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.

Abstract

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.

• Authors: L Grélot, J Dapzol, E Estève, A Frugière, A L Bianchi, R L Sheldrick, C J Gardner, P Ward
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 124 Issue 8 Pg. 1643-50 (Aug 1998) ISSN: 0007-1188 [Print] England
• PMID: 9756379 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiemetics
• Antineoplastic Agents
• Neurokinin-1 Receptor Antagonists
• Piperidines
• Tetrazoles
• vofopitant
• Cisplatin

Topics

• Animals
• Antiemetics (pharmacokinetics, pharmacology)
• Antineoplastic Agents (antagonists & inhibitors)
• Cisplatin (antagonists & inhibitors)
• Dose-Response Relationship, Drug
• Female
• Injections, Intravenous
• Male
• Nausea (chemically induced, prevention & control)
• Neurokinin-1 Receptor Antagonists
• Piperidines (pharmacokinetics, pharmacology)
• Swine
• Tetrazoles (pharmacokinetics, pharmacology)
• Vomiting (chemically induced, prevention & control)