Preclinical Efficacy of Emedastine, a Potent, Selective Histamine H₁ Antagonist for Topical Ocular Use

Abstract

Emedastine [l-(2-ethoxyethyl)-2-(4-methyl-l-homopiperazinyl)-benzimidazole difumarate] was evaluated for topical ocular anti-histaminic activity in histamine and antigen stimulated conjunctivitis models. Concentration-dependent inhibition of histamine induced vascular permeability changes occurring in the conjunctiva was observed when the time interval between topical ocular administration and histamine challenge ranged from 1 min to 8 hr. The calculated ED50 values obtained using intervals of 1 min, 30 min, 2,4 and 8 hr were 0.0002%, 0.000035%, 0.0029%, 0.019% and 0.19%, w/v, respectively. Comparisons of relative potency 30 min post dosing between emedastine and other anti-histamines demonstrated that emedastine is equipotent to ketotifen, and 7, 7, 10, 10, 100, 357, 3333, and 5813 times more potent than brompheniramine, chlorpheniramine, clemastine, pyrilamine, levocabastine, pheniramine, diphenhydramine, and antazoline, respectively. Emedastine (0.1%) failed to significantly attenuate either serotonin or platelet-activating-factor induced vascular permeability changes indicating high selectivity for the histamine H, receptor. In a passive conjunctival anaphylaxis model in guinea pigs, significant inhibition of the allergic response was observed following topical ocular administration of emedastine 5 min or 30 min prior to antigen challenge (ED50s 0.0046% and 0.00022%, respectively). These data clearly indicate that emedastine has potential as a topical ocular anti-histamine for treating allergic conjunctivitis.

Mast cell hyperplasia induced by multiple challenge with cedar pollen in sensitised guinea pigs

“…Similar to other models [2,8,9], oral administration of an anti-histaminic drug potently suppressed the symptoms at the acute stage. However, symptoms at the chronic stage were resistant to the drug [7].…”

Histamine-Stimulated Cytokine Secretion from Human Conjunctival Epithelial Cells: Inhibition by the Histamine H₁ Antagonist Emedastine

“…In vivo, emedastine potently inhibited (ED 50 = 0.0002%) histamine-induced conjunctival vascular permeability in guinea pigs immediately following topical ocular drug application [5]. In an antigen stimulated conjunctivitis model, emedastine inhibited the allergic response with an ED 50 of 0.0046% [5]. The dissociation constants for the affinity of emedastine to the H 1 , H 2 and H 3 receptors in rodent brain homogenates are 1.3, 49,067 and 12,430 nM, respectively, demonstrating high selectivity of emedastine for the H 1 receptor [6].…”

“…In vivo, emedastine potently inhibited (ED 50 = 0.0002%) histamine-induced conjunctival vascular permeability in guinea pigs immediately following topical ocular drug application [5]. In an antigen stimulated conjunctivitis model, emedastine inhibited the allergic response with an ED 50 of 0.0046% [5].…”

“…Emedastine, 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)-benzimidazole difumarate, is a potent and selective antagonist of the histamine H 1 receptor with an immediate onset and long duration of action [5]. In vivo, emedastine potently inhibited (ED 50 = 0.0002%) histamine-induced conjunctival vascular permeability in guinea pigs immediately following topical ocular drug application [5].…”

Safety and Efficacy Comparison of Emedastine 0.05% Ophthalmic Solution Compared to Levocabastine 0.05% Ophthalmic Suspension in Pediatric Subjects with Allergic Conjunctivitis

“…It effectively relieves both itching and redness (2-4). Emedastine, a new benzimidazole derivative, is a novel compound with a promising in vitro and in vivo pre-clinical performance and an excellent safety and topical clinical efficacy profile (5)(6)(7)(8)(9)(10)(11). It is a very potent, long acting and selective H 1 antagonist.…”