mdl-100907 and Ventricular-Dysfunction

Paliperidone (9-hydroxyrisperidone) is a second-generation antipsychotic. As observed with risperidone, QT interval prolongation was reported with paliperidone.. The aim was to evaluate the effects of paliperidone on cardiac ventricular repolarization.. (1) Patch-clamp experiments: Human ether-a-go-go-related gene (HERG)- or KCNQ1 + KCNE1-transfected cells were exposed to 0.1-100 μmol/L paliperidone (N = 39 cells, total) to assess the drug effect on HERG and KCNQ1 + KCNE1 currents. (2) Langendorff perfusion experiments: Hearts isolated from male Hartley guinea pigs (N = 9) were exposed to 0.1 μmol/L paliperidone to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization. (3) In vivo cardiac telemetry experiments: Guinea pigs (N = 8) implanted with transmitters were injected a single intraperitoneal dose of 1 mg/kg of paliperidone, and 24-hour electrocardiogram recordings were made.. (1) The estimated concentration at which 50% of the maximal inhibitory effect is observed (IC(50)) for paliperidone on HERG current was 0.5276 μmol/L. In contrast, 1 μmol/L paliperidone had hardly any effect on KCNQ1 + KCNE1 current (4.0 ± 1.6% inhibition, N = 5 cells). (2) While pacing the hearts at cycle lengths of 150, 200, or 250 milliseconds, 0.1 μmol/L paliperidone prolonged monophasic action potential duration measured at 90% repolarization by, respectively, 6.1 ± 3.1, 9.8 ± 2.7, and 12.8 ± 2.7 milliseconds. (3) Paliperidone (1 mg/kg) intraperitoneal caused a maximal 15.7 ± 5.3-millisecond prolongation of QTc.. Paliperidone prolongs the QT interval by blocking HERG current at clinically relevant concentrations and is potentially unsafe.

Topics: Animals; Antipsychotic Agents; Cardiac Pacing, Artificial; CHO Cells; Cricetinae; Cricetulus; Dopamine Antagonists; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Guinea Pigs; Heart; HEK293 Cells; Humans; In Vitro Techniques; Isoxazoles; KCNQ1 Potassium Channel; Male; Paliperidone Palmitate; Patch-Clamp Techniques; Potassium Channel Blockers; Potassium Channels, Voltage-Gated; Pyrimidines; Recombinant Proteins; Serotonin 5-HT2 Receptor Antagonists; Ventricular Dysfunction