Prucalopride Improves Bowel Function and Colonic Transit Time in Patients With Chronic Constipation: An Integrated Analysis

Abstract

Objectives:Constipation is often characterized by slow colonic transit, but the relationship between colonic transit time (CTT) and symptoms is unclear. The aims of this study were to investigate the effect of prucalopride, a 5-hydroxytryptamine receptor-4 agonist, on CTT and assess the relationship between CTT and symptoms.Methods:This was an integrated analysis of three randomized, placebo-controlled, phase 2 dose-finding trials of prucalopride in patients with chronic constipation (ClinicalTrials.gov identifiers: NCT00617513; NCT00631813; and NCT00596596). Measurements of CTT were analyzed using radio-opaque markers at the start and end (4 or 12 weeks) of treatment. At these visits, patients assessed the presence and severity of their symptoms.Results:In total, 280 patients had CTT measurements before and at the end of treatment and were included in the analysis. Their mean age was 43 years, 93% were women, and mean duration of constipation was 19 years. After a once daily treatment with prucalopride 2 mg (n=98) and 4 mg (n=70), CTT was reduced by 12.0 h (95% confidence interval (CI): –18.9, –5.1) and 13.9 h (95% CI: –20.5, –7.4), respectively; CTT increased by 0.5 h (95% CI: –4.5, 5.5) with placebo (n=112). At the end of the trial, symptoms including bloating/flatulence/distension and straining were rated as severe or very severe by a higher proportion of patients with slow or very slow CTT (>48 h) than by those with normal CTT.Conclusions:There was a clear relationship between increased CTT and increased symptom severity in patients with chronic constipation. Treatment with prucalopride accelerated CTT in these individuals.

Use of Prucalopride for Chronic Constipation: A Systematic Review and Meta-analysis of Published Randomized, Controlled Trials

“…However, there are several systematic reviews and meta-analyses evaluating the role of prucalopride [59][60][61][62][63][64][65][66][67][68] in the management of chronic constipation and their findings are consistent with the findings of the current study. Although the scope of the current article is the evaluation of clinical effectiveness and adverse events related to prucalopride only, previously reported systematic reviews [59][60][61][62][63][64][65][66][67][68] have reported its safety, efficacy, pharmacokinetics, and tolerability providing supporting evidence to our conclusions. As reported by Tack et al 69 "Prucalopride is an important addition to the therapeutic abilities for treating chronic constipation, especially in females poorly responding to laxatives.…”

“…45,46,54,57,63,65 Like other 5-HT 4 agonists such as cisapride, there were concerns about the risk of cardiac side effects after the use of prucalopride because prucalopride has not been found to interact with either the human ether-à-go-go-related gene (hERG) potassium channel (responsible for cisapride-induced arrhythmias) or 5-HT 1B receptors (mechanism behind tegaserod induced side effects), both assumed to be responsible for the bradycardia and cardiovascular adverse events. 45,46,51,56,57,59,63,69 In a similar study evaluating the cardiovascular safety profile of prucalopride in a relatively high-risk population of old-age care home patients with 80% having a prior history of cardiovascular disease, no significant hemodynamic or electrocardiographic changes were reported. Explicitly, there was no increased incidence of prolongation of the QT interval or bradycardia in the prucalopride group compared to placebo.…”

“…[59][60][61][62][63][64][65][66][67] However, this study provides up to date, comprehensive and cumulative evidence on the use of prucalopride that meaningfully reduce symptoms related to chronic constipation. One review 59 reported the combined analysis of 3 trials, 4 reviews 62,64,65,67 reported the combined analysis of 4 trials each, 2 reviews 64,66 reported systematic review of the trials evaluating four 5-HT 4 agonist agents, whereas 3 reviews 60,61,68 were evidence reviews.…”

Prucalopride induces high‐amplitude propagating contractions in the colon of patients with chronic constipation: a randomized study

“…15 A previous study in dogs demonstrated that prucalopride induces giant migrating contractions in the colon, 16 and it has been demonstrated to accelerate colonic transit both in healthy controls and in patients with chronic constipation, 14,17,18 possibly by mediating an increase in HAPCs, as was observed in healthy volunteers.…”

Efficacy and safety of prucalopride in the treatment of chronic constipation

“…4,16 The proportions of patients in the present study with at least three SCBMs per week (responders) were 44.2% ( Another study conducted by Emmanuel A et al, had shown responder rate of 42% at 4 weeks which is similar to our study. 18 Prucalopride had a good safety profile and was well tolerated in this study. Common adverse effects reported in our study were gastrointestinal disorders like diarrhea, nausea and abdominal pain and nervous system disorders like headache and dizziness.…”