Olvanil, a non-pungent vanilloid enhances the gastrointestinal toxicity of cisplatin in the ferret

Pungent transient receptor potential vanilloid (TRPV1) channel activators have been shown to have broad inhibitory anti-emetic activity against centrally- and peripherally acting challenges but only at doses that have adverse effects on the cardiovascular system and on temperature homeostasis In the present studies, we investigated the anti-emetic potential of the non-pungent TRPV1 activator. olvanil (0 05-5 mg/kg, s.c, 3 times per day, for 3 days) to antagonise the acute and delayed emesis induced by cisplatin (5 mg/kg, 1 p) in ferrets that had been implanted with radiotelemetry devices to enable an analysis of heart rate and temperature Cisplatin induced an acute (day 1 48 0 +/- 18 3 retches+ vomits) and delayed (day 2. 111 7 +/- 35 5, day 3 147 5 +/- 20 2 retches + vomits)emetic response that was associated with reduced food (-98.7% at day 3, P < 0.001) and water consumption (-70 2% at day 3, P< 0.001) and progressive weight loss (-12 0% at day 3, P < 0.001). Olvanil did not prevent either emesis or the weight loss and negative effects on food and water consumption (P> 0.05); the effect on food consumption appeared potentiated by a further 21.2% at 0 05 mg/kg (P< 0.05) and 19 9% at 0 5 mg/kg (P< 0 05) Cisplatin did not alter body temperature (basal 37.7 +/- 0 1 degrees C) or heart rate (basal. 233 7 +/- 5 5 beats per min (BPM); P> 0.05), but hypothermia (-16 degrees C) and increases in locomotor activity (50-90%) were recorded in animals concomitantly treated with olvanil (P< 0 05). These data indicate that non-pungent activators as exemplified by olvanil are unlikely to be useful clinically for the control of the gastrointestinal side effects induced by cisplatin (C) 2009 Elsevier Ireland Ltd All rights reserved