benzofurans and prucalopride

Postoperative ileus is common and is a major clinical problem. It has been widely studied in patients and in experimental models in laboratory animals. A wide variety of treatments have been tested to prevent or modify the course of this disorder.. This review draws together information on animal studies of ileus with studies on human patients. It summarizes some of the conceptual advances made in understanding the mechanisms that underlie paralytic ileus. The treatments that have been tested in human subjects (both pharmacological and non-pharmacological) and their efficacy are summarized and graded consistent with current clinical guidelines. The review is not intended to provide a comprehensive overview of ileus, but rather a general understanding of the major clinical problems associated with it, how animal models have been useful to elucidate key mechanisms and, finally, some perspectives from both scientists and clinicians as to how we may move forward with this debilitating yet common condition.

Topics: Anesthesia, Epidural; Animals; Benzofurans; Chewing Gum; Cholinergic Agents; Contrast Media; Cyclooxygenase Inhibitors; Diatrizoate Meglumine; Digestive System Surgical Procedures; Enhanced Recovery After Surgery; Enteral Nutrition; Enteric Nervous System; Fluid Therapy; Gastrointestinal Agents; Gastrointestinal Motility; Ghrelin; Humans; Ileus; Inflammation; Intestinal Pseudo-Obstruction; Intubation, Gastrointestinal; Laparoscopy; Mast Cells; Piperidines; Postoperative Complications; Serotonin 5-HT4 Receptor Agonists; Sympathetic Nervous System; Sympatholytics

This study aims to explore the incremental benefit of different doses of prucalopride in treating chronic idiopathic constipation (CIC).. PubMed, EMBASE, MEDLINE, Cochrane Library, Chinese Biomedical Database, China National Knowledge Infrastructure, VIP medicine information and Wanfang databases were comprehensively searched up to March 2020. Prospective trials with different doses of prucalopride versus placebo were selected. The frequency of spontaneous bowel movements (SBMs) per week and the treatment-emergent adverse events (TEAEs), such as headache, arrhythmia, diarrhoea, dizziness, nausea and vomiting, were first synthesised in a meta-analysis. The probability of optimal dose of prucalopride was then ranked by random-effects within Bayesian analysis.. 14 high-quality randomised controlled trials with 4328 patients were ultimately included. SBMs per week increased significantly after using 1 mg (OR: 2.40, 95% CI 1.32 to 4.37), 2 mg (OR: 2.55, 95% CI 1.93 to 3.36) and 4 mg (OR: 2.51, 95% CI 1.92 to 3.28) prucalopride. Bayesian analysis demonstrated 1 mg dose obtained the maximum SBMs per week (OR: 3.31, 95% credible interval 1.72 to 6.16, probability rank=0.70) indirectly compared with 2 mg and 4 mg doses. TEAEs were higher significantly in 2 mg (risk ratio (RR): 1.20, 95% CI 1.09 to 1.33) and 4 mg (RR: 1.14, 95% CI 1.07 to 1.22) prucalopride. The 1 mg dose did not reach statistical significance (RR: 1.17, 95% CI 0.94 to 1.44).. The study concludes that 1 mg dose at commencement could be safer in treating CIC and that 2 mg prucalopride could be more efficacious in terms of SBMs per week outcome receiving.. CRD42019136679.

Topics: Bayes Theorem; Benzofurans; China; Constipation; Humans; Prospective Studies; Randomized Controlled Trials as Topic

Prucalopride, a high affinity, selective serotonin type 4 (5-HT

Topics: Animals; Benzofurans; Endocrine Gland Neoplasms; Humans; Liver Neoplasms; Receptors, Serotonin, 5-HT4; Risk Assessment; Serotonin 5-HT4 Receptor Agonists

Adequate bowel preparation is a vital determinant for the success of colonoscopy. However, individuals who undergo bowel preparation for colonoscopy can experience major discomfort. To solve this problem, adding prucalopride to the prepared solution may reduce intake volume, decreasing discomfort and side effects. We performed meta-analyses and systematic review of available randomized controlled trials.. Meta-analyses were conducted to evaluate the overall relative risk and 95% confidence intervals in the combined studies for the assessment of primary outcome, which is the efficacy of bowel preparation with the addition of prucalopride.. Four randomized controlled trials involving 581 patients were included. When data were pooled for all patients in two non-inferiority studies, no significant difference in the quality of bowel preparation was observed between patients receiving prucalopride plus bowel preparation solution at a lower volume and those receiving the existing solution (relative risk: 0.94; 95% confidence interval: 0.86-1.03). The effects of prucalopride on acceptability, adverse events, adenoma detection rate, and polyp detection rate did not significantly differ from those of traditional solutions.. The combination of prucalopride and bowel preparation solution at a lower volume has similar effects on bowel preparation, and its use did not increase the occurrence of adverse effects.

Topics: Benzofurans; Cathartics; Colonoscopy; Female; Humans; Male; Middle Aged; Polyethylene Glycols; Randomized Controlled Trials as Topic

The prokinetic effects of 5-HT

Topics: Azabicyclo Compounds; Benzamides; Benzofurans; Colon; Constipation; Gastrointestinal Motility; Humans; Intestinal Mucosa; Laxatives; Molecular Targeted Therapy; Pyrimidines; Quinuclidines; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists

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

Prucalopride is a prokinetic drug, that has been commercially available in recent years for the treatment of chronically constipated patients. In this update of a previous 2016 article, we reviewed the more recent data supporting its role in the treatment of constipation and constipation-associated conditions. Areas covered: We carried out an extensive literature review on the effects of prucalopride for the years 2012-2018 by means of scientific databases and manual research. More evidence was found on its possible therapeutic role in conditions in which constipation plays a role as an associated symptom, such as opioid-induced constipation, constipation-predominant irritable bowel syndrome, post-operative ileus, colonic diverticular disease, drug-related constipation, and chronic intestinal pseudo-obstruction. Expert opinion: Based on the added literature evidence, we feel that prucalopride is an effective, although expensive, drug for the treatment of primary and secondary forms of constipation, and of other clinical conditions associated with constipation.

Topics: Benzofurans; Constipation; Cost-Benefit Analysis; Defecation; Drug Costs; Gastrointestinal Motility; Humans; Intestines; Laxatives; Recovery of Function; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome

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

Postoperative ileus (POI) is an impairment of coordinated gastrointestinal (GI) motility that develops as a consequence of abdominal surgery and is a major factor contributing to patient morbidity and prolonged hospitalisation. Despite the availability of various options its treatment is still under debate. This review will focus on effect of Prucalopride (5-HT

Topics: Animals; Benzofurans; Gastrointestinal Motility; Hospitalization; Humans; Ileus; Length of Stay; Postoperative Complications; Randomized Controlled Trials as Topic; 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

Constipation is a disorder frequently complained about by patients in daily clinical practice. However, to date, its treatment is still commonly unsatisfactory, especially concerning patients' quality of life, when using conventional measures. Prucalopride, a selective 5-hydroxytryptamine receptor 4 agonist, was introduced to the market in 2009 and has been commercially available in Europe since 2010. The main effect of prucalopride is to stimulate colonic motility, which explains its efficacy to treat constipated patients unresponsive to other regimens. Literature search was carried out to look for effects of prucalopride on constipated patients. Several papers were found demonstrating that prucalopride is effective in treatment of constipated patients. Due to its few side effects, the lack of cardiovascular effects and interactions with other drugs, prucalopride may be safely used in elderly people as well.

Topics: Animals; Benzofurans; Colon; Constipation; Defecation; Gastrointestinal Motility; Humans; Laxatives; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome

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

Prucalopride is a new prokinetic agent, recently available in Europe for the treatment of functional constipation in adults in whom treatment with laxatives failed to provide adequate relief. However, due to its intrinsic properties (highly selective agonist activity and high affinity for 5-HT4 receptors, neuroprotection), this drug has shown the potential to be used in other pathologic conditions, in and outside of the gastrointestinal tract. We performed a systematic review of the evidence supporting these possible alternative uses of prucalopride. Further studies in this area are, however, mandatory.

Topics: Analgesics, Opioid; Benzofurans; Colonic Diseases; Constipation; Humans; Ileus; Intestinal Pseudo-Obstruction; Multiple Sclerosis; Serotonin 5-HT4 Receptor Agonists; Spinal Cord Injuries

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

The diagnosis of irritable bowel syndrome (IBS) remains a diagnosis of exclusion, whereby an extensive investigation is performed to exclude other organic diseases that may explain the symptoms of patients. Attempts to have a positive diagnosis based on symptom assessments failed to achieve widely use in clinical practice. Abnormalities in the gastrointestinal endocrine cells in IBS patients have been reported recently, providing evidence that IBS is an organic disorder, and opening the door to the use of these abnormalities as markers for a positive diagnosis of IBS. New and promising drugs for the treatment of IBS with constipation as the predominant symptom are currently on the market, and the treatment results have been satisfactory thus far.

Topics: Benzofurans; Biomarkers; Constipation; Humans; Irritable Bowel Syndrome; Peptides; 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

There has been no definitive synthesis of the evidence for any benefit of available pharmacological therapies in opioid-induced constipation (OIC). We conducted a systematic review and meta-analysis to address this deficit.. We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane central register of controlled trials through to December 2012 to identify placebo-controlled trials of μ-opioid receptor antagonists, prucalopride, lubiprostone, and linaclotide in the treatment of adults with OIC. No minimum duration of therapy was required. Trials had to report a dichotomous assessment of overall response to therapy, and data were pooled using a random effects model. Effect of pharmacological therapies was reported as relative risk (RR) of failure to respond to therapy, with 95% confidence intervals (CIs).. Fourteen eligible randomized controlled trials (RCTs) of μ-opioid receptor antagonists, containing 4,101 patients, were identified. These were superior to placebo for the treatment of OIC (RR of failure to respond to therapy=0.69; 95% CI 0.63-0.75). Methylnaltrexone (six RCTs, 1,610 patients, RR=0.66; 95% CI 0.54-0.84), naloxone (four trials, 798 patients, RR=0.64; 95% CI 0.56-0.72), and alvimopan (four RCTs, 1,693 patients, RR=0.71; 95% CI 0.65-0.78) were all superior to placebo. Total numbers of adverse events, diarrhea, and abdominal pain were significantly commoner when data from all RCTs were pooled. Reversal of analgesia did not occur more frequently with active therapy. Only one trial of prucalopride was identified, with a nonsignificant trend toward higher responder rates with active therapy. Two RCTs of lubiprostone were found, with significantly higher responder rates with lubiprostone in both, but reporting of data precluded meta-analysis.. μ-Opioid receptor antagonists are safe and effective for the treatment of OIC. More data are required before the role of prucalopride or lubiprostone in the treatment of OIC are clear.

Topics: Alprostadil; Analgesics, Opioid; Benzofurans; Constipation; Female; Gastrointestinal Agents; Humans; Lubiprostone; Male; Naloxone; Naltrexone; Narcotic Antagonists; Peptides; Piperidines; Quaternary Ammonium Compounds; Receptors, Opioid, mu

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 common medical problem and when standard laxatives fail it can be difficult to treat. Different aetiologies require tailored therapeutic approaches. Simple constipation may only require dietary manipulation while severe neurological or slow transit constipation may need pharmacologic intervention. Recently new drug therapies have been introduced. PubMed and Ovid were searched for reviews, systematic reviews and meta-analysis published since 2003 using the terms: constipation, prucalopride, linaclotide and lubiprostone. This review summarizes potential novel therapies identified as effective in the management of chronic constipation. Prucalopride is a selective 5-hydroxytryptamine receptor agonist. The prucalopride study was in patients, largely women with idiopathic constipation showed improved spontaneous complete bowel movement (SCBM) at a dose of 2 mg a day with few adverse events reported. Linaclotide is a 14-amino acid peptide guanylate cyclase-C agonist. The linaclotide study was carried out in patients with irritable bowel syndrome, constipation group (IBS-C). There was significant improvement of bowel evacuation and symptom resolution in patients on the active treatment arm. Lubiprostone activates type-2 chloride channels, increasing intestinal fluid secretion. In the trials of this drug, the lubiprostone arms had a greater mean number of SCBM. The novel therapies, prucalopride, lubiprostone, and linaclotide had very different modes of action yet, all three have been shown to be efficacious and safe in the treatment dose for constipation.

Topics: Alprostadil; Animals; Benzofurans; Calcium Channel Agonists; Constipation; Defecation; Enzyme Activators; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Lubiprostone; Peptides; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome

Conservative treatment of fecal incontinence and obstructive defecation can be treated by many conservative treatment modalities. This article presents the options of medication therapy, spincter exercises, electric stimulation, transcutaneous tibial nerve stimulation, anal irrigation and injection of bulking agents. These methods are presented with reference to the currently available literature but the evidence-based data level for all methods is low. For minor disorders of anorectal function these conservative methods can lead to an improvement of anorectal function and should be individually adapted.

Topics: Anal Canal; Antidiarrheals; Benzofurans; Combined Modality Therapy; Electric Stimulation Therapy; Evidence-Based Medicine; Fecal Incontinence; Female; Humans; Intestinal Obstruction; Loperamide; Male; Pelvic Floor Disorders; Physical Therapy Modalities; Polyethylene Glycols; Randomized Controlled Trials as Topic; Serotonin 5-HT4 Receptor Agonists; Surface-Active Agents; Transcutaneous Electric Nerve Stimulation

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

Topics: Algorithms; Anti-Infective Agents; Benzofurans; Diagnosis, Differential; Diet, Carbohydrate-Restricted; Evidence-Based Medicine; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Rifamycins; Rifaximin

Patients with functional gastrointestinal disorders constitute the majority of patients seeking healthcare for gastrointestinal symptoms in primary and secondary care. Of these disorders irritable bowel syndrome (IBS) is one of the most common and affects 10-20% in the Western world. IBS is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. Sex and gender aspects are important in understanding differences between men and women in their risk and experience of IBS. Relative to men, women are diagnosed more frequently with IBS. Female patients are more likely to be constipated, complain of abdominal distension and of certain extracolonic symptoms. Given the variability of IBS, the most successful treatment will be comprehensive, involving multiple strategies. Efficacy, safety and tolerability are important in the evaluation of IBS therapies, as patients are likely to require long-term treatment. Laxatives, antidiarrheals or antispasmodics are common in the treatment of IBS but the majority of patients receive antispasmodics followed by prokinetic agents. In treatment of IBS there appears to be a greater clinical response to serotonergic agents developed for IBS in women compared to men. There is an absence of drugs licensed specifically for the treatment of IBS. Further studies with novel agents are needed, to evaluate new approaches to IBS management including gender specific behavioral therapies and better characterization of patient subgroups with regard to drug therapy so that personalized therapy can be tested.

Topics: Antidepressive Agents; Antidiarrheals; Benzofurans; Female; Gonadal Steroid Hormones; Humans; Irritable Bowel Syndrome; Laxatives; Male; Parasympatholytics; Probiotics; Sex Characteristics

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 constipation has a high prevalence, and current medical and pharmacological therapies do not restore normal bowel function in all patients.. A PubMed search (1965 - 2009) using the following terms alone or in combination: prucalopride, 5-HT(4), R093877, safety, toxicity, pharmacokinetics, pharmacodynamics, transit, cardiac, hERG, arrhythmia, potassium current, elderly.. Understanding of the mechanisms of action, safety, efficacy and indications for prucalopride in patients with chronic constipation.. Prucalopride is an efficacious and generally safe, new therapeutic option in the management of chronic constipation.

Topics: Aged; Benzofurans; Constipation; Defecation; Gastrointestinal Transit; Humans; Laxatives; Serotonin

This review introduces new therapeutic options in the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation. Therefore, prucalopride and lubiprostone are discussed including their mechanisms and side effects. In addition, other substances that are currently under evaluation such as renzapride and linaclotide are described, since recent results showed a significant effect in patients with constipation. Thus, after the withdrawal of tegaserod due to cardiac side effects, new potent drugs are now available for the treatment of constipation.

Topics: Alprostadil; Benzamides; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Cathartics; Chloride Channel Agonists; Constipation; Humans; Irritable Bowel Syndrome; Lubiprostone; Peptides; Randomized Controlled Trials as Topic; Receptors, Guanylate Cyclase-Coupled; Receptors, Serotonin, 5-HT4

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

Since metoclopramide was first described (in 1964) there have been several attempts to develop compounds which retained gastrointestinal prokinetic activity (via 5-HT(4) receptor activation) but without the limiting side effects associated with dopamine D(2) receptor antagonism. Early compounds (mosapride, cisapride, renzapride, tegaserod) were identified before several of the 5-HT receptors were even described (including 5-HT(4) and 5-HT(2B)), whereas prucalopride came later. Several compounds were hampered by non-selectivity, introducing cardiac liability (cisapride: activity at human Ether-a-go-go Related Gene) or potentially, a reduced intestinal prokinetic activity caused by activity at a second 5-HT receptor (renzapride: antagonism at the 5-HT(3) receptor; tegaserod: antagonism at the 5-HT(2B) receptor). Poor intrinsic activity at gastrointestinal 5-HT(4) receptors has also been an issue (mosapride, tegaserod). Perhaps prucalopride has now achieved the profile of good selectivity of action and high intrinsic activity at intestinal 5-HT(4) receptors, without clinically-meaningful actions on 5-HT(4) receptors in the heart. The progress of this compound for treatment of chronic constipation, as well as competitor molecules such as ATI-7505 and TD-5108, will now be followed with interest as each attempts to differentiate themselves from each other. Perhaps at last, 5-HT(4) receptor agonists are being given the chance to show what they can do.

Topics: Aged; Animals; Benzofurans; Dopamine Antagonists; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Metoclopramide; Receptors, G-Protein-Coupled; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists

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

The estimated prevalence of irritable bowel syndrome (IBS) in Western countries is 7-15%, with a female:male ratio of 2-2.5:1 in IBS patients who seek healthcare services; however, the female predominance is lower in the general population. IBS has a significant impact on health-related quality of life and is associated with a significant healthcare and economic burden. Management of IBS is comprised of general measures and pharmacologic and nonpharmacologic treatment. However, there are ongoing efforts to find more effective therapeutic approaches. As advancements in the understanding of the pathophysiology of IBS continue to grow, new and effective treatments with novel mechanisms of action that have the potential to improve relief of IBS symptoms over current treatments are likely to be developed. This article provides an overview of current and emerging therapies for IBS and also highlights sex and gender differences in clinical trials and treatment response.

Topics: Benzofurans; Complementary Therapies; Diet Therapy; Female; Fibrinolytic Agents; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Male; Randomized Controlled Trials as Topic; Sex Distribution

Topics: Antidepressive Agents; Benzofurans; Carbazoles; Carbolines; Colonic Diseases, Functional; Gastrointestinal Agents; Humans; Indoles; Physical Examination; Pyridines

Gastrointestinal motility disorders represent a diagnostic and therapeutic challenge. Disorders of gastrointestinal motility may result in accelerated transit, delayed transit, impaired relaxation, or inappropriate relaxation. The delayed transit disorders are the most important motility disorders of companion animals and may involve the esophagus (hypomotility and megaesophagus), stomach (delayed gastric emptying), small intestine (postoperative ileus and intestinal pseudo-obstruction), or colon (constipation and megacolon).

Topics: Animals; Benzofurans; Cisapride; Dog Diseases; Dogs; Gastrointestinal Agents; Gastrointestinal Motility; Indoles; Intestinal Diseases; Motilin

Functional gastrointestinal disorders are characterised by central and peripheral physiological changes, associated with psychological factors. Successful drug development has been hindered by lack of adequate characterisation of the nature of symptoms and their physiological and psychological correlates. Animal models of chronic stress are lacking. High levels of drug safety are now demanded for treating non-life threatening conditions. Once close to market, patient pressure groups, health care providers and insurers, government, and the internet can all influence a drug's success. Serotonin-modifying drugs have been the main recent focus of development, with mixed results. Cisapride has been withdrawn because of concerns related to QT prolongation and cardiac arrhythmias. The 5-HT3 antagonists have been developed on the questionable assumption that they modify visceral sensation in patients. Problems have arisen with alosetron being associated with ischaemic colitis and a high incidence of constipation. The 5-HT4 agonists have their major effect on inducing peristalsis, and may modify gut secretion and sensory function. Tegaserod and prucalopride show promise in patients with constipation and related symptoms. 5-HT1 agonists may play a role in treating functional dyspepsia, partly by improving impaired gastric accommodation to a meal. Antidepressants, often found to be clinically beneficial in these disorders, also affect serotonin metabolism. Past successes, such as loperamide or the somatostatin analogue octreotide, involved targeting end organ receptors influencing motor function or secretion. Modifying sensory function is much more challenging. Future research with novel compounds need to keep these recent lessons in mind.

Topics: Antidepressive Agents; Benzofurans; Carbolines; Cisapride; Constipation; Drug Industry; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists; Serotonin Receptor Agonists

Existing pharmacotherapeutic options for the treatment of patients with irritable bowel syndrome (IBS) are limited in treating the multiple symptoms associated with the disorder. There is much interest in the use of serotonin agents as new therapeutics. Acting primarily through 5-HT3 and 5-HT4 receptors, serotonin elicits changes in motor function and possibly visceral sensation. Two serotonin agents were developed specifically for IBS: tegaserod, a 5-HT4 receptor partial agonist, and alosetron, a 5-HT3 receptor antagonist (which is no longer available). Phase III clinical trial data show that during a 12-week treatment period with tegaserod, IBS patients with abdominal pain and discomfort, bloating, and constipation experienced significant global relief (i.e., improvement in overall well-being, abdominal pain, and bowel habit) compared with placebo. Improvement in bowel movement frequency and consistency was achieved and pain was relieved by 1 week. During 12 weeks of treatment, alosetron was shown to elicit significant relief of abdominal pain and discomfort compared with placebo or mebeverine in female IBS patients with diarrhea. Alosetron slowed colonic transit and treatment efficacy was apparent after a week of treatment. Another 5-HT4 receptor agonist, prucalopride, which is being developed for chronic constipation, accelerates colonic transit and increases stool frequency. Therefore, this agent may be of benefit in IBS patients with constipation.

Topics: Abdominal Pain; Benzofurans; Clinical Trials as Topic; Colonic Diseases, Functional; Constipation; Gastrointestinal Motility; Humans; Indoles; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; United States

Irritable bowel syndrome (IBS) is common and can be disabling. Several drugs that modulate serotonin (5HT) and other neurotransmitters in the gut (neuroenteric modulators) have either become available or are in development, but progress has been slowed by toxicity. Blockade of 5HT(3) receptors slows colonic transit, increases fluid absorption and increases left colon compliance. Alosetron, a potent 5HT(3) receptor antagonist, has, in women but not in men, a clinically significant but modest therapeutic gain over placebo in the relief of abdominal pain and discomfort and bowel-habit disturbance (but not bloating) in diarrhoea-predominant IBS. However, the drug unexpectedly was associated with ischaemic colitis and, very rarely, severe constipation-induced complications, and alosetron has been withdrawn. Cilansetron may have similar efficacy in men and women. 5HT(4) receptor stimulation results in accelerated colonic transit, and tegaserod, a partial 5HT(4) receptor agonist, has modest but clinically significant advantage over placebo in constipation-predominant IBS; the benefit seems to be confined to females. Long-term published data are lacking and safety concerns have been raised. Prucalopride, a full 5HT(4) agonist that has been promising in idiopathic chronic constipation, may also be limited by toxicity. Other 5HT receptor antagonists and agonists are under development for IBS. However, for modulators of single receptors to achieve a substantial therapeutic gain, and to do so safely, drug targets based on the pathophysiology of IBS need to be better defined.

Topics: Benzofurans; Carbolines; Clinical Trials as Topic; Colonic Diseases, Functional; Female; Humans; Indoles; Male; Serotonin Antagonists; Serotonin Receptor Agonists

Topics: Benzofurans; Buspirone; Double-Blind Method; Humans; Serotonin 5-HT4 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

Delayed return to gut function and prolonged postoperative ileus (PPOI) delay recovery after colorectal surgery. Prucalopride is a selective serotonin-4-receptor agonist that may improve gut motility.. This was a multicentre, double-blind, parallel, placebo-controlled randomized trial of 2 mg prucalopride versus placebo in patients undergoing elective colorectal resection. Patients with inflammatory bowel disease and planned ileostomy formation were excluded, but colostomy formation was allowed. The study medication was given 2 h before surgery and daily for up to 6 days after operation. The aim was to determine whether prucalopride improved return of gut function and reduced the incidence of PPOI. The primary endpoint was time to passage of stool and tolerance of diet (GI-2). Participants were allocated in a 1 : 1 ratio, in blocks of 10. Randomization was computer-generated. All study personnel, medical staff, and patients were blinded.. This study was completed between October 2017 and May 2020 at two tertiary hospitals in New Zealand. A total of 148 patients were randomized, 74 per arm. Demographic data were similar in the two groups. There was no difference in median time to GI-2 between prucalopride and placebo groups: 3.5 (i.q.r. 2-5) versus 4 (3-5) days respectively (P = 0.124). Prucalopride improved the median time to passage of stool (3 versus 4 days; P = 0.027) but not time to tolerance of diet (2 versus 2 days; P = 0.669) or median duration of hospital stay (4 versus 4 days; P = 0.929). In patients who underwent laparoscopic surgery (125, 84.5 per cent), prucalopride improved median time to GI-2: 3 (2-4) days versus 4 (3-5) days for placebo (P = 0.012). The rate of PPOI, complications, and adverse events was similar in the two groups.. Prucalopride did not improve time to overall recovery of gut function after elective colorectal surgery. Registration number: NCT02947269 (http://www.clinicaltrials.gov).

Topics: Benzofurans; Colorectal Surgery; Double-Blind Method; Elective Surgical Procedures; Humans; Ileus; New Zealand; Postoperative Complications; Recovery of Function; Tertiary Care Centers

Paralytic ileus is a common intestinal dysfunction in critically ill patients, which results in complications and poor hospital outcomes. There are still no established effective medications, except correcting the primary causes and prokinetics trial, which have limited efficacy and potential adverse events. This study aims to evaluate the efficacy of prucalopride on paralytic ileus in critically ill patients.. A randomized, double-blind, placebo-controlled trial of five consecutive days treatment periods was conducted. Critically ill patients with paralytic ileus were included. The primary endpoint was the improvement of bowel dilatation on plain abdominal radiography. The secondary endpoint was the change of abdominal circumference.. Twenty patients were consecutively enrolled in the study. There was no significant difference in baseline characteristics of patients. The common causes of hospitalization were infection and respiratory problems. The maximum large bowel diameters dramatically decreased in prucalopride group and reached maximum point on the third day after intervention when compared with placebo (-2.1 [± 1.8] vs 0.3 [± 1.5] cm, P = 0.01). The maximum small bowel diameters were noticeably less decreased and were not significantly different when compared with placebo. The abdominal circumferences notably decreased and significantly diverged from placebo on the third day.. Prucalopride was an effective enterokinetic agent to improve non-severe inflammatory/ischemic bowel conditions related paralytic ileus in critically ill patients. Its effect was predominant on large intestine but could not be well demonstrated on small bowel in this study. Future study or concomitant other prokinetics for upper gut motility should be further evaluated.

Topics: Benzofurans; Critical Illness; Double-Blind Method; Female; Humans; Intestinal Pseudo-Obstruction; Intestine, Large; Intestine, Small; Male; Middle Aged; Pilot Projects; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome

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

Topics: Adult; Benzofurans; Cross-Over Studies; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Gastric Emptying; Gastroparesis; Humans; Male; Middle Aged; Mitral Valve Prolapse; Myopia; Pilot Projects; Quality of Life; Radionuclide Imaging; Scleroderma, Systemic; Serotonin 5-HT4 Receptor Agonists; Skin Diseases; 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

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

Topics: Adult; Benzofurans; Bisacodyl; Colon; Cross-Over Studies; Female; Gastrointestinal Motility; Healthy Volunteers; Humans; Laxatives; Male; Manometry; Peristalsis; Polyethylene Glycols; Single-Blind Method

5-HT4 receptor stimulation has pro-cognitive and antidepressant-like effects in animal experimental studies; however, this pharmacological approach has not yet been tested in humans. Here we used the 5-HT4 receptor partial agonist prucalopride to assess the translatability of these effects and characterise, for the first time, the consequences of 5-HT4 receptor activation on human cognition and emotion.. Forty one healthy volunteers were randomised, double-blind, to a single dose of prucalopride (1 mg) or placebo in a parallel group design. They completed a battery of cognitive tests measuring learning and memory, emotional processing and reward sensitivity.. Prucalopride increased recall of words in a verbal learning task, increased the accuracy of recall and recognition of words in an incidental emotional memory task and increased the probability of choosing a symbol associated with a high likelihood of reward or absence of loss in a probabilistic instrumental learning task. Thus acute prucalopride produced pro-cognitive effects in healthy volunteers across three separate tasks.. These findings are a translation of the memory enhancing effects of 5-HT4 receptor agonism seen in animal studies, and lend weight to the idea that the 5-HT4 receptor could be an innovative target for the treatment of cognitive deficits associated with depression and other neuropsychiatric disorders. Contrary to the effects reported in animal models, prucalopride did not reveal an antidepressant profile in human measures of emotional processing.

Topics: Adult; Benzofurans; Double-Blind Method; Female; Healthy Volunteers; Humans; Male; Mental Recall; Serotonin 5-HT4 Receptor Agonists; Task Performance and Analysis; Verbal Learning; Young Adult

The objectives of the present study were to evaluate the bioequivalence of 2 tablet formulations of prucalopride, generic and branded, and to investigate relevant pharmacokinetic and safety profiles. This study was designed as a randomized, open-label, fasting, single-dose, crossover, and dual-period trial. After overnight fasting, 12 subjects were given prucalopride tablets via oral administration, and blood specimens were obtained up to 96 hours after dosing. Prucalopride concentrations in plasma were measured using ultraprecision liquid chromatography-tandem mass spectrometry followed by calculation of pharmacokinetic parameters. The safety of prucalopride was assessed throughout the study. The pharmacokinetics of prucalopride can be defined as a 2-compartment model with a long elimination phase. No significant differences were observed between the pharmacokinetic profiles of the generic and branded prucalopride tablets. Bioequivalence was evaluated using 90%CIs for the ratio test/reference of log area under the concentration-time curve over 96 hours, log area under the concentration-time curve to infinity, and log peak concentration from generic and branded tablets, which were 100.06-109.94%, 100.63-110.32%, and 95.84-113.08%, respectively. During administration of the medication, there were 18 adverse events in 6 subjects in the test formulation group and 19 cases of adverse events in 6 subjects in the reference formulation group (P > .05). No severe adverse effects were detected. These results suggest that generic and branded prucalopride tablets are bioequivalent and show similar safety profiles.

Topics: Administration, Oral; Adolescent; Adult; Area Under Curve; Asian People; Benzofurans; Chromatography, High Pressure Liquid; Cross-Over Studies; Drugs, Generic; Female; Humans; Male; Serotonin 5-HT4 Receptor Agonists; Tablets; Tandem Mass Spectrometry; Therapeutic Equivalency; Young Adult

Vagus nerve stimulation (VNS), most likely via enteric neurons, prevents postoperative ileus (POI) by reducing activation of alpha7 nicotinic receptor (α7nAChR) positive. EFS reduced the ATP-induced Ca. Enteric neurons dampen mMφ activation, an effect mimicked by prucalopride. Preoperative, but not postoperative treatment with prucalopride prevents intestinal inflammation and shortens POI in both mice and human, indicating that preoperative administration of 5-HT4R agonists should be further evaluated as a treatment of POI.. NCT02425774.

Topics: Adult; alpha7 Nicotinic Acetylcholine Receptor; Animals; Benzofurans; Disease Models, Animal; Female; Gastrointestinal Motility; Humans; Ileus; Inflammation; Intestine, Small; Macrophages; Male; Mice; Muscle, Smooth; Pancreaticoduodenectomy; Pilot Projects; Postoperative Complications; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome

Sodium phosphate solution (NaP) in oral form is well known and frequently used for good quality bowel cleansing before a colonoscopy, but it carries the potential risk of electrolyte disturbance and dehydration. Prucalopride mitigates severe constipation by promoting colon motility. We evaluated the hypothesis that prucalopride plus one single dose of 45 mL NaP could be used as an alternative bowel preparation.. Consenting adult patients undergoing a screening colonoscopy were randomized to receive 90 mL NaP (90-NaP) in two split doses or prucalopride 2 mg plus 45 mL NaP (P-NaP). Patients completed a questionnaire about adverse gastrointestinal symptoms and acceptability for bowel preparation. The effectiveness of colon preparation was evaluated according to the Ottawa bowel preparation scale.. Bowel cleansing was achieved in 92 patients with 90-NaP and in 97 patients with P-NaP. There was no significant difference in bowel cleansing level and adverse gastrointestinal symptoms between the two groups. However, more patients in the P-NaP group were willing to undertake the same regimen for a subsequent colonoscopy bowel preparation than those in 90-NaP group (82/97; 85% vs 51/92; 55%, P < 0.001).. The combination of 2 mg prucalopride and 45 mL NaP appeared to provide the same level of bowel cleansing, but it was more acceptable than the 90 mL NaP in split doses.

Topics: Benzofurans; Cathartics; Colonoscopy; Female; Humans; Laxatives; Male; Middle Aged; Patient Acceptance of Health Care; Phosphates; Preoperative Care; Prospective Studies; Single-Blind Method; Treatment Outcome

Prokinetics are considered the preferred treatment option for gastroparesis, but evidence of their efficacy is scarce. Prucalopride, a selective 5-hydroxytryptamine 4 receptor agonist used in the treatment of constipation, is able to enhance the gastric emptying rate. In a double-blind, randomized, placebo-controlled crossover study, we evaluated the efficacy of prucalopride to improve the gastric emptying rate and symptoms in patients with gastroparesis.. Thirty-four patients with gastroparesis (28 idiopathic, 7 men, mean age 42 ± 13 years) were evaluated in a double-blind crossover trial of 4-week treatment periods with placebo or prucalopride 2 mg q.d., separated by 2 weeks of washout. The primary end point was the change in symptom severity, assessed by the Gastroparesis Cardinal Symptom Index; secondary end points comprised the Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index, the Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life, and daily diaries, and the gastric emptying rate was assessed by the C-octanoic acid breath test.. Three patients were lost to follow-up. One serious adverse event occurred (small bowel volvulus in the prucalopride group), and 3 patients dropped out because of adverse events of nausea and headache (all prucalopride). For the entire patient group, compared with placebo, prucalopride significantly improved the total Gastroparesis Cardinal Symptom Index (1.65 ± 0.19 vs 2.28 ± 0.20, P < 0.0001) and the subscales of fullness/satiety, nausea/vomiting, and bloating/distention. Prucalopride significantly improved the overall Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life score (1.15 ± 0.16 vs 1.44 ± 0.16, P < 0.05) and the domains of clothing and diet. The gastric half emptying time was significantly enhanced by prucalopride compared with placebo and baseline (98 ± 10 vs 143 ± 11 and 126 ± 13 minutes, P = 0.005 and <0.001, respectively). These significant improvements were also found when considering only the idiopathic gastroparesis subgroup.. In a cohort of patients with predominantly idiopathic gastroparesis, 4 weeks of prucalopride treatment significantly improved symptoms and quality of life and enhanced gastric emptying compared with placebo.

Topics: Adult; Benzofurans; Breath Tests; Cross-Over Studies; Double-Blind Method; Female; Gastric Emptying; Gastroparesis; Humans; Male; Quality of Life; Serotonin 5-HT4 Receptor Agonists; Severity of Illness Index

Ineffective esophageal motility (IEM) is associated with gastroesophageal reflux disease. Secondary peristalsis contributes to esophageal clearance. Prucalopride promotes secondary peristalsis by stimulating 5-hydroxytrypatamine 4 receptors in the esophagus. We aimed to determine whether prucalopride would augment secondary peristalsis in gastroesophageal reflux disease patients with IEM.. After a baseline recording of primary peristalsis, secondary peristalsis was stimulated by slow and rapid mid-esophageal injections of air in 15 patients with IEM. Two separate sessions with 4-mg oral prucalopride or placebo were randomly performed.. Prucalopride significantly increased primary peristaltic wave amplitude (68.1 ± 10.0 vs 55.5 ± 8.8 mmHg, P = 0.02). The threshold volume for triggering secondary peristalsis was significantly decreased by prucalopride during slow (9.3 ± 0.8 vs 12.0 ± 0.8 mL; P = 0.04) and rapid air injection (4.9 ± 0.3 vs 7.1 ± 0.1 mL; P = 0.01). Secondary peristalsis was triggered more frequently after application of prucalopride (55% [43-70%]) than placebo (45% [33-50%]) (P = 0.008). Prucalopride did not change pressure wave amplitudes during slow air injection (84.6 ± 8.1 vs 57.4 ± 13.8 mmHg; P = 0.19) or pressure wave amplitudes during rapid air injection (84.2 ± 8.6 vs 69.5 ± 12.9 mmHg; P = 0.09).. Prucalopride enhances primary peristalsis and mechanosensitivity of secondary peristalsis with limited impact on secondary peristaltic activities in IEM patients. Our study suggests that prucalopride appears to be useful in augmenting secondary peristalsis in patients with IEM only via sensory modulation of esophageal secondary peristalsis.

Topics: Adult; Aged; Benzofurans; Esophagus; Female; Gastroesophageal Reflux; Gastrointestinal Motility; Humans; Male; Middle Aged; Peristalsis; Serotonin 5-HT4 Receptor Agonists; Stimulation, Chemical; Treatment Outcome

Fluoxetine and prucalopride might change phosphocreatine (PCr) levels via the cAMP-PKA pathway, an interesting target in the neurodegenerative mechanisms of MS.. We conducted a two-center double-blind, placebo-controlled, randomized trial including 48 relapsing-remitting MS patients. Patients were randomized to receive placebo (n = 13), fluoxetine (n = 15), or prucalopride (n = 14) for 6 weeks. Proton (. No significant changes were observed for both. Both fluoxetine and prucalopride had a symptomatic effect on upper limb function, fatigue, and depression, but this should be interpreted with caution. No effect of treatment was found on

Topics: Adult; Benzofurans; Brain; Double-Blind Method; Female; Fluoxetine; Gray Matter; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Multiple Sclerosis, Relapsing-Remitting; Neuroprotective Agents; Organ Size; Phosphocreatine; Phosphorus Isotopes; Protons; Treatment Outcome; White Matter

Bowel cleansing is a major patient complaint during colonoscopy. Adding laxatives to the bowel preparation is effective in replacing a portion of bowel preparation solution and reducing its volume. Prucalopride is a serotonin receptor agonist that stimulates gastrointestinal motility and provides propulsive force for defecation. This study aimed to compare 1 L polyethylene glycol (PEG) with ascorbic acid (Asc) plus 2 mg prucalopride (1LP/AP) and 2 L PEG with Asc (2LP/A) for colonoscopy preparation with respect to bowel-cleansing quality and side effects.. A single-center, randomized, prospective study was conducted with 260 outpatients administered either 1LP/AP or 2LP/A. The primary endpoint was bowel preparation quality, which was evaluated using the Boston Bowel Preparation Scale and Aronchick Bowel Preparation Scale, and the secondary endpoints were patient tolerability and acceptability, assessed by a questionnaire-based survey.. The adequate bowel preparation rates were 88.5% and 83.1% in the 2LP/A and 1LP/AP groups, respectively, and the efficacy of 1LP/AP was equivalent to the control regimen (p=.216). Other colonoscopic variables including adenoma detection rate were similar in both groups. Patient tolerability and acceptability were not significantly different, but patients in the 1LP/AP group were more willing to repeat the same regimen (p=.039).. Bowel preparation quality with 1LP/AP was equivalent to that with 2LP/A, which did not increase the occurrence of side effects, but it reduced the volume of the solution ingested, and increased patient satisfaction.

Topics: Abdominal Pain; Adult; Aged; Ascorbic Acid; Benzofurans; Cathartics; Colonoscopy; Female; Humans; Male; Middle Aged; Patient Satisfaction; Polyethylene Glycols; Prospective Studies; Single-Blind Method; Surveys and Questionnaires

Prokinetics are used to treat enteric dismotility symptoms in systemic sclerosis (SSc) patients, but they often lack adequate efficacy. The most effective prokinetics belonging to the serotonin (5-HT. Forty patients with self-reported mild to moderately severe enteric symptoms were enrolled in a cross-over 2 × 2 study. Subjects were randomized 1:1 to prucalopride 2 mg/day or no treatment for one month and vice versa after a 2-week washout period. Before and after each sequence the patients compiled the University of California Los Angeles gastrointestinal tract (UCLA GIT) 2.0 questionnaire and the numbers of complete intestinal movements were recorded. Oro-cecal transit time (OCTT) was evaluated by lactulose breath test in a subgroup of patients. Data were evaluated by mixed linear models corrected for the number of laxatives used during the study periods.. There were 29 subjects who completed the study; 7 subjects withdrew due to side-effects and 4 subjects were not compliant with the study procedures. As compared to dummy treatment, prucalopride was associated with more intestinal evacuations (p < 0.001), improvement of UCLA GIT constipation (-0.672 ± 0.112 vs 0.086 ± 0.115; p < 0.001), reflux (-0.409 ± 0.094 vs 0.01 ± 0.096; p < 0.005) and bloating (-0.418 ± 0.088 vs -0.084 ± 0.09; p = 0.01) scores. Treatment was ranked moderately to more than moderately effective by 22 patients (72.4%). OCTT was significantly reduced during prucalopruide consumption (prucalopride: -20.1 ± 20.1 vs no treatment: 45.8 ± 21.3 minutes; treatment effect = -65.9 minutes; p = 0.035).. The safety profile of prucalopride in SSc is similar to what is known from the literature. In patients with mild to severe gastrointestinal problems, prucalopride may be effective in treating dismotility symptoms, increasing the number of complete bowel movements and improving bowel transit, reducing reflux disease and bloating.. EU Clinical Trial Registry, EudraCT2012-005348-92 . Registered on 19 February 2013.

Topics: Adult; Aged; Benzofurans; Constipation; Cross-Over Studies; Female; Gastrointestinal Diseases; Humans; Laxatives; Middle Aged; Scleroderma, Systemic; Treatment Outcome

Patients with functional bowel disorders develop gas retention and symptoms in response to intestinal gas loads that are well tolerated by healthy subjects. Stimulation of 5HT-4 receptors in the gut has both prokinetic and antinociceptive effects. The aim of this study is to determine the effect of prucalopride, a highly selective 5HT-4 agonist, on gas transit and tolerance in women with functional bowel disorders complaining of constipation.. Twenty-four women with functional bowel disorders complaining of constipation were included in the study. Patients were studied twice on separate days in a cross-over design. On each study day, an intestinal gas challenge test was performed. During the five previous days, prucalopride (2 mg/day) or placebo was administered. Abdominal symptoms, stool frequency, and stool consistency were recorded during the treatment period on daily questionnaires.. During the gas challenge test, prucalopride did not decrease the volume of gas retained in the subset of patients who had significant gas retention (≥ 200 mL) while on placebo. However, in those patients who had increased symptoms during the gas test (≥ 3 on a 0 to 6 scale) when on placebo, prucalopride did significantly reduce the perception of symptoms (2.3 ± 0.5 mean score vs 3.5 ± 0.3 on placebo; P = 0.045). During the treatment period with prucalopride, patients exhibited an increase in the total number of bowel movements and decreased stool consistency compared with placebo.. Prucalopride reduces abdominal symptoms without modifying gas retention when patients with functional bowel disorders are challenged with the gas transit and tolerance test. European Clinical Trials Database (EudraCT2011-006354-86).

Topics: Benzofurans; Constipation; Cross-Over Studies; Double-Blind Method; Female; Gases; Gastrointestinal Transit; Humans; Irritable Bowel Syndrome; Serotonin Receptor Agonists; Treatment Outcome

Previous studies have shown that recovery of colonic transit is a major determinant of post-operative ileus and clinical recovery after gastrointestinal surgery. Prucalopride is a highly selective 5-hydroxytryptamine receptor-4 agonist with colonic pro-motility effects.. To evaluate the effect and safety of prucalopride on post-operative ileus and surgical outcomes after elective gastrointestinal surgery.. In this phase II randomised clinical trial, 110 patients undergoing elective gastrointestinal surgery were randomised to either oral prucalopride (2 mg/day) (n = 55) or placebo (n = 55). Intervention was started 24 h after surgery and stopped after defecation or maximally at 7 days. The primary outcome was time to defecation. Secondary outcomes included time to first passage of flatus, tolerance of solid food, nasogastric tube reinsertion, post-operative length of stay, hospital readmission, overall cost, time to walk independently, surgical complications and inflammatory parameters.. Patients who received prucalopride had a shorter time to defecation (65.0 vs. 94.5 h, P = 0.001), passage of flatus (53.0 vs. 73.0 h, P < 0.001), and post-operative length of stay (7.0 vs. 8.0 days, P = 0.001) than controls. The number of patients with prolonged ileus (>5 days) (16.4% vs. 34.5%, P = 0.026) and the C-reactive protein level on post-operative day 5 (35.67 vs. 59.07 mg/L, P = 0.040) were lower in the prucalopride group. There was no significant difference in post-operative Clavien-Dindo grade III and IV complications (P = 0.606) between the groups.. Prucalopride is a safe and effective treatment to reduce post-operative ileus and systemic inflammation without affecting post-operative complications in patients undergoing elective gastrointestinal surgery. ClinicalTrials.gov: NCT02004652.

Topics: Adolescent; Adult; Aged; Benzofurans; Colon; Digestive System Surgical Procedures; Elective Surgical Procedures; Female; Gastrointestinal Motility; Humans; Ileus; Male; Middle Aged; Postoperative Complications; Time Factors; Treatment Outcome; Young Adult

Topics: Benzofurans; Constipation; Double-Blind Method; Humans; Male

This study compared prucalopride, a selective, prokinetic, 5-HT4 receptor agonist, with polyethylene glycol 3350 + electrolytes (PEG3350), an osmotic laxative, on colonic motility parameters, primarily high-amplitude propagating contractions (HAPCs) in patients with chronic constipation.. This randomized, cross-over, reader-blinded study was conducted at a single site in the USA. The study was open to men and women aged 18-75 years who met study inclusion criteria. Colonic manometry catheters were inserted the day before investigation. On the investigation days, patients received oral 2 mg prucalopride or 2 × 13.8 g PEG3350 in solution. The primary endpoint was HAPC count (threshold: mean amplitude ≥100 mmHg, propagation ≥20 cm [HAPC1 ]) in the 12 h after treatment administration. Analyses were also conducted at two co-primary thresholds: mean amplitude ≥75 mmHg, propagation ≥20 cm (HAPC2 ); and mean amplitude ≥75 mmHg, propagation ≥10 cm (HAPC3 ). Secondary endpoints included HAPC area under the curve (AUC), contraction force, amplitude, duration, and propagation velocity.. Thirteen women were enrolled, with 12 completing the study. Significantly more HAPC1 (8.7 ± 2.06 vs 2.9 ± 2.06; p = 0.012) and HAPC2 (9.0 ± 2.11 vs 3.3 ± 2.11; p = 0.017) were observed in the 12-h periods with prucalopride than with PEG3350. Prucalopride significantly increased mean propagation distance and velocity (HAPC2 ) and mean AUC, force, and amplitude (HAPC3 ) compared with PEG3350. Adverse events were mild or moderate.. Prucalopride was superior to PEG3350 in inducing HAPCs in patients with chronic constipation. ClinicalTrials.gov number NCT01707667.

Topics: Adult; Benzofurans; Colon; Constipation; Cross-Over Studies; Defecation; Female; Gastrointestinal Motility; Humans; Laxatives; Manometry; Middle Aged; Serotonin 5-HT4 Receptor Agonists; Single-Blind Method; Treatment Outcome

Chronic constipation is a prevalent gastrointestinal disorder globally. It is often treated with medications such as laxatives. Newer therapies to improve gastric motility include the selective 5-hydroxytryptamine receptor-4 agonist prucalopride, which is licensed for the treatment of chronic constipation in adults. The aim of this study was to investigate the pharmacokinetic properties and excretion of prucalopride in healthy individuals, using a microtracer approach with (14)C radioactivity detection using liquid scintillation counting and accelerator mass spectrometry.. This was a single-period, open-label, nonrandomized absorption, metabolism, and excretion study of [(14)C]prucalopride. Participants were 6 healthy men aged 18 to 50 years. After screening, participants were administered a single dose of [(14)C]prucalopride succinate 2 mg (~200 nCi). Postadministration, urine, feces, and blood samples were collected over a 10-day period. Safety and adverse event data were also collected.. Almost 100% of the administered dose of radioactivity was recovered, with a mean (SD) of 84.2% (8.88%) recovered in urine and 13.3% (1.73%) recovered in feces. The mean blood-to-plasma concentration ratio of 1.9 indicated uptake of prucalopride into blood cells. The renal clearance of prucalopride was 17.0 (2.5) L/h, which is higher than the glomerular filtration rate in healthy individuals, suggesting active renal transport of prucalopride. Prucalopride was well tolerated, with no serious adverse events reported.. Prucalopride was well absorbed and excreted mainly by the kidneys, including both passive and active transporter mechanisms. Quantitative recovery of the radioactive dose was achieved. Consistent with previous studies, prucalopride was generally well tolerated. ClinicalTrials.gov identifier: NCT01807000.

Topics: Administration, Oral; Adolescent; Adult; Benzofurans; Carbon Radioisotopes; Feces; Healthy Volunteers; Humans; Intestinal Absorption; Laxatives; Male; Middle Aged; Young Adult

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

The 5-HT4 receptor agonist prucalopride is a prokinetic drug which improves colonic motility. Animal data and in vitro studies suggest that prucalopride also affects gastric and esophageal motor function. We aimed to assess the effect of prucalopride on gastric emptying, esophageal motility, and gastro-esophageal reflux in man.. In this double-blind, placebo-controlled, randomized, crossover study, we included 21 healthy volunteers who received 4 mg prucalopride or placebo per day for 6 days. We performed high-resolution manometry (HRM) followed by 120-min HRM-pH-impedance monitoring after a standardized meal, ambulatory 24-h pH-impedance monitoring, and gastric emptying for solids.. Prucalopride decreased (median [IQR]) total acid exposure time (3.4 [2.5-5.6] vs 1.7 [0.8-3.5] %, p < 0.05). The total number of reflux events was unaffected by prucalopride, however, the number of reflux events extending to the proximal esophagus was reduced by prucalopride (15.5 [9.8-25.5] vs 10.5 [5.3-17.5], p < 0.05). Furthermore, prucalopride improved acid clearance time (77.5 [47.8-108.8] vs 44.0 [30.0-67.8] s, p < 0.05). Prucalopride did not affect the number of transient lower esophageal sphincter (LES) relaxations or their association with reflux events. Esophageal motility and basal pressure of the LES were not affected by prucalopride. Prucalopride increased gastric emptying (T1/2 ; 32.7 [27.9-44.6] vs 49.8 [37.7-55.0] min, p < 0.05) and decreased residue after 120 min (8.8 [4.4-14.8] vs 2.7 [1.3-5.4] %, p < 0.05).. Prucalopride reduces esophageal acid exposure and accelerates gastric emptying in healthy male volunteers. These findings suggest that the drug could be effective for treatment of patients with reflux disease and functional dyspepsia.

Topics: Benzofurans; Cross-Over Studies; Double-Blind Method; Gastric Acidity Determination; Gastric Emptying; Gastroesophageal Reflux; Healthy Volunteers; Humans; Hydrogen-Ion Concentration; Male; Manometry; Serotonin 5-HT4 Receptor Agonists

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

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

Topics: Adolescent; Benzofurans; Child; Child, Preschool; Constipation; Defecation; Double-Blind Method; Fecal Impaction; Female; Humans; Infant; Male; Serotonin 5-HT4 Receptor Agonists; Treatment Failure

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

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

Topics: Administration, Oral; Area Under Curve; Benzofurans; Child; Child, Preschool; Constipation; Defecation; Fecal Incontinence; Feces; Female; Gastrointestinal Motility; Humans; Laxatives; Male; Serotonin 5-HT4 Receptor Agonists; Tablets; Treatment Outcome

Prucalopride is a selective, high-affinity, 5-hydroxytryptamine 4 (5-HT4) receptor agonist, which is approved for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. Women of childbearing potential, many of whom will be using oral contraceptives, comprise a large proportion of patients seeking medical therapy for constipation.. The aim of this study was to evaluate the effect of prucalopride on the absorption and steady-state pharmacokinetics of oral contraceptives in healthy women.. Sixteen women (aged 18-45 years) were enrolled in this open-label, two-way crossover trial (ClinicalTrials.gov identifier: NCT01036893) and given two 5-day treatments with a once-daily oral contraceptive (ethinylestradiol 0.035 mg + norethisterone 1 mg), alone and in combination with prucalopride 2 mg once daily. Treatments were separated by a 7 ± 2-day washout period. On days 1 and 5, blood samples were obtained pre-dose and at regular intervals post-dose up to 24 and 48 hours, respectively, to determine ethinylestradiol and norethisterone plasma concentrations. Prucalopride plasma concentrations were determined pre-dose and 3 hours post-dose on days 1 and 5, and 24 hours post-dose on day 6. Safety was assessed.. Thirteen participants completed the study. One participant was thought to be non-compliant on days 3 and/or 4, and was excluded from the day 5 analysis. On days 1 and 5, maximum plasma concentrations of both oral contraceptive constituents were attained in ~1 hour and were unaffected by prucalopride administration. On day 5, steady-state prucalopride and oral contraceptive concentrations had been achieved. Prucalopride did not affect the pharmacokinetics of the oral contraceptives: point estimates for the maximum plasma concentration and area under the plasma concentration-time curve values and their associated 90 % confidence intervals were contained within predefined equivalence limits (80-125 %). Prucalopride was well tolerated, with a safety profile consistent with those observed in previous studies.. Co-administration of prucalopride with an oral contraceptive did not result in any clinically meaningful pharmacokinetic interactions and was well tolerated.

Topics: Adult; Benzofurans; Contraceptives, Oral, Combined; Cross-Over Studies; Drug Interactions; Female; Humans; 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

To assess steady-state effects of therapeutic and supra-therapeutic doses of prucalopride on the QT interval using a novel design involving a parallel placebo group with nested crossover for positive control.. A double-blind, double-dummy, placebo- and active-controlled study was conducted in 120 healthy male and female volunteers (NCT00903747). Volunteers were randomized to receive prucalopride 2-10 mg once daily (therapeutic and supratherapeutic doses, respectively) (group 1), placebo with 400 mg moxifloxacin on day 1 (group 2a), or placebo with moxifloxacin on day 15 (group 2b). Twelve-lead 24 h Holter ECGs recorded at various time-points were evaluated blind and centrally.. Estimated mean difference in study specific corrected QT interval (QT(c)SS) time-matched change from baseline between prucalopride (2 and 10 mg) and placebo was <5 ms at all time points (maximum mean difference: 3.83 ms at 3.5 h post dose on day 5 with 2 mg [90% Cl -0.33, 6.38 ms]). Upper limits of the two-sided 90% CI for QT(c)SS were all <10 ms. There were no outlying QT(c)SS values >450 ms and no subjects had an increase >60 ms following prucalopride. Moxifloxacin produced the expected significant changes in QT(c)SS (>5 ms, maximum of +12.7 ms at 5 h post dose) at all time-points except 1 h post dose. Prucalopride resulted in small increases in heart rate (maximum of 5.8 beats min(-1)), which were similar for 2 and 10 mg. Prucalopride was well tolerated after first day of treatment.. Prucalopride at both therapeutic and supra therapeutic doses has no clinically significant effects on cardiac repolarisation in healthy volunteers.

Topics: Adolescent; Adult; Analysis of Variance; Benzofurans; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Female; Heart; Heart Rate; Humans; Male; Middle Aged; Serotonin 5-HT4 Receptor Agonists; Young Adult

Chronic intestinal pseudo-obstruction is a disabling condition for which there are no established drug therapies. The condition is caused by a diverse range of intestinal myopathies and neuropathies.. To assess the therapeutic efficacy of prucalopride, a selective high-affinity 5-HT(4) receptor agonist, we employed a multiple n = 1 study design. Each patient acted as his/her own control, each day counting as one treatment episode, allowing comparison of 168 days on each of active drug and placebo.. Double-blind, randomised, placebo-controlled, cross-over trial of four 12-week treatment periods, with 2-4 mg prucalopride or placebo daily. In each of the first and second 6 months there was a prucalopride and a placebo treatment. Patients with proven chronic intestinal pseudo-obstruction, including dilated gut, were included. Evaluation was by patient diary and global evaluation.. Seven patients participated (mean 42 years, five female, median symptom duration 11 years). Three discontinued, two due to study length, and one on prucalopride due to unrelated malnutrition and bronchopneumonia. Four patients (three visceral myopathy and one visceral neuropathy) completed the study; prucalopride significantly improved pain in three of four patients, nausea in two, vomiting in one, bloating in four and analgesic intake. Bowel function was not changed substantially.. n = 1 studies in rare conditions allow drug efficacy assessment. Prucalopride relieves symptoms in selected patients with chronic pseudo-obstruction.

Topics: Adult; Aged; Benzofurans; Colonic Pseudo-Obstruction; Cross-Over Studies; Defecation; Double-Blind Method; Female; Gastrointestinal Transit; Humans; Male; Middle Aged; Research Design; Serotonin 5-HT4 Receptor Agonists; 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

This study investigated the pharmacokinetics of prucalopride in Chinese healthy volunteers.. This single-center, open-label study was conducted in 14 healthy males and 14 healthy females, aged 18 - 45 years. Fasted subjects received a single dose of 2 mg prucalopride, and after a 7-day wash-out period, they received the same dose once-daily for 7 days at fasted condition. Serial blood samples were taken at predefined time-points to measure plasma concentrations of prucalopride during the single-dose and multi-dose period. Daily evaluations were made on defecation frequency and stool consistency. Safety assessments were performed throughout the study.. After oral administration, prucalopride reached the peak plasma level (Cmax) of 4.92 ± 0.78 ng/ml with a median time to Cmax (tmax) of 2 hours and resulted in an area under concentration-time curve (AUC0-∞) of 89.3 ± 15.82 h×ng/ml. Steady state was attained 3 days after repeated dosing, when Cmax was 8.09 ± 1.21 ng/ml and AUC0-24h was 103.6 ± 14.35 h×ng/ml. Pharmacokinetic profiles were similar between genders except males had a slightly lower exposure level. Marked increase of defecation frequencies and predominance of "watery" or "loose" stools were seen after a single dose. The responses during multi-dose period were less remarkable and returned to baseline in 3 days.. The pharmacokinetics of prucalopride 2 mg oral dose in Chinese healthy volunteers are similar to those observed in Caucasians. Compared to females, males exhibited a slightly lower exposure of prucalopride but similar changes of bowel habits were observed in both genders suggesting the inter-gender pharmacokinetic differences are not clinically relevant.

Topics: Administration, Oral; Adolescent; Adult; Area Under Curve; Asian People; Benzofurans; China; Defecation; Drug Administration Schedule; Female; Gastrointestinal Agents; Humans; Male; Metabolic Clearance Rate; Middle Aged; Serotonin 5-HT4 Receptor Agonists; Sex Factors; Tablets; Young Adult

To evaluate the pharmacokinetics of prucalopride in individuals with renal impairment (RI).. This open-label Phase I study (ClinicalTrials.gov identifier: NCT01674192) enrolled men and women aged 18-75 years who were classified by renal function: normal renal function (creatinine clearance ≥ 80 mL/min/1.73 m²), mild RI (50-79 mL/min/1.73 m²), moderate RI (25-49 mL/min/1.73 m²), and severe RI (≤ 24 mL/min/1.73 m²). All received a single oral dose of prucalopride 2 mg.. Thirty-four individuals (normal renal function: 10; mild RI: 8; moderate RI: 7; severe RI: 9) received prucalopride. In all groups, maximum plasma concentration was reached within 2-4 hours. There was no significant difference in exposure (area under the plasma concentration-time curve from time zero to infinity) between participants with mild RI and those with normal renal function. However, area under the plasma concentration-time curve from time zero to infinity values were 1.5- and 2.3-fold higher (P = 0.002 and P < 0.001) in patients with moderate RI and severe RI, respectively, than in those with normal renal function. The proportion of total body clearance accounted for by renal clearance was significantly reduced in those with RI.. Clinically meaningful reductions in renal clearance were seen in participants with severe RI, which supports a decrease from the standard dose of prucalopride 2 mg daily to 1 mg daily in these individuals.

Topics: Administration, Oral; Adult; Aged; Area Under Curve; Benzofurans; Case-Control Studies; Creatinine; Female; Humans; Male; Middle Aged; Renal Insufficiency; Serotonin 5-HT4 Receptor Agonists; Severity of Illness Index; Time Factors

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

Opioid-induced constipation (OIC) has negative effects on quality of life (QOL). Prucalopride is a new, selective 5-HT(4) agonist and enterokinetic with strong clinical data in chronic constipation. This study investigated the efficacy, safety, and tolerability of prucalopride in patients with noncancer pain and OIC.. A phase II, double-blind, placebo-controlled study of 196 patients randomized to placebo (n = 66), prucalopride 2 mg (n = 66) or 4 mg (n = 64), for 4 weeks, was carried out. The primary endpoint was the proportion of patients with increase from baseline of ≥ 1 spontaneous complete bowel movement (SCBM)/week. Secondary endpoints [proportion of patients with ≥ 3 SCBM/week, weekly frequency of (SC)BM, severity of constipation, and efficacy of treatment], adverse events (AEs), and safety parameters were also monitored.. More patients had an increase from baseline of ≥ 1 SCBM per week (weeks 1-4) in the prucalopride groups [35.9% (2 mg) and 40.3% (4 mg)] versus placebo (23.4%), reaching statistical significance in week 1. Over weeks 1-4, more patients in the prucalopride groups achieved an average of ≥ 3 SBM per week versus placebo (60.7% and 69.0% versus 43.3%), reaching significance at week 1. Prucalopride 4 mg significantly improved patient-rated severity of constipation and effectiveness of treatment versus placebo. Patient Assessment of Constipation-Symptom (PAC-SYM) total scores and Patient Assessment of Constipation-Quality of Life (PAC-QOL) total and satisfaction subscale scores were improved. The most common AEs were abdominal pain and nausea. There were no clinically relevant differences between groups in vital signs, laboratory measures or electrocardiogram parameters.. In this population with OIC, prucalopride improved bowel function and was safe and well tolerated.

Topics: Abdominal Pain; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Benzofurans; Constipation; Double-Blind Method; Drug Therapy, Combination; Electrocardiography; Female; Humans; Laxatives; Male; Middle Aged; Placebo Effect; Serotonin Receptor Agonists; Treatment Outcome; Vital Signs; Young Adult

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

Chronic constipation is common among nursing home residents. The aim of this study was to evaluate safety, tolerability and pharmacokinetics of the selective 5HT(4) receptor agonist prucalopride in elderly, chronically constipated patients in nursing homes. A multicentre, phase II, randomized, double-blind dose-escalation study in 89 elderly constipated nursing home residents treated with placebo, 0.5, 1 or 2 mg prucalopride once daily for 28 days was analysed. Adverse events, vital signs, ECG, Holter monitor and pharmacokinetics were assessed (Clinicaltrials.gov identifier: NCT00627692). Patients' mean age was 83 years; 88% had a history of cardiovascular diseases. Most frequent adverse events, at least possibly related to prucalopride, were diarrhoea and abdominal pain. Relative to placebo, there were no differences in vital signs, ECG corrected QT interval, ECG morphology parameters, or incidence of supraventricular or ventricular arrhythmias on Holter monitoring. Plasma prucalopride concentrations increased proportionally with administered dose. Prucalopride up to 2 mg once daily for 4 weeks was safe and well-tolerated by constipated elderly patients, with no differences vs placebo in ECG or a range of Holter-monitoring parameters.

Topics: Aged; Aged, 80 and over; Arrhythmias, Cardiac; Benzofurans; Cohort Studies; Constipation; Double-Blind Method; Electrocardiography; Electrocardiography, Ambulatory; Female; Gastrointestinal Agents; Hemodynamics; Humans; Male; Middle Aged; Serotonin Receptor Agonists

Prucalopride, a first-in-class dihydrobenzofuran-carboxamide derivative, is a potent, selective and specific serotonin 5-HT(4) receptor agonist with enterokinetic properties. Over a 12-week treatment period, prucalopride 2 and 4 mg once daily significantly improved bowel habit assessments (based on patient diary data) relative to placebo in three large, randomized, double-blind, multicentre trials in patients (aged 17-95 years) with severe chronic constipation, the majority of whom were women who experienced inadequate relief with previous therapies. There was no additional benefit with the 4 mg/day over the 2 mg/day dosage of prucalopride. Patient assessments of constipation symptoms and severity, treatment efficacy, satisfaction with bowel habit and treatment, and health-related quality of life were also significantly improved with prucalopride compared with placebo. The improvement in patient satisfaction with bowel habit and treatment was maintained for up to 24 months in open-label, multicentre, long-term follow-up studies. Prucalopride therapy was generally well tolerated; most adverse events in the 12-week studies were transient and of mild to moderate severity. In terms of cardiovascular tolerability, the incidence of QT interval prolongation with prucalopride at dosages of 2 and 4 mg/day was low and similar to that with placebo. Moreover, prucalopride at dosages up to 20 mg/day (10-fold higher than the recommended therapeutic dosage) had no clinically relevant effects on cardiovascular parameters in healthy volunteers.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Benzofurans; Cathartics; Child; Child, Preschool; Constipation; Cost of Illness; Defecation; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gastrointestinal Agents; Gastrointestinal Transit; Humans; Infant; Laxatives; Male; Meta-Analysis as Topic; Middle Aged; Patient Satisfaction; Placebos; Quality of Life; Receptors, Serotonin, 5-HT4; Serotonin; 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

Laxatives are frequently ineffective in treating constipation. An alternative therapeutic approach is to target serotonin-4 receptors, which are involved in initiating peristalsis.. In a double-blind, placebo-controlled trial, to assess the efficacy and safety of a systemically active serotonin-4 agonist, prucalopride.. Seventy-four women with constipation were stratified into slow or normal transit groups, and each group was randomized to receive either placebo or 1 mg prucalopride daily for 4 weeks. A bowel function diary was maintained. Whole-gut and orocaecal transit, visceral sensitivity, quality of life and psychological state were assessed before and after treatment.. Prucalopride, not placebo, increased spontaneous stool frequency (P=0.008) and reduced time to first stool (P < 0.001). Prucalopride reduced the number of retained markers in all patients compared to placebo (P=0.004). Prucalopride reduced the mean number of retained markers in slow transit (P=0.069), but did not alter the marker count in normal transit (P=0.86). Orocaecal transit was accelerated by prucalopride, not placebo (P=0.004). Prucalopride, notplacebo, increased rectal sensitivity to distension (urge volume, P=0.01) and electrical stimulation (P=0.001). Prucalopride significantly improved several domains of the Short Form Health Status Survey and the disease-specific quality of life. Adverse effects were similar for prucalopride and placebo.. Prucalopride improves symptoms, upper gut transit and gut sensitivity in constipated patients with both slow and normal transit. It improves transit in patients with slow transit. These changes are associated with improved well-being.

Topics: Adult; Benzofurans; Cathartics; Constipation; Defecation; Double-Blind Method; Female; Gastrointestinal Transit; Humans; Patient Compliance; Quality of Life; Rectum; Serotonin Receptor Agonists; Treatment Outcome

Prucalopride is a selective and specific 5-hydroxytryptamine(4) receptor agonist that is known to increase stool frequency and to accelerate colonic transit.. To investigate the effect of prucalopride on high-amplitude propagated contractions and segmental pressure waves in healthy volunteers.. After 1 week of dosing (prucalopride or placebo in a double-blind, randomized, crossover fashion), colonic pressures were recorded in 10 healthy subjects using a solid-state pressure catheter with six sensors spaced 10 cm apart. Subjects kept diary records of their bowel habits (frequency, consistency and straining). High-amplitude propagated contractions were analysed visually, comparing their total numbers and using 10-min time windows. Segmental pressure waves were analysed using computer algorithms, quantifying the incidence, amplitude, duration and area under the curve of all detected peaks.. When taking prucalopride, stool frequency increased, consistency decreased and subjects strained less. Prucalopride just failed to increase the total number of high-amplitude propagated contractions (P=0.055). The number of 10-min time windows containing high-amplitude propagated contractions was increased by prucalopride (P=0.019). Prucalopride increased the area under the curve per 24 h (P=0.026).. The 5-hydroxytryptamine(4) receptor agonist prucalopride stimulates high-amplitude propagated contractions and increases segmental contractions, which is likely to be the underlying mechanism of its effect on bowel habits in healthy volunteers.

Topics: Adult; Aged; Benzofurans; Cross-Over Studies; Defecation; Double-Blind Method; Feces; Female; Gastrointestinal Motility; Humans; Male; Middle Aged; Serotonin Receptor Agonists

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 (PRU) is a selective benzofuran 5-hydroxytryptamine(4)-receptor agonist with gastrointestinal and colonic prokinetic activities. We evaluated the effects of PRU on gastrointestinal and colonic transit in patients with constipation.. Gastrointestinal and colonic transit were measured over 48 hours in 40 patients who fulfilled modified Rome I criteria for functional constipation. Patients had no evidence of a rectal evacuation disorder. Subjects were randomized to receive a daily dose of 2 or 4 mg PRU or placebo in a double-blind, parallel-group design. Each treatment lasted 7 days. The transit test was performed over the last 48 hours of the study. Effects on gastric emptying, small bowel transit, and colonic transit were analyzed using Kruskal-Wallis and Wilcoxon rank sum tests.. Of 61 patients screened, 40 were eligible and randomized. Two patients withdrew because of adverse events. PRU accelerated overall gastric emptying and small bowel transit. PRU tended to accelerate overall colonic transit with significantly faster overall colonic transit and ascending colon emptying with the 4-mg dose.. PRU accelerates transit through the stomach, small bowel, and colon in patients with constipation unassociated with a rectal evacuation disorder.

Topics: Adult; Benzofurans; Colon; Constipation; Female; Gastric Emptying; Gastrointestinal Motility; Humans; Male; Radionuclide Imaging; Rectal Diseases; Serotonin Receptor Agonists; Treatment Outcome

Prucalopride (R093877) is a selective and specific 5HT4 agonist, the first of a new chemical class of benzofurans, with gastrointestinal prokinetic activities in vitro.. To evaluate the effects of prucalopride on gastrointestinal and colonic transit.. A validated scintigraphic technique was used to measure gastrointestinal and colonic transit over 48 hours in 50 healthy volunteers. For seven days, each subject received a daily dose of 0. 5, 1, 2, or 4 mg prucalopride, or placebo in a double blind, randomised fashion. The transit test was performed over the last 48 hours.. There were significant accelerations of overall colonic transit at 4, 8, 24, and 48 hours (p<0.05) and proximal colonic emptying t1/2 (p<0.05). The 0.5, 2, and 4 mg doses of prucalopride were almost equally effective and accelerated colonic transit compared with placebo. Prucalopride did not significantly alter gastric emptying (p>0.5) or small bowel transit (overall p=0. 12). The medication appeared to be well tolerated during the seven day treatment of healthy subjects.. Prucalopride accelerates colonic transit, partly by stimulating proximal colonic emptying, but does not alter gastric or small bowel transit in healthy human subjects. Prucalopride deserves further study in patients with constipation.

Topics: Adolescent; Adult; Benzofurans; Colon; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gastric Emptying; Gastrointestinal Agents; Gastrointestinal Transit; Humans; Intestine, Small; Male; Middle Aged; Serotonin Receptor Agonists

Prucalopride (PR) is a novel 5-HT4 agonist enterokinetic compound.. To evaluate its effect on bowel function, gut transit and anorectal function in healthy volunteers using a double-blind, placebo-controlled crossover study.. Twenty-four healthy volunteers (12 men, 12 women, mean age 25 years, range 20-53 years) were randomly assigned to 1 mg/placebo or 2 mg/placebo (PL). The trial consisted of five consecutive 1 week periods: no drug treatment, PR treatment or PL, washout, PL or PR, no treatment. Subjects maintained a diary of bowel function during the entire study period. Total intestinal transit time (TITT), mean colonic transit time (MCTT) and anorectal function (anal manometry, rectal sensitivity and rectal compliance) were assessed at the end of both treatment periods. Electrocardiography and blood sampling were performed for safety analysis; blood sampling was also used to check compliance.. No subjects withdrew from the study. Treatment with PR 2 mg showed a statistically significant increase in mean number of weekly stools (11.5 vs. 7.1 compared to PL, P = 0.04) and in the percentage of loose/watery stools (48 vs. 12% compared to PL, P = 0.005). Within 1 week, stool frequency and consistency returned to baseline values when treatment was stopped. MCTT was shortened significantly with both doses, i.e. from 35 h on PL to 25 h on PR 1 mg (P = 0.01) and from 43 h on PL to 22 h on PR 2 mg (P = 0.02). Anorectal function was unaffected by PR. Transient and moderate headache occurred in nine subjects during PR treatment and in six subjects during PL treatment.. Prucalopride is well tolerated by healthy subjects and has a marked and consistent effect on stool frequency and consistency, and on colonic transit. In the present study prucalopride did not affect visceral sensitivity or sphincter function. It holds promise for patients with slow transit constipation.

Topics: Adult; Anal Canal; Benzofurans; Colon; Cross-Over Studies; Defecation; Double-Blind Method; Female; Gastrointestinal Agents; Gastrointestinal Transit; Humans; Male; Middle Aged; Rectum; Serotonin Antagonists

An economical & eco-friendly spectrofluorometric method has been developed for the determination of prucalopride succinate (PRU) in human urine on the basis of the drug's native fluorescence. The type of solvent and the wavelengths of excitation and emission have been carefully selected for optimal experimental conditions. In deionized water, the fluorescence intensity was measured at λ emission 362 nm upon excitation at 310 nm. This bio-validated method was carried out using 30uL urine without any preliminary steps. The calibration curve for prucalopride succinate shows a linear relationship in a concentration range of 0.75-5.5 µg/mL. Accuracy and precision were obtained using 4 quality control samples which are: 0.75 μg/ mL (LLOQ), 2.25 μg/mL (QCL), 2.5 μg/mL (QCM) & 4.125 µg/mL (QCH). The validation of this proposed technique obeys European Medicines Agency (EMA) Guidelines for validating bioanalytical methods and the greenness assessment was evaluated according to the Analytical GAPI approach.

Topics: Benzofurans; Humans; Solvents; Spectrometry, Fluorescence; Succinates

Upper gastrointestinal (GI) symptoms are common in pediatrics, and few prokinetics for children exist. The goal of this study was to determine the efficacy of prucalopride for treatment of upper GI symptoms and feeding difficulties in children.. This was a retrospective study of patients prescribed prucalopride for upper GI symptoms at a single tertiary care center from July 2019 to January 2021. Demographic data, the indication for prucalopride, comorbidities, and feeding data were recorded. The primary outcome was improvement in the primary upper GI symptom at first follow-up after prucalopride initiation. Univariable and multivariable analyses were used to assess for factors associated with improvement.. The final study population included 71 patients who received prucalopride for treatment of upper GI symptoms. The most common indications were nausea (44%), feeding difficulties (20%), and reflux (11%). Patients had a median age of 16.7 years (range 1.9-21.8 years), and they had received 4 ± 4.8 years of care in our GI clinic and trialed 3.0 ± 2.0 other GI medications by the time of the prucalopride prescription. At follow-up 3.6 ± 2.9 months after the prucalopride was prescribed, 46 patients (65%) had symptomatic improvement of the upper GI symptom. Improvement was more likely in patients with enteral tubes (p = 0.04), pulmonary comorbidities (p = 0.006), and neurologic comorbidities (p = 0.02). Amongst patients with feeding difficulties, 79% of patients showed improvements in oral or tube feeding.. In this sample of children treated for refractory upper GI symptoms at a single tertiary care center, patients showed improvements in symptoms like nausea, reflux, and feeding difficulties after starting prucalopride.

Topics: Adolescent; Adult; Benzofurans; Child; Child, Preschool; Gastrointestinal Agents; Gastrointestinal Diseases; Humans; Infant; Retrospective Studies; Treatment Outcome; Young Adult

Prucalopride has been used in adults with gastroparesis, accelerating gastric emptying. There are no studies with this drug in gastroparetic children. An 8-year-old boy is presented who consulted for a month of postprandial symptoms, with a diagnosis of gastroparesis by gastric emptying scintigraphy. He did not improve with metoclopramide, domperidone, erythromycin, and esomeprazole. He received prucalopride for two periods (for 178 and 376 days) at doses: 0.03 - 0.04 mg/ kg/day, presenting improvement in the follow-up with the cardinal gastroparesis symptom index and gastric emptying scintigraphy. Due to the good response, prucalopride may be a therapeutic option in pediatric gastroparesis.. La prucaloprida acelera el vaciamiento gástrico en adultos con gastroparesia. No existen estudios con este medicamento en niños con gastroparesia. Se presenta un niño de 8 años que consultó por síntomas posprandiales de un mes de duración, con diagnóstico de gastroparesia por gammagrafía de vaciamiento gástrico. No mejoró con metoclopramida, domperidona, eritromicina y esomeprazol. Recibió prucaloprida durante dos períodos (durante 178 y 376 días) a dosis de 0,03-0,04 mg/kg/ día. Presentó mejoría en el seguimiento con el índice cardinal de síntomas de gastroparesia y gammagrafías de vaciamiento gástrico. Por la buena respuesta, la prucaloprida podría ser una opción terapéutica en la gastroparesia pediátrica.

Topics: Adult; Benzofurans; Child; Domperidone; Gastric Emptying; Gastroparesis; Humans; Male

The present study aimed to investigate whether prucalopride, as a 5‑hydroxytryptamine 4 (5‑HT4) receptor agonist, improved intestinal motility by promoting the regeneration of the enteric nervous system (ENS) in rats with diabetes mellitus (DM). A rat model of DM was established using an intraperitoneal injection of streptozotocin. The rats were randomly divided into four groups of 6 rats/group: Control, DM (DM model), DM + A (5 µg/kg prucalopride) and DM + B (10 µg/kg prucalopride). The rats in the Control group were given an equal volume of citric acid solvent. After successful model establishment, high blood glucose levels were maintained for 2 weeks before administration of prucalopride. The colonic transit time was measured using the glass bead discharge method. It was revealed that the colonic transit time of diabetic rats was the longest, and this was significantly shortened in the DM + B group. Subsequently, the colons were collected. The expression levels of Nestin, glial fibrillary acidic protein (GFAP), SOX10, RNA‑binding protein human antigen D (HuD) and ubiquitin thiolesterase (PGP9.5) were determined via immunohistochemical analysis. Immunofluorescence double staining of 5‑HT4 + Nestin and Ki67 + Nestin was performed. The 5‑HT level was measured using ELISA. Compared with that in the control group, Nestin expression was significantly increased in the DM and DM + A groups, and it was concentrated in columnar epithelial cells and the mesenchyme. Furthermore, the expression levels of Nestin in the DM + A group were higher than those in the DM group. No difference was observed in the expression levels of Nestin between the DM + B group and the Control group. The expression levels of 5‑HT protein were highest in the Control group; however, the expression levels of 5‑HT protein in the DM group, DM + A group and DM + B group exhibited an increasing trend. Similar trends in the expression of 5‑HT4 and Nestin were not observed; however, similar trends in the expression of Nestin and Ki67 were observed. The expression levels of GFAP, SOX10, PGP9.5 and Ki67 in the DM + A and DM + B groups were higher compared with those in the DM group. In the DM + A group, HuD expression was decreased compared with that in the Control group but it was markedly higher compared with that in the DM group. In conclusion, prucalopride may improve intestinal motility by promoting ENS regeneration in rats with DM.

Topics: Animals; Benzofurans; Diabetes Mellitus, Experimental; Enteric Nervous System; Gastrointestinal Motility; Ki-67 Antigen; Nestin; Rats; Serotonin

Topics: Benzofurans; Bipolar Disorder; Humans; Male; Mania; Middle Aged; Receptors, Serotonin, 5-HT4

Topics: Benzofurans; Colorectal Surgery; Digestive System Surgical Procedures; Elective Surgical Procedures

Cognitive deficits commonly accompany psychiatric disorders but are often underrecognised, and difficult to treat. The 5-HT

Topics: Benzofurans; Hippocampus; Humans; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin 5-HT4 Receptor Agonists

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

Prucalopride, a high-affinity 5-hydroxytryptamine 4 receptor agonist, promotes esophageal peristalsis, while phosphodiesterase type 5 inhibitor sildenafil inhibits esophageal peristalsis. The present study was aimed to evaluate whether prucalopride would augment esophageal peristalsis subsequent to the application of sildenafil.. Seventeen healthy adults underwent high-resolution manometry by a catheter with one injection port located in the mid-esophagus. Secondary peristalsis was assessed by rapid air injections after water swallows. Two sessions were randomly performed including acute administration of sildenafil 50 mg after pretreatment with prucalopride or the placebo.. The frequency of primary peristalsis subsequent to the administration of sildenafil was significantly increased by prucalopride (P = 0.02). Prucalopride also significantly increased distal contractile integral of primary peristalsis subsequent to the administration of sildenafil (P = 0.03). No difference in the frequency of secondary peristalsis subsequent to the administration of sildenafil for air injects of 10 mL (P = 0.14) or 20 mL (P = 0.21) was found between prucalopride and placebo. Prucalopride did not change distal contractile integral of secondary peristalsis subsequent to the administration of sildenafil for air injections of 10 mL (P = 0.09) or 20 mL (P = 0.12).. Prucalopride modulates sildenafil-induced inhibition of primary peristalsis by increasing its effectiveness and peristaltic wave amplitude. Our findings suggest that activation of 5-hydroxytryptamine 4 receptors plays a role in mediating sildenafil-induced inhibition of esophageal primary peristalsis rather than secondary peristalsis.

Topics: Adult; Benzofurans; Drug Interactions; Esophagus; Female; Healthy Volunteers; Humans; Male; Manometry; Peristalsis; Phosphodiesterase 5 Inhibitors; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Sildenafil Citrate; Young Adult

The aim of this study was to compare the effects of colonic electrical stimulation (CES) and prucalopride on gastrointestinal transit and defecation and to verify the safety of CES in a canine model of constipation.. Eight beagles received CES implantation and induction drugs for slow transit constipation (STC). In the STC model, the gastrointestinal transit time (GITT), colonic transit time (CTT), stool frequency and stool consistency were assessed to compare the effects of CES and prucalopride on gastrointestinal transit and defecation. The histocompatibility of the implantable device was evaluated.. The individualized parameters for CES varied greatly among the animals, and the GITTs were not significantly shortened by CES or prucalopride; however, both the CES and prucalopride treatment significantly accelerated CTT and improved stool consistency compared with sham stimulation. CES treatment also resulted in significantly higher stool frequency than prucalopride treatment, which did not significantly change the stool frequency. No severe inflammation response was detected in the gross and microscopic appearance around the implants.. CES and prucalopride treatment may yield similar short-term effects for improving gastrointestinal transit and stool consistency, and CES outperformed prucalopride treatment in terms of defecation inducement in the short term. There were ideal levels of endurance and histocompatibility for the animals that underwent CES.

Topics: Animals; Benzofurans; Colon; Constipation; Defecation; Dogs; Electric Stimulation; Gastrointestinal Transit

A multinational post-authorization safety study assessed cardiovascular safety in initiators of prucalopride for chronic constipation compared with a matched cohort of polyethylene glycol 3350 initiators. The primary safety outcome was major adverse cardiovascular events (MACE), a composite of hospitalization for acute myocardial infarction, stroke, or in-hospital cardiovascular death. We report the validation process for MACE endpoints in United Kingdom (UK) data sources: Clinical Practice Research Datalink (CPRD GOLD), The Health Improvement Network (THIN), and the Information Services Division (ISD) Scotland.. Modified electronic algorithms from prior research identified potential MACE cases. Validation followed a common protocol, adapted for each database, with all information anonymized: (1) direct confirmation via linkage to hospital records (CPRD GOLD); (2) requests for additional clinical information through questionnaires (CPRD GOLD), free-text (THIN), or abstraction of hospital records (ISD); (3) manual review of electronic records of potential events retrieved by the algorithm (CPRD GOLD/THIN); and (4) event adjudication by three clinicians, blinded to exposure, for all remaining events.. Electronic algorithms identified 260 potential MACE cases: 38 confirmed via linkage to hospital records (CPRD GOLD), 56 ruled out as non-cardiovascular death cases (THIN), and three unavailable for review (ISD), leaving 163 potential cases. After manual review with additional information (steps 2 and 3), 45 were considered noncases (CPRD GOLD/THIN). Upon final adjudication (step 4), remaining potential events were adjudicated as definite (n = 62), probable (n = 10), possible (n = 13), or noncases (n = 33).. Given the limitations of relying solely on computer algorithms to identify cardiovascular outcomes, validation with clinical review is essential to guide interpretation.

Topics: Benzofurans; Databases, Factual; Electronic Health Records; Humans; Information Storage and Retrieval; Myocardial Infarction; United Kingdom

Gastric motor function alterations have been implicated in the pathogenesis of functional dyspepsia with postprandial distress syndrome (PDS). Prucalopride, a 5-TH4 agonist, is known to stimulate gastrointestinal motility. We aimed to evaluate the effect of prucalopride on gastric sensorimotor function in healthy subjects (HV).. Barostat and intragastric pressure (IGP) measurements were performed in 17 HV (59% females, age 29.4 ± 2.7 y) after treatment with placebo or prucalopride (2 mg) (single-blind cross-over). Isobaric stepwise distensions and gastric sensations were assessed to determine gastric compliance and sensitivity. Gastric accommodation (GA) with the barostat was quantified before and after ingestion of 200 ml of a nutrient drink (ND). GA measured by IGP was quantified as the drop of IGP from baseline during the intragastric infusion of ND until maximal satiation (60 ml/min).. Prucalopride did not affect barostat assessed gastric compliance or sensitivity. No differences were observed in GA after prucalopride. During the barostat study, 10 min after the meal, 7 HVs reported significantly higher ratings for nausea after prucalopride (p < 0.001), and vomiting was induced in 4 of the HVs. A positive correlation was observed between the delta mean perception of nausea with the delta mean increase of intra-balloon volume before and after meal ingestion (r = 0.37, p = 0.03). During IGP measurements, no effect on nutrient tolerance was observed and increased cramp severity scores were observed which were associated with a significant increase of distal IGP (r = 0.78, p < 0.0001).. Prucalopride does not enhances gastric accommodation but it might increase sensitivity to gastric distention. Furthermore, the increase in sensitivity seems to be related to an increase in nausea with distension. Clinicaltrials.gov: NCT04429802.

Topics: Adult; Benzofurans; Female; Gastrointestinal Motility; Healthy Volunteers; Humans; Male; Nausea; Satiation; Serotonin 5-HT4 Receptor Agonists; Single-Blind Method

Evidence suggests constipation precedes motor dysfunction and is the most common gastrointestinal symptom in Parkinson's disease (PD). 5-HT4 receptor (5-HT4R) agonist prucalopride has been approved to treat chronic constipation. Here, we reported intraperitoneal injection of prucalopride for 7 days increased dopamine and decreased dopamine turnover. Prucalopride administration improved motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-induced PD mouse models. Prucalopride treatment also ameliorated intestinal barrier impairment and increased IL-6 release in PD model mice. However, prucalopride treatment exerted no impact on JAK2/STAT3 pathway, suggesting that prucalopride may stimulate IL-6 via JAK2/STAT3-independent pathway. In conclusion, prucalopride exerted beneficial effects in MPTP-induced Parkinson's disease mice by attenuating the loss of dopamine, improving motor dysfunction and intestinal barrier.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Benzofurans; Body Weight; Disease Models, Animal; Dopamine; Eating; Inflammation; Interleukin-6; Intestinal Mucosa; Janus Kinase 2; Male; Mice; Mice, Inbred C57BL; Motor Skills; MPTP Poisoning; Neostriatum; Parkinson Disease; Parkinson Disease, Secondary; STAT3 Transcription Factor

Topics: Acupuncture Therapy; Benzofurans; Constipation; Humans; Laxatives

This article reviews seven drugs recently approved by the FDA, including indications, precautions, adverse reactions, and nursing considerations.

Topics: Antibodies, Monoclonal; Benzofurans; Carbamates; Drug Approval; Humans; Phenylalanine; Piperidines; Purines; Tetracyclines; United States; United States Food and Drug Administration

Muscarinic receptor 1 positive allosteric modulators (M1PAMs) enhance colonic propulsive contractions and defecation through the facilitation of M1 receptor (M1R)-mediated signaling. We examined M1R expression in the colons of 5 species and compared colonic propulsion and defecation caused by the M1PAM, T440, the 5-HT. M1R expression was profiled by immunostaining and in situ hybridization. In vivo studies utilized male SD rats and beagle dogs. Colonic propulsive contractions were recorded by manometry in anesthetized rats. Gut contractions in dogs were assessed using implanted force transducers in the ileum, proximal, mid, and distal colons.. M1R was localized to neurons of myenteric and submucosal plexuses and the epithelium of the human colon. A similar receptor localization was observed in rat, dog, mouse, and pig. T440 enhanced normal defecation in rats in a dose-dependent manner. Prucalopride also enhanced defecation in rats, but the maximum effect was half that of T440. Neostigmine and T440 were similarly effective in enhancing defecation, but the effective dose of neostigmine was close to its lethal dose. In rats, all 3 compounds induced colonic contractions, but the associated propulsion was strongest with T440. In dogs, intestinal contractions elicited by T440 propagated from ileum to distal colon. Prucalopride and neostigmine also induced intestinal contractions, but these were less well coordinated. No loss of effectiveness of T440 on defecation occurred after 5 days of repeated dosing.. These results suggest that M1PAMs produce highly coordinated propagating contraction by actions on the enteric nervous system of the colon. The localization of M1R to enteric neurons in both animals and humans suggests that the M1PAM effects would be translatable to human. M1PAMs provide a potential novel therapeutic option for constipation disorders.

Topics: Animals; Benzofurans; Cholinesterase Inhibitors; Colon; Defecation; Dogs; Gastrointestinal Agents; Gastrointestinal Motility; Male; Muscarinic Agonists; Myenteric Plexus; Neurons; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M1; Serotonin 5-HT4 Receptor Agonists; Submucous Plexus

The enteric nervous system (ENS) is essential for normal gastrointestinal function. Although the embryonic origin of enteric neurons from the neural crest is well established, conflicting evidence exists regarding postnatal enteric neurogenesis. Here, we address this by examining the origin of

Topics: Animals; Benzofurans; Cell Differentiation; Enteric Nervous System; Neural Crest; Neurogenesis; Schwann Cells; Serotonin 5-HT4 Receptor Agonists; Zebrafish

Topics: Benzofurans; Constipation; Cross-Over Studies; Gastroparesis; Humans

Topics: Benzofurans; Cross-Over Studies; Gastric Emptying; Gastroparesis; Humans

Enteric serotonin may function as a mucosal growth factor. Previous work demonstrated increased crypt cell proliferation and intestinal mucosal surface area with potentiation of serotonin. While an indirect mechanism was postulated to explain these effects, the presence of 5-HT4 receptors on enterocytes raises the possibility of a direct action of serotonin. We hypothesized that a 5-HT4 specific agonist, prucalopride, would stimulate intestinal mucosal growth and enhance absorptive function in the murine small intestine.. Adult wild-type mice were treated parenterally with prucalopride for 14 days via surgically implanted osmotic pumps. In vivo D-xylose absorption was assessed by oral gavage and serum D-xylose measurements. On day 14, glucose absorption was assessed by instilling a glucose solution into isolated segments of small intestine. The bowel was harvested and examined for morphologic parameters and crypt cell proliferation.. Villus height, crypt depth, and crypt proliferation were significantly increased in the distal small bowel of prucalopride-treated mice compared with control animals. Crypt depth was also increased in the proximal and middle small intestine in treated mice. There was no difference in D-xylose absorption throughout the study period; however, glucose absorption was significantly increased in the distal small intestine of prucalopride-treated mice.. Parenteral administration of the 5-HT4 receptor specific agonist, prucalopride, results in morphologic and functional changes in the murine small intestine that are most prominent in the distal small bowel. While further studies are necessary to delineate the mechanism, it is plausible that the effects are mediated by 5-HT4 receptors on enterocytes.

Topics: Animals; Benzofurans; Carbohydrate Metabolism; Cell Proliferation; Enterocytes; Female; Ileum; Intestinal Mucosa; Male; Mice; Mice, Inbred BALB C; Models, Animal; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists

Topics: Benzofurans; Cholinergic Agents; Humans; Ileus; Inflammation; Neurons; Postoperative Complications; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists

Activating luminal 5-HT. Colonic motor patterns were studied ex vivo using simultaneous spatiotemporal diameter mapping and pressure sensing.. Intraluminal prucalopride and intraluminal exogenous 5-HT strongly evoked or enhanced the colonic motor complex at all levels of excitation beginning with generation of clusters of fast propagating contractions (FPCs), then development of long-distance contractions (LDCs) within the clusters, and finally forceful LDCs as the highest level of excitation. Intraluminal prucalopride and intraluminal exogenous 5-HT stimulated propulsive motor activity in a dose-dependent and antagonist-sensitive manner by increasing the contraction amplitude, intraluminal pressure, frequency, velocity, and degree of propagation of the colonic motor complex.. Activating mucosal 5-HT

Topics: Administration, Topical; Animals; Benzofurans; Colon; Female; Gastrointestinal Motility; Intestinal Mucosa; Male; Myoelectric Complex, Migrating; Peristalsis; Rabbits; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists

The serotonin 5-HT. This observational population-based cohort study (EUPAS9200) conducted in five data sources (three in the UK, one in Sweden, and one in Germany [which was subsequently excluded from the pooled analyses]) aimed to estimate the pooled adjusted incidence rate ratio for major adverse cardiovascular events (defined as hospitalization for non-fatal acute myocardial infarction or stroke, and in-hospital cardiovascular death) in adult initiators of prucalopride compared with initiators of polyethylene glycol 3350 (PEG) following a common protocol. Standardized incidence rates and incidence rate ratios of major adverse cardiovascular events were derived using propensity score stratification. Sensitivity analyses explored the impact of exposure definition, outcome categories, interim cancer, and unmeasured confounding.. The pooled analyses included 5715 initiators of prucalopride and 29,372 initiators of PEG. Average duration of use was 175 days for prucalopride and 82 days for PEG. The pooled standardized incidence rate per 1000 person-years (95% confidence interval) of major adverse cardiovascular events was 6.57 (3.90-10.39) for patients initiating prucalopride and 10.24 (6.97-14.13) for PEG. The pooled adjusted incidence rate ratio for major adverse cardiovascular events was 0.64 (95% confidence interval 0.36-1.14). Results remained consistent in various sensitivity analyses.. The pooled incidence rate ratio estimate was consistent with no indication of an increased risk above the pre-specified safety threshold of 3.00 for major adverse cardiovascular events in patients with chronic constipation using prucalopride as compared with PEG.

Topics: Benzofurans; Cardiovascular Diseases; Cohort Studies; Constipation; Humans; Incidence; Internationality; Laxatives; Polyethylene Glycols; Risk Factors; Treatment Outcome

Given prior safety experience with other 5-HT. 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.

Topics: Benzofurans; Cohort Studies; Constipation; Databases, Factual; Female; Germany; Humans; Laxatives; Male; Polyethylene Glycols; Propensity Score; Research Design; Sweden; United Kingdom

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

Gastroprokinetic properties of 5-HT. Circular smooth muscle strips were prepared from human large intestine; after incubation with [³H]-choline, electrically induced tritium outflow was determined as a measure for acetylcholine release. The influence of PDE inhibition on the facilitating effect of prucalopride on electrically induced acetylcholine release was studied.. The non-selective PDE inhibitor IBMX enhanced the facilitating effect of prucalopride on electrically induced acetylcholine release. The selective inhibitors vinpocetine (PDE1), EHNA (PDE2) and cilostamide (PDE3) did not influence, while rolipram and roflumilast (PDE4) enhanced the prucalopride-induced facilitation to the same extent as IBMX.. In human large intestinal circular muscle, the intracellular pathway of 5-HT

Topics: 1-Methyl-3-isobutylxanthine; Acetylcholine; Aged; Benzofurans; Cyclic Nucleotide Phosphodiesterases, Type 4; Female; Humans; Intestine, Large; Male; Middle Aged; Muscle, Smooth; Phosphodiesterase Inhibitors; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists

Patients with chronic constipation benefit from treatment with 5-hydroxytryptamine 4 (5-HT

Topics: Animals; Benzofurans; Cardiovascular System; Dogs; Dose-Response Relationship, Drug; Electrophysiological Phenomena; Guinea Pigs; Heart Atria; Heart Rate; HEK293 Cells; Humans; Myocardial Contraction; Myocardium; Rabbits; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists

Topics: Benzofurans; Clozapine; Constipation; Humans; Male; Middle Aged

Glioma is the most fatal primary brain glioma in central nervous system mainly attributed to its high invasion. Prucalopride, a Serotonin-4 (5-HT4) receptor agonist, has been reported to regulate neurodevelopment. This study aimed to investigate the influence of the Prucalopride on glioma cells and unveil underlying mechanism.. In this study, glioma cells proliferation was evaluated by Cell counting kit-8 (CCK8). Wound healing and transwell assay were used to test cellular migration and invasion. Flow cytometry was utilized to determine cellular apoptosis rate. Apoptosis related markers, autophagy markers, and protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway key molecules were detected using western blot assay.. As a result, the proliferation, migration and invasiveness of glioma cells were impaired by Prucalopride treatment, the apoptosis rate of glioma cells was enhanced by Prucalopride stimulation, accompanied by the increased pro-apoptosis proteins Bax and Cleaved caspase-3 and decreased anti-apoptosis protein Bcl-2. Prucalopride significantly promoted autophagy by increased expression level of Beclin 1 and LC3-II, while decreased expression level of p62. Prucalopride administration resulted in obvious inhibitions of key molecules of AKT-mTOR pathway, including phosphorylated- (p-) AKT, p-mTOR and phosphorylated-ribosomal p70S6 kinase (p-P70S6K).. Taking together, these results indicate that Prucalopride may be likely to play an anti-tumor role in glioma cells, which suggests potential implications for glioma promising therapy alternation in the further clinics.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Benzofurans; Cell Line, Tumor; Cell Movement; Cell Proliferation; Glioma; Humans; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

BACKGROUND Ovarian cancer is the second most common malignant tumor of the female reproductive system and is the leading cause of death of gynecological malignancies, but at present there is no effective and safe therapy. There is no previously published report on the anti-cancer effect of prucalopride, which is a high-affinity 5-HT4 receptor. The aim of the present study was to determine whether prucalopride can inhibit proliferation of ovarian cancer cells. MATERIAL AND METHODS The cell viability was detected by use of the Cell Counting Kit-8 (CCK-8) assay. The invasion and migration of SKOV3 and OVCAR3 cells was detected by Transwell assay. The cell apoptosis was detected by apoptosis flow detection and Caspase-Glo 3/7 Assay Systems. The apoptosis-related proteins, autophagy marker proteins, and the related-factors of phosphatidylinositol 3-kinase (PI3K) were detected by Western blot. RESULTS The CCK-8 proliferation test showed that prucalopride inhibited the growth of ovarian cancer cell lines SKOV3 and OVCAR3. In the Transwell assay, prucalopride inhibited cell invasion and migration. Furthermore, we found the expression of anti-apoptotic protein Bcl-2 decreased, whereas the expression of pro-apoptotic protein Caspase3 and Bax increased in the SKOV3 cell line treated with prucalopride, as well as cleaved PARP. In addition, the expression of p-AKT, p-mTOR, and p70S6K decreased in the prucalopride-treated group, and the expression of autophagy marker protein LC3-II/I and Beclin1 significantly increased, whereas the expression of p62 protein decreased. CONCLUSIONS The present study reveals that in ovarian cancer cells, prucalopride inhibits proliferation, migration, and invasion, and induces apoptosis and autophagy, which may be regulated by the PI3K signaling pathway. These results suggest prucalopride has potential as a new drug for clinical ovarian cancer treatment.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Benzofurans; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Female; Humans; Ovarian Neoplasms; Phosphatidylinositol 3-Kinase; Signal Transduction

Cisapride and prucalopride act as 5-HT

Topics: Animals; Arrhythmias, Cardiac; Atrial Function; Benzofurans; Cardiotonic Agents; Cisapride; Heart Rate; In Vitro Techniques; Mice, Transgenic; Myocardial Contraction; Receptors, Serotonin, 5-HT4; Serotonin Receptor Agonists

In the gastrointestinal tract of several species, facilitating 5-HT. In circular smooth muscle strips from murine fundus, jejunum and colon, contractions were induced by electrical field stimulation in the presence of guanethidine, L-NAME and for colon also MRS 2500. Submaximal contractions were induced to study the influence of prucalopride.. Electrical field stimulation at reduced voltage induced reproducible submaximal neurogenic and cholinergic contractions as the contractions were abolished by tetrodotoxin and atropine. Hexamethonium had no systematic inhibitory effect but mecamylamine reduced the responses, suggesting that part of the cholinergic response is due to activation of preganglionic neurons. Prucalopride concentration-dependently increased the submaximal cholinergic contractions in the three tissue types, reaching maximum from 0.03 μmol/L onwards. The facilitation in the different series with 0.03 μmol/L prucalopride ranged from 41% to 104%, 30% to 76% and 24% to 74% in fundus, jejunum, and colon, respectively. The effect of 0.03 μmol/L prucalopride was concentration-dependently inhibited by GR 113808.. In the murine gastrointestinal tract, activation of 5-HT

Topics: Acetylcholine; Animals; Benzofurans; Colon; Deoxyadenine Nucleotides; Electric Stimulation; Gastric Fundus; Gastrointestinal Tract; Guanethidine; Hexamethonium; Jejunum; Male; Mecamylamine; Mice, Inbred C57BL; Muscle Contraction; Muscle, Smooth; NG-Nitroarginine Methyl Ester; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Synaptic Transmission

Postoperative ileus (POI) remains an important cause of death in horses. The recently developed selective 5-HT. To identify functional 5-HT. In vitro experimental study.. Circular and longitudinal smooth muscle strips (mid-jejunum) were mounted in organ baths between 2 platinum electrodes allowing electrical field stimulation (EFS). To delineate the conditions to obtain purely cholinergic responses, voltage-response curves were studied. To investigate the influence of prucalopride and 5-HT, submaximal cholinergic contractions at a single voltage were induced.. In circular and longitudinal strips, EFS induced voltage-dependent neurogenic on-contractions when the bathing medium contained a NO-synthesis inhibitor and apamin to prevent inhibitory responses to NO and ATP. Contractions at a voltage inducing 50% of maximal amplitude were cholinergic, as they were blocked by atropine. These contractions were not influenced by prucalopride (up to 3μM), even in the presence of the phosphodiesterase inhibitor isobutyl-methyl-xanthine to inhibit breakdown of the second messenger of 5-HT. There are no functional 5-HT

Topics: Acetylcholine; Animals; Benzofurans; Cholinergic Neurons; Electric Stimulation; Horses; Jejunum; Male; Muscle Contraction; Muscle, Smooth; Serotonin 5-HT4 Receptor Agonists; Synaptic Transmission; Tissue Culture Techniques

The inpatient status is a well-known risk factor for incomplete video capsule endoscopy (VCE) examinations due to prolonged transit time. We aimed to evaluate the effect of prucalopride on small bowel transit time for hospitalized patients undergoing VCE.. We included all hospitalized patients who underwent VCE at a tertiary academic center from October 2011 through September 2016. A single 2 mg dose of prucalopride was given exclusively for all patients who underwent VCE between March 2014 and December 2015. VCE studies were excluded if the capsule was retained or endoscopically placed, if other prokinetic agents were given, in cases with technical failure, or if patients had prior gastric or small bowel resection.. 442 VCE were identified, of which 68 were performed in hospitalized patients. 54 inpatients were included, of which 29 consecutive patients received prucalopride. The prucalopride group had a significantly shorter small bowel transit time compared to the control group (92 versus 275.5,. Our results suggest that the administration of prucalopride prior to VCE is a simple and effective intervention to decrease small bowel transit time.

Topics: Aged; Benzofurans; Capsule Endoscopy; Female; Gastrointestinal Agents; Gastrointestinal Transit; Hospitalization; Humans; Inpatients; Intestine, Small; Male; Middle Aged; Prospective Studies; Retrospective Studies; Time Factors; Treatment Outcome

Abnormalities of gastrointestinal motility are often a challenge in horses; however, the use of prokinetic drugs in such conditions must be firmly established yet. For this reason we carried out a preliminary study on the effects of prucalopride on intestinal motor activity of horses with gut hypomotility. The effect of prucalopride per os by oral dose syringe (2 mg/100 kg body weight) was assessed by abdominal ultrasound (evaluating duodenal, cecal, and colonic motor activity) in six horses with gut hypomotility. After administration of prucalopride, a significant increase of contractile activity was found in the duodenum at 30 minutes (p = 0.0005), 60 minutes (p = 0.01) and 90 minutes (p = 0.01), whereas in the cecum and in the left colon the increase was only present at 60 minutes (p = 0.03, and p = 0.02, respectively). No changes from baseline heart and respiratory rate or behavior side effects were observed after administration of the drug and throughout the observation period. Prucalopride may be a useful adjunct to the therapeutic armamentary for treating hypomotile upper gut conditions of horses. Dosing information is however needed to establish its actual clinical efficacy and its proper effects on the large bowel in these animals.

Topics: Animals; Benzofurans; Cecum; Colon; Dose-Response Relationship, Drug; Duodenum; Female; Gastrointestinal Motility; Heart Rate; Horses; Intestines; Muscle Contraction; Respiratory Rate

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

Topics: Aged; Atrial Fibrillation; Benzofurans; Catheter Ablation; Cryosurgery; Female; Gastroparesis; Humans; Postoperative Complications; Serotonin 5-HT4 Receptor Agonists; Severity of Illness Index; Tomography, X-Ray Computed

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

Topics: Aged; Benzofurans; Brazil; Diverticulosis, Colonic; Europe; Female; Gastrointestinal Agents; Humans; Male; Middle Aged; Retrospective Studies; Treatment Outcome; Venezuela

Serotonin (5-hydroxytryptamine, 5-HT) and its transporters and receptors are involved in a wide array of digestive functions. In particular, 5-HT4 receptors are known to mediate intestinal peristalsis and recent data in experimental animals have shown their role in neuronal maintenance and neurogenesis. This study has been designed to test whether prucalopride, a well-known full 5-HT4 agonist, exerts protective effects on neurons, including enteric neurons, exposed to oxidative stress challenge. Sulforhodamine B assay was used to determine the survival of SH-SY5Y cells, human enteric neurospheres, and ex vivo submucosal neurons following H2O2 exposure in the presence or absence of prucalopride (1 nM). Specificity of 5-HT4-mediated neuroprotection was established by experiments performed in the presence of GR113808, a 5-HT4 antagonist. Prucalopride exhibited a significant neuroprotective effect. SH-SY5Y cells pretreated with prucalopride were protected from the injury elicited by H2O2 as shown by increased survival (73.5 ± 0.1% of neuronal survival vs. 33.3 ± 0.1%, respectively; P < 0.0001) and a significant reduction of proapoptotic caspase-3 and caspase-9 activation in all neurons tested. The protective effect of prucalopride was reversed by the specific 5-HT4 antagonist GR113808. Prucalopride promotes a significant neuroprotection against oxidative-mediated proapoptotic mechanisms. Our data pave the way for novel therapeutic implications of full 5-HT4 agonists in gut dysmotility characterized by neuronal degeneration, which go beyond the well-known enterokinetic effect.

Topics: Adult; Animals; Apoptosis; Benzofurans; Cell Line, Tumor; Female; HEK293 Cells; Humans; Intestines; Male; Mice; Middle Aged; Neurons; Neuroprotective Agents; Oxidative Stress; Serotonin 5-HT4 Receptor Agonists

Topics: Benzofurans; Enteric Nervous System; Inflammation; Neurons; Neuroprotective Agents; Oxidative Stress; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists

Dysmotility in the gastrointestinal (GI) tract often leads to impaired transit of luminal contents leading to symptoms of diarrhea or constipation. The aim of this research was to develop a technique using high resolution X-ray imaging to study pharmacologically induced aged rat models of chronic GI dysmotility that mimic accelerated transit (diarrhea) or constipation. The 5-hydroxytryptamine type 4 (5-HT4 ) receptor agonist prucalopride was used to accelerate transit, and the opioid agonist loperamide was used to delay transit.. Male rats (18 months) were given 0, 1, 2, or 4 mg/kg/day prucalopride or loperamide (in dimethyl sulfoxide, DMSO) for 7 days by continuous 7-day dosing. To determine the GI region-specific effect, transit of six metallic beads was tracked over 12 h using high resolution X-ray imaging. An established rating scale was used to classify GI bead location in vivo and the distance beads had propagated from the caecum was confirmed postmortem.. Loperamide (1 mg/kg) slowed stomach emptying and GI transit at 9 and 12 h. Prucalopride (4 mg/kg) did not significantly alter GI transit scores, but at a dose of 4 mg/kg beads had moved significantly more distal than the caecum in 12 h compared to controls.. We report a novel high-resolution, non-invasive, X-ray imaging technique that provides new insights into GI transit rates in live rats. The results demonstrate that loperamide slowed overall transit in aged rats, while prucalopride increased stomach emptying and accelerates colonic transit.

Topics: Animals; Benzofurans; Colon; Digestion; Disease Models, Animal; Gastric Emptying; Gastrointestinal Agents; Gastrointestinal Diseases; Gastrointestinal Motility; Gastrointestinal Transit; Loperamide; Male; Rats; Rats, Sprague-Dawley

The present study reports the degradation behaviour of a new prokinetic agent, Prucalopride succinate, under various stress conditions as per International Conference on Harmonization guidelines (ICH, Q1A (R2)). The investigation involved monitoring decomposition of the drug under hydrolytic (acidic, basic and neutral), oxidative, photolytic and thermal stress conditions followed by characterization of the degradation products (DPs) and process related impurities (IMPs). A rapid, precise, accurate and robust reverse phase high performance liquid chromatography (RP-HPLC) method has been developed involving mobile phase of 20mM ammonium bicarbonate buffer and acetonitrile: methanol (80:20v/v) on a Waters Xbridge-C8 (150mm×4.6mm i.d., 3.5μm) column using gradient elution. The drug was found to be degraded in hydrolytic (acidic) and oxidative conditions, whereas it was stable under basic and neutral hydrolytic, photolytic and thermal stress conditions. The method was extended to LC-ESI-QTOF-MS/MS for the structural characterization of DPs and process related IMPs. Structural characterization was carried out based on the generated molecular formula of DPs and its fragment ions. It has been observed that two major DPs were formed under each acid hydrolysis and oxidative stress conditions. The most probable mechanisms involved in the formation of DPs were also proposed. Finally, the method was validated in the term of specificity, linearity, accuracy, precision, and robustness as per ICH guidelines, Q2 (R1).

Topics: Benzofurans; Chromatography, High Pressure Liquid; Oxidative Stress; Tandem Mass Spectrometry

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

5-HT4 receptor agonists have a gastroprokinetic effect by facilitating acetylcholine release from cholinergic nerves innervating gastrointestinal smooth muscle. The role of phosphodiesterase (PDE) 4 in the signal transduction pathway of the 5-HT4 receptors located on the cholinergic neurons towards the circular muscle layer in pig stomach was investigated by analysis of acetylcholine release. Circular muscle strips were prepared from pig proximal stomach and tritium outflow, induced by electrical field stimulation, was studied as a marker for acetylcholine release after incubation with [(3)H]-choline. The PDE4-inhibitor roflumilast concentration-dependently (0.1-1µM) enhanced the facilitating effect of a submaximally effective concentration of the 5-HT4 receptor agonist prucalopride (0.01µM) on electrically induced acetylcholine release. Roflumilast (0.3µM) enhanced acetylcholine release per se but in the combined presence of roflumilast and prucalopride, acetylcholine release was enhanced more than the sum of the effect of the 2 compounds alone. The 5-HT4 receptor agonist velusetrag concentration-dependently (0.01-0.1µM) enhanced acetylcholine release; the effect of the minimally effective concentration (0.01µM) was significantly enhanced by 1µM of the PDE4-inhibitor rolipram, again to a level higher than the sum of the effect of the 2 compounds alone. The synergistic effect between 5-HT4 receptor agonists and PDE4-inhibitors demonstrates that the intracellular pathway of the 5-HT4 receptors located on cholinergic neurons towards pig gastric circular muscle is controlled by PDE4. Combining a 5-HT4 receptor agonist with a PDE4-inhibitor might thus enhance its gastroprokinetic effect.

Topics: Acetylcholine; Aminopyridines; Animals; Azabicyclo Compounds; Benzamides; Benzofurans; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclopropanes; Dose-Response Relationship, Drug; Drug Synergism; Gastrointestinal Motility; Male; Muscle Contraction; Muscle, Smooth; Phosphodiesterase 4 Inhibitors; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Stomach; Sus scrofa

Topics: Animals; Benzimidazoles; Benzofurans; Bile Acids and Salts; Carbolines; Colesevelam Hydrochloride; Colestipol; Disease Models, Animal; Enteric Nervous System; Female; Humans; Imidazoles; Indoles; Irritable Bowel Syndrome; Loperamide; Lubiprostone; Male; Mice; Natriuretic Peptides; Peptides; Phenylalanine; Receptors, Serotonin, 5-HT3; Receptors, Serotonin, 5-HT4; Rifamycins; Rifaximin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Visceral Pain

We investigated the effect of cisapride, a selective serotonin 5-HT4-receptor agonist, on voltage-dependent K(+) (Kv) channels using freshly isolated smooth muscle cells from the coronary arteries of rabbits. The amplitude of Kv currents was reduced by cisapride in a concentration-dependent manner, with an IC50 value of 6.77 ± 6.01 μM and a Hill coefficient of 0.51 ± 0.18. The application of cisapride shifted the steady-state inactivation curve toward a more negative potential, but had no significant effect on the steady-state activation curve. This suggested that cisapride inhibited the Kv channel in a closed state by changing the voltage sensitivity of Kv channels. The application of another selective serotonin 5-HT4-receptor agonist, prucalopride, did not affect the basal Kv current and did not alter the inhibitory effect of cisapride on Kv channels. From these results, we concluded that cisapride inhibited vascular Kv current in a concentration-dependent manner by shifting the steady-state inactivation curve, independent of its own function as a selective serotonin 5-HT4-receptor agonist.

Topics: Animals; Benzofurans; Cisapride; Coronary Vessels; Ion Channel Gating; Male; Myocytes, Smooth Muscle; Potassium Channels, Voltage-Gated; Rabbits; Receptors, Serotonin

A rapid, sensitive, selective and accurate ultra high performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for the quantitation of prucalopride in rat plasma using carbamazepine as an internal standard (IS). Separation was achieved on a Waters ACQUITY UHPLC(®) HSS C18 column (2.1mm×50mm, 1.8μm) column with a gradient mobile phase consisting of acetonitrile-water (containing 0.1% formic acid) as mobile phase at a flow rate of 0.2mL/min. Prucalopride and IS were monitored using positive electrospray triple quadrupole mass spectrometer (Waters Xevo TQD) via multiple reaction monitoring (MRM) mode. The monitored transitions were set at m/z 367.99→195.89 and m/z 236.97→194.04 for prucalopride and IS, respectively. The achieved lower limit of quantitation was 0.1ng/mL. The validated method had an excellent linearity in the range of 0.1-100ng/mL (r>0.996). The intra- and inter-day precisions were both≤7.8% for prucalopride and IS, and the average intra- and inter-day accuracies ranged from -3.0% to 8.5%. Extraction recoveries at three levels QC concentrations were in the range of 90.0-110.0% for prucalopride and 99.6% for IS. Matrix effects were found to be acceptable. The validated assay was successfully applied to a pharmacokinetic study of prucalopride following oral administration of 0.25, 0.5, 1.0mg/kg to female and male rats respectively.

Topics: Administration, Oral; Animals; Benzofurans; Calibration; Chromatography, High Pressure Liquid; Drug Stability; Female; Male; Rats, Sprague-Dawley; Reference Standards; Reproducibility of Results; Tandem Mass Spectrometry; Time Factors

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

This integrated analysis aimed to identify the factors associated with the most frequently re-ported treatment-emergent adverse events (TEAEs) in Asian and non-Asian patients with chronic constipation (CC) who receive prucalopride or placebo over 12 weeks.. Pooled data from four randomized, double-blind, placebo-controlled, multicenter, phase III studies (NCT00488137, NCT00483886, NCT00485940, and NCT01116206) on pa-tients treated with prucalopride 2 mg or placebo were ana-lyzed. The associations between predictors and TEAEs were evaluated based on a logistic regression model.. Overall, 1,821 patients (Asian, 26.1%; non-Asian, 73.9%) were analyzed. Prucalopride treatment was significantly as-sociated with diarrhea, headache, and nausea (p<0.001), but not with abdominal pain, compared with placebo. Differ-ences in the prevalence of TEAEs between prucalopride and placebo decreased greatly after the first day of treatment. Compared with non-Asians, Asians were more likely to expe-rience diarrhea and less likely to develop abdominal pain, headache, and nausea. Prior laxative use, CC duration, and body weight were not predictive of any of these TEAEs. Con-clusions Prucalopride treatment was positively associated with diarrhea, headache, and nausea. Asian patients tended to have a higher frequency of diarrhea but lower frequencies of headache, abdominal pain, and nausea compared with non-Asians. (Gut Liver, 2015;9208-213).

Topics: Abdominal Pain; Adult; Aged; Aged, 80 and over; Asian People; Benzofurans; Clinical Trials, Phase III as Topic; Constipation; Diarrhea; Double-Blind Method; Female; Headache; Humans; Male; Middle Aged; Multicenter Studies as Topic; Nausea; Randomized Controlled Trials as Topic; Regression Analysis

Topics: Abdominal Pain; Animals; Benzofurans; Dogs; Female; Humans; Nociception; Serotonin 5-HT4 Receptor Agonists

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

Topics: Awards and Prizes; Benzofurans; Constipation; Gastrointestinal Motility; Germany; Humans; Periodicals as Topic; Serotonin 5-HT4 Receptor Agonists

Topics: Animals; Benzofurans; Brain; Dopamine; Dopamine Agents; Functional Laterality; Indoles; Levodopa; Microdialysis; Oxidopamine; Parkinsonian Disorders; Rats; Serotonin 5-HT4 Receptor Agonists; Serotonin 5-HT4 Receptor Antagonists; Sulfonamides

Topics: Adult; Benzofurans; Humans; Intestinal Pseudo-Obstruction; Male; MELAS Syndrome

Motilin agonists promote human gastric motility and cholinergic activity, but excitatory and inhibitory actions are reported in the esophagus. The effect of 5-HT₄ agonists in esophagus is also unclear. Perhaps the use of drugs with additional actions explains the variation. The aim, therefore, was to examine how motilin and prucalopride, selective motilin and 5-HT₄ receptor agonists, modulate neuromuscular functions in human esophagus and gastric fundus.. Electrical field stimulation (EFS) evoked nerve-mediated contractions of circular and longitudinal muscle from human esophageal body and circular muscle from gastric fundus.. In esophageal circular muscle EFS evoked brief contraction, followed by another contraction on termination of EFS, each prevented by atropine. Nitric oxide synthase inhibition facilitated contraction during EFS and the overall contraction became monophasic. In esophagus longitudinal muscle and gastric fundus, EFS evoked cholinergically mediated, monophasic contractions, attenuated by simultaneous nitrergic activation. Motilin (100-300 nM) reduced esophagus circular muscle contractions during EFS, unaffected by L-NAME or apamin. Motilin 300 nM also reduced EFS-evoked contractions of longitudinal muscle. Similar concentrations of motilin facilitated cholinergic activity in the fundus and increased baseline muscle tension. Prucalopride facilitated EFS-evoked contractions in esophagus (tested at 30 μM) and fundus (0.1-30 μM).. Selective motilin and 5-HT₄ agonists have different, region-dependent abilities to modulate human esophageal and stomach neuromuscular activity, exemplified by weak inhibition (motilin) or excitation (5-HT₄) in esophageal body and excitation for both in stomach. In different patients with motility dysfunctions, motilin and 5-HT₄ agonists may reduce gastro-esophageal reflux in different ways.

Topics: Aged; Aged, 80 and over; Benzofurans; Electric Stimulation; Esophagus; Female; Gastric Fundus; Humans; Male; Middle Aged; Motilin; Neuromuscular Agents; Serotonin 5-HT4 Receptor Agonists

Topics: Benzofurans; Constipation; Defecation; Fecal Impaction; Female; Humans; Male; Serotonin 5-HT4 Receptor Agonists

Our objective was to investigate the role of phosphodiesterase (PDE)3 and PDE4 and cGMP in the control of cAMP metabolism and of phosphorylation of troponin I (TnI) and phospholamban (PLB) when 5-HT4 receptors are activated in pig left atrium. Electrically paced porcine left atrial muscles, mounted in organ baths, received stimulators of particulate guanylyl cyclase (pGC) or soluble guanylyl cyclase (sGC) and/or specific PDE inhibitors followed by 5-HT or the 5-HT4 receptor agonist prucalopride. Muscles were freeze-clamped at different moments of exposure to measure phosphorylation of the cAMP/protein kinase A targets TnI and PLB by immunoblotting and cAMP levels by enzyme immunoassay. Corresponding with the functional results, 5-HT only transiently increased cAMP content, but caused a less quickly declining phosphorylation of PLB and did not significantly change TnI phosphorylation. Under combined PDE3 and PDE4 inhibition, the 5-HT-induced increase in cAMP levels and PLB phosphorylation was enhanced and sustained, and TnI phosphorylation was now also increased. Responses to prucalopride per se and the influence thereupon of PDE3 and PDE4 inhibition were similar except that responses were generally smaller. Stimulation of pGC together with PDE4 inhibition increased 5-HT-induced PLB phosphorylation compared to 5-HT alone, consistent with functional responses. sGC stimulation hastened the fade of inotropic responses to 5-HT, while cAMP levels were not altered. PDE3 and PDE4 control the cAMP response to 5-HT4 receptor activation, causing a dampening of downstream signalling. Stimulation of pGC is able to enhance inotropic responses to 5-HT by increasing cAMP levels, while sGC stimulation decreases contraction to 5-HT cAMP independently.

Topics: 1-Methyl-3-isobutylxanthine; Animals; Atrial Function; Benzofurans; Calcium-Binding Proteins; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 4; Heart Atria; In Vitro Techniques; Male; Myocardial Contraction; Phosphodiesterase Inhibitors; Phosphorylation; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin 5-HT4 Receptor Agonists; Swine; Troponin I

The objective of the current investigation was to develop a simple, rapid method for determining in-vivo 5-hydroxytryptamine type 4 receptor (5-HT4 R) occupancy in rat brain using non-radiolabelled SB207145 as a tracer for accelerating the drug discovery process.. In-vivo tracer optimization studies for tracer dose, survival intervals and brain distribution profile were carried out in rats. The tracer was pharmacologically validated using potent well-characterized 5-HT4 R ligands. The brain regional concentrations of tracer (SB207145); plasma and brain concentrations of 5-HT4 R ligands were quantified using high-performance liquid chromatography coupled with a tandem mass spectrometric detector (LC-MS/MS).. SB207145 showed a higher specific binding in striatum (1.96 ng/g) and lower binding in cerebellum (0.66 ng/g), which is consistent with findings of other published 5-HT4 R expression studies. Pretreatment with potent 5-HT4 ligands dose-dependently reduced striatal SB207145 concentration and the effective dose to achieve 50% receptor occupancy (ED50 ) values were 4.8, 2.0, 7.4, 9.9, 3.8 and 0.02 mg/kg for GR113808, piboserod, prucalopride, RS67333, TD8954 and PF04995274, respectively.. Results from the mass spectrometry approach to determine 5-HT4 R occupancy in rat brain are comparable with those reported using radiolabelled scintillation spectroscopy methods. In conclusion, the LC-MS/MS characterization permits use of tracer at a preclinical stage in high-throughput fashion as well as characterization of target expression.

Topics: Aniline Compounds; Animals; Benzofurans; Binding, Competitive; Brain; Drug Discovery; Indoles; Ligands; Male; Oxazines; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT4; Serotonin Receptor Agonists; Sulfonamides; Tandem Mass Spectrometry; Tissue Distribution

Prucalopride is a selective serotonin receptor agonist with prokinetic activity, indicated for women with chronic constipation in whom laxatives have failed to provide adequate relief. Data suggests an improvement in about 50 % of such patients but whether the therapeutic effect is on patients with slow transit constipation (STC) and/or obstructed defaecation syndrome (ODS), or even those with constipation-predominant irritable bowel syndrome (IBS-C) is unknown. We therefore assessed whether there is any association between prucalopride efficacy and constipation type.. All patients receiving prucalopride between June 2010 and April 2012 at our institution were identified, and data analysed following a 4-week "test" period. Patients were sub-grouped as those suffering with ODS, STC, mixed (ODS and STC) or IBS-C based on symptomatology and investigations. Subjective assessment of patient satisfaction and continuation of medication were taken as positive outcomes and analysed for each sub-type along with any side effects.. Sixty-nine patients met our criteria. Data were available for 59 women (median age 46 years, range 17-79 years). Sixty-five per cent of prescriptions came from colorectal surgeons. Overall, 25 out of 59 (42 %) patients improved, according to our criteria, after the 4-week trial period. Seventeen patients (29 %) had ODS, 26 (44 %) had STC, 7 (12 %) had mixed symptoms and 9 (15 %) had IBS-C. At 4 weeks, 10 out of 17 patients (59 %) with ODS had improved compared with 4 out of 9 patients (44 %) with IBS-C, 3 out of 7 patients (43 %) with mixed symptoms and 8 out of 26 (31 %) patients with STC. The underlying disorder did not predict whether or not a patient responded to the 4-week trial period (p = 0.32). Nine patients (15 %) experienced side effects that precluded further use.. Patients with all categories of constipation may respond to prucalopride. A trial regime may be indicated regardless of the aetiology of the constipation.

Topics: Adolescent; Adult; Aged; Benzofurans; Cohort Studies; Constipation; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Gastrointestinal Transit; Humans; Intestinal Obstruction; Middle Aged; Patient Satisfaction; Retrospective Studies; Serotonin Receptor Agonists; Severity of Illness Index; Syndrome; Treatment Outcome; Young Adult

Topics: Benzofurans; Constipation; Female; Humans; Intestinal Obstruction; Serotonin Receptor Agonists

Postoperative ileus (POI) is an impairment of coordinated gastrointestinal (GI) motility that develops as a consequence of abdominal surgery and is a major factor contributing to patient morbidity and prolonged hospitalization. The aim of this study was to investigate the effects of different 5-hydroxytryptamine 4 (5-HT₄) receptor agonists, which stimulate excitatory pathways, on a POI model.. The experimental model of POI in guinea pigs was created by laparotomy, gentle manipulation of the cecum for 60 seconds, and closure by suture, all under anesthesia. Different degrees of restoration of GI transit were measured by the migration of charcoal. Colonic transit was indirectly assessed via measurement of fecal pellet output every hour for 5 hours after administration of various doses of mosapride, tegaserod, prucalopride, and 5-HT.. Charcoal transit assay showed that various 5-HT₄ receptor agonists can accelerate delayed upper GI transit in a dose-dependent manner. However, fecal pellet output assay suggested that only prucalopride had a significant effect in accelerating colonic motility in POI.. Although mosapride, tegaserod, and prucalopride produce beneficial effects to hasten upper GI transit in the POI model, prucalopride administered orally restores lower GI transit as well as upper GI transit after operation in a conscious guinea pig. This drug may serve as a useful candidate for examination in a clinical trial for POI.

Topics: Administration, Oral; Animals; Benzamides; Benzofurans; Charcoal; Colon; Dose-Response Relationship, Drug; Gastrointestinal Motility; Guinea Pigs; Ileus; Indoles; Laparotomy; Male; Morpholines; Postoperative Complications; Serotonin; Serotonin 5-HT4 Receptor Agonists

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

Cholinesterase inhibitors such as neostigmine are used for acute colonic pseudo-obstruction, but cardio-bronchial side-effects limit use. To minimize side-effects, lower doses could be combined with a 5-HT4 receptor agonist, which also facilitates intestinal cholinergic activity. However, safety concerns, especially in the elderly, require drugs with good selectivity of action. These include the AChE inhibitor donepezil (used for Alzheimer's disease, with reduced cardio-bronchial liability) and prucalopride, the first selective, clinically available 5-HT4 receptor agonist. This study examined their individual and potential synergistic activities in human colon.. Neuronally mediated muscle contractions and relaxations of human colon were evoked by electrical field stimulation (EFS) and defined phenotypically as cholinergic, nitrergic or tachykinergic using pharmacological tools; the effects of drugs were determined as changes in 'area under the curve'.. Prucalopride increased cholinergically mediated contractions (EC50 855 nM; 33% maximum increase), consistent with its ability to stimulate intestinal motility; donepezil (477%) and neostigmine (2326%) had greater efficacy. Concentrations of donepezil (30-100 nM) found in venous plasma after therapeutic doses had minimal ability to enhance cholinergic activity. However, donepezil (30 nM) together with prucalopride (3, 10 μM) markedly increased EFS-evoked contractions compared with prucalopride alone (P = 0.04). For example, the increases observed with donepezil and prucalopride 10 μM together or alone were, respectively, 105 ± 35%, 4 ± 6% and 35 ± 21% (n = 3-7, each concentration).. Potential synergy between prucalopride and donepezil activity calls for exploration of this combination as a safer, more effective treatment of colonic pseudo-obstruction.

Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Cholinesterase Inhibitors; Colon; Donepezil; Drug Synergism; Female; Gastrointestinal Motility; Humans; In Vitro Techniques; Indans; Male; Middle Aged; Muscle Contraction; Piperidines; Serotonin 5-HT4 Receptor Agonists

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

In addition to the amyloidogenic pathway, amyloid precursor protein (APP) can be cleaved by α-secretases, producing soluble and neuroprotective APP alpha (sAPPα) (nonamyloidogenic pathway) and thus preventing the generation of pathogenic amyloid-β. However, the mechanisms regulating APP cleavage by α-secretases remain poorly understood. Here, we showed that expression of serotonin type 4 receptors (5-HT(4)Rs) constitutively (without agonist stimulation) induced APP cleavage by the α-secretase ADAM10 and the release of neuroprotective sAPPα in HEK-293 cells and cortical neurons. This effect was independent of cAMP production. Interestingly, we demonstrated that 5-HT(4) receptors physically interacted with the mature form of ADAM10. Stimulation of 5-HT(4) receptors by an agonist further increased sAPPα secretion, and this effect was mediated by cAMP/Epac signaling. These findings describe a new mechanism whereby a GPCR constitutively stimulates the cleavage of APP by α-secretase and promotes the nonamyloidogenic pathway of APP processing.

Topics: ADAM Proteins; ADAM10 Protein; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Benzofurans; Cerebral Cortex; Cyclic AMP; HEK293 Cells; Humans; Membrane Proteins; Neuroprotective Agents; Receptors, G-Protein-Coupled; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists

Topics: Acute Disease; Benzofurans; Colonic Pseudo-Obstruction; Colonoscopy; Gastrointestinal Transit; Humans; Male; Middle Aged; Recurrence

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

Topics: Animals; Benzofurans; Cholinergic Neurons; Cyclic Nucleotide Phosphodiesterases, Type 4; Gastric Mucosa; Male; Muscle Contraction; Muscle, Smooth; Serotonin 5-HT4 Receptor Agonists; Stomach; Swine; Synaptic Transmission

Topics: Abdominal Pain; Analgesics, Opioid; Benzofurans; Constipation; Female; Hemangioma; Humans; Middle Aged; Pain Measurement; Serotonin 5-HT4 Receptor Agonists; Spinal Neoplasms

Besides acting as gastrointestinal prokinetic agents, 5-hydroxytryptamine(4) (5-HT(4)) receptor agonists can induce positive inotropism in human isolated atrium, but not in ventricles. We pharmacologically evaluated the gastroprokinetic 5-HT(4) receptor agonists tegaserod, prucalopride, R199715, cisapride, the cisapride metabolite norcisapride, and the 5-HT(3) receptor agonist MKC773 on human isolated myocardial trabeculae, and compared their effects with those induced by 5-HT and 5-methoxytryptamine (5-MeOT).. Atrial and ventricular trabeculae were paced and changes in contractile force were studied in the absence or presence of the 5-HT(4) receptor antagonist GR113808. Partial agonism was assessed using 5-HT(4) receptor agonists as antagonists against 5-HT. To test the contribution of L-type calcium channels, the inotropic responses to 5-HT and 5-MeOT were studied in the absence or presence of verapamil.. Like 5-HT and 5-MeOT, cisapride and tegaserod, but not prucalopride, R19971 and MKC-733, induced concentration-dependent positive inotropic responses on atrial trabeculae, which were abolished by GR113808. The L-type calcium channel blocker verapamil attenuated inotropic responses to 5-HT and 5-MeOT. None of the agonists affected the contraction of left ventricular trabeculae. Concentration response curves to 5-HT were shifted to the right in the presence of prucalopride, cisapride, tegaserod and R199715, but not MKC-773.. We conclude that (i) inotropic responses to 5-HT and 5-MeOT seem to depend on L-type calcium channels, (ii) tegaserod and cisapride behave as partial 5-HT(4) receptor agonists, while prucalopride, norcisapride and MKC-733 cause no significant effects on human atrial trabeculae, (iii) R199715 seems to behave as a 5-HT(4) receptor antagonist.

Topics: 5-Methoxytryptamine; Adolescent; Adult; Aged; Benzofurans; Calcium Channels; Child; Cisapride; Female; Gastrointestinal Agents; Heart Atria; Heart Ventricles; Humans; Indoles; Male; Middle Aged; Muscle Contraction; Myocardium; Pyridines; Quinuclidines; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists; Sulfonamides; Young Adult

5-Hydroxytryptamine (5-HT)(4) receptor agonists reportedly stimulate brain acetylcholine (ACh) release, a property that might provide a new pharmacological approach for treating cognitive deficits associated with Alzheimer's disease. The purpose of this study was to compare the binding affinities, functional activities, and effects on neuropharmacological responses associated with cognition of two highly selective 5-HT(4) receptor agonists, prucalopride and 6,7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N-[3-(piperidin-1-yl)propyl]thieno[2,3-b]pyridine-5-carboxamide (PRX-03140). In vitro, prucalopride and PRX-03140 bound to native rat brain 5-HT(4) receptors with K(i) values of 30 nM and 110 nM, respectively, and increased cAMP production in human embryonic kidney-293 cells expressing recombinant rat 5-HT(4) receptors. In vivo receptor occupancy studies established that prucalopride and PRX-03140 were able to penetrate the brain and bound to 5-HT(4) receptors in rat brain, achieving 50% receptor occupancy at free brain exposures of 330 nM and 130 nM, respectively. Rat microdialysis studies revealed that prucalopride maximally increased ACh and histamine levels in the prefrontal cortex at 5 and 10 mg/kg, whereas PRX-03140 significantly increased cortical histamine levels at 50 mg/kg, failing to affect ACh release at doses lower than 150 mg/kg. In combination studies, donepezil-induced increases in cortical ACh levels were potentiated by prucalopride and PRX-03140. Electrophysiological studies in rats demonstrated that both compounds increased the power of brainstem-stimulated hippocampal θ oscillations at 5.6 mg/kg. These findings show for the first time that the 5-HT(4) receptor agonists prucalopride and PRX-03140 can increase cortical ACh and histamine levels, augment donepezil-induced ACh increases, and increase stimulated-hippocampal θ power, all neuropharmacological parameters consistent with potential positive effects on cognitive processes.

Topics: Acetylcholine; Animals; Area Under Curve; Benzofurans; Chromatography, High Pressure Liquid; Electroencephalography; Hippocampus; Histamine; Humans; Male; Microdialysis; Prefrontal Cortex; Pyridones; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin 5-HT4 Receptor Agonists; Tandem Mass Spectrometry; Thiophenes

We studied how 5-HT(4) receptor-mediated inotropic responses are regulated at the level of cAMP in porcine left atrium. We used selective phosphodiesterase (PDE) inhibitors to assess which PDE subtypes are responsible for the fade with time of inotropic responses to 5-HT(4) receptor activation with 5-HT and the 5-HT(4) receptor agonist prucalopride. A possible cross-talk via PDEs between cGMP and 5-HT(4) receptor-induced cAMP signalling was evaluated. Electrically paced left atrial pectinate muscles from young male pigs (15-25 kg) were studied in vitro. Simultaneous inhibition of PDE3 plus PDE4 subtypes was necessary to increase the amplitude and completely prevent the fade of the inotropic response to 5-HT and prucalopride. When responses to 5-HT or prucalopride had faded 1 h after addition, the nonspecific PDE-inhibitor IBMX still fully recovered inotropic responses. Stimulation of particulate guanylyl cyclase, together with PDE2 and PDE4 inhibition, delayed the fade of the response to 5-HT, while stimulation of soluble guanylyl cyclase independently of PDEs accelerated the fade of the response to 5-HT. In conclusion, both PDE3 and PDE4 subtypes are responsible for the suppression and the fade of the inotropic response to 5-HT and prucalopride. Signalling through the 5-HT(4) receptor remains fully active for at least 90 min with PDEs continuously regulating the response. cGMP levels, elevated by activation of particulate guanylyl cyclase under PDE2 inhibition, can indirectly enhance 5-HT(4) receptor-mediated signalling, at least when also PDE4 is inhibited, presumably through inhibition of PDE3. Elevation of cGMP generated by soluble guanylyl cyclase attenuates responses to 5-HT independently of PDEs.

Topics: Animals; Atrial Function; Benzofurans; Cyclic AMP; Cyclic GMP; Guanylate Cyclase; Heart Atria; In Vitro Techniques; Isometric Contraction; Male; Natriuretic Peptide, C-Type; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Receptors, Cytoplasmic and Nuclear; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin 5-HT4 Receptor Agonists; Soluble Guanylyl Cyclase; Swine

Topics: Alprostadil; Benzofurans; Biomedical Research; Chloride Channels; Constipation; Drug Approval; Humans; Lubiprostone; Peptides

Topics: Benzofurans; Constipation; Female; Gastrointestinal Motility; Humans; Women's Health

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

A UPLC-MS/MS assay was developed and validated for simultaneous quantification of acetylcholine (ACh), histamine (HA), tele-methylhistamine (t-mHA), and tele-methylimidazolacetic acid (t-MIAA) in rat cerebrospinal fluid (CSF). The biological stability of ACh in rat CSF was investigated. Following fit-for-purpose validation, the method was applied to monitor the drug-induced changes in ACh, HA, t-mHA, and t-MIAA in rat CSF following administration of donepezil or prucalopride. The quantitative method utilizes hydrophilic interaction chromatography (HILIC) Core-Shell HPLC column technology and a UPLC system to achieve separation with detection by positive ESI LC-MS/MS. This UPLC-MS/MS method does not require extraction or derivatization, utilizes a stable isotopically labeled internal standard (IS) for each analyte, and allows for rapid throughput with a 4 min run time. Without an acetylcholinesterase (AChE) inhibitor present, ACh was found to have 1.9±0.4 min in vitro half life in rat CSF. Stability studies and processing modification, including the use of AChE inhibitor eserine, extended this half life to more than 60 min. The UPLC-MS/MS method, including stabilization procedure, was validated over a linear concentration range of 0.025-5 ng/mL for ACh and 0.05-10 ng/mL for HA, t-mHA, and t-MIAA. The intra-run precision and accuracy for all analytes were 1.9-12.3% CV and -10.2 to 9.4% RE, respectively, while inter-run precision and accuracy were 4.0-16.0% CV and -5.3 to 13.4% RE, respectively. By using this developed and validated method, donepezil caused increases in ACh levels at 0.5, 1, 2, and 4h post dose as compared to the corresponding vehicle group, while prucalopride produced approximately 1.6- and 3.1-fold increases in the concentrations of ACh and t-mHA at 1h post dose, respectively, compared to the vehicle control. Overall, this methodology enables investigations into the use of CSF ACh and HA as biomarkers in the study of these neurotransmitter systems and related drug discovery efforts.

Topics: Acetylcholine; Animals; Benzofurans; Cholinesterase Inhibitors; Chromatography, High Pressure Liquid; Donepezil; Drug Stability; Histamine; Hydrophobic and Hydrophilic Interactions; Imidazoles; Indans; Male; Methylhistamines; Piperidines; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry

The aim of this study was to investigate whether the pig colon descendens might be a good model for the responses mediated via the different locations of human colonic 5-HT(4) receptors. The intrinsic excitatory and inhibitory motor neurotransmission in pig colon descendens was therefore first characterized. In circular smooth muscle strips, electrical field stimulation (EFS) at basal tone induced only in the combined presence of the NO synthase inhibitor N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME) and the SK channel blocker apamin voltage-dependent on-contractions. These on-contractions were largely reduced by the neuronal conductance blocker tetrodotoxin (TTX) and by the muscarinic receptor antagonist atropine, illustrating activation of cholinergic neurons. The 5-HT(4) receptor agonist prucalopride facilitated submaximal EFS-evoked cholinergic contractions and this effect was prevented by the 5-HT(4) receptor antagonist GR113808, supporting the presence of facilitating 5-HT(4) receptors on the cholinergic nerve endings innervating circular muscle in pig colon descendens. Relaxations were induced by EFS in strips pre-contracted with substance P in the presence of atropine. The responses at lower stimulation voltages were abolished by TTX. L-NAME or apamin alone did not influence or only moderately reduced the relaxations, but L-NAME plus apamin abolished the relaxations at lower stimulation voltages, suggesting that NO and ATP act as inhibitory neurotransmitters in a redundant way. Prucalopride did not influence the EFS-induced relaxations at lower stimulation voltage, nor did it per se relax contracted circular muscle strips. No evidence for relaxing 5-HT(4) receptors, either on inhibitory neurons or on the muscle cells was thus obtained in pig colon descendens circular muscle.

Topics: Animals; Benzofurans; Choline; Colon, Descending; Electric Stimulation; In Vitro Techniques; Male; Motor Neurons; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Nitric Oxide; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin 5-HT4 Receptor Agonists; Swine; Synaptic Transmission

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

5-HT₄ receptor (5-HT₄R) activation induces procognitive effects. This might be related to stimulation of hippocampal acetylcholine release, which has been shown for 5-HT₄R agonists in in-vivo models. We investigated the influence of the 5-HT₄R agonists, prucalopride and BIMU-8, on acetylcholine release in rat hippocampal brain slices. In contrast to the report by Siniscalchi et al., no facilitating effect of 5-HT₄R agonists on electrically evoked acetylcholine could be shown. The in our hands absence of an effect by 5-HT₄R agonists illustrates that an in-vitro evaluation of 5-HT₄R agonists on hippocampal acetylcholine release is not a straightforward model to study the relationship between hippocampal 5-HT₄Rs and hippocampal acetylcholine release.

Topics: Acetylcholine; Animals; Benzimidazoles; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Guinea Pigs; Hippocampus; Male; Models, Animal; Organ Culture Techniques; Presynaptic Terminals; Rats; Rats, Wistar; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Synaptic Transmission

The 5-HT(4) receptor agonist prucalopride enhances large intestinal contractility by facilitating acetylcholine release through activation of 5-HT(4) receptors on cholinergic nerves and is effective in patients with constipation. Patients with intestinal endometriosis can present with constipation. We investigated in vitro whether large intestinal endometriotic infiltration influences contractility and facilitation of acetylcholine release by prucalopride.. Sigmoid colon or rectum circular muscle strips were obtained at the level of an endometriotic nodule with infiltration of the Auerbach plexus, and at a macroscopically healthy site at least 5 cm cranially from the nodule, in patients undergoing laparoscopic colorectal resection because of symptomatic bowel endometriosis. Responses to muscarinic receptor stimulation and to electrical field stimulation (EFS), and the facilitating effect of prucalopride on acetylcholine release were evaluated.. The EC50 and E(max) of the contractile responses to the muscarinic receptor agonist carbachol did not differ between healthy and lesioned strips. EFS-induced on-contractions were not different between the healthy and lesioned strips, while the non-nitrergic relaxant responses induced by EFS were decreased in the lesioned strips. The facilitating effect of prucalopride on acetylcholine release in healthy strips was similar to that reported before in macroscopically healthy colon tissue of patients with colon cancer; in lesioned strips, the effect of prucalopride was fully maintained in 6/8 patients and absent in two.. Large intestinal endometriosis does not lead to a systematic interference with the cholinergic facilitating effect of prucalopride.

Topics: Acetylcholine; Adult; Area Under Curve; Benzofurans; Electric Stimulation; Endometriosis; Female; Humans; Intestinal Diseases; Intestine, Large; Middle Aged; Muscle Contraction; Muscle, Smooth; Receptors, Serotonin, 5-HT4; Serotonin Receptor Agonists; Signal Processing, Computer-Assisted

We have recently reported that serotonin(4) (5-HT(4)) receptor agonists have a promising potential as fast-acting antidepressants. Here, we assess the extent to which this property may be optimized by the concomitant use of conventional antidepressants.. We found that, in acute conditions, the 5-HT(4) agonist prucalopride was able to counteract the inhibitory effect of the selective serotonin reuptake inhibitors (SSRI) fluvoxamine and citalopram on 5-HT neuron impulse flow, in Dorsal Raphé Nucleus (DRN) cells selected for their high (>1.8 Hz) basal discharge. The co-administration of both prucalopride and RS 67333 with citalopram for 3 days elicited an enhancement of DRN 5-HT neuron average firing rate, very similar to what was observed with either 5-HT(4) agonist alone. At the postsynaptic level, this translated into the manifestation of a tonus on hippocampal postsynaptic 5-HT(1A) receptors, that was two to three times stronger when the 5-HT(4) agonist was combined with citalopram. Similarly, co-administration of citalopram synergistically potentiated the enhancing effect of RS 67333 on CREB protein phosphorylation within the hippocampus. Finally, in the Forced Swimming Test, the combination of RS 67333 with various SSRIs (fluvoxamine, citalopram and fluoxetine) was more effective to reduce time of immobility than the separate administration of each compound.. These findings strongly suggest that the adjunction of an SSRI to a 5-HT(4) agonist may help to optimize the fast-acting antidepressant efficacy of the latter.

Topics: Action Potentials; Aniline Compounds; Animals; Antidepressive Agents; Benzofurans; CA3 Region, Hippocampal; Citalopram; Cyclic AMP Response Element-Binding Protein; Drug Synergism; Fluvoxamine; Male; Motor Activity; Neurons; Phosphorylation; Piperazines; Piperidines; Pyridines; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists; Serotonin Receptor Agonists

This study examined whether the drug-receptor-binding sites of 5 selected human 5-HT(4) receptor splice variants [h5-HT4(a), h5-HT4(b), h5-HT4(c), h5-HT4(d) and h5-HT4(g)] display preferential affinities towards agonists. The agonists selected on the basis of chemical diversity and clinical relevance were: 5-HT4 benzamides, renzapride, zacopride and prucalopride; the benzimidazolones, DAU 6236 and BIMU 1; the aromatic ketone, RS67333, and the indole carbazimidamide tegaserod. The rank order of affinities ranging across the splice variants was: tegaserod (pKi: 7.38-7.91) > or = Y-36912 (pKi: 7.03-7.85) = BIMU 1 (pKi: 6.92-7.78) > or = DAU 6236 (pKi: 6.79-7.99) > or = 5-HT (pKi: 5.82-7.29) > or = 5-MeOT (pKi: 5.64-6.83) > or = renzapride (pKi: 4.85-5.56). We obtained affinity values for the 5-HT4(b), (d) and (g) variants for RS67333 (pKi: 7:48-8.29), prucalopride (pKi: 6.86-7.37) and zacopride (pKi: 5.88-7.0). These results indicate that the ligands interact with the same conserved site in each splice variant. Some splice variants have a higher affinity for certain agonists and the direction of selectivity followed a common trend of lowest affinity at the (d) variant. However, this trend was not evident in functional experiments. Our findings suggest that it may be possible to design splice variant selective ligands, which may be of relevance for experimental drugs but may be difficult to develop clinically.

Topics: Aniline Compounds; Animals; Benzamides; Benzimidazoles; Benzofurans; Binding Sites; Binding, Competitive; Bridged Bicyclo Compounds, Heterocyclic; Chlorocebus aethiops; COS Cells; Cyclic AMP; Dose-Response Relationship, Drug; Humans; Indoles; Kinetics; Ligands; Piperidines; Protein Isoforms; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists

Topics: Adult; Aged; Benzofurans; Constipation; Drug Interactions; Humans; Middle Aged

The time dependency of the effect of 5-HT(4) receptor agonists depends on many specific regulatory mechanisms, which vary between tissues. This has important implications with regard to the effects of endogenous 5-HT, as well as to the clinical use of 5-HT(4) receptor agonists, and might contribute to tissue selectivity of agonists.. The progression and desensitization of 5-HT(4) receptor-mediated responses were evaluated in an organ bath set-up using two, clinically relevant, porcine in vitro models: gastric cholinergic neurotransmission and atrial contractility.. Exposure of gastric tissue to 5-HT or to the selective 5-HT(4) receptor agonists prucalopride and M0003 results in a sustained non-transient effect during exposure; after washout, the response to a subsequent challenge with 5-HT shows no clear desensitization. Incubation of left atrial tissue with 5-HT resulted in a transient response, leading after washout to a marked desensitization of the subsequent response to 5-HT. The selective 5-HT(4) receptor agonists prucalopride and M0003 induce only very weak atrial responses whereas they are very effective in desensitizing the atrial response to 5-HT. The observations also suggest that the properties of prucalopride and M0003 to bind to and/or activate the 5-HT(4) receptor differ from those of 5-HT. This difference might have contributed to the observed desensitization.. The high potency of prucalopride and M0003 in desensitizing the response to 5-HT together with their low efficacy in the atrium emphasizes the cardiac safety of this class of 5-HT(4) receptor agonists.

Topics: Animals; Atrial Function, Left; Benzofurans; Female; In Vitro Techniques; Models, Biological; Muscle Contraction; Muscle, Smooth; Myocardial Contraction; Organ Specificity; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Serotonin 5-HT4 Receptor Antagonists; Stomach; Swine; Synaptic Transmission; Tachyphylaxis

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

A number of new, novel strategies for managing constipation in the elderly have emerged over the past few years. Prucalopride is one such new agent that is highly efficacious in managing chronic constipation. In fact, Camilleri et al in a recent study reported that the average number of bowel movements increased by at least one in nearly 47% of the patients who were administered a dose of 4 mg. Lubiprostone is another new agent recently approved by the FDA that shows efficacy in managing the symptoms of constipation. Neostigmine has also been successfully used for the management of recalcitrant constipation. Most of these studies have used subcutaneous neostigmine. Symbiotic yogurt containing components, such as Bifidobacterium and fructoligosaccharide, have also been recently shown to be highly effective in improving symptoms of constipation. Elderly patients especially those in hospices and nursing homes are often on opioids for pain management. Constipation secondary to opioid use is extremely common in nursing homes. Subcutaneous methylnaltrexone has recently been shown to be highly effective in the management of opioid-related constipation, and was recently approved by the FDA. Sacral nerve stimulation is another emerging strategy. A recent analysis by Mowatt et al supports the efficacy of this technique. Botulinum toxin is another agent that has already been successfully used for the management of chronic, refractory constipation in children and may be very effective for elderly constipation. Further larger studies are needed to confirm the findings noted in these studies. Constipation is clearly a major issue in the elderly and these new, emerging strategies will hopefully improve the quality of life and relieve the symptoms of constipation in this population.

Topics: Age Factors; Aged; Aged, 80 and over; Alprostadil; Benzofurans; Constipation; Humans; Lubiprostone; Neostigmine

It is known that 5-HT(4) receptor agonists increase sAPPalpha levels in the cortex and hippocampus of mice as well as in a model of Alzheimer's disease (AD). As sAPPalpha is thought to have pro-mnesic properties, we assessed whether its increase induces cognitive improvement in a spatial memory task and whether it reverses a scopolamine-induced memory deficit. Mice treated or not treated with scopolamine were trained in the Morris water maze for 3 days. Before the probe test, they received an injection of either a 5-HT(4) receptor agonist (prucalopride or RS 67333), or an acetylcholinesterase inhibitor (donepezil), or both drugs. As expected, scopolamine decreased performance, an effect that was not reversed by the drugs tested when injected alone. However, prucalopride (5 mg kg(-1), s.c.) acted synergistically with donepezil (0.75 mg kg(-1), s.c.) to counteract completely scopolamine-induced amnesia. Western blot analysis of tissue homogenates in the cortex and hippocampus shows that sAPPalpha levels did not differ between saline- and scopolamine-treated mice. Furthermore, a region-dependent drug action was observed since the scopolamine-treated mice display a tendency to increase sAPPalpha levels in the hippocampus after donepezil or in the cortex after prucalopride. Our results suggest that a combined treatment with a 5-HT(4) receptor agonist with an acetylcholinesterase inhibitor has beneficial effects on memory in mice. Moreover, it seems to enhance sAPPalpha levels in two brain regions highly affected in AD. Thus, a drug polytherapy could be interesting not only to enhance cognitive performance and decrease drawbacks but also to get the best action in each brain region.

Topics: Amyloid beta-Protein Precursor; Analysis of Variance; Aniline Compounds; Animals; Benzofurans; Cerebral Cortex; Cholinesterase Inhibitors; Donepezil; Drug Synergism; Hippocampus; Indans; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Motor Activity; Nootropic Agents; Piperidines; Scopolamine; Serotonin 5-HT4 Receptor Agonists; Statistics, Nonparametric

5-HT(4) receptors are present in human and porcine atrial myocytes while they are absent from the hearts of small laboratory animals. The pig is therefore the only available nonprimate animal model in which to study cardiac 5-HT(4) receptor function under physiological conditions. While several human splice variants of the 5-HT(4) receptor have been described, the splicing behavior of this receptor in porcine tissue is currently unknown. Here we report on the identification of nine novel COOH-terminal splice variants of the porcine 5-HT(4) receptor, which were named 5-HT(4(b2, j, k, l, m, o, p, q, r)). The internal h-variant was found in combination with several COOH-terminal exons. In addition, splice variants were found that comprised duplicated exons fused to the common region of the 5-HT(4) receptor, thereby providing evidence for a duplication of the porcine HTR4 gene. One of these variants putatively encoded a nine transmembrane-spanning domain homofusion receptor, 5-HT(4(9TM)); also the other variants with a duplicated region might translate into functional, transcriptionally fused dimeric 5-HT(4) receptor variants. The elucidation of the genomic context confirmed that the variants were not genomic artefacts but originated from alternative splicing. This was further corroborated by a functional analysis of the variants 5-HT(4(a)), 5-HT(4(r)), and 5-HT(4(9TM)). To our knowledge, our data are the first to report on a functional GPCR with more than seven predicted transmembrane domains. These findings urge for caution when interpreting data on 5-HT(4) receptor-related pharmacology obtained in the pig; validation at the molecular level might be needed before extrapolating results to human.

Topics: Alternative Splicing; Amino Acid Sequence; Animals; Benzofurans; Cell Line; Cell Membrane; Cloning, Molecular; Cyclic AMP; Exons; Female; Gene Expression Profiling; Genome; Green Fluorescent Proteins; Humans; Kinetics; Molecular Sequence Data; Protein Isoforms; Receptors, Serotonin, 5-HT4; Recombinant Fusion Proteins; Sequence Alignment; Serotonin; Serotonin 5-HT4 Receptor Agonists; Swine; Transfection

The human ether-à-go-go related gene (HERG) encodes the alpha-subunit of a delayed rectifier potassium channel important in the repolarisation of the cardiac action potential. Excessive action potential prolongation through HERG channel inhibition is associated with a risk of torsade de pointes arrhythmias and is a major challenge for drug development. The acute effects of the novel prokinetic prucalopride were examined on heterologously expressed HERG channels in human embryonic kidney (HEK) 293 cells using the whole-cell patch-clamp technique. Prucalopride inhibited HERG channels in a concentration-dependent manner with an IC(50) of 4.1 microM. Prucalopride significantly slowed channel deactivation and recovery from inactivation, accelerated and altered the extent of inactivation. Similar concentration-dependency and kinetic changes were observed with the minor T897 polymorphic HERG variant. Prucalopride block was frequency-independent due to rapid state-dependent block, with binding occurring in the open and inactivated states. Though prucalopride blocks HERG channels this is unlikely to be significant at clinically relevant concentrations.

Topics: Benzofurans; Cell Line; Dose-Response Relationship, Drug; Ether-A-Go-Go Potassium Channels; Genotype; Humans; Kinetics; Membrane Potentials; Patch-Clamp Techniques; Polymorphism, Single Nucleotide; Time Factors; Transfection

A strategy to treat Alzheimer's disease (AD) is to increase the soluble form of amyloid precursor protein (sAPPalpha), a promnesic protein, in the brain. Because strong evidence supports beneficial effects of 5-hydroxytryptamine 5-HT(4) receptor agonists in memory and learning, we investigated the role of 5-HT(4) receptors on APP processing in 8 weeks-old male C57BL/6j mice.. Mice were given, subcutaneously, prucalopride or ML 10302 (s.c.), two highly selective 5-HT(4) receptor agonists and, up to 240 min later, the hippocampus and cortex were analysed by Western blot for sAPPalpha determination.. Prucalopride (5 or 10 mg kg(-1)) significantly increased sAPPalpha levels in the hippocampus and cortex, but did not modify the expression level of APP mRNA as detected by quantitative RT-PCR. A selective 5-HT(4) receptor antagonist, GR125487 (1 mg kg(-1), s.c.) inhibited prucalopride induced- increase in sAPPalpha levels. In addition, levels of sAPPalpha were increased by ML10302 only at 20 mg kg(-1) and was limited to the cortex. Also, prucalopride increased sAPPalpha levels in the cortex of a transgenic mouse model of AD, expressing the London mutation of APP. Furthermore, the combined injection of a selective acetylcholinesterase inhibitor, donepezil and prucalopride induced a synergic increase in sAPPalpha levels in the cortex and hippocampus.. Our results demonstrate that the 5-HT(4) receptor plays a key role in the non-amyloidogenic pathway of APP metabolism in vivo and give support to the beneficial use of 5-HT(4) agonists for AD treatment.

Topics: Aminobenzoates; Amyloid beta-Protein Precursor; Animals; Benzofurans; Cerebral Cortex; Cholinesterase Inhibitors; Donepezil; Hippocampus; Indans; Indoles; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; para-Aminobenzoates; Piperidines; RNA, Messenger; Serotonin 5-HT4 Receptor Agonists; Serotonin 5-HT4 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists; Sulfonamides

1.--In this study, we aimed to characterize in vitro the effects of the benzofuran 5-HT(4) receptor agonists prucalopride, R149402 and R199715 and the indolic agents tegaserod and 5-HT in the atria of young pigs (10-11 weeks) and newborn piglets. 2.--In the paced left atrium of young pigs, only 5-HT results in positive inotropic responses when administered cumulatively (maximal effect relative to isoprenaline=53%, pEC(50)=6.8); however, all agonists showed lusitropic effects. Noncumulative administration results in greater positive inotropic responses for 5-HT and induces moderate positive inotropic responses for the other agonists; these responses fade. 3.--Phosphodiesterase (PDE) enzyme inhibition with 3-isobutyl-1-methylxanthine (IBMX; 20 microM) enhances the responses to cumulatively administered 5-HT (maximal effect=89%, pEC(50)=7.7) and reveals clear positive inotropic effects for prucalopride, tegaserod, R149402 and R199715; fading is abolished. The maximal effect of the benzofurans is less pronounced than that of the indoles. 4.--In the spontaneously beating right atrium of young pigs, all agonists show chronotropic activity when administered cumulatively in the absence of IBMX, without fade. Benzofurans behaved as partial agonists compared to 5-HT (maximal effect=54%, pEC(50)=6.5). 5.--In newborns, the inotropic activity of the agonists in the IBMX-treated left atrium was less pronounced than in the young pig; the same applied for the chronotropic response in the right atrium, except for 5-HT. 6.--In conclusion, the atrial responses to 5-HT(4) receptor activation increase in the first months of life; the inotropic response is regulated by PDEs. Prucalopride, R149402 and R199715 are partial agonists compared to 5-HT.

Topics: Animals; Animals, Newborn; Benzamides; Benzofurans; Heart Atria; Heart Rate; In Vitro Techniques; Indoles; Myocardial Contraction; Myocardium; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin 5-HT4 Receptor Agonists; Sinoatrial Node; Stimulation, Chemical; Swine

A failure of tight control of MHC class II expression on astrocytes may play a role in the development of autoimmune responses in multiple sclerosis. The 5-HT(4) serotonin receptor agonists cisapride and prucalopride, at concentrations between 10(-10) M and 10(-8) M, reduced interferon-gamma-induced MHC class II immunostaining in cultured astrocytes derived from newborn Wistar rats by approximately 50-60%. The magnitude of MHC class II inhibition by 5-HT(4) agonists was comparable to that of interferon-beta. The alpha(1)-adrenergic receptor agonist phenylephrine was without effect. Cisapride (10(-9) M) also prevented interferon-gamma-induced B7-1 and B7-2 immunostaining. Our results suggest that 5-HT(4) agonists may have therapeutic potential in multiple sclerosis by inhibiting the up-regulation of immune responsiveness of astrocytes in the central nervous system.

Topics: Adrenergic alpha-Agonists; Animals; Astrocytes; B7-1 Antigen; Benzofurans; Cells, Cultured; Cisapride; Histocompatibility Antigens Class II; Immunohistochemistry; Interferon-gamma; Phenylephrine; Rats; Rats, Wistar; Receptors, Serotonin; Serotonin Receptor Agonists

Previous studies have demonstrated mixed inhibitory and facilitatory effects of 5-hydroxytryptamine-4 (5-HT(4)) receptor agonists on electrical field stimulation (EFS)-induced responses in human isolated colon. Here we report three types of responses to EFS in human isolated colon circular muscle: monophasic cholinergic contraction during EFS, biphasic response (nitrergic relaxation during EFS followed by cholinergic contraction after termination of EFS) and triphasic response (cholinergic contraction followed by nitrergic relaxation during EFS and a tachykininergic contraction after EFS). The effects of two 5-HT(4) receptor agonists, prucalopride and tegaserod were then investigated on monophasic responses only. Each compound inhibited contractions during EFS in a concentration-dependent manner. In the presence of N(omega)-nitro-l-arginine methyl ester (l-NAME) however, prucalopride and tegaserod enhanced the contractions in a concentration-dependent manner. In strips where the tone was elevated with substance-P and treated with scopolamine, EFS-induced relaxations were enhanced by the two agonists. The above observed effects by the two agonists were abolished by 5-HT(4) receptor antagonist SB-204070. The two agonists did not alter the tone raised by substance-P in the presence of scopolamine and l-NAME and did not affect carbachol-induced contractions in the presence of tetrodotoxin. These results suggest that in the circular muscle of human colon, 5-HT(4) receptor agonists simultaneously facilitate the activity of neurones which release the inhibitory and excitatory neurotransmitters, nitric oxide and acetylcholine respectively.

Topics: Acetylcholine; Adult; Aged; Aged, 80 and over; Benzofurans; Colon; Dose-Response Relationship, Drug; Electric Stimulation; Enzyme Inhibitors; Female; Humans; Indoles; Male; Middle Aged; Muscarinic Antagonists; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Neurokinin-1 Receptor Antagonists; Neurotransmitter Agents; NG-Nitroarginine Methyl Ester; Nitric Oxide; Organ Culture Techniques; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Scopolamine; Serotonin 5-HT4 Receptor Agonists; Substance P

Prucalopride is a selective 5-hydroxytryptamine type 4 (5-HT4) receptor agonist developed for the treatment of gastrointestinal disorders. The endogenous agonist 5-HT acting via 5-HT4 receptors increases the L-type Ca2+ current (I(CaL)) with potentially proarrhythmic consequences (Pau et al., 2003). The aims of this study were to investigate the effects of prucalopride on I(CaL), action potentials, refractory period, and arrhythmic activity in human atrial myocytes, and to compare these with the effects of 5-HT, using the whole-cell perforated patch-clamp technique. Prucalopride (10(-9) to 10(-4) M) produced a concentration-dependent increase in I(CaL) amplitude, with a maximum response at 10 microM, from -5.3 +/- 0.6 to -10.9 +/- 1.5 pA/pF (p < 0.05; n = 22 cells, 10 patients), without affecting its voltage-dependence. Subsequent application of 10 microM 5-HT further increased I(CaL) to -17.7 +/- 2.8 pA/pF (p < 0.05; n = 16 cells, 9 patients). The increase in I(CaL) by prucalopride, 98 +/- 15%, was significantly smaller than that by 5-HT, 233 +/- 26% (p < 0.05). Prucalopride (10 microM) significantly increased the action potential duration at 50% repolarization (APD50) from 12 +/- 2 to 17 +/- 3 ms (p < 0.05; n = 22 cells, 9 patients). Following washout of prucalopride, 5-HT (10 microM) increased APD50, to a greater extent, from 14 +/- 3 to 32 +/- 7 ms (p < 0.05; n = 11 cells; 8 patients). The APD75, APD90, and effective refractory period were unaffected by prucalopride or 5-HT. Furthermore, 5-HT induced abnormal depolarizations in 27% of the cells studied, whereas prucalopride induced none (p < 0.05). In conclusion, in human atrial cells, prucalopride, at concentrations markedly above those used therapeutically, acted as partial agonist on I(CaL) and APD50, with no effect on late repolarization or refractory period, and was devoid of arrhythmic activity.

Topics: Action Potentials; Adrenergic beta-Antagonists; Anti-Arrhythmia Agents; Benzofurans; Calcium Channel Blockers; Calcium Channels, L-Type; Coronary Artery Bypass; Dose-Response Relationship, Drug; Electrophysiology; Heart Atria; Humans; In Vitro Techniques; Indoles; Myocytes, Cardiac; Patch-Clamp Techniques; Refractory Period, Electrophysiological; Serotonin; Sulfonamides

We recently identified a facilitory control exerted by serotonin4 (5-HT4) receptors on the in vivo firing activity of dorsal raphe nucleus (DRN) serotonergic (5-HT) neurons. However, these findings were based on acute administrations of 5-HT4 receptor agonists and antagonists, which were active only in a subpopulation of 5-HT neurons. We had no evidence that this influence was significant when considering the entire DRN, nor if it was persistent after chronic treatments. In addition, the poor distribution of 5-HT4 receptors within the DRN raised the question of the neuroanatomical bases underlying this control.. Here we show that the subacute intraperitoneal (IP) injection of the 5-HT4 receptor agonists prucalopride (2.5 mg/kg) and RS 67333 (1.5 mg/kg) 30 minutes before the beginning of recordings augment the mean firing rate of DRN neurons by 40% and 66%, respectively. These increases remain stable when the compounds are administered continuously during 3 and 21 days; the effects of the 3-day treatment are blocked by the 5-HT4 receptor antagonist GR 125487 (1000 microg/kg, intravenous [i.v.]). In addition, stereotaxic microinjections of herpes simplex viruses, transformed to overexpress 5-HT4 receptors, increase DRN 5-HT neuronal mean activity when performed in the medial prefrontal cortex (mPFC) but not in the striatum or in the hippocampus.. This finding suggests the existence of a 5-HT(4)-dependent activation of DRN that may involve the mPFC, unveiling the 5-HT4 receptor as a putative player in the physiopathology of several disorders related to central 5-HT dysfunction.

Topics: Aniline Compounds; Animals; Benzofurans; Electrophysiology; Extracellular Space; Feedback; Frontal Lobe; Gene Transfer Techniques; Genetic Vectors; Herpesvirus 1, Human; In Situ Hybridization; Indoles; Iontophoresis; Male; Neurons; Piperidines; Pyramidal Cells; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT4; RNA Probes; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sulfonamides

5-Hydroxytryptamine 4 (5-HT4) receptor agonists promote colonic propulsion. The alteration of circular muscle (CM) motility underlying this involves inhibition of contractility via smooth muscle 5-HT4 receptors and proximal colonic motility stimulation, the mechanism of the latter not having been characterized. Our aim was to identify and characterize a 5-HT4 receptor-mediated stimulation of human colon CM contractile activity. 5-HT4 receptor ligands were tested on electrical field stimulation (EFS)-induced contractions of human colonic muscle strips cut in the circular direction (called 'whole tissue' strips). Additionally, after incubation of tissues with [3H]-choline these compounds were tested on EFS-induced release of tritium in whole tissue strips and in 'isolated' CM strips, obtained by superficial cutting in the CM layer. Tetrodotoxin and atropine blocked EFS-induced contractions of whole tissue CM strips. Prucalopride (0.3 micromol L-1) evoked a heterogenous response on EFS-induced contraction, ranging from inhibition (most frequently observed) to enhancement. In the release experiments, EFS-induced tritium efflux was blocked by tetrodotoxin. Prucalopride increased EFS-induced tritium and [3H]-acetylcholine efflux in whole tissue and in isolated CM strips. All effects of prucalopride were antagonized by the selective 5-HT4 receptor antagonist GR113808. The results obtained indicate the presence of excitatory 5-HT4 receptors on cholinergic nerves within the CM of human colon.

Topics: Acetylcholine; Benzofurans; Chromatography, High Pressure Liquid; Colon; Electric Stimulation; Enzyme Inhibitors; Humans; In Vitro Techniques; Muscle Contraction; Muscle, Smooth; Nitric Oxide Synthase; Nitroarginine; Parasympathetic Nervous System; Receptors, Serotonin, 5-HT4; Serotonin Antagonists; Serotonin Receptor Agonists; Tetrodotoxin

Prucalopride is a gastrointestinal prokinetic drug that acts through 5-HT4 receptors, but its potential effects on cardiac atrial function are unknown. We investigated the effects of prucalopride on human right atrium, piglet left atrium, and piglet sinoatrial node. The effects of prucalopride on 5-HT4 receptor splice variants a, b, g and i, known to be expressed in human atrium, were studied for comparison. Prucalopride was an inotropic partial agonist, compared with 5-HT, on paced human atrial trabeculae (-logEC50M=7.4) and porcine left atria (-logEC50M=7.2), with intrinsic activity of 0.77 and 0.63 respectively. Prucalopride (1 microM) surmountably antagonized the positive inotropic effects of 5-HT on human (pK(P)=7.2) and porcine (pK(P)=7.1) atrium. Prucalopride was also a chronotropic partial agonist (-logEC50M=7.4, intrinsic activity=0.72 with respect to 5-HT) on spontaneously beating piglet atria. The cardiostimulant effects of prucalopride were prevented by GR113808 (1 microM), consistent with mediation through 5-HT4 receptors. Prucalopride bound to recombinant 5-HT4(a), 5-HT4(b), 5-HT4(g), and 5-HT4(i) receptors, labeled by [3H]GR113808, with pKi values of 7.6, 7.5, 7.4, and 7.8 respectively. Prucalopride stimulated adenylyl cyclase as a partial agonist on 5-HT4(a), 5-HT4(b), and 5-HT4(i) receptors with intrinsic activities of 0.82, 0.86, and 0.78 and -logEC50 values of 7.2, 7.3, and 7.2 respectively. At the 5-HT4(g) receptor prucalopride acted as a full agonist (-logEC50M=8.0) compared with 5-HT in the cell line tested, which was probably due to high receptor expression levels. We conclude that prucalopride is a cardiostimulatory partial agonist through human and porcine 5-HT4 receptors. Since prucalopride acts similarly through 5-HT4(a), 5-HT4(b), 5-HT4(g), and 5-HT4(i) receptors, any of these variants could be involved in the mediation of cardiostimulation.

Topics: Adenylyl Cyclases; Aged; Animals; Benzofurans; Cell Line; Female; Heart Atria; Humans; Indoles; Male; Middle Aged; Protein Isoforms; Receptors, Serotonin, 5-HT4; Recombinant Proteins; Serotonin; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists; Sulfonamides; Swine

5-HT(4) receptors are widely distributed in both peripheral and central nervous systems where they couple, via a G-protein, to the activation of adenylate cyclase. In the brain, the highest 5-HT(4) receptor densities are found in the limbic system, including the hippocampus and frontal cortex. It has been suggested that activation of these receptors may be of therapeutic benefit in diseases that produce cognitive deficits such as Alzheimer's disease (AD). Previous electrophysiological studies have shown that the 5-HT(4) agonist, Zacopride, can increase population spike amplitude recorded in region CA1 of rat hippocampal slices in a cyclic AMP (cAMP)/cAMP-dependent protein kinase A-dependent manner. We report here that the 5-HT(4) agonist, Prucalopride, and the 5-HT(4) partial agonist, SL65.0155, produce a similar effect in rat hippocampal slices and that the specific 5-HT(4) antagonist, GR113808, blocks these effects. To investigate the potential use of 5-HT(4) agonists in the treatment of AD, Prucalopride was applied to hippocampal slices from a transgenic mouse line that overexpresses the Abeta peptide. Despite the deficit in synaptic transmission present in these mice, the percentage increase of the CA1 population spike induced by Prucalopride was the same as that observed in wild-type mice. These data support 5-HT(4) receptors as a target for cognitive enhancement and suggest that a partial agonist would be sufficient to produce benefits, while reducing potential peripheral side effects. In addition, we show that 5-HT(4) receptors remain functional in the presence of excess Abeta peptide and may therefore be a useful target in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Genetically Modified; Benzofurans; Dioxanes; Disease Models, Animal; Excitatory Postsynaptic Potentials; Hippocampus; Humans; Indoles; Male; Neurons; Organ Culture Techniques; Oxadiazoles; Patch-Clamp Techniques; Rats; Receptors, Serotonin, 5-HT4; Serotonin Antagonists; Serotonin Receptor Agonists; Sulfonamides

To evaluate the effects of prucalopride on intestinal prokinetic activity in fast rats and to provide experimental basis for clinical treatment of gastrointestinal motility diseases.. Gastrointestinal propulsion rate was measured by the migration rate of activated charcoal, which reflexes gastrointestinal motility function. 120 Spraque-Dawley rats were randomly divided into four groups and received an intravenous injection of physiological saline (served as control), prucalopride 1 mg/kg, prucalopride 2 mg/kg and cisapride 1 mg/kg, respectively. The gastrointestinal propulsion rate was measured 1, 2 or 4 hours after intravenous injection of the drugs.. Significant accelerations of gastrointestinal propulsion rate in prucalopride 1 mg/kg and 2 mg/kg groups were found compared with control group at 2 and 4 hours(83.2 %+/-5.5 %, 81.7 %+/-8.5 % vs 70.5 %+/-9.2 %, P<0.01; 91.2 %+/-2.2 %, 91.3 %+/-3.9 % vs 86.8 %+/-2.6 %, P<0.01). The gastrointestinal propulsion rates at 1, 2 or 4 hours were faster in prucalopride 1 mg/kg and 2 mg/kg groups than in cisapride group (84.0 %+/-11.7 %, 77.1 %+/-11.9 % vs 66.3 %+/-13.6 %, P<0.01, P<0.05; 83.2 %+/-5.5 %, 81.7 %+/- 8.5 % vs 75.4 %+/-5.9 %, P<0.01, P<0.05; 91.2 %+/-2.2 %, 91.3 %+/-3.9 % vs 88.6 %+/-3.5 %,P<0.05, P<0.05). No difference of gastrointestinal propulsion rate was found between prucalopride 1 mg/kg group and prucalopride 2 mg/kg group (P>0.05).. Prucalopride accelerates intestinal motility in fast rats, and has no dose dependent effect.

Topics: Animals; Benzofurans; Fasting; Gastrointestinal Motility; Male; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Serotonin Receptor Agonists; Time Factors

We investigated, using single-unit recordings in chloral hydrate-anaesthetized rats, the role of serotonin 4 (5-HT4) receptors in the control of dorsal raphé nucleus (DRN) 5-HT neuron activity. About one-half (36) of the 76 neurons recorded were affected by either the preferential 5-HT4 agonist cisapride (500 and 1000 micro g/kg, i.v.) or the selective 5-HT4 antagonist, GR 125487 (200- 2000 micro g/kg, i.v.). Responding neurons displayed a significantly higher mean basal firing rate (1.93 +/- 0.1 Hz) than non-responders (1.31 +/- 0.1 Hz). The firing rate of responding 5-HT neurons was enhanced dose-dependently by cisapride (+47 and +94% at 500 and 1000 micro g/kg, respectively), an effect abolished by GR 125487 (500 micro g/kg) and reduced by the 5-HT4 antagonist, SDZ 205557 (500 micro g/kg, i.v). Conversely, GR 125487 induced a dose-dependent inhibition of responders activity, which was almost completely suppressed at the dose of 2000 micro g/kg. In a separate set of experiments, the selective 5-HT4 agonist, prucalopride (500 micro g/kg, i.v), increased the firing activity (+35%) of 5-HT neurons displaying a high basal firing rate; subsequent injection of GR 125487 (500 micro g/kg, i.v.) suppressed this effect. These results indicate that 5-HT4 receptors exert both a tonic and a phasic, positive, frequency-related control on DRN 5-HT neuronal activity. The existence of such a control might open new avenues for therapeutic research in the antidepressant field.

Topics: 4-Aminobenzoic Acid; Action Potentials; Animals; Benzofurans; Cisapride; Electrophysiology; Indoles; Male; Neurons; para-Aminobenzoates; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sulfonamides

1. This study investigates whether the cholinergic neurones, innervating the human proximal stomach, can be modulated by nitric oxide (NO) or vasoactive intestinal polypeptide (VIP), or via presynaptic muscarinic, alpha(2)- or 5-hydroxytryptamine(4) (5-HT(4)-) receptors. 2. Circular muscle strips, without mucosa, were incubated with [(3)H]-choline to incorporate [(3)H]-acetylcholine into the cholinergic transmitter stores. The basal and electrically-induced release of tritium and [(3)H]-acetylcholine were analysed in a medium containing guanethidine (4 x 10(-6) M), hemicholinium-3 (10(-5) M), physostigmine (10(-5) M) and atropine (10(-6) M). Tissues were stimulated twice for 2 min (S(1) and S(2): 40 V, 1 ms, 4 Hz) and drugs were added before S(2). 3. The NO synthase inhibitor L-N(G)-nitroarginine methyl ester (3 x 10(-4) M) and the NO donor sodium nitroprusside (10(-5) M), as well as VIP (10(-7) M) did not influence the basal release nor the electrically-evoked release. 4. The alpha(2)-adrenoceptor agonist UK-14,304 (10(-5) M) significantly inhibited the electrically-evoked release of [(3)H]-acetylcholine, and this was prevented by the alpha(2)-adrenoceptor antagonist rauwolscine (2 x 10(-6) M). 5. The 5-HT(4)-receptor agonist prucalopride (3 x 10(-7) M) significantly enhanced the electrically-evoked release of [(3)H]-acetylcholine, and the 5-HT(4)-receptor antagonist SB204070 (10(-9) M) prevented this. 6. When atropine (10(-6) M) was omitted from the medium and added before the second stimulation, it significantly increased the release of [(3)H]-acetylcholine. 7. These results suggest that the release of acetylcholine from the cholinergic neurones, innervating the circular muscle in the human proximal stomach, can be inhibited via presynaptic muscarinic auto-receptors and alpha(2)-adrenoceptors, and stimulated via presynaptic 5-HT(4)-receptors. No evidence for modulation by NO or VIP was obtained.

Topics: Acetylcholine; Adrenergic alpha-Agonists; Adult; Aged; Aged, 80 and over; Atropine; Benzofurans; Brimonidine Tartrate; Dioxanes; Enzyme Inhibitors; Evoked Potentials; Female; Gastric Fundus; Gastrointestinal Agents; Humans; Male; Middle Aged; Muscarinic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitroprusside; Piperidines; Quinoxalines; Receptors, Cholinergic; Receptors, Muscarinic; Receptors, Presynaptic; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Receptors, Vasoactive Intestinal Peptide; Serotonin Antagonists; Stomach; Synaptic Transmission; Vasoactive Intestinal Peptide; Yohimbine

Scleroderma is a multisystem disorder frequently resulting in disturbed GI motility. Although, especially early in the disease, symptomatic improvement is achieved with prokinetic agents, more severe GI manifestations of scleroderma may be difficult to treat, leading to parenteral feeding and hospitalization. Recently, a new serotonin (5-HT4) receptor agonist prucalopride was shown to have remarkable prokinetic properties, resulting in symptomatic improvement and increased frequency of defecation in patients with chronic functional constipation. Here we report two cases of scleroderma with GI manifestation in which previous prokinetic treatment failed, but where the patients were successfully treated with prucalopride. Our data suggest that prucalopride may be a promising and effective drug to treat GI motility disorders in scleroderma. However, further placebo-controlled double blind studies are needed for full documentation of the usefulness of prucalopride in patients with scleroderma.

Topics: Adult; Benzofurans; Female; Follow-Up Studies; Gastrointestinal Agents; Gastrointestinal Diseases; Gastrointestinal Motility; Gastrointestinal Transit; Humans; Manometry; Middle Aged; Scleroderma, Systemic; Treatment Outcome

We aimed to study 5-HT(4) receptors in canine stomach contractility both in vivo and in vitro. In anaesthetized Beagle dogs, the selective 5-HT(4) receptor agonist prucalopride (i.v.) induced dose-dependent tonic stomach contractions under isobaric conditions, an effect that was antagonized by the selective 5-HT(4) receptor antagonist GR 125487 (10 microg kg(-1), i.v.). Electrical field stimulation (EFS) of corpus longitudinal muscle strips resulted in atropine- and tetrodotoxin-sensitive contractions (L-NOARG (0.1 mM) present in all organ bath solutions). Prucalopride increased these contractions (maximal response after single-dose addition (0.3 microM): 165% of initial value, or after cumulative addition: 188%). In the presence of methysergide (3 microM), 5-HT also increased EFS-contractions (after single-dose addition (0.3 microM): increase to 192%, after cumulative addition: 148%). The selective 5-HT(4) receptor antagonists GR 113808 (0.1 microM) or GR 125487 (10 nM) antagonized the prucalopride (0.3 microM)-induced contraction increments. When EFS-induced contractions were blocked by atropine or tetrodotoxin, prucalopride was ineffective. In the presence of methysergide (3 microM), the contraction increases to 5-HT (0.3 microM) were prevented by GR 113808 (0.1 microM). The prucalopride curve (pEC(50) 7.9) was shifted in parallel to the right by GR 113808 3 nM (pA(2) 9.4). In the presence of methysergide (3 microM), the curve to 5-HT (pEC(50) 8.1) was competitively antagonized by GR 113808, yielding a Schild slope of 0.8+/-0.2 (pK(B) of 9.1 with unit Schild slope). In corpus circular muscle strips, the prucalopride (0.3 microM)-induced augmentation of EFS-contractions (258%) was also prevented by GR 113808 (0.1 microM) (124%). In conclusion, the effects of 5-HT(4) receptor agonists on proximal stomach motor activity in vivo can be explained by an effect on 5-HT(4) receptors on cholinergic nerves within the gastric muscle wall.

Topics: Animals; Benzofurans; Dogs; Electric Stimulation; Female; In Vitro Techniques; Indoles; Manometry; Muscle Contraction; Muscle, Smooth; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Stomach; Sulfonamides

Prucalopride is a novel enterokinetic compound and is the first representative of the benzofuran class. We set out to establish its pharmacological profile in various receptor binding and organ bath experiments. Receptor binding data have demonstrated prucalopride's high affinity to both investigated 5-HT(4) receptor isoforms, with mean pK(i) estimates of 8.60 and 8.10 for the human 5-HT(4a) and 5-HT(4b) receptor, respectively. From the 50 other binding assays investigated in this study only the human D(4) receptor (pK(i) 5.63), the mouse 5-HT(3) receptor (pK(i) 5.41) and the human sigma(1) (pK(i) 5.43) have shown measurable affinity, resulting in at least 290-fold selectivity for the 5-HT(4) receptor. Classical organ bath experiments were done using isolated tissues from the rat, guinea-pig and dog gastrointestinal tract, using various protocols. Prucalopride was a 5-HT(4) receptor agonist in the guinea-pig colon, as it induced contractions (pEC(50)=7.48+/-0.06; insensitive to a 5-HT(2A) or 5-HT(3) receptor antagonist, but inhibited by a 5-HT(4) receptor antagonist) as well as the facilitation of electrical stimulation-induced noncholinergic contractions (blocked by a 5-HT(4) receptor antagonist). Furthermore, it caused relaxation of a rat oesophagus preparation (pEC(50)=7.81+/-0.17), in a 5-HT(4) receptor antagonist sensitive manner. Prucalopride did not cause relevant inhibition of 5-HT(2A), 5-HT(2B), or 5-HT(3), motilin or cholecystokinin (CCK(1)) receptor-mediated contractions, nor nicotinic or muscarinic acetylcholine receptor-mediated contractions, up to 10 microM. It is concluded that prucalopride is a potent, selective and specific 5-HT(4) receptor agonist. As it is intended for treatment of intestinal motility disorders, it is important to note that prucalopride is devoid of anti-cholinergic, anticholinesterase or nonspecific inhibitory activity and does not antagonise 5-HT(2A), 5-HT(2B) and 5-HT(3) receptors or motilin or CCK(1) receptors.

Topics: Acetylcholine; Animals; Benzofurans; Binding, Competitive; Carbachol; Cell Line; CHO Cells; Colon; Cricetinae; Dioxanes; Dogs; Dose-Response Relationship, Drug; Electric Stimulation; Esophagus; Female; Gallbladder; Gastrointestinal Agents; Granisetron; Guinea Pigs; Humans; Ileum; In Vitro Techniques; Indoles; Indomethacin; Male; Motilin; Muscle Contraction; Piperidines; Rabbits; Rats; Rats, Wistar; Receptors, Cholecystokinin; Receptors, Dopamine D2; Receptors, Dopamine D4; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sincalide; Stomach; Sulfonamides; Vasodilator Agents

The serotonin 5-HT(4) receptor has recently gained a lot of attention for its functional roles in central processes such as memory and cognition. In this study, we show that activation of the human 5-HT(4) (h5-HT(4)) receptor stimulates the secretion of the non-amyloidogenic soluble form of the amyloid precursor protein (sAPPalpha). 5-HT enhanced the level of secreted sAPPalpha in a time- and dose-dependent manner in Chinese hamster ovary cells stably expressing the h5-HT(4(e)) receptor isoform. The increase was inhibited by the selective 5-HT(4) receptor antagonist, GR113808. The 5-HT(4) selective agonists, prucalopride and renzapride, also increased secreted sAPPalpha in IMR32 human neuroblastoma cells. The stimulatory effect of 5-HT was mimicked by forskolin, a direct activator of adenylyl cyclase, and 8-bromo-cAMP, a membrane-permeant cAMP analogue. On the contrary, inhibition of protein kinase A (PKA) by H89 potentiated the 5-HT-induced increase in both secreted and cellular sAPPalpha. This phenomenon involves a novel PKA-independent stimulatory process that overcomes a PKA-dependent inhibitory one. Finally, activation of the h5-HT(4(e)) receptor did not modify extracellular amyloid beta-protein in Chinese hamster ovary cells transfected with the human APP695. Given the neuroprotective and enhancing memory effects of sAPPalpha, our results may open a new avenue for the treatment of Alzheimer's disease.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Adenylyl Cyclases; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Benzamides; Benzofurans; Blotting, Western; Bridged Bicyclo Compounds, Heterocyclic; CHO Cells; Colforsin; Cricetinae; Cyclic AMP-Dependent Protein Kinases; Dose-Response Relationship, Drug; Humans; Indoles; Ligands; Memory; Polymerase Chain Reaction; Protein Binding; Protein Isoforms; Radioimmunoassay; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Serotonin; Sulfonamides; Time Factors; Transfection; Tumor Cells, Cultured

The novel enterokinetic drug prucalopride was tested at various intravenous and oral doses in fasted dogs to assess: (i) the effects on colonic contractile motility patterns; and (ii) the mediation of these effects by 5-hydroxytryptamine (5-HT4) receptors. Colonic motility patterns were assessed in conscious dogs with four chronically implanted strain-gauge force transducers that were sutured on the serosal side of the colon. Prucalopride altered colonic contractile motility patterns in a dose-dependent fashion by stimulating high-amplitude clustered contractions in the proximal colon and by inhibiting contractile activity in the distal colon. Prucalopride was equipotent after oral and intravenous administration, as reflected by the values for the effective dose that induced 50% of maximum effect (95% confidence limits): 0.04 mg kg(-1) p.o. (0.01-0.1 mg kg(-1)) and 0.01 mg kg(-1) i.v. (0.006-0.04 mg kg(-1)). Prucalopride also caused a dose-dependent decrease in the time to the first giant migrating contraction (GMC); at higher doses of prucalopride, the first GMC generally occurred within the first half-hour after treatment. Subcutaneous pretreatment with the 5-HT4 receptor antagonist GR125487 (40 microg kg(-1) bodyweight) completely prevented the effects of orally administered prucalopride (0.31 mg kg(-1) bodyweight). Prucalopride, given orally or intravenously, alters colonic motility in the fasted conscious dog in a dose-dependent fashion. It induces GMCs and causes proximal colon stimulation and distal colon inhibition of contractile motility patterns by stimulating 5-HT4 receptors.

Topics: Administration, Oral; Animals; Benzofurans; Colon; Dogs; Dose-Response Relationship, Drug; Fasting; Female; Gastrointestinal Agents; Gastrointestinal Motility; Indoles; Injections, Intravenous; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Serotonin Antagonists; Sulfonamides

Agonists of the serotonin 5-hydroxytryptamine 4 (5-HT4) receptor are widely used to activate motility in the gastrointestinal tract. Among these, cisapride was recently withdrawn from the U.S. market because of its proarrhythmic effects. Cisapride is a potent blocker of human ether-à-gogo (HERG) K(+) channels and prolongs the cardiac action potential in a reverse use dependence manner. We compared the effects of four different 5-HT4 receptor agonists (cisapride, prucalopride, renzapride and mosapride) on cloned HERG channels with the objective to evaluate and compare their proarrhythmic potential. K(+) currents from HERG-transfected COS-7 cells were recorded under physiological conditions using the whole cell configuration of the patch-clamp technique. Short (500 ms) depolarizing prepulses were used and following deactivating HERG currents were measured. Cisapride inhibited the HERG channels in a concentration-dependent manner with an IC(50) of 2.4 10(-7) M. The IC(50) value for prucalopride to block HERG (5.7 10(-6) M) was 20-fold higher than that of cisapride. Renzapride was slightly more potent than prucalopride (IC(50) = 1.8 10(-6) M). Mosapride produced no significant effects on the recombinant HERG current. The voltage dependence of HERG block was also investigated. The block mediated by cisapride or renzapride was voltage-dependent whereas that produced by prucalopride was not. We conclude that the rank order of potency of 5-HT4 agonists to block HERG is cisapride > renzapride > prucalopride > mosapride. We also conclude that 5-HT4 agonists devoid of side effects on the HERG current such as mosapride can be found as a safe alternative to cisapride.

Topics: Animals; Arrhythmias, Cardiac; Benzamides; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Cation Transport Proteins; Cisapride; DNA-Binding Proteins; Electrophysiology; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Gastrointestinal Agents; Glycosaminoglycans; Humans; Morpholines; Potassium Channels; Potassium Channels, Voltage-Gated; Recombinant Proteins; Serotonin Antagonists; Trans-Activators; Transcriptional Regulator ERG

The anatomical localization of 5-HT(4) receptor mRNA and 5-HT(4) receptor protein was examined in sections of post-mortem human brain by in situ hybridization histochemistry and radioligand receptor autoradiography. In the in situ hybridization study, the highest levels of 5-HT(4) receptor mRNA were found in caudate nucleus, putamen, nucleus accumbens, and in the hippocampal formation. No 5-HT(4) receptor mRNA was detected in globus pallidus and substantia nigra. For receptor autoradiography, two new and highly selective radioligands were compared: [(3)H]prucalopride, which preferentially labels the G-protein coupled fraction of receptors, and [(3)H]R116712, which labels the entire receptor population at subnanomolar concentrations. [(3)H]Prucalopride and [(3)H]R116712 binding was performed on human brain hemisphere sections. The highest densities for both radioligands were found in the basal ganglia (caudate nucleus, putamen, nucleus accumbens, globus pallidus, substantia nigra). Moderate to low densities were detected in the hippocampal formation and in the cortical mantle. Mismatches between 5-HT(4) receptor mRNA and binding sites in the globus pallidus and the substantia nigra suggested that the binding sites may be localized on axonal projections originating from the striatum. To compare densities of binding sites, concentration binding curves with [(3)H]prucalopride, [(3)H]R116712 and [(3)H]GR113808 were performed on membranes from homogenates of several human brain regions. Comparison of B(max)-values obtained with [(3)H]prucalopride and [(3)H]R116712 indicated that the G-protein coupled fraction of 5-HT(4) receptors in the substantia nigra was exceptionally high (54%) in comparison with percentages (16-27%) found in the frontal cortex, the striatum and the hippocampus. Such a high percentage (40%) of [(3)H]prucalopride vs. [(3)H]R116712 binding was also observed in the substantia nigra in the receptor autoradiography experiments. The [(3)H]prucalopride binding was GppNHp-sensitive, whereas [(3)H]R116712 and [(3)H]GR113808 was not. These data indicate that in the substantia nigra 5-HT(4) receptors are more strongly coupled to their signal transduction pathway than in other brain regions.

Topics: Aged; Autoradiography; Benzofurans; Binding Sites; Brain; Brain Chemistry; Brain Mapping; Female; GTP-Binding Proteins; Humans; In Situ Hybridization; Indoles; Kinetics; Ligands; Male; Membranes; Middle Aged; Nerve Tissue Proteins; Radioligand Assay; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; RNA, Messenger; Serotonin Antagonists; Serotonin Receptor Agonists; Sulfonamides

Topics: Benzofurans; Carbolines; Colonic Diseases, Functional; Female; Gastrointestinal Agents; Guanidines; Humans; Indoles; Male; Serotonin Antagonists