The novel NK1 receptor antagonist MK-0869 (L-754,030) and its water soluble phosphoryl prodrug, L-758,298, inhibit acute and delayed cisplatin-induced emesis in ferrets.
The anti-emetic profile of the novel brain penetrant tachykinin NK1 receptor antagonist MK-0869 (L-754,030) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluor o)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine and its water soluble prodrug, L-758,298, has been examined against emesis induced by cisplatin in ferrets. In a 4 h observation period, MK-0869 and L-758,298 (3 mg/kg i.v. or p.o.) inhibited the emetic response to cisplatin (10 mg/kg i.v.). The anti-emetic protection afforded by MK-0869 (0.1 mg/kg i.v.) was enhanced by combined treatment with either dexamethasone (20 mg/kg i.v.) or the 5-HT3 receptor antagonist ondansetron (0.1 mg/kg i.v.). In a model of acute and delayed emesis, ferrets were dosed with cisplatin (5 mg/kg i.p.) and the retching and vomiting response recorded for 72 h. Pretreatment with MK-0869 (4-16 mg/kg p.o.) dose-dependently inhibited the emetic response to cisplatin. Once daily treatment with MK-0869 (2 and 4 mg/kg p.o.) completely prevented retching and vomiting in all ferrets tested. Further when daily dosing began at 24 h after cisplatin injection, when the acute phase of emesis had already become established, MK-0869 (4 mg/kg p.o. at 24 and 48 h after cisplatin) prevented retching and vomiting in three out of four ferrets. These data show that MK-0869 and its prodrug, L-758,298, have good activity against cisplatin-induced emesis in ferrets and provided a basis for the clinical testing of these agents for the treatment of emesis associated with cancer chemotherapy.
Tattersall
F D
FD
Department of Pharmacology, Merck, Sharp and Dohme, Neuroscience Research Centre, Harlow, Essex, UK. david_tattersall@merck.com
Rycroft
W
W
Cumberbatch
M
M
Mason
G
G
Tye
S
S
Williamson
D J
DJ
Hale
J J
JJ
Mills
S G
SG
Finke
P E
PE
MacCoss
M
M
Sadowski
S
S
Ber
E
E
Cascieri
M
M
Hill
R G
RG
MacIntyre
D E
DE
Hargreaves
R J
RJ
D000080:Acetals / Q000494:pharmacology*; D000208:Acute Disease; D000818:Animals; D000932:Antiemetics / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077608:Aprepitant; D016466:CHO Cells; D019556:COS Cells; D002945:Cisplatin / Q000633:toxicity*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005289:Ferrets; D006801:Humans; D008297:Male; D009025:Morpholines / Q000378:metabolism / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D012995:Solubility; D014839:Vomiting / Q000188:drug therapy*
D000080:Acetals; D000932:Antiemetics; D000970:Antineoplastic Agents; C400262:L 758298; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D011355:Prodrugs; D018040:Receptors, Neurokinin-1; D000077608:Aprepitant; D002945:Cisplatin