{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T00:38:20Z","timestamp":1792197500934,"version":"4.4.0"},"reference-count":62,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T00:00:00Z","timestamp":1729123200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Heavy alcohol intake is one of the most common causes of acute pancreatitis (AP). We have previously shown that ethanol (EtOH) decreases the expression and activity of the cystic fibrosis transmembrane conductance regulator (CFTR), which plays a key role in alcohol\u2010induced AP development. The prescription drug, Orkambi (a combination of ivacaftor and lumacaftor) can correct impaired CFTR function and expression in cystic fibrosis (CF) patients. Thus, the present study aimed to investigate whether Orkambi can mitigate alcohol\u2010induced AP. Intact guinea\u2010pig pancreatic ducts were pre\u2010treated with different concentrations of ethanol (EtOH; 30, 50 and 100\u00a0m<jats:sc>m<\/jats:sc>) for 12\u00a0h alone or in combination with ivacaftor (VX770) and\/or lumacaftor (VX\u2010809), and CFTR expression and activity were evaluated by immunostaining and by the patch clamp technique, respectively. Alcoholic AP was induced in Orkambi\u2010treated guinea\u2010pigs, and standard laboratory and histological parameters were measured. Ivacaftor and lumacaftor alone or in combination dose\u2010dependently restored the apical expression and activity of CFTR after EtOH treatment <jats:italic>in vitro<\/jats:italic>. Oral administration of Orkambi reduced the severity of alcohol\u2010induced AP and restored impaired CFTR activity and expression. Orkambi is able to restore the CFTR defect caused by EtOH and decreases the severity of alcohol\u2010induced pancreatitis. This is the first in vivo pre\u2010clinical evidence of Orkambi efficacy in the treatment of alcohol\u2010induced AP.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16382-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Acute pancreatitis is one of the leading causes of hospital admission among gastrointestinal diseases in which the lack of a specific drug therapy plays a crucial role.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The cystic fibrosis transmembrane conductance regulator (CFTR) plays an essential role in pancreatic ductal HCO<jats:sub>3<\/jats:sub><jats:sup>\u2013<\/jats:sup> secretion; inappropriate CFTR function, as seen in heavy alcohol consumption, increases the risk of pancreatitis development.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>CFTR modulators are able to prevent the inhibitory effect of ethanol and reduce pancreatic ductal injury and the severity of alcohol\u2010induced pancreatitis.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>CFTR modulators present a novel option in the pharmacotherapy of alcohol\u2010induced pancreatitis by enhancing pancreatic functions or preventing recurrence.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp287289","type":"journal-article","created":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T15:54:42Z","timestamp":1729180482000},"page":"6153-6170","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Restoring CFTR function with Orkambi decreases the severity of alcohol\u2010induced acute pancreatitis"],"prefix":"10.1113","volume":"602","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2316-7247","authenticated-orcid":false,"given":"Vikt\u00f3ria","family":"Venglovecz","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy University of Szeged  Szeged Hungary"},{"name":"Translational Pancreatology Research Group, Interdisciplinary Center of Excellence for Research Development and Innovation University of Szeged  Szeged Hungary"},{"name":"Institute for Translational Medicine, Medical School University of P\u00e9cs  P\u00e9cs Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Grassalkovich","sequence":"additional","affiliation":[{"name":"Translational Pancreatology Research Group, Interdisciplinary Center of Excellence for Research Development and Innovation University of Szeged  Szeged Hungary"},{"name":"Department of Medicine University of Szeged  Szeged 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Interdisciplinary Center of Excellence for Research Development and Innovation University of Szeged  Szeged Hungary"},{"name":"Institute for Translational Medicine, Medical School University of P\u00e9cs  P\u00e9cs Hungary"},{"name":"Centre for Translational Medicine Semmelweis University  Budapest Hungary"},{"name":"Institute for Pancreatic Disorders Semmelweis University  Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,10,17]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pan.2019.09.014"},{"key":"e_1_2_5_3_1","article-title":"An experimental model of diet\u2010induced metabolic syndrome in rabbit: Methodological considerations, development, and assessment","volume":"134","author":"Arias\u2010Mutis O. 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