title: Preclinical comparison of ebastine and other second generation H1-antihistamines.
abstract: The present study was performed to compare the properties of ebastine--the long duration of antiallergic effect and less penetration to the CNS--with those of other H1-antihistamines. Passive cutaneous anaphylactic reaction was induced and the dye leakage from the skin measured after oral administration of the various H1-antihistamines in guinea pigs. The H1-antihistamines examined inhibited passive cutaneous anaphylactic reactions, with ED50 values of 1.55-5.77 mg/kg administered orally. Evaluation at doses close to the ED50 values determined that the rank order of the various H1-antihistamines for the duration of antiallergic effects, calculated from the AUC, was as follows: ebastine>cetirizine> or =oxatomide=loratadine=epinastine. The inhibition of [3H]-mepyramine binding to the cortical membrane was examined ex vivo after oral administration of the drugs in rats. Ketotifen as a positive control of sedative antihistamine, oxatomide, cetirizine, ebastine and epinastine dose-dependently inhibited the [3H]-mepyramine binding to rat cortical membranes. However, ebastine and epinastine did not show 50% [3H]-mepyramine binding inhibition even at 100 mg/kg orally In conclusion, ebastine was shown to be a potent and long-lasting H1-antihistamine with less effect to the CNS. Consequently, in conjunction the two experimental models used in this study--passive cutaneous anaphylactic reaction in guinea pigs and ex vivo [3H]-mepyramine binding to rat cortical membrane--may be important to estimate the duration of antiallergic effects of drugs and to detect their sedative effects, which are important indicators in the development of new antiallergic drugs.
authors.affiliation: Department of Safety Pharmacology, Developmental Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Suita/Osaka, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Yakuo
authors.forename: M
authors.initials: M
authors.lastname: Yabuuchi
authors.forename: T
authors.initials: T
authors.lastname: Ito
mesh_terms: D000818:Animals; D002090:Butyrophenones / Q000493:pharmacokinetics / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects* / Q000502:physiology; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011738:Pyrilamine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011969:Receptors, Histamine H1 / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism
chemical_list: D002090:Butyrophenones; D006634:Histamine H1 Antagonists; D010880:Piperidines; D011969:Receptors, Histamine H1; D011738:Pyrilamine; C058249:ebastine