The Antiemetic 5-HT3 Receptor Antagonist Palonosetron Inhibits Substance P-Mediated Responses In Vitro and In Vivo
Palonosetron is the only 5-HT3 receptor antagonist approved for the treatment of delayed chemotherapy-induced nausea and vomiting (CINV) in moderately emetogenic chemotherapy (MEC). Accumulating evidence suggests that Substance P (SP), the endogenous ligand acting preferentially on NK-1 receptors, not serotonin, is the dominant mediator of delayed emesis. However, palonosetron does not bind to the NK-1 receptor. Recent data has revealed crosstalk between the NK-1 and 5HT3 receptor signaling pathways; we postulated that if palonosetron differentially inhibited NK-1/5-HT3 crosstalk, it could help explain its efficacy profile in delayed emesis. Consequently, we evaluated the effect of palonosetron, granisetron and ondansetron on SP-induced responses in vitro and in-vivo. NG108-15 cells were preincubated with palonosetron, granisetron or ondansetron; antagonists were removed and the effect on serotonin enhancement of SP-induced calcium release was measured. In the absence of antagonist, serotonin enhanced SP-induced calcium-ion release; following preincubation with palonosetron, but not ondansetron or granisetron, inhibited the serotonin enhancement of the SP response. Rats were treated with cisplatin and either palonosetron, granisetron or ondansetron. At various times post-dosing, single neuronal recordings from nodose ganglia were collected following stimulation with SP; nodose ganglia neuronal responses to SP were enhanced when the animals were pretreated with cisplatin. Palonosetron, but not ondansetron or granisetron, dose-dependently inhibited the cisplatin-induced SP enhancement. The results are consistent with previous data showing that palonosetron exhibits distinct pharmacology versus the older 5-HT3 receptor antagonists and provide a rationale for the efficacy observed with palonosetron in delayed CINV in the clinic.
Version: za2963e q8zaa q8zb0 q8zc6 q8zdf q8ze8 q8zf6 q8zg2