HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Fossa, A. A. Articles by Dunne, M. Search for Related Content PubMed PubMed Citation Articles by Fossa, A. A. Articles by Dunne, M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Arrhythmia Hazardous Substances DB CHLOROQUINE Related Collections Malaria

Azithromycin/Chloroquine Combination Does Not Increase Cardiac Instability despite an Increase in Monophasic Action Potential Duration in the Anesthetized Guinea Pig

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 (~10 ms). Azithromycin alone and in combination with chloroquine showed no increase in alternans beyond vehicle baseline responses indicating no additional arrhythmia liability.

Received May 31, 2007. Accepted for publication August 15, 2007.

Acknowledgments: We thank Eric Wolfgang, William Gorczyca, and Jian Lin for their technical assistance in generation of the animal and pharmacokinetic data.

Disclosure: Some of the authors are employed by and/or hold stock in Pfizer, the makers of azithromycin, and are conducting research sponsored by this company. This statement is made in the interest of full disclosure and not because the authors consider this to be a conflict of interest.

^* Address correspondence to Anthony A. Fossa, Pfizer Global Research and Development, Eastern Point Rd, MS 8260-2630, Groton, CT 06340. E-mail: Anthony.a.fossa{at}pfizer.com

Authors’ addresses: Anthony A. Fossa, Todd Wisialowski, J. Neil Duncan, Shibing Deng, and Michael Dunne, Pfizer Global Research and Development, Eastern Point Rd, MS 8260-2630, Groton, CT 06340, Telephone: 860-441-4094, Fax: 860-715-7636, E-mail: anthony.a.fossa{at}pfizer.com.

Reprint requests: Anthony A. Fossa, Pfizer Global Research and Development, Eastern Point Rd, MS 8260-2630, Groton, CT 06340, Telephone: 860-441-4094, Fax: 860-715-7636, E-mail: anthony.a.fossa{at}pfizer.com.