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Abstract: Current therapy for ocular allergy includes H1 antihistamines, mast cell stabilizers, dual action antihistamines (H1 antihistamines + mast cell stabilizers), and steroids. In this report, we describe the in vivo and in vitro characterization of alcaftadine, a recently approved antihistamine that exhibits a distinct set of therapeutic properties. When tested in a guinea pig model of conjunctivitis, alcaftadine prevented immediate allergic responses with an efficacy comparable with that of ketotifen, and was also able to attenuate delayed eosinophil influx with a potency similar to that of dexamethasone. Given recent reports suggesting a possible role for histamine H2 or H4receptors in the etiology of ocular allergy, we examined the binding properties of alcaftadine at all histamine receptor types. Alcaftadine is a high affinity ligand for the H1 receptor, with a pKi (8.5) that is comparable with that of other H1 antihistamines. It also shows an higher affinity for the H2receptor than ketotifen. Alcaftadine exhibited modest binding affinity for the H4 receptor (pKi = 5.8) with no affinity for the H3 receptor. The affinity for the H4 is higher than the value for ketotifen (pKi< 5). Using a cellular assay of H4 receptor activity, alcaftadine was shown to act as a functional antagonist of H4 receptor signaling. Overall, the studies suggest that alcaftadine is a histamine receptor antagonist with a broad spectrum of antihistamine activity and a unique combination of therapeutic effects. As such, it represents a new therapeutic option for the treatment of allergic conditions.
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