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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Elsevier
2005-01-01
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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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