新型免疫抑制:R348 JAK3——Syk-inhibitor急性移植物排斥反应变弱。
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Deuse T, Velotta JB,霍伊特G, Govaert是的,泰勒V,此外E, Herlaar E, G,卡罗尔D, Pelletier MP,罗宾斯RC, Schrepfer年代
新型免疫抑制:R348 JAK3——Syk-inhibitor急性移植物排斥反应变弱。
移植。2008年3月27日,85 (6):885 - 92。doi: 10.1097 / TP.0b013e318166acc4。
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18360272 (在PubMed]
- 文摘
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背景:Janus激酶(激酶)3是至关重要的各种细胞因子受体下游信号转导的免疫细胞。这是第一个报告小说R348 JAK3抑制剂。方法:(1)在大鼠获得详细的药代动力学数据;(2)多个体外酶抑制试验进行的药物;(3)预防急性排斥动物研究不同剂量处理R348或雷帕霉素5天;和(4)移植物存活10天的治疗期之后R348研究各种方案,他克莫司,或雷帕霉素;结合指数计算评估药物的相互作用。R348结果:(1)血浆水平的活性代谢物R333持续高8小时或者更多,这取决于剂量。(2)体外酶化验显示,有效的抑制JAK3 Syk-dependent通路。(3)R348 40毫克/公斤保存移植肾功能,显著降低贪污渗透,减少组织学ISHLT拒绝分数术后第五天。 Results were similar to those of rapamycin 3 mg/kg. Likewise, both drugs significantly reduced the cellular Th1 and Th2 immune responses, as determined by enzyme-linked immunosorbent assays. Intragraft inflammatory cytokine upregulation was similarly suppressed by R348 and rapamycin. R348 10 mg/kg was subtherapeutic. (4) Allograft survival was similar for R348 20 and 40 mg/kg, which was comparable with therapeutically dosed tacrolimus or rapamycin. In combination regimens, R348 demonstrated highly beneficial synergistic interactions with tacrolimus. CONCLUSIONS: R348 is a promising novel JAK3/Syk-inhibitor with favorable pharmacokinetics and biological activity. It effectively diminishes acute cardiac allograft rejection and is suitable for combination regimens with tacrolimus.
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- 药物