Pharmacodynamic and pharmacokinetic studies with azelastine in the guinea pig: evidence for preferential distribution into the lung

Chand, N.; Adusumalli, V E; Nolan, K.; Diamantis, W.; Wichmann, Joseph K.; Pivonka, J.; Langevin, C. N.; Wong, Karina; Kucharczyk, N.; Sofia, R. D.

doi:10.1111/j.1398-9995.1993.tb02170.x

Cited by 9 publications

(3 citation statements)

References 18 publications

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“…Indeed, weak bases, including H1-receptor antagonists, have been shown to accumulate in the lung where their concentration can be over 100-fold higher than in the plasma [46][47][48]. In A549 lung epithelial cells, RANTES release and the activity of transcription factors were inhibited in a histamine H1-receptor-independent manner by mizolastine and desloratadine at 10 À 6 or 10 À 5 M, which are concentrations likely to be reached in the lung.…”

Section: Discussionmentioning

confidence: 96%

Histamine H1‐receptor antagonists inhibit nuclear factor‐kappaB and activator protein‐1 activities via H1‐receptor‐dependent and ‐independent mechanisms

Roumestan

Henriquet

Gougat

et al. 2008

Clin Experimental Allergy

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Background Histamine H1-receptor antagonists are used to relieve the symptoms of an immediate allergic reaction. They have additional anti-inflammatory effects that could result from an inhibition of the transcription factors activator protein-1 (AP-1) and nuclear factorkappa B (NF-kB). The implication of the H1-receptor in these effects is controversial. Diphenhydramine is a first-generation H1-receptor antagonist while mizolastine and desloratadine are second-generation compounds. Mizolastine is also an inhibitor of 5-lipoxygenase (5-LO), an enzyme that has been involved in NF-kB activation. Objective We measured the ability of antihistamines to reverse histamine-induced smooth muscle contraction, an effect that involves the H1-receptor. We then investigated whether these drugs affect NF-kB and AP-1 activities in A549 lung epithelial cells, and whether this potential regulation involves H1-receptor and 5-LO. Methods Muscle tone was measured on tracheal segments of guinea-pigs. The H1-receptor was overexpressed by transfection and detected by Western blotting and immunofluorescence microscopy. NF-kB and AP-1 activities were assessed by reporter gene assays in cells overexpressing or not overexpressing the H1-receptor. Production of regulated upon activation, normal T cell expressed andsecreted (RANTES), a chemokine whose expression is induced through NF-kB, was measured using an immunoassay. Results H1-receptor antagonists reversed histamine-induced contraction in a dose-dependent manner. Induction of AP-1 and NF-kB activities by histamine and the down-regulatory effect of antihistamines required overexpression of the H1-receptor. In contrast, when tumour necrosis factor-a and a phorbol ester were used to stimulate NF-kB and AP-1 activities, respectively, repression of these activities did not involve the H1-receptor. Indeed, repression was triggered only by a subset of H1-receptor antagonists and was not stronger after overexpression of the H1-receptor. Mizolastine and desloratadine dose-dependently decreased tumour necrosis factor-a-induced production of RANTES. Diphenhydramine, H2-and H3-receptor antagonists as well as selective inhibitors of 5-LO were ineffective in this assay. Conclusion Repression of NF-kB and AP-1 activities by H1-receptor antagonists involves H1-receptor-dependent and -independent mechanisms but not 5-LO.

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Section: Discussionmentioning

confidence: 96%

Histamine H1‐receptor antagonists inhibit nuclear factor‐kappaB and activator protein‐1 activities via H1‐receptor‐dependent and ‐independent mechanisms

Roumestan

Henriquet

Gougat

et al. 2008

Clin Experimental Allergy

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“…It also exhibited activities such as antagonism of the chemical mediators adenosine, leukotriene C 4 (LTC 4 ), LTD 4 , endothelin-1, and platelet activation factor, and inhibition of the generation and/or release of interleukin-1 and LTs [486]. Azelastine was 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 [487][488][489][490]. Desmethylazelas-tine has been also detected in human plasma as a metabolite of azelastine after oral administration [491].…”

Section: Azelastinementioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

149

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Cytochrome P450 2C9 (CYP2C9) is one of the most abundant CYP enzymes in the human liver. CYP2C9 metabolizes more than 100 therapeutic drugs, including tolbutamide, glyburide, diclofenac, celecoxib, torasemide, phenytoin losartan, and S-warfarin). Some natural and herbal compounds are also metabolized by CYP2C9, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Many CYP2C9 substrates are weak acids, but CYP2C9 also has the capacity to metabolise neutral, highly lipophilic compounds. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Data from the site-directed mutagenesis studies have revealed that a number of residues (e.g. Arg97, Phe110, Val113, Phe114, Arg144, Ser286, Asn289, Asp293 and Phe476) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. CYP2C9 is subject to induction by rifampin, phenobarbital, and dexamethasone, indicating the involvement of pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor in the regulation of CYP2C9. A number of compounds have been found to inhibit CYP2C9 and this may provide an explanation for some clinically important drug interactions. Tienilic acid, suprofen and silybin are mechanism-based inhibitors of CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates, inducer or inhibitors of CYP2C9 in drug development and drug discovery scientists should develop drugs with minimal interactions with this enzyme. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.

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“…Terfenadine (a new Hi-receptor antagonist) and diphenhydramine (a traditional Hi-histamine receptor blocker) did not exert any mucolytic activity in mice and rats. Thus, mucolytic activity of azelastine, a drug preferentially distributed to the lungs [5], is probably related to properties other than H~-histamine receptor blockade in the airways. Furthermore, the long-lasting antiallergic (anti-PCA) activity [25], the inhibition of superoxide generation (O ~) in human neutrophils and eosinophils [26], nonspecific anti-infammatory activities in mice [15], and inhibition of bronchial hyperreactivity in rabbits [8] have all been shown to be dissociated from its antihistaminic activities.…”

Section: Discussionmentioning

confidence: 99%

Mucolytic activity of azelastine in mice and rats

et al. 1993

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The mucolytic activity of azelastine, an antiallergic/antiasthmatic drug, in mice and rats was investigated. The oral administration of test compounds 30 min before phenol red i.p. injection stimulated dye secretion in the trachea of mice. The resulting oral ED50's (mg/kg) were: azelastine, 0.16; salbutamol, 2.5; N-acetylcysteine, 61.8; S-Carboxymethyl-l-cysteine, < 100; bromhexine, > 100; and potassium iodide, approximately 200. In rats, several drugs stimulated secretion of fluorescein sodium (FINa) in the tracheobronchial lumen. The resulting oral ED50's (mg/kg) were: azelastine, 0.33; terbutaline, 0.3; salbutamol, 0.89; and S-carboxymethyl-l-cysteine, 56.8. Terfenadine and diphenhydramine (1-10 mg/kg, p.o.) did not stimulate tracheal secretion in rats and mice. The mucolytic activity of azelastine may contribute to its overall effectiveness, including antitussive activity in asthmatics. Finally, this activity seems to be dissociated from its H1-histamine receptor blocking activity.

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Pharmacodynamic and pharmacokinetic studies with azelastine in the guinea pig: evidence for preferential distribution into the lung

Cited by 9 publications

References 18 publications

Histamine H1‐receptor antagonists inhibit nuclear factor‐kappaB and activator protein‐1 activities via H1‐receptor‐dependent and ‐independent mechanisms

Histamine H1‐receptor antagonists inhibit nuclear factor‐kappaB and activator protein‐1 activities via H1‐receptor‐dependent and ‐independent mechanisms

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Mucolytic activity of azelastine in mice and rats

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