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

• Published in: British journal of pharmacology Vol. 124; no. 8; pp. 1643 - 1650
• Main Authors: Grélot, Laurent, Dapzol, Julien, Estève, Eric, Frugière, Alain, Bianchi, Armand L, Sheldrick, Robert L G, Gardner, Christopher J, Ward, Peter
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.1998; Nature Publishing
• Subjects: acute emesis; Animals; Antiemetics - pharmacokinetics; Antiemetics - pharmacology; Antineoplastic Agents - antagonists & inhibitors; anti‐emetic; Biological and medical sciences; cisplatin; Cisplatin - antagonists & inhibitors; delayed emesis; Dose-Response Relationship, Drug; Drug toxicity and drugs side effects treatment; Female; GR205171; Injections, Intravenous; Male; Medical sciences; Nausea - chemically induced; Nausea - prevention & control; nausea‐like behaviour; Neurokinin-1 Receptor Antagonists; NK1 antagonist; Pharmacology. Drug treatments; piglets; Piperidines - pharmacokinetics; Piperidines - pharmacology; Swine; Tetrazoles - pharmacokinetics; Tetrazoles - pharmacology; Toxicity: digestive system; Vomiting - chemically induced; Vomiting - prevention & control; Antineoplastic agent; NK1 Tachykinin receptor; Intravenous administration; Substance P; Toxicity; Nausea; Cisplatin; Pig; Prevention; Vertebrata; Chemotherapy; Mammalia; Treatment; Vomiting; Animal; Digestive diseases; Artiodactyla; Antagonist; Ungulata; Antiemetic; Platinum II Complexes
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0702019

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. British Journal of Pharmacology (1998) 124, 1643–1650; doi:10.1038/sj.bjp.0702019