BACKGROUND & PURPOSE: The therapeutically available quinolone antibiotic moxifloxacin has been used as a positive control for prolonging the QT interval in both clinical and non-clinical studies designed to assess the potential of new drugs to delay cardiac repolarization. Despite moxifloxacin prolonging QT, it has not been shown to cause torsades de pointes arrhythmias (TdP). Azithromycin is a macrolide antibiotic that has rarely been associated, clinically, with cases of proarrhythmia. As there is a lack of clinical data available, the cardiac safety of these drugs was assessed in a TdP-susceptible animal model by evaluating their repolarization and proarrhythmia effects. EXPERIMENTAL APPROACH & KEY RESULTS: In transfected HEK cells, the IC(50)s for I (hERG) were 45+/-6 and 856+/-259 microg ml(-1) for moxifloxacin and azithromycin, respectively. Intravenous administration of 2 and 8 mg kg(-1) moxifloxacin (total peak-plasma concentrations 4.6+/-1.5 and 22.9+/-6.8 microg ml(-1)) prolonged the QT(c) in 6 anaesthetized dogs with chronic AV block by 7+/-3 and 21+/-19%, respectively. Similar intravenous doses of azithromycin (total peak-plasma concentrations 5.4+/-1.3 and 20.8+/-4.9 microg ml(-1)) had no electrophysiological effects in the same dogs. The reference compound, dofetilide (25 microg kg(-1) i.v.) caused QT(c) prolongation (29+/-15%) and TdP in all dogs. Beat-to-beat variability of repolarization (BVR), quantified as short-term variability of the left ventricular monophasic action potential duration, was only increased after dofetilide (1.8+/-0.7 to 3.8+/-1.5 ms; P<0.05). CONCLUSION & IMPLICATIONS: As neither moxifloxacin nor azithromycin caused TdP or an increase in the BVR, we conclude that both drugs can be used safely in clinical situations.
BACKGROUND & PURPOSE: The therapeutically available quinolone antibiotic moxifloxacin has been used as a positive control for prolonging the QT interval in both clinical and non-clinical studies designed to assess the potential of new drugs to delay cardiac repolarization. Despite moxifloxacin prolonging QT, it has not been shown to cause torsades de pointes arrhythmias (TdP). Azithromycin is a macrolide antibiotic that has rarely been associated, clinically, with cases of proarrhythmia. As there is a lack of clinical data available, the cardiac safety of these drugs was assessed in a TdP-susceptible animal model by evaluating their repolarization and proarrhythmia effects. EXPERIMENTAL APPROACH & KEY RESULTS: In transfected HEK cells, the IC(50)s for I (hERG) were 45+/-6 and 856+/-259 microg ml(-1) for moxifloxacin and azithromycin, respectively. Intravenous administration of 2 and 8 mg kg(-1) moxifloxacin (total peak-plasma concentrations 4.6+/-1.5 and 22.9+/-6.8 microg ml(-1)) prolonged the QT(c) in 6 anaesthetized dogs with chronic AV block by 7+/-3 and 21+/-19%, respectively. Similar intravenous doses of azithromycin (total peak-plasma concentrations 5.4+/-1.3 and 20.8+/-4.9 microg ml(-1)) had no electrophysiological effects in the same dogs. The reference compound, dofetilide (25 microg kg(-1) i.v.) caused QT(c) prolongation (29+/-15%) and TdP in all dogs. Beat-to-beat variability of repolarization (BVR), quantified as short-term variability of the left ventricular monophasic action potential duration, was only increased after dofetilide (1.8+/-0.7 to 3.8+/-1.5 ms; P<0.05). CONCLUSION & IMPLICATIONS: As neither moxifloxacin nor azithromycin caused TdP or an increase in the BVR, we conclude that both drugs can be used safely in clinical situations.
Authors: Xian Chen; Jessica D Cass; Jenifer A Bradley; Corinn M Dahm; Zhuoqian Sun; Edmund Kadyszewski; Michael J Engwall; Jun Zhou Journal: Br J Pharmacol Date: 2005-11 Impact factor: 8.739
Authors: H van der Linde; A Van de Water; W Loots; B Van Deuren; H R Lu; K Van Ammel; M Peeters; D J Gallacher Journal: J Pharmacol Toxicol Methods Date: 2005 Jul-Aug Impact factor: 1.950
Authors: Morten B Thomsen; S Cora Verduyn; Milan Stengl; Jet D M Beekman; Geert de Pater; Jurren van Opstal; Paul G A Volders; Marc A Vos Journal: Circulation Date: 2004-10-11 Impact factor: 29.690
Authors: L Nalos; R Varkevisser; M K B Jonsson; M J C Houtman; J D Beekman; R van der Nagel; M B Thomsen; G Duker; P Sartipy; T P de Boer; M Peschar; M B Rook; T A B van Veen; M A G van der Heyden; M A Vos Journal: Br J Pharmacol Date: 2012-01 Impact factor: 8.739
Authors: Nikunjkumar Patel; Oliver Hatley; Alexander Berg; Klaus Romero; Barbara Wisniowska; Debra Hanna; David Hermann; Sebastian Polak Journal: AAPS J Date: 2018-03-14 Impact factor: 4.009
Authors: T R G Stams; V J A Bourgonje; H D M Beekman; M Schoenmakers; R van der Nagel; P Oosterhoff; J M van Opstal; M A Vos Journal: Br J Pharmacol Date: 2014-02 Impact factor: 8.739