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, i.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 °C) or heart rate (basal: 233.7 ± 5.5 beats per min (BPM); P > 0.05), but hypothermia (−1.6 °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.