CN107106602A - 肝纤维化改善剂 - Google Patents
肝纤维化改善剂 Download PDFInfo
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- CN107106602A CN107106602A CN201580072411.4A CN201580072411A CN107106602A CN 107106602 A CN107106602 A CN 107106602A CN 201580072411 A CN201580072411 A CN 201580072411A CN 107106602 A CN107106602 A CN 107106602A
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Abstract
需要解决的技术问题：本发明提供并证明了在使用硫代乙酰胺造成的肝功能障碍模型中，对于肝炎肝硬化中显现的肝纤维化，具有优势性的改善药品及改善效果。解决技术问题的技术手段：通过锌硒配合剂来得到。
Description
背景技术
本发明涉及用于改善伴随慢性肝炎向肝硬化的发展而生成的肝纤维化的营养功能食品和医药品。其为一种锌硒配合剂，相比于锌制剂聚普瑞锌(Polaprezinc)(L-肌肽锌酸盐)显示出优势性。
慢性肝炎按致病原因可大体分为两类。一类是由肝炎病毒引起的病毒性慢性肝炎。另一类并未感染肝炎病毒，称之为慢性肝功能障碍。病毒性慢性肝炎分为乙型慢性肝炎和丙型慢性肝炎等。非病毒性慢性肝炎分为酒精性肝炎，自身免疫性肝炎，药物性肝炎，脂肪肝，中毒性肝炎等。
这些慢性肝炎继续发展就变成肝硬化。其病理观点为引起肝细胞的崩坏。在病情不太严重，障碍度还比较低的时候，可以通过肝细胞的再生进行修复；但当炎症反应长期持续，反复发作，会使肝内纤维增多变硬，残存的肝细胞强烈再生，新生成的肝细胞和纤维化及硬化的肝组织相互缠绕，使肝内形成结节。该结节压迫血管系统，加重肝内血液循环障碍。由此引起肝门静脉压升高，肝血流减少等，进一步加重肝细胞障碍，产生恶性循环。
慢性肝炎在向肝硬化发展的过程中，肝细胞的纤维化亢进，形成肝硬化。慢性肝炎和初期的肝硬化是可逆的状态，而随着肝纤维化的进展，逐渐演变为不可逆状态的肝硬化。因此，抑制进行性慢性肝炎并发产生的肝纤维化的营养功能食品及药品，作为抑制慢性肝炎进展为肝硬化的治疗药物是十分重要的。
现有已知的慢性肝炎治疗药物，有以干扰素(Interferon)、利巴韦林(Ribavirin)、拉米夫定(Lamivudine)和特拉匹韦(Telaprevir)为代表的抗病毒药物，以及以胆烷酸(URSODEOXYCHOLIC ACID)为代表的肝保护剂等。但它们各自虽然显示出抗病毒作用、抑制肝细胞炎症的作用，但没有显示出改善肝纤维化的作用。
锌制剂聚普瑞锌(Polaprezinc)(L-肌肽锌酸盐)作为胃溃疡治疗药被广泛使用。有报道称其对于慢性肝炎的肝纤维化有一定的抑制效果(专利文献1)，并已经作为日本专利第JP 4802470号获得授权。
硒是人体中存在的一种微量元素，具有抗氧化作用。有报道称，血清中的硒值随着慢性肝炎向肝硬化、肝癌的推进过程中逐渐减少(非专利文献1)。除此之外，有研究表明，硒可以抑制由四氯化碳诱发的试验白鼠的肝纤维化进展，但是其改善作用并不明确。在服用硒的试验组中，肝纤维化的标志性指标：Ⅰ型胶原α链基因mRNA(和组织内羟脯氨酸(Hydroxyproline)含量具有相关性)显现出上升趋势。但不能证明其具有改善肝纤维化的作用(非专利文献2)。
分别有研究报告认为，锌和硒各自具有一定的抗纤维化作用。但是，并没有任何相关文件表明，将两者进行配比使用后会产生协同增效作用。而且现有研究主要是针对抑制炎症方面，对于表示纤维化状态的羟脯氨酸含量或I型胶原蛋白基因的值并没有提及(非专利论文3)。
都是涉及施用硒所带来的肝脏的“抗炎症作用”，还没有关于“改善”纤维化方面的报道。
甚至，更有研究认为硒和锌一起使用会产生拮抗反应，即相互抑制作用。从未有人对硒和锌的配合剂具有预防肝功能障碍，特别是对肝纤维化的药效进行过研究(非专利文件4)。
近年来，随着老龄社会的发展，以拥有疗养型病床的医院为中心，对患者采用经由导管喂食使其摄取营养的病例逐渐增加。通过实施经皮内视镜下胃造瘘术(以下称之为PEG)，用经导管给药的方式，对患者的营养进行管理。以此类患者为对象，通过PEG孔向胃内给药聚普瑞锌(Polaprezinc)(L-肌肽锌酸盐)后，观察到血清含锌值有显著的上升。另一方面血清含硒值有明显的下降，大幅度地下降至正常下限以下(非专利文件5)。
现有技术文献
专利文献1：专利第JP 4802470号
非专利文献
非专利文献1：CHING-CHIANG LIN等3人，《Selenium、Iron、Copper、and ZincLevels and Copper-to-Zinc Ratios in Serum of Patients at Different Stages ofViral Hepatic Diseases》,、Biological Trace Element Research、(美国)、SpringerUS、2006年1月1日、volume 109、Issue 1、P.15-23
非专利文献2：Ming Ding等4人，《Selenium Supplementation DecreasesHepatic Fibrosis in Mice After Chronic Carbon Tetrachloride Administration》、Biological Trace Element Research、(美国)、Springer US，2010年1月1日，Volume 133、Issue 1、P.83-97
非专利文献3：Lai、Yurong et al、The protective role of Se and Zn onliver injury induced by carbon tetrachloride、Weisheng Dulixue Zazhi、1995年9(2)、pp.80-83
非专利文献4：J.Chmielnicka等3人，《Zinc-selenium interaction in therat》、Biological Trace Element Research(美国)、Humana Press、1988年1月1日、volume15、Issue1、p.267-276
非专利文件5：伊藤明彦、《经管摄取营养和锌的长期管理中的问题点和对策》、锌的营养治疗，近畿地区锌营养治疗研究会，2012年3月31日、第2卷，第2号，p.27-34
发明内容
需要解决的技术问题
因为我们观察到由肝炎向肝硬化发展的过程中，体内锌硒含量会随着肝脏功能恶化而下降，产生显著的肝纤维化；又因为活性氧能起到促进肝纤维化进行的作用；所以我们猜想，将具有抑制肝纤维化作用的锌和具有抗氧化作用的硒并用，能够得到更加优秀的抗纤维化药品，因此进行了本发明研究。在本研究中使用的硫代乙酰胺肝功能障碍模型，是重症非代偿性肝硬化模型；肝纤维化高度发展，改善起来比从原始状态抑制其进展更为困难。因此选取其作为重症肝功能障碍模型进行研究。
本发明的目的是将锌硒配合剂和作为锌制剂的聚普瑞锌(L-肌肽锌酸盐)相比较，证明并提供了在使用硫代乙酰胺的肝功能障碍模型的肝炎、肝硬化中的肝纤维化改善效果方面具有显著的优势性。
本发明中，与单独使用锌制剂聚普瑞锌(L-肌肽锌酸盐)相比，使用锌硒配合剂显示出更优异的抗纤维化改善作用。锌和硒被吸收后会进入到肝脏中，均会反映到肝功能上。在单独给药锌时，硒会根据给药量而减少，我们不否认其可能对肝脏中的硒的比例带来影响。这是最初的临床病例报告，其给出了通过给药锌和硒两种制剂能够维持血清中硒的浓度，能够使肝脏中各个成分的比例变得有效且灵活的启示。
解决技术问题的技术手段
本发明者采用硫代乙酰胺造成的肝功能障碍模型探索肝纤维化改善药物的时候，发现和聚普瑞锌(L-肌肽锌酸盐)单独使用相比，锌硒配合剂呈现出更加优异的抗纤维化改善效果,从医学和科学的角度将此配比的意义明确化。
本发明是通过锌硒配合剂来得到的肝纤维化改善剂，用于慢性肝炎、自身免疫性肝炎、酒精性及非酒精性脂肪性肝炎和肝硬化中的肝纤维化的改善。
此外，本发明是通过锌硒配合剂来得到的肝纤维化改善剂，用于慢性肝炎、自身免疫性肝炎、酒精性及非酒精性脂肪性肝炎和肝硬化中的肝纤维化的改善，其为至少含有铬、镁、钾及维他命C中的一种以上的肝纤维化改善剂。
发明的效果
本发明能够改善肝炎向肝硬化发展过程中产生的肝纤维化，防止其发展为重症肝硬化，或治疗肝硬化，促进肝脏细胞的再生。
附图说明
图1是分别服用作为锌制剂的聚普瑞锌(L-肌肽锌酸盐)和本发明的一种实施例的锌硒配合剂后，表示对肝脏中羟脯胺酸含量产生的作用的图。
图2是分别服用作为锌制剂的聚普瑞锌(L-肌肽锌酸盐)和本发明的一种实施例的锌硒配合剂后，表示对纤维溶解类酶前体proMMP-9的表达产生的作用的图。
图3是服用本发明的一种实施例的锌硒配合剂后，表示对血清中硒含量产生的作用的图。
图4是服用本发明的一种实施例的锌硒配合剂后的肝脏组织图。
具体实施方式
本发明的锌硒配合剂的效果，是在先服用硫代乙酰胺使其致病为肝硬化，在确认到肝纤维化后，再服用本发明的锌硒配合剂后得到的结果，这一点极为重要。使得肝脏组织中的羟脯氨酸的含量降低，按组织学的原理显著地抑制肝纤维化，可以治疗肝炎，肝硬化，抑制其向肝癌发展。和聚普瑞锌(L-肌肽锌酸盐)相比，在临床上极为有用。
本发明的营养功能食品及医药品，倾向于经口服用。剂型优选片剂，胶囊剂，颗粒剂，散剂，液剂等。作为肝纤维化改善剂的服用量，和年龄、体重、病状、服用时间、服用期限有关，优选每次的服用量为：锌7.5mg-15mg，硒25μg至50μg，每天口服2-3次。
制造此配合剂可以适当采用添加剂，可以适当选择并组合使用如麦芽糖醇、明胶、纤维素、蔗糖酯、阿拉伯树胶、普鲁兰多糖、玉米蛋白、还原淀粉糖化物、卵壳钙等。也可以和其他的矿物质如铬、镁、钾、蜂王浆、维生素C等组合使用。
实施例
列举以下实施例对本发明进行更详细的说明，但并不仅限于该实施例。
实施例1
将大鼠每十只分为一组。对照组以硫代乙酰胺水溶液(300mg/L)作为饮料水，连续令大鼠服用10周或者20周；试验组以硫代乙酰胺水溶液(300mg/L)作为饮料水，连续服用20周后，继续服用10周聚普瑞锌200mg/天/kg或继续服用10周锌硒配合剂(Zn 45mg/天/kg,Se150μg/天/kg)。两者一天所摄取的锌量相同。
在服用结束后，杀死对照组和试验组的大鼠，取出肝脏，使用盐酸处理后的氯胺及欧利布试剂(Ehrlich's reagent)，以吸光度测定肝组织纤维化的指标羟脯胺酸。
肝脏中的羟脯胺酸含量如图1所示。改善肝纤维化的纤维溶解类酶前体proMMP-9的表达量如图2所示。血清硒含量的测定结果如图3所示。
图1表明，本发明的锌硒配合剂，尽管在硫代乙酰胺投入20周后才进行给药，作为肝纤维化指标的羟脯胺酸量有明显的降低，和作为锌制剂的聚普瑞锌(L-肌肽锌酸盐)相比处于明显的优势。
图2表明，proMMP-9为用于溶解肝纤维而起作用的纤维溶解类酶前体。本发明的锌硒配合剂使proMMP-9的含量激增，和服用聚普瑞锌(L-肌肽锌酸盐)后相比有明显的增加，确认了本发明的肝纤维化改善效果。
图3显示出服用硫代乙酰胺20周后，血清硒含量有明显的减少。但是服用锌硒配合剂10周后，血清硒值有明显的增加，比服用硫代乙酰胺前含量更高，有明显的改善。在服用作为锌制剂的聚普瑞锌(L-肌肽锌酸盐)组，未见血清硒含量增加，可以认为血清硒的增加是因服用锌硒配合剂而导致的。
因此，可以认为锌硒配合剂在肝功能障碍时不会发生拮抗，补充本发明物可以使其吸收率提高。
图4是分别服用锌制剂聚普瑞锌(L-肌肽锌酸盐)和本发明的一种实施例锌硒配合剂后，表征肝纤维化改善作用的肝组织染色图。
明确地体现了锌硒配合剂具有改善炎症，改善肝纤维化的效果。
Claims (2)
1.一种肝纤维化改善剂，其通过锌硒配合剂得到，用于慢性肝炎、自身免疫性肝炎、酒精性及非酒精性脂肪性肝炎和肝硬化。
2.根据权利要求1所述的肝纤维化改善剂，其至少含有铬、镁、钾、钙及维生素C中的一种以上。
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