Summary
The antiemetic activity of DAU 6215, a novel antagonist of 5-HT3 receptors, was investigated in animal models of cytotoxic treatment-evoked emesis and compared with the antiemetic activity of ondansetron and metoclopramide. In dogs, vomiting was induced by i.v. cisplatin; in ferrets, the emetic response was elicited by i.v. doxorubicin or X-ray exposure. Pretreatment with 0.1–1 mg/kg DAU 6215 given i.v. or p.o. prevented the vomiting response to the different emetic agents. In the dog, the antiemetic potency of metoclopramide was 30 times lower than that of DAU 6215. Ondansetron was less potent than DAU 6215 against cisplatin and doxorubicin but was equally effective in the radiotherapy protocol. In this model, lengthening of the pretreatment time to 2 h did not affect the antiemetic efficacy of DAU 6215, whereas it decreased that of ondansetron. The results demonstrate that DAU 6215 is a highly effective and long-lasting inhibitor of cytotoxic treatment-induced emesis in different animal species.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Andrews PLR, Davidson HIM (1990) Activation of vagal afferent terminals by 5-hydroxytryptamine is mediated by the 5-HT3 receptor in the anaesthetized ferret. J. Physiol 422: 92
Andrews PLR, Hawthorn J (1987) Evidence for an extra-abdominal site of action for the 5-HT3 receptor antagonist BRL 24924 in the inhibition of radiation-induced emesis in the ferret. Neuropharmacology 26: 1367
Andrews PLR, Rapeport WG, Sanger GJ (1988) Neuropharmacology of emesis induced by anti-cancer therapy. Trends Pharmacol Sci 9: 334
Andrews PLR, Davis CJ, Bingham S, Davidson HIM, Hawthorn J, Maskell L (1990) The abdominal visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity. Can J Physiol Pharmacol 68: 325
Carmichael J, Cantwell BMJ, Edwards CM, Rapeport WG, Harris AL (1988) The serotonin type 3 receptor antagonist BRL 43694 and nausea and vomiting induced by cisplatin. BMJ 297: 110
Costall B, Domeney AM, Naylor RJ, Tattersall FD (1986) 5-Hydroxytryptamine M-receptor antagonism to prevent cisplatin-induced emesis. Neuropharmacology 25 (8): 959
Cubeddu LX, Hoffmann IS, Fuenmayor NT, Finn AL (1990) Efficacy of ondansetron (GR 38032F) and the role of serotonin in cisplatin-induced nausea and vomiting. N Engl J Med 322: 810
Fozard JR, Host M (1982) Selective inhibition of the Bezold-Jarisch effect of 5-HT in the rat by antagonists at neuronal 5-HT receptors. Br J Pharmacol 77: 520
Fozard JR, Mobarok Ali ATM (1978) Blockade of neuronal tryptamine receptors by metoclopramide. Eur J Pharmacol 49: 109
Fukui H, Kyoji I, Masahiro C, Masaki Y, Shuzo S (1991) Visceral afferent fibers and peripheral 5-HT3 receptor mediate cisplatin-induced emesis in dogs. Jpn J Pharmacol 55 [Suppl 1]: 152
Gralla RJ (1983) Metoclopramide: a review of antiemetic trials. Drugs 25: 63
Hamik A, Peroutka SJ (1989) Differential interactions of traditional and novel antiemetics with dopamine D2 and 5-hydroxytryptamine3 receptors. Cancer Chemother Pharmacol 24: 307
Miner WD, Sanger GJ (1986) Inhibition of cisplatin-induced vomiting by selective 5-hydroxytryptamine M-receptor antagonism. Br J Pharmacol 88: 497
Peroutka SJ, Snyder SH (1982) Antiemetics: neurotransmitter receptor binding predicts therapeutic actions. Lancet I: 658
Pratt GD, Bowery NG, Kilpatrick GJ, Leslie RA, Barnes NM, Naylor RJ, Jones BJ, Nelson DR, Palacios JM, Slater P, Reynolds DJM (1990) Consensus meeting agrees on distribution of 5-HT3 receptors in mammalian hindbrain. Trends Pharmacol Sci 11: 135
Robertson DW, Cohen ML, Krushinski JH, Wong DT, Parli CJ, Gidda JS (1990) LY1911617, a 5-HT3 receptor antagonist which does not cross the blood-brain barrier. Proceedings, Meeting on Serotonin, Basel, Switzerland, 2nd IUPHAR Satellite, July 11–13, 1990; Abstr. 149
Sagrada A, Nicola M, Micheletti R, Templeton D (1990) Antiemetic activity of DAU 6215 against vomiting induced by different chemotherapeutic agents. Proceedings, Meeting on Serotonin, Basel, Switzerland, 2nd IUPHAR Satellite, July 11–13, 1990; Abstr. 154
Schworer H, Racké K (1989) Effects of cisplatin on the release of 5-hydroxytryptamine from guinea-pig small intestine. Involvement of 5-HT3 receptors. Naunyn-Schmiedeberg's Arch Pharmacol 339 [Suppl]: 96
Seigel LJ, Longo DL (1981) The control of chemotherapy-induced emesis. Ann Intern Med 95: 352
Stables R, Andrews PLR, Bailey HE, Costall B, Gunning SJ, Hawthorn J, Naylor RJ, Tyers MB (1987) Antiemetic properties of the 5-HT3 receptor antagonist, GR38032F. Cancer Treat Rev 14: 333
Turconi M, Nicola M, Gil Quintero M, Maiocchi L, Micheletti R, Giraldo E, Donetti A (1990) Synthesis of a new class of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid derivatives as highly potent 5-HT3 receptor antagonists. J Med Chem 33: 2101
Turconi M, Donetti A, Montagna E, Schiavone A, Sagrada A, Nicola M, Cesana R, Rizzi C, Micheletti R (1991) Pharmacological properties of a novel class of 5-HT3 receptor antagonists. Eur J Pharmacol (in press)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sagrada, A., Turconi, M., Bonali, P. et al. Antiemetic activity of the new 5-HT3 antagonist DAU 6215 in animal models of cancer chemotherapy and radiation. Cancer Chemother. Pharmacol. 28, 470–474 (1991). https://doi.org/10.1007/BF00685825
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00685825