Thomas Ajit G, Stathis Marigo, Rojas Camilo, Slusher Barbara S
Brain Science Institute, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD, 21205, USA.
Exp Brain Res. 2014 Aug;232(8):2637-44. doi: 10.1007/s00221-014-4017-7. Epub 2014 Jun 27.
Current therapy for chemotherapy-induced nausea and vomiting includes the use of both 5-HT3 and NK1 receptor antagonists. Acute emesis has largely been alleviated with the use of 5-HT3 receptor antagonists, while an improvement in preventing delayed emesis has been achieved with NK1 receptor antagonists. Delayed emesis, however, remains a problem with a significant portion of cancer patients receiving highly emetogenic chemotherapy. Like other drugs in its class, palonosetron, a 5-HT3 receptor antagonist, has shown efficacy against acute emesis. However, palonosetron has also shown consistent improvement in the suppression of delayed emesis. Since both 5-HT3 and NK1 receptor antagonists are often simultaneously administered to patients, the question remains if palonosetron's effect on delayed emesis would remain distinct when co-administered with an NK1 receptor antagonist. Recent mechanistic studies using NG108-15 cells have shown that palonosetron and netupitant, an NK1 receptor antagonist currently in phase 3 clinical trials, exhibited synergistic effects when inhibiting the substance P response. The present studies showed that both netupitant and palonosetron-induced NK1 receptor internalization in NG108-15 cells and that when used together receptor internalization was additive. Palonosetron-induced NK1 receptor internalization was dependent on the presence of the 5-HT3 receptor. Results provide a possible explanation for palonosetron's enhancement of the inhibition of the SP response and suggest that the effect of palonosetron and NK1 receptor antagonists on prevention of delayed emesis could be additive.
目前针对化疗引起的恶心和呕吐的治疗方法包括使用5-HT3和NK1受体拮抗剂。5-HT3受体拮抗剂的使用在很大程度上缓解了急性呕吐，而NK1受体拮抗剂在预防延迟性呕吐方面取得了进展。然而，对于接受高致吐性化疗的很大一部分癌症患者来说，延迟性呕吐仍然是一个问题。与同类的其他药物一样，5-HT3受体拮抗剂帕洛诺司琼已显示出对急性呕吐的疗效。然而，帕洛诺司琼在抑制延迟性呕吐方面也显示出持续的改善。由于5-HT3和NK1受体拮抗剂经常同时给予患者，问题仍然存在，即帕洛诺司琼与NK1受体拮抗剂共同给药时，其对延迟性呕吐的作用是否仍然显著。最近使用NG108-15细胞进行的机制研究表明，帕洛诺司琼和目前处于3期临床试验的NK1受体拮抗剂奈妥吡坦在抑制P物质反应时表现出协同作用。目前的研究表明，奈妥吡坦和帕洛诺司琼均可诱导NG108-15细胞中的NK1受体内化，并且一起使用时受体内化是相加的。帕洛诺司琼诱导的NK1受体内化依赖于5-HT3受体的存在。研究结果为帕洛诺司琼增强对P物质反应的抑制作用提供了一种可能的解释，并表明帕洛诺司琼和NK1受体拮抗剂对预防延迟性呕吐的作用可能是相加的。
