Abstract. The fluoroquinolone antibiotic ciprofloxacin has been reported to block delayed rectifier K + channels at much higher concentrations than those at which it exerts its bactericidal activity. In this study using the halothane-anesthetized guinea pig, we assessed whether ciprofloxacin has a proarrhythmic activity. Ciprofloxacin at a clinically relevant dose of 3 mg/kg, i.v. did not affect any electrocardiographic parameters. At 10 mg/kg, it prolonged the QT interval and the duration of the monophasic action potential of the ventricle under sinus rhythm and constant ventricular pacing (n = 6). The extents of its effects on the ventricular repolarization phase were comparable to those of another fluoroquinolone antibiotic moxifloxacin at a clinically relevant dose of 3 mg/kg (n = 6). Meanwhile, the PR interval and QRS width were also increased by ciprofloxacin at 10 mg/kg, suggesting that the drug inhibited cardiac K + channels as well as Na + and Ca 2+ channels in vivo. These results suggest that ciprofloxacin exerted a multi-ion channelblocking action in the heart within the supra-therapeutic dose range. Therefore, careful observation may be necessary for patients with heart disease receiving a higher dose of ciprofloxacin in order to prevent the emergence of resistance.

Abstract. Antihistamines are known to belong to the chemical class that may induce long QT syndrome. Among them, cyproheptadine has been shown to exert multifaceted actions on the ventricular repolarization phase; namely, shortening of the action potential duration at supratherapeutic concentrations of 2 -8 mM and prolongation of the QT interval at ≥ 10 mM. Since information is limited regarding the in vivo electrophysiological effects of cyproheptadine, we assessed it using the halothane-anesthetized guinea-pig model, which was compared with effects of another antihistamine drug, hydroxyzine. Sub-therapeutic to therapeutic doses of hydroxyzine at 1 and 10 mg/kg, i.v. prolonged the QT interval and duration of monophasic action potential, whereas therapeutic to supra-therapeutic doses of cyproheptadine at 0.1 and 1 mg/kg, i.v. hardly affected the indices of ventricular repolarization. These results suggest that cyproheptadine may be categorized into antihistamines with little effect on the ventricular repolarization.

Guiding principle in the use of antihistamines for patients with long QT syndrome (LQTs) has not been sufficiently discussed, although suspected adverse drug reactions (ADR) relating to drug-induced LQTs were reported in some antihistamines. To clarify the causality between ADR and each drug, we exhaustively assessed the electropharmacological properties of 11 antihistamines with ADR reports by using anesthetized guinea-pig model under the monitoring of ECG parameters and monophasic action potential duration (MAP 90 ) of the right ventricle. Cetirizine, clemastine, diphenhydramine, ebastine, epinastine, fexofenadine, hydroxyzine, levocetirizine, loratadine, mequitazine, and promethazine were administered intravenously. Diphenhydramine and hydroxyzine at therapeutic dose and clemastine at 10 times higher therapeutic dose prolonged the QT interval and MAP 90 . On the other hand, other 8 antihistamines did not prolong the QT interval nor MAP 90 even though they were administered at 10 times higher therapeutic dose. These data indicated that diphenhydramine, hydroxyzine, and clemastine essentially have a potential to be a causative drug of drug-induced LQTs, whereas the cases using other 8 antihistamines should be reinvestigated on the case information such as the presence of cardiovascular diseases and concomitant medications.