Power spectral analysis of heart rate variability in cynomolgus monkeys in safety pharmacology studies: comparative study with beagle dogs.

Introduction: Power spectral analysis of heart rate variability is a tool known to provide information of interest on the autonomic control of heart rate in human. However, its use and its conditions of application and interpretation for safety purposes are not well defined for cardiovascular safety pharmacology studies. Likewise, data of power spectral analysis of heart rate variability in cynomolgus monkeys, a species often appropriate for use as second non rodent species in preclinical safety programmes, are not available.

A step towards characterisation of electrophysiological profile of torsadogenic drugs.

Introduction: In a previous study, two electrophysiological patterns for torsadogenic drugs were characterised in the model of isolated canine Purkinje fibres from their respective effects on action potential. This study was designed to elucidate the possible mechanisms underlying these two electrophysiological profiles.

Methods: Effects of representative torsadogenic agents and non torsadogenic drugs on I(Kr), I(Ks), I(K1), I(Na) and I(CaL) were studied in transfected HEK 293 cells using the path-clamp method as well as in conscious beagle dogs and cynomolgus monkeys by telemetry.

Interferences of the autonomic nervous system with drug induced QT prolongation: a point to consider in non-clinical safety studies.

Introduction: QT interval assessment by telemetry has become one of the most useful models in testing strategies adopted for detection of drug induced QT prolongation in non-clinical safety pharmacology studies. This study reports experimental data showing that the autonomic nervous system might influence drug induced QT prolongation.

Methods: Animals were instrumented with telemetric transmitters and epicardial ECG leads.

Calculation of QT shift in non clinical safety pharmacology studies.

Introduction: Drug-induced QT interval prolongation is a major concern in new drug candidate development. This study presents a method of assessment of drug-induced QT interval prolongation without need for QT correction in conscious Beagle dogs and Cynomolgus monkeys monitored by telemetry. Accuracy and reliability are analysed by comparison with a reference QT correction method (Holzgrefe) from experiments performed with reference substances terfenadine, thioridazine and sotalol.

Prediction of the risk of Torsade de Pointes using the model of isolated canine Purkinje fibres.

Torsade de Pointes (TdP) is a well-described major risk associated with various kinds of drugs. However, prediction of this risk is still uncertain both in preclinical and clinical trials. We tested 45 reference compounds on the model of isolated canine Purkinje fibres.