CN116509840A - 洋川芎内酯i在制备防治器官纤维化的制品中的应用 - Google Patents
洋川芎内酯i在制备防治器官纤维化的制品中的应用 Download PDFInfo
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Abstract
本发明提供洋川芎内酯I在制备用于预防或治疗器官纤维化的制品中的应用；所述的制品，为功能性食品或药品。本发明发现洋川芎内酯I具有缓解器官纤维化作用，可明显降低肝纤维化实验动物的肝脏指数以及丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平，减轻肝组织病理变化，改善肝纤维化导致的肝损伤，活性与临床常用保肝药水飞蓟宾相当或更优。洋川芎内酯I的抗肾纤维化作用与阳性药厄贝沙坦相当。
Description
技术领域
本发明属于药物筛选应用技术领域，具体涉及洋川芎内酯I在制备防治器官纤维化的制品中的应用。
背景技术
纤维化是一种以组织瘢痕为特征的病理过程，可由创伤、医源性损伤或疾病引发，主要表现为组织过度生长、瘢痕或硬化。损伤组织修复是人体的一个正常的生理过程，主要涉及2个方面：
①再生过程，新生相同类型细胞替换损伤组织的细胞；
②纤维增生，结缔组织代替正常组织。
但是如果修复过程失控，导致细胞外基质(extracellular matrix,ECM)大量沉积，从而使得正常组织变成永久性的组织瘢痕。
器官纤维化是由多种急慢性病变引起的器官组织内纤维结缔组织增多和实质细胞减少的病理变化过程。常见的与纤维化相关的疾病包括特发性肺纤维化、非酒精性脂肪肝炎、病毒性肝炎、肝硬化、慢性肾病、心肌梗死、心力衰竭、糖尿病以及硬皮病等。持续性进展的器官纤维化可发展成器官硬化，最终造成器官结构破坏和功能减退，严重威胁人类生命健康，导致患者致残甚至死亡。从全球范围看，纤维化相关损伤始终是众多疾病致残致死的主要原因之一。受纤维化相关疾病影响的群体已占全球总人口数的近1/4，给社会和个人带来沉重医疗负担。
目前关于纤维化的发病机制尚未完全阐明，涉及炎症反应、氧化应激、上皮间质转化、成纤维细胞分化、胶原沉积等多种复杂机制。虽然活化的成纤维细胞被认为是纤维化的主要效应细胞，组织修复过程中肌成纤维细胞过度增殖、胶原等ECM过度沉积是纤维化形成的生物学基础，但是血管内皮细胞在纤维化过程中也发挥关键调控作用。
人体内几乎所有器官都可能发生纤维化。现代医学认为肺纤维化发病机制涉及炎症反应、氧化应激、上皮间质转化、成纤维细胞异常增殖分化等，病理表现为弥漫性肺泡炎、肺间质大量胶原沉积以及纤维化病灶，引起组织结构破坏、进行性瘢痕形成，最终导致呼吸衰竭和死亡。吡非尼酮和尼达尼布能够有效逆转特发性肺纤维化患者的肺功能低下，是目前治疗该疾病仅有的两款上市药物。然而，这两种药物仍存在服药后恶心、呕吐、厌食、光过敏、皮疹，或者导致肝功能损害等不良反应。
肝纤维化是各种慢性肝病引起的肝组织损伤后过度修复反应的结果，其发生发展的关键环节是肝星状细胞增殖活化、表型改变并转分化为肌成纤维细胞，同时分泌大量的ECM沉积在损伤部位，破坏肝脏正常结构。
肾纤维化是许多慢性肾脏疾病进展至终末端常见的病理过程，涉及的机制有炎症反应、上皮间质转化、成纤维细胞分化等，其会引起ECM大量合成并沉积在肾内，导致肾组织正常结构破坏。
心肌间质纤维化是由多种损伤因素所致心力衰竭发展的持续病理过程，病理特征为心脏间质中ECM过量沉积，导致心肌正常结构破坏、心肌僵硬，引起心肌舒张和收缩功能障碍，最终导致心力衰竭。
目前一些药用植物所含天然成分也可通过干预相关信号通路来缓解肝脏、肾脏及其他器官的纤维化，如五味子乙素、水飞蓟素、水飞蓟宾、黄芪甲苷、芍药苷、芹菜素、槲皮素、姜黄素、熊果酸、大黄素、甘草酸二铵、松果菊苷等。
遗憾的是，目前还没有针对心、肝、肾等重要器官纤维化病变的治疗药物成功获批上市。临床上主要是通过自体或异体的器官移植予以治疗，但往往都面临供体不足以及移植排异反应等问题。因此，研制安全有效的抗器官纤维化药物具有显著的临床需求和广阔的应用前景。
发明内容
本发明的目的是提供洋川芎内酯I在制备防治器官纤维化的制品中的应用，从而弥补现有技术的不足。
本发明首先提供洋川芎内酯I的一种用途，是在制备用于预防或治疗器官纤维化的制品中的应用；
所述的制品，为功能性食品或药品；
本发明再一个方面提供一种用于预防或治疗器官纤维化的制品，其中包含有药理有效浓度的洋川芎内酯I；
所述的药理有效浓度，其满足服用量范围为1-72mg/kg；
更进一步的，所述的药理药效浓度，其满足服用量范围为2-20mg/kg；
所述的制品，为液体制剂或其它剂型；包括片剂、胶囊剂、丸剂、颗粒剂、散剂、锭剂、注射剂、冻干粉针、糖浆剂、口服液、透皮贴剂、喷雾剂，经口服、静脉注射、肌肉注射、皮下注射、舌下、透皮、口腔喷雾、鼻腔喷雾途径给药。
本发明发现洋川芎内酯I具有缓解器官纤维化作用，可明显降低肝纤维化实验动物的肝脏指数以及丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平，减轻肝组织病理变化，改善肝纤维化导致的肝损伤，活性与临床常用保肝药水飞蓟宾相当或更优。洋川芎内酯I的抗肾纤维化作用与阳性药厄贝沙坦相当。
附图说明
图1：洋川芎内酯I的化学结构式。
图2：洋川芎内酯I对肝纤维化小鼠肝脏指数的影响图，其中实验数据表示为mean±SEM(n＝10)。与Model组比较，**P<0.01。
图3：洋川芎内酯I对肝纤维化小鼠肝功能及血浆HA的影响图，其中实验数据表示为mean±SEM。每组n＝10，与Model组比较，*P<0.05,**P<0.01。
图4：洋川芎内酯I对肝纤维化小鼠肝脏组织病理学及肝纤维化的影响图，其中(A)小鼠肝脏HE染色、天狼星红染色、α-SMA免疫组织化学染色结果的代表图。(B)肝纤维化的天狼星红染色结果分析。(C)肝纤维化的α-SMA免疫组织化学染色结果分析。实验数据表示为mean±SEM。每组n＝8，与Model组比较，*P<0.05，**P<0.01。
图5：洋川芎内酯I对小鼠肾脏纤维化的影响图，其中(A)小鼠肾脏天狼星红染色结果的代表图。(B)小鼠肾脏纤维化的天狼星红染色结果分析。实验数据表示为mean±SEM。每组n＝5，与Model组比较，*P<0.05，**P<0.01。
具体实施方式
洋川芎内酯I(SI)化学结构如图1所示，属于苯酞类天然产物。植物中的洋川芎内酯I为一对光学异构体按1：1比例组成的外消旋体，主要存在于伞形科当归属和藁本属植物中，如中药当归、川芎、藁本等。上述植物的挥发油中含有较多苯酞类成分，其中含量较高的为藁本内酯(通常0.5-2％)，而洋川芎内酯I的含量相对较少(低于0.1％)。受限于成分在植物中的含量、纯化难度及制备成本等原因，目前对藁本内酯的研究较多，而对洋川芎内酯I的药效研究较少。
申请人研究发现，洋川芎内酯I具有缓解器官纤维化作用。在CCl4诱导的小鼠肝纤维化模型上，灌胃给予洋川芎内酯I(6.25、12.5或25mg/kg)，可发挥剂量相关的抗肝纤维并减轻肝损伤的作用：
1)抗肝纤维化作用：洋川芎内酯I(12.5、25mg/kg)可明显降低血浆透明质酸HA含量、减少天狼星红染色的肝脏胶原纤维含量、减少肝纤维化蛋白标志物a-SMC的表达水平；
2)对肝纤维化所致肝损伤的保护作用：洋川芎内酯I(12.5、25mg/kg)可明显降低丙氨酸氨基转移酶和天冬氨酸氨基转移酶活性，减轻HE染色的肝脏组织病理损伤。洋川芎内酯I(25mg/kg)与临床临床常用保肝药水飞蓟宾(50mg/kg，临床等效剂量)的作用未见差异。在输尿管结扎诱导的小鼠肾纤维化模型上，灌胃给予洋川芎内酯I(25、50mg/kg)，可明显减少天狼星红染色的肾脏胶原纤维的含量，洋川芎内酯I(25、50mg/kg)作用与临床抗肾纤维化药物——厄贝沙坦(19.5mg/kg，临床等效剂量)未见差异。
除活性外，洋川芎内酯I还具有较好的溶解性、稳定性和生物利用度，且安全性良好，小鼠静脉给药最大耐受量大于900mg/kg。
下面结合实施例和附图对本发明进行详细的描述。
实施例1：洋川芎内酯I的抗肝纤维化作用
1.实验方法
1.1分组给药
6周龄雄性ICR小鼠，购自成都达硕实验动物有限公司【合格证号：SCXK(川)2020-030】。适应性喂养后，禁食不禁水12小时后称重，动物随机分为6组：对照组(Sham)，模型组(Model)，50mg/kg水飞蓟宾组(SF-50，临床等效剂量)，6.25、12.5、25mg/kg洋川芎内酯I组(SI-6.25，SI-12.5，SI-25)，每组10只。小鼠分别灌胃给予水飞蓟宾胶囊(天津天士力圣特制药有限公司，批号250703025)内容物、不同剂量的洋川芎内酯I，给药体积为0.1ml/10g，每日1次，连续给药4周；Sham组及Model组灌胃给予等体积生理盐水。Model组和各给药组小鼠腹腔注射20％CCl4(橄榄油配制，2.5ml/kg)，每周2次，连续4周；Sham组腹腔注射等体积橄榄油。每周称量体重，按照体重调整给药剂量。末次药后24小时，收集小鼠血样及肝脏标本。
1.2标本收集
(1)血液标本：采用眼眶取血的方法收集小鼠血液于EDTA抗凝管中，低温离心分离血浆，分装后保存于-80℃冰箱。
(2)肝脏标本：采用颈椎脱臼法处死小鼠，立即解剖取出肝脏，用生理盐水冲洗干净，充分吸干组织表面水分后，电子天平上称量肝重。将肝脏组织放入4％多聚甲醛溶液固定、石蜡包埋、切片，用于组织病理学检查。
1.3检测指标
1.3.1肝脏指数(Liver index)：Liver index＝(肝重/体重)×100％。
1.3.2血浆肝功能指标的检测：按照试剂盒操作说明检测小鼠血浆丙氨酸氨基转移酶(ALT)和天冬氨酸氨基转移酶(AST)的酶活性。
1.3.3血浆透明质酸(HA)含量：按照试剂盒操作说明，采用ELIAS法测定小鼠血浆HA的含量。
1.3.4肝脏病理组织学观察
(1)HE染色：肝脏石蜡切片，进行苏木精伊红(HE)染色。在显微镜下观察各组小鼠肝脏组织的病理变化。
(2)天狼星红染色：肝脏石蜡切片，采用天狼星红染色法观察肝脏中胶原纤维的沉积情况。显微镜下每个样本选取五个视野，用ImageJ软件对天狼星红染色结果进行半定量分析，分别测量每个视野的胶原纤维面积及对应视野的组织面积，胶原纤维面积百分比(％)＝胶原纤维面积/组织面积×100％。
(3)免疫组织化学染色检测α-SMA表达：肝脏石蜡切片，用柠檬酸(pH6.0)抗原修复液对组织抗原进行微波修复，冷却至室温，切片放入3％双氧水溶液除去内源性过氧化物酶，在组化圈内滴加3％BSA均匀覆盖组织，室温封闭30min，加一抗α-SMA封闭过夜后滴加二抗(与一抗相应种属的二抗，HRP标记)室温孵育50min。PBS冲洗后DAE显色，苏木素复染细胞核，封片胶封片，于镜下观察。每个样本选取五个视野，用ImageJ软件对α-SMA表达进行半定量分析，分别测量每个视野的阳性染色面积及对应视野的组织面积，阳性表达面积比例(％)＝阳性面积/组织面积×100％。
1.3.5统计分析方法
实验数据均用均数±标准误(mean±SEM)表示，用统计软件SPSS22.0中的单因素方差分析，组间两两比较采用LDS-t检验，P<0.05表示差异具有统计学意义。
具体的实验结果如下：
3.1对肝纤维化小鼠肝脏指数的影响
如图2所示，与Sham组比较，Model组小鼠肝脏指数明显增加(P<0.01)。与Model组比较，SF、SI-12.5和SI-25给药组小鼠肝脏指数均明显降低(P<0.01)，但SI-6.25低剂量组小鼠的肝脏指数未见变化。且中剂量、高剂量SI给药组(12.5、25mg/kg)的肝脏指数与50mg/kg临床等效剂量的SF给药组未见统计学差异(P>0.05)。
3.2对肝纤维化小鼠肝功能及血浆HA含量的影响
如图3所示，与Sham组相比，Model组小鼠的血浆肝功能指标ALT和AST活性显著升高(P<0.01)、肝纤维化相关指标血浆HA含量显著升高(P<0.01)。与Model组比较，SF-50、SI-12.5和SI-25给药组小鼠血浆ALT和AST酶活性、以及血浆HA含量明显降低(P<0.05或P<0.01)，SI-6.25组的三个指标均未见明显变化。与50mg/kg临床等效剂量的SF-50组比较，中剂量SI-12.5组和高剂量SI-25组(12.5、25mg/kg)的血浆ALT和AST酶活性、以及血浆HA含量均未见统计学差异(P>0.05)。
3.3对肝纤维化小鼠肝脏病理组织学及肝纤维化的影响
图4的HE染色结果显示，Sham组小鼠的肝脏的肝小叶结构清晰正常。与Sham组相比，Model组小鼠肝组织有明显的纤维组织增生，增生的纤维组织形成纤维间隔和假小叶，有明显的炎性浸润。与Model组相比较，SF-50组和SI-25组小鼠的肝脏纤维增生及炎性细胞浸润均明显减轻。
天狼星红结果显示，与Sham组相比，Model组小鼠肝脏中天狼星红阳性染色面积显著增加，表明小鼠肝纤维化模型构建成功。与Model组相比，SF-50组和SI-25组小鼠肝脏中的天狼星红阳性面积率显著降低(P<0.01)。SF-50组和SI-25组两组的天狼星红阳性面积率未见统计学差异。
免疫组织化学染色结果显示，与Sham组相比，Model组小鼠肝脏中棕色阳性面积明显增加，表明肝脏中α-SMA蛋白表达水平明显升高，小鼠肝纤维化模型构建成功。与Model组相比，S-50F组和SI-25组的α-SMA表达水平显著降低(P<0.01)。SF-50组和SI-25组的α-SMA表达水平未见统计学差异。
上述结果表明，洋川芎内酯I对CCl4所致小鼠肝纤维化的肝损伤有剂量相关的保护作用。
实施例2：洋川芎内酯I抗肾纤维化作用
6周龄雄性C57BL/6小鼠，购自成都达硕实验动物有限公司【合格证号：SCXK(川)2020-030】。适应性喂养后，禁食不禁水12小时称重，采用单侧输尿管结扎法建立小鼠肾纤维化模型。小鼠麻醉后，在腹部中线行垂直切口，暴露腹腔并剥离右侧输尿管，用6-0丝线进行输尿管结扎，然后逐层缝合关闭腹腔。假手术组(Sham)进行相同的手术操作，但不结扎输尿管。在手术过程，用加热板保持动物体温恒定。
术后24小时，肾纤维化建模动物随机分为4组：模型组(Model)，19.5mg/kg厄贝沙坦组(IrbeST-19.5，临床等效剂量；浙江华海药业股份有限公司，批号H20030016)，25、50mg/kg洋川芎内酯I组(SI-25，SI-50)，每组5只。灌胃给药，给药体积0.1ml/10g，每日1次，连续给药14天，Sham组和Model组灌胃给予等体积生理盐水。每周称量体重，按照体重变化调整给药剂量。
末次药后24小时，采用颈椎脱臼法处死小鼠，立即解剖取出肾脏，多聚甲醛溶液固定、石蜡包埋、切片，采用天狼星红染色法观察肾脏中胶原纤维的沉积情况。显微镜下每个样本选取五个视野，用ImageJ软件对天狼星红染色结果进行半定量分析，分别测量每个视野的胶原纤维面积及对应视野的组织面积，胶原纤维面积百分比(％)＝胶原纤维面积/组织面积×100％。实验数据均用均数±标准误(mean±SEM)表示，用统计软件SPSS22.0中的单因素方差分析，组间两两比较采用LDS-t检验，P<0.05表示差异具有统计学意义。
如图5所示，与Sham组比较，Model组小鼠肾脏中天狼星红阳性染色面积显著增加，表明单侧输尿管结扎方法成功构建小鼠肾纤维化模型(P<0.01)。与Model组相比，IrbeST-19.5组、SI-25组和SI-50组小鼠肾脏中的天狼星红阳性面积率显著降低(P<0.05)，并且3个给药组间未见统计学差异(P>0.05)。
上述结果表明，口服洋川芎内酯I(25、50mg/kg)具有显著的抗肾纤维化作用，且与阳性对照药厄贝沙坦临床等效剂量(19.5mg/kg)的作用未见统计学差异。
实施例3：急性毒性测试
SPF级ICR小鼠，雌雄各半，购自成都达硕实验动物有限公司，实验动物生产许可证号SCXK(川)2020-030。洋川芎内酯I为自制(HPLC检测含量>97％)。受试药物经尾静脉注射(300mg/次，一天三次)，观察记录小鼠出现的毒性反应情况。
结果显示，小鼠注射后洋川芎内酯I当天无死亡，连续观察14天，与空白组比较，洋川芎内酯I对小鼠体重增长无明显影响，体重变化与空白组相比无明显差异(P>0.05)。因此，洋川芎内酯I的最大耐受量>900mg/kg。
Claims (8)
1.洋川芎内酯I在制备用于预防或治疗器官纤维化的制品中的应用。
2.如权利要求1所述应用，其特征在于，所述的制品为功能性食品或药品。
3.一种用于预防或治疗器官纤维化的制品，其特征在于，所述的制品中包含有药理有效浓度的洋川芎内酯I。
4.如权利要求3所述的制品，其特征在于，所述的药理有效浓度是满足患者服用量范围为1-72mg/kg。
5.如权利要求4所述的制品，其特征在于，所述的药理有效浓度是满足服用量范围为2-20mg/kg。
6.如权利要求4所述的制品，其特征在于，所述的药理有效浓度是满足服用量范围为12-25mg/kg。
7.如权利要求3-6任一项所述的制品，其特征在于，所述的制品为液体制剂或其它药物剂型。
8.如权利要求7所述的制品，其特征在于，所述的药物剂型，为片剂、胶囊剂、丸剂、颗粒剂、散剂、锭剂、注射剂、冻干粉针、糖浆剂、透皮贴剂或喷雾剂。
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