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首页> 外文期刊>Clinical immunology: The official journal of the Clinical Immunology Society >Mechanism of action for leflunomide in rheumatoid arthritis.
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Mechanism of action for leflunomide in rheumatoid arthritis.

机译：来氟米特在类风湿关节炎中的作用机理。

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Leflunomide (Arava) has recently been approved by the Food and Drug Administration for the treatment of rheumatoid arthritis (RA). This approval was based on data from a double-blind, multicenter trials in the United States (leflunomide versus methotrexate versus placebo) in which leflunomide was superior to placebo and similar to methotrexate (Strand et al., Arch. Intern. Med., in press, 1999). In a multicenter European trial, leflunomide was similar to sulfasalazine in efficacy and side effects (Smolen et al., Lancet 353, 259-266, 1999). Both methotrexate and leflunomide retarded the rate of radiolographic progression, entitling them to qualify as disease-modifying agents (Strand et al., Arch. Intern. Med., in press, 1999). Leflunomide is an immunomodulatory drug that may exert its effects by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), which plays a key role in the de novo synthesis of the pyrimidine ribonucleotide uridine monophosphate (rUMP). The inhibition of human DHODH by A77 1726, the active metabolite of leflunomide, occurs at levels (approximately 600 nM) that are achieved during treatment of RA. We propose that leflunomide prevents the expansion of activated and autoimmune lymphocytes by interfering with the cell cycle progression due to inadequate production of rUMP and utilizing mechanisms involving p53. The relative lack of toxicity of A77 1726 on nonlymphoid cells may be due to the ability of these cells to fulfill their ribonucleotide requirements by use of salvage pyrimidine pathway, which makes them less dependent on de novo synthesis. Copyright 1999 Academic Press.
机译：来氟米特（Arava）最近已获得美国食品药品监督管理局（FDA）的批准用于治疗类风湿关节炎（RA）。该批准是基于美国一项双盲，多中心试验（来氟米特与氨甲蝶呤与安慰剂）的数据，其中来氟米特优于安慰剂且类似于甲氨蝶呤（Strand等人，Arch。Intern。Med。出版社，1999）。在一项欧洲的多中心试验中，来氟米特在功效和副作用方面与柳氮磺胺吡啶相似（Smolen等人，柳叶刀353，259-266，1999）。甲氨蝶呤和来氟米特都可延缓放射线照相进展的速度，使其有资格作为疾病缓解剂（Strand等人，Arch。Intern。Med。，印刷中，1999）。来氟米特是一种免疫调节药物，可通过抑制线粒体酶二氢乳清酸脱氢酶（DHODH）发挥作用，该酶在嘧啶核糖核苷酸尿苷单磷酸（rUMP）的从头合成中起关键作用。来氟米特的活性代谢物A77 1726对人DHODH的抑制作用发生在RA治疗期间达到的水平（约600 nM）。我们建议来氟米特通过干扰由于rUMP产量不足而引起的细胞周期进程并利用涉及p53的机制来阻止活化和自身免疫淋巴细胞的扩增。 A77 1726对非淋巴样细胞毒性的相对缺乏可能是由于这些细胞通过使用挽救性嘧啶途径来满足其核糖核苷酸需求的能力，这使得它们较少依赖从头合成。版权所有1999，学术出版社。

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