Study of cardiac repolarization in healthy volunteers performed with mizolastine, a new H1-receptor antagonist.
OBJECTIVE
The occurrence of serious dysrhythmias, such as torsades de pointes, with terfenadine and astemizole had led to a reexamination of the potential effect of H1 antihistamines on cardiac repolarization. Mizolastine is a potent, selective, nonsedating peripherally acting H1-receptor antagonist which is registered for rhinitis and urticaria at a recommended dose of 10 mg once daily. The present study was carried out to investigate the effects of therapeutic and supratherapeutic doses of mizolastine, on ventricular repolarization in healthy volunteers.


METHODS
Twenty-four healthy young volunteers participated in a double-blind, placebo-controlled, randomised study with three parallel groups. Each group consisted of 2 way cross-over 7 day treatment periods where mizolastine (10, 20 or 40 mg) and placebo were randomly administered. On day 1 and day 7, 12-lead ECG recordings were performed prior and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, and 20 h after dosing and from day 2 to day 6, before dosing and 1, 2, 3, and 4 h after.


RESULTS
Whatever the analysis used (raw data, changes from baseline, incidence of individual out-of-range values) no significant differences were observed at any dose level vs placebo, on any of ECG parameters (HR, PR, QRS, QT, and QTc). In particular, no effect of mizolastine vs placebo was shown on QT and QTc although 95% CIs were wide. The only subject who exhibited a QTc>/=450 ms received placebo for 7 days.


CONCLUSIONS
This study found no evidence of an effect of mizolastine up to 40 mg (four times the therapeutic dose) on ventricular repolarization in healthy volunteers.
Chaufour
S
S
Synthélabo Recherche, 31 Av. Paul-Vaillant Couturier, BP110, 92225 Bagneux, France.
Caplain
H
H
Lilienthal
N
N
L'héritier
C
C
Deschamps
C
C
Dubruc
C
C
Rosenzweig
P
P
D000328:Adult; D019540:Area Under Curve; D001562:Benzimidazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D015716:Electrocardiography, Ambulatory; D006261:Headache / Q000139:chemically induced; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D012894:Sleep Stages / Q000187:drug effects
D001562:Benzimidazoles; D006634:Histamine H1 Antagonists; C076170:mizolastine