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Healthy male subjects received either single (10\u20131000\u00a0mg) or multiple doses (30\u2013600\u00a0mg) administered once daily for 14\u00a0days of<jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010178882, placebo, or 20\u00a0mg enalapril in the fasted state. Following a 2\u2010week washout, the single dose of 30\u00a0mg<jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010178882 was also administered in the fed state. In the multiple\u2010ascending\u2010dose part, subjects were dosed with midazolam on days \u22122, 2, and 12 to investigate interactions with<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>3A4. Dizziness and headache were the most frequently reported adverse events. No clinically relevant changes occurred for body weight, vital signs, clinical laboratory variables, and<jats:styled-content style=\"fixed-case\">ECG<\/jats:styled-content>although both enalapril and<jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010178882 tended to decrease systolic blood pressure. Following single doses of<jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010178882,<jats:italic>t<\/jats:italic><jats:sub>1\/2<\/jats:sub>and<jats:italic>t<\/jats:italic><jats:sub>max<\/jats:sub>varied from 18.7 to 24.7\u00a0h and from 3 to 5\u00a0h, respectively, and food had no significant effect. Steady\u2010state conditions were achieved after 4\u20136\u00a0days of dosing and accumulation was minimal.<jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010178882 pharmacokinetics were dose proportional.<jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010178882 but not enalapril dose\u2010dependently increased<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>and area under the concentration\u2010time curve of midazolam. Single and multiple doses of<jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010178882 dose\u2010dependently increased active renin and decreased plasma renin activity, whereas enalapril increased both variables. No effects on urinary excretion of creatinine, potassium, and the 6\u03b2\u2010hydroxycortisol\/cortisol ratio were observed, whereas sodium and aldosterone excretion was decreased by both<jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010178882 and enalapril. The current results with<jats:styled-content style=\"fixed-case\">ACT<\/jats:styled-content>\u2010178882 warrant further clinical investigation of this renin inhibitor in hypertensive patients.<\/jats:p>","DOI":"10.1111\/j.1472-8206.2012.01060.x","type":"journal-article","created":{"date-parts":[[2012,6,26]],"date-time":"2012-06-26T14:52:46Z","timestamp":1340722366000},"page":"698-710","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Clinical pharmacology of single\u2010 and multiple\u2010ascending doses of<scp>ACT<\/scp>\u2010178882, a new direct renin inhibitor, and its pharmacokinetic interaction with food and midazolam"],"prefix":"10.1111","volume":"27","author":[{"given":"Jasper","family":"Dingemanse","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurent","family":"Nicolas","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"Binkert","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery Biology Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2012,7,31]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)17741-1"},{"key":"e_1_2_8_3_1","doi-asserted-by":"crossref","first-page":"531","DOI":"10.4103\/IJMR.2010_132_05_531","article-title":"Strategies for initial management of hypertension","volume":"132","author":"Gupta R.","year":"2010","journal-title":"Indian J. 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