Effects of the enterokinetic prucalopride (R093877) on colonic motility in fasted dogs

Briejer, M.R.; Prins, Nicolaas H.; Schuurkes, J. A. J.

doi:10.1046/j.1365-2982.2001.00280.x

Cited by 89 publications

(74 citation statements)

References 19 publications

(23 reference statements)

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“…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.…”

mentioning

confidence: 99%

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

Miner

Camilleri

Burton

et al. 2016

Neurogastroenterology Motil

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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

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mentioning

confidence: 99%

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

Miner

Camilleri

Burton

et al. 2016

Neurogastroenterology Motil

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“…Prins et al 28 have reported that pD 2 value of cisapride for 5-HT 4 receptors in canine isolated rectum circular smooth muscle is 6.870. 25. 28 Whereas in our study, we found pD 2 values for cisapride and metoclopramide to be 5.55 and 5.40, respectively.…”

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confidence: 52%

“…This finding was further supported by the lack of effect of GR125487 and GR113808 (potent 5-HT 4 receptor antagonists) on the contraction-response curves to prucalopride in our study. The enterokinetic effects of prucalopride have been reported to be antagonized by GR125487 24,25 and by GR113808. 26 Moreover, our results are in accordance with the finding showing that in human CCP, selective 5-HT 4 antagonist fails to suppress the relaxation caused by 5-HT 4 agonist.…”

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confidence: 99%

Investigation of serotonin receptors in the isolated penile bulb of rats

2006

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The aim of this study was to investigate serotonin (5-HT) receptors in the penile bulb, which have been suggested to play a role in penile erection. Serotonin (10 À5 M) and L-NOARG (nitric oxide synthase inhibitor, 10 À4 M) had no effect on prucalopride-induced relaxation. These results suggest the existence of a 1 -adrenergic, 5-HT 1A and 5-HT 2A serotonergic receptors in the penile bulb of rats, which are responsible for 5-HT-induced contraction. Additionally, a serotonergic receptor resembling a 5-HT 4 -type plays a role in the relaxation. The latter receptor is activated by 5-HT 4 agonists, but is not antagonized by 5-HT 4 antagonists.

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“…25 In the canine colon, prucalopride induced a dose-dependent stimulation of clustered contractile activity in the proximal colon and inhibition in the distal colon. 27 More importantly, prucalopride stimulated giant migratory contractions; the high-amplitude contractions that traverse the length of the colon in an abroad direction and initiate the urge to defecate. 27 The absence, diminution in frequency and/or lower amplitude of these contractions has been linked to the pathophysiology of CC.…”

Section: -Ht4 Receptor Agonists In CCmentioning

confidence: 99%

“…27 More importantly, prucalopride stimulated giant migratory contractions; the high-amplitude contractions that traverse the length of the colon in an abroad direction and initiate the urge to defecate. 27 The absence, diminution in frequency and/or lower amplitude of these contractions has been linked to the pathophysiology of CC. 28,29 Initial studies in healthy human subjects indicated that prucalopride's prokinetic effects were selective for the colon where an acceleration of overall colonic transit and an increase in proximal colon emptying were observed.…”

Section: -Ht4 Receptor Agonists In CCmentioning

confidence: 99%

An update on prucalopride in the treatment of chronic constipation

Aras

Quigley

2017

Therap Adv Gastroenterol

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Chronic constipation (CC) is a highly prevalent and often under-appreciated gastrointestinal disorder associated with significant impairment in quality of life. Symptoms of constipation are typically present for a number of years prior to a patient seeking help. Lifestyle modifications followed by, or coupled with, over-the-counter laxatives represent the initial treatment option; however, relief for many is limited and dissatisfaction rates for these approaches remain high. Over recent years, therefore, considerable effort has been exerted on the development of novel pharmacological approaches. Two major targets have emerged, motility and secretion. Research on the former led to the development of a number of prokinetic agents capable of stimulating colonic motility and, thus, accelerating colonic transit. Of these, earlier prototypes such as cisapride and tegaserod, though effective, were ultimately withdrawn due to cardiovascular adverse events due in part to receptor nonselectivity. Highly selective serotonergic receptor agonists have since emerged which appear to be equally effective in stimulating gut motility but are devoid of cardiac side effects. One such agent is prucalopride, which has now been approved for the management of chronic idiopathic constipation in several countries, but not in the United States. Multiple multicenter, randomized placebo-controlled clinical trials have demonstrated superiority for prucalopride compared to placebo in the short to medium term in relieving the major symptoms of constipation in both men and women across a broad spectrum of ages, ethnicities and geographic locations. To date, prucalopride has enjoyed a favorable safety profile and there have been no signals to suggest arrythmogenicity. Efficacy over longer periods of treatment remains to be confirmed. Evidence for efficacy in other forms of constipation, such as opioidinduced constipation and that related to Parkinson's disease is beginning to emerge; its status in the management of constipation-predominant irritable bowel syndrome or foregut motility disorders, such as gastroparesis, remains to be established.

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Effects of the enterokinetic prucalopride (R093877) on colonic motility in fasted dogs

Cited by 89 publications

References 19 publications

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

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

Investigation of serotonin receptors in the isolated penile bulb of rats

An update on prucalopride in the treatment of chronic constipation

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