olopatadine-hydrochloride and Anaphylaxis

To study the effects of ketotifen fumarate, olopatadine, and levocabastine on ocular active anaphylaxis in guinea pigs and on ocular immediate hypersensitivity in albino rats.. Clinical grading scores and Evans blue dye leakage to eyelids and to eyeballs were assessed in five treatment groups (n = 10): ketotifen fumarate 0.025%, olopatadine 0.1%, levocabastine 0.05%, negative control, and positive control.. At 20 minutes after challenge, edema scores for ketotifen-treated guinea pigs were statistically significantly lower than those for levocabastine or olopatadine. Active treatment significantly reduced vascular leakage in both models. Ketotifen significantly reduced vascular leakage in eyelids compared with the other drugs. In guinea pigs, vascular leakage in eyeballs was significantly reduced with ketotifen fumarate compared with olopatadine and levocabastine.. In the guinea pig model, ketotifen was more effective than olopatadine and levocabastine at reducing conjunctival edema and vascular permeability in eyelids and eyeballs. In the rat model, ketotifen was more effective at reducing vascular permeability in eyelids than olopatadine and levocabastine.

Topics: Anaphylaxis; Animals; Capillary Permeability; Conjunctivitis, Allergic; Dibenzoxepins; Disease Models, Animal; Edema; Eyelids; Guinea Pigs; Histamine H1 Antagonists; Ketotifen; Male; Olopatadine Hydrochloride; Ophthalmic Solutions; Ovalbumin; Piperidines; Rats

Olopatadine (AL-4943A; KW-4679) [(z)-11-[3-(dimethylamino)propylidene]-6, 11-dihydrodibenz[b,e]oxepine-2 acetic acid hydrochloride] is an anti-allergic agent which inhibits mast cell mediator release and possesses histamine H1 receptor antagonist activity. Studies were conducted to characterize the in vitro and in vivo pharmacological profile of this drug relevant to its topical ocular use. AL-4943A inhibits histamine release in a concentration-dependent fashion (IC50 = 559 microM) from human conjunctival mast cell preparations in vitro. Histamine release was not stimulated by AL-4943A at concentrations as high as 10 mM. In contrast, ketotifen stimulated histamine release at concentrations slightly higher than effective inhibitory concentrations. AL-4943A did not display any in vitro cyclooxygenase or 5-lipoxygenase inhibition. Topical ocular application of AL-4943A effectively inhibits antigen- and histamine-stimulated conjunctivitis in guinea pigs. Passive anaphylaxis in guinea pig conjunctiva was attenuated by AL-4943A applied 30 min prior to intravenous or topical ocular antigen challenge (ED50 values 0.0067% and 0.0170%, w/v, respectively). Antihistaminic activity in vivo was demonstrated using a model of histamine-induced vascular permeability in guinea pig conjunctiva. AL-4943A applied topically from 5 min to 24 hrs prior to histamine challenge effectively and concentration-dependently inhibited the vascular permeability response, indicating the compound has an acceptable onset and a long duration of action. Drug concentrations 5-fold greater than those effective against histamine-stimulated conjunctival responses failed to inhibit vascular permeability responses induced with either serotonin or Platelet-Activating-Factor. These data indicate that the anti-histaminic effect observed with AL-4943A is specific. These anti-allergic/antihistaminic activities of AL-4943A observed in preclinical model systems have been confirmed in clinical trials in allergic patients.

Topics: Administration, Topical; Anaphylaxis; Animals; Anti-Allergic Agents; Capillary Permeability; Conjunctiva; Conjunctivitis, Allergic; Dibenzoxepins; Dose-Response Relationship, Drug; Guinea Pigs; Histamine; Histamine H1 Antagonists; Histamine Release; Humans; Ketotifen; Male; Mast Cells; Olopatadine Hydrochloride; Ophthalmic Solutions; Rats; Rats, Sprague-Dawley