{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T23:49:55Z","timestamp":1773964195047,"version":"3.50.1"},"reference-count":45,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T00:00:00Z","timestamp":1664236800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:p>High saturated fat diets have been shown to raise blood levels of cholecystokinin (CCK) and induce nonalcoholic steatohepatitis (NASH). CCK receptors are expressed on stellate cells and are responsible for hepatic fibrosis when activated. The purpose of this study was to test the safety and dose of a CCK receptor antagonist, proglumide, in human participants with NASH. An open\u2010label single ascending dose study was conducted in 18 participants with clinical NASH based upon steatosis by liver ultrasound, elevated hepatic transaminases, and a component of the metabolic syndrome. Three separate cohorts (<jats:italic>N<\/jats:italic>\u00a0=\u20096 each) were treated with oral proglumide for 12\u2009weeks in a sequential ascending fashion with 800 (Cohort 1), 1,200 (Cohort 2), and 1,600 (Cohort 3) mg\/day, respectively. Blood hematology, chemistries, proglumide levels, a biomarker panel for fibrosis, and symptom surveys were determined at baseline and every 4\u2009weeks. Abdominal ultrasounds and transient elastography utilizing FibroScan were obtained at baseline and at Week 12. Proglumide was well tolerated at all doses without any serious adverse events. There was no change in body weight from baseline to Week 12. For Cohorts 1, 2, and 3, the median percent change in alanine aminotransferase was 8.42, \u22125.05, and \u221222.23 and median percent change in fibrosis score by FibroScan was 8.13, \u22125.44, and \u221228.87 (kPa), respectively. Hepatic steatosis as measured by controlled attenuation parameter score significantly decreased with proglumide, (<jats:italic>P<\/jats:italic>\u00a0&lt;\u20090.05). Blood microRNA biomarkers and serum 4\u2010hydroxyproline were consistent with decreased fibrosis at Week 12 compared with baseline. These findings suggest proglumide exhibits anti\u2010inflammatory and anti\u2010fibrotic properties and this compound is well tolerated in participants with NASH.<\/jats:p>","DOI":"10.1002\/cpt.2745","type":"journal-article","created":{"date-parts":[[2022,9,10]],"date-time":"2022-09-10T15:09:25Z","timestamp":1662822565000},"page":"1271-1279","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Safety and Dosing Study of a Cholecystokinin Receptor Antagonist in Non\u2010alcoholic Steatohepatitis"],"prefix":"10.1111","volume":"112","author":[{"given":"Atoosa","family":"Rabiee","sequence":"first","affiliation":[{"name":"Department of Medicine Washington DC Veterans Affairs Medical Center  Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martha D.","family":"Gay","sequence":"additional","affiliation":[{"name":"Department of Medicine Georgetown University Medical Center  Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Narayan","family":"Shivapurkar","sequence":"additional","affiliation":[{"name":"Department of Medicine Georgetown University Medical Center  Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Medicine Georgetown University Medical Center  Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandeep","family":"Nadella","sequence":"additional","affiliation":[{"name":"Departments of Gastroenterology and Transplant Surgery MedStar Georgetown University Hospital  Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Coleman I.","family":"Smith","sequence":"additional","affiliation":[{"name":"Departments of Gastroenterology and Transplant Surgery MedStar Georgetown University Hospital  Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James H.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Departments of Gastroenterology and Transplant Surgery MedStar Georgetown University Hospital  Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6066-7841","authenticated-orcid":false,"given":"Sunil","family":"Bansal","sequence":"additional","affiliation":[{"name":"Department of Medicine Georgetown University Medical Center  Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amrita","family":"Cheema","sequence":"additional","affiliation":[{"name":"Department of Medicine Georgetown University Medical Center  Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Kwagyan","sequence":"additional","affiliation":[{"name":"Department of Statistics Howard University  Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0835-4802","authenticated-orcid":false,"given":"Jill P.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Medicine Washington DC Veterans Affairs Medical Center  Washington DC USA"},{"name":"Department of Medicine Georgetown University Medical Center  Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,9,27]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30251"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2017.3055"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29466"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12876-015-0382-3"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0035-1550065"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2019.11.311"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI24282"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2021.154822"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2015.04.005"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/82.1.222S"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.7602"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2028395"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0907929"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19072069"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)33041-7"},{"key":"e_1_2_10_16_1","first-page":"1","article-title":"Non\u2010alcoholic fatty liver: current management and future trends","volume":"3","author":"Sourianarayanane A.","year":"2020","journal-title":"Gut. Gastroenterol."},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1097\/MED.0b013e32834eb77d"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c120019"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.125534"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-019-05722-3"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02088134"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10993"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.14317"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2020.172927"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2017.11.010"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0020687"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840220144"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics14030627"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1596"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1158\/1940-6207.CAPR-20-0220"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2018.00402"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-33596-4"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-94-007-7675-3_26"},{"key":"e_1_2_10_34_1","first-page":"314","article-title":"Efficient treatment of gastric ulcer with proglumide (Milid) in outpatients (double blind trial)","volume":"26","author":"Miederer S.E.","year":"1979","journal-title":"Acta Hepatogastroenterol. (Stuttg)"},{"key":"e_1_2_10_35_1","first-page":"639","article-title":"Pharmacokinetic approach to proglumide long\u2010term activity","volume":"29","author":"Bignamini A.A.","year":"1979","journal-title":"Arzneimittelforschung"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1097\/00006676-199209000-00003"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.1978.235.6.E714"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.2174\/156802607780960519"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-019-05863-5"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13194949"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20030312"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23031899"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.5152\/dir.2018.17525"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.07.014"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2015.2468"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.2745","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.2745","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.2745","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T13:37:28Z","timestamp":1699364248000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.2745"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,27]]},"references-count":45,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["10.1002\/cpt.2745"],"URL":"https:\/\/doi.org\/10.1002\/cpt.2745","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,27]]},"assertion":[{"value":"2022-05-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-09-06","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-09-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}