Development of a murine gastric distension model for testing the emetic potential of new drugs and efficacy of antiemetics.
A small animal model for emesis would allow preclinical testing of antiemetics and new drugs. Mice treated with cisplatinum develop stomachs distended with food. This effect is reduced by metoclopramide and parallels the gastric nausea experienced by patients receiving cisplatinum. To assess gastric distension as a more general model for paralleling the human emetic response, groups of five BALB/c mice were given intravenous nitrogen mustard, adriamycin, cyclophosphamide, 5-fluoruracil (5FU), vincristine and intraperitoneal DTIC at doses equivalent to those used clinically (mg/kg mouse = 12 X mg/kg per man). The mice were allowed free access to food pellets and water. At 48 h they were sacrificed and gastric distension quantitated as a ratio of average stomach to body weight. Significant gastric distension occurred with nitrogen mustard, DTIC, adriamycin and cyclophosphamide but not 5FU or vincristine. This parallels the emetic potential of these drugs in humans. Similarly cisplatinum was compared to its analogues, carboplatin and JM40 and produced gastric distension at lower doses than carboplatin. The model was then used to test the antiemetic efficacy of escalating doses of prochlorperazine against cisplatinum induced gastric distension in groups of 10 BALB/c mice. Doses ranged from 2.5 mg/kg. Only a high dose (19.2 mg/kg) significantly reduced the gastric distension. This parallels a clinical dose response relationship recently reported for prochlorperazine and suggests the further potential use of this model.
Olver
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IN
Department of Cancer Medicine, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia.
Roos
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IA
Thomas
K
K
Hillcoat
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BL
D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology; D004639:Emetics; D051379:Mice; D008815:Mice, Inbred Strains; D011346:Prochlorperazine / Q000494:pharmacology; D012016:Reference Values; D013270:Stomach / Q000187:drug effects / Q000502:physiology*
D000932:Antiemetics; D000970:Antineoplastic Agents; D004639:Emetics; D002945:Cisplatin; D011346:Prochlorperazine