A TOXICOLOGIC STUDY OF TWO HISTAMINE ANTAGONISTS OF THE BENZHYDRYL ALKAMINE ETHER GROUP

¹ Research Laboratories, Parke, Davis & Company, Detroit, Michigan

Two compounds, -dimethylaminoethyl benzhydryl ether hydrochloride (Benadryl), and -morpholinoethyl benzhydryl ether hydrochloride (A-446), possessed in experimental animals pharmacologic properties similar in type, but different in intensity. The intensity of reactions and toxicity of Benadryl was roughly twice that of the morpholino compound.

In aminals both substances caused a complex syndrome of excitant reactions predominantly neurogenic in origin involving motor, sensory and autonomic nervous systems. Small doses increased the cardiac and respiratory rates.

Irrespective of the mode of administration, toxic doses of either compound caused excitement, spastic ataxia, extreme irritability, sensitivity to sound, mydriasis, painful hyperaesthesia, convulsive attacks, and respiratory and myocardial embarrassment. Death occurred from respiratory and myocardial depression following violent excitement and terminal prostration.

Duration of reactions varied with the route of administration. Dogs recovered in 15 minutes to about 3 hours from intravenous and 2 to 8 hours from peroral administration of non-lethal amounts.

Intravenously to dogs 2.5 mg./kg. of Benadryl and 5.0 mg./kg. of A-446 caused no reaction. Perorally 12.5 to 20 mg./kg. of Benadryl, and 20 to 30 mg./kg. of A-446 twice daily were well tolerated. Neither Benadryl or A-446 caused somnolence or cumulative toxic action in animals. No tolerance, sensiti zation or anaphylactic reactions occurred.

The histopathologic changes produced by toxic doses of both compounds were related to vasodilation, congesticn and stasis. In tolerated doses no acute or cumulative degenerative tissue changes occurred. The hematologic picture and physiologic function of liver and kidneys were essentially unaffected by either compound.

Barbiturates controlled excitant neurologic reactions, but did not prevent respiratory-cardiac depression.

Benadryl and A-446 were well tolerated in animals in appropriate dosage range for a period of six months. The former was the more active compound and on the basis of this study was submitted to clinical trials, results of which have been reported elsewhere.