ABSTRACT
INTRODUCTION: This real-world US-based claims study compared constipation-related symptoms and complications 6 months before and after prucalopride initiation in adults with chronic idiopathic constipation (CIC). METHODS: This observational, retrospective cohort analysis used the IBM MarketScan Commercial Claims and Encounters Database and the Medicare Supplemental Database (January 2015-June 2020). Prucalopride-treated patients (≥18 years old) who had ≥1 constipation-related International Classification of Diseases, Tenth Revision, Clinical Modification ( ICD-10-CM ) diagnosis code during the baseline or study period were included. The proportions of patients with constipation-related symptoms (abdominal pain, abdominal distension [gaseous], incomplete defecation, and nausea) and constipation-related complications (anal fissure and fistula, intestinal obstruction, rectal prolapse, hemorrhoids, perianal venous thrombosis, perianal/perirectal abscess, and rectal bleeding) were examined. Constipation-related symptoms and complications were identified using ICD-10-CM , ICD-10 - Procedure Coding System , or Current Procedural Terminology codes. Data were stratified by age (overall, 18-64 years, and ≥65 years). RESULTS: This study included 690 patients: The mean (SD) patient age was 48.0 (14.7) years, and 87.5% were women. The proportions of patients overall with constipation-related symptoms decreased 6 months after prucalopride initiation (abdominal pain [50.4% vs 33.3%, P < 0.001]; abdominal distension [gaseous] [23.9% vs 13.3%, P < 0.001]; and nausea [22.6% vs 17.7%, P < 0.01]; no improvements observed for incomplete defecation). Similarly, the proportions of patients overall with constipation-related complications decreased 6 months after prucalopride initiation (intestinal obstruction [4.9% vs 2.0%, P < 0.001]; hemorrhoids [10.7% vs 7.0%, P < 0.05]; and rectal bleeding [4.1% vs 1.7%, P < 0.05]). DISCUSSION: This study suggests that prucalopride may be associated with improved constipation-related symptoms and complications 6 months after treatment initiation.
Subject(s)
Benzofurans , Constipation , Humans , Constipation/drug therapy , Benzofurans/therapeutic use , Benzofurans/adverse effects , Female , Male , Middle Aged , Adult , United States/epidemiology , Retrospective Studies , Chronic Disease , Aged , Young Adult , Treatment Outcome , Adolescent , Abdominal Pain/drug therapy , Abdominal Pain/etiology , Serotonin 5-HT4 Receptor Agonists/therapeutic use , Serotonin 5-HT4 Receptor Agonists/adverse effects , Serotonin 5-HT4 Receptor Agonists/administration & dosageABSTRACT
BACKGROUND AND OBJECTIVE: SUVN-D4010 is a novel, potent, highly selective 5-HT4 partial agonist intended for the treatment of cognitive disorders. The objective of the clinical study was to characterize the safety, tolerability, and pharmacokinetics of SUVN-D4010 in healthy adults after single and multiple doses, and to evaluate the effect of food, sex, and age on the pharmacokinetics. METHODS: Single-ascending dose and multiple-ascending dose studies for 14 days were conducted in healthy adults using a randomized, double-blind design. The effects of food, sex, and age on SUVN-D4010 pharmacokinetics (25 mg single dose) were evaluated using an open-label, two-period, randomized, fed and fasted, crossover design. Pharmacokinetics and safety assessments were conducted throughout the study. RESULTS: SUVN-D4010 at a single dose up to 45 mg and multiple doses up to 40 mg once daily was found to be safe and well tolerated in healthy adults. The most frequently reported adverse events were headache and nausea. SUVN-D4010 exposure was dose proportional across the tested doses. Steady state was achieved on day 2 after once-daily dosing for 14 days. Food had no significant effect on the exposures but an increase in median time to attain the maximum plasma concentration (tmax) from 2 h in a fasted state to 3.5 h in fed state was observed. The maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) of SUVN-D4010 was 37% and 39%, respectively, lower in adult females compared to males following administration of a single 25 mg dose. In the elderly population, Cmax and AUC of SUVN-D4010 were 42% and 37%, respectively, lower compared to adult males following administration of a single 25 mg dose. SUVN-D4010 was well tolerated and safe in elderly subjects (≥ 65 years) following a single 25 mg dose. CONCLUSION: SUVN-D4010 was found to be safe and well tolerated in healthy human subjects. SUVN-D4010 followed linear pharmacokinetics across the dose range. Accumulation was in the range of 1.3- to 1.4-fold after multiple dosing. Renal excretion is not the major route of elimination. Food had no effect on the exposures but increased the tmax of SUVN-D4010. Exposures were lower in females and elderly subjects suggesting sex and age effects on the pharmacokinetics of SUVN-D4010 and possible dose adjustment in these populations. SUVN-D4010 was well tolerated and safe in elderly subjects after a single dose. Clinical trial identifiers: NCT02575482 and NCT03031574.
Subject(s)
Serotonin 5-HT4 Receptor Agonists/administration & dosage , Adult , Aged , Area Under Curve , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Male , Serotonin 5-HT4 Receptor Agonists/adverse effects , Serotonin 5-HT4 Receptor Agonists/pharmacokinetics , Young AdultABSTRACT
INTRODUCTION: Tegaserod, an orally active, potent 5-hydroxytryptamine-4 serotonin receptor agonist, was previously indicated for irritable bowel syndrome but was voluntarily withdrawn due to potential cardiovascular side effects. In vitro studies suggested that tegaserod increased platelet aggregation, but these results were not reproduced or were inconclusive. We sought to assess ex vivo effects of tegaserod on platelet aggregation. METHODS: In this double-blind, placebo-controlled, crossover study, we randomized a majority of healthy patients with no history of cardiovascular risk factors (n = 21) to receive tegaserod or matching placebo for 7 + 2 days followed by a 7- to 10-day washout period, and then patients were crossed over to the other study drug for the next 7 + 2 days. Unstimulated and agonist-stimulated platelet aggregation; P-selectin expression; serum thromboxane (Tx)B2 and urinary 11-dehydro (11-dh) TxB2; and tegaserod and M29.0 concentrations were serially assessed. RESULTS: There was no significant difference in percentage change in unstimulated or adenosine diphosphate (ADP)- and ADP + serotonin-, collagen- and thrombin receptor activating peptide-induced maximum platelet aggregation and in platelet P-selectin expression in the presence of tegaserod at any time point when compared to placebo. Similarly, there was no significant difference in percentage change in serum TxB2 or urinary 11-dhTxB2 levels between placebo and tegaserod. No new or unexpected findings were observed in evaluations of safety or pharmacokinetic parameters. CONCLUSION: This comprehensive pharmacodynamic study, by employing established markers used in prior investigations, which have been considered by the Food and Drug Administration to indicate drug-related platelet effects, does not demonstrate any influence of tegaserod treatment on platelet function.
Subject(s)
Blood Platelets/drug effects , Indoles/administration & dosage , Platelet Activation/drug effects , Serotonin 5-HT4 Receptor Agonists/administration & dosage , Administration, Oral , Adult , Blood Platelets/metabolism , Cross-Over Studies , Double-Blind Method , Female , Healthy Volunteers , Humans , Indoles/adverse effects , Indoles/pharmacokinetics , Male , Platelet Aggregation/drug effects , Platelet Function Tests , Serotonin 5-HT4 Receptor Agonists/adverse effects , Serotonin 5-HT4 Receptor Agonists/pharmacokinetics , Treatment Outcome , Young AdultABSTRACT
Minesapride is a novel 5-hydroxytryptamine 4 (5-HT4) receptor partial agonist that is expected to show efficacy in patients with irritable bowel syndrome with predominant constipation and functional constipation. An open-label study was conducted to evaluate pharmacokinetics (PK) and safety of minesapride. Japanese subjects, 12 elderly and 12 young, received a single oral dose of minesapride 40 mg/day in the fasted state. Metabolite profiles were also investigated in this clinical study and in an in vitro study using cryopreserved hepatocytes. Clinical results showed that minesapride was rapidly absorbed (Cmax: 2302.1 ng/mL in the elderly group, 2117.5 ng/mL in the young group), and the plasma concentration then decreased with half-life of approximately 7 h. There were no notable PK differences between elderly and young groups. No serious adverse events (AEs) were observed. The only AE that occurred in 2 or more subjects was diarrhea. Metabolite profiles in plasma and urine were similar between elderly and young groups. No major metabolites exceeded 10% of unchanged minesapride, and results of the in vitro study suggested that there were no human-specific metabolites. From the viewpoints of PK and metabolite profiling, no dose adjustment of minesapride is warranted in elderly population without renal or hepatic impairment.
Subject(s)
Hepatocytes/metabolism , Morpholines/pharmacokinetics , Piperidines/pharmacokinetics , Serotonin 5-HT4 Receptor Agonists/pharmacokinetics , Administration, Oral , Adult , Age Factors , Aged , Animals , Biotransformation , Dogs , Drug Partial Agonism , Female , Healthy Volunteers , Humans , Japan , Macaca fascicularis , Male , Mice , Models, Biological , Morpholines/administration & dosage , Morpholines/adverse effects , Patient Safety , Piperidines/administration & dosage , Piperidines/adverse effects , Rabbits , Rats, Sprague-Dawley , Risk Assessment , Serotonin 5-HT4 Receptor Agonists/administration & dosage , Serotonin 5-HT4 Receptor Agonists/adverse effects , Young AdultABSTRACT
BACKGROUND: Agonists of 5-hydroxytryptamine 4 receptor are potential agents for irritable bowel syndrome with predominant constipation (IBS-C). However, only tegaserod has been approved for a very limited population in the US. AIM: To evaluate the efficacy and safety of minesapride in patients with Rome IV defined IBS-C. METHODS: A double-blind, placebo-controlled, dose-finding study was performed. Overall, 411 patients were randomised to receive minesapride at 10, 20 or 40 mg/d, or placebo for 12 weeks. The primary endpoint was Food and Drug Administration (FDA) composite endpoint (responder: a patient who reported an increase in one or more complete spontaneous bowel movements from baseline and improvement of ≥30% from baseline in weekly average of worst abdominal pain score, both in the same week for ≥6/12 weeks). RESULTS: The FDA composite responder rate was 13.6% (14/103) in the placebo group, 13.6% (14/103) in the 10 mg group, 19.2% (20/104) in the 20 mg group and 14.9% (15/101) in the 40 mg group, and no dose-response relationship was found. A greater percentage of minesapride 40 mg-treated patients than placebo-treated patients met both responder requirements for ≥9/12 weeks as the stricter composite evaluation (P < 0.05). Furthermore, minesapride 40 mg significantly increased SBM frequency compared with placebo (adjusted P < 0.001 at Week 12). The most common adverse event was mild diarrhoea. CONCLUSIONS: Minesapride was safe and well-tolerated. Although the primary endpoint was negative, minesapride 40 mg is likely to improve the stricter composite endpoint and SBM frequency. Japan Pharmaceutical Information Center Number: Japic CTI-163459.
Subject(s)
Abdominal Pain/drug therapy , Constipation/drug therapy , Gastrointestinal Agents/therapeutic use , Irritable Bowel Syndrome/drug therapy , Morpholines/therapeutic use , Piperidines/therapeutic use , Serotonin 5-HT4 Receptor Agonists/therapeutic use , Adult , Diarrhea/chemically induced , Double-Blind Method , Female , Gastrointestinal Agents/adverse effects , Humans , Male , Middle Aged , Morpholines/adverse effects , Piperidines/adverse effects , Serotonin 5-HT4 Receptor Agonists/adverse effects , Treatment Outcome , Young AdultABSTRACT
INTRODUCTION: Numerous chemotypes have been described over time in order to generate potent and selective 5-HT4R ligands. Both agonists and antagonists have demonstrated their interest in several disease models. This culminates with the FDA approval of tegaserod and prucalopride in the recent years. AREAS COVERED: This review summarizes the patent applications from 2014 to present, dedicated to the use or the description of novel 5-HT4R modulators. Several novel ligands and scaffolds have been industrially protected mainly in the field of central nervous system (CNS) pathologies as well as gastrointestinal disorders, including the combination with other drugs or for veterinary uses. EXPERT OPINION: The therapeutic potential of 5-HT4R modulators has been explored for several years in animal models, but also linked to potential safety issues with initial ligands. The current use of prucalopride in humans demonstrates that its toxicity is not linked to the target and that 5-HT4R modulators are safe in humans. Therefore, an important number of studies and patents has continued in the recent years to expand the use of 5-HT4R modulators, not only to treat gastrointestinal disorders, but also for CNS pathologies. This article details current efforts in this development.
Subject(s)
Receptors, Serotonin, 5-HT4/drug effects , Serotonin 5-HT4 Receptor Agonists/pharmacology , Serotonin 5-HT4 Receptor Antagonists/pharmacology , Animals , Central Nervous System Diseases/drug therapy , Central Nervous System Diseases/physiopathology , Drug Development , Gastrointestinal Diseases/drug therapy , Gastrointestinal Diseases/physiopathology , Humans , Ligands , Patents as Topic , Receptors, Serotonin, 5-HT4/metabolism , Serotonin 5-HT4 Receptor Agonists/adverse effects , Serotonin 5-HT4 Receptor Antagonists/adverse effectsABSTRACT
Minesapride (drug code: DSP-6952) is a potential gastrointestinal prokinetic agent with high selectivity for 5-hydroxytryptamine 4 (5-HT4 ) receptor that acts as a partial agonist. Although 5-HT4 receptor agonists are expected to show efficacy in patients with irritable bowel syndrome with constipation, only tegaserod is available for female patients, with limitations, in the United States. Previously, another 5-HT4 receptor agonist, cisapride, was widely used for the treatment of upper gastrointestinal diseases, but was withdrawn from the market because of arrhythmia with QT prolongation. Chemically, benzamide is one of the most common structures among 5-HT4 receptor agonists. Some benzamide derivatives, such as cisapride, are responsible for QT prolongation, while some, such as mosapride, are not. Thus, we planned a thorough QT/QTc study to investigate the effects of minesapride, a newly designed benzamide derivative, on the QT/QTc. This was a randomized, placebo-controlled, 4-arm, 4-period, crossover study conducted in healthy adults, with administration of single oral doses of minesapride (40 mg and 120 mg), placebo, and moxifloxacin in the fasted state. Minesapride and placebo were administered in a double-blind fashion, while the positive control moxifloxacin was administered in an open-label fashion. Japanese subjects (48 total: 24 males and 24 females) were randomized, and 47 subjects completed all treatment periods. A review of other electrocardiographic data revealed that neither therapeutic (40 mg) nor supratherapeutic (120 mg) doses of minesapride were associated with increased risk of prolonged QT interval.
Subject(s)
Irritable Bowel Syndrome/drug therapy , Long QT Syndrome/chemically induced , Morpholines/adverse effects , Piperidines/adverse effects , Serotonin 5-HT4 Receptor Agonists/adverse effects , Administration, Oral , Adult , Anti-Bacterial Agents/administration & dosage , Arrhythmias, Cardiac/chemically induced , Asian People/ethnology , Benzamides/pharmacokinetics , Case-Control Studies , Cisapride/administration & dosage , Cisapride/adverse effects , Cisapride/therapeutic use , Cross-Over Studies , Double-Blind Method , Electrocardiography/methods , Electrocardiography/statistics & numerical data , Female , Humans , Indoles/administration & dosage , Indoles/adverse effects , Indoles/therapeutic use , Male , Morpholines/administration & dosage , Morpholines/pharmacokinetics , Moxifloxacin/administration & dosage , Piperidines/administration & dosage , Piperidines/pharmacokinetics , Placebos/administration & dosage , Serotonin 5-HT4 Receptor Agonists/administration & dosage , Serotonin 5-HT4 Receptor Agonists/pharmacokinetics , Serotonin Receptor Agonists/administration & dosage , Serotonin Receptor Agonists/adverse effects , Serotonin Receptor Agonists/therapeutic useABSTRACT
Prucalopride, a high affinity, selective serotonin type 4 (5-HT4) receptor agonist, was associated with increased neoplasia incidence (in endocrine tissues and liver) in 2-year rodent bioassays, without evidence of a genotoxic mechanism of action. Proposed mechanisms of action involve prolactin and the constitutive androstane receptor (CAR). Epigenetic mechanisms and their relevance to humans are discussed. Data from in vitro and in vivo rodent studies demonstrated that prucalopride-related stimulation of prolactin secretion (via dopamine receptor D2 antagonism at high doses) is a rodent-specific, non-genotoxic mechanism for inducing hyperplasia and neoplasia in prolactin receptor-expressing endocrine tissues. Additional data demonstrated that CAR-mediated liver enzyme induction underlies the observed hepatocellular adenomas and thyroid follicular adenomas in rodents. A 12-month neonatal mouse carcinogenicity study confirmed the lack of a genotoxic mechanism of action. Furthermore, tumors were observed only at very high exposures (200 and 63 fold higher in mice and rats, respectively, than human exposure after a daily therapeutic dose of 2 mg). The studies indicate that non-genotoxic, rodent-specific, epigenetic mechanisms that are considered clinically irrelevant are responsible for the increased incidence of neoplasias associated with very high exposure to prucalopride in rodents, and that prucalopride does not pose a carcinogenic safety risk to humans.
Subject(s)
Benzofurans/adverse effects , Endocrine Gland Neoplasms/chemically induced , Liver Neoplasms/chemically induced , Receptors, Serotonin, 5-HT4/metabolism , Serotonin 5-HT4 Receptor Agonists/adverse effects , Animals , Benzofurans/blood , Benzofurans/pharmacology , Humans , Risk Assessment , Serotonin 5-HT4 Receptor Agonists/blood , Serotonin 5-HT4 Receptor Agonists/pharmacologyABSTRACT
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.
Subject(s)
Asian People , Benzofurans/administration & dosage , Drugs, Generic/administration & dosage , Serotonin 5-HT4 Receptor Agonists/administration & dosage , Administration, Oral , Adolescent , Adult , Area Under Curve , Benzofurans/adverse effects , Benzofurans/pharmacokinetics , Chromatography, High Pressure Liquid , Cross-Over Studies , Drugs, Generic/adverse effects , Drugs, Generic/pharmacokinetics , Female , Humans , Male , Serotonin 5-HT4 Receptor Agonists/adverse effects , Serotonin 5-HT4 Receptor Agonists/pharmacokinetics , Tablets , Tandem Mass Spectrometry , Therapeutic Equivalency , Young AdultABSTRACT
We hypothesized that DSP-6952, a partial agonist of the 5-hydroxytryptamine type-4 receptor and a gastrointestinal prokinetic agent, can induce natural bowel movements by enhancing gastrointestinal motility and colonic transit in patients with chronic constipation and irritable bowel syndrome with constipation. This 3-part phase 1 study evaluated the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of DSP-6952. Eighty-eight Japanese subjects (64 healthy volunteers and 24 subjects with spontaneous bowel movements ≤3 times/wk) were randomized to DSP-6952 or placebo. The overall incidence of treatment-emergent adverse events (TEAEs) was similar for DSP-6952 and placebo. The most frequent TEAEs were gastrointestinal disorders; diarrhea was more common with DSP-6952, but only when it was administered to healthy volunteers. Peak plasma concentration (Cmax ) and area under the concentration-time curve (AUC) of DSP-6952 were dose-proportional within a range of 4-120 mg. Under fed conditions, the Cmax and AUC of DSP-6952 were approximately half those of fasting conditions. No abnormal drug accumulation was observed with repeated administration. In subjects with spontaneous bowel movements ≤3 times/wk, the median change in the frequency of bowel movements from baseline increased, although the difference did not reach statistical significance. DSP-6952 was well tolerated at single and multiple doses up to 120 mg/d, with a linear pharmacokinetic profile among all subjects.
Subject(s)
Constipation/drug therapy , Gastrointestinal Agents/administration & dosage , Serotonin 5-HT4 Receptor Agonists/administration & dosage , Adult , Area Under Curve , Asian People , Chronic Disease , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Female , Gastrointestinal Agents/adverse effects , Gastrointestinal Agents/pharmacokinetics , Humans , Male , Middle Aged , Receptors, Serotonin, 5-HT4/drug effects , Serotonin 5-HT4 Receptor Agonists/adverse effects , Serotonin 5-HT4 Receptor Agonists/pharmacokinetics , Young AdultSubject(s)
Benzofurans/administration & dosage , Constipation/drug therapy , Laxatives/administration & dosage , Serotonin 5-HT4 Receptor Agonists/administration & dosage , Adult , Benzofurans/adverse effects , Benzofurans/pharmacology , Chronic Disease , Constipation/physiopathology , Humans , Laxatives/adverse effects , Laxatives/pharmacology , Serotonin 5-HT4 Receptor Agonists/adverse effects , Serotonin 5-HT4 Receptor Agonists/pharmacologyABSTRACT
Introduction: Prucalopride is a selective 5-HT4 receptor agonist with colonic prokinetic activity. It was recently approved by the FDA for the treatment of chronic idiopathic constipation. Before this approval, there were limited options to improve colonic motility in the treatment of chronic idiopathic constipation. Areas covered: We systematically searched PubMed, Embase, ClinicalTrials.gov, and international conference presentations, and we reviewed all studies that evaluated prucalopride for the treatment of chronic idiopathic constipation in adults. In this review, we discuss the pharmacokinetics, pharmacodynamics, receptor interactions, phase I-IV clinical trials, and safety outcomes of prucalopride in adults, including the elderly. Expert opinion: Prucalopride is an effective agent to improve colonic motility, decrease colonic transit time, and increase complete spontaneous bowel movements in patients with chronic idiopathic constipation. Unlike previously available 5-HT4 receptor agonists such as cisapride and tegaserod, prucalopride does not interact with the cardiac hERG potassium channels or other serotonergic receptors in blood vessels and is not associated with an increase in major adverse cardiovascular events. Additionally, prucalopride has demonstrated promise in the treatment of gastroparesis, post-operative ileus, and opioid-induced constipation. Prucalopride directly stimulates colonic motility, differentiating it from all other medications (exclusively osmotic or chloride secretagogues) approved for chronic constipation in the last decade.
Subject(s)
Benzofurans/therapeutic use , Constipation/drug therapy , Laxatives/therapeutic use , Adult , Benzofurans/adverse effects , Benzofurans/pharmacology , Chronic Disease , Constipation/physiopathology , Gastrointestinal Motility/drug effects , Humans , Laxatives/adverse effects , Laxatives/pharmacology , Serotonin 5-HT4 Receptor Agonists/adverse effects , Serotonin 5-HT4 Receptor Agonists/pharmacology , Serotonin 5-HT4 Receptor Agonists/therapeutic useABSTRACT
BACKGROUND: Tegaserod, a serotonin (5-HT4) agonist initially approved for constipation but withdrawn from use in 2007 because of concerns about cardiovascular adverse effects, was resubmitted to the Food and Drug Administration (FDA) in 2018 for use in a restricted population. AREAS OF UNCERTAINTY: Despite an 18-year regulatory history, there remain pharmacology and clinical trial concerns that have not been addressed but are critical for proper assessment of the drug safety and efficacy profile. SOURCES: Original FDA reviews, FDA and developer advisory committee briefing documents, and published literature. RESULTS: The major pharmacology concern is that the fate and effects of half of the molecule, the pentylaminoguanidine moiety, are unknown. There is evidence that pentylaminoguanidine may contribute to both efficacy and safety. There are other metabolites that are poorly characterized, and potential receptor interactions that suggest cardiovascular effects are possible. The major clinical trial concern is that, while the trial data support a low but definite cardiovascular risk, both subject follow-up and cardiovascular event descriptions were incomplete such that an accurate estimate of cardiovascular risk is not possible. CONCLUSIONS: The uncertainties and lack of reliable evidence regarding tegaserod metabolism and cardiovascular risk estimates may discourage clinical use. Signals for cardiovascular toxicity in typical drug development programs are subtle and must be pursued aggressively, with complete case follow-up and cardiovascular event capture in the clinical trials.
Subject(s)
Cardiovascular Diseases/chemically induced , Indoles/administration & dosage , Irritable Bowel Syndrome/drug therapy , Serotonin 5-HT4 Receptor Agonists/administration & dosage , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/prevention & control , Clinical Trials as Topic , Drug Approval/legislation & jurisprudence , Electrocardiography/drug effects , Humans , Indoles/adverse effects , Serotonin 5-HT4 Receptor Agonists/adverse effects , United States , United States Food and Drug Administration/legislation & jurisprudenceABSTRACT
INTRODUCTION: 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.
Subject(s)
Benzofurans/therapeutic use , Constipation/drug therapy , Defecation/drug effects , Gastrointestinal Motility/drug effects , Intestines/drug effects , Laxatives/therapeutic use , Serotonin 5-HT4 Receptor Agonists/therapeutic use , Benzofurans/adverse effects , Benzofurans/economics , Constipation/diagnosis , Constipation/economics , Constipation/physiopathology , Cost-Benefit Analysis , Drug Costs , Humans , Intestines/physiopathology , Laxatives/adverse effects , Laxatives/economics , Recovery of Function , Serotonin 5-HT4 Receptor Agonists/adverse effects , Serotonin 5-HT4 Receptor Agonists/economics , Treatment OutcomeABSTRACT
BACKGROUND: Irritable bowel syndrome (IBS) is a chronic, recurrent bowel disorder with an unknown etiology, which is most likely multifactorial. Increased mucosal permeability, visceral hypersensitivity and activation status of intestinal mucosal immune cells cause changes in gastrointestinal (GI) motility, secretion and sensation observed in the course of IBS. Permanent, cumbersome symptoms, such as diarrhea, constipation and abdominal pain greatly lower the quality of life of IBS patients. On this basis, according to the Rome IV criteria, different forms of IBS can be distinguished. OBJECTIVE: This article focuses on the role of serotonin system in the pathophysiology of IBS as a potential therapeutic target. We shortly describe several molecules, associated with serotonin receptors, mainly 5-HT3 receptor antagonists and 5-HT4 receptor agonists, that are used in the treatment of motility disorders and visceral pain in IBS patients. We summarize the findings obtained in the clinical trials and elaborate on the safety of the serotonin ligands. Although the majority of serotonin receptor ligands relieve global symptoms, there are also some adverse effects, which can be dangerous for patients. RESULTS AND CONCLUSION: We postulate that currently, among all serotonin-targeting compounds, ramosetron is the best treatment option for IBS-D patients, due to its exceptional efficacy in both genders as well as good tolerability. Whereas, tegaserod is highly recommended for IBS-C sufferers. Nevertheless, numerous studies on the new serotonin receptor ligands are conducted to ensure the delivery of novel compounds with improved efficacy and safety profiles.
Subject(s)
Irritable Bowel Syndrome/drug therapy , Serotonin 5-HT3 Receptor Antagonists/therapeutic use , Serotonin 5-HT4 Receptor Agonists/therapeutic use , Clinical Trials as Topic , Humans , Indoles/adverse effects , Indoles/therapeutic use , Irritable Bowel Syndrome/metabolism , Lactones/adverse effects , Lactones/therapeutic use , Ligands , Quality of Life , Serotonin 5-HT3 Receptor Antagonists/adverse effects , Serotonin 5-HT4 Receptor Agonists/adverse effects , Sesquiterpenes/adverse effects , Sesquiterpenes/therapeutic useABSTRACT
INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.
Subject(s)
Azabicyclo Compounds/therapeutic use , Constipation/drug therapy , Serotonin 5-HT4 Receptor Agonists/therapeutic use , Animals , Azabicyclo Compounds/adverse effects , Azabicyclo Compounds/pharmacology , Chronic Disease , Humans , Quality of Life , Serotonin 5-HT4 Receptor Agonists/adverse effects , Serotonin 5-HT4 Receptor Agonists/pharmacologyABSTRACT
BACKGROUND: Gastroparesis is a chronic gastric disorder characterized by delayed gastric emptying without mechanical obstruction, and clinical symptoms as postprandial fullness, early satiety, bloating, nausea, vomiting, and abdominal pain. Prokinetic agents are used for the treatment of gastroparesis. Revexepride, a 5-hydroxytryptamine (serotonin) receptor (5-HT4 R) agonist, could be a good candidate drug for the gastroparesis treatment. AIM: In the current phase II, exploratory, double-blind, randomized, stratified, placebo-controlled, repeated dose trial (EudraCT number 2007-004997-23), the efficacy on gastrointestinal symptoms and gastric emptying rate, safety, and pharmacokinetic profile of three oral doses of revexepride (0.02, 0.1, and 0.5 mg administered orally t.i.d. for 4 weeks) was evaluated in trial participants (diabetic and non-diabetic) with upper gastrointestinal tract symptoms suggestive for gastroparesis. METHODS: Eighty participants, enrolled in four parallel treatment groups, were asked to score their symptom diary data, gastroparesis cardinal symptom index (GCSI), patient assessment of upper gastrointestinal disorders-symptom severity index (PAGI-SYM), quality of life questionnaires, and meal-related symptom score. Gastric emptying rate was evaluated by (13) C-octanoic acid breath test. KEY RESULTS: The severity of the symptoms assessed by means of GCSI and PAGI-SYM decreased at Week 2 and decreased further at Week 4 in all treatment groups including placebo, with similar trends in all treatment groups. Quality of life improved in all treatment groups after 4 weeks of treatment. No differences on gastric emptying rate were shown between any of the active treatment groups and placebo. Revexepride was generally safe and well-tolerated. CONCLUSIONS & INFERENCES: Four weeks of revexepride treatment did not improve symptoms or gastric emptying over placebo in patients with symptoms suggestive of gastroparesis.
Subject(s)
Benzofurans/administration & dosage , Gastroparesis/drug therapy , Serotonin 5-HT4 Receptor Agonists/administration & dosage , Benzofurans/adverse effects , Benzofurans/pharmacokinetics , Dose-Response Relationship, Drug , Double-Blind Method , Female , Gastric Emptying/drug effects , Humans , Male , Middle Aged , Pilot Projects , Quality of Life , Serotonin 5-HT4 Receptor Agonists/adverse effects , Serotonin 5-HT4 Receptor Agonists/pharmacokinetics , Surveys and QuestionnairesABSTRACT
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.
Subject(s)
Benzofurans/adverse effects , Constipation/drug therapy , Defecation/drug effects , Laxatives/adverse effects , Serotonin 5-HT4 Receptor Agonists/adverse effects , Cardiovascular Diseases/chemically induced , Chronic Disease , Constipation/diagnosis , Constipation/physiopathology , Contraindications, Drug , Controlled Clinical Trials as Topic , Depression/chemically induced , Female , Humans , Male , Risk Assessment , Suicidal Ideation , Treatment OutcomeABSTRACT
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.
Subject(s)
Benzofurans/therapeutic use , Colon/drug effects , Constipation/drug therapy , Defecation/drug effects , Gastrointestinal Motility/drug effects , Laxatives/therapeutic use , Serotonin 5-HT4 Receptor Agonists/therapeutic use , Animals , Benzofurans/adverse effects , Benzofurans/pharmacokinetics , Colon/physiopathology , Constipation/diagnosis , Constipation/physiopathology , Humans , Laxatives/adverse effects , Laxatives/pharmacokinetics , Serotonin 5-HT4 Receptor Agonists/adverse effects , Serotonin 5-HT4 Receptor Agonists/pharmacokinetics , Treatment OutcomeABSTRACT
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.