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

Abstract

Key Points• The aim of this study was to compare the effects on colonic motility of prucalopride vs polyethylene glycol 3350 + electrolytes (PEG3350) in patients with chronic constipation (n = 12).• The primary endpoint was the number of high-amplitude propagating contractions (HAPCs), which were measured using colonic manometry catheters.• In the 12-h period following treatment, a significant increase in HAPCs (p < 0.05) was observed in patients treated with prucalopride compared with those receiving PEG3350. Significant increases in co-primary and secondary endpoints were also observed in patients receiving prucalopride.• Prucalopride was found to be superior to PEG3350 in increasing colonic motility in the cleansed colon, as measured by HAPCs, in patients with chronic constipation. AbstractBackground This study compared prucalopride, a selective, prokinetic, 5-HT 4 receptor agonist, with polyethylene glycol 3350 + electrolytes (PEG3350), an osmotic laxative, on colonic motility parameters, primarily high-amplitude propagating contractions (HAPCs) in patients with chronic constipation. Methods This randomized, cross-over, reader-blinded study was conducted at a single site in the USA. The study was open to men and women aged 18-75 years who met study inclusion criteria. Colonic manometry catheters were inserted the day before investigation.On the investigation days, patients received oral 2 mg prucalopride or 2 9 13.8 g PEG3350 in solution. The primary endpoint was HAPC count (threshold: mean amplitude ≥100 mmHg, propagation ≥20 cm [HAPC 1 ]) in the 12 h after treatment administration. Analyses were also conducted at two co-primary thresholds: mean amplitude ≥75 mmHg, propagation ≥20 cm (HAPC 2 ); and mean amplitude ≥75 mmHg, propagation ≥10 cm (HAPC 3 ). Secondary endpoints included HAPC area under the curve (AUC), contraction force, amplitude, duration, and propagation velocity. Key Results Thirteen women were enrolled, with 12 completing the study. Significantly more HAPC 1 (8.7 AE 2.06 vs 2.9 AE 2.06; p = 0.012) and HAPC 2 (9.0 AE 2.11 vs 3.3 AE 2.11; p = 0.017) were observed in the 12-h periods with prucalopride than with PEG3350. Prucalopride significantly increased mean propagation distance and velocity (HAPC 2 ) and mean AUC, force, and amplitude (HAPC 3 ) compared with PEG3350. Adverse events were mild or moderate. Conclusions & Inferences Prucalopride was superior to PEG3350 in inducing HAPCs in patients with

Luminal 5‐HT4 receptors—A successful target for prokinetic actions

“…In particular, prucalopride, used by Shokrollahi et al to demonstrate prokinetic effects on propulsive motor patterns in rabbit proximal colon, has emerged as a popular and effective therapeutic agent for promoting gut motility. Prucalopride displays high‐affinity binding to human 5‐HT 4(a) and 5‐HT 4(b) receptor isoforms which is consistent with its clinical success since these isoforms are expressed in the human colon (Table ). Other high‐affinity agonists have also been developed including naronapride (ATI‐7505), velusetrag (TD‐5108), and YH12852.…”

“…Notwithstanding these complexities, clinical studies in humans and many pharmacological studies in isolated preparations in small animals reveal a common theme: 5‐HT 4 Rs initiate and/or enhance peristaltic reflexes and/or propulsion. This has been demonstrated in guinea pig ileum and colon, mouse, rat and dog colon, and human jejunum and colon . Use of early 5‐HT 4 R agonists in humans including cisapride, mosapride, and tegaserod was limited by their adverse secondary effects on other systems following their systemic absorption.…”

Comparison of efficacy of pharmacological treatments for chronic idiopathic constipation: a systematic review and network meta-analysis

“…Several of the agents evaluated in this network meta-analysis accelerate colonic transit, including intestinal secretagogues (lubiprostone,37 linaclotide,38 and the bile acid transport inhibitor, elobixibat39) and prokinetic agents (prucalopride,40 tegaserod,41 and bisacodyl42). However, among all these drugs, only prucalopride43 and bisacodyl have been shown to increase the number of high amplitude propagated contractions, which are highly propulsive in the colon 44. Lubiprostone did not induce colonic high amplitude contractions 45…”

An update on prucalopride in the treatment of chronic constipation

“…31 In a more recent study, prucalopride was shown not only to increase frequency of giant or high-amplitude contractions in the colon, but also to augment their amplitude, propagation distance and velocity; effects that were all significantly greater than those observed with polyethylene glycol (PEG) 3350 plus electrolytes. 32 Prucalopride is not extensively metabolized in the body and does not influence the function of cytochrome P450 or P glycoprotein; hence, it does not have clinically significant interactions with other drugs. 33 While prucalopride has been shown to interact with cardiac hERG potassium channels, blockade occurs only at very high concentrations; 150 times greater than the therapeutic dose.…”

“…35 However, there were no effects on late repolarizations or the refractory period and there was no evidence of any arrhythmic activity. 35 Prucalopride: clinical evidence in chronic idiopathic constipation Based on the aforementioned effects of prucalopride on colonic motility and transit, [30][31][32] it should come as no surprise that a major clinical focus has been on its therapeutic role in constipation. Efficacy, tolerability, safety and impact on quality of life have been demonstrated in a number of large, randomized, placebo-controlled trials 36 which have led to the approval of prucalopride in several countries, with the usual recommended dose being 2 mg per day in patients under 65 years of age and 1 mg per day in patients over 65 years.…”