CN111973604A - 雷公藤红素在制备治疗胆汁淤积性肝病的药物中的应用 - Google Patents
雷公藤红素在制备治疗胆汁淤积性肝病的药物中的应用 Download PDFInfo
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- CN111973604A CN111973604A CN202011001798.3A CN202011001798A CN111973604A CN 111973604 A CN111973604 A CN 111973604A CN 202011001798 A CN202011001798 A CN 202011001798A CN 111973604 A CN111973604 A CN 111973604A
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Abstract
本发明公开了一种雷公藤红素在制备治疗胆汁淤积性肝病的药物中的应用。雷公藤红素对小鼠α‑萘异硫氰酸苯酯(ANIT)诱导的肝内胆汁淤积、及硫代乙酰胺(TAA)诱导的胆汁淤积性肝病均显示出改善胆汁淤积、减轻肝损伤的作用，能显著降低这两个模型血浆中天冬氨酸氨基转移酶(AST)、丙氨酸氨基转移酶(ALT)、及碱性磷酸酶(ALP)水平，降低血浆中胆酸含量，促进胆汁排泄，具有保肝利胆的功效，将其应用于保肝利胆药物的研发能创造良好的经济效益和广泛的社会效益。
Description
技术领域：
本发明属于胆汁淤积药物技术领域，具体地说，涉及一种用雷公藤红素作为治疗胆汁淤积性肝病的药物的应用。
背景技术：
胆汁酸(TBA)是胆固醇经肝组织代谢的最终产物，是肝脏分泌到胆汁中最多的有机酸，人胆汁中的主要成分，它的生成与代谢和肝脏密切相关，胆汁酸由肝细胞内的微粒体、线粒体、溶酶体合成，主要以结合的形式分泌到胆汁中，在胆汁中的含量可达69％，胆汁进入肠腔后，在回肠和结肠，绝大部分胆汁酸被肝细胞所摄取，又因肝肠循环基本上属于闭锁式的，故外周血循环中胆汁酸的浓度较低，然而当肝功能轻微损伤时，胆汁酸的代谢即发生相应变化，血液中TBA浓度会有不同程度的升高，往往在丙氨酸氨基转移酶(ALT)、天门冬氨基转移酶(AST)无变化之前，其值就已升高，因此其是肝功能的敏感性指标之一。血清胆汁酸水平与肝胆疾病密切相关，血清总胆汁酸是反映急慢性肝细胞损伤的一敏感指标，血清总胆汁酸升高可见于各种急慢性肝炎、病毒性肝炎或酒精性或非酒精性肝炎，还可见于绝大部分肝外胆管堵塞和肝内胆汁淤积性病变、肝硬化、阻塞性黄疸，药物性肝损伤等。比如，党京丹等在研究胆汁酸测定在肝脏疾病中的应用时，证明病毒性肝炎(乙肝)、阻塞性黄疸、慢性肝炎、肝癌患者中TBA的含量要显著升高；王跃明在研究血清总胆汁酸在肝病诊断中的应用时，发现，急性肝炎、慢性肝炎、肝硬化、肝癌患者的TBA水平均要显著高于正常人(党京丹等.中国误诊学杂志，2005,5(5):847-848；王悦明.血清总胆汁酸在肝病诊断中的临床应用.临床和实验医学杂志.2008,7(2):93)。多项研究表明，在NAFLD(非酒精性脂肪性肝炎)患者血清中，胆汁酸水平明显升高(Yang ZX,et al.Effects of nuclear receptorFXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease[J].Hepatol Int,2010,4(4):741-748)，而病情严重程度与胆汁酸合成及血清胆汁酸水平呈正相关，血清胆汁酸水平越高，病情相对发展更为严重(Bechmann LP,et al.Free fatty acids repress small heterodimer partner(SHP)activation and adiponectin counteracts bile acid-induced liver injury insuperobese patients with nonalcoholic steatohepatitis[J].Hepatology,2013,57(4):1394-1406)，肝纤维化程度与血清总胆汁酸浓度升高有关(Shlomai A,et al.Serumbile acid levels as a predictor for the severity of liver fibrosis inpatients with chronic hepatitis C.J Viral Hepat,2013,20(2):95-102).袁爱丽等也在文章中(袁爱丽等.胆汁酸测定对肝脏疾病的诊断价值.临床肝胆病杂志，1985,1(2)：79-)披露，急性肝炎、慢性肝炎、肝硬化、药物中毒性肝炎、先天性黄疸及胆汁淤积及阻塞性黄疸患者中，均表现出明显的血清胆汁酸总量增加。
胆汁淤积发生的最根本原因是肝细胞内积聚的毒性胆汁酸，是一种肝内的紊乱现象。胆汁淤积可导致肝纤维化、肝硬化、肝功能衰竭、甚至死亡。胆汁淤积分为肝外胆汁淤积及肝内胆汁淤积两种：肝外胆汁淤积由胆管肿瘤、囊肿、胆管结石等疾病引起；肝内胆汁淤积由败血症、药物、原发性胆汁性肝硬化、原发性硬化胆道炎、病毒性肝炎、酒精肝、及妊娠等引起；此外，也存在许多遗传引起的进行性家族性肝内胆汁淤积(PFIC)。-到目前为止，熊去氧胆酸(UDCA)和奥贝胆酸是美国食品药品监督管理局(FDA)认证的仅有的两种治疗胆汁淤积性肝病的药物。UDCA可有效治疗I期及II期原发性胆汁性肝硬化(PBC)，但UDCA对原发性硬化性胆道炎(PSC)的治疗效果不佳，且许多病人对UDCA长期单一疗法存在耐受性，因此其使用仍存在争议。奥贝胆酸是2016年FDA批准的治疗胆汁淤积性肝病的药物，该药的副作用还未完全被人们了解，目前临床观察，奥贝胆酸最常见的副作用包括皮肤瘙痒和疲劳。目前，临床上大量患者因胆汁淤积性肝病急需药物治疗，但已上市的保肝药物极少或疗效不可靠，数以万计的胆汁淤积性肝病患者不能得到有效的药物治疗；肝脏移植可以显著提高病人的存活率，但是这种移植手术的安全性在很大程度上取决于患者残余肝脏的再生能力，只适合患有晚期肝病或急性肝衰竭的病人，因此研发治疗胆汁淤积性肝病药物迫在眉睫。
中药雷公藤为卫矛科植物雷公藤的根，又名黄藤、黄腊藤、菜虫药、红药、及水莽草，主产于福建、安徽、浙江、河南等地，中医用于治疗关节炎、麻风病、湿疹、肺结核等疾病。雷公藤中主要化学成分主要为二萜、三萜、生物碱等，其中三萜类化合物雷公藤红素(celastrol)是雷公藤中活性最强的有效成分之一。
雷公藤红素(又名南蛇藤素)作为中药雷公藤中重要的三萜类活性成分，广泛存在于卫矛科植物雷公藤、南蛇藤、及独子藤等中，其CAS号为34157-83-0，分子式为C29H38O4，分子量450.6096，其化学结构式为：
雷公藤红素在抗炎、免疫抑制、抗肿瘤、抗神经退行性疾病以及减肥等研究中展示出良好的生物活性，具有广阔的开发前景。但是将雷公藤红素用于治疗胆汁淤积性肝病的应用，至今未见报道。
发明内容：
本发明的目的在于克服现有技术的局限，对雷公藤红素针对胆汁淤积性肝病的保护作用效果进行研究，明确雷公藤红素对胆汁淤积性肝病的保护作用。同时，为传统的卫矛科雷公藤属雷公藤提取物雷公藤红素拓展新的应用领域，本发明将雷公藤红素应用于胆汁淤积性肝病的治疗，具有明显效果。
本发明的目的是通过以下技术方案实现的：
雷公藤红素在制备治疗胆汁淤积性肝病的药物中的应用。
如所述的应用，其中所述的胆汁淤积性肝病为化学性胆汁淤积性肝病或药物性胆汁淤积性肝病或原发性胆汁淤积性肝病。
如所述的应用，其中所述的胆汁淤积性肝病是由体内雌激素过高引起的。
雷公藤红素在制备具有降低血清总胆汁酸异常升高的药物中的应用。
雷公藤红素在制备具有降低血清总胆汁酸异常升高及血清转氨酶异常升高的药物中的应用。
根据所述的应用，其中所述血清总胆汁酸异常升高是由于肝胆疾病而引起的。
根据所述的应用，其中所述肝胆疾病为肝炎、肝纤维化、肝硬化、肝癌、阻塞性黄疸、胆汁淤积性肝病或药物性肝损伤。
根据所述的应用，其中所述肝炎为急慢性肝炎、病毒性肝炎、非酒精性肝炎或酒精性肝炎。
根据所述的应用，其中所述血清胆汁酸包括胆酸ca、熊去氧胆酸udca、猪脱氧胆酸hdca、鹅去氧胆酸cdca、脱氧胆酸dca、牛磺胆酸tca、甘氨胆酸gca、牛磺脱猪样胆酸thdca、牛磺脱氧胆酸tdca、牛磺石胆酸tlca、ω-鼠胆酸、牛磺-β-鼠胆酸、牛磺熊脱氧胆酸tudca、β-鼠胆酸、牛磺-α-鼠胆酸中的任意一种或多种。
根据所述的应用，其中所述的血清转氨酶包括AST、ALT或ALP中的任意一种或多种。
如所述的应用，其中所述的治疗胆汁淤积性肝病的药物的给药方式为口服，对应相应患者的体重，其用量为1.1mg/kg·d，使用对象为胆汁淤积性肝病患者。
一种用于降低血清总胆汁酸的药物组合物，所述组合物包含治疗有效量的雷公藤红素，以及制药上可接受的赋形剂。
一种用于降低血清总胆汁酸及血清转氨酶的药物组合物，所述组合物包含治疗有效量的雷公藤红素，以及制药上可接受的赋形剂。
所述雷公藤红素提取于卫矛科雷公藤属雷公藤，生产厂家为成都瑞芬思生物科技有限公司，结构式为：
其治疗胆汁淤积的作用机制为：雷公藤红素通过调节胆酸的合成基因如CYP7a1、CYP8b1减少体内胆汁酸的形成，从源头抑制胆酸进一步合成。还可通过CYP3A4、SULT2A1、UGT2B4、UGT2B7等基因促进胆酸脱毒，降低有害胆酸含量。此外，雷公藤红素可能抑制胆酸吸收转运体(如Ntcp、Oatp1、Oatp4)的表达，降低进入肝脏的胆酸；增加胆酸流出转运体(如Ostβ、Mrp4、Bsep、Mrp2)的表达，促进胆酸排泄，从而达到治疗胆汁淤积性肝病的作用。
使用要求：给药方式为口服，对应相应患者的体重，其用量为1.1mg/kg·d。
使用对象：胆汁淤积性肝病患者。
与现有技术相比，本发明的有益效果为：本发明通过ANIT及TAA诱导的小鼠胆汁淤积性肝损伤模型，研究并证实了雷公藤红素可用于治疗胆汁淤积性肝损伤，能显著降低血浆中各种胆汁酸成分，从而显著降低由胆汁淤积引起的肝损伤、肝脏坏死，显著抑制由胆汁淤积引起的炎症，对胆汁淤积有显著的疗效。
附图说明：
图1：空白组小鼠肝脏组织切片图；
图2：TAA模型小鼠肝脏病理切片图；
图3：雷公藤红素治疗TAA诱导的胆汁淤积性肝病病理切片图。
具体实施方式：
下面结合本发明的具体实施例来进一步说明本发明的实质性内容，应理解，以下实施例仅用于说明本发明，但并不以此来限定本发明的保护范围。
实施例1：
雷公藤红素对ANIT诱导的小鼠胆汁淤积性肝病的治疗作用：
动物：C57BL/6小鼠，SPF级，37～40日龄，体重20～23g，雄性；合格证号均为：SCXK(湘)2013-0004，购自湖南斯莱克景达实验动物有限公司。
药品与试剂：雷公藤红素，红色无定型结晶粉末，成都瑞芬思生物科技有限公司，批号L-003-150420。天冬氨酸氨基转移酶(AST)试剂盒(货号C010-3，批号20161031)、丙氨酸氨基转移酶(ALT)试剂盒(货号C009-3，批号20161031)、及碱性磷酸酶(ALP)试剂盒(货号A059-3，批号20161031)，均为南京建成生物工程研究所生产。α-萘异硫氰酸苯酯(ANIT，货号N4525-10G，批号101734146)、DMSO(货号V900090-500ml，批号101669350)、吐温80(货号P1754-500ml，批号101761909)均购自Sigma公司。玉米油(货号C116025-500G，批号l1524089)购自阿拉丁公司。
主要仪器：精密电子天平，Sartorius公司；全自动酶标仪，BioTek Instruments公司；水浴恒温振荡器SHA-C，常州中诚仪器制造有限公司；冷冻离心机，Eppendorf公司。
实验方法：
实验分组：实验共需18只雄性C57BL/6小鼠，分为三组：空白组(n＝6)；造模组(n＝6)；治疗组(雷公藤红素+ANIT，n＝6)。
药物溶解及剂量：雷公藤红素采用1％DMSO、2％吐温80、及97％水(v：v：v)溶解，灌胃给药，给药剂量10mg/kg·d，给药容积为5μl/g·d。ANIT采用玉米油溶解，灌胃给药，给药剂量75mg/kg·d，给药容积为5μl/g·d。
实验流程：治疗组雷公藤红素采用灌胃给药，给药剂量为10mg/kg·d，连续给药五天；空白组及造模组喂以等剂量1％DMSO、2％吐温、及97％水，连续给药五天。在实验第三天，造模组及治疗组在雷公藤红素处理4h后进行ANIT造模，空白组喂以等剂量玉米油。ANIT处理48h后，小鼠CO2麻醉处死。小鼠摘眼球取血，血浆样品于冰上放置1-2h后，在4℃下4000g离心5min，取上清血浆样品，测定血浆生化指标AST、ALT、及ALP水平。
实验结果：表1结果显示，空白组、模型组及治疗组3组小鼠体重均匀，无显著差异。但模型组小鼠处死时肝重(1.22g)显著高于空白组(1.00g)，且模型组小鼠肝重/体重(5.78％)显著高于空白组(4.56％)，表明ANIT模型组肝损伤严重。治疗组小鼠处死时肝重(1.01g)显著低于模型组(1.22g)，与空白组间无显著性差异；且治疗组小鼠肝重/体重(4.66％)显著低于模型组(5.78％)，与空白组间无显著性差异，表明雷公藤红素对ANIT诱导的胆汁淤积模型有显著的治疗作用，可显著降低治疗组肝重、及肝重/体重。
表1雷公藤红素治疗小鼠ANIT诱导的胆汁淤积体重及肝重变化
模型组与空白组相比：##P<0.01；治疗组与模型组相比**P<0.01。
表2结果显示，模型组血浆中AST、ALT、及ALP水平均显著高于空白组(P<0.01)，表明模型组肝部损伤严重。治疗组AST、ALT、及ALP水平均较模型组显著降低(P<0.01)，与空白组相比均无显著性差异，表明雷公藤红素对ANIT诱导的胆汁淤积性肝病的显著的治疗作用，可显著降低治疗组AST、ALT、及ALP水平。
表2雷公藤红素治疗小鼠ANIT诱导的胆汁淤积血浆AST、ALT、及ALP变化
模型组与空白组相比：##P<0.01；治疗组与模型组相比**P<0.01。
实施例2：
雷公藤红素对TAA诱导的小鼠胆汁淤积性肝病的治疗作用：
动物：C57BL/6小鼠，SPF级，37～40日龄，体重20～23g，雄性；合格证号均为：SCXK(湘)2013-0004，购自湖南斯莱克景达实验动物有限公司。
药品与试剂：雷公藤红素，红色无定型结晶粉末，成都瑞芬思生物科技有限公司，批号L-003-150420。天冬氨酸氨基转移酶(AST)试剂盒(货号C010-3，批号20161031)、丙氨酸氨基转移酶(ALT)试剂盒(货号C009-3，批号20161031)、及碱性磷酸酶(ALP)试剂盒(货号A059-3，批号20161031)，均为南京建成生物工程研究所生产。硫代乙酰胺(TAA，货号C1290-25G，批号1002213299)、DMSO(货号V900090-500ml，批号101669350)、吐温80(货号P1754-500ml，批号101761909)、甲酸(货号94318-250ml-F，批号101721592)、氯磺丙脲(货号C1290-25G，批号1002213299)、胆酸(CA，货号C1129-25G)、熊脱氧胆酸(UDCA，货号U5127-1G)、猪脱氧胆酸(HDCA，货号U5127-1G)、鹅脱氧胆酸(CDCA，货号C9377-5G)、脱氧胆酸(DCA，货号D2510-10G)、牛磺胆酸(TCA，货号T4009-1G)、甘氨胆酸(GCA，货号G2878-500MG)、牛磺猪脱氧胆酸(THDCA，货号T0682-250MG)、牛磺鹅脱氧胆酸(TCDCA，货号T6260-25MG)、牛磺脱氧胆酸(TDCA，货号T0875-1G)、牛磺石胆酸(TLCA，货号T7515-100MG)购自Sigma公司。色谱级乙腈(货号1.00030.4008)购自默克。NaCl注射液(批号B16080E1)购自浙江国镜药业有限公司。ω-鼠胆酸(ω-MCA，货号sc-396738)、牛磺-β-鼠胆酸(T-β-MCA，货号SC-361829)购自Santa cruz公司。牛磺熊脱氧胆酸(TUDCA，货号HY-19696A)购自MCE公司。β-鼠胆酸(β-MCA，货号C008852)、牛磺-α-鼠胆酸(T-α-MCA，货号C1893-000)购自Steraloids公司。
主要仪器：精密电子天平，Sartorius公司；全自动酶标仪，BioTek Instruments公司；水浴恒温振荡器SHA-C，常州中诚仪器制造有限公司；冷冻离心机，Eppendorf公司；超高效液相色谱四极杆飞行时间质谱，包含1290进样器、1290泵、柱温箱、XDB-C18色谱柱(2.1×100mm,1.8μM)、及6530四极杆飞行时间质谱，Agilent公司。
实验方法：
实验分组：实验共需18只雄性C57BL/6小鼠，分为三组：空白组(n＝6)；模型组(n＝6)；治疗组(雷公藤红素+TAA，n＝6)。
药物溶解及剂量：雷公藤红素采用1％DMSO、2％吐温、及97％水(v：v：v)溶解，灌胃给药，给药剂量10mg/kg·d，给药容积为5μl/g·d。TAA采用0.9％NaCl溶解，腹腔注射给药，给药剂量300mg/kg，给药容积为5μl/g·d。
实验流程：治疗组采用灌胃给药，给药剂量为10mg/kg·d，连续给药4天；空白组及模型组喂以等剂量1％DMSO、2％吐温、及97％水。TAA造模在第4天，在雷公藤红素处理1h后腹腔注射TAA 300mg/kg，TAA处理24h后CO2麻醉处死。小鼠摘眼球取血，血浆样品于冰上放置1-2h后，在4℃下4000g离心5min，取上清血浆样品，测定血浆生化指标ALT、AST、及ALP水平。同时，制备液质血样处理液：取10μl血浆样品，与190μl 67％的乙腈(含内标氯磺丙脲5μM)混合，在4℃下18000g离心20min，取上清进样。液相条件如下：进样体积5μl；柱温45℃；流动相流速0.3ml/min；洗脱梯度：在16min的运行时间内，乙腈浓度由5％变至95％，流动相(水及乙腈)均含0.01％的甲酸。质谱条件如下：干燥气温度350℃，喷雾器压力35psi，毛细管电压3.5kV。
实验结果：
表3结果显示，空白组、模型组及治疗组3组小鼠体重均匀，无显著差异。但模型组小鼠处死时肝重(1.54g)显著高于空白组(1.18g)，且模型组小鼠肝重/体重(6.37％)显著高于空白组(4.92％)，表明TAA模型组肝损伤严重。治疗组小鼠处死时肝重(1.55g)与造模组间无显著性差异；且治疗组小鼠肝重/体重(6.48％)与造模组间无显著性差异，表明雷公藤红素对TAA模型的治疗作用对小鼠肝重影响不大。
表3雷公藤红素治疗小鼠TAA诱导的胆汁淤积体重及肝重变化
模型组与空白组相比：##P<0.01。
表4结果显示，模型组血浆AST、ALT、及ALP水平均显著高于空白组(P<0.05)，表明模型组严重的肝损伤。治疗组AST、ALT、及ALP水平均较模型组降低(P<0.01)，表明雷公藤红素对TAA诱导的胆汁淤积的治疗作用，可显著降低治疗组血浆中AST、ALT、及ALP水平。
表4雷公藤红素治疗小鼠TAA诱导的胆汁淤积性肝病血浆AST、ALT、及ALP变化
模型组与空白组相比：#P<0.05，##P<0.01；治疗组与模型组相比**P<0.01。
表5结果显示，模型组血浆中多种胆酸水平均显著高于空白组(P<0.01)，如ω-MCA、β-MCA、T-β-MCA/T-α-MCA、TCA、THDCA/TUDCA、TCDCA、TDCA、及血浆总胆酸水平，表明模型组严重的肝损伤，造成肝脏胆汁淤积。治疗组多种胆酸水平均较模型组降低(P<0.01)，如T-β-MCA/T-α-MCA、TCA、THDCA/TUDCA、TCDCA、TDCA、及总胆酸水平，表明雷公藤红素对TAA诱导的胆汁淤积的治疗作用，显著降低了治疗组血浆中多种胆酸及总胆酸的含量。
表5雷公藤红素治疗小鼠TAA诱导的胆汁淤积血浆中胆酸变化
模型组与空白组相比：#P<0.05，##P<0.01；治疗组与模型组相比*P<0.05，**P<0.01。
Claims (9)
1.雷公藤红素在制备具有降低血清总胆汁酸异常升高的药物中的应用。
2.雷公藤红素在制备具有降低血清总胆汁酸异常升高及血清转氨酶异常升高的药物中的应用。
3.根据权利要求1或2所述的应用，其中所述血清总胆汁酸异常升高是由于肝胆疾病而引起的。
4.根据权利要求3所述的应用，其中所述肝胆疾病为肝炎、肝纤维化、肝硬化、肝癌、阻塞性黄疸、胆汁淤积性肝病或药物性肝损伤。
5.根据权利要求4所述的应用，其中所述肝炎为急慢性肝炎、病毒性肝炎、非酒精性肝炎或酒精性肝炎。
6.根据权利要求1或2所述的应用，其中所述血清胆汁酸包括胆酸ca、熊去氧胆酸udca、猪脱氧胆酸hdca、鹅去氧胆酸cdca、脱氧胆酸dca、牛磺胆酸tca、甘氨胆酸gca、牛磺脱猪样胆酸thdca、牛磺脱氧胆酸tdca、牛磺石胆酸tlca、ω-鼠胆酸、牛磺-β-鼠胆酸、牛磺熊脱氧胆酸tudca、β-鼠胆酸、牛磺-α-鼠胆酸中的任意一种或多种。
7.根据权利要求2所述的应用，其中所述的血清转氨酶包括AST、ALT或ALP中的任意一种或多种。
8.一种用于降低血清总胆汁酸的药物组合物，所述组合物包含治疗有效量的雷公藤红素，以及制药上可接受的赋形剂。
9.一种用于降低血清总胆汁酸及血清转氨酶的药物组合物，所述组合物包含治疗有效量的雷公藤红素，以及制药上可接受的赋形剂。
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