Budde Klemens, Schütz Manuela, Glander Petra, Peters Harm, Waiser Johannes, Liefeldt Lutz, Neumayer Hans-H, Böhler Torsten
Department of Nephrology, Charité Universitatsmedizin Berlin, Berlin, Germany.
Clin Transplant. 2006;20 Suppl 17:17-24. doi: 10.1111/j.1399-0012.2006.00596.x.
FTY720 (Fingolimod) is a novel immunomodulator with a mode of action that is completely different from classical immunosuppressants. FTY is a structural and functional analogue of the natural serum lipid, sphingosine, and is the first in a new class of drugs called sphingosine 1-phosphate receptor (S1P-R) modulators. This review discusses the recent findings on the mechanism of action, preclinical models and outlines the results of the ongoing clinical development program. FTY is highly effective in prolonging allograft survival in preclinical models of transplantation and in experimental models of autoimmune diseases. In clinical trials, this novel compound was investigated in de novo renal transplantation and in multiple sclerosis. Pharmacokinetics are characterized by a prolonged absorption phase, a large volume of distribution, and a long elimination half-life. FTY induces a rapid and transient decrease in lymphocyte counts, which supports the modulatory effects of the drug on lymphocyte sequestration. The most common adverse event was asymptomatic transient bradycardia, a pharmacodynamic effect modulated by atrial S1 P-R. FTY failed to show an improvement in efficacy for the prevention of renal allograft rejection in two large phase III studies. FTY treatment regimens were associated with impaired renal function and the development of macula edema. Consequently, the further development in renal transplantation was stopped. Because initial clinical studies strongly suggest that FTY is highly effective in multiple sclerosis FTY is now being explored in phase III studies for the treatment of demyelinating diseases, Ongoing studies in multiple sclerosis are eagerly awaited because they may provide novel therapeutic options for patients with autoimmune diseases.
FTY720（芬戈莫德）是一种新型免疫调节剂，其作用方式与传统免疫抑制剂完全不同。FTY是天然血清脂质鞘氨醇的结构和功能类似物，是一类名为鞘氨醇-1-磷酸受体（S1P-R）调节剂的新型药物中的首个药物。本综述讨论了关于其作用机制、临床前模型的最新研究结果，并概述了正在进行的临床开发项目的结果。FTY在移植临床前模型和自身免疫性疾病实验模型中延长同种异体移植物存活方面非常有效。在临床试验中，这种新型化合物在初次肾移植和多发性硬化症中进行了研究。其药代动力学特征为吸收期延长、分布容积大以及消除半衰期长。FTY可导致淋巴细胞计数迅速且短暂地下降，这支持了该药物对淋巴细胞隔离的调节作用。最常见的不良事件是无症状短暂性心动过缓，这是一种由心房S1P-R调节的药效学效应。在两项大型III期研究中FTY未能显示出预防肾移植排斥反应疗效的改善。FTY治疗方案与肾功能受损和黄斑水肿的发生有关。因此，肾移植方面的进一步开发被停止。由于最初的临床研究强烈表明FTY在多发性硬化症中非常有效，目前正在进行III期研究以探索其用于治疗脱髓鞘疾病，人们热切期待正在进行的多发性硬化症研究，因为它们可能为自身免疫性疾病患者提供新的治疗选择。
