CN1278168A - 肝病治疗药 - Google Patents
肝病治疗药 Download PDFInfo
- Publication number
- CN1278168A CN1278168A CN98810728A CN98810728A CN1278168A CN 1278168 A CN1278168 A CN 1278168A CN 98810728 A CN98810728 A CN 98810728A CN 98810728 A CN98810728 A CN 98810728A CN 1278168 A CN1278168 A CN 1278168A
- Authority
- CN
- China
- Prior art keywords
- valine
- hepatopathy
- liver
- compositions
- treatment
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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Abstract
用于治疗或改善肝病的药物或食品,其特征在于含有缬氨酸作为有效成分,而且完全不含有缬氨酸以外的氨基酸,或实质上不含有缬氨酸以外的氨基酸作为有效成分。使用这种药物或食品,比以前的药物疗法副作用小,可以治疗肝炎、肝衰竭等肝脏疾病,并可以使这些肝脏疾病引起的发热、倦怠、食欲不振、呕吐、腹痛、腹水等症状、异常或并发症(除肝性脑病外)得到改善、缓和、恢复。
Description
技术领域
本发明涉及用于治疗肝病或用于改善肝功能的组合物,其特征在于:含有缬氨酸作为有效成分,而且实质上不含有缬氨酸以外的氨基酸作为有效成分。详细的说,涉及含有对急性肝炎、肝衰竭、慢性肝炎、肝硬化等肝病具有治疗或改善效果的缬氨酸作为有效成分,而且实质上不含有缬氨酸以外的氨基酸作为有效成分的药物或食品组合物。
背景技术
以前,对肝衰竭、肝硬化等肝病,使用了各种氨基酸制剂。例如,Aminoleban(注册商标)、Morihepamin(注册商标)、Aminoleban(注册商标)EN、Hepan(注册商标)ED和Livact(注册商标)颗粒等氨基酸制剂可以用于改善伴随肝硬化、肝衰竭等肝病的肝性脑病及血白蛋白减少症。但是,这些氨基酸制剂不是直接治疗、改善这些肝病,而是用于改善肝病引起的营养不良,即希望通过校正血浆氨基酸的不平衡改善氨代谢或降低血中氨值。另外,这些制剂是氨基酸的混合物,几乎没有发现单一的氨基酸能够改善这些肝病。另一方面,在特公昭57-29446号公报中主要记载了L-缬氨酸注射液单独使用时对治疗肝性脑病有效,但是,肝性脑病是伴随肝病恶化引起的一种并发症,是血液中增多的氨等有毒物质引起中枢神经系统障碍,导致的各种神经症状,与本发明中所说的肝病是不同的。另外,该公报并未提示可以直接治疗或改善肝病本身。事实上,目前是使用乳果糖等降低血液中氨的制剂治疗肝性脑病,而且尚无使用肝病治疗药治疗肝性脑病的病例,这一点也说明本发明并不能轻易从该公报推出。
另一方面,本发明者首先发现缬氨酸具有在肝病、肝硬化等的肝脏切除后使肝细胞再生的作用,并申请了专利(参照特开平8-67628号公报)。该公报中记载了缬氨酸对肝细胞再生的效果,但没有公开缬氨酸对肝炎、肝硬化等肝病自身的效果,也没有提示。
另外,已知的一些慢性肝炎、肝硬化等治疗药在有效性和安全性方面并不令人满意。例如,对于这些肝病可以使用Minophagen C等甘草酸制剂,但由于在肠内失活,主要作为注射剂使用,口服给药不能得到期望的效果。另外,关于其副作用,有报告指出基于其醛固酮样作用,有血压上升、低血钾症、由于钠潴留造成水分潴留的倾向,特别是在有腹水的重度肝病时或长期给药时会出现问题。
另外,特公昭57-29446号公报中,指出L-缬氨酸作为单独的氨基酸对肝性脑病的治疗有效,但这是通过将缬氨酸分解成柠檬酸循环中的琥珀酰辅酶A降低氨浓度,只适用于组织中氨浓度非常高的肝性脑病。如上所述,肝性脑病不是肝脏本身的疾病,是伴随肝病恶化而引起的并发症,因此,该公报中并未提示能够直接治疗或改善肝病本身。
发明描述
本发明人鉴于这种状况,对有效性高、在安全性方面没有问题、不仅注射有效口服给药也有效的肝病治疗药进行了悉心研究,这次发现氨基酸之一的缬氨酸,以完全不含有缬氨酸以外的氨基酸或实质上不含有缬氨酸以外的氨基酸作为有效成分的形式,经口服或非口服给药,对肝衰竭、急性肝炎、慢性肝炎、肝硬化等肝病具有优良的改善作用,而且在安全性方面没有问题,从而完成了本发明。
缬氨酸对肝病的效果,可以如后述实施例所示的那样从肝病动物模型及肝病患者中得到确认。关于急性肝炎与肝衰竭,可以使用半乳糖胺或四氯化碳等药物性急性肝病模型与90%肝切除的肝衰竭模型评价;关于慢性肝炎·肝硬化,可以使用四氯化碳等药物诱发性慢性肝病模型评价,对于这些模型,缬氨酸均有效。另外,对慢性肝炎患者采用口服给药时,缬氨酸能够改善肝功能(GOT、GPT、血小板等)。由此说明缬氨酸作为肝病用药对于包括人在内的动物是有效的。发明的最佳实施方式
本发明中使用的缬氨酸可以使用市售品、合成品,与其制备方法无关。另外,可以使用D型、L型、DL型中的任何一种,特别优选使用L型。
本发明中的缬氨酸具有治疗或改善急性肝炎、慢性肝炎、肝衰竭、肝硬化等各种肝病的效果,特别是对急性肝炎、肝衰竭具有优良的治疗效果。作为可望有治疗效果的肝炎,例如有由A型、B型、C型、D型、E型等肝炎病毒引起的急性和慢性肝炎。另外,肝衰竭例如急性肝衰竭和慢性肝衰竭。而且,本发明的缬氨酸对这些肝炎及肝衰竭等疾病表现出的各种症状、异常或不受氨浓度影响的并发症,例如发热、倦怠、食欲不振、呕吐、腹痛、腹水及胸水等,具有改善、缓和、恢复的效果。这里所举的并发症不包括受氨浓度影响的肝性脑病。
将本发明用于治疗或改善肝脏疾病的组合物投给生物体时,可以口服给药或通过直肠、皮下、髓腔、肌肉、静脉、动脉、透皮等非口服形式给药,优选口服或静脉给药。
将本发明的缬氨酸投给生物体时,缬氨酸优选制成适当的剂型后使用,例如片剂、散剂、颗粒剂、细粒剂、丸剂、胶囊、糖锭剂、咀嚼剂、液体制剂、乳剂、悬浊剂、栓剂、糖浆剂、洗剂、软膏剂、巴布剂等制剂。在制备这些剂型时,可以使用可药用的适当载体、赋形剂、添加剂等。
本发明用于治疗或改善肝脏疾病的组合物在静脉给药时,优选的剂型是液体制剂,配制液体制剂时,可以使用精制水、生理盐水、乙醇·丙二醇·甘油·聚乙二醇等醇类、甘油三乙酸酯等溶剂。在这些制剂中也可以进一步加入防腐剂、润湿剂、乳化剂、分散剂、稳定剂等辅剂。另外,也可以作为悬浊剂给药。
另外,在制备片剂、丸剂、散剂、颗粒剂、细粒剂、糖锭剂、咀嚼剂等固体制剂时,可以加入碳酸氢钠、碳酸钙、淀粉、蔗糖、甘露醇、羧甲基纤维素等载体,硬脂酸钙、硬脂酸镁、甘油等添加剂,按照常规方法进行。另外,也可以喷上邻苯二甲酸乙酸纤维素、邻苯二甲酸羟丙基甲基纤维素、邻苯二甲酸聚乙烯醇、苯乙烯-马来酸酐共聚物、甲基丙烯酸-甲基丙烯酸甲酯共聚物等肠溶性物质在有机溶剂或水中的溶液,包肠溶性衣,制成肠溶性制剂。可药用载体中包括必要时使用的其它常规辅助剂、芳香剂、稳定剂或防腐剂。而且,本发明用于治疗或改善肝脏疾病的组合物也可以与高营养(热量)输液剂等输液制剂并用,或将缬氨酸添加到其它输液制剂中使用。
本发明用于治疗或改善肝脏疾病的组合物也适于用作肝功能改善用食品。这时,可以将缬氨酸直接添加到现有的食品或饮料等中,或将缬氨酸直接添加到口胶、糖果、果冻、树胶、家常小甜饼、饼干、巧克力等甜点,果汁等清凉饮料,干酪、黄油、酸乳酪等乳制品,冰淇淋、火腿等农产加工品,筒状鱼卷(竹轮)、鱼肉山芋方形蒸饼(半平)等水产加工品,荞麦面条、面条等面类,面包、蛋糕等小麦粉加工品,罐头或盐、酱油、糖、人工甜味剂等调味食品中,或在这些食品的加工阶段混合缬氨酸,进行加工后使用。也可以作为用于改善肝功能的特定保健用药品使用。将缬氨酸添加或混合到食品中时,可以使用粉末、细粒、颗粒等固体形状的缬氨酸,也可以使用液态的物质。另外,加工含有缬氨酸的食品时,可以按照常规的食品加工方法进行。
本发明用于治疗或改善肝脏疾病的组合物含有缬氨酸作为有效成分,而且与以前已知的其它氨基酸混合制剂不同,完全不含有缬氨酸以外的氨基酸,或不含有缬氨酸以外的氨基酸作为肝病治疗药的有效成分,即实质上不含有缬氨酸以外的氨基酸作为有效成分,是消除了以前所担心的有效性和安全性方面的问题的优良组合物。
本发明用于治疗或改善肝病的组合物作为药物使用时,可以用于急性肝炎、肝衰竭、慢性肝炎、肝硬化等肝病患者,其给药量根据患者的性别、体型、体质、年龄、症状或给药剂型等有所不同,一般以缬氨酸作为有效成分可以在每日0.1~300g(优选1~100g)的范围内适当选择。给药次数根据患者的症状或给药剂型等有所不同,1日给药1次乃至数次比较合适。
实施例
以下结合实施例更详细的说明本发明,但是本发明并不受其任何限定。实施例1:对急性肝损伤的作用1)试验方法
使用8~9周龄250g左右的Crj:Donryu雄性大鼠。在试验过程中,让其自由摄取大鼠用饲料MF(Oriental酵母公司生产)和水。将D-Galactosamine·HCl(D-半乳糖胺盐酸盐,Sigma公司生产)用生理盐水溶解,用1N NaOH调节为pH7.0之后,制成D~Galactosamine(以下称为“半乳糖胺”)100mg/ml溶液后使用。将四氯化碳(和光纯药工业公司生产)用橄榄油(和光纯药工业公司生产)配制成50%(v/v)溶液后使用。禁食12小时后,以10ml/kg的体积通过腹腔给药将半乳糖胺投给大鼠,或以4ml/kg的容量通过皮下给药将四氯化碳溶液投给大鼠,引起肝病。之后立即在乙醚麻醉下将导管插入到右颈静脉中,留于中心静脉中。中心静脉导管通过皮下由肩胛骨之间抽出,安装Harness后,通过protective coil,连接在Swivel(Bio-Cannula,Biomedica公司生产)上。将大鼠移至代谢笼中,在无麻醉·无拘束的条件下进行试验。将给药速度设定为100ml/kg/日,通过泵持续投给试验液。试验液的给药时间为1~4天,试验液组分为乳酸林格氏液(Lactec(注册商标),大冢制药公司生产)组(对照组)以及缬氨酸组(在乳酸林格氏液中加入L-缬氨酸,将L-缬氨酸的浓度调节为16.88g/l。 L-Val组)。另外,也设定了未处理组(Non-treat,NT组)。试验液给药结束后,在乙醚麻醉下由腹主动脉取血后进行尸体解剖,取出肝脏。2)结果
a)半乳糖胺诱发急性肝病大鼠模型
结果如表1所示。
通过投给半乳糖胺,使大鼠产生肝病,通过投给L-缬氨酸可以使之得到改善。另外,Fischer比(BCAA(Val、Leu、Ile)/AAA(Phe、Tyr、Trp))也得到了改善。
表1
对半乳糖胺诱发急性肝病大鼠模型的效果(试验液给药1日)
TP(g/dl) | Alb(g/dl) | GOT(IU/l) | GPT(IU/l) | LDH(IU/l) | Fisher比BCAA/AAA | |
NT组(n=6) | 5.6±0.1 | 2.7±0.1 | 136.0±52.8 | 69.5±19.0 | 813.0±310.5 | 2.63±0.16 |
对照组(n=5) | 4.6±0.2** | 2.4±0.1** | 1461.8±21.5** | 938.6±523.2** | 2213.0±1050.7** | 2.23±0.26* |
L-Val组(n=6) | 4.9±0.3**,## | 2.5±0.1 | 760.2±215.4*,## | 415.7±180.8*,## | 973.7±362.0## | 6.42±0.40**,## |
mean±SD ,*、**:分别表示相对于NT组有p<0.05、p<0.01的显著差异。#、##:分别表示相对于对照组有p<0.05、p<0.01的显著差异(Student t-检验)。
b)四氯化碳诱发急性肝病大鼠模型
结果如表2所示。
通过投给四氯化碳,使大鼠产生肝病,通过投给L-缬氨酸可以使之得到改善。另外,Fischer比(BCAA(Val、Leu、Ile)/AAA(Phe、Tyr、Trp))也得到了改善。
表2
对四氯化碳诱发急性肝病大鼠模型的效果(试验液给药2日)
TP(g/dl) | Alb(g/dl) | GOT(IU/l) | GPT(IU/l) | LDH(IU/l) | Fisher比BCAA/AAA | |
NT组(n=10) | 5.5±0.3 | 2.9±0.1 | 112.9±30.3 | 59.9±18.9 | 928.8±316.3 | 3.47±0.39 |
对照组(n=14) | 4.8±0.5** | 2.3±0.2** | 5485.3±3277.6** | 3010.6±1770.6** | 5320.3±9495.1** | 1.21±1.07** |
L-Val组(n=14) | 5.1±0.4*,# | 2.4±0.2**,# | 3241.9±2567.2**,# | 1951.2±1730.9** | 3040.1±4163.3** | 4.32±1.74## |
mean±SD,*、**:分别表示相对于NT组有p<0.05、p<0.01的显著差异。#、##:分别表示相对于对照组有p<0.05、p<0.01的显著差异(Student t-检验)。实施例2:对肝衰竭的作用1)试验方法
使用8~9周龄250g左右的Crj:Donryu雄性大鼠。在试验过程中,让其自由摄取大鼠用饲料MF(Oriental酵母公司生产)和水。断食12小时后,在乙醚麻醉下将导管插入到右颈静脉中,留于中心静脉中。然后,按照Gaub等的方法(J.Gaub等,《肝病学》Hepatology,4,902-904,1984年),切除肝的90%。中心静脉导管通过皮下由肩胛骨之间抽出,安装Harness后,通过protective coil,连接在Swivel(Bio-Cannula,Biomedica公司生产)上。将大鼠移至代谢笼中,在无麻醉·无拘束的条件下进行试验。将给药速度设定为100ml/kg/日,通过泵持续投给试验液。另外,肝切除之后立即通过皮下给药投给20%葡萄糖溶液3ml,肝切除后让其饮用10%葡萄糖溶液3天,之后让其饮用自来水。试验液的给药时间为4天或6天。试验液组分为乳酸林格氏液(Lactec(注册商标),大冢制药公司生产)组(对照组)以及缬氨酸组(在乳酸林格氏液中加入L-缬氨酸,将L-缬氨酸的浓度调节为16.88g/l。L-Val组)。另外,也设定了未处理组(Non-treat,NT组)。试验液给药结束后,在乙醚麻醉下由腹主动脉取血后进行尸体解剖,取出肝脏。2)结果
a)对切除肝90%引起肝衰竭大鼠模型的存活率的效果
结果如表3所示。
通过切除肝的90%,使大鼠出现肝衰竭状态,观察6天,发现约有半数死亡。然而,通过6天投给L-缬氨酸,可以使存活率得到显著改善。表3 对切除肝90%引起肝衰竭大鼠模型的存活率的效果(试验液给药6天)
动物数 | 存活数 | 死亡数 | 存活率 | 检验(Fisher的直接概率计算法) | |
对照组 | 20 | 10 | 10 | 50% | p<0.01 |
L-Val组 | 20 | 19 | 1 | 95% |
b)对切除肝90%引起肝衰竭大鼠模型的效果
结果如表4所示。
通过切除肝的90%,使大鼠出现肝衰竭状态,通过投给L-缬氨酸可以使之得到改善。另外,Fischer比(BCAA(Val、Leu、Ile)/AAA(Phe、Tyr、Trp))也得到了改善。
表4对切除肝90%引起肝衰竭大鼠模型的效果(试验液给药4日)
TP(g/dl) | Alb(g/dl) | GOT(IU/l) | GPT(IU/l) | Fisher比(BCAA/AAA) | |
NT组(n=5) | 5.6±0.3 | 2.6±0.1 | 159.0±35.1 | 86.2±25.6 | 3.56±0.33 |
对照组(n=9) | 2.8±0.8** | 1.5±0.3** | 549.9±335.4** | 168.0±82.5** | 0.78±0.27** |
L-Val组(n=10) | 3.6±0.5**,# | 1.8±0.2**,# | 402.3±302.4** | 134.9±76.3** | 3.33±1.11## |
mean±SD,*、**:分别表示相对于NT组有p<0.05、p<0.01的显著差异。#、##:分别表示相对于对照组有p<0.05、p<0.01的显著差异(Student t-检验)。实施例3:对慢性肝病的作用1)试验方法
使用8~9周龄的Crj:Donryu雄性大鼠。在试验过程中,让其自由摄取大鼠用饲料MF(Oriental Yeast公司生产)和水。将四氯化碳(和光纯药工业公司生产)用橄榄油(和光纯药工业公司生产)配制成50%(v/v)溶液后使用,通过皮下给药投给大鼠,1次给药2ml/kg,每周2次,给药14周(28次),制成慢性肝病模型。在14周的试验过程中给予试验饲料,对照组使用大鼠用饲料MF,L-Val组使用在大鼠用饲料MF中添加有3%重量的L-缬氨酸的饲料。另外,也设定了未处理组(Non-treat,NT组)。14周的试验结束后,在乙醚麻醉下由腹主动脉取血后进行尸体解剖,取出肝脏。2)结果
结果如表5所示。
通过投给四氯化碳14周,使大鼠产生慢性肝病,也发现了死亡例。另一方面,通过投给混有L-缬氨酸的饲料14周,可以改善肝病状态。表5
$、$$:分别表示有p<0.05以及p<0.01的显著差异(Fischer的直接概率计算法)。
a)mean±SD;**:表示相对于NT组有p<0.01的显著差异。##:表示相对于对照组有p<0.01的显著差异(Student t-检验)。实施例4:口服L-缬氨酸对C型慢性肝炎患者的效果
给C型慢性肝炎患者(女性)口服L-缬氨酸,1次1克,1日3次。该患者在服用L-缬氨酸前4个月的GOT和GPT平均值(mean±SD,每月1次,检查4次的平均值)分别为89.0±21.9IU/l和91.5±23.1IU/l,但是从开始服用第2个月后4个月的GOT和GPT平均值(mean±SD,每月1次,检查4次的平均值)分别为68.3±20.4IU/l和73.0±24.3IU/l,均显著(p<0.05,t检验)降低。另外,血小板数也可见改善效果,服用L-缬氨酸前6个月的血小板平均值(mean±SD,1或2个月1次,检查4次的平均值)为15.7±1.7(×104),但是从开始服用第2个月后4个月的血小板平均值(mean±SD,每月1次,检查4次的平均值)为20.4±0.9(×104),显著(p<0.01,t检验)增加。因此说明L-缬氨酸对慢性肝炎患者也有效。
工业实用性
本发明组合物是优良的用于治疗肝病或改善肝功能的组合物,比以前的药物疗法副作用少,可以治疗急性肝炎、肝衰竭、慢性肝炎、肝硬化等肝脏疾病,并可以使这些肝脏疾病引起的发热、倦怠、食欲不振、呕吐、腹痛、腹水等症状、异常或并发症(除肝性脑病外)得到改善、缓和、恢复。
Claims (10)
1、用于治疗肝病或改善肝功能的组合物,其特征在于含有缬氨酸作为有效成分,而且完全不含有缬氨酸以外的氨基酸,或实质上不含有缬氨酸以外的氨基酸作为有效成分。
2、用于改善肝功能的食品组合物,其特征在于含有缬氨酸作为有效成分,而且完全不含有缬氨酸以外的氨基酸,或实质上不含有缬氨酸以外的氨基酸作为有效成分。
3、如权利要求2所述的组合物,是功能性食品。
4、如权利要求1或2所述的用于治疗或改善的组合物,肝病为肝炎。
5、如权利要求1或2所述的用于治疗或改善的组合物,肝病为肝衰竭。
6、如权利要求1或2所述的用于治疗或改善的组合物,肝病为肝硬化。
7、如权利要求1~6中任意一项所述的用于治疗或改善的组合物,缬氨酸为L-缬氨酸。
8、如权利要求1或4~7中任意一项所述的用于治疗或改善的组合物,为注射剂。
9、如权利要求1或4~7中任意一项所述的用于治疗或改善的组合物,为输液制剂。
10、如权利要求1~7中任意一项所述的用于治疗或改善的组合物,为口服制剂。
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WO2001013912A1 (fr) | 1999-08-23 | 2001-03-01 | Chugai Seiyaku Kabushiki Kaisha | Medicaments destines a la regeneration d'un foie transplante |
EP1325743A4 (en) | 2000-10-13 | 2004-12-15 | Chugai Pharmaceutical Co Ltd | COMPOSITIONS TO IMPROVE FAT METABOLISM |
WO2003063853A1 (fr) * | 2002-01-31 | 2003-08-07 | Chugai Seiyaku Kabushiki Kaisha | Compositions de reduction de la graisse mesenterique |
JOP20190146A1 (ar) | 2016-12-19 | 2019-06-18 | Axcella Health Inc | تركيبات حمض أميني وطرق لمعالجة أمراض الكبد |
CU20200012A7 (es) | 2017-08-14 | 2021-02-04 | Axcella Health Inc | Composiciones de aminoácidos para el tratamiento de enfermedad hepática |
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JPS61186320A (ja) * | 1985-02-12 | 1986-08-20 | Morishita Seiyaku Kk | アミノ酸製剤 |
JP2618653B2 (ja) * | 1987-09-22 | 1997-06-11 | ルセル森下株式会社 | 肝性脳症患者用アミノ酸製剤 |
EP0605742A4 (en) * | 1992-06-26 | 1996-01-03 | Nonna Dmitrievna Kislyakova | Agent with adaptogenic activity. |
KR100322404B1 (ko) * | 1994-06-23 | 2002-05-09 | 나가야마 오사무 | 간재생용치료제 |
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DE69835609T2 (de) | 2007-08-09 |
KR100562739B1 (ko) | 2006-03-20 |
WO1999016433A1 (fr) | 1999-04-08 |
CA2305206A1 (en) | 1999-04-08 |
CN1149988C (zh) | 2004-05-19 |
ZA988924B (en) | 1999-03-30 |
EP1714649A3 (en) | 2007-09-05 |
EP1025844B1 (en) | 2006-08-16 |
ATE336241T1 (de) | 2006-09-15 |
KR20010030820A (ko) | 2001-04-16 |
HK1033275A1 (en) | 2001-08-24 |
DE69835609D1 (de) | 2006-09-28 |
EP1025844A1 (en) | 2000-08-09 |
EP1025844A4 (en) | 2002-10-02 |
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