olopatadine-hydrochloride and Eye-Diseases

This post hoc analysis used data from a previous study to more precisely evaluate the efficacy of olopatadine hydrochloride and epinastine hydrochloride in alleviating various levels of severity of ocular itching and conjunctival redness and to determine whether there were any significant differences in the number of responders to treatment.. The original study was a randomized, double-masked allergen challenge comparison assessment. Adult patients with allergic conjunctivitis were screened (visits 1 and 2); those who exhibited positive allergic reactions at both visits were randomized to 1 of 3 groups. olopatadine/epinastine, olopatadine/placebo, or epinastine/placebo. At visit 3, each eye was treated with study medication, and then challenged with allergen. Itching, redness, and chemosis assessments were recorded. For the present post hoc analysis, each eye in the olopatadine/epinastine group was separately classified at each time point, based on the pretreatment severity of their symptom (itching) and sign (conjunctival redness) scores, as moderate, moderate/severe, or severe. Data were analyzed to determine responders (eyes with itching and/or conjunctival redness scores of 0 [none]).. Of 96 patients screened, 66 were randomized to treatment (36 women, 30 men; mean age, 44.38 years [range, 20-71 years]). Olopatadine-treated eyes exhibited lower mean itching scores than epinastine-treated eyes in the moderate/severe and severe groups at all 3 time points (3, 5, and 7 minutes), with significance in the moderate/severe group at 5 minutes (P = 0.05) and in the severe group at 5 and 7 minutes (P = 0.017 and P = 0.02, respectively). Olopatadine-treated eyes had mean conjunctival redness scores similar to epinastine-treated eyes in all severity groups at all time points (10, 15, and 20 minutes) except in the severe group at 10 minutes (P = 0.03). On response analysis, for itching, the proportion of responders was significantly greater in the olopatadine group versus the epinastine group 7 minutes after challenge (27 [50.9%] vs 14 [26.4%]; P = 0.016). For conjunctival redness, the proportion of responders was significantly greater with olopatadine treatment versus epinastine treatment at 15 and 20 minutes after challenge (15 minutes, 12 [22.6%] vs 1 [1.9%] [P = 0.002]; 20 minutes, 10 [18.9%] vs 1 [1.9%] [P = 0.008]).

Topics: Adult; Aged; Dibenzazepines; Dibenzoxepins; Eye Diseases; Female; Humans; Hypersensitivity; Imidazoles; Male; Middle Aged; Olopatadine Hydrochloride; Placebos; Treatment Outcome

Olopatadine (AL-4943A; KW-4679) [(Z)-11-[3-(dimethylamino)propylidene]-6, 11-dihydrodibenz[b,e]oxepine-2-acetic acid hydrochloride] is an antiallergic/antihistaminic drug under development for topical ocular use. The effects of the compound on release of proinflammatory mediators (histamine, tryptase and prostaglandin D2) from monodispersed human conjunctival mast cells were assessed. Histamine receptor subtype binding affinities and functional potencies were determined with ligand binding and phosphoinositide turnover assays, respectively. Olopatadine inhibited the release of histamine, tryptase and prostaglandin D2, in a concentration-dependent manner (IC50 = 559 microM). Evaluation of the interaction of olopatadine with histamine receptors revealed a relatively high affinity for the H1 receptor (Ki = 31.6 nM, pKi = 7.5 +/- 0.1, n = 7) but lower affinities for H2 receptors (Ki = 100 microM, pKi = 4.0 +/- 0.19, n = 7) and H3 receptors (Ki = 79.4 microM, pKi = 4.1 +/- 0.16, n = 7). The H1 selectivity of olopatadine was superior to that of other ocularly used antihistamines studied, such as ketotifen, levocabastine, antazoline and pheniramine. The profiling of olopatadine in 42 nonhistamine receptor binding assays revealed that olopatadine interacts with only two nonhistamine receptor/uptake sites to any significant degree (pIC50 < or = 5-6). Olopatadine inhibited histamine-induced phosphoinositide turnover in human conjunctival epithelial cells (IC50 = 10 nM, pIC50 = 8.0, n = 4) and in other human ocular cells (IC50 = 15.8-31.6 nM, pIC50 = 7.5-7.8) and exhibited apparent noncompetitive antagonist properties in these cells, with an estimated dissociation constant (Kb) of 19.9 nM (pKb = 7.7, n = 6). This combination of mast cell mediator release inhibition and selective H1 receptor antagonism suggests that olopatadine may be particularly useful in the treatment of ocular allergic diseases. Indeed, olopatadine has recently shown clinical efficacy in an allergic conjunctivitis model in human subjects.

Topics: Anti-Allergic Agents; Binding, Competitive; Chymases; Conjunctiva; Dibenzoxepins; Eye Diseases; Histamine H1 Antagonists; Histamine Release; Humans; In Vitro Techniques; Ketotifen; Mast Cells; Olopatadine Hydrochloride; Phosphatidylinositols; Prostaglandin D2; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3; Serine Endopeptidases; Tryptases