The anaesthetised methoxamine-sensitised rabbit model of torsades de pointes.
Current guidelines describe strategies on how the potential of non-antiarrhythmic drugs to delay ventricular repolarisation should be assessed. However, the non-clinical guidelines recommend repolarisation assays only and do not advocate experimental models that express the proarrhythmia of concern, torsades de pointes (TdP). Although the repolarisation assays may predict QT interval prolongation in man they cannot alone sufficiently predict proarrhythmia risk. Furthermore, there is also a need for more robust surrogate markers of drug-induced proarrhythmia and such validated markers are on the horizon as a result of the availability of sensitive animal models of TdP. This review will describe the methoxamine-sensitised rabbit model of TdP, one of the most frequently used proarrhythmia models, and present some of it characteristics, its pros and cons and how it historically has been used for assessing proarrhythmia liability of drugs.
AstraZeneca R&D Mölndal, Bioscience, S-431 83 Mölndal, Sweden. leif.g.carlsson@astrazeneca.com
Leif
L
Carlsson
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D064420:Drug-Related Side Effects and Adverse Reactions; D017408:Guidelines as Topic; D006801:Humans; D008729:Methoxamine / Q000494:pharmacology; D011817:Rabbits; D016171:Torsades de Pointes / Q000139:chemically induced*; D018675:Toxicity Tests / Q000379:methods
D000316:Adrenergic alpha-Agonists; D008729:Methoxamine