{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T06:43:59Z","timestamp":1694673839744},"reference-count":10,"publisher":"Wiley","issue":"s1","license":[{"start":{"date-parts":[[2014,2,5]],"date-time":"2014-02-05T00:00:00Z","timestamp":1391558400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Colorectal Disease"],"published-print":{"date-parts":[[2014,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aims<\/jats:title><jats:p>The application of \u03b1\u2010adrenoceptor agonists can improve faecal incontinence symptoms. The aim of this study was to investigate the pharmacokinetic and systemic effects of <jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001 administered as different strengths in 1 or 2\u00a0g suppositories.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This randomised, double\u2010blind, placebo controlled study included 48 healthy subjects. Group 1 consisted of two cohorts of 12 subjects administered either four single doses of 1 or 2\u00a0g rectal suppository with either 5, 7.5 or 10\u00a0mg <jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001, or matching placebo. Group 2 consisted of two cohorts of 12 subjects administered either four single doses of 1 or 2\u00a0g rectal suppository with either 10, 12.5 or 15\u00a0mg <jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001, or matching placebo. Doses were given in an escalating manner with placebo at a random position within the sequence.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>T<\/jats:italic><jats:sub>max<\/jats:sub> was at ~4.5\u00a0h post\u2010dose for all <jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001 doses. Median <jats:styled-content style=\"fixed-case\">AUC<\/jats:styled-content><jats:sub>0\u2013tz<\/jats:sub>, <jats:styled-content style=\"fixed-case\">AUC<\/jats:styled-content><jats:sub>0\u2013\u221e<\/jats:sub> and <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> increased with increasing dose for both suppository sizes. The estimate of ratios of geometric means comparing 2\u00a0g with 1\u00a0g suppository, and regression analysis for dose proportionality, was close to 1 for the variables <jats:styled-content style=\"fixed-case\">AUC<\/jats:styled-content><jats:sub>0\u2013tz<\/jats:sub>, <jats:styled-content style=\"fixed-case\">AUC<\/jats:styled-content><jats:sub>0\u2013\u221e<\/jats:sub> and <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> (<jats:italic>P<\/jats:italic>\u00a0&gt;\u00a00.05). For both suppository sizes, 20\u2010min mean pulse rate was significantly decreased compared with placebo with all doses (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Blood pressure decreased overall. There were 144 adverse events (<jats:styled-content style=\"fixed-case\">AE<\/jats:styled-content>s) and no <jats:styled-content style=\"fixed-case\">serious AE<\/jats:styled-content>s reported during the study. All <jats:styled-content style=\"fixed-case\">AE<\/jats:styled-content>s were mild in severity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The regression analysis concluded that the doses were dose proportional.<\/jats:p><\/jats:sec>","DOI":"10.1111\/codi.12542","type":"journal-article","created":{"date-parts":[[2014,2,6]],"date-time":"2014-02-06T02:21:30Z","timestamp":1391653290000},"page":"16-26","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Randomised clinical trial: study of escalating doses of <scp>NRL<\/scp>001 given in rectal suppositories of different weights"],"prefix":"10.1111","volume":"16","author":[{"given":"D.","family":"Bell","sequence":"first","affiliation":[{"name":"Bio\u2010Kinetic Europe Limited Belfast UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C.","family":"Pediconi","sequence":"additional","affiliation":[{"name":"Norgine Limited Uxbridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Jacobs","sequence":"additional","affiliation":[{"name":"Dianthus Medical Limited London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,2,5]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"Rome III Diagnostic Criteria for Functional Gastrointestinal Disorders.http:\/\/www.romecriteria.org\/assets\/pdf\/19_RomeIII_apA_885-898.pdf(accessed 25 September 2013)."},{"key":"e_1_2_10_3_1","unstructured":"National Institute for Health and Clinical Excellence.Faecal Incontinence: The Management of Faecal Incontinence in Adults. NICE Clinical Guideline 49 (2007).www.nice.org.uk\/CG049(accessed 25 September 2013)."},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/codi.12540"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.10.8.674"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2982.2005.00659.x"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.48.3.356"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/bjs.4120"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/bjs.5171"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/codi.12541"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/codi.12545"}],"container-title":["Colorectal Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcodi.12542","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/codi.12542","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,13]],"date-time":"2023-09-13T05:15:30Z","timestamp":1694582130000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/codi.12542"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,2,5]]},"references-count":10,"journal-issue":{"issue":"s1","published-print":{"date-parts":[[2014,3]]}},"alternative-id":["10.1111\/codi.12542"],"URL":"https:\/\/doi.org\/10.1111\/codi.12542","archive":["Portico"],"relation":{},"ISSN":["1462-8910","1463-1318"],"issn-type":[{"value":"1462-8910","type":"print"},{"value":"1463-1318","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,2,5]]},"assertion":[{"value":"2013-10-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-12-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-02-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}