vofopitant and Nausea

In man a neurokinin-1 (NK1) receptor antagonist has previously been shown to be ineffective in the prevention of motion-induced nausea. The antiemetic efficacy of NK1 receptor antagonists against chemotherapy-induced emesis is, however, enhanced when combined with a 5-HT3 receptor antagonist. Hence the efficacy of the NK1 antagonist GR205171 in combination with the 5-HT3 antagonist ondansetron (Zofrantrade mark) was assessed in motion-induced nausea.. GR205171 25 mg i.v., with and without concomitant administration of ondansetron 8 mg i.v., and hyoscine hydrobromide 0. 6 mg orally (positive control) were compared with placebo in a model of motion-induced nausea. The study was performed to a four-period, randomized, balanced, double-blind, crossover design in 16 healthy subjects. The end-point was the exposure to the motion stimulus required to produce moderate nausea in the subjects.. The motion stimulus required to produce moderate nausea was significantly greater for the positive control than placebo (P < 0. 001). There was no significant difference between either GR205171 or GR205171 plus ondansetron and placebo (P = 0.648 and 0.342, respectively).. The enhancement of NK1 receptor antagonist antiemetic activity through combination with a 5-HT3 receptor antagonist is not replicated in motion-induced nausea.

Topics: Adolescent; Adult; Antiemetics; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Motion Sickness; Nausea; Neurokinin-1 Receptor Antagonists; Ondansetron; Piperidines; Scopolamine; Serotonin Antagonists; Tetrazoles

This study aimed to dissect the mechanisms involved in malaise induced by the anti-cancer drug cisplatin by attempting to uncouple its effects on locomotor activity, arguably at least partly indicative of fatigue, from those effects indicative of emesis (pica, gastric stasis, reduced food intake) using pharmacological agents in the rat. Over 2 days cisplatin (6 mg/kg i.p.) reduced food intake, stimulated kaolin consumption, increased the wet weight of gastric contents and reduced locomotor activity. In animals treated with cisplatin: the 5-HT3 receptor antagonist ondansetron (1 mg/kg s.c. bd.) had no effect on either activity or weight of gastric contents but did increase food intake on day 1 (P<0.05) and the total over both days (27.6+/-1.8 vs. 19.9+/-2.3g, P<0.05), reducing kaolin consumption on day 2 (P<0.01) but not the total over both days; the NK1 receptor antagonist GR205171 (1 mg/kg s.c. bd.) was without effect on activity, but reduced the wet weight of gastric contents (P<0.05), increased food intake on day 2 (P<0.01) and total consumption over both days (28.1+/-1.7 g vs. 19.9+/-2.3 g; P<0.05) and reduced kaolin consumption on day 2 (P<0.05) but not over both days; dexamethasone (2 mg/kg s.c. bd.) blocked the cisplatin-induced reduction in activity on days 1 and 2 (P<0.01), reduced the wet weight of gastric contents by 43% (P<0.01), reduced kaolin consumption on both days (P<0.01) and arguably decreased the reduction in food intake caused by cisplatin. This study has revealed novel insights into the different spectra of activities of 5-HT3 and NK1 receptor antagonists and dexamethasone, which have implications for therapeutic strategies to alleviate the emetic, anorectic, dyspeptic and activity-reducing effects of anti-cancer chemotherapy.

Topics: Animals; Antiemetics; Antineoplastic Agents; Cisplatin; Dexamethasone; Eating; Gastric Emptying; Male; Motor Activity; Nausea; Neurokinin-1 Receptor Antagonists; Ondansetron; Pica; Piperidines; Rats; Rats, Wistar; Serotonin 5-HT3 Receptor Antagonists; Serotonin Antagonists; Tetrazoles

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.

Topics: Animals; Antiemetics; Antineoplastic Agents; Cisplatin; Dose-Response Relationship, Drug; Female; Injections, Intravenous; Male; Nausea; Neurokinin-1 Receptor Antagonists; Piperidines; Swine; Tetrazoles; Vomiting

The effects of a NK1 antagonist, GR205171, and a 5-HT3 antagonist, ondansetron, in a novel model of post-anaesthesia-induced emesis in Suncus murinus is described. GR205171 (1 and 3 mg k(-1) s.c) and ondansetron (3 mg kg(-1) s.c.) each significantly inhibited emesis. This model may be useful for studying drugs to treat post-operative nausea and vomiting in man.

Topics: Anesthesia; Animals; Halothane; Humans; Male; Nausea; Neurokinin-1 Receptor Antagonists; Ondansetron; Piperidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Shrews; Tetrazoles; Vomiting