Action of ( R)-sila-venlafaxine and reboxetine to antagonize cisplatin-induced acute and delayed emesis in the ferret

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-HT 3 receptor antagonist, a glucocorticoid, and an NK 1 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 ∼ 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.