Emesis: antiemetic effect of cyclophosphamide at central receptors of multitransmitter system in the cat.
The antiemetic and emetic actions of the anticancer drug cyclophosphamide injected intracerebroventricularly (i.c.v.) and intravenously (i.v.) through chronically implanted cannulae were investigated in unanaesthetized cats. Cyclophosphamide in single doses was injected into the cerebral ventricles and intravenously for 5 consecutive days. The antiemetic effect was regularly obtained, whereas the emetic effect was unpredictable and of low incidence. The antiemetic effect of i.c.v. and i.v. cyclophosphamide was assessed, when the neurotoxic (mydriasis, restlessness, emesis, ataxia, muscular weakness) signs subsided, against i.c.v. noradrenaline- and clonidine-induced emesis. Noradrenaline-induced emesis was dose-dependently and dose-independently inhibited with i.c.v. and i.v. cyclophosphamide. On the other hand, i.c.v. cyclophosphamide inhibited the clonidine-induced emesis in dose-independent manner, while i.v. injection of the anticancer drug had no significant effect on the emesis. The inhibition of emesis was consistently obtained and no significant differences in the antiemetic potency were found between 1 and 5 consecutive days of treatment with cyclophosphamide. However, the inhibition of noradrenaline-induced emesis was dose-dependent only after first administration of i.c.v. cyclophosphamide. It is assumed that noradrenaline acts at alpha-adrenoceptors within the area postrema and clonidine at alpha-adrenoceptors within and outside the area postrema as well as at muscarinic cholinoceptors, 5-hydroxytryptamine, dopamine and histamine H1 and H2 receptors, outside the area postrema, of multitransmitter system subserving the central regulation of emesis. It is suggested, therefore, that the antiemetic effect of cyclophosphamide at the receptors of the multitransmitter central emetic system is non-specific. In general, the antiemetic effect, even non-specific, of an anticancer drug could have practical implication. Namely, when a combination of two or more anticancer drugs are used for chemotherapy, the emesis could not occur if one of them could antagonize the emesis induced by other anticancer drug/s. Finally, cyclophosphamide injected i.c.v., but not i.v., evoked shortlasting emesis in about 20% of cats. Since the emesis was unpredictable and of low incidence it was not possible to study the mechanism/s and site/s of action of the anticancer drug.
Bosnjak
Snezana
S
Department of Pharmacology, Medical Faculty, P.O. Box 662, Belgrade 11000, Serbia, Yugoslavia. bosnjaks@ncrc.ac.yu
Beleslin
D B
DB
D000818:Animals; D000932:Antiemetics / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D002415:Cats; D003000:Clonidine / Q000494:pharmacology; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*; D014839:Vomiting / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*
D000932:Antiemetics; D017981:Receptors, Neurotransmitter; D003520:Cyclophosphamide; D003000:Clonidine; D009638:Norepinephrine