PDF(Pubmed)
Abstract：
Rheumatoid arthritis is a systemic autoimmune disease characterized by synovial inflammation and bone destruction. Identifying drugs with time-varying efficacy and toxicity, and elucidating the mechanisms would help to improve treatment efficacy and reduce adverse effects. Here, we aimed to determine the chronoefficacy of semen strychni (SS) and tripterygium glycoside tablet (TGT) against rheumatoid arthritis in mice, and to investigate a potential role of circadian pharmacokinetics in generating chronoefficacy. SS extract and TGT suspension were prepared with ultrasonication. Effects of SS and TGT on collagen-induced arthritis (CIA) were evaluated by measuring TNF-α and IL-6 levels. SS dosed at ZT18 was more effective in protecting against CIA than drug dosed at ZT6 (i.e., lower levels of key inflammatory factors at ZT18 than at ZT6). This was accompanied by higher systemic exposure levels of strychnine and brucine (two main putative active ingredients of SS) in ZT18-treated than in ZT6-treated CIA mice. TGT dosing at ZT2 showed a better efficacy against CIA as compared to herb doing at ZT14. Consistently, ZT2 dosing generated a higher exposure of triptolide (a main putative active ingredient of TGT) as compared to ZT14 dosing in CIA mice. Moreover, strychnine, brucine, and triptolide significantly inhibited the proliferation of fibroblast-like synoviocytes, and reduced the production of TNF-α and IL-6 and the mRNAs of TNF-α, IL-6, COX-2, and iNOS, suggesting that they possessed an anti-arthritis activity. In conclusion, SS and TGT display chronoefficacy against rheumatoid arthritis in mice, that is attributed to circadian pharmacokinetics of main active ingredients. Our findings have implications for improving treatment outcomes of SS and TGT via timed delivery.
摘要：
类风湿性关节炎是以滑膜炎和骨破坏为特征的全身性自身免疫性疾病。识别具有随时间变化的疗效和毒性的药物，阐明其机制将有助于提高治疗效果并减少不良反应。这里,我们的目的是确定精液马钱子（SS）和雷公藤多苷片（TGT）对小鼠类风湿关节炎的时间功效，并研究昼夜节律药代动力学在产生计时功效中的潜在作用。超声处理制备SS提取物和TGT混悬液。通过测量TNF-α和IL-6水平来评估SS和TGT对胶原诱导性关节炎（CIA）的影响。在ZT18时服用的SS比在ZT6时服用的药物更有效地保护了CIA(即，ZT18的关键炎症因子水平低于ZT6）。与ZT6治疗的CIA小鼠相比，ZT18治疗的士的宁和马钱子碱（SS的两种主要推定活性成分）的全身暴露水平更高。与ZT14时的草药相比，ZT2时的TGT给药对CIA显示出更好的疗效。始终如一，与CIA小鼠中的ZT14给药相比，ZT2给药产生了更高的雷公藤甲素（TGT的主要推定活性成分）暴露量。此外，马钱子碱,马钱子碱,雷公藤甲素显著抑制成纤维细胞样滑膜细胞的增殖，并减少TNF-α和IL-6的产生以及TNF-α的mRNA，IL-6、COX-2和iNOS,表明它们具有抗关节炎活性.总之,SS和TGT在小鼠中显示出对类风湿关节炎的慢性功效，这归因于主要活性成分的昼夜节律药代动力学。我们的发现对于通过定时给药改善SS和TGT的治疗结果具有重要意义。
