TY - JOUR

T1 - Decreasing the infusion rate reduces the proarrhythmic risk of NS-7

T2 - confirming the relevance of short-term variability of repolarisation in predicting drug-induced torsades de pointes

AU - Detre, Elke

AU - Thomsen, Morten Bækgaard

AU - Beekman, Jet D

AU - Petersen, Karl-Uwe

AU - Vos, Marc A

PY - 2005/6

Y1 - 2005/6

N2 - 1 The rate of infusion has been suggested to be important for drug-induced torsades de pointes (TdP) arrhythmias. We investigated the repolarisation-prolonging effects and proarrhythmic properties of NS-7, a neuroprotective drug in development, using two different infusion rates. 2 A fast (5 min intravenously (i.v.)) escalating dosing regimen (0.3 and 3.0 mg kg(-1), n=4) of NS-7 was investigated in anaesthetised control dogs in sinus rhythm (SR). This was compared to a slow infusion (60 min i.v.) of one dose (3.0 mg kg(-1), n=4) NS-7. The similar dosing regimens were investigated in anaesthetised dogs with chronic, complete AV block (CAVB), an animal model of TdP (n=6). 3 No electrophysiological effects were seen after 0.3 mg kg(-1) NS-7. Fast infusion of 3.0 mg kg(-1) caused prolongation of repolarisation, for example, heart rate corrected QT interval (QT(c)): in SR: 6+/-1%; in CAVB: 10+/-7%, which was accompanied by TdP in three of six CAVB dogs. No TdP were seen in SR dogs. 4 Slow infusion did not cause TdP in the same CAVB dogs, although NS-7 caused repolarisation to prolong with a similar magnitude (QT(c): 12+/-7%) as in the fast-infusion experiment. 5 Short-term variability (STV) is a novel parameter for the prediction of drug-induced TdP analysing the beat-to-beat variability of repolarisation. STV was only increased after the fast infusion in CAVB dogs (2.6+/-0.3 versus 6.0+/-1.4 ms, P

AB - 1 The rate of infusion has been suggested to be important for drug-induced torsades de pointes (TdP) arrhythmias. We investigated the repolarisation-prolonging effects and proarrhythmic properties of NS-7, a neuroprotective drug in development, using two different infusion rates. 2 A fast (5 min intravenously (i.v.)) escalating dosing regimen (0.3 and 3.0 mg kg(-1), n=4) of NS-7 was investigated in anaesthetised control dogs in sinus rhythm (SR). This was compared to a slow infusion (60 min i.v.) of one dose (3.0 mg kg(-1), n=4) NS-7. The similar dosing regimens were investigated in anaesthetised dogs with chronic, complete AV block (CAVB), an animal model of TdP (n=6). 3 No electrophysiological effects were seen after 0.3 mg kg(-1) NS-7. Fast infusion of 3.0 mg kg(-1) caused prolongation of repolarisation, for example, heart rate corrected QT interval (QT(c)): in SR: 6+/-1%; in CAVB: 10+/-7%, which was accompanied by TdP in three of six CAVB dogs. No TdP were seen in SR dogs. 4 Slow infusion did not cause TdP in the same CAVB dogs, although NS-7 caused repolarisation to prolong with a similar magnitude (QT(c): 12+/-7%) as in the fast-infusion experiment. 5 Short-term variability (STV) is a novel parameter for the prediction of drug-induced TdP analysing the beat-to-beat variability of repolarisation. STV was only increased after the fast infusion in CAVB dogs (2.6+/-0.3 versus 6.0+/-1.4 ms, P

KW - Animals

KW - Arrhythmias, Cardiac

KW - Dogs

KW - Infusion Pumps

KW - Infusions, Intravenous

KW - Predictive Value of Tests

KW - Pyrimidines

KW - Time Factors

KW - Torsades de Pointes

U2 - 10.1038/sj.bjp.0706203

DO - 10.1038/sj.bjp.0706203

M3 - Journal article

C2 - 15778734

VL - 145

SP - 397

EP - 404

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 3

ER -