PMID- 24499495 OWN - NLM STAT- MEDLINE DCOM- 20141017 LR - 20140206 IS - 1463-1318 (Electronic) IS - 1462-8910 (Linking) VI - 16 Suppl 1 DP - 2014 Mar TI - A double-blind, placebo-controlled, randomised, parallel-group, dose-escalating, repeat dose study in healthy volunteers to evaluate the safety, tolerability, pharmacodynamic effects and pharmacokinetics of the once daily rectal application of NRL001 suppositories for 14 days. PG - 36-50 LID - 10.1111/codi.12544 [doi] AB - AIMS: The 1R,2S stereoisomer of methoxamine hydrochloride, NRL001, is a highly selective alpha1-adrenoceptor agonist being developed for the local treatment of non-structural faecal incontinence caused by weak internal anal sphincter tone. This study investigated the steady state pharmacokinetics (PK) and safety of 2 g rectal suppositories containing NRL001 in different strengths (7.5, 10, 12.5 or 15 mg). METHODS: Healthy volunteers aged 18-45 years received 14 daily doses of NRL001 2 g suppositories or matching placebo. In each dose group nine participants received NRL001 and three received placebo. Blood samples to determine NRL001 concentrations were taken on Days 1, 7 and 14. Cardiovascular parameters were collected via electrocardiograms, Holter monitoring (three lead Holter monitor) and vital signs. RESULTS: Forty-eight volunteers were enrolled; 43 completed the study and were included in the PK analysis population. AUC and Cmax broadly increased with increasing dose, Tmax generally occurred between 4.0 and 5.0 h. 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 < 1. NRL001 did not accumulate over time for any dose. Increasing NRL001 concentrations were related to changes in vital sign variables, most notably decreased heart rate. The most commonly reported adverse events (AEs) in the active treatment groups were paraesthesia and piloerection. CONCLUSIONS: Treatment with NRL001 was generally well tolerated over 14 days once daily dosing and plasma NRL001 did not accumulate over time. Treatment was associated with changes in vital sign variables, most notably decreased heart rate. AEs commonly reported with NRL001 treatment were events indicative of a systemic alpha-adrenergic effect. CI - Colorectal Disease (c) 2014 The Association of Coloproctology of Great Britain and Ireland. FAU - Bell, D AU - Bell D AD - Bio-Kinetic Europe Limited, Belfast, UK. FAU - Duffin, A AU - Duffin A FAU - Jacobs, A AU - Jacobs A FAU - Pediconi, C AU - Pediconi C FAU - Gruss, H J AU - Gruss HJ LA - eng SI - ClinicalTrials.gov/NCT01099670 PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - England TA - Colorectal Dis JT - Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland JID - 100883611 RN - 0 (Adrenergic alpha-1 Receptor Agonists) RN - 0 (Suppositories) RN - HUQ1KC1YLI (Methoxamine) SB - IM MH - Administration, Rectal MH - Adolescent MH - Adrenergic alpha-1 Receptor Agonists/*administration & dosage/pharmacokinetics/pharmacology/therapeutic use MH - Adult MH - Double-Blind Method MH - Drug Tolerance MH - Electrocardiography MH - Electrocardiography, Ambulatory MH - Fecal Incontinence/drug therapy MH - Female MH - Heart Rate/drug effects MH - Humans MH - Male MH - Methoxamine/*administration & dosage/pharmacokinetics/pharmacology/therapeutic use MH - Middle Aged MH - Stereoisomerism MH - Suppositories MH - Vital Signs/drug effects OTO - NOTNLM OT - 1R,2S-methoxamine OT - Faecal incontinence OT - NRL001 OT - pharmacodynamics OT - pharmacokinetics EDAT- 2014/02/07 06:00 MHDA- 2014/10/18 06:00 CRDT- 2014/02/07 06:00 PHST- 2013/10/02 00:00 [received] PHST- 2013/12/29 00:00 [accepted] PHST- 2014/02/07 06:00 [entrez] PHST- 2014/02/07 06:00 [pubmed] PHST- 2014/10/18 06:00 [medline] AID - 10.1111/codi.12544 [doi] PST - ppublish SO - Colorectal Dis. 2014 Mar;16 Suppl 1:36-50. doi: 10.1111/codi.12544.