These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: A step towards characterisation of electrophysiological profile of torsadogenic drugs.
    Author: Champeroux P, Ouillé A, Martel E, Fowler JS, Maurin A, Richard S, Le Guennec JY.
    Journal: J Pharmacol Toxicol Methods; 2011; 63(3):269-78. PubMed ID: 21224008.
    Abstract:
    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. RESULTS: Patch-clamp studies confirmed that torsadogenic molecules could be discriminated into at least two subgroups. The first subgroup can be defined as apparently pure I(Kr) blockers. The second subgroup can be defined as I(Kr) blockers with ancillary properties on sodium and/or calcium channels which counterbalance the I(Kr) prolongation component. This discrimination is transposable to the telemetered cynomolgus monkey model in terms of QT prolongation but not to the telemetered beagle dog model. This latter inter-species difference could be related to the sympathetic/parasympathetic balance and could involve reserve repolarisation dependent mechanisms. DISCUSSION: The confirmation that torsadogenic drugs might have at least two different electrophysiological profiles should be taken into consideration in preclinical safety pharmacology studies because it increases the value of the cynomolgus monkey model in two particular situations: firstly when an NCE causes sympathetic activation and secondly, when an NCE exhibits a pure I(Kr) blocker pattern independently of its potency to block HERG channels.
    [Abstract] [Full Text] [Related] [New Search]