{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T07:16:09Z","timestamp":1694675769369},"reference-count":6,"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 1R,2S stereoisomer of methoxamine hydrochloride, <jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001, is a highly selective \u03b11\u2010adrenoceptor agonist being developed for the local treatment of non\u2010structural faecal incontinence caused by weak internal anal sphincter tone. This study investigated the steady state pharmacokinetics (<jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content>) and safety of 2\u00a0g rectal suppositories containing <jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001 in different strengths (7.5, 10, 12.5 or 15\u00a0mg).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Healthy volunteers aged 18\u201345\u00a0years received 14 daily doses of <jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001 2\u00a0g suppositories or matching placebo. In each dose group nine participants received <jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001 and three received placebo. Blood samples to determine <jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001 concentrations were taken on Days 1, 7 and 14. Cardiovascular parameters were collected via electrocardiograms, Holter monitoring (three lead Holter monitor) and vital signs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Forty\u2010eight volunteers were enrolled; 43 completed the study and were included in the <jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content> analysis population. <jats:styled-content style=\"fixed-case\">AUC<\/jats:styled-content> and <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> broadly increased with increasing dose, <jats:italic>T<\/jats:italic><jats:sub>max<\/jats:sub> generally occurred between 4.0 and 5.0\u00a0h. Although the data did not appear strongly dose proportional, dose proportionality analysis did not provide evidence against dose proportionality as the log(dose) coefficients were not significantly &lt;\u00a01. <jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001 did not accumulate over time for any dose. Increasing <jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001 concentrations were related to changes in vital sign variables, most notably decreased heart rate. The most commonly reported adverse events (<jats:styled-content style=\"fixed-case\">AE<\/jats:styled-content>s) in the active treatment groups were paraesthesia and piloerection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Treatment with <jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001 was generally well tolerated over 14\u00a0days once daily dosing and plasma <jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001 did not accumulate over time. Treatment was associated with changes in vital sign variables, most notably decreased heart rate. <jats:styled-content style=\"fixed-case\">AE<\/jats:styled-content>s commonly reported with <jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001 treatment were events indicative of a systemic \u03b1\u2010adrenergic effect.<\/jats:p><\/jats:sec>","DOI":"10.1111\/codi.12544","type":"journal-article","created":{"date-parts":[[2014,2,6]],"date-time":"2014-02-06T02:21:30Z","timestamp":1391653290000},"page":"36-50","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A double\u2010blind, placebo\u2010controlled, randomised, parallel\u2010group, dose\u2010escalating, repeat dose study in healthy volunteers to evaluate the safety, tolerability, pharmacodynamic effects and pharmacokinetics of the once daily rectal application of <scp>NRL<\/scp>001 suppositories for 14\u00a0days"],"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":"A.","family":"Duffin","sequence":"additional","affiliation":[{"name":"Bio\u2010Kinetic Europe Limited Belfast UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Jacobs","sequence":"additional","affiliation":[{"name":"Dianthus Medical Limited London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C.","family":"Pediconi","sequence":"additional","affiliation":[{"name":"Norgine Limited Uxbridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H. J.","family":"Gruss","sequence":"additional","affiliation":[{"name":"Medical &amp; Safety Services ICON Clinical Research Eastleigh UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,2,5]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.48.3.356"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2168.2000.01306.x"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/bjs.4120"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/bjs.5171"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/codi.12541"},{"key":"e_1_2_10_7_1","unstructured":"International Conference on Harmonization (ICH)Guidance for Industry: E14 Clinical Evaluation of QT\/QTCInterval Prolongation and Proarrhythmic Potential for Non\u2010Antiarrhythmic Drugs. Available athttp:\/\/www.fda.gov\/downloads\/Drugs\/GuidanceComplianceRegulatoryInformation\/Guidances\/ucm073161.pdf(accessed 30 July 2012)."}],"container-title":["Colorectal Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcodi.12544","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/codi.12544","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,13]],"date-time":"2023-09-13T05:15:34Z","timestamp":1694582134000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/codi.12544"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,2,5]]},"references-count":6,"journal-issue":{"issue":"s1","published-print":{"date-parts":[[2014,3]]}},"alternative-id":["10.1111\/codi.12544"],"URL":"https:\/\/doi.org\/10.1111\/codi.12544","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"}}]}}