TOXICOLOGIC AND PHARMACOLOGIC PROPERTIES OF AMANTADINE HYDROCHLORIDE

Amantadine HCl (1-adamantanamine HCl) is an antiviral drug effective against A2 (Asian) influenza in animals and man. The acute oral LD50's of amantadine HCl were: guinea pig, 360 mg/kg; mouse, 700 mg/kg; and male rat, 1275 mg/kg. In the monkey, dog, and horse estimates of the LD50 ranged from >75 mg/kg to >500 mg/kg. Amantadine HCl was adequately tolerated on long term (6 months to 2 years) chronic administration to rats, dogs, and monkeys at doses more than 13 to 33 times the projected human doses without evidence of organ pathology. Central nervous system stimulation, anorexia, emesis and some convulsions at high doses were noted and were the direct or indirect cause of toxic manifestations including mortality. Studies in rats and rabbits revealed good reproductive tolerance and no indication of teratogenicity. Amantadine HCl caused several pharmacologic effects at relatively high doses including signs of central nervous system stimulation (increased spontaneous motor activity, antagonism of tetrabenazine-induced sedation), a mild, transient vasodepressor effect, some cardiac arrhythmias at high doses, some block of uptake of norepinephrine into labile stores (potentiation of norepinephrine vasopressor effect, block of phenethylamine vasopressor response, increase of myocardial contractile force, radioactive norepinephrine distribution studies, and antagonism of tetrabenazine effects), and a weak ganglionic-blocking effect. Amantadine HCl caused these effects at doses much higher than those employed in viral chemotherapy. © 1969.