Abstract. We investigated the effect of FK1052 [(+)-8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one hydrochloride], a 5-HT 3 -and 5-HT 4 -receptor antagonist, on the emesis induced by motion stimuli, copper sulfate, or cisplatin in either Suncus murinus or ferrets and also clarified the role of the 5-HT 3 and 5-HT 4 receptors in these models. In Suncus murinus, oral administration of FK1052 (100 µg / kg) completely prevented emesis induced by cisplatin (18 mg / kg, i.p.). Intraperitoneal injection of scopolamine (10 mg / kg) and promethazine (32 mg / kg), but not FK1052 (1 mg / kg), significantly reduced the emetic responses by motion stimuli. In ferrets, copper sulfate (40 mg / kg, p.o.)-induced emesis was moderately prevented by FK1052 (3.2 mg / kg), but not by granisetron (3.2 mg / kg). Cisplatin-induced acute (10 mg / kg, i.v.) and delayed (5 mg / kg, i.p.) emesis were significantly reduced by single and multiple intravenous injection of both FK1052 (3.2 mg / kg) and granisetron (3.2 mg / kg), respectively. The present study suggests that FK1052 may be useful against both acute and delayed emesis induced by cancer chemotherapy. Moreover, it is suggested that blockades of 5-HT 3 and 5-HT 4 receptors are not relevant to the control of motion sickness; and furthermore, it suggested that blocking 5-HT 4 receptors in addition to 5-HT 3 receptors does not have an additional effect on the control of cisplatin-induced emesis, but that 5-HT 4 receptors are at least partly involved in the mechanism of emesis induced by copper sulfate.

Abstract. We evaluated the antiemetic effect of zacopride, a potent 5-HT 3 -receptor antagonist with 5-HT 4 -receptor agonist properties, on delayed emesis caused by cisplatin (5 mg / kg, i.p.) in ferrets, compared with granisetron, a selective 5-HT 3 -receptor antagonist. Multiple intravenous injections of zacopride at 1 mg / kg, a dose that completely inhibited acute emesis caused by cisplatin (10 mg / kg, i.v.), significantly reduced delayed emesis. Granisetron (3.2 mg / kg) also reduced delayed emesis but this failed to reach statistical significance. The present study suggests that a combined 5-HT 3 -receptor antagonist / 5-HT 4 -receptor agonist, like zacopride, may be useful against both acute and delayed emesis induced by cancer chemotherapy.

Abstract. Previous studies showed that diphenidol was effective on emetogens-induced pica, eating of non-nutritive substances, in rats, a model analogous to emesis in other species. We evaluated the actual antiemetic activity of diphenidol against four emetic stimuli in the dog and ferret, animals that possess an emetic reflex. In dogs, emetic responses to apomorphine were significantly prevented by diphenidol (3.2 mg / kg, i.v.), whereas diphenidol (3.2 mg / kg, i.v.´2) showed a weak inhibition to the vomiting evoked by cisplatin. In ferrets, diphenidol (10 mg / kg, i.p.) exhibited a weak antiemetic activity on the emesis induced by copper sulfate and had no activity on emesis by loperamide. On the other hand, CP-122,721, a NK 1 -receptor antagonist, significantly reduced the emetic episodes to all four stimuli. These results suggest that the prediction of antiemetic activity of compounds in animals lacking an emetic reflex does not always correspond with actual antiemetic activity.

showed rapid onset of antiemetic activity after oral administration. At doses of 0.32 mg/kg or more, a pretreatment time of 0.5 h was sufficient for complete inhibition of apomorphine-induced emetic responses. This fast onset after oral administration was supported by pharmacokinetic data, which demonstrated plasma levels of FK886 after oral administration reached levels similar to those 30 min after intravenous administration. These results suggest that FK886 has excellent antiemetic properties in dogs, and that its rapid-onset and long-lasting properties might make it a promising antiemetic agent.

The antiemetic effect of a potent and selective neurokinin-1 (NK 1 ) receptor antagonist, FK886 ([3,5-bis(trifluoromethyl) phenyl][(2R)-2-(3-hydroxy-4-methylbenzyl)-4-{2-[(2S)-2-(methoxymethyl)morpholin-4-yl]ethyl}piperazin-1-yl] methanone dihydrochloride), on cisplatin-induced acute and delayed emesis in ferrets was studied. Intravenous administration of FK886 dose-dependently inhibited cisplatin (10 mg/kg)-induced acute emesis with a minimum effective dose (MED) of 0.32 mg/kg. In the same study, oral FK886 administered 8 h prior to cisplatin also dose-dependently inhibited the acute emesis during the 4-h observation period with an MED of 3.2 mg/kg. Further, when given by repeated oral administration of ≥1.6 mg/kg at 12-h intervals, the first dose being administered 1 min before cisplatin, FK886 significantly decreased the number of emetic responses in cisplatin (5 mg/kg)-induced delayed emesis. In the same study, oral FK886 (3.2 mg/kg) repeatedly administrated at 12-h intervals, the first dose being administered 36 h post cisplatin, also significantly attenuated the delayed emesis. Pharmacokinetic data in ferrets showed that plasma FK886 reached a maximum concentration within 0.5 h of administration, suggesting rapid oral absorption. In addition, rapid brain penetration of FK886 was suggested by complete and near complete inhibition of GR73632-and copper sulfate-induced emesis, respectively, by low-dose intravenous FK886 administered shortly before the emetogens. These results suggest that FK886 is an orally available NK 1 receptor antagonist which is effective against both the acute and delayed emesis induced by cisplatin. Because of its therapeutic efficacy on the delayed emesis and rapid brain distribution after oral administration, FK886 may have potential as an antiemetic agent that can be used for interventional treatment of chemotherapy-induced delayed emesis.Key words FK886; neurokinin-1 antagonist; ferret emesis; cisplatin; GR73632; copper sulfate Nausea and vomiting are distressing symptoms that significantly detract from a patient's overall quality of life and their recovery during medical treatment. Nausea and vomiting both occur as symptoms of many diseases and as side effects of medical treatments, including cancer chemotherapy, radiotherapy, and general anesthesia in surgery. 1) Chemotherapy-induced nausea and vomiting (CINV) is perceived to be a major adverse effect of treatment by patients. 2) CINV may occur within hours of chemotherapy (acute phase) or be delayed until after the first 24 h, and then persist for several days (delayed phase). During the acute phase, chemotherapeutic agents induce serotonin (5-HT) release from enterochromaffin cells which stimulates local 5-HT 3 receptors on gastrointestinal vagal afferent nerves to initiate the vomiting reflex. [3][4][5] This may explain why 5-HT 3 antagonists have been shown to sufficiently control chemotherapy-induced acute emesis. [6][7][8] In contrast, 5-HT 3 antagonists are poorly effective against delayed emesis, 9,10) and the underlying ...