Cisplatin administered by either the intravenous (i.v.) or intra-cerebroventricular (i.c.v.) route produced emesis in cats. The average time to onset of emesis was decreased significantly (4.0 min versus 100.6 min) when cisplatin was administered i.c.v. Zacopride administered either i.c.v. (0.02 mg) or i.v. (0.1 mg kg-1) completely blocked the emesis due to cisplatin given by either route. Their data show that cisplatin possesses a central emetic component and that this is blocked by zacopride.

The antiemetic activity, gastric motor activity, and dopamine receptor effects of metoclopramide, dazopride, and sulpiride were assessed to establish if enhancement of gastric motility or antagonism of central dopamine receptors is the predominant action for drug-induced suppression of cisplatin-induced emesis. Emesis produced in dogs by cisplatin is antagonized by metoclopramide and dazopride. The antiemetic actions of metoclopramide and dazopride are associated with their ability to enhance gastric motor activity. Dazopride, unlike metoclopramide, has minimal dopamine receptor antagonist properties. Sulpiride is a potent dopamine receptor antagonist; however, it had no effect on the stomach and was ineffective in suppressing cisplatin-induced emesis.

No abstract

A method is described for the surgical preparation, feeding and care of a chronic denervated gastric pouch in the rat. The basal secretion of the denervated pouch is approximately 0.24 ml/hr. and the hourly free HCl output is nearly zero after a fast of 12 hours. The volume of secretion and the free HCl output both increased after feeding with 3–5 gm of canned dog food. Insulin, 0.5 u, stimulated the output of free HCl from the innervated total gastric fistula but failed to stimulate the volume flow or the acid output of the denervated pouch. A denervated pouch prepared from the squamous or nonglandular portion of the stomach was also described. This portion of the stomach never secreted any free acid at any time over a period of 6 months postoperatively. This is the first physiologic proof that the white portion of the rat stomach is nonacid secreting. The advantages of using a denervated gastric pouch for physiologic and pharmacologic studies are discussed.

The antiemetic activity of zacopride against a variety of emetogenic agents has been determined in dogs. Zacopride was highly effective in inhibiting emesis due to a wide range of cancer chemotherapeutic agents, particularly cisplatin. It was well absorbed orally since the dose of zacopride required to inhibit cisplatin-induced emesis in dogs by 90% was 28 micrograms kg-1 both by i.v. and p.o. routes. Further, zacopride (1 mg kg-1 p.o.), administered after the onset of cisplatin-induced emesis, reduced the number of subsequent emetic episodes by 91%. Zacopride at 0.1, 1, or 3.16 mg kg-1 p.o. or i.v., reduced the number of emetic episodes due to dacarbazine, mechlorethamine, adriamycin, actinomycin D, or peptide YY by 100, 100, 86, 96 and 79%, respectively. However, zacopride was not effective in inhibiting emesis due to either apomorphine, copper sulphate, protoveratrine A, histamine, or pilocarpine. No adverse effects attributed to zacopride were observed. Zacopride is thus a unique and potent antiemetic agent as it selectively inhibits the emetic response to cancer chemotherapy agents and peptide YY.