Blower P R
Medicinal Research Centre SmithKline, Beecham Pharmaceuticals, Harlow, Essex, U.K.
Eur J Cancer. 1990;26 Suppl 1:S8-11.
Work on the pharmacological effects of high-dose metoclopramide led Beecham scientists to identify the role of 5-HT3 receptors in the emetic response to cytostatic drugs and X-irradiation in animals. Further studies have confirmed and extended knowledge of the novel 5-HT3 antagonist granisetron. Dose-dependent inhibition of the 5-HT-induced Bezold-Jarisch reflex in anaesthetized rats was shown by doses of 0.1-10 micrograms/kg i.v. granisetron. Radioligand binding studies in rat brain revealed a high affinity (Ki 0.26 nM) for 5-HT3 sites and much lower affinities (Ki 1000 - greater than 10,000 nM) for 5-HT1, 5-HT2, 5-HT1A, 5-HT1B/C, 5-HT1C, alpha 1, alpha 2, dopamine D2, benzodiazepine, picrotoxin, beta, histamine H1 or opioid mu, kappa or delta binding sites. Granisetron was effective prophylactically after oral or i.v. doses or by intervention after i.v. doses (0.005-0.5 mg/kg) against cisplatin, cyclophosphamide and doxorubicin or X-irradiation-induced emesis in the conscious ferret in the absence of any side effects. It was concluded therefore, that granisetron is a selective and potent anti-emetic worthy of clinical investigation.
对高剂量甲氧氯普胺药理作用的研究使Beecham公司的科学家们确定了5-HT3受体在动物对细胞毒性药物和X射线照射所致呕吐反应中的作用。进一步的研究证实并扩展了对新型5-HT3拮抗剂格拉司琼的认识。静脉注射0.1-10微克/千克剂量的格拉司琼可使麻醉大鼠对5-HT诱导的贝佐尔德-雅里什反射产生剂量依赖性抑制。大鼠脑内放射性配体结合研究显示，格拉司琼对5-HT3位点具有高亲和力（Ki 0.26纳摩尔），而对5-HT1、5-HT2、5-HT1A、5-HT1B/C、5-HT1C、α1、α2、多巴胺D2、苯二氮䓬、苦味毒、β、组胺H1或阿片μ、κ或δ结合位点的亲和力则低得多（Ki 1000 - 大于10,000纳摩尔）。格拉司琼经口服或静脉给药后有效，或在静脉给药（0.005-0.5毫克/千克）后进行干预，可有效预防清醒雪貂因顺铂、环磷酰胺和阿霉素或X射线照射引起的呕吐，且无任何副作用。因此得出结论，格拉司琼是一种值得临床研究的选择性强效止吐药。
