QT interval monitoring during clinical studies with mizolastine, a new H<sub>1</sub> antihistamine

Delauche–Cavallier, M. C.; Chaufour, S.; Guérault, E.; Lacroux, Annie; Murrieta, M.; Wajman, A

doi:10.1046/j.1365-2222.1999.0290s3206.x

Cited by 17 publications

(8 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the first of these studies, Chaufour et al 89 measured the effect on QTc of 10, 20 and 40 mg mizolastine given as single or repeated daily doses for 7 days, without any significant change in ventricular repolarization. Similar results were obtained in the second study, by Delauche-Cavallier et al, 91 who tested the effect of mizolastine up to 75 mg single dose and 40 mg repeated dose, again without any drug-induced QTc prolongation. Therefore, available evidence suggests that mizolastine can be safely updosed fourfold without inducing any significant change in cardiac risk.…”

Section: Mizolastinesupporting

confidence: 82%

Cardiac safety of second‐generation H₁‐antihistamines when updosed in chronic spontaneous urticaria

Cataldi

Maurer

Taglialatela

et al. 2019

Clin Experimental Allergy

View full text Add to dashboard Cite

The symptoms of chronic urticaria, be it chronic spontaneous urticaria (CSU) or chronic inducible urticaria (CindU), are mediated primarily by the actions of histamine on H1 receptors located on endothelial cells (the weal) and on sensory nerves (neurogenic flare and pruritus). Thus, second‐generation H1 antihistamines (sgAHs) are the primary treatment of these conditions. However, many patients are poorly responsive to licensed doses of antihistamines. In these patients, the current EAACI/GA2LEN/EDF/WAO guideline for urticaria suggests updosing of sgAHs up to fourfold. However, such updosing is off‐label and the responsibility resides with the prescribing physician. Therefore, the safety of the drug when used above its licensed dose is of paramount importance. An important aspect of safety is potential cardiotoxicity. This problem was initially identified some 20 years ago with cardiotoxic deaths occurring with astemizole and terfenadine, two early sgAHs. In this review, we discuss the mechanisms and assessments of potential cardiotoxicity of H1 antihistamines when updosed to four times their licensed dose. In particular, we have focused on the potential of H1 antihistamines to block hERG (human Ether‐a‐go‐go‐Related Gene) voltage‐gated K+ channels, also known as Kv11.1 channels according to the IUPHAR classification. Blockade of these channels causes QT prolongation leading to torsade de pointes that may possibly degenerate into ventricular fibrillation and sudden death. We considered in detail bilastine, cetirizine, levocetirizine, ebastine, fexofenadine, loratadine, desloratadine, mizolastine and rupatadine and concluded that all these drugs have an excellent safety profile with no evidence of cardiotoxicity even when updosed up to four times their standard licensed dose, provided that the prescribers carefully consider and rule out potential risk factors for cardiotoxicity, such as the presence of inherited long QT syndrome, older age, cardiovascular disorders, hypokalemia and hypomagnesemia, or the use of drugs that either have direct QT prolonging effects or inhibit sgAH metabolism.

show abstract

Section: Mizolastinesupporting

confidence: 82%

Cardiac safety of second‐generation H₁‐antihistamines when updosed in chronic spontaneous urticaria

Cataldi

Maurer

Taglialatela

et al. 2019

Clin Experimental Allergy

View full text Add to dashboard Cite

show abstract

“…No cases of mizolastine‐induced LQTS have been reported. Mizolastine is limitedly metabolised via the P450 cytochrome system (Delauche‐Cavallier et al ., 1999). As fexofenadine neither blocks HERG channels in vitro , nor is it metabolized in the liver, the first case of QT lengthening after intake of fexofenadine was surprising (Pinto et al ., 1999).…”

Section: Discussionmentioning

confidence: 99%

The antihistamine fexofenadine does not affect I_Kr currents in a case report of drug‐induced cardiac arrhythmia

Scherer

Lerche

Decher

et al. 2002

British J Pharmacology

View full text Add to dashboard Cite

1 The human HERG gene encodes the cardiac repolarizing K + current I Kr and is genetically inactivated in inherited long QT syndrome 2 (LQTS2). The antihistamine terfenadine blocks HERG channels, and can cause QT prolongation and torsades de pointes, whereas its carboxylate fexofenadine lacks HERG blocking activity. 2 In the present study the ability of fexofenadine to block the K897T HERG channel variant was investigated. The underlying single nucleotide polymorphism (SNP) A2960C was identi®ed in a patient reported to develop fexofenadine-associated LQTS. 3 K897T HERG channels produced wild-type-like currents in Xenopus oocytes. Even at a concentration of 100 mM, fexofenadine did not inhibit wild-type or K897T HERG channels. Coexpression of wild-type and K897T HERG with the û-subunit MiRP1, slightly changed current kinetics but did not change sensitivity to terfenadine and fexofenadine. 4 Western blot analysis and immunostaining of transiently transfected COS-7 cells demonstrated that overall expression level, glycosylation pattern and subcellular localization of K897T HERG is indistinguishable from wild-type HERG protein, and not altered in the presence of 1 mM fexofenadine. 5 We provide the ®rst functional characterization of the K897T HERG variant. We demonstrated that K897T HERG is similar to wild-type HERG, and is insensitive to fexofenadine. Although the polymorphism changes PKA and PKC phosphorylation sites, regulation of K897T HERG by these kinases is not altered. 6 Our results strongly indicate that QT lengthening and cardiac arrhythmia in the reported case of drug-induced LQT are not due to the K897T exchange or to an inhibitory e ect of fexofenadine on cardiac I Kr currents.

show abstract

“…When used experimentally, in higher than therapeutic doses, it blocked the potassium channels to some degree [31]. Human trials, however, did not result in QT interval changes, neither with normal doses, nor overdosed [32, 33]. Mizolastine is unavailable in Poland.…”

mentioning

confidence: 99%

Cardiovascular safety of antihistamines

Olasińska-Wiśniewska¹,

Olasiński²,

Grajek³

2014

pdia

View full text Add to dashboard Cite

Histamine is a mediator, which increases the permeability of capillaries during the early phase of allergic reaction, causes smooth muscle contraction of bronchi and stimulates mucous glands in the nasal cavity. Antihistamines are the basis of symptomatic treatment in the majority of allergic diseases, especially allergic rhinitis, allergic conjunctivitis, urticaria and anaphylaxis. The cardiotoxic effects of the two withdrawn drugs, terfenadine and astemizole, were manifested by prolonged QT intervals and triggering torsades de pointes (TdP) caused by blockade of the ‘rapid’ IKr potassium channels. These phenomena, however, are not a class effect. This review deals with a new generation of antihistamine drugs in the context of QT interval prolongation risk.

show abstract

QT interval monitoring during clinical studies with mizolastine, a new H₁ antihistamine

Abstract: ECG monitoring of volunteers and patients included in clinical studies conducted with mizolastine showed no significant effect of mizolastine on cardiac repolarization.

Cited by 17 publications

References 13 publications

Cardiac safety of second‐generation H₁‐antihistamines when updosed in chronic spontaneous urticaria

Cardiac safety of second‐generation H₁‐antihistamines when updosed in chronic spontaneous urticaria

The antihistamine fexofenadine does not affect I_Kr currents in a case report of drug‐induced cardiac arrhythmia

Cardiovascular safety of antihistamines

Contact Info

Product

Resources

About

QT interval monitoring during clinical studies with mizolastine, a new H1 antihistamine

Abstract: ECG monitoring of volunteers and patients included in clinical studies conducted with mizolastine showed no significant effect of mizolastine on cardiac repolarization.

Cited by 17 publications

References 13 publications

Cardiac safety of second‐generation H1‐antihistamines when updosed in chronic spontaneous urticaria

Cardiac safety of second‐generation H1‐antihistamines when updosed in chronic spontaneous urticaria

The antihistamine fexofenadine does not affect IKr currents in a case report of drug‐induced cardiac arrhythmia

Cardiovascular safety of antihistamines

Contact Info

Product

Resources

About

QT interval monitoring during clinical studies with mizolastine, a new H₁ antihistamine

Cardiac safety of second‐generation H₁‐antihistamines when updosed in chronic spontaneous urticaria

Cardiac safety of second‐generation H₁‐antihistamines when updosed in chronic spontaneous urticaria

The antihistamine fexofenadine does not affect I_Kr currents in a case report of drug‐induced cardiac arrhythmia