Blinded test in isolated female rabbit heart reliably identifies action potential duration prolongation and proarrhythmic drugs: importance of triangulation, reverse use dependence, and instability.
Drug-induced proarrhythmia is a rare but potentially lethal adverse drug reaction. To test whether the SCREENIT system (an automated computerized test apparatus), using an isolated perfused heart obtained from female rabbits, could correctly identify agents that lengthen the action potential duration (APD) and drugs known to induce proarrhythmia, 14 drugs (penicillin G, haloperidol, adriamycin, indapamide, verapamil, aspirin, lidocaine, clomipramine, propranolol, erythromycin, quinidine, terfenadine, amiodarone, and thioridazine) were coded and submitted for a blinded test. Of these drugs, eight are reported to induce QT prolongation in the clinic (adriamycin, clomipramine, quinidine, amiodarone, and thioridazine), while three do not lengthen and three shorten the QT. To test for reproducibility, four drugs were given in duplicate (haloperidol, aspirin, erythromycin, and terfenadine). The drug effects on monophasic APD, conduction, instability (index of variability of APD), triangulation (index of duration of fast repolarization), and reverse use dependence were measured at five drug concentrations (0.05, 0.15, 0.5, 1.5, and 5 mg/l). All 14 blinded drugs, in the concentrations used, were correctly identified as to their effects on APD and conduction. The drugs eliciting drug-induced proarrhythmia in patients were also identified as promoting instability, triangulation, and reverse use dependence in the rabbit heart. Importantly, none of the safe agents was labeled as proarrhythmic, and the results were very consistent between duplications. In conclusion, SCREENIT correctly identifies prolongation of APD, accurately separates safe agents form proarrhythmic drugs, and has highly reproducible results. Thus, the isolated perfused rabbit heart can be a valuable tool in a preclinical proarrhythmia test battery in drug development.
Hondeghem
Luc M
LM
Department of Pharmacology, Catholic University of Leuven, Leuven, Belgium. LucHondeghem@yahoo.com
Hoffmann
Peter
P
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D003201:Computers; D064420:Drug-Related Side Effects and Adverse Reactions; D004594:Electrophysiology; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D015203:Reproducibility of Results; D016171:Torsades de Pointes / Q000139:chemically induced*