The
antiemetic and locomotor effects of two substituted
benzamides,
zacopride and
batanopride (BMY25801), were compared in ferrets after bilateral 60Co irradiation at 2, 4 or 6 Gy. Both
zacopride and BMY25801 were effective against
emesis and related signs.
Zacopride, tested at several doses (0.003, 0.03 and 0.3 mg/kg), appeared to be more potent because it abolished
emesis at 100-fold lower doses than did BMY25801 (3 mg/kg). The ED50 value for the
antiemetic effect of
zacopride was 0.026 mg/kg (confidence levels = 0.0095, 0.072 mg/kg). However, analysis of
emetic parameters recorded from
vomiting animals (e.g., latency to first
emesis) demonstrated that BMY25801 provided greater
antiemetic protection in this population than
zacopride without any apparent side effects. Locomotor activity was significantly depressed by both radiation (all doses) and
zacopride alone (0.03 mg/kg and 0.3 mg/kg). BMY25801 alone did not affect locomotor activity, and protected against the radiation-induced locomotor decrement. Although
zacopride potentiated the locomotor decrement to radiation, no clear dose-response relationship was evident. Bilateral abdominal
vagotomy significantly increased the latency to the first
emetic episode and significantly reduced the number of retches, but did not alter the duration of the prodromal response to 4-Gy irradiation. Unilateral
vagotomies had no effect.
Zacopride (at 0.03 mg/kg and 0.3 mg/kg) remained an effective
antiemetic in animals that received a bilateral
vagotomy, abolishing
emesis in four of eight and two of eight ferrets, respectively. These data suggest that the
antiemetic action of
zacopride does not fully depend on intact vagal innervation and also acts via other pathways.