Alcaftadine, a new antihistamine with combined antagonist activity at histamine H1, H2, and H4 receptors

Abstract

Current therapy for ocular allergy includes H 1 antihistamines, mast cell stabilizers, dual action antihistamines (H 1 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 H 2 or H 4 receptors 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 H 1 receptor, with a pK i (8.5) that is comparable with that of other H 1 antihistamines. It also shows an higher affinity for the H 2 receptor than ketotifen. Alcaftadine exhibited modest binding affinity for the H 4 receptor (pK i = 5.8) with no affinity for the H 3 receptor. The affinity for the H 4 is higher than the value for ketotifen (pK i , 5). Using a cellular assay of H 4 receptor activity, alcaftadine was shown to act as a functional antagonist of H 4 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.