CN115089583A - 一种化合物在制备预防或治疗椎间盘退变的药物中的应用 - Google Patents
一种化合物在制备预防或治疗椎间盘退变的药物中的应用 Download PDFInfo
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Abstract
本发明涉及药物技术领域，具体公开了一种化合物在制备预防或治疗椎间盘退变的药物中的应用。发明人在实验中发现：椎间盘退变模型大鼠，其椎间盘高度及信号均较正常对照组降低；而治疗组进行式Ⅰ所示结构的化合物局部注射后，椎间盘高度及信号均较造模组高；实验结果表明式Ⅰ所示结构的化合物对椎间盘退变具有治疗作用；因此，将式Ⅰ所示结构的化合物作为活性成分用于制备预防或治疗椎间盘退变的药物具有重要的应用价值。
Description
技术领域
本发明涉及药物技术领域，具体涉及一种化合物在制备预防或治疗椎间盘退变的药物中的应用。
背景技术
下腰痛(Low back pain)是一种临床上广泛存在的骨骼肌肉疾病。据报道，高达80％的人在其一生中会受到下腰痛的影响，造成了巨大的经济和医疗负担。椎间盘退变(Intervertebral disc degeneration，IDD)是引起下腰痛最常见的原因，约占40％。然而，目前临床上尚无针对椎间盘退变的治疗药物。
椎间盘退变是一种多因素过程，如异常受力、局部营养缺乏以及先天基因异常等，而炎症是椎间盘退变的重要发病机制之一，其中炎症因子介导的髓核细胞细胞外基质合成代谢紊乱是椎间盘退变过程中极为关键的一环。因此，近年来针对炎症因子介导的髓核细胞细胞外基质降解、流失的研究已成为治疗椎间盘退变的重要途径，以期从根本上解决椎间盘退变的问题。
目前临床使用的治疗药物多针对具体症状，而对退变椎间盘本身进行保护及改善的相关药物种类少，患者选择余地小。同时，目前使用相关药物疗效有限，且长期应用有一定副作用，所以在一定程度上限制了使用。手术治疗主要为腰椎融合术和椎间盘置换术，腰椎融合术是摘除椎间盘，后植入内固定和椎间融合器，创伤大，存在相关术中和术后并发症等问题，术后的固定节段活动度丢失；经济上，高昂的内植物和器械耗材给社会和家庭带来承重负担。因此，开发一种预防或治疗椎间盘退变的药物具有重要的应用价值。
发明内容
为了解决现有背景技术中指出的至少之一的技术问题，本发明提供了一种化合物在制备预防或治疗椎间盘退变的药物中的应用。
本发明所要解决的上述技术问题，通过以下技术方案予以实现：
一种化合物在制备预防或治疗椎间盘退变的药物中的应用，所述的化合物具有式Ⅰ所示的结构；
式Ⅰ所示结构的化合物为已知的化合物，发明人在实验中惊奇的发现，椎间盘退变模型大鼠，其椎间盘高度及信号均较正常对照组降低；而治疗组进行式Ⅰ所示结构的化合物局部注射后，椎间盘高度及信号均较造模组高；实验表明式Ⅰ所示结构的化合物对椎间盘退变具有治疗作用。
式Ⅰ所示结构的化合物具有预防或治疗椎间盘退变的；因此，将其作为
优选地，所述的药物以式Ⅰ所示结构的化合物为活性成分。
优选地，所述的药物还包含药学上可接受的辅料。
优选地，所述药物的剂型包括：注射液、口服液、胶囊、片剂、颗粒剂、缓释剂以及滴丸剂。
有益效果：本发明提供了一种式Ⅰ所示结构的化合物在制备预防或治疗椎间盘退变的药物中的全新的应用。发明人在实验中发现：椎间盘退变模型大鼠，其椎间盘高度及信号均较正常对照组降低；而治疗组进行式Ⅰ所示结构的化合物局部注射后，椎间盘高度及信号均较造模组高；实验结果表明式Ⅰ所示结构的化合物对椎间盘退变具有治疗作用；因此，将式Ⅰ所示结构的化合物作为活性成分用于制备预防或治疗椎间盘退变的药物具有重要的应用价值。
附图说明
图1为大鼠尾椎MRI图(其中，CTR为对照组；IDD为单纯椎间盘退变组组；IDD+TAK为椎间盘退变+式Ⅰ所示结构的化合物治疗组)。
图2为大鼠尾椎HE与翻红O固绿染色图(其中，CTR为对照组；IDD为单纯椎间盘退变组组；IDD+TAK为椎间盘退变+式Ⅰ所示结构的化合物治疗组)。
具体实施方式
以下结合具体实施例来进一步解释本发明，但实施例对本发明不做任何形式的限定。
实施例1式Ⅰ所示结构的化合物对椎间盘退变具有治疗作用
1)大鼠尾椎穿刺模型及使用TAK-715挽救
取8周龄雄性SD大鼠(中山大学中山医学院动物实验室)在26-28℃和50-65％湿度条件下，昼夜12小时。给动物喂食标准的啮齿动物食物，并且可以随意获得淡水。手术前，通过腹腔注射戊巴比妥钠(5mg/100g体重)麻醉大鼠。尾部消毒，指端触诊判断针刺节段(Co8/9)，(21G)穿刺针刺入椎间盘正中并横穿整个纤维环(AF)层，针刺深度约为4mm，且穿刺针留置于椎间盘中1分钟，拔出穿刺针，消毒穿刺部位，即椎间盘退变模型建立完成。
大鼠进行分组：组1(对照组，图1中Control)，组2(单纯椎间盘退变组，图1中IDD)，组3(椎间盘退变+式Ⅰ所示结构的化合物治疗组，图1中IDD+TAK)。
组1采用正常的雄性SD大鼠，组2和组3分别采用椎间盘退变模型大鼠；每组6只。
2)应用式Ⅰ所示结构的化合物及对照进行体内注射
组3大鼠分别向椎间盘注射5μl的式Ⅰ所示结构的化合物(1μM)。给予大鼠8周的治疗后恢复。
3)检测各组大鼠椎间盘退变情况
对大鼠尾椎进行MRI扫描，处死所有大鼠，取尾，然后清除软组织，用4％PFA固定脊柱。将椎间盘组织切片成5μm厚的石蜡切片进行组织学评估，石蜡切片按照标准的实验室规程进行番红O固绿和HE染色，结果见图2。
实验结果发现，椎间盘退变模型大鼠，其椎间盘高度及信号均较对照组降低。治疗组进行式Ⅰ所示结构的化合物局部注射后，椎间盘高度及信号均较造模组高。这证实式Ⅰ所示结构的化合物对椎间盘退变具有治疗作用。
Claims (4)
1.一种化合物在制备预防或治疗椎间盘退变的药物中的应用，其特征在于，所述的化合物具有式Ⅰ所示的结构；
2.根据权利要求1所述的化合物在制备预防或治疗椎间盘退变的药物中的应用，其特征在于，所述的药物以式Ⅰ所示结构的化合物为活性成分。
3.根据权利要求1所述的化合物在制备预防或治疗椎间盘退变的药物中的应用，其特征在于，所述的药物还包含药学上可接受的辅料。
4.根据权利要求1所述的化合物在制备预防或治疗椎间盘退变的药物中的应用，其特征在于，所述药物的剂型包括：注射液、口服液、胶囊、片剂、颗粒剂、缓释剂以及滴丸剂。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090162376A1 (en) * | 2007-12-21 | 2009-06-25 | Brown Laura J | Trans-capsular administration of p38 map kinase inhibitors into orthopedic joints |
| WO2022016267A1 (en) * | 2020-07-21 | 2022-01-27 | Haglund Lisbet Agneta | Senotherapeutic drugs for age-related diseases and cancer |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090162376A1 (en) * | 2007-12-21 | 2009-06-25 | Brown Laura J | Trans-capsular administration of p38 map kinase inhibitors into orthopedic joints |
| WO2022016267A1 (en) * | 2020-07-21 | 2022-01-27 | Haglund Lisbet Agneta | Senotherapeutic drugs for age-related diseases and cancer |
Non-Patent Citations (2)
| Title |
|---|
| REBECCA K. STUDER等: "p38 MAPK Inhibition in Nucleus Pulposus Cells： A Potential Target for Treating Intervertebral Disc Degeneration", SPINE, vol. 32, no. 25, pages 2827 - 2833 * |
| SEIJI MIWATASHI等: "Novel Inhibitor of p38 MAP Kinase as an Anti-TNF-αα Drug: Discovery of N-[4-[2-Ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (TAK-715) as a Potent and Orally Active Anti-Rheumatoid Arthritis Agent", J. MED. CHEM., vol. 48, no. 19, pages 5966 - 5979, XP009156155, DOI: 10.1021/jm050165o * |
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