prucalopride and Chronic-Disease

Prokinetic agents, specifically 5-hydroxytryptamine type 4 (5-HT 4 ) receptor agonists, have been shown to provide relief in chronic idiopathic constipation (CIC). The first-generation 5-HT 4 agonists were initially withdrawn from use owing to associations with serious cardiovascular (CV) events. This review summarizes CV safety data for prucalopride, a high-affinity 5-HT 4 agonist approved in the United States in 2018 for adults with CIC. No significant effects of prucalopride on CV safety were observed in animal models or early-phase clinical studies, including a thorough QT study at therapeutic (2 mg) or supratherapeutic (10 mg) doses. Among 1,750 patients with CIC who received prucalopride (2-4 mg) in 5 phase 3 studies, no trends in CV adverse events, electrocardiogram parameters, or blood pressure were documented; ≤1.0%-2.0% of patients had prolonged QT interval corrected for heart rate (HR) using Fridericia formula after placebo or prucalopride treatment, and low HR occurred in ≤6.1% and ≤3.3% of these patients, respectively. In two 24-month observational studies among 2,468 patients, changes in electrocardiogram parameters over time were minor, except at occasional time points when significant changes from baseline were reported for HR or QT interval. In a real-world European CV safety study among 35,087 patients (prucalopride, 5,715; polyethylene glycol 3350 [PEG3350], 29,372), results were consistent for no evidence of increased risk of major adverse CV events among patients treated with prucalopride vs PEG3350 (incidence rate ratio = 0.64; 95% confidence interval 0.36-1.14). Studies to date have not raised concerns regarding the impact of prucalopride treatment on CV parameters.

Topics: Chronic Disease; Constipation; Humans; Laxatives; Serotonin; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome

Topics: Benzofurans; Chronic Disease; Clinical Trials as Topic; Constipation; Half-Life; Humans; Laxatives; Receptors, Serotonin, 5-HT4; Treatment Outcome

Topics: Adult; Benzofurans; Chronic Disease; Constipation; Gastrointestinal Motility; Humans; Laxatives; Serotonin 5-HT4 Receptor Agonists

Prucalopride (Resolor®), a highly selective serotonin 5-HT4 receptor agonist, is indicated in the European Economic Area for the treatment of adults with chronic idiopathic constipation (CIC) in whom laxatives have failed to provide adequate relief. This article reviews the pharmacological properties of prucalopride and its clinical efficacy and tolerability in patients with CIC. In five well-designed, 12-week trials in patients with CIC, oral prucalopride 2 mg/day was significantly more effective than placebo at improving bowel function, including the number of bowel movements and a range of other constipation symptoms, as well as health-related quality of life and patient satisfaction; however, no significant differences in bowel function measures were observed between prucalopride and placebo in a 24-week trial. Oral PEG-3350 + electrolytes reconstituted powder was found to be noninferior but not superior to prucalopride according to primary endpoint data from a 4-week, controlled-environment trial. Prucalopride was generally well tolerated in clinical trials; the most common adverse events were headache, diarrhoea, nausea and abdominal pain. No cardiovascular safety issues have arisen with prucalopride treatment. Although further long-term and comparative data would be beneficial, prucalopride provides an additional treatment option for patients with CIC.

Topics: Benzofurans; Chronic Disease; Constipation; Humans; Laxatives; Serotonin 5-HT4 Receptor Agonists

Topics: Benzofurans; Chronic Disease; Combined Modality Therapy; Constipation; Diagnosis, Differential; Dietary Fiber; General Practice; Guideline Adherence; Humans; Laxatives

Chronic constipation (CC) is a debilitating condition with high prevalence rates both in children and adults. Despite the broad range of medical and pharmaceutical treatments, the bowel function does not restore in a fair amount of patients. Prucalopride is a first-in-class selective, high affinity serotonin 5-hydroxytryptamine type 4 (5-HT4) receptor agonist promoting gastro-intestinal prokinetic activity and has been evaluated for the treatment of CC.. A PubMed search (1965 - 2014) using the following terms alone or in combination: prucalopride, 5-HT4, R093877, safety, toxicity, pharmacokinetics, pharmacodynamics, transit, cardiac, human ether-a-go-go related gene (hERG), arrhythmia, potassium current, elderly, children.. Prucalopride, a highly selective 5-HT4 receptor agonist, stimulates gastrointestinal motility and has been proven to be effective in the treatment of CC in adults by increasing stool frequency, reducing constipation-related symptoms and improving quality of life (QoL). The safety and tolerability have been proven to be excellent. More research would be preferable on the effect of prucalopride on men, children and in other gastrointestinal motility disorders.

Topics: Adult; Benzofurans; Child; Chronic Disease; Constipation; Gastrointestinal Motility; Humans; Quality of Life; Serotonin 5-HT4 Receptor Agonists

Highly selective 5-HT4 agonists have been suggested for the treatment of chronic constipation (CC).. 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.. 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).. 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.. 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.

Topics: Adult; Azabicyclo Compounds; Benzamides; Benzofurans; Chronic Disease; Constipation; Defecation; Humans; Polyethylene Glycols; Quality of Life; Quinuclidines; Serotonin 5-HT4 Receptor Agonists

Chronic constipation is a frequent pathological condition bearing relevant socioeconomic burdens, mainly due to uncertain management and unsatisfactory response to traditional laxatives. Prucalopride is a novel enterokinetic drug, that has been demonstrated to improve bowel functions and relieve a broad spectrum of digestive symptoms in patients with severe chronic constipation who had failed to respond to various traditional laxatives. In this paper we discussed the practical aspects of chronic constipation treatment, in particular focusing on some questions about the practical use of prucalopride. Prucalopride is a potent, selective, high-affinity agonist of the 5-HT4 receptors widely expressed in the gastrointestinal tract. Unlike other 5-HT4 agonists, such as cisapride and tegaserod, it is devoid of adverse cardiovascular effects. Furthermore, it is characterized by a low potential for interactions with other drugs, due to its pharmacokinetic characteristics. Prucalopride was approved, in 2009, by the European Medicines Agency for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief, however, there are ongoing studies to extend the use of the drug even to males.

Topics: Benzofurans; Chronic Disease; Constipation; Defecation; Dose-Response Relationship, Drug; Humans; Laxatives; Practice Guidelines as Topic; Quality of Life; Randomized Controlled Trials as Topic; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome

A number of new medications were recently demonstrated to be more effective than placebo in treating chronic constipation, including the intestinal chloride channel activator lubiprostone, the prokinetic selective 5-HT4 receptor agonist prucalopride and the guanylate cyclase-C agonist linaclotide. Recent publications have also revisited traditional laxatives like PEG. Moreover, a number of pharmacological treatments are in development and these include another guanylate cyclase-C agonist, plecanatide and an ileal bile acid transporter inhibitor, elobixibat.. This review focuses on the pharmacology, efficacy and safety profile of prucalopride, linaclotide, plecanatide and elobixibat.. The possible present or future clinical application of prucalopride, linaclotide, plecanatide and elobixibat in both chronic constipation and irritable bowel syndrome with constipation is reported, and some considerations on the possible role of PEG taking into account recent literature are advanced.

Topics: Benzofurans; Chronic Disease; Constipation; Dipeptides; Humans; Irritable Bowel Syndrome; Laxatives; Natriuretic Peptides; Peptides; Thiazepines

Chronic constipation is a frequent condition often treated pharmacologically. The laxatives available belong to very different pharmacologic groups.. This is a short but comprehensive review of the pharmacology, efficacy and safety of currently available laxatives for chronic constipation. Pertinent publications were retrieved from reference lists of publications and by literature searches via PubMed, lastly performed in November 2012.. The most relevant laxative groups are the older representatives osmotic salts, sugars and sugar alcohols, macrogol, anthraquinones, diphenolic laxatives or diphenyl methanes (bisacodyl and sodium picosulfate) and the newer compounds prucalopride, lubiprostone and linaclotide. For all of these laxatives efficacy has been shown in controlled trials. Electrolyte losses do not occur when laxatives are given in therapeutic doses (rare exceptions with phosphate salts and salinic laxatives). The older laxatives are also safe regarding teratogenicity, abortion and lactation. For the newer compounds no respective data are available as yet. It is questionable whether the newer compounds offer advantages over the older ones. Unfortunately, comparative trials are lacking.

Topics: Alprostadil; Anthraquinones; Benzofurans; Bisacodyl; Chronic Disease; Constipation; Dose-Response Relationship, Drug; Humans; Laxatives; Lubiprostone; Peptides; Polyethylene Glycols; Randomized Controlled Trials as Topic; Treatment Outcome

The highly selective serotonin 5-HT4 receptor agonist prucalopride (Resolor(®), Resotran(®), Resotrans(®)) is indicated for the treatment of chronic constipation. In four randomized, double-blind, multicentre, 12-week trials in patients (predominantly women) with chronic constipation, oral prucalopride 2 mg once daily improved bowel function to a significantly greater extent than placebo, with a significantly greater proportion of prucalopride than placebo recipients achieving an average of ≥3 spontaneous, complete bowel movements per week (primary endpoint). Significantly greater improvements in health-related quality of life, patient satisfaction with treatment and bowel habit, and a range of constipation-related symptoms were also seen with prucalopride than with placebo. Satisfaction with treatment and bowel habit was maintained with prucalopride in the longer term. Prucalopride was generally well tolerated in patients with chronic constipation, with the most commonly reported adverse events (headache, nausea, abdominal pain, diarrhoea) primarily occurring on the first day of treatment. During the clinical trials, no cardiovascular safety issues have arisen in patients with chronic constipation receiving prucalopride. In conclusion, prucalopride is an important option for use in patients with chronic constipation who have not experienced adequate relief with laxatives.

Topics: Benzofurans; Chronic Disease; Constipation; Humans; Patient Satisfaction; Quality of Life; Randomized Controlled Trials as Topic; Serotonin 5-HT4 Receptor Agonists; Time Factors

Constipation is a highly prevalent disorder. Some patients suffer from acute, intermittent episodes of constipation. Others, however, suffer from chronic constipation, a term that refers to those patients with symptoms of constipation for more than 6 months. In clinical practice, chronic constipation is often used interchangeably with the term functional constipation, which is currently defined using the Rome III criteria. Symptoms can be burdensome, leading to a reduction in patients' quality of life. In addition, chronic constipation is important because it imposes a significant economic impact to the health care system. Some patients with chronic constipation have persistent symptoms despite implementing lifestyle changes and using either over-the-counter agents or prescription medications. These patients may be categorized as having difficult constipation. This report will focus on recent advances in the management of difficult constipation, and include a discussion of new and upcoming medications as well as new diagnostic tests and procedures.

Topics: Benzofurans; Chronic Disease; Constipation; Electric Stimulation Therapy; Humans; Laxatives; Magnetic Resonance Imaging; Manometry; Peptides

Prucalopride is the first member of a novel class of 5-HT(4) receptor agonist which has been extensively evaluated for the treatment of chronic constipation. Predominantly, prucalopride is currently used to treat patients that show an insufficient response to laxatives as an alternative form of therapy.. The following article provides the reader with a systematic review of the literature on prucalopride. Specifically, the article reviews the currently literature on the pharmacokinetics and the pharmacodynamics of the drugs as well as reviewing literature on its efficacy. Furthermore, the authors also highlight the safety and tolerability of the drug that have been demonstrated in its clinical development.. Prucalopride is an important addition to the therapeutic abilities for treating chronic constipation, especially in females poorly responding to laxatives. The safety profile of the drug, to date, is favorable. There is also the possibility that prucalopride might be of benefit to other disorders of gastrointestinal motility with a number of studies currently in progress, which are evaluating alternative applications.

Topics: Benzofurans; Chronic Disease; Constipation; Gastrointestinal Motility; Humans; Laxatives; Quality of Life; Serotonin 5-HT4 Receptor Agonists

There has been no definitive systematic review and meta-analysis to date examining the effect of laxatives and pharmacological therapies in chronic idiopathic constipation (CIC).. To assess efficacy of these therapies systematically in CIC.. Systematic review and meta-analysis of randomised controlled trials (RCTs).. MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (up to September 2010).. Placebo-controlled trials of laxatives or pharmacological therapies in adult CIC patients were eligible. Minimum duration of therapy was 1 week. Trials had to report either a dichotomous assessment of overall response to therapy at last point of follow-up in the trial, or mean number of stools per week during therapy.. Symptom data were pooled using a random effects model. Effect of laxatives or pharmacological therapies compared to placebo was reported as RR of failure to respond to therapy, or a weighted mean difference (WMD) in mean number of stools per week, with 95% CIs.. Twenty-one eligible RCTs were identified. Laxatives (seven RCTs, 1411 patients, RR=0.52; 95% CI 0.46 to 0.60), prucalopride (seven trials, 2639 patients, RR=0.82; 95% CI 0.76 to 0.88), lubiprostone (three RCTs, 610 patients, RR=0.67; 95% CI 0.56 to 0.80), and linaclotide (three trials, 1582 patients, RR=0.84; 95% CI 0.80 to 0.87) were all superior to placebo in terms of a reduction in risk of failure with therapy. Treatment effect remained similar when only RCTs at low risk of bias were included in the analysis. Diarrhoea was significantly more common with all therapies.. Only two RCTs were conducted in primary care, and total adverse events data for laxatives and linaclotide were sparse.. Laxatives, prucalopride, lubiprostone and linaclotide are all more effective than placebo for the treatment of CIC.

Topics: Alprostadil; Benzofurans; Chronic Disease; Constipation; Diarrhea; Humans; Laxatives; Lubiprostone; Peptides; Randomized Controlled Trials as Topic; Treatment Outcome

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of prucalopride for the treatment of women with chronic constipation in whom standard laxative regimens have failed to provide adequate relief. The ERG report is based on the manufacturer's submission (MS) to the National Institute for Health and Clinical Excellence as part of the single technology appraisal process. In the submission, quality-of-life data [Patient Assessment of Constipation Quality of Life (PAC-QOL) and Patient Assessment of Constipation Symptoms (PAC-SYM) questionnaires] from trials of prucalopride were extrapolated to EQ-5D (European Quality of Life-5 Dimensions) data and used to inform effectiveness in an economic model. Response rates to prucalopride were derived from observed response rates in trials, defined as the proportion of patients achieving an average of three or more spontaneous complete bowel movements over the 4- or 12-week trial periods. Adult (18-64 years) and elderly (≥ 65 years) patients were considered separately in the model. Cost-effectiveness was determined from estimated improvements in EQ-5D and anticipated response rates, adjusted for baseline severity of chronic constipation. The ERG considered that the patients participating in these trials were not representative of those in the licensed indication. They were not all refractory to laxatives, and baseline EQ-5D scores showed a large spread in quality of life, with many patients experiencing little baseline dissatisfaction. The mapping of quality-of-life data from trials (PAC-QOL and PAC-SYM data) to EQ-5D was unclear and invalidated. The assumption of the long-term effectiveness and safety of prucalopride to 1 year was considered unjustified. There was no justification or sources given for coefficients used to predict effectiveness in the economic model, and no costs other than the cost of prucalopride were incorporated into the model. Owing to the many areas of uncertainty, particularly the effectiveness of prucalopride in the licensed patient group and its long-term effectiveness and safety, it was considered that the MS provided no evidence for whether prucalopride is effective or not in women with laxative-refractory chronic constipation. Further subgroup analysis of the actual patient group of interest may have better guided decision-making. However, long-term efficacy data, with validated estimates of quality of life incorporate

Topics: Adult; Aged; Benzofurans; Chronic Disease; Clinical Trials as Topic; Constipation; Cost-Benefit Analysis; Female; Humans; Laxatives; Middle Aged; Models, Economic; Quality of Life

▾Prucalopride (Resolor - Shire Pharmaceuticals Ltd) is licensed, only in women, for symptomatic treatment of chronic constipation when laxatives fail to provide adequate relief. It is promoted as being "effective in helping to restore normal bowel movements and alleviating a broad range of constipation symptoms in women." Here we review the evidence for prucalopride and consider the drug's place as a treatment for chronic constipation.

Topics: Benzofurans; Chronic Disease; Constipation; Data Collection; Dose-Response Relationship, Drug; Drug Approval; Drug Costs; Female; Humans; Laxatives; Male; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Treatment Outcome

Constipation is a common functional gastrointestinal disorder that affects patients of all ages. In 2007, a consensus group of 10 Canadian gastroenterologists developed a set of recommendations pertaining to the management of chronic constipation and constipation dominant irritable bowel syndrome. Since then, tegaserod has been withdrawn from the Canadian market. A new, highly selective serotonin receptor subtype 4 agonist, prucalopride, has been examined in several large, randomized, placebo-controlled trials demonstrating its efficacy and safety in the management of patients with chronic constipation. Additional studies evaluating the use of stimulant laxatives, polyethylene glycol and probiotics in the management of chronic constipation have also been published. The present review summarizes the previous recommendations and new evidence supporting different treatment modalities - namely, diet and lifestyle, bulking agents, stool softeners, osmotic and stimulant laxatives, prucalopride and probiotics in the management of chronic constipation. A brief summary of lubiprostone and linaclotide is also presented. The quality of evidence is presented by adopting the Grading of Recommendations, Assessment, Development and Evaluation system. Finally, a management pyramid for patients with chronic constipation is proposed based on the quality of evidence, impact of each modality on constipation and on general health, and their availabilities in Canada.

Topics: Alprostadil; Benzofurans; Chloride Channels; Chronic Disease; Constipation; Feedback, Physiological; Gastrointestinal Motility; Humans; Laxatives; Life Style; Lubiprostone; Peptides

Chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (C-IBS) are commonly reported gastrointestinal (GI) disorders that have a major impact on health and quality of life. Patients experience a range of symptoms of which infrequency of bowel movement is but one and report that straining, the production of hard stools, and unproductive urges are more bothersome than stool infrequency. Additionally, in C-IBS, patients report abdominal pain and bloating as particularly troubling. Traditional treatments, such as laxatives, are often ineffective, especially in more severe constipation over the long term. In a population-based survey of constipation sufferers, half were not satisfied with their current treatment, due predominantly to poor efficacy. 5-Hydroxytryptamine receptor 4 (5-HT4) agonists stimulate GI motility and intestinal secretion, and tegaserod has demonstrated efficacy in improving bowel habit. Tegaserod also improves constipation-associated symptoms including bloating, abdominal discomfort, stool consistency, and straining in patients with both CIC and C-IBS. However, tegaserod has been withdrawn due to an association with serious adverse cardiovascular effects. Further 5-HT(4) receptor agonists, including prucalopride and TD-5108 are in development and show exciting results in clinical studies in CIC patients, suggesting further product approvals are likely. Headache and diarrhea are the most commonly reported adverse event with this class of agent. Recently a novel prosecretory agent has been approved for the treatment of both CIC and C-IBS. Lubiprostone stimulates chloride secretion through activation of type-2 chloride channels, increasing intestinal secretion and transit, and its use has been associated with improvements in bowel habit and symptoms of constipation. Nausea, diarrhea, and headache are the most commonly reported adverse events. Linaclotide also stimulates intestinal chloride secretion, but this molecule achieves this indirectly, through the activation of guanylate cyclase C. Data are emerging, but the efficacy and safety profile of this agent in the treatment of CIC and C-IBS appears encouraging.

Topics: Alprostadil; Azabicyclo Compounds; Benzofurans; Chloride Channels; Chronic Disease; Constipation; Gastrointestinal Agents; Gastrointestinal Motility; Guanylate Cyclase; Humans; Indoles; Irritable Bowel Syndrome; Laxatives; Lubiprostone; Peptides; Safety; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists; Treatment Outcome

Prucalopride belongs to a novel class of 5-hydroxytryptamine-4 receptor agonists, and has been evaluated extensively for the treatment of chronic constipation. Prucalopride has a stimulatory effect on gastrointestinal motility and transit, as established by in vivo and in vitro studies in animals and humans. Its therapeutic efficacy, tolerability and safety have been evaluated in Phase II and Phase III studies in chronic constipation. The cardiovascular safety profile of the drug was studied in vitro and in vivo in animal studies, in clinical studies in chronic constipation patients, as well as in specific additional clinical cardiovascular studies. Phase II studies identified a dose-dependent effect of prucalopride on bowel pattern and associated symptoms in chronic constipation. The Phase III studies mainly recruited patients with insufficient response to laxatives, and showed consistent efficacy and excellent tolerability for prucalopride.

Topics: Animals; Benzofurans; Chronic Disease; Constipation; Dose-Response Relationship, Drug; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists; Treatment Outcome

Chronic constipation is a frequently reported medical disorder that reduces patients' quality of life and imposes a significant economic burden on the health care system. Symptoms of constipation are diverse and include infrequent bowel movements, hard stool, straining at stool, sensations of anorectal obstruction and feelings of incomplete evacuation. Patients with chronic constipation can be categorized into one of three main groups based on their underlying pathophysiology: normal transit constipation; colonic inertia; and pelvic floor dyssynergia. Specialized tests (i.e., anorectal manometry, radio-opaque marker study) may be required in some patients to help distinguish the different subtypes of constipation and to guide appropriate therapy. Although the underlying mechanism of constipation differs among patients, serotonin (5-hydroxytryptamine (5-HT)) appears to have an important role in colonic motility in some patients. Previous research has demonstrated that stimulation of 5-HT4 receptors improves symptoms of chronic constipation in some patients. Prucalopride, a selective 5-HT4 agonist, relieved symptoms of constipation in phase II and phase III clinical trials. In this monograph, we review the pharmacology, mechanism of action, efficacy and safety of the selective 5-HT4 agonist prucalopride in patients with chronic constipation.

Topics: Animals; Benzofurans; Chronic Disease; Clinical Trials as Topic; Constipation; Drug Evaluation, Preclinical; Humans; Quality of Life; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists

This post hoc analysis evaluated the effect of prucalopride on abdominal bloating in participants with chronic idiopathic constipation (CIC) who had moderate to very severe bloating at baseline.. Data from 6 phase 3/4 studies of prucalopride in participants with CIC were pooled. Abdominal bloating was assessed weekly using a 5-point scale (0-4).. The proportion of bloating responders (≥1-point improvement in abdominal bloating score at week 12) was higher in participants treated with prucalopride (62.1%) vs placebo (49.6%).. The prucalopride arm had a higher proportion of bloating responders vs placebo in this study population.

Topics: Abdominal Pain; Aged; Benzofurans; Chronic Disease; Constipation; Double-Blind Method; Female; Humans; Laxatives; Male; Pain Measurement; Severity of Illness Index; Treatment Outcome

This multicenter, randomized, noninferiority trial compared electroacupuncture with prucalopride for the treatment of severe chronic constipation (SCC).. Participants with SCC (≤ 2 mean weekly complete spontaneous bowel movements [CSBMs]) were randomly assigned to receive either 28-session electroacupuncture over 8 weeks with follow-up without treatment over 24 weeks or prucalopride (2 mg/d before breakfast) over 32 weeks. The primary outcome was the proportion of participants with ≥3 mean weekly CSBMs over weeks 3-8, based on the modified intention-to-treat population, with -10% as the noninferior margin.. Five hundred sixty participants were randomized, 280 in each group. Electroacupuncture was noninferior to prucalopride for the primary outcome (36.2% vs 37.8%, with a difference of -1.6% [95% confidence interval, -8% to 4.7%], P < 0.001 for noninferiority); almost the same results were found in the per-protocol population. The proportions of overall CSBM responders through weeks 1-8 were similar in the electroacupuncture and prucalopride groups (24.91% vs 25.54%, with a difference of -0.63% [95% confidence interval, -7.86% to 6.60%, P = 0.864]). Except during the first 2-week treatment, no between-group differences were found in outcomes of excessive straining, stool consistency, and quality of life. Adverse events occurred in 49 (17.69%) participants in the electroacupuncture group and 123 (44.24%) in the prucalopride group. One non-treatment-related serious adverse event was recorded in the electroacupuncture group.. Electroacupuncture was noninferior to prucalopride in relieving SCC with a good safety profile. The effects of 8-week electroacupuncture could sustain for 24 weeks after treatment. Electroacupuncture is a promising noninferior alternative for SCC (see Visual Abstract, http://links.lww.com/AJG/B776).

Topics: Benzofurans; China; Chronic Disease; Constipation; Electroacupuncture; Equivalence Trials as Topic; Female; Humans; Laxatives; Male; Middle Aged

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.. 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.. 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).. 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.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Benzofurans; Chronic Disease; Constipation; Double-Blind Method; Female; Humans; Male; Middle Aged; Quality of Life; Serotonin 5-HT4 Receptor Agonists; Severity of Illness Index; Treatment Outcome; Young Adult

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).. 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.. 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.. 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.

Topics: Adult; Aged; Benzofurans; Chronic Disease; Constipation; Double-Blind Method; Female; Humans; Longitudinal Studies; Male; Middle Aged; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome

Prucalopride is effective at alleviating symptoms of chronic constipation in women. The aim of this study was to assess the efficacy of 12 weeks of prucalopride treatment compared with placebo in men with chronic constipation.. This was a multicenter, stratified, randomized, parallel-group, double-blind, placebo-controlled, phase 3 study (ClinicalTrials.gov identifier: NCT01147926). The primary end point was the proportion of patients with a mean of three or more spontaneous complete bowel movements (SCBMs) per week across the treatment period. Efficacy end points were assessed using daily electronic diaries, global assessment of the severity of constipation and efficacy of treatment, and Patient Assessment of Constipation-Symptoms (PAC-SYM) and Patient Assessment of Constipation-Quality of Life (PAC-QOL) questionnaires.. In total, 374 patients were enrolled in the study. Significantly more patients achieved a mean of three or more SCBMs per week in the prucalopride group (37.9%) than in the placebo group (17.7%, P<0.0001). The proportion of patients rating their constipation treatment as "quite a bit" to "extremely" effective at the final on-treatment visit was 46.7 and 30.4% in the prucalopride and placebo groups, respectively. The difference between treatment groups was statistically significant (P<0.0001). The proportion of patients with an improvement of at least 1 point in PAC-QOL satisfaction subscale score was 52.7 and 38.8% in the prucalopride and placebo groups, respectively (P=0.0035). Prucalopride had a good safety profile and was well tolerated.. Prucalopride is effective, has a good safety profile, and is well tolerated for the treatment of men with chronic constipation.

Topics: Abdominal Pain; Adult; Aged; Benzofurans; Chronic Disease; Defecation; Diarrhea; Double-Blind Method; Headache; Humans; Male; Medical Records; Middle Aged; Nausea; Quality of Life; Serotonin 5-HT4 Receptor Agonists; Severity of Illness Index; Surveys and Questionnaires

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.. 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).. 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.. Prucalopride 2 mg q.d. for 12 weeks alleviates common constipation symptoms in women in whom laxatives had failed to provide adequate relief.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Benzofurans; Chronic Disease; Constipation; Double-Blind Method; Female; Humans; Laxatives; Middle Aged; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome; Young Adult

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.. 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.. 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.. 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.

Topics: Adolescent; Adult; Aged; Benzofurans; Chronic Disease; Colon; Constipation; Female; Gastrointestinal Transit; Humans; Male; Middle Aged; Serotonin 5-HT4 Receptor Agonists; Severity of Illness Index; Treatment Outcome; Young Adult

Acupuncture is safe and may be effective for severe chronic constipation. The World Gastroenterology Organisation recommends prucalopride for patients for whom previous laxative use failed to provide satisfactory relief.. In this prospective, multi-centre, randomised controlled trial, five hundred sixty patients with severe chronic constipation (two or less spontaneous complete bowel movements per week) from 14 centres will be randomised to receive either electroacupuncture or prucalopride. Participants in the electroacupuncture group will receive electroacupuncture for eight weeks, while participants in the control group will take prucalopride (2 mg once daily) for 32 weeks. The primary outcome measure is the proportion of patients having ≥ 3 spontaneous, complete bowel movements per week, averaged over week three to eight. The secondary outcome measures include eight items, including the proportion of patients having ≥ 3 spontaneous, complete bowel movements per week averaged over week 9-32, the proportion of patients with one or more increases in spontaneous, complete bowel movements per week from baseline, mean Bristol Stool Scale, etc. Statistical analysis will include the CMH test, nonparametric tests and t tests.. We aimed to compare the effect of electroacupuncture versus prucalopride for severe chronic constipation. The limitation of this study is that participants and acupuncturists will not be blinded.. ClinicalTrials.gov Identifier: NCT 02047045.

Topics: Benzofurans; Chronic Disease; Constipation; Electroacupuncture; Humans; Laxatives; Prospective Studies; Randomized Controlled Trials as Topic

Constipation is a common condition for which PEG 3350 is an established treatment and prucalopride has recently been approved for this indication.. To compare the efficacy, safety and impact on quality of life (QoL) of PEG 3350 plus electrolytes (PEG 3350+E) vs. prucalopride in females with chronic constipation (CC) in whom laxatives have previously failed to provide adequate relief.. In this single-centre, randomised, double-blind, double-dummy study, patients with CC [<3 spontaneous complete bowel movements (SCBM)/week] remained in a controlled environment and received either a 26 g split dose of PEG 3350+E (N = 120) or 1-2 mg prucalopride (N = 120) daily for 28 days following a 14-day run-in period. The primary endpoint was the proportion of patients having ≥3 SCBMs during the last treatment week.. Non-inferiority of PEG 3350+E to prucalopride was demonstrated in the per-protocol population [difference, 10.1% (66.67% vs. 56.52%), 97.5% lower confidence interval (CI) -2.7%, above the preset margin of -20%] and approached superiority in the modified intent-to-treat population (difference, 9.8%, 97.5% lower CI, -3.1%). Statistically significant differences in favour of PEG 3350+E were observed for most secondary variables (bowel movements, stool weight, consistency, time to next SCBM, patient perception of straining and completeness of defecation). Colonic transit time was dramatically reduced in both arms. Both treatments were well tolerated.. PEG 3350+E was at least as effective as and generally better tolerated than prucalopride as a treatment for chronic constipation in this study population (NCT01251822; http://www.clinicaltrials.gov).

Topics: Adolescent; Adult; Aged; Benzofurans; Chronic Disease; Constipation; Defecation; Double-Blind Method; Environment, Controlled; Female; Humans; Laxatives; Middle Aged; Polyethylene Glycols; Quality of Life; Serotonin 5-HT4 Receptor Agonists; Surface-Active Agents; Treatment Outcome; Young Adult

To evaluate the efficacy of the enterokinetic prucalopride (resolor) in patients with chronic constipation.. The effect of treatment with prucalopride (resolor) in 109 patients with chronic constipation was analyzed.. The effect was noted in 82% of the patients; 61 patients were fully satisfied with treatment results. Among the adverse reactions, headache that was particularly significant on the first days of use, diarrhea, and cramping abdominal pain were reported by 35, 17, and 13% of the included patients, respectively. The authors' experience with prucalopride demonstrated that the patients with chronic constipation displayed the good efficacy of the drug in both the frequency of stool and the elimination of all other constipation symptoms (straining effort, incomplete bowel emptying sensation, solid stool, bloating), and its good tolerability.. Prucalopride (resolor) exerts a predictable effect, can extend a physician's capacity to arrest chronic constipation, and, when the drug is used, requires no long-term dose adjustment.

Topics: Adult; Benzofurans; Chronic Disease; Constipation; Female; Humans; Middle Aged; Treatment Outcome

The study evaluated efficacy and safety of the 2 mg dose of prucalopride compared to placebo in patients with chronic constipation (CC) from the Asia-Pacific region.. Randomized, placebo-controlled, parallel-group, phase III study with 2-week run-in, 12-week treatment phase, and 1-week follow-up. Adult patients with CC (≤2 spontaneous bowel movements per week) received 2 mg prucalopride or placebo, once-daily, for 12 weeks. Primary efficacy measure was percentage of patients with average of ≥3 spontaneous complete bowel movements (SCBMs) per week (Responders) during the 12-week treatment. A key secondary endpoint was Responders during first 4 weeks of treatment. Other efficacy assessments were based on patient diaries, their assessments of symptoms and quality of life, and investigator's assessment on efficacy of treatment. Safety assessments included adverse events, laboratory values, and cardiovascular events.. Efficacy and safety were evaluated for 501 patients who received study drug. On the primary endpoint, prucalopride was significantly more effective than placebo with 83 (33.3%) vs 26 (10.3%) patients having a weekly average of ≥3 SCBMs during the 12-week treatment (P < 0.001). Respective percentages were 34.5%vs 11.1% over first 4 weeks (P < 0.001). On other secondary endpoints, clinical improvement was generally larger and statistically superior (P < 0.001) in the prucalopride group. Most frequently reported adverse events were diarrhea, nausea, abdominal pain, and headache.. Prucalopride 2 mg given once-daily significantly improved bowel function, associated symptoms, and satisfaction in CC over a 12-week treatment period, and was safe and well tolerated by patients in the Asia-Pacific region.

Topics: Adolescent; Adult; Aged; Asian People; Benzofurans; Chronic Disease; Constipation; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Male; Middle Aged; Young Adult

The Patient Assessment of Constipation-Quality of Life (PAC-QOL) is a self-reported questionnaire measuring health-related quality of life (HRQL) of constipated patients and was used as secondary endpoint in three identical double-blind, randomized, placebo-controlled Phase III clinical trials. These 12-week trials in subjects with severe chronic constipation evaluated the effects of prucalopride, a selective 5-HT(4) agonist given orally once daily.. To consolidate the main treatment effect results observed in the prucalopride trial populations, analyses were undertaken on the pooled data of the three trials to confirm the psychometric properties of the PAC-QOL and to provide guidance for the interpretation of the clinical significance of its scores.. The evaluation of the psychometric properties confirmed the PAC-QOL reliability, validity and responsiveness to measure the impact of chronic constipation symptoms on HRQL in the prucalopride trials. The 1-point improvement in PAC-QOL scores used as target response level for the main treatment effect analyses was validated as a relevant definition of response for treatment group comparisons. Cumulative distribution curves, drawn for each treatment group to provide more complete information on treatment effects than single minimal important difference point estimates, demonstrated consistent superior effects of prucalopride over placebo on all PAC-QOL scores.. The PAC-QOL questionnaire is a useful measurement tool to assess, from a patient perspective, the potential therapeutic value of chronic constipation treatments in clinical trials and, by directly reflecting the patient's own perspective on constipation and its treatment, eventually also for informing daily medical practice.

Topics: Adult; Benzofurans; Chronic Disease; Constipation; Double-Blind Method; Female; Health Status; Humans; Male; Middle Aged; Patient Satisfaction; Psychometrics; Quality of Life; Reproducibility of Results; Severity of Illness Index; Surveys and Questionnaires; Treatment Outcome

Constipation affects up to 50% of the elderly; this study evaluates the efficacy, safety, and tolerability of the selective 5-HT(4) agonist prucalopride in chronically constipated elderly patients.. Three hundred chronic constipation patients aged >or=65 years were randomized to prucalopride (1, 2, or 4 mg once daily) or placebo for 4 weeks. The primary endpoint was the percentage of patients with >or=3 spontaneous complete bowel movements (SCBM) per week. Secondary endpoints included the percentage with an increase of >or=1 SCBM per week, BM frequency, constipation-related symptoms, quality of life (QoL), safety, and tolerability.. More patients achieved >or=3 SCBM per week with prucalopride than with placebo. This difference was largest and significant during the first week of 4 mg prucalopride (P or=1 SCBM per week from baseline vs placebo (e.g. 60% with 1 mg prucalopride vs 34% with placebo at week 4; P or=1 with 1 mg prucalopride than with placebo (P

Topics: Aged; Aged, 80 and over; Benzofurans; Chi-Square Distribution; Chronic Disease; Constipation; Defecation; Double-Blind Method; Female; Humans; Intention to Treat Analysis; Male; Quality of Life; Treatment Outcome

Prucalopride is approved in Europe for symptomatic treatment of chronic constipation in women with inadequate relief from laxatives.. To evaluate efficacy of prucalopride during long-term treatment of patients with chronic constipation.. 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.. 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.. 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).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Benzofurans; Chronic Disease; Constipation; Defecation; Female; Follow-Up Studies; Humans; Laxatives; Male; Middle Aged; Pilot Projects; Quality of Life; Randomized Controlled Trials as Topic; Serotonin 5-HT4 Receptor Agonists; Statistics as Topic; Time Factors; Treatment Outcome; Young Adult

To determine the efficacy, impact on quality of life (QOL) and safety of prucalopride, a selective, high-affinity 5-HT(4) receptor agonist, in patients with chronic constipation.. In this multicentre, randomised, placebo controlled, parallel-group, phase III study, patients with chronic constipation (two or fewer spontaneous complete bowel movements (SCBM)/week) received 2 mg or 4 mg prucalopride or placebo, once daily, for 12 weeks. The primary efficacy endpoint was the proportion of patients reaching three or more SCBM/week. The key secondary efficacy endpoint was the proportion of patients having an increase of one or more SCBM/week. The primary QOL endpoint was the patient assessment of constipation QOL satisfaction subscale score. Safety parameters included adverse events, laboratory values and cardiovascular events.. Efficacy was evaluated over 713 patients. Averaged over 12 weeks, higher proportions of patients on prucalopride 2 mg (19.5%; p<0.01), 4 mg (23.6%; p<0.001) had three or more SCBM/week (or normalisation of bowel function) compared with placebo (9.6%). Similar results were seen in the subgroup (83%) of patients dissatisfied with previous laxative treatment. Both doses of prucalopride also significantly improved secondary efficacy and QOL endpoints, including the proportion of patients with an increase of one or more SCBM/week, evacuation completeness, perceived disease severity and treatment effectiveness and QOL. Prucalopride 4 mg significantly reduced the need for straining versus placebo (p<0.05). The most frequent treatment-related adverse events were headache and diarrhoea. Both doses of prucalopride were safe and well tolerated.. Prucalopride significantly and consistently improved bowel function, associated symptoms and satisfaction in chronically constipated patients.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Benzofurans; Chronic Disease; Constipation; Defecation; Female; Gastrointestinal Transit; Humans; Laxatives; Male; Middle Aged; Patient Satisfaction; Quality of Life; Serotonin Receptor Agonists; Surveys and Questionnaires; Treatment Outcome; Young Adult

Chronic constipation may result in disabling symptoms, is often unsatisfactorily treated by laxatives and negatively impacts quality of life (QoL).. A randomized, double-blind, placebo-controlled, phase III trial to evaluate the efficacy and safety of a selective, high-affinity 5-HT(4) receptor agonist, prucalopride, in patients with chronic constipation [or=3 SCBMs/week, averaged over 12 weeks. Other assessments included BM frequency, constipation-related QoL and symptoms and tolerability.. Among 641 patients, significantly more patients taking prucalopride 2 or 4 mg (24%) than placebo (12%), achieved the primary efficacy endpoint (>or=3 SCBMs/week) or an increase of >or=1 SCBMs/week; 43% and 47% vs. 28% respectively. Prucalopride-treated patients also achieved significantly greater satisfaction with treatment and bowel function, and improved perception of constipation severity and constipation-related QoL, compared with placebo. Most frequent treatment-related adverse events were headache, abdominal pain, nausea and diarrhoea (mainly during day 1). There were no differences in comparison to placebo in the incidence of serious adverse effects or cardiovascular events.. Over 12 weeks, prucalopride was effective and well tolerated in chronic constipation.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Benzofurans; Chronic Disease; Constipation; Defecation; Double-Blind Method; Female; Gastrointestinal Transit; Humans; Male; Middle Aged; Patient Satisfaction; Placebos; Quality of Life; Serotonin Receptor Agonists; Surveys and Questionnaires; Treatment Outcome; Young Adult

In this 12-week trial, we aimed to determine the efficacy of prucalopride, a selective, high-affinity 5-hydroxytryptamine4 receptor agonist, in patients with severe chronic constipation.. In our multicenter, randomized, placebo-controlled, parallel-group, phase 3 trial, patients with severe chronic constipation (< or =2 spontaneous, complete bowel movements per week) received placebo or 2 or 4 mg of prucalopride, once daily, for 12 weeks. The primary efficacy end point was the proportion of patients having three or more spontaneous, complete bowel movements per week, averaged over 12 weeks. Secondary efficacy end points were derived from daily diaries and validated questionnaires completed by patients. Adverse events, clinical laboratory values, and cardiovascular effects were monitored.. Efficacy was analyzed in 620 patients. The proportion of patients with three or more spontaneous, complete bowel movements per week was 30.9% of those receiving 2 mg of prucalopride and 28.4% of those receiving 4 mg of prucalopride, as compared with 12.0% in the placebo group (P<0.001 for both comparisons). Over 12 weeks, 47.3% of patients receiving 2 mg of prucalopride and 46.6% of those receiving 4 mg of prucalopride had an increase in the number of spontaneous, complete bowel movements of one or more per week, on average, as compared with 25.8% in the placebo group (P<0.001 for both comparisons). All other secondary efficacy end points, including patients' satisfaction with their bowel function and treatment and their perception of the severity of their constipation symptoms, were significantly improved with the use of 2 or 4 mg of prucalopride as compared with placebo, at week 12. The most frequent treatment-related adverse events were headache and abdominal pain. There were no significant cardiovascular effects of treatment.. Over 12 weeks, prucalopride significantly improved bowel function and reduced the severity of symptoms in patients with severe chronic constipation. Larger and longer trials are required to further assess the risks and benefits of the use of prucalopride for chronic constipation. (ClinicalTrials.gov number, NCT00483886 [ClinicalTrials.gov].).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Benzofurans; Chronic Disease; Constipation; Defecation; Double-Blind Method; Electrocardiography; Female; Humans; Laxatives; Male; Middle Aged; Quality of Life; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists; Surveys and Questionnaires

Chronic constipation (CC) is common and there is a need for more effective and better-tolerated agents that normalize bowel function without affecting secretion. Prucalopride is a novel, selective serotonin(4) receptor agonist with enterokinetic properties.. Pilot study to compare the efficacy and tolerability of prucalopride and placebo in patients with severe CC referred to a tertiary centre.. After 4-weeks' run in, patients were randomized to 4 weeks' once daily, double-blind treatment with either prucalopride 4 mg (n = 27) or placebo (n = 26). A 50% dose reduction after 2 weeks' treatment was possible for patients with an excessive gastrointestinal response to the study medication (severe cramps, abdominal pain, and diarrhea). Patients assessed efficacy using a visual analogue scale (VAS) and recorded bowel function in daily diaries. The investigator assessed efficacy and total gut transit time (marker study).. Patient VAS assessment demonstrated that prucalopride was significantly more effective than placebo in softening stools, and decreasing straining and time to first stool. Prucalopride also had a positive effect on stool frequency, feeling of complete evacuation and total gut transit time, although these differences were not statistically significant compared with placebo. The most common adverse events were gastrointestinal symptoms and headache; most were mild to moderate. There were no clinically relevant effects on cardiovascular or laboratory parameters.. Once-daily prucalopride 4 mg for 4 weeks is effective and well tolerated in patients with severe CC. It improves whole gut transit, reducing straining, softening stools and reducing time to first bowel movement.

Topics: Adult; Benzofurans; Cathartics; Chronic Disease; Constipation; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gastrointestinal Transit; Humans; Male; Middle Aged; Pilot Projects; Safety; Serotonin Antagonists; Severity of Illness Index

There is a need for better tolerated drugs to normalize bowel function in chronic constipation. Prucalopride is a highly selective, specific, serotonin4 receptor agonist with enterokinetic properties.. To evaluate the effects of prucalopride on bowel function, colonic transit and anorectal function in patients with chronic constipation.. Twenty-eight patients were enrolled in this double-blind, placebo-controlled, crossover study (prucalopride: 1 mg, n=12; 2 mg, n=16). Patients kept a bowel function diary. Colonic transit times and anorectal function (anal manometry, rectal sensitivity and rectal compliance) were assessed.. Prucalopride (1 mg) compared to placebo significantly increased the mean number of spontaneous complete, spontaneous and all bowel movements per week. Prucalopride (1 mg) significantly decreased the percentage of bowel movements with hard/lumpy stools and straining and increased the urge to defecate. Prucalopride (1 and 2 mg) decreased the mean total colonic transit time by 12.0 h (prucalopride 42.8 h vs. placebo 54.8 h; P=0.074). No statistically significant effects were found in any of the anorectal function parameters. Prucalopride was well tolerated. There were no clinically relevant changes in standard safety parameters.. Prucalopride significantly improves stool frequency and consistency, and the urge to defecate, and may decrease colonic transit times in patients with chronic constipation.

Topics: Adolescent; Adult; Aged; Anal Canal; Benzofurans; Chronic Disease; Constipation; Cross-Over Studies; Defecation; Double-Blind Method; Female; Gastrointestinal Transit; Humans; Male; Middle Aged; Serotonin Receptor Agonists

Chronic constipation (CC) often occurs after spinal cord injury (SCI). Prucalopride is a novel, highly selective, specific serotonin4 receptor agonist with enterokinetic properties. We evaluate the tolerability and pilot efficacy of prucalopride in the treatment of CC due to SCL.. Double-blind, placebo-controlled, pilot, phase 11, dose-escalation study. After 4 weeks' run in, patients received prucalopride 1 mg (n = 8) or placebo (n = 4); 11 new patients were randomized to prucalopride 2 mg (n = 8) or placebo (n = 3) once daily for 4 weeks. Patients recorded bowel function (diary) and assessed constipation severity and treatment efficacy (visual analogue scale (VAS) 0-100 mm). Colonic transit times were determined.. Compared with run in. mean changes in constipation severity (VAS) increased with placebo, but decreased with prucalopride 1 and 2 mg. The VAS score for treatment efficacy showed a clear dose response (medians 4, 52 and 73 for placebo, 1 and 2 mg, respectively). Diary data showed an improvement in average weekly frequency of all bowel movements over 4 weeks within the 2 mg group (median 0.6; 95% CI 0.2; 1.2). There was a significant reduction in median colonic transit time with 2 mg (n = 4; -38.5 h (95% CI -80; -5)). Four patients (2 mg) reported moderate/severe abdominal pain, and two of these discontinued treatment. There were no clinically relevant effects on any of the safety parameters.. This pilot study indicates that prucalopride can play an important role in the management of patients with CC due to SCI.

Topics: Adolescent; Adult; Benzofurans; Chronic Disease; Constipation; Defecation; Double-Blind Method; Female; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Male; Middle Aged; Pilot Projects; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Serotonin Receptor Agonists; Spinal Cord Injuries

Prucalopride is a selective, high-affinity serotonin type 4 receptor agonist approved for the treatment of chronic idiopathic constipation (CIC) in adults. We investigated the impact of prucalopride cessation and re-treatment on efficacy and safety.. Data were from two randomized controlled trials in adults with CIC. In a dose-finding trial, complete spontaneous bowel movements (CSBMs) and treatment-emergent adverse events (TEAEs) were assessed during a 4-week run-out period after a 4-week treatment period (TP; prucalopride 0.5-4 mg once daily or placebo). In a re-treatment trial, CSBMs and TEAEs were assessed during two 4-week TPs (prucalopride 4 mg once daily or placebo) separated by a 2- or 4-week washout period.. In the dose-finding trial (N = 234; 43-48 patients/group), mean CSBMs/week and the proportion of responders (≥3 CSBMs/week) were higher with prucalopride than placebo during the TP, but similar in all groups 1-4 weeks after treatment cessation. TEAEs were less frequent following treatment cessation. In the re-treatment trial (efficacy analyses: prucalopride, n = 189; placebo, n = 205), the proportion of responders was similar in both TPs and significantly higher (p ≤ 0.001) with prucalopride (TP1, 38.6%; TP2, 36.0%) than placebo (TP1, 10.7%; TP2, 11.2%). Most patients who responded to prucalopride in TP1 responded again in TP2 (71.2%). TEAEs were less frequent in TP2 than TP1.. Prucalopride cessation resulted in a loss of clinical effect to baseline levels within 7 days. Similar efficacy and safety were observed between TP1 and TP2 after prucalopride was re-initiated following a washout period.

Topics: Adult; Chronic Disease; Constipation; Double-Blind Method; Humans; Randomized Controlled Trials as Topic; Treatment Outcome; Withholding Treatment

Constipation is a common gastrointestinal disorder. Prucalopride is a dihydrobenzofurancarboxamide derivative with gastrointestinal prokinetic activities and is recommended as an appropriate choice in patients unresponsive to laxatives. This study assessed the safety and efficacy of prucalopride in Korean patients with chronic constipation, in whom laxatives were ineffective.. This prospective, non-interventional post-marketing surveillance of prucalopride was conducted from 2012 to 2018 at 28 hospitals in Korea. Adults who received prucalopride for the symptomatic treatment of chronic constipation were included. The patients received 2 mg of prucalopride once daily or 1 mg once daily in patients older than 65 years. The baseline characteristics, adverse events (AEs), and seven-point scale of Clinical Global Impression-Improvement were collected.. Of 601 patients, 67.7% were female, and the mean age was 62.3 years. Three hundred patients (49.9%) were older than 65 years. At the baseline, 70.0% of patients reported less than two instances of spontaneous complete bowel movements per week. AEs were reported in 107 patients (17.7%), including headache (3.2%) and diarrhea (2.8%). Seven serious AEs (SAEs) were reported in five patients (0.8%). The SAEs were resolved without complications; there were no cases of death. All SAEs were assessed as 'unlikely' causality with prucalopride. In 72.7% of patients, chronic constipation was improved by the prucalopride treatment during the study period.. This study demonstrated the promising safety and efficacy profile of prucalopride in clinical practice. Thus, prucalopride should be considered in patients with chronic constipation when bowel symptoms are refractory to simple laxatives.

Topics: Adult; Benzofurans; Chronic Disease; Constipation; Double-Blind Method; Female; Humans; Laxatives; Middle Aged; Product Surveillance, Postmarketing; Prospective Studies; Republic of Korea; Treatment Outcome

Topics: Adult; Benzofurans; Chronic Disease; Constipation; Humans; Laxatives; Serotonin 5-HT4 Receptor Agonists

Topics: Algorithms; Benzofurans; Canada; Chronic Disease; Constipation; Dietary Fiber; Dietary Supplements; Disease Management; Gastroenterologists; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Laxatives; Needs Assessment; Peptides; Practice Guidelines as Topic; Practice Patterns, Physicians'; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Receptors, Peptide; Serotonin 5-HT4 Receptor Agonists; Surveys and Questionnaires

In a placebo-controlled trial in 374 men, prucalopride was only effective in a minority of cases, as previously observed in women. In addition to its cardiovascular harms, there is evidence that prucalopride may cause depression and suicidal ideation.

Topics: Benzofurans; Cardiovascular Diseases; Chronic Disease; Constipation; Contraindications, Drug; Controlled Clinical Trials as Topic; Defecation; Depression; Female; Humans; Laxatives; Male; Risk Assessment; Serotonin 5-HT4 Receptor Agonists; Suicidal Ideation; Treatment Outcome

Prucalopride, a selective, high-affinity 5-hydroxytryptamine 4 receptor agonist, stimulates gastrointestinal and colonic motility and alleviates common symptoms of chronic constipation (CC) in adults. The relative efficacy by gender has not been evaluated.. To evaluate the global efficacy and safety of prucalopride 2 mg daily in men and women with CC using data from six large, randomized, controlled clinical trials.. Data were combined from six phase 3 and 4, double-blind, randomized, placebo-controlled, parallel-group trials. The primary efficacy endpoint was the percentage of patients with a mean of ≥3 spontaneous complete bowel movements (SCBMs) per week over 12 weeks of treatment. Safety was assessed throughout all the trials.. Overall, 2484 patients (597 men; 1887 women; prucalopride, 1237; placebo, 1247) were included in the integrated efficacy analysis and 2552 patients were included in the integrated safety analysis. Significantly more patients achieved a mean of ≥3 SCBMs/week over the 12 weeks of treatment in the prucalopride group (27.8 %) than in the placebo group [13.2 %, OR 2.68 (95 % CI 2.16, 3.33), p < 0.001]. Prucalopride had a favorable safety and tolerability profile. Efficacy and safety outcomes were not significantly different between men and women.. The integrated analysis demonstrates the efficacy and safety of prucalopride in the treatment of CC in men and women.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Benzofurans; Chronic Disease; Clinical Trials, Phase III as Topic; Clinical Trials, Phase IV as Topic; Constipation; Double-Blind Method; Female; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome; Young Adult

Topics: Benzofurans; Bisacodyl; Chronic Disease; Citrates; Constipation; Humans; Organometallic Compounds; Picolines

Topics: Adult; Benzofurans; Chronic Disease; Constipation; Female; Humans; Intestinal Pseudo-Obstruction; Myotonic Dystrophy; Recurrence; Serotonin 5-HT4 Receptor Agonists

The aim of this study was to measure any incremental costs or savings within the health system associated with the introduction of the new technology, prucalopride, for the management of chronic constipation.. The study design was based on a budget impact analysis conducted by the National Institute of Clinical Excellence (NICE). To validate the findings of the NICE costing template, a case series audit capturing real world data was used to determine the financial impact of adopting prucalopride in 40 women suffering with chronic constipation. This facilitated the application of local unit costs to the resources used and determined whether the use of prucalopride, as an alternative treatment to laxatives, resulted in a reduction in the use of secondary care resources.. Patients were treated with an average of 2.6 laxatives in the baseline (laxatives only) scenario. The total medication costs in the baseline (laxatives only) and the new treatment (prucalopride) scenario amounted to €17,440.84 and €18,417.62, respectively. There was a significant reduction in the number of investigations and procedures in the 12 months after commencing prucalopride, with cost savings of €41,923.28 (€1,048.08 per patient per year) demonstrated. Input cost variables were adjusted as part of sensitivity analysis.. This study validated the findings of the NICE costing template and suggests that the use of prucalopride for the treatment of chronic constipation in women refractory to laxatives has the potential to reduce secondary care resource use and hence led to cost savings.

Topics: Adult; Benzofurans; Chronic Disease; Constipation; Cost Savings; Economics, Pharmaceutical; Female; Humans; Laxatives; Retrospective Studies; Secondary Care Centers

Newer 5-hydroxytryptamine agonists, such as prucalopride, have been demonstrated to be effective in the short term for treatment of chronic constipation. To date, few studies have investigated their medium- and long-term effectiveness.. An analysis was carried out of a prospectively maintained database of all patients started on prucalopride for chronic constipation between April 2011 and April 2014. Cleveland Clinic Constipation Score (CCCS) questionnaires were administered before starting treatment with prucalopride and at the first follow-up visit to assess change in CCCS scores in 50 randomly selected patients.. A total of 155 patients (median age: 47 years; seven men) were started on prucalopride in this period. Of these, 16 (10%) had slow-transit constipation, 31 (20%) had obstructive defaecation syndrome and 30 (19%) had a combination of both. Of these 155 patients, 78% patients were on three or more laxatives at the time of starting prucalopride. Patients were started on 1 mg or 2 mg according to their age. The median follow-up period was 24 (range: 4-40) months. At the first follow-up visit, 106 (68%) patients reported good symptomatic improvement, whereas the remainder had no response. Third of initial responders showed decreased efficacy after a median duration of 6 months and needed regular laxatives/irrigation. Of the 50 patients who filled in the CCCS questionnaires (15 patients were nonresponders), 32 (64%) reported improved scores with a median improvement of two points per criterion.. This study provides evidence that prolonged use of prucalopride is effective in achieving a sustained benefit in the majority of patients.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Benzofurans; Chronic Disease; Constipation; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Laxatives; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Surveys and Questionnaires; Time Factors; Treatment Outcome

Chronic constipation is very frequent in the general population. Although usually considered banal, this disorder has considerable personal, social and healthcare impact. Several studies have shown that the psychological impact exceeds that caused by rheumatoid arthritis or haemodialysis. Recently, prucalopride, a highly selective 5-HT4 receptor agonist has been shown to improve the symptoms of chronic constipation and to have a beneficial effect on social and healthcare impact. The drug was approved by the European Medicine Agency, in 2009 at a dose of 2 mg/day, 'for symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief'. Neurological side effects or psychiatric disorders have not been reported previously with prucalopride. We present the case of a 61-year-old woman, who developed such adverse effects when given prucalopride for the treatment for chronic constipation.. A few hours after oral administration of this drug at therapeutic dose (2 mg/day), the patient experienced life-threatening neurological effects that included visual hallucination, loss of balance and memory, disorientation, exhaustion and suicidal ideation. Analysis with the Naranjo algorithm indicated a 'possible' relationship between prucalopride and these disorders.. This is the first report of prucalopride-induced neurological side effects and psychiatric disorders with prucalopride. The absence of other similar reports suggests that prucalopride rarely causes these adverse effects.

Topics: Benzofurans; Chronic Disease; Constipation; Female; Hallucinations; Humans; Memory Disorders; Mental Disorders; Middle Aged; Nervous System Diseases; Orientation; Postural Balance; Serotonin; Serotonin 5-HT4 Receptor Agonists; Suicidal Ideation

Topics: Benzofurans; Chronic Disease; Constipation; Dietary Fiber; Enema; Gastrointestinal Motility; Health Behavior; Humans; Laxatives; Life Style; Narcotic Antagonists; Practice Guidelines as Topic

Many clinical trials that generate evidence on the quality-of-life (QOL) improvements provided by new health technologies do not incorporate a preference-based generic measure, but generate only disease-specific data. However, in order to meet the information needs of regulators such as the UK National Institute for Health and Clinical Excellence (NICE), such disease-specific data need to be converted into a broader generic measure; for NICE, the preferred instrument is the EQ-5D. The process of converting QOL data from one instrument to another is known as 'mapping'.. The objective of this study was to examine the extent to which disease-specific measures generated in the clinical trials for a new treatment for chronic constipation (prucalopride) can be 'mapped' onto a preference-based generic measure (EQ-5D and SF-6D) to generate robust and reliable utility estimates.. Disease-specific QOL data generated in the clinical trials of prucalopride (PAC-QOL scores) were converted into utility values estimated using the preference-based generic measure EQ-5D. SF-36 data were also collected in the clinical trials and used to generate SF-6D estimates for comparative purposes. Regression analysis was used to derive a range of mapping functions to identify the extent to which increasing the complexity of the hypothesized underlying mapping function enhanced the robustness and reliability of the obtained mapping relationship.. The mean utility observed at baseline for chronic constipation, based on SF-36 data, was 0.813 with the EQ-5D and 0.723 with the SF-6D. An examination of the differences between predicted and observed values generally found that the mapping functions generated were robust and reliable, with little evidence of bias across the range of the dependent variable. However, the nature of the symptoms explored in the PAC-QOL measure was, in general, less severe than those explored in the EQ-5D. For example, the condition-specific measures explored the degree to which patients experienced 'discomfort', rather than 'pain' as evaluated in the EQ-5D. Given this limitation in the severity range covered in the disease-specific measures, it is perhaps not surprising that a 'floor effect' was identified, with certain health dimensions mapping only to the upper range of the EQ-5D measure.. In circumstances where direct utility measurement is not available, mapping provides a valuable method by which to estimate utility data for incorporation into cost-effectiveness analyses. Our findings emphasize the importance of the structure and nature of the mapping analysis undertaken as being a fundamental determinant of the utility estimates generated. Unfortunately, the theoretical guidance available to steer such analyses is still comparatively underdeveloped and this remains an area of health economic analysis in which empiricism largely rules. Ensuring that such mapping is undertaken and interpreted in as transparent and robust a manner as possible is therefore crucial in allowing regulators to accurately compare the clinical and cost effectiveness of new drugs across therapeutic areas.

Topics: Benzofurans; Chronic Disease; Clinical Trials as Topic; Constipation; Cost-Benefit Analysis; Health Status; Humans; Quality of Life; Regression Analysis; Reproducibility of Results; Severity of Illness Index; Surveys and Questionnaires

Constipation is a frequent complaint, especially in women and the elderly. It is sometimes drug-induced, and is only occasionally secondary to a functional or organic disorder. The risks associated with constipation are often overestimated. Prucalopride, a 5-HT4 serotonin receptor agonist, chemically related to some neuroleptics, has been authorised in the European Union for symptomatic treatment of chronic constipation in women dissatisfied with laxatives. A combined analysis of 3 randomised double-blind trials in a total of 1999 patients (87.9% women) complaining of chronic constipation showed that about 36% of women considered it effective at a dose of 2 or 4 mg/day, versus 18% of women receiving placebo. Normal bowel movements resumed in respectively 23.6% and 24.7% of patients taking 2 and 4 mg/day prucalopride, versus 11.3% of patients on placebo (p < 0.001). No statistically significant difference was found between the 2 doses of prucalopride. Palpitations were more frequent in patients treated with prucalopride. The incidence of ischaemic cardiovascular events was 0.2% with prucalopride versus 0.1% with placebo. Increases in heart rate and blood pressure were observed in pigs and dogs treated with prucalopride. Prucalopride seems to increase prolactin levels. Tumours of the liver and thyroid were observed in rats. Prucalopride also carries a risk of poorly defined pharmacokinetic and pharmacodynamic interactions. Prucalopride may reduce the efficacy of oral contraceptives. Miscarriages were reported in clinical trials. Prucalopride should not be taken during pregnancy. In addition, all women of child-bearing age should use effective contraception while taking prucalopride. In practice, prucalopride should be avoided. It is better to focus on lifestyle and behavioural changes, and rational use of laxatives.

Topics: Animals; Benzofurans; Chronic Disease; Constipation; Drug Approval; European Union; Female; Humans; Male; Pregnancy; Serotonin 5-HT4 Receptor Agonists

Topics: Benzofurans; Chronic Disease; Constipation; Female; Gastrointestinal Motility; Humans; Laxatives; Male; Serotonin 5-HT4 Receptor Agonists

Topics: Benzofurans; Chronic Disease; Constipation; Gastrointestinal Motility; Humans; Randomized Controlled Trials as Topic; Serotonin 5-HT4 Receptor Agonists

Topics: Benzofurans; Chronic Disease; Constipation; Defecation; Electrocardiography; Humans; Laxatives; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists