Antiemetic Activity of FK1052, a 5-HT3- and 5-HT4-Receptor Antagonist, in Suncus murinus and Ferrets

• Published in: Journal of Pharmacological Sciences Vol. 98; no. 4; pp. 396 - 403
• Main Authors: Nakayama, Hiroe, Yamakuni, Hisashi, Higaki, Mika, Ishikawa, Hirofumi, Imazumi, Katsunori, Matsuo, Masahiko, Mutoh, Seitaro
• Format: Journal Article
• Language: English
• Published: Japan Elsevier B.V 2005; The Japanese Pharmacological Society; Elsevier
• Subjects: acute emesis; Animals; Antiemetics - pharmacology; Cisplatin; Copper Sulfate; delayed emesis; Female; Ferrets; Imidazoles - pharmacology; Indoles - pharmacology; Male; Motion Sickness; Receptors, Serotonin, 5-HT3; Receptors, Serotonin, 5-HT4; Serotonin Antagonists - pharmacology; Shrews; Vomiting - chemically induced; Vomiting - physiopathology; Vomiting - prevention & control; motion sickness; delayed emesis; cisplatin; copper sulfate; acute emesis
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1254/jphs.fpj05001x

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 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-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.