CN1190346A - 一种包含植物乳杆菌和精氨酸的药物组合物 - Google Patents
一种包含植物乳杆菌和精氨酸的药物组合物 Download PDFInfo
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- CN1190346A CN1190346A CN96195399A CN96195399A CN1190346A CN 1190346 A CN1190346 A CN 1190346A CN 96195399 A CN96195399 A CN 96195399A CN 96195399 A CN96195399 A CN 96195399A CN 1190346 A CN1190346 A CN 1190346A
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- lactobacillus plantarum
- pharmaceutical composition
- arginine
- lactobacillus
- strain
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Abstract
本发明涉及药物组合物,其包含有具有体内于人肠粘膜移生的能力的植物乳杆菌菌株,与精氨酸和可药用载体相组合,本组合物用于哺乳动物,包括人的肝损伤和衰竭以及相关细菌转移的预防和/或治疗。
Description
本发明是关于一种药物组合物,它包括可移生或粘附于人类肠粘膜的植物乳杆菌菌株和精氨酸。所述组合物可用于急性肝损伤或肝衰竭的预防和治疗,也可以用于伴随粘膜屏障缺损和细菌转移(franslocatian)增加的相关情况。
发明背景
细菌转移,即微生物或毒性化合物通过穿过肠粘膜屏障或肠壁从肠腔中逃出,在很多疾病的发生中都很重要。例如细菌转移可发生于免疫妥协病人,疾病危象和多器官衰竭的病人,多创伤及烧伤病人,肝病或感染性肠病,及营养不良病人。病毒性肝炎,爆发性肝功能衰竭,肝硬变,酒精性肝炎,胆管炎和自身免疫性疾病如慢性活动性肝炎都是可发生细菌转移的肝脏疾病。肝炎,中毒或大的肝手术后发生急性肝功能衰竭时,细菌从肠腔的转移会增加。这可能可以解释在这些情况下所发生的某些感染性并发症。急性肝衰竭有很高的死亡率,其中很大比例的死亡可归结于脓毒症的高发率。疾病危象或免疫妥协病人的大部分感染是由病人自身的微生物区系引起的,许多死于脓毒症或多系统器官衰竭的病人均有肠菌血症,却没有发现脓毒症病灶,表明这些感染可能发源于肠。由于爆发性肝衰竭中临床有意义的细菌性脓毒症有很高的发生率,使预防性治疗也很有必要。
细菌转移可导致脓毒症及败血病,后者使肝衰竭成为可能,也可导致多器官衰竭。细菌感染增加的治疗可通过使用抗生素,但抗生素有许多副作用,还能影响肠粘膜屏障和微生物区系。
这些发现导致对有益于宿主体内微生物平衡的微生物种类的研究兴趣大增,这些微生物通过产生抗微生物组分或竞争性生长来维持宿主体内微生物平衡。其中乳杆菌是研究最多的种类之一,在某些情况中已显示了对病原体增殖的对抗作用。乳杆菌是构成正常胃肠微生态的必要部分,并参与宿主的代谢。用乳杆菌进行菌疗已报道在假膜性及溃疡性结肠炎中有效。
精氨酸对机体的免疫系统,尤其在创伤后有很大的影响。而且,精氨酸是多胺的已知前体,多胺是细胞生长和分化中重要的介质。精氨酸还可刺激局部和系统免疫系统。现有技术
SE9501056-7是关于特定的乳杆菌菌株在制备引发免疫反应的药物组合物及治疗完整肠上皮上的致病菌或潜在致病菌的转移中的应用,这种菌株具有粘附素,使其粘附于人类肠上皮细胞的受体。所述应用尤指植物乳杆菌299,DSM6595,植物乳杆菌299v,DSM9843,及其它属于所说明的群体的植物乳杆菌菌株的应用。
Gianotti,Luca等,外科学年报,217卷,第6期,644-654,考察了饮食的精氨酸对细菌转移的影响。给予添加精氨酸饮食的动物存活率升高。定量菌落计数和剩余可存活细菌的百分比计算表明接受精氨酸的动物,其杀死转移微生物的能力显著增强。
Daly,John E.,等,外科学,112卷:55-67,1992,显示手术后病人的肠道营养添加精氨酸,RNA和ω-3-脂肪酸后病人的免疫防御能力实现了不同的机制的提高。
发明详述
目前已惊奇地发现特定乳杆菌菌株和精氨酸的结合可显著地降低与细菌转移相关的肝损伤和衰竭的程度。
本发明是关于一种药物组合物,它包括
-具有体内移生于人肠粘膜能力的植物乳杆菌菌株;
-精氨酸;和
-可药用的载体。
本发明尤指一种药物组合物,其中乳杆菌株具有粘附素,使其粘附于人类肠上皮细胞的受体。糖蛋白受体和粘附素之间的粘附可被糖α-甲基甘露糖苷抑制,提示受体是包含甘露糖的。而这种受体与1型大肠杆菌菌毛的含甘露糖的受体不同,这一点通过血球凝集试验可显示。现认为受体包含有甘露糖α1-2甘露糖的序列。
本发明尤指一种药物组合物,其中植物乳杆菌菌株属于这样一族,其限制性内切酶谱分析利用Pearson乘积矩相关系数和与算术平均数的非加权对组算法(UPGMA;GelCompare3.0,应用数学,Kortrujk,Beljium)与保藏号为DSM6595的植物乳杆菌299菌株有70%以上相似性。
限制性内切酶谱分析,REA,是指对琼脂糖凝胶电泳上限制性酶所消化的细菌染色体DNA断裂方式的分析,方法则依照下文基因型确定中所描述。对菌株REA型特征的确认,可确定所用分离物。
本发明特指一种组合物,它包括以下任何菌株
植物乳杆菌299 DSM6595
植物乳杆菌299v DSM9843
植物乳杆菌79
植物乳杆菌105
植物乳杆菌107或REA与植物乳杆菌299有70%以上相似性的其它菌株。
优选的植物乳杆菌菌株在我们共同未决的申请SE9501056-7中有描述在此引入作为参考作为参考。
组合物中的精氨酸优选L-精氨酸。但用富含精氨酸的蛋白如棉籽蛋白或来自大豆或豌豆的蛋白也是可能的。
本发明的药物组合物除乳杆菌菌株和精氨酸外,还包括可药用的载体。传统的载体,例如,被所述细菌发酵的,生理学上可接受的底物及各种食料,尤其是以淀粉或牛奶为基础的食物,同时还必须是惰性的固体或液体物质,例如盐水或水。合适的底物应含有在胃肠道不被吸收的液体或固体纤维,当它们与乳杆菌发酵时,形成短的脂肪酸。谷类,如燕麦及小麦,玉米,根类蔬菜如马铃薯及某些水果如未熟香蕉等均可作为合适的,含淀粉的底物的例子。
根据本发明,组合物可通过任何适当的方式给药,优选口服或直肠,如灌肠剂。也可以通过经胃插入小肠或直接插入小肠的导管肠道给药。试验表明如果提供食物纤维,例如燕麦粥或β-葡聚糖,疗效会有所提高。治疗应每日一至数次,持续1-2周。
与肝外科手术或肝炎等有关的肝衰竭中,肝脏无法行使其正常功能,使得氨,含氮化合物,内毒素和其它细菌产物未经代谢而通过肝脏,而危及人体。在这些情况下,减少肝负荷的一个办法就是给患者灌肠或促使其腹泻,以冲洗肠道。但这样做同时会使肠正常功能所需的许多产物被冲掉。本发明的组合物优选以灌肠剂用于这种情况。
药物组合物中的所用乳杆菌株优选浓度为107-109CFU/ml。人体所用精氨酸的优选剂量为25-20克/天。
口服给药优选的载体为乳酸发酵的食品,如以燕麦为基质的营养液,象WO89/08405中所述,或以牛奶为基质的营养液如奶酪。另一种优选的载体是食物纤维产品,如β-葡聚糖,果料,寡糖,它们均属于乳酸发酵食品。口服给药的优选量为每天100-200毫升,1-5次服用。
口服用的组合物优选含被保护免于在小肠内被消化的精氨酸组分,例如可通过成胶寡糖将精氨酸预先聚集的方法,当在胃肠道胀起时,就会在表面覆盖一层保护性胶,直至在结肠中发酵。这种覆盖胶可采用果胶,瓜耳子粉及Konjac植物中的葡甘露聚糖,如商品Propal(Shimizu Co.,日本)
直肠给药的载体优选一种生理性溶液,使精氨酸,乳杆菌及一种选择的食物纤维如β-葡聚糖或果胶悬浮于其中。每天用药1-2次,优选量为20-50毫升。
附图简述
图1是所检测的不同乳杆菌菌株相似性的树状图。这些乳杆菌菌株已由基于Pearson乘积矩相关系数和UPGMA的REA法鉴定。
菌株的确认
从正常人体肠粘膜所分离得到的菌株299和299v,已分别于1991年7月2日和1995年3月16日存放于德国微生物菌种和细胞保藏中心GmbH,保藏号分别为DSM6595(299)及DSM9843(299v)。
表型的确定菌株299,299v,79,105及107是在PH5.5下,生长于Rogosa琼脂上的革兰氏阳性,过氧化氢酶阴性的菌株。它们可在厌氧条件下由葡萄糖产生乳酸。这些菌株发酵不同的碳水化合物的能力列于表1。所有测试均遵照生产商的建议通过API 50 CH进行。
表1
API 50CH上,30℃, 37℃乳酸杆菌Planterum299,299v,107,105及275的发酵方式碳水化合物 植物乳杆菌 植物乳杆菌 植物乳杆菌 植物乳杆菌 植物乳杆菌
299 299v 107 105 79
30℃ 37℃ 30℃ 37℃ 30℃ 37℃ 30℃ 37℃ 30℃ 37℃甘油 - - - - - - - - - -赤藓醇 - - - - - - - - - -D-阿拉白糖 - - - - - - - - --L-阿拉伯糖 + + + + + + + + ++核糖 + + + + + + + + + +D-木糖 - - - - - - - - - -L-木糖 - - - - - - - - - -阿东糖醇 - - - - - - - - - -β-甲基- - - - - - - - - - -木糖苷半乳糖 + + + + + + + + + +D-葡萄糖 + + + + + + + + + +D-果糖 + + + + + + + + + +D-甘露糖 + + + + + + + + + +L-山梨糖 - - - - - - - - - -鼠李糖 - - - - - - - - - -卫矛糖 - - - - - - - - - -肌醇 - - - - - - - - - -甘露醇 + + + + + + + + + +山梨醇 + + + + + + + + + +α-甲基-D- + + + + + + + + + +甘露糖苷α-甲基-D- - - - - - - - -葡萄糖胺N-乙酰基- + + + + + + + + + +葡萄糖胺苦杏仁苷 + + + + + + + + + +熊果苷 + + + + + + + + + +七叶灵 + + + + + + + + + +水杨苷 + + + + + + + + + +纤维素二糖 + + + + + + + + + +麦芽糖 + + + + + + + + + +乳糖 + + + + + + + + + +蜜二糖 + + + + + + + + + +蔗糖 + + + + + + + + + +海藻糖 + + + + + + + + + +菊粉 - - - - - - - - - -松三糖 + + + + + + + + + +D-棉子糖 - + - + - - - - - -淀粉 - - - - - - - - - -糖原 - - - - - - - - - -木糖醇 - - - - - - - - - -β-葡二糖 + + + + + + + + + +D-松二糖 + + + + + + + + + +D-来苏糖 - - - - - - - - - -D-塔格糖 - - - - - - - - - -D-岩藻糖 - - - - - - - - - -L-岩藻糖 - - - - - - - - - -D-阿拉白 - - + - + - + - + -糖醇L-阿拉白 - - - - - - - - - -糖醇葡糖酸酯 + + + + + + + + + +2-鲸蜡醇 - - - - - - - - - -葡糖酸酯5-鲸蜡醇 - - - - - - - - - -葡糖酸酯
菌株的表型被确定为植物乳杆菌。
基因型的确认
REA
通过限制性内切酶分析-REA-法测试了菌株的染色体DNA的断裂方式,所用REA法依照Stahl M,Molin G,Perss;on A,Ahrne S及Stahl S.,国际系统细菌学杂志,1990,40:189-193及更进一步为Jahansson,M-L,等发展的,国际系统细菌学杂志,1995,45:670-75。概要地说,REA可描述如下:制备并以限制性内切酶切割所研究菌株的染色体DNA。0.75微克的各种DNA均分别以10个单位的HindIII,ClaI及EcoRI在37℃消化4小时;每种内切酶单独使用。Stahl等,同上,以Asp718代替HindIII,但以Asp718消化产生太多较大的带,对现有方法不是最佳的。切割所得的DNA片段通过浸没的水平琼脂糖厚凝胶电泳按大小分开。凝胶包括150毫升0.9%琼脂糖(DNA级超纯;低电渗;BioRad实验室,Richmond,USA),并形成胶块(150×235毫米)。以0.2微克的高分子量的DNA标准物(Bethesda研究室,BRL)和DNA分子量标准物IV(Boehringer Mannheim,德国)作为标准。另外,在每个孔内加入被EcoRI消化的pHC(79分子量为4.2×106;Boehringer Mannheim)作为内标。样品DNA用Ficoll上样缓冲液(2克Ficoll,8毫升水,0.25%溴酚兰)可达到最小带扭曲和最大清晰度。8.5℃,40V稳压下跑胶18小时。在跑胶过程中循环缓冲液(89mMTris,2mM EDTA Na,PH8.3)。然后在溴乙锭(2微克/毫升)染色20分钟,蒸馏水中脱色,紫外灯(UVP Inc.,San Gabriel,USA)302纳米观察,照像。这种跑凝胶电泳的方法可得到分布较好,分离相对好的带,允许分子量甚至低至1.2×106。
底片上的带图像用激光密度扫描仪(UltroScan XL;LKB-ProdukterAB,Bromma,瑞典)扫描。分辨率是每行1000点,每行约50毫米长。用LKB2400 GelScan XL软件包(LKB-Produkter AB)获得数据。用GelCompar 3.0程序的滚盘算法来校正带型和减除背景噪音。每个菌株三次切割(被HindIII,ClaI及EcoRI)所得数据组合起来(用GelCompar3.0)。
数据集用Pearson乘积矩相关系数(r)和形成与算术平均数的非加权配对算法(UPGMA)(Romersburg,H.C.1984,研究用集分析。Lifeimelearning出版,Belmont,California,USA)进行分析。用GelCompar 3.0程序计算全数据集的Pearson乘积矩相关系数和UPGMA值。图1中与植物乳杆菌299有>70%相似性的集被标记出。
质粒图谱
依照Chassy等(1976)所述方法检测菌株的质粒成分。植物乳杆菌299,299v,79和105具有相同的质粒图谱,即4,9,15,21和>30MDa的五个质粒。植物乳杆菌107有三个质粒,4,15,和21Mda。
大鼠体内的生物学试验
本试验的目的在于研究急性肝损伤模型中,直肠补充含精氨酸和不含精氨酸的不同菌株的乳杆菌,对肝损伤和细菌转移程度的影响。
试验用了五种不同的乳杆菌菌株:从大鼠肠粘膜分离得到的L.reuteriR2LC,从人结肠分离得到的鼠李糖乳杆菌DSM6594(菌株271),从人空肠分离得到的乳杆菌DSM8704:3(菌株245),从人空肠分离得到的L.reuteri 108及从人空肠和直肠分离得到的植物乳杆菌DSM9843(菌株299v)。所有菌株均由瑞典Lund大学,食品技术系,食品卫生实验室提供。
将体重在200-300克范围内的雄性Sprague-Dawley大鼠分成13组,每组六只:正常组,急性肝损害对照组(ALI),补充精氨酸组(SA),补充乳杆菌reuteri R2CL组(SR),补充乳杆菌reuteri R2CL+精氨酸组(SRA),补充鼠李糖乳杆菌271组(SS),补充鼠李糖乳杆菌271+精氨酸组(SSA),补充植物乳杆菌299v组(SP),补充植物乳杆菌299v+精氨酸组(SPA),补充发酵乳杆菌8704:3组(SF),补充发酵乳杆菌8704:3+精氨酸组(SFA),补充乳杆菌reuteri 108组(ST),补充乳杆菌reuteri108+精氨酸组(STA)。整个试验过程中给所有的大鼠以正常的食物(R3,丙氨酸AB,Stockholm)和水ad libitum,12小时光照/黑暗循环及保持22℃室温。通过直肠插管每天直肠给含和不含精氨酸的不同乳杆菌菌株一次,共8天。乳杆菌菌株的每天补充量为每个动物3毫升,约3×109CFU。第8天时,腹膜内注射D-氨基半乳糖(Sigma Chemical Co.,St louis,USA)1.1克/千克体重,这种剂量的D-氨基半乳糖可引起细菌由肠腔向远处器官泄漏的增加,来诱导急性肝损伤。急性肝损伤对照组8天内每天补充正常盐水,第8天时诱导肝损伤。诱导肝损伤后24和48小时采样。乙醚麻醉,无菌条件下进行中线切口剖腹。收集门静脉血用于细菌学试验,动脉血用于细菌学和肝酶试验。肝脏尾叶和肠系膜淋巴结(MLN)处采到的样用于细菌学和肝脏的组织学研究。
细菌转移的发生率细菌学分析中,样品立即放入含EDTA的无菌试管中。组织样品放入5毫升无菌转移介质中。超声浴中超5分钟后,在Chiltern(Terma-Glas,瑞典)上旋转2分钟。将1.0毫升样品置于脑心扩散琼脂BHI(Oxoid)上,37℃孵育3天,进行整个需氧平皿计数。将样品置于BHI上,厌氧条件下37℃培育进行整个厌氧平皿计数。3天后对每个平皿上的克隆计数,并对原组织重量进行校正。每组六只动物中的每个大鼠的不同部位细菌转移的发生率见下表1。表1 24小时后细菌转移的发生率
与急性肝对照组比较,*代表p<0 05,**代表p<0.01
组别 | 门脉血 | 动脉血 | 肝 | MLN |
Normal | 0/6 | 0/6 | 0/6 | 0/6 |
ALL | 5/6 | 6/6 | 6/6 | 6/6 |
SA | 5/6 | 3/6 | 6/6 | 4/6 |
SRA | 1/6* | 1/6** | 4/6 | 2/6* |
SR | 2/6 | 1/6** | 5/6 | 3/6 |
SSA | 5/6 | 4/6 | 6/6 | 6/6 |
SS | 3/6 | 3/6 | 6/6 | 6/6 |
SPA | 2/6 | 1/6** | 5/6 | 5/6 |
SP | 3/6 | 2/6* | 4/6 | 2/6* |
SFA | 1/6* | 2/6* | 5/6 | 5/6 |
SF | 5/6 | 2/6* | 5/6 | 5/6 |
STA | 1/6* | 1/6** | 4/6 | 4/6 |
ST | 2/6 | 1/6** | 4/6 | 4/6 |
上述细菌转移发生率的计数表明了在大鼠血液或组织中细菌的存在与否;也就是说,如果找到至少一个细菌,该大鼠就得一正值。细菌转移的发生率用Fisher的准确测试法进行评价。小于0.05的可能性水平就认为是有意义的。
正如表1可以看出,与正常对照组相比,急性肝损伤组细菌转移至血液中的发生率有明显提高。而补充含和不含精氨酸的植物乳杆菌299v,乳杆菌reuteri R2CL和108,发酵乳杆菌8704:3的各组,细菌转移的发生率则均显著降低。与急性肝损伤组比较,所有组的肝脏和肠系膜淋巴结的细菌转移发生率均稍显降低。
血液中的肝酶按照斯堪的那维亚临床化学和临床生理学会的酶学委员会推荐(Scan J Clin Lab Inves 1974;33:291-306),将血液在Kodak,Echa chem 700XRC上离心(1000xg,10分钟)后,进行动脉血中肝酶,血清胆红素(Bil),碱性磷酸酶(ALP),天冬氨酸氨基转移酶(ASAT),丙氨酸氨基转移酶(ALAT)的水平的测定。血清氨基转移酶是肝细胞损伤的敏感标志,对于识别肝细胞损伤最有帮助,它们常被用作肝疾病的测量标识物。肝胆管疾病会导致血清碱性磷酸酶的上升。肝细胞损伤中,血清胆红素的水平也较高。血清胆红素的升高,ASAT或ALAT的升高,及碱性磷酸酶水平升高,可准确预测肝脏疾病的存在。
所有值均为平均值±SEM。结果用所有成对多重比较法进行了统计学评价。表2动脉血肝酶水平
*利用Neuman-Keuls全组多重比较法与ALI组相比,p<0.05
组别 | ALP(μKaat/l) | Bil(μKat/l) | ASAT(μKat/l) | ALAT(μKat/l) |
ALI | 16.43±1.41 | 16.17±3.36 | 97.83±15.90 | 86.17±16.44 |
SA | 14.86±1.12 | 14.57±2.20 | 59.83±12.54 | 50.50+8.89 |
SRA | 14.55±1.48 | 14.50±4.15 | 60.42±12.92 | 48.87±12.04 |
SR | 14.83±0.60 | 15.00±1.46 | 62.67±3.76 | 58.83±9.64 |
SSA | 15.60±1.69 | 15.80±4.72 | 65.17±21.13 | 60.50±17.99 |
SS | 16.20+2.58 | 15.62+4.20 | 65.57±23.35 | 64.03±13.97 |
SPA | 12.83±0.83 | 6.58±1.56 | 23.00±4.57* | 25.32±5.16 |
SP | 13.67v1.28 | 10.85±2.40 | 45.18+10.23 | 44.67±10.84 |
SFA | 14.67±1.43 | 13.83±2.98 | 55.50±16.67 | 56.55±17.03 |
SF | 14.92±0.84 | 14.83±5.69 | 57.35±13.53 | 57.67±13.20 |
STA | 13.67±1.33 | 12.00±5.14 | 46.17±11.63 | 41.83±10.68 |
ST | 14.17±1.19 | 14.00±1.98 | 59.67+12.93 | 58.33±11.57 |
从上表可以看出,补充含精氨酸和不含精氨酸的乳杆菌的各组,肝酶水平均下降,在补充以精氨酸和植物乳杆菌的组中,这种下降最为显著。
肝脏的组织形态学将从肝叶取得的样品置于含4%磷酸缓冲液的甲醛中。将石蜡封藏的样品进行组织切片,苏木紫和伊红染色后在光学显微镜下观察。每种至少观察3张切片。按照Chojkier,M等,胃肠病学1985;88:115-21,和Shiratori,Y.等,肝脏病学1988;8(4):815-21,稍作改进的方法进行肝脏形态学计数。肝细胞坏死程度和感染性细胞浸润均在Lund大学病理系进行定量如下肓测:
1小量
2中等量
3亚大量
4大量结果列于下表3。表3
*利用Dunn全组多重比较法与ALI组相比,p<0.05
24小时 | 48小时 | ||
组别 | 总计数 | 组别 | 总计数 |
ALISASRASRSSASSSPASPSFASFSTAST | 4.8±0.34.3±0.23.5±0.64.0±0.34.3±0.24.2±0.42.8±0.2*4.0±0.04.2±0.54.0±0.54.0±0.04.3±0.3 | ALISASRASP | 5.3±0.53.3±0.2*3.0±0.6*3.7±+0.2 |
肝损伤后24小时和48小时,补充以植物乳杆菌+精氨酸的组与急性肝损伤对照组显示出明显不同的肝形态学。小结
不同病因学的,伴有急性肝衰竭的病人肠道细菌的感染发生率很高,约30-40%。细菌向肠外的转移能诱导肝衰竭,并能导致浓毒症和多器官衰竭。从上述试验可以看出,本发明的含精氨酸和植物乳杆菌菌株的组合物在预防肝损伤和衰竭及相关细菌转移方面,比其它的测试菌株优越,这可从其可使肝酶和胆红素的释放明显减少,细菌转移减少和肝脏形态学计数中得以证实。
Claims (10)
1.一种药物组合物,包括
-体内能够移生于人肠粘膜的植物乳杆菌菌株;
-精氨酸;及
-可药用的载体。
2.权利要求1的药物组合物,其中植物乳杆菌菌株具有粘附素,使其粘附于人类肠上皮细胞的受体。
3.权利要求1或2的药物组合物,其中乳杆菌菌株是一类植物乳杆菌,它属于限制性内切酶谱分析与贮存号DSM6595的植物乳杆菌299菌株,用Pearson乘积矩相关系数(r)和与算术平均数的非加权配对算法(UPGMA;GelCompare 3.0,Applied Maths,Kortrijk,Belgium)分析有70%以上相似性的一族。
4.权利要求1-3的任意项的药物组合物,其中植物乳杆菌菌株选自植物乳杆菌299,DSM6595和植物乳杆菌299v,DSM9843。
5.权利要求1-4的任意项的药物组合物,其中精氨酸是L-精氨酸。
6.权利要求1-5的任意项的药物组合物,用于口服或直肠给药。
7.权利要求1-6的任意项的药物组合物,用于治疗哺乳动物,包括人的急性肝损伤和衰竭及相关的细菌转移。
8.一种用于哺乳动物,包括人的急性肝损伤和衰竭及相关的细菌转移的,治疗性和/或预防性处置的方法,它包括权利要求1-6的药物组合物的治疗有效剂量的给药。
9.一种药物组合物,包括植物乳杆菌菌株和精氨酸的结合用于治疗。
10.权利要求1-6和9的任一的组合物,在制造哺乳动物,包括人,的急性肝损伤和衰竭及相关的细菌转移的治疗性和/或预防性处置药物的应用。
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CN1322111C (zh) * | 2004-12-17 | 2007-06-20 | 上海交大昂立股份有限公司 | 一种植物乳杆菌 |
CN1798831B (zh) * | 2003-04-04 | 2011-05-18 | 普罗比公司 | 含有与丹宁组合的植物乳杆菌菌株的组合物和新植物乳杆菌菌株 |
CN102618456A (zh) * | 2012-02-28 | 2012-08-01 | 江南大学 | 一种能够缓解慢性酒精性肝损伤的鼠李糖乳杆菌及其用途 |
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KR100376954B1 (ko) * | 1995-07-31 | 2003-07-18 | 프로비 에이비 | 장에서집락화하는유산간균 |
JP2003527432A (ja) | 2000-03-24 | 2003-09-16 | ソシエテ デ プロデユイ ネツスル ソシエテ アノニム | 腹膜炎の治療のための乳酸菌の使用 |
KR100585391B1 (ko) * | 2002-01-24 | 2006-06-01 | 주식회사 프로바이오닉 | 돼지 전염성위장염 (TGE) 코로나바이러스 및 유해 미생물 억제 활성을 갖는 신규 락토바실러스 프란타럼 Probio-38 및 이를 함유하는 생균활성제 |
EP1736164A4 (en) | 2004-03-31 | 2009-06-24 | Calpis Co Ltd | MEANS FOR THE PREVENTION OR SUPPRESSION OF HEPATOPATHY AND FUNCTIONAL FOOD FOR THE PREVENTION OR SUPPRESSION OF HEPATOPATHY |
KR100592717B1 (ko) * | 2004-11-20 | 2006-06-26 | 주식회사 알엔에이 | 간 손상 보호 및 예방에 유용한 활성을 갖는 조성물 |
CN100337653C (zh) * | 2004-12-21 | 2007-09-19 | 上海交大昂立股份有限公司 | 一种含有植物乳杆菌的组合物 |
AU2006296837B2 (en) | 2005-09-28 | 2012-12-13 | Nordic Rebalance A/S | Treatment of IBD and IBS using both probiotic bacteria and fermented cereal as treatment effectors |
JP5413819B2 (ja) * | 2008-02-08 | 2014-02-12 | 国立大学法人広島大学 | 肝機能改善剤およびその製造用ツール、ならびにこれらの利用 |
KR101075557B1 (ko) | 2008-12-03 | 2011-10-20 | 씨제이제일제당 (주) | 신규한 락토바실러스 플란타룸 및 이를 포함하는 조성물 |
JP5823695B2 (ja) * | 2008-12-03 | 2015-11-25 | 国立大学法人広島大学 | 肝機能障害予防剤 |
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KR101255050B1 (ko) | 2009-07-14 | 2013-04-16 | 씨제이제일제당 (주) | 신규한 락토바실러스 플란타룸 및 이를 포함하는 조성물 |
KR101486999B1 (ko) | 2009-07-22 | 2015-01-28 | 씨제이제일제당 주식회사 | 신규한 락토바실러스 플란타룸 및 이를 포함하는 조성물 |
TWI463986B (zh) * | 2012-08-29 | 2014-12-11 | Univ China Medical | 胚芽乳酸桿菌cmu995菌株之新用途 |
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1995
- 1995-05-09 SE SE9501719A patent/SE9501719D0/xx unknown
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1996
- 1996-05-08 DE DE69622855T patent/DE69622855T2/de not_active Expired - Fee Related
- 1996-05-08 CA CA002220498A patent/CA2220498A1/en not_active Abandoned
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- 1996-05-08 DE DE0825869T patent/DE825869T1/de active Pending
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1798831B (zh) * | 2003-04-04 | 2011-05-18 | 普罗比公司 | 含有与丹宁组合的植物乳杆菌菌株的组合物和新植物乳杆菌菌株 |
CN1322111C (zh) * | 2004-12-17 | 2007-06-20 | 上海交大昂立股份有限公司 | 一种植物乳杆菌 |
CN102618456A (zh) * | 2012-02-28 | 2012-08-01 | 江南大学 | 一种能够缓解慢性酒精性肝损伤的鼠李糖乳杆菌及其用途 |
CN102618456B (zh) * | 2012-02-28 | 2013-08-21 | 江南大学 | 一种能够缓解慢性酒精性肝损伤的鼠李糖乳杆菌及其用途 |
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DE69622855D1 (de) | 2002-09-12 |
SE9501719D0 (sv) | 1995-05-09 |
EE9700269A (et) | 1998-04-15 |
NO975136D0 (no) | 1997-11-07 |
ES2112818T3 (es) | 2003-02-16 |
BR9608284A (pt) | 1999-06-08 |
AU5784696A (en) | 1996-11-29 |
AU704886B2 (en) | 1999-05-06 |
WO1996035440A1 (en) | 1996-11-14 |
PL184603B1 (pl) | 2002-11-29 |
CA2220498A1 (en) | 1996-11-14 |
EP0825869A1 (en) | 1998-03-04 |
JPH11504936A (ja) | 1999-05-11 |
CN1152678C (zh) | 2004-06-09 |
JP4058560B2 (ja) | 2008-03-12 |
EE03597B1 (et) | 2002-02-15 |
EP0825869B1 (en) | 2002-08-07 |
DE69622855T2 (de) | 2003-04-10 |
PL323320A1 (en) | 1998-03-16 |
NO317668B1 (no) | 2004-11-29 |
NO975136L (no) | 1997-11-07 |
KR19990008403A (ko) | 1999-01-25 |
ATE221783T1 (de) | 2002-08-15 |
GR980300028T1 (en) | 1998-04-30 |
ES2112818T1 (es) | 1998-04-16 |
DE825869T1 (de) | 1998-07-16 |
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