Darmani Nissar A, Chebolu Seetha, Zhong Weixia, Kim William D, Narlesky Matthew, Adams Joia, Dong Fanglong
Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA.
Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA.
Eur J Pharmacol. 2017 Aug 15;809:20-31. doi: 10.1016/j.ejphar.2017.05.014. Epub 2017 May 10.
The introduction of second generation serotonin 5-HT receptor (5-HT) antagonist palonosetron combined with long-acting substance P neurokinin NK receptor (NK) antagonists (e.g. netupitant) has substantially improved antiemetic therapy against early- and delayed-phases of emesis caused by highly emetogenic chemotherapeutics such as cisplatin. However, the improved efficacy comes at a cost that many patients cannot afford. We introduce a new class of antiemetic, the antiasthmatic leukotriene CysLT1 receptor antagonist pranlukast for the suppression of cisplatin-evoked vomiting. Pranlukast (10mg/kg) by itself significantly reduced the mean frequency of vomits (70%) and fully protected least shrews from vomiting (46%) during the delayed-phase of cisplatin (10mg/kg)-evoked vomiting. Although, pranlukast tended to substantially reduce both the mean frequency of vomits and the number of shrews vomiting during the early-phase, these reductions failed to attain significance. When combined with a first (tropisetron)- or a second (palonosetron)-generation 5-HT receptor antagonist, pranlukast potentiated their antiemetic efficacy during both phases of vomiting. In addition, pranlukast by itself prevented several intracellular signal markers of cisplatin-evoked delayed-vomiting such as phosphorylation of ERK1/2 and PKA. When pranlukast was combined with either palonosetron or tropisetron, these combinations suppressed the evoked phosphorylation of: i) ERK1/2 during both acute- and delayed-phase, ii) PKCα/β at the peak acute-phase, and iii) PKA at the peak delayed-phase. The current and our published findings suggest that overall behavioral and intracellular signaling effects of pranlukast via blockade of CysLT1 receptors generally appear to be similar to the NK receptor antagonist netupitant with some differences.
第二代5-羟色胺5-羟色胺受体（5-HT）拮抗剂帕洛诺司琼与长效P物质神经激肽NK受体（NK）拮抗剂（如奈妥匹坦）联合使用，已显著改善了针对由高致吐性化疗药物（如顺铂）引起的呕吐的早期和延迟期的止吐治疗。然而，疗效的提高是以许多患者无法承受的成本为代价的。我们引入了一类新的止吐药，即抗哮喘白三烯CysLT1受体拮抗剂普仑司特，用于抑制顺铂诱发的呕吐。普仑司特（10mg/kg）单独使用时，在顺铂（10mg/kg）诱发呕吐的延迟期，显著降低了平均呕吐频率（70%），并使至少46%的小家鼠免受呕吐。虽然普仑司特在早期倾向于显著降低平均呕吐频率和呕吐小家鼠的数量，但这些降低未达到显著水平。当与第一代（托烷司琼）或第二代（帕洛诺司琼）5-羟色胺受体拮抗剂联合使用时，普仑司特在呕吐的两个阶段均增强了它们的止吐疗效。此外，普仑司特单独使用可预防顺铂诱发的延迟性呕吐的几种细胞内信号标志物，如ERK1/2和PKA的磷酸化。当普仑司特与帕洛诺司琼或托烷司琼联合使用时，这些组合抑制了以下物质的诱发磷酸化：i）急性和延迟期的ERK1/2，ii）急性期峰值时的PKCα/β，以及iii）延迟期峰值时的PKA。目前和我们已发表的研究结果表明，普仑司特通过阻断CysLT1受体产生的整体行为和细胞内信号转导作用，总体上似乎与NK受体拮抗剂奈妥匹坦相似，但也存在一些差异。
