{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:44:54Z","timestamp":1747183494404,"version":"3.40.5"},"reference-count":28,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T00:00:00Z","timestamp":1608681600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100014369","name":"Organon BioSciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014369","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:sec><jats:title>Aim<\/jats:title><jats:p>To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of the highly selective oral p38alpha\/beta mitogen\u2010activated protein (MAP) kinase inhibitor Org 48,775\u20100 in a first\u2010in\u2010human study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In the single ascending dosing (SAD) study, an oral dose of Org 48,775\u20100 (0.3\u2010600 mg) was evaluated in healthy males. In the multiple ascending dosing (MAD) study, levels of 30, 70 and 150 mg were dosed for six consecutive days, twice daily. Both studies were performed in a double\u2010blind, randomized, placebo\u2010controlled, cross\u2010over fashion and evaluated pharmacokinetics, pharmacodynamics (ex vivo inhibition of lipopolysaccharide [LPS]\u2010induced tumor necrosis factor (TNF\u03b1) release) and routine clinical and laboratory data. Pharmacokinetic and pharmacodynamic parameters of Org 48,775\u20100 were compared between healthy males and postmenopausal females, and the effect of a standardized fat meal was evaluated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>All adverse events observed in the SAD (16; dizziness and headache, diarrhoea and catheter\u2010related phlebitis) and MAD (43; mainly somnolence, dizziness, headache and nasopharyngitis) cohorts were mild, transient and completely reversible. Pharmacokinetics were linear up to single doses of 400 mg. Median <jats:italic>T<\/jats:italic><jats:sub>max<\/jats:sub> ranged from 0.5 to 1.8 hours, geometric mean for <jats:italic>T<\/jats:italic><jats:sub>1\/2<\/jats:sub> from 7.0 to 14.4 hours. Org 48,775\u20100 doses equal to and greater than 30 mg significantly inhibited LPS\u2010induced TNF\u03b1 release (42.3%; 95% CI = \u221265.2, \u22124.3) compared to placebo. In the MAD study, Org 48,775\u20100 treatment inhibited LPS\u2010induced TNF\u03b1 release during the entire steady\u2010state period. Levels of inhibition amounted 30\u201075% for 30 mg, 53\u201080% for 70 mg and 77\u201092% for 150 mg Org 48,775\u20100.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Org 48,775\u20100 has the capacity to significantly inhibit MAP kinase activity in humans without safety concerns.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.14655","type":"journal-article","created":{"date-parts":[[2020,11,17]],"date-time":"2020-11-17T17:22:31Z","timestamp":1605633751000},"page":"2321-2332","source":"Crossref","is-referenced-by-count":0,"title":["Proof of pharmacology of Org 48775\u20100, a p38 MAP kinase inhibitor, in healthy volunteers"],"prefix":"10.1111","volume":"87","author":[{"given":"Matthijs","family":"Moerland","sequence":"first","affiliation":[{"name":"Centre for Human Drug Research  Leiden the Netherlands"},{"name":"Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea J.","family":"Kales","sequence":"additional","affiliation":[{"name":"Former affiliation Centre for Human Drug Research  Leiden the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7216-3162","authenticated-orcid":false,"given":"Karen","family":"Broekhuizen","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulla","family":"N\u00e4ssander","sequence":"additional","affiliation":[{"name":"Former affiliation Organon\/Schering Plough  Oss the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rob","family":"Nelissen","sequence":"additional","affiliation":[{"name":"Former affiliation Organon\/Schering Plough  Oss the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marieke L.","family":"de Kam","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierre A.M.","family":"Peeters","sequence":"additional","affiliation":[{"name":"Former affiliation Organon\/Schering Plough  Oss the Netherlands"},{"name":"Present affiliation Curare Consulting, Etten\u2010Leur  the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacobus","family":"Burggraaf","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden the Netherlands"},{"name":"Leiden University Medical Center  Leiden The Netherlands"},{"name":"Leiden Academic Centre for Drug Research  Leiden the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,12,23]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.52.1.144"},{"issue":"4","key":"e_1_2_10_3_1","first-page":"421","article-title":"Tamayo N. p38 MAP kinase inhibitors: many are made, but few are chosen","volume":"8","author":"Dominguez C","year":"2005","journal-title":"Curr Opin Drug Discov Devel"},{"key":"e_1_2_10_4_1","first-page":"253","article-title":"MAPK signalling pathways as molecular targets for anti\u2010inflammatory therapy\u2014from molecular mechanisms to therapeutic benefits. 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