Potent inhibition of both the acute and delayed emetic responses to cisplatin in piglets treated with GR205171, a novel highly selective tachykinin NK1 receptor antagonist.
The effects of GR205171, a selective tachykinin NK1 receptor antagonist, were investigated on both the acute and delayed phases of cisplatin-induced nausea-like behaviour and vomiting in the conscious piglet. Animals receiving cisplatin (5.5 mg kg(-1), i.v.) were observed for 60 h. Fifteen min prior to cisplatin infusion (T0(-15 min)), eight piglets acting as controls received an intravenous injection of saline solution (1 ml kg(-1)), whereas experimental animals received a single i.v. administration of GR205171 (1 ml kg(-1)) at a dose of 0.01 (n=8), 0.03 (n=8), 0.1 (n = 8), 0.3 (n = 16) or 1.0 (n = 13) mg kg(-1). In eight additional piglets, GR205171 (1 mg kg(-1)) was administered 15 min before the onset of the delayed phase (T16(-15 min)). A further five piglets received GR205171 (1 mg kg(-1)) every 6 h throughout the experiment. The latencies of the first emetic episode (EE) and nausea-like behavioural episode (NE) increased in all experimental groups treated at T0(-15 min), and the total number of both EE and NE during the 60 h was reduced in a dose-dependent manner. In piglets treated at T0(-15 min) with GR205171 1 mg kg(-1), eight out of 13 (62%) did not vomit throughout the experiment. Animals treated with GR205171 (1 mg kg(-1)) at T16(-15 min) exhibited an acute response to cisplatin but did not vomit during the delayed phase. The greatest inhibition of both nausea-like behaviour and vomiting was observed in piglets receiving multiple injections of GR205171. These results demonstrate the long-lasting anti-emetic effects of GR205171, and confirm the key role of substance P within the emetic reflex.
Département de Physiologie et Neurophysiologie (UPRES A CNRS 6034), Laboratoire de Neurophysiologie et Neurobiologie Fonctionnelles, Faculté des Sciences et Techniques St Jérôme, Marseille, France.
L
L
Grélot
J
J
Dapzol
E
E
Estève
A
A
Frugière
A L
AL
Bianchi
R L
RL
Sheldrick
C J
CJ
Gardner
P
P
Ward
D000818:Animals; D000932:Antiemetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors*; D002945:Cisplatin / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007275:Injections, Intravenous; D008297:Male; D009325:Nausea / Q000139:chemically induced / Q000517:prevention & control; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D013552:Swine; D013777:Tetrazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D014839:Vomiting / Q000139:chemically induced* / Q000517:prevention & control*
D000932:Antiemetics; D000970:Antineoplastic Agents; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D013777:Tetrazoles; C103207:vofopitant; D002945:Cisplatin