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Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Oxatomide is a piperazine antihistamine and antiallergic drug used in the treatment of chronic urticaria, skin itching, atopic dermatitis, allergic rhinitis, and bronchial asthma (Hayashi et al. 2003; Richards et al. 1984). Oxatomide is well absorbed and almost completely metabolized. The major metabolic pathways of oxatomide included oxidative N-dealkylations at the piperazine nitrogens and at the benzimidazolone nitrogen and aromatic hydroxylation at the benzimidazolone moiety (Figure 3.80) (Meuldermans et al. 1984). The main urinary metabolite in the human is 2,3-dihydro-2-oxo-1H-benzimid-azole-1-propanoic acid (M5), resulting from the oxidative N-dealkylation at the 1-piperazine nitrogen (Meuldermans et al. 1984). Oxatomide is mainly metabolized by CYP2D6 and 3A4 (Goto et al. 2004). Glucuronidation of the hydroxy substituents on the benzimidazolone moiety is the main conjugating pathway. The aromatic hydroxylation is of greater importance in humans than in rats, since the total contribution of the hydroxylated metabolites including M1, M3, M6, M7, M9, M11, M12, and probably M4 and M10 is more abundant in humans (Meuldermans et al. 1984). Aromatic hydroxylation of oxatomide occurs mainly at the 6- but also at the 5-position of the benzimidazolone moiety. Oxidative N-dealkylation of oxatomide at the benzimidazolone nitrogen is more abundant in humans than in rats. This pathway together with aromatic hydroxylation results in the hydroxybenzimidazolone metabolite M3 and its glucuronide M1. Oxidative N-dealkylation at the 4-piperazine nitrogen is much more abundant in rats than in humans, resulting in M8 (Meuldermans et al. 1984). In addition, oxidative N-dealkylation at the 1-piperazine nitrogen is a major metabolic pathway in rats, dogs, and humans, resulting in the acid metabolite M5, which is the main urinary metabolite (Meuldermans et al. 1984). Notably, this metabolite is also the major urinary metabolite of the structurally related drug domperidone (Meuldermans et al. 1981).
The clinical evidence of second-generation H1-antihistamines in the treatment of allergic rhinitis and urticaria in children over 2 years with a special focus on rupatadine
Published in Expert Opinion on Pharmacotherapy, 2021
Antonio Nieto, María Nieto, Ángel Mazón
Regarding the efficacy of antihistamines in the management of CSU in children there are also very limited data (Table 2) [34–50]. It is very noticeable that clinical efficacy studies have not been conducted with ebastine, fexofenadine, levocetirizine, bilastine, or desloratadine in pediatric patients with CSU and only one single study assessed the use of cetirizine in children under the age of 6 [36]. In Italy, La Rosa et al. evaluated the efficacy and tolerability of cetirizine in comparison to a more commonly used antihistamine in pediatrics (oxatomide) in children with idiopathic chronic urticaria. This double-blind multicenter study recruited 62 children with ages ranging from 2 to 6 years (mean 3.85 years). The clinical study and the statistical evaluation were finally conducted on 57 children (28 on cetirizine and 29 on oxatomide). In general, the effectiveness of both drugs in the treatment of erythema, papules, edema, and itching demonstrated comparable therapeutic activity (P < 0.001). None of the medications was associated with significant adverse effects and there was no evidence of changes in hematochemical and urinary values [36].
Manifesto on united airways diseases (UAD): an Interasma (global asthma association – GAA) document
Published in Journal of Asthma, 2022
Angelica Tiotiu, Plamena Novakova, Ilaria Baiardini, Andras Bikov, Herberto Chong-Neto, Jaime Correia- de-Sousa, Alexander Emelyanov, Enrico Heffler, Guillermo Guidos Fogelbach, Krzysztof Kowal, Marina Labor, Stefan Mihaicuta, Denislava Nedeva, Sylvia Novakova, Paschalis Steiropoulos, Ignacio J. Ansotegui, Jonathan A. Bernstein, Louis-Philippe Boulet, Giorgio Walter Canonica, Lawrence Dubuske, Carlos Nunes, Juan Carlos Ivancevich, Pierachille Santus, Nelson Rosario, Tommaso Perazzo, Fulvio Braido
Antihistamines are the cornerstone of the treatment of AR. The use of the first-generation antihistamines (e.g. brompheniramine, chlorpheniramine, cyproheptadine, diphenhydramine, deschlorpheniramine, doxylamine, hydroxyzine, ketotifen, oxatomide, promethazine, tripelennamine) is considerably limited by side effects (i.e. drowsiness, dry mouth, nose, and throat, headache) (54).
Management of adult asthma and chronic rhinitis as one airway disease
Published in Expert Review of Respiratory Medicine, 2021
Angelica Tiotiu, Plamena Novakova, Guidos Guillermo, Jaime Correira de Sousa, Fulvio Braido
Antihistamines prevent histamine binding to the H1-receptor and its activation, and are frequently prescribed as treatment for AR. Both oral and local antihistamines are effective in AR. The use of the first generation oral antihistamines (e.g. brompheniramine, chlorpheniramine, cyproheptadine, diphenhydramine, deschlorpheniramine, doxylamine, hydroxyzine, ketotifen, oxatomide, promethazine, tripelennamine) is limited by side effects such as sedation and/or anticholinergic effect [2,75,76]. The second generation oral antihistamines (e.g. acrivastine, astemizole, azelastine, cetirizine, ebastine, epinastine, loratadine, mizolastine, terfenadine) are largely used in raison of fewer undesirable effects than the first-generation [2,77]. The preferable choice in practice is represented by new-generation oral antihistamines (e.g. desloratadine, fexofenadine, levocetirizine, rupatadine) able to control the symptoms with less side effects [78–81]. Bilastine is a recent highly selective oral H1-antihistamine approved for the treatment of AR without central nervous system penetration, anticholinergic or cardiotoxic effects and with minimal sedative properties [82,83]. Using antihistamines to treat AR delays asthma development [84], and improves asthma outcomes [85–87]. H1-antihistamines administration for AR is associated with an improvement in both nasal and asthma symptoms [86,88,89] and related QoL [90] without a significant impact on the lung function [88,91]. The association of antihistamines and intranasal decongestant improves rhinitis and asthma symptoms, lung function, and QoL compared to placebo in patients with seasonal AR and mild/moderate asthma [92]. Intranasal antihistamines administration proved high effectiveness, with a fast action onset and minimal systemic side effects [75,76,79,93]. Intranasal H1-antihistamines are superior to their oral administration as an add-on therapy to nCS in improving AR symptoms [94]. In patients with seasonal AR, intranasal administration of olopatadine–mometasone combination showed a higher benefit compared to olopatadine in monotherapy in nasal symptoms improvement [95,96]. Similarly, nasal treatment by azelastine hydrochloride-fluticasone propionate is associated with an improvement of rhinitis symptom scores and related QoL in patients with AR independently of the presence of asthma, but also with a decrease of asthma symptoms and reliever medication use in asthmatics [97].