Interaction studies in mice of SCH 29851, a potential nonsedating antihistamine, with commonly used therapeutic agents

Abstract

SCH 29851 was studied for its ability to interact with selected drugs used in man. The non-sedating antihistamine terfenadine and the sedating antihistamine diphenhydramine were also studied for comparison. SCH 29851 at 80 mg/kg po in mice, a dose about 50 times its ED₅₀ for blocking histamine-induced paw edema in the same species, potentiated the anticonvulsant effects of diazepam. At the high dose of 320 mg/kg po, about 80 times its ED₅₀ for antihistamine effects, SCH 29851 potentiated the ability of high doses of ethanol and hexobarbital to induce loss of righting reflexes (LRR). However, no potentiation was seen when SCH 29851 was studied with lower doses of ethanol or phenobarbital that had anticonvulsant effects but did not cause LRR. At this high dose of 320 mg/kg po, SCH 29851 also did not interact with the antihypertensive drugs propranolol and α-methyldopa, the anti-ulcer drug cimetidine, the nasal decongestant pseudoephedrine, or the CNS stimulant d-amphetamine. A nearly identical profile of interactions was seen with terfenadine, including potentiation of diazepam at 50 times its antihistamine ED₅₀, potentiation of ethanol- and barbiturate-induced LRR at 80 times its antihistamine ED₅₀, and lack of interaction effects at 320 mg/kg po with each of the other tested drugs. The demonstration in this study of the significant interactions between diphenhydramine and many of the tested drugs is consistent with the clinical experience in man that this drug does have sedating properties and significant interactions with drugs like ethanol and diazepam. The similarity of the results obtained in this study with SCH 29851 and terfenedine suggests that these drugs will not differ significantly in clinical use. It seems likely, therefore, that antihistaminic effects will be achieved without significant sedative-hypnotic actions or interactions with drugs commonly used in man, e.g. ethanol, barbituates, and benzodizepines. However, confirmation of this prediction necessarily awaits the results of clinical trials.