Potential of substance P antagonists as antiemetics

The introduction of serotonin 5-HT3 receptor antagonists into clinical prac tice allowed for a dramatic improvement in the management of nausea and vom iting. Despite this, postoperative and chemotherapy-induced emesis remains a significant cant, unresolved issue in many patients even when a combinati on of antiemetic drugs is used. Numerous neurotransmitters have been implic ated in triggering emesis: however, the tachykinin substance P, by virtue o f its localisation within both the gastrointestinal vagal afferent nerve fi bres and brainstem emetic circuitry, and its ability to induce vomiting whe n administered intravenously, is thought to play a key role in emetic respo nses. Because substance P is the most likely endogenous ligand for the neur okinin-l (NK1) receptor, the development of nonpeptide NK1 receptor antagon ists led scientists to evaluate these compounds as antiemetics. The five NK 1 receptor inhibitors that have been studied initially in humans are: vofop itant (GR-205171), CP-122721, ezlopitant (CJ-11974), MK-869 (L-754030) and its prodrug L-758298. Except for monotherapy in acute cisplatin-induced eme sis, this new class of drugs has proven to be highly effective in the contr ol of both chemotherapy-induced nausea and vomiting, and postoperative naus ea and vomiting. No major adverse event was reported in the preliminary tri als. Further investigation is mandatory in order to assess the optimal trea tment regimen and to make sure the wide spectrum activity of the NK1 recept or inhibitors does not cause significant adverse effects in the context of the treatment of nausea and vomiting.