In animals, amantadine hydrochloride caused several pharmacologic effects at relatively high doses. Signs of motor activity stimulation (increased spontaneous motor activity and antagonism of tetrabenazine- induced sedation) occurred in mice at oral doses of 35-40 mg/kg and above. A transient vasodepressor effect, cardiac arrhythmias and a weak ganglionic-blocking effect in dogs were observed following intravenous doses of 13.5 mg/kg or above. EEG activation has been reported in the rat and rabbit with high parenteral doses.
In addition, the observations summarized in the table below have afforded evidence that amantadine HCl causes norepinephrine release and blockade of norepinephrine re-uptake at peripheral autonomic neuron storage sites.
|Blockade by reserpine pre-treatment of amantadine-induced transient increase in myocardial contractile force.||dog||1 to 3||intravenous|
|Potentiation of norepine-phrine vasopressor response.||dog||40.5||intravenous|
|Block of phenethylamine vasopressor response.||dog||>13.5||intravenous|
|Block of norepinephrine uptake into the heart.||mouse||>31||intraperitoneal|
Amantadine hydrochloride is well absorbed by the oral route in all species studied; the rate of excretion of the drug is first order. The metabolism of amantadine hydrochloride in the monkey and mouse is somewhat similar to that in man. The monkey and mouse metabolize the drug less than the rat, dog and rabbit. The urine appears to be the major route of elimination. The dog has been shown to convert a portion of the administered drug to its N-methyl derivative which is excreted in the urine. No other metabolites have been identified.
The results of acute oral, intraperitoneal and intravenous toxicity studies in several species of laboratory animals are shown in Table Acute Toxicity Of Amantadine Hydrochloride LD50 (95% confidence limits). Oral LD50 values for dogs and rhesus monkeys could not be obtained because the animals vomited. One dog, which did not vomit, died at 93 mg/kg following signs of central nervous system stimulation, including clonic convulsions. In monkeys at doses of 200-500 mg/kg, emesis always occurred and convulsions appeared irregularly. At levels near the LD50, signs of central nervous system stimulation followed by tremors and brief clonic convulsions were common to the three rodent species by all routes of administration. All deaths occurred promptly, usually within a few minutes, or at the most within a few hours after compound administration.
Table Acute Toxicity Of Amantadine Hydrochloride LD50 (95% confidence limits)
|Mouse||F||700 (621,779)||205 (194,216)||97 (88,106)|
|Rat, neonatal||M,F||150 (111,189)|
|Guinea pig||F||360 (316,404)|
|* Emesis occurred|
Chronic oral toxicity experiments were carried out with rats (88-94 weeks), dogs (2 years) and monkeys (6 months). The amantadine hydrochloride dose levels were 16, 80 and 100-160 mg/kg; 8, 40 and 40-80 mg/kg; and 10, 40 and 100 mg/kg, respectively, administered daily (5 days per week). In rats, at the high dose only, a statistically significant decrease in body weight and excess mortality was seen; signs of central nervous system stimulation after each dosing, reduced food intake, and susceptibility to infection were noted. In dogs, tremors, hyperexcitability and emesis were seen at the middle and high levels, and food intake was reduced. One dog in the middle, and three dogs in the high-level group died. In an additional dog experiment, 30 mg/kg of amantadine hydrochloride divided into two doses six hours apart, was given seven days per week for six months. No drug-related effects were seen. In the monkey experiment, stimulation was continuously evident in the high level and was seen sporadically in the middle-level group. No other effects were noted. In none of these experiments with rats, dogs and monkeys were any amantadine hydrochloride-related pathological or histomorpho-logical changes seen.
Effects on Reproduction
In rats, a 3-litter reproduction study was performed. Amantadine hydrochloride 10 mg/kg in the diet, resulted in no observed abnormality. When the dose was raised to 32 mg/kg, fertility and lactation indices were somewhat depressed. No fetal abnormalities were noted in this experiment.
In a different study virgin rats were dosed orally with amantadine hydrochloride (50 or 100 mg/kg) from 5 days prior to mating until day 6 of pregnancy. Autopsy performed on day 14 of gestation showed significant decreases in the number of implantations and number of resorptions at 100 mg/kg. Teratology studies were performed in rats by administering the drug (37, 50 or 100 mg/kg) orally on days 7-14 of gestation. Autopsy just before parturition showed increases in resorption and decreases in the number of pups per litter at 50 and 100 mg/kg. Malformation of pups occurred with a frequency of 0% at the 37 mg/kg, 4.7% at the 50 mg/kg and 17% at the 100 mg/kg level. The majority of changes were skeletal (mainly spinal column and rib deficits), but some visceral changes (edema, undescended ovaries and testes) were also mentioned.
In a teratology study carried out in Japan, pregnant rats received amantadine hydrochloride (40 or 120 mg/kg) orally on days 9 to 14 of gestation. At the higher dose the dams had a slightly decreased rate of increase in body weight, the mortality rate of the fetus was increased and the surviving pups showed decreased body weight. This difference, however, disappeared after the end of the first postnatal week. There were no malformations or skeletal abnormalities.
In a teratogenetic study mice received amantadine hydrochloride 10 or 40 mg/kg, p.o., from the 7th to the 12th day of pregnancy. The most important findings include, at the high dose level, increased fetus mortality and reduced body weight of the dams as well as of the surviving offspring. One case of exencephalia was found in the high-level group which, in the opinion of the investigators, was not drug-related.
Rabbits were mated and dosed six days later with 8 or 32 mg/kg through day 16 and sacrificed on day 28. A separate study was reported in which rabbits received amantadine hydrochloride orally, 100 mg/kg, on days 7 to 14 of gestation. No teratogenic or other adverse effects were seen in these rabbit experiments.