How to Discover Anti-Emetic Potential
Chemotherapy-Induced Emesis
Motion-Induced Emesis
Post-Operative Nausea and Emesis (PONV)
Studies Against Other Emetogens
- In the late 1980s, we worked on the development of 5-HT3 receptor antagonists and also explored the concept of the use of broad inhibitory anti-emetic drugs for use in man.
- In 1994, we developed the ferret model of cisplatin-induced acute and delayed emesis, which successfully identified the clinical utility of the tachykinin NK1 receptor antagonists to prevent chemotherapy-induced emesis in man. The model reliably identifies the interaction of 5-HT3 and NK1 receptor antagonists with dexamethasone, to antagonize the acute and delayed phases of emesis.
- We now have 20 years experience with this model, having investigated many compounds for anti-emetic potential and effects on other side effects associated with chemotherapy.
- We have also been using Suncus murinus since 1995 to evaluate the anti-emetic potential of novel compounds to prevent cisplatin-induced emesis.
Motion-Induced Emesis
- The incidence of motion sickness ranges from 25-40 % and current anti-emetic drugs (e.g. histamine and muscarinic receptor antagonists) are associated with a slow onset of activity and side effects of sedation and other unwanted actions.
- It is also known that individuals that are susceptible to motion sickness also are more likely to experience nausea and emesis during chemotherapy-induced emesis, and also on recovery following surgery with anaesthesia (post-operative nausea and emesis).
- We therefore specialize on testing novel chemical entities for a potential to reduce motion-induced emesis.
- The ferret is not reported to exhibit emesis to motion, or on recovery from surgery with anaesthesia. However, Suncus murinus is exceptionally sensitive to provocative motion. We therefore use Suncus murinus for all of our motion sickness studies.
Post-Operative Nausea and Emesis (PONV)
- PONV may be experienced by 8-92 % of patients undergoing surgery with anaesthesia. In the past, anti-emetic development was hindered by the absence of a reliable animal model (e.g. ferrets, cat and dogs do not usually vomit after being anaesthetized with inhalation gases). Suncus murinus does develop emesis on recovery from anaesthesia. We therefore also have this model available for studies on emesis control and for the evaluation of novel anti-emetic drugs.
Studies Against Other Emetogens
- It is sometimes necessary to know if a novel anti-emetic drug can prevent emesis induced by several challenges. For example, can a novel drug prevent the emesis induced by activation of the area postrema or vagal afferents? If a new drug prevents emesis induced by more than once challenge, it would be classified as a broad inhibitory anti-emetic drug, and it may have a wider therapeutic potential.
- We have investigated the potential of drugs to prevent the emesis induced by classical challenges including: apomorphine, loperamide, morphine and other opioids, ipecacuanha, selective 5-HT3 receptor agonists (m-chlorophenylbiguanide, 2-methyl-5-HT) and intragastric copper sulphate. We have also evaluated a potential to inhibit emesis induced by a wide variety of peptides (e.g. substance P NK1, NK2, and NK3 receptor agonists), vanilloids, prostanoids, phosphodiesterase inhibitors, anti-cholinesterases, nicotine, glucagon-like 1 peptide (GLP-1) agonists, antibiotics, steroids, protein synthesis inhibitors (e.g. cycloheximide), anti-depressants (e.g. selective serotonin reuptake inhibitors; SSRIs) and other chemotherapeutic drugs (e.g. cyclophosphamide).