title: Olvanil, a non-pungent vanilloid enhances the gastrointestinal toxicity of cisplatin in the ferret.
abstract: 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 degrees C) or heart rate (basal: 233.7+/-5.5 beats per min (BPM); P>0.05), but hypothermia (-1.6 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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
authors.forename: Kit-Man
authors.initials: KM
authors.lastname: Chu
authors.forename: Man-Piu
authors.initials: MP
authors.lastname: Ngan
authors.forename: Man-Keung
authors.initials: MK
authors.lastname: Wai
authors.forename: Chi-Kong
authors.initials: CK
authors.lastname: Yeung
authors.forename: Paul L R
authors.initials: PL
authors.lastname: Andrews
authors.forename: Nathalie
authors.initials: N
authors.lastname: Percie du Sert
authors.forename: Ge
authors.initials: G
authors.lastname: Lin
authors.forename: John A
authors.initials: JA
authors.lastname: Rudd
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001831:Body Temperature / Q000187:drug effects; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002945:Cisplatin / Q000009:adverse effects*; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005289:Ferrets; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D050916:TRPV Cation Channels / Q000819:agonists*; D014839:Vomiting / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D050916:TRPV Cation Channels; C054256:olvanil; D002945:Cisplatin; D002211:Capsaicin