Effects of zacopride and BMY25801 (batanopride) on radiation-induced emesis and locomotor behavior in the ferret.
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.
King
G L
GL
Department of Physiology, Armed Forces Radiobiology Research Institute, Bethesda, Maryland.
Landauer
M R
MR
D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D004307:Dose-Response Relationship, Radiation; D005289:Ferrets; D005684:Gait / Q000187:drug effects* / Q000528:radiation effects; D007274:Injections, Intraperitoneal; D008297:Male; D008787:Metoclopramide / Q000031:analogs & derivatives* / Q000494:pharmacology; D011833:Radiation Injuries, Experimental / Q000188:drug therapy; D014628:Vagotomy; D014839:Vomiting / Q000188:drug therapy* / Q000209:etiology
D000932:Antiemetics; D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds; C060190:batanopride; C055971:zacopride; D008787:Metoclopramide