Preformulation Laboratory, PK-PD Toxicology & Formulation Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
Preformulation Laboratory, PK-PD Toxicology & Formulation Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India.
J Ethnopharmacol. 2020 May 23;254:112758. doi: 10.1016/j.jep.2020.112758. Epub 2020 Mar 9.
Rheumatoid arthritis is a chronic inflammatory disease of joints. Dysoxylum binectariferum Hook.f (Family: Meliaceae) is a Indian medicinal plant which is traditionally being used to heal inflammation of joints.
This work was aimed to carry out chemical standardization, in-vitro/in-vivo validation, oral pharmacokinetics and formulation development of anti-arthritic botanical lead, the rohitukine-enriched fraction of D. binectariferum.
The rohitukine-enriched fraction of D. binectariferum was standardized using four chemical markers and was checked for microbial load, heavy metal content, aflatoxins and pesticides. Its in-vitro inhibitory effect on the lipopolysaccharide (LPS) induced production of pro-inflammatory cytokines TNF-α and IL-6 was studied in THP-1 cells. The in-vivo anti-arthritic activity was investigated in collagen-induced arthritis model in DBA/1J mice. The sustained release capsule formulation was developed and characterized for physicochemical and pharmacokinetic properties.
Rohitukine and schumaniofioside A were found to be major chemical constituents of the botanical lead. The rohitukine-enriched fraction of D. binectariferum significantly reduced the production of both pro-inflammatory cytokines TNF-α and IL-6 (>50% inhibition at 3.12 μg/mL) in THP-1 cells. In LPS-treated wild-type mice model, the rohitukine-enriched fraction at 200 mg/kg (PO, QD) completely reduced serum TNF-α levels. In transgenic mice model (collagen-induced arthritis in DBA/1J mice), rohitukine-enriched fraction at 100 mg/kg (PO, QD) dose has resulted in >75% reduction of TNF-α/IL-6 serum levels, 68% reduction in anti-mouse type II collagen IgG1 antibody levels, decreased joint proteoglycan loss and reduced paw edema in DBA/1J mice. The sustained release capsule formulation of rohitukine-enriched fraction showed sustained-release of rohitukine over the period of 24 h, and resulted in an improved plasma-exposure of rohitukine in SD rats.
The data presented herein demonstrated anti-arthritic potential of rohitukine-enriched fraction of D. binectariferum and this study will serve as the benchmark for further research on this botanical lead and developed sustained release capsule formulation.
类风湿性关节炎是一种慢性关节炎症。Dysoxylum binectariferum Hook.f（Meliaceae 科）是一种印度药用植物，传统上用于治疗关节炎症。
本工作旨在对 Rheumatoid arthritis 的植物药先导 Rohitukine 进行化学标准化、体外/体内验证、口服药代动力学和制剂开发，该植物药先导 Rohitukine 来自 Dysoxylum binectariferum 的 Rohitukine 富集部分。
使用四种化学标志物对 Dysoxylum binectariferum 的 Rohitukine 富集部分进行标准化，并检查其微生物负荷、重金属含量、黄曲霉毒素和农药残留。在 THP-1 细胞中研究了其对脂多糖 (LPS) 诱导的促炎细胞因子 TNF-α 和 IL-6 产生的体外抑制作用。在 DBA/1J 小鼠胶原诱导关节炎模型中研究了体内抗关节炎活性。开发并表征了缓释胶囊制剂的物理化学和药代动力学特性。
发现 Rohitukine 和 Schumaniofioside A 是植物药先导物的主要化学成分。Dysoxylum binectariferum 的 Rohitukine 富集部分可显著降低 THP-1 细胞中两种促炎细胞因子 TNF-α 和 IL-6 的产生（在 3.12μg/mL 时抑制率超过 50%）。在 LPS 处理的野生型小鼠模型中，Rohitukine 富集部分以 200mg/kg（PO，QD）的剂量完全降低了血清 TNF-α 水平。在转化型小鼠模型（DBA/1J 小鼠胶原诱导关节炎）中，Rohitukine 富集部分以 100mg/kg（PO，QD）的剂量可使 TNF-α/IL-6 血清水平降低 75%以上，抗小鼠 II 型胶原 IgG1 抗体水平降低 68%，减少关节糖胺聚糖丢失，并减轻 DBA/1J 小鼠的爪肿胀。Rohitukine 富集部分的缓释胶囊制剂可在 24 小时内持续释放 Rohitukine，从而改善 SD 大鼠体内 Rohitukine 的暴露水平。
本文提供的数据表明，Dysoxylum binectariferum 的 Rohitukine 富集部分具有抗关节炎潜力，本研究将为该植物药先导物的进一步研究和开发的缓释胶囊制剂提供基准。
