CN111000854B - 曲札茋苷在制备治疗和/或预防非酒精性脂肪肝病产品中的应用 - Google Patents
曲札茋苷在制备治疗和/或预防非酒精性脂肪肝病产品中的应用 Download PDFInfo
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- CN111000854B CN111000854B CN201911393441.1A CN201911393441A CN111000854B CN 111000854 B CN111000854 B CN 111000854B CN 201911393441 A CN201911393441 A CN 201911393441A CN 111000854 B CN111000854 B CN 111000854B
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Abstract
本发明属于生物制药技术领域,公开了曲札茋苷在制备治疗和/或预防非酒精性脂肪肝病产品中的应用。本发明研究表明,连续4周给予非酒精性脂肪肝病(NAFLD)模型小鼠曲札茋苷后,其血清中TC、TG、LDL含量均显著减少,HDL含量均显著增加,说明该药具有调脂作用;血清中AST、ALT活性均显著减弱,并减轻肝组织中炎性因子的浸润,说明该药具有保肝作用;既能降低肝脏的脂肪含量,又能改善脂肪肝的病理形态,表明对NASH有对抗作用。本试验结果提示,曲札茋苷在防治非酒精性脂肪肝病方面具有很好的开发应用价值。
Description
技术领域
本发明属于医药技术领域,具体地说,涉及曲札茋苷在制备治疗和/或预防非酒精性脂肪肝病产品中的应用。
背景技术
非酒精性脂肪性肝病(NAFLD)是指除外长期大量饮酒和其他明确的损肝因素所引起的,以甘油三酯为主的脂质在肝细胞中蓄积为病理改变的肝脏代谢性疾病。NAFLD患者肝脏脂肪代谢功能出现障碍,使得大量脂肪类物质蓄积于肝细胞(单纯性脂肪肝),进而导致肝细胞发生脂肪变性、肝细胞损伤、炎症反应、肝脏纤维化(非酒精性脂肪性肝炎,NASH)。单纯性脂肪肝是NAFLD的较为良性的阶段,容易被逆转。10%-20%的单纯性脂肪肝可以进展为NASH。目前认为NASH是NAFLD进展为肝硬化、肝细胞肝癌、肝衰竭等终末期肝病的重要环节,在未来可能成为肝移植的首要原因。NAFLD已成为目前临床常见的肝病之一。流行病学调查表明,我国NAFLD发病率约为15%,而欧美地区NAFLD的发病率则在20%以上。因此,探寻NAFLD的有效疗法具有非常重要的意义。
NAFLD在病理上一般包括单纯性脂肪肝以及由其演变的脂肪性肝炎(NASH)和肝硬化三种类型。尽管丙型肝炎、自身免疫性肝病、Wilson病等亦可导致肝脂肪变,但因其病变主体在汇管区,且有特定命名,故不属于普通脂肪性肝病的范畴。脂肪肝的发病机制至今尚未完全清楚。目前认为,“二次打击”学说可能是酒精性脂肪肝和非酒精性脂肪肝共同的发病机制。酒精、肥胖、糖尿病等作为初次打击,通过引起肝细胞内甘油三酯合成和代谢之间失衡导致脂肪贮积形成单纯性脂肪肝;第二次打击是指氧应激相关的脂质过氧化及炎性细胞因子的作用,导致脂肪变的肝细胞发生炎症、坏死和纤维化。不同的是脂肪肝的发生在酒精性主要由乙醇及其代谢产物所致,而在非酒精性则主要与胰岛素抵抗有关(范建高.酒精性与非酒精性脂肪性肝病.中华肝脏病杂志,2003,11(11):692)。在NAFLD患者中,脂质代谢紊乱比较常见。肝脏在体内脂质代谢过程中发挥着主要的作用,它能够摄入游离脂肪酸,加工、贮存和输出脂质,过程中的任何一环出现问题都可能导致NAFLD的产生。游离脂肪酸在细胞中发挥着重要作用,例如合成细胞膜、作为能量存储以及参与细胞内的信号通路。然而,在很多器官中慢性的游离脂肪酸含量的增加会破坏代谢途径,诱导胰岛素抵抗(insulin resistance,IR)。肝脏中脂质的积累与限密切相关。脂肪组织胰岛素抵抗能增加脂解并且能增加游离脂肪酸从脂肪组织到肝脏的输入,减少输出。除此之外,体内活性氧(reaCtive OX-ygen species,ROS)含量增加,多种细胞因子(例如肿瘤坏死因子α(TNF-α)和白细胞介素-6(IL-6)等)也可能导致肝脏细胞脂质代谢功能异常,从而导致NAFLD的发生或者加重。
NAFLD目前尚无特异有效的治疗方法。临床上用于治疗脂肪肝的药物主要包括三类:一是针对原发病的药物,例如肥胖患者可采用塞尼可减肥;2型糖尿病患者可以采用二甲双胍、曲格列酮等。二是保肝药物,可使用抗氧化剂、消炎利胆药、保肝降酶中药等。三是降血脂药物,通过降低血浆脂类含量,而改善肝脏脂肪沉积。但上述三类药物均存在疗效不肯定,部分药物具有肝毒性、副作用多等问题,而且脂肪肝常规治疗中的一些促进血液中脂质运输至肝脏进行代谢的降血脂药物,在降低血脂的同时却可能升高肝脂,加重肝脏脂肪沉积。目前已有几种药物被应用于NAFLD和NASH的临床试验中,但是由于出现了与预期不一致的结局和(或)在随机对照试验中缺乏治疗效益,尚未被推荐使用。因此,开发有效的药物进行干预,阻止NAFLD疾病进展就显得尤为重要。
曲札茋苷((E)-1-(3,5-二羟苯基)-2-(3-羟基-4-O-β-D-吡喃葡萄糖苯基)乙烯或3,5,3',4'-四羟基茋-3'-O-β-葡萄糖苷),其植物来源为拉萨大黄根茎。安全性研究表明曲札茋苷安全性良好,急性毒性试验中,未出现动物出现毒副反应和死亡;遗传性试验中未见致染色体畸变、致突变作用。曲札茋苷的结构式如式I中所示:
申请号为201010116358.2的中国专利中公开了曲札茋苷在制备防治心脑缺血基本制剂中的应用及其制备方法;申请号为2011110371198.0的中国专利中公开了一种测定拉萨大黄中曲札茋苷含量的高效液相色谱方法,公开了曲札茋苷的提取工艺、检测方法。现有技术表明,曲札茋苷具有治疗缺血性心脑血管疾病方面的活性,但目前没有可以用于治疗和预防NAFLD的报道。
有鉴于此特提出本发明。
发明内容
本发明要解决的技术问题在于克服现有技术的不足,提供曲札茋苷在制备治疗和/或预防非酒精性脂肪肝病产品中的应用。
为解决上述技术问题,本发明采用技术方案的基本构思是:
本发明的第一目的是提供曲札茋苷在制备治疗和/或预防非酒精性脂肪肝病产品中的应用。
本发明中所述的曲札茋苷可以是曲札茋苷提取物,也可以是曲札茋苷纯品。曲札茋苷的制备方法可以参考申请号为201010116358.2的中国专利。
本发明研究表明,连续4周给予非酒精性脂肪肝病(NAFLD)模型小鼠曲札茋苷后,其血清中TC、TG、LDL含量均显著减少,HDL含量均显著增加,说明该药具有调脂作用;血清中AST、ALT活性均显著减弱,并减轻肝组织中炎性因子的浸润,说明该药具有保肝作用;既能降低肝脏的脂肪含量,又能改善脂肪肝的病理形态,表明对NASH有对抗作用。本试验结果提示,曲札茋苷在防治非酒精性脂肪肝病方面具有很好的开发应用价值。
进一步的方案,所述非酒精性脂肪肝病包括单纯性脂肪肝、脂肪性肝炎和肝硬化。
本发明的第二目的是提供曲札茋苷在制备治疗和/或预防非酒精性脂肪肝患病机体体重和/或肝脏重量增加的产品中的应用。
本发明的第三目的是提供曲札茋苷在制备治疗和/或预防非酒精性脂肪肝患病机体的血清中总胆固醇、和/或甘油三酯增加的产品中的应用。
特别是,曲札茋苷在制备治疗和/或预防非酒精性脂肪肝患病机体的肝脏中总胆固醇、和/或甘油三酯增加的产品中的应用。
本发明的第四目的是提供曲札茋苷在制备治疗和/或预防非酒精性脂肪肝患病机体的血清中天冬氨酸氨基转移酶、和/或丙氨酸氨基转移酶增加的产品中的应用。
本发明的第五目的是提供曲札茋苷在制备治疗和/或预防非酒精性脂肪肝患病机体的血清中低密度脂蛋白增加的产品中的应用。
本发明的第六目的是提供曲札茋苷在制备治疗和/或预防非酒精性脂肪肝患病机体的血清中高密度脂蛋白减少的产品中的应用。
进一步的方案,所述产品包括食品、保健品和药物。
进一步的方案,所述治疗和/或预防非酒精性脂肪肝病的产品为药物,所述药物中包括曲札茋苷与药学上可接受的辅料。
进一步的方案,所述治疗和/或预防非酒精性脂肪肝病的药物包括各种可接受的剂型;
优选的,所述剂型包括注射剂、片剂、胶囊剂、粉剂、丸剂或口服液。
本发明的第七目的是一种治疗和/或预防非酒精性脂肪肝病的产品,所述产品的成分中包括曲札茋苷。
本方案中,治疗和/或预防非酒精性脂肪肝病的产品的有效成分中包括曲札茋苷,可以为食品、保健品或者药物。
优选的,所述产品为药物,包括曲札茋苷与药学上可接受的辅料。
采用上述技术方案后,本发明与现有技术相比具有以下有益效果:
本发明公开了曲札茋苷的一种新的医药用途,本发明通过体内和体外研究证明,曲札茋苷具有明显治疗脂肪肝和改善培养肝细胞脂肪变性作用;可显著降低肝指数、血清TG和肝组织TG含量,同时抑制脂质过氧化反应,明显改善肝细胞脂肪变性,对脂肪肝的防治具有重要的临床应用价值。研究成果可以开发治疗NAFLD的现代中药有效成分产品,为研制拥有自主知识产权的治疗NAFLD的现代中成药奠定了良好的基础。本发明的有效成分易于从植物中分离提取,可用于工业化生产,疗效肯定,具有良好的市场前景。
下面结合附图对本发明的具体实施方式作进一步详细的描述。
附图说明
附图作为本发明的一部分,用来提供对本发明的进一步的理解,本发明的示意性实施例及其说明用于解释本发明,但不构成对本发明的不当限定。显然,下面描述中的附图仅仅是一些实施例,对于本领域普通技术人员来说,在不付出创造性劳动的前提下,还可以根据这些附图获得其他附图。在附图中:
图1是本发明显微镜下小鼠肝脏病理学变化图(HE,×200);
其中,A是正常对照组,B是模型组,C是曲札茋苷低剂量组,D是曲札茋苷高剂量组。
需要说明的是,这些附图和文字描述并不旨在以任何方式限制本发明的构思范围,而是通过参考特定实施例为本领域技术人员说明本发明的概念。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将结合本发明实施例中的附图,对实施例中的技术方案进行清楚、完整地描述,以下实施例用于说明本发明,但不用来限制本发明的范围。
实施例1:探讨曲札茋苷对非酒精性肝细胞损伤的保护作用
1实验材料
1.1供试品
曲札茋苷,分子量406,白色结晶或结晶性粉末,纯度99.6%,批号20120402;
1.2实验动物
选择44只健康雄性C57BL/6小鼠,体质量19~23g,均购于湖南斯莱克景达实验动物有限公司,实验动物生产许可证号:SCXK(湘)2016-0002,饲养于昆药集团研究院,PVC透明塑料盒群养,每盒≤6只,每日喂饲对应饲料,自由饮水,视情况更换笼具和垫料。温度20~25℃(日温差≤3℃),湿度40%~70%,照明12h:12h明暗交替,照度150~300lx,噪音≤60dB,实验动物使用许可证:SYCK(滇)K2019-0001,发证单位:昆明市科学技术局。
1.3饲料
高糖高脂饲料,来源于鼠一鼠二生物科技有限公司,DO9100310,辐照:15kGy,含40%脂肪、20%果糖、2%胆固醇;普通饲料,来源于江苏省协同医药生物工程有限责任公司,许可证号:苏饲证(2014)01008。
1.4试剂及仪器
多聚甲醛(分析纯,国药集团化学试剂有限公司)、磷酸氢二钠(分析纯,天津市风船化学试剂科技有限公司)、磷酸二氢钠(分析纯,天津市风船化学试剂科技有限公司)。丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)等试剂盒,均为南京建成生物工程研究所配套原装试剂。二甲苯、无水乙醇、甲醛、丙酮、苏木素、苏丹Ⅳ、伊红、盐酸酒精、中性树胶、甘油明胶等为病理检测所需试剂;苦味酸、氯化钠注射液、消毒酒精等为实验室常用试剂。96孔平底细胞培养板、包埋盒、石蜡、载玻片、盖玻片、切片刀等。
组织匀浆机、高速冷冻离心机、酶标仪、电子秤、分析天平等;脱水机,LEICAASP300S;冰冻切片机,LEICA CM1950;包埋机,LEICA EG1150H;冷冻台,LEICA EG1130;轮转式切片机,LEICA RM2235;烘片机,LEICA HI1220等。
2试验方法
2.1动物模型制备
44只C57小鼠适应性喂养1周后,按随机数字法分为对照组(12只)和模型组(32只),正常对照组给予普通饲料,模型组给予高糖高脂饲料。喂饲8周,随机抽取对照组和模型组各2只动物,经病理检查确认建模成功后,将模型动物分组。
2.2分组给药
按随机数字法将模型动物分为3组:模型对照组(等体积氯化钠注射液)、曲札茋苷高、低剂量(20、10mg/kg)组,每组10只。各给药组小鼠均灌胃相应药物,每天1次,连续4周,同时继续饲喂高糖高脂饲料;正常对照组(等体积氯化钠注射液)饲喂普通饲料。
2.3观察指标
2.3.1一般状况观察
末次给药后禁食不禁水12h,取血后处死小鼠,称量各鼠体质量和肝质量,并计算肝指数:肝指数=(肝湿重/体质量)×100%。(肝湿质量/体质量)。
2.3.2测定血清TC、TG、HDL、LDL、AST和ALT水平
经小鼠眼球取血约1mL,置于1.5mL离心管中,3000r/min离心10min,取上清液,用酶标仪测定血清中TC、TG、HDL、LDL、AST和ALT的水平,严格按照测定试剂盒说明书操作。
2.3.3肝组织TC、TG含量测定
称取约100mg的肝组织,置于900μL无水乙醇中,于冰浴下制成10%的组织匀浆,3000r/min、15min,取上清液分装于1.5mL离心管中用于肝组织TC、TG含量测定。
2.4.4肝脏HE染色
将新鲜肝组织浸入4%甲醛溶液中固定过夜24h,经75%-95%-100%酒精梯度脱水,石蜡包埋、4μm切片,作常规苏木素-伊红染色,光镜下观察肝脏组织病理改变(HE,200×)。
4实验结果
4.1对小鼠一般情况及体重、肝湿重和肝指数的影响
实验过程中各组小鼠状态良好,食欲旺盛。其中,正常组小鼠性情较为温顺,皮毛光滑,活动正常;NAFLD模型组小鼠体重增长迅速,且性情较为烦躁,不喜动。高糖高脂饲喂12周后,与正常对照组(普通饲料)相比,模型组(高糖高脂饲料)小鼠体重增长、肝湿重及肝指数均明显高于正常对照组(P<0.01);与模型组比较,曲札茋苷给药组有降低高糖高脂诱导小鼠肥胖的趋势,并明显降低模型动物的肝湿重及肝指数(P<0.05),结果见表1。
组别 | N | 体重(g) | 肝湿重(g) | 肝指数(%) |
正常组 | 10 | 25.7±0.63 | 0.99±0.22 | 0.38±0.02 |
模型组 | 10 | 36.2±0.55## | 2.14±0.21## | 0.59±0.14## |
曲札低剂量组 | 10 | 35.0±0.62 | 1.84±3.0* | 0.53±0.0.4* |
曲札高剂量组 | 10 | 33.8±0.74 | 1.72±2.7* | 0.51±0.05* |
注:与正常对照组比较,##P<0.01;与模型组比较,*P<0.05
4.2对血清中TC、TG、HDL、LDL及AST、ALT水平比较
与正常对照组比较,模型组小鼠血清中TC、TG、LDL含量及AST、ALT活性均显著增加,HDL含量显著减少(P<0.05/0.01);与模型组比较,曲札茋苷高剂量组小鼠血清中TC、TG、LDL含量均显著减少,AST、ALT活性均显著减弱,HDL含量均显著增加(P<0.01),表明曲札茋苷对高糖高脂诱导的非酒精性脂肪性肝病的肝功能具有良好的保护作用,结果详见表2。
注:与正常对照组比较,#P<0.05,##P<0.01;与模型组比较,*P<0.05,**P<0.01
4.3对小鼠肝组织中TC、TG含量的影响
肝脂含量的变化更能反映脂肪肝的程度,应作为判断抗脂肪肝药物疗效的重要指标之一。小鼠在给予高糖高脂饲料12周后,其肝脏TG、TC水平均显著增加,曲札茋苷可显著降低脂肪肝小鼠肝脏的TG、TC水平,与模型对照组比较有统计学差异(P<0.05/0.01),结果详见表3。
分组 | TC(mg/g) | TG(mg/g) |
正常组 | 3.08±0.54 | 1.34±0.18 |
模型组 | 7.22±0.85## | 3.25±0.81## |
曲札低剂量组 | 6.53±0.59* | 2.12±0.58 |
曲札高剂量组 | 4.23±0.87** | 1.96±0.99** |
注:与正常对照组比较,##P<0.01;与模型组比较,*P<0.05,**P<0.01
4.4小鼠肝脏大体观察及肝组织病理观察
4.4.1小鼠肝脏大体观察
正常对照组小鼠肝脏呈黯红色,色泽鲜亮,质地柔软而脆弱,肝略呈楔形,右端圆钝而厚,左端窄而薄,无油腻感;模型组小鼠肝脏肿大表面颜色发黄,质地较硬,捏之有颗粒及油腻感;曲札茋苷低、高剂量组小鼠肝脏颜色介于正常对照组与模型组之间,质地和形态趋于正常组。
4.4.2小鼠肝脏HE观察
HE染色,显微镜下可见正常组小鼠肝组织结构完整清晰、肝小叶结构正常,肝细胞排列成肝索,在中央静脉周围呈放射状分布,细胞中央有大而圆的核,细胞质均匀,无脂滴;模型组小鼠肝脏脂肪变性明显,肝细胞肿大,内含大的脂肪滴,部分细胞可见细胞核挤向细胞膜,呈以大泡性为主的脂肪变性,并可见炎性细胞浸润,部分细胞出现点状坏死和灶状坏死,已进展至非酒精性脂肪肝炎阶段。曲札茋苷组与模型组比较,脂肪滴较小、较少,肝组织病理形态明显改善,脂肪变性空泡状肝细胞明显减少,炎性细胞浸润不明显,细胞排列相对整齐完整,表明曲札茋苷减轻了高糖高脂引起的肝脏炎细胞浸润,见图1。
图1是本发明显微镜下小鼠肝脏病理学变化图(HE,×200);其中,A是正常对照组,B是模型组,C是曲札茋苷低剂量组,D是曲札茋苷高剂量组。
从图1中的实验结果中可以看出,连续4周给予模型小鼠曲札茋苷后,其血清中TC、TG、LDL含量均显著减少,HDL含量均显著增加,说明该药具有调脂作用;其血清中AST、ALT活性均显著减弱,说明该药具有改善肝功能的作用;其肝脏病理形态可见肝组织脂肪变性情况改善,减轻炎性因子浸润,说明该药具有保护肝脏的作用,在防治非酒精性脂肪肝(NAFLD)方面具有很好的临床使用价值。
实施例2
本实施例的片剂由如下组分组成:曲札茋苷10g、微晶纤维素20g、预胶化淀粉20g、交联聚乙烯吡咯烷酮20g、微粉硅胶1g。
将上述原料混合,按照常规方法制备获得曲札茋苷片剂。
实施例3
本实施例的胶囊剂由如下组分组成:曲札茋苷10g、微晶纤维素30g、乳糖5g、聚维酮K-30适量、硬脂酸镁1g。
将上述原料混合,按照常规方法制备获得曲札茋苷胶囊剂。
实施例4
本实施例的颗粒剂由如下组分组成:曲札茋苷10g、甘露醇20g、乳糖20g、甜蜜素1g、固体食用香精0.5g、黄原胶1g。
将上述原料混合,按照常规方法制备获得曲札茋苷颗粒剂。
实施例5
本实施例的滴丸剂由如下组分组成:曲札茋苷5、聚乙二醇6000 15g。
将上述原料混合,按照常规方法制备获得曲札茋苷滴丸剂。
以上所述仅是本发明的较佳实施例而已,并非对本发明作任何形式上的限制,虽然本发明已以较佳实施例揭露如上,然而并非用以限定本发明,任何熟悉本专利的技术人员在不脱离本发明技术方案范围内,当可利用上述提示的技术内容作出些许更动或修饰为等同变化的等效实施例,但凡是未脱离本发明技术方案的内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰,均仍属于本发明方案的范围内。
Claims (4)
1.曲札茋苷在制备治疗和/或预防非酒精性脂肪肝病产品中的应用。
2.根据权利要求1所述的应用,其特征在于,所述治疗和/或预防非酒精性脂肪肝病的产品为药物,所述药物中包括曲札茋苷与药学上可接受的辅料。
3.根据权利要求2所述的应用,其特征在于,所述治疗和/或预防非酒精性脂肪肝病的药物包括各种可接受的剂型。
4.根据权利要求3所述的应用,其特征在于,所述剂型包括注射剂、片剂、胶囊剂、粉剂、丸剂或口服液。
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