[Experimental study on the control of cisplatin-induced emesis in dogs]

In order to search for methods of controlling cisplatin-induced emesis, a series of experiments were performed with dogs. Cisplatin was administered i.v. to dogs at three-day intervals, and the number of emetic episodes and latency period to the first episode following injection were examined. The dose of cisplatin was 0.3mg/kg at the first injection, and thereafter square root 2-fold higher doses than the preceding ones were injected up to a maximum of 2.4 mg/kg. Emesis was observed from 0.42 g/kg. The number of emetic episodes increased with escalation of the dose up to 0.85 mg/kg, but decreased at higher doses. On the other hand, the latency period shortened with increase of the dose up to the highest one. From these results, the latency period is concluded to be a reliable parameter for evaluating the emetic activity of cisplatin and the efficacy of anti-emetics. The anti-emetic effect of vagotomy, ethyl amino-benzoate or metoclopramide was then examined. When 1 mg/kg of cisplatin was administered i.v., mean values of latency period and the number of episodes in dogs of a control group were 200 minutes and 20 times, respectively. In vagotomized dogs, no emesis was observed. When ethyl amino-benzoate was administered p.o. at doses of 12, 24 and 48 mg/kg 30 minutes before and 90 minutes after cisplatin injection, the number of episodes decreased to between 8 and 4.3 times, but the latency period was not prolonged. When s.c. injections of 1 mg/kg metoclopramide were combined with cisplatin in a similar manner to ethyl amino-benzoate, the latency period was prolonged up to 343 minutes, and the number of episodes decreased to 2.7 times. These results suggest that the peripheral autonomic nervous system is involved in the mechanism of emesis induction by cisplatin. Finally, the anti-emetic effect of metoclopramide was examined using the following administration schedules of cisplatin: a single i.v. injection of 3.75 mg/kg and daily i.v. injections of 1.25 mg/kg for three days. Metoclopramide showed a superior anti-emetic effect in the latter schedule, when the dose of 2 mg/kg was given i.v. 30 minutes before and 90 and 210 minutes after the cisplatin injection.