title: Bepotastine besilate, a highly selective histamine H(1) receptor antagonist, suppresses vascular hyperpermeability and eosinophil recruitment in in vitro and in vivo experimental allergic conjunctivitis models.
abstract: To elucidate the ocular pharmacological properties of bepotastine besilate, a selective histamine H(1) receptor antagonist, when compared with other histamine H(1) receptor antagonists, using guinea pig allergic conjunctivitis models and in vitro models of eosinophil recruitment and mast cell membrane stabilization. Conjunctival vascular hyperpermeability was studied in guinea pigs passively sensitized with anti-ovalbumin antiserum or following subconjunctival injection of histamine. Modulation of eosinophil recruitment was evaluated for both platelet-activating factor (PAF)-induced eosinophil infiltration in guinea pigs and leukotriene B(4)-induced in vitro chemotaxis of guinea pig peritoneal eosinophils. Membrane-stabilizing effects of bepotastine also were studied with rat peritoneal mast cells stimulated with the ionophore A23187. Histamine H(1) receptor antagonists including bepotastine besilate were topically administered before ovalbumin, histamine or PAF challenges for in vivo experiments or were added directly to mast cell and eosinophil medium in vitro. Bepotastine besilate significantly inhibited conjunctival vascular hyperpermeability in a dose-dependent manner with maximal effect for bepotastine besilate 1.5%. In separate in vivo experiments, bepotastine besilate 1.0% was significantly more effective than levocabastine 0.025% in the passive sensitization model or olopatadine 0.1% in the histamine-induced hyperpermeability model. Bepotastine besilate 1.0% further suppressed PAF-induced eosinophil infiltration into conjunctival tissue more effectively than ketotifen 0.05%. Chemotaxis of guinea pig peritoneal eosinophils and histamine release from rat peritoneal mast cells in vitro were also inhibited by addition of bepotastine. Olopatadine had a weak effect as compared to that of bepotastine on eosinophil chemotaxis and no effect on mast cell histamine release in our study conditions. Bepotastine besilate was more potent than olopatadine, ketotifen, or levocabastine in reducing vascular hyperpermeability in various animal models of allergic conjunctivitis. Mast cell function and eosinophil chemotaxis were also inhibited in vitro with bepotastine, suggesting bepotastine acts as an inhibitor of allergic response through multiple mechanisms: histamine H(1) receptor antagonism, mast cell stabilization, and inhibition of eosinophil migration to ocular inflammatory sites.
authors.affiliation: Research Laboratories, Senju Pharmaceutical Co., Ltd., 1-5-4, Murotani, Nishi-ku, Kobe, Hyogo 651-2241, Japan. tkida@senju.co.jp
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kida
authors.forename: Atsuko
authors.initials: A
authors.lastname: Fujii
authors.forename: Osamu
authors.initials: O
authors.lastname: Sakai
authors.forename: Masahito
authors.initials: M
authors.lastname: Iemura
authors.forename: Ikuyo
authors.initials: I
authors.lastname: Atsumi
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Wada
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sakaki
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003228:Conjunctiva / Q000098:blood supply; D003233:Conjunctivitis, Allergic / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000187:drug effects*; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects; D007975:Leukotriene B4 / Q000494:pharmacology; D008297:Male; D008407:Mast Cells / Q000187:drug effects; D010047:Ovalbumin; D010529:Peritoneal Cavity / Q000166:cytology; D010880:Piperidines / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D006634:Histamine H1 Antagonists; D010880:Piperidines; D010972:Platelet Activating Factor; D011725:Pyridines; D007975:Leukotriene B4; C511534:bepotastine besilate; D006632:Histamine; D010047:Ovalbumin