In vivo experimental approach for the risk assessment of fluoroquinolone antibacterial agents-induced long QT syndrome.

Abstract

The proarrhythmic effects of fluoroquinolone antibacterial agents, sitafloxacin, gatifloxacin and moxifloxacin, were compared using three in vivo models. In the halothane-anesthetized dogs (n=5), intravenous 10-min infusion of gatifloxacin and moxifloxacin (1-3 mg/kg) prolonged the ventricular effective refractory period and the repolarization period to a similar extent, whereas sitafloxacin (1-3 mg/kg) prolonged the former only. No significant change was detected in other cardiovascular parameters. In the chronic complete atrioventricular block dogs (n=4), oral administration of 100 mg/kg of gatifloxacin (2 of 4) and moxifloxacin (3 of 4) induced torsades de pointes, which was not observed by sitafloxacin. In the alpha-chloralose-anesthetized rabbits (n=5), intravenous 20-min infusion of 60 mg/kg of gatifloxacin induced torsades de pointes (1 of 5) in the presence of methoxamine infusion, which was not observed by sitafloxacin or moxifloxacin. Thus, the halothane-anesthetized model is suitable for assessing QT prolongation, whereas the chronic complete atrioventricular block model is sensitive for detecting torsadogenic action of drugs. The alpha-chloralose-anesthetized model is the simplest and least expensive method, but its sensitivity to detect proarrhythmic action may be less great.

• Authors: Katsuyoshi Chiba, Atsushi Sugiyama, Takehiro Hagiwara, Shin-ichi Takahashi, Kiyoshi Takasuna, Keitaro Hashimoto
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 486 Issue 2 Pg. 189-200 (Feb 20 2004) ISSN: 0014-2999 [Print] Netherlands
• PMID: 14975708 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Aza Compounds
• Fluoroquinolones
• Quinolines
• Chloralose
• sitafloxacin
• Gatifloxacin
• Moxifloxacin
• Halothane

Topics

• Administration, Oral
• Animals
• Aza Compounds (administration & dosage, adverse effects)
• Blood Pressure (drug effects)
• Chloralose
• Disease Models, Animal
• Dogs
• Electrocardiography
• Female
• Fluoroquinolones (administration & dosage, adverse effects)
• Gatifloxacin
• Halothane
• Heart Block (etiology, physiopathology)
• Heart Rate (drug effects)
• Infusions, Intravenous
• Long QT Syndrome (chemically induced, physiopathology)
• Male
• Moxifloxacin
• Quinolines (administration & dosage, adverse effects)
• Rabbits
• Risk Assessment
• Time Factors
• Torsades de Pointes (chemically induced, physiopathology)
• Ventricular Function, Left (drug effects)