{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T16:38:56Z","timestamp":1758127136864,"version":"3.44.0"},"reference-count":16,"publisher":"BMJ","issue":"1","funder":[{"name":"Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open Ophth"],"accepted":{"date-parts":[[2017,4,8]]},"published-print":{"date-parts":[[2017,6]]},"abstract":"<jats:sec>\n                  <jats:title>Background\/aims<\/jats:title>\n                  <jats:p>Cortisol is involved in the regulation of intraocular pressure (IOP). This study aimed to assess the effect of 11\u03b2-hydroxysteroid-dehydrogenase type 1 (11\u03b2HSD1) inhibition by oral administration of RO5093151 on IOP.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>The exposure of key ocular compartments following oral administration was assessed in rabbits. An adaptive, randomised, placebo-controlled study gated by a Bayesian decision criterion was performed in 35 patients with primary open angle glaucoma (POAG) or ocular hypertension (OHT). Following a 7-day placebo-controlled run-in period, 200\u2009mg twice daily RO5093151 or placebo (4:1) were administered for 7 days. The extent of 11\u03b2HSD1 inhibition was assessed by the ratio of urinary tetrahydrocortisol (5\u03b1 and 5\u03b2)\/tetrahydrocortisone (THF\/THE). Time-matched IOP assessments were performed.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>A high distribution of RO5093151 into the rabbit eye was observed. In humans, a high and sustained inhibition of 11\u03b2HSD1 was shown by the decrease of THF\/THE from 0.9 at baseline to 0.18 on day 7. There was no statistically significant difference in change of IOP from baseline. In the \u2018worse eye\u2019, the adjusted least square mean change from baseline was \u22122.7\u2009mm Hg (95%\u2009CI \u22124.2 to \u20131.2) and \u22122.9(95% CI \u22125.9 to 0.1) in the RO5093151 and placebo group, respectively.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Despite high inhibition of 11\u03b2HSD1 and expected moderate to high tissue distribution in ocular tissues, a 7-day treatment with a high oral dose of RO5093151 did not result in a clinically meaningful effect on IOP in patients with POAG or OHT.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/bmjophth-2016-000063","type":"journal-article","created":{"date-parts":[[2017,6,29]],"date-time":"2017-06-29T20:20:25Z","timestamp":1498767625000},"page":"e000063","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["Oral administration of the 11\u03b2-hydroxysteroid-dehydrogenase type 1 inhibitor RO5093151 to patients with glaucoma: an adaptive, randomised, placebo-controlled clinical study"],"prefix":"10.1136","volume":"1","clinical-trial-number":[{"clinical-trial-number":"nct01493271","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Dietmar","family":"Schwab","sequence":"first","affiliation":[{"name":"Roche Innovation Center Basel, Clinical Pharmacology, Roche Pharmaceutical Research and Early Development, Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolina","family":"Sturm","sequence":"additional","affiliation":[{"name":"Roche Innovation Center Basel, Clinical Pharmacology, Roche Pharmaceutical Research and Early Development, Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agn\u00e8s","family":"Portron","sequence":"additional","affiliation":[{"name":"Roche Innovation Center Basel, Clinical Pharmacology, Roche Pharmaceutical Research and Early Development, Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabine","family":"Fuerst-Recktenwald","sequence":"additional","affiliation":[{"name":"Roche Innivation Center Basel, Translational Medicine, Cardiovascular and Metabolism, Roche Pharmaceutical Research and Early Development, Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominik","family":"Hainzl","sequence":"additional","affiliation":[{"name":"Roche Innovation Center Basel, Pharmaceutical Sciences, Roche Pharmaceutical Research and Early Development, Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Jordan","sequence":"additional","affiliation":[{"name":"Department of Biometrics, Product Development, Roche Pharmaceutical Research and Early Development, Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William C","family":"Stewart","sequence":"additional","affiliation":[{"name":"PRN Pharmaceutical Research Network, LLC, Cheyenne, Wyoming, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael E","family":"Tepedino","sequence":"additional","affiliation":[{"name":"Cornerstone Eye Care, Division of Health Care, High Point, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harvey","family":"DuBiner","sequence":"additional","affiliation":[{"name":"Eye Care Centers Management, Inc., Clayton Eye Center, Morrow, Georgia, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2017,6,29]]},"reference":[{"key":"2025090110072695000_1.1.e000063.1","doi-asserted-by":"publisher","DOI":"10.1136\/bjo.2005.081224"},{"key":"2025090110072695000_1.1.e000063.2","doi-asserted-by":"publisher","DOI":"10.1517\/14728214.2011.521631"},{"key":"2025090110072695000_1.1.e000063.3","unstructured":"EUGS. Terminology and guidelines for Glaucoma. 3rd ed, 2008. www.eugs.org."},{"key":"2025090110072695000_1.1.e000063.4","doi-asserted-by":"publisher","DOI":"10.1136\/bjo.76.5.280"},{"key":"2025090110072695000_1.1.e000063.5","doi-asserted-by":"publisher","DOI":"10.1016\/S1043-2760(03)00134-6"},{"key":"2025090110072695000_1.1.e000063.6","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.02-0514"},{"key":"2025090110072695000_1.1.e000063.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-4835(03)00088-5"},{"key":"2025090110072695000_1.1.e000063.8","doi-asserted-by":"publisher","DOI":"10.1093\/qjmed\/hcg085"},{"key":"2025090110072695000_1.1.e000063.9","first-page":"2037","article-title":"Expression and putative role of 11 beta-hydroxysteroid dehydrogenase isozymes within the human eye","volume":"42","author":"Rauz","year":"2001","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2025090110072695000_1.1.e000063.10","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M112.019745"},{"key":"2025090110072695000_1.1.e000063.11","doi-asserted-by":"publisher","DOI":"10.1210\/er.2012-1050"},{"key":"2025090110072695000_1.1.e000063.12","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1111\/dom.12317","article-title":"Safety, efficacy and weight effect of two 11\u03b2-HSD1 inhibitors in metformin-treated patients with type 2 diabetes","volume":"16","author":"Heise","year":"2014","journal-title":"Diabetes Obes Metab"},{"key":"2025090110072695000_1.1.e000063.13","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/S2213-8587(13)70170-0","article-title":"Inhibition of 11\u03b2-HSD1 with RO5093151 for non-alcoholic fatty liver disease: a multicentre, randomised, double-blind, placebo-controlled trial","volume":"2","author":"Stefan","year":"2014","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2025090110072695000_1.1.e000063.14","doi-asserted-by":"publisher","DOI":"10.1001\/archopht.1987.01060060063034"},{"key":"2025090110072695000_1.1.e000063.15","doi-asserted-by":"crossref","first-page":"5951","DOI":"10.1021\/jm300592r","article-title":"Discovery of a potent, selective, and orally bioavailable acidic 11\u03b2-hydroxysteroid dehydrogenase type 1 (11\u03b2-HSD1) inhibitor: discovery of 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acetic acid (AZD4017)","volume":"55","author":"Scott","year":"2012","journal-title":"J Med Chem"},{"key":"2025090110072695000_1.1.e000063.16","unstructured":"A phase IIa study to assess the tolerability, safety, and efficacy of AZD4017 for raised Intra-ocular pressure. NCT01173471 at ClinicalTrials.gov 2013."}],"container-title":["BMJ Open Ophthalmology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjophth-2016-000063","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T17:07:35Z","timestamp":1756746455000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjophth.bmj.com\/lookup\/doi\/10.1136\/bmjophth-2016-000063"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6]]},"references-count":16,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,6,29]]},"published-print":{"date-parts":[[2017,6]]}},"alternative-id":["10.1136\/bmjophth-2016-000063"],"URL":"https:\/\/doi.org\/10.1136\/bmjophth-2016-000063","relation":{},"ISSN":["2397-3269"],"issn-type":[{"type":"electronic","value":"2397-3269"}],"subject":[],"published":{"date-parts":[[2017,6]]}}}