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

@article{Wisialowski2006DifferentiationOA,
  title={Differentiation of Arrhythmia Risk of the Antibacterials Moxifloxacin, Erythromycin, and Telithromycin Based on Analysis of Monophasic Action Potential Duration Alternans and Cardiac Instability},
  author={Todd A. Wisialowski and Kimberly Crimin and Juntyma J Engtrakul and John O'Donnell and Bernard Fermini and Anthony A Fossa},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2006},
  volume={318},
  pages={352 - 359}
}
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… 
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Antibiotic-induced cardiac arrhythmias.
TLDR
The use of macrolides and fluoroquinolones antibiotics in the appropriate settings of infection should not be altered because of the rare risk of TdP, except among cases with high-risk factors.
Azithromycin/chloroquine combination does not increase cardiac instability despite an increase in monophasic action potential duration in the anesthetized guinea pig.
TLDR
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.
Preclinical electrophysiology assays of mitemcinal (GM-611), a novel prokinetic agent derived from erythromycin.
TLDR
The findings of a wide safety margin and the absence of TdP within this margin suggest that mitemcinal may provide sufficient safety in clinical use.
T-Wave Alternans as a Therapeutic Marker for Antiarrhythmic Agents
TLDR
Qualitative analysis of TWA has considerable potential to guide pharmacologic therapy and the emerging collective evidence indicates the broad utility of T WA in estimating antiarrhythmic and proarrhythmmic effects of diverse agents across differing pathologies.
No proarrhythmic properties of the antibiotics Moxifloxacin or Azithromycin in anaesthetized dogs with chronic‐AV block
TLDR
The cardiac safety of Azithromycin and moxifloxacin was assessed in a TdP‐susceptible animal model by evaluating their repolarization and proarrhythmia effects.
Electrophysiologic, Pharmacokinetic, and Pharmacodynamic Values Indicating a Higher Risk of Torsades de Pointes
TLDR
The results showed that drugs in group 1 induced greater inhibition of human ether‐a‐a-go‐go‐related gene (HERG) potassium current or the rapid component of the delayed rectifier potassium current (Ikr), had lower half‐maximal inhibitory concentration (IC50) values for inhibition of HERG/Ikr, and induced greater QTc increases in humans.
Erythromycin, QTc interval prolongation, and torsade de pointes: Case reports, major risk factors and illness severity
TLDR
It is believed that major risk factors for erythromycin-associated QTc interval prolongation and torsade de pointes (TdP) arrhythmia are female sex, heart disease and old age, particularly against a background of severe illness.
The hERG channel and risk of drug-acquired cardiac arrhythmia: an overview.
TLDR
Current knowledge of the cardiac rapidly activating delayed rectifier potassium current (I(Kr), and its connection to drug-acquired QT prolongation and the associated risk of ventricular arrhythmia and fibrillation is summarized.
Acquired (Drug-Induced) Long and Short QT Syndromes
TLDR
There is in depth discussion of various molecular and electrophysiological mechanisms that underpin induction of torsade de pointes, the relationship between QT interval and the proarrhythmic risk it poses and how this relationship is modulated by a number of ancillary properties of a drug.
Drug-Induced Prolongation of the QT Interval: Present and Future Challenges for Drug Discovery
TLDR
The basis for this important cardiovascular liability facing all small molecule drug candidates, various preclinical proarrhythmia models available to characterize proarrHythmic risk related to delayed repolarization, and evolving future approaches focused on cellular and subcellular mechanism-based in vitro and in silico evaluations of proarr hythmia are described are described.
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