The Antiemetic 5-HT₃ Receptor Antagonist Palonosetron Inhibits Substance P-Mediated Responses In Vitro and In Vivo

Abstract

Palonosetron is the only 5-HT 3 receptor antagonist approved for the treatment of delayed chemotherapy-induced nausea and vomiting (CINV) in moderately emetogenic chemotherapy. Accumulating evidence suggests that substance P (SP), the endogenous ligand acting preferentially on neurokinin-1 (NK-1) receptors, not serotonin (5-HT), is the dominant mediator of delayed emesis. However, palonosetron does not bind to the NK-1 receptor. Recent data have revealed cross-talk between the NK-1 and 5HT 3 receptor signaling pathways; we postulated that if palonosetron differentially inhibited NK-1/5-HT 3 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. After preincubation with palonosetron, but not ondansetron or granisetron, the serotonin enhancement of the SP response was inhibited. Rats were treated with cisplatin and either palonosetron, granisetron, or ondansetron. At various times after dosing, single neuronal recordings from nodose ganglia were collected after stimulation with SP; nodose ganglia neuronal responses to SP were enhanced when the animals were pretreated with cisplatin. Palonosetron, but not ondansetron or granisetron, dosedependently inhibited the cisplatin-induced SP enhancement. The results are consistent with previous data showing that palonosetron exhibits distinct pharmacology versus the older 5-HT 3 receptor antagonists and provide a rationale for the efficacy observed with palonosetron in delayed CINV in the clinic.

Palonosetron versus ondansetron for prevention of chemotherapy-induced nausea and vomiting in paediatric patients with cancer receiving moderately or highly emetogenic chemotherapy: a randomised, phase 3, double-blind, double-dummy, non-inferiority study

“…[13][14][15] _ENREF_12 Palonosetron has also been shown to have greater receptor selectivity, longer duration of action, and unique structural characteristics compared with other 5-HT 3 receptor antagonists. 13,[16][17][18][19][20] Palonosetron also appears to have an advantageous safety profile compared with ondansetron, granisetron, dolasetron, and tropisetron, which have been associated with electrocardiographic changes and arrhythmias, sometimes leading to the potentially fatal heart rhythm torsades de pointes. 13,14,[21][22][23][24] Palonosetron has been shown not to cause arrhythmias or symptomatic electrocardiographic changes.…”

Efficacy of palonosetron for preventing postoperative nausea and vomiting: a systematic review and meta-analysis

“…[13][14][15][16][17] Palonosetron may also have other advantages for perioperative care. For example, a recent study reported by Cho et al 34 found that palonosetron 0.075 mg iv administered before induction of anesthesia reduced injection pain associated with rocuronium administration; the NNT was 2.94.…”

“…Méthodes Nous avons effectué une recherche systématique dans les bases de données MEDLINE Ò , EMBASE TM , le Registre central Cochrane des essais cliniques contrô lés et Web of Science Ò pour identifier les essais randomisés contrô lés qui ont abordé la comparaison de l'efficacité antiémétique dans les 24 premières heures suivant une chirurgie, du palonosétron et de l'ondansétron administrés à titre prophylactique. Les principaux critères d'évaluation étaient le pourcentage de participants éprouvant des nausées postopératoires (NPO), des vomissements postopératoires (VPO) ou les deux, dans la période précoce (0-6 heures) ou tardive (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) Postoperative nausea and vomiting (PONV), the big ''little problem'', 1 is the most common postoperative medical problem. From the perspective of both patients and healthcare providers, prophylaxis of PONV is equally as important as postoperative analgesia.…”

“…13,14 In addition, Rojas et al [15][16][17] showed features that differentiate palonosetron from other 5-HT 3 RAs: allosteric binding and positive cooperativity with 5-HT 3 R, triggering of 5-HT 3 R internalization and prolonged inhibition of receptor function, and inhibition of substance P (a mediator of emesis)-mediated responses. [15][16][17] Due to these unique characteristics, palonosetron may be a promising agent that could achieve long-lasting efficacy in the prevention of PONV. Importantly, preliminary studies have already shown that palonosetron is safer and more effective than other 5-HT 3 RAs in preventing chemotherapy-induced nausea and vomiting, although this requires more rigorous confirmation.…”

Palonosetron compared with ondansetron in pediatric cancer patients: multicycle analysis of a randomized Phase III study

“…Its unique interaction with the 5-HT 3 receptor at the molecular level, and its effects on the NK 1 signaling pathway may offer an advantage for efficacy over older agents in this class [11][12][13]. In a large meta-analysis of 16 randomized studies, in predominantly adult patients, palonosetron was reported to be more effective than other 5-HT 3 antagonists for the prevention of CINV associated with MEC or HEC regimens in studies that did not allow dexamethasone [14].…”