{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T20:54:35Z","timestamp":1791665675879,"version":"4.3.4"},"reference-count":41,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2016,1,17]],"date-time":"2016-01-17T00:00:00Z","timestamp":1452988800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2016,5]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Endothelial\u2010derived epoxyeicosatrienoic acids may regulate vascular tone and are metabolized by soluble epoxide hydrolase enzymes (sEH). GSK2256294 is a potent and selective sEH inhibitor that was tested in two phase I studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Single escalating doses of GSK2256294 2\u201320\u00a0mg or placebo were administered in a randomized crossover design to healthy male subjects or obese smokers. Once daily doses of 6 or 18\u00a0mg or placebo were administered for 14\u00a0days to obese smokers. Data were collected on safety, pharmacokinetics, sEH enzyme inhibition and blood biomarkers. Single doses of GSK2256294 10\u00a0mg were also administered to healthy younger males or healthy elderly males and females with and without food. Data on safety, pharmacokinetics and biliary metabolites were collected.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>GSK2256294 was well\u2010tolerated with no serious adverse events (AEs) attributable to the drug. The most frequent AEs were headache and contact dermatitis. Plasma concentrations of GSK2256294 increased with single doses, with a half\u2010life averaging 25\u201343\u00a0h. There was no significant effect of age, food or gender on pharmacokinetic parameters. Inhibition of sEH enzyme activity was dose\u2010dependent, from an average of 41.9% on 2\u00a0mg (95% confidence interval [CI] \u201351.8, 77.7) to 99.8% on 20\u00a0mg (95% CI 99.3, 100.0) and sustained for up to 24\u00a0h. There were no significant changes in serum VEGF or plasma fibrinogen.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>GSK2256294 was well\u2010tolerated and demonstrated sustained inhibition of sEH enzyme activity. These data support further investigation in patients with endothelial dysfunction or abnormal tissue repair, such as diabetes, wound healing or COPD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.12855","type":"journal-article","created":{"date-parts":[[2015,12,1]],"date-time":"2015-12-01T09:56:48Z","timestamp":1448963808000},"page":"971-979","source":"Crossref","is-referenced-by-count":167,"title":["Pharmacokinetics, pharmacodynamics and adverse event profile of GSK2256294, a novel soluble epoxide hydrolase inhibitor"],"prefix":"10.1111","volume":"81","author":[{"given":"Aili L.","family":"Lazaar","sequence":"first","affiliation":[{"name":"GSK R&amp;D  King of Prussia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Yang","sequence":"additional","affiliation":[{"name":"Experimental Medicine &amp; Immunotherapeutics, Department of Medicine University of Cambridge, and Cambridge Clinical Trials Unit  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