Clinical Pharmacokinetics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
J Pharmacol Sci. 2011;116(3):264-73. doi: 10.1254/jphs.11029fp. Epub 2011 Jun 18.
Stiffness and cytokine in blood levels show 24-h rhythms in rheumatoid arthritis (RA) patients. We previously revealed that higher therapeutic effects were obtained in RA patients and RA model animals when the dosing time of methotrexate was chosen according to the 24-h rhythms to cytokine. In this study, we examined whether a dosing time-dependency of the therapeutic effect of tacrolimus (TAC) could be detected in collagen-induced arthritis (CIA) and MRL/lpr mice. To measure the levels of cytokines and serum amyloid A (SAA), blood was collected from CIA mice at different times. TAC was administered at two different dosing times based on these findings and its effects on arthritis and toxicity were examined. Plasma tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), and SAA concentrations showed obvious 24-h rhythms with higher levels during the light phase and lower levels during the dark phase after RA crisis. The arthritis score and leukocyte counts were significantly lower in the group treated at 2 h after the light was turned on (HALO) than in the control and 14 HALO-treated groups. Our findings suggest that choosing an optimal dosing time could lead to the effective treatment of RA by TAC.
僵硬和细胞因子在血液水平显示出类风湿关节炎（RA）患者的 24 小时节律。我们之前已经揭示，当根据细胞因子的 24 小时节律选择甲氨蝶呤的给药时间时，RA 患者和 RA 模型动物可以获得更高的治疗效果。在这项研究中，我们检查了他克莫司（TAC）的治疗效果是否存在给药时间依赖性在胶原诱导性关节炎（CIA）和 MRL/lpr 小鼠中。为了测量细胞因子和血清淀粉样蛋白 A（SAA）的水平，从 CIA 小鼠在不同时间采集血液。根据这些发现，TAC 分两次给药，并检查其对关节炎和毒性的影响。血浆肿瘤坏死因子（TNF）-α、白细胞介素 6（IL-6）和 SAA 浓度在 RA 危机后表现出明显的 24 小时节律，光相期间水平较高，暗相期间水平较低。与对照组和 14HALO 治疗组相比，在光开启后 2 小时（HALO）治疗的组中关节炎评分和白细胞计数明显降低。我们的研究结果表明，选择最佳的给药时间可能会导致 TAC 有效治疗 RA。
