Probable involvement of the 5-hydroxytryptamine(4) receptor in methotrexate-induced delayed emesis in dogs.
Delayed emesis in cancer patients undergoing chemotherapy remains a significant problem. The pathogenesis of delayed emesis is still obscure. It was recently demonstrated that methotrexate (MTX), an anticancer drug, evoked delayed emesis in dogs in a manner similar to its actions in humans. We evaluated the antiemetic activity of FK1052, a potent antagonist for both the 5-hydroxytryptamine (HT)(3) and 5-HT(4) receptors, on delayed emesis induced by MTX in beagle dogs. Animal behavior was recorded for 3 days using a video camera. Delayed emesis lasting up to 72 h was observed in dogs treated with MTX (2.5 mg/kg i.v.), but acute emesis did not occur. The following antiemetics, at the dose that prevents cisplatin-induced acute emesis in dogs, were administered i.v. as multiple injections every 12 h during days 2 to 3. FK1052 (1 and 3.2 mg/kg) significantly reduced the emetic episodes caused by MTX, whereas ondansetron (1 mg/kg), a selective 5-HT(3) receptor antagonist, was not effective. The emetic episodes induced by MTX were also inhibited by another 5-HT(3/4) receptor antagonist, tropisetron (1 mg/kg). CP-122,721 (0. 1 mg/kg), a potent selective tachykinin NK(1) receptor antagonist, significantly reduced the emetic responses to MTX. Copper sulfate-induced emesis in dogs was also prevented by FK1052, tropisetron, and CP-122,721 but not by ondansetron. FK1052, tropisetron, and ondansetron had negligible affinity for the NK(1) receptor at 1 microM. These results suggest that the 5-HT(4) receptor may be in part involved in the production of delayed emesis induced by MTX in dogs and that FK1052 may be a useful drug against both acute and delayed emesis induced by cancer chemotherapy.
Yamakuni
H
H
Department of Metabolic Diseases, Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan. hisashi_yamakuni@po.fujisawa.co.jp
Sawai
H
H
Maeda
Y
Y
Imazumi
K
K
Sakuma
H
H
Matsuo
M
M
Mutoh
S
S
Seki
J
J
D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D002945:Cisplatin / Q000633:toxicity; D019327:Copper Sulfate / Q000494:pharmacology; D004285:Dogs; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008727:Methotrexate / Q000633:toxicity*; D010880:Piperidines / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000502:physiology; D011985:Receptors, Serotonin / Q000187:drug effects*; D044406:Receptors, Serotonin, 5-HT3; D044422:Receptors, Serotonin, 5-HT4; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013997:Time Factors; D014839:Vomiting / Q000139:chemically induced* / Q000517:prevention & control
D000932:Antiemetics; D007093:Imidazoles; D007211:Indoles; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; C081308:FK 1052; D044422:Receptors, Serotonin, 5-HT4; D019327:Copper Sulfate; D002945:Cisplatin; C099414:(2S,3S)-2-phenyl-3-((5-trifluoromethoxy-2-methoxy)benzylamino)piperidine; D008727:Methotrexate