title: Effects of first- and second-generation histamine-H1-receptor antagonists on the pentobarbital-induced loss of the righting reflex in streptozotocin-induced diabetic mice.
abstract: The second-generation histamine-H(1)-receptor antagonists, such as epinastine and cetirizine, are used as non-sedating antihistamines for treating allergic symptoms due to their poor ability to penetrate blood-brain barrier. Because it has been reported that the blood-brain barrier system is disturbed in diabetes, it is possible that second-generation histamine-H(1)-receptor antagonists may easily penetrate the blood-brain barrier and cause potent sedation in diabetics. In the present study, we investigated the effects of first-generation (diphenhydramine) and second-generation (epinastine and cetirizine) histamine-H(1)-receptor antagonists on the duration of pentobarbital-induced loss of the righting reflex (LORR) in non-diabetic and diabetic mice. Systemic treatment with diphenhydramine (3 - 30 mg/kg, s.c.), and intracerebroventricular treatment with epinastine (0.03 - 0.3 microg/mouse) and cetirizine (0.03 - 0.3 microg/mouse) dose-dependently and significantly increased the duration of pentobarbital-induced LORR in both non-diabetic and diabetic mice. Although systemic treatment with epinastine (3 - 30 mg/kg, s.c.) and cetirizine (3 - 30 mg/kg, s.c.) did not affect the duration of pentobarbital-induced LORR in non-diabetic mice, these treatments significantly prolonged it in diabetic mice. Our results suggest that the systemic administration of second-generation histamine-H(1)-receptor antagonists may produce a central nervous system depressant effect in diabetes.
authors.affiliation: Department of Pathophysiology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Tokyo, Japan. kamei@hoshi.ac.jp
authors.forename: Junzo
authors.initials: J
authors.lastname: Kamei
authors.forename: Shoko
authors.initials: S
authors.lastname: Hirano
authors.forename: Shigeo
authors.initials: S
authors.lastname: Miyata
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Saitoh
authors.forename: Kenji
authors.initials: K
authors.lastname: Onodera
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D002492:Central Nervous System Depressants / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D039563:Histamine H1 Antagonists, Non-Sedating / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010424:Pentobarbital / Q000633:toxicity*; D004856:Postural Balance / Q000187:drug effects* / Q000502:physiology; D011969:Receptors, Histamine H1 / Q000502:physiology; D012018:Reflex / Q000187:drug effects / Q000502:physiology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002492:Central Nervous System Depressants; D006634:Histamine H1 Antagonists; D039563:Histamine H1 Antagonists, Non-Sedating; D011969:Receptors, Histamine H1; D010424:Pentobarbital