Betamethasone does not prevent nausea and vomiting induced by ipecacuanha.

BACKGROUND: Corticosteroids reduce the incidence of PONV but the mode of action is not known. The purpose of this study was to evaluate if betamethasone has serotonin (5-HT) antagonistic effects. Ipecacuanha is known to release serotonin and therefore it was used to induce nausea and vomiting. The 5-HT3 antagonist ondansetron was used as a control substance. METHODS: In a randomized, double-blind, cross-over, placebo-controlled study 10 healthy male and female volunteers (6 M/4F), mean age 19.5 (18-23) years, mean weight 69.7 (53-84) kg, were studied on three occasions separated by at least 1 week. They were randomly allocated to receive pretreatment with betamethasone 8 mg, ondansetron 8 mg, or normal saline 2 ml as placebo on each occasion, 15 min before oral ingestion of 30 ml of Ipecacuanha syrup. After ingestion of ipecacuanha, vomitings were recorded and the intensity of nausea was estimated with a visual analog scale during 2 h. RESULTS: During the first 2 h after ingestion of ipecacuanha nine of the 10 volunteers vomited both after betamethasone and placebo. No volunteer vomited after ondansetron (P < 0.01 vs. betamethasone and placebo). The max VAS for nausea was significantly higher after betamethasone and placebo compared to ondansetron (P < 0.01). There were no statistically significant differences of the max VAS for nausea between betamethasone and placebo. CONCLUSION: This study in volunteers has shown that betamethasone does not prevent nausea and vomiting induced by oral intake of ipecacuanha syrup. As ipecacuanha releases 5-hydroxytryptamin, it can be concluded that betamethasone does not have 5-HT3 antagonistic effects.

Studies for the emetic mechanisms of ipecac syrup (TJN-119) and its active components in ferrets: involvement of 5-hydroxytryptamine receptors.

Ipecac syrup, prepared from a galentical ipecac, contains the nauseant alkaloids cephaeline and emetine. The involvement of receptors and serotonin- and dopamine-metabolizing enzymes in the emesis induced by ipecac syrup and these components was investigated. 1) In ferrets, the selective 5-HT3-receptor antagonist ondansetron (0.5 mg/kg, p.o.) prevented each emesis induced by TJN-119 (0.5 mL/kg, p.o.), cephaeline (0.5 mg/kg, p.o.) and emetine (5.0 mg/kg, p.o.), but the intraperitoneal administration of the selective dopamine D2-receptor antagonist sulpiride failed to significantly suppress the TJN-119, cephaeline and emetine-induced emesis at a dose of 0.1 mg/kg that blocked apomorphine-induced emesis. 2) In the receptor binding assays, cephaeline and emetine had a distinct affinity to 5-HT4 receptor, but no or weak affinity to 5-HT1A, 5-HT3, nicotine, M3, beta1, NK1, and D2 receptors. 3) Cephaeline and emetine did not affect activities of metabolic enzymes of 5-HT and dopamine (MAO-A, MAO-B, tryptophan 5-hydroxylase and tyrosine hydroxylase) in vitro. These results suggest that 5-HT3 receptor plays an important role in the emetic action of TJN-119, cephaeline and emetine, and the 5-HT4 receptor may be involved in their mechanisms.

Volunteer models for predicting antiemetic activity of 5-HT3-receptor antagonists.

1. Selective 5-HT3-receptor antagonists are highly effective in preventing nausea and vomiting associated with chemotherapy, radiotherapy and surgery. Their pharmacological activity may be determined in vitro and in animal models of emesis. However, these methods may not give an accurate indication of the antiemetic dose range of 5-HT3-receptor antagonists in patients. Two volunteer models have been used to predict more accurately clinically effective antiemetic doses of 5-HT3-receptor antagonists. 2. The flare response to intradermal 5-HT is thought to be mediated by excitation of 5-HT3-receptors on cutaneous afferents, with release of substance P and subsequent vasodilation. Antagonism of the flare response appears to provide an indication of the effective antiemetic dose of 5-HT3-receptor antagonists but data on duration of action are conflicting. 3. Ipecacuanha-induced emesis is thought to be mediated through both peripheral and central 5-HT3-receptors. Antagonism of this response has demonstrated a close correlation with clinically effective antiemetic doses of the specific 5-HT3-receptor antagonist, ondansetron, and has the advantage of being more conceptually relevant than the flare model. 4. Further work, with newer 5-HT3-receptor antagonists, will clarify the role of these models as predictive of the use of these drugs in clinical practice.

Ipecacuanha-induced emesis: a human model for testing antiemetic drug activity.

In a double-blind, randomized, parallel-group study, five groups of 10 healthy men received single 5-minute infusions of 8 mg, 4 mg, 1 mg, 0.25 mg, or 0.1 mg ondansetron (as hydrochloride dihydrate) 30 minutes before oral administration of 30 ml syrup of ipecacuanha. Emetic episodes and nausea (100 mm visual analog scale) were assessed over an 8-hour period. There were no emetic episodes after 8 or 4 mg ondansetron. Seven, nine, and 10 subjects vomited after 1 mg, 0.25 mg and 0.1 mg ondansetron, respectively, with median times to onset of 62, 31, and 37 minutes. Median peak nausea scores were 0 mm for both 8 and 4 mg ondansetron and 30, 53, and 26 mm for 1, 0.25, and 0.1 mg ondansetron. Adverse events were mild. This model showed a close correlation with clinically effective doses of ondansetron. It may be successfully and safely used to assess the antiemetic potential of 5-HT3-receptor antagonists in healthy subjects.

Drug-induced purposeless chewing: animal model of dyskinesia or nausea?

Drug-induced purposeless chewing movements in rodents are often considered to represent movement disorders or dyskinesias. We have compared the ability of drugs to induce chewing and retching or emesis in squirrel monkeys; such studies are not possible in rodents, which do not vomit. Acute administration of oxotremorine (3.3-33 micrograms/kg IM), SKF38393 (1-30 mg/kg SC) or ipecacuanha (0.5-0.75 mg/kg PO) caused dose-related increases in purposeless chewing which was frequently associated with retching and emesis. Treatment with haloperidol (0.015-0.06 mg/kg IM) did not induce chewing. Rather, haloperidol decreased spontaneous chewing at doses of 0.03 and 0.06 mg/kg. Our findings indicate that at least some drug-induced oral behaviours in rodents may reflect nausea rather than dyskinesia.

Preserving the emetic effect of syrup of ipecac with concurrent activated charcoal administration: a preliminary study.

Activated charcoal is reported to block the emetic effect of syrup of ipecac. Therefore, activated charcoal administration is commonly delayed until syrup of ipecac induced emesis is complete. The advantages of early administration of activated charcoal have been well documented. Preservation of the emetic effect of syrup of ipecac in the presence of activated charcoal may produce a synergistic effect by enhancing toxin elimination. A study was conducted in ten human volunteers to determine if activated charcoal prevents the emetic effect of syrup of ipecac when a temporal separation exists between administration of the two substances. Syrup of ipecac 60 ml plus water 480 ml was administered via an 18 French nasogastric tube followed by an aqueous slurry of activated charcoal 50 g five minutes later. Eight (80%) of the subjects had emesis in a mean time of 20.25 minutes (range 16-26 min). The total dose of activated charcoal was retained for a mean time of 6.75 minutes (range 0-17 min). Two subjects (20%) failed to have emesis. This study illustrates that activated charcoal may not completely block the emetic effect of syrup of ipecac.

In vitro evidence for ipecac inactivation by activated charcoal.

The in vitro adsorption of the alkaloid emetine, a primary constituent of ipecac, on activated charcoal was studied. The results support the supposition that syrup of ipecac should not be given to counteract poisonings if activated charcoal is also to be administered.