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S. C. Wolff, K. Brubaker, R. C. Wright, J. L. Boyer; The Pharmacological Properties of Epinastine on Histamine H2 and H4 Receptors. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2303.
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Histamine is a central mediator of the allergic response. In addition to the H1 receptor, effector cells of the allergic response such as mast cells and eosinophils express H2 and H4 receptors. The purpose of this study was to characterize the pharmacological properties of epinastine, the active ingredient in Elestat®, on histamine H2 and H4 receptors.
Human eosinophils were used to perform chemotaxis, degranulation and cytokine secretion assays induced by histamine, or histamine receptor subtype specific agonists. Intracellular calcium mobilization and cAMP assay were used on cells expressing the human H2 or H4 receptors.
Histamine induced a dose-dependant release of ECP from peripheral blood eosinophils. The release occurred via piecemeal degranulation, and a maximum effect was seen with 1 µM histamine. The effects of specific agonists for the H1, H2, and H4 receptors, 1-methylhistamine, amthamine, and 4-methylhistamine respectively, suggest that the release of ECP was produced by stimulation of the H4 receptor. Neither 1-methylhistamine, nor amthamine induced a release of ECP from eosinophils, while 1 µM 4-methylhistamine elicited a response equivalent to a 1 µM histamine challenge. Histamine induced chemotaxis with a maximal response achieved with a 10 µM concentration. In an eosinophils enriched population of isolated white blood cells (19%), a 1 µM histamine challenge resulted in specific cytokine release. IL-4 and IFN-g increased the greatest amount over background, while more modest increases occurred with IL-1ß and GM-CSF. In recombinant CHO-K1 cells stably expressing the human H4 receptor, epinastine potently inhibited a histamine-mediated increase in intracellular calcium (IC50 = 0.9 nM). Additionally, epinastine inhibited a histamine mediated increase in the accumulation of intracellular cAMP in CHO-K1 cells stably expressing the human H2 receptor (IC50 = 78 µM).
Epinastine rapidly and potently inhibits histamine-mediated activation of the H1 receptor. This study shows that epinastine also blocks the H2 and H4 receptors. Stimulation of the H2 receptor has been previously shown to increase ocular redness (hyperemia), while the H4 receptor has been implicated in mast cell and eosinophil migration. The results presented here suggest that the H4 receptor is also involved in eosinophil activation and degranulation. The combined action of epinastine as an antagonist of the H1, H2 and H4 receptors may provide the pharmacological basis for the efficacy of Elestat to block the early and late phase inflammatory response in SAC patients.
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