Antiemetic L-758298
Nausea and vomiting can be serious problems for patients undergoing cancer chemotherapy treatments, as they are the body's reflex response to the ingestion of toxic substances.
Nausea and vomiting can be serious problems for patients undergoing cancer chemotherapy treatments, as they are the body's reflex response to the ingestion of toxic substances.
The mechanism by which nausea and vomiting develop is complex, and several different neurotransmitters are implicated in the process, which is thought to take place in the medulla of the brain stem. Substance P, which is found in both the gastrointestinal neurons and the medulla, is believed to be involved, and non-peptide NK1 receptor antagonists are being looked at as potential antiemetic drugs. A promising tachykinin NK1 receptor antagonist, aprepitant, was developed by Merck & Co., which is both highly selective and has a long duration of action, and penetrates the brain well.1 However, it has low water solubility, and this has been solved by preparing the N-phosphorylated pro-drug derivative, coded as L-758298.2 Both drugs are undergoing clinical investigation.
A number of clinical trials have examined its efficacy in the treatment of cisplatin-induced emesis. In a randomised, double blind Phase IIb trial on the effects of the drug on acute and delayed emesis, 159 cisplatin-naïve patients were randomised into three groups, who received L-758298 plus dexamethasone before treatment with cisplatin and either aprepitant or placebo for four days afterwards, or ondansetron plus dexamethasone before cisplatin, and placebo afterwards. Those in the ondansetron group had a lower incidence of emesis in the acute phase, but a larger proportion of those given L-758298 had no delayed phase emesis. No serious side-effects were seen with either L-758298 or aprepitant, with diarrhoea being the main adverse effect reported.3
In a second multi-centre, randomised, double blind, ondansetron controlled study, 53 cisplatin-naïve patients were given either L-758298 or ondansetron before treatment with cisplatin, and no antiemetic afterwards. Similar effects were seen for both drugs in the acute phase, but 72% of the L-758298 group had no emetic effects in the delayed phase, compared with 30% of those given ondansetron.4
Phase III trials continue, and these drugs may be an advance in the control of chemotherapy induced nausea. They are also being looked at as potential antidepressants.