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Pharmacokinetic-Pharmacodynamic Correlations of Antihistamines
Published in Hartmut Derendorf, Günther Hochhaus, Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
Eric Snoeck, Achiel Van Peer, Jos Heykants
Ebastine is a new histamine H1-antagonist which is extensively metabolized to its carboxylic acid metabolite carebastine, which appears to exert most, if not all, of the pharmacological actions. Vincent et al.71 investigated the pharmacokinetics, the antihistaminic effects, and the plasma concentration-effect relationship of ebastine in healthy subjects after a single oral dose of 10 and 50 mg. The pharmacokinetics of the metabolite carebastine was linear in the dose range studied and the terminal half-life averaged 10.6 and 12.5 h after 10 and 50 mg ebastine, respectively.
Drug Targeting to the Lung: Chemical and Biochemical Considerations
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Peter A. Crooks, Narsimha R. Penthala, Abeer M. Al-Ghananeem
Structural modification of the antihistamine azatadine (10a) by replacing the N-methyl group with various carbamate groups eliminates CNS activity (Villani et al. 1986). Loratidine (10b), the most potent compound in this series of carbamates, shows no sedation liability in experimental animals and binds selectively to peripheral histamine receptors (Ahn and Barnett 1986). Other non-sedatory H1 antihistamines are temelastine (11), tazifylline (12), cetrizine (13), levocabastine (14), and epinastine (15) (Brown et al. 1986, Nicholson and Stone 1986, deVos et al. 1986). Tazifylline is reported to have ten times the bronchodilator activity exhibited by either astemizole or terfenadine. The pre-clinical pharmacology of AHR-11325 (16) and PR 1036-654 (17) suggests that both these new compounds are potent, non-sedating, long-acting H1 antagonists (Nolan et al. 1989, Palmer et al. 1989). Ebastine (18a), a structural analogue of terfenadine, has been reported to be a potent, selective, long-lasting antihistamine devoid of sedation at an oral dose of 10 mg (Vincent et al. 1988). Its mode of action is thought to be due to metabolism to the active form (18b) (Vincent et al. 1988).
Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Like CYP3A4, CYP2J2 metabolizes antihistamine drugs such as terfenadine, astemizole, and ebastine; tyrosine kinase inhibitors such as dasatinib, imatinib, nilotinib, sorafenib, and sunitinib; tamoxifen; amiodarone; vorapaxar; thioridazine; mesoridazine; danazol; albendazole; fenbendazole; ritonavir; and cyclosporine (Hashizume et al. 2002; Kaspera et al. 2014; C.A. Lee et al. 2010; Matsumoto et al. 2002; Narjoz et al. 2014; Z. Wu et al. 2013). CYP2J2 and 2C19 are the major enzymes responsible for metabolism of albendazole and fenbendazole (Z. Wu et al. 2013). CYP2J2 plays a dominant role in the first-pass intestinal metabolism of ebastine to its pharmacologically active metabolite carebastine (Hashizume et al. 2002; J.I. Lee et al. 2010). A number of drugs are potent and selective CYP2J2 inhibitors (Ren et al. 2013). In particular, telmisartan and flunarizine inhibit CYP2J2 with Ki values of 0.19 μM and 0.13 μM, respectively. Norfloxacin and metoprolol are selective CYP2J2 inhibitors (Ren et al. 2013). Danazol is a potent CYP2J2 inhibitor, with a Ki value of 20 nM, although it also inhibits CYP2C9 and 2D6 (Lee et al. 2012).
Carbopol emulgel loaded with ebastine for urticaria: development, characterization, in vitro and in vivo evaluation
Published in Drug Delivery, 2022
Barkat Ali Khan, Arshad Ali, Khaled M. Hosny, Abdulrahman A. Halwani, Alshaimaa M. Almehmady, Muhammad Iqbal, Waleed S. Alharbi, Walaa A. Abualsunun, Rana B. Bakhaidar, Samar S. A. Murshid, Muhammad Khalid Khan
The topical drug delivery system is considered to be an important therapeutic technique for skin disorders. It minimizes the chances of systemic toxicity and provides a quick onset of action compared with oral therapy. Ebastine is a second-generation H1 antagonist antihistamine drug that is prescribed for all types of allergies. It is especially the drug of choice for urticaria and allergic rhinitis. To overcome the side effects associated with oral ebastine therapy and to achieve benefits related to topical therapy, ebastine topical gels were prepared and evaluated successfully. From the results of the study, we concluded that an ebastine emulgel formulation prepared with Carbopol 940 showed acceptable physical characteristics upon storage for 28 days. The prepared emulgel showed excellent anti-allergic activity and high drug release when compared with the marketed cream. Therefore, ebastine emulgel can be used as topical anti-allergic therapy for the treatment of urticaria.
Local immune response as novel disease mechanism underlying abdominal pain in patients with irritable bowel syndrome
Published in Acta Clinica Belgica, 2022
J. Aguilera-Lizarraga, M. Florens, H. Hussein, G. Boeckxstaens
The concept of food-mediated VHS proposed has major implications with respect to exploring novel treatments for IBS and related disorders. Our findings indicating H1R-mediated sensitization of visceral afferents [55] is in line with our previous pilot study evaluating the effect of the H1R receptor antagonist ebastine [54]. In this study, 55 IBS patients were enrolled in a placebo-controlled double-blind and randomized trial evaluating the effect of 12 weeks treatment with the H1R-antagonist ebastine. Of note, 46% of ebastine treated patients reported at least considerable relief (primary outcome) compared to 13% of placebo treated patients, yielding a therapeutic gain of 33%. A phase II study is ongoing to confirm this pilot study. Moreover, our findings set the stage for further studies exploring the potential of therapies targeting upstream mechanisms of mast cell-sensitization and/or activation, such as IgE neutralization or spleen tyrosine kinase (Syk) inhibitors, as the latter is a pivotal signaling transducer coupling antigen-IgE/FcεRI complexes regulating mast cell degranulation.
Second-generation antihistamines: a study of poisoning in children
Published in Clinical Toxicology, 2020
Eva Verdu, Ingrid Blanc-Brisset, Géraldine Meyer, Gaël Le Roux, Chloé Bruneau, Marie Deguigne
With regards to the cardiotoxicity of second-generation antihistamines, there was no evidence of lengthening of the QT interval in this study. No cases of arrythmia, repolarisation troubles or cardiac conduction disorders were reported. The first second-generation antihistamines, astemizole and terfenadine, lengthened the QT interval, leading to torsades de pointes and arrythmia due to a lengthening of the action potential by inhibiting the hERG potassium channels [24–26]. For substances in this study, pre-clinical studies showed that at an elevated concentration, the hERG potassium channels are blocked by ebastine and mizolastine and that the duration of the action potential is noticeably increased by ebastine [27–30]. In contrast, fexofenadine, desloratadine and cetirizine are very weak inhibitors of these channels [31–33]. Other in vivo studies showed that intravenous ebastine lengthened the QT interval in the ECG (34). During clinical trials, it was shown that ebastine, at five times the therapeutic dose, significantly lengthened the QT interval [29]. Clinical trials did not find any cardiotoxicity for children with cetirizine, loratadine, levocetirizine, desloratadine, ebastine, fexofenadine and mizolastine [8,12,19,27,32,35]. Pharmacovigilance and case reports demonstrate rare cases of arrhythmias and long QT interval with fexofenadine and cetirizine, primarily with predisposing conditions [8].