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J. L. Boyer, K. Brubaker, S. C. Wolff, E. H. Fulcher, J. R. Lankford, T. Navratil; Assessment of Antimuscarinic Activity of Topical and Oral Antihistamines. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3616. doi: https://doi.org/.
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To evaluate the ability of topical and oral administered antihistamines to inhibit muscarinic receptor activity using in vitro functional cell-based assays.
C6 rat glioma cell lines stably expressing one of the five human muscarinic receptors (M1-M5) were established and validated for their use in pharmacological in vitro assays. Cells expressing separately each of the five muscarinic receptors were pretreated with antihistamine (azelastine, cetirizine, desloratadine, epinastine, fexofenadine, ketotifen and olopatadine) for 45 minutes followed by stimulation with a maximally effective concentration of acetylcholine and the muscarinic receptor response was measured as increases in intracellular calcium.
None of the antihistamines had agonist activity on any of the muscarinic receptor cell lines. In contrast, desloratadine and ketotifen inhibited all five muscarinic receptor subtypes with potencies (IC50 values) ranging between 22 and 1,400 nM. Azelastine and olopatadine tested up to 100 µM concentrations produced partial or complete inhibition of the muscarinic response, depending on the receptor subtype with apparent IC50 values ranging from 580 to 16,800 nM. Little to no antimuscarinic activity was observed for cetirizine, epinastine and fexofenadine.
Seasonal allergy relief by antihistamines is achieved by antagonism of one or more histamine receptors. However, non-selective properties of these drugs such as antimuscarinic activity have the potential to cause unwanted and uncomfortable side effects in the eye, nose or mouth. Indeed, our experiments reveal that several antihistamines (azelastine, desloratadine, ketotifen and olopatadine) possess marked anticholinergic activity in vitro thus having potential to cause adverse ocular side effects.
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