Dazopride

Abstract: The tachycardic response to 5-HT in the anaesthetized pig was mimicked by the indole derivatives, 5-methoxytryptamine and α-methyl-5-HT, and, to a lesser extent, by the benzamide derivatives (in order of potency) zacopride, renzapride, cisapride, metoclopramide and dazopride; the latter derivatives behaved as partial agonists. ICS 205–930 in high doses (1 and 3 mg/kg), but not other 5-HT receptor antagonists (methiothepin, metergoline, methysergide, mesulergine, ketanserin, cyproheptadine, mianserin, pizotifen, granisetron and MDL 72222) or dopamine antagonists (haloperidol and domperidone), antagonized this response. These results definitely exclude the involvement of 5-HT1-like, 5-HT2, 5-HT3, or dopamine receptors and strongly suggest that the putative 5-HT4 receptor mediates the positive chronotropic action of 5-HT in the anaesthetized pig. This receptor displays a pharmacological profile which indicates similarity with the 5-HT4 receptor present on the neurons of the mouse embryo colliculi and guinea-pig ileum, as well as to that in the human heart. Since the pig heart is devoid of other 5-HT receptors, the heart rate responses to 5-HT in the pig can be utilized as a convenient experimental model for discovering drugs selective at the 5-HT4 receptor. Lastly, the involvement of this novel 5-HT receptor in the above functional responses argues in favour of the extension of the 5-HT receptor classification to include the 5-HT4 receptor.

Abstract: Dazopride, a substituted benzamide structurally related to metoclopramide, is a potent gastric prokinetic agent that prevents cisplatin-induced emesis in animals. Unlike metoclopramide, dazopride has no effect on dopamine receptors and therefore should not produce extrapyramidal side effects. In this dose-ranging trial, 23 patients with cancer receiving chemotherapy known to produce nausea and vomiting received three i.v. infusions of dazopride every 2 h beginning 30 min before the chemotherapy. Seven dose levels were explored ranging from 0.5 to 4.0 mg/kg in each of the three infusions. Toxicities were mild and included sedation, dizziness, visual disturbances, and headaches. All side effects were transient and were not dose-related. Antiemetic effects were observed. Dazopride can be safely given on this schedule at doses of up to 4.0 mg/kg to patients receiving chemotherapy. On the basis of the results of this trial, further studies of this agent are warranted.