修回日期: 2016-06-09
接受日期: 2016-06-20
在线出版日期: 2016-07-08
肠易激综合征作为一种常见的功能紊乱性肠病, 发病率有逐年增高的趋势, 其发病机制不完全清楚, 目前治疗以改善症状为主. 近年来, 随着对其发病机制的深入研究, 一些新的药物和治疗方法被研发, 如改善肠道微生态(抗生素、粪便移植)、美沙拉嗪、新型的改善肠道分泌、动力和敏感性药物、植物药, 有些已正式应用于临床, 有些具有良好的应用前景, 本文对其作一综述.
核心提示: 肠易激综合征(irritable bowel syndrome, IBS)主要表现为腹痛、腹部不适、大便形状改变, 既往临床上的治疗主要是解痉止痛、通便、止泻、促进胃肠动力, 但多因素与IBS相关, 其中包括炎症、肠道菌群失调, 所以抗炎以及调节肠道菌群的治疗也不容忽视.
引文著录: 邓振华, 常江. 肠易激综合征的治疗进展. 世界华人消化杂志 2016; 24(19): 3009-3017
Revised: June 9, 2016
Accepted: June 20, 2016
Published online: July 8, 2016
Irritable bowel syndrome is a common functional bowel disorder whose incidence has a tendency to increase year by year. At present, the pathogenesis of irritable bowel syndrome is not completely clear, and treatments are mainly symptomatic. In recent years, with the better understanding of its pathogenesis, some new drugs and treatments have been developed, such as methods of improving intestinal micro-ecology (antibiotics, fecal transplantation), mesalazine, and new drugs of improving intestinal secretion, motiligy and sensitivity, plant drugs, some of which have been applied clinically. This article will make a review of the current progress in treatment of irritable bowel syndrome.
- Citation: Deng ZH, Chang J. Progress in treatment of irritable bowel syndrome. Shijie Huaren Xiaohua Zazhi 2016; 24(19): 3009-3017
- URL: https://www.wjgnet.com/1009-3079/full/v24/i19/3009.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v24.i19.3009
肠易激综合征(irritable bowel syndrome, IBS)是一种功能紊乱性肠病, 以腹痛或腹部不适伴排便习惯改变为主要特征, 患病率达10%-20%[1]. IBS主要分为3种类型: 腹泻型(IBS-D)、便秘型(IBS-C)、混合型(IBS-M), 其病因及发病机制尚不完全明确, 认为与结肠动力异常、内脏敏感性增高、脑肠轴功能异常、炎症、免疫、饮食、肠道菌群失调等因素相关[2]. 目前的治疗仍是以对症治疗为主, 近年来一些新的药物和治疗方法在改善IBS症状方面显示出了良好效果.
肠道微生态系统主要由肠道菌群构成, 肠道菌群种类繁多, 主要分为: 生理菌群、条件致病菌、致病菌. 肠道微生态系统维持在动态平衡状态对于人体健康起着非常重要的作用. 正常情况下, 肠道菌群保持一定的数量、比例, 一旦菌群失衡, 可能影响肠内、外多种疾病的发生、发展. 研究[3-5]表明, IBS患者与健康人群在肠道细菌分布、数量、比例、菌种性质上有明显的差异, 主要表现为结肠有害菌的增加、有益菌的减少和小肠细菌过度生长(small intestinal bacterial overgrowth, SIBO), 说明肠道菌群失衡与IBS相关. 肠道菌群失衡导致肠道屏障功能完整性的丧失, 激活黏膜免疫反应, 肥大细胞、T淋巴细胞等炎症细胞浸润, 引起炎症介质释放, 使肠道功能的紊乱, 从而引起IBS临床症状[6].
益生菌可改善肠道黏膜通透性, 减少毒素的吸收, 还可刺激肠黏膜产生抗炎因子, 改善肠道局部及系统免疫功能[7]. 通过摄入外源性益生菌补充肠道有益菌, 可阻止病原菌的入侵、定植和生长. 研究[8,9]表明, 益生菌可缓解IBS患者腹痛、腹胀、腹部不适症状, 能改变大便性状, 对经过益生菌或安慰剂治疗的IBS患者的粪便进行菌群分析, 发现益生菌组患者有益菌菌种和数量增加更多. 一项Meta分析结果显示益生菌能改善IBS患者的症状, 但具体是哪个菌种或菌株在治疗各型IBS中起主要作用, 目前仍不清楚, 有待进一步研究[10,11].
既往通过氢气/甲烷气呼气试验以及希腊研究者对IBS患者小肠培养标本的检测均证实SIBO与IBS相关, 根除过度生长的小肠细菌能改善IBS症状. SIBO包含厌氧菌和需氧菌, 理想的抗生素应具有抗菌谱广、肠道局部药物浓度高、不良反应少、耐药性好的特点[12]. 最早提出的抗生素是新霉素, 实验证实新霉素能有效改善IBS患者临床症状, 并且使氢气呼气试验阳性转为阴性[13]. 但因其较多的不良反应以及耐药性使其在IBS治疗中的应用受到限制. 利福昔明因具有治疗IBS理想抗生素的特性而备受关注. 利福昔明是利福霉素衍生物, 口服时不经肠道吸收, 肠道局部药物浓度高, 杀灭肠道致病菌的作用强, 并且不良反应少、耐药性好. 崔立红等[14]研究表明, 经利福昔明治疗后SIBO阴转率达70.73%, IBS的症状积分较治疗前改善, SIBO阴转者的症状积分低于未阴转者. Pimentel等[15]进行的临床试验显示利福昔明治疗组全身症状、腹胀、腹痛及大便性状有效率明显高于安慰剂组, 并能持续至停药后10 wk, 而两组不良反应的发生率并无明显差别. 然而, 许多研究发现仅少数IBS患者存在SIBO, 认为只有少数患者能通过利福昔明的治疗症状得以改善, 但临床医生却认为利福昔明对无SIBO的IBS患者治疗仍然有效, 可能与抗生素能减少结肠总细菌量有关[16]. 利福昔明最常见的不良反应是头痛、上呼吸道感染、腹泻和腹痛, 严重的罕见. Schoenfeld等[17]对利福昔明的一些Ⅱb和Ⅲ期临床试验中不良反应事件进行汇总分析, 发现接受利福昔明和接受安慰剂治疗的患者药物相关性不良反应差异无统计学意义, 可见其安全性和耐受性良好. 利福昔明已获美国食品和药物管理局(Food and Drug Administration, FDA)批准用于治疗IBS-D.
粪便移植(fecal microbiota transplantation, FMT)是指将经过处理的健康人的粪便液灌入患者的肠道, 重建肠道菌群, 改善肠道微生态, 从而达到治疗疾病的目的. 有人认为粪便移植比益生菌更能使患者获益, 因为粪菌是人类的终极细菌[18]. FMT用于治疗肠道疾病的历史悠久, 我国可追溯到东晋时期, 西方国家最早的报道是1958年美国一名医生用粪便灌肠治疗伪膜性肠炎, 并取得了较好的疗效. 近年来, FMT在肠道疾病的应用成为研究的热点. 澳大利亚的一项研究[19]使用肠镜行FMT治疗IBS和慢性便秘患者, 结果显示, FMT的治愈率可达36%. 而美国的研究人员报道的一项FMI治疗13例难治性IBS患者的研究, 结果症状改善者占70%, 改善的症状包括腹痛、腹胀及排便频率等[20]. 目前FMT主要用于艰难梭菌感染(Clostridium difficile infection, CDI)的治疗, 并被推荐为复发性CDI最有效的治疗方法[21].
美沙拉嗪能抑制环氧合酶和前列腺素的合成, 对肠道炎症具有抑制作用[22]. Dorofeyev等[23]进行的一项随机对照试验, 结果显示, 经美沙拉嗪治疗4 wk的IBS患者腹痛、腹胀、大便性状明显改善, 组织学检查示肠黏膜白细胞和巨噬细胞浸润减少. 一项Meta分析显示美沙拉嗪治疗IBS有良好的疗效, 可改善患者腹痛、大便性状异常, 且有良好的安全性[24]. 而Barbara等[25]以及英国的一个研究团队[26]在针对美沙拉嗪对IBS-D疗效的研究中并未显示出IBS患者从美沙拉嗪的治疗中获益. 美沙拉嗪可能对IBS某些亚型有效, 其疗效尚需进一步的各亚型IBS的临床研究证实.
利那洛肽是一种最新的鸟苷酸环化酶C(guanylyl cyclase C, GC-C)受体激动剂, 他通过与肠道上皮细胞GC-C结合使细胞内环磷酸鸟苷(cGMP)浓度升高, 激活依赖cGMP的蛋白激酶Ⅱ(PKG-Ⅱ), 使囊性纤维化跨膜转导调节因子(cystic fibrosis transmembrane conductance regulator, CFTR)活化, 活化的CFTR刺激氯离子和碳酸氢根离子分泌入肠腔, 抑制钠离子的吸收, 水分被动进入肠腔, 肠液分泌增加, 加快胃肠道移行, 并可降低痛觉神经的灵敏度[27]. Rao等[28]在一项Ⅲ期临床试验中证实, 经过12 wk治疗, 口服利那洛肽290 μg/d的IBS-C患者腹痛、腹部不适明显改善, 完全自主排便增加. 在接着进行的四周随机交叉试验中, 一直服用利那洛肽的患者症状持续改善, 转而服用安慰剂的患者症状也未较用药前的基线水平加重. 一项荟萃分析[29]证实, 与安慰剂相比, 利那洛肽可改善肠道功能, 减轻IBS-C患者的腹痛和整体症状. 腹泻是利那洛肽最常见的不良反应, 但一般较轻. 2012年FDA批准利那洛肽290 μg用于治疗IBS-C, 欧洲药品管理局批准利那洛肽290 μg剂量用于治疗中重度IBS-C.
鲁比前列酮是一种前列腺素E1衍生物, 可选择性激活胃肠道管腔侧表皮细胞膜上的2型氯离子通道(chloride channel 2, ClC-2), 刺激氯离子分泌, 伴钠、水的被动分泌, 肠液分泌增加, 从而软化粪便[30,31]. 肠液分泌增加致肠道膨胀, 可提高胃肠动力, 鲁比前列酮还可作用于胃肠道上的PGE受体加强胃结肠平滑肌的收缩[32,33]. 一些高质量的随机对照试验评估了鲁比前列酮的有效性和耐受性. 在一项纳入192例成人IBS-C患者(女性92%)的Ⅱ期试验中, 鲁比前列酮在改善自发性排便频率、粪便硬度、排便费力、便秘、腹胀和腹痛方面优于安慰剂[34]. 两项Ⅲ期临床研究中, 共纳入1171例IBS-C患者(女性91.6%), 予鲁比前列酮或安慰剂口服, 结果治疗组症状缓解率明显高于对照组[35]. 因为在相关的研究中成年女性患者占绝大多数, 所以FDA批准用于治疗成年女性的IBS-C. 鲁比前列酮常见的不良反应是恶心、腹泻[36]. Sherid等[37]报道了1例鲁比前列酮相关的缺血性结肠炎, 其发生机制尚不明确, 认为可能与肠液快速分泌入肠腔致局部灌注不足、肠腔压力增加、刺激前列腺素受体致血管收缩有关.
分布在胃肠道的阿片受体分为μ、δ、κ三型, 在调节胃肠动力、分泌以及内脏感觉中发挥着重要作用[38]. 艾沙度林(eluxadoline)是一种具混合阿片受体活性、作用于局部的治疗药物, 可激活μ受体, 拮抗δ受体[39]. 一项艾沙度林Ⅱ期临床试验中[40], 807例IBS-D患者被随机分为5组, 分别口服5 mg、25 mg、100 mg、200 mg艾沙度林或安慰剂, 2次/d, 服用12 wk. 结果显示, 口服25 mg和200 mg艾沙度林在改善腹痛和粪便硬度方面较安慰剂效果更好; 口服100 mg和200 mg艾沙度林的患者在肠蠕动频率及整体症状、生活质量方面改进更大. 两项相同设计的临床Ⅲ期随机双盲对照试验[41], 2427例IBS-D患者被随机给予艾沙度林75 mg/100 mg、bid或安慰剂口服, 结果艾沙度林组患者腹痛及粪便硬度改善效果更好. 艾沙度林最常见的不良反应有恶心、便秘, 最严重的不良反应是Oddi括约肌痉挛, 可导致胰腺炎. 艾沙度林不能用于有胆管阻塞或Oddi括约肌功能障碍、胰腺炎、严重肝损伤、既往有严重便秘病史、机械性胃肠梗阻的患者以及酒精成瘾、每天饮用3种以上酒精饮料的患者[42]. 2015-05 FDA批准艾沙度林为IBS-D患者提供缓解治疗.
阿西马朵林是一种外周选择性的κ受体激动剂, 有良好的耐受性. 一项临床试验纳入596例各亚型IBS患者, 随机给予阿西马朵林0.15 mg、0.50 mg、1.00 mg或安慰剂口服, 2次/d, 共12 wk, 结果0.50 mg阿西马朵林在改善腹痛或腹部不适、排便急迫感和排便频率方面疗效更好[43]. 然而, 在该试验中, 这些显著的改善仅见于IBS-D患者.
Crofelemer是南非巴豆树茎皮乳胶中提取出的化合物, FDA批准的第一例口服植物药. 该药主要作用于胃肠道, 是CFTR和钙激活的氯离子通道(calcium activated chloride channel, CaCC)的部分拮抗剂, 可同时抑制CFTR和CaCC, 通过抑制Cl离子向肠道的分泌以减少水分向肠腔的分泌量, 从而缓解患者腹泻[44]. 研究发现[45], Crofelemer对各种病理因素相关的腹泻型疾病包括IBS-D均有效. 最常见的不良反应有上呼吸道感染、支气管炎、咳嗽、胃肠胀气和胆红素升高[46]. 在一项临床Ⅱa期研究中[47], 242例IBS-D患者分别口服125 mg、250 mg、500 mg Crofelemer或安慰剂, 2次/d, 共12 wk, 结果显示口服500 mg Crofelemer的女性患者腹痛得以改善, 但所有剂量都未能明显改善大便性状、排便频率和急迫性.
胰高血糖素样肽-1(glucagon-like peptide-1, GLP-1)由肠道L细胞分泌, 主要作用是促进胰岛素分泌、抑制胰高血糖素分泌、延缓胃排空、减少摄食, 目前临床上主要用于2型糖尿病的治疗. 动物和人体试验证实, GLP-1还有抑制肠蠕动和解痉、减少内脏超敏性的作用[48,49]. 研究者进行的一项临床试验纳入了166例腹痛急性发作的IBS患者, 随机予100 μg或300 μg的GLP-1类似物ROSE-010或安慰剂单次皮下注射, 结果ROSE-010组的缓解率是安慰剂组的2倍, ROSE-010能有效治疗IBS的急性腹痛发作[50].
胆汁酸可刺激肠道蠕动和分泌[51]. 正常人排入肠道的胆汁酸95%以上通过回肠末端的重吸收而进入肝肠Ñ环[52]. Elobixibat是一种回肠胆汁酸转运蛋白(intestinal bile acid transporter, IBAT)抑制剂, 使进入结肠肠腔内的胆汁酸量增加, 刺激结肠的蠕动和分泌, 从而达到排便频率增加、大便软化的效果. Chey等[53]进行的一项评估Elobixibat对慢性特发性便秘疗效的Ⅱb期试验中, Elobixibat以剂量依赖方式明显改善了自然排便频率、粪便硬度和腹胀, 在8 wk试验期内疗效维持. 最常见的不良反应是腹痛、腹泻, 无严重不良事件发生. 鉴于Elobixibat的作用原理, 可能治疗IBS-C同样具有效果, 但目前未见报道.
人体中的5-羟色胺(5-hydroxytryptamine, 5-HT)大约90%-95%是由肠嗜铬细胞以及肠道神经元亚群产生, 通过与其受体作用, 调节胃肠道运动、感觉、分泌和吸收[54]. 胃肠道中以5-HT3受体和5-HT4受体最为重要.
昂丹司琼在临床上广泛用于恶心、呕吐的治疗. 曾在一些试验中, 昂丹司琼对IBS治疗显效[55,56]. 近期有研究[57]表明, 昂丹司琼能有效改善IBS-D患者腹胀、大便性状、排便频率和排便急迫感, 但不能改善腹痛症状.
阿洛司琼可减缓肠道传输、增强肠道液体重吸收和减轻IBS相关的内脏疼痛感[58]. Cremonini等[59]进行的一临床试验中, 口服不同剂量阿洛司琼(0.5 mg, qd, 1.0 mg, qd, 1.0 mg, bid)12 wk的IBS-D患者临床症状、生活质量改善效果较口服安慰剂者更好, 对治疗的满意度更高. 阿洛司琼最常见的不良反应是便秘, 但有发生缺血性结肠炎严重不良反应的风险. 有报道[60]称, 阿洛司琼发生便秘与剂量相关, 而缺血性结肠炎的发生无剂量相关性. 该试验中阿洛司琼主要的不良反应仍是便秘, 且呈剂量依赖, 有两例接受阿洛司琼0.5 mg qd的患者分别发生了肠梗阻和缺血性结肠炎, 另有一例发生粪块嵌塞, 但不良反应在停药后不久即缓解[59]. 阿洛司琼目前仅用于常规治疗失败的严重IBS-D女性患者.
雷莫司琼比阿洛司琼不良反应小. Matsueda等[61,62]同年报道了两项研究. 一项研究[61]中, 将418例IBS-D患者随机分为4组, 一组口服安慰剂, 另三组分别口服雷莫司琼1 μg、5 μg、10 μg, 最后口服雷莫司琼5 μg和10 μg组总体症状缓解率明显较安慰剂组高, 与安慰剂组的应答率差异在男性和女性中是相似的. 另一项研究招募539例IBS-D患者, 随机口服安慰剂或5 μg盐酸雷莫司琼, 1次/d, 共12 wk, 结果分析, 盐酸雷莫司琼更能有效缓解IBS-D男性患者的腹痛、腹部不适以及改善排便习惯[62]. 在日本的另一项多中心、随机双盲、安慰剂对照试验中[63], 将招募的296例IBS-D男性患者随机分配到安慰剂组(n = 149)或者口服雷莫司琼5 μg组(n = 147), 1次/d, 维持12 wk. 结果显示, 雷莫司琼能有效改善IBS-D男性患者的大便性状、IBS总体症状以及生活质量.
5-HT4受体激动剂可以引起神经递质的释放如乙酰胆碱, 并且能增强肠液分泌和结肠动力.
替加色罗是5-HT4受体部分激动剂, 选择性地作用于胃肠道5-HT4受体. 多项研究结果显示替加色罗能显著改善肠易激综合征患者的临床症状[64-67], 曾被FDA批准用于IBS-C女性患者的治疗. 后因替加色罗有诱发严重心血管事件的风险而停止应用于临床, 但FDA认为可能有一部分人使用替加色罗获得的利益大于风险, 所以又在限制性条件下被重新使用.
伦扎必利是5-HT4受体完全激动剂, 同时也有5-HT3受体拮抗作用. 研究显示其可改善胃肠运动和增加结肠传输速度, 在治疗IBS-C方面较有前景[68,69]. 一项在IBS-C患者中进行的研究也显示其在改善排便频率、粪便硬度以及缓解女性患者腹痛、腹部不适方面有一定的疗效[70]. Lembo等[71]在IBS-C女性患者中进行的研究显示伦扎必利可改善排便频率、粪便硬度和腹胀症状, 但其并不明显优于安慰剂, 并且伦扎必利治疗组有缺血性肠炎的发生. 而在对1992-2013关于伦扎必利治疗IBS疗效的安慰剂对照试验进行Meta分析显示, 其疗效并不优于安慰剂, 只可能增加患者的成本负担[72].
解痉剂是一类松弛胃肠道平滑肌从而达到缓解腹痛等症状的药物, 目前主要应用于临床的解痉剂主要包括抗胆碱药物、选择性钙通道阻滞剂以及外周阿片受体激动剂. 研究表明, 解痉剂能短期内缓解IBS患者腹痛症状, 安全性和有效性均良好, 目前已广泛应用于IBS的治疗.
薄荷油作为一种植物药, 通过对钙离子通道的阻滞作用而松弛胃肠道平滑肌. Cappello等[73]行了一项用薄荷油治疗IBS患者的双盲、对照试验, 治疗4 wk后, 患者总体症状评分较基线期减低50%以上的比例, 治疗组明显高于安慰剂组. 最新的一项研究显示[74], 薄荷油治疗6 wk后的IBS患者腹痛明显改善, 但试验结束后2 wk疼痛评分再次增加, 提示薄荷油改善IBS患者的腹痛症状可能只是暂时的. 一项Meta分析显示[75], 薄荷油短期治疗IBS是安全有效的, 他改善IBS总体症状、腹痛的效果优于安慰剂.
肠易激综合征有着较高的发病率, 严重困扰着患者. 近年来, 一些新的药物和治疗方法在临床试验中可显著改善IBS患者的临床症状, 有些已获批准用于临床, 有些也显示出良好的应用前景但风险、效益和长期的安全性仍待进一步评估. 然而仍然没有能完全有效地治疗各型IBS的药物和方法. 随着对IBS病理机制的深入研究, 相信将来会有更好的药物和方法、更优化的治疗方案用于临床从而使患者获益.
肠易激综合征(irritable bowel syndrome, IBS)长期和反复发作的特征严重困扰患者, 影响患者生活质量. 在生活节奏快、压力大的当今社会, IBS的发病率有明显增高趋势, 所以对IBS治疗的研究意义重大. 本文通过搜集国内外最新资料, 对IBS的治疗研究进展作一综述, 以期在临床治疗上提供参考.
王小众, 教授, 福建医科大学附属协和医院消化内科; 潘秀珍, 教授, 主任医师, 福建省立医院消化科
IBS的病因和发病机制复杂多样, 目前并不明确, 所以对于IBS的治疗尚无最为优化的治疗方案, 尤其是难治性IBS. 此文参考了大量的国内外相关文献, 力求找到更为安全有效的治疗药物和方法. 文中针对近年来关注的IBS的发病机制, 介绍了以往常应用于其他肠道疾病的粪便移植、美沙拉嗪在IBS中的应用, 在改善大便性状和腹痛方面还提到了正在进行试验但有较好前景的新药.
本文应用大量国内外研究数据和结果说明, 而且介绍了粪便移植这一近年来备受关注的治疗方式在IBS中的应用.
本文重视引用文献的新颖和权威性, 综合分析不同文章的治疗措施, 选择可信度高以及更优的治疗, 并对其不良反应和安全性进行陈述, 有一定的临床价值. 文章中还综述了一些前沿东西, 可对以后的研究提供参考.
小肠细菌过度生长: 又称小肠污染综合征或盲袢综合征, 是远端肠道内的细菌移位至小肠, 引起小肠内厌氧菌过度生长而造成吸收不良.
本文立题有意义, 文字简洁, 参考较多且近期的文献, 对IBS治疗进展作了较全面综述, 有一定的深度和创新, 具有一定的临床指导价值.
编辑:于明茜 电编:都珍珍
| 1. | Peyton L, Greene J. Irritable bowel syndrome: current and emerging treatment options. P T. 2014;39:567-578. [PubMed] |
| 2. | Lee YJ, Park KS. Irritable bowel syndrome: emerging paradigm in pathophysiology. World J Gastroenterol. 2014;20:2456-2469. [PubMed] [DOI] |
| 4. | Pyleris E, Giamarellos-Bourboulis EJ, Tzivras D, Koussoulas V, Barbatzas C, Pimentel M. The prevalence of overgrowth by aerobic bacteria in the small intestine by small bowel culture: relationship with irritable bowel syndrome. Dig Dis Sci. 2012;57:1321-1329. [PubMed] [DOI] |
| 5. | Codling C, O'Mahony L, Shanahan F, Quigley EM, Marchesi JR. A molecular analysis of fecal and mucosal bacterial communities in irritable bowel syndrome. Dig Dis Sci. 2010;55:392-397. [PubMed] [DOI] |
| 6. | Martínez C, González-Castro A, Vicario M, Santos J. Cellular and molecular basis of intestinal barrier dysfunction in the irritable bowel syndrome. Gut Liver. 2012;6:305-315. [PubMed] [DOI] |
| 8. | Yoon JS, Sohn W, Lee OY, Lee SP, Lee KN, Jun DW, Lee HL, Yoon BC, Choi HS, Chung WS. Effect of multispecies probiotics on irritable bowel syndrome: a randomized, double-blind, placebo-controlled trial. J Gastroenterol Hepatol. 2014;29:52-59. [PubMed] [DOI] |
| 9. | Sisson G, Ayis S, Sherwood RA, Bjarnason I. Randomised clinical trial: A liquid multi-strain probiotic vs. placebo in the irritable bowel syndrome--a 12 week double-blind study. Aliment Pharmacol Ther. 2014;40:51-62. [PubMed] [DOI] |
| 10. | Hosseini A, Nikfar S, Abdollahi M. Are probiotics effective in management of irritable bowel syndrome? Arch Med Sci. 2012;8:403-405. [PubMed] [DOI] |
| 11. | Moayyedi P, Ford AC, Talley NJ, Cremonini F, Foxx-Orenstein AE, Brandt LJ, Quigley EM. The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut. 2010;59:325-332. [PubMed] [DOI] |
| 12. | Basseri RJ, Weitsman S, Barlow GM, Pimentel M. Antibiotics for the treatment of irritable bowel syndrome. Gastroenterol Hepatol (N Y). 2011;7:455-493. [PubMed] |
| 13. | Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. a double-blind, randomized, placebo-controlled study. Am J Gastroenterol. 2003;98:412-419. [PubMed] |
| 15. | Pimentel M, Lembo A, Chey WD, Zakko S, Ringel Y, Yu J, Mareya SM, Shaw AL, Bortey E, Forbes WP. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011;364:22-32. [PubMed] [DOI] |
| 16. | Drossman DA. Rifaximin for treatment of irritable bowel syndrome. Gastroenterol Hepatol (N Y). 2011;7:180-181. [PubMed] |
| 17. | Schoenfeld P, Pimentel M, Chang L, Lembo A, Chey WD, Yu J, Paterson C, Bortey E, Forbes WP. Safety and tolerability of rifaximin for the treatment of irritable bowel syndrome without constipation: a pooled analysis of randomised, double-blind, placebo-controlled trials. Aliment Pharmacol Ther. 2014;39:1161-1168. [PubMed] [DOI] |
| 18. | Aroniadis OC, Brandt LJ. Intestinal microbiota and the efficacy of fecal microbiota transplantation in gastrointestinal disease. Gastroenterol Hepatol (N Y). 2014;10:230-237. [PubMed] |
| 19. | Borody TJ, Brandt LJ, Paramsothy S. Therapeutic faecal microbiota transplantation: current status and future developments. Curr Opin Gastroenterol. 2014;30:97-105. [PubMed] [DOI] |
| 20. | Pinn DM, Aroniadis OC, Brandt LJ. Follow-up study of fecal microbiota transplantation(FMT) for the treatment of refractory irritable bowel syndrome(IBS). Presented at: American College of Gastroenterology Annual Meeting 2013; . |
| 21. | Borody TJ, Paramsothy S, Agrawal G. Fecal microbiota transplantation: indications, methods, evidence, and future directions. Curr Gastroenterol Rep. 2013;15:337. [PubMed] [DOI] |
| 22. | Bellini M, Gambaccini D, Stasi C, Urbano MT, Marchi S, Usai-Satta P. Irritable bowel syndrome: a disease still searching for pathogenesis, diagnosis and therapy. World J Gastroenterol. 2014;20:8807-8820. [PubMed] [DOI] |
| 23. | Dorofeyev AE, Kiriyan EA, Vasilenko IV, Rassokhina OA, Elin AF. Clinical, endoscopical and morphological efficacy of mesalazine in patients with irritable bowel syndrome. Clin Exp Gastroenterol. 2011;4:141-153. [PubMed] [DOI] |
| 25. | Barbara G, Cremon C, Annese V, Basilisco G, Bazzoli F, Bellini M, Benedetti A, Benini L, Bossa F, Buldrini P. Randomised controlled trial of mesalazine in IBS. Gut. 2016;65:82-90. [PubMed] [DOI] |
| 26. | Lam C, Tan W, Leighton M, Hastings M, Lingaya M, Falcone Y, Zhou X, Xu L, Whorwell P, Walls AF. A mechanistic multicentre, parallel group, randomised placebo-controlled trial of mesalazine for the treatment of IBS with diarrhoea (IBS-D). Gut. 2016;65:91-99. [PubMed] [DOI] |
| 27. | Layer P, Stanghellini V. Review article: Linaclotide for the management of irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2014;39:371-384. [PubMed] [DOI] |
| 28. | Rao S, Lembo AJ, Shiff SJ, Lavins BJ, Currie MG, Jia XD, Shi K, MacDougall JE, Shao JZ, Eng P. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 2012;107:1714-1724; quiz p.1725. [PubMed] |
| 29. | Videlock EJ, Cheng V, Cremonini F. Effects of linaclotide in patients with irritable bowel syndrome with constipation or chronic constipation: a meta-analysis. Clin Gastroenterol Hepatol. 2013;11:1084-1092.e3; quiz e68. [PubMed] [DOI] |
| 30. | Shailubhai K, Comiskey S, Foss JA, Feng R, Barrow L, Comer GM, Jacob GS. Plecanatide, an oral guanylate cyclase C agonist acting locally in the gastrointestinal tract, is safe and well-tolerated in single doses. Dig Dis Sci. 2013;58:2580-2586. [PubMed] [DOI] |
| 31. | Lembo AJ, Johanson JF, Parkman HP, Rao SS, Miner PB, Ueno R. Long-term safety and effectiveness of lubiprostone, a chloride channel (ClC-2) activator, in patients with chronic idiopathic constipation. Dig Dis Sci. 2011;56:2639-2645. [PubMed] [DOI] |
| 32. | Saad RJ. Peripherally acting therapies for the treatment of irritable bowel syndrome. Gastroenterol Clin North Am. 2011;40:163-182. [PubMed] [DOI] |
| 33. | Chan WW, Mashimo H. Lubiprostone Increases Small Intestinal Smooth Muscle Contractions Through a Prostaglandin E Receptor 1 (EP1)-mediated Pathway. J Neurogastroenterol Motil. 2013;19:312-318. [PubMed] [DOI] |
| 34. | Johanson JF, Drossman DA, Panas R, Wahle A, Ueno R. Clinical trial: phase 2 study of lubiprostone for irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2008;27:685-696. [PubMed] [DOI] |
| 35. | Drossman DA, Chey WD, Johanson JF, Fass R, Scott C, Panas R, Ueno R. Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome--results of two randomized, placebo-controlled studies. Aliment Pharmacol Ther. 2009;29:329-341. [PubMed] [DOI] |
| 36. | Chey WD, Drossman DA, Johanson JF, Scott C, Panas RM, Ueno R. Safety and patient outcomes with lubiprostone for up to 52 weeks in patients with irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2012;35:587-599. [PubMed] [DOI] |
| 37. | Sherid M, Sifuentes H, Samo S, Deepak P, Sridhar S. Lubiprostone induced ischemic colitis. World J Gastroenterol. 2013;19:299-303. [PubMed] [DOI] |
| 38. | Lazaraki G, Chatzimavroudis G, Katsinelos P. Recent advances in pharmacological treatment of irritable bowel syndrome. World J Gastroenterol. 2014;20:8867-8885. [PubMed] [DOI] |
| 39. | Wade PR, Palmer JM, McKenney S, Kenigs V, Chevalier K, Moore BA, Mabus JR, Saunders PR, Wallace NH, Schneider CR. Modulation of gastrointestinal function by MuDelta, a mixed µ opioid receptor agonist/ µ opioid receptor antagonist. Br J Pharmacol. 2012;167:1111-1125. [PubMed] [DOI] |
| 40. | Dove LS, Lembo A, Randall CW, Fogel R, Andrae D, Davenport JM, McIntyre G, Almenoff JS, Covington PS. Eluxadoline benefits patients with irritable bowel syndrome with diarrhea in a phase 2 study. Gastroenterology. 2013;145:329-38.e1. [PubMed] [DOI] |
| 41. | Lembo AJ, Lacy BE, Zuckerman MJ, Schey R, Dove LS, Andrae DA, Davenport JM, McIntyre G, Lopez R, Turner L. Eluxadoline for Irritable Bowel Syndrome with Diarrhea. N Engl J Med. 2016;374:242-253. [PubMed] [DOI] |
| 43. | Mangel AW, Bornstein JD, Hamm LR, Buda J, Wang J, Irish W, Urso D. Clinical trial: asimadoline in the treatment of patients with irritable bowel syndrome. Aliment Pharmacol Ther. 2008;28:239-249. [PubMed] [DOI] |
| 45. | Cottreau J, Tucker A, Crutchley R, Garey KW. Crofelemer for the treatment of secretory diarrhea. Expert Rev Gastroenterol Hepatol. 2012;6:17-23. [PubMed] [DOI] |
| 47. | Mangel AW, Chaturvedi P. Evaluation of crofelemer in the treatment of diarrhea-predominant irritable bowel syndrome patients. Digestion. 2008;78:180-186. [PubMed] [DOI] |
| 48. | Hellström PM. GLP-1 playing the role of a gut regulatory compound. Acta Physiol (Oxf). 2011;201:151-156. [PubMed] [DOI] |
| 49. | Yang Y, Cui X, Chen Y, Wang Y, Li X, Lin L, Zhang H. Exendin-4, an analogue of glucagon-like peptide-1, attenuates hyperalgesia through serotonergic pathways in rats with neonatal colonic sensitivity. J Physiol Pharmacol. 2014;65:349-357. [PubMed] |
| 50. | Hellström PM, Hein J, Bytzer P, Björnssön E, Kristensen J, Schambye H. Clinical trial: the glucagon-like peptide-1 analogue ROSE-010 for management of acute pain in patients with irritable bowel syndrome: a randomized, placebo-controlled, double-blind study. Aliment Pharmacol Ther. 2009;29:198-206. [PubMed] [DOI] |
| 51. | Bajor A, Gillberg PG, Abrahamsson H. Bile acids: short and long term effects in the intestine. Scand J Gastroenterol. 2010;45:645-664. [PubMed] [DOI] |
| 52. | Pattni S, Walters JR. Recent advances in the understanding of bile acid malabsorption. Br Med Bull. 2009;92:79-93. [PubMed] [DOI] |
| 53. | Chey WD, Camilleri M, Chang L, Rikner L, Graffner H. A randomized placebo-controlled phase IIb trial of a3309, a bile acid transporter inhibitor, for chronic idiopathic constipation. Am J Gastroenterol. 2011;106:1803-1812. [PubMed] [DOI] |
| 54. | Hasler WL. Serotonin and the GI tract. Curr Gastroenterol Rep. 2009;11:383-391. [PubMed] [DOI] |
| 55. | Steadman CJ, Talley NJ, Phillips SF, Zinsmeister AR. Selective 5-hydroxytryptamine type 3 receptor antagonism with ondansetron as treatment for diarrhea-predominant irritable bowel syndrome: a pilot study. Mayo Clin Proc. 1992;67:732-738. [PubMed] [DOI] |
| 56. | Goldberg PA, Kamm MA, Setti-Carraro P, van der Sijp JR, Roth C. Modification of visceral sensitivity and pain in irritable bowel syndrome by 5-HT3 antagonism (ondansetron). Digestion. 1996;57:478-483. [PubMed] [DOI] |
| 57. | Garsed K, Chernova J, Hastings M, Lam C, Marciani L, Singh G, Henry A, Hall I, Whorwell P, Spiller R. A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut. 2014;63:1617-1625. [PubMed] [DOI] |
| 58. | Olden KW. Targeted therapies for diarrhea-predominant irritable bowel syndrome. Clin Exp Gastroenterol. 2012;5:69-100. [PubMed] [DOI] |
| 59. | Cremonini F, Nicandro JP, Atkinson V, Shringarpure R, Chuang E, Lembo A. Randomised clinical trial: alosetron improves quality of life and reduces restriction of daily activities in women with severe diarrhoea-predominant IBS. Aliment Pharmacol Ther. 2012;36:437-448. [PubMed] [DOI] |
| 60. | Chang L, Tong K, Ameen V. Ischemic colitis and complications of constipation associated with the use of alosetron under a risk management plan: clinical characteristics, outcomes, and incidences. Am J Gastroenterol. 2010;105:866-875. [PubMed] [DOI] |
| 61. | Matsueda K, Harasawa S, Hongo M, Hiwatashi N, Sasaki D. A phase II trial of the novel serotonin type 3 receptor antagonist ramosetron in Japanese male and female patients with diarrhea-predominant irritable bowel syndrome. Digestion. 2008;77:225-235. [PubMed] [DOI] |
| 62. | Matsueda K, Harasawa S, Hongo M, Hiwatashi N, Sasaki D. A randomized, double-blind, placebo-controlled clinical trial of the effectiveness of the novel serotonin type 3 receptor antagonist ramosetron in both male and female Japanese patients with diarrhea-predominant irritable bowel syndrome. Scand J Gastroenterol. 2008;43:1202-1211. [PubMed] [DOI] |
| 63. | Fukudo S, Ida M, Akiho H, Nakashima Y, Matsueda K. Effect of ramosetron on stool consistency in male patients with irritable bowel syndrome with diarrhea. Clin Gastroenterol Hepatol. 2014;12:953-959.e4. [PubMed] [DOI] |
| 64. | Novick J, Miner P, Krause R, Glebas K, Bliesath H, Ligozio G, Rüegg P, Lefkowitz M. A randomized, double-blind, placebo-controlled trial of tegaserod in female patients suffering from irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2002;16:1877-1888. [PubMed] [DOI] |
| 65. | Müller-Lissner S, Holtmann G, Rueegg P, Weidinger G, Löffler H. Tegaserod is effective in the initial and retreatment of irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2005;21:11-20. [PubMed] [DOI] |
| 66. | Chey WD, Paré P, Viegas A, Ligozio G, Shetzline MA. Tegaserod for female patients suffering from IBS with mixed bowel habits or constipation: a randomized controlled trial. Am J Gastroenterol. 2008;103:1217-1225. [PubMed] [DOI] |
| 67. | Kim YS, Choi SC, Park JM, Choi CH, Lee DH, Son HJ, Sung IK, Jeong JJ, Lee JS, Shim KN. The effect of tegaserod on symptoms and quality of life in korean women with irritable bowel syndrome with constipation. J Neurogastroenterol Motil. 2010;16:61-70. [PubMed] [DOI] |
| 68. | Camilleri M, McKinzie S, Fox J, Foxx-Orenstein A, Burton D, Thomforde G, Baxter K, Zinsmeister AR. Effect of renzapride on transit in constipation-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol. 2004;2:895-904. [PubMed] [DOI] |
| 69. | Tack J, Middleton SJ, Horne MC, Piessevaux H, Bloor JS, Meyers NL, Palmer RM. Pilot study of the efficacy of renzapride on gastrointestinal motility and symptoms in patients with constipation-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2006;23:1655-1665. [PubMed] [DOI] |
| 70. | George AM, Meyers NL, Hickling RI. Clinical trial: renzapride therapy for constipation-predominant irritable bowel syndrome--multicentre, randomized, placebo-controlled, double-blind study in primary healthcare setting. Aliment Pharmacol Ther. 2008;27:830-837. [PubMed] [DOI] |
| 71. | Lembo AJ, Cremonini F, Meyers N, Hickling R. Clinical trial: renzapride treatment of women with irritable bowel syndrome and constipation - a double-blind, randomized, placebo-controlled, study. Aliment Pharmacol Ther. 2010;31:979-990. [PubMed] [DOI] |
| 72. | Mozaffari S, Nikfar S, Abdollahi M. Efficacy and tolerability of renzapride in irritable bowel syndrome: a meta-analysis of randomized, controlled clinical trials including 2528 patients. Arch Med Sci. 2014;10:10-18. [PubMed] [DOI] |
| 73. | Cappello G, Spezzaferro M, Grossi L, Manzoli L, Marzio L. Peppermint oil (Mintoil) in the treatment of irritable bowel syndrome: a prospective double blind placebo-controlled randomized trial. Dig Liver Dis. 2007;39:530-536. [PubMed] [DOI] |
| 74. | Alam MS, Roy PK, Miah AR, Mollick SH, Khan MR, Mahmud MC, Khatun S. Efficacy of Peppermint oil in diarrhea predominant IBS - a double blind randomized placebo - controlled study. Mymensingh Med J. 2013;22:27-30. [PubMed] |
| 75. | Khanna R, MacDonald JK, Levesque BG. Peppermint oil for the treatment of irritable bowel syndrome: a systematic review and meta-analysis. J Clin Gastroenterol. 2014;48:505-512. [PubMed] [DOI] |