title: Decreasing the infusion rate reduces the proarrhythmic risk of NS-7: confirming the relevance of short-term variability of repolarisation in predicting drug-induced torsades de pointes.
abstract: 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<0.05), while there was no increase (2.1+/-0.2 versus 2.5+/-1.0 ms) after the slow infusion of NS-7. 6 Peak plasma concentrations attained were lower in slow (0.5+/-0.1 microg ml(-1) after 50 min) than in fast-infusion regimen (2.1+/-0.4 microg ml(-1) after 5 min; P<0.05). 7 The results support the conclusion that limiting peak plasma concentration by decreasing the rate of infusion of NS-7 reduces the proarrhythmic risk despite comparable prolongation in repolarisation parameters. The relevance of STV in predicting drug-induced TdP was confirmed.
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute Maastricht, Academic Hospital Maastricht, Maastricht, The Netherlands.
authors.forename: Elke
authors.initials: E
authors.lastname: Detre
authors.forename: Morten B
authors.initials: MB
authors.lastname: Thomsen
authors.forename: Jet D
authors.initials: JD
authors.lastname: Beekman
authors.forename: Karl-Uwe
authors.initials: KU
authors.lastname: Petersen
authors.forename: Marc A
authors.initials: MA
authors.lastname: Vos
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology; D004285:Dogs; D007260:Infusion Pumps; D007262:Infusions, Intravenous; D011237:Predictive Value of Tests; D011743:Pyrimidines / Q000008:administration & dosage*; D013997:Time Factors; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology*
chemical_list: C106144:4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride; D011743:Pyrimidines