Inhibition of Histamine-Induced Human Conjunctival Epithelial Cell Responses by Ocular Allergy Drugs

Abstract

To evaluate the effects of topical ocular drugs with histamine H 1 -antagonist activity on histaminestimulated phosphatidylinositol turnover and interleukin (IL) 6 and IL-8 secretion from human conjunctival epithelial cells.Methods: Primary human conjunctival epithelial cell cultures were stimulated with histamine in the presence or absence of test drugs. Phosphatidylinositol turnover was quantified by ion exchange chromatography and cytokine contentofsupernatantsbyenzyme-linkedimmunosorbentassay.Results: Antazoline hydrochloride, emedastine difumarate, levocabastine hydrochloride, olopatadine hydrochloride, and pheniramine maleate attenuated histaminestimulated phosphatidylinositol turnover and IL-6 and IL-8 secretion. Emedastine was the most potent in ligand binding, phosphatidylinositol turnover, and IL-6 secretion, with dissociation constant and 50% inhibitory concentrations of 1-3 nmol/L. Olopatadine, antazoline, and pheniramine exhibited similar H 1 -binding affinities (32-39 nmol/L). However, olopatadine was approximately 10-fold more potent as an inhibitor of cytokine secretion (50% inhibitory concentration, 1.7-5.5 nmol/L) than predicted from binding data, while antazoline and pheniramine were far less potent (20-to 140-fold) in functional assays. Levocabastine (dissociation constant, 52.6 nmol/L) exhibited greater functional activity (50% inhibitory concentration, 8-25 nmol/L) than either antazoline or pheniramine.Conclusions: Histamine-stimulated phosphatidylinositol turnover and cytokine secretion by human conjunctival epithelial cells are attenuated by compounds with H 1 -antagonist activity. However, antihistaminic potency alone does not predict anti-inflammatory potential. Olopatadine, emedastine, and levocabastine were notably more potent than pheniramine and antazoline.Clinical Relevance: Selected topical ocular drugs with antihistaminic activity may offer therapeutic advantages to patients with allergic conjunctivitis by inhibiting proinflammatory cytokine secretion from human conjunctival epithelial cells.

Comparative Study of Clinical Efficacy and Tolerance in Seasonal Allergic Conjunctivitis Management with 0.1% Olopatadine Hydrochloride versus 0.05% Ketotifen Fumarate

“…Olopatadine hydrochloride 0.1% has a rapid initial action (minutes) that extends for hours, which allows a BID dosing schedule. It has strong, selective antihistaminic and mast cell stabilizing action with an important inhibitory effect on pro-inflammatory cytokine production (7,8). It is very well tolerated (less than 5% incidence of mild discomfort) when instillated.…”

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

“…Thus, inhibition of a cytokine-driven secondary histamine effect is plausible, and may help explain the statistically superior effects of emedastine that were seen in the later time points (Days 30 and 42). Emedastine was shown to have ten times greater potency in inhibiting cytokines in this same study (8)(9)(10).…”

Pharmacological, Pharmacokinetic and Clinical Properties of Olopatadine Hydrochloride, a New Antiallergic Drug

“…It promotes integrin expression, neutrophil degranulation, and chemotaxis of basophils and eosinophils. Yanni et al reported that olopatadine inhibited the histamine-induced secretion of IL-6 and IL-8 from human conjunctival epithelial cell with IC 50 values of 5.5 and 1.7 nmol / L, respectively (25). Results presented herein indicate that the compound is more potent as an inhibitor of cytokine secretion than would have been predicted from its histamine H 1 -receptor affinity (36 nmol/ L).…”