Pralnacasan, an inhibitor of interleukin-1β converting enzyme, reduces joint damage in two murine models of osteoarthritis
Pralnacasan, an inhibitor of interleukin-1β converting enzyme, reduces joint damage in two murine models of osteoarthritis
复制标题
DOI：
10.1016/s1063-4584(03)00153-5
复制
发表时间：
2003-10-01
影响因子：
7
通讯作者：
van den Berg, W
中科院分区：
文献类型：
--
作者：
Rudolphi, K;Gerwin, N;van den Berg, W
目的：研究有效的白介素-1 β转换酶（ICE）非肽抑制剂RU 36384/VRT-18858的口服前药pralnacasan对两种膝关节骨性关节炎（OA）模型小鼠关节损伤的影响。设计：在胶原酶诱导的CA模型中，雌性Balb/c小鼠分别以0、12.5、25和50 mg/kg的剂量灌胃给予普拉那卡珊，每天2次。在第二项研究中，pralnacasan在自发发生OA的雄性STR/1N小鼠中进行了测试，通过随意给予浓度为0,700和4200 ppm （mg/kg食物）的食物-药物混合物。两项研究均采用半定量组织病理学评分评估OA关节损伤。在STR/1N小鼠研究中，在基线、治疗3周和6周后，采用高压液相色谱法测定尿液中胶原交联羟基吡啶啉（HP）和赖氨酸吡啶啉（LP）的水平，并在6周后测定血浆中RU 36384/VRT-18858的浓度。结果：在两项研究中，小鼠在关节内侧腔室（胫骨平台和股骨髁）出现中度至重度膝关节CA，未治疗对照组的组织病理学中位数评分为18至21分，最高评分为32分。Pralnacasan的耐受性良好。在12.5和50 mg/kg剂量的胶原酶诱导的OA小鼠和4200 ppm的高剂量的STR/1N小鼠中，普萘卡森显著降低了13-22%的CA。在STR/1N小鼠中，高剂量组尿HP交联水平和HP/LP比值（OA关节损伤指标）分别显著降低59%和84%。结论：ICE抑制剂普拉那卡珊减轻了两种实验性OA模型的关节损伤，有可能成为OA治疗的一种疾病改善药物。(C) 2003国际骨关节炎研究学会。Elsevier Ltd.出版。版权所有。
Objective: To study the effect of pralnacasan, the orally bioavailable pro-drug of a potent, non-peptide inhibitor of interleukin-1beta converting enzyme (ICE), RU 36384/VRT-18858, on joint damage in two mouse models of knee osteoarthritis (OA).Design: In a collagenase-induced CA model, pralnacasan was given orally by gavage to female Balb/c mice at 0, 12.5, 25 and 50 mg/kg twice a day. In the second study, pralnacasan was tested in male STR/1N mice, which develop OA spontaneously, by administering food-drug mixtures ad libitum at concentrations of 0, 700 and 4200 ppm (mg/kg food). OA joint damage was assessed by a semi-quantitative histopathological score in both studies. In the STR/1N mouse study, urinary levels of collagen cross-links hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) were determined by high-pressure liquid chromatography at baseline, after 3 and 6 weeks of treatment and RU 36384/VRT-18858 plasma concentrations was measured after 6 weeks.Results: In both studies, the mice developed moderate to severe knee joint CA in the medial joint compartments (tibial plateau and femoral condyle), the non-treated control groups showing median histopathological scores from 18 to 21 of a maximal score of 32. Pralnacasan was well tolerated. At the doses of 12.5 and 50 mg/kg in collagenase-induced OA and at the high dose of 4200 ppm in STR/1N mice pralnacasan treatment significantly reduced CA by 13-22%. In the STR/1N mice, urinary levels of HP cross-links and the ratio of HP/LP, which are indicators of joint damage in OA, were significantly reduced in the high dose group by 59 and 84%, respectively.Conclusions: The ICE inhibitor pralnacasan reduced joint damage in two experimental models of OA and has the potential to become a disease-modifying drug for the treatment of OA. (C) 2003 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved.