Prucalopride

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Rene Kerstens - One of the best experts on this subject based on the ideXlab platform.

  • © 2012 Smith et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Drug Design, Development and Therapy 2012:6 407–415 Drug Des
    2016
    Co-Authors: William B Smith, Rene Kerstens, Lieve Vandeplassche, Erik Mannaert, Tom Verhaeghe, Vera Van De Velde
    Abstract:

    Effect of renal impairment on the pharmacokinetics of Prucalopride: a single-dose open-label Phase I stud

  • a randomized double blind placebo controlled trial to evaluate the efficacy safety and tolerability of long term treatment with Prucalopride
    Neurogastroenterology and Motility, 2015
    Co-Authors: Hubert Piessevaux, Marina Cools, Rene Kerstens, Enrico Corazziari, Enrique Rey, Magnus Simren, Anna Wiechowskakozlowska, Karen Barrett, Amy Levine
    Abstract:

    Background Randomized trials have confirmed the efficacy of Prucalopride for the treatment of chronic constipation up to 12 weeks. This study aimed to assess the efficacy of Prucalopride over a 24-week period (ClinicalTrials.gov: NCT01424228). Methods Adults with chronic constipation and ≤2 spontaneous complete bowel movements (SCBMs)/week were randomized to receive Prucalopride 2 mg or placebo daily for 24 weeks. The primary endpoint was the proportion of patients achieving a mean of ≥3 SCBMs/week over the treatment period, assessed using daily e-diaries. Secondary outcomes and safety parameters were assessed throughout the study. Key Results Overall, 361 patients were randomized and received Prucalopride or placebo. Baseline characteristics were similar in the Prucalopride (N = 181) and placebo (N = 180) groups. Mean age was 48.9 years (standard deviation, 16.0) and most patients were women. The proportion of participants achieving the primary endpoint was not statistically different between the Prucalopride and placebo groups (25.1% vs 20.7%; p = 0.367). There was also no statistically significant difference between groups over the first 12-week period (Prucalopride, 25.1%; placebo, 20.1%; p = 0.341). There were no statistically significant differences between groups for most secondary endpoints. No new safety concerns were identified. Conclusions & Inferences This trial did not show statistically significant improvements in primary or secondary outcomes with Prucalopride compared with placebo over 24 or 12 weeks. This is in contrast to the results of four previous 12-week trials, which demonstrated Prucalopride to be significantly more effective than placebo. An extensive evaluation did not provide an explanation for the null efficacy results of this study.

  • association between health related quality of life and symptoms in patients with chronic constipation an integrated analysis of three phase 3 trials of Prucalopride
    Neurogastroenterology and Motility, 2015
    Co-Authors: Jan Tack, Lieve Vandeplassche, Michael Camilleri, Dominique Dubois, Alain Joseph, Rene Kerstens
    Abstract:

    Background Prucalopride is a high-affinity 5-HT4 receptor agonist for the treatment of chronic constipation. The aims of this study were to investigate the relationship between health-related quality of life (HRQoL) and symptoms of constipation, and to assess the response of HRQoL to treatment using integrated data from three phase III trials of Prucalopride. Methods This was an integrated analysis of data from three pivotal multicenter, double-blind, randomized, placebo-controlled, parallel-group trials (ClinicalTrials.gov Identifiers: NCT00488137, NCT00483886 and NCT00485940). Relationships were investigated between Patient Assessment of Constipation Quality of Life (PAC-QOL) scores, Patient Assessment of Constipation Symptoms (PAC-SYM) scores, bowel movement frequency (assessed using daily diaries), and treatment. Key Results Patients treated with Prucalopride 2 mg (n = 659) and placebo (n = 661) were included in the analysis. An improvement in PAC-SYM scores correlated well with an improvement in PAC-QOL overall score (r = 0.711) and satisfaction subscale score (r = 0.589). After 12 weeks, PAC-QOL overall score and satisfaction subscale score significantly (p < 0.001) improved by ≥1 point (clinically relevant) in 36.5% and 44.1% of patients treated with Prucalopride, compared with 18.5% and 22.4% with placebo respectively. Moreover, 39.0% of patients with an improvement in satisfaction of ≥1 point achieved ≥3 spontaneous complete bowel movements/week, compared with 7.4% of those with no improvement in satisfaction (<1 point). Conclusions & Inferences Improvements in PAC-QOL overall score and satisfaction score were associated with improvements in symptoms of chronic constipation. Compared with placebo, treatment with Prucalopride significantly improved HRQoL.

  • Prucalopride is no more effective than placebo for children with functional constipation
    Gastroenterology, 2014
    Co-Authors: Suzanne M Mugie, Rene Kerstens, Jannie Ausma, Amy Levine, Bartosz Korczowski, Piroska Bodi, Alexandra Green, Magnus Ruth, Marc A Benninga
    Abstract:

    Background & Aims Prucalopride is a selective, high-affinity agonist of the 5-hydroxytryptamine (serotonin) receptor 4 that enhances motility in the gastrointestinal tract. We performed a multicenter, randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of Prucalopride in children (6 months to 18 years old) with functional constipation. Methods Children with functional constipation, based on the Rome III criteria, were given Prucalopride (children ≤50 kg were given a 0.04 mg/kg oral solution; children >50 kg were given a 2-mg tablet) or placebo once daily for 8 weeks. The primary efficacy end point was the proportion of children with toileting skills who had a mean of ≥3 spontaneous bowel movements/week and ≤1 episode of fecal incontinence/2 weeks, from study weeks 5–8 (responders). Adverse events, clinical laboratory values, and electrocardiograms were monitored. Results Efficacy and safety were assessed in 213 children (106 Prucalopride, 107 placebo). Twenty-five percent were younger than 4 years old, 50% were 4–11 years old, and 25% were 12–18 years old; 55.4% were girls. At screening, 62.3% of patients in the Prucalopride group and 55.1% in the placebo group had a history of fecal incontinence; 60.4% and 55.1% in the Prucalopride and placebo groups, respectively, had a mean of ≤1 spontaneous bowel movements/week. The proportion of responders was similar between groups (Prucalopride, 17.0% and placebo, 17.8%). There were no statistically significant differences in the primary efficacy end point when patients were stratified by sex, age group, or country. The incidence of treatment-emergent adverse events was similar in the Prucalopride (69.8%) and placebo (60.7%) groups. Conclusions Prucalopride, although generally well tolerated, was not more effective than placebo in children with functional constipation. ClinicalTrials.gov Number: NCT01330381.

  • Prucalopride improves bowel function and colonic transit time in patients with chronic constipation an integrated analysis
    The American Journal of Gastroenterology, 2014
    Co-Authors: Anton Emmanuel, Marina Cools, Lieve Vandeplassche, Rene Kerstens
    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-fi nding trials of Prucalopride in patients with chronic constipation (ClinicalTrials.gov identifi ers: 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 % confi dence 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 / fl atulence / 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.

Lieve Vandeplassche - One of the best experts on this subject based on the ideXlab platform.

  • © 2012 Smith et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Drug Design, Development and Therapy 2012:6 407–415 Drug Des
    2016
    Co-Authors: William B Smith, Rene Kerstens, Lieve Vandeplassche, Erik Mannaert, Tom Verhaeghe, Vera Van De Velde
    Abstract:

    Effect of renal impairment on the pharmacokinetics of Prucalopride: a single-dose open-label Phase I stud

  • association between health related quality of life and symptoms in patients with chronic constipation an integrated analysis of three phase 3 trials of Prucalopride
    Neurogastroenterology and Motility, 2015
    Co-Authors: Jan Tack, Lieve Vandeplassche, Michael Camilleri, Dominique Dubois, Alain Joseph, Rene Kerstens
    Abstract:

    Background Prucalopride is a high-affinity 5-HT4 receptor agonist for the treatment of chronic constipation. The aims of this study were to investigate the relationship between health-related quality of life (HRQoL) and symptoms of constipation, and to assess the response of HRQoL to treatment using integrated data from three phase III trials of Prucalopride. Methods This was an integrated analysis of data from three pivotal multicenter, double-blind, randomized, placebo-controlled, parallel-group trials (ClinicalTrials.gov Identifiers: NCT00488137, NCT00483886 and NCT00485940). Relationships were investigated between Patient Assessment of Constipation Quality of Life (PAC-QOL) scores, Patient Assessment of Constipation Symptoms (PAC-SYM) scores, bowel movement frequency (assessed using daily diaries), and treatment. Key Results Patients treated with Prucalopride 2 mg (n = 659) and placebo (n = 661) were included in the analysis. An improvement in PAC-SYM scores correlated well with an improvement in PAC-QOL overall score (r = 0.711) and satisfaction subscale score (r = 0.589). After 12 weeks, PAC-QOL overall score and satisfaction subscale score significantly (p < 0.001) improved by ≥1 point (clinically relevant) in 36.5% and 44.1% of patients treated with Prucalopride, compared with 18.5% and 22.4% with placebo respectively. Moreover, 39.0% of patients with an improvement in satisfaction of ≥1 point achieved ≥3 spontaneous complete bowel movements/week, compared with 7.4% of those with no improvement in satisfaction (<1 point). Conclusions & Inferences Improvements in PAC-QOL overall score and satisfaction score were associated with improvements in symptoms of chronic constipation. Compared with placebo, treatment with Prucalopride significantly improved HRQoL.

  • Prucalopride improves bowel function and colonic transit time in patients with chronic constipation an integrated analysis
    The American Journal of Gastroenterology, 2014
    Co-Authors: Anton Emmanuel, Marina Cools, Lieve Vandeplassche, Rene Kerstens
    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-fi nding trials of Prucalopride in patients with chronic constipation (ClinicalTrials.gov identifi ers: 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 % confi dence 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 / fl atulence / 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.

  • effect of Prucalopride on symptoms of chronic constipation
    Neurogastroenterology and Motility, 2014
    Co-Authors: Jan Tack, Lieve Vandeplassche, Dominique Dubois, Alain Joseph, Vincenzo Stanghellini, Rene Kerstens
    Abstract:

    Background Prucalopride is a 5-HT4 receptor agonist with gastrointestinal prokinetic activities. This integrated analysis of data from three 12-week, double-blind trials evaluated the effect of Prucalopride 2 mg q.d. on common constipation symptoms in women in whom laxatives had failed to provide adequate relief. The effect of Prucalopride on bowel function was outside the scope of the analysis and has been described elsewhere. Methods Women with self-reported inadequate relief from laxatives and included in the Prucalopride 2 mg or placebo arm of the trials were selected for analysis. Symptom severity was determined with the Patient Assessment of Constipation Symptoms (PAC–SYM) questionnaire. Observed changes from baseline in individual item scores were also evaluated by calculating Cohen's D effect sizes using baseline standard deviation (SD) (>0.2–0.5, >0.5–0.8 and >0.8 for small, moderate and large effects, respectively). Key Results Data were analyzed for 936 women. The proportion of women with a PAC-SYM severity score >2 at baseline was 50.0% for abdominal symptoms, 71.4% for stool symptoms, and 15.5% for rectal symptoms. Excluding the women without presence of a symptom at baseline from the effect size calculations showed that Prucalopride 2 mg had a large effect (>0.8) on all PAC-SYM items, including abdominal pain, abdominal discomfort, bloating, straining, and painful bowel movements. For abdominal symptoms and stool symptoms, effect sizes with Prucalopride 2 mg were 1.3–2.3 times larger than those with placebo. Conclusions & Inferences Prucalopride 2 mg q.d. for 12 weeks alleviates common constipation symptoms in women in whom laxatives had failed to provide adequate relief.

  • oral Prucalopride in children with functional constipation
    Journal of Pediatric Gastroenterology and Nutrition, 2013
    Co-Authors: Harland S Winter, Lieve Vandeplassche, Carlo Di Lorenzo, Marc A Benninga, Mark A Gilger, Gregory L Kearns, Paul E Hyman, Jannie Ausma, Mieke Hoppenbrouwers
    Abstract:

    BACKGROUND AND OBJECTIVES Prucalopride is a selective, high-affinity 5-HT4 receptor agonist with gastrointestinal prokinetic activities. The aim of this study was to evaluate the pharmacokinetics, efficacy, safety, and tolerability of Prucalopride oral solution in children, ages 4 years or older to 12 years or younger, with functional constipation. METHODS A single oral dose of 0.03 mg/kg Prucalopride was administered to 38 children to characterize Prucalopride pharmacokinetics (NCT01674166). Thereafter, 37 children entered an open-label extension period in which 0.01 to 0.03 mg/kg of Prucalopride was administered once per day for 8 weeks to investigate efficacy, safety, and tolerability (NCT01670669). RESULTS Mean (standard deviation [SD]) Cmax, tmax, and AUC∞ (area under the plasma concentration-time curve from time 0 to infinity) were 3.8 (0.6) ng/mL, 1.8 (0.9) hour, and 65.3 (10.6) ng · h · mL, respectively, with limited (16%) variability in Cmax and AUC∞. Mean (SD) t1/2 was 19.0 (3.1) hours. On average, mean (SD) renal clearance (0.25 [0.08] L · h · kg) accounted for 54% of the apparent total plasma clearance (0.46 [0.07] L · h · kg). The apparent volume of distribution was 12.6 (2.6) L/kg. Prucalopride treatment resulted in a mean bowel movement frequency of 6.8/week, normal stool consistency, and reduced frequency of fecal incontinence. During the 8-week extension, 70% of study participants had at least 1 adverse event (all but 1 of mild/moderate intensity, 19% considered related to Prucalopride). No children discontinued Prucalopride because of adverse events. CONCLUSIONS The pharmacokinetic profile of a single dose of Prucalopride oral solution (0.03 mg · kg · day) generally resembled the profile in adults (2-mg tablet) but reflected lower systemic exposure in children. Prucalopride treatment for 8 weeks demonstrated an apparent favorable efficacy and tolerability profile in children with functional constipation.

Jan Tack - One of the best experts on this subject based on the ideXlab platform.

  • Prucalopride in diabetic and connective tissue disease related gastroparesis randomized placebo controlled crossover pilot trial
    Neurogastroenterology and Motility, 2021
    Co-Authors: Christopher N Andrews, Jan Tack, Matthew Woo, Michelle Buresi, Michael Curley, Milli Gupta, Lynn Wilsack, Yasmin Nasser
    Abstract:

    BACKGROUND Gastroparesis, defined by delayed gastric emptying in the absence of mechanical outlet obstruction, is a frequent neuropathic complication of diabetes mellitus, and effective treatments are lacking. Prucalopride is a pan-gut prokinetic with selective agonist effects on serotonin 5-HT4 receptors in the gut. This study aimed to assess the effect of Prucalopride 4 mg daily on Gastroparesis Cardinal Symptom Index (GCSI), meal-related symptom score (MRSS), and gastric emptying rate in diabetic or connective tissue disease (CTD)-related gastroparesis patients. METHODS This was a double-blind crossover trial of four-week treatment periods with Prucalopride or placebo divided by two weeks of washout. GSCI, MRSS, gastric emptying scintigraphy, PAGI-SYM, and PAGI-QoL were assessed at baseline and the end of each treatment period. Daily bowel movement (BM) frequency and gastrointestinal symptoms were recorded in each period. KEY RESULTS Fifteen gastroparesis patients (13 diabetic, 2 CTD) were enrolled. GCSI scores were lower than baseline but not different between treatment arms. MRSS scores over time or cumulative score were not significantly different between groups. Gastric emptying was more rapid in the Prucalopride treatment period, with mean four-hour meal retention of 22 ± 6% in PRU period vs 40 ± 9% in the placebo period (P = 0.05). Weekly BM frequency was significantly higher in Prucalopride than placebo periods (10.5 ± 1.8 vs 7.5 ± 0.8, P < 0.0001). Perception of weight loss was higher in patients on Prucalopride. Analysis of diabetic gastroparesis (n = 13) population did not change the conclusions. CONCLUSION AND INFERENCE Prucalopride at 4 mg accelerates gastric emptying and bowel movement frequency but does not appear to ameliorate gastroparesis or meal-related symptoms in this study.

  • high resolution manometry reveals different effect of polyethylene glycol bisacodyl and Prucalopride on colonic motility in healthy subjects an acute open label randomized crossover reader blinded study with potential clinical implications
    Neurogastroenterology and Motility, 2020
    Co-Authors: Maura Corsetti, Alexander Thys, Alexander Harris, Giuseppe Pagliaro, Eveline Deloose, I Demedts, Jan Tack
    Abstract:

    BACKGROUND Polyethylene glycol (PEG), bisacodyl, and Prucalopride have been reported to be more effective than placebo in treating patients with constipation but about 50% of the patients still do not respond to these medications. Only bisacodyl and Prucalopride are expected to directly stimulate the colonic motility in humans in vivo. As no previous study has done this, the aim of the study was to investigate the effect of PEG, bisacodyl, and Prucalopride as compared to placebo on colonic motility assessed by means of the high-resolution manometry (HRM) in healthy subjects. METHODS Ten healthy subjects have been enrolled in an acute, open label, randomized, reader-blinded, crossover study and requested to undergo a colonoscopy-assisted HRM measuring their colonic motility before and after oral administration of 13.8 g (two doses) PEG, 10 mg bisacodyl, 2 mg Prucalopride, and placebo. KEY RESULTS In the human prepared colon, oral administration of PEG significantly increases the number of low-amplitude long distance propagating contractions (p = 0.007 vs placebo) while bisacodyl significantly increases the number of high-amplitude propagating contractions (HAPCs) (all p < 0.01 vs PEG, Prucalopride, and placebo). Prucalopride has no major effect on the number of propagating contractions but increases HAPCs amplitude (p = 0.01). CONCLUSIONS & INFERENCES In humans, PEG, Prucalopride, and bisacodyl have distinct effects on colonic motility. This information has clinical implication, as it indicates that the combination of Prucalopride and bisacodyl, normally not considered in clinical practice, could be effective in treating patients with constipation refractory to single medications.

  • factors predictive of treatment emergent adverse events of Prucalopride an integrated analysis of four randomized double blind placebo controlled trials
    Gut and Liver, 2015
    Co-Authors: Somchai Leelakusolvong, Jan Tack, Eamonn Martin Quigley, Duowu Zou, Suck Chei Choi, Andy Liu, Jinyong Kim
    Abstract:

    Background/Aims: This integrated analysis aimed to identify the factors associated with the most frequently re- ported treatment-emergent adverse events (TEAEs) in Asian and non-Asian patients with chronic constipation (CC) who receive Prucalopride or placebo over 12 weeks. Methods: Pooled data from four randomized, double-blind, placebo- controlled, multicenter, phase III studies (NCT00488137, NCT00483886, NCT00485940, and NCT01116206) on pa- tients treated with Prucalopride 2 mg or placebo were ana- lyzed. The associations between predictors and TEAEs were evaluated based on a logistic regression model. Results: Overall, 1,821 patients (Asian, 26.1%; non-Asian, 73.9%) were analyzed. Prucalopride treatment was significantly as- sociated with diarrhea, headache, and nausea (p<0.001), but not with abdominal pain, compared with placebo. Differ- ences in the prevalence of TEAEs between Prucalopride and placebo decreased greatly after the first day of treatment. Compared with non-Asians, Asians were more likely to expe- rience diarrhea and less likely to develop abdominal pain, headache, and nausea. Prior laxative use, CC duration, and body weight were not predictive of any of these TEAEs. Con- clusions: Prucalopride treatment was positively associated with diarrhea, headache, and nausea. Asian patients tended to have a higher frequency of diarrhea but lower frequencies of headache, abdominal pain, and nausea compared with non-Asians. (Gut Liver, 2015;9:208-213)

  • association between health related quality of life and symptoms in patients with chronic constipation an integrated analysis of three phase 3 trials of Prucalopride
    Neurogastroenterology and Motility, 2015
    Co-Authors: Jan Tack, Lieve Vandeplassche, Michael Camilleri, Dominique Dubois, Alain Joseph, Rene Kerstens
    Abstract:

    Background Prucalopride is a high-affinity 5-HT4 receptor agonist for the treatment of chronic constipation. The aims of this study were to investigate the relationship between health-related quality of life (HRQoL) and symptoms of constipation, and to assess the response of HRQoL to treatment using integrated data from three phase III trials of Prucalopride. Methods This was an integrated analysis of data from three pivotal multicenter, double-blind, randomized, placebo-controlled, parallel-group trials (ClinicalTrials.gov Identifiers: NCT00488137, NCT00483886 and NCT00485940). Relationships were investigated between Patient Assessment of Constipation Quality of Life (PAC-QOL) scores, Patient Assessment of Constipation Symptoms (PAC-SYM) scores, bowel movement frequency (assessed using daily diaries), and treatment. Key Results Patients treated with Prucalopride 2 mg (n = 659) and placebo (n = 661) were included in the analysis. An improvement in PAC-SYM scores correlated well with an improvement in PAC-QOL overall score (r = 0.711) and satisfaction subscale score (r = 0.589). After 12 weeks, PAC-QOL overall score and satisfaction subscale score significantly (p < 0.001) improved by ≥1 point (clinically relevant) in 36.5% and 44.1% of patients treated with Prucalopride, compared with 18.5% and 22.4% with placebo respectively. Moreover, 39.0% of patients with an improvement in satisfaction of ≥1 point achieved ≥3 spontaneous complete bowel movements/week, compared with 7.4% of those with no improvement in satisfaction (<1 point). Conclusions & Inferences Improvements in PAC-QOL overall score and satisfaction score were associated with improvements in symptoms of chronic constipation. Compared with placebo, treatment with Prucalopride significantly improved HRQoL.

  • effect of Prucalopride in the treatment of chronic constipation in asian and non asian women a pooled analysis of 4 randomized placebo controlled studies
    Journal of Neurogastroenterology and Motility, 2014
    Co-Authors: Jan Tack, Eamonn Martin Quigley, Somchai Leelakusolvong, Duowu Zou, Suck Chei Choi, Andy Liu, Jinyong Kim
    Abstract:

    BACKGROUND/AIMS To compare the efficacy and safety of Prucalopride, a novel selective high-affinity 5-hydroxytryptamine type 4 receptor agonist, versus placebo, in Asian and non-Asian women with chronic constipation (CC). METHODS Data of patients with CC, receiving once-daily Prucalopride 2-mg or placebo for 12-weeks, were pooled from 4 double-blind, randomized, phase-III trials (NCT00488137, NCT00483886, NCT00485940 and NCT01116206). The efficacy endpoints were: average of ≥ 3 spontaneous complete bowel movements (SCBMs)/week; average increases of ≥ 1 SCBMs/week; and change from baseline in each CC-associated symptom scores (bloating, abdominal pain, hard stool and straining). RESULTS Overall, 1,596 women (Asian [26.6%], non-Asian [73.4%]) were included in this analysis. Significantly more patients in the Prucalopride group versus placebo experienced an average of ≥ 3 SCBMs/week in Asian (34% vs. 11%, P < 0.001) and non-Asian (24.6% vs. 10.6%, P < 0.001) subgroups. The number of patients reporting an increase of≥ 1 SCBMs/week from baseline was significantly higher in the Prucalopride group versus placebo among both Asian (57.4% vs. 28.3%, P < 0.001) and non-Asian (45.3% vs. 24.0%, P < 0.001) subgroups. The difference between the subgroups was not statistically significant. Prucalopride significantly reduced the symptom scores for bloating, hard stool, and straining in both subgroups. CONCLUSIONS Prucalopride 2-mg once-daily treatment over 12-weeks was more efficacious than placebo in promoting SCBMs and improve-ment of CC-associated symptoms in Asian and non-Asian women, and was found to be safe and well-tolerated. There were numeric differences between Asian and non-Asian patients on efficacy and treatment emergent adverse events, which may be partially due to the overlap with functional gastrointestinal disorders in non-Asian patients.(J Neurogastroenterol Motil 2014;20:458-468).

Michael Camilleri - One of the best experts on this subject based on the ideXlab platform.

  • Prucalopride induces high amplitude propagating contractions in the colon of patients with chronic constipation a randomized study
    Neurogastroenterology and Motility, 2016
    Co-Authors: P B Miner, Michael Camilleri, D Burton, H Achenbach, H Wan, J Dragone, B Mellgard
    Abstract:

    Background This study compared Prucalopride, a selective, prokinetic, 5-HT4 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 × 13.8 g PEG3350 in solution. The primary endpoint was HAPC count (threshold: mean amplitude ≥100 mmHg, propagation ≥20 cm [HAPC1]) in the 12 h after treatment administration. Analyses were also conducted at two co-primary thresholds: mean amplitude ≥75 mmHg, propagation ≥20 cm (HAPC2); and mean amplitude ≥75 mmHg, propagation ≥10 cm (HAPC3). 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 HAPC1 (8.7 ± 2.06 vs 2.9 ± 2.06; p = 0.012) and HAPC2 (9.0 ± 2.11 vs 3.3 ± 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 (HAPC2) and mean AUC, force, and amplitude (HAPC3) compared with PEG3350. Adverse events were mild or moderate. Conclusions & Inferences Prucalopride was superior to PEG3350 in inducing HAPCs in patients with chronic constipation. ClinicalTrials.gov number NCT01707667.

  • association between health related quality of life and symptoms in patients with chronic constipation an integrated analysis of three phase 3 trials of Prucalopride
    Neurogastroenterology and Motility, 2015
    Co-Authors: Jan Tack, Lieve Vandeplassche, Michael Camilleri, Dominique Dubois, Alain Joseph, Rene Kerstens
    Abstract:

    Background Prucalopride is a high-affinity 5-HT4 receptor agonist for the treatment of chronic constipation. The aims of this study were to investigate the relationship between health-related quality of life (HRQoL) and symptoms of constipation, and to assess the response of HRQoL to treatment using integrated data from three phase III trials of Prucalopride. Methods This was an integrated analysis of data from three pivotal multicenter, double-blind, randomized, placebo-controlled, parallel-group trials (ClinicalTrials.gov Identifiers: NCT00488137, NCT00483886 and NCT00485940). Relationships were investigated between Patient Assessment of Constipation Quality of Life (PAC-QOL) scores, Patient Assessment of Constipation Symptoms (PAC-SYM) scores, bowel movement frequency (assessed using daily diaries), and treatment. Key Results Patients treated with Prucalopride 2 mg (n = 659) and placebo (n = 661) were included in the analysis. An improvement in PAC-SYM scores correlated well with an improvement in PAC-QOL overall score (r = 0.711) and satisfaction subscale score (r = 0.589). After 12 weeks, PAC-QOL overall score and satisfaction subscale score significantly (p < 0.001) improved by ≥1 point (clinically relevant) in 36.5% and 44.1% of patients treated with Prucalopride, compared with 18.5% and 22.4% with placebo respectively. Moreover, 39.0% of patients with an improvement in satisfaction of ≥1 point achieved ≥3 spontaneous complete bowel movements/week, compared with 7.4% of those with no improvement in satisfaction (<1 point). Conclusions & Inferences Improvements in PAC-QOL overall score and satisfaction score were associated with improvements in symptoms of chronic constipation. Compared with placebo, treatment with Prucalopride significantly improved HRQoL.

  • Systematic review with meta-analysis: highly selective 5-HT4 agonists (Prucalopride, velusetrag or naronapride) in chronic constipation.
    Alimentary Pharmacology & Therapeutics, 2013
    Co-Authors: Andrea Shin, Michael Camilleri, Gururaj J. Kolar, Patricia J. Erwin, Colin Patrick West, Mohammad Hassan Murad
    Abstract:

    Summary Background Highly selective 5-HT4 agonists have been suggested for the treatment of chronic constipation (CC). Aim To assess the effects of highly selective 5-HT4 agonists (Prucalopride, velusetrag or naronapride) on patient-important clinical efficacy outcomes and safety in adults with CC. Methods We searched the medical literature in January 2013 using MEDLINE/Pubmed, Embase, Cochrane Library, and Web of Science/Scopus for randomised, controlled trials of highly selective 5-HT4 agonists in adults with CC, with no minimum duration of therapy (maximum 12 weeks) or date limitations. Data were extracted from intention-to-treat analyses, pooled using a random-effects model, and reported as relative risk (RR), mean differences, or standardised mean differences with 95% confidence intervals (CI). Results Main outcomes included stool frequency, Patient-Assessment of Constipation Quality of Life (PAC-QOL), PAC of symptoms (PAC-SYM) and adverse events. Thirteen eligible trials were identified: 11 Prucalopride, 1 velusetrag, 1 naronapride. Relative to control, treatment with highly selective 5-HT4 agonists was superior for all outcomes: mean ≥3 spontaneous complete bowel movements (SCBM)/week (RR = 1.85; 95% CI 1.23–2.79); mean ≥1 SCBM over baseline (RR = 1.57; 95% CI 1.19, 2.06); ≥1 point improvement in PAC-QOL and PAC-SYM scores. The only active comparator trial of Prucalopride and PEG3350 suggested PEG3350 is more efficacious for some end points. Adverse events were more common with highly selective 5-HT4 agonists, but were generally minor; headache was the most frequent. Most trials studied Prucalopride. Conclusion Demonstration of efficacy on patient-important outcomes and a favourable safety profile support the continued use and development of highly selective 5–HT4 agonists in the treatment of chronic constipation.

  • safety and adverse event profiles of oral Prucalopride are similar in elderly and adult patients with chronic constipation
    Gastroenterology, 2011
    Co-Authors: Michael Camilleri, Rene Kerstens, Patricia A Robinson, Lieve Vandeplassche
    Abstract:

    • Adverse events from Phase II/III double-blind placebo-controlled studies with a duration of 4 to 12 weeks were pooled. • Patients received placebo or Prucalopride for the treatment of chronic constipation at a once-daily dose of 0.5, 1, 2 or 4 mg. • Adverse events reported in elderly (≥65 years) patients were compared to those reported in adult (18-65 years) patients included in the studies. • Three elderly patients died during the studies (versus no patients in the younger age group): − Two who received Prucalopride died from pneumonia or bronchitis, both considered not related to study treatment by the investigator. − One who received placebo died from arrhythmia and myocardial infarction. • Prucalopride is a selective, high-affinity 5-HT4 receptor agonist with enterokinetic activities. The high affinity and selectivity for 5-HT4 receptors differentiates Prucalopride from older-generation compounds such as cisapride and tegaserod, by minimizing the potential for target-unrelated side effects.1-3 • In the European Union, Prucalopride is approved for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. The recommended dose is 2 mg once daily for adults and 1 mg once daily (with an increase to 2 mg once daily, if needed) for elderly patients.4

  • clinical trial the efficacy of open label Prucalopride treatment in patients with chronic constipation follow up of patients from the pivotal studies
    Alimentary Pharmacology & Therapeutics, 2010
    Co-Authors: Michael Camilleri, Rene Kerstens, M J Van Outryve, Greet Beyens, P Robinson, Lieve Vandeplassche
    Abstract:

    Aliment Pharmacol Ther 2010; 32: 1113–1123 Summary Background  Prucalopride is approved in Europe for symptomatic treatment of chronic constipation in women with inadequate relief from laxatives. Aim  To evaluate efficacy of Prucalopride during long-term treatment of patients with chronic constipation. Methods  Patients from three pivotal double-blind, placebo-controlled, 12-week studies with Prucalopride could continue treatment in open-label studies up to 24 months. Efficacy was evaluated every 3 months using the Patient Assessment of Constipation-Quality of Life (PAC-QOL) satisfaction scale. Laxative use and reasons for study discontinuation were recorded. Results  Eighty-six percent of patients who completed the pivotal studies continued Prucalopride treatment in the open-label studies (n = 1455, 90% female). Improvement in average PAC-QOL satisfaction score observed after 12-week, double-blind Prucalopride was maintained during open-label treatment for up to 18 months; in each 3 month period, 40–50% of patients did not use any laxatives. Most frequent adverse events (AEs) resulting in discontinuation were gastrointestinal events (3.3%) and headache (1.0%). Only 10% of patients who had normalized bowel function on Prucalopride at the end of pivotal trials discontinued due to insufficient response during open-label treatment. Conclusion  Satisfaction with bowel function is maintained for up to 18 months of treatment with Prucalopride. Gastrointestinal events and headache cause discontinuation of Prucalopride treatment in ∼5% of patients (ClinicalTrials.gov identifiers: NCT01070615 and NCT00987844).

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  • the 5 ht4 receptor agonist Prucalopride does not facilitate cholinergic neurotransmission in circular and longitudinal smooth muscle preparations of equine mid jejunum
    Research in Veterinary Science, 2017
    Co-Authors: Romain Lefebvre, Inge Van Colen, Chana Callens, Catherine Delesalle
    Abstract:

    Postoperative ileus (POI) remains an important cause of death in horses. The recently developed selective 5-HT4 receptor agonists such as Prucalopride target 5-HT4 receptors on myenteric cholinergic neurons to enhance acetylcholine release and GI motility. No clearcut in vitro evaluation whether highly selective 5-HT4 receptor agonists enhance submaximal cholinergic neurotransmission towards the muscle layer has been performed in horses.To identify functional 5-HT4 receptors in equine jejunum.In vitro experimental study.Circular and longitudinal smooth muscle strips (mid-jejunum) were mounted in organ baths between 2 platinum electrodes allowing electrical field stimulation (EFS). To delineate the conditions to obtain purely cholinergic responses, voltage-response curves were studied. To investigate the influence of Prucalopride and 5-HT, submaximal cholinergic contractions at a single voltage were induced.In circular and longitudinal strips, EFS induced voltage-dependent neurogenic on-contractions when the bathing medium contained a NO-synthesis inhibitor and apamin to prevent inhibitory responses to NO and ATP. Contractions at a voltage inducing 50% of maximal amplitude were cholinergic, as they were blocked by atropine. These contractions were not influenced by Prucalopride (up to 3μM), even in the presence of the phosphodiesterase inhibitor isobutyl-methyl-xanthine to inhibit breakdown of the second messenger of 5-HT4 receptors, cAMP. Also the full 5-HT4 receptor agonist 5-HT did not influence the EFS-induced submaximal cholinergic contractions. Moreover, Prucalopride did not influence muscle tone continuously enhanced with KCl.There are no functional 5-HT4 receptors on myenteric cholinergic neurons nor muscular 5-HT4 receptors in equine jejunum.

  • Synergy between 5-HT4 receptor stimulation and phosphodiesterase 4 inhibition in facilitating acetylcholine release in human large intestinal circular muscle
    Neurogastroenterology and Motility, 2017
    Co-Authors: Vicky Pauwelyn, Wim Ceelen, Romain Lefebvre
    Abstract:

    Background: Gastroprokinetic properties of 5-HT4 receptor agonists, such as Prucalopride, are attributed to activation of 5-HT4 receptors on cholinergic nerves innervating smooth muscle in the gastrointestinal smooth muscle layer, increasing acetylcholine release and muscle contraction. In porcine stomach and colon, phosphodiesterase (PDE) 4 has been shown to control the signaling pathway of these 5-HT4 receptors. The aim of this study was to investigate the PDE-mediated control of these 5-HT4 receptors in human large intestine. Methods: Circular smooth muscle strips were prepared from human large intestine; after incubation with [H-3]-choline, electrically induced tritium outflow was determined as a measure for acetylcholine release. The influence of PDE inhibition on the facilitating effect of Prucalopride on electrically induced acetylcholine release was studied. Key Results: The non-selective PDE inhibitor IBMX enhanced the facilitating effect of Prucalopride on electrically induced acetylcholine release. The selective inhibitors vinpocetine (PDE1), EHNA (PDE2) and cilostamide (PDE3) did not influence, while rolipram and roflumilast (PDE4) enhanced the Prucalopride-induced facilitation to the same extent as IBMX. Conclusions & Inferences: In human large intestinal circular muscle, the intracellular pathway of 5-HT4 receptors facilitating cholinergic neurotransmission to large intestinal circular smooth muscle is controlled by PDE4. If the synergy between 5-HT4 receptor agonism and PDE4 inhibition is confirmed in a functional assay with electrically induced cholinergic contractions of human large intestinal circular smooth muscle strips, combination of a selective 5-HT4 receptor agonist with a selective PDE4 inhibitor might enhance the in vivo prokinetic effect of the 5-HT4 receptor agonist in the large intestine.

  • the facilitating effect of Prucalopride on cholinergic neurotransmission in pig gastric circular muscle is regulated by phosphodiesterase 4
    Neuropharmacology, 2012
    Co-Authors: Evelien K V Priem, Inge Van Colen, Joris H De Maeyer, Romain Lefebvre
    Abstract:

    Abstract The influence of the selective 5-HT 4 receptor agonist Prucalopride on acetylcholine release from cholinergic nerve endings innervating pig gastric circular muscle and the possible regulation of this effect by phosphodiesterases (PDEs) was investigated, as PDEs have been shown to control the response to 5-HT 4 receptor activation in pig left atrium. Circular muscle strips were prepared from pig proximal stomach and either submaximal cholinergic contractions or tritium outflow after incubation with [ 3 H]-choline, induced by electrical field stimulation, were studied. Prucalopride concentration-dependently increased the amplitude of submaximal cholinergic contractions and of acetylcholine release induced by electrical field stimulation. The effect of the highest concentration tested (0.3 μM) on cholinergic contractions was antagonized by the selective 5-HT 4 receptor antagonist GR113808 but not by granisetron or methysergide; the antagonism of Prucalopride by GR113808 was confirmed in the release assay. The non-selective PDE-inhibitor 3-isobutyl-methyl-xanthine (IBMX) concentration-dependently reduced the amplitude of the cholinergic contractions; 3 μM IBMX reduced the cholinergic contractions maximally by 16% but it enhanced the facilitating effect of Prucalopride from 51 to 83%. IBMX (10 μM) induced and enhanced the facilitating effect of Prucalopride on electrically induced acetylcholine release. The selective inhibitors vinpocetine (PDE1), EHNA (PDE2) and cilostamide (PDE3) did not influence the effect of Prucalopride on acetylcholine release but the PDE4-inhibitor rolipram (1 μM) enhanced the facilitating effect of Prucalopride to the same extent as IBMX. These results demonstrate that 5-HT 4 receptors are present on the cholinergic nerves towards the pig gastric circular muscle, facilitating acetylcholine release; the intracellular transduction pathway of this facilitation is regulated by PDE4. Combination of a 5-HT 4 receptor agonist with selective inhibition of the PDE involved in this regulation of transmitter release might enhance the prokinetic effect of the 5-HT 4 receptor agonist.

  • Selective desensitization of the 5‐HT4 receptor‐mediated response in pig atrium but not in stomach
    British Journal of Pharmacology, 2009
    Co-Authors: Jeroen De Maeyer, Jan A J Schuurkes, Romain Lefebvre
    Abstract:

    Background and purpose:  The time dependency of the effect of 5-HT4 receptor agonists depends on many specific regulatory mechanisms, which vary between tissues. This has important implications with regard to the effects of endogenous 5-HT, as well as to the clinical use of 5-HT4 receptor agonists, and might contribute to tissue selectivity of agonists. Experimental approach:  The progression and desensitization of 5-HT4 receptor-mediated responses were evaluated in an organ bath set-up using two, clinically relevant, porcine in vitro models: gastric cholinergic neurotransmission and atrial contractility. Key results:  Exposure of gastric tissue to 5-HT or to the selective 5-HT4 receptor agonists Prucalopride and M0003 results in a sustained non-transient effect during exposure; after washout, the response to a subsequent challenge with 5-HT shows no clear desensitization. Incubation of left atrial tissue with 5-HT resulted in a transient response, leading after washout to a marked desensitization of the subsequent response to 5-HT. The selective 5-HT4 receptor agonists Prucalopride and M0003 induce only very weak atrial responses whereas they are very effective in desensitizing the atrial response to 5-HT. The observations also suggest that the properties of Prucalopride and M0003 to bind to and/or activate the 5-HT4 receptor differ from those of 5-HT. This difference might have contributed to the observed desensitization. Conclusions and implications:  The high potency of Prucalopride and M0003 in desensitizing the response to 5-HT together with their low efficacy in the atrium emphasizes the cardiac safety of this class of 5-HT4 receptor agonists.

  • RESEARCH PAPER Selective desensitization of the 5-HT4 receptor- mediated response in pig atrium but not in stomach
    2009
    Co-Authors: Jeroen De Maeyer, Jan A J Schuurkes, Romain Lefebvre
    Abstract:

    Background and purpose: The time dependency of the effect of 5-HT4 receptor agonists depends on many specific regulatory mechanisms, which vary between tissues. This has important implications with regard to the effects of endogenous 5-HT, as well as to the clinical use of 5-HT4 receptor agonists, and might contribute to tissue selectivity of agonists. Experimental approach: The progression and desensitization of 5-HT4 receptor-mediated responses were evaluated in an organ bath set-up using two, clinically relevant, porcine in vitro models: gastric cholinergic neurotransmission and atrial contractility. Key results: Exposure of gastric tissue to 5-HT or to the selective 5-HT4 receptor agonists Prucalopride and M0003 results in a sustained non-transient effect during exposure; after washout, the response to a subsequent challenge with 5-HT shows no clear desensitization. Incubation of left atrial tissue with 5-HT resulted in a transient response, leading after washout to a marked desensitization of the subsequent response to 5-HT. The selective 5-HT4 receptor agonists Prucalopride and M0003 induce only very weak atrial responses whereas they are very effective in desensitizing the atrial response to 5-HT. The observations also suggest that the properties of Prucalopride and M0003 to bind to and/or activate the 5-HT4 receptor differ from those of 5-HT. This difference might have contributed to the observed desensitization. Conclusions and implications: The high potency of Prucalopride and M0003 in desensitizing the response to 5-HT together with their low efficacy in the atrium emphasizes the cardiac safety of this class of 5-HT4 receptor agonists.

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