Efficacy of Ondansetron (Gr 38032F) and the Role of Serotonin in Cisplatin-Induced Nausea and Vomiting

Abstract

We compared the efficacy and safety of ondansetron (GR 38032F), a selective antagonist of serotonin S3 receptors, with that of placebo in controlling the nausea and vomiting induced by cisplatin treatment in 28 patients with cancer. The patients received either three intravenous doses of ondansetron (0.15 mg per kilogram of body weight) or normal saline (placebo) at four-hour intervals, beginning 30 minutes before the administration of cisplatin. Nausea and vomiting were markedly diminished in the group given ondansetron. The median time to the first episode of emesis was 2.8 hours in the placebo group and 11.6 hours in the ondansetron group (P less than 0.001); the median number of episodes in 24 hours was 5.5 in the placebo group and 1.5 in the ondansetron group (P less than 0.001); the mean (+/- SEM) number of regurgitations or dry heaves per episode was 3.2 +/- 0.5 in the placebo group and 1.17 +/- 0.1 in the ondansetron group (P less than 0.001). None of the 14 patients given ondansetron, but 12 of 14 given placebo, required treatment with antiemetic-rescue agents for the control of nausea and vomiting. There were no adverse effects attributable to ondansetron. The urinary excretion of 5-hydroxyindoleacetic acid, the main metabolite of serotonin, was increased in all patients two to six hours after they received cisplatin chemotherapy, and the increases paralleled the episodes of emesis. We conclude that ondansetron is an effective and safe agent for controlling the nausea and vomiting induced by cisplatin treatment. We suggest that cisplatin treatment increases the release of serotonin from enterochromaffin cells, and that ondansetron acts by blocking S3 receptors for serotonin.

Comparison of the anti-emetic efficacy of different doses of ondansetron, given as either a continuous infusion or a single intravenous dose, in acute cisplatin-induced emesis. A multicentre, double-blind, randomised, parallel group study

“…The patterns of emesis observed with ondansetron and metoclopramide were similar for the remainder of the 24 h period. The urinary excretion of 5-hydroxyindole acetic acid (5HIAA), a metabolite of 5-HT, also has been shown to increase in the 4-6 h period after cisplatin paralleling the onset of emesis (Cubeddu et al, 1990). These observations suggested that shorter treatment regimens of ondansetron may be as effective as the continuous infusion or multiple dose schedules employed in the initial comparative studies.…”

“…This emphasises that the period up to 12 h following the cisplatin infusion may be the critical period for acute anti-emetic control. During this period, elevations in urinary levels of 5-HIAA, a urinary metabolite of 5HT, have been observed (Cubeddu et al, 1990). The plasma levels afforded by the 8 mg single dose are probably adequate for antagonising 5HT-mediated emesis at 5HT3 receptors, providing protection in the majority of patients.…”

“…Although serotonin is a significant mediator of acute emesis (Cubeddu et al, 1990), failure to completely protect all patients indicates that other mechanism(s) may also be involved. The addition of dexamethasone to ondansetron has been shown to significantly improve anti-emetic control .…”

Reduction of carboplatin induced emesis by ondansetron

“…In randomised studies it has been proven superior to both placebo (Cubeddu et al, 1990) and high dose metoclopramide (Marty et al, 1990) in controlling cisplatin induced emesis. In non-cisplatin containing chemotherapy regimens it has been shown superior to metoclopramide in four randomised studies (Schmoll, 1989;Kaasa et al, 1990).…”

Phase I/II study of a short course of weekly cisplatin in patients with advanced solid tumours

“…Until recently, even with the use of the most active antiemetic combination regimen (metoclopramide with lorazepam and dexamethasone), a considerable proportion of patients suffered from nausea and vomiting whereas the new 5HT3-antagonists are now found to be more effective in preventing acute nausea and vomiting induced by cisplatin (Cubbedu et al, 1990;Marty et al, 1990;Smith et al, 1990; de Mulder et al, 1990). …”