CN117599123A - 用于治疗肝脏和维持肝脏健康的组合物、方法和药物组合物 - Google Patents
用于治疗肝脏和维持肝脏健康的组合物、方法和药物组合物 Download PDFInfo
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Abstract
公开了用于治疗肝脏和维持肝脏健康的组合物和方法,其包括植物提取物的混合物,其中所述植物提取物包含至少一种肉豆蔻属提取物、至少一种黄芪属提取物和至少一种五味子属提取物。公开了用于治疗肝脏和维持肝脏健康的组合物和方法,其包括植物提取物的混合物,其中植物提取物包含至少一种富含一种或多种包括苯丙素、二聚体和聚合物的木酚素的肉豆蔻属提取物,至少一种富含一种或多种多糖和三萜类化合物的黄芪属提取物,以及至少一种富含一种或多种木酚素和有机酸的五味子属提取物。公开了用于治疗肝脏和维持肝脏健康的组合物和方法,其包括植物提取物的混合物,其中植物提取物包含至少一种肉豆蔻属提取物、至少一种黄芪属提取物和至少一种茯苓提取物。
Description
本申请是申请日2016年7月13日,申请号201680053400.6(PCT/US2016/042034),发明名称为“用于治疗肝脏和维持肝脏健康的组合物、方法和药物组合物”的发明专利申请的分案申请。
本申请要求2015年7月15日提交的名称为“Compositions and Methods forLiver Health(用于肝脏健康的组合物和方法)”的美国临时专利申请序列No.:62192727以及2016年7月13日提交的名称为“Compositions,Methods,and Medical Compositions forTreatment of and Maintaining the Health of the Liver(用于治疗肝脏和维持肝脏健康的组合物、方法和药物组合物)”的美国实用申请序列No.:15208934的优先权,它们是共同拥有的,并且通过引用将其全部内容并入本文。
技术领域
主题的领域是用于肝脏健康管理的化合物和组合物,包括公开的化合物的立体异构体、药学上或保健上可接受的盐、互变异构体、糖苷和前药,改善和维持肝脏健康的组合物和相关方法。
背景技术
肝脏是在各种内源性和外源性有害物质的代谢和解毒中起关键作用的重要器官。据信在肝脏中发生了超过500种化学反应。已知各种异生素或外来化学物质会引起肝脏毒性,其中对乙酰氨基酚(n-乙酰基-对氨基苯酚或APAP)和四氯化碳(CCl4)通常用于开发模拟具有类似的作用机制的人类肝脏毒性类型的动物模型。来自血清或肝脏匀浆的一系列生物标志物已被用于检查和/或分析肝脏的健康状况,其中偏离正常范围被认为是对器官的损伤的指示。在这些生物标志物中,最常用的是:ALT(丙氨酸转氨酶)、AST(天冬氨酸转氨酶)、MDA(丙二醛)、GSH(谷胱甘肽)、SOD(超氧化物歧化酶)、c-Jun N-末端激酶(JNK)、GSH-Px(谷胱甘肽过氧化物酶)、CAT(过氧化氢酶)和TNF-α(肿瘤坏死因子-α)。已经将肝脏功能面板(liver panel)如AST、ALT、总胆红素、结合和非结合胆红素、胆汁酸、总蛋白、白蛋白、球蛋白和碱性磷酸酶用作肝脏健康的标准筛检方法。虽然认识到ALT和AST对于肝脏损伤为非特异性的,但ALT对肝脏已显示出相对特异性。例如,AST具有肝脏(9000:1)相对肌肉(5200:1)的起始比率;相比之下,ALT具有肝脏(7600:1)相对肌肉(750:1)的起始比率。总AST和ALT的半衰期分别为17±5小时和47±10小时。ALT在室温下稳定3天,在冰箱里稳定3周,在全血中稳定24小时;然而,ALT随着反复冻融而迅速劣化。在我们的研究中,血清ALT被用于植物提取物的功效筛选。
APAP是治疗剂量下非常安全有效的止痛药和退热药。这是美国急性肝功能衰竭的最常见原因。APAP诱导的肝脏毒性在临床上是相关的,已充分研究,可以用单剂量在体内快速诱导,并已成为评估光疗法的潜在肝保护作用的常规模型。
APAP诱导的细胞死亡不是由关闭细胞的重要功能的单一不幸事件引起的,相反,其诱导由反应性代谢物形成和引发线粒体功能障碍开始的一系列事件,所述线粒体功能障碍通过JNK途径扩增,最终导致非功能性线粒体和大量DNA降解,导致细胞坏死。
APAP毒性以非常复杂的作用机制途径发生。如先前所确定的,APAP诱导的细胞死亡的细胞内信号传导机制是由给药剂量的一小部分被P450酶(主要是Cyp 2e1和1a2(Zaher等人,1998))代谢成n-乙酰基对苯醌亚胺(NAPQI)所引发的。在正常情况下,这种高活性代谢物将被GSH解毒,导致广泛的肝GSH耗竭(Mitchell等人,197),这在过量给药时变得至关重要。同时,越来越多的NAPQI与蛋白巯基反应,导致细胞蛋白的共价加合(Jollow等,1973)。有趣的是,研究表明细胞中的总蛋白质结合不如线粒体中的加合物重要(Tirmenstein和Nelson,1989;Qiu等人,2001)。线粒体蛋白结合触发线粒体氧化应激(Jaeschke,1990),其引起细胞凋亡信号调节激酶1(Nakagawa等人,2008)和c-Jun N末端激酶(JNK)(Hanawa等人,2008)的激活,和线粒体氧化应激和线粒体JNK易位的过氧化亚硝酸盐形成的扩增(Saito等人,2010a)。广泛的氧化应激最终触发线粒体中膜通透性转变(MPT)孔的开放,伴随膜电位崩溃(Kon等人,2004;Masubuchi等人,2005;Ramachandran等人,2011a;Loguidice和Boelsterli,2011),随后从线粒体释放膜间蛋白,例如核酸内切酶G和细胞凋亡诱导因子(AIF)(Kon等人,2004;Bajt等人,2008)。核酸内切酶G和AIF都转移到细胞核并造成DNA片段化(Cover等人,2005;Bajt等人,2006,2011)并最终发生细胞死亡。伴随ATP耗竭和核降解的线粒体膜电位崩溃是导致细胞坏死的关键事件。因此,在设计用于肝脏保护的治疗干预时,存在多个可以拦截这些机制的干扰点。
了解模型病理过程的按时间排列事件为治疗干预提供了指导。虽然氧化应激和无菌炎症在APAP毒性中发挥重要作用,但模型的病理生理学的特征在于一系列事件,包括在0和2小时之间的代谢活化,在前30分钟内的GSH耗竭,2和12小时之间的细胞死亡的细胞内机制,在6-24小时的时间范围内的炎性反应,以及在APAP毒性后24-72小时的时间范围内的再生(Jaeschke等人,2012a)。
如上所述,APAP过量给药可导致以蛋白质加合物形成(Davern等人,2006;James等人,2009),线粒体损伤和导致细胞死亡的核DNA片段化(McGill等人,2012a)为特征的人类的严重肝脏毒性。因此,在测试用于保护肝脏的植物提取物时,需要利用可能具有相似病理生理学特征的动物模型。因此,对于体内实验,小鼠是优选的模型,因为在机制和剂量依赖性方面,损伤与人类病理生理学非常相似。实际上,一些人认为小鼠和人之间APAP肝脏毒性的主要显著差异是人类的较延迟的毒性,其在接触后24-48小时显示ALT峰,而小鼠ALT峰在6-12小时(Larson,2007)。这种差异可以部分地解释为是因为这两个物种之间的吸收差异。相反,大鼠虽然常用于天然产物检测,但是由于大多数大鼠品系对APAP毒性基本不敏感(Mitchell等人,1973;McGill等人,2012b),因而大鼠是差的模型。即使在≥1g/kg的高剂量时,APAP也基本不会引起相关的肝脏损伤(Jaeschke等人,2013)。尽管可以测量GSH耗竭和蛋白质加合物,但与小鼠相比,大鼠肝线粒体中较低量的加合物显得不足以引发足够的线粒体功能障碍和随后的扩增事件以导致坏死性细胞死亡(McGill等人,2012b)。这两个物种之间的这些基本差异已经在植物疗法的评估过程中反映出来。例如,在大鼠研究中,与基线相比,3g/kg的APAP剂量导致血浆ALT水平增加至约3倍,并且植物疗法使这种中等的肝脏损伤减轻了33%(Ajith等人,2007)。该大鼠模型中的任何组织学变化都很小且难以检测。另一方面,在小鼠研究中,300mg/kgAPAP剂量后,ALT增加>基线的60倍,被植物疗法减少75%(Wan等人,2012)。容易观察到由APAP毒性引起的组织学变化和药物的保护作用。
CCl4是限制使用的卤代烷烃工业化学品,是众所周知的肝毒素,广泛用于诱导大量实验室动物的急性中毒性肝脏损伤。人类已接触职业环境中和来自环境污染(例如受污染的饮用水)的CCl4。尽管如此,该化学品现在仍然作为模型化合物提供重要的用途,以阐明肝脏毒性作用的作用机制,如脂肪变性、纤维化、肝细胞死亡和致癌性(Slater 1981;Renner H.1985;Reynolds 1963)。它被认为是经典的化学诱导肝脏毒性动物模型之一,主要与自由基的形成和脂质过氧化有关。
像APAP一样,CCl4毒性由主要为(CYP)2E1、CYP2B1或CYP2B2(Nelson andHarrison,1987)的细胞色素P450引发,产生反应性代谢物三氯甲基自由基(CCl3-),其可引发脂质过氧化并最终导致活性氧物类(ROS)的过度产生和肝细胞损伤(Poyer等人,1980;Albano等人,1982)。在这个过程中,这些自由基可以与细胞分子(核酸、蛋白质和脂质)结合,损害关键的细胞过程,如脂质代谢,其可能的结果是脂肪变性(脂肪变性)和对这些大分子的直接损伤(Weddle等人,1976)。这些自由基也可以与氧反应形成三氯甲基过氧自由基CCl3OO-,这是一种高活性物类。一旦产生,它就会启动脂质过氧化的连锁反应,从而攻击和破坏多不饱和脂肪酸,特别是与磷脂有关的多不饱和脂肪酸。这影响线粒体、内质网和质膜的通透性,导致细胞钙螯合和内稳态的丧失,这可能显著地促成随后的细胞损伤。在这方面,抗氧化剂和自由基清除剂已被用于研究CCl4毒性的机制以及通过破坏脂质过氧化的连锁反应来保护肝细胞免于CCl4诱导的损伤(Cheeseman等人,1987)。在分子水平上,CCl4激活细胞中的TNF-α(Czaja等人,1995)、一氧化氮(NO)(Chamulitrat等人,1994,1995)和转化生长因子(TGF)(Luckey等人,2001),该过程显示将细胞主要导向破坏或纤维化。这些表明具有抗炎活性的植物提取物可能具有潜在的肝脏保护应用。尽管大剂量CCl4的急性给予导致严重的坏死,但常常使用较低剂量的慢性给予来诱导肝纤维化。
氧化应激是自由基产生与身体通过与各种内源性抗氧化防御网络相互作用抵消或中和其有害作用的固有能力之间的不平衡。当身体抗氧化防御系统缺乏适当的调节时,活性氧物类的积累将导致应激敏感的细胞内信号传导途径的激活,从而促进导致坏死的细胞损伤。虽然氧化应激的损害影响作为系统的整个身体,但当它涉及重要的器官,如肝脏时(在肝脏中发生主要的解毒以去除和代谢有害的毒素如酒精),这种影响变得更加有害。因此,肝脏易受酒精引起的损伤,因为酒精及其主要代谢物乙醛产生活性氧物类(ROS)和羟基自由基(OH),从而改变肝脏抗氧化防御系统。由于反复接触酒精而造成的酒精相关的肝脏疾病中观察到了最常见的病理状况,如脂肪肝、肝炎、纤维化和硬化。与细胞脂质、蛋白质和DNA氧化有关的这些结果已经在多种实验动物中得到证实(Wu and Cederbaum,2003)。在这里,我们使用了最常用的具有实际临床意义的动物模型,如APAP,并证实了经典CCl4诱导的肝脏毒性模型的发现。无论用于诱导肝脏毒性的化学试剂如何,APAP和CCl4模型都共有由过量中间代谢物产生的活性氧物类引起的氧化应激的关键步骤,导致蛋白质氧化、脂质过氧化和DNA损伤。
为此目的,开发、产生和利用旨在治疗肝脏和维持肝脏健康的组合物、化合物、药物组合物和相关方法将是合乎需要的。理想的化合物、药物组合物和组合物将足以实现治疗,包括以下任何一项或多项:(1)治疗或预防哺乳动物肝细胞的损伤;(2)促进肝脏健康;(3)保护哺乳动物的解毒和抗氧化肝酶;(4)增加哺乳动物的肝脏解毒能力;(5)治疗或预防哺乳动物的肝脏疾病;(6)减轻哺乳动物肝脏的炎症;和(7)改善肝脏更新功能。理想的化合物和组合物可以来源于或包含至少一种植物提取物,其中植物提取物可以富集或不富集。作为本开发的一部分,使用常用和可接受的模型来测试预期的化合物和组合物将是理想的。通过拦截肝脏降解机制中的要点并研究那些结果来可靠地设计肝脏健康的治疗干预也是合乎需要的。
发明内容
公开了用于治疗肝脏和维持肝脏健康的组合物和方法,其包括植物提取物的混合物,其中所述植物提取物包含至少一种肉豆蔻属(Myristica)提取物、至少一种黄芪属(Astragalus)提取物和至少一种五味子属(Schizandra)提取物。
公开了用于治疗肝脏和维持肝脏健康的组合物和方法,其包括植物提取物的混合物,其中植物提取物包含至少一种富含一种或多种包括苯丙素、二聚体和聚合物的木酚素的肉豆蔻属提取物,至少一种富含一种或多种多糖和三萜类化合物的黄芪属提取物,以及至少一种富含一种或多种木酚素和有机酸的五味子属提取物。
公开了用于治疗肝脏和维持肝脏健康的组合物和方法,其包括植物提取物的混合物,其中植物提取物包含至少一种肉豆蔻属提取物,至少一种黄芪属提取物和至少一种茯苓(Poria)提取物。
公开了用于治疗肝脏和维持肝脏健康的组合物和方法,其包括植物提取物的混合物,其中植物提取物包含至少一种富含一种或多种包括苯丙素、二聚体和聚合物的木酚素的肉豆蔻属提取物,至少一种富含一种或多种多糖和三萜类化合物的黄芪属提取物,以及至少一种富含一种或多种多糖和三萜类化合物的茯苓提取物。
也公开了用于哺乳动物维持肝功能,使肝细胞损伤最小化,促进健康肝脏,保护肝脏抗氧化完整性,中和毒素,减少影响肝脏健康的自由基作用,清除活性氧物类,减少氧化应激,防止有毒代谢形成,改善肝脏解毒能力和/或功能,清肝,恢复肝脏结构,保护肝细胞以防毒素,帮助肝脏血液流动和循环,支持肝功能,增强和舒缓肝脏,平息和补养肝脏,缓解肝脏疼痛,清除有害的化学物质和生物体,支持肝脏的代谢过程,减轻肝脏不适,减轻脂肪肝,改善肝脏解毒能力,降低肝酶,提供天然氧化剂,增加SOD,增加GSH,减少肝细胞过氧化,减少脂肪酸积累,保持健康的抗炎过程,改善肝脏免疫功能,促进肝脏细胞再生,改善肝脏更新功能,模拟胆汁释放,促进健康胆汁流动,预防、治疗和处理宿醉以及与化学品、药物和处方药过量相关的症状,肝脏复原等的药物组合物,其中药物组合物含有预期的组合物作为有效成分。
附图说明
图1显示肉豆蔻(Myristicafragrans)70%乙醇提取物的HPLC色谱图。
具体实施方式
简而言之,本公开涉及用于肝脏健康管理的化合物和组合物,包括公开的化合物的立体异构体、药学上或保健上可接受的盐、互变异构体、糖苷和前药,以及改善肝脏健康的相关方法。
预期的化合物和组合物来源于或包含至少一种植物提取物,其中植物提取物可以富集或不富集。作为本开发的一部分,使用常用和可接受的模型来测试预期的化合物和组合物。另外,通过拦截肝脏降解机制中的要点并研究那些结果来设计肝脏健康的治疗干预。预期的化合物、药物组合物和组合物足以实现治疗,包括以下任何一项或多项:(1)治疗或预防哺乳动物肝细胞的损伤;(2)促进肝脏健康;(3)保护哺乳动物的解毒和抗氧化肝酶;(4)增加哺乳动物的肝脏解毒能力;(5)治疗或预防哺乳动物的肝脏疾病;(6)减轻哺乳动物肝脏的炎症;和(7)改善肝脏更新功能。
公开了用于治疗肝脏和维持肝脏健康的组合物和方法,其包括植物提取物的混合物,其中所述植物提取物包含至少一种肉豆蔻属(Myristica)提取物、至少一种黄芪属(Astragalus)提取物和至少一种五味子属(Schizandra)提取物。
公开了用于治疗肝脏和维持肝脏健康的组合物和方法,其包括植物提取物的混合物,其中植物提取物包含至少一种富含一种或多种包括苯丙素、二聚体和聚合物的木酚素的肉豆蔻属提取物,至少一种富含一种或多种多糖和三萜类化合物的黄芪属提取物,以及至少一种富含一种或多种木酚素和有机酸的五味子提取物。
公开了用于治疗肝脏和维持肝脏健康的组合物和方法,其包括植物提取物的混合物,其中植物提取物包含至少一种肉豆蔻属提取物,至少一种黄芪属提取物和至少一种茯苓(Poria)提取物。
公开了用于治疗肝脏和维持肝脏健康的组合物和方法,其包括植物提取物的混合物,其中植物提取物包含至少一种富含一种或多种包括苯丙素、二聚体和聚合物的木酚素的肉豆蔻属提取物,至少一种富含一种或多种多糖和三萜类化合物的黄芪属提取物,以及至少一种富含一种或多种多糖和三萜类化合物的茯苓提取物。
也公开了用于哺乳动物维持肝功能,使肝细胞损伤最小化,促进健康肝脏,保护肝脏抗氧化完整性,中和毒素,减少影响肝脏健康的自由基作用,清除活性氧物类,减少氧化应激,防止有毒代谢形成,改善肝脏解毒能力和/或功能,清肝,恢复肝脏结构,保护肝细胞以防毒素,帮助肝脏血液流动和循环,支持肝功能,增强和舒缓肝脏,平息和补养肝脏,缓解肝脏疼痛,清除有害的化学物质和生物体,支持肝脏的代谢过程,减轻肝脏不适,减轻脂肪肝,改善肝脏解毒能力,降低肝酶,提供天然氧化剂,增加SOD,增加GSH,减少肝细胞过氧化,减少脂肪酸积累,保持健康的抗炎过程,改善肝脏免疫功能,促进肝脏细胞再生,改善肝脏更新功能,模拟胆汁释放,促进健康胆汁流动,预防、治疗和处理宿醉以及与化学品、药物和处方药过量相关的症状,肝脏复原等的药物组合物,其中药物组合物含有预期的组合物作为有效成分。
在预期的实施方案中,可使用组合物、化合物或药物组合物来帮助缓解或帮助至少一种肝脏病症,其中肝脏病症包括病毒性肝炎,酒精性肝炎,自身免疫性肝炎,酒精肝病,脂肪肝病,脂肪变性,脂肪性肝炎,非酒精性脂肪肝病,药物引起的肝脏疾病,硬化,纤维化,肝衰竭,药物引起的肝衰竭,代谢综合征,肝细胞癌,胆管癌,原发性胆汁性肝硬化,毛细胆管,吉伯特综合征,黄疸或任何其它肝脏毒性相关适应症,并且通常对患者具有可接受的毒性,或任何其它肝脏相关适应症,或其任何组合。
在该过程中,观察到一些植物提取物仅在一种模型中显示出血清ALT降低,因此设定了标准,对于先导物,必须在两种模型中都显示出效果才能被视为真正的中选物。这个基准有助于缩小筛选的阳性中选数。在这个过程中,选择了肉豆蔻属、黄芪属、五味子属、茯苓和蒿属(Artemisia),因为它们在两种模型中都具有显著的和可重现的效果。
属于肉豆蔻科(Myristicaceae family)的肉豆蔻(Myristica fragrans)是香料肉豆蔻种子(nutmeg)和肉豆蔻皮(mace)的重要的来源,也是众所周知的药用草药。它在热带国家例如印度尼西亚、马来西亚、中国的广东和云南、加勒比的格林纳达、印度的喀拉拉邦、斯里兰卡和南美洲国家广泛种植,具有多种药理性质,包括抗腹泻、抗呕吐、舒缓胃痛、止痛、催眠、神经保护和食欲刺激。
芳香油是这种草药的关键活性成分。肉豆蔻的主要化学成分是肉豆蔻醚、肉豆蔻酸、榄香素、黄樟素、丁子香酚、棕榈酸、油酸、月桂酸和其它酸。精油可以作为调味剂或在香料中使用,也可用于治疗瘫痪和风湿病。据报道,精油的主要成分之一肉豆蔻醚在脂多糖/D-半乳糖胺诱导的肝脏损伤模型中具有有效的肝保护活性。肉豆蔻醚还具有有效的抗真菌、抗氧化、抗炎性质。
黄芪(Astragalus membranaceus)根是一种来源于豆科(豆科植物)的普遍的中草药,通称黄芪(Radix Astragali)、黄芪根(Astragalus root)或黄芪(中文)。黄芪是传统中医药中使用的五十种基本中草药之一,被包含在许多具有广泛生物学功能的TCM制剂中。它最初被描述为甜味的,本质上略呈蠕虫状,具有补养和利尿作用,缓解肺部和胸部疾病,滋养气血,和治疗痔疮的草药。它最近被研究对心血管疾病、肝炎、肾脏疾病和糖尿病的治疗。据报道,黄芪的根提取物具有对四氯化碳(CCl4)在动物中产生的肝脏损伤的保护作用。
黄芪提取物中的主要活性成分是黄酮类,皂苷类和多糖类。黄酮类,主要是异黄酮,作为抗氧化剂,有利于循环和舒缓胃肠系统。在黄芪中报道的40多种皂苷中,黄芪苷被确定是主要的标志化合物,具有涉及心血管、免疫、消化、神经和癌症疾病的广泛药理活性。黄芪多糖被称为astragalans,发现在根中含量较高。市售黄芪提取物中的多糖含量可以标准化至10%至90%的定制水平。黄芪的免疫调节作用归因于其多糖,特别是用于癌症治疗中的放疗和化疗患者。在不同的研究中还报道了黄芪多糖具有抗炎、抗肿瘤和肝保护活性。
茯苓(Poria cocos wolf)是多孔菌科的真菌,是在中国赤松树或其它针叶树的根上生长的药用蕈类,在中国常用名称为茯苓(fuling),在日本常用名称为matsuhodo,也被称为hoelen、poria、tuckahoe或中国根。其拉丁语术语已经多次修订,其中Wolfiporiaextensa为当前的植物学名称。茯苓作为TCM的主要成分之一,已被包含在许多即使在今天仍广泛使用的古代汤剂和配方中,如茯苓五配方(fuling five formula)、四君子汤(fourmajor herbs combination)、肉桂和茯苓配方(cinnamon and Fuling formula)等。茯苓的性质包括作为利尿剂、镇静剂和补养剂。茯苓的传统用途包括治疗恶心、呕吐、腹泻、食欲不振、胃溃疡以及失眠和健忘症。已经报道了这种真菌或真菌提取物的许多生物活性,包括抗微生物、抗真菌、抗氧化、神经保护、抗炎、抗血管生成和抗癌功效。通过在脂多糖(LPS)-刺激的RAW 264.7巨噬细胞中NF-κB信号传导途径的失活抑制iNOS、COX-2、IL-1β和TNF-α,证明了茯苓乙醇提取物的抗炎机制。还报道了茯苓对不同细胞因子从人外周血单核细胞的分泌的抑制作用。
茯苓的主要成分是β-葡聚糖形式的多糖(Pachyman),其为干燥真菌子实体的91-98%。已经报道了茯苓多糖的多种生物学功能,如抗氧化、抗高血糖、舒缓胃痛、抗炎、抗癌和免疫调节。报道了多糖在体内和体外针对不同癌系具有抗肿瘤活性。三萜类化合物也被确定为茯苓的活性成分,正在积极研究,主要是研究抗癌、抗炎作用和潜在的免疫活性。尽管茯苓的抗炎机制尚未完全明了,但几项研究已证实了磷脂酶A酶抑制。
茵陈蒿(Artemisia capillaris)根据不同的采收季节具有中文的常用名称“茵陈”或“茵陈蒿”,在韩文中也被称为“yinjin”,是各种古代中国处方集中包含的常用TCM之一。“神农本草经”(草药经典)—关于农业和药用植物的中国书籍—最早记录了茵陈蒿用于治疗黄疸,清除湿气和作为利尿剂。已报道水提取物和乙醇提取物在体外测定和体内动物研究中都具有肝保护效果。已报道儿茶素、香豆素、黄酮类、有机酸、水溶性多糖和多肽作为导致茵陈蒿肝保护活性的活性成分。
肉豆蔻属提取物是可用作目标化合物或组合物的一部分的预期组分或成分。肉豆蔻属提取物可以从任何合适的来源获得,包括M.alba,M.ampliata,M.andamanica,M.arfakensis,M.argentea,M.atrescens,M.basilanica,M.brachypoda,M.brevistipes,M.buchneriana,M.byssacea,M.ceylanicaM.cinnamomea,M.coacta,M.colinridsdalei,M.conspersa,M.corticata,M.crassa,M.dactyloides,M.dasycarpa,M.depressa,M.devogelii,M.elliptica,M.extensa,M.fasciculata,M.filipes,M.fissurata,M.flavovirens,M.frugifera,M.gigantea,M.gillespieana,M.globosa,M.hollrungii,M.inaequalis,M.incredibilis,M.iners,M.inundata,M.irya,M.kalkmanii,M.kjellbergii,M.lasiocarpa,M.leptophylla,M.longipetiolata,M.lowiana,M.macrantha,M.magnifica,M.magnifica,M.maingayi,M.malabarica,M.malabarica,M.maxima,M.mediterranea,M.millepunctata,M.nana,M.olivacea,M.ornata,M.ovicarpa,M.pachycarpidia,M.papillatifolia,M.perlaevis,M.petiolata,M.philippensis,M.pilosella,M.pilosigemma,M.polyantha,M.psilocarpa,M.pubicarpa,M.pygmaea,M.robusta,M.sangowoensis,M.sarcantha,M.schlechteri,M.simulans,M.sinclairii,M.sogeriensis,M.succadanea,M.tamrauensis,M.teijsmannii,M.trianthera,M.ultrabasica,M.verruculosa,M.yunnanensis和其它富含肉豆蔻醚的植物,茴香子(茴芹,Pimpinella vulgare,莽草,八角茴香),欧芹(香芹),小茴香(莳萝),藁本(ligusticum sinense Oliv.and L.jeholense),Queen Anne’s lace(Daucus carota L.subsp.carota),胡萝卜(Daucus carota L.subsp.sativus(Hoffm.)Arcang.)或其任何组合。
在一些实施方案中,预期的肉豆蔻属提取物包含约0.01%至约99.9%的苯丙素或木酚素二聚体和聚合物。在预期的实施方案中,提取物可以通过利用水、乙醇、甲醇、醇、混合水溶剂或其组合来提取。
如所预期的,合适的木酚素包含黄樟素、异肉豆蔻醚、1-(3,4,5-三羟基苯基)-2-丙烯1,2-亚甲基,3-Me醚、峨参树脂醇、4-烯丙基紫丁香醇、峨参树脂醇、3-(3-甲氧基-4,5-亚甲基二氧基苯基)-2-丙烯-1-醇、榄香素、异榄香素、3',4',5'-三甲氧基肉桂醇、3'-甲氧基-4',5'-亚甲基二氧基肉桂醇、甲氧基丁香酚、木兰素A、4,7'-环氧-3,8'-双木质素-7-烯-3',4',5-三醇5-甲醚、奥托肉豆蔻脂素、Cagayanin、Austrobailignan 5、1,2-二氢脱氢愈创木酸、脱氢二异丁香酚、Isodihydrocarinatidin、Isolicarin A、奥托肉豆蔻酚脂素、肉豆蔻木酚素、3',4,4',5-四羟基-3,8'-双木质素-8-烯、愈创木素、二氢愈创木脂酸、5-[3-(4-羟基-3-甲氧基苯基)-1,2-二甲基丙基]-3-甲氧基-1,2-苯二酚、Otobanone、Cagayanone、Zuihonin B、3,4:3',4'-双(亚甲基二氧基)-7,7'-环氧木酚素、羟基奥托肉豆蔻脂素、Isogalcatin、Austrobailignan 7、Machilin F、7-Hydroxyaustrobailignan 5、Saururinol、2-(4-烯丙基-2-甲氧基苯氧基)-1-(4-羟基-3-甲氧基苯基)-1-丙醇、Fragransin A2、Nectandrin B、Myristargenol A、Myristargenol B、2,3-二氢-7-甲氧基-2-(3-甲氧基-4,5-亚甲基二氧基苯基)-3-甲基-5-(1-丙烯基)苯并呋喃、Fragransol C、Fragransol D、2-(4-烯丙基-2,6-二甲氧基苯氧基)-1-(3,4-亚甲基二氧基苯基)-1-丙醇、2-(4-烯丙基-2,6-二甲氧基苯氧基)-1-(4-羟基-3-甲氧基苯基)-1-丙醇、Fragransin C2、Fragransin C3b、Fragransin C3a、Fragransin C1、Fragransol A、Myrisisolignan、2-(4-烯丙基-2,6-二甲氧基苯氧基)-1-(3,4-二甲氧基苯基)-1-丙醇、Fragransin D3、Fragransin D2、Fragransin D1、Virolongin B、2-(4-烯丙基-2,6-二甲氧基苯氧基)-1-(3-羟基-4,5-二甲氧基苯基)-1-丙醇、Fragransin B2、Fragransin B3、Fragransin B1、肉豆蔻衣脂醇B、3,4-亚甲基,3',5'-二甲醚,Ac,2-(4-烯丙基-2,6-二甲氧基苯氧基)-1-(3,4,5-三甲氧基苯基)-1-丙醇、肉豆蔻衣脂醇A、3,4-亚甲基,3',5'-二甲醚,苯甲酰基,Argenteane或其任何组合。
黄芪属提取物是可用作目标化合物或组合物的一部分的预期组分或成分。黄芪属提取物可以从任何合适的来源获得,包括内蒙黄芪(A.mongholius),A.tongolensis,西藏黄芪(A.tibetanus),弯齿黄芪(A.camptodontus),A.aksusis,A.floridus,金翼黄芪(A.chrysopterus),茂汶黄芪(A.maowenensis),A.yunnanensis Franch.,梭果黄芪(A.ernestii Comb),多序岩黄芪(Hedysarum polybotrys),A.pubiflorus,紫花苜蓿(Medicago sativa L.),草木犀(Melilotus suaveolens Ledeb.),白花草木犀(Melilotusalbus Desr.),金雀花(Caragana sinica),蓝花棘豆(Oxytropis caerulea),小花棘豆(Oxytropis glabra),野扁豆(Dunbaria villosa Makino),圆叶锦葵(Malvarotundifolia L.),药用蜀葵(Althaea officinalis)或其任何组合。预期的提取物可以包含0.01%至约100%多糖和约0.01%至约100%三萜类化合物。
在一些实施方案中,预期的三萜类化合物可包含至少一种合适的三萜类化合物,包括Askendoside A,乙酰黄芪苷I,Agroastragaloside I,Agroastragaloside II,Agroastragaloside III,Agroastragaloside IV,Agroastragaloside V,AlexandrosideI,虎刺楤木皂苷I,虎刺楤木皂苷II,梭果黄芪苷A,梭果黄芪苷B,梭果黄芪苷C,Askendoside B,Askendoside C,Askendoside D,Askendoside F,Askendoside G,Askendoside K,Astrachrysoside A,黄芪苷I,黄芪苷II,黄芪苷III,黄芪苷IV,黄芪苷V,黄芪苷VI,黄芪苷VII,黄芪醇,膜荚黄芪苷元,膜荚黄芪苷II,Astramembranoside A,Astramembranoside B,绵毛黄芪总苷I,绵毛黄芪总苷II,绵毛黄芪总苷III,绵毛黄芪总苷IX,绵毛黄芪总苷V,绵毛黄芪总苷XI,绵毛黄芪总苷XII,绵毛黄芪总苷XIII,绵毛黄芪总苷XV,Astraverrucin I,Astraverrucin II,Astraverrucin III,Astraverrucin IV,Astraverrucin V,Astraverrucin VI,Astraverrucin VII,Astrojanoside A,Azukisaponin II,Baibutoside,Bicusposide A,Bicusposide B,Bicusposide C,Bicusposide D,Bicusposide E,Bicusposide F,Brachyoside A,Brachyoside B,Brachyoside C,Caspicuside I,Caspicuside II,Cephalotoside A,Ciceroside A,Ciceroside B,Cloversaponin IV,Complanatin,Cycloadsurgenin,Cycloalpigenin,Cycloalpigenin A,Cycloalpigenin B,Cycloalpigenin C,Cycloalpioside,Cycloalpioside A,Cycloalpioside B,Cycloalpioside C,Cycloalpioside D,Cycloaraloside B,Cycloaraloside C,Cycloaraloside D,Cycloaraloside E,Cycloaraloside F,Cycloascauloside A,Cycloascauloside B,Cycloascidoside A,Cycloasgenin A,Cycloasgenin B,Cycloasgenin C,Cyclocanthogenin,CyclocanthosideA,Cyclocanthoside B,Cyclocanthoside C,Cyclocanthoside D,Cyclocanthoside E,Cyclocanthoside F,Cyclocanthoside G,Cyclocarposide,Cyclocarposide A,Cyclocarposide B,Cyclocarposide C,Cyclocephalogenin,Cyclocephaloside I,Cyclocephaloside II,Cyclochivinoside B,Cyclochivinoside C,Cyclochivinoside D,Cyclodissectoside,Cycloexoside,Cyclogaleginoside A,Cyclogaleginoside B,Cyclogaleginoside D,Cyclogaleginoside E,Cyclogalgeginin,Cycloglobiceposide A,Cycloglobiceposide B,Cycloglobiseposide C,Cyclomacrogenin B,Cyclomacroside A,Cyclomacroside B,Cyclomacroside C,Cyclomacroside D,Cyclomacroside E,Cycloorbicoside A,Cycloorbicoside B,Cycloorbicoside C,Cycloorbicoside D,Cycloorbigenin,Cycloorbigenin A,Cycloorbigenin B,Cycloorbigenin C,Cyclopycnanthogenin,Cyclosieversioside C,Cyclosieversioside H,Cyclosiversioside E,Cyclostipuloside A,Cyclostipuloside B,Cyclotrisectoside,Cyclounifolioside A,Cyclounifolioside B,Cyclounifolioside D,Dasyanthogenin,Dihydrocycloorbigenin A,Elongatoside,Eremophiloside A,Eremophiloside B,Eremophiloside C,Eremophiloside D,Eremophiloside E,Eremophiloside F,remophiloside G,Eremophiloside H,Eremophiloside I,Eremophiloside J,Eremophiloside K,Hareftoside C,Hareftoside D,Hareftoside E,Hispidacin,Huangqiyegenin I,Huangqiyenin A,Huangqiyenin B,Huangqiyenin D,Huangqiyenin E,Huangqiyenin F,Huangqiyenin G,Huangqiyenin H,Huangqiyenin I,Huangqiyenin J,异黄芪皂苷I,异黄芪皂苷II,异黄芪皂苷IV,Isocomplanatin,Kahiricoside I,Kahiricoside II,Kahiricoside III,Kahiricoside IV,Kahiricoside V,Macrophyllosaponin A,Macrophyllosaponin B,Macrophyllosaponin C,Macrophyllosaponin D,Macrophyllosaponin E,Malonylastragaloside I,Mongholicoside A,Mongholicoside B,Mongholicoside I,Mongholicoside II,Oleifolioside A,Oleifolioside B,Orbicoside,Orbigenin,Prusianoside A,Prusianoside B,Quisquagenin,Quisvaloside B,Rubixanthin,almitate,Rubixanthin,Sapogenin A,Sapogenin III,Secomacrogenin B,Sieberoside I,Sieberoside II,Soyasapogenol B,Tomentoside I,Tomentoside II,Trigonoside I,Trigonoside III,Trojanoside A,Trojanoside B,Trojanoside C,Trojanoside D,Trojanoside E,Trojanoside F,Trojanoside I,Trojanoside J,黄芪苷VIII,11-p-Coumaroylnepeticin或其任何组合。
茯苓提取物是可用作目标化合物或组合物的一部分的预期组分或成分。茯苓提取物可以从任何合适的来源获得,包括多孔菌蕈类(polypore mushrooms),巴西菇(Agaricussubrufescens),姬松茸(Agaricus blazei),牛樟菇(Antrodia camphorate),美味牛肝菌(Boletus edulis),Coriolus pargamenus,Coriolus heteromorphus,Crytodermacitrinum,毛柄金钱菌(Flammulina velutiper),红颊拟层孔菌(Formitopsis cytisina),松生拟层孔菌(Formitopsis.pinicola),赤芝(Ganoderma lucidum),紫芝(Ganodermasinense),松杉灵芝(Ganoderma tsugae),Gloephyllum saepiarium,灰树花(Grifolafrondosa),猴头菇(Hericium erinaceus),佩氏亚齿菌(Hydnellumpeckii),香菇(Lentinus edodes),扇形小孔菌(Microporusflabelliformis),可食羊肚菌(Morchellaesculenta),冬虫夏草(Ophiocordyceps sinensi),Piptororus betulinus,白灵侧耳(Pleurotus nebrodensis),猪苓(Polyporus umbellatus),Polyporus tuberaster,茯苓(Poria cocos),裂褶菌(Schizophyllum commune),常见硬皮菌(Skeletocutisvulgaris),偏肿栓菌(Trametes gibbosa),变色栓菌(Trametes versicolor)(采绒革盖菌(Coriolus versicolor)),玉米黑粉菌(Ustilago maydis)或其任何组合。预期的提取物可以包含0.01%至约100%多糖和约0.01%至约100%三萜类化合物。
在一些实施方案中,从茯苓提取物分离的预期的三萜类化合物可以包含至少一种合适的三萜类化合物,包括25-羟基茯苓酸(pachymic acid),25-羟基-3-表土莫酸,16,25-二羟基齿孔酮酸,3,16,25-三羟基-24-亚甲基羊毛甾-7,9(11)-二烯-21-酸,16,25-二羟基脱氢齿孔酸,15-羟基脱氢土莫酸,6-羟基脱氢茯苓酸,3,16,26-三羟基羊毛甾-7,9(11),24-三烯-21-酸,3,4-开环羊毛甾-4(28),7,9(11),24-四烯-3,26-二酸;(24Z)-型孕-7-烯-3,11,15,20-四醇,茯苓酸(Poricoic acid)DM,26-羟基茯苓酸DM,茯苓酸D,茯苓酸CM,茯苓酸C;25-羟基茯苓酸CE,茯苓酸C,茯苓酸BM,茯苓酸B;脱氧茯苓酸B,齿孔二醇,茯苓酸G,茯苓酸GM,茯苓酸A,茯苓酸AM,茯苓酸AE,25-甲氧基茯苓酸A,茯苓酸H,25-羟基茯苓酸H,茯苓酸HM,6,7-脱氢茯苓酸H,脱氢齿孔酮酸,3-羟基羊毛甾-7,9(11),24-三烯-21-酸,5,8-表二氧基-3,16-二羟基-24-亚甲基羊毛甾-6,9(11)-二烯-21-酸,茯苓酸E,Poriacosone A,Poriacosone B,茯苓酸F,29-羟基猪苓酸C,29-羟基脱氢土莫酸,29-羟基脱氢茯苓酸,茯苓酸,乙酰茯苓酸,脱氢茯苓酸,3,16-二羟基-24-亚甲基羊毛甾-7,9(11)-二烯-21-酸;3-O-(4-羟基苯甲酰基),3-表脱氢土莫酸,3-表脱氢茯苓酸,3,16-二羟基羊毛甾-7,9(11),24-三烯-21-酸,16-Hydroxytrametenoic acid,3,16-二羟基羊毛甾-8,24-二烯-21-酸或其任何组合。
蒿属提取物是可用作目标化合物或组合物的一部分的预期组分或成分。蒿属提取物可以从任何合适的来源获得,包括中亚苦蒿(Artemisia absinthium),南木蒿(Artemisia abrotanum L.),非洲蒿(Artemisia afra),黄花蒿(Artemisia annua L),树蒿(Artemisia arborescens),亚细亚蒿(Artemisia asiatica),荒野蒿(Artemisiacampestris),Artemisia deserti,Artemisia iwayomogi,灰蒿(Artemisialudoviciana),北艾(Artemisia vulgaris),Artemisia oelandica,魁蒿(Artemisiaprinceps Pamp),白莲蒿(Artemisia sacrorum),滨蒿(Artemisia scoparia),白蒿(Artemisia stelleriana),冷蒿(Artemisia frigida Willd),莳萝蒿(Artemisiaanethoides Mattf.),碱蒿(Artemisia anethifolia Weber.),Artemisia faurierNakai,牛至(Origanum vulgare),阴行草(Siphenostegia chinensis)或其任何组合。
如本文所预期的,蒿属提取物可富含一种或多种生物聚合物。从蒿属提取物中分离的预期聚合物和生物聚合物用任何合适的溶剂提取,包括水、甲醇、乙醇、醇、水混合溶剂或其组合。在预期的实施方案中,蒿属提取物包含约0.01%至约99.9%具有高于约500g/mol的单独或中值分子量的生物聚合物。在一些预期的实施方案中,蒿属提取物包含约0.01%至约99.9%具有高于约750g/mol的单独或中值分子量的生物聚合物。在其它预期的实施方案中,蒿属提取物包含约0.01%至约99.9%具有高于约1000g/mol的单独或中值分子量的生物聚合物。
五味子(Schisandra chinensis)又名五味子(Wuweizi)和Wurenchum,传统上用于肺和肾虚(lung and kidney insufficiency)的情况。其还适用于慢性咳嗽和呼吸困难,腹泻,盗汗,消瘦疾病,易怒,心悸和失眠的情况,以及治疗与疾病有关的疲劳的一般补养。在现代药物治疗中,越来越多的实验和临床证据表明五味子属提取物的肝保护性质,可防止四氯化碳诱导的肝脏毒性,谷胱甘肽消耗和刺激谷胱甘肽还原酶的活性。五味子属的主要活性成分是称为五味子总素的木酚素,其通过增加参与氧化磷酸化过程的一些酶的活性而具有增能性质,也增加大鼠肝细胞溶质中的超氧化物歧化酶和过氧化氢酶活性,并且能够抑制大鼠肝微粒体中棉子酚诱导的超氧化物阴离子的生成。中文文献报道了五味子果实提取物对肝炎患者的肝脏保护作用,在临床对照试验中,在4周和8周内,使得血清ALT水平提高了68%(72/107)和44%(36/72)。
五味子属提取物是可用作目标化合物或组合物的一部分的预期组分或成分。五味子属提取物可以从任何合适的来源获得,包括五味子(Schisandra chinensis),Schisandra elongate,Schisandra glabra,金山五味子(Schisandra glaucescens),翼梗五味子(Schisandra henryi),Schisandra incarnate,狭叶五味子(Schisandralancifolia),滇藏五味子(Schisandra neglecta),Schisandra nigra,合蕊五味子(Schisandra propinqua),毛脉五味子(Schisandra pubescens),二色五味子(Schisandrarepanda),红花五味子(Schisandra rubriflora),Schisandra rubrifolia,Schisandrasinensis,球蕊五味子(Schisandra sphaerandra),华中五味子(Schisandrasphenanthera),柔毛五味子(Schisandra tomentella),瘤枝五味子(Schisandratuberculata),毛叶五味子(Schisandra vestita),绿叶五味子(Schisandra viridis),鹤庆五味子(Schisandra wilsoniana)或其组合。
如本文所设想的,五味子属提取物可富含一种或多种木酚素和有机酸。预期从五味子属提取物中分离出的木酚素为五味子素,脱氧五味子素,γ-五味子素,伪-γ-五味子素,五味子素B,五味子素C,异五味子素,Pregomisin,eoschizandrin,五味子醇,五味子醇A,五味子醇B,五味子酯A,B,C,D,E,红花五味子酯,五味子酚乙酸酯(Schisanhenolacetdte),五味子酚B,五味子酚,戈米辛A,B,C,D,E,F,G,H,J,N,O,R,S,T,U,表戈米辛O,当归酰戈米辛H,O,Q,T,igloylgomisin H,P,当归酰异戈米辛O,苯甲酰基-戈米辛H,O,P,Q,苯甲酰基-异戈米辛或其组合。预期从五味子属提取物分离的有机酸包括苹果酸、柠檬酸、莽草酸或其组合。
因此,对于实际应用,关注酒精引起的肝脏损伤、一般性疲劳和疲惫,想到了发现具有增强的功效的特殊混合物以保护肝脏以防重复接触氧化应激的想法。历史上,据报道一些植物药物与生物系统中的抗氧化作用有关,充当自由基的清除剂,使其在草药中用于各种人类疾病。在预期的实施方案中,具有历史的肝脏相关功效和安全性数据的植物材料被组合并且被认为对其用于整体肝脏健康的适应症产生了有益的推进。
预期的材料和成分表现出不同程度的抑制作用。肉豆蔻属提取物显得对于对乙酰氨基酚引起的肝脏损伤有较高的保护作用(剂量为400mg/kg时高达94.4%),在较高剂量(即500mg/kg)下,该提取物在四氯化碳诱导的肝脏毒性模型中仅显示37.6%的抑制。类似地,在对乙酰氨基酚模型中,黄芪显示出血清ALT的统计学上非显著的50.6%的抑制,而在四氯化碳诱导的肝脏毒性模型中,证实了血清ALT的统计学上显著的34.1%的减少。另一方面,在四氯化碳诱导的肝脏毒性模型中,五味子属在剂量为400mg/kg时显示出47.6%的血清ALT水平的降低;相反,在较高剂量如500mg/kg时,与载体对照相比,在对乙酰氨基酚诱导的肝脏损伤模型中观察到的抑制作用为41.4%。茯苓和蒿在两种模型中都显示出相似和中等的肝脏保护活性。鉴于对每种植物在单独模型中观察到对这些强的单独表现,将这些植物提取物结合以便在两种模型中都获得更好的结果的想法得到增强。以前的研究证实了具有不同程度肝脏保护能力的单独植物材料肉豆蔻属(“M”)、黄芪属(“A”)、五味子属(“S”)和茯苓(“P”)的抗氧化活性。然而,它们之前从未以特定比率组合在一起以产生称为“MAP”(肉豆蔻属、黄芪属和茯苓)或“MAS”(肉豆蔻属、黄芪属和五味子属)的组合物。
通过使用CCl4诱导的肝脏毒性模型以特定比率,如1:1、1:2、2:1、1:4和4:1开发先导物来最初配制预期的组合物。由于其高度的血清ALT抑制,选择肉豆蔻(Myristicafragrance)作为以CCl4模型中公开的比率与每种植物材料(五味子、茵陈蒿、黄芪或茯苓)配对的主要组分,并且以剂量400mg/kg测试。当肉豆蔻与五味子、茵陈蒿、黄芪或茯苓配制时,在所有比率下都观察到血清ALT的不同程度的统计学显著的抑制,并因此推定肝脏保护作用而免于损伤。尽管当肉豆蔻与蒿配制时观察到最高的血清ALT抑制,但对于肉豆蔻和黄芪的共混物,观察到最低的抑制。
进而,考虑到肉豆蔻的最佳功效阈值,选择具有最低抑制百分比并因此具有低含量肉豆蔻的比率(即,MA=肉豆蔻:黄芪为1:4的比率),并且添加第三组分如茯苓或五味子以产生如先前概述的称为MAP和MAS的组合物。令人惊讶的是,在MA中加入茯苓或五味子在给定比率下引起了血清ALT水平抑制动力学的显著变化。这次对于组合物MAS(通过加入20%重量五味子至1:4比率的MA,剂量为400mg/kg)和组合物MAP(通过加入20%重量茯苓至1:4比率的MA,剂量为400mg/kg),分别在CCl4模型中观察到82.0%和80.8%的抑制。当与相同剂量(400mg/kg)的1:4比率的MA共混物观察到的41.3%抑制作用相比时,MAS(82.0%)和MAP(80.8%)观察到的当前的抑制几乎是两倍,并因此表明组合物的增加的组分对于增强肝脏保护的重要性。这些发现也在APAP诱导的模型中得到了重现。
当配制这三种植物材料(肉豆蔻:黄芪:茯苓或肉豆蔻:黄芪:五味子)的优点被确定时,显然还引人关注的是,由这三种植物材料的组合观察到了意想不到的协同作用,即MAP或MAS组合物治疗所看到的有益效果超过了基于剂量为200mg/kg的给定比率下的其每种成分所观察到的效果的简单加合所预料的结果。
总而言之,应理解的是,将这些传统上众所周知的民间药用植物组合成特定比率以产生MAP或MAS为该组合物提供了新颖性,如其在多种动物模型中的显著的肝脏保护活性所证明的。
在预期的实施方案中,肉豆蔻属提取物和黄芪属提取物以约4:1至约1:4的重量比共混。在其它预期的实施方案中,茯苓提取物进一步与MA混合物以约5至约50%的重量百分比共混。在预期的实施方案中,MAP的比率为约4:16:5。在其它实施方案中,五味子属提取物进一步与MA混合物以约5至约50%的重量百分比共混。在预期的实施方案中,MAS的比率为约4:16:5。
预期的化合物、药物组合物和组合物可包含或另外包含或组成自至少一种肝脏保护剂。在一些实施方案中,所述至少一种肝脏保护剂可以包含以下或由以下组成:奶蓟、姜黄、柴胡、甘草、鼠尾草、桑、枳集、仙鹤草、构棘、lyceum、柑橘、李、黄梅、Korea gim、蒲公英、葡萄、葡萄籽、悬钩子、山茶、绿茶、磷虾油、酵母、大豆的植物粉末或植物提取物;分离和富集的水飞蓟素、黄酮类、磷脂、thios、碧萝芷、明胶、大豆卵磷脂、胰酶;天然或合成的N-乙酰半胱氨酸、牛磺酸、核黄素、烟酸、吡哆醇、叶酸、胡萝卜素、维生素A、维生素B2、B6、B16、维生素C、维生素E、谷胱甘肽、支链氨基酸、硒、铜、锌、锰、辅酶Q10、L-精氨酸、L-谷氨酰胺、磷脂酰胆碱等和/或其组合。
本文还涵盖所公开的化合物的体内代谢产物。这些产物可能由例如所给予的化合物的氧化、还原、水解、酰胺化、酯化等引起,主要是由于酶促过程。因此,所预期的化合物是通过包括将所预期的化合物或组合物给予哺乳动物足以产生其代谢产物的时间的方法产生的那些化合物。通常通过以可检测的剂量将本公开的放射性标记的化合物给予动物(例如大鼠、小鼠、豚鼠、狗、猫、猪、绵羊、马、猴或人),允许足够时间供代谢的发生,然后从尿液、血液或其它生物样品中分离其转化产物,从而鉴定这样的产物。
如本文所用,短语“稳定化合物”和“稳定结构”可互换使用,并用于指示足够稳健以便经受从反应混合物中分离至有用的纯度并经受配制成有效的治疗剂的化合物。
如本文所用,术语“哺乳动物”包括人类和家养和非家养动物,家养动物例如实验室动物或家庭宠物,例如大鼠、小鼠、豚鼠、猫、狗、猪、牛、绵羊、山羊、马、兔、灵长类动物,非家养动物例如野生动物等。
如本文所使用的,术语“任选”或“任选地”可以互换使用,并且意味着随后描述的要素、组件、事件或情况可能发生或可能不发生,并且包括发生所述要素、组件、事件或情况的情形以及它们没有发生的情形。例如,“任选取代的芳基”是指芳基可以被取代或可以不被取代—换句话说,该描述包括取代的芳基和不具有取代基的芳基。
预期的化合物、药物组合物和组合物可以包含或另外包含或组成自至少一种药学上或保健上可接受的载体、稀释剂或赋形剂。
如本文所用,短语“药学上或保健上可接受的载体、稀释剂或赋形剂”包括任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增味剂、表面活性剂、润湿剂、分散剂、悬浮剂、稳定剂、等渗剂、溶剂或乳化剂,其已被美国食品和药物管理局批准为可接受用于人类或家养动物。
预期的化合物、药物组合物和组合物可以包含或另外包含或组成自至少一种药学上或保健上可接受的盐。如本文所用,短语“药学上或保健上可接受的盐”包括酸加成盐和碱加成盐。
如本文所用,短语“药学上或保健上可接受的酸加成盐”是指保留游离碱的生物学有效性和性质的那些盐,其不是在生物学上或其它方面不希望的,并且是与无机酸和有机酸形成的,无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等,有机酸如乙酸、2,2-二氯乙酸、己二酸、海藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯甲酸、4-乙酰胺基苯甲酸、樟脑酸、樟脑-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基乙磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、葡糖酸、葡糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸、乙醇酸、马尿酸、异丁酸、乳酸、乳糖酸、月桂酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、粘酸、萘-1,5-二磺酸、萘-2磺酸、1-羟基-2-萘甲酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、焦谷氨酸、丙酮酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、琥珀酸、酒石酸、硫氰酸、对甲苯磺酸、三氟乙酸、十一碳烯酸等。
如本文所用,短语“药学上或保健上可接受的碱加成盐”是指保留游离酸的生物学有效性和性质的那些盐,其不是在生物学上或其它方面不希望的。这些盐通过向游离酸添加无机碱或有机碱来制备。来源于无机碱的盐包括钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等。在某些实施方案中,无机盐是铵盐、钠盐、钾盐、钙盐或镁盐。来源于有机碱的盐包括以下的盐:伯胺、仲胺和叔胺,包括天然存在的取代胺的取代胺,环胺和碱性离子交换树脂,如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、二甲基乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、普鲁卡因、哈胺、胆碱、甜菜碱、苯乙苄胺、苄星、乙二胺、葡糖胺、甲基葡糖胺、可可碱、三乙醇胺、氨丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。特别有用的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱或咖啡因。
通常结晶产生所预期的化合物的溶剂化物或包括所预期的化合物。如本文所用,术语“溶剂化物”是指包含预期的化合物、药物组合物或组合物的一个或多个分子以及一个或多个溶剂分子的聚集体。溶剂可以是水,在这种情况下溶剂化物可以是水合物。或者,溶剂可以是有机溶剂。因此,所预期的化合物、药物组合物或组合物可作为水合物存在,包括一水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等以及相应的溶剂化形式。所预期的化合物、药物组合物或组合物可以是真溶剂化物,而在其它情况下,预期的化合物、药物组合物或组合物可以仅保留外来的水或者是水和一些外来溶剂的混合物。
“药物组合物”或“保健组合物”是指所预期的化合物、药物组合物或组合物以及本领域通常接受的用于将生物活性化合物递送至哺乳动物(例如人)的介质的制剂。例如,可以将预期的药物化合物、药物组合物或组合物配制成或用作独立组合物,或作为处方药、非处方(OTC)药物、植物药、草药、顺势疗法药物或由政府机构审查和批准的任何其它形式的保健产品中的组分。示例性和预期的保健组合物可以配制成或用作独立组合物,或者作为食物、新型食物、功能性食物、饮料、棒(bar)、食物香料、食物添加剂、药物食品、膳食补充剂或草药产品中的保健或生物活性组分。本领域通常接受的介质包括用于本领域的所有药学上或保健上可接受的载体、稀释剂或赋形剂。
如本文所用,短语“富含”是指植物提取物或其它制备物具有的一种或多种活性化合物的量或活性与所述重量的提取之前的植物材料或其它来源或其它制备物中发现的所述一种或多种活性化合物的量或活性相比增加到至少约2倍直至至多约1000倍。在某些实施方案中,在提取之前的植物材料或其它来源或其它制备物的重量可以是干重、湿重或其组合。
如本文所用,“主要活性成分”或“主要活性组分”是指在植物提取物或其它制备物中发现的或在植物提取物或其它制备物中富集的一种或多种活性预期化合物,其能够产生至少一种生物活性。在某些实施方案中,富集提取物的主要活性成分将是在该提取物中富含的一种或多种活性化合物。通常,与其它提取物组分相比,一种或多种主要活性组分将直接或间接地赋予大部分(即大于50%)的一种或多种可测量的生物活性或效果。在某些实施方案中,根据提取物重量百分比的主要活性成分可以是较少组分(例如,在提取物中所含的小于约50%,25%,20%,15%,10%,5%或1%的组分),但仍提供大部分所需的生物活性。任何包含主要活性成分的预期组合物还可以含有次要活性成分,其可以或可以不有助于富集组合物的药物或保健活性,但没有达到主要活性组分的水平,并且仅次要活性成分在没有主要活性成分的情况下可能不是有效的。
如本文所用,短语“有效量”或“治疗有效量”是指所预期的化合物、药物组合物或组合物的量,在给予哺乳动物例如人时,所述量足以实现治疗,包括以下任何一项或多项:(1)治疗或预防哺乳动物肝细胞的损伤;(2)促进肝脏健康;(3)保护哺乳动物的解毒和抗氧化肝酶;(4)增加哺乳动物的肝脏解毒能力;(5)治疗或预防哺乳动物的肝脏疾病;(6)减轻哺乳动物肝脏的炎症;和(7)改善肝脏更新功能。构成“治疗有效量”的预期化合物、药物组合物或组合物的量将根据化合物、所治疗的病症及其严重程度、给予方式、治疗持续时间或治疗对象的体重和年龄而变化,但是可以由本领域的普通技术人员根据其自己的知识和本公开来确定。
本文使用的“补充剂”是指改善、促进、支持、增加、调节、管理、控制、维持、优化、修饰、减少、抑制或防止与天然状态或生物过程相关的特定状况、结构或功能的产品(即不用于诊断、治疗、减轻、治愈或预防疾病)。在某些实施方案中,补充剂是膳食补充剂。例如,对于与肝脏健康有关的疾病,膳食补充剂可以用于维持肝功能,最大限度地减少肝细胞损伤,通过保护抗氧化完整性来促进健康的肝脏,减少影响肝脏健康的自由基的作用,改善肝脏解毒能力和/或功能,支持肝功能,缓解肝脏疼痛,缓解肝脏不适,减轻脂肪肝,改善肝脏解毒能力,改善肝脏免疫功能,改善肝脏更新功能等。在某些实施方案中,膳食补充剂是特殊类别的膳食、食物或两者,并且不是药物。
术语“治疗的”或“治疗”或“改善”可以互换使用,并且指的是对患有或怀疑患有关注的疾病或病症的哺乳动物(例如人)的关注的疾病或病症进行治疗性治疗或预防的/预防性治疗,并且包括:(i)预防哺乳动物中发生疾病或病症,特别是当这种哺乳动物易患该病症但尚未诊断出患有该病症时;(ii)抑制疾病或病症,即阻止其发展;(iii)缓解疾病或病症,即导致疾病或病症消退;或(iv)在不解决潜在疾病或病症的情况下减轻由疾病或病症引起的症状(例如缓解疼痛,减轻炎症,减少解毒能力的丧失)。
如本文所用,术语“疾病”和“病症”可以互换使用,或者可以是不同的,不同之处在于特定的病情或病症可能不具有已知的病因因素(因此病因还没有得出),因此尚未被认为是疾病,而只认为是不良的病症或综合征,其中临床医师已经确定了差不多特定组的症状。在某些实施方案中,所预期的化合物、药物组合物、组合物和方法用于治疗例如肝炎、酒精肝病、硬化或两者。
如本文所用,“统计显著性”是指使用Students t检验计算的0.050或更小的p值,并且表示特定事件或测量结果不太可能是偶然发生的。
本文使用的化学命名协议和任何结构图是I.U.P.A.C.命名系统的修改形式,使用ACD/Name Version 9.07软件程序或ChemDraw Ultra Version 11.0软件命名程序(CambridgeSoft),其中本公开的化合物在本文中被命名为中心核心结构,例如咪唑并吡啶结构的衍生物。对于本文所用的复杂化学名称,取代基在其连接的基团之前被命名。例如,环丙基乙基包含具有环丙基取代基的乙基骨架。
在某些实施方案中,预期的化合物和组合物(例如药物的、保健的)可以一定量给予,所述量足以促进肝脏健康;改善肝脏健康;保持肝脏健康;治疗或管理肝脏健康;支持肝脏健康;支持正常和舒适范围的肝脏解毒功能;提高肝脏的自由基清除能力;减少由化学品、药物、代谢物和生物毒素衍生的有害自由基的损害;保护影响肝脏健康的酶,防止由于乙型肝炎/丙型肝炎病毒感染、饮酒、代谢紊乱、非酒精性脂肪肝疾病(NAFLD)、非酒精性脂肪性肝炎(NASH)、酒精肝病、肝性脑病、肝纤维增殖性疾病(肝纤维化)、缺氧/复氧期间的肝细胞损伤或其任何组合引起的肝脏损伤造成的慢性氧化应激;或本文所述的任何其它相关适应症,并且通常对患者具有可接受的毒性。
在某些其它实施方案中,本公开的化合物和组合物(例如药物的、保健的)可以一定量给予,所述量足以治疗肝炎、酒精肝病、脂肪肝病、硬化、纤维化、代谢综合征、肝衰竭、肝细胞癌、原发性胆汁性肝硬化或任何其它相关适应症,并且通常对患者具有可接受的毒性。
所预期的化合物、药物组合物或组合物或其药学上或保健上可接受的盐以纯形式或在合适的药物或保健组合物中的给予可以通过用于提供类似用途的药物的任何接受的给予模式来进行。预期的药物或保健组合物可以通过将所预期的化合物与合适的药学上或保健上可接受的载体、稀释剂或赋形剂组合来制备,并且可以配制成固体、半固体、液体或气体形式的制剂,例如片剂、胶囊剂、粉末、颗粒剂、软膏剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球剂和气雾剂。给予此类药物或保健组合物的典型途径包括口服、局部、透皮、吸入、肠胃外、舌下、口腔、直肠、阴道或鼻内。
在一些实施方案中,预期的药物或保健制剂包含约0.5重量%至约90重量%的提取物混合物的活性成分。在一些实施方案中,预期的组合物以约0.01至约500mg/kg人或动物的体重的剂量给予。
如本文所用,术语“肠胃外”包括皮下注射、静脉内、肌内、胸骨内注射或输注技术。预期的药物或保健组合物被配制成使得其中包含的活性成分在组合物给予患者时或之后不久是生物可利用的。在一些实施方案中,所预期的组合物和化合物可以被设计或配制成使得它们可以在给予后择时释放。
在某些实施方案中,所预期的组合物以一个或多个剂量单位的形式给予受试者或患者,其中例如片剂可以是单剂量单位,并且气雾剂形式的预期化合物的容器可以容纳多个剂量单位。制备这种剂型的实际方法对于本领域技术人员来说是已知的或将是显而易见的;例如,参见Remington:The Science and Practice ofPharmacy,20th Edition(Philadelphia College of Pharmacy and Science,2000)。根据本公开内容的教导,待给予的预期组合物在任何情况下都将含有治疗有效量的预期化合物或其药学上或保健上可接受的盐,用于治疗关注的疾病或病症。
预期的药物或保健组合物可以是固体或液体形式。在一个方面,载体是颗粒状的,使得组合物例如呈片剂或粉末形式。载体可以是液体,其中组合物是例如口服糖浆、可注射液体或气雾剂,其可用于例如吸入给予。
当意图用于口服给予时,药物或保健组合物为固体或液体形式,其中半固体、半液体、悬浮液和凝胶形式被包括在本文认为是固体或液体的形式内。
作为用于口服给予的固体组合物,药物或保健组合物可以配制成粉末、颗粒剂、压片剂、丸剂、胶囊剂、口香糖、干胶片、棒或类似形式。这种固体组合物通常将含有一种或多种惰性稀释剂或可食用载体。另外,可以存在一种或多种以下物质:粘合剂,例如羧甲基纤维素、乙基纤维素、环糊精、微晶纤维素、黄蓍胶或明胶;赋形剂,如淀粉、乳糖或糊精;崩解剂,如海藻酸、海藻酸钠、玉米淀粉等;润滑剂,如硬脂酸镁或/>助流剂,如胶体二氧化硅;甜味剂,如蔗糖或糖精;调味剂,如薄荷、水杨酸甲酯或橙味调味剂;和着色剂。
当药物或保健组合物为胶囊形式,例如明胶胶囊时,除了上述类型的材料外,其还可以含有液体载体如聚乙二醇或油。
预期的药物或保健组合物可以是液体形式,例如酏剂、糖浆、凝胶、溶液、乳剂或混悬剂。作为两个例子,液体可以用于口服给予或通过注射递送。当用于口服给予时,除了本发明化合物之外,有用的组合物还含有甜味剂、防腐剂、染料/着色剂和增味剂的一种或多种。在意欲通过注射给予的组合物中,可以包括表面活性剂、防腐剂、润湿剂、分散剂、悬浮剂、缓冲剂、稳定剂和等渗剂中的一种或多种。
所预期的液体药物或保健组合物,无论它们是溶液、悬浮液还是其它类似形式,可以包括一种或多种以下佐剂:无菌稀释剂,例如注射用水,盐水溶液,诸如生理盐水、林格氏溶液、等渗氯化钠,可用作溶剂或悬浮介质的固定油,例如合成的甘油单酯或甘油二酯,聚乙二醇,甘油,丙二醇或其它溶剂;抗菌剂,如苯甲醇或对羟基苯甲酸甲酯;抗氧化剂,如抗坏血酸或亚硫酸氢钠;螯合剂,如乙二胺四乙酸;缓冲剂,如乙酸盐,柠檬酸盐或磷酸盐;以及调节张力的试剂,如氯化钠或葡萄糖。肠胃外制剂可以封装在安瓿、一次性注射器或由玻璃或塑料制成的多剂量小瓶中。生理盐水是通常有用的佐剂。可注射的药物或保健组合物是无菌的。
意图用于肠胃外或口服给予的预期的液体药物或保健组合物应包含一定量的预期化合物、药物组合物或组合物,以便获得合适的剂量。
预期的药物或保健组合物可以意图用于局部给予,在这种情况下,载体可以适当地包含溶液、乳液、乳膏、洗剂、软膏或凝胶基质。例如,所述基质可以包含以下一种或多种:凡士林、羊毛脂、聚乙二醇、蜂蜡、矿物油、例如水和醇的稀释剂,以及乳化剂和稳定剂。增稠剂可以存在于用于局部给予的药物或保健组合物中。如果打算用于透皮给予,组合物可以包括透皮贴剂或离子电渗装置。
预期的药物或保健组合物可以意图用于直肠给予,例如以栓剂的形式给予,其将在直肠中熔化并释放药物。用于直肠给予的组合物可以含有作为合适的非刺激性赋形剂的油性基质。这种基质包括羊毛脂、可可脂和聚乙二醇。
预期的药物或保健组合物可以包括改变固体或液体剂量单位的物理形式的各种材料。例如,组合物可以包括在活性成分周围形成包衣壳的材料。形成包衣壳的材料通常是惰性的,并且可以选自例如糖、虫胶和其它肠溶包衣剂。或者,可将活性成分装入明胶胶囊中。
所预期的固体或液体形式的药物或保健组合物可以包括与所预期的化合物结合从而有助于递送化合物的试剂。可以这种能力起作用的合适试剂包括单克隆或多克隆抗体、蛋白质或脂质体。
所预期的固体或液体形式的药物或保健组合物可以包括减小颗粒的尺寸以例如改善生物利用度。在有或没有赋形剂的情况下,组合物中的粉末、颗粒、微粒、微球等的尺寸可以是宏观的(例如,对眼睛可见或尺寸至少为100μm),微米级的(例如可以是范围从约100μm到约100nm的尺寸),纳米级的(例如,可以是不大于100nm的尺寸)以及在它们之间的任何尺寸或其任何组合以改善尺寸和堆密度。
预期的药物或保健组合物可以包含或组成自可以作为气雾剂给予的剂量单位。术语气雾剂用于表示从胶体性质的系统到由加压包装组成的系统的各种系统。可通过液化或压缩气体或通过分配活性成分的合适的泵系统进行递送。本公开化合物的气雾剂可以以单相、双相或三相系统递送以递送活性成分。气雾剂的递送包括必要的容器、活化剂、阀门、亚容器等,它们一起可以形成套件。本领域技术人员在没有过度实验的情况下可以确定最合适的气雾剂。
预期的药物或保健组合物可以通过药学或保健领域众所周知的方法制备。例如,意图通过注射给予的药物或保健组合物可以通过将所预期的化合物与无菌蒸馏水组合以形成溶液来制备。可加入表面活性剂以促进形成均匀溶液或悬浮液。表面活性剂是与所预期的化合物非共价相互作用,以促进化合物在水性递送系统中的溶解或均匀悬浮的化合物。
预期的化合物、组合物和药物组合物或其药学上或保健上可接受的盐以治疗有效量给予,所述治疗有效量将根据多种因素而变化,包括所使用的具体化合物的活性;化合物的代谢稳定性和作用时间长度;患者的年龄、体重、一般健康状况、性别和饮食;给予的方式和时间;排泄率;药物组合;特定疾病或病症的严重程度;和受试者正在接受的治疗。
预期的化合物、组合物和药物组合物或其药学上或保健上可接受的衍生物也可以与一种或多种其它治疗剂的给予同时给予,或在一种或多种其它治疗剂的给予之前或之后给予。此类组合疗法包括给予含有预期的化合物和一种或多种另外的活性剂的单一药物或保健剂量制剂,以及以其自身分开的药物或保健剂量制剂给予预期的化合物和每种活性剂。例如,所预期的化合物和另一种活性剂可以以单一口服剂量组合物(例如片剂或胶囊)一起给予患者,或者每种药物可以以分开的口服剂量制剂给予。当使用分开的剂量制剂时,所预期的化合物和一种或多种另外的活性剂可在基本上相同的时间给予,即同时给予,或者在分开的交错时间给予,即依次给予;组合疗法被理解为包括所有这些方案。
应该理解的是,在本说明书中,只有当这样的贡献产生稳定的化合物时,所描述的式的取代基或变量的组合才是允许的。
本领域技术人员还应该理解的是,在本文所述的方法中,中间体化合物的官能团可能需要被合适的保护基团保护。这种官能团包括羟基、氨基、巯基和羧酸。适用于羟基的保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。氨基、脒基和胍基的合适保护基包括叔丁氧基羰基、苄氧基羰基等。适用于巯基的保护基包括C(O)R”(其中R”是烷基、芳基或芳基烷基)、对甲氧基苄基、三苯甲基等。羧酸的合适保护基包括烷基、芳基或芳基烷基酯。保护基可以根据本领域技术人员已知的和本文所述的标准技术添加或去除。“Green,T.W.and P.G.M.Wutz,Protective Groups in Organic Synthesis(1999),3rd Ed.,Wiley”中详细描述了保护基的使用,其全部内容通过引用并入本文。如本领域技术人员将理解的,保护基还可以是聚合物树脂,例如Wang树脂、Rink树脂或2-氯三苯甲基氯树脂。
本领域技术人员还会理解,尽管所预期的化合物的这种被保护的衍生物本身可能不具有药理学活性,但它们可以被给予哺乳动物,然后在体内代谢以形成具有药理活性的化合物。因此这些衍生物可以被描述为“前药”。所预期的化合物的所有前药都包括在本公开的范围内。
此外,通过本领域技术人员已知的方法,通过用合适的无机或有机碱或酸处理,可以将以游离碱或酸形式存在的预期化合物转化为其药学上或保健上可接受的盐。所预期的化合物的盐可以通过标准技术转化为它们的游离碱或酸形式。
在一些实施方案中,所预期的化合物、组合物和/或药物组合物可以从植物来源分离,例如从实施例中和整个本申请的其它地方包括的那些植物分离。用于分离预期提取物和化合物的合适的植物部分包括叶、树皮、树干、树干树皮、茎、茎皮、枝条、块茎、根、根皮、树皮表面(如周皮或复周皮,可包括木栓、木栓形成层、栓内层或其任何组合)、嫩枝、根茎、种子、果实、雄蕊群、雌蕊、花萼、雄蕊、花瓣、萼片、心皮(雌蕊)、花或其任何组合。预期的植物提取物源自选自以下的至少一种植物部分:茎、茎皮、树干、树干树皮、枝条、块茎、根、根皮、嫩枝、种子、根茎、花和其它生殖器官、叶、其它气生部分或其组合。在一些相关的实施方案中,预期的化合物从植物来源分离并合成修饰以包含任何所述的取代基。就这一点而言,从植物中分离的预期化合物的合成修饰可以使用本领域已知的并且完全在本领域普通技术人员的知识范围内的任何数量的技术来完成。
实施例
实施例1:动物
从Charles River Laboratories(Wilmington,MA)购买体重为25-30g的7-8周龄目的培育小鼠。动物在抵达后适应一周,然后被称重并随机分配到它们各自的组。将ICR小鼠(5只/笼)置于聚丙烯笼中,并通过其尾部上的数字分别识别。每个笼子都覆盖着金属丝栏盖和过滤顶部(wire bar lid and filtered top)(Allentown,NJ)。每个单独的笼子都用笼子卡片识别,笼子卡片表明项目编号、测试物品、剂量水平、组别和动物编号。使用Harlan T7087软玉米穗轴基床(soft cob bedding),每周更换至少两次。向动物随意提供新鲜水和啮齿动物食物#T2018(Harlan Teklad,370W,Kent,WA),并且将动物容纳在12小时光暗循环的温度控制室(22.2℃)中。所有的动物实验均根据规定的指南进行,并与实验动物的护理和使用指南一致。
实施例2:对乙酰氨基酚(APAP)或四氯化碳(CCL4)诱导的肝脏损伤动物模型如下产生和优化平衡的治疗方案,以解决预防和干预:对于APAP诱导的肝脏毒性模型,将400mg/kg剂量的溶于温盐水(Lot#132908来自G-Biosciences,Lot#720729来自QualityBiological)(加热至60℃并冷却至环境温度)中的APAP(Lot#MKBQ8028V,来自Sigma)口服给予过夜禁食的ICR/CD-1小鼠以诱导毒性。对于CCl4诱导的肝脏毒性模型,将25μl/kg剂量的溶于玉米油中的CCl4(Lot#SHBD5351V,来自Sigma)腹膜内给予过夜禁食的ICR/CD-1小鼠以诱导毒性。对于这两种模型,在APAP或CCl4给予之前的-48hr,-24hr,-2hr以及诱导后+6hr给予材料。总的来说,小鼠在化学诱导前接受3次剂量,化学诱导后接受1次剂量。使用10%吐温-20(Lot#0134C141,来自Amresco)、1%CMC(Lot#NH0454,来自Spectra)或1%MC(Lot#SLBK4357V)作为所有材料的载体媒介物。没有APAP或CCl4的对照小鼠仅接受载体媒介物。在T24(Phoenix Laboratories,Everett,WA)测定血清ALT。
实施例3:有机提取物的制备和肝保护功效的筛选
收集植物并根据其活性化合物性质用不同的溶剂制备,并在我们的小鼠肝脏毒性动物模型中筛选。表1中的以下植物显示了在小鼠的对乙酰氨基酚诱导的模型或CCl4诱导的模型中不同水平的血清ALT抑制。只有在两种模型中都具有功效的植物将被选择用于进一步研究。
表1:植物提取物的总结
实施例4:植物提取物对APAP和CCL4-诱导的肝脏毒性模型的肝脏保护活性
基于其对肝脏保护和更新的历史用途而被收集的来自遗产挖掘(legacy mining)的植物材料使用70%乙醇提取,并筛选其在APAP和CCl4诱导的肝脏毒性中的功效。材料以表2中规定的剂量口服给予动物。如下表所示,当用公开剂量的提取物治疗小鼠时,观察到不同程度的血清ALT的抑制和显著性。对肉豆蔻提取物和五味子提取物分别观察到最高抑制率,APAP模型中为94.4%,CCl4模型中为47.6%。
表2:在APAP/CCl4诱导的肝脏毒性模型中植物提取物的血清ALT的抑制百分比
虽然对于其它提取物在两种模型中都观察到非常相似水平的抑制,但在所汇编的植物材料中,野葛和赤芝的功效主要限于CCl4模型并且在APAP模型中没有显示百分比或显著性的重现性。特别是,无论显著性如何,在任一模型中具有大于或等于30%抑制率的提取物都进行进一步评估。
实施例5:黄芪和茯苓提取物的制备
可将研磨的黄芪根粉末用水提取,得到水提取物,规格为用紫外比色法测得不低于20%的多糖,用HPLC法测得不低于0.3%的黄芪苷。用甲醇或乙醇代替该溶剂以分别提供甲醇提取物(ME)或乙醇提取物(EE),乙醇:H2O(7:3)提取物,乙醇:H2O(1:1)提取物和乙醇:H2O(3:7)提取物,得到了类似的结果。
首先用乙醇然后用水提取茯苓的干燥研磨的果实体,以提取非极性组分和极性组分。将乙醇提取物和水提取物合并在一起,得到最终的茯苓提取物,规格为通过UV比色法测得不少于20%多糖,通过HPLC或比色法测得不少于10%的三萜类化合物。用甲醇或乙醇代替该溶剂以分别提供甲醇提取物(ME)或乙醇提取物(EE),乙醇:H2O(7:3)提取物,乙醇:H2O(1:1)提取物,乙醇:H2O(3:7)提取物和水提取物,得到了类似的结果。
实施例6:茵陈蒿有机提取物的制备
将干燥研磨的气生部分茵陈蒿(2.5kg)切割、粉碎,然后用约15倍体积(37.5L)的70%乙醇/水(v/v)提取。提取在85℃进行3小时。过滤后,将乙醇溶液在40℃真空下通过旋转蒸发器浓缩。用10倍体积(25L)的70%乙醇/水(v/v)重复该提取和浓缩程序两次,历时2小时。通过真空干燥箱将浓缩的提取物溶液蒸发至干燥,得到480g茵陈蒿70%乙醇提取物粉末(lot#RN367-3-60M),提取产率为19.2%。
干燥的研磨的茵陈蒿草药(180.4)g用70%乙醇/水提取三次,每次回流1小时。将有机溶液合并并真空蒸发以提供37.7g的70%乙醇提取物(R594-70EE),产率为20.9%。使用相同的程序获得类似的结果,但用甲醇或乙醇代替该有机溶剂以分别提供甲醇提取物(ME)或乙醇提取物(EE),乙醇:H2O(7:3)提取物,乙醇:H2O(1:1)提取物,乙醇:H2O(3:7)提取物和水提取物。
实施例7:五味子果实的有机提取物的制备
将总计20g五味子干燥果实装入两个100ml不锈钢管中,并使用ASE 300自动提取器在80度和1500psi压力下用有机70%EtOH/水提取两次。提取溶液自动过滤和收集。通过旋转蒸发器将合并的溶液蒸发至干燥,得到粗制70%EtOH提取物(9.65g,49.5%)。
使用相同的程序获得类似的结果,但用甲醇或乙醇代替该有机溶剂以分别提供甲醇提取物(ME)或乙醇提取物(EE),乙醇:H2O(7:3)提取物,乙醇:H2O(1:1)提取物,乙醇:H2O(3:7)提取物和水提取物。
用70%乙醇/30%水(v/v)提取干燥果实制备五味子提取物。进一步处理提取物以得到粉末形式(Lot#)提取物,具有不少于2%总五味子素,包括五味子素、schisantherinA、五味子素A(脱氧五味子素)和五味子素B。
实施例8:五味子提取物的HPLC分析和定量
五味子果实用水提取。过滤后,通过喷雾干燥将水溶液进一步浓缩至干燥。将坚果干燥并研磨成粉末并用乙醇提取。将乙醇溶液过滤、浓缩,并在与麦芽糖糊精混合后通过喷雾干燥进一步干燥。将水提取物和乙醇提取物共混在一起,制备最终的五味子提取物,含7.1%的总五味子素,包括五味子素、schisantherinA、五味子素A(脱氧五味子素)和五味子素B。
四种活性标志化合物五味子素(lot#110857,National institute for food andcontrol,china)、schisantherin A(lot#11529-200503,National institute for foodand control,china)、五味子素A(脱氧五味子素,lot#110764-200107,Nationalinstitute for food and control,china)和五味子素B(lot#110765-200508,Nationalinstitute for food and control,china)在五味子提取物中被鉴别,并用五味子参考标准材料确证(lot#140217,National Institute for Food and Control,China)。
通过HPLC来定量活性标志化合物,在Hitachi HPLC系统中使用C18反相柱(Phenomenex,Luna C18,10μm,250mm x 4.6mm),采用250nm的UV波长,通过与参考标准材料比较来进行。用水和乙腈以1mL/min的流速洗脱柱子。表3显示了该实施例的梯度表。对各个峰进行鉴定和积分,然后基于RSM计算四种化合物的总含量,包括五味子素、schisantherinA、五味子素A和五味子素B,该信息如表4所示。可见五味子果实提取物中的总五味子素范围为1-8%。
表3:五味子提取物定量的HPLC流动相梯度表
时间(min) | H2O(%) | MeOH(%) |
0 | 35 | 65 |
20 | 32 | 68 |
21 | 25 | 75 |
36 | 25 | 75 |
37 | 35 | 65 |
45 | 35 | 65 |
表4:五味子提取物中的五味子素的含量
实施例9:五味子果实提取物中有机酸的HPLC定量
由不同收集品在内部产生的70%EtOH提取物中苹果酸、莽草酸和柠檬酸的存在已经被证实并列于表5中。通过HPLC定量分析有机酸,使用Hypersil GOLD aQ柱(4.6x250mm,5μm)在等度条件下在5℃进行20分钟,用50mM磷酸二氢钾(用H3PO4将pH调节至2.8)作为流动相,流速为0.7ml/min。使用UV检测器在205nm处检测有机酸,并通过与有机酸标准品比较基于保留时间鉴定。
表5:五味子提取物中有机酸含量的HPLC定量
实施例10:肉豆蔻提取物的制备
干燥研磨的肉豆蔻种子(304g)用70%乙醇/水回流提取三次,每次1小时。将有机溶液合并并真空蒸发,提供46.3g的70%乙醇提取物(R603-70E),产率为15.2%。使用相同的程序获得类似的结果,但用甲醇或乙醇代替该有机溶剂以分别提供甲醇提取物(ME)或乙醇提取物(EE),乙醇:H2O(7:3)提取物,乙醇:H2O(1:1)提取物,乙醇:H2O(3:7)提取物和水提取物。
实施例11:肉豆蔻提取物的HPLC分析和定量
肉豆蔻醚是报道的来自肉豆蔻的具有肝脏保护性质的maceligan化合物。通过HPLC定量肉豆蔻醚(15201,Cayman,USA)来分析肉豆蔻提取物,在Hitachi HPLC系统中使用C18反相柱(Phenomenex,Luna C18,10μm,250mm x 4.6mm)。使用在18分钟内由40%MeOH/水至100%MeOH的梯度洗脱来洗脱柱子,流速为1mL/min,使用250nm的UV波长。将肉豆蔻种子提取物以10mg/mL的浓度溶解于MeOH中,并通过注射20μL溶液进行分析。70%乙醇提取物中的肉豆蔻醚含量范围为2%至6%。在水提取物(L530-WE)中不能检测到明显的肉豆蔻醚峰。在CCl4诱导的肝脏毒性小鼠模型中测试了70%乙醇提取物和水提取物。水提取物和70%乙醇提取物均显示出400mg/kg下的肝脏保护活性,水提取物的抑制率为32.63%,70%乙醇提取物的抑制率为95.61%。表6显示肉豆蔻提取物中的肉豆蔻醚含量和体内数据。
表6:肉豆蔻提取物中的肉豆蔻醚含量和体内数据
样品名 | 肉豆蔻醚含量 | 剂量(mg/kg)ALT%变化 | p值 |
L530-WE | ND | 40032.63 | 0.060 |
L532-70E | 2.07% | 40095.61 | 0.000 |
R603-70E | 5.92% | 20099.50 | 0.000 |
*ND-未检测到
实施例12:肉豆蔻提取物的分离
将肉豆蔻70%乙醇提取物(R603-70E,10g)在己烷(100mL)和水(150mL)之间分配三次。合并的己烷溶液通过真空除去溶剂,得到己烷提取物(HE)5.6g。水层用乙酸乙酯(100mL)提取三次。将合并的乙酸乙酯层真空干燥,得到乙酸乙酯提取物(EA)1.3g。用丁醇(100mL)进一步提取水层三次,得到丁醇提取物(BU)0.7g。将剩余的水层冷冻干燥,得到水提取物(WA)2.3g。通过HPLC进一步分析HE、EA、BU和WA,并在CCl4诱导的小鼠肝脏毒性模型中进行测试。
肉豆蔻醚主要发现于HE中,在EA、BU和WA中未检测到。在相同的模型中测试肉豆蔻醚(15201,Cayman,USA),并且显示出强效的功效,在50mg/kg下产生99.7%的ALT抑制。含有高达27.5%肉豆蔻醚的HE表现出类似的抑制作用,与50mg/kg剂量的肉豆蔻醚相比,在200mg/kg水平下,其具有95.3%的ALT水平降低,P≤0.01,表明肉豆蔻醚是造成粗提取物的肝脏保护功效的主要活性化合物之一。在相同剂量200mg/kg下,发现EA、BU和WA在该CCl4模型中无活性。表7显示肉豆蔻分配级分的肉豆蔻醚含量和体内功效。
表7:肉豆蔻分配级分的肉豆蔻醚含量和体内功效
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*ND-未检测到
实施例13:肉豆蔻提取物及其级分在CCl4诱导的肝脏毒性模型中的剂量反应效果利用CCl4诱导的肝脏毒性模型评估肉豆蔻及其级分的剂量相关性肝脏保护活性。尽管在200mg/kg的剂量下测试每个级分,但选择50-200mg/kg剂量范围进行剂量反应研究。在这项研究中,还测试了剂量为50mg/kg的可能的活性标志物肉豆蔻醚。如下表8所示,对于用50-200mg/kg肉豆蔻治疗的小鼠观察到明显的剂量相关性抑制(即,44.8-99.5%抑制)。当以200mg/kg的剂量用肉豆蔻治疗小鼠时,观察到由四氯化碳引起的肝脏损伤几乎完全抑制。这些数据表明,为了发生血清ALT的50%抑制,小鼠可能需要用肉豆蔻以50-75mg/kg的剂量水平治疗。
虽然在该模型中丁醇、乙醇和水提取物级分是无活性的,但与媒介物治疗的损伤小鼠相比时,用己烷提取物部分治疗的小鼠显示血清ALT的95.3%的抑制。
表8:肉豆蔻及其级分在CCL4诱导的肝脏毒性模型中的剂量相关性肝脏保护作用
当与媒介物治疗的受损小鼠相比,用50mg/kg的肉豆蔻醚治疗的小鼠显示血清ALT的99.7%的抑制,证实肉豆蔻醚可能是肉豆蔻中的主要活性化合物。
实施例14:肉豆蔻提取物与五味子、茵陈蒿、黄芪或茯苓在CCl4诱导的肝脏毒性模型中的肝脏保护活性
证明了先导植物的单独的肝脏保护数据,通过以特定的比率如1:1、1:2、2:1、1:4和4:1将它们配制,开始寻求对这些植物材料采用不可预料的共混所得的意外或增强的结果。由于其抑制程度最高,选择肉豆蔻作为主要组分,与每种植物材料配对成指定比率用于CCL4模型中,并以400mg/kg的剂量进行测试。如下表9所示,当肉豆蔻与五味子、茵陈蒿、黄芪或茯苓配制时,对于所有比率都观察到血清ALT的统计学上显著的抑制并因此推定针对四氯化碳诱导的损伤的肝脏保护作用。当肉豆蔻与五味子、黄芪、茵陈蒿和茯苓共混时,抑制范围分别为42.4-70.0%、41.3-80.7%、88.8-99.8%和91.0-99.8%。当肉豆蔻与茵陈蒿(2:1和4:1)和茯苓(1:1)共混时观察到最高的肝脏保护活性;当肉豆蔻与黄芪以1:1的比率配制时观察到最低的肝脏保护活性。
表9:与五味子、黄芪、茵陈蒿或茯苓共混的肉豆蔻组合物在CCL4诱导的肝脏毒性模型中的功效
实施例15:特定比率的肉豆蔻提取物与五味子、茵陈蒿、黄芪或茯苓在CCl4诱导的肝脏毒性模型中的肝脏保护活性的评估鉴于肉豆蔻与黄芪以1:4比率配制导致血清ALT的最低抑制(即,41.3%)的事实,选择第三种成分(五味子或茯苓)以相对于400mg/kg的总剂量的10%重量或20%重量加入,并评估CCL4和APAP诱导的肝脏毒性模型中肝脏保护活性的反应变化。“MA”分别代表肉豆蔻和黄芪1:4比率的组合物。如下表10所示,事实上,五味子或茯苓的添加引起给定比率下的血清ALT水平抑制动力学的显著变化。这次在CCL4模型中观察到的抑制作用对于组合物MAS2(通过加入20%五味子)和组合物MAP2(通过加入20%茯苓)分别为82.0%和80.8%。当与肉豆蔻仅和黄芪(MA)的1:4比率共混物所观察到的41.3%抑制作用相比时,MAS2和MAP2观察到的当前的抑制几乎是两倍,因此表明组合物的添加的组分对于增强肝脏保护的重要性。另一方面,无论添加到组合物MA中以产生MAS的五味子的百分比(10%或20%),在APAP诱导的肝脏毒性模型中观察到超过90%的血清ALT抑制。当茯苓以20%重量加入到MA中以产生MAP时,也同样产生了这些更大的抑制作用,即在APAP模型中92.7%。
这些收集的数据表明,尽管多种组合物显示出保护肝脏的功效,可以实现不可预料的增强的肝脏保护活性,当20%重量的茯苓或五味子提取物添加到两种模型中1M:4A的比率中产生对于组合物MAP或MAS最终的4m:16A:5p或4m:16A:5s的比率时,观察到最高的保护作用。结果,该比率4:16:5被认为是先导组合物。通过以上述特定比率组合三种历史上公知的植物。
表10:组合物MAP或MAS在APAP/CCL4诱导的肝脏毒性模型中的功效
MAP=肉豆蔻:黄芪:茯苓
MAS=肉豆蔻:黄芪:五味子
R603=肉豆蔻
L497=黄芪
L501=茯苓
L498=五味子
实施例16:以特定比率包含肉豆蔻提取物与五味子、黄芪和/或茯苓的组合物在APAP和CCl4诱导的肝脏毒性模型中的剂量-反应效果
一旦通过将20%重量的第三组分添加到1:4比率的肉豆蔻和黄芪证明了组合物MAP和MAS的优异的肝脏保护能力,评估了这些组合物在APAP和CCL4诱导的模型中引起显著的肝脏保护的最佳剂量。小鼠以悬浮于10%吐温20中的200mg/kg,300mg/kg和400mg/kg的剂量经口管饲组合物MAP和MAS。媒介物对照组仅接受载体溶液。如表11所示,在CCL4诱导的毒性模型中,观察到组合物血清ALT的剂量相关性抑制。对于用200mg/kg,300mg/kg和400mg/kg剂量治疗的小鼠,对于MAP,分别观察到66.9%(p=0.0015),80.0%(p=0.0002)和83.7%(p=0.0002)的抑制,对于MAS,分别观察到54.1%(p=0.0109),74.9%(p=0.0004)和79.7%(p=0.0002)的抑制。类似地,在APAP诱导的损伤模型中,观察到组合物血清ALT的剂量相关性抑制。对于用200mg/kg,300mg/kg和400mg/kg剂量治疗的小鼠,对于MAP,分别观察到25.8%(p=0.49),62.9%(p=0.01)和88.1%(p=0.0001)的抑制,对于MAS,分别观察到32.4%(p=0.16),62.7%(p=0.02)和78.7%(p=0.0007)的抑制。即便两种组合物在APAP模型中在200mg/kg剂量下观察到的抑制作用在统计学上并不显著,但观察到的血清ALT抑制作用远大于组合物的单独组分,表明配制这三种单独材料以产生组合物MAP和MAS对于获得更好的肝脏保护活性的明显优势。尽管CCL4模型中所有组的存活率均为100%,但APAP模型中MAP的该比率范围为50-100%,MAS的该比率范围为70-700%。与效果匹配的是,在APAP模型中观察到的存活率与给予动物的组合物的量相关。例如,当接受200mg/kg的MAP或MAS的小鼠分别具有50%和70%的存活率时,给予最高剂量(400mg/kg)时两种组合物都观察到100%的存活率。
在这里,我们测试了各植物如肉豆蔻、黄芪、五味子和茯苓的效果,其剂量等于每种植物在组合物MAP和MAS中的比率,如同它们出现在最低测试剂量(200mg/kg)中。如表11所示,在CCL4模型中,剂量为32mg/kg的肉豆蔻导致血清ALT的40.7%抑制,在CCL4模型中的存活率为100%。当与媒介物治疗的损伤小鼠相比时,组合物的其余组分加重毒性,程度范围在13.5-18.1%之间。另一方面,在APAP模型中,与媒介物对照相比,用40mg/kg茯苓治疗的小鼠显示出4.3%的血清ALT抑制,而其它组分在6.8-33.1%的范围内增加肝脏损伤。
表11:组合物MAP和MAS在APAP/CCL4诱导的肝脏毒性模型中的剂量相关性肝脏保护
实施例17:MAP和MAS组合物的协同作用的评价
利用广泛使用的协同作用计算方程Colby方程(Colby,1967)来评价结合肉豆蔻、黄芪、茯苓和五味子在APAP和CCL4模型中的益处。在该方法中,如果某个终点测量的观测值大于或等于假设计算值,则将推定两种或更多种材料一起配制具有协同作用。如下表12所示,在目前的研究中,在任一模型中观测值大于预期理论值,表明以特定比率配制三种成分以产生组合物MAP或MAS时存在协同作用。放置肉豆蔻、黄芪和茯苓,或肉豆蔻、黄芪和五味子的优点被其对由APAP或CCL4引起的肝脏损伤的预料不到的增强的保护所证实。
表12:肉豆蔻、黄芪、茯苓和五味子在肝脏保护中的预料不到的协同活性。
注:(-:负)值表示肝脏损伤严重程度增加。
实施例18:MAP和MAS组合物在CCL4诱导的肝脏毒性模型中的效果确认研究一旦组合物MAP和MAS在APAP和CCL4模型中的一致的肝脏保护活性被证明,使用CCL4诱导的肝脏毒性模型进行了另外的综合确证研究。对小鼠经口管饲150、200和300mg/kg剂量的组合物MAS或MAS。包括剂量为200mg/kg的奶蓟作为参考。10%吐温20 用作所有材料的载体媒介物。对照小鼠仅接受吐温20。除血清丙氨酸转氨酶(ALT)外,还在T24对于对照、CCL4、奶蓟、MAP(150、200和300mg/kg)和MAS(150、200和300mg/kg)测量了肝脏功能面板如总蛋白、总胆红素、直接和间接胆红素、白蛋白、球蛋白、天冬氨酸转氨酶(AST)、胆汁酸、碱性磷酸酶(ALP)和γ-谷氨酰转移酶(GTT)。
如下表13和14所示,在许多主要的肝脏毒性指示生物标志物方面,显示了明确的剂量相关性抑制。尽管两种组合物(MAP和MAS)均显示出显著的肝脏保护活性,但组合物MAS显示出比组合物MAP略强的功效。鉴于对重要生物标志物而言这些数据的显著减轻,可以推断,两种组合物的最小有效剂量可以是150mg/kg。继续使用组合物功效分析的类似方法,组合物MAP与媒介物治疗的损伤小鼠相比,产生ALT的30.8-71.1%的抑制,和AST的41.7-75.7%的抑制。类似地,与媒介物治疗的损伤小鼠相比,组合物MAS观察到ALT的47.5-82.6%的抑制和AST的55.6-85.4%的抑制。总体而言,组合物MAP和MAS在多次频繁监测的肝脏生物标志物方面提供了更大的肝脏损伤保护。
表13:CCL4-诱导的肝脏毒性模型中用MAP/MAS治疗的小鼠的肝脏功能面板分析物水平的总结。
*P≤0.05;
表14:在CCL4模型中,与媒介物治疗的小鼠相比,MAP/MAS组的肝脏功能面板标志物的百分比变化的总结。
(+):↓相比APAP/CCL4(+)媒介物下降
(-):↑相比APAP/CCL4(+)媒介物增加
实施例19:MAP组合物在急性乙醇诱导的肝脏毒性模型中的肝脏保护作用模型诱导:使用“暴饮”的急性酒精诱导的肝脏毒性模型评估MAP组合物的肝保护活性。在该研究中,购买8周龄的重18-24g的雄性CD-1小鼠(Charles River Laboratories,Inc.,Wilmington,MA)并适应一周。动物以300mg/kg的口服剂量总共接受4剂量的组合物。基于先前进行的对乙酰氨基酚(APAP)和四氯化碳(CCl4)诱导的肝脏毒性模型进行剂量选择。小鼠用三次口服剂量的MAP或水飞蓟素预治疗,接着用50%的乙醇(lot#:SHBG1307V,Sigma,St.Louis,MO)以12ml/kg的剂量体积管饲,然后每12小时一次,总共3剂量[69]。最后的口服治疗剂量在第二次和第三次乙醇给予之间给予。最后一次给予乙醇后,小鼠禁食12小时以收集血清和组织。在该研究中,以200mg/kg的口服剂量使用水飞蓟素(产品号:S0292;Lot#BCBJ0393V;Sigma,Saint Louis,MO)作为阳性对照。没有乙醇的对照小鼠仅接受载体媒介物。使用10%的吐温-20(Lot#0134C141,来自Amresco,Solon,OH)作为所有测试材料的载体媒介物。没有乙醇的对照小鼠仅接受载体媒介物。尸体解剖后立即收集肝脏组织并置于干冰中直至转移至-80℃冰箱。然后将材料在干冰中运送到合同实验室(BrunswickLaboratories,200Turnpike Rd,MA 01772,USA)以进行最终样本处理和生物标志物(SOD、GSH和TG)分析。将每只小鼠的左叶的肝脏部分固定在10%缓冲甲醛中,并送到NationwideHistology(Veradale,WA)进行组织处理和组织学检查。
实施例20:MAP对来自急性乙醇诱导的肝脏毒性模型的肝功能的影响在室温下30分钟凝血后,用血清分离管从在T24抽取的血液中分离血清,并在3000rpm下旋转10分钟,以便在Phoenix Laboratories(Everett,WA)使用Beckman Coulter AU2700在自动比色测定中监测ALT(丙氨酸转氨酶)、AST(天冬氨酸转氨酶)、总蛋白、白蛋白、总胆红素、胆固醇(CHOL)、甘油三酯(TRIG)、高密度脂蛋白(HDL)和低密度脂蛋白(LDL)。
动物ALT和AST血清水平的显著升高通常反映肝脏损伤[70]。如表15所示,在单独用酒精处理的小鼠中发现ALT和AST均显著升高,表明诱导了急性酒精诱导的肝脏损伤。当用口服剂量为300mg/kg的MAP总共连续4天治疗小鼠时,这些标志物的过度增加在46.3%(ALT)和43.6%(AST)下被显著抑制。MAP的肝脏保护活性也得到了血清白蛋白和总蛋白产生的统计上的显著增加的支持(表15)。这些结果证实该组合物保护肝脏以对抗急性酒精诱导的损伤。至少在本研究中,对于用200mg/kg剂量的水飞蓟素治疗的小鼠,观察到所有监测的血清参数没有显著变化(表15)。
表15:作为肝功能测量的临床化学输出
数据表示为平均值±SD。*P-值相对于乙醇≤0.05。
实施例21:MAP对来自急性乙醇诱导的肝脏毒性模型的肝脏匀浆中氧化应激生物标志物(GSH和SOD)和甘油三酯含量的影响谷胱甘肽(GSH)、超氧化物歧化酶(SOD)和甘油三酯(TG)的测量:A)样品制备-使用粉碎机将冷冻组织研磨成粗粉末。将1mL包含19.6μM的EDTA(乙二胺四乙酸)的PBS(磷酸盐缓冲盐水)加至约0.2g研磨的组织,并使用来自OmniInternational的均化器在冰浴中均化1min。然后将混合物在4℃以10,000rpm离心15分钟。一部分上清液用于SOD、甘油三酯和蛋白质分析。剩余的上清液进一步加工用于GSH分析。B)对于GSH分析,将一部分上清液与相同体积的100mg/mL巯基丙酸(MPA)溶液混合以脱蛋白,以避免来自蛋白质的干扰。涡旋后让混合物在室温静置5分钟,然后在4℃以10,000rpm离心15分钟。使用来自CAYMAN Chemical Co.,Inc.(Ann Arbor,MI)的谷胱甘肽测定试剂盒评估脱蛋白的上清液的GSH含量。C)SOD分析-SOD测定法是比色测定法,它使用四唑鎓盐来测量由黄嘌呤氧化酶和黄嘌呤诱导的超氧化物自由基的歧化,并且给定样品中SOD的活性是通过使用SOD标准品产生的标准曲线进行量化的。一个单位的SOD定义为显示超氧化物自由基50%歧化所需的酶量。来自CAYMAN Chemical Co.,Inc.(Ann Arbor,MI)的超氧化物歧化酶测定试剂盒被用于分析。通过用PierceTM BCA蛋白测定试剂盒评估抑制剂的蛋白质浓度来确定组织匀浆的蛋白质浓度。D)甘油三酯分析-通过涉及脂蛋白脂肪酶、甘油激酶、甘油-3-磷酸氧化酶和甘油-3-磷酸过氧化物酶的酶反应级联来检测甘油三酯,所述酶反应级联导致形成比色检测的产物(540nm),醌亚胺。来自CAYMAN Chemical Co.,Inc.(Ann Arbor,MI)的甘油三酯测定试剂盒用于该分析。E)材料和设备-使用来自Omni International(Kennesaw,GA)的均化器(cat no TH-01);来自Omni International(Kennesaw,GA)的硬组织Omni TipTM塑料均化探针(7mm x 110mm);来自Eppendorf(Hauppauge,NY)的冷冻离心机(型号5402);来自Biotek(Shoreline,WA)的微板读板仪(型号Synergy HT)。
谷胱甘肽是保护细胞以对抗内源性或外源性化学损害及其活性氧物类副产物的第II阶段抗氧化酶之一,其过量消耗可诱导氧化应激和肝脏损伤。如表16所示,在用组合物MAP治疗的动物中发现肝脏组织总谷胱甘肽水平显著更高。与正常对照小鼠相比,用酒精和媒介物对照处理的小鼠也观察到GSH水平增加。先前有报道禁食动物的GSH水平较低[71]。同时,在最后一次给予乙醇后12小时,与正常对照相比,乙醇组的SOD活性显著降低至36.9%。如表16所示,MAP补充消耗的超氧化物歧化酶超过60%(与乙醇组相比)。事实上,SOD水平的增加与没有肝脏毒性诱导的正常对照动物相当。第II阶段酶的这些增加相互证实,以提供MAP组合物的强抗氧化活性。另外,乙醇的给予诱导肝脏中TG的显著积聚(表16)。MAP口服治疗明显将肝脏TG水平的增加抑制了12%,MAP的作用与正常对照小鼠观察到的相当(表16)。这些结果表明MAP可能对酒精性脂肪变性有效。
表16:MAP对肝脏氧化生物标志物的影响
*P-值相对于对照≤0.000001.60%与暴露于乙醇的媒介物治疗的小鼠相比,SOD增加60%。
实施例22:来自急性乙醇诱导的肝脏毒性模型的MAP的抗酒精性脂肪性肝炎(ASH)活性来自正常对照(N=12),乙醇+媒介物(N=10)和乙醇+MAP(300mg/kg,N=12)治疗组的肝脏组织在10%缓冲甲醛中固定,并包埋在石蜡中用于组织学检查。样本在ShandonExcelsior ES组织处理器上使用分级醇和二甲苯在过夜周期中处理。然后将组织切成4微米并使用sakura DRS-601载玻片染色器使用渐进苏木精和伊红染色剂进行染色。在多个放大倍数下评估整个染色区域的任何细胞和结构变化,并使用改良的非酒精性脂肪性肝炎(NASH)临床研究网络[72]对其进行组织病理学评分,针对气球样变性(严重性评分0-4),微血管脂肪变性(严重性评分0-4),细胞质浓缩(严重性评分0-4),肝细胞空泡化(严重性评分0-4)和坏死(严重性评分0-4)。
未治疗的对照动物的肝脏组织显示肝细胞的正常结构,具有明确的细胞质,正常的kupffer细胞和正常的大核。在媒介物治疗的乙醇激发的小鼠中,肝组织显示扭曲的结构,具有大面积的肝脂肪变性,细胞质浓缩和显著的核收缩。在这些组中还观察到一些气球样变性、空泡化和门静脉周围炎症。另一方面,可辨别的正常细胞结构,较小程度的结构变化在用MAP治疗的小鼠中是明显的(表17)。如表17所示,与媒介物治疗的酒精诱导的疾病模型相比,MAP显示出气球样变性、微血管和大血管脂肪变性、细胞质或核浓聚和收缩以及门静脉周围和坏死周围炎症的统计学显著的减少。然后使用这些定量值确定酒精性脂肪性肝炎评分(ASH评分)。将这些组织病理学发现汇总在一起导致用300mg/kg的MAP组合物口服治疗的小鼠与乙醇组相比的酒精性脂肪性肝炎评分的统计学显著的降低(表18)。
表17:来自乙醇诱导的肝脏毒性模型中用MAP治疗的小鼠的肝脏组织的H&E染色分析
a.媒介物-10%吐温20。*P-值相对于乙醇≤0.05;**P-值相对于乙醇≤0.001;在乙醇+媒介物治疗组中发现两只小鼠死亡。
表18:酒精性脂肪性肝炎(ASH)评分
P-值相对于媒介物治疗的乙醇小鼠
因此,已公开了用于肝脏健康管理的化合物和组合物的具体实施方案和方法,包括公开化合物的立体异构体、药学上或保健上可接受的盐、互变异构体、糖苷和前药以及改善和维持肝脏健康的相关方法。然而,对于本领域技术人员显而易见的是,在不脱离本文的发明构思的情况下,除了已经描述的那些以外,还可以进行更多的修改。因此,本发明的主题不受限制,除了在本文公开的精神范围内。此外,在解释说明书和权利要求书时,所有术语应该以与上下文一致的最宽泛可能的方式解释。具体而言,术语“包括”和“包含”应该被解释为以非排他性方式提及元件、组分或步骤,指示所提及的元件、组分或步骤可以与未明确提及的其它元件、组分或步骤一起存在、利用或组合。
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Claims (13)
1.用于治疗肝脏和维持肝脏健康的组合物,其包括富集植物提取物的混合物,其中所述富集植物提取物的混合物由至少一种富含一种或多种木酚素的富集肉豆蔻属提取物、至少一种富含一种或多种多糖和三萜类化合物的富集黄芪属提取物以及至少一种富含一种或多种木酚素和有机酸的富集五味子属提取物组成,其中所述至少一种肉豆蔻属提取物、所述至少一种黄芪属提取物和所述至少一种五味子属提取物的混合物以4:16:5的比率共混,并且其中所述一种或多种有机酸包含苹果酸、柠檬酸、莽草酸或其组合。
2.根据权利要求1所述的用于治疗肝脏和维持肝脏健康的组合物,其中所述一种或多种木酚素包括苯丙素、二聚体、聚合物或其组合。
3.根据权利要求1所述的组合物,其中所述至少一种肉豆蔻属提取物包含0.01%至99.9%的苯丙素或木酚素二聚体和聚合物。
4.根据权利要求1所述的组合物,其中所述至少一种肉豆蔻属提取物包含肉豆蔻(Myristica fragrans)提取物。
5.根据权利要求1所述的组合物,其包含至少一种富含一种或多种苯丙素和木酚素的肉豆蔻属提取物,其中所述至少一种提取物用水、乙醇、甲醇、醇和水混合溶剂从肉豆蔻属植物提取。
6.根据权利要求1所述的组合物,其中所述至少一种黄芪属提取物包含黄芪(Astragalus membranaceus)提取物。
7.根据权利要求1所述的组合物,其中所述至少一种黄芪属提取物包含0.01%至100%的多糖和0.01%至100%的三萜类化合物。
8.根据权利要求1所述的组合物,其中所述至少一种五味子属提取物包含五味子(Schisandra chinensis)提取物。
9.根据权利要求1所述的组合物,其中所述至少一种富含一种或多种木酚素的富集肉豆蔻属提取物、至少一种富含一种或多种多糖和三萜类化合物的富集黄芪属提取物以及至少一种富含一种或多种木酚素和有机酸的富集五味子属提取物提取自茎、茎皮、树干、树干树皮、枝条、块茎、根、根皮、嫩枝、种子、根茎、花、果实、种子或叶。
10.根据权利要求1所述的组合物,其中所述组合物另外包含:奶蓟、芦荟、姜黄、柴胡、甘草、鼠尾草、桑、枳集、仙鹤草、构棘、lyceum、柑橘、李、黄梅、蒲公英、葡萄(vitis)、葡萄籽、悬钩子、山茶、绿茶、磷虾油、酵母、大豆的植物粉末或植物提取物,分离和富集的水飞蓟素、EGCG、儿茶酚、黄酮类、磷脂、碧萝芷、明胶、大豆卵磷脂、胰酶,N-乙酰半胱氨酸、牛磺酸、核黄素、烟酸、吡哆醇、叶酸、胡萝卜素、维生素A、维生素B2、B6和B16、维生素C、维生素E、谷胱甘肽、支链氨基酸、硒、铜、锌、锰、辅酶Q10、L-精氨酸、L-谷氨酰胺或磷脂酰胆碱。
11.根据权利要求1所述的组合物,其中所述组合物还包含药学上或保健上可接受的载体、稀释剂或赋形剂,其中所述组合物包含约0.5重量百分比(wt%)至约90重量百分比的所述提取物混合物的活性成分。
12.根据权利要求11所述的组合物,其中所述组合物被配制成片剂、硬胶囊、软凝胶胶囊、粉末、颗粒、液体、酊剂、sache、即饮饮料单剂或锭剂。
13.根据权利要求1所述的组合物,其中所述组合物以0.01至500mg/kg人或动物体重的剂量给予。
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