Investigation of mechanism of drug-induced cardiac injury and torsades de pointes in cynomolgus monkeys.

ABSTRACT:

Background and purpose

Drug candidates must be thoroughly investigated for their potential cardiac side effects. During the course of routine toxicological assessment, the compound RO5657, a CCR5 antagonist, was discovered to have the rare liability of inducing torsades de pointes (polymorphic ventricular arrhythmia) in normal, healthy animals. Studies were conducted to determine the molecular mechanism of this arrhythmia.

Experimental approach

Toxicological effects of repeat dosing were assessed in naïve monkeys. Cardiovascular effects were determined in conscious telemetry-implanted monkeys (repeat dosing) and anaesthetized instrumented dogs (single doses). Mechanistic studies were performed in guinea-pig isolated hearts and in cells recombinantly expressing human cardiac

SUBMITTER: Misner DL 

PROVIDER: S-EPMC3423261 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature