QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.101881v1 318/1/352    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wisialowski, T. Articles by Fossa, A. A. Search for Related Content PubMed PubMed Citation Articles by Wisialowski, T. Articles by Fossa, A. A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Arrhythmia Hazardous Substances DB ERYTHROMYCIN

CARDIOVASCULAR

Differentiation of Arrhythmia Risk of the Antibacterials Moxifloxacin, Erythromycin, and Telithromycin Based on Analysis of Monophasic Action Potential Duration Alternans and Cardiac Instability

Pfizer Global Research and Development, Groton, Connecticut

Antibacterial drugs are known to have varying degrees of cardiovascular liability associated with QT prolongation that can lead to the ventricular arrhythmia torsade de pointes. The purpose of these studies was to compare the assessment for the arrhythmogenic risk of moxifloxacin, erythromycin, and telithromycin. Each drug caused dose-dependent inhibition of the rapidly activating delayed rectifier potassium current encoded by the human ether-á-go-go-related gene (hERG) with IC₂₀ concentrations of 31 µM (moxifloxacin), 21 µM (erythromycin), and 11 µM (telithromycin). These drugs were also evaluated in an anesthetized guinea pig model to measure changes in monophasic action potential duration (MAPD) and to quantify beat-to-beat alternations in MAPD during rapid ventricular pacing. Moxifloxacin dose dependently increased MAPD and caused a rate-dependent increase in alternans at the highest achieved free drug concentration (41 µM). Erythromycin also increased MAPD at its highest free drug concentration (58 µM), but alternans occurred at a relatively lower therapeutic multiple (13.9 µM), and the magnitude of alternans at higher concentrations was independent of pacing rate. Further analysis of the data showed that the beat-to-beat pattern of alternans with erythromycin was less stable than that with moxifloxacin and suggestive of greater arrhythmogenic liability. In contrast to erythromycin and moxifloxacin, telithromycin decreased both MAPD and alternans at the highest achievable drug concentration (7.9 µM). The relative risk at therapeutic concentrations is erythromycin > moxifloxacin > telithromycin and appears to be consistent with clinical observations of torsade de pointes in patients.

Address correspondence to: Dr. Anthony A. Fossa, Pfizer Global Research and Development, Eastern Point Rd., Building 274, Groton, CT 06340. E-mail: anthony.a.fossa{at}pfizer.com

This article has been cited by other articles:

				A. A. Fossa, T. Wisialowski, J. N. Duncan, S. Deng, and M. Dunne Azithromycin/Chloroquine Combination Does Not Increase Cardiac Instability despite an Increase in Monophasic Action Potential Duration in the Anesthetized Guinea Pig Am J Trop Med Hyg, November 1, 2007; 77(5): 929 - 938. [Abstract] [Full Text] [PDF]