CN113209117A - 一种治疗酒精性脂肪肝和酒精性肝纤维化的药物 - Google Patents
一种治疗酒精性脂肪肝和酒精性肝纤维化的药物 Download PDFInfo
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Abstract
本发明属于医药技术领域，提供了一种治疗酒精性脂肪肝和酒精性肝纤维化的药物，本发明通过对化合物金线莲苷对酒精性脂肪肝和酒精性肝纤维化的治疗活性进行评价，发现该化合物能够有效缓解酒精性脂肪肝和酒精性肝纤维化的发展，在体内产生减轻酒精性脂肪肝和酒精性肝纤维化、改善肝功能和氧化应激损伤、降低炎性因子分泌等活性，能作为治疗酒精性脂肪肝和酒精性肝纤维化的药物。
Description
技术领域
本发明属于医药技术领域，涉及治疗肝脏疾病的药物，具体涉及治疗酒精性脂肪肝和酒精性肝纤维化的药物，即一种糖苷类化合物在制备用于治疗酒精性脂肪肝和酒精性肝纤维化药物中的应用。
背景技术
酒精性肝病(Alcoholic Liver Disease,ALD)是由于长期大量饮酒而引起的一种常见的肝脏疾病。据统计,在美国44.0％的肝病死亡率可归因于酒精；在我国,随着经济发展、酒精消费量不断增长,ALD的发病率也呈现逐年升高的趋势,酒精已成为仅次于肝炎病毒的肝损害第二大病因，严重影响了人们的身心健康(参考文献：贠建蔚，苌新明.酒精性肝病研究进展[J].国际消化病杂志)。
酒精性肝病的影响因素很多，包括饮酒量、饮酒年限、酒精饮料品种、饮酒方式、性别、种族、肥胖、肝炎病毒感染、遗传因素、营养状况等。流行病学调查资料显示，酒精所造成的肝损伤具有阈值效应，即达到一定饮酒量或饮酒年限，就会大大增加肝损伤风险。临床诊断标准首先要有长期饮酒史，一般超过5年，折合乙醇量男性≥40g/d，女性≥20g/d；或2周内有大量饮酒史，折合乙醇量＞80g/d。然而，饮酒量与肝损伤的量效关系存在个体差异(参考文献：厉有名,范建高.酒精性肝病防治指南(2018更新版)[J].中华肝脏病杂志)。
在酒精性肝病的早期阶段，通常表现为酒精性脂肪肝(Alcoholic Fatty Liver，AFL)，进一步发展为酒精性肝炎、酒精性肝纤维化(Alcoholic Liver Fibrosis)和酒精性肝硬化[3](参考文献：魏华，叶志伟.中西医结合治疗酒精性肝病的临床观察[J].湖北中医药大学学报)。
在我国，酒精性脂肪肝发病率逐年升高，且酒精性脂肪肝不易及时发现而容易使病情发展为严重的肝炎甚至肝纤维化和肝硬化。临床治疗主要以戒酒为主，但是部分病人依从性较差，导致病情治疗缓慢。
肝纤维化(fibrosis of liver)的本质是慢性肝病过程中的一种可逆的肝组织损伤过度修复反应，肝纤维化的持续存在导致肝实质逐步被ECM形成的瘢痕组织取代，最终形成肝硬化(参考文献：徐列明,刘平等.肝纤维化中西医结合诊疗指南(2019年版)[J].中国中西医结合杂志)。及时有效地抗纤维化治疗是防止慢性肝病向终末期肝病转化的必要措施。酒精性肝纤维化是肝纤维化中较为常见的一种，近10年来我国的发病率显著提高，目前针对酒精性肝纤维化的主要治疗策略是：戒酒和营养支持，抑制肝星状细胞活化，减轻炎症和免疫反应。临床用药以抗氧化抗炎药物为主，例如水飞蓟素类、甘草酸制剂等,但这些药物疗效有限，因此，探索研究开发一种治疗酒精性肝纤维化的有效药物，是该领域长期以来一项重要课题。
天然产物是药物最常见的来源，据统计，从上世纪八十年代年至今，每年30-40％的上市药物直接或间接来源于天然产物，其中2010年，天然产物相关来源的药物比例高达50％。植物次生代谢产物的种类极为丰富，随着近年对其研究的不断增多，越来越多活性强的化合物被发现，为新药的研发奠定了一定的基础。本发明旨在从天然产物中寻找治疗酒精性肝纤维化的有效药物。
发明内容
本发明的任务是提供一种治疗酒精性脂肪肝和酒精性肝纤维化的药物。
实现本发明的技术方案是：本发明提供治疗酒精性脂肪肝和酒精性肝纤维化的药物是金线莲苷(Kinsenoside(3-(R)-3-β-D-Glucopyranosyloxybutanolide))。
金线莲苷为兰科开唇兰属植物特质性成分，在花叶开唇兰、恒春金线莲和金线兰等3种常见的开唇兰属植物中含量分别为16％、15％及16％(干重)(王建栋，王红珍，张爱莲等.金线莲苷研究进展[J].中国医院药学杂志)。文献金线莲苷具有较为广泛的药理活性，包括降血糖、治疗糖尿病作用、降血脂和减肥作用、保肝护肝作用、对内皮细胞的保护作用、改善骨质疏松作用、抑制炎症反应等(参考文献：何春年，王春兰，郭顺星等.兰科开唇兰属植物的化学成分和药理活性的研究[J].中国药学杂志)。对于金线莲苷的保肝护肝活性研究，目前主要集中在四氯化碳诱导的小鼠急、慢性肝损伤模型，研究结果显示，该化合物可有效改善小鼠谷丙转氨酶、谷草转氨酶、肝脏系数(肝脏质量/体质量)及脾脏系数(脾脏质量/体质量)，而组织病理学分析表明，金线莲苷给药组小鼠肝脏表面比较光滑，颜色为红褐色，肝细胞肿胀、坏死和炎症细胞浸润程度明显轻于模型对照组(参考文献：胡光华.金线莲苷保肝降酶活性及其全乙酰化合物的合成[M].华中科技大学)。目前，对于金线莲苷的应用仅见研究性报道，该化合物尚无正式药物上市，针对酒精导致的脂肪肝、酒精与四氯化碳联合应用导致的酒精性肝纤维化这两种经典的肝纤维化模型造模研究更是尚未开展，发明人针对这一问题，对酒精导致的脂肪肝和酒精与四氯化碳联合应用导致的酒精性肝纤维化模型的治疗作用进行了探讨，并取得了较显著的成果。
金线莲苷属于糖苷类化合物，金线莲苷的结构式如式1所示：
本发明研究使用的金线莲苷购买自上海同田生物技术股份有限公司，纯度>98.0％。HPLC测定KD纯度色谱图见图2。
以下为核磁共振谱图鉴定KD数据。
本专利申请发明人通过对化合物金线莲苷治疗酒精性脂肪肝和酒精性肝纤维化活性进行评价，发现该化合物能够有效减轻酒精性脂肪肝和酒精性肝纤维化的发展，在体内产生减轻酒精性脂肪肝和酒精性肝纤维化、改善肝功能和氧化应激损伤、降低炎性因子分泌等活性，可以作为治疗酒精性脂肪肝和酒精性肝纤维化的药物。以金线莲苷为活性成分，加上制药学上可接受的载体、添加剂或/和赋形剂，能制成用于治疗酒精性脂肪肝和/或酒精性肝纤维化的药物制剂。金线莲苷(kinsenosid；KD)治疗酒精性脂肪肝作用的实验资料见实施例1；实施例2：金线莲苷(Kinsenosid；KD)治疗酒精性肝纤维化作用的实验资料见实施例2。
附图说明
图1.其中A至G为:
A.AFL实验小鼠肝脏H&E染色。通过H&E染色观察KD在酒精性脂肪肝中的治疗作用，发现KD可减轻肝脏组织病理学损伤，使小鼠肝脏中脂肪空泡减少。
B.ALF实验小鼠肝脏H&E染色。结果显示，KD给药组炎症细胞较模型组减少，Mallory小体数量得到控制，KD可减轻ALF损伤。
C.ALF实验小鼠肝脏Masson染色。Masson染色结果显示，对于酒精性肝纤维化，KD的治疗能显著减轻小鼠纤维化程度。
D.生化试剂盒测定AFL和ALF小鼠血清ALT。结果显示，KD降低AFL和ALF小鼠血清谷丙转氨酶(ALT)，具有肝保护作用。
D.生化试剂盒测定AFL和ALF小鼠肝脏SOD。结果显示，KD升高AFL和ALF小鼠肝脏中超氧化物歧化酶(SOD)的活性，具有抗氧化作用。
E.F.G.Elisa法测定AFL和ALF小鼠血清中的炎性因子。KD对AFL和ALF中小鼠炎性因子TNFα、IL6的分泌有抑制作用。
图2：HPLC测定KD纯度色谱图。
具体实施方式
实施例1：金线莲苷(kinsenosid；KD)治疗酒精性脂肪肝作用。
本实验取7-8周龄的C57BL/6J小鼠，，饲养于华中科技大学同济医学院SPF级实验动物中心，给予标准饮食和饮水，房间温度控制在23±2℃，适应喂养7天后开始灌胃给药。实验中涉及小鼠的实验方案经华中科技大学同济医学院动物实验伦理委员会批准。小鼠分为空白组(Control group)、模型组(Model group)、高剂量组(40mg/kg KD)、中剂量组(20mg/kg KD)和低剂量组(10mg/kg KD)。通过给与含5％酒精的Lieber-DeCarli液体饲料致小鼠产生酒精性脂肪肝。对除空白组外的小鼠进行造模。给与酒精饲料的同时开始灌胃给药，空白和模型组灌胃饮用水，给药组按不同剂量灌胃给药，造模5周(其中造模第一周为适应期，酒精浓度由0逐步提高至5％)即能在肝脏造成原发性酒精性脂肪肝模型。观察KD的治疗作用。苏木精-伊红(H&E)染色结果显示，模型组小鼠肝组织存在大量脂肪空泡，高剂量组(40mg/kg KD)、中剂量组(20mg/kg KD)脂肪空泡减少，KD可减轻肝脏组织病理学损伤(见图1.A)。
在酒精性脂肪肝中，肝功能检查结果提示，模型组血清谷丙转氨酶(ALT)水平较对照组上升(见图C)，造模后肝脏超氧化物歧化酶(SOD)活性下降，给予KD治疗可以逆转这些氧化应激损伤(见图1.E)。
同时，KD的治疗降低了高剂量组、中剂量组小鼠炎症因子——TNF-α、IL-6的分泌(见图1.F、G)。
实施例2：金线莲苷(Kinsenosid；KD)治疗酒精性肝纤维化作用。
取8周龄的C57BL/6J小鼠，饲养于华中科技大学同济医学院SPF级实验动物中心，给予标准饮食和饮水，房间温度控制在23±2℃，适应喂养7天后开始灌胃给药。实验中涉及小鼠的实验方案经华中科技大学同济医学院动物实验伦理委员会批准。小鼠分为空白组(Control group)、模型组(Model group)、高剂量组(40mg/kg KD)、中剂量组(20mg/kg KD)和低剂量组(10mg/kg KD)。通过给与含5％酒精的Lieber-DeCarli液体饲料和联合腹腔注射CCl4(最后四周腹腔注射CCl4，每周两次)致小鼠产生酒精性肝纤维化。对除空白组外的小鼠进行造模。给与酒精饲料的同时开始灌胃给药，空白和模型组灌胃饮用水，给药组分别按不同剂量灌胃给药，造模9周(其中造模第一周为适应期，酒精浓度由0逐步提高至5％)即能在肝脏造成原发性ALF模型。观察KD的治疗作用。苏木精-伊红(H&E)染色结果显示，模型组小鼠肝组织出现大量炎症细胞浸润，且可见Mallory小体，高剂量组(40mg/kg KD)、中剂量组(20mg/kg KD)炎症细胞较模型组减少，Mallory小体数量减少，KD可减轻肝脏组织病理学损伤(见图1.B)；Masson染色结果显示，模型组肝纤维化严重，出现桥接坏死，高剂量组(40mg/kg KD)和中剂量组(20mg/kg KD)纤维化程度减轻(见图1.C)。
在酒精性肝纤维化中，肝功能检查结果提示，模型组血清谷丙转氨酶(ALT)水平较对照组上升，给予KD治疗后下降(见图1.D)；模型组肝脏匀浆超氧化物歧化酶(SOD)活性下降，给予KD治疗可以逆转这些氧化应激损伤(见图1E.)。
在酒精性肝纤维化中，KD的治疗降低了高剂量组、中剂量组小鼠促炎细胞分泌的炎症因子——TNF-α、IL-6的分泌。(见图1.F、G)
实验结论：金线莲苷对酒精性脂肪肝和酒精性肝纤维化具有较好的治疗作用，能够有效缓解酒精性脂肪肝和酒精性肝纤维化的发展，在体内产生减轻酒精性脂肪肝和酒精性肝纤维化、改善肝功能和氧化应激损伤、降低炎性因子分泌等活性，能作为治疗酒精性脂肪肝和酒精性肝纤维化的药物。
Claims (3)
1.金线莲苷(Kinsenoside(3-(R)-3-β-D-Glucopyranosyloxybutanolide)在制备用于治疗酒精性脂肪肝或/和酒精性肝纤维化药物中的应用。
2.一种用于治疗酒精性脂肪肝或/和酒精性肝纤维化的药物制剂，其特征在于，含有有效量的金线莲苷和制药学上可接受的载体、添加剂或/和赋形剂。
3.权利要求1中所述的金线莲苷具有以下式1所示结构
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| CN117860678B (zh) * | 2024-03-13 | 2024-05-28 | 中国农业大学 | 一种治疗酒精性脂肪肝的药物组合物及其制备方法 |
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