Deuse Tobias, Velotta Jeffrey B, Hoyt Grant, Govaert Johannes A, Taylor Vanessa, Masuda Esteban, Herlaar Ellen, Park Gary, Carroll David, Pelletier Marc P, Robbins Robert C, Schrepfer Sonja
Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
Transplantation. 2008 Mar 27;85(6):885-92. doi: 10.1097/TP.0b013e318166acc4.
Janus kinase (JAK)3 is crucial for signal transduction downstream of various cytokine receptors in immune cells. This is the first report on the novel JAK3 inhibitor R348.
(1) Detailed pharmacokinetic data were obtained in rats; (2) multiple in vitro enzyme inhibition assays were performed to characterize the drug; (3) prevention of acute rejection was investigated in animals treated with different doses of R348 or rapamycin for 5 days; and (4) cardiac allograft survival after a 10-day treatment period was studied for various regimens of R348, tacrolimus, or rapamycin; combination indices were calculated to evaluate drug interactions.
(1) Plasma levels of R348's active metabolite R333 sustained high for 8 hr or more, depending on the dose. (2) In vitro enzyme assays showed potent inhibition of JAK3- and Syk-dependent pathways. (3) R348 40 mg/kg preserved graft function, significantly reduced graft infiltration, and decreased histologic ISHLT rejection scores on postoperative day 5. 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.
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.
Janus激酶（JAK）3对免疫细胞中各种细胞因子受体下游的信号转导至关重要。这是关于新型JAK3抑制剂R348的首次报告。
（1）在大鼠中获得详细的药代动力学数据；（2）进行多种体外酶抑制试验以表征该药物；（3）在接受不同剂量R348或雷帕霉素治疗5天的动物中研究急性排斥反应的预防；（4）研究了R348、他克莫司或雷帕霉素的各种给药方案在10天治疗期后的心脏同种异体移植存活情况；计算联合指数以评估药物相互作用。
（1）R348的活性代谢物R333的血浆水平持续高8小时或更长时间，具体取决于剂量。（2）体外酶试验显示对JAK3和Syk依赖性途径有强效抑制作用。（3）R348 40mg/kg可维持移植物功能，显著减少移植物浸润，并在术后第5天降低组织学ISHLT排斥评分。结果与雷帕霉素3mg/kg相似。同样，两种药物均显著降低了细胞Th1和Th2免疫反应，这通过酶联免疫吸附试验确定。R348和雷帕霉素同样抑制了移植物内炎性细胞因子的上调。R348 10mg/kg治疗效果不佳。（4）R348 20mg/kg和40mg/kg的同种异体移植存活情况相似，与治疗剂量的他克莫司或雷帕霉素相当。在联合给药方案中，R348与他克莫司表现出高度有益的协同相互作用。
R348是一种有前景的新型JAK3/Syk抑制剂，具有良好的药代动力学和生物学活性。它能有效减轻急性心脏同种异体移植排斥反应，适用于与他克莫司联合给药方案。
