td-5108 and Chronic-Disease

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 The first-generation 5-HT 4 agonists were initially withdrawn from use owing to associations with serious cardiovascular (CV) events.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

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

Topics: Chronic Disease; Constipation; Cost-Benefit Analysis; Gastrointestinal Agents; Humans; Laxatives; Serotonin 5-HT4 Receptor Agonists

Constipation is common in patients with Parkinson's disease (PD). Due to the considerable negative outcomes of constipation, significant efforts have been made to prevent and manage chronic constipation in these patients.. Herein, the authors review some of the known pathophysiological causes for slow gastrointestinal (GI) transit in PD patients and the different pharmacological options. All relevant clinical and experimental data found through online databases were included. Bulking agents, osmotic and stimulant laxatives, chloride channel activators, ghrelin agonists, 5-HT4 receptor agonists, and probiotics are some of the proposed medicinal agents. of the authors further review the evidence on alpha-synuclein and botulinum neurotoxin in these patients. It should be noted, however, that some of these interventions are required to be further validated.. Reduction of GI transit and dysfunction of the anorectum is obvious in PD, affecting the incidence of constipation and thus, quality of life (QOL). Furthermore, due to an inadequate and delayed absorption of oral anti PD medications, dose adjustments and changes in the route of administration are recommended.

Topics: Chronic Disease; Constipation; Dose-Response Relationship, Drug; Gastrointestinal Transit; Humans; Laxatives; Parkinson Disease; Probiotics; Quality of Life; Serotonin 5-HT4 Receptor Agonists

Chronic constipation (CC) is a recurrent functional bowel disorder worldwide. The purpose of this study is to examine its pooled placebo response rate and compare placebo response level in randomized controlled trials (RCTs) with different endpoint assessments.. PubMed, Cochrane Library, and Embase were electronically searched for therapeutic RCTs of CC with placebo control. Data extraction and assessment of risk of bias were performed independently by 2 reviewers. All the statistical calculation and analysis were performed using R 3.6.0. Our protocol has registered in PROSPERO with registration number: CRD42019121287.. There were 46 studies included with 5,992 constipated patients allocated to the placebo arm in total. The pooled placebo response rate was 28.75% (95% confidence interval: 23.83%-33.67%) with significant heterogeneity among trials ((Equation is included in full-text article.)= 93.6%). Treatment efficacy assessed using subjective improvement had a significantly higher placebo response rate than that assessed with improvement in complete (spontaneous) bowel movements or composite improvement (41.40% vs 18.31% or 20.35%, P < 0.001). According to the results of meta-regression, active treatment and endpoint assessment were most likely to lead to the huge heterogeneity among studies.. Patients with CC have significant response level to placebo. Based on findings in this study, we do not recommend subjective improvement as endpoint while designing therapeutic RCTs for chronic constipated patients.

Topics: Chronic Disease; Constipation; Cross-Over Studies; Dietary Supplements; Humans; Laxatives; Outcome Assessment, Health Care; Placebo Effect; Placebos; Randomized Controlled Trials as Topic; Serotonin 5-HT4 Receptor Agonists

Constipation is a common functional problem of the digestive system and may occur secondary to diet, drugs, endocrine diseases, metabolic diseases, neurological diseases, psychiatric disorders, or gastrointestinal obstruction. When there is no secondary cause, constipation is diagnosed as functional constipation. The first steps that should be taken to relieve symptoms are diet and lifestyle modifications, and if unsuccessful, laxative therapy should be initiated. If a patient does not respond to laxative therapy, diagnostic anorectal physiological tests are performed, though they are not routinely recommended. However, these tests may be considered earlier in patients strongly suspected to have a defecatory disorder. The revised guideline on the diagnosis and treatment of chronic constipation will undoubtedly aid the individualized management of chronic constipation in clinical practice.

Topics: Biofeedback, Psychology; Chronic Disease; Constipation; Diet; Digital Rectal Examination; Humans; Laxatives; Life Style; Serotonin 5-HT4 Receptor Agonists

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

The aim of this review is to provide an overview of the clinical assessment and evidence-based treatment options for managing diabetes-associated chronic constipation.. A literature search of published medical reports in English language was performed using the OVID Portal, from PUBMED and the Cochrane Database of Systematic Reviews, from inception to October 2015. A total of 145 abstracts were identified; duplicate publications were removed and 95 relevant full-text articles were retrieved for potential inclusion.. Chronic constipation is one of the most common gastrointestinal symptoms in patients with diabetes, and occurs more frequently than in healthy individuals. Treatment goals include improving symptoms and restoring bowel function by accelerating colonic transit and facilitating defecation. Based on guidelines and data from published literature, food and dietary change with exercise and lifestyle change should be the first step in management. For patients recalcitrant to these changes, laxatives should be the next step of treatment. Treatment should begin with bulking agents such as psyllium, bran or methylcellulose followed by osmotic laxatives if response is poor. Lactulose, polyethylene glycol and lactitol are the most frequently prescribed osmotic agents. Lactulose has a prebiotic effect and a carry-over effect (continued laxative effect for at least 6 to 7 days, post cessation of treatment). Stimulants such as bisacodyl, sodium picosulphate and senna are indicated if osmotic laxatives are not effective. Newer agents such as chloride-channel activators and 5-HT4 agonist can be considered for severe or resistant cases.. The primary aim of intervention in diabetic patients with chronic constipation is to better manage the diabetes along with management of constipation. The physician should explain the rationale for prescribing laxatives and educate patients about the potential drawbacks of long-term use of laxatives. They should contact their physician if short-term use of prescribed laxative fails to provide relief.

Topics: Bisacodyl; Chloride Channel Agonists; Chronic Disease; Citrates; Constipation; Diabetes Complications; Dietary Fiber; Evidence-Based Medicine; Exercise Therapy; Healthy Lifestyle; Humans; Laxatives; Methylcellulose; Organometallic Compounds; Picolines; Psyllium; Senna Extract; 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

Chronic constipation is a frequent complaint in daily clinical practice. Notwithstanding the availability of numerous drugs, its treatment it is still unsatisfactory. However, new emerging treatments are in the pipeline and some drugs seem to be promising; among these velusetrag, a selective 5-HT4 receptors agonist.. An in depth Medline literature search was performed concerning topics related to the treatment of constipated patients with velusetrag. In addition, abstracts concerning the topic were searched by hand in our libraries.. After analyzing the available data, the authors feel that velusetrag may likely improve symptoms and the quality of life of chronically constipated subjects. However, additional data is needed to fully understand the safety and efficacy of velusetrag, particularly in patients on long-term therapy. Thanks to the once-daily dosing and the pharmacologic properties, velusetrag could be used as a single agent or in association with other drugs. In the future, this drug holds the potential to be an effective adjunct to the therapeutic armamentarium for chronic constipation.

Topics: Animals; Azabicyclo Compounds; Chronic Disease; Constipation; Humans; Quality of Life; Serotonin 5-HT4 Receptor Agonists

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

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

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

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

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

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

Chronic constipation is a very common clinical problem with its prevalence of up to 14% in the general population. It is not a life-threatening disease, but since patient's satisfaction to the treatment is known to be as low as 50%, chronic constipation still remains a clinically challenging problem. Fortunately, many new treatments have been introduced or are to be introduced in the near future. This article will review the basic concepts and the results of recent studies on the new treatments for chronic constipation.

Topics: Chloride Channel Agonists; Chronic Disease; Constipation; Humans; Laxatives; Polyethylene Glycols; Prevalence; Probiotics; Serotonin 5-HT4 Receptor Agonists

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

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

The present review has several objectives, the first of which is to review the pharmacology and selectivity of serotonergic agents to contrast the older serotonergic agents (which were withdrawn because of cardiac or vascular adverse effects) with the newer generation serotonin receptor subtype 4 agonists. Second, the chloride ion secretagogues that act through the guanylate cyclase C receptor are appraised and their pharmacology is compared with the approved medication, lubiprostone. Third, the efficacy and safety of the application of bile acid modulation to treat constipation are addressed. The long-term studies of surgically induced excess bile acid delivery to the colon are reviewed to ascertain the safety of this therapeutic approach. Finally, the new drugs for opiate-induced constipation are introduced. Assuming these drugs are approved, practitioners will have a choice; however, patient responsiveness will be based on trial and error. Nevertheless, the spectrum of mechanisms and demonstrated efficacy and safety augur well for satisfactory treatment outcomes.

Topics: Alprostadil; Bile Acids and Salts; Chloride Channels; Chronic Disease; Constipation; Gastrointestinal Agents; Humans; Indoles; Lubiprostone; Organic Anion Transporters, Sodium-Dependent; Peptides; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Serotonin Agents; Symporters

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

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

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

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

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

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

Constipation is a common gastrointestinal disease affecting 2-27% of the population in Western hemisphere. Approximately in half of patients the diagnosis of functional constipation is made after having ruled out secondary causes. Treatment of chronic functional constipation primarily addresses education on toilet habits, dietary advice, and patient reassurance. Further therapies are guided according to functional subtype slow-transit constipation, dyssynergic defecation, and constipation-predominant irritable bowel syndrome (IBS-C). Traditionally, the pharmacologic treatment of constipation uses primarily bulking agents and/or laxatives (osmotic or secretory). However, often these therapies do not provide the desired improvement, have a short-lived efficacy and/or are accompanied by side-effects such as bloating and abdominal cramps. Thus, there is a clinical need for new, more potent drugs particularly for patients who are not satisfactorily treated by conventional therapies. This review discusses recent developments in the pharmacologic treatment of chronic constipation including recently FDA-approved lubiprostone, emerging 5-HT receptors modifiers, investigational substances, and probiotics.

Topics: Alprostadil; Animals; Chronic Disease; Constipation; Drug Therapy; Drugs, Investigational; Humans; Irritable Bowel Syndrome; Lubiprostone; Probiotics; Serotonin 5-HT4 Receptor Agonists

Topics: Cathartics; Chronic Disease; Constipation; Humans; Life Style; Patient Education as Topic; Serotonin 5-HT4 Receptor Agonists; Serotonin Agents

Topics: Adult; Area Under Curve; Asian People; Chronic Disease; Constipation; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Male; Middle Aged; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; 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

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

Velusetrag is an orally active 5-HT(4) receptor agonist of potential benefit in treating chronic idiopathic constipation.. To evaluate the efficacy, safety and tolerability of velusetrag in chronic idiopathic constipation.. After a 2-week baseline period, patients [<3 spontaneous bowel movements (SBM)/week] received placebo or velusetrag (15, 30 or 50 mg) daily for 4 weeks in a randomized, double-blind design, followed by a 1-week follow-up period. The primary endpoint was the change from baseline in weekly SBM frequency averaged over the 4-week treatment period.. Patients receiving velusetrag (15, 30 and 50 mg) achieved statistically and clinically significant increases in weekly SBM frequency relative to those receiving placebo. Mean increases were 3.6, 3.3 and 3.5 SBM/week respectively, compared with 1.4 SBM/week for placebo (P < 0.0001). Statistically significant increases in the weekly frequency of complete SBM (CSBM) were also reported (mean increases of 2.3, 1.8 and 2.3 for 15, 30 and 50 mg velusetrag respectively, compared with 0.6 for placebo). Common adverse events associated with velusetrag were diarrhoea, headache, nausea and vomiting, generally occurring during the initial days of dosing.. Velusetrag was efficacious and well tolerated in patients with chronic idiopathic constipation (ClinicalTrials.gov identifier NCT00391820).

Topics: Adult; Azabicyclo Compounds; Chronic Disease; Constipation; Defecation; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Male; Middle Aged; Serotonin 5-HT4 Receptor Agonists; Statistics as Topic; 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

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

To evaluate the potential role of tegaserod in the management of functional dyspepsia (FD) and gastroesophageal reflux disease (GERD) in patients with chronic constipation and to determine the possible efficacy of tegaserod on solid-phase gastric emptying and gastric hypersensitivity.. This was an exploratory open-label trial of tegaserod therapy for dyspepsia and reflux symptoms in patients with chronic constipation. The study cohort consisted of 90 patients randomized to three treatment groups for a study period of 4 weeks (tegaserod 6 mg, twice daily; esomeprazole 40 mg, once daily; tegaserod 6 mg, twice daily plus esomeprazole 40 mg, once daily). Twenty healthy volunteers provided control values. Clinical symptoms were evaluated by one of the investigators using a Gastrointestinal Symptom Rating Scale (GSRS). Solid-phase gastric emptying and colonic transit were measured by the radiopaque barium marker method, and the water load test (WLT) was used to evaluate gastric sensation and the function of proximal stomach. The proportions of patients with complete relief of epigastric pain /discomfort, epigastric fullness, early satiety and heartburn in the tegaserod group and the tegaserod plus esomeprazole group were compared with the esomeprazole group, respectively.. The mean global gastrointestinal (GI) scores of all three treatment groups reported using the GSRS showed the same trend, with decreasing scores over the 4-week study period indicating a reported decreasing severity of symptoms that was significantly different from baseline values. Patients in the tegaserod plus esomeprazole group reported the lowest global GI scores after 4 weeks, as expected. Solid-phase gastric emptying (GER) and colonic transit (CTT) increased significantly in the tegaserod 6 mg twice daily group compared with baseline. These parameters did not change in the esomeprazole group at week 4 compared with baseline. In terms of gastric sensation, in the tegaserod group, the proportions of patients with hypersensitivity of the first perception threshold did not change at week 2 or week 4 compared with baseline; however, in this group and in the tegaserod plus esomeprazole group, the proportions of patients with hypersensitivity of discomfort threshold decreased significantly at week 4 compared with baseline. In the esomeprazole group, there were no changes in the proportions of patients with hypersensitivity of the first perception threshold and discomfort threshold at week 2 or 4 compared with baseline. No severe adverse events were recorded, and the medications were in general well-tolerated.. Tegaserod is effective and safe at improving dyspepsia and reflux symptoms in patients with chronic constipation, and tegaserod plus esomeprazole is superior to esomeprazole alone in the resolution of epigastric pain/discomfort and heartburn.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analysis of Variance; Anti-Ulcer Agents; Chronic Disease; Cohort Studies; Constipation; Drug Therapy, Combination; Dyspepsia; Esomeprazole; Female; Gastric Emptying; Gastroesophageal Reflux; Gastrointestinal Transit; Heartburn; Humans; Indoles; Male; Middle Aged; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome

Polyethylene glycol (PEG) 3350 (MiraLax) and tegaserod (Zelnorm), a serotonin subtype 4 receptor partial agonist, are currently approved for treatment of constipation. This study was designed to compare the efficacy of each product over a 4-wk treatment period.. Study patients who met defined criteria for chronic constipation were randomized in this open-labeled, parallel, multicenter study to receive the PEG laxative as a single daily dose of 17 g or tegaserod tablets 6 mg b.i.d., for 28 days. As a primary end point, treatment success was defined for each patient as relief of modified ROME criteria for constipation for 50% or more of their treatment weeks. Various secondary measures were also assessed. An interactive voice response system (IVRS) recorded patient reported daily bowel movement experience and study efficacy and safety information.. A total of 237 patients were enrolled and received treatment at one of 25 centers. Successful treatment according to the primary end point was seen in 50.0% of the PEG and 30.8% of tegaserod patients (P= 0.003). By treatment weeks 3 and 4, significantly more PEG patients were successfully treated according to primary and secondary response definitions. PEG patients experienced more bowel movements per week (P= 0.019) and had significantly greater improvement in constipation symptoms (P= 0.016) based on results from a validated patient self-reported questionnaire. Tegaserod patients experienced a significantly higher incidence of headaches. Otherwise, there were no significant differences in adverse events.. While PEG laxative and tegaserod are safe for their intended use in chronic constipation, PEG had superior efficacy, caused fewer headaches, and produced greater improvement of constipation symptoms.

Topics: Adult; Aged; Aged, 80 and over; Cathartics; Chronic Disease; Constipation; Female; Gastrointestinal Agents; Humans; Indoles; Male; Middle Aged; Polyethylene Glycols; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome

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

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

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

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

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

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

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

Despite the evidence that the hyperpolarization-activated current (If) is highly modulated in human cardiomyopathies, no definite data exist in chronic atrial fibrillation (cAF). We investigated the expression, function, and modulation of If in human cAF.. Right atrial samples were obtained from sinus rhythm (SR, n = 49) or cAF (duration >1 year, n = 31) patients undergoing corrective cardiac surgery. Among f-channel isoforms expressed in the human atrium (HCN1, 2 and 4), HCN4 mRNA levels measured by RT-PCR were significantly reduced. However, protein expression was preserved in cAF compared to SR (+85% for HCN4); concurrently, miR-1 expression was significantly reduced. In patch-clamped atrial myocytes, current-specific conductance (gf) was significantly increased in cAF at voltages around the threshold for If activation (-60 to -80 mV); accordingly, a 10-mV rightward shift of the activation curve occurred (P < 0.01). β-Adrenergic and 5-HT4 receptor stimulation exerted similar effects on If in cAF and SR cells, while the ANP-mediated effect was significantly reduced (P < 0.02), suggesting downregulation of natriuretic peptide signaling.. In human cAF modifications in transcriptional and posttranscriptional mechanisms of HCN channels occur, associated with a slight yet significant gain-of-function of If , which may contribute to enhanced atrial ectopy.

Topics: Action Potentials; Adrenergic beta-Agonists; Adult; Aged; Aged, 80 and over; Atrial Fibrillation; Atrial Natriuretic Factor; Chronic Disease; Female; Heart Atria; Humans; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Male; MicroRNAs; Middle Aged; Muscle Proteins; Potassium Channels; RNA Processing, Post-Transcriptional; RNA, Messenger; Serotonin 5-HT4 Receptor Agonists; Transcription, Genetic

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

Utilization of Theravance's multivalent approach to drug discovery towards 5-HT(4) receptor agonists with a focus on identification of neutral (non-charged at physiological pH) secondary binding groups is described. Optimization of a quinolone-tropane primary binding group with a chiral 2-propanol linker to a range of neutral secondary binding group motifs, for binding affinity and functional potency at the 5-HT(4) receptor, selectivity over the 5-HT(3) receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, afforded velusetrag (TD-5108). Velusetrag has achieved proof-of-concept in patients with chronic idiopathic constipation.

Topics: Animals; Azabicyclo Compounds; Chronic Disease; Constipation; Drug Discovery; Guinea Pigs; Humans; Molecular Structure; Rats; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Structure-Activity Relationship

Respiratory depression is the most well-known and dangerous side-effect of opioid analgesics. Clinical investigations have revealed that this opioid-induced respiratory depression is less severe in patients with chronic pain, but the mechanisms that underlie this phenomenon are unknown. Therefore, the present study was designed to examine the influence of chronic pain on morphine-induced respiratory depression. Respiration was detected by double-chamber, flow-through whole-body plethysmography. Respiratory frequency was dose-dependently and significantly decreased after morphine administration. This effect peaked at 30 min after administration and lasted 3 h. In contrast, tidal volume was increased. Minute volume was significantly decreased by morphine at a higher dose, but not a lower dose. In nerve-ligated mice, a morphine-induced decrease in respiratory frequency was observed, whereas the increase of tidal volume was more prominent. A decrease in minute volume was not observed in nerve-ligated mice. This attenuation of the morphine-induced decrease in minute volume in nerve-ligated mice was reversed by treatment with the serotonin (5-HT)4a receptor antagonist GR125487. Moreover, treatment with the 5-HT4 receptor agonist mosapride antagonized the morphine-induced decrease in minute volume, due to the enhancement of tidal volume. Finally, the expression of 5-HT4a receptor in the brainstem was enhanced in nerve-ligated mice compared to that in sham-operated mice. These results suggest that the decrease in morphine-induced respiratory depression under chronic pain is mediated by the enhancement of 5-HT4a receptor systems in the brainstem.

Topics: Analgesics, Opioid; Animals; Benzamides; Brain Stem; Chronic Disease; Indoles; Ligation; Male; Mice; Mice, Inbred ICR; Morphine; Morpholines; Pain; Peripheral Nervous System Diseases; Receptors, Serotonin, 5-HT4; Respiration; Respiratory Insufficiency; Sciatic Nerve; Serotonin 5-HT4 Receptor Agonists; Serotonin 5-HT4 Receptor Antagonists; Sulfonamides

Topics: Chronic Disease; Constipation; Humans; Randomized Controlled Trials as Topic; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome

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

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

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

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

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

Distension-evoked reflex of rectorectal (R-R) contractions and rectointernal anal sphincter (R-IAS) relaxations can be generated in guinea pigs through an extrinsic sacral excitatory neural pathway (pelvic nerves) as well as intrinsic cholinergic excitatory and nitrergic inhibitory pathways. The aim of the present study was to create intrinsic R-R and R-IAS reflex models by pithing (destruction of the lumbar and sacral cords; PITH) and to evaluate whether the prokinetic benzamide mosapride, a 5-HT(4) receptor agonist, enhances these reflexes. The mechanical activities of the R-R and R-IAS were recorded in the anesthetized guinea pig on days 2-9 after PITH. Although the basal rectal pressure at distension after PITH was significantly lower than control, the reflex indexes of R-R contractions and synchronous R-IAS relaxations were unchanged between days 4 and 9 after PITH. The frequency of spontaneous rectal and IAS motility were also unchanged. Immunohistochemical studies revealed that the distribution of myenteric and intramuscular interstitial cells of Cajal (ICC) were not altered after PITH. Mosapride (0.1-1.0 mg/kg iv) dose-dependently increased both intrinsic R-R (maximum: 1.82) and R-IAS reflex indexes (maximum: 2.76) from control (1.0) 6-9 days after PITH. The 5-HT(4) receptor antagonist, GR-113808 (1.0 mg/kg iv) decreased the R-R and R-IAS reflex indexes by approximately 50% and antagonized the effect of mosapride (1.0 mg/kg iv). The present results indicate that mosapride moderately enhanced intrinsic R-R and R-IAS reflexes functionally compensated after deprivation of extrinsic nerves, mediated through endogenously active intrinsic 5-HT(4) receptors.

Topics: Acute Disease; Anal Canal; Animals; Benzamides; Chronic Disease; Denervation; Disease Models, Animal; Gastrointestinal Agents; Gastrointestinal Motility; Guinea Pigs; Indoles; Male; Morpholines; Rectum; Reflex; Serotonin 5-HT4 Receptor Agonists; Serotonin 5-HT4 Receptor Antagonists; Serotonin Antagonists; Spinal Cord Injuries; Sulfonamides