Comparative study of various H1-blockers on neuropharmacological and behavioral effects including 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (KB-2413), a new antiallergic agent.
In a conditioned avoidance response tested in rats, all of the H1-blockers employed caused a dose-related inhibition at doses 5-20 mg/kg (i.v.) except for ketotifen that elicited significant suppression even at a dose of 1 mg/kg. No inhibition was seen after administration of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (KB-2413). ED50s were ranged from 4.1 to 7.4 mg/kg in diphenhydramine, pyrilamine and promethazine. In laminectomized rats, diphenhydramine, pyrilamine, promethazine and ketotifen suppressed the amplitudes of monosynaptic reflex potentials at doses higher than 2 mg/kg (i.v.). In the case of chlorpheniramine, significant inhibition was observed at a dose of 20 mg/kg. In a polysynaptic reflex, similar but less prominent inhibitions were affected by those drugs. However, KB-2413 did not influence spinal reflexes even at a dose of 20 mg/kg. In the rat phrenic nerve-diaphragm preparation, perfusion of H1-blockers at a concentration of 10(-5) M decreased the amplitudes of end-plate potentials except for chlorpheniramine and KB-2413. At 10(-4) M, all the test drugs caused significant inhibition. When the action potential of superior cervical ganglion was measured by the sucrose gap method, promethazine inhibited the action potential significantly at 10(-6) M, but the rest of the test drugs depressed the potentials at 10(-5) M. In spontaneous EEG, all H1-blockers caused a marked drowsy pattern at lower doses (2-5 mg/kg) except for chlorpheniramine, while in higher doses (10-20 mg/kg) epileptic signs in EEG with or without convulsive behavior were noticed. However, after KB-2413 (5-20 mg/kg) neither drowsy nor seizure pattern was observed, in EEG or behavior.
Tasaka
K
K
Kamei
C
C
Katayama
S
S
Kitazumi
K
K
Akahori
H
H
Hokonohara
T
T
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology*; D004569:Electroencephalography; D005727:Ganglia, Spinal / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D008297:Male; D009045:Motor Endplate / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012018:Reflex / Q000187:drug effects; D013997:Time Factors
D001562:Benzimidazoles; D006634:Histamine H1 Antagonists; C043345:emedastine