CN116585327A - 环巴胺或其衍生物在制备治疗和/或预防非酒精性脂肪肝疾病中的应用 - Google Patents
环巴胺或其衍生物在制备治疗和/或预防非酒精性脂肪肝疾病中的应用 Download PDFInfo
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Abstract
本发明涉及药物的新用途领域，具体涉及环巴胺或其衍生物的医药用途。本发明公开了环巴胺或其衍生物具有改善非酒精性脂肪肝，降低血脂，改善胰岛素抵抗和抑制肝脏炎症以及纤维化的作用。本发明首次发现环巴胺或其衍生物对非酒精性脂肪肝疾病的改善作用，为非酒精性脂肪肝疾病的治疗提供了更多的选择。
Description
技术领域
本发明涉及药物新用途领域，具体涉及环巴胺或其衍生物在制备治疗和/或预防非酒精性脂肪肝疾病中的应用。
背景技术
在过去的40年中，非酒精性脂肪肝病(Non-alcoholic fatty liver disease，NAFLD)已成为最常见的慢性肝病(全球成人患病率约为25％)。非酒精性脂肪肝疾病包括非酒精性脂肪肝(Non-alcoholic fatty liver，NAFL)和非酒精性脂肪性肝炎(Non-alcoholic steatohepatitis，NASH)。约4％的NAFL患者会发展成肝硬化或肝癌，而NASH患者发展为肝硬化的风险则更大，超过20％。肝脏脂肪变性，即肝细胞中脂肪的积累，存在于NAFL和NASH中。每当脂肪的吸收或合成超过脂肪外排或降解时，就会发生脂质累积。在长期吸收脂质过剩的情况下，脂肪组织产生脂肪细胞因子，阻止脂肪细胞同化脂肪酸并促进脂肪酸从脂肪库中释放。这导致脂肪酸向肝脏的输送增加，并促进肝细胞甘油三酯和其他有肝毒性脂质的合成，进而产生炎症。炎症是对组织损伤或感染的生理反应，导致各种炎症介质的分泌，例如细胞因子和趋化因子，它们协调细胞防御机制和组织修复。随着时间的推移，炎症活动的持续性导致慢性炎症变化，加剧组织损伤，并可能导致异常的伤口愈合反应。肝脏炎症反应是NAFL向NASH转变的重要驱动力，因为它促进持续的肝纤维化，最终导致肝硬化。流行病学研究发现膳食胆固醇摄入与NASH的风险和严重程度有关。在患有NASH的人和小鼠的肝脏中都发现了胆固醇积累。NASH患者的肝活检样本中游离胆固醇水平高于健康对照组个体，胆固醇喂养促进饮食诱导NASH小鼠模型中的强烈炎症反应。游离胆固醇也会在库普弗细胞和肝星状细胞中积聚，从而激活炎症和纤维化。在小鼠中与高脂肪高胆固醇饮食相比，去除胆固醇后的饮食，降低了血浆极低密度脂蛋白胆固醇水平，并防止了肝脏炎症和泡沫细胞的发展
环巴胺分子式为C27H41NO2，分子量为411.62，白色结晶粉末，化学结构式如下：
发明内容
发明目的：本发明的目的为提供一种改善非酒精性脂肪肝，降低血脂，改善胰岛素抵抗和抑制肝脏炎症以及纤维化作用的环巴胺或其衍生物在制备治疗和/或预防非酒精性脂肪肝疾病药物中的应用。
技术方案：本发明的环巴胺或其衍生物在制备治疗和/或预防非酒精性脂肪肝疾病药物中的应用。
发明人在对环巴胺的药理活性研究中发现，环巴胺能有效的降低高脂饮食诱导的小鼠体重，血清中胆固醇和甘油三酯的水平，改善其胰岛素抵抗和抑制肝脏炎症以及纤维化。
进一步地，衍生物包括环巴胺的异构体、非对映异构体、对映异构体、互变异构体、溶剂化物、溶剂化物的盐或药学上可接受的盐。
本发明的含有环巴胺或其衍生物的组合物在制备治疗和/或预防非酒精性脂肪肝疾病药物中的应用。
进一步地，组合物是以环巴胺或其衍生物作为活性成分，加上药学上可接受的载体或辅料所制成的药物制剂。药物制剂为片剂、胶囊、糖浆、悬浮剂或注射剂。辅料为香料、甜味剂、液体/固体填料或稀释剂。
有益效果：与现有技术相比，本发明具有如下显著优点：
(1)环巴胺及其衍生物和药物组合物可有效降低血脂，总胆固醇降低了33.0％，甘油三酯降低了37.2％；环巴胺及其衍生物和药物组合物还可有效改善机体葡萄糖耐量和胰岛素抵抗，分别降低达21.3％和26.4％；
环巴胺及其衍生物和药物组合物还可改善炎症和纤维化指标，降低肝损伤指标ALT和AST分别为55.0％和30.4％。
(2)环巴胺及其衍生物和药物组合物应用广泛，可制备为治疗和/或预防酒精性脂肪肝的药物；所述药物治疗效果更优异，体重改善最优可达到13.9％。
下面结合实施例对环巴胺改善非酒精性脂肪肝活性进行进一步的阐述。
附图说明
图1是小鼠体重的实验结果；
图2是小鼠肝重/体重的实验结果；
图3是小鼠附睾白色脂肪重量/体重的实验结果；
图4是口服糖耐量实验(OGTT)结果；
图5是口服糖耐量实验(OGTT)曲线下面积结果
图6是胰岛素耐量实验(ITT)结果；
图7是胰岛素耐量实验(ITT)曲线下面积结果；
图8是血清中总胆固醇的实验结果；
图9是血清中甘油三酸酯的实验结果；
图10是血清中谷丙转氨酶(ALT)的实验结果；
图11是血清中谷草转氨酶(AST)的实验结果；
图12是小鼠肝脏炎症相关基因的mRNA测定；
图13是小鼠肝脏纤维化相关基因的mRNA测定。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
实施例：环巴胺对非酒精性脂肪肝的作用
1、实验方法
模型组(HFFC)：取6周大的C57BL/6J雄性小鼠，喂养高脂高果糖高胆固醇(highfat，fructose and cholesterol，HFFC)饲料，并腹腔注射溶媒，两天一次，持续9周。每周记录体重。
环巴胺给药组：取6周大的C57BL/6J雄性小鼠，喂养HFFC高脂饮食，并腹腔注射环巴胺(20mg/kg)，两天一次，持续9周。每周记录体重。
2、实验结果
与HFFC高脂饲料喂养的小鼠相比，环巴胺给药组的体重降低了5.67g(图1)。另外环巴胺给药组小鼠的肝重占体重的比例由模型组的5.23％降低到了环巴胺给药组的3.68％(图2)。附睾脂肪重量占小鼠体重的比例由模型组的5.73％降低到了环巴胺给药组的3.40％(图3)。
经化合物环巴胺处理的高脂喂养的小鼠中，葡萄糖耐量和胰岛素抵抗得到了明显的改善(图4-7)。此外，环巴胺给药组小鼠的血清TC相比高脂模型组降低了3.84mM(图8)。环巴胺给药组小鼠的血清TG水平相比高脂模型组的小鼠降低了1.15mM(图9)。随后，对临床肝脏损伤的常用指标ALT和AST进一步检测发现，环巴胺给药组的ALT和AST显著降低，也即环巴胺可以缓解高脂饮食HFFC引起的肝脏损伤(图10-11)。最终，对小鼠肝脏的炎症和纤维化相关基因的mRNA水平进行测定，验证发现环巴胺给药组的小鼠肝脏炎症和纤维化的指标也同样明显的降低了(图12-13)，这个数据提示我们，环巴胺还可以缓解肝脏炎症和纤维化进程。综上所述，化合物环巴胺改善了C57BL/6J小鼠的高脂饮食诱导的非酒精性脂肪肝，并且疗效显著。
Claims (6)
1.环巴胺或其衍生物在制备治疗和/或预防非酒精性脂肪肝疾病药物中的应用。
2.根据权利要求1所述的应用，其特征在于：所述衍生物包括环巴胺的异构体、非对映异构体、对映异构体、互变异构体、溶剂化物、溶剂化物的盐或药学上可接受的盐。
3.含有环巴胺或其衍生物的组合物在制备治疗和/或预防非酒精性脂肪肝疾病药物中的应用。
4.根据权利要求3所述的应用，其特征在于：所述组合物是以环巴胺或其衍生物作为活性成分，加上药学上可接受的载体或辅料所制成的药物制剂。
5.根据权利要求4所述的应用，其特征在于：所述药物制剂为片剂、胶囊、糖浆、悬浮剂或注射剂。
6.根据权利要求4所述的应用，其特征在于：所述辅料为香料、甜味剂、液体/固体填料或稀释剂。
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