prucalopride and Arrhythmias--Cardiac

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

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

Cisapride and prucalopride act as 5-HT

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

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 Among these, cisapride was recently withdrawn from the U.S. market because of its proarrhythmic effects.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

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