{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T07:16:07Z","timestamp":1694675767807},"reference-count":13,"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><jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001 is a highly specific \u03b1<jats:sub>1<\/jats:sub>\u2013adrenoceptor agonist currently under evaluation for the treatment of faecal incontinence caused by a weak internal anal sphincter. The aim of this meta\u2010analysis was to quantify the effect of <jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001 on cardiovascular parameters including heart rate, blood pressure and <jats:styled-content style=\"fixed-case\">QT<\/jats:styled-content> interval.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Data from the four Phase I healthy volunteer studies <jats:styled-content style=\"fixed-case\">SUM<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">NCT<\/jats:styled-content>00857467), <jats:styled-content style=\"fixed-case\">SURD<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">NCT<\/jats:styled-content>01099670), <jats:styled-content style=\"fixed-case\">SUSD<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">NCT<\/jats:styled-content>00850590) and <jats:styled-content style=\"fixed-case\">SAGE<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">NCT<\/jats:styled-content>01099683) were pooled and analyses were performed on individual subject data. Mixed effects regression analysis was used to determine the effect of <jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001 on heart rate, blood pressure and <jats:styled-content style=\"fixed-case\">QT<\/jats:styled-content> intervals. A multivariate statistical model was used to determine the effect of covariates on heart rate.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Subjects given <jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001 experienced a dose related decrease in heart rate of up to 9.48\u00a0bpm compared with subjects in the placebo arms. No statistically significant evidence for a threshold effect was found. There was no clear evidence of dose effect of <jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001 on blood pressure. <jats:styled-content style=\"fixed-case\">QT<\/jats:styled-content> interval increased in all <jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001 subject as expected; <jats:styled-content style=\"fixed-case\">QT<jats:sub>C<\/jats:sub>F<\/jats:styled-content> also showed a statistically significant increase. However, <jats:styled-content style=\"fixed-case\">QT<jats:sub>C<\/jats:sub>B<\/jats:styled-content> was shortened with no significant treatment effect.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001 was found to have a dose\u2010dependent effect on heart rate; however clinically\u2013relevant bradycardia was not reported, indicating the decrease in heart rate was not of clinical significance. Furthermore, no clinically\u2010significant drug effect on blood pressure or mean arterial pressure was observed. <jats:styled-content style=\"fixed-case\">QT<\/jats:styled-content> intervals were affected by changes in heart rate. However, trends were dependant on the correction factor used. No consistent <jats:styled-content style=\"fixed-case\">QT<\/jats:styled-content> effect was observed, but a thorough <jats:styled-content style=\"fixed-case\">QT<jats:sub>C<\/jats:sub><\/jats:styled-content> study will be required to confirm the effects of rectally applied <jats:styled-content style=\"fixed-case\">NRL<\/jats:styled-content>001.<\/jats:p><\/jats:sec>","DOI":"10.1111\/codi.12545","type":"journal-article","created":{"date-parts":[[2014,2,6]],"date-time":"2014-02-06T02:21:30Z","timestamp":1391653290000},"page":"51-58","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Meta\u2010analysis for cardiovascular effects of <scp>NRL<\/scp>001 after rectal application in healthy volunteers"],"prefix":"10.1111","volume":"16","author":[{"given":"H. J.","family":"Gruss","sequence":"first","affiliation":[{"name":"Medical &amp; Safety Services ICON Clinical Research Eastleigh 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","doi-asserted-by":"publisher","DOI":"10.1136\/gut.48.3.356"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.10.8.674"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2168.1999.01021.x"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/bjs.4120"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/codi.12541"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/codi.12544"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/codi.12542"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/codi.12543"},{"key":"e_1_2_10_10_1","unstructured":"ICH Harmonized Tripartite Guideline E14. The Clinical Evaluation of QT\/QTc Interval Prolongation and Proarrhythmic Potential for Non\u2010Antiarrhythmic Drugs;2005. Available athttp:\/\/www.fda.gov\/downloads\/RegulatoryInformation\/Guidances\/ucm129357.pdf(accessed August 2013)."},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2125.2003.01791.x"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1213\/01.ane.0000265665.15722.70"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-200602000-00009"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/heart.86.2.199"}],"container-title":["Colorectal Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcodi.12545","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/codi.12545","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,13]],"date-time":"2023-09-13T05:15:37Z","timestamp":1694582137000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/codi.12545"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,2,5]]},"references-count":13,"journal-issue":{"issue":"s1","published-print":{"date-parts":[[2014,3]]}},"alternative-id":["10.1111\/codi.12545"],"URL":"https:\/\/doi.org\/10.1111\/codi.12545","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"}}]}}