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非甾体类抗炎药致小肠损伤及药物防治的研究进展

  • 李雨宸
  • 潘子倩
  • 肖梦雪
  • 张媛媛
中国药科大学中药学院中药药理与中医药学系,南京 211198

中图分类号: R965

最近更新:2023-05-08

DOI:10.11665/j.issn.1000-5048.20220930001

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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

1,其中胃肠道不良反应最为常见。长期以来,人们多关注NSAIDs引起的上消化道损伤,但随着NSAIDs肠溶制剂的出现以及胶囊内镜和气囊辅助式小肠镜等临床检查方法的普及,对NSAIDs引起的小肠损伤(NSAIDs-induced small intestinal injuries,NSIs)的重视也日益增加。NSIs包括空肠及回肠出现黏膜红斑、糜烂、溃疡、出血、肠壁穿孔、梗阻、蛋白质丢失性肠病以及先前存在的炎症性肠病加重。临床观察发现,402例肠道出血的患者中,49例被诊断为由NSAIDs引起,NSAIDs引起肠病患者的再出血率为20.4%,平均持续时间为23.4个2。在所有NSAIDs引起的严重胃肠道事件中,下消化道事件占比40%,临床上长期使用NSAIDs的患者出现小肠损伤的概率为50% ~ 70%3-4,而患有肠道炎症的概率高达 60% ~ 70%5。随着胃黏膜保护剂使用的增加、幽门螺杆菌感染率的下降以及NSAIDs缓释剂型和肠溶剂型的普及,导致住院的胃肠道事件的整体情况发生了渐进式变化,上消化道不良反应的发生率普遍下降,但下消化道(包括空肠、回肠和结肠)不良反应的发生率正在上升。治疗NSIs的首要措施是停药,但NSAIDs往往用于治疗慢性炎症或心脑血管疾病的二级预防(阿司匹林),因此停药很可能引起在临床中严重的心血管事件发生率升高。随着我国人口老龄化的发展,NSAIDs的使用量将持续增加,应尽快寻求合适的预防和治疗手段。本文就近5年NSIs的病理机制及其防治药物的研究进展予以综述,以期为研制防治NSIs的创新药物提供可能的线索和依据。

1 NSAIDs导致小肠损伤的病理机制

NSIs是多因素影响的结果,其病理机制与上消化道损伤不

3-4,治疗和预防NSAIDs引起的胃和十二指肠损伤的质子泵抑制剂(proton pump inhibitors,PPIs)和组胺 H2受体拮抗剂(histamine H2 receptor antagonists,H2RAs)等胃酸分泌抑制药物对NSIs的改善作用十分有限,甚至可能会加重损6-8

1.1 前列腺素耗竭

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

9。越来越多的研究表明,抑制环氧合酶导致PG耗竭可能并非NSIs的主要原因,胃和小肠黏膜中的PG减少95%~98%或COX-2的短期抑制不会造成黏膜损伤,但NSAIDs的长期使用引起小肠损伤是显而易见10

1.2 “三击假说”

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

10。其次,线粒体损伤后释放钙离子并产生大量自由基,进而导致细胞间连接的破坏以及肠道通透性增加。细胞质钙离子浓度升高还会增强细胞脂质过氧化作用。最后,肠道细胞通透性增加使得黏膜暴露于肠腔内侵袭性因子(如胆汁酸、肠道细菌、蛋白水解酶、食物大分11等),进一步损伤肠道屏障,革兰氏阴性菌侵入黏膜层并激活Toll样受体-4(Toll-like receptor-4,TLR-4),引发炎症级联反应,激活NOD样受体热蛋白3(NOD-like receptor pyrin domain-containing 3,NLRP3)炎症小体,诱导肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、白介素-1β(interleukin-1β,IL-1β)的过度表达,中性粒细胞募集到小肠黏膜,导致肠道溃4

1.3 肝肠循环

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

4,不经过肠肝循环的NSAIDs(如阿司匹林)不会引起明显的肠道溃疡,而抑制β-葡萄糖醛酸酶活性预防或改善双氯芬酸等NSAIDs诱导的小肠损12

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

13。此外,NSAIDs可以与胆汁酸竞争性结合磷脂酰胆碱,形成更具毒性的胆盐胶束,从而破坏细胞膜磷脂层,加重肠肝循环引起的小肠损14。然而,一项新的研究发现NSAIDs增加回肠中结合胆汁酸比例,但不增加胆汁疏水性,同时表明肠道黏膜损伤与游离胆汁酸和革兰氏阳性菌呈负相关,与结合胆汁酸和革兰氏阴性菌呈正相15,提示了胆汁酸在 NSIs中的复杂机制。

1.4 肠道微生物群失调

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

16-17,肠道出现溃疡后,以革兰氏阴性菌为主的多种肠道细菌迅速在溃疡定植,从而延迟溃疡的愈14。灌胃给予双氯芬酸(4 mg/kg,bid,14 d)可导致大鼠回肠中变形杆菌和拟杆菌的相对丰度增加和厚壁菌的相对丰度减17

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

18。心理应激显著增加肠道细菌总数和革兰氏阴性菌比例,破坏肠上皮屏障完整性,加剧小鼠NSIs16。使用NSAIDs会增加患艰难梭菌感染(Clostridium difficile infection,CDI)的风险、加重CDI的严重程度,并通过释放外毒素加重肠道损19-20。质子泵抑制剂(proton pump inhibitor,PPI)对肠道损伤的影响也与肠道细菌有关。PPI可使小鼠肠道乳酸杆菌的相对丰度增加、梭状芽孢杆菌的相对丰度降低,导致肠道微生物群生态失调,增加肠道通透8。高果糖饮食、阿司匹林和PPI联用可显著减少小鼠空肠中双歧杆菌的相对丰度、增加嗜黏蛋白阿克曼菌的相对丰度,减少空肠黏液层的厚度和杯状细胞数量,从而加剧小肠的损伤;而同时给予双歧杆菌G9-1可抑制嗜黏蛋白阿克曼菌的生长,恢复空肠黏液层和杯状细胞数量,改善NSIs21。为了确定PPI诱导肠道生态失调加重NSIs是由于PPI特定的药物类效应还是对于胃酸的抑制作用,一项研究将PPI与钾离子竞争性酸阻滞剂瑞伐拉赞(revaprazan)进行了比较,发现PPI和瑞伐拉赞均通过抑制胃酸分泌减少约氏乳杆菌在小鼠小肠中的数量,从而加重NSAID诱导的小肠损6。然而,近期一项临床研究则表明PPI与低剂量阿司匹林(low-dose aspirin,LDA)联用和瑞伐拉赞与LDA联用均增加了乳杆菌在LDA使用者肠道微生物群中的比22。不同的胃酸抑制剂对于肠道微生物群的影响不同,奥美拉唑、艾普拉唑和瑞伐拉赞可使NSIs小鼠肠道中乳杆菌显著增加,而雷贝拉唑则体现为拟杆菌的显著增23。这些研究结果提示治疗上消化道溃疡的胃酸分泌抑制类药物可能通过诱导肠道生态失调加重NSIs。

2 NSAIDs导致小肠损伤的药物防治

2.1 米索前列醇治疗NSAIDs致小肠损伤的作用

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%

24,然而这项研究招募的NSAIDs使用者仅有小肠隐匿性出血,且未说明研究中的患者在治疗期间是否停用NSAIDs。同年另一项研究证明米索前列醇对LDA使用者有显著的促进小肠溃疡愈合和改善并发小肠出血的作用,米索前列醇组和安慰剂组的溃疡完全愈合率分别为28.6%和9.5%25,这是第1项未停用LDA的同时治疗小肠损伤的临床研究。

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。

2.2 黏膜保护剂对NSAIDs致小肠损伤的防治作用

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

26

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

27。灌胃给予瑞巴派特(300 mg/kg,5 d)可通过下调TLR-4/NF-κB信号通路抑制IL-1β、白介素-6(interleukin-6,IL-6)、白介素-8(interleukin-8,IL-8)和TNF-α的表达,改善双氯芬酸诱导的ZO-1和Claudin-1的减少,有效缓解大鼠肠黏膜损28。临床试验表明,使用NSAIDs超过3个月的类风湿性关节炎(rheumatoid arthritis,RA)和骨性关节炎(osteoarthritis,OA)患者在给予瑞巴派特治疗12周后,小肠糜烂和溃疡的发生率低于PPI治疗29

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

30-31,灌胃给予替普瑞酮(100 mg/kg,14 d)可显著改善双氯芬酸诱导的大鼠小肠损伤,其作用机制可能与抑制蛋白酶激活受体1(protease activated receptor 1,PAR1)和蛋白酶激活受体2(protease activated receptor 2,PAR2)的表达有32。近期研究表明依卡倍特钠对于LDA使用2周引起的小肠黏膜损伤也具有预防作33

2.3 抗生素和益生菌改善NSAIDs所致的小肠损伤

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

1416,而抗生素可能通过减少革兰氏阴性菌、恢复肠道微生态平衡改善NSIs。利福昔明(50 mg/kg,bid,14 d)可显著抑制抑制TLR4/MyD88/NF-кB信号通路以及天冬氨酸蛋白水解酶1(cysteinyl aspartate specific proteinase-1,caspase-1)的活化,降低髓过氧化物酶(MPO)、丙二醛(MDA)和IL-1β的水平以及紧密连接蛋白的表达,降低变形杆菌和拟杆菌的相对丰度并增加乳杆菌的相对丰度,降低组织炎症和氧化应激水平,显著改善双氯芬酸诱导的大鼠肠道损17。临床试验表明利福昔明可显著改善双氯芬酸(75 mg,bid,14 d)与奥美拉唑(20 mg,qd,14 d)联合给药引起的肠道黏膜损34。然而,抗生素在一些研究中并非始终有效。对吲哚美辛诱导小肠损伤的小鼠给予新霉素、多霉素和甲硝唑后可能因肠道微生物群消耗导致小鼠死亡率增35。抗生素和NSAIDs之间的药物相互作用也应引起重5。阿莫西林可能通过减弱肠道菌群对阿司匹林的代谢活性,影响阿司匹林的疗效,并引起更显著的胃肠道不良反36

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

37。临床试验证明短双歧杆菌Bif195可以安全地降低阿司匹林(300 mg,6 w)引起的小肠黏膜损伤风38。双歧杆菌G9-1和干酪乳杆菌可以抑制阿司匹林与奥美拉唑联用引起的噬黏蛋白阿克曼菌生长、黏液层变薄和空肠中杯状细胞数量减21。长双歧杆菌(2.5 × 106 CFU,bid,14 d)和益生元乳铁蛋白(100 mg/kg,bid,14 d)联用可以通过调节TLR-2/-4/NF-κB 途径恢复MPO和血红蛋白水平,抑制肠道炎症,改善双氯芬酸诱导的小肠损39。含有干酪乳杆菌ATCC 393的硒纳米颗粒可以通过Nrf2信号通路介导的线粒体途径缓解过氧化氢诱导的肠上皮屏障功能障40。补充益生菌(干酪乳杆菌和副干酪乳杆菌)可抑制氧化应激和炎症因子表达,增加潘氏细胞数量,促进调节性T细胞分泌白介素-10(interleukin-10,IL-10),增强肠道上皮屏障功能,维持肠道微生态平衡,改善NSAIDs引起的肠道炎41。格式乳杆菌OLL2716可显著改善使用阿司匹林超过1个月的患者胃食管反流病症状频率量表(FSSG)和胃肠道症状评分量表(GSRS)评分,减少小肠糜烂和出42

2.4 中药及其活性成分治疗NSAIDs致小肠损伤的作用

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

43

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

44

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

45。预给药异甘草素(7.5、75 mg/kg)可抑制NLRP3炎症小体活化及吲哚美辛诱导的caspase-1和IL-1β蛋白水平的增加以及从而改善NSIs46

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

47。木瓜总三萜(25、50、100 mg/kg,7 d)可以调节内源性SOD/GPX1/CAT抗氧化系统功能、ERK/Nrf2/HO-1和线粒体凋亡信号通路,剂量依赖性地显著降低吲哚美辛诱导的大鼠小肠黏膜损48。纳入96例NSIs患者的临床试验表明,木瓜三萜(0.375 g,tid,8 w)可降低血液中TNF-α、IL-1β、IL-6、干扰素-γ(interferon-γ,IFN-γ)含量和MPO活性水平,升高IL-4、IL-10、黏蛋白2(mucoprotein 2,Muc2)、肠三叶因子(trefoil factor 3,TFF3)含量,显著改善腹痛、腹胀和腹泻症49

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

50,其作用机制可能与通过AMPK/TFEB信号通路促进线粒体自噬改善氧化应激诱导的肠屏障损伤和线粒体损伤有51

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

52

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

53。体内和体外实验表明柑橘类总黄酮(新橙皮苷、橙皮苷、柚皮苷和柚皮芸香苷)可显著降低自噬相关蛋白5(autophagy-related protein 5,Atg5)、微管结合蛋白1轻链3-II(microtubule-associated protein light chain 3-II,LC3-II)和紧密连接蛋白ZO-1、claudin-1和occludin的表达水平,通过PI3K/Akt信号通路促进自噬保护肠道屏障的完整性,改善NSIs54。槲皮素(35、50、100 mg/kg,10 d)可能通过抑制黄嘌呤氧化酶的活性降低胃肠道组织的氧化应激,改善雷尼替丁和双氯芬酸联用引起的大鼠胃肠道出血性损55。白藜芦醇(30 mg/kg,14 d)可以上调寡肽转运蛋白1、提高JBP485二肽的生物利用度,显著降低MDA水平,增加超氧化物歧化酶(superoxide dismutase,SOD)、过氧化氢酶(catalase,CAT)、MPO和炎症细胞因子水平,提高Bcl-2/Bax的比例,抑制炎症反应、减少肠道上皮细胞凋亡,改善吲哚美辛诱导的小肠损56

2.5 营养补充剂改善NSAIDs所致的小肠损伤

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

57

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

58。PAG中的葡甘露聚糖可促进β-Catenin的核转位,增加肠道干细胞的数量,通过Wnt/β-Catenin途径促进肠道干细胞介导的上皮细胞再59。预给药PAG两周可通过ERK依赖途径上调小肠细胞中黏蛋白MUC2的表达,保护肠道黏液层,减少细菌易位从而改善NSAIDs所致小鼠小肠溃60

2.6 其他药物对NSAIDs致小肠损伤的预防作用

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

61,显示出比母体药物萘普生更高的胃肠道安全性。灌胃给予H2S-酮洛芬衍生物(14 mg/kg,7 d)与酮洛芬(10 mg/kg,7 d)相比,肠道损伤评分以及COX-1、COX-2、低氧诱导因子-1α(hypoxia inducible factor-1α,HIF-1α)、IL-1RA、IL-1β和TNF-α的表达显著降62

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

63

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

64

3 总结与展望

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表1所示。

表1  药物防治非甾体类抗炎药引起的小肠损伤(NSIs)的临床试验及临床前研究
药物类别临床试验临床前研究
前列腺素衍生物 米索前列24-25 /
黏膜保护剂 瑞巴派29;依卡倍特33 瑞巴派27-28;替普瑞32
抗生素 利福昔34 利福昔17
益生菌 短双歧杆菌Bif19538;干酪乳杆菌ATCC39340 双歧杆菌G9-1和干酪乳杆21;长双歧杆39;干酪乳杆菌和副干酪乳杆41;格式乳杆菌OLL271642
中药及其活性成分 木瓜三49 复方:黄连、黄芩、槐花、侧柏叶、荆芥、枳壳、蒲黄、五灵脂、石榴43;小檗44;异甘草46;木瓜提取47;木瓜总三48;姜黄50-51;灵芝多52;柑橘总黄54;槲皮55;白藜芦56
营养补充剂 / 牛初乳和无菌鸡蛋57;芦荟凝60
其他药物 ATB-34661 ATB-35262;5-ASA63;瑞伐拉64

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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