The anti-emetic potential of the 5-hydroxytryptamine3 receptor antagonist BRL 43694.
In ferrets, the selective 5-hydroxytryptamine (5-HT) 5-HT3 receptor antagonist BRL 43694 given as a single injection (0.05-0.5 mg kg-1 i.v.) before cisplatin, or by divided dose (2 x 0.005-2 x 0.5 mg kg-1 i.v.) before and after cisplatin dramatically reduced or abolished the severe cisplatin-induced vomiting. BRL 43694 also substantially reduced the vomiting induced by cyclophosphamide:doxorubicin, and prevented the trimelamol-induced emesis. The severe emesis caused by whole body exposure to X-irradiation was prevented by intravenous or oral BRL 43694. A single i.v. dose of BRL 43694 given during an emetic episode or within the peak emetic period, abolished the vomiting induced by the cytotoxic drugs and by X-irradiation, usually within 30 s. Where the induction of emesis was prevented or subsequently abolished by BRL 43694, the associated behaviour (subjectively assessed as nausea) was also absent or greatly attenuated. BRL 43694 (0.1 mg kg-1 i.v.) did not affect the emesis evoked in dogs by the dopamine agonist apomorphine. The potent anti-emetic activity of BRL 43694 is discussed in terms of potential clinical use, and of the fundamental role that 5-HT3 receptors may play in the mechanisms of nausea and vomiting.
Bermudez
J
J
Beecham Pharmaceuticals Research Division, Harlow, Essex, UK.
Boyle
E A
EA
Miner
W D
WD
Sanger
G J
GJ
D000818:Animals; D001058:Apomorphine / Q000009:adverse effects; D002945:Cisplatin / Q000009:adverse effects; D003520:Cyclophosphamide / Q000009:adverse effects; D004285:Dogs; D004317:Doxorubicin / Q000009:adverse effects; D005289:Ferrets; D017829:Granisetron; D007191:Indazoles / Q000627:therapeutic use*; D008297:Male; D011720:Pyrazoles / Q000627:therapeutic use*; D014227:Triazines / Q000009:adverse effects; D014839:Vomiting / Q000188:drug therapy* / Q000209:etiology; D014916:Whole-Body Irradiation
D001058:Apomorphine; D002945:Cisplatin; D003520:Cyclophosphamide; D004317:Doxorubicin; D017829:Granisetron; D007191:Indazoles; D011720:Pyrazoles; D014227:Triazines; C049507:trimelamol