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: Hiroe Nakayama, Hisashi Yamakuni, Mika Higaki, Hirofumi Ishikawa, Katsunori Imazumi, Masahiko Matsuo, Seitaro Mutoh
• Journal: Journal of pharmacological sciences (J Pharmacol Sci) Vol. 98 Issue 4 Pg. 396-403 (Aug 2005) ISSN: 1347-8613 [Print] Japan
• PMID: 16079468 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Antiemetics
• Imidazoles
• Indoles
• Receptors, Serotonin, 5-HT3
• Serotonin Antagonists
• FK 1052
• Receptors, Serotonin, 5-HT4
• Copper Sulfate
• Cisplatin

Topics

• Animals
• Antiemetics (pharmacology)
• Cisplatin
• Copper Sulfate
• Female
• Ferrets
• Imidazoles (pharmacology)
• Indoles (pharmacology)
• Male
• Motion Sickness
• Receptors, Serotonin, 5-HT3
• Receptors, Serotonin, 5-HT4
• Serotonin Antagonists (pharmacology)
• Shrews
• Vomiting (chemically induced, physiopathology, prevention & control)