title: Azithromycin/chloroquine combination does not increase cardiac instability despite an increase in monophasic action potential duration in the anesthetized guinea pig.
abstract: Prolongation of the electrocardiogram QT interval by some, but not all drugs, has been associated with increased incidence of sudden cardiac death. Current preclinical regulatory assays cannot discriminate the arrhythmia liability of these drugs. Consequently, many new medications that prolong the QT interval are not developed despite their potential therapeutic benefit. Alternans (action potential duration alternations) is a measure of cardiac instability in humans and animals associated with the onset of ventricular fibrillation. Due to potential arrhythmia risk from observed QT prolongation, alternans was assessed in the anesthetized guinea pig after azithromycin or chloroquine alone and after combination treatment at clinically relevant concentrations proposed for the management of malaria. Chloroquine alone, but not azithromycin, caused a profound increase in action potential duration but with only minimal effects on alternans (approximately 10 ms). Azithromycin alone and in combination with chloroquine showed no increase in alternans beyond vehicle baseline responses indicating no additional arrhythmia liability.
authors.affiliation: Pfizer Global Research and Development, Department of Translational and Molecular Medicine, Groton, Connecticut 06340, USA. Anthony.a.fossa@pfizer.com
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Fossa
authors.forename: Todd
authors.initials: T
authors.lastname: Wisialowski
authors.forename: J Neil
authors.initials: JN
authors.lastname: Duncan
authors.forename: Shibing
authors.initials: S
authors.lastname: Deng
authors.forename: Michael
authors.initials: M
authors.lastname: Dunne
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000758:Anesthesia; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000009:adverse effects; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D017963:Azithromycin / Q000008:administration & dosage* / Q000009:adverse effects*; D001794:Blood Pressure / Q000187:drug effects; D002738:Chloroquine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D008297:Male
chemical_list: D000962:Antimalarials; C023676:chloroquine diphosphate; D017963:Azithromycin; D002738:Chloroquine