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Title: Detecting drug-induced prolongation of the QRS complex: New insights for cardiac safety assessment

Abstract

Background: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I{sub Na}) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I{sub Na}, this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation. Methods: Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1 h period from 1 h pre-dose to 5 h post-dose. Results: Compared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (E{sub max} 13% and 20% respectively, P < 0.01–0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of + 0.7 ± 0.5 ms (quinidine, NS), + 1.8 ± 0.8 ms (mexiletine, P < 0.05) and + 2.8 ± 0.8 ms (flecainide, P < 0.01) (calculated as QRSmore » at basal HR-QRS at high HR). Conclusion: Electrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function. -- Highlights: ► We aimed to improve detection of drug-induced QRS prolongation in safety screening. ► We used telemetered dogs to test class I antiarrhythmics at low and high heart rate. ► At low heart rate only quinidine and flecainide induced an increase in QRS duration. ► At high heart rate the effects of two out of three antiarrhythmics were enhanced. ► Detection of a drug-induced prolongation of QRS was improved at high heart rate.« less

Authors:
 [1];  [1];  [1];  [2];  [1]
  1. Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom)
  2. Sanofi-Aventis R and D, 371, rue du Pr Joseph Blayac, 34184 Montpellier Cedex 04 (France)
Publication Date:
OSTI Identifier:
22215990
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 265; Journal Issue: 2; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CONCENTRATION RATIO; DOGS; DRUGS; ELECTROCARDIOGRAMS; ETHERS; HEART; SODIUM; TELEMETRY

Citation Formats

Cros, C., E-mail: caroline.cros@hotmail.co.uk, Skinner, M., E-mail: Matthew.Skinner@astrazeneca.com, Moors, J., Lainee, P., and Valentin, J.P. Detecting drug-induced prolongation of the QRS complex: New insights for cardiac safety assessment. United States: N. p., 2012. Web. doi:10.1016/J.TAAP.2012.10.007.
Cros, C., E-mail: caroline.cros@hotmail.co.uk, Skinner, M., E-mail: Matthew.Skinner@astrazeneca.com, Moors, J., Lainee, P., & Valentin, J.P. Detecting drug-induced prolongation of the QRS complex: New insights for cardiac safety assessment. United States. doi:10.1016/J.TAAP.2012.10.007.
Cros, C., E-mail: caroline.cros@hotmail.co.uk, Skinner, M., E-mail: Matthew.Skinner@astrazeneca.com, Moors, J., Lainee, P., and Valentin, J.P. Sat . "Detecting drug-induced prolongation of the QRS complex: New insights for cardiac safety assessment". United States. doi:10.1016/J.TAAP.2012.10.007.
@article{osti_22215990,
title = {Detecting drug-induced prolongation of the QRS complex: New insights for cardiac safety assessment},
author = {Cros, C., E-mail: caroline.cros@hotmail.co.uk and Skinner, M., E-mail: Matthew.Skinner@astrazeneca.com and Moors, J. and Lainee, P. and Valentin, J.P.},
abstractNote = {Background: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I{sub Na}) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I{sub Na}, this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation. Methods: Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1 h period from 1 h pre-dose to 5 h post-dose. Results: Compared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (E{sub max} 13% and 20% respectively, P < 0.01–0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of + 0.7 ± 0.5 ms (quinidine, NS), + 1.8 ± 0.8 ms (mexiletine, P < 0.05) and + 2.8 ± 0.8 ms (flecainide, P < 0.01) (calculated as QRS at basal HR-QRS at high HR). Conclusion: Electrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function. -- Highlights: ► We aimed to improve detection of drug-induced QRS prolongation in safety screening. ► We used telemetered dogs to test class I antiarrhythmics at low and high heart rate. ► At low heart rate only quinidine and flecainide induced an increase in QRS duration. ► At high heart rate the effects of two out of three antiarrhythmics were enhanced. ► Detection of a drug-induced prolongation of QRS was improved at high heart rate.},
doi = {10.1016/J.TAAP.2012.10.007},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 265,
place = {United States},
year = {Sat Dec 01 00:00:00 EST 2012},
month = {Sat Dec 01 00:00:00 EST 2012}
}