WO2023122869A1 - 瑞舒伐他汀钙在制备用于预防和治疗胆汁淤积及肝纤维化的药物中的用途 - Google Patents

瑞舒伐他汀钙在制备用于预防和治疗胆汁淤积及肝纤维化的药物中的用途 Download PDF

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WO2023122869A1
WO2023122869A1 PCT/CN2021/141579 CN2021141579W WO2023122869A1 WO 2023122869 A1 WO2023122869 A1 WO 2023122869A1 CN 2021141579 W CN2021141579 W CN 2021141579W WO 2023122869 A1 WO2023122869 A1 WO 2023122869A1
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cholestasis
liver
liver fibrosis
rosuvastatin calcium
use according
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PCT/CN2021/141579
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English (en)
French (fr)
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李译
林惠湦
李琪
吴忠伟
陈妮
毛剑琴
林赟
张冲
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浙江海正药业股份有限公司
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Priority to PCT/CN2021/141579 priority Critical patent/WO2023122869A1/zh
Publication of WO2023122869A1 publication Critical patent/WO2023122869A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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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  • the invention relates to the technical field of medicine, in particular to the use of rosuvastatin calcium in the preparation of medicines for preventing and treating cholestasis and liver fibrosis.
  • Cholestasis is a pathological process caused by bile secretion and excretion disorders, mainly manifested as excessive accumulation of cholesterol, bile acid, and bilirubin in the liver, which in turn causes liver cell damage.
  • the main cause of liver injury caused by cholestasis is the continuous retention of toxic bile salts in the liver, which damages cholangiocytes, induces bile duct reaction, and causes excessive fibrous ECM deposition in the portal area. hardening formation.
  • Cholesterol conversion is the main way to form bile acids, and bile acids synthesized by the classical route account for 75% of the total bile acids. Reducing the amount of cholesterol can effectively reduce the generation of toxic bile salts.
  • cholestasis There are many causes of cholestasis, including primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), cholestasis of pregnancy, cholestasis from total parenteral nutrition, and drug-induced Cholestasis, biliary atresia, common bile duct stones, autoimmune diseases, etc.
  • PBC primary biliary cirrhosis
  • PSC primary sclerosing cholangitis
  • Cholestasis biliary atresia
  • common bile duct stones autoimmune diseases, etc.
  • autoimmune diseases etc.
  • Hepatic fibrosis is a reversible pathological process formed during the self-repair process of liver tissue after external or internal chronic damage. Early intervention and arresting the progression of liver fibrosis is the key to preventing liver disease from developing into cirrhosis. There are many reasons for liver damage, and most chronic liver diseases can lead to liver fibrosis, among which liver damage caused by cholestasis is a major clinical inducement. In the initial stage of liver fibrosis, repairing the damaged part of the liver and reducing the production of fibrosis factors can effectively reduce the risk of liver cirrhosis and improve the survival rate of patients. How to effectively reduce the generation of cholestasis and the liver damage caused by cholestasis is a major research hotspot in reducing the formation of liver fibrosis.
  • the invention provides a use of rosuvastatin calcium in the preparation of medicines for preventing and treating cholestasis and liver fibrosis.
  • the cholestasis includes cholestasis caused by intrahepatic and extrahepatic causes.
  • the cholestasis caused by the intrahepatic causes includes primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), cholestasis during pregnancy, cholestasis caused by total parenteral nutrition and And/or drug-induced cholestasis, cholestasis from extrahepatic causes including choledocholithiasis, cholangiocarcinoma, sclerosing cholangitis, and/or pancreatic duct carcinoma.
  • PBC primary biliary cirrhosis
  • PSC primary sclerosing cholangitis
  • cholestasis during pregnancy cholestasis caused by total parenteral nutrition and And/or drug-induced cholestasis
  • cholestasis from extrahepatic causes including choledocholithiasis, cholangiocarcinoma, sclerosing cholangitis, and/or pancreatic duct carcinoma.
  • the liver fibrosis includes liver fibrosis caused by cholestasis and liver fibrosis caused by other reasons.
  • the liver fibrosis caused by other reasons includes liver fibrosis caused by viral hepatitis, fatty liver, alcoholic liver, poisons and/or drugs.
  • the rosuvastatin calcium reduces the cholestasis-related detection indicators in the individual's blood and the damage of bile ducts and liver cells at the cholestasis site.
  • the rosuvastatin calcium reduces the increase of liver fibrosis-related detection indicators and inhibits the expression of liver fibrosis-related signaling pathways.
  • the rosuvastatin calcium inhibits the generation of oxidative stress response.
  • the effective dose of rosuvastatin calcium is 1 mg/kg body weight per day.
  • the rosuvastatin calcium is administered orally.
  • the effective dose of 1 mg/kg rosuvastatin calcium per day can effectively reduce the four indexes of ALP, ALT/AST and ⁇ -GGT related to cholestasis injury. At the same time, it also reduces the three related indicators of bile secretion, TBiL, DBiL, and TBA in the blood.
  • rosuvastatin calcium can effectively improve the damage of the bile duct and surrounding liver cells at the site of cholestasis.
  • Rosuvastatin calcium can inhibit the generation of bile acids by reducing the content of cholesterol, and reduce the generation of toxic bile salts in the state of cholestasis, thereby effectively alleviating the toxicity of bile ducts and liver cells caused by bile salt stasis.
  • Rosuvastatin calcium can effectively improve the overexpression of fibrosis indicators LN, HA and HYP in plasma, and further signaling pathway research also found that rosuvastatin calcium can effectively inhibit TGF ⁇ 1/ ⁇ -catenin in the model group The expression of signaling pathways, and the expression of corresponding fibrosis-related proteins ⁇ -SMA and Collagen III also decreased significantly. Rosuvastatin calcium can act on the TGF ⁇ 1/ ⁇ -catenin signaling pathway to reduce the expression of fibrosis-related proteins and improve liver fibrosis caused by cholestasis.
  • Nrf2 in the liver of BDL rats intervened with rosuvastatin calcium was significantly increased, and its downstream antioxidant kinase NQO-1 was also significantly increased, thereby inhibiting the activation of TGF- ⁇ 1/ ⁇ -catenin signaling pathway, Play the role of anti-oxidation and anti-fibrosis.
  • the staining results of the pathological sections of the liver also found that the area of collagen, the degree of fibrosis, the degree of inflammatory infiltration and the degree of liver cell damage in the BDL rats given rosuvastatin calcium group were significantly improved compared with the model group.
  • rosuvastatin calcium can slow down the formation and deposition of bile acids by lowering cholesterol, and at the same time exert an antioxidant effect by activating the Keap-1/Nrf2 signaling pathway, neutralize the ROS produced by cholestasis, and alleviate The damage caused by bile salts and ROS; it can also further inhibit the activation of TGF ⁇ 1/ ⁇ -catenin signaling pathway by enhancing the expression of Nrf2, reduce the production of fibrosis factors, delay the process of liver fibrosis, reduce the area of collagen, and improve liver function due to bile The degree of fibrosis caused by stasis plays a therapeutic role.
  • Fig. 1 is the result of liver tissue score after oral administration of rosuvastatin calcium in SD rats of cholestasis model.
  • Figure 2 shows the expression levels of fibrosis-related proteins in liver tissue of SD rats in the cholestasis model after oral administration of rosuvastatin calcium.
  • Figure 3 shows the fibrosis-related mRNA expression levels in the liver tissue of SD rats in the cholestasis model after oral administration of rosuvastatin calcium.
  • the yellow staining of the rat mucosa was regarded as the successful establishment of the model, and the model rats were evenly divided into 3 groups, and the drug was started, once a day, for 4 consecutive weeks.
  • Rats in each group were anesthetized, blood was collected from the orbit, the plasma was separated, and frozen at -80°C. Rats were sacrificed under CO 2 anesthesia, and liver samples were collected and divided into two parts, one part was fixed in 10% formalin, and the rest was frozen at -80°C.
  • Rat plasma is used to detect AST, ALT, ALP, ⁇ -GGT, DBil, TBil, HA, and LN; tissue detection: weigh a certain quality of liver tissue, homogenize it with normal saline on ice, and detect HYP in the tissue according to the kit (Hydroxyproline); Take another liver tissue of certain quality, after lysing with RIPA, perform WB experiment to detect the protein levels of TGF- ⁇ 1, ⁇ -SMA and ⁇ -catenin in the tissue; after lysing the liver tissue with Trizol, extract total RNA , RT-PCR was performed to detect the expression levels of Collagen III, TGF- ⁇ 1, ⁇ -SMA, ⁇ -catenin, NRF2 and NQO-1 mRNA in the tissue. Liver tissues fixed in formalin were dehydrated, embedded and sectioned for Masson staining, and the percentage of collagen area was evaluated by Image J software. Hepatocyte necrosis and fibrosis were observed by pathological examination after HE
  • the livers of the normal control group and the sham operation group were normal in size, ruddy in color, and soft in texture; the livers of the rats in the model group were significantly enlarged, yellowish brown in color, strong in graininess on the surface, and tough in texture; the liver of the rats in the adenosylmethionine group and Compared with the model group, the degree of tan was reduced, the texture was more brittle and softer, and the liver of the rats in the rosuvastatin calcium group was significantly smaller than that of the model group, and the color was ruddy and the texture was softer.
  • liver tissue showed that compared with the control group and the sham operation group, the liver cells around the bile duct in the model group had obvious necrosis, and the area of fibrosis was significantly increased; the degree of necrosis and fibrosis in the SAMe group was significantly weaker than that in the model group; The necrosis of liver cells and fibrosis of liver tissue in the RSV group were also significantly weaker than those in the model group.
  • the plasma TBiL and DBiL contents and the ALT and AST activities of rats in the Model group were significantly increased (P ⁇ 0.001); compared with the Model group, the plasma TBiL and DBiL contents and the ALT and AST activities of the rats in the SAMe group were Activity decreased significantly (P ⁇ 0.001 or P ⁇ 0.01 or P ⁇ 0.05), RSV group rat plasma TBiL, DBiL content and ALT, AST activity also significantly decreased (P ⁇ 0.001 or P ⁇ 0.01 or P ⁇ 0.05), the results see Table 1.
  • the plasma TBA, ⁇ -GGT content and ALP activity of the rats in the Model group were significantly increased (P ⁇ 0.001 or P ⁇ 0.01); compared with the Model group, the plasma TBA, ⁇ - The GGT content and ALP activity decreased significantly (P ⁇ 0.001 or P ⁇ 0.05); the plasma TBA, ⁇ -GGT content and ALP activity of rats in the RSV group also decreased significantly (P ⁇ 0.001 or P ⁇ 0.05).
  • the results are shown in Table 1.
  • Table 2 The levels of related indicators of rat fibrosis
  • the protein levels of ⁇ -catenin, TGF ⁇ 1 and ⁇ -SMA in the liver tissue of the rats in the Model group were significantly increased; compared with the Model group, the ⁇ -catenin, TGF ⁇ 1 and ⁇ - The level of SMA protein decreased, and the expression level of TGF ⁇ 1 decreased significantly (P ⁇ 0.0001); compared with the Model group, the protein levels of ⁇ -catenin, TGF ⁇ 1 and ⁇ -SMA in the liver tissue of the RSV group decreased significantly (P ⁇ 0.0001). 0.0001 or P ⁇ 0.05 or P ⁇ 0.0001), the results are shown in Figure 2 and Table 3.
  • the mRNA levels of TGF- ⁇ 1, ⁇ -catenin, ⁇ -SMA, and Collagen III in the liver tissue of the rats in the Model group were significantly increased; compared with the Model group, the TGF- ⁇ 1, ⁇ -catenin, ⁇ -SMA, Collagen III mRNA levels decreased significantly (P ⁇ 0.05 or P ⁇ 0.001 or P ⁇ 0.001 or P ⁇ 0.001), TGF- ⁇ 1, ⁇ -catenin, ⁇ -SMA, Collagen III mRNA levels also decreased significantly (P ⁇ 0.05 or P ⁇ 0.001 or P ⁇ 0.01 or P ⁇ 0.001); compared with the Model group, the mRNA levels of NRF2 and NQO-1 in the liver tissue of the SAMe group were not significantly lower Significant changes were seen, and the mRNA levels of NRF2 and NQO-1 in the liver tissue of the rats administered with RSV were significantly up-regulated (P ⁇ 0.01 or P ⁇ 0.001); the results are shown in FIG. 3 .
  • Rosuvastatin calcium can slow down the formation and deposition of bile acids by lowering cholesterol, and at the same time play an antioxidant role by activating the Keap-1/Nrf2 signaling pathway, neutralize the ROS produced by cholestasis, and alleviate the effects of bile salts and ROS. It can also further inhibit the activation of TGF ⁇ 1/ ⁇ -catenin signaling pathway by enhancing the expression of Nrf2, reduce the production of fibrosis factors, delay the process of liver fibrosis, reduce the area of collagen, and improve liver fibrosis caused by cholestasis degree, play a therapeutic role.

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Abstract

本发明提供了一种瑞舒伐他汀钙在制备用于预防和治疗胆汁淤积及肝纤维化的药物中的用途。通过研究发现，瑞舒伐他汀钙可以显著性改善大鼠肝脏部位的胆汁淤积情况和肝纤维化相应的生化指标，具有预防和治疗胆汁淤积及其导致的肝纤维化的应用潜质。

Description

瑞舒伐他汀钙在制备用于预防和治疗胆汁淤积及肝纤维化的药物中的用途 技术领域
本发明涉及医药技术领域，具体涉及一种瑞舒伐他汀钙在制备用于预防和治疗胆汁淤积及肝纤维化的药物中的用途。
背景技术
胆汁淤积是由于胆汁的分泌和排泄障碍引起的一种病理过程，主要表现为肝脏内胆固醇、胆酸以及胆红素等成分过度堆积，进而造成肝细胞的损伤。胆汁淤积导致肝脏损伤的主要原因是毒性胆汁酸盐在肝中的持续滞留，损伤胆管细胞，诱发胆管反应引起汇管区出现过量纤维状ECM沉积，进一步的纤维化范围扩大、严重程度增强将导致肝硬化的形成。胆固醇转化是形成胆汁酸的主要途径，其中经典途径合成的胆汁酸占总胆汁酸的75％，降低胆固醇的量可有效降低毒性胆汁酸盐的生成。引起胆汁淤积的原因有许多种，包括原发性胆汁性肝硬化(PBC)、原发性硬化性胆管炎(PSC)、妊娠期胆汁淤积、全胃肠外营养导致的胆汁淤积和药物诱导性胆汁淤积，胆道闭锁、胆总管结石、自身免疫性疾病等。目前临床上用于胆汁淤积治疗的药物十分有限，开发新的有效治疗的药物可以满足临床上未满足的需求。
肝纤维化是在肝脏组织受到外界或者内在慢性损伤后，自身修复过程中形成的，是一个可逆的病理过程。早期干预和阻止肝纤维化的进展是预防肝病发展成为肝硬化的关键。导致肝脏损伤的原因有很多，大部分的慢性肝病均可导致肝纤维化的产生，其中胆汁淤积导致的肝脏损伤是临床上一大诱因。在肝纤维化形成的初期修复肝脏的损伤部位，降低纤维化因子的产生可有效降低肝硬化产生的风险，提高患者的生存率。如何有效减少胆汁淤积的产生以及胆汁淤积导致的肝脏损伤，是减少肝纤维化的形成的一大研究热点。
鉴于此，亟需开发一种能够有效预防和/或治疗胆汁淤积和肝纤维化且自身毒副作用较低的药物。
发明内容
本发明提供一种瑞舒伐他汀钙在制备用于预防和治疗胆汁淤积及肝纤维化的药物中的用途。
优选的，所述胆汁淤积包含肝内及肝外原因导致的胆汁淤积。
优选的，所述肝内原因导致的胆汁淤积包括原发性胆汁性肝硬化(PBC)、原发性硬化性胆管炎(PSC)、妊娠期胆汁淤积、全胃肠外营养导致的胆汁淤积和/或药物诱导性胆汁淤积，肝外原因导致的胆汁淤积包括胆总管结石、胆管癌、硬化性胆管炎和/或胰管癌原因导致的胆汁淤积。
优选的，所述肝纤维化包含胆汁淤积导致的肝纤维化及其他原因导致的肝纤维化。
优选的，所述其他原因导致的肝纤维化包括病毒性肝炎、脂肪肝、酒精肝、毒物和/或药物等导致的肝纤维化。
优选的，所述瑞舒伐他汀钙降低个体血液中胆汁淤积相关检测指标和胆汁淤积部位胆管和肝细胞的损伤情况。
优选的，所述瑞舒伐他汀钙降低肝纤维化相关检测指标的升高和抑制肝纤维化相关信号通路的表达。
优选的，所述瑞舒伐他汀钙抑制氧化应激反应的产生。
优选的，所述瑞舒伐他汀钙的有效剂量为每日给予1mg/kg体重。
优选的，所述瑞舒伐他汀钙是以口服方式给予。
与现有技术相比，本发明的有益效果主要体现在：
1.在胆管结扎的SD大鼠胆汁淤积模型中，有效剂量为每日给予1mg/kg瑞舒伐他汀钙可以有效降低胆汁淤积损伤相关的ALP、ALT/AST、γ-GGT四项指标的升高情况，同时也降低了血液中的TBiL、DBiL、TBA三项胆汁分泌相关指标。通过对肝脏部位的病理观察发现，瑞舒伐他汀钙可以有效改善了胆汁淤积部位胆管及周围肝细胞的损伤情况。瑞舒伐他汀钙可以通过降低胆固醇的含量抑制胆汁酸的生成，在胆汁淤积状态下降低毒性胆汁盐的生成，从而有效缓解胆汁盐淤积导致的胆管和肝细胞毒性。
2.瑞舒伐他汀钙可以有效改善血浆中的纤维化指标LN、HA和HYP的过度表达情况，同时进一步的信号通路研究也发现瑞舒伐他汀钙能有效抑制模型组中TGFβ1/β-catenin信号通路的表达，相应的纤维化相关蛋白α-SMA、Collagen III的表达也显著性降低。瑞舒伐他汀钙可以作用于TGFβ1/β-catenin信号通路降低纤维化相关蛋白的表达，改善胆汁淤积所导致的肝纤维化。
3.瑞舒伐他汀钙干预的BDL大鼠其肝脏部位的Nrf2表达显著性增加，其 下游的抗氧化激酶NQO-1也显著性提高，从而抑制TGF-β1/β-catenin信号通路的激活，发挥抗氧化和抗纤维化的作用。肝脏的病理切片染色结果也发现，给与瑞舒伐他汀钙组的BDL大鼠肝脏胶原面积，纤维化程度，炎症浸润以及肝细胞损伤程度均较模型组有明显的改善。
4.本次发明中发现瑞舒伐他汀钙可以通过降低胆固醇减缓胆汁酸的形成和淤积，同时通过激活Keap-1/Nrf2信号通路发挥抗氧化作用，中和因胆汁淤积而产生的ROS，缓解胆汁盐和ROS导致的损伤作用；也可以通过增强Nrf2的表达进一步抑制TGFβ1/β-catenin信号通路的活化，减少纤维化因子的产生，延缓肝纤维化的进程，降低胶原面积、改善肝脏因胆汁淤积导致的纤维化程度，发挥治疗作用。
附图说明
图1为胆汁淤积模型SD大鼠经瑞舒伐他汀钙口服连续给药后的肝脏组织评分结果。
图2为胆汁淤积模型SD大鼠经瑞舒伐他汀钙口服连续给药后的肝脏组织纤维化相关蛋白表达水平。
图3为胆汁淤积模型SD大鼠经瑞舒伐他汀钙口服连续给药后的肝脏组织纤维化相关mRNA表达水平。
具体实施方式
以下实施例对本发明作进一步说明，但有必要指出以下实施例只用于对发明内容的描述，并不构成对本发明保护范围的限制，本发明保护范围以权利要求为准。
实施例
1.模型建立方法
慢性大鼠梗阻性黄疸模型的建立：实验大鼠术前12h禁食、不禁水，40mg/kg舒泰和10mg/kg赛拉嗪(腹腔注射，0.33ml/100g)，腹部剃毛备皮，碘伏消毒手术区域。剑突下正中切口进腹，暴露并分离胆总管，距十二指肠上缘1cm处横穿两条线，分别结扎，两线结扎中间部分胆总管剪断，随后关腹,缝合，再次消毒，结束手术。假手术组仅分离胆总管，但不结扎。
2.实验分组及给药方案：
术后第二天，大鼠黏膜黄染视为模型建立成功，并将成模大鼠均匀分为3组，并开始给药，每日一次，连续给药4周。
Figure PCTCN2021141579-appb-000001
3.样品采集、处理及检测指标
给药4周后，麻醉各组大鼠，眼眶取血，分离血浆，-80℃冻存。大鼠CO 2麻醉处死，留取肝脏标本，分为2个部分，一部分10％福尔马林固定，剩余部分冻存于-80℃。大鼠血浆用于检测AST、ALT、ALP、γ-GGT、DBil、TBil、HA、LN；组织检测：称取一定质量的肝脏组织，生理盐水冰上匀浆后，根据试剂盒检测组织中HYP(羟脯氨酸)；另取一定质量的肝脏组织，RIPA裂解后，进行WB实验，检测组织中TGF-β1、α-SMA及β-catenin蛋白水平；肝脏组织经Trizol裂解后，提取总RNA，进行RT-PCR，检测组织中Collagen III、TGF-β1、α-SMA、β-catenin、NRF2和NQO-1mRNA表达水平。固定于福尔马林的肝组织经脱水、包埋切片后后进行Masson染色，并用Image J软件评估胶原面积百分比。用HE染色后进行病理检查，观察肝细胞坏死及纤维化情况。
4.统计学方法
结果采用SPSS17.0统计软件进行数据处理，实验数据进行Dunnett’s test检验。P＜0.05为显著性差异，P＜0.01为极显著差异。
5.结果及结论
大鼠大体解剖观察及病理结果
正常对照组及假手术组大鼠肝脏大小正常，颜色红润，质地柔软；模型组大鼠肝脏明显增大，颜色呈黄褐色，表面颗粒感强，质地偏韧；腺苷蛋氨酸组大鼠肝脏与模型组相比，黄褐色程度减轻，质地较脆，更为柔软，瑞舒伐他汀钙组大鼠与模型组相比，肝脏明显变小，且颜色偏红润、质地较为柔软。肝脏组织Masson结果显示：与对照组(Control)及假手术组(Sham)相比，模型组(Model)组 织切片胶原面积明显增加；给予腺苷蛋氨酸组(SAMe)大鼠肝脏组切片胶原面积减小，差异具有显著性；给予瑞舒伐他汀钙组(RSV)大鼠肝脏组切片胶原面积减小，差异具有显著性(与Model组相比，***：P＜0.0001)，结果见图1。
肝脏组织HE结果显示：与对照组和假手术组相比，模型组胆管周围的肝细胞出现明显坏死现象，且纤维化区域明显增多；SAMe组坏死和纤维化程度均显著性弱于模型组；RSV组的肝细胞坏死和肝脏组织的纤维化程度也均显著性弱于模型组。
瑞舒伐他汀钙对大鼠血浆生化指标的影响
与Control组及Sham组相比，Model组大鼠血浆TBiL、DBiL含量及ALT、AST活性显著上升(P＜0.001)；与Model组相比，SAMe组大鼠血浆TBiL、DBiL含量及ALT、AST活性显著下降(P＜0.001或P＜0.01或P＜0.05)，RSV组大鼠血浆TBiL、DBiL含量及ALT、AST活性也显著下降(P＜0.001或P＜0.01或P＜0.05)，结果见表1。与Control组及Sham组相比，Model组大鼠血浆TBA、γ-GGT含量及ALP活性显著上升(P＜0.001或P＜0.01)；与Model组相比，SAMe组大鼠血浆TBA、γ-GGT含量及ALP活性显著下降(P＜0.001或P＜0.05)；RSV组大鼠血浆TBA、γ-GGT含量及ALP活性也显著下降(P＜0.001或P＜0.05)，结果见表1。
表1大鼠血浆肝功能及胆汁淤积相关指标水平
Figure PCTCN2021141579-appb-000002
注：*P＜0.05，**P＜0.01，***P＜0.001，P：vs Model
瑞舒伐他汀钙对大鼠肝脏纤维化相关指标的影响
与Control组及Sham组相比，Model组大鼠血浆层黏连蛋白(LN)、透明质酸(HA)及肝脏组织匀浆羟脯氨酸(HYP)含量显著上升(P＜0.001或P＜0.01或P＜0.05)；与Model组相比，SAMe组大鼠血浆血浆层黏连蛋白(LN)、 透明质酸(HA)及肝脏组织匀浆羟脯氨酸(HYP)含量未见明显改变；与Model组相比，RSV组大鼠血浆血浆层黏连蛋白(LN)、透明质酸(HA)及肝脏组织匀浆羟脯氨酸(HYP)含量显著下降(P＜0.001或P＜0.01或P＜0.05)，结果见表2。
表2大鼠纤维化相关指标水平
Figure PCTCN2021141579-appb-000003
瑞舒伐他汀钙对大鼠肝脏蛋白表达的影响
与Control组及Sham组相比，Model组大鼠肝脏组织β-catenin、TGFβ1及α-SMA蛋白水平明显上升；与Model组相比，给予SAMe组大鼠肝脏组织β-catenin、TGFβ1及α-SMA蛋白水平下降，其中TGFβ1表达水平下降具有显著性差异(P＜0.0001)；与Model组相比，给予RSV组大鼠肝脏组织β-catenin、TGFβ1及α-SMA蛋白水平均显著下降(P＜0.0001或P＜0.05或P＜0.0001)，结果见图2、表3。
表3大鼠肝脏组织纤维化相关蛋白表达水平
Figure PCTCN2021141579-appb-000004
瑞舒伐他汀钙对大鼠肝脏mRNA表达的影响
与Control组及Sham组相比，Model组大鼠肝脏组织TGF-β1、β-catenin、α-SMA、Collagen III的mRNA水平明显上升；与Model组相比，给予SAMe组大鼠肝脏组织TGF-β1、β-catenin、α-SMA、Collagen III mRNA水平明显下降(P ＜0.05或P＜0.001或P＜0.001或P＜0.001)，给予RSV组大鼠肝脏组织TGF-β1、β-catenin、α-SMA、Collagen III mRNA水平也明显下降(P＜0.05或P＜0.001或P＜0.01或P＜0.001)；与Model组相比，给予SAMe组大鼠肝脏组织NRF2、NQO-1的mRNA水平未见明显改变，给予RSV组大鼠肝脏组织NRF2、NQO-1的mRNA水平显著性上调(P＜0.01或P＜0.001)；结果见图3。
结论：瑞舒伐他汀钙可以通过降低胆固醇减缓胆汁酸的形成和淤积，同时通过激活Keap-1/Nrf2信号通路发挥抗氧化作用，中和因胆汁淤积而产生的ROS，缓解胆汁盐和ROS导致的损伤作用；也可以通过增强Nrf2的表达进一步抑制TGFβ1/β-catenin信号通路的活化，减少纤维化因子的产生，延缓肝纤维化的进程，降低胶原面积、改善肝脏因胆汁淤积导致的纤维化程度，发挥治疗作用。

Claims (10)

  1. 瑞舒伐他汀钙在制备用于预防和治疗胆汁淤积及肝纤维化的药物中的用途。
  2. 根据权利要求1所述的用途，其特征在于：所述胆汁淤积包含肝内及肝外原因导致的胆汁淤积。
  3. 根据权利要求2所述的用途，其特征在于：所述肝内原因导致的胆汁淤积包括原发性胆汁性肝硬化、原发性硬化性胆管炎、妊娠期胆汁淤积、全胃肠外营养导致的胆汁淤积和/或药物诱导性胆汁淤积，肝外原因导致的胆汁淤积包括胆总管结石、胆管癌、硬化性胆管炎和/或胰管癌原因导致的胆汁淤积。
  4. 根据权利要求1所述的用途，其特征在于：所述肝纤维化包含胆汁淤积导致的肝纤维化及其他原因导致的肝纤维化。
  5. 根据权利要求4所述的用途，其特征在于：所述其他原因导致的肝纤维化包括病毒性肝炎、脂肪肝、酒精肝、毒物和/或药物导致的肝纤维化。
  6. 根据权利要求1所述的用途，其特征在于：所述瑞舒伐他汀钙降低个体血液中胆汁淤积相关检测指标和胆汁淤积部位胆管和肝细胞的损伤情况。
  7. 根据权利要求1所述的用途，其特征在于：所述瑞舒伐他汀钙降低肝纤维化相关检测指标的升高和抑制肝纤维化相关信号通路的表达。
  8. 根据权利要求1所述的用途，其特征在于：所述瑞舒伐他汀钙抑制氧化应激反应的产生。
  9. 根据权利要求1所述的用途，其特征在于，所述瑞舒伐他汀钙的有效剂量为每日给予1mg/kg体重。
  10. 根据权利要求1所述的用途，其特征在于：所述瑞舒伐他汀钙是以口服方式给予。
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CN109152760A (zh) * 2016-04-11 2019-01-04 基恩菲特公司 胆汁淤积性和纤维化疾病的治疗方法

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