title: Action of (R)-sila-venlafaxine and reboxetine to antagonize cisplatin-induced acute and delayed emesis in the ferret.
abstract: The chemotherapeutic drug cisplatin is associated with severe gastrointestinal toxicity that can last for several days. A recent strategy to treat the nausea and emesis includes the combination of a 5-HT3 receptor antagonist, a glucocorticoid, and an NK1 receptor antagonist. The present studies explore the use of the selective noradrenaline reuptake inhibitors, (R)-sila-venlafaxine, (R,R)-reboxetine and (S,S)-reboxetine to prevent cisplatin (5 mg/kg, i.p.)-induced acute (0-24 h) and delayed (24-72 h) emesis in ferrets. The positive control regimen of ondansetron and dexamethasone, both at 1 mg/kg/8 h, reduced acute and delayed emesis by 100 (P<0.001) and 61% (P<0.05). (R)-sila-venlafaxine at 5 and 15 mg/kg/4 h reduced acute emesis by 86 (P<0.01) and 66% (P<0.05), respectively and both enantiomers of reboxetine at 1 mg/kg/12 h also reduced the response by approximately 70-90% (P<0.05). Out of the reuptake inhibitors, only (R)-sila-venlafaxine at 15 mg/kg/4 h was active to reduce delayed emesis (a 57% reduction was observed (P<0.05)); its terminal plasma levels were positively correlated with an inhibition of emesis during the delayed phase (P<0.05). (R)-sila-venlafaxine was also examined against a higher dose of cisplatin 10 mg/kg, i.p. (3 h test) and it dose-dependently antagonized the response (maximum reduction was 94% at 10 mg/kg, p.o.; P<0.01) but it was ineffective against apomorphine (0.125 mg/kg, s.c.) and ipecacuanha (2 mg/kg, p.o.)-induced emesis (P>0.05). In conclusion, the studies provide the first evidence for an anti-emetic potential of noradrenaline reuptake inhibitors to reduce chemotherapy-induced acute and delayed emesis.
authors.affiliation: Takeda Cambridge Limited(1), 418 Cambridge Science Park, Cambridge, CB4 0PA, UK.
authors.forename: Julie B
authors.initials: JB
authors.lastname: Warneck
authors.forename: Frankie H M
authors.initials: FH
authors.lastname: Cheng
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Barnes
authors.forename: John S
authors.initials: JS
authors.lastname: Mills
authors.forename: John G
authors.initials: JG
authors.lastname: Montana
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Naylor
authors.forename: Man-P
authors.initials: MP
authors.lastname: Ngan
authors.forename: Man-K
authors.initials: MK
authors.lastname: Wai
authors.forename: Jürgen O
authors.initials: JO
authors.lastname: Daiss
authors.forename: Reinhold
authors.initials: R
authors.lastname: Tacke
authors.forename: John A
authors.initials: JA
authors.lastname: Rudd
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000633:toxicity*; D001058:Apomorphine / Q000633:toxicity; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D003511:Cyclohexanols / Q000097:blood / Q000494:pharmacology*; D005289:Ferrets; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D000077593:Reboxetine; D012702:Serotonin Antagonists / Q000494:pharmacology; D000069470:Venlafaxine Hydrochloride; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control*
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000932:Antiemetics; D000970:Antineoplastic Agents; D003511:Cyclohexanols; D009025:Morpholines; D012702:Serotonin Antagonists; D000069470:Venlafaxine Hydrochloride; D000077593:Reboxetine; D001058:Apomorphine; D002945:Cisplatin