{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T12:18:14Z","timestamp":1789561094079,"version":"build-2803163510"},"reference-count":20,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T00:00:00Z","timestamp":1646265600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014468","name":"Mallinckrodt Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014468","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hepatic encephalopathy (HE) is a serious neurocognitive complication of liver dysfunction, often associated with elevated plasma ammonia. Ornithine phenylacetate (OP), a potent ammonia scavenger, is being evaluated for the treatment of acute\/overt HE. The pharmacokinetics and pharmacodynamics of OP in patients with HE were characterized in this phase IIb study (NCT01966419). Adult patients hospitalized with an overt HE episode, cirrhosis, and plasma ammonia above the upper limit of normal (ULN) who failed to improve after 48\u00a0hours\u2019 standard care were randomly assigned to continuous intravenous OP (10, 15, or 20\u00a0g\/day, based on Child\u2013Turcotte\u2013Pugh score) or matching placebo for 5\u00a0days. Plasma levels of ornithine and phenylacetic acid (PAA) and plasma\/urinary levels of phenylacetylglutamine (PAGN) (primary metabolite of PAA) were regularly assessed; plasma ammonia level was the primary pharmacodynamic variable. PAA demonstrated dose\u2010dependent pharmacokinetics; ornithine and PAGN levels increased with dose. PAGN urinary excretion represented ~50%\u201360% of administered PAA across all doses. Mean reduction in plasma ammonia with OP at 3\u00a0hours postinfusion was significantly greater versus placebo (<jats:italic>p\u00a0<\/jats:italic>=\u00a00.014); and time to achieve plasma ammonia less than or equal to the ULN was significantly reduced (<jats:italic>p\u00a0<\/jats:italic>=\u00a00.028). Achievement of clinical response based on HE stage was associated with a greater reduction in mean plasma ammonia level (<jats:italic>p\u00a0<\/jats:italic>=\u00a00.009). OP effects on plasma ammonia were consistent with its proposed mechanism of action as a primary ammonia scavenger, with a significant association between reduced plasma ammonia and improvement in HE stage. OP should be further evaluated as a promising treatment for hyperammonemia in patients with overt HE.<\/jats:p>","DOI":"10.1111\/cts.13257","type":"journal-article","created":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T10:47:09Z","timestamp":1646304429000},"page":"1449-1459","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Pharmacokinetics\/pharmacodynamics of L\u2010ornithine phenylacetate in overt hepatic encephalopathy and the effect of plasma ammonia concentration reduction on clinical outcomes"],"prefix":"10.1111","volume":"15","author":[{"given":"Rifaat","family":"Safadi","sequence":"first","affiliation":[{"name":"Director of The Liver Institute Hadassah Medical Organization Hadassah Hebrew University Medical Center, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert S.","family":"Rahimi","sequence":"additional","affiliation":[{"name":"Baylor Scott and White Hospital Baylor University Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Thabut","sequence":"additional","affiliation":[{"name":"Brain Liver Piti\u00e9\u2010Salp\u00eatri\u00e8re (B\u2010LIPS) Study Group Paris Sorbonne Universit\u00e9, Assistance Publique\u2013H\u00f4pitaux de Paris  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmohan S.","family":"Bajaj","sequence":"additional","affiliation":[{"name":"Department of Medicine Virginia Commonwealth University and McGuire VA Medical Center  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalyan","family":"Ram Bhamidimarri","sequence":"additional","affiliation":[{"name":"Miller School of Medicine University of Miami  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos","family":"Pyrsopoulos","sequence":"additional","affiliation":[{"name":"Rutgers New Jersey Medical School and University Hospital  Newark New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Potthoff","sequence":"additional","affiliation":[{"name":"Ocera Therapeutics, Inc.  Redwood City California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stan","family":"Bukofzer","sequence":"additional","affiliation":[{"name":"Ocera Therapeutics, Inc.  Redwood City California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurene","family":"Wang","sequence":"additional","affiliation":[{"name":"INDAPharma, LLC  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khurram","family":"Jamil","sequence":"additional","affiliation":[{"name":"Mallinckrodt Pharmaceuticals  Hampton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna R.","family":"Devarakonda","sequence":"additional","affiliation":[{"name":"Mallinckrodt Pharmaceuticals  Webster Groves Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,3,3]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27210"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.14218\/jcth.2016.00069"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.5009\/gnl15419"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1357\u20102725(02)00396\u20105"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.12788\/jhm.2794"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/cld.468"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2006.12.061"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD012410.pub2"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2010.07.024"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011\u2010016\u20109858\u20102"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011\u2010016\u20109908\u20109"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2013.10.012"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41395\u2010018\u20100179\u20104"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2012.10.015"},{"issue":"7","key":"e_1_2_10_16_1","first-page":"1690","article-title":"A phase I and pharmacokinetic study of intravenous phenylacetate in patients with cancer","volume":"54","author":"Thibault A","year":"1994","journal-title":"Cancer Res"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(12)60620-5"},{"issue":"1","key":"e_1_2_10_18_1","first-page":"275A","article-title":"An open\u2010label crossover study of the pharmacokinetics of ornithine phenylacetate (OCR\u2010002) after IV and oral doses in subjects with cirrhosi [Abstract 501]","volume":"66","author":"Hassanein TI","year":"2017","journal-title":"Hepatology"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1097\/MCG.0b013e318299c789"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2020.10.019"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22917"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.13257","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cts.13257","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.13257","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T19:25:40Z","timestamp":1692818740000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.13257"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,3]]},"references-count":20,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022,6]]}},"alternative-id":["10.1111\/cts.13257"],"URL":"https:\/\/doi.org\/10.1111\/cts.13257","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,3]]},"assertion":[{"value":"2021-10-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-02-08","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-03-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}