NSAIDs所致消化性溃疡、消化道出血或穿孔等不良事件的发生
日本汉方药黄连解毒汤(orengedokuto,OGT)由黄连、黄芩、黄柏和栀子组成,已被广泛用于治疗胃溃疡和黑便等胃肠道疾病。小檗碱是OGT的主要活性成分,可以上调肠神经元标志物和肠神经胶质细胞的标志物的表达,修复肠道神经系统对NSIs具有剂量依赖性的保护作
甘草性甘、平,入心、肺、脾、胃经,具有抗炎、抗病毒、保肝和抗溃疡等多种药理作用,其活性成分甘草查耳酮A、异甘草素和甘草甜素均可抑制NLRP3炎症小体激活,产生广泛的抗炎作
中药木瓜有舒筋活络、和胃化湿的功效,药理研究表明其具有抗氧化、抗炎、抗菌以及免疫调节等多种作用。灌胃给予木瓜提取物(75、300 mg/kg,6 d)可以降低内质网应激介导的小鼠小肠黏膜炎症反应,下调葡萄糖调节蛋白78(glucose-regulated protein 78,GRP78)、C/EBP同源蛋白(C/EBP homologous protein,CHOP)、TLR-4和TNF-α的表达,预防小鼠小肠黏膜通透性的改变,改善双氯芬酸钠诱导的小鼠小肠黏膜损
活血化瘀药姜黄的提取物姜黄素(25、50、100 mg/kg,10 d)具有良好的抗炎和抗氧化效果,改善双氯芬酸钠引起的大鼠胃肠道失血、肠道通透性改变和氧化应
灵芝最早记载于两千多年前的《神农本草经》中,含有多糖类、三萜类、甾醇类等多种活性成分,其中灵芝多糖在免疫调节、抗肿瘤、抗病毒、抗氧化等方面具有较好的药理作用。在体外通过灵芝多糖刺激腹膜巨噬细胞后将其转移到小鼠腹膜内可显著改善吲哚美辛诱导的小肠溃疡并发挥抗炎作
其他中药活性成分也具有保护胃肠道、改善NSIs的作用。柑橘类黄酮可以调节肠道屏障通透性、保护黏液层、调节肠道免疫系统、对抗氧化应激以及改善肠道微生物生态失
此外,营养干预也是潜在的治疗方式之一。 牛初乳含有多种生长因子,如参与维持上皮功能的转化生长因子-α(transforming growth factor-α,TGF-α)和促进伤口愈合的血小板衍生生长因子(platelet-derived growth factor,PDGF),以及抗菌肽和溶菌酶等。体外给予牛初乳和无菌鸡蛋粉混合物(1 mg/mL)可显著增加大鼠小肠上皮-1(RIE1)细胞的增殖和迁移活性,以质量比3∶2混合的牛初乳和无菌鸡蛋粉(20 mg/kg,7 d)可显著改善吲哚美辛引起的小鼠小肠绒毛缩
体内和体外实验均表明加工过的芦荟凝胶(processed Aloe vera gel,PAG)可上调肠道紧密连接蛋白的表达,改善因肠道屏障受损导致的肠道细胞通透性增
硫化氢(H2S)作为内源性气体信号分子,具有血管舒张、抗氧化、抗炎、调节黏膜血流和黏液分泌,维持胃肠道黏膜完整性的作用。H2S供体药物与萘普生结合而成的H2S-萘普生衍生物(ATB-346)可以部分降低胆汁的细胞毒性、预防NSAIDs诱导的肠道微生态失调并有效预防大鼠的NSIs,目前已通过Ⅱ期临床试
5-氨基水杨酸(5-ASA)可减少吲哚美辛诱导的大鼠肠上皮细胞的凋亡,降低细胞内ROS水平,增加SOD2活性以及ZO-1和occludin的表达,促进了吲哚美辛诱导损伤后肠上皮细胞的愈
体内和体外实验均表明钾离子竞争性酸阻滞剂瑞伐拉赞可抑制胞外信号调节激酶和肌球蛋白轻链激酶的磷酸化以及Rho活化,上调ZO-1、Occludin和Claudin-1的表达,腹腔注射瑞伐拉赞可显著降低小肠病变指数和小肠绒毛损伤,下调IL-1β、IL-6、一氧化氮合酶(iNOS)和TNF-α的表达,预防吲哚美辛诱导的大鼠肠道损
以上研究表明,临床应用NSAIDs可引起小肠糜烂、溃疡、出血、梗阻等小肠损伤,其病理机制包括PG耗竭减弱黏膜防御;NSAIDs的局部作用致线粒体功能障碍,破坏肠道屏障,革兰氏阴性菌侵入黏膜层引发炎症级联反应;肝肠循环致使肠道反复暴露于NSAIDs,加剧NSAIDs的局部作用;肠道菌群失调等。预防或治疗NSIs的相关药物临床试验及临床前研究总结如
药物类别 | 临床试验 | 临床前研究 |
---|---|---|
前列腺素衍生物 |
米索前列 | / |
黏膜保护剂 |
瑞巴派 |
瑞巴派 |
抗生素 |
利福昔 |
利福昔 |
益生菌 |
短双歧杆菌Bif19 |
双歧杆菌G9-1和干酪乳杆 |
中药及其活性成分 |
木瓜三 |
复方:黄连、黄芩、槐花、侧柏叶、荆芥、枳壳、蒲黄、五灵脂、石榴 |
营养补充剂 | / |
牛初乳和无菌鸡蛋 |
其他药物 |
ATB-34 |
ATB-35 |
米索前列醇和MP药物均通过提高血清和小肠黏膜中的PG水平,增加黏膜血流量、碳酸氢盐分泌以及黏液产生,促进黏膜防御,从而改善NSIs。但PG耗竭并非NSIs的主要原因,且使用米索前列醇易引起其他胃肠道不良反应,因此考虑与其他药物联用可能会取得更好的疗效。抗生素或益生菌通过调节肠道微生物群的组成,改善NSAIDs所致革兰氏阴性菌在肠道中过度繁殖,恢复肠道微生态平衡,抑制TLR4/MyD88/NF-κB信号通路,降低组织炎症和氧化应激水平。许多中药及其活性成分具有抗炎、抗氧化以及保护上皮屏障的特性,其作用机制包括抑制MAPK和TLR4/My D88/NF-κB信号通路、抑制 NLRP3 炎症小体活化,抑制炎症因子的表达;下调GRP78和CHOP的表达,抑制内质网应激;调节ERK/Nrf2/HO-1、AMPK/TFEB、PI3K/Akt等信号通路促进线粒体自噬,改善氧化应激,减少肠道上皮细胞凋亡,保护肠道屏障的完整性等。此外,进行营养干预以及使用经化学结构修饰的NSAIDs衍生物也是潜在的治疗方式。
上述各种预防或治疗NSIs的候选药物仍需要更多相关基础研究以及更大规模的临床试验支持以验证疗效。NSAIDs多用于治疗类RA、OA等慢性炎症或心脑血管疾病的二级预防,治疗NSIs时停用NSAIDs很可能加重其他疾病或提高患病风险,因此进行未停用NSAIDs的防治NSIs候选药物的临床试验或临床前研究十分重要。PPI等治疗上消化道溃疡药物可能加重NSIs,因此在临床中面对NSAIDs长期使用者时应慎重选择联用PPI治疗,避免进一步加重下消化道损伤,且长期使用NSAIDs的患者多为患有高血压、糖尿病等基础性疾病的老年患者,预防或治疗NSIs的候选药物应尽量避免增加其他药物的肝脏代谢。目前尚缺乏针对NSIs的有效预防和治疗手段,许多中药及其活性成分在防治NSIs方面已显示出一定的疗效,且中药具有多靶点活性和不良反应较少等特点,具有广阔的临床应用前景,值得进一步深入研究。
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