The role of specific 5-HT3 receptor antagonism in the control of cytostatic drug-induced emesis.

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.