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

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...

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Main Authors: Hiroe Nakayama, Hisashi Yamakuni, Mika Higaki, Hirofumi Ishikawa, Katsunori Imazumi, Masahiko Matsuo, Seitaro Mutoh
Format: Article
Language:English
Published: Elsevier 2005-01-01
Series:Journal of Pharmacological Sciences
Online Access:http://www.sciencedirect.com/science/article/pii/S1347861319321553
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author Hiroe Nakayama
Hisashi Yamakuni
Mika Higaki
Hirofumi Ishikawa
Katsunori Imazumi
Masahiko Matsuo
Seitaro Mutoh
author_facet Hiroe Nakayama
Hisashi Yamakuni
Mika Higaki
Hirofumi Ishikawa
Katsunori Imazumi
Masahiko Matsuo
Seitaro Mutoh
author_sort Hiroe Nakayama
collection DOAJ
description 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. Keywords:: motion sickness, cisplatin, acute emesis, delayed emesis, copper sulfate
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spelling doaj.art-9c01ee585e994c918725eef19bc59a922022-12-22T00:07:51ZengElsevierJournal of Pharmacological Sciences1347-86132005-01-01984396403Antiemetic Activity of FK1052, a 5-HT3- and 5-HT4-Receptor Antagonist, in Suncus murinus and FerretsHiroe Nakayama0Hisashi Yamakuni1Mika Higaki2Hirofumi Ishikawa3Katsunori Imazumi4Masahiko Matsuo5Seitaro Mutoh6Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Kashima 2-1-6, Yodogawa-ku, Osaka 532-8514, JapanMedicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Kashima 2-1-6, Yodogawa-ku, Osaka 532-8514, Japan; Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Kashima 2-1-6, Yodogawa-ku, Osaka 532-8514, Japan; Corresponding author. Present address for correspondence: Department of Urology, Pharmacology Research Laboratories, Astellas Pharma Inc., Miyukigaoka 21, Tsukuba, Ibaraki 305-8585, Japan. FAX: +81-29-856-2558 E-mail: hisashi.yamakuni@jp.astellas.comNew Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Kashima 2-1-6, Yodogawa-ku, Osaka 532-8514, JapanMedicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Kashima 2-1-6, Yodogawa-ku, Osaka 532-8514, Japan; New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Kashima 2-1-6, Yodogawa-ku, Osaka 532-8514, JapanMedicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Kashima 2-1-6, Yodogawa-ku, Osaka 532-8514, JapanMedicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Kashima 2-1-6, Yodogawa-ku, Osaka 532-8514, JapanMedicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Kashima 2-1-6, Yodogawa-ku, Osaka 532-8514, JapanWe 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. Keywords:: motion sickness, cisplatin, acute emesis, delayed emesis, copper sulfatehttp://www.sciencedirect.com/science/article/pii/S1347861319321553
spellingShingle Hiroe Nakayama
Hisashi Yamakuni
Mika Higaki
Hirofumi Ishikawa
Katsunori Imazumi
Masahiko Matsuo
Seitaro Mutoh
Antiemetic Activity of FK1052, a 5-HT3- and 5-HT4-Receptor Antagonist, in Suncus murinus and Ferrets
Journal of Pharmacological Sciences
title Antiemetic Activity of FK1052, a 5-HT3- and 5-HT4-Receptor Antagonist, in Suncus murinus and Ferrets
title_full Antiemetic Activity of FK1052, a 5-HT3- and 5-HT4-Receptor Antagonist, in Suncus murinus and Ferrets
title_fullStr Antiemetic Activity of FK1052, a 5-HT3- and 5-HT4-Receptor Antagonist, in Suncus murinus and Ferrets
title_full_unstemmed Antiemetic Activity of FK1052, a 5-HT3- and 5-HT4-Receptor Antagonist, in Suncus murinus and Ferrets
title_short Antiemetic Activity of FK1052, a 5-HT3- and 5-HT4-Receptor Antagonist, in Suncus murinus and Ferrets
title_sort antiemetic activity of fk1052 a 5 ht3 and 5 ht4 receptor antagonist in suncus murinus and ferrets
url http://www.sciencedirect.com/science/article/pii/S1347861319321553
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