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Palonosetron (Aloxi) is the only 5-HT3 receptor antagonist approved for treatment of delayed chemotherapy-induced nausea and vomiting (CINV) following administration of moderately emetogenic chemotherapeutic agents. At a platform presentation held during the 6th Annual Hematology/Oncology Pharmacy Association (HOPA) Meeting, Barbara S. Slusher, PhD, chief scientific officer, Brain Science Institute, NeuroTranslational Program, Johns Hopkins School of Medicine, Baltimore, Maryland, presented the results of a study that used in vitro and in vivo approaches to determine why palonosetron is effective in preventing delayed CINV compared with other agents. Slusher and colleagues postulated that palonosetron differentially inhibits “crosstalk” between NK-1 receptors and 5-HT3 signaling pathways. Previous studies have suggested that substance P (SP) acting on NK-1 receptors is the dominant mediator of delayed emesis, with recent data revealing significant “crosstalk” between the NK-1 receptors and 5-HT3 signaling pathways.
For the in vitro assessment, NG108-15 cells were preincubated with palonosetron, granisetron, or ondansetron. After these antagonists were removed, Slusher and colleagues measured SP-induced calciumion release in the NG108-15 cells. They found that palonosetron inhibited the serotonin enhancement of SP-induced calcium-ion release whereas the other antiemetics did not.
For the in vivo assessment, rats treated with cisplatin were given palonosetron, granisetron, or ondansetron. After stimulation with SP, single neuronal recordings of nodose ganglia expressing both NK-1 and 5-HT3 receptors were collected. Slusher and colleagues found that cisplatin significantly enhanced neuronal responses to SP. When palonosetron was administered 30 minutes before or 5 or 10 hours after cisplatin, the antiemetic inhibited cisplatin’s enhancement of SP in a dose-dependent fashion. Granisetron and ondansetron did not inhibit the cisplatin-induced SP enhancement.
According to Slusher et al, this is the first study to show that palonosetron inhibits SP-induced calciumion release in vitro as well as SP-induced neuronal responses in vivo. These findings may help explain the unique efficacy observed with palonosetron versus granisetron and ondansetron in the setting of delayed CINV. Palonosetron was recently launched in Japan, the 63rd country to approve the drug.
Slusher B, Ying L, Xiaoyin W, et al. Palonosetron uniquely inhibits substance P-mediated responses in vitro and in vivo. 6th Annual Hematology Oncology Pharma Association Meeting. March 24-27, 2010. New Orleans, LA.
For updates in CINV, see the March 2010 issue of Contemporary Oncology
, and for a complete guide to treatment of CINV, see the review article by Rudolph Navari, MD, which appeared in the December 2009 issue of Contemporary Oncology
and is available online at https://www.onclive.com/ cinvguidelines.pdf