Substrates of Human CYP2D6
Shufeng Zhou in Cytochrome P450 2D6, 2018
Azelastine is a long-acting antiallergy and antiasthmatic drug, possessing histamine H1 receptor blocking activity (Chand and Sofia 1995). It is used for the treatment of hay fever and as eye drops for allergic conjunctivitis. It also exhibits activities such as antagonism of the chemical mediators adenosine, LTC4, LTD4, endothelin-1, and platelet activation factor, and inhibition of the generation or release of IL-1β and LTs (Chand and Sofia 1995). Azelastine is metabolized to desmethylazelastine, 6-hydroxyazelatine, 7- oxoazelastine, 4-[(4-chlorophenyl)methyl]-2-(5-methylamino-1-carboxy-2-pentyl)-1(2H)-phthalazinone, and 4-[(4-chlorophenyl)methyl]-2-(5-methylamino-1-carboxy-3-pentyl)-1(2H)-phthalazinone in rats and guinea pigs (Adusumalli et al. 1992; Chand et al. 1993; Tatsumi et al. 1980, 1984). Desmethylazelastine has also been detected in human plasma as a metabolite of azelastine after oral administration (Pivonka et al. 1987). In vitro studies indicate that azelastine is metabolized mainly by CYP3A4 and 2D6 via N-demethylation to desmethylazelastine, with minor contribution from CYP1A2 (Figure 3.73) (Nakajima et al. 1999). The estimated contribution of these three enzymes is 76.6%, 21.8%, and 3.9%, respectively. Desmethylazelastine shows pharmacological activity equivalent to the parent drug. In microsomes from B-lymphoblast cells, CYP2D6, 1A1, 3A4, 2C19, 2C9, and 1A2 catalyze azelastine N-demethylation, while in microsomes from baculovirus-infected insect cells, CYP2D6, 1A1, 1A2, 3A4, 3A5, 2C19, 2C9, and 2C8 catalyze this reaction (Nakajima et al. 1999).
The Pharmacotherapy of Rhinitis and Asthma
Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial in Textbook of Allergy for the Clinician, 2021
Two intranasal antihistamines preparations are available (azelastine and olopatadine). Their onset of action is within 15 to 30 minutes. In comparison studies they have proven of equal or occasionally slightly superior efficacy to the second-generation oral antihistamines (Wallace and Dykewicz 2008). Intranasal antihistamines are equally effective but faster in onset of action as compared with intranasal corticosteroids (Kaliner et al. 2009). In one study comparing intranasal azelastine to intranasal fluticasone, intranasal fluticasone was superior to reducing rhinorrhea, but intranasal azelastine showed comparable efficacy for all other nasal and ocular symptoms. Additionally, compared to baseline ocular symptoms, there was a larger percentage (53.0%) of patients on intranasal azelastine as opposed to intranasal fluticasone (39.6%) that exhibited a 50% reduction in reflective total ocular symptom score by day 14 of treatment (Carr et al. 2012b). The use of intranasal antihistamines in combination with intranasal corticosteroids demonstrates additional symptom reduction and improved quality of life as compared to intranasal antihistamine monotherapy (Brozek et al. 2017). Intranasal antihistamines may have greater efficacy for nasal congestion than oral antihistamines (Brozek et al. 2017). Azelastine is associated with taste perversion and somnolence in some patients (Bousquet et al. 2008), while these symptoms are less frequent with olopatadine (Lieberman et al. 2011).
Ear, nose and throat
Gina Johnson, Ian Hill-Smith, Chirag Bakhai in The Minor Illness Manual, 2018
If usual treatment ineffective, consider trying: MontelukastPB (as effective as antihistamines in children)Ranitidine (unlicensed indication) 150mg twice daily for adults (for more information, see the Members’ section of the NMIC website)Fluticasone/azelastinePBC nasal spray (Dymista®PBC, 1 spray twice daily into each nostril)
Azelastine a potent antihistamine agent, as hypolipidemic and modulator for aortic calcification in diabetic hyperlipidemic rats model
Published in Archives of Physiology and Biochemistry, 2022
Mohamed M. Elseweidy, Gehad M. Elnagar, Marwa M. Elsawy, Nabila Zein
The relationship between increased histamine levels and the progression of atherosclerosis was previously demonstrated in patients with allergy (Liu et al.2016). A previous study in confirm showed that histamine downregulated low-density lipoprotein receptors (LDL-R) in liver and reduced plasma HDL-c levels (Herink and Ito 2018). The latter was mediated by H1-receptor signalling. Conversely, fexofenadine (a histamine H1-receptor antagonist) increased HDL-c levels in experimental rats (Haas et al., 2018). Haas et al. (2018) showed that certain antihistamine agents attenuated atherosclerosis in-apo E-/- mice fed a high-fat diet (Haas et al., 2018). A previous report in addition indicated that histamine can mediate smooth muscle cell proliferation, neointimal changes and atherosclerosis promotion (Wang et al.2017). Among the selective H1 antagonists, azelastine is a well-known anti-allergic agent that inhibits the release of histamine from mast cells in the presence of antigen and non-antigen stimuli (Williams et al.2010). Azelastine has been shown to increase hepatic mRNA expression and protein levels of apolipoprotein A (apo A) (Haas et al., 2018). These findings have encouraged us to test azelastine as a possible inhibitor of aortic calcification in diabetic hyperlipidemic rats.
Chronic rhinosinusitis: pathogenesis, therapy options, and more
Published in Expert Opinion on Pharmacotherapy, 2018
Umut Can Kucuksezer, Cevdet Ozdemir, Mubeccel Akdis, Cezmi A. Akdis
Th2 predominance and nasal mucosal inflammation mainly caused by the increased recruitment of eosinophils are marked findings observed in AR. It is evident that, in patients with AR, nasal mucosal inflammation may influence the predisposition to CRS [80]. Thus, it may be reasonable to accept that AR treatment may also improve CRS outcomes [81]. Recently, the combined use of azelastine hydrochloride and fluticasone propionate as MP29-02 was reported to reduce the levels of inflammatory mediators and nasal hyperreactivity in patients with AR, thereby restoring nasal epithelial barrier function [82]. In addition to pharmacotherapy, the two other best-known strategies in the management of allergic diseases are avoidance measures for the responsible allergen and allergen immunotherapy (AIT) [83]. AIT is a unique and effective therapy option for allergic disorders, as it pursues the underlying mechanisms and possibly alters the disease course through the induction of long-lasting allergen tolerance. Few studies have evaluated the effectiveness of AIT in atopic CRS patients, including both CRSwNP and CRSsNP patients. A systematic review focusing on the role of AIT in CRS reported that in non-randomized controlled trials, the symptom scores in patients receiving AIT were improved compared with those at the baseline and those of the control patients. It also commented on the lack of available data on the efficacy of AIT for CRS-specific treatment outcome measures when used as an adjunct to conventional therapies [84].
Comorbid allergic rhinitis and asthma: important clinical considerations
Published in Expert Review of Clinical Immunology, 2022
E Nappi, G Paoletti, L Malvezzi, S Ferri, F Racca, M R Messina, F Puggioni, E Heffler, G W Canonica
Fixed combinations of INCS and INAH combine the high efficacy of the former and the rapidness of the latter and are indeed more effective than INCS or INAH alone [11]. On the other hand, combined INCS and oral anti-histamine (OAH) treatment does not appear to be superior to INCS alone [104,105]. INCS-INAH combinations should be considered for patients who do not achieve a desirable disease control with INCS alone or prefer to treat their symptoms on demand [11]. The fluticasone-azelastine combination was the first entry in the market and gained success due to its high efficacy and rapidness in alleviating symptoms, requiring approximately 5–15 minutes to achieve a significant reduction in symptoms [112]. Subsequently, mometasone-olopatadine combinations have been recently developed and proved to be highly effective and to have a quick onset of action, in the range of 10–15 minutes [105–117]. It appeared that the latter combination had an improved clinically meaningful impact on symptom reduction than the fluticasone-azelastine combination, but without reaching statistical significance [115]. Mometasone-olopatadine combination is a promising new tool for allergic rhinitis treatment and may provide an added benefit for these patients. Future studies specifically aimed at comparing the efficacy, onset of action, and safety of fixed INCS-INAH combinations are needed.
Related Knowledge Centers
- Allergic Conjunctivitis
- Allergic Rhinitis
- Asthma
- Nasal Spray
- Rash
- Pregnancy
- H1 Antagonist
- Eye Drop
- Breastfeeding
- Antihistamine