Anti-inflammatory and Anti-arthritic Effects of a Novel Leflunomide Analogue, UTL-5b (GBL-5b).
Anti-inflammatory and Anti-arthritic Effects of a Novel Leflunomide Analogue, UTL-5b (GBL-5b).
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DOI：
10.5099/aj110100031
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发表时间：
2011-01-01
期刊：
影响因子：
--
通讯作者：
Zeng D
中科院分区：
文献类型：
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作者：
Shaw J;Chen B;Wooley P;Huang WH;Lee AR;Zeng D
类风湿性关节炎（RA）是一种以关节软骨和骨的慢性炎症和不可逆性破坏为特征的常见疾病。在这份报告中，我们研究了一种新的来氟米特类似物UTL-5 b（也称为GBL-5 b）的抗炎和抗关节炎作用，用于潜在的RA治疗。使用角叉菜胶诱导的大鼠水肿研究，UTL-5 b显示出比来氟米特及其代谢产物更好的抗炎作用。使用II型胶原诱导的关节炎（CIA）小鼠模型检查UTL-5 b的慢性功效。UTL-5 b以剂量依赖性方式发挥抗关节炎作用，给予30 mg/kg的小鼠在试验早期表现出疾病改善，但随着时间的推移失去统计学显著性。相比之下，用60 mg/kg处理的小鼠在试验早期显示出降低的临床疾病参数，并且这些作用在10周的试验期内持续。机制研究表明UTL-5 b是体内TNF-α产生的抑制剂。在腹腔注射致死剂量的脂多糖（LPS）/D-氨基半乳糖之前口服UTL-5 b可显著降低血清TNF-α水平，并增加感染性休克诱导死亡的动物的存活率。使用接受增加剂量的UTL-5 b的小鼠的急性毒性研究显示，在2，000 mg/kg（LD 50> 2，000 mg/kg）下没有动物被UTL-5 b杀死。我们的研究表明，UTL-5 b代表了一种新的抗炎和抗关节炎剂，具有潜在的治疗RA的治疗应用。
Rheumatoid arthritis (RA) is a common disease characterized by chronic inflammation and irreversible destruction of articular cartilage and bone. In this report, we examined the anti-inflammatory and anti-arthritic effects of a novel leflunomide analogue, UTL-5b (also known as GBL-5b), for potential RA treatment. Using a carrageenan-induced edema study in rats, UTL-5b exhibited a better anti-inflammatory effect as compared with leflunomide and its metabolite. The chronic efficacy of UTL-5b was examined using type II collagen-induced arthritis (CIA) mouse model. UTL-5b exerted an anti-arthritic effect in a dose-dependant manner with mice given 30 mg/kg exhibiting amelioration of disease early in the trial, but losing statistical significance over time. In contrast, mice treated with 60 mg/kg showed reduced clinical disease parameters early in the trial and these effects were sustained over the ten week trial period. Mechanistic studies indicate that UTL-5b is an inhibitor of TNF-α production in vivo. Oral administration of UTL-5b prior to i.p. injection with lethal dose of lipopolysaccharide (LPS)/D-galactosamine markedly reduced the levels of serum TNF-α and increased survival rates of animals from septic shock-induced death. Acute toxicity study using mice receiving increasing doses of UTL-5b showed that no animals were killed by UTL-5b at 2,000 mg/kg (LD50 >2,000 mg/kg). Our studies show that UTL-5b represents a novel anti-inflammatory and anti-arthritic agent with potential therapeutic application for RA treatment.