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Michael Camilleri - One of the best experts on this subject based on the ideXlab platform.
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Systematic review with meta-analysis: highly selective 5-HT4 Agonists (prucalopride, velusetrag or naronapride) in chronic constipation.
Alimentary Pharmacology & Therapeutics, 2013Co-Authors: Andrea Shin, Michael Camilleri, Gururaj J. Kolar, Patricia J. Erwin, Colin Patrick West, Mohammad Hassan MuradAbstract: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.
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Role of prucalopride, a serotonin (5-HT4) receptor agonist, for the treatment of chronic constipation
Dove Medical Press, 2010Co-Authors: Banny S Wong, Noriaki Manabe, Michael CamilleriAbstract:Banny S Wong, Noriaki Manabe, Michael CamilleriClinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic, Rochester, Minnesota, USAAbstract: Constipation affects up to a quarter of the population in developed countries and is associated with poor quality of life and significant economic burden. Many patients with chronic constipation are dissatisfied with current therapy due to lack of long-term efficacy or side effects. Previous nonselective 5-hydroxytryptamine receptor 4 (5-HT4) Agonists have been associated with significant interactions with other receptors (5-HT1B, 5-HT1D, and 5-HT2B for tegaserod; hERG for cisapride), leading to adverse cardiovascular events resulting in withdrawal of these drugs from the market. Prucalopride is a novel gastrointestinal prokinetic agent. It acts as a high affinity, highly-selective 5-HT4 agonist. Its efficacy in patients with chronic constipation has been demonstrated in several phase II and phase III clinical trials showing significant improvements in bowel transit, bowel function, gastrointestinal symptoms, and quality of life, with benefit maintained for up to 24 months in open label, multicenter, follow-up studies. Prucalopride’s high selectivity for the 5-HT4 receptor may explain its favorable safety and tolerability profiles, even in elderly subjects with stable cardiovascular disease. Prucalopride is a well tolerated and efficacious prokinetic medication that should enhance the treatment of chronic constipation unresponsive to first-line treatments.Keywords: prucalopride, 5-HT4 agonist, serotonin agonist, efficacy, prokineti
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does co administration of a non selective opiate antagonist enhance acceleration of transit by a 5 ht4 agonist in constipation predominant irritable bowel syndrome a randomized controlled trial
Neurogastroenterology and Motility, 2007Co-Authors: Amy E Foxxorenstein, Michael Camilleri, Lawrence A Szarka, S Mckinzie, D D Burton, G Thomforde, K Baxter, Alan R ZinsmeisterAbstract:Abstract Opioid neurons exhibit tonic restraint on intestinal motility; opioid antAgonists stimulate peristalsis and increase transit. In vitro, 5-hydroxytryptamine (5-HT4) Agonists combined with selective opioid antAgonists significantly increased colonic propulsion relative to a 5-HT4 agonist alone. We hypothesized that the combination of 5-HT4 agonist and non-selective opioid antagonist enhances intestinal transit more than either treatment alone in female constipation-predominant irritable bowel syndrome (C-IBS) patients. Our aim was to examine the effect of tegaserod 6 mg b.i.d. alone and combined with naltrexone 50 mg on intestinal transit and stool characteristics in females with C-IBS. Forty-eight patients were randomized to tegaserod alone, naltrexone alone or in combination with tegaserod or placebo for 6 days. Small bowel, ascending colon half-life (in pharmacokinetics) (t1/2), and colonic geometric centre (8, 24, 48 h) were assessed by scintigraphy. Tegaserod increased small bowel (P < 0.01) and colon transit (P < 0.01). Naltrexone did not accelerate colonic transit relative to placebo. Combination treatment did not significantly accelerate transit relative to tegaserod alone. Tegaserod and tegaserod with naltrexone resulted in looser stool form (P < 0.01). In female C-IBS patients, tegaserod accelerates small bowel and colon transit and contributed to looser stool consistency. Use of naltrexone, 50 mg, does not support the hypothesis that combination of 5-HT4 agonist and non-selective opioid antagonist enhances intestinal transit.
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Effects of a serotonin 5-HT4 receptor antagonist SB-207266 on gastrointestinal motor and sensory function in humans
Gut, 2000Co-Authors: Adil Eddie Bharucha, S Haydock, Irene Ferber, D Tompson, R Higgins, Michael Camilleri, Duane Burton, S Cooper, K Fitzpatrick, Alan R ZinsmeisterAbstract:BACKGROUND—Serotonin 5-HT4 receptors are located on enteric cholinergic neurones and may regulate peristalsis. 5-HT4 receptors on primary afferent neurones have been postulated to modulate visceral sensation. While 5-HT4 Agonists are used as prokinetic agents, the physiological role of 5-HT4 receptors in the human gut is unknown. AIMS—Our aim was to characterise the role of 5-HT4 receptors in regulating gastrointestinal motor and sensory function in healthy subjects under baseline and stimulated conditions with a 5-HT4 receptor antagonist. METHODS—Part A compared the effects of placebo to four doses of a 5-HT4 receptor antagonist (SB-207266) on the cisapride mediated increase in plasma aldosterone (a 5-HT4 mediated response) and orocaecal transit in 18 subjects. In part B, 52 healthy subjects received placebo, or 0.05, 0.5, or 5 mg of SB-207266 for 10-12 days; gastric, small bowel, and colonic transit were measured by scintigraphy on days 7-9, and fasting and postprandial colonic motor function, compliance, and sensation during distensions were assessed on day 12. RESULTS—Part A: 0.5, 5, and 20 mg doses of SB-207266 had significant and quantitatively similar effects, antagonising the cisapride mediated increase in plasma aldosterone and acceleration of orocaecal transit. Part B: SB-207266 tended to delay colonic transit (geometric centre of isotope at 24 (p=0.06) and 48 hours (p=0.08)), but did not have dose related effects on transit, fasting or postprandial colonic motor activity, compliance, or sensation. CONCLUSION—5-HT4 receptors are involved in the regulation of cisapride stimulated orocaecal transit; SB 207266 tends to modulate colonic transit but not sensory functions or compliance in healthy human subjects. Keywords: 5-HT4 receptors; colon transit; gastrointestinal motor function; gastrointestinal sensory function
Thomas M Macdonald - One of the best experts on this subject based on the ideXlab platform.
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study design and cohort comparability in a study of major cardiovascular events in new users of prucalopride versus polyethylene glycol 3350
Drug Safety, 2019Co-Authors: Joan Fortuny, Alicia W Gilsenan, Miguel Cainzosachirica, Oscar F Cantero, Robert W V Flynn, Luis A Garciarodriguez, Bianca Kollhorst, Par Karlsson, Love Linner, Thomas M MacdonaldAbstract:Given prior safety experience with other 5-HT4 Agonists for chronic constipation, an observational, population-based cohort study in five data sources from Germany, Sweden, and the UK was conducted to evaluate the cardiovascular safety of prucalopride. Our objective is to describe the methods and resulting comparability of cohorts in a multi-database, multinational study of prucalopride initiators and polyethylene glycol 3350 (PEG) initiators following a harmonized protocol. Prucalopride initiators were matched on age, sex, and index date to PEG initiators (1:5 ratio). Study exposures, cardiovascular risk factors, and other covariates were identified from healthcare utilization codes harmonized across databases. Cardiovascular outcomes were identified using database-specific algorithms based on diagnosis codes. The propensity score (PS) in each database was estimated using logistic regression, with prucalopride versus PEG as the outcome and including clinically relevant variables associated with major adverse cardiovascular events. In total, 12,030 prucalopride initiators and 59,985 PEG initiators were identified. After matching and trimming, cohorts from the UK and Sweden were well-balanced for cardiovascular risk factors and cancer. However, in Germany, PEG initiators remained older and sicker than prucalopride initiators. The prevalence of these characteristics also differed from those in the UK and Sweden. The pooled analyses included only data from the UK and Sweden. Matching, trimming, and PS stratification yielded comparable cohorts in four of five data sources. Use of these methods could not achieve balance for key covariates within the German cohort, likely due to reimbursement differences in Germany.
Alan R Zinsmeister - One of the best experts on this subject based on the ideXlab platform.
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does co administration of a non selective opiate antagonist enhance acceleration of transit by a 5 ht4 agonist in constipation predominant irritable bowel syndrome a randomized controlled trial
Neurogastroenterology and Motility, 2007Co-Authors: Amy E Foxxorenstein, Michael Camilleri, Lawrence A Szarka, S Mckinzie, D D Burton, G Thomforde, K Baxter, Alan R ZinsmeisterAbstract:Abstract Opioid neurons exhibit tonic restraint on intestinal motility; opioid antAgonists stimulate peristalsis and increase transit. In vitro, 5-hydroxytryptamine (5-HT4) Agonists combined with selective opioid antAgonists significantly increased colonic propulsion relative to a 5-HT4 agonist alone. We hypothesized that the combination of 5-HT4 agonist and non-selective opioid antagonist enhances intestinal transit more than either treatment alone in female constipation-predominant irritable bowel syndrome (C-IBS) patients. Our aim was to examine the effect of tegaserod 6 mg b.i.d. alone and combined with naltrexone 50 mg on intestinal transit and stool characteristics in females with C-IBS. Forty-eight patients were randomized to tegaserod alone, naltrexone alone or in combination with tegaserod or placebo for 6 days. Small bowel, ascending colon half-life (in pharmacokinetics) (t1/2), and colonic geometric centre (8, 24, 48 h) were assessed by scintigraphy. Tegaserod increased small bowel (P < 0.01) and colon transit (P < 0.01). Naltrexone did not accelerate colonic transit relative to placebo. Combination treatment did not significantly accelerate transit relative to tegaserod alone. Tegaserod and tegaserod with naltrexone resulted in looser stool form (P < 0.01). In female C-IBS patients, tegaserod accelerates small bowel and colon transit and contributed to looser stool consistency. Use of naltrexone, 50 mg, does not support the hypothesis that combination of 5-HT4 agonist and non-selective opioid antagonist enhances intestinal transit.
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Effects of a serotonin 5-HT4 receptor antagonist SB-207266 on gastrointestinal motor and sensory function in humans
Gut, 2000Co-Authors: Adil Eddie Bharucha, S Haydock, Irene Ferber, D Tompson, R Higgins, Michael Camilleri, Duane Burton, S Cooper, K Fitzpatrick, Alan R ZinsmeisterAbstract:BACKGROUND—Serotonin 5-HT4 receptors are located on enteric cholinergic neurones and may regulate peristalsis. 5-HT4 receptors on primary afferent neurones have been postulated to modulate visceral sensation. While 5-HT4 Agonists are used as prokinetic agents, the physiological role of 5-HT4 receptors in the human gut is unknown. AIMS—Our aim was to characterise the role of 5-HT4 receptors in regulating gastrointestinal motor and sensory function in healthy subjects under baseline and stimulated conditions with a 5-HT4 receptor antagonist. METHODS—Part A compared the effects of placebo to four doses of a 5-HT4 receptor antagonist (SB-207266) on the cisapride mediated increase in plasma aldosterone (a 5-HT4 mediated response) and orocaecal transit in 18 subjects. In part B, 52 healthy subjects received placebo, or 0.05, 0.5, or 5 mg of SB-207266 for 10-12 days; gastric, small bowel, and colonic transit were measured by scintigraphy on days 7-9, and fasting and postprandial colonic motor function, compliance, and sensation during distensions were assessed on day 12. RESULTS—Part A: 0.5, 5, and 20 mg doses of SB-207266 had significant and quantitatively similar effects, antagonising the cisapride mediated increase in plasma aldosterone and acceleration of orocaecal transit. Part B: SB-207266 tended to delay colonic transit (geometric centre of isotope at 24 (p=0.06) and 48 hours (p=0.08)), but did not have dose related effects on transit, fasting or postprandial colonic motor activity, compliance, or sensation. CONCLUSION—5-HT4 receptors are involved in the regulation of cisapride stimulated orocaecal transit; SB 207266 tends to modulate colonic transit but not sensory functions or compliance in healthy human subjects. Keywords: 5-HT4 receptors; colon transit; gastrointestinal motor function; gastrointestinal sensory function
Joan Fortuny - One of the best experts on this subject based on the ideXlab platform.
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study design and cohort comparability in a study of major cardiovascular events in new users of prucalopride versus polyethylene glycol 3350
Drug Safety, 2019Co-Authors: Joan Fortuny, Alicia W Gilsenan, Miguel Cainzosachirica, Oscar F Cantero, Robert W V Flynn, Luis A Garciarodriguez, Bianca Kollhorst, Par Karlsson, Love Linner, Thomas M MacdonaldAbstract:Given prior safety experience with other 5-HT4 Agonists for chronic constipation, an observational, population-based cohort study in five data sources from Germany, Sweden, and the UK was conducted to evaluate the cardiovascular safety of prucalopride. Our objective is to describe the methods and resulting comparability of cohorts in a multi-database, multinational study of prucalopride initiators and polyethylene glycol 3350 (PEG) initiators following a harmonized protocol. Prucalopride initiators were matched on age, sex, and index date to PEG initiators (1:5 ratio). Study exposures, cardiovascular risk factors, and other covariates were identified from healthcare utilization codes harmonized across databases. Cardiovascular outcomes were identified using database-specific algorithms based on diagnosis codes. The propensity score (PS) in each database was estimated using logistic regression, with prucalopride versus PEG as the outcome and including clinically relevant variables associated with major adverse cardiovascular events. In total, 12,030 prucalopride initiators and 59,985 PEG initiators were identified. After matching and trimming, cohorts from the UK and Sweden were well-balanced for cardiovascular risk factors and cancer. However, in Germany, PEG initiators remained older and sicker than prucalopride initiators. The prevalence of these characteristics also differed from those in the UK and Sweden. The pooled analyses included only data from the UK and Sweden. Matching, trimming, and PS stratification yielded comparable cohorts in four of five data sources. Use of these methods could not achieve balance for key covariates within the German cohort, likely due to reimbursement differences in Germany.
Oscar F Cantero - One of the best experts on this subject based on the ideXlab platform.
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study design and cohort comparability in a study of major cardiovascular events in new users of prucalopride versus polyethylene glycol 3350
Drug Safety, 2019Co-Authors: Joan Fortuny, Alicia W Gilsenan, Miguel Cainzosachirica, Oscar F Cantero, Robert W V Flynn, Luis A Garciarodriguez, Bianca Kollhorst, Par Karlsson, Love Linner, Thomas M MacdonaldAbstract:Given prior safety experience with other 5-HT4 Agonists for chronic constipation, an observational, population-based cohort study in five data sources from Germany, Sweden, and the UK was conducted to evaluate the cardiovascular safety of prucalopride. Our objective is to describe the methods and resulting comparability of cohorts in a multi-database, multinational study of prucalopride initiators and polyethylene glycol 3350 (PEG) initiators following a harmonized protocol. Prucalopride initiators were matched on age, sex, and index date to PEG initiators (1:5 ratio). Study exposures, cardiovascular risk factors, and other covariates were identified from healthcare utilization codes harmonized across databases. Cardiovascular outcomes were identified using database-specific algorithms based on diagnosis codes. The propensity score (PS) in each database was estimated using logistic regression, with prucalopride versus PEG as the outcome and including clinically relevant variables associated with major adverse cardiovascular events. In total, 12,030 prucalopride initiators and 59,985 PEG initiators were identified. After matching and trimming, cohorts from the UK and Sweden were well-balanced for cardiovascular risk factors and cancer. However, in Germany, PEG initiators remained older and sicker than prucalopride initiators. The prevalence of these characteristics also differed from those in the UK and Sweden. The pooled analyses included only data from the UK and Sweden. Matching, trimming, and PS stratification yielded comparable cohorts in four of five data sources. Use of these methods could not achieve balance for key covariates within the German cohort, likely due to reimbursement differences in Germany.