QT prolongation in guinea pigs for preliminary screening of torsadogenicity of drugs and drug-candidates. II.
Experimental approaches on anaesthetised guinea pigs have been shown recently to be satisfactorily predictive of the torsadogenic risk of drugs. This work aimed at obtaining additional data, for a further understanding of the reliability and/or the limits of this model. Clonidine (non-torsadogenic in humans) induced a lengthening of the ECG parameter of RR in anaesthetised guinea pigs, without any corresponding increase of QT (corrected by the algorithms of Bazett and Fridericia). Thus, 'QT correct' prolonging effects produced by drugs torsadogenic in humans, on the guinea pig model are primarily due to inhibition of cardiac repolarisation. The corresponding RR prolongation is a consequence (not the cause) of this primary effect. Astemizole, haloperidol and terfenadine, torsadogenic in humans, produced in Langendorff perfused guinea pig hearts a prolongation of the QT interval. Chlorprotixene (non-torsadogenic) did not produce any significant effect on QT. These results are fully consistent with previous observations in anaesthetised guinea pigs. In Langendorff perfused hearts, pentobarbital does not affect cardiac repolarisation and does not potentiate the QT-prolonging effect of astemizole. Together with the findings reported by many authors, these data suggest that ECG recording in anaesthetised guinea pigs is a reliable model for cardiac safety studies evaluating the influence of drugs on the repolarisation process.
Testai
L
L
Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università di Pisa-Via Bonanno, 6 I-56126 Pisa, Italy.
Breschi
M C
MC
Martinotti
E
E
Calderone
V
V
D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000633:toxicity; D016589:Astemizole / Q000008:administration & dosage / Q000633:toxicity; D003000:Clonidine / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced / Q000503:physiopathology; D004562:Electrocardiography / Q000187:drug effects; D006168:Guinea Pigs; D006220:Haloperidol / Q000008:administration & dosage / Q000633:toxicity; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D010477:Perfusion / Q000379:methods; D016593:Terfenadine / Q000008:administration & dosage / Q000633:toxicity; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology
D000959:Antihypertensive Agents; D016593:Terfenadine; D016589:Astemizole; D006220:Haloperidol; D003000:Clonidine