Related Experiment Videos
Volunteer models for predicting antiemetic activity of 5-HT3-receptor antagonists
1Clinical Pharmacology Division, Glaxo Group Research Ltd, Greenford, Middlesex, UK.
Abstract:
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.
Insights
Volunteer models accurately predict effective antiemetic doses for 5-HT3-receptor antagonists. These models, including ipecacuanha-induced emesis, correlate well with clinical efficacy, unlike traditional in vitro or animal studies.
Area of Science:
- Pharmacology
- Neuroscience
Background:
- Selective 5-HT3-receptor antagonists are crucial for managing chemotherapy, radiotherapy, and surgery-induced nausea and vomiting.
- In vitro and animal models may not accurately reflect clinical antiemetic efficacy.
- Predicting clinically effective doses requires validated human volunteer models.
Purpose of the Study:
- To evaluate the predictive accuracy of human volunteer models for determining clinically effective antiemetic doses of 5-HT3-receptor antagonists.
- To compare the utility of the 5-HT flare response and ipecacuanha-induced emesis models.
Main Methods:
- Utilized two human volunteer models: 5-HT flare response and ipecacuanha-induced emesis.
- Assessed the antagonism of these responses by 5-HT3-receptor antagonists.
- Correlated model outcomes with known clinical antiemetic effectiveness.
Main Results:
- The 5-HT flare response model provides an indication of effective antiemetic doses, but duration data is conflicting.
- Ipecacuanha-induced emesis, involving central and peripheral 5-HT3-receptors, showed a strong correlation with clinical antiemetic doses of ondansetron.
- The ipecacuanha model is considered more conceptually relevant than the flare model.
Conclusions:
- Human volunteer models, particularly ipecacuanha-induced emesis, offer a more accurate prediction of clinically effective antiemetic doses for 5-HT3-receptor antagonists.
- Further research with newer antagonists is needed to fully establish the predictive role of these models.