title: Antiemetic activity of FK1052, a 5-HT3- and 5-HT4-receptor antagonist, in Suncus murinus and ferrets.
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-HT3- and 5-HT4-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-HT3 and 5-HT4 receptors in these models. In Suncus murinus, oral administration of FK1052 (100 microg/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-HT3 and 5-HT4 receptors are not relevant to the control of motion sickness; and furthermore, it suggested that blocking 5-HT4 receptors in addition to 5-HT3 receptors does not have an additional effect on the control of cisplatin-induced emesis, but that 5-HT4 receptors are at least partly involved in the mechanism of emesis induced by copper sulfate.
authors.affiliation: Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd, Kashima 2-1-6, Osaka 532-8514, Japan.
authors.forename: Hiroe
authors.initials: H
authors.lastname: Nakayama
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yamakuni
authors.forename: Mika
authors.initials: M
authors.lastname: Higaki
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ishikawa
authors.forename: Katsunori
authors.initials: K
authors.lastname: Imazumi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Matsuo
authors.forename: Seitaro
authors.initials: S
authors.lastname: Mutoh
mesh_terms: D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D002945:Cisplatin; D019327:Copper Sulfate; D005260:Female; D005289:Ferrets; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009041:Motion Sickness; D044406:Receptors, Serotonin, 5-HT3; D044422:Receptors, Serotonin, 5-HT4; D012702:Serotonin Antagonists / Q000494:pharmacology*; D012788:Shrews; D014839:Vomiting / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control
chemical_list: D000932:Antiemetics; D007093:Imidazoles; D007211:Indoles; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; C081308:FK 1052; D044422:Receptors, Serotonin, 5-HT4; D019327:Copper Sulfate; D002945:Cisplatin