CN1756543A - 肝癌发生·发展抑制剂 - Google Patents
肝癌发生·发展抑制剂 Download PDFInfo
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- CN1756543A CN1756543A CNA2003801100079A CN200380110007A CN1756543A CN 1756543 A CN1756543 A CN 1756543A CN A2003801100079 A CNA2003801100079 A CN A2003801100079A CN 200380110007 A CN200380110007 A CN 200380110007A CN 1756543 A CN1756543 A CN 1756543A
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- leucine
- valine
- isoleucine
- hepatocarcinoma
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Abstract
本发明提供了一种肝癌发生·发展抑制剂,其为用于抑制肝癌的发生与发展的人及其他动用的预防·治疗剂、医药组合物及保健功能食品,其主要成分是异亮氨酸、亮氨酸和缬氨酸的,三者重量比为1∶1.5~2.5∶0.8~1.7且一日的给药量为2.0g~50.0g。
Description
技术领域
本发明涉及以抑制肝癌的发生、发展为目的的医药组合物,特别涉及以抑制肝炎或肝硬化患者的肝癌的发生与发展为特征的医药组合物。另外,本发明涉及有效抑制肝炎、肝硬化患者的肝癌发生与发展的保健功能食品。本发明的医药组合物及保健功能食品,有效成分为异亮氨酸、亮氨酸、缬氨酸的氨基酸。
背景技术
由肝炎、肝硬化发展为肝癌的机制虽然还没有完全明确,但人们考虑到为了抑制肝癌的发生,除去肝炎、肝硬化的病因是很重要的。
例如,据报告通过干扰素治疗除去肝炎病毒时,显著地抑制了肝癌的发生(Ann Intern Med(1998)129:94)。作为除去肝炎病毒的方法,也有使用抗病毒剂的治疗方法(N Engl J Med(1998)339:1485和J Viral Hepatitis(1996)3:211)。
但是,在任何情况下都不能把所有患者的病毒除去,无法完全预防肝癌。
曾经试着通过肝保护剂等来抑制慢性炎症,进而抑制肝癌的发生,但是也不能够完全预防肝癌(Cancer(1995)76:743和Cancer(1997)79:1494)。
另外,也做过以下尝试:蛋氨酸缺乏、缬氨酸缺乏、天冬氨酸缺乏、赖氨酸缺乏、胱氨酸缺乏,或者是苯丙氨酸缺乏、精氨酸加量投药、谷氨酰胺加量投药之类通过特定氨基酸缺乏或者过量投药来进行癌症的治疗、抑制,但还是没有达到满意的状况(JJPEN(1997)19∶195-199和《营养评价与治疗)》(1992)vol.9 No.2p.142-146)。
可是,对于肝硬化患者会有由于蛋白、氨基酸的代谢异常会伴随着血中的费希尔比(フイツシヤ一比)(支链氨基酸mol(异亮氨酸+亮氨酸+缬氨酸)/芳香氨基酸mol(苯丙氨酸+酪氨酸))下降、血清白蛋白浓度下降,这样的病例中显示血清白蛋白浓度与费希尔比正向相关(日本医事新报(1983)3101:3),已知血清白蛋白浓度降低会缩短预期寿命(JJPEN(1995)17:208)。
因此,为了改善肝硬化患者这种伴随氨基酸代谢异常的低白蛋白血症,进行了名为Livact(注册商标)的支链氨基酸(BCAA)配合剂的给药。
据报道,关于Aminoleban EN(注册商标),其为伴有肝性脑病的慢性肝功能衰竭患者的营养状态改善药,当将含有此药的饲料投喂给化学诱发肝癌的大鼠时,与投喂正常饲料的对照组相比,具有抑制肝癌发生的倾向(《营养评价与治疗》(1992)vol.9 No.2p.142-146),但是在此文献中并未记载以表示这种抑癌效果与Aminoleban EN(注册商标)中的特定成分相关,其成分为在糖、蛋白质、脂质中添加有各种维生素和矿物质的均衡营养物。
同样,据报道,将添加有BCAA的饲料长期投喂给自发癌症模型的LEC大鼠时,与对照组相比较,癌的发生数没有差异,但对癌的发展有抑制作用(《肝脏)》(2002)43 Supplement(2):A359),但是此文献中也并未记载BCAA的种类、混合比等,也未指出该作用与BCAA中的特定成分相关联。
上述的Livact(注册商标)是由3种支链氨基酸:异亮氨酸、亮氨酸和缬氨酸制成的制剂,是以通过口服补充适当比例的支链氨基酸,改正费希尔比,提高血清白蛋白浓度,改善病情为目的而开发的药剂,但是并不知道其对癌症的发生有抑制作用。也不知道低白蛋白血症与癌症发生的技术关联性。
发明内容
本发明想解决的课题是,提供有效抑制肝癌的发生、发展的人及其它动物用的医药组合物,特别是提供对肝硬化患者的肝癌的发生、发展具有抑制作用的医药组合物。进一步,本发明的另一目的是提供新型的肝癌预防·治疗方法。
本发明人为了解决上述课题进行了深入的研究,结果发现,由异亮氨酸、亮氨酸和缬氨酸3种氨基酸为有效成分的组合物对于肝癌的发生、发展,特别是对肝硬化患者的肝癌的发生与发展具有抑制效果,从而完成本发明。本发明,包含以下项目:
(1)一种人及其他动物用的医药组合物,其含有异亮氨酸、亮氨酸和缬氨酸3种氨基酸,用于抑制肝癌的发生、发展。
(2)(1)中所述的医药组合物,其特征在于,上述的肝癌的发生与发展是指肝硬化患者的肝癌的发生与发展。
(3)(1)或(2)中所述的医药组合物,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。
(4)(1)~(3)任何1项申所述的医药组合物,其特征在于,每日的投药量为2.0g~50.0g。
(5)一种肝癌发生、发展抑制剂,其含有异亮氨酸、亮氨酸和缬氨酸3种氨基酸。
(6)(5)中所述的肝癌发生·发展抑制剂,其特征在于,上述肝癌的发生与发展是指肝硬化患者的肝癌的发生与发展。
(7)(5)或(6)中所述的肝癌发生·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是1∶1.5~2.5∶0.8~1.7。
(8)(5)~(7)任何1项中所述的肝癌发生·发展抑制剂,其特征在于,每日的投药量为2.0g~50.0g。
(9)一种肝癌的预防·治疗方法,其包含向患者给予有效量的异亮氨酸、亮氨酸和缬氨酸3种氨基酸。
(10)(9)中所述的方法,其特征在于,上述肝癌的发生与发展是指肝硬化患者的肝癌的发生与发展。
(11)(9)或(10)中所述的方法,其特征在于,异亮氨酸、亮氨酸和缬氨酸的重量比是1∶1.5~2.5∶0.8~1.7。
(12)(9)~(11)任何1项中所述的方法,其特征在于异亮氨酸、亮氨酸和缬氨酸的每日给予量的总和为2.0g~50.0g。
(13)一种异亮氨酸、亮氨酸和缬氨酸的用途,其目的在于,为了制造由异亮氨酸、亮氨酸和缬氨酸3种氨基酸构成的肝癌发生·发展抑制剂。
(14)(13)中所述的用途,其特征在于,上述肝癌的发生与发展是指肝硬化患者的肝癌的发生与发展。
(15)(13)或者(14)中所述的用途,其特征在于,使异亮氨酸、亮氨酸和缬氨酸的重量比达到1∶1.5~2.5∶0.8~1.7,进而使用。
(16)(13)~(15)任何1项中所述的用途,其特征在于,含有异亮氨酸、亮氨酸和缬氨酸3种氨基酸的肝癌发生·发展抑制剂的每日给予量为2.0g~50.0g。
(17)一个商业包装,其包含有人或其他动物用的医药组合物和记载物,前者含有异亮氨酸、亮氨酸和缬氨酸3种氨基酸并且用于抑制肝癌的发生与发展;后者记载了与使用该医药用途的相关的说明。
(18)一个商业包装,其包含有肝癌发生·发展的抑制剂和记载物,前者含有异亮氨酸、亮氨酸和缬氨酸3种氨基酸;后者记载了与使用该医药用途的相关的说明。
(19)含有异亮氨酸、亮氨酸和缬氨酸3种氨基酸的保健功能食品。
附图说明
图1表示添加了胆碱缺乏氨基酸的鼠料引发肝癌的大鼠的癌症发生率。
具体实施方式
以下对本发明的实施方式加以说明。
本发明的医药组合物的给药方式·剂型可以是口服给药,也可以是非口服给药,作为口服给药的剂型来说可以举出散剂、颗粒剂、胶囊剂、片剂、咀嚼剂等固体制剂,溶液剂、糖浆剂等液体制剂,另外,作为非口服给药的剂型,可以列举出注射剂、喷雾剂等。
作为人以外的动物,除了家畜类、家禽类之外,还包括实验动物。作为给人以外的动物的给药方式,也可以添加到饲料中。
在包含有本发明的医药组合物和记载有关于医药用途的使用说明的记载物的商业包装中,作为记载物,可以列举出记载有关于用途、功能、给药方法等说明事项所谓的使用说明书等。
作为本发明的保健功能食品,可以是含有香料、甜味剂的散剂、颗粒剂、胶囊剂、片剂、咀嚼剂等固体形态,或者也可以是溶液剂、糖浆剂等液体形态,甚至可以是添加到糖果、小甜饼、蛋糕等糖果类或是向加工食品中添加的食物添加剂。
作为本发明的医药组合物所适用的疾病,包括肝炎、肝硬化、肝癌等肝脏疾病,对于预防癌变危险很高的肝炎、肝硬化等肝脏疾病所发生的癌变,以及对于抑制以往肝脏疾病治疗剂治疗效果不充分的肝癌的发展并治愈是非常有效的。
用于这些疾病时,血清白蛋白值的降低并不是其适用条件。
本发明的异亮氨酸、亮氨酸和缬氨酸,D型和L型均可,但是优选L型。
3种氨基酸的混合比按重量比为1∶1.5~2.5∶0.8~1.7,特别优选范围是1∶1.9~2.2∶1.1~1.3。偏离该范围,难以得到有效的作用效果。
按照对象患者的年龄、体重、病情和给药方式的不同,给药剂量有所不同。通常的1日量的大致标准是异亮氨酸0.5~30.0g,亮氨酸1.0~60.0g,缬氨酸0.5~30.0g。对于一般成人来说,优选的一日量为异亮氨酸2.0~10.0g,亮氨酸3.0~20.0g,缬氨酸2.0~10.0g,更优选为异亮氨酸2.5~3.5g,亮氨酸5.0~7.0g,缬氨酸3.0~4.0g,3种氨基酸的每日总量优选为2.0g~50.0g左右,分1~6次给予,优选为1~3次。
本发明的有效成分异亮氨酸、亮氨酸和缬氨酸,可以单独或者是任意组合包含于制剂中,也可以在一种制剂中全部含有。将通过其它途径制成的制剂进行给药时,它们的给药途径、给药剂型可以相同或者也可以不同,另外,各自的给药时间可以是同时给药或者是分别给药。通过并用的药剂种类和效果适宜决定。
在本发明中,所谓的“重量比”是指制剂中各个成分的重量之比。例如在一个制剂中含有异亮氨酸、亮氨酸和缬氨酸各有效成分时是指每个的含量之比,当在多个制剂中分别单独含有各有效成分或者是以任意组合含有各有效成分时,是指各制剂中所含有的各有效成份的重量之比。
另外,在本发明中的实际给药量之比是指,每个给药对象(即患者)1次或者是1日各有效成份的给药量之比。例如,在一个制剂中含有异亮氨酸、亮氨酸和缬氨酸各有效成分,将其向给药对象进行给药时,重量比相当于给药比。但用单独含有各有效成分或者是以任意组合含有各有效成分多个制剂进行给药时,1次或者是1日中所给予的各制剂中的各有效成分的总量之比相当于重量比。
异亮氨酸、亮氨酸和缬氨已己在医药、食品领域被广泛使用,安全性明确,例如以1∶2∶1.2的比例含有这些氨基酸的本发明的医药组合物的对小鼠口服给药的急性毒性(LD50)为10g/Kg或以上。
本发明的医药组合物,用常规的方法,可以制成散剂、颗粒剂、胶囊剂、片剂、咀嚼剂等固体制剂,溶液剂、糖浆剂等液体制剂以及注射剂、喷雾剂等剂型。
根据制剂上的所需,配合适当的药学上被允许的载体例如,赋形剂、粘合剂、润滑剂、溶剂、崩解剂、助溶剂、助悬剂、乳化剂、等渗调节剂、稳定剂、无痛剂、防腐剂、抗氧化剂、矫味剂、着色剂等并制成制剂。
作为赋形剂,可举出乳糖、葡萄糖、D-甘露醇等糖类,淀粉类、结晶纤维素等纤维素类等的有机系赋形剂,碳酸钙、高岭土等无机系赋形剂等;作为粘合剂,可举出α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,可举出纯净水、生理盐水等;作为崩解剂,可举出低取代羟丙基纤维素、化学修饰的纤维素和淀粉类等;作为助溶剂,可举出聚乙二醇、丙二醇、海藻糖、苯甲酸苄酯、乙醇、碳酸钠、柠檬酸钠、水杨酸钠、醋酸钠等;作为助悬剂或者是乳化剂,可举出月桂基硫酸钠,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、羧甲基纤维素钠等的纤维素类,聚山梨醇酯类、聚氧乙烯氢化蓖麻油等;作为等渗调节剂,可举出氯化钠、氯化钾、糖类、甘油、尿素等;作为稳定剂,可举出聚乙二醇、葡聚糖硫酸钠、其他的氨基酸类等;作为无痛剂,可举出葡萄糖、葡糖酸钙、盐酸普鲁卡因等;作为防腐剂,可举出对羟基苯甲酸酯类、三氯叔丁醇、苄醇、苯乙醇、脱氢醋酸、山梨酸等;作为抗氧化剂,可举出亚硫酸盐、抗坏血酸等;作为矫味剂,可举出医药及食品领域中通常使用的甜味剂、香料等;作为着色剂,可举出医药及食品领域中通常使用的着色料等。
本发明的医药组合物,可以与其它肝脏疾病治疗药,如干扰素、甘草甜素、熊去氧胆酸、利巴韦林、中药小柴胡汤等配合使用。
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式进行给药。
本发明中的肝癌预防·治疗方法,包含抑制肝癌的发生·发展。
所谓的保健功能食品,是指含有对身体的生理机能及生物学活动具有影响的保健功能成分的食品。与在饮食中以特定的保健目的所摄取的物质相比,摄取保健功能食品能够达到所希望的保健目的。
保健功能食品根据场合的不同,也被称为功能性食品、健康食品(含有营养强化剂)等。所谓的功能性食品,是指利用食品中所含有的生物体调节成分的功能而制成的食品,所谓的健康食品,一般来说是指具有健康增进功能的一类食品。这其中也含有以特定营养素为主要成分的营养强化剂。
本发明的保健功能食品,含有特定保健用食品和营养功能食品,作为患有肝炎或肝硬化的患者的日常营养补充食品来摄食,可以预防肝癌的发生与发展。
保健功能食品的制造,可以按照与上述的医药组合物相同的制剂技术,或者是一般的食品制造技术进行。另外,可以添加维生素类及其他的强化剂。
实施例
以下通过实施例更详细地说明本发明,但下述的实施例应该看作是有助于对本发明的具体的认识,而本发明的范围不受下述实施例的任何限制。
实施例1
将6周龄的Fischer344系大鼠分为两组,其中对照组N=30,支链氨基酸组N=28,自由进食实验鼠料。向对照组提供的实验鼠料为添加了胆碱缺乏氨基酸鼠料+2.0%氨基酸混合物*,向支链氨基酸组提供的实验鼠料为添加了胆碱缺乏氨基酸鼠料+2.5%支链氨基酸**(BCAA组)。
死亡时或者是给药64周时解剖检查,通过组织学探讨其是否有肝癌的发生,计算癌症发生率,结果如图1所示。
(添加了胆碱缺乏氨基酸鼠料从Dyets公司购入。*;添加的氨基酸混合物中各氨基酸的比例与Dyets公司的胆碱缺乏鼠料中的氨基酸比例相同。2.0%氨基酸混合物与2.5%支链氨基酸含氮量相同。**;异亮氨酸∶亮氨酸∶缬氨酸=1∶2∶1.2重量比)。
如图1所示,对于由于食用添加了胆碱缺乏氨基酸鼠料而引发肝癌的大鼠,支链氨基酸组的癌症发生率显著低于对照组的癌症发生率,明确了配合本发明的支链氨基酸可以有效抑制癌的发生。
工业实用性
综上所述,通过本发明提供了一种肝癌发生、发展抑制剂,其含有异亮氨酸、亮氨酸、缬氨酸3种支链氨基酸,抑制肝癌的发生与发展,特别是抑制肝炎、肝硬化患者的肝癌的发生与发展。
另外,本发明的医药组合物,由于以氨基酸作为有效成分,因此安全性高、几乎无副作用,可以长期给药,因此在肝癌未发生时的长期过程中可以使用进行有利地预防·治疗。另外,做为保健功能食品,也可以长期服用,有效地预防癌症的发生。
本申请是以日本专利申请2002-377803为基础,本说明书中包含其所有内容。
Claims (19)
1.一种人及其他动物用的医药组合物,含有异亮氨酸、亮氨酸和缬氨酸3种氨基酸,其用于抑制肝癌的发生与发展。
2.根据权利要求1所述的医药组合物,其特征在于,上述肝癌的发生与发展是指肝硬化患者的肝癌的发生与发展。
3.根据权利要求1或2所述的医药组合物,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。
4.根据权利要求1~3任何1项中所述的医药组合物,其特征在于,每日的投药量为2.0g~50.0g。
5.一种肝癌发生·发展抑制剂,其含有异亮氨酸、亮氨酸和缬氨酸3种氨基酸。
6.根据权利要求5中所述的肝癌发生·发展抑制剂,其特征在于,上述肝癌的发生与发展是指肝硬化患者的肝癌的发生与发展。
7.根据权利要求5或6中所述的肝癌发生·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是1∶1.5~2.5∶0.8~1.7。
8.根据权利要求5~7任何1项中所述的肝癌发生·发展抑制剂,其特征在于,每日的投药量为2.0g~50.0g。
9.一种肝癌的预防·治疗方法,其包含向患者给予有效量的异亮氨酸、亮氨酸和缬氨酸3种氨基酸。
10.根据权利要求9中所述的方法,其特征在于,上述肝癌的发生与发展是指肝硬化患者的肝癌的发生与发展。
11.根据权利要求9或10中所述的方法,其特征在于,异亮氨酸、亮氨酸和缬氨酸的重量比是1∶1.5~2.5∶0.8~1.7。
12.根据权利要求9~11任何1项中所述的方法,其特征在于,异亮氨酸、亮氨酸和缬氨酸的每日给予量的总和为2.0g~50.0g。
13.一种异亮氨酸、亮氨酸和缬氨酸的用途,其目的在于,为了制造含有异亮氨酸、亮氨酸和缬氨酸3种氨基酸的肝癌发生·发展抑制剂。
14.根据权利要求13中所述的用途,其特征在于,上述肝癌的发生与发展是指肝硬化患者的肝癌的发生与发展。
15.根据权利要求13或14中所述的用途,其特征在于,使异亮氨酸、亮氨酸和缬氨酸的重量比达到1∶1.5~2.5∶0.8~1.7,进而使用。
16.根据权利要求13~15任何1项中所述的用途,其特征在于,含有异亮氨酸、亮氨酸和缬氨酸3种氨基酸的肝癌发生·发展抑制剂的每日给予量为2.0g~50.0g。
17.一个商业包装,其包含有人或其他动物用的医药组合物和记载物,前者含有异亮氨酸、亮氨酸和缬氨酸3种氨基酸并且用于抑制肝癌的发生与发展;后者记载了与使用该医药用途的相关的说明。
18.一个商业包装,其包含有肝癌发生·发展的抑制剂和记载物,前者含有异亮氨酸、亮氨酸和缬氨酸3种氨基酸;后者记载了与使用该医药用途的相关的说明。
19.一种含有异亮氨酸、亮氨酸和缬氨酸3种氨基酸的保健功能食品。
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US20060004101A1 (en) | 2006-01-05 |
US9271521B2 (en) | 2016-03-01 |
CN101108001A (zh) | 2008-01-23 |
EP1582207A1 (en) | 2005-10-05 |
CN1329030C (zh) | 2007-08-01 |
KR20110120981A (ko) | 2011-11-04 |
EP1582207A4 (en) | 2008-03-05 |
AU2003296176A1 (en) | 2004-07-22 |
WO2004058243A1 (ja) | 2004-07-15 |
JP5074661B2 (ja) | 2012-11-14 |
CN101108001B (zh) | 2011-12-14 |
JPWO2004058243A1 (ja) | 2006-04-27 |
KR20050089857A (ko) | 2005-09-08 |
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