Effects of azelastine hydrochloride, a novel anti-allergic drug, on the central nervous system

The effects of 4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1-(2H)-phthalazinone hydrochloride (azelastine hydrochloride), a new anti-allergic drug, on the central nervous system were studied in mice, rats and rabbits in comparison to clemastine, chlorpheniramine and diphenhydramine. In mice, azelastine showed a definite central action with the same dose range (10--40 mg/kg p.o.) as the reference drugs. However, the central action profile of azelastine was considerably different from those of the reference antihistaminics. Clemastine and diphenhydramine produced potent anti-tremorine and anti-pilocarpine activities, while azelastine was less active than the two drugs. Chlorpheniramine and diphenhydramine produced a marked anti-reserpine activity and a marked potentiation of the caffeine-induced hypermotility, while clemastine had little effect in this animal model; on the contrary, 40 mg/kg of azelastine suppressed the caffeine-induced hypermotility. In rats, a high dose of 100 mg/kg azelastine produced a slight suppression of the paradoxical sleep. But the drug affected neither the rectal temperature nor the conditioned avoidance response at oral doses up to 100 mg/kg. In unanesthetized and restrained rabbits, azelastine in a dose of 0.5 to 8 mg/kg i.v. showed no significant change in the spontaneous EEG activity and in the susceptibility of the ascending reticular activating system, whereas an i.v. dose of 2 mg/kg clemastine produced a marked high voltage and slow wave pattern in EEG activity and suppressed the reticular activating system.