{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T18:41:50Z","timestamp":1774032110393,"version":"3.50.1"},"reference-count":35,"publisher":"BMJ","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Gut"],"published-print":{"date-parts":[[1996,5]]},"abstract":"<jats:p>BACKGROUND\/AIMS--Reducing oesophageal acid exposure by suppressing acid secretion with omeprazole is highly effective in healing reflux oesophagitis. Some patients with severe oesophagitis, fail to heal and whether this results from inadequate acid suppression or other factors is unclear. The aim of this study, was to investigate the relation between oesophageal acid exposure and healing in patients with severe reflux oesophagitis treated with omeprazole. METHODS--Sixty one patients with grade 3 or 4 ulcerative oesophagitis were treated for eight weeks with omeprazole 20 mg every morning. Those patients unhealed at eight weeks were treated with 40 mg every morning for a further eight weeks. Endoscopy and 24 hour oesophageal pH monitoring were performed before treatment and at the end of each treatment phase while receiving treatment. RESULTS--Thirty per cent of patients failed to heal with the 20 mg dose. Unhealed patients had greater total 24 hour oesophageal acid exposure before treatment, and while receiving treatment also had greater acid exposure and a smaller reduction in acid exposure than did patients who healed. Forty seven per cent of the unhealed patients also failed to heal with the 40 mg dose. These patients had similar levels of acid exposure before treatment to those who healed, but had greater acid exposure while receiving treatment, particularly at night when supine. CONCLUSIONS--Patients with severe ulcerative oesophagitis who are refractory to omeprazole have greater oesophageal acid exposure while receiving treatment than responding patients. This is due to a reduced responsiveness to acid suppression, and is likely to be an important factor underlying the failure of the oesophagitis to heal.<\/jats:p>","DOI":"10.1136\/gut.38.5.649","type":"journal-article","created":{"date-parts":[[2007,9,18]],"date-time":"2007-09-18T17:41:31Z","timestamp":1190137291000},"page":"649-654","source":"Crossref","is-referenced-by-count":91,"title":["Relation between oesophageal acid exposure and healing of oesophagitis with omeprazole in patients with severe reflux oesophagitis."],"prefix":"10.1136","volume":"38","author":[{"given":"R H","family":"Holloway","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J","family":"Dent","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F","family":"Narielvala","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A M","family":"Mackinnon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[1996,5,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1136\/gut.28.5.519","article-title":"Daytime gastro-oesophageal reflux is important in oesophagitis","volume":"28","author":"de Caestecker JS; JN, Blackwell; A, Pryde; RC, Heading","year":"1987","unstructured":"de Caestecker JS, Blackwell JN, Pryde A, Heading RC. 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Am J Gastroenterol 1991; 86: 1142-6.","journal-title":"Am J Gastroenterol"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"810","DOI":"10.3109\/00365529008999219","article-title":"Pattern of acid reflux in patients with reflux esophagitis 'resistant' to H2-receptor antagonists","volume":"25","year":"1990","unstructured":"Bianchi-Porro G, Pace F, Sangaletti 0. Pattern of acid reflux in patients with reflux esophagitis 'resistant' to H2-receptor antagonists. ScandJ Gastroenterol 1990; 25: 810-4.","journal-title":"ScandJ Gastroenterol"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/0016-5085(90)90285-9","article-title":"Gastric acid hypersecretion in refractory gastroesophageal reflux disease","volume":"98","author":"Collen, M.J.; Lewis, J.H.; Benjamin, S.B.","year":"1990","unstructured":"Collen MJ, Lewis JH, Benjamin SB. Gastric acid hypersecretion in refractory gastroesophageal reflux disease. 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Gastroenterology 1995; 108: A249."},{"key":"ref_24","first-page":"1149","article-title":"A critical analysis, with appropriate controls, of gastric acid and pepsin secretion","volume-title":"clinical esophagitis. Gastroenterology 1991; 101","author":"Hirschowitz, B.I.","unstructured":"Hirschowitz BI. A critical analysis, with appropriate controls, of gastric acid and pepsin secretion in clinical esophagitis. Gastroenterology 1991; 101: 1149-58."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1001\/archsurg.1989.01410080069011","article-title":"The significance of the gastric secretory state in gastroesophageal reflux disease","volume":"124","author":"Barlow, A.; DeMeester, T.; Ball, C.; Eypasch, E.","year":"1989","unstructured":"Barlow A, DeMeester T, Ball C, Eypasch E. The significance of the gastric secretory state in gastroesophageal reflux disease. Arch Surg 1989; 124: 937-40.","journal-title":"Arch Surg"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1007\/BF01538064","article-title":"Elevated gastric acid secretion in patients with Barrett's metaplastic epithelium","volume":"34","author":"Mulholland, M.W.; Reid, B.J.; Levine, D.S.; Rubin, C.E.","year":"1989","unstructured":"Mulholland MW, Reid BJ, Levine DS, Rubin CE. Elevated gastric acid secretion in patients with Barrett's metaplastic epithelium. Dig Dis Sci 1989; 34: 1329-35.","journal-title":"Dig Dis Sci"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1007\/BF02090216","article-title":"Basal acid output and gastric acid hypersecretion in gastroesophageal reflux disease. Correlation with ranitidine therapy","volume":"39","author":"Collen, M.J.; Johnson, D.A.; Sheridan, M.J.","year":"1994","unstructured":"Collen MJ, Johnson DA, Sheridan MJ. Basal acid output and gastric acid hypersecretion in gastroesophageal reflux disease. Correlation with ranitidine therapy. Dig Dis Sci 1994; 39: 410-7.","journal-title":"Dig Dis Sci"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/BF02090077","article-title":"Variability in individual response to various doses of omeprazole. Implications for antiulcer therapy","volume":"39","author":"Savarino, V.; Mela, G.S.; Zentilin, P.; Cutela, P.; Mele, M.R.; Vigneri, S.","year":"1994","unstructured":"Savarino V, Mela GS, Zentilin P, Cutela P, Mele MR, Vigneri S, et al. Variability in individual response to various doses of omeprazole. Implications for antiulcer therapy. Dig Dis Sci 1994; 39: 161-8.","journal-title":"Dig Dis Sci"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1136\/gut.25.9.957","article-title":"Optimal dose of oral omeprazole for maximal 24-hour decrease of intragastric acidity","volume":"25","author":"Sharma, B.K.; Walt, R.P.; Pounder, R.E.; Gomes, M.D.F.A.; Wood, E.C.; Logan, L.H.","year":"1984","unstructured":"Sharma BK, Walt RP, Pounder RE, Gomes MDFA, Wood EC, Logan LH. Optimal dose of oral omeprazole for maximal 24-hour decrease of intragastric acidity. Gut 1984; 25: 957-64.","journal-title":"Gut"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"620","DOI":"10.3109\/00365529109043636","article-title":"24-hour intragastric acidity and plasma gastrin during long-term treatment with omeprazole or ranitidine in patients with reflux esophagitis","volume":"26","author":"Lind, T.; Cederberg, C.; Idstrom, J.-P.; Lonroth, H.; Olbe, L.; Lundell, L.","year":"1991","unstructured":"Lind T, Cederberg C, Idstrom J-P, Lonroth H, Olbe L, Lundell L. 24-hour intragastric acidity and plasma gastrin during long-term treatment with omeprazole or ranitidine in patients with reflux esophagitis. Scand J Gastroenterol 1991; 26: 620-6.","journal-title":"Scand J Gastroenterol"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1111\/j.1365-2036.1987.tb00622.x","article-title":"Twenty-four-hour intragastric acididty and plasma gastrin concentration in healthy subjects and patients with duodenal or gastric ulcer, or pernicious anaemia","volume":"1","author":"Lanzon-Miller, S.; Pounder, R.E.; Hamilton, M.R.; Chronos, N.A.F.; Ball, S.; Mercieca, J.E.","year":"1987","unstructured":"Lanzon-Miller S, Pounder RE, Hamilton MR, Chronos NAF, Ball S, Mercieca JE, et al. Twenty-four-hour intragastric acididty and plasma gastrin concentration in healthy subjects and patients with duodenal or gastric ulcer, or pernicious anaemia. Aliment Pharmacol Ther 1987; 1: 225-37.","journal-title":"Aliment Pharmacol Ther"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1097\/00004836-199112000-00005","article-title":"Significant role of aspirin use in patients with esophagitis","volume":"13","author":"Lanas, A.; Hirschowitz, B.","year":"1991","unstructured":"Lanas A, Hirschowitz B. Significant role of aspirin use in patients with esophagitis. Jf Clin Gastroenterol 1991; 13: 622-7.","journal-title":"Jf Clin Gastroenterol"},{"key":"ref_33","first-page":"587","article-title":"Bile acid concentrations in the refluxate of patients with reflux oesophagitis","volume-title":"BrJ7 Surg","volume":"75","author":"Gotley, D.; Morgan, A.; Cooper, M.","year":"1988","unstructured":"Gotley D, Morgan A, Cooper M. Bile acid concentrations in the refluxate of patients with reflux oesophagitis. BrJ7 Surg 1988; 75: 587-90."},{"key":"ref_34","first-page":"103","article-title":"daily given in the morning or evening: a comparison of effects on gastric acidity, plasma gastrin and omeprazole concentration","volume":"6","author":"Chiverton, S.G.; Howden, C.W.; Burget, D.W.","year":"1992","unstructured":"Chiverton SG, Howden CW, Burget DW. Omeprazole (20mg) daily given in the morning or evening: a comparison of effects on gastric acidity, plasma gastrin and omeprazole concentration. Aliment Pharmacol Ther 1992; 6: 103-11.","journal-title":"Omeprazole"},{"key":"ref_35","first-page":"1034","article-title":"Omeprazole 20mg bid provides better acid suppression than a single dose","volume-title":"of 40mg. [Abstract]. Gastroenterology","volume":"106","author":"Kuo, B.; Castell, D.O.","year":"1994","unstructured":"Kuo B, Castell DO. Omeprazole 20mg bid provides better acid suppression than a single dose of 40mg. [Abstract]. Gastroenterology 1994; 106: A1034."}],"container-title":["Gut"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/gut.38.5.649","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T16:15:18Z","timestamp":1765642518000},"score":1,"resource":{"primary":{"URL":"https:\/\/gut.bmj.com\/lookup\/doi\/10.1136\/gut.38.5.649"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1996,5]]},"references-count":35,"journal-issue":{"issue":"5","published-online":{"date-parts":[[1996,5,1]]},"published-print":{"date-parts":[[1996,5]]}},"alternative-id":["10.1136\/gut.38.5.649"],"URL":"https:\/\/doi.org\/10.1136\/gut.38.5.649","relation":{},"ISSN":["0017-5749","1468-3288"],"issn-type":[{"value":"0017-5749","type":"print"},{"value":"1468-3288","type":"electronic"}],"subject":[],"published":{"date-parts":[[1996,5]]}}}