CN101014334B - 丙型肝炎病毒阳性人肝硬化患者用肝癌发生和发展抑制剂 - Google Patents
丙型肝炎病毒阳性人肝硬化患者用肝癌发生和发展抑制剂 Download PDFInfo
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Abstract
本发明提供含有异亮氨酸、亮氨酸和缬氨酸3种氨基酸的丙型肝炎病毒阳性人肝硬化患者用肝癌发生和/或发展抑制剂，作为对于丙型肝炎病毒阳性人肝硬化患者的肝癌发生和/或发展具有抑制效果的药剂。
Description
技术领域
本发明涉及一种药剂，其特征在于：抑制在丙型肝炎病毒阳性人肝硬化患者中的肝癌的发生、发展。
背景技术
虽然从肝炎、肝硬化转变为肝癌的机理还不十分清楚，但认为除去肝炎、肝硬化的病因对抑制肝癌尤为重要。
根据其病因，肝硬化被分为：丙型肝炎病毒(HCV)相关的肝硬化(丙型肝硬化)、乙型肝炎病毒(HBV)相关的肝硬化(乙型肝硬化)、酒精性肝硬化、其他(非乙非丙型、特殊型等)。往往还有同时感染HCV和HBV的情况(HBV·HCV混合型)。在这些病因中，由丙型肝炎病毒导致的肝硬化患者(以下也称为丙型肝炎病毒阳性人肝硬化患者)最多。
还有报告指出，丙型肝硬化患者的肝癌发病率与乙型肝硬化患者的情况不同，随着时间的经过而增加(参照K.Ikeda et al.，“肝脏病学(Hepatology)”(1993)18：47～53)。可以说，在肝癌的发病中，约有70～80％以丙型肝炎病毒感染为原因。因此，丙型肝炎病毒阳性人肝硬化患者中，抑制肝癌的发生对预后的改善非常重要，目前需要有效的丙型肝炎病毒阳性人肝硬化患者用肝癌发生、发展抑制剂。
作为目前肝硬化的治疗方法，例如，有人报告了如果通过干扰素治疗除去肝炎病毒，则可有意义地抑制癌发生(参照Y.Imai et al.，“内科学学会(Annals Internal Medicine)”(1998)129：94)。作为除去肝炎病毒的方法，还有使用抗病毒剂的治疗方法(参照J.G.McHutchison et al.，“新英格兰医学杂志(The New England Journal of Medicine)”(1998)339：1485和J.Main et al.，“病毒性肝炎杂志(Journal of Viral Hepatitis)”(1996)3：211)。
但是，在任何情况下都不能将所有患者中的病毒除去，不能达到完全地预防肝癌的发生。
虽然也进行了通过利用保肝药物等抑制慢性炎症来抑制肝癌发病的尝试，但还是不能完全地预防肝癌的发生(参照H.Oka et al.，“癌症(Cancer)”(1995)76：743和Y.Arase et al.，”癌症(Cancer)”(1997)79：1494)。
另外，还进行了利用蛋氨酸缺乏、缬氨酸缺乏、天冬氨酸缺乏、赖氨酸缺乏、半胱氨酸缺乏或苯基丙氨酸缺乏、多量投给精氨酸或多量投给谷氨酰胺之类的特定氨基酸缺乏或者过量投给来治疗、抑制癌症的尝试，但还并未达到令人满意的状况(参照西平哲郎等，“日本肠外与肠内营养杂志(JJPEN)”(1997)19：195～199和黑川典枝等“营养-评价与治疗”(1992)vol.9 No.2 p.142～146)。
可是，在肝硬化患者中，往往伴随着由于蛋白质、氨基酸的代谢异常而导致血液中Fischer比(支链氨基9酸mol(异蛋氨酸+亮氨酸+缬氨酸)/芳香族氨基酸mol(苯基丙氨酸+酪氨酸))的降低、血清白蛋白浓度的降低，在这种病例中，血清白蛋白浓度与Fischer比呈正相关(参照武藤泰敏等，日本医事新报(1983)3101：3)，已知如果血清白蛋白浓度变低则导致生命预后恶化(参照武藤泰敏等，“日本肠外与肠内营养杂志(JJPEN)”(1995)17：208)。
因此，为了改善肝硬化患者中伴随着这种氨基酸代谢异常的低白蛋白血症，投给了称为リ-バクト(LIVACT，注册商标)的支链氨基酸(BCAA)混合剂。
对于作为伴随肝性脑病的慢性肝衰竭患者的营养状态改善药物的アミノレバン(Aminoleban)EN(注册商标)，有人报告了将含有该药剂的饲料投给化学诱发肝癌的大鼠时，与给与通常饲料的对照组进行比较中有抑制肝癌发生的倾向(参照黑川典枝等，“营养-评价与治疗”(1992)vol.9 No.2 p.142～146)，但在同文献中并未暗示这种抑癌效果与作为在糖质、蛋白质、脂质中添加有各种维生素和矿物的平衡营养药的アミノレバンEN(注册商标)中的特定成分有关。
同样，有人报告了当将BCAA添加饲料长期投给作为自然发癌模型的LEC大鼠中时，与对照组比较，虽然癌症的发生数没有差别，但对癌症的进展具有抑制性作用(参照奥濑纪晃等，“肝脏”(2002)43增刊(2)：A359)，但在同文献中也没有记载BCAA的种类、混合比等，也没有暗示该作用与BCAA中的特定成分有关。
上述的リ-バクト(注册商标)为含有异亮氨酸、亮氨酸和缬氨酸3种支链氨基酸的制剂，是通过以适当比例口服补充支链氨基酸，用以矫正Fischer比、提高血清白蛋白浓度、改善病态而开发的药剂，但并不了解其抑制发癌的作用。也不了解低白蛋白血症和癌症发生的技术关联性。
发明内容
本发明所要解决的课题在于提供具有抑制丙型肝炎病毒阳性人肝硬化患者的肝癌发生、发展效果的药剂。
本发明人等为了解决上述课题进行了深入研究，结果发现以异亮氨酸、亮氨酸和缬氨酸3种氨基酸作为有效成分的组合物具有抑制丙型肝炎病毒阳性人肝硬化患者的肝癌发生、发展的效果，进而完成了本发明。本发明包括以下内容。
(1)一种丙型肝炎病毒阳性人肝硬化患者用肝癌发生和/或发展抑制剂，该抑制剂含有异亮氨酸、亮氨酸和缬氨酸3种氨基酸。
(2)(1)的肝癌发生和/或发展抑制剂，其中肝硬化患者为男性。
(3)(1)或(2)的肝癌发生和/或发展抑制剂，其中肝硬化为失代偿性肝硬化。
(4)(1)～(3)中任一项的肝癌发生和/或发展抑制剂，其特征在于：异亮氨酸、亮氨酸和缬氨酸的重量比为1∶1.5～2.5∶0.8～1.7。
(5)(1)～(4)中任一项的肝癌发生和/或发展抑制剂，其特征在于：每日的给药量为2.0g～50.0g。
(6)一种用于抑制丙型肝炎病毒阳性人肝硬化患者的肝癌发生和发展的医药组合物，该组合物含有异亮氨酸、亮氨酸和缬氨酸3种氨基酸以及药学上可接受的载体。
(7)(6)的医药组合物，其中肝硬化患者为男性。
(8)(6)或(7)的医药组合物，其中肝硬化为失代偿性肝硬化。
(9)(6)～(8)中任一项的医药组合物，其特征在于：异亮氨酸、亮氨酸和缬氨酸的重量比为1∶1.5～2.5∶0.8～1.7。
(10)(6)～(9)中任一项的医药组合物，其特征在于：每日的给药量以异亮氨酸、亮氨酸和缬氨酸总量计为2.0g～50.0g。
(11)一种预防、治疗肝癌的方法，该方法包括将异亮氨酸、亮氨酸和缬氨酸3种氨基酸的有效量对丙型肝炎病毒阳性人肝硬化患者进行给药。
(12)(11)的方法，其中肝硬化患者为男性。
(13)(11)或(12)的方法，其中肝硬化为失代偿性肝硬化。
(14)(11)～(13)中任一项的方法，其特征在于：异亮氨酸、亮氨酸和缬氨酸的重量比为1∶1.5～2.5∶0.8～1.7。
(15)(11)～(14)中任一项的方法，其特征在于：异亮氨酸、亮氨酸和缬氨酸的每日给药量总计为2.0g～50.0g。
(16)异亮氨酸、亮氨酸和缬氨酸在制造含有异亮氨酸、亮氨酸和缬氨酸3种氨基酸的丙型肝炎病毒阳性人肝硬化患者用肝癌发生和/或发展抑制剂中的应用。
(17)(16)的应用，其中肝硬化患者为男性。
(18)(16)或(17)的应用，其中肝硬化为失代偿性肝硬化。
(19)(16)～(18)中任一项的应用，其特征在于：使用异亮氨酸、亮氨酸和缬氨酸使之重量比为1∶1.5～2.5∶0.8～1.7。
(20)(16)～(19)中任一项的应用，其特征在于：含有异亮氨酸、亮氨酸和缬氨酸3种氨基酸的丙型肝炎病毒阳性人肝硬化患者用肝癌发生和/或发展抑制剂的每日给药量为2.0g～50.0g。
(21)一种商业包装，该包装包括含有异亮氨酸、亮氨酸和缬氨酸3种氨基酸的丙型肝炎病毒阳性人肝硬化患者用肝癌发生和/或发展抑制剂以及记载有该药剂在抑制肝癌发生和/或发展的应用中相关说明的书面文件。
(22)一种含有异亮氨酸、亮氨酸和缬氨酸3种氨基酸的食品，该食品带有用于抑制丙型肝炎病毒阳性人肝硬化患者的肝癌发生和/或发展的表示。
附图简述
图1表示进行食物治疗和リ-バクト颗粒给药的HCV阳性男性肝硬化患者的肝癌累积非表现率。
实施发明的最佳方式
以下对本发明的实施方式加以说明。
本发明的丙型肝炎病毒阳性人肝硬化患者用肝癌发生、发展抑制剂(以下称为本发明的药剂)的给药方式、剂型可以是口服给药，也可以是胃肠外给药，作为口服给药剂可以举出散剂、粒剂、胶囊剂、片剂、咀嚼剂等固形剂，溶液剂、糖浆剂等液体剂，作为胃肠外给药剂可以举出注射剂、喷雾剂等。
本发明的药剂对于人、特别是男性的患者有效。
本发明药剂所适应的病态，对预防丙型肝炎病毒阳性人肝硬化患者的肝癌发生和对现有肝病治疗剂无法得到充分治疗效果的丙型肝炎病毒阳性人肝硬化患者的肝癌发生、发展的抑制、治愈有效。特别对肝硬化为失代偿性肝硬化的情况有效。
虽然已知以异亮氨酸、亮氨酸和缬氨酸3种氨基酸作为有效成分的组合物改善肝硬化患者的低白蛋白血症，但在对于本发明丙型肝炎病毒阳性人肝硬化患者的肝癌发生、发展的抑制等适用中，血清白蛋白值的降低并非适用条件。
已知肝脏有很大的功能性储备，但在肝硬化患者中，该功能性储备显著降低，对于出现了消化管出血、腹水、脑病、感染症等的病期使用所谓失代偿性肝硬化的病名。与此相对，对于功能性储备并未如此降低的病期使用所谓代偿性肝硬化的病名。
特定丙型肝硬化、乙型肝硬化或混在型的患者，只要检查肝硬化患者中HCV和HBV的感染即可。HCV或HBV的感染分别使用HBs抗原的测定(RIA法、EIA法等)或HCV抗体的测定(市售HCV抗体测定试剂盒)。即使HCV抗体阴性，也存在利用PCR法测定HCV-RNA为阳性的肝硬化患者，因此对HCV抗体阴性患者利用PCR法进一步测定HCV-RNA是有效的。通过上述方法和其他能够确认HCV或HBV感染的方法确认为阳性的肝硬化患者，被特定为HCV型·HBV型·混合型的肝硬化患者。即，本发明中，所谓的丙型肝炎病毒阳性人肝硬化患者是确认为HCV感染的人肝硬化患者，是来自于丙型肝炎(相关)的肝硬化患者。
本发明中的异亮氨酸、亮氨酸和缬氨酸可以是D体，也可以是L体，优选为L体。
3种氨基酸的混合比以重量比计为1∶1.5～2.5∶0.8～1.7，特别优选为1∶1.9～2.2∶1.1～1.3的范围。如果脱离该范围，则难以得到有效的作用效果。
给药量随对象患者的年龄、体重、病态、给药方法等的不同而不同，通常一日量以0.5～30.0g异亮氨酸、1.0～60.0g亮氨酸、0.5～30.0g缬氨酸作为标准。在一般成人的情况，优选一日量为2.0～10.0g异亮氨酸、3.0～20.0g亮氨酸、2.0～10.0g缬氨酸，更优选为2.5～3.5g异亮氨酸、5.0～7.0g亮氨酸、3.0～4.0g缬氨酸，3种氨基酸的总量优选每日为2.0g～50.0g左右，将其分为1～6次、优选1～3次进行给药。
作为本发明有效成分的异亮氨酸、亮氨酸和缬氨酸可以各自单独或以任意组合含有在制剂中或者可以全部含有在一种制剂中。单独制成制剂进行给药时，它们的给药途径、给药剂型可相同、也可不同，另外，分别给药的时间可以相同也可以不同。根据并用药剂的种类或效果适当决定。即，本发明的肝癌发生和/或发展抑制剂还可以是同时含有3种氨基酸的制剂，或者还可以是单独制剂化后进行并用的并用剂。是包括所有这些形态的制剂。同一制剂中含有3种氨基酸的形态特别优选，因为能够简单地给药。
本发明中，“重量比”表示制剂中各个成分的重量之比。例如在一种制剂中含有异亮氨酸、亮氨酸和缬氨酸各有效成分时的各个含量之比，当各有效成分分别单独或以任意组合含有在多种制剂中时，为各制剂中所含各有效成分的重量之比。
本发明中，实际给药量的比为每个给药对象(即患者)的各有效成分一次给药量或一日给药量之比。例如，当在一种制剂中含有异亮氨酸、亮氨酸和缬氨酸各有效成分，将其投给给药对象时，重量比相当于给药量比。当在多种制剂中单独或者以任意组合含有各有效成分进行给药时，一次或一日给药的各制剂中的各有效成分总量之比相当于重量比。
异亮氨酸、亮氨酸和缬氨酸已经在医药、食品领域中广泛使用，安全性已经确立，例如，以1∶2∶1.2的比例含有这些氨基酸的本发明医药组合物的急性毒性(LD50)在大鼠口服给药中为10g/Kg以上。
本发明的药剂可以通过通常的方法制剂化成散剂、粒剂、胶囊剂、片剂、咀嚼剂等固形剂，溶液剂、糖浆剂等液体剂，或者注射剂，喷雾剂等。
根据制剂上的要求，还可以混合适宜的药学上可接受的载体，例如赋形剂、粘合剂、润滑剂、溶剂、崩解剂、溶解辅助剂、悬浮剂、乳化剂、等张化剂、稳定化剂、安慰剂、防腐剂、抗氧化剂、矫味剂、着色剂等制成制剂。
作为赋形剂可以举出乳糖、葡萄糖、D-甘露醇等糖类，淀粉类，结晶纤维素等纤维素类等有机系赋形剂，碳酸钙，高岭土等无机系赋形剂等；作为粘合剂可以举出α化淀粉、明胶、阿拉伯胶、甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、结晶纤维素、D-甘露醇、海藻糖、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、聚乙烯醇等；作为润滑剂可以举出硬脂酸、硬脂酸盐等脂肪酸盐，滑石、硅酸盐类等；作为溶剂可以举出精制水、生理盐水等；作为崩解剂可以举出低取代度羟丙基纤维素、化学修饰的纤维素或淀粉类等；作为溶解辅助剂可以举出聚乙二醇、丙二醇、海藻糖、苯甲酸苄酯、乙醇、碳酸钠、柠檬酸钠、水杨酸钠、乙酸钠等；作为悬浮剂或乳化剂可以举出十二烷基硫酸钠、阿拉伯胶、明胶、卵磷脂、单硬脂酸甘油酯、聚乙烯醇、聚乙烯吡咯烷酮、羧甲基纤维素钠等纤维素类，聚山梨醇酯类，聚氧化乙烯氢化蓖麻油等；作为等张化剂可以举出氯化钠、氯化钾、糖类、甘油、尿素等；作为稳定化剂可以举出聚乙二醇、硫酸葡聚糖钠、其它氨基酸类等；作为安慰剂可以举出葡萄糖、葡萄糖酸钙、盐酸普鲁卡因等；作为防腐剂可以举出对羟基苯甲酸酯类、氯丁醇、苄醇、苯乙醇、脱氢醋酸、山梨酸等；作为抗氧化剂可以举出亚硫酸盐、抗坏血酸等；作为矫味剂可以举出在医药和食品领域中通常使用的甜味料、香料等；作为着色剂可以举出在医药和食品领域中通常使用的着色剂。
在本发明的药剂中还可以混合其它肝脏疾病治疗药物，例如干扰素、甘草酸、熊去氧胆酸、利巴韦林、中药小柴胡汤等。
这些制剂可以通过口服、注射或者局部给药等任意的给药方法进行给药。
由于本发明的有效成分为氨基酸，因此安全性优异，即使是饮食品的形态也可以简单地使用。将本发明用于饮食品中时，没有特别的困难，例如可以混合在果汁、牛奶、糕点、果冻等中进行饮食。还可以将这种食品作为保健功能食品提供，在该保健功能食品中还包括带有用于抑制丙型肝炎病毒阳性人肝硬化患者的肝癌发生·发展的表示的饮食品，特别是特定的健康用食品等。
对于含有本发明药剂和记载有与其用途相关说明的书面文件的包装而言，作为书面文件可以举出记载有与用途、功能或给药方法等相关说明事项的所谓能书等。
实施例
以下，通过实施例详细地说明本发明，但下述实施例只不过有助于得到与本发明相关的具体认识，本发明的范围并不受下述实施例的任何限定。
(实施例1)
对于抑制本发明的丙型肝炎病毒阳性人肝硬化患者的肝癌进行了研究。
不投给白蛋白制剂时的血清白蛋白值均为3.5g/dl以下，对于现有腹水、浮肿或肝性脑病或者有既往史的年龄20岁以上75岁以下的失代偿性肝硬化患者，研究了リ-バクト给药相对于食物治疗的效果。特定失代偿性肝硬化患者的感染病毒使用通常所用的检测方法，例如HCV抗体测定试剂盒或HCV-RNA测定等。
食物治疗组是仅实施食物疗法，按照不会产生蛋白质不足进行食物指导。リ-バクト给药组以食物疗法为基础，在每日3餐后口服异亮氨酸、亮氨酸和缬氨酸的重量比为1∶2∶1.2(异亮氨酸：0.952g、亮氨酸：1.904g、缬氨酸：1.144g)的支链氨基酸制剂リ-バクト(注册商标)颗粒(味素株式会社)，1次1包。
对88例食物治疗组、94例リ-バクト给药组的HCV阳性的男性肝硬化患者的肝癌表现状况(利用图像分析、细胞诊断等)进行研究的结果(图1)，在试验期间中，食物治疗组中有25例表现肝癌，与此相对，在リ-バクト给药组中有17例表现肝癌，肝癌被显著抑制(Wilcoxon p＝0.0489)。图中，直线表示リ-バクト颗粒给药组、虚线表示食物治疗组(リ-バクト颗粒非给药组)。
产业实用性
本发明提供的含有异亮氨酸、亮氨酸和缬氨酸3种支链氨基酸的丙型肝炎病毒阳性人肝硬化患者用肝癌发生、发展抑制剂抑制了丙型肝炎病毒阳性人肝硬化患者的肝癌的发生、发展。尤其对男性丙型肝炎病毒阳性人肝硬化患者有效。另外，在肝硬化为失代偿性肝硬化时尤为有效。而且，因为本发明的医药组合物以氨基酸作为有效成分，安全性高，几乎没有副作用，因此可以长期给药，可以在直到肝癌发生的长期过程中有利地用于预防、治疗。
本申请以在日本申请的特愿2004-207693为基础，其内容全部包含在本说明书中。
Claims (6)
1.异亮氨酸、亮氨酸和缬氨酸在制造含有异亮氨酸、亮氨酸和缬氨酸这3种氨基酸的丙型肝炎病毒阳性人肝硬化患者用肝癌发生和/或发展抑制剂中的应用，其中，异亮氨酸、亮氨酸和缬氨酸以重量比计为1∶1.5～2.5∶0.8～1.7。
2.权利要求1的应用，其中肝硬化患者为男性。
3.权利要求1或2的应用，其中肝硬化为失代偿性肝硬化。
4.权利要求1或2的应用，其特征在于：含有异亮氨酸、亮氨酸和缬氨酸这3种氨基酸的丙型肝炎病毒阳性人肝硬化患者用肝癌发生和/或发展抑制剂的每日给药量为2.0g～50.0g。
5.一种商业包装物，该包装物中包括含有异亮氨酸、亮氨酸和缬氨酸这3种氨基酸的丙型肝炎病毒阳性人肝硬化患者用肝癌发生和/或发展抑制剂以及说明书，其中，异亮氨酸、亮氨酸和缬氨酸以重量比计为1∶1.5～2.5∶0.8～1.7，该说明书记载有与所述抑制剂在抑制肝癌的发生和/或发展方面的应用有关的说明。
6.一种含有异亮氨酸、亮氨酸和缬氨酸这3种氨基酸的食品，其中，异亮氨酸、亮氨酸和缬氨酸以重量比计为1∶1.5～2.5∶0.8～1.7，该食品上注有说明，该说明表示所述食品是用于抑制丙型肝炎病毒阳性人肝硬化患者的肝癌发生和/或发展的食品。
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| CN103068381A (zh) * | 2010-08-11 | 2013-04-24 | 兴和株式会社 | 用于肝细胞癌的预防和／或治疗的医药 |
| KR101919747B1 (ko) | 2011-02-17 | 2018-11-20 | 각꼬호우진 구루메 다이가쿠 | 화학요법제의 항종양 활성 증강제 |
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Also Published As
| Publication number | Publication date |
|---|---|
| JP5555401B2 (ja) | 2014-07-23 |
| EP1774966A1 (en) | 2007-04-18 |
| KR20070032818A (ko) | 2007-03-22 |
| JPWO2006006729A1 (ja) | 2008-05-01 |
| CN101014334A (zh) | 2007-08-08 |
| RU2007105500A (ru) | 2008-08-27 |
| KR20150055100A (ko) | 2015-05-20 |
| KR20120125993A (ko) | 2012-11-19 |
| WO2006006729A1 (ja) | 2006-01-19 |
| RU2372900C2 (ru) | 2009-11-20 |
| EP1774966A4 (en) | 2008-03-05 |
| US20070197647A1 (en) | 2007-08-23 |
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