Horikoshi K, Yokoyama T, Kishibayashi N, Ohmori K, Ishii A, Karasawa A
Drug Development Research Laboratories, Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Sunto-gun, Shizuoka, Japan.
Jpn J Pharmacol. 2001 Jan;85(1):70-4. doi: 10.1254/jjp.85.70.
To clarify the mechanism for the severe emesis concomitant with intensive chemotherapy, we investigated the effects of 5-HT3- and 5-HT4-receptor antagonists on the emesis induced by the high-dose of cisplatin in Suncus murinus. The emesis induced by 50 mg/kg of cisplatin was reduced by the oral pretreatment with tropisetron, which is known as a 5-HT3- and 5-HT4-receptor dual antagonist in vitro, with the ID50 value of 0.52 mg/kg. On the contrary, granisetron, a selective 5-HT3-receptor antagonist, did not markedly inhibit the emesis at up to 30 mg/kg. Moreover, GR125487, a selective 5-HT4-receptor antagonist, did not inhibit the emesis. However, co-administration of GR125487 and granisetron significantly reduced the number of emetic episodes. The study of the co-administration of GR125487 with tropisetron showed that GR125487 did not further enhance the inhibitory effect of tropisetron alone, suggesting that the anti-emetic effect of tropisetron is mediated via the blockade of both 5-HT3 and 5-HT4 receptors. These results suggest that both the 5-HT3 and 5-HT4 receptors are involved in the emesis induced by the high-dose of cisplatin in Suncus murinus.
为阐明强化化疗伴随的严重呕吐的机制，我们研究了5-羟色胺3（5-HT3）和5-羟色胺4（5-HT4）受体拮抗剂对大剂量顺铂诱导的麝鼩呕吐的影响。5-HT3和5-HT4受体双重拮抗剂托烷司琼经口预处理可减轻50mg/kg顺铂诱导的呕吐，其半数抑制剂量（ID50）值为0.52mg/kg。相反，选择性5-HT3受体拮抗剂格拉司琼在高达30mg/kg时并未显著抑制呕吐。此外，选择性5-HT4受体拮抗剂GR125487也未抑制呕吐。然而，GR125487与格拉司琼联合给药可显著减少呕吐发作次数。GR125487与托烷司琼联合给药的研究表明，GR125487并未进一步增强托烷司琼单独的抑制作用，提示托烷司琼的止吐作用是通过阻断5-HT3和5-HT4受体介导的。这些结果表明，5-HT3和5-HT4受体均参与了大剂量顺铂诱导的麝鼩呕吐。
