Action of (R)-sila-venlafaxine and reboxetine to antagonize cisplatin-induced acute and delayed emesis in the ferret
- Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge, CB4 0PA (United Kingdom)
- Emesis Research Group, Brain-Gut Laboratory, Department of Pharmacology, Faculty of Medicine, Chinese University of Hong Kong, Shatin, N.T., Hong Kong (China)
- Postgraduate Studies in Pharmacology, The School of Pharmacy, University of Bradford, Bradford, BD7 1DP (United Kingdom)
- Institut fur Anorganische Chemie, Universitaet Wuerburg, Am Hubland, D-97074 Wuerzburg (Germany)
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{sub 3} receptor antagonist, a glucocorticoid, and an NK{sub 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 {approx} 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.
- OSTI ID:
- 21180447
- Journal Information:
- Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 232; ISSN TXAPA9; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
Similar Records
On the mechanism of radiation-induced emesis: The role of serotonin
Various effects of antidepressant drugs on bone microarchitectecture, mechanical properties and bone remodeling