{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T20:01:23Z","timestamp":1791489683333,"version":"4.3.4"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2018,11,21]],"date-time":"2018-11-21T00:00:00Z","timestamp":1542758400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Dig Dis Sci"],"published-print":{"date-parts":[[2019,3]]},"DOI":"10.1007\/s10620-018-5377-9","type":"journal-article","created":{"date-parts":[[2018,11,20]],"date-time":"2018-11-20T23:33:44Z","timestamp":1542756824000},"page":"823-831","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Adding Acotiamide to Gastric Acid Inhibitors Is Effective for Treating Refractory Symptoms in Patients with Non-erosive Reflux Disease"],"prefix":"10.1007","volume":"64","author":[{"given":"Hiroshi","family":"Yamashita","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiko","family":"Okada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohji","family":"Naora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Hongoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshikazu","family":"Kinoshita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,11,21]]},"reference":[{"key":"5377_CR1","doi-asserted-by":"publisher","first-page":"S62","DOI":"10.1007\/s11605-009-1015-3","volume":"14","author":"PO Katz","year":"2010","unstructured":"Katz PO, Zavala S. Proton pump inhibitors in the management of GERD. J Gastrointest Surg. 2010;14:S62\u2013S66.","journal-title":"J Gastrointest Surg"},{"key":"5377_CR2","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1136\/gut.2007.145581","volume":"58","author":"R Fass","year":"2009","unstructured":"Fass R, Sifrim D. Management of heartburn not responding to proton pump inhibitors. Gut. 2009;58:295\u2013309.","journal-title":"Gut"},{"key":"5377_CR3","doi-asserted-by":"publisher","first-page":"1398","DOI":"10.1136\/gut.2005.087668","volume":"55","author":"I Mainie","year":"2006","unstructured":"Mainie I, Tutuian R, Shay S, et al. Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicenter study using combined ambulatory impedance-pH monitoring. Gut. 2006;55:1398\u20131402.","journal-title":"Gut"},{"key":"5377_CR4","doi-asserted-by":"publisher","first-page":"1956","DOI":"10.1111\/j.1572-0241.2006.00711.x","volume":"101","author":"F Zerbib","year":"2006","unstructured":"Zerbib F, Romans S, Ropert A, et al. Esophageal pH-impedance monitoring and symptom analysis in GERD: a study in patients off and on therapy. Am J Gastroenterol. 2006;101:1956\u20131963.","journal-title":"Am J Gastroenterol"},{"key":"5377_CR5","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1111\/j.1365-2036.2010.04565.x","volume":"33","author":"BF Kessing","year":"2011","unstructured":"Kessing BF, Conchillo JM, Bredenoord AJ, et al. Review article: the clinical relevance of transient lower oesophageal sphincter relaxations in gastrooesophageal reflux disease. Aliment Pharmacol Ther. 2011;33:650\u2013661.","journal-title":"Aliment Pharmacol Ther"},{"key":"5377_CR6","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1111\/j.1742-7843.2005.pto_273.x","volume":"97","author":"T Piche","year":"2005","unstructured":"Piche T, Galmiche JP. Pharmacological targets in gastro-oesophageal reflux disease. Basic Clin Pharmacol Toxicol. 2005;97:333\u2013341.","journal-title":"Basic Clin Pharmacol Toxicol"},{"key":"5377_CR7","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1007\/s11894-005-0033-x","volume":"7","author":"S Emerenziani","year":"2005","unstructured":"Emerenziani S, Sifrim D. Gastroesophageal reflux and gastric emptying, revisited. Curr Gastroenterol Rep. 2005;7:190\u2013195.","journal-title":"Curr Gastroenterol Rep"},{"key":"5377_CR8","doi-asserted-by":"publisher","first-page":"533","DOI":"10.5056\/jnm16211","volume":"23","author":"S Ishii","year":"2017","unstructured":"Ishii S, Fukahori S, Asagiri K, et al. Severe delayed gastric emptying induces non-acid reflux up to proximal esophagus in neurologically impaired patients. J Neurogastroenterol Motil. 2017;23:533\u2013540.","journal-title":"J Neurogastroenterol Motil"},{"key":"5377_CR9","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1111\/j.1365-2036.2010.04517.x","volume":"33","author":"H Miwa","year":"2011","unstructured":"Miwa H, Inoue K, Ashida K, et al. Randomised clinical trial: efficacy of the addition of a prokinetic, mosapride citrate, to omeprazole in the treatment of patients with non-erosive reflux disease\u2014a double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2011;33:323\u2013332.","journal-title":"Aliment Pharmacol Ther"},{"key":"5377_CR10","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.1111\/nmo.12359","volume":"26","author":"BF Kessing","year":"2014","unstructured":"Kessing BF, Smout AJPM, Bennink RJ, et al. Prucalopride decreases esophageal acid exposure and accelerate gastric emptying in healthy subjects. Neurogastroenterol Motil. 2014;26:1079\u20131086.","journal-title":"Neurogastroenterol Motil"},{"key":"5377_CR11","first-page":"256","volume":"27","author":"J Tack","year":"2015","unstructured":"Tack J, Zerbib F, Blondeau K, et al. Randomized clinical trial: effect of the 5-TH4 receptor against revexepride on reflux parameters in patients with persistent reflux symptoms despite PPI treatment. Neurogastroenterol Motil. 2015;27:256\u2013268.","journal-title":"Neurogastroenterol Motil"},{"key":"5377_CR12","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/S0022-3565(24)39036-6","volume":"294","author":"M Ogishima","year":"2000","unstructured":"Ogishima M, Kaibara M, Ueki S, et al. Z-338 facilitates acetylcholine release from enteric neurons due to blockade of muscarinic autoreceptors in guinea pig stomach. J Pharmacol Exp Ther. 2000;294:33\u201337.","journal-title":"J Pharmacol Exp Ther"},{"key":"5377_CR13","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1540\/jsmr.36.69","volume":"36","author":"T Nakajima","year":"2000","unstructured":"Nakajima T, Nawata H, Ito Y. Z-338, a newly synthetized carboxyamide derivative, stimulates gastric motility through enhancing the excitatory neurotransmission. J Smooth Muscle Res. 2000;36:69\u201381.","journal-title":"J Smooth Muscle Res"},{"key":"5377_CR14","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1111\/j.1365-2982.2012.01897.x","volume":"24","author":"H Kusunoki","year":"2012","unstructured":"Kusunoki H, Haruma K, Manabe N, et al. Therapeutic efficacy of acotiamide in patients with functional dyspepsia based on enhanced postprandial gastric accommodation and emptying: randomized controlled study evaluation by real-time ultrasonography. Neurogastroenterol Motil. 2012;24:540\u2013545.","journal-title":"Neurogastroenterol Motil"},{"key":"5377_CR15","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1159\/000437301","volume":"92","author":"H Yamashita","year":"2015","unstructured":"Yamashita H, Kanamori A, Fukuchi T, et al. Novel prokinetic acotiamide reduces transient lower esophageal sphincter relaxation in healthy subjects. Digestion. 2015;92:90\u201398.","journal-title":"Digestion"},{"key":"5377_CR16","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1016\/j.cgh.2007.03.004","volume":"5","author":"M Camilleri","year":"2007","unstructured":"Camilleri M, Drossman A, Fehnel S, et al. Primary endpoints for FGID trials: a review of binary and integrated symptoms assessments. Clin Gastroenterol Hepatol. 2007;5:534\u2013540.","journal-title":"Clin Gastroenterol Hepatol"},{"key":"5377_CR17","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1111\/nmo.12477","volume":"27","author":"PJ Kahrilas","year":"2015","unstructured":"Kahrilas PJ, Bredenoord AJ, Fox M, et al. The Chicago classification of esophageal motility disorders, v3.0. Neurogastroenterol Motil. 2015;27:160\u2013174.","journal-title":"Neurogastroenterol Motil"},{"key":"5377_CR18","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1136\/gutjnl-2011-301454","volume":"61","author":"K Matsueda","year":"2012","unstructured":"Matsueda K, Hongo M, Tack J, et al. A placebo-controlled trial of acotiamide for meal-related symptoms of functional dyspepsia. Gut. 2012;61:821\u2013828.","journal-title":"Gut"},{"key":"5377_CR19","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1007\/s00535-011-0446-2","volume":"46","author":"T Furuta","year":"2011","unstructured":"Furuta T, Shimatani T, Sugimoto M, et al. Investigation of pretreatment prediction of proton pump inhibitor (PPI)-resistant patients with gastroesophageal reflux disease and the dose escalation challenge of PPIs-TORNADO study: a multicenter prospective study by the Acid-Related Symptom Research Group in Japan. J Gastroenterol. 2011;46:1271\u20131283.","journal-title":"J Gastroenterol"},{"key":"5377_CR20","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1007\/s00535-016-1260-7","volume":"52","author":"K Nakamura","year":"2017","unstructured":"Nakamura K, Tomita T, Oshima T, et al. A double-blind placebo controlled study of acotiamide hydrochloride for efficacy on gastrointestinal motility of patients with functional dyspepsia. J Gastroenterol. 2017;52:602\u2013610.","journal-title":"J Gastroenterol"},{"key":"5377_CR21","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.1007\/s00535-015-1073-0","volume":"50","author":"N Matsuhashi","year":"2015","unstructured":"Matsuhashi N, Kudo M, Yoshida N, et al. Factors affecting response to proton pump inhibitor therapy in patients with gastroesophageal reflux disease: a multicenter prospective observational study. J Gastroenterol. 2015;50:1173\u20131183.","journal-title":"J Gastroenterol"},{"key":"5377_CR22","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1111\/dote.12374","volume":"29","author":"A Garros","year":"2016","unstructured":"Garros A, Mion F, Marjoux S, et al. Factors associated with nonresponse to proton pump inhibitors therapy in patients referred for esophageal pH-impedance monitoring. Dis Esophagus. 2016;29:787\u2013793.","journal-title":"Dis Esophagus"},{"key":"5377_CR23","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1111\/j.1365-2982.2009.01306.x","volume":"21","author":"AJ Bredenoord","year":"2009","unstructured":"Bredenoord AJ, Hemmink GJM, Smout AJPM. Relationship between gastro-oesophageal reflux pattern and severity of mucosal damage. Neurogastroenterol Motil. 2009;21:807\u2013812.","journal-title":"Neurogastroenterol Motil"},{"key":"5377_CR24","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1136\/gut.2007.133470","volume":"57","author":"F Zerbib","year":"2008","unstructured":"Zerbib F, Duriez A, Roman S, et al. Determinants of gastro-oesophageal reflux perception in patients with persistent symptoms despite proton pump inhibitors. Gut. 2008;57:156\u2013160.","journal-title":"Gut"},{"key":"5377_CR25","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1111\/j.1365-2036.2006.02968.x","volume":"24","author":"R Tutuian","year":"2006","unstructured":"Tutuian R, Mainie I, Allan R, et al. Effects of a 5-HT(4) receptor agonist on oesophageal function and gastro-oesophageal reflux: studies using combined impedance-manometry and combined impedance-pH. Aliment Pharmacol Ther. 2006;24:155\u2013162.","journal-title":"Aliment Pharmacol Ther"},{"key":"5377_CR26","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1111\/j.1365-2036.2007.03281.x","volume":"25","author":"D Sifrim","year":"2007","unstructured":"Sifrim D, Mittal R, Fass R, et al. Review article: acidity and volume of the refluxate in the genesis of gastro-oesophageal reflux disease symptoms. Aliment Pharmacol Ther. 2007;25:1003\u20131015.","journal-title":"Aliment Pharmacol Ther"},{"key":"5377_CR27","doi-asserted-by":"publisher","first-page":"S42","DOI":"10.1159\/000151254","volume":"78","author":"J Tack","year":"2008","unstructured":"Tack J. Is there a unifying role for visceral hypersensitivity and irritable bowel syndrome in non-erosive reflux disease? Digestion. 2008;78:S42\u2013S45.","journal-title":"Digestion"},{"key":"5377_CR28","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1111\/j.1365-2982.2006.00868.x","volume":"19","author":"S Emerenziani","year":"2007","unstructured":"Emerenziani S, Cicala M, Zhang X, et al. Effect of oesophagitis on proximal extent of gastro-oesophageal reflux. Neurogastroenterol Motil. 2007;19:459\u2013464.","journal-title":"Neurogastroenterol Motil"},{"key":"5377_CR29","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1007\/s10388-016-0559-z","volume":"14","author":"S Hoshino","year":"2017","unstructured":"Hoshino S, Takenouchi N, Hanada Y, et al. Effect of acotiamide on esophageal motility in healthy subjects: a randomized, double-blind, placebo-controlled crossover study. Esophagus. 2017;14:146\u2013152.","journal-title":"Esophagus"},{"key":"5377_CR30","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1053\/j.gastro.2004.08.014","volume":"128","author":"WJ Barlow","year":"2005","unstructured":"Barlow WJ, Orlando RC. The pathogenesis of heartburn in nonerosive reflux disease: a unifying hypothesis. Gastroenterology. 2005;128:771\u2013778.","journal-title":"Gastroenterology"},{"key":"5377_CR31","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1136\/gut.2009.194191","volume":"59","author":"R Farr\u00e9","year":"2010","unstructured":"Farr\u00e9 R, Fornari F, Blondeau K, et al. Acid and weakly acidic solutions impair mucosal integrity of distal exposed and proximal non-exposed human oesophagus. Gut. 2010;59:164\u2013169.","journal-title":"Gut"},{"key":"5377_CR32","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1111\/j.1443-9573.2006.00266.x","volume":"7","author":"EM Quigley","year":"2006","unstructured":"Quigley EM. Non-erosive reflux disease, functional heartburn and gastroesophageal reflux disease; insights into pathophysiology and clinical presentation. Chin J Dig Dis. 2006;7:186\u2013190.","journal-title":"Chin J Dig Dis"},{"key":"5377_CR33","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1111\/j.1365-2982.2012.01912.x","volume":"24","author":"K Nagahama","year":"2012","unstructured":"Nagahama K, Matsunaga Y, Kawachi M, et al. Acotiamide, a new orally active acetylcholinesterase inhibitor, stimulates gastrointestinal motor activity in conscious dogs. Neurogastroenterol Motil. 2012;24:566\u2013574.","journal-title":"Neurogastroenterol Motil"}],"container-title":["Digestive Diseases and Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s10620-018-5377-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10620-018-5377-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10620-018-5377-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T04:23:35Z","timestamp":1775276615000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s10620-018-5377-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,21]]},"references-count":33,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2019,3]]}},"alternative-id":["5377"],"URL":"https:\/\/doi.org\/10.1007\/s10620-018-5377-9","relation":{},"ISSN":["0163-2116","1573-2568"],"issn-type":[{"value":"0163-2116","type":"print"},{"value":"1573-2568","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,21]]},"assertion":[{"value":"13 July 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 November 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 November 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"YK received research funding and speaker fees from Astellas and Zeria, but this work was independent of these companies. The remaining authors declare no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}