Abstract：
OBJECTIVE: To establish the pharmacokinetics of the cyclin-dependent kinase-9 inhibitor flavopiridol in equine middle carpal joints, using an extended-release poly lactic-co-glycolic acid (PLGA) microparticle formulation.
METHODS: 4 healthy horses without evidence of forelimb lameness.
METHODS: A 6-week longitudinal pharmacokinetic study was conducted in 2 phases (6 weeks each) in 4 healthy horses. The PLGA microparticles containing 122 μg flavopiridol in 3 mL saline were administered by intra-articular injection into 1 middle carpal joint, with empty PLGA microparticles injected into the contralateral joint as a control. Synovial fluid and plasma were collected at time points out to 6 weeks, and drug concentrations in synovial fluid and plasma were determined using validated protocols. Synovial fluid total protein and total nucleated cell count and differential, CBC, serum biochemistry, and lameness exams were performed at each of the time points.
RESULTS: Synovial fluid flavopiridol averaged 19 nM at week 1, gradually reduced to 1.4 nM by 4 weeks, and was generally below the detection limit at 5 and 6 weeks. There was no detectable flavopiridol in the plasma samples, and no adverse effects were observed at any time point.
CONCLUSIONS: Intra-articular injection of PLGA microparticle-encapsulated flavopiridol was well tolerated in horses, with detectable levels of flavopiridol in the synovial fluid out to 4 weeks with negligible systemic exposure. Flavopiridol is a cyclin-dependent kinase-9 inhibitor with potent anti-inflammatory and analgesic activity. The extended-release microparticle formulation promotes intra-articular retention of the drug and it may be an alternative to other intra-articular medications for treatment of equine joint disease.
METHODS: 4 healthy horses without evidence of forelimb lameness.
METHODS: A 6-week longitudinal pharmacokinetic study was conducted in 2 phases (6 weeks each) in 4 healthy horses. The PLGA microparticles containing 122 μg flavopiridol in 3 mL saline were administered by intra-articular injection into 1 middle carpal joint, with empty PLGA microparticles injected into the contralateral joint as a control. Synovial fluid and plasma were collected at time points out to 6 weeks, and drug concentrations in synovial fluid and plasma were determined using validated protocols. Synovial fluid total protein and total nucleated cell count and differential, CBC, serum biochemistry, and lameness exams were performed at each of the time points.
RESULTS: Synovial fluid flavopiridol averaged 19 nM at week 1, gradually reduced to 1.4 nM by 4 weeks, and was generally below the detection limit at 5 and 6 weeks. There was no detectable flavopiridol in the plasma samples, and no adverse effects were observed at any time point.
CONCLUSIONS: Intra-articular injection of PLGA microparticle-encapsulated flavopiridol was well tolerated in horses, with detectable levels of flavopiridol in the synovial fluid out to 4 weeks with negligible systemic exposure. Flavopiridol is a cyclin-dependent kinase-9 inhibitor with potent anti-inflammatory and analgesic activity. The extended-release microparticle formulation promotes intra-articular retention of the drug and it may be an alternative to other intra-articular medications for treatment of equine joint disease.
摘要：
目的：建立细胞周期蛋白依赖性激酶-9抑制剂黄酮吡啶醇在马中腕关节中的药动学,使用缓释聚乳酸-羟基乙酸共聚物(PLGA)微粒制剂。
方法：4匹健康马没有前肢跛行的证据。
方法：在4匹健康马中进行了为期6周的纵向药代动力学研究，分为2个阶段（每个6周）。通过关节内注射到1个中腕关节中，将在3mL盐水中含有122μg黄酮吡啶醇的PLGA微粒，用空的PLGA微粒注射到对侧关节中作为对照。在至6周的时间点收集滑液和血浆，滑液和血浆中的药物浓度使用经过验证的方案确定。滑液总蛋白和总有核细胞计数和差异，CBC,血清生物化学,在每个时间点进行跛行检查.
结果：滑液黄皮醇在第1周平均为19nM，到第4周逐渐降低至1.4nM，并且在5周和6周时通常低于检测极限。在血浆样品中没有检测到的黄酮吡啶醇，并且在任何时间点均未观察到不良反应。
结论：关节内注射PLGA微粒包裹的黄酮吡啶醇在马匹中具有良好的耐受性，在滑液中可检测到的黄酮吡啶醇水平达到4周，全身暴露可忽略不计。Flavopiridol是一种细胞周期蛋白依赖性激酶-9抑制剂，具有有效的抗炎和镇痛活性。缓释微粒制剂可促进药物的关节内滞留，并且可以替代其他关节内药物治疗马关节疾病。
方法：4匹健康马没有前肢跛行的证据。
方法：在4匹健康马中进行了为期6周的纵向药代动力学研究，分为2个阶段（每个6周）。通过关节内注射到1个中腕关节中，将在3mL盐水中含有122μg黄酮吡啶醇的PLGA微粒，用空的PLGA微粒注射到对侧关节中作为对照。在至6周的时间点收集滑液和血浆，滑液和血浆中的药物浓度使用经过验证的方案确定。滑液总蛋白和总有核细胞计数和差异，CBC,血清生物化学,在每个时间点进行跛行检查.
结果：滑液黄皮醇在第1周平均为19nM，到第4周逐渐降低至1.4nM，并且在5周和6周时通常低于检测极限。在血浆样品中没有检测到的黄酮吡啶醇，并且在任何时间点均未观察到不良反应。
结论：关节内注射PLGA微粒包裹的黄酮吡啶醇在马匹中具有良好的耐受性，在滑液中可检测到的黄酮吡啶醇水平达到4周，全身暴露可忽略不计。Flavopiridol是一种细胞周期蛋白依赖性激酶-9抑制剂，具有有效的抗炎和镇痛活性。缓释微粒制剂可促进药物的关节内滞留，并且可以替代其他关节内药物治疗马关节疾病。
