Emesis induced in domestic pigs: a new experimental tool for detection of antiemetic drugs and for evaluation of emetogenic potential of new anticancer agents.
The domestic pig was used to develop a new model for evaluating the emetogenic potential of anticancer drugs and determining the antiemetic activity of drugs. Emesis was characterized by expulsion of solid or liquid material. In each animal, the number of vomits after infusion of the emetogenic drug (infusion in ketamine and xylazine anesthesia) was recorded in 1-hr periods during the first 4 hr and then in a 4- and a 16-hr period. Intravenous infusion of cisplatin caused a concentration-dependent emetic response. Anti-cancer drugs other than cisplatin such as carboplatin, dactinomycin, cyclophosphamide, and ifosfamide, also induced emesis, indicating that the domestic pig is suitable to detect the emetogenic potential of chemotherapeutic agents. A cisplatin dose of 2 mg/kg i.v. proved to be most suitable for studying the effect of potential antiemetic drugs (applied as i.v. injection), because this cisplatin dose caused consistent emetic responses without other toxic signs in the 24 hr following its infusion. Emesis induced by cisplatin was reduced by high doses of metoclopramide (25 mg/pig; approximately 0.8 mg/kg). The more selective dopamine D2 receptor antagonists, alizapride and domperidone, even at high doses (25-50 mg/pig; approximately 0.8-1.6 mg/kg), did not inhibit cisplatin-induced emesis, nor did haloperidol up to 20 mg/pig (approximately 0.6 mg/kg). Sulpride (50 mg/pig; approximately 1.6 mg/kg) halved the occurrence of vomits in the first 4 hr after cisplatin, but this effect was followed by an increase in the frequency of vomits; thus, no change in the total number of vomits was observed in the 24-hr observation period.(ABSTRACT TRUNCATED AT 250 WORDS)
Szelenyi
I
I
Department of Pharmacology, ASTA-Medica AG, Frankfurt/Main, Federal Republic of Germany.
Herold
H
H
Göthert
M
M
D000818:Animals; D000932:Antiemetics / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000633:toxicity*; D016190:Carboplatin / Q000008:administration & dosage / Q000633:toxicity; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000633:toxicity; D003609:Dactinomycin / Q000008:administration & dosage / Q000633:toxicity; D004195:Disease Models, Animal; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005260:Female; D007069:Ifosfamide / Q000008:administration & dosage / Q000633:toxicity; D007262:Infusions, Intravenous; D007649:Ketamine / Q000008:administration & dosage / Q000633:toxicity; D008297:Male; D008787:Metoclopramide / Q000494:pharmacology / Q000627:therapeutic use; D012702:Serotonin Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D013552:Swine; D014839:Vomiting / Q000139:chemically induced* / Q000188:drug therapy; D014991:Xylazine / Q000008:administration & dosage / Q000633:toxicity
D000932:Antiemetics; D000970:Antineoplastic Agents; D065127:Dopamine D2 Receptor Antagonists; D012702:Serotonin Antagonists; D003609:Dactinomycin; D014991:Xylazine; D007649:Ketamine; D003520:Cyclophosphamide; D016190:Carboplatin; D008787:Metoclopramide; D002945:Cisplatin; D007069:Ifosfamide