Proarrhythmic potential of halofantrine, terfenadine and clofilium in a modified in vivo model of torsade de pointes

Abstract

1 This study was designed to compare the proarrhythmic activity of the antimalarial drug, halofantrine and the antihistamine, terfenadine, with that of clo®lium a K + channel blocking drug that can induce torsade de pointes. 3 Clo®lium and halofantrine caused dose-dependent increases in the rate-corrected QT interval (QTc), whereas terfenadine prolonged PR and QRS intervals rather than prolonging cardiac repolarization. Progressive bradycardia occurred in all groups. After administration of the highest dose of each drug halofantrine caused a modest decrease in blood pressure, but terfenadine had profound hypotensive eects resulting in death of most rabbits. 4 The total number of ventricular premature beats was highest in the clo®lium group. Torsade de pointes occurred in 6 out of 8 clo®lium-treated rabbits and 4 out of 6 of those which received halofantrine, but was not seen in any of the seven terfenadine-treated rabbits. 5 These results show that, like clo®lium, halofantrine can cause torsade de pointes in a modi®ed anaesthetized rabbit model whereas the primary adverse eect of terfenadine was cardiac contractile failure.

Proarrhythmic Potential of Antimicrobial Agents

“…In anaesthetized rabbits increasing iv doses of halofantrine caused dose-dependent prolongation of the QT c interval with progressive bradycardia. TdP occurred in four out of six in halofantrine-treated rabbits [68].…”

From Mouse to Whale

“…[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] The collected data fall into 4 different categories based on the mode in which they were reported in the literature for each of the 3 parameters (ie, PR, HR, and BM): (1) measurements from single animals, (2) multiple animal measurements reported as mean values without SD, (3) multiple animal measurements reported as means with SDs, and (4) values reported as ranges without means or SDs. For convenience, the allometric equation YϭY 0 · BM b can be transformed into a logarithmic form, lnYϭlnY 0 ϩb · lnBM, which describes a straight line of the form yϭinterceptϩbx.…”

Noninvasive cardiac activation imaging of ventricular arrhythmias during drug-induced QT prolongation in the rabbit heart

“…We performed simultaneous body surface potential mapping and 3D intra-cardiac mapping 11–13 in a closed-chest condition 8,14 in rabbits. The class III antiarrhythmic drug clofilium 15 and phenylephrine were infused in the in vivo rabbit model to prolong QT interval and induce ventricular arrhythmias 16 including premature ventricular complex (PVC), couplet, and TdP. The imaged activation sequence was also compared with the simultaneously measured activation sequence from 3D intra-cardiac mapping.…”