title: Antiemetic effects of YM060, a potent and selective serotonin (5HT)3-receptor antagonist, in ferrets and dogs.
abstract: YM060, (R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride, is a new serotonin (5HT)3-receptor antagonist. We examined the effects of YM060 on chemotherapeutic agent-, apomorphine- and copper sulfate-induced emesis. Intravenous YM060 potently prevented cisplatin (10 mg/kg, i.v.)-induced emesis with ED50 values of 0.06 (0.05-0.07) micrograms/kg, i.v. in ferrets. Based on the ED50 values, YM060 was 300, 20 and 100 times more potent than ondansetron, granisetron and the S-isomer of YM060, respectively. The relative potencies of these drugs described above were similar to those in the previously reported 5HT3-receptor antagonism. YM060 given orally also potently inhibited cisplatin (10 mg/kg, i.p.)- and cyclophosphamide (200 mg/kg, i.p.)-induced emesis in ferrets with ED50 values of 0.1 (0.09-0.11) and 0.02 (0.16-0.27) micrograms/kg, p.o., respectively. All tested 5HT3-receptor antagonists including YM060 failed to prevent apomorphine (0.1 mg/kg, s.c.)-induced emesis in dogs and copper sulfate (1%, 10 ml, p.o.)-induced emesis in ferrets. Our data indicate that YM060 is a highly potent inhibitor of chemotherapeutic agent-induced emesis and that the antiemetic effect of YM060 may be depend on 5HT3-receptor antagonism.
authors.affiliation: Medicinal Research Laboratories I, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kamato
authors.forename: K
authors.initials: K
authors.lastname: Miyata
authors.forename: H
authors.initials: H
authors.lastname: Ito
authors.forename: H
authors.initials: H
authors.lastname: Yuki
authors.forename: M
authors.initials: M
authors.lastname: Yamano
authors.forename: K
authors.initials: K
authors.lastname: Honda
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D001058:Apomorphine / Q000009:adverse effects; D001562:Benzimidazoles / Q000494:pharmacology*; D002945:Cisplatin / Q000009:adverse effects; D003300:Copper / Q000009:adverse effects; D019327:Copper Sulfate; D003520:Cyclophosphamide / Q000009:adverse effects; D004285:Dogs; D005260:Female; D005289:Ferrets; D007275:Injections, Intravenous; D008297:Male; D012702:Serotonin Antagonists; D013237:Stereoisomerism; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control
chemical_list: D000932:Antiemetics; D001562:Benzimidazoles; D012702:Serotonin Antagonists; D003300:Copper; C071315:ramosetron; D003520:Cyclophosphamide; D019327:Copper Sulfate; D001058:Apomorphine; D002945:Cisplatin