FTY720 (fingolimod) in renal transplantation
FTY720 (fingolimod) in renal transplantation
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DOI：
10.1111/j.1399-0012.2006.00596.x
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发表时间：
2006-01-01
影响因子：
2.1
通讯作者：
Boehler, Torsten
中科院分区：
文献类型：
--
作者：
Budde, Klemens;Schuetz, Manuela;Boehler, Torsten
FTY720 （Fingolimod）是一种新型的免疫调节剂，其作用方式与传统的免疫抑制剂完全不同。它是一种结构和功能上类似天然血清脂质鞘氨醇的药物，是一类被称为鞘氨醇1-磷酸受体（SIP-R）调节剂的新药。这篇综述讨论了作用机制、临床前模型的最新发现，并概述了正在进行的临床开发计划的结果。在临床前移植模型和自身免疫性疾病的实验模型中，FTY在延长同种异体移植存活方面非常有效。在临床试验中，这种新型化合物在新生肾移植和多发性硬化症中进行了研究。药代动力学的特点是吸收期长，分布量大，消除半衰期长。FTY诱导淋巴细胞计数快速和短暂的减少，这支持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的短暂性心动过缓，这是一种由心房S1 P-R调节的药效学效应。在两项大型III期研究中，FTY未能显示出预防同种异体肾移植排斥反应的疗效改善。FTY治疗方案与肾功能受损和黄斑水肿的发展有关。因此，肾移植的进一步发展被停止。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，目前正处于治疗脱髓鞘疾病的III期研究中，人们热切期待正在进行的多发性硬化症研究，因为它们可能为患有自行性疾病的患者提供新的治疗选择。
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 (SIP-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 autominnue diseases.