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Meta‐analysis for cardiovascular effects of NRL 001 after rectal application in healthy volunteers
Author(s) -
Gruss H. J.,
Pediconi C.,
Jacobs A.
Publication year - 2014
Publication title -
colorectal disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.029
H-Index - 89
eISSN - 1463-1318
pISSN - 1462-8910
DOI - 10.1111/codi.12545
Subject(s) - medicine , heart rate , blood pressure , bradycardia , qt interval , placebo , cardiology , confidence interval , anesthesia , alternative medicine , pathology
Aims NRL 001 is a highly specific α 1 –adrenoceptor agonist currently under evaluation for the treatment of faecal incontinence caused by a weak internal anal sphincter. The aim of this meta‐analysis was to quantify the effect of NRL 001 on cardiovascular parameters including heart rate, blood pressure and QT interval. Methods Data from the four Phase I healthy volunteer studies SUM ( NCT 00857467), SURD ( NCT 01099670), SUSD ( NCT 00850590) and SAGE ( NCT 01099683) were pooled and analyses were performed on individual subject data. Mixed effects regression analysis was used to determine the effect of NRL 001 on heart rate, blood pressure and QT intervals. A multivariate statistical model was used to determine the effect of covariates on heart rate. Results Subjects given NRL 001 experienced a dose related decrease in heart rate of up to 9.48 bpm 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 NRL 001 on blood pressure. QT interval increased in all NRL 001 subject as expected; QT C F also showed a statistically significant increase. However, QT C B was shortened with no significant treatment effect. Conclusions NRL 001 was found to have a dose‐dependent effect on heart rate; however clinically–relevant bradycardia was not reported, indicating the decrease in heart rate was not of clinical significance. Furthermore, no clinically‐significant drug effect on blood pressure or mean arterial pressure was observed. QT intervals were affected by changes in heart rate. However, trends were dependant on the correction factor used. No consistent QT effect was observed, but a thorough QT C study will be required to confirm the effects of rectally applied NRL 001.