Based on determinations of LD50, ED50 and therapeutic index, both in mice and rats, morphine sulfate was found to be at least six times as toxic and three times as effective in the cold (4°C) as: at room temperature (22 to 24°C). In the rat, however, morphine showed a very wide margin of safety in the cold as well as at room temperature, the therapeutic index being about 180. With pentobarbital, the margin of safety as indicated by therapeutic index in mice and rats in the cold was only one-third that at room temperature, while no significant differences were noted in the ED50 (median hypnotic dose) of the drug in all species of animals tested at 4°C and at 22°C. No significant differences were found in the plasma concentrations of the test drugs at different temperatures to account for the markedly increased toxicity of morphine and pentobarbital in all animals studied, as well as the apparent increased efficacy of morphine in mice and rats acutely exposed to cold. Greater-percentage pressor response to norepinephrine was demonstrated in dogs with or without hemorrhagic hypotension at 4°C than those at 22°C. The analgesic-potentiating effect of chlorpromazine was found to be greater in rats in the cold than those at room temperature when subeffective doses of morphine were administered simultaneously with a given dose of chlorpromazine. The clinical implications of these findings are discussed and recommendations are offered.
In rats acutely exposed to cold as compared to room temperature, the toxic responses to parenteral injections of meperidine hydrochloride, of dextroamphetamine sulfate and of prochlorperazine ethanesulfonate were invariably greater in cold than at room temperature. With further experiments an even greater increase was noted in the acute oral toxicity of prochlorperazine dimaleate at 4° C; the acute oral toxicity of this drug was 144 times greater at 4° C than at room temperature. This large difference in toxicity appeared to be an additive effect of the inherent hypothermic action of the drug and of the temperature-lowering action in the cold environment. Tests with larger animals, monkeys and dogs, indicated that the differences in toxicity between the room temperature and cold environments were not as great as in rats. The ability of large animals to retain body heat in the cold for a longer time than rats can may have contributed to the lesser effect. The results with monkeys injected with prochlorperazine in increasing dosage may have revealed the possibility of a tolerance development to the drug. Dextroamphetamine sulfate was about equally effective at either environment in inhibiting sleep in monkeys induced with pentobarbital. The tranquilizing effect of prochlor.perazine, as shown by avoidance behavior in monkeys subjected to a mild electric shock, was found to be about the same at 4° C as at room temperature. In dogs, injections of prochlorperazine at room temperature were about as effective as at 4° C in preventing emesis by an emetic dose of apomorphine.