CN114469972B - 白头翁皂苷b4和/或白头翁皂苷b5在制备预防或治疗药物性肝损伤药物中的应用 - Google Patents
白头翁皂苷b4和/或白头翁皂苷b5在制备预防或治疗药物性肝损伤药物中的应用 Download PDFInfo
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Abstract
本发明涉及白头翁皂苷B4和/或白头翁皂苷B5在制备预防或治疗药物性肝损伤药物中的应用,属于医药技术领域。白头翁皂苷B4和/或白头翁皂苷B5能够降低血清中的ALT、AST和ALP反映肝功能指标的转氨酶,改善肝功能;同时能够有效减缓血清中TG含量下降趋势,改善APAP药物诱导后导致的机体代谢异常,进而起到对肝脏的保护作用,达到有效预防或治疗药物性肝损伤病变,为药物性肝损伤的预防和治疗提供新的策略和临床研究依据,进一步为指导治疗药物性肝损伤的临床用药提供科学依据。
Description
技术领域
本发明涉及白头翁皂苷B4和/或白头翁皂苷B5在制备预防或治疗药物性肝损伤药物中的应用,属于医药技术领域。
背景技术
药物性肝损伤(Drug-induced liver injury,DILI)是由药物本身或其代谢产物以及特殊体质对药物的超敏或耐受性降低所导致的肝损伤。一般将药物性肝损伤的致病机制分为两类,一类是损伤程度具有剂量依赖性,由药物及其中间代谢产物对肝脏直接发挥的毒性作用;另一类是机体对药物的特异质反应,此类药物性肝损伤具有不可预测性,受到遗传等因素的影响,是一种严重的药物不良反应,它给患者和医疗系统带来沉重的负担。
在过去50年中,肝毒性一直是由于安全性导致药物撤市的最常见单一原因。据美国急性肝衰竭研究会数据显示,一半以上的急性肝衰竭是由药物引起的,美国每年的住院患者约有1‰-3‰是药物性肝损伤患者,并且药物性肝损伤导致近600例患者肝移植和120例患者死亡,这也是导致死于急性肝衰竭的最主要原因。我国药物性肝损伤占急性肝损害住院病例的10%。
乙酰氨基酚(acet‐aminophen, APAP) ,商品名为扑热息痛 (paracetamol),是世界范围内广泛使用的解热镇痛药,在常规剂量 (<4 g·d-1) 内安全有效,但过量服用可能导致严重肝损伤,甚至死亡。APAP所致肝损伤是DILI和急性肝衰竭 (acute liverfailure, ALF)的主要来源。
临床上含有对APAP的药品多为非处方药,国家非处方药手册中收载了68种含有对APAP的药品,并且除常用西药外,部分中成药中也加入了APAP(如维C银翘片、银菊解毒片等)。在大多数药物包装上并没有明确标注APAP的肝毒性;且由于非处方药物的便利性,临床实践中存在重复用药、不恰当联合用药等情况,从而易导致APAP的过量使用或重复使用造成的肝损伤。
APAP在肝内的主要代谢产物是葡萄糖醛酸和硫酸盐偶联物,少量被细胞色素P4502E1(CYP2E1)转化为一种具有高度活性的毒性代谢产物N-乙酰-对苯醌亚胺(NAPQI)。正常情况下,NAPQI与肝脏中还原型谷胱甘肽(GSH)结合,然后在胆汁和尿液中排泄为半胱氨酸和巯基酸。APAP摄取过多或与其他药物相互作用时,生成的NAPQI过多,葡萄糖醛酸内酯和硫酸盐途径饱和,过量的APAP通过CYP系统代谢产生大量的NAPQI,过量的NAPQI与GSH共价结合后与细胞蛋白硫醇共价结合,促进肝细胞氧化,降低肝抗氧化能力,导致急性肝坏死。肝细胞坏死后,细胞通透性增强,使细胞内的转氨酶释放入血,从而造成血浆转氨酶升高。因此,检测血浆中转氨酶的含量可间接表明肝损伤的程度。
APAP诱导的小鼠肝损伤模型组织形态学表现以小叶中心区域坏死为特征,这是APAP毒性的标志。该模型方便、廉价,代谢机理接近临床,因此逐渐成为近年来研究过量服用解热镇痛药导致急性肝损伤的治疗药物筛选的动物模型。
申请公布号CN105213410A、CN110755441A的中国发明专利申请分别公开了白头翁皂苷B4在急性炎症和糖尿病并发症引起的肝损伤具有保护作用;而对于药物性肝损伤的治疗效果并不清楚。
发明内容
本发明的目的是提供白头翁皂苷B4和/或白头翁皂苷B5在制备预防或治疗药物性肝损伤药物中的应用,为药物性肝损伤的预防和治疗提供新的策略和临床研究依据,进一步为指导治疗药物性肝损伤的临床用药提供依据。
为了实现以上目的,本发明采用的技术方案为:
白头翁皂苷B4和/或白头翁皂苷B5在制备预防或治疗药物性肝损伤药物中的应用。
白头翁是毛茛科(Ranunculaceae)白头翁属植物,白头翁(Pulsatilla chinensis(Bunge) Regel)的干燥根,具有清热解毒、凉血止痢的功效。白头翁的主要药理作用包括抗菌、抗阿米巴原虫、抗病原体、抗癌、杀精子和镇静镇痛,其中主要有效成分包括白头翁素和白头翁皂苷等。
白头翁皂苷具有增强免疫功能、抗炎、抗肿瘤、保护肾损伤、抗病原微生物等作用。其中白头翁皂苷B4和白头翁皂苷B5为五环三萜皂苷,白头翁皂苷B4和白头翁皂苷B5,属于纯天然成分,安全可靠无毒副作用。但白头翁皂苷B4和白头翁皂苷B5的结构存在很大的差异,苷元母核不一样,白头翁皂苷B4为羽扇豆烷型皂苷,白头翁皂苷B5为齐墩果烷型皂苷。
白头翁皂苷B4和白头翁皂苷B5结构式如图7和图8所示。
本发明基于临床上引起药物性肝损伤的APAP为造模药物,制备经典药物性肝损伤动物模型并结合病理检测等业内金标准,验证了白头翁皂苷B4和/或白头翁皂苷B5作为制备预防或治疗药物性肝损伤药物的活性成分,能够通过降低血清中的ALT、AST和ALP肝功能指标水平来改善肝功能;同时通过调节机体代谢机制,减缓APAP药物诱导的血清甘油三酯(TG)下降趋势,改善APAP药物诱导后导致的机体代谢异常,进而起到对肝脏的保护作用,达到有效预防或治疗药物性肝损伤引起的病变。
为进一步优化药物性肝损伤的预防或治疗疗效,将白头翁皂苷B4和白头翁皂苷B5联合用药;优选地,白头翁皂苷B4和白头翁皂苷B5的质量比为1:1。
进一步地,所述药物通过改善机体代谢异常来预防或治疗药物性肝损伤。
进一步地,所述改善机体代谢异常包括减缓血清中甘油三酯下降的趋势。
进一步地,所述药物通过改善肝功能来预防或治疗药物性肝损伤。
进一步地,所述改善肝功能包括降低血清中ALT、AST和ALP肝功能指标水平。
为了更好地用药,进一步地,所述药物为溶液剂,优选地,溶液剂中的溶剂为生理盐水。
附图说明
图1为本发明预防给药方案;
图2为白头翁皂苷B4、白头翁皂苷B5预防给药小鼠肝脏损伤情况(HE染色);
图3为白头翁皂苷B4、白头翁皂苷B5预防给药小鼠肝脏损伤情况(生化检测);
图4为本发明治疗给药方案;
图5为白头翁皂苷B4、白头翁皂苷B5治疗给药小鼠肝脏损伤情况(HE染色);
图6为白头翁皂苷B4、白头翁皂苷B5治疗给药小鼠肝脏损伤情况(生化检测);
图7为白头翁皂苷B4的结构式图;
图8为白头翁皂苷B5的结构式图。
具体实施方式
下面结合具体实施例及附图对本发明作进一步说明。
实验例 白头翁皂苷B4和/或白头翁皂苷B5在制备预防或治疗药物性肝损伤药物中的应用,具体说明如下:
本实施例中采用的动物:雄性C57BL/6J 小鼠,8 周龄,体质量 18~22 g,购自于北京维通利华实验动物有限责任公司;
模型:APAP诱导药物性肝损伤模型;
血清生化分析:分析血清中指标ALT、AST、ALP和TG,采用全自动生化分析仪(TBA-120FR,TOSHIBA,日本)。
受试物配制方法:白头翁皂苷B4和白头翁皂苷B5用生理盐水溶解配置成浓度为:1.5mg/ml;APAP浓度为20mg/ml。
实施例1
白头翁皂苷B4和/或白头翁皂苷B5在预防药物性肝损伤药物中的应用,具体说明如下:
1、实验方法
在对小鼠APAP诱导药物性肝损伤造模前禁食12h,禁食期间小鼠可自由饮水。将小鼠随机分成5组,每组5只,分别为:对照组(Control),APAP模型组(Model),APAP +白头翁皂苷B4组,APAP +白头翁皂苷B5组,APAP +白头翁皂苷B4和白头翁皂苷B5联用组。
对APAP +白头翁皂苷B4组,APAP +白头翁皂苷B5组,APAP +白头翁皂苷B4和白头翁皂苷B5联用组各组的小鼠分别预给药15 mg·kg-1的白头翁皂苷B4、15 mg·kg-1的白头翁皂苷B5、7.5 mg·kg-1的白头翁皂苷B4和7.5 mg·kg-1白头翁皂苷B5联用,连续腹腔注射给药7天,具体给药方式见附图1;白头翁皂苷B4、白头翁皂苷B5用生理盐水溶解,APAP模型组和对照组给予注射同体积的生理盐水。
7天后,对对照组小鼠腹腔注射等剂量的生理盐水溶剂,再对另外4组的小鼠分别腹腔注射400 mg·kg-1APAP。
12h后戊巴比妥麻醉处死收集血和肝脏样本,立即将肝脏的一部分固定在 4%的多聚甲醛中以进行组织固定,石蜡包埋、切片,然后进行苏木精-伊红(H&E)染色以评估形态变化组织;并将其余组织在液氮中速冻并保存在-80 ℃以便进一步使用。
2、实验结果
2.1 白头翁皂苷B4和/或白头翁皂苷B5预防给药小鼠肝脏损伤情况
APAP诱导型的药物性肝损伤的组织形态学上的典型表现为以小叶中心区域坏死为特征。对小鼠肝脏进行切片、染色进行形态学特征分析,详见附图2。
从图2中可知,APAP模型组相对于正常对照组出现了明显的细胞肿胀、轻微细胞融合现象,这些损伤主要分布于汇管周围,小叶中心区域出现坏死。而经白头翁皂苷B4、白头翁皂苷B5和白头翁皂苷B4与白头翁皂苷B5联用组预防给药后,肝损伤情况有所改善,细胞肿胀有所缓解;并且白头翁皂苷B4和白头翁皂苷B5联用组的效果优于白头翁皂苷B4和白头翁皂苷B5组,细胞肿胀明显缓解,发现极少数的炎症细胞浸润,小叶中心区域坏死区面积减少。
2.2 小鼠血清中肝脏生化指标
肝细胞坏死后,细胞通透性增强,使细胞内的转氨酶释放入血,从而造成血浆转氨酶升高。因此,检测血浆中转氨酶的含量可间接表明肝损伤的程度。
测定各组小鼠血清中的生化指标,如肝脏损伤指标ALT、AST、ALP和甘油三酯(TG)指标;详细数据见附图3, ##P<0.01, ###P<0.001表示与正常对照组相比,具有显著差异性;*P<0.05, **P<0.01表示与APAP模型组相比,具有显著差异性。
从图中数据可知,APAP模型组相对于空白对照组,ALT, AST 和ALP 水平显著上升,而提前给予白头翁皂苷B4、白头翁皂苷B5以及二者联合药物后,可以一定程度上缓解ALT, AST 和ALP 水平上升的趋势,表明白头翁皂苷B4和/或白头翁皂苷B5预防给药后,在一定程度上能够改善APAP药物对肝造成的药物性损伤,进而起到对肝脏的保护作用。
此外,与空白对照组相比,APAP模型组中甘油三脂(TG)明显下降,而经白头翁皂苷B4、白头翁皂苷B5和两者联用分别预防给药后,小鼠血清中TG的含量得到明显升高,表明白头翁皂苷B4和/或白头翁皂苷B5预防给药后能缓减APAP诱导的TG下降趋势;说明白头翁皂苷B4、白头翁皂苷B5和二者联用可以一定程度上改善APAP诱导的代谢异常,进而起到对肝脏的保护作用。
实施例2
白头翁皂苷B4和/或白头翁皂苷B5在治疗药物性肝损伤药物中的应用,具体说明如下:
1、实验方法
在对小鼠APAP诱导药物性肝损伤造模前禁食12h,禁食期间小鼠可自由饮水。将小鼠随机分成5组,每组5只,分别为:对照组(Control),APAP模型组(Model),APAP +白头翁皂苷B4组,APAP +白头翁皂苷B5组,APAP +白头翁皂苷B4和白头翁皂苷B5联用组。
对APAP模型组,APAP +白头翁皂苷B4组,APAP +白头翁皂苷B5组,APAP +白头翁皂苷B4和白头翁皂苷B5联用组,各组小鼠分别腹腔注射400 mg·kg-1的APAP药物,然后再对APAP +白头翁皂苷B4组,APAP +白头翁皂苷B5组,APAP +白头翁皂苷B4和白头翁皂苷B5联用组分别腹腔注射15 mg·kg-1的白头翁皂苷B4、15 mg·kg-1的白头翁皂苷B5、7.5 mg·kg-1的白头翁皂苷B4和7.5 mg·kg-1白头翁皂苷B5联用,连续腹腔注射给药7天;同时给对照组和APAP模型组小鼠腹腔注射等剂量的生理盐水溶剂,为避免小鼠自身自愈能力对评价结果的影响,最后一次给药前各组小鼠分别再进行腹腔注射400 mg·kg-1的APAP造模,具体给药方式见附图4。
12h后戊巴比妥麻醉处死收集血和肝脏样本,立即将肝脏的一部分固定在 4%的多聚甲醛中以进行组织固定,石蜡包埋、切片,然后进行苏木精-伊红(H&E)染色以评估形态变化组织;并将其余组织在液氮中速冻并保存在-80 ℃以便进一步使用。
2、实验结果
2.1 白头翁皂苷B4和/或白头翁皂苷B5治疗小鼠肝脏损伤情况
H&E染色结果显示(见附图5),APAP模型组相对于空白对照组出现了细胞肿胀,炎症细胞浸润,轻微充血和细胞融合现象,这些损伤主要分布于汇管周围。而白头翁皂苷B4、白头翁皂苷B5和白头翁皂苷B4与白头翁皂苷B5联用治疗后这些病理有明显改善,尤其白头翁皂苷B4与白头翁皂苷B5联合用药后效果明显优于白头翁皂苷B4和白头翁皂苷B5单独用药,肝脏细胞肿胀明显减轻,汇管周围炎性细胞浸润数量减少、小叶中心区域坏死区面积减少。
2.2 小鼠血清中肝脏生化指标
测定各组小鼠血清中的生化指标,如肝脏损伤指标ALT、AST、ALP和甘油三酯(TG)指标;详细数据见附图6, ##P<0.01, ###P<0.001表示与正常对照组相比,具有显著差异性;*P<0.05, **P<0.01表示与APAP模型组相比,具有显著差异性。
从图中数据可知,APAP模型组相对于空白对照组,小鼠血清中ALT、AST和ALP指标水平显著上升,而白头翁皂苷B4、白头翁皂苷B5和两者联用可以一定程度上逆转这现象,在一定程度上能够改善APAP药物对肝形成的药物性损伤,进而改善肝功能;尤其是白头翁皂苷B4和白头翁皂苷B5联合用药组,治疗后几乎达到正常水平。
此外,与空白对照组相比,APAP模型组中甘油三脂(TG)明显下降,而经白头翁皂苷B4、白头翁皂苷B5和两者联用分别给药治疗后,小鼠血清中TG的含量得到显著提高,表明白头翁皂苷B4和/或白头翁皂苷B5给药治疗后能缓减APAP诱导的TG下降趋势;说明白头翁皂苷B4、白头翁皂苷B5和二者联用可以一定程度上改善APAP诱导的代谢异常,进而起到对肝脏的保护作用。
上述实施例1和实施例2结果表明,白头翁皂苷B4和/或白头翁皂苷B5在作为制备预防或治疗药物性肝损伤的药物,能够有效减缓血清中TG含量下降趋势,改善APAP药物诱导后机体的代谢异常;同时通过降低血清中的ALT、AST和ALP肝功能指标水平来改善肝功能,进而起到对肝脏的保护作用,达到有效预防或治疗药物性肝损伤病变,为药物性肝损伤的预防和治疗提供新的策略和临床研究依据,进一步为指导治疗肝损伤的临床用药提供依据。
Claims (7)
1.白头翁皂苷B4和白头翁皂苷B5在制备预防或治疗药物性肝损伤药物中的应用,其特征在于,所述肝损伤由对乙酰氨基酚导致;白头翁皂苷B4和白头翁皂苷B5联合用药,白头翁皂苷B4和白头翁皂苷B5的质量比为1:1。
2.根据权利要求1所述白头翁皂苷B4和白头翁皂苷B5在制备预防或治疗药物性肝损伤药物中的应用,其特征在于,所述药物通过改善机体代谢异常来预防或治疗药物性肝损伤。
3.根据权利要求2所述白头翁皂苷B4和白头翁皂苷B5在制备预防或治疗药物性肝损伤药物中的应用,其特征在于,所述改善机体代谢异常包括减缓血清中甘油三酯下降的趋势。
4.根据权利要求1所述白头翁皂苷B4和白头翁皂苷B5在制备预防或治疗药物性肝损伤药物中的应用,其特征在于,所述药物通过改善肝功能来预防或治疗药物性肝损伤。
5.根据权利要求4所述白头翁皂苷B4和白头翁皂苷B5在制备预防或治疗药物性肝损伤药物中的应用,其特征在于,所述改善肝功能包括降低血清中ALT、AST和ALP肝功能指标水平。
6.根据权利要求1-5任意一项所述的白头翁皂苷B4和白头翁皂苷B5在制备预防或治疗药物性肝损伤药物中的应用,其特征在于,所述药物为溶液剂。
7.根据权利要求6所述的白头翁皂苷B4和白头翁皂苷B5在制备预防或治疗药物性肝损伤药物中的应用,其特征在于,所述溶液剂中的溶剂为生理盐水。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105213410A (zh) * | 2015-10-20 | 2016-01-06 | 刘琦 | 白头翁皂苷b4作为免疫调节剂在治疗急性炎症药物中的应用 |
CN111110728A (zh) * | 2020-02-14 | 2020-05-08 | 广西英路维特药物有限公司 | 一种白头翁提取物及其在制备预防和/或治疗奶牛乳房炎中的用途 |
CN113730422A (zh) * | 2021-09-30 | 2021-12-03 | 苏州大学 | 白头翁皂苷b4在制备预防或者治疗非酒精性脂肪肝的药物中的应用 |
-
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- 2022-04-06 CN CN202210352588.1A patent/CN114469972B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105213410A (zh) * | 2015-10-20 | 2016-01-06 | 刘琦 | 白头翁皂苷b4作为免疫调节剂在治疗急性炎症药物中的应用 |
CN111110728A (zh) * | 2020-02-14 | 2020-05-08 | 广西英路维特药物有限公司 | 一种白头翁提取物及其在制备预防和/或治疗奶牛乳房炎中的用途 |
CN113730422A (zh) * | 2021-09-30 | 2021-12-03 | 苏州大学 | 白头翁皂苷b4在制备预防或者治疗非酒精性脂肪肝的药物中的应用 |
Non-Patent Citations (4)
Title |
---|
Comparison of cytoprotective effects of saponins isolated from leaves of Aralia elata Seem. (Araliaceae) with synthesized bisdesmosides of oleanoic acid and hederagenin on carbon tetrachloride-induced hepatic injury;SAITO, Setsuo等;《Chemical & Pharmaceutical Bulletin》;19931231;第41卷(第8期);第1395-1401页 * |
Hederasaponin C的体内抗炎作用研究;郭文霞;《中国优秀硕士学位论文全文数据库》;20211231;第1,13页 * |
一些三萜类化合物抗小鼠肝损伤活性比较;叶文才等;《中国药科大学学报》;19961231;第27卷(第7期);第425-428页 * |
白头翁中三萜皂苷类成分的药理研究进展;查正霞等;《中药新药与临床药理》;20200131;第31卷(第1期);第120-124页 * |
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