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 |
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Authors: | Laurent Gr lot,Julien Dapzol,Eric Est ve,Alain Frugi re,Armand L Bianchi,Robert L G Sheldrick,Christopher J Gardner,Peter Ward |
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Affiliation: | 1.Département de Physiologie et Neurophysiologie (UPRES A CNRS 6034), Laboratoire de Neurophysiologie et Neurobiologie Fonctionnelles, Faculté des Sciences et Techniques St Jérôme, Case 351, 13397 Marseille cedex 20, France;2.GlaxoWellcome Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, UK |
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Abstract: | - The effects of {"type":"entrez-nucleotide","attrs":{"text":"GR205171","term_id":"238470896","term_text":"GR205171"}}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 {"type":"entrez-nucleotide","attrs":{"text":"GR205171","term_id":"238470896","term_text":"GR205171"}}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, {"type":"entrez-nucleotide","attrs":{"text":"GR205171","term_id":"238470896","term_text":"GR205171"}}GR205171 (1 mg kg−1) was administered 15 min before the onset of the delayed phase (T16−15 min). A further five piglets received {"type":"entrez-nucleotide","attrs":{"text":"GR205171","term_id":"238470896","term_text":"GR205171"}}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 {"type":"entrez-nucleotide","attrs":{"text":"GR205171","term_id":"238470896","term_text":"GR205171"}}GR205171 1 mg kg−1, eight out of 13 (62%) did not vomit throughout the experiment. Animals treated with {"type":"entrez-nucleotide","attrs":{"text":"GR205171","term_id":"238470896","term_text":"GR205171"}}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 {"type":"entrez-nucleotide","attrs":{"text":"GR205171","term_id":"238470896","term_text":"GR205171"}}GR205171.
- These results demonstrate the long-lasting anti-emetic effects of {"type":"entrez-nucleotide","attrs":{"text":"GR205171","term_id":"238470896","term_text":"GR205171"}}GR205171, and confirm the key role of substance P within the emetic reflex.
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Keywords: | __tag_821560930" class=" tag_hotlink" href=" /nuccore/GR205171" ref=" /nuccore/GR205171" >{" type" :" entrez-nucleotide" " attrs" :{" text" :" GR205171" " term_id" :" 238470896" " term_text" :" GR205171" }}GR205171 NK1 antagonist anti-emetic acute emesis delayed emesis nausea-like behaviour cisplatin piglets |
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