Sustained efficacy of a single intra-articular dose of FX006 in a rat model of repeated localized knee arthritis
Sustained efficacy of a single intra-articular dose of FX006 in a rat model of repeated localized knee arthritis
复制标题
DOI：
10.1016/j.joca.2014.09.019
复制
发表时间：
2015-01-01
影响因子：
7
通讯作者：
Bodick, N.
中科院分区：
文献类型：
--
作者：
Kumar, A.;Bendele, A. M.;Bodick, N.
目的：评估单次关节内 (IA) 剂量的 FX006（聚乳酸-乙醇酸 (PLGA) 微球中的曲安奈德 (TCA) 缓释制剂）对滑膜炎反复发作后遗症的疗效。 设计：在单次 IA 注射不同剂量的 FX006、Kenalog 后，在 4 周内诱导大鼠右膝出现 3 次局部滑膜炎。 (R)（TCA 立即释放或 TCA IR）或车辆。采用步态评分来评估镇痛效果，并在研究结束时通过组织学评估关节。通过研究监测了 TCA 血浆浓度和皮质酮水平。结果：单次 IA 剂量 0.28 mg FX006 显着改善了所有三种重新激活的步态评分。 0.06 mg 的 TCA IR（提供相当的血浆 TCA 暴露量，C-max 高 10 倍）仅通过第一次重新激活显示出相当的益处，此后功效降低至无。有效剂量的 FX006 观察到组织学关节评分显着改善，但 TCA IR 未观察到。 TCA IR 和 FX006 治疗后皮质酮水平最初下降，但在第 14 天恢复。结论：在大鼠局部反复滑膜炎中，单次 IA 注射 FX006 后持续释放 TCA 相对于 TCA IR 显着延长镇痛时间，并显着改善组织学评分，且对 HPA 轴没有不利影响。由于滑膜炎可能导致骨关节炎 (OA)、RA 和痛风等多种关节疾病的病理生理学，因此 FX006 可能是这些疾病的重要治疗选择。 (C) 2014 年国际骨关节炎研究协会。由爱思唯尔有限公司出版。保留所有权利。
Objective: To evaluate the efficacy of a single intra-articular (IA) dose of FX006, an extended-release formulation of triamcinolone acetonide (TCA) in poly(lactic-co-glycolic acid) (PLGA) microspheres, on the sequelae of repeated episodes of synovitis.Design: Three flares of localized synovitis in the right knee of rats were induced over 4 weeks following a single IA injection of various doses of FX006, Kenalog (R) (TCA immediate release or TCA IR), or vehicle. Gait scores were employed to assess analgesic effect, and the joints were evaluated by histology at the end of the study. TCA plasma concentrations and corticosterone levels were monitored through the study.Results: A single IA dose of 0.28 mg FX006 significantly improved gait scores through all three reactivations. TCA IR at 0.06 mg (providing comparable plasma TCA exposure, 10-fold higher C-max) demonstrated comparable benefit through the first reactivation only and reduced-to-no efficacy thereafter. Significantly improved histological joint scores were observed with effective doses of FX006 but not with TCA IR. Corticosterone levels were initially decreased following both TCA IR and FX006 treatment, but recovered by Day 14.Conclusions: In localized, repeated synovitis in rats, sustained release of TCA following a single IA injection of FX006 significantly prolonged analgesia relative to TCA IR and significantly improved histological scores with no adverse effect on the HPA axis. Since synovitis can contribute to the pathophysiology of multiple joint diseases such as osteoarthritis (OA), RA and gout, FX006 may be an important treatment option for these conditions. (C) 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.