Nausea and
vomiting are among the most common and distressing consequences of cytotoxic
chemotherapies.
Nausea and
vomiting can be acute (0-24h) or delayed (24-72 h) after
chemotherapy administration. The introduction of 5-HT(3) receptor antagonists in the 90s was a major advance in the prevention of acute
emesis. These receptor antagonists exhibited similar control on acute
emesis but had no effect on delayed
emesis. These findings led to the hypothesis that
serotonin plays a central role in the mechanism of acute
emesis but a lesser role in the pathogenesis of delayed
emesis. In contrast, delayed
emesis has been largely associated with the activation of neurokinin 1 (
NK(1)) receptors by
substance P. However, in 2003, a new 5-HT(3) receptor antagonist was introduced into the market; unlike first generation 5-HT(3) receptor antagonists,
palonosetron was found to be effective in preventing both acute and delayed
chemotherapy induced
nausea and
vomiting. Recent mechanistic studies have shown that
palonosetron, in contrast to first generation receptor antagonists, exhibits allosteric binding to the 5-HT(3) receptor, positive cooperativity, persistent inhibition of receptor function after the
drug is removed and triggers 5-HT(3) receptor internalization. Further, in vitro and in vivo experiments have shown that
palonosetron can inhibit
substance P-mediated responses, presumably through its unique interactions with the 5-HT(3) receptor. It appears that the crossroads of acute and delayed emeses include interactions among the 5-HT(3) and
NK(1) receptor neurotransmitter pathways and that inhibitions of these interactions lend the possibility of improved treatment that encompasses both acute and delayed emeses.