td-5108 and Gastroesophageal-Reflux

Proton pump inhibitors (PPIs) are currently the most effective and most widely used agents for gastroesophageal reflux disease (GERD). Despite the efficacy of these agents in healing and symptom relief, a substantial proportion of patients require twice-daily therapy with PPIs, and break-through symptoms cause others to use over-the-counter antacids and histamine 2-receptor antagonists to supplement their PPI therapy. Major strategies that are being pursued include the development of agents that have a faster onset of action for on-demand therapy; have better control of acid secretion, resulting in improved healing in advanced grades of esophagitis and better symptom control; and agents that decrease transient lower esophageal sphincter relaxations (TLESRs), thereby reducing distal acid exposure and weakly acidic refluxate. A number of new pharmaceutical agents are currently undergoing clinical evaluation for the treatment of GERD. These include agents that reduce TLESRs, serotonergic agents/ prokinetics, long-acting PPIs, mucosal protectants, and antigastrin agents. One or more of these agents may be the future of GERD therapy.

Topics: Anti-Ulcer Agents; Benzamides; Cisapride; Esophageal Sphincter, Lower; Gastroesophageal Reflux; Humans; Imidazoles; Proton Pump Inhibitors; Pyridines; Quinuclidines; Serotonin 5-HT4 Receptor Agonists

Gastroesophageal reflux disease (GERD) is increasingly common worldwide; symptoms differ between individuals and endoscopically visible injury is present in only about 50% of cases. Although GERD is a disorder of gastrointestinal motility and structure, the most effective therapy is based on the use of acid antisecretory drugs. Proton pump inhibitors (PPIs), the most effective class of acid suppression agents to date, have revolutionised the management of GERD. However, PPIs do have some shortcomings and recent developments include documentation of increased healing rates with more prolonged acid suppression, more prolonged acid suppression with a new PPI (tenatoprazole) and more rapid onset of acid suppression with a new class of drugs, the reversible, potassium-competitive acid blockers. Studies with motility agents, such as the 5-HT(4) partial agonist tegaserod and the GABA(B) agonist baclofen, indicate that motility is important in the pathogenesis of GERD but, for several reasons, it will be a challenge to develop new classes of drug that outperform current PPIs with respect to efficacy, broad applicability and safety.

Topics: Animals; GABA-A Receptor Agonists; Gastroesophageal Reflux; Histamine H2 Antagonists; Humans; Indoles; Proton Pump Inhibitors; Serotonin 5-HT4 Receptor Agonists

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

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

Approximately, 20-30% of patients with gastro-esophageal reflux disease (GERD) experience persistent symptoms despite treatment with proton pump inhibitors (PPIs). These patients may have underlying dysmotility; therefore, targeting gastric motor dysfunction in addition to acid inhibition may represent a new therapeutic avenue. The aim of this study was to assess the pharmacodynamic effect of the prokinetic agent revexepride (a 5-HT4 receptor agonist) in patients with GERD who have persistent symptoms despite treatment with a PPI.. This was a phase II, exploratory, multicenter, randomized, placebo-controlled, double-blind, parallel-group study in patients with GERD who experienced persistent symptoms while taking a stable dose of PPIs (ClinicalTrials.gov identifier: NCT01370863). Patients were randomized to either revexepride (0.5 mg, three times daily) or matching placebo for 4 weeks. Reflux events and associated characteristics were assessed by pH/impedance monitoring and disease symptoms were assessed using electronic diaries and questionnaires.. In total, 67 patients were enrolled in the study. There were no significant differences between study arms in the number, the mean proximal extent or the bolus clearance times of liquid-containing reflux events. Changes from baseline in the number of heartburn, regurgitation, and other symptom events were minimal for each treatment group and no clear trends were observed.. No clear differences were seen in reflux parameters between the placebo and revexepride groups.

Topics: Adolescent; Adult; Aged; Benzofurans; Double-Blind Method; Esophageal pH Monitoring; Female; Gastroesophageal Reflux; Humans; Male; Middle Aged; Proton Pump Inhibitors; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome; Young Adult

A substantial proportion of patients with gastro-oesophageal reflux disease (GERD) have only a partial response to proton pump inhibitor (PPI) therapy. Prokinetic drugs may improve reflux symptoms by enhancing oesophageal motility and gastric emptying.. To evaluate the effect of revexepride, a novel prokinetic 5-hydroxytryptamine type 4 (5-HT4 ) receptor agonist, compared with placebo, in patients with GERD who have a partial response to PPIs.. A phase 2b, double-blind, parallel-group study was conducted, in which patients were randomised to one of three revexepride treatment groups (0.1, 0.5 and 2.0 mg three times daily) or placebo (1:1:1:1 ratio). Daily e-diary data captured patients' symptoms over an 8-week treatment period. The primary efficacy outcome was the weekly percentage of regurgitation-free days in the second half of the study (weeks 5-8).. In total, 480 patients were randomised and 477 received treatment (mean age 47.9 years; 61% women). The mean percentage of regurgitation-free days increased from baseline (range, 15.0-18.8%) to week 8 (62.3-70.5%) in all four study arms; however, there were no statistically significant differences in this change between placebo and the three treatment arms. No dose-dependent relationship in treatment effect was observed for any of the study endpoints. The incidence of treatment-emergent adverse events (TEAEs) was revexepride dose-dependent. Only one serious TEAE occurred and none resulted in death.. Revexepride was no more effective than placebo in controlling regurgitation in patients with GERD symptoms partially responsive to PPIs. Revexepride was well tolerated. ClinicalTrials.gov Identifier: NCT01472939.

Topics: Adult; Aged; Area Under Curve; Benzofurans; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gastric Emptying; Gastroesophageal Reflux; Humans; Male; Middle Aged; Proton Pump Inhibitors; Quality of Life; Serotonin 5-HT4 Receptor Agonists

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

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

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

To evaluate the efficiency of the 5-HT4 agonist and 5-HT3 antagonist mosapride, as compared with cisapride, on oesophageal acid reflux variables and oesophageal motor function in patients with chronic gastro-oesophageal reflux disease (GORD).. Forty-one patients with proven GORD were included in a double-blind, randomised, double-dummy, three-way crossover study. All patients received mosapride 60 mg twice daily, mosapride 30 mg three times daily, and cisapride 20 mg twice daily for seven days in a randomised order, separated by a washout period of at least five days. Twenty-three patients underwent four combined ambulatory 24-h motility and pH recordings within two weeks before the start of treatment and on day seven of each treatment period. The remaining 18 patients underwent three ambulatory 24-h pH recordings only, i.e. on treatment day seven of each treatment period.. Mosapride had no significant effect on the total number of contractions in the oesophagus, or on the effectiveness, or possible effectiveness, of the propagations. Significant but numerically small effects on peristaltic durations and amplitudes were noted during both mosapride and cisapride treatment as compared with baseline values. The effect on acid reflux for both mosapride and cisapride was most pronounced for the duration of the longest reflux episode. The fraction of time with pH less than 4 was reduced by mosapride 30 mg three times daily in the supine position and by cisapride both totally and in the supine position. The number of reflux episodes was reduced significantly only by cisapride. Oesophageal clearance was reduced significantly by cisapride only in the supine position.. Mosapride had small but statistically significant effects, comparable to those of cisapride, on acid reflux variables and oesophageal motor function in patients with GORD.

Topics: Adult; Aged; Benzamides; Cisapride; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Esophagus; Female; Gastroesophageal Reflux; Gastrointestinal Agents; Humans; Hydrogen-Ion Concentration; Male; Manometry; Middle Aged; Morpholines; Peristalsis; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists

The pharmacological profile of PF-00885706, a selective 5-HT(4) receptor partial agonist, was investigated. PF-00885706 displayed a high binding affinity for the human 5-HT(4d) receptor with a K(i) of 3.7 nM that translates to functional agonist activity in vitro with EC(50) values of 4.0 nM and 6.6 nM in cell-based assays of human recombinant 5-HT(4d) receptors and rat tunica muscularis mucosae tissues, respectively. In both assays, partial agonism was confirmed with E(max) values of 84% and 78%, respectively. Notably, PF-00885706 was highly selective, displaying >1000-fold higher affinity for 5-HT(4d) receptors compared to 5-HT(1A), 5-HT(1B), 5-HT(1D), 5-HT(2A), 5-HT(2B), 5-HT(2C), 5-HT(3), 5-HT(7), and D(2long) receptors. Furthermore, in vitro binding assays demonstrated that PF-00885706 had no biologically significant interaction with physiologically important enzymes, ion channels including hERG channel, or receptors at concentrations up to 10 microM except for binding to the sigma(2) receptor. PF-00885706 exhibited weak binding affinity for the sigma(2) receptor yielding a K(i) value of 3 microM, which is more than 800-fold weaker than that for the 5-HT(4d) receptor. Oral administration of PF-00885706 to dogs resulted in marked and long-lasting stimulation of gastric motility with a minimum effective dose of 0.001 mg/kg. Pharmacokinetic analysis revealed that PF-00885706 has a low to moderate volume of distribution and the complete absorption in dogs. Pharmacokinetic and pharmacodynamic analysis of PF-00885706 in the dog gastric motility model showed a correlation between plasma concentrations and enhancement of gastric motility. Thus, PF-00885706 is an orally active, highly selective partial agonist for 5-HT(4) receptors that is expected to be effective for the treatment with gastrointestinal dysmotility disorders with reduced adverse effects mediated by other related receptors.

Topics: Animals; Benzimidazoles; Cell Line; Cyclobutanes; Dogs; Esophagus; Ether-A-Go-Go Potassium Channels; Gastroesophageal Reflux; Gastrointestinal Motility; Humans; Male; Muscle, Smooth; Piperidines; Protein Binding; Rats; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists