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Matt J Chapin, Laura Belen, Andy Whitlock, Jac Wijkmans, Tiffany van de Meer, Mounir Andaloussi, Rogier A Smits, Iwan de Esch, Rob Leurs; The third generation of antihistamines: Assessment of Histamine H1/H4 Receptor Antagonists in a Murine Model of Allergic Conjunctivitis. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2482.
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© ARVO (1962-2015); The Authors (2016-present)
This study tested the hypothesis that drugs antagonizing both the H1 and the H4 histamine receptors (H1R and H4R) may provide superior relief for the signs and symptoms of allergic conjunctivitis when compared to traditional allergy therapies.
The study employed a murine conjunctival allergen challenge (CAC) model to test two structurally unrelated dual-action H1R/H4R antagonists: GD134 and GD136, as well as selective H4R antagonist GD135. Two positive comparators (olopatadine and prednisolone) and a vehicle control were also tested. Test articles were masked to investigators for the duration of the study. Animals (female balb/c mice) were sensitized by injection with a short ragweed allergen (SRW)/adjuvant mixture, and then challenged with topical SRW 17 days later to confirm an allergic response. Nine animals were randomly assigned to each of the 6 treatment groups. Animals received topical applications of test agent on 3 consecutive days, and then underwent CAC twice daily for 4 successive days; test agents were also applied on these days. Mean group values for hyperemia and squinting were compared with vehicle and with baseline to determine test agent effects.
Positive comparators reduced post-CAC hyperemia scores relative to the vehicle controls; these reductions were significant for prednisolone at challenge 1, 4, 6 and 8 (p <0.05). Both H1R/H4R antagonists reduced hyperemia significantly (GD136, 3 of 4 challenges significant at p<0.05; GD134, 4 challenges significantly lower at p<0.05). Selective H4R antagonist GD135 did not significantly reduce hyperemia. Squinting scores exhibited a progressive decline with each successive challenge, however only the scores for olopatadine at challenge 8 were significantly reduced when compared to controls (p<0.05).
Current antihistamine therapy for allergic conjunctivitis focuses on antagonism of the H1R signaling pathway. Despite this, recent studies have revealed not only a role for H4 receptors in the etiology of itch, the hallmark symptom of ocular allergy, but also identified the H4R as a new target to treat inflammation. Our studies provide evidence that two of our test compounds, GD134 and GD136, may have potential efficacy in the treatment of allergic conjunctivitis. Future studies, such as dose-ranging trials or studies in humans will help to clarify their potential.
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