CN110327466A - 用于治疗肝纤维化的药物组合物及其应用 - Google Patents
用于治疗肝纤维化的药物组合物及其应用 Download PDFInfo
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- serotonin reuptake
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- A61K31/33—Heterocyclic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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Abstract
本发明涉及用于治疗肝纤维化的药物组合物及其应用,属于化学药物领域。所述药物组合物包含选择性5‑羟色胺再摄取抑制剂和马洛替酯。选择性5‑羟色胺再摄取抑制剂和马洛替酯的重量比为0.01‑2:10。本发明意外发现马洛替酯和氯西汀联合用药后对细胞肝纤维化模型和动物肝纤维化模型均产生了明显的协同作用,这种协同作用体现在抑制HSC增殖及活化,并保护肝细胞防止外界因素损伤。
Description
技术领域
本发明涉及用于治疗肝纤维化的药物组合物及其应用,属于化学药物领域。
背景技术
肝纤维化(hepatic fibrosis)是以胶原为主的细胞外基质(extracellularmatrix,ECM)在肝脏过度沉积的过程,也是许多慢性肝病(例如,病毒性肝炎、血吸虫病、乙醇性肝炎等)晚期共有的、渐进的病理改变,是肝硬化的前驱阶段。
目前认为,肝纤维化时肝组织中ECM的病理性改变是由于控制ECM形成及降解的稳态机制失调所致。任何原因使得ECM形成过多或降解减少均可导致ECM过度沉积。肝纤维化过程中肝细胞会发生持续、反复的坏死或炎症,大量纤维增生同时伴有纤维降解的相对或绝对不足,细胞外基质在肝内大量沉积并最终演变为肝硬化。而一旦发展为肝硬化,患者则处于极高危的患肝细胞癌的风险中。肝纤维化如果进展为肝硬化甚至肝细胞癌,会出现一系列并发症如食管静脉曲张破裂出血、肝性脑病、腹水、肝肾综合征等,给患者带来巨大的痛苦甚至威胁其生命。
对于肝纤维化的治疗,除了控制发病原以及肝移植以外,临床上在常用去氧熊果酸、干扰素、己酮可可碱、脯氨酸羟化酶抑制剂、佛他醇酯、甲苯吡啶酮、马洛替酯、多烯磷脂酰胆碱、前列腺素E、沙格雷酯以及中草药等进行治疗;随着分子生物学的发展,基因治疗、细胞治疗等也初步应用于肝纤维化治疗。对于肝纤维化治疗来说,其是一个可逆的过程。这种肝纤维化逆转现象早在上世纪70年代已经被研究学者发现,截止目前,很多文献也表明了上述药物具有一定的肝纤维化逆转作用。但是由于肝纤维化初期临床表现不明显,容易被患者忽视,而发现时使用上述药物得到的临床效果不佳;很多时候仅能减缓肝纤维化向肝硬化转变的进程,但是很少发现逆转现象。
研究表明,肝纤维化逆转的主要机制在于肝星状细胞(hepatic stellate cell,HSC)的活化减少,或者是HSC的凋亡。因此抑制HSC活化或者诱导HSC凋亡是治疗或逆转肝纤维化的重要靶点。
发明内容
本发明的第一方面是提供一种用于治疗肝纤维化的药物组合物,其包含选择性5-羟色胺再摄取抑制剂(Selective Serotonin Reuptake Inhibitor,SSRI)和马洛替酯。
优选地,所述选择性5-羟色胺再摄取抑制剂选自:氟西汀、帕罗西汀、舍曲林和西酞普兰。
优选地,在所述药物组合物中,选择性5-羟色胺再摄取抑制剂和马洛替酯的重量比为0.01-2:10。更优选地,选择性5-羟色胺再摄取抑制剂和马洛替酯的重量比为0.05-0.2:10;或者选择性5-羟色胺再摄取抑制剂和马洛替酯的重量比可以为0.05:10、0.1:10、0.15:10或者0.2:10。
进一步地,所述药物组合物由选择性5-羟色胺再摄取抑制剂、齐墩果酸和马洛替酯组成。
优选地,选择性5-羟色胺再摄取抑制剂、齐墩果酸和马洛替酯的重量比为0.01-2:1-5:10。
优选地,选择性5-羟色胺再摄取抑制剂、齐墩果酸和马洛替酯的重量比为0.1:2:10。
本发明第二方面是提供一种包含所述药物组合物的制剂,其由所述药物组合物和药学上可接受的载体组成。
优选地,所述药物制剂为口服制剂。
本发明第三方面是提供所述药物组合物在制备治疗肝纤维化或肝硬化药物中的应用。
本发明意外发现马洛替酯和氯西汀联合用药后对细胞肝纤维化模型和动物肝纤维化模型均产生了明显的协同作用,这种协同作用体现在抑制HSC增殖及活化,并保护肝细胞防止外界因素损伤。我们在这基础上,结合马洛替酯常见的联用用药方式,继续考察添加齐墩果酸后的影响,结果发现这种协同作用在添加齐墩果酸后进一步增强,所保护的药物组合物具有一定的市场开发价值。
具体实施方式
还可进一步通过实施例来理解本发明,其中所述实施例说明了一些制备或使用方法。然而,要理解的是,这些实施例不限制本发明。现在已知的或进一步开发的本发明的变化被认为落入本文中描述的和以下要求保护的本发明范围之内。
本发明对试验中所使用到的材料以及试验方法进行一般性和/或具体的描述。虽然为实现本发明目的所使用的许多材料和操作方法是本领域公知的,但是本发明仍然在此作尽可能详细的描述。
实施例1氯西汀和马洛替酯对HSC-T6细胞的影响
试验方法:取生长状态良好的HSC-T6细胞(ATCC,上海歌凡生物科技有限公司),用含10%FBS的DMEM培养基稀释成5×104个/ml;铺于96孔板中,置于37℃及5%CO2的孵箱培养,待培养24小时后,弃去培养基,用PBS缓冲液冲洗细胞2次后,分别加入DMEM培养基、含药培养基(每组4个复孔)继续培养;培养72小时后,吸取部分上清用于相关检测;然后采用MTT法测定各组细胞活性,计算细胞抑制率=(正常组OD值-给药组OD值)/正常组OD值×100%
各给药组给药剂量如下:
实验结果:
1、氯西汀和马洛替酯对HSC-T6细胞增殖抑制的影响
抑制率(%) | |
给药组1 | 0.07±0.06 |
给药组2 | 0.08±0.03 |
给药组3 | 0.21±0.09 |
给药组4 | 23.41±3.04 |
给药组5 | 37.29±4.51 |
给药组6 | 48.07±3.96 |
给药组7 | 47.82±5.23 |
给药组8 | 56.29±5.57 |
给药组9 | 41.27±4.93 |
2、细胞培养液中TGF-β1和α-SMA含量检测
TGF-β1(ng/ml) | α-SMA(ng/ml) | |
正常组 | 31.6±12.7 | 119.3±18.2 |
给药组1 | 32.3±10.4 | 101.5±13.9 |
给药组2 | 30.1±9.2 | 112.7±21.6 |
给药组3 | 31.8±11.6 | 107.1±17.4 |
给药组4 | 23.7±8.3<sup>*</sup> | 91.6±20.5<sup>*</sup> |
给药组5 | 20.4±8.8<sup>*</sup> | 76.9±19.7<sup>**</sup> |
给药组6 | 16.2±9.5<sup>**</sup> | 63.1±16.3<sup>**</sup> |
给药组7 | 17.3±7.8<sup>**</sup> | 60.8±13.4<sup>**</sup> |
给药组8 | 13.8±6.4<sup>**</sup> | 51.4±12.9<sup>**</sup> |
给药组9 | 19.7±8.1<sup>**</sup> | 67.9±18.7<sup>**</sup> |
*和**表示经T-test检验,与正常组相比,P<0.05和P<0.01
研究表明,HSC(肝星状细胞)增殖是肝纤维化的重要影响因素,HSC增殖后分泌大量的ECM,是导致肝纤维化的决定因素。结果表明,氯西汀在较低剂量下对HSC增殖没有明显影响,马洛替酯对HSC增殖具有明显的抑制作用,并且成剂量依赖性。两者联合后,在HSC抑制增殖方面呈现的明显协同作用;以0.1:10的效果最佳。
为了进一步地了解两者之间产生协同作用的活性路径,我们根据马洛替酯的作用机制(TGF-β1/smad通路),通过ELISA方法对通路标记物进行了相关检测,结果表明,氯西汀和马洛替酯对TGF-β1和α-SMA均具有明显抑制作用,这提示两者的协同作用通路之一可能在抑制TGF-β1分泌上。
实施例2氯西汀、齐墩果酸和马洛替酯对HSC-T6细胞的影响
在实施例1中获得了氯西汀和马洛替酯的最佳配比,我们通过文献调研,进一步研究了在临床上与马洛替酯联用的药物,与氯西汀在抑制HSC增殖方面是否产生了协同作用。
试验方法同实施例1
实验结果:
氯西汀 | 马洛替酯 | 齐墩果酸 | 抑制率(%) | |
给药组1 | - | - | 8mg/ml | 30.17±4.12 |
给药组2 | 0.04mg/ml | 4mg/ml | 0.4mg/ml | 57.69±4.33 |
给药组3 | 0.04mg/ml | 4mg/ml | 0.8mg/ml | 61.34±4.17 |
给药组4 | 0.04mg/ml | 4mg/ml | 1.6mg/ml | 62.84±4.25 |
实施例3氯西汀、齐墩果酸和马洛替酯对LO2细胞(人肝细胞系)的影响
文献表明,肝细胞受到外界因素(酒精、病毒或高血脂等)影响,导致ROS(氧自由基)损伤,进而产生慢性炎症,从而激活HSC,激活的HSC分泌大量的ECM;进而导致肝纤维化。因此有必要考察氯西汀、齐墩果酸和马洛替酯对肝细胞的影响,以期明确药物组合物在抗肝纤维化方面的具体机制。
试验方法:取对数生长期的LO2细胞(中国医学科学院细胞库),用含10%FBS的DMEM培养基稀释成1×105个/ml;铺于96孔板中,置于37℃及5%CO2的孵箱培养,培养48小时细胞贴壁后去除培养基进行相关试验。细胞分为对照组(添加正常培养基)、四氯化碳组(添加含15mmol/L CCl4的培养基)、给药组(添加含药培养基);给药方案如下:
培养24小时后,取上清液采用试剂盒检测(南京建成生物工程研究所)SOD和MDA;然后然后采用MTT法测定各组细胞活性,计算细胞存活率=给药组OD值/正常组OD值×100%
实验结果:
1、氯西汀、齐墩果酸和马洛替酯对四氯化碳导致损伤的肝细胞存活率影响
存活率(%) | |
四氯化碳组 | 42.26±3.79 |
给药组1 | 41.91±3.05 |
给药组2 | 39.03±4.21 |
给药组3 | 51.54±3.68<sup>*</sup> |
给药组4 | 59.23±3.57<sup>**</sup> |
给药组5 | 43.17±2.93 |
给药组6 | 46.48±4.16 |
给药组7 | 71.37±4.82<sup>**</sup> |
给药组8 | 82.62±5.13<sup>**</sup> |
*和**表示经T-test检验,与正常组相比,P<0.05和P<0.01
结果表明,添加四氯化碳培养48小时后对LO2细胞存活率造成了明显影响,说明造模成功。氯西汀对四氯化碳造成的损伤没有明显保护作用,马洛替酯和齐墩果酸单独给药时对LO2细胞有明显的保护作用,并且成计量依赖性。三者结合后,LO2细胞的存活率大幅提高,说明氯西汀和马洛替酯之间、以及与齐墩果酸三者之间在保护肝细胞损伤方面产生了明显协同作用。
2、细胞上清液中SOD和MDA含量
SOD(U/L) | MDA(nmol/L) | |
对照组 | 78.6±12.1 | 0.21±0.03 |
四氯化碳组 | 31.3±8.7<sup>##</sup> | 0.97±0.07<sup>##</sup> |
给药组1 | 32.8±7.9 | 1.04±0.09 |
给药组2 | 31.4±8.3 | 1.15±0.12 |
给药组3 | 48.4±6.3<sup>**</sup> | 0.65±0.04 |
给药组4 | 54.9±9.2<sup>**</sup> | 0.53±0.06 |
给药组5 | 33.8±6.1 | 0.93±0.11 |
给药组6 | 36.2±7.7 | 0.89±0.08 |
给药组7 | 63.7±7.2<sup>**</sup> | 0.41±0.06<sup>**</sup> |
给药组8 | 69.6±8.9<sup>**</sup> | 0.32±0.03<sup>**</sup> |
*和**表示经t-test检验,与正常组相比,P<0.05和P<0.01
四氯化碳损伤会导致肝细胞内产生大量ROS,进而引发连锁反应,导致肝细胞凋亡或死亡,另外ROS还可以激活HSC,导致肝硬化的形成。从上述结果可以看出;氯西汀和马洛替酯在抑制ROS产生方面产生了明显协同作用,提示其可能是保护肝细胞的通路之一。
实施例4对刀豆蛋白诱导的小鼠肝纤维化模型的影响
取6-8周龄昆明种小鼠,饲养24小时后,随机分组(每组8只);正常组尾静脉注射生理盐水,模型组和给药组按12.5mg/kg尾静脉注射刀豆蛋白A;每周一次,连续8周;造模后一天,给药组腹腔注射给药,正常组和模型组给与等量生理盐水,每天一次。8周后,腹主动脉取血,3000rpm离心,取血清,用生化分析仪测定血清中AST和ALT的含量。处死小鼠后取肝脏组织按照Hyp测定试剂盒测定组织中Hyp含量。
实验结果:
1、各组小鼠血清中ALT和AST含量
2、各组小鼠肝脏组织中Hyp水平
本发明内容仅仅举例说明了要求保护的一些具体实施方案,其中一个或更多个技术方案中所记载的技术特征可以与任意的一个或多个技术方案相组合,这些经组合而得到的技术方案也在本申请保护范围内,就像这些经组合而得到的技术方案已经在本发明公开内容中具体记载一样。
Claims (9)
1.一种用于治疗肝纤维化的药物组合物,其包含选择性5-羟色胺再摄取抑制剂(Selective Serotonin Reuptake Inhibitor,SSRI)和马洛替酯。
2.根据权利要求1所述的药物组合物,其特征在于,所述选择性5-羟色胺再摄取抑制剂选自:氟西汀、帕罗西汀、舍曲林和西酞普兰。
3.根据权利要求1所述的药物组合物,其特征在于,在所述药物组合物中,选择性5-羟色胺再摄取抑制剂和马洛替酯的重量比为0.01-2:10。
4.根据权利要求3所述的药物组合物,其特征在于,选择性5-羟色胺再摄取抑制剂和马洛替酯的重量比为0.05-0.2:10。
5.根据权利要求1所述的药物组合物,其特征在于,所述药物组合物由选择性5-羟色胺再摄取抑制剂、齐墩果酸和马洛替酯组成。
6.根据权利要求5所述的药物组合物,其特征在于,选择性5-羟色胺再摄取抑制剂、齐墩果酸和马洛替酯的重量比为0.01-2:1-5:10。
7.一种包含权利要求1-6所述药物组合物的制剂,其由所述药物组合物和药学上可接受的载体组成。
8.根据权利要求7所述的药物制剂,所述药物制剂为口服制剂。
9.权利要求1-6所述药物组合物在制备治疗肝纤维化或肝硬化药物中的应用。
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罗奕: "齐墩果酸对四氯化碳所致大鼠肝纤维损伤的保护作用", 《中国药师》 * |
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CN113337454B (zh) * | 2021-07-21 | 2023-02-21 | 中国人民解放军总医院第五医学中心 | 3d肝纤维化模型的构建方法及其应用 |
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