Study of cardiac repolarization in healthy volunteers performed with mizolastine, a new H<sub>1</sub>‐receptor antagonist

Chaufour, S.; Caplain, H; Lilienthal, N.; LʼHéritier, C.; Deschamps, Chloé; Dubruc, C.; Rosenzweig, P.

doi:10.1046/j.1365-2125.1999.00927.x

Cited by 20 publications

(9 citation statements)

References 17 publications

(1 reference statement)

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“…These results indicate that mizolastine, 10–15 mg/day, did not prolong the ventricular repolarization interval in patients treated on a long‐term basis. This is in agreement with other studies that show no evidence of mizolastine causing relevant changes in QTc, 35 even when administered at four times the therapeutic dose in healthy volunteers, 36 or in combination with other agents. 37,38 Thus, mizolastine appears safe in the studies so far, but more data are still needed and should be obtained from postmarketing surveillance.…”

Section: Discussionsupporting

confidence: 93%

One‐year treatment of chronic urticaria with mizolastine: efficacy and safety

Lorette

Giannetti

Pereira

et al. 2000

Acad Dermatol Venereol

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Section: Discussionsupporting

confidence: 93%

One‐year treatment of chronic urticaria with mizolastine: efficacy and safety

Lorette

Giannetti

Pereira

et al. 2000

Acad Dermatol Venereol

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“…Mizolastine, more recently commercialized, is a well tolerated antihistamine agent [19–22] with antiallergic properties [23, 24]. Efficacy of mizolastine has been extensively reported in clinical studies in seasonal and perennial allergic rhinitis and rhinoconjunctivitis [25–30] and chronic urticaria [31, 32].…”

Section: Introductionmentioning

confidence: 99%

Comparative activity of cetirizine and mizolastine on histamine‐induced skin wheal and flare responses at 24 h

Purohit

Mélac

Pauli

et al. 2002

Brit J Clinical Pharma

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Aims The aim of our study was to compare the activity of cetirizine 10 mg with that of mizolastine 10 mg vs placebo at 24 h after intake in healthy volunteers. Methods This was a double-blind, randomized, placebo controlled, three-way crossover study with a wash-out period of 7t2 days between each period. The study included 36 healthy volunteers (18±50 years, mean age=32 years; 9 males). The objective measurement was the cutaneous reactivity to increasing concentrations of histamine (0,5,10,20,40, 80, 160 mg ml x1 ) administered by prick tests. The reactivity was evaluated by the wheal and¯are areas (mm 2 ). The AUC (area under curves) values of the wheal and¯are areas as a function of the log 2 transformed histamine concentration were calculated for each subject and treatment, and compared. Results A highly signi®cant treatment effect was evidenced both for wheal and are responses (P=0.0001). This indicates the good activity of both cetirizine 10 mg and mizolastine 10 mg in inhibiting skin wheal and¯are reactions to histamine. In addition, the mean AUC values signi®cantly differed between cetirizine and mizolastine (64.8 and 117.8 log 2 (mg ml x1 )rmm 2 for wheal, and 939.4 and 2340.8 for¯are, respectively; P=0.0001), with a superior activity of cetirizine than mizolastine at 24 h after intake both on wheal and¯are responses. The tolerance of cetirizine and mizolastine was good. The severity of the adverse events was never more than`moderate',`fatigue' being the most frequent reported symptom [cetirizine (6 subjects), placebo (3), mizolastine (5)], followed by`somnolence' [cetirizine (0), placebo (1), mizolastine (3)]. There was no serious adverse event. Conclusions This study shows that cetirizine (10 mg) suppresses skin reactivity to histamine more effectively than mizolastine (10 mg) 24 h after intake in healthy volunteers.

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“…The potential clinical relevance of a certain inhibitory action by mizolastine on HERG1 K + channels is worth considering, since the drug reached a C MAX of 0.3–1 μ M during standard therapy (10–20 mg die −1 ) ( Chosidow et al ., 1996 ; Chaufour et al ., 1999 ), a concentration range which clearly showed significant HERG1 inhibitory action, particularly in eukaryotic cells. However, it should be noted that the steady‐state levels achieved by the drug in therapeutic settings are much lower than the C MAX , and that the potency for HERG1 K + channels blockade by mizolastine is much lower than that exerted by the same drug at the level of H 1 receptors in vitro (the K D for mizolastine antagonism at H 1 receptors is 1 n M ) ( Benavides et al ., 1995 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of HERG1 K⁺ channels by the novel second‐generation antihistamine mizolastine

Taglialatela

Pannaccione

Castaldo

et al. 2000

British J Pharmacology

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1 Ventricular arrhythmias are rare but life-threatening side eects of therapy with the secondgeneration H 1 receptor antagonists terfenadine and astemizole. Blockade of the K + channels encoded by the Human Ether-aÁ -go-go-Related Gene 1 (HERG1) K + channels, which is the molecular basis of the cardiac repolarizing current I Kr , by prolonging cardiac repolarization, has been recognized as the mechanism underlying the cardiac toxicity of these compounds. 2 In the present study, the potential blocking ability of the novel second-generation H 1 receptor antagonist mizolastine of the HERG1 K + channels heterologously expressed in Xenopus oocytes and in HEK 293 cells or constitutively present in SH-SY5Y human neuroblastoma cells has been examined and compared to that of astemizole. 3 Mizolastine blocked HERG1 K + channels expressed in Xenopus oocytes with an estimated IC 50 of 3.4 mM. Mizolastine blockade was characterized by a fast dissociation rate when compared to that of astemizole; when ®tted to a monoexponential function, the time constants for drug dissociation from the K + channel were 72.4+11.9 s for 3 mM mizolastine, and 1361+306 s for 1 mM astemizole. 4 In human embryonic kidney 293 cells (HEK 293 cells) stably transfected with HERG1 cDNA, extracellular application of mizolastine exerted a dose-related inhibitory action on I HERG1 , with an IC 50 of 350+76 nM. Furthermore, mizolastine dose-dependently inhibited HERG1 K + channels constitutively expressed in SH-SY5Y human neuroblastoma clonal cells. 5 The results of the present study suggest that the novel second-generation H 1 receptor antagonist mizolastine, in concentrations higher than those achieved in vivo during standard therapy, is able to block in some degree both constitutively and heterologously expressed HERG1 K + channels, and con®rm the heterogeneity of molecules belonging to this therapeutical class with respect to their HERG1-inhibitory action.

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Study of cardiac repolarization in healthy volunteers performed with mizolastine, a new H₁‐receptor antagonist

Abstract: 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.

Cited by 20 publications

References 17 publications

One‐year treatment of chronic urticaria with mizolastine: efficacy and safety

One‐year treatment of chronic urticaria with mizolastine: efficacy and safety

Comparative activity of cetirizine and mizolastine on histamine‐induced skin wheal and flare responses at 24 h

Inhibition of HERG1 K⁺ channels by the novel second‐generation antihistamine mizolastine

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Study of cardiac repolarization in healthy volunteers performed with mizolastine, a new H1‐receptor antagonist

Abstract: 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.

Cited by 20 publications

References 17 publications

One‐year treatment of chronic urticaria with mizolastine: efficacy and safety

One‐year treatment of chronic urticaria with mizolastine: efficacy and safety

Comparative activity of cetirizine and mizolastine on histamine‐induced skin wheal and flare responses at 24 h

Inhibition of HERG1 K+ channels by the novel second‐generation antihistamine mizolastine

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Study of cardiac repolarization in healthy volunteers performed with mizolastine, a new H₁‐receptor antagonist

Inhibition of HERG1 K⁺ channels by the novel second‐generation antihistamine mizolastine