{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T04:20:31Z","timestamp":1773030031850,"version":"3.50.1"},"reference-count":17,"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":"Abstract<\/jats:title>Aims<\/jats:title>This study aimed to assess the dose and volume effects of suppository preparations and safety of NRL<\/jats:styled-content>001 (one of four possible stereoisomers of methoxamine hydrochloride) on anal sphincter tone using rectal suppositories in healthy adult volunteers.<\/jats:p><\/jats:sec>Methods<\/jats:title>This was a Phase I, single\u2010centre, randomised, double\u2010blind, three\u2010way crossover study during which subjects received three single doses of 1\u00a0g rectal suppositories (containing 5 or 10\u00a0mg NRL<\/jats:styled-content>001 or matching placebo) or 2\u00a0g rectal suppositories (containing 10 or 15\u00a0mg NRL<\/jats:styled-content>001 or matching placebo) on three separate dosing days. The outcome measures were mean anal resting pressure (MARP<\/jats:styled-content>) variables (monitored continuously for 20\u201330\u00a0min before and up to 6\u00a0h after dosing), pharmacokinetics (PK<\/jats:styled-content>) and safety assessments.<\/jats:p><\/jats:sec>Results<\/jats:title>Twenty\u2010six subjects were dosed with study medication. Two subjects were withdrawn prematurely and were not included in the main analysis. There was a dose\u2010dependent increase in anal sphincter tone (MARP<\/jats:styled-content>) when comparing the 5 and 10\u00a0mg doses of NRL<\/jats:styled-content>001; however, the 15\u00a0mg dose did not have a significantly greater effect than the 10\u00a0mg dose. Suppository size (1 or 2\u00a0g) did not appear to have an effect on sphincter tone. There was no evidence against dose proportionality for the PK<\/jats:styled-content> variables, but the mean maximum plasma concentration (C<\/jats:italic>max<\/jats:sub>) for the 1\u00a0g suppository group was higher than for the 2\u00a0g group. Twenty\u2010one adverse events were reported in 8 (30.8%) subjects. A dose dependent decrease in heart rate was noted; however, there were no adverse events reported that were related to this reduction in heart rate.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>The increase in anal sphincter tone supports the potential therapeutic use of NRL<\/jats:styled-content>001 in treating faecal incontinence, with further studies in patients required. NRL<\/jats:styled-content>001 was well tolerated in single doses of up to 15\u00a0mg.<\/jats:p><\/jats:sec>","DOI":"10.1111\/codi.12541","type":"journal-article","created":{"date-parts":[[2014,2,6]],"date-time":"2014-02-06T02:21:30Z","timestamp":1391653290000},"page":"5-15","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A randomised, controlled, crossover study to investigate the safety and response of 1R,2S\u2010methoxamine hydrochloride (NRL<\/scp>001) on anal function in healthy volunteers"],"prefix":"10.1111","volume":"16","author":[{"given":"J. A. 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