CN1175887A - 氨基酸组合物及其在临床营养中的应用 - Google Patents
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- CN1175887A CN1175887A CN96192066A CN96192066A CN1175887A CN 1175887 A CN1175887 A CN 1175887A CN 96192066 A CN96192066 A CN 96192066A CN 96192066 A CN96192066 A CN 96192066A CN 1175887 A CN1175887 A CN 1175887A
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Abstract
本发明提供选自包含甘氨酸,丙氨酸和丝氨酸的组的至少一种氨基酸,或其生理学上可接受盐的应用,用于制备供在肿瘤坏死因子(TNF)水平升高到超出调节生理平衡和局部炎症的水平的病人中降低TNF水平的药物或营养制剂。这种TNF水平的下降的获得尤其是通过抑制或降低:(i)巨噬型细胞产生肿瘤坏死因子(TNF);(ii)TNF从巨噬型细胞释放;和/或(iii)TNF被TNF受体结合。
Description
本发明涉及特殊氨基酸在药物或营养制剂的制备中的应用,这些药物或营养制剂可治疗性施用于患多种疾病和疾病状态的病人。
现已出乎意料地发现,特别地,甘氨酸适合防止和/或将多种疾病状态和由TNF水平升高诱导的损伤性或其它疾病状态的代谢性效应降至最低。
鉴于上述效应,提供了包含甘氨酸的药物组合物,制剂和食物以及使用甘氨酸的方法。为在本发明的组合物、制剂、食物和方法中应用,甘氨酸方便地以游离氨基酸形式,处于甘氨酸前体形式,特别是丙氨酸或丝氨酸,同样也制成游离氨基酸形式,所述氨基酸的生理学上可接受盐形式,或所述氨基酸和/或其生理学上可接受盐的混合物形式使用。甘氨酸优选以游离氨基酸形式,生理学可接受盐形式或游离氨基酸形式的甘氨酸与生理学上可接受盐形式的甘氨酸的混合物形式应用,最优选甘氨酸处于游离氨基酸形式使用。
后文使用的术语“本发明的氨基酸”指处于游离氨基酸形式和/或生理学上可接受盐形式的甘氨酸,丙氨酸和/或丝氨酸。
本发明因此提供在药物或营养制剂制备中选自包含甘氨酸、丙氨酸或丝氨酸的至少一种氨基酸或其生理学上可接受盐的应用。这种药物或营养制剂用于在肿瘤坏死因子(TNF)水平高于调节生理体内平衡和局部炎症的水平的病人中降低TNF水平。这种TNF水平降低的获得尤其可通过抑制或降低:
(i)巨噬型细胞类产生的肿瘤坏死因子(TNF);
(ii)TNF从巨噬型细胞类的释放;和/或
(iii)TNF被TNF受体的结合。
“高于调节生理体内平衡和局部炎症的水平”是指高于调节体温、睡眠和食欲的生理节律最低所需或在产生或分泌TNF的并缺乏远离这些细胞的全身性炎症效应的,细胞的邻近细胞中行使自分泌和旁分泌作用最低所需的TNF量。
本发明还提供选自包含甘氨酸、丙氨酸和丝氨酸的至少一种氨基酸或其生理学上可接受盐在制备药物或营养制剂中的应用。这些药物或营养制剂用于防止或降低巨噬细胞诱导的-TNF介导的-至少一种蛋白的产生,这些蛋白选自白介素1,白介素2,白介素6,白介素8,白介素10,内皮细胞,血小板和白细胞选择蛋白,白细胞功能相关抗原1,极迟活化抗原4,细胞间粘附分子,血小板因子4,嗜中性细胞吸引/激活蛋白,Sialyl-Lewis-X,γ干扰素诱导的多肽,巨噬细胞炎性蛋白α和β,上皮细胞衍生的嗜中性细胞吸引剂,粒细胞趋化蛋白2,单核细胞趋化蛋白1,血管细胞粘附分子1,和淋巴细胞功能抗原3。
虽然按照本发明的应用特别涉及血中的巨噬细胞类(单核细胞或单核吞噬细胞),胆肝(库否细胞),神经***(星形胶原细胞),消化***(肠系膜/肠),心脏,肾和骨(骨细胞衍生的巨噬细胞),所有产生,结合或释放TNF的细胞均为本发明的氨基酸的靶细胞。特别地设想到,TNF对肺衍生或定位于肺的巨噬细胞的产生,释放或结合,将因施用按照本发明的药物或制剂于病人而受影响。
本发明还提供一种方法,用于降低内毒素性休克和/或缺氧性再灌注损伤,特别是创伤(多处创伤,烧伤和手术后病人以及败血症病人)后的死亡危险,包括施用有效量的本发明的氨基酸。内毒素性休克和缺氧性再灌注损伤均为可导致病人死亡并涉及TNF水平升高的疾病。
本发明还提供至少一种选自甘氨酸、丙氨酸和丝氨酸的氨基酸,或其生理学上可接受盐在制备药物或营养制剂中的应用,这些药物或营养制剂用于在需要这种治疗的病人中防止或降低由于饮酒过多所致肝病和其所导致的肠或胰腺疾病的危险。对于此适应症,甘氨酸和/或丝氨酸或其生理学上可接受盐的应用是优选的,而甘氨酸或其生理学上可接受盐的应用是特别优选的。
本发明还提供至少一种选自甘氨酸、丙氨酸和丝氨酸的氨基酸,或其生理学上可接受盐在制备药物或营养制剂中的应用,这些药物或营养制剂用于在需要这种治疗的病人中防止或降低乙醇毒性。对于此适应症,甘氨酸和/或丝氨酸或其生理学上可接受盐的应用是优选的,而甘氨酸或其生理学上可接受盐的应用是特别优选的。
本发明也提供选自甘氨酸、丙氨酸和丝氨酸的至少一种氨基酸,或其生理学上可接受盐在药物或营养制剂制备中的应用,这些药物或营养制剂用于在需要这种治疗的病人中在乙醇进入全身血液循环前从胃中消除乙醇。
本发明还提供了本发明的氨基酸作为用于治疗乙醇毒性的食物、软饮料、维生素或药物制剂的添加剂的应用,以及采用有效量的本发明的氨基酸防止乙醇毒性的方法。
优选将本药物或制剂以使本发明的氨基酸降低循环***中TNF水平至低于250pg/ml(±10%)的量施用于病人,特别适用于遭受严重(II或III度)烧伤的创伤病人,在这些病人中可能已有一些细菌内毒素漏入体循环中但却无明显的败血症临床表现。更优选本发明的氨基酸降低循环***中的TNF水平至低于80pg/ml(±10%),还更优选TNF水平被降低至20pg/ml(±10%)以下。技术人员熟知如何检测TNF水平,特别是通过公知的酶联免疫吸附或放射免疫测定法。
本发明还提供选自甘氨酸、丙氨酸或丝氨酸的至少一种氨基酸或其生理学上可接受盐在用于防止或减轻TNF诱导的(acturial)同种异体移植排异的药物或营养制剂制备中的应用。同种异体移植可涉及任何器官,但对病人最有意义的见于涉及肺、心脏、肝、肠/肠系膜和肾的移植或注射手术情况中。
在本药物或制剂施用于移植病人的情况,适宜进一步包含至少一种下列化合物:针对TNF产生的中和抗体,TNF可溶性受体或其衍生物或一部分,和环状多肽免疫抑制因子。适合包含在本药物中的公知的环状多肽免疫抑制因子的一个实例是环胞霉素,或其有效衍生物。一种特别适合的TNF可溶性受体包含一种合成二聚可溶性融合蛋白结构,该结构将两个p60TNF受体用一个IgG分子的Fc片段结合在一起。此融合蛋白结构具有更高的亲合力,并且与天然单体TNF受体(p80或p60)或抗-TNF抗体两者相比是TNF生物活性的更强抑制因子。
本营养制剂或药物可预防性地,即术前,或在急性期,即术后,也可在两种情况下都用药。
本营养制剂或药物可经胃肠道或胃肠外向病人用药。优选经胃肠用药途径,特别是随后或预防性治疗,特别考虑的经胃肠用药途径是口服用药,经鼻用药和/或管饲。该药物或制剂方便地以水溶液形式用药。因此,适合经胃肠应用的形式的药物或制剂优选为水性或为粉剂形式,而粉剂方便地在使用前加入水中。特别地,对于在管饲中使用,加水总量取决于病人的液体需求和疾病。应认识到,对于紧急治疗,优选胃肠外应用途径。另外,例如当目标为控制慢性内毒素血症效应时,也适合胃肠外应用途径。
该药物或制剂也可配制为每24小时向病人输送1至80g本氨基酸。应用的药物或制剂的量在很大程度上取决于病人的特殊需求。本发明的氨基酸的这种每日总量适合所希望的效应的治疗和预防/预治疗。在该药物或制剂包含本发明的一种氨基酸(L-构型)时,可按照使病人血浆中该氨基酸浓度升至0.5和2.0mM,优选1.0mM的剂量向病人用药。当期望比此更高浓度时,也期望如果氨基酸浓度提高将获得显著临床效果,作为施用本制剂或药物的后果,因此其范围在1.2至1.5mM。在创伤,高分解代谢病人中,即使是将血浆甘氨酸、丝氨酸或丙氨酸水平升高至相当于健康个体血浆甘氨酸水平的约0.2-0.3mM也是有益的。
最优选的用于掺入供按照本发明使用的药物或制剂的本发明氨基酸是甘氨酸或其生理学上可接受盐。
通常,需要将本发明的氨基酸与一或多种下列成分合并使用:(i)ω-3多不饱合脂肪酸(PUFAs),希望与ω-6PUFAs混合在一起;(ii)L-精氨酸或其它与多胺合成相关的生理学上可接受化合物,或其混合物;和(iii)一种核碱基(nucleobase)来源。
使用包含本发明的氨基酸加上精氨酸或其它与多胺合成相关的生理学上可接受化合物如乌氨酸的药物或营养制剂是优选的。使用包含本发明的氨基酸,精氨酸或鸟氨酸以及ω-3多不饱合脂肪酸(PUFAs)的药物或营养制剂也是优选的。
适合与本发明的氨基酸一同使用的核碱基来源包含或包括天然核碱基、核苷、核苷酸、RNA、DNA,其等价物和/或包含一或多种这些化合物的混合物。
天然核碱基包括嘌呤腺嘌呤和乌嘌呤以及嘧啶胞嘧啶,胸腺嘧啶和尿嘧啶。当核碱基来源为游离碱基形式时,尿嘧啶是优选的。
天然核苷包括核糖核苷腺苷、乌苷、尿苷和胞苷以及脱氧核糖核苷脱氧腺苷,脱氧鸟苷、脱氧胸苷和脱氧胞苷。
天然核苷酸包括天然核苷的磷酸酯,如单磷酸腺苷酸(AMP),鸟苷酸(GMP),尿苷酸(UMP),胞苷酸(CMP),脱氧胸苷酸(dTMP)脱氧胞苷酸(dCMP),和天然核苷的二磷酸和三磷酸酯,如ADP和ATP。
优选经提纯的核碱基来源,如酵母。然而,其它来源如肉类等也可使用。优选核碱基来源为RNA。
因而,本发明提供包含有效量的下述物质的药物或营养制剂:
(a)本发明的一种氨基酸(成分(a))以及一或多种下列成分:
(b)ω-3PUFAs,最好与ω-6PUFAs混合(成分(b));
(c)精氨酸或其它与多胺合成相关的生理学上可接受化合物,或其混合物(成分(c));和
(d)一种核碱基来源(成分(d))。
所述药物和营养制剂在下文称为“本发明的食物”。
剂量应足以使该药物或营养制剂降低病人中的肿瘤坏死因子(TNF)水平,在这些病人中TNF水平高于调节生理平衡和局部炎症的水平。
这种药物或营养制剂的单位剂量优选包含1.5至80份重量的成分(a)以及选自(b)至(d)的下列量的一种或多种成分:0.1至20份重量的成分(b),3至40份重量的成分(c)和0.1至4.0份重量的成分(d)。特别优选的单位剂量包含1.5至80份重量的成分(a)以及选自(b)至(d)的下列量的一或多种成分:2至5份重量的成分(b),7.5至20份重量的成分(c)和1.7至2.0份重量的成分(d)。
化合物(a)至(d)每日用药量方便地对应于成分(a)1.5至80g,成分(b)0.1至20g,优选2至5g,成分(c)3至40g,优选7.5至20g,和成分(d)0.1至4.0g,优选1.7至2.0g。
对于成分(d),上述剂量适用于RNA,DNA,核苷或核苷酸。对于核碱基,1重量单位的核碱基被认为等价于2.5至3重量单位的RNA,DNA,核苷或核苷酸。
当使用包含一种本发明的氨基酸以及上述成分(b),(c)和(d)之一或多种的药物或营养制剂时,这种药物或营养制剂在1个单位剂量中方便地包含
(a)1.5至80份重量的选自甘氨酸、丙氨酸或丝氨酸组的一或多种氨基酸,处于游离形式或生理学上可接受盐形式,或其混合物,以及选自包含下列成分的组的一或多种化合物:
(b)2至5份重量的ω-3多不饱合脂肪酸;
(c)7.5至20份重量的L-精氨酸或L-鸟氨酸,或其混合物;
和
(d)1.7至2.0份重量的RNA。
优选的药物或营养制剂在单位剂量中包含:
(a)选自包含甘氨酸、丙氨酸和丝氨酸的组的1.5至80份重量的
一种氨基酸,处于游离形式或生理学上可接受盐形式,或其
混合物,以及
(c)3至40份重量,优选7.5至20份重量的精氨酸或等当量的与
多胺合成相关的一或多种其它生理学上可接受化合物,或等当
量的精氨酸与这种化合物的混合物。
更优选本发明的药物或营养制剂以重量比为1∶2至4∶1包含成分(a)和成分(c),特别优选重量比为1∶1至2∶1。
更优选的药物或营养制剂在单位剂量中包含:
(a)1.5至80份重量的选自包含甘氨酸、丙氨酸和丝氨酸的一种
氨基酸,处于游离形式或生理学上可接受盐形式,或其混合
物,以及
(b)0.1至20份重量,优选2至5份重量的ω-3PUFAs;和
(c)3至40份重量,优选7.5至20份重量的精氨酸或等当量的与
多胺合成相关的一或多种其它生理学上可接受化合物;或等当
量的精氨酸与这种化合物的混合物。
方便地保护ω-3PUFAs以防止过氧化作用。
保护ω-3PUFAs以防止过氧化作用的生理学上可接受方法在本领域中是公知的,这些方法包括生理学上可接受的对ω-3PUFAs的微包被和生理学上可接受的抗氧化剂的应用。
适合用作生理学上可接受微胶囊剂的典型实例是淀粉。微胶囊包装可按本来已知的方式起作用。微胶囊包装可按本来已知的方法包被,通过生理学上可接受的包被剂如***胶。
适合用于本发明方法中的抗氧化剂典型实例包括抗氧化剂维生素如维生素C,维生素E或其混合物。
加入的抗氧化剂量应是以防止ω-3PUFAs的过氧化作用。这种量易于计算。通常,为方便起见,防止过氧化作用所使用的抗氧化剂以过量使用。应认识到任何其它与ω-3PUFAs一起施用的药物的存在可能要求调整使用的抗氧化剂量。
ω-3PUFAs可以适合ω-3PUFAs生理应用的形式采用,如,以游离酸形式,以甘油三酯形式,或以生理学上可接受的ω-3PUFAs天然来源形式。这种天然来源包括亚麻子油和鱼油如步鱼油,鲑鱼油,鲭鱼油,金枪鱼油,鳕鱼肝油和鳀油。所述天然来源,特别是鱼油,包含大量的ω-3脂肪酸。在ω-3PUFAs以甘油三酯形式采用的情况,所述甘油三酯可包含与其它生理学上可接受脂肪酸的酯。优选的ω-3PUFAs包括二十碳五烯酸(EPA)和二十二碳六烯酸(DHA),以游离酸形式,以甘油三酯形式或以具有高EPA和/或DHA含量的天然来源形式存在。
当本发明的氨基酸以药物形式施用时,这种药物每100克包含1至99克本发明的氨基酸。
通常,以制剂食物形式施用本发明的食物可获得有利的效果,这种制剂食物根据具体情况可为完全制剂饮食(即,食物补充基本所有需要的能量,氨基酸,维生素,矿物质和微量元素)或食物补充。该食物方便地采用水溶液形式。一种制剂食物可包含一种碳水化合物源,脂质脂肪(脂肪源)和蛋白质(氮源),和至少一种选自包含甘氨酸、L-丙氨酸和L-丝氨酸的氨基酸,或其生理学上可接受盐,其特征在于该酸或盐以约每100g 0.5至10g的量存在于制剂食物中。该配制食物优选进一步包含其它营养学上有利的成分如维生素,矿物质,微量元素,纤维(优选可溶性纤维)。
适当氮源的实例包括营养学上可接受的蛋白如大豆或乳清来源的蛋白,酪蛋白酸盐(Caseinate)和/或蛋白水解产物。适当的碳水化合物源包括糖如麦芽糖糊精。适当的脂肪来源实例包括甘油三酯,以及二-和单甘油酯。
适合掺入本发明的药物或制剂的维生素实例包括营养上可接受的维生素E,维生素A,维生素D,维生素K,叶酸,硫胺,核黄素,维生素B1、B2、B6和B12,烟碱酸,生物素和泠酸。
适合掺入本药物或制剂的矿物元素和微量元素实例包括营养学上可接受形式的钠、钾、钙、磷、镁、锰、铜、锌、铁、硒、铬和钼。
特别地,本药物或制剂优选包含β-胡萝卜素(维生素A),维生素E,维生素C,硫胺,维生素B12,胆碱,硒和锌的营养学上可接受形式。
本文使用的术语“可溶性纤维”是指能在结肠中基本被酵解最终产生短链脂肪酸的纤维。适当可溶性纤维的实例包括果胶,瓜尔豆胶,刺槐豆胶,黄原增胶,可被或不被水解。对于成人,每日可溶性纤维量方便地在3至30g范围内。
应认识到ω-3PUFAs可以高于上述的剂量施用,并且这种更高的剂量一般不损害所期望的作用或产生不期望的副作用。
在本发明的制剂中特别适合用作成为(c)的化合物包括L-精氨酸和L-鸟氨酸,最优选L-精氨酸。成分(c)可采取游离形式,生理学上可接受盐形式,如磷酸,构橼酸,酒石酸,富马酸,己二酸或乳酸盐形式,或小肽形式。优选采用游离形式的L-精氨酸。
本文使用的术语小肽指具有2至6,优选2至4个氨基酸的肽。
如已指出的,ω-3PUFAs方便地以鱼油形式用药,针对过氧化作用保护或未保护。这种鱼油也包含ω-6PUFAs。
ω-6PUFAs对于免疫反应和对于在手术情况下对感染的抵抗也具有有利效应。因而,本发明的食物将方便地进一步包含ω-6PUFAs。
为本发明的目的,ω-6PUFAs可处于游离酸形式或适合ω-6PUFAs生理应用的形式,如甘油三酯。特别适合按照本发明的应用的ω-6PUFAs的实例包括亚油酸和花生四烯酸,亚由酸最为优选。适当ω-6PUFA来源的实例在本领域是公知的。它们包括鱼油和植物油。具有高亚油酸含量的ω-6PUFA来源实例如红花油,葵花油,大豆油,棉籽油和玉米油。
以1.5~5.0g的每日总量施用ω-6PUFAs通常足以维持有利作用。上述药物或营养制剂的单位剂量因此可进一步包含1.5至5份重量的ω-6PUFAs。
除成分(b),(c)和(d)和ω-6PUFAs外,还可向本发明的食物加入其它成分并对本发明的氨基酸的活性具有有利效应。这种有利成分的一个实例是ω-9PUFAs。这种脂肪酸混合物的一种优选天然来源是鱼油。在口服应用形式中,为口味和其它原因,该鱼油优选以胶囊形式应用。
由于本发明的制剂食物意在用作营养补充(例如,手术前治疗),其提供的能量不应过高以免不必要地抑制病人的食欲。该营养补充应方便地包含提供总量为600至1000Kcal/日的能量来源。为用作完全制剂食物(如,术后治疗,创伤治疗),本发明的食物方便地提供600至1500Kcal/日氮源,碳水化合物来源和脂质来源对每日热卡的供给可在很大范围内变动。在本发明的优选制剂中,碳水化合物来源提供本制剂总能量供给的40~70%,氮和脂肪酸来源各提供总能量供给的15~40%。为用作完全食物,本发明的食物方便地以水溶液形式以500ml至3000ml的量给药。为用作一种补充,可以粉末或液体形式给药。
可按照本发明治疗的病人具有升高的TNF水平的疾患或疾病包括下列:骨质疏松;关节炎;(癌)转移;肺疾病如成人呼吸窘迫综合症(ARDS);炎性肠病如溃疡性结肠炎和克隆氏病;冠状动脉疾病;肝硬化-不管是酒精性的还是病毒诱导的;败血症,包括内毒素性休克;缺氧性再灌注损伤,在AIDS和癌症病人中所见的消耗性综合症;肝炎;肾炎;病理性血管形成,损害骨髓的放疗和化疗等治疗,器官排异;创伤,缺血后心脏损害;溃疡症;与神经***相关的退行性疾病如运动神经原疾病和多发性硬化;脑损伤和炎症;胰腺炎;肾功能衰竭;糖尿病;中风;哮喘和感染。在败血症,内毒素性休克;感染和缺氧性再灌注损伤的治疗中获得特别好的治疗效果,特别是在内毒素性休克和败血症中。在炎性肠病,败血症,慢性肝病。病理性血管形成,动脉粥样硬化和创伤的治疗中也获得特别好的效果。感染可为损伤性感染,积脓,菌血症,脓肿,败血症等。它们可由多种感染性因素引起,包括细菌、病毒、寄生虫、真菌和内毒素。
一般而言,本发明的氨基酸的治疗适用于TNF水平可能会或确实至少短暂地高于调节生理平衡和局部炎症所需水平的病人。这种病人包括如:创伤性病人(多发创伤,烧伤,大手术);全身炎性反应综合征(SIRC)病人;败血症病人;成人呼吸窘迫综合征(ARDS)病人;急性肝衰竭而不可能进行预治疗但却期望急性效应的病人;具感染危险的病人如由于免疫抑制而抵抗力低下的病人,进行放疗和/或化疗的病人,患糖尿病的病人,患蛋白营养不良的病人,胃肠癌手术病人,心血管手术病人,进行移植的病人,由于摄入酒精过量而肝病危险增加的病人和遭受人类免疫缺陷病毒相关感染的病人;和大手术过程,即任何需要全身麻醉的手术过程如心血管搭桥手术和大型上胃肠道手术,前后的病人。
含有本发明的氨基酸以及成分(c)的药物或营养制剂的施用特别适用于骨质疏松的治疗。
甘氨酸或其它本发明的氨基酸在TNF水平高于调节生理平衡和局部炎症所需的病人中对降低TNF水平的意外药理学活性是有用的,在于它能够减轻内毒素血症,缺氧性再灌注损伤和感染的效应并降低内毒素性休克和败血症的危险,并从而降低或防止死亡的危险。
上述本发明的氨基酸,特别是本发明的食物特别适用于拟行手术病人的治疗。当以营养补充的形式施用本发明的食物时,这种预治疗最有效。该营养补充有利地施用3天或更长时间。通常,预治疗开始于手术前3至6天,并且通过所述3-6天期间足以获得期望的效果。为预治疗或预防目的施用营养补充,这种营养补充含1.5g至80g本发明的氨基酸以及2至5g成分(b)(ω-3PUFAs)和/或成分(c),补充每日7.5至20g L-精氨酸或L-鸟氨酸,通常将产生期望的效果。
这种营养补充可以并优选也包含有效量的成分(d),ω-6PUFAs或上述其它成分。
本营养补充可方便地以适合每日用药3至4次的单位剂量形式用药。由于本发明的食物包含能量来源,提供不超过1500Kcal/日是适当的。除能量补充方面的限制外,用于降低TNF水平的本发明的食物补充可以方便地以上述完全制剂食物形式施用。
在大量酒精摄入的病人需要紧急治疗的情况下,本发明的氨基酸可方便地经胃肠道外施用。适合这种紧急治疗的典型用药形式为例如下文所公开的水溶液。
在期望通过甘氨酸诱导的胃中酒精消除作用而减少酒精摄入血液的情况下,本发明的氨基酸可方便地以常规口服用药形式,如颗粒、片剂、胶囊,液体(包括汤和饮料如软饮料,止渴饮料)、粉剂、制剂食物等形式提供。当以生理学上可接受制剂形式如胶囊或片剂形式制剂时,这种制剂优选包含按重量为0.2至90%,优选按重量为30至50%的本发明氨基酸。通常,以每kg体重游离形式和/或生理学上可接受盐形式施用选自甘氨酸、丙氨酸和丝氨酸的1或多种氨基酸0.01至5.0g,可获得酒精(乙醇)从胃中的满意消除。用药方便地为口服,并在酒精摄入前。
典型的供口服用药的药物学可接受制剂形式将进一步包含生理学上可接受的稀释剂,载体,维生素,调味剂,色素和/或技术人员公知的适合掺入这种制剂的其它辅药。
本发明的食物和制剂可以已知的方法,如混合各种成分,而获得。
适合按照本发明的应用特别是适合治疗由于过量摄入酒精而肝病危险增加的病人的典型制剂包括多种水溶液,这些水溶液主要包含按重量为0.1%至90%的至少一种选自甘氨酸、丙氨酸和丝氨酸的氨基酸,和药物学可接受的盐,用蒸馏水配衡。本发明的氨基酸可以溶液的浓缩形式存在,量为15至90%(按溶液的重量)。浓缩溶液适合稀释为应用形式或用于紧急治疗。具有低含量(如0.1至5%)的本发明氨基酸的应用形式通常适合预防性目的;溶液的浓缩形式具有较高含量(如5%至40%,按重量)的本发明氨基酸,通常更适合紧急治疗。
适合包含在本发明的药物或制剂中,特别是供胃肠道外应用的其它制剂,包括输注溶液如林格氏注射液,乳酸林格氏注射液,类晶体类,胶体类,或其它血浆替代物,以及或用每升输注溶液约0.1至5.0g甘氨酸、丝氨酸和/或丙氨酸增强。林格氏液是一种灭菌溶液,含3.23~3.54g钠(相当于8.2~9.0g氯化钠),0.149~0.165g钾(相当于0.285~0.315g氯化钾),0.082~0.098g钙(相当于0.3~0.36g氯化钙,以CaCl2·2H2O形式),5.23~5.80g氯(作为NaCl、KCl和CaCl2·2H2O),和足够量的水以得到1000ml溶液。乳酸林格氏注射液是一种灭菌溶液,含2.85g~3.15g钠(作为氯化物和乳酸),0.141~0.173g钾(相当于0.27g~0.33g氯化钾),0.049~0.060g钙(相当于0.18g~0.22g CaCl2·2H2O),2.31g~2.61g乳酸,3.68~4.08g氯化物(作为NaCl、KCl和CaCl2·2H2O),以及足够量的水以得到1000ml溶液。
与液体治疗相关的术语类晶体类和胶体在本领域中是公知的。它们包含血浆替代物如Haemaccel(基于polygeline)和Gelofusine(基于明胶)。
通过参照下列特殊描述,本发明将被进一步理解。实施例1.食物甘氨酸对大鼠中存活和肝损害的作用
在注射LPS前3天雄性Sprague-Dawley大鼠(200-250g)被自由喂以按重量含酪蛋白为20%(对照食物)或按重量含5%甘氨酸和15%酪蛋白(甘氨酸食物)的粉状食物。通过尾静脉对这些大鼠注射脂多糖(分别为LPS;10,20和30mg/kg),并在注射后24小时评价死亡率。如果大鼠存活24小时,则认为是安全的,因为未观察到过晚期死亡。结果a)对于10mg/kg的LPS剂量,5%甘氨酸食物提供100%的保护,与对照组50%死亡率相比有显著差异,P<0.05。在20mg/kg的LPS剂量,5%甘氨酸食物组观察到30%的死亡率而对照组观察到70%的死亡率。在30mg/kg LPS剂量,甘氨酸治疗组动物中死亡率增加至90%,对照组中为100%。b)对于存活者,测定肝酶AST(天冬氨酸氨基转移酶;一种转氨酶)作为肝损害的指标。在喂以甘氨酸的大鼠中AST水平显著降低(用10mg/kg LPS剂量处理的未治疗喂养大鼠中为2000IU/L)。c)在平行实验系列中,甘氨酸食物对肿瘤坏死因子(TNF)的作用被测定。血清TNF通过ELISA测定。在注射10mg/kg LPS后,在用对照食物喂养的大鼠中血清TNF在注射后60分钟迅速增加至超过6000pg/ml随后再降至对照值。在用5%甘氨酸食物喂养的大鼠中这种增加被显著抑制(至少50%;P<0.05),而且峰值在注射后150分钟达得。d)供组织学检查的肝和肺标本在注射LPS(10mg/kg)后24小时采取并进行苏木精-伊红染色。喂以对照食物的大鼠在肝中显示很多坏死区和嗜中性细胞浸润并在肺中显示显著的间质水肿伴嗜中性细胞浸润。喂以甘氨酸食物的大鼠与喂以对照食物的大鼠相比,在肝中显示较少的坏死并显示较轻的肺水肿。e)对于分别喂以对照食物和甘氨酸食物,并各自给予LPS注射(10mg/kg,通过尾静脉静脉内注射)的两组大鼠,通过HPLC测定血清甘氨酸浓度。用甘氨酸食物喂养而不进行LPS处理的大鼠与用对照食物喂养而不进行LPS处理的大鼠(150μM)相比显示显著更高的甘氨酸浓度(1892μM)。在LPS注射后6小时,用甘氨酸食物喂养的大鼠保持高浓度甘氨酸(1727±515μM);在LPS注射后6小时,用对照食物喂养的大鼠血清甘氨酸浓度为278μM。实施例2.甘氨酸对低流-回流肝灌注模型中再灌注损伤的作用方法使用的动物:雄性Sprague-Dawleg大鼠,体重180-210g,喂以Purina食物。大鼠在手术前禁食24小时。肝灌注:在手术前用戊巴比妥钠麻醉大鼠(50mg),并手术取肝,在非再循环***(Krebs-Henseleit,1932)中使用用氧气-二氧化碳(95∶5)混合物饱和的Krebs-Henseleit碳酸氢盐缓冲液(pH7.4,37℃),通过***门静脉的导管进行灌注。手术后,以约1ml/g/分的流速对肝灌注75分钟(低流)。随后,以正常流速(4ml/g/分)对肝灌注40分钟(再流)。将甘氨酸溶于Krebs-Henseleit碳酸氢钠缓冲液(pH7.4,37℃)中并在再流前10分钟开始以使终浓度为0.06~2mM的速度连续灌注入肝中。乳酸脱氢酶(LDH)。在灌注液中的LDH活性使用标准酶技术(Bergmeyer,1988)检测。将3ml灌注液与含15%三氯乙酸,0.375%硫巴比土酸和0.25N盐酸的试剂彻底混合并在沸水浴中加热15分钟。冷却后,以1000g离心样本10分钟并在535nm处测定上清液的吸光率。LDH释放率以每小时每克肝湿重表达。台盼蓝分布时间和组织学方法:
为评价肝中的微循环和细胞死亡,在所有实验结束时将台盼蓝以0.2mM的终浓度输注入肝(Belinsky等,1984)。记录肝表面变为均匀深蓝色的时间。通过用Krebs-Henseleit缓冲液灌注额外的10分钟去除过量染料。随后,用1%聚甲醛灌注肝10分钟,并将固定的组织埋入石蜡和加工供光镜检查。切片只用伊红,即一种胞浆染料染色,以便台盼蓝能在破碎细胞的核中被鉴别出来。
在从肝门周围或中央周围区放射5个细胞的区中的所有***核被鉴定为台盼蓝阳性或阴性。在任何给定区中着染的百分比通过着染的核数除以总细胞数来计算。统计学分析,根据需要使用Student’s-t-检验或ANOVA。当P<0.05时认为有显著差异。结果
在低流,再流灌注模型中甘氨酸对肝细胞损害的效应。
在低流阶段,LDH释放很低(在75分钟时约1IU/g/h)。然而,当流速增加至4ml/g/分时,LDH释放逐渐增加,在约30分钟时达到新的稳态。在对照组中在再灌注期间最大LDH释放在35IU/g/h左右,但经甘氨酸治疗以剂量依赖方式显著下降。当甘氨酸浓度增加至2mM时,LDH释放降至约5IU/g/h左右,半最大下降剂量为180μM甘氨酸。
台盼蓝摄取表明肝叶中细胞活性的不可逆丧失。在75分钟的低流缺氧后再流40分钟引起中央周围区实质细胞约30%的死亡,但仅影响预先为正常氧的肝门周围区细胞的约2%。甘氨酸(2mM)的输注降低中央周围区中细胞死亡至9%。总之发生于氧气再导入预先缺氧的肝叶中央周围区时的再灌注损伤可以剂量依赖方式通过紧急甘氨酸输注而明显降低。甘氨酸对台盼蓝分布的效应
当在再灌注5分钟后将台盼蓝输注入肝时,台盼蓝分布时间(一种肝微循环的指标)在甘氨酸输注肝中稍微但有显著差异地低于对照组(在甘氨酸处理肝中约190秒而在对照中为225秒,P<0.05,n=5)。然而,当台盼蓝在再灌注40分钟结束时输注时,这些值以剂量依赖方式被甘氨酸显著降低。在对照组中台盼蓝均匀分布需要约460秒,而当输注2mM甘氨酸时该值降至约250秒。引起台盼蓝分布时间半最大下降的浓度也在约180μM。
在再灌注期间甘氨酸以剂量依赖方式使LDH释放和细胞死亡几乎完全最小化。因此,对于大鼠中低流,再流肝灌注模型中的再灌注损伤,甘氨酸具有强的细胞保护效应。
台盼蓝分布时间以剂量依赖方式被甘氨酸降低,其半最大效应类似于甘氨酸的细胞保护效应(180μM)。由于台盼蓝分布时间不仅受肝微循环紊乱的影响,而且也受肝细胞损伤的影响,因此在再流仅5分钟后测定台盼蓝分布时间,此时再灌注损伤很小。此值也被甘氨酸有显著意义的降低,但程度较小,表明肝微循环改善。
与缺氧和再灌注损伤相关的其它可能机制如ATP耗竭和线粒体功能改变也得到了研究。胆汁产生,一种高能量依赖的步骤,不受甘氨酸影响,表明甘氨酸不减轻ATP耗竭,另外,氧摄取,即线粒体功能的一种指标,也不被甘氨酸改变。总之,甘氨酸改善肝微循环和防止依赖氧的再灌注损伤。实施例3.甘氨酸预处理对部分性肝缺血/再灌注和LPS注射后死亡率的
作用
在分别用对照食物和甘氨酸食物喂养3天后,使大鼠部分性缺血达90分钟,在甲氧氟乙烷麻醉下。再灌注后6小时经尾静脉注射亚致死剂量的LPS(5mg/kg)。结果:
所有未注射LPS的对照组大鼠在90分钟部分性肝缺血/再灌注后存活24小时(n=4)。所有喂以对照食物并予以90分钟部分性肝缺血/再灌注的大鼠在(亚致死量)LPS注射后24小时内死亡(n=4)。
用甘氨酸食物预处理显著提高在相同条件下(90分钟部分性肝缺血/再灌注并给予LPS注射)在观察期间(注射后24小时)的存活率(6只大鼠中5只存活);P<0.05,Fisher’s检验)。实施例4.食物甘氨酸对酒精诱导的肝损害的作用4.1材料和方法a.动物
在每只体重300至320g的雄性Wistar大鼠中,按Tsukamoto和French所述***胃管。胃管经皮下通至颈部背侧并通过弹性系链装置和旋转接头方式连接于输入泵,使大鼠在代谢笼中能够自由活动。用含乙醇的高脂肪液体食物对这些动物连续输注4周。所有动物都受到符合惯例准则的人道照管。b.食物
使用Thompson和Reitz描述的液体食物。它含有玉米油作为脂肪(总卡路里的37%),蛋白质(23%),碳水化合物(5%),矿物质和维生素,加上乙醇或等卡路里的麦芽糖-环糊精(35%),下文中称为液体对照食物。甘氨酸(按重量2或5%)被加至液体对照食物中;这种食物在下文分别称为液体2%甘氨酸食物和液体5%甘氨酸食物。c.尿的收集和乙醇测定
每日测定代表血中乙醇水平的尿中乙醇浓度。大鼠在能将尿与粪便分离的代谢笼中饲养,将24小时尿收集在含矿物油以防止蒸发的瓶中。每天上午9点更换尿液收集瓶并将1ml样本于-20℃贮存于微管中供以后进行乙醇测定。通过测定乙醇脱氢引起的NAD+向NADH的还原所致360nm处吸光率来确定乙醇浓度。d.血液收集和天冬氨酸氨基转移酶(AST)
通过尾静脉每周收集血液并离心。血清置于微管中贮存于-20℃,直至通过标准酶方法测定AST。全血(100μl)也如下述测定乙醇,另外,当在乙醇处理后第2和4周进行肝活检时也收集肝门脉血。e.呼吸,外周和门脉血,粪便和胃内容物中的乙醇测定
为测定呼吸中的乙醇浓度,强迫大鼠向密闭加热室(37℃)中呼吸20秒,并用气密闭注射器收集1ml呼吸气。乙醇浓度通过气相色谱(GC)测定。外周和门脉血中的乙醇也通过GC测定。将血液(100μl)与900μl蒸馏水在封闭烧瓶中混合37℃温育30分钟,收集1ml气相并通过GC测定。大鼠粪便直接从***收集,在蒸馏水中匀浆并如上对血液所述温育和测定。当用乙醇处理后4周处死大鼠时也收集胃内容物,并如对于血液所述进行测定。f.血中甘氨酸浓度的测定
在乙醇处理4周后,收集500μl血浆并贮存于-80℃,供通过HPLC测定血中甘氨酸浓度。在肝素化的血浆中甘氨酸的定量测定使用PICP-TAG(Waters,Milford,MA)方法进行。血浆样本首先用HCl水解,然后用异硫氰酸苯酯(PITC)衍生以产生苯硫代氨基甲酰基(PTC)氨基酸。包括甘氨酸在内的氨基酸通过自动化梯度反相高压液相色谱法(HPLC)测定。g.病理学评价
在用乙醇处理2和4周后对大鼠进行肝活检和尸检。肝用***固定,石蜡包埋并用苏木精和伊红染色以评价脂肪变性,炎症和坏死。肝病理学按照Nanji等人所述进行评价。如下:脂肪变性(含脂肪的肝细胞百分比):<25%=1+;<50%=2+;<75%=3+;>75%=4+;炎症和坏死:每低倍视野1个灶=1+;2或多个=2+。h.统计学
根据需要使用ANOVA或Student’s t-检验确定统计学差异。为病理学评分的比较,使用用于分级的Kruskal-Wallis ANOVA。在研究前选择P<0.05作为显著差异的水平。4.2结果
观察到在此研究过程中,用液体对照食物,液体/甘氨酸食物和液体5%甘氨酸食物喂养的大鼠体重在第一周有一个下降的趋势。在用酒精处理的随后3周中体重稳定不变。在不同研究组间体重无显著差异。
在手术后第1周乙醇摄入逐渐增加至9~10g/kg/日。在2-4周摄入在10~13g/kg/日,各组间无显著差异。在接受含5%甘氨酸的液体食物的大鼠中4周处理后血浆中甘氨酸浓度为779±66μmol/L,在用乙醇喂养的大鼠中为198±16μmol/L。
测定用液体对照食物和液体甘氨酸食物喂养的大鼠中每日尿乙醇浓度的代表性散点图。在用液体对照食物喂养的大鼠中,即使乙醇输注是连续的,乙醇水平仍以循环形式从0至大于300mg/dl波动。在用一种液体甘氨酸食物喂养的大鼠中,乙醇浓度很低但仍是循环的。平均尿乙醇浓度以剂量依赖方式显著降低;通过用液体2%甘氨酸食物喂养获得平均尿乙醇浓度下降50%,用液体5%甘氨酸食物获得下降70%。
用液体对照食物喂养的大鼠中血清AST随暴露时间而逐渐增加并在4周后达到183IU/L的水平(对照值70IU/L)。两种甘氨酸治疗在研究的每个点均显著减弱这种增加。治疗4周后,在用液体2%甘氨酸食物喂养的2%甘氨酸治疗大鼠中血清AST水平为66IU/L,而在用液体5%甘氨酸食物喂养的组中为100’IU/L。
在用液体对照食物喂养的大鼠中,只在处理后2周观察到轻度脂肪变性。在用所述液体对照食物处理4周后,在未用乙醇处理的对照大鼠中未出现明显的脂肪变性。在用液体2%甘氨酸和液体5%甘氨酸食物喂养的大鼠中,脂肪变性减轻并且几乎完全没有坏死和炎症。用液体甘氨酸食物喂养后脂肪变性和坏死的减轻有统计学意义;由于变化性,在用液体甘氨酸食物喂养后只观察到炎症减轻的趋势。
最后,在甘氨酸治疗的大鼠中胃内容物中的乙醇也明显下降。因此,很明显甘氨酸降低了胃中的乙醇浓度,可能是通过对乙醇代谢的作用。
表1
在Tsukamoto-French模型中甘氨酸对大鼠中乙醇浓度的作用处理 呼吸气 粪便 尿 血液 胃
上午 24hr 尾 门静脉乙醇 108±12 82+21 184+12 211±16 199+45 357+65 761+625乙醇+ 5±4*** 15±11*26+25** 24+8*** 21±13**10±7*** 26+41*5%甘氨酸从大鼠收集呼吸气、粪便、血液和胃内容物并通过液上气相色谱测定。尿样本用酶学法测定。从总共6只大鼠采取样本。结果表达为平均值±标准误差通过Student’s t-检验比较乙醇与乙醇+甘氨酸喂养组大鼠的值。*P<0.05,**P<0.01;***P<0.001。实施例5.胃肠道组合物
在下列组合物中MM代表“矿物质混合物”,SM代表“微量元素混合物”而VM代表“维生素混合物”。这三种混合物的成分如下:MM成分 g/100g麦芽糖糊精 34.40枸橼酸/磷酸钾 34.60二枸橼酸镁 8.20氯化钙 8.00枸橼酸/氯化钠 9.00枸橼酸 3.50酒石酸胆碱 2.30VM成分 g/100g麦芽糖糊精 43.44抗坏血酸钠 35.00维生素E-Ac.50% 16.00尼克酰胺 1.55乙酸维生素A 1.20Ca-D-泠酸(Panthothenat) 0.98维生素K1 1% 0.71维生素B12 0.1% 0.30维生素D3 0.28维生素B6 0.20维生素B1 0.17维生素B2 0.15叶酸 0.02生物素 0.01SM成分 g/100g麦芽糖糊精 47.79钼-酵母 18.00铬-酵母 9.20硫酸锌 7.00硒-酵母 7.00硫酸亚铁(II) 6.92葡萄糖酸铜(II) 2.24硫酸镁(II) 1.12氟化钠 0.70碘化钾 0.03包含甘氨酸的组合物成分 g/100g水 77.40麦芽糖糊精 10.10酪蛋白酸(Caseinates)钠/钙 4.60甘氨酸 3.00MM 2.00SM 0.05VM 0.10β-胡萝卜素(Carotine) 0.03脂类棕榈油 2.33葵花油 0.26乳化剂Nathin E 0.13
100.00包含甘氨酸和精氨酸的组合物成分 g/100g水 77.40麦芽糖糊精 8.93酪蛋白酸钠/钙 4.60甘氨酸 3.00精氨酸 1.17MM 2.00SM 0.05VM 0.10β-胡萝卜素 0.03脂类棕榈油 2.36葵花油 0.23乳化剂Nathin E 0.13
100.00包含甘氨酸和鱼油(ω-3脂肪酸)的组合物成分 g/100g水 77.40麦芽糖糊精 10.10酪蛋白酸钠/钙 4.60甘氨酸 3.00MM 2.00SM 0.05VM 0.10β-胡萝卜素 0.03脂类棕榈油 1.32葵花油 0.23乳化剂Nathin E 0.13鱼油EPAX 3000TG 1.04
100.00包含甘氨酸和RNA的组合物成分 g/100g水 77.40麦芽糖糊精 9.96酪蛋白酸钠/钙 4.60甘氨酸 3.00酵母提取RNA 0.14MM 2.00SM 0.05VM 0.10β-胡萝卜素 0.03棕榈油 2.33葵花油 0.26乳化剂Nathin E 0.13
100.00包含甘氨酸,精氨酸和鱼油(ω-3脂肪酸)的组合物成分 g/100g水 77.40麦芽糖糊精 8.93酪蛋白酸钠/钙 4.60甘氨酸 3.00精氨酸 1.17MM 2.00SM 0.05VM 0.10β-胡萝卜素 0.03脂类棕榈油 1.32葵花油 0.23乳化剂Nathin E 0.13鱼油EPAX 3000TG 1.04
100.00包含甘氨酸,精氨酸和RNA的组合物成分 g/100g水 77.40麦芽糖糊精 8.79酪蛋白酸钠/钙 4.60甘氨酸 3.00精氨酸 1.17酵母提取RNA 0.14MM 2.00SM 0.05VM 0.10β-胡萝卜素 0.03脂类棕榈油 2.33葵花油 0.26乳化剂Nathin E 0.13
100.00包含甘氨酸,RNA和鱼油(ω-3脂肪酸)的组合物成分 g/100g水 77.40麦芽糖糊精 9.96酪蛋白酸钠/钙 4.60甘氨酸 3.00酵母提取RNA 0.14MM 2.00SM 0.05VM 0.10β-胡萝卜素 0.03脂类棕榈油 1.32葵花油 0.23乳化剂Nathin E 0.13鱼油EPAX 3000TG 1.04
100.00包含甘氨酸,精氨酸,RNA和鱼油(ω-3脂肪酸)的组合物成分 g/100g水 77.40麦芽糖糊精 8.79酪蛋白酸钠/钙 4.60甘氨酸 3.00精氨酸 1.17酵母提取RNA 0.14MM 2.00SM 0.05VM 0.10β-胡萝卜素 0.03脂类棕榈油 1.32葵花油 0.23乳化剂Nathin E 0.13鱼油EPAX 3000TG 1.04
100.00
如上文所述,鱼油是ω-3PUFAs的天然来源而葵花油是ω-6PUFAs的天然来源。
本发明以关于甘氨酸抑制TNF的增加从而使大鼠中内毒素性休克和缺血性再灌注损伤作用降至最低的能力为例进行阐述,但利用本公开的技术人员会认识到本发明包括所特别公开的以外的其它方面。例如,本发明还提供了选自包含甘氨酸、丙氨酸和丝氨酸的组的至少一种氨基酸或其前体,或其生理学上可接受盐的应用,用于协同加强针对TNF或可溶性TNF受体产生的环状多肽免疫抑制剂,中和抗体的免疫抑制效应。这种应用还提供了关于免疫抑制剂,如环胞霉素或FK-506的安全效应。而且,患有许多种疾病和/或病症的病人可得益于向他们施用本发明的药物或制剂。这种疾病和病症包括,骨质疏松;关节炎;癌转移;ARDS/肺病;炎症性肠病如溃疡性结肠炎和克隆氏病;冠状动脉疾病;肝硬化-不管是酒精还是病毒诱导的;败血症,包括内毒素性休克;在AIDS和癌症病人中观察到的消耗性综合症;肝炎;肾炎;病理性血管形成,抑制骨髓的治疗如放疗和化疗;器官排异;创伤;缺血后心脏损害;溃疡病;退行性疾病;如与神经***相关的运动神经原疾病和多发性硬化;大脑损伤和炎症;胰腺炎;肾功能衰竭;糖尿病;中风和哮喘。
Claims (12)
1.选自甘氨酸、丙氨酸和丝氨酸的至少一种氨基酸或其生理 上可接受的盐在制备用于减低病人中的肿瘤坏死因子(TNF)水平的药物或营养制剂中的应用,其中所说TNF的水平超过了其介导生理平衡和局部炎症的水平。
2.根据权利要求1的应用,其中TNF水平的减低可通过对如下各项抑制或减低进行;
(i)吞噬细胞型细胞肿瘤坏死因子(TNF)的产生;
(ii)吞噬细胞型细胞TNF的释放;和/或
(iii)TNF受体对TNF的结合。
3.选自甘氨酸、丙氨酸和丝氨酸的至少一种氨基酸或其前体,或者它们生理上可接受的盐,在制备用于在需要此类治疗的病人中抑制或减轻由于酒精摄入过量而引起的肝病及由此而导致的肠和胰腺疾病中的应用。
4.选自甘氨酸、丙氨酸和丝氨酸的至少一种氨基酸或其前体,或者它们生理上可接受的盐在制备用于在需要此类治疗的病人中抑制或减轻酒精毒性的药物或营养制剂中的应用。
5.选自甘氨酸、丙氨酸和丝氨酸的至少一种氨基酸或其前体,或者它们生理上可接受的盐在制备用于在需要此类治疗的病人中在酒精进入血液循环之前从胃中去除酒精的药物或营养制剂中的应用。
6.一种基本上由蒸馏水和0.1~90%重量份的选自甘氨酸、丙氨酸和丝氨酸的一种或多种氨基酸组成的药物,其游离形式或其药学上可接受的盐形式或者它们的混合物。
7.一种输注液,它包含每升所述输注液0.1至5.0g的选自甘氨酸、丙氨酸和丝氨酸的一种或多种氨基酸,以游离形式或药学上可接受盐形式或其混合物形式存在。
8.一种药物或营养制剂,它包含有效量的:
(a)选自包含甘氨酸、丙氨酸和丝氨酸的一或多种氨基酸,以游离形式或生理学上可接受盐形式,或其混合物形式存在(成分(a))以及一或多种下列成分:
(b)ω-3PUFAs,最好与ω-6PUFAs混合(成分(b));
(c)L-精氨酸或与多胺合成有关的其它生理学上可接受化合物;或 其混合物(成分(c));
(d)一种核碱基来源(成分(d))。
9.按照权利要求8的药物或营养制剂,它以单位剂量形式包含,(a)按重量1.5至80份的选自甘氨酸、丙氨酸和丝氨酸的一或多种氨基酸,以游离形式或生理学上可接受盐形式,或其混合物形式存在,以及一或多种下列化合物:(b)按重量2至5份ω-3多不饱和脂肪酸;(c)按重量7.5至20份L-精氨酸或L-鸟氨酸或其混合物,和(d)按重量1.7至2.0份RNA。
10.按照权利要求8或9的药物或营养制剂,它包含成分(a)和成分(c)。
11.按照权利要求8或9的药物或营养制剂,它包含成分(a)和成分(b)及(c)。
12.按照权利要求8或9的药物或营养制剂,它包含成分(a)和成分(b),(c)及(d)。
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---|---|
EP (1) | EP0810829B1 (zh) |
JP (1) | JPH11501301A (zh) |
KR (1) | KR19980702436A (zh) |
CN (1) | CN1175887A (zh) |
AT (1) | ATE191615T1 (zh) |
AU (1) | AU710527B2 (zh) |
BR (1) | BR9607336A (zh) |
CA (1) | CA2210499A1 (zh) |
CZ (1) | CZ266797A3 (zh) |
DE (1) | DE69607750T2 (zh) |
DK (1) | DK0810829T3 (zh) |
ES (1) | ES2145997T3 (zh) |
FI (1) | FI972744A (zh) |
HU (1) | HUP9800049A3 (zh) |
NO (1) | NO973884L (zh) |
PL (1) | PL182205B1 (zh) |
PT (1) | PT810829E (zh) |
WO (1) | WO1996025861A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101472612B (zh) * | 2006-06-14 | 2011-06-08 | 纽崔西亚公司 | 包含甘氨酸和乳铁蛋白的抗炎组合物及其应用 |
CN108348493A (zh) * | 2015-10-02 | 2018-07-31 | 荷兰纽迪希亚公司 | 甘氨酸用于过敏性患者的耐受性诱导 |
Families Citing this family (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9512100D0 (en) * | 1995-06-14 | 1995-08-09 | Sandoz Nutrition Ltd | Improvements in or relating to organic compounds |
CA2260886A1 (en) * | 1996-07-30 | 1998-02-05 | Novartis Nutrition Ag | Amino acid composition and use thereof in treating tumor growth and metastasis |
US6096785A (en) * | 1996-07-30 | 2000-08-01 | Novartis Nutrition Ag | Amino acid compositions and use thereof in treating renal dysfunction |
GB9701674D0 (en) * | 1997-01-28 | 1997-03-19 | Novartis Nutrition Ag | Use of organic compounds |
ATE266395T1 (de) * | 1997-06-05 | 2004-05-15 | Novartis Nutrition Ag | Glycin zur vorbeugung oder behandlung von transplantatabstossungen |
WO1999004781A1 (fr) * | 1997-07-28 | 1999-02-04 | The Institute Of Physical And Chemical Research | Agent promoteur de protection et de survie des cellules du systeme nerveux central |
US6143786A (en) * | 1999-02-02 | 2000-11-07 | Novartis Nutrition Ag | Oral arginine and insulin secretion |
US6808902B1 (en) | 1999-11-12 | 2004-10-26 | Amgen Inc. | Process for correction of a disulfide misfold in IL-1Ra Fc fusion molecules |
CN1547486A (zh) | 2001-06-26 | 2004-11-17 | 抗opgl抗体 | |
NL1019368C2 (nl) | 2001-11-14 | 2003-05-20 | Nutricia Nv | Preparaat voor het verbeteren van receptorwerking. |
DE10257360A1 (de) * | 2002-12-09 | 2004-07-08 | Fresenius Kabi Deutschland Gmbh | Gastro-intestinal verabreichbare Formulierung und deren Verwendung |
US20060280776A1 (en) | 2003-09-02 | 2006-12-14 | Masafumi Koide | Diet food |
EP1591118A1 (en) | 2004-04-27 | 2005-11-02 | Nutri-Fit GmbH & Co. KG | Use of melatonin in preventing postoperative complications |
KR100555904B1 (ko) * | 2004-05-19 | 2006-03-03 | 주식회사 오스코텍 | 큰느타리버섯과 오가피의 혼합 생약재 추출물 및 이를유효성분으로 하는 골다공증 예방 및 치료용 조성물 |
CA2709660C (en) | 2008-01-04 | 2018-06-05 | Nestec S.A. | Compositions comprising unsaturated fatty acids and nitric oxide releasing compounds and use thereof for enhancing cognitive and related functions |
US20100179089A1 (en) * | 2009-01-13 | 2010-07-15 | Deutz Nicolaas E P | Compositions and Methods to Manage the Inflammatory Basis of Chronic Disease Conditions and Maintain an Optimal Immune Response in Elderly |
AU2010258888B2 (en) * | 2009-06-08 | 2014-08-07 | Ocera Therapeutics, Inc. | Treatment of portal hypertension and restoration of liver function using L-ornithine phenylacetate |
KR101213825B1 (ko) * | 2010-07-16 | 2012-12-18 | 서울대학교산학협력단 | 세린을 유효성분으로 함유하는 지방간 질환의 예방 및 치료용 조성물 |
JP6000253B2 (ja) | 2010-09-24 | 2016-09-28 | ユニバーシティ オブ フロリダ リサーチ ファンデーション インコーポレーティッド | 胃腸機能を改善するための材料および方法 |
MX361647B (es) | 2013-03-11 | 2018-12-13 | Univ Florida | Materiales y métodos para mejorar la función pulmonar y para la prevención y/o tratamiento de complicaciones pulmonares inducidas por radiación. |
US20170326088A1 (en) | 2014-11-24 | 2017-11-16 | Entrinsic Health Solutions, Llc | Amino acid compositions for the treatment of symptoms of disease |
FR3041882B1 (fr) * | 2015-10-06 | 2019-04-12 | Universite D'angers | Preparation pharmaceutique pour le traitement preventif de lesions d'ischenie reperfusion |
BR112019006742A2 (pt) | 2016-10-04 | 2019-09-03 | Entrinsic Health Solutions Inc | composições de aminoácido e usos das mesmas |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2591893B1 (fr) * | 1985-12-19 | 1988-11-10 | Centre Nat Rech Scient | Compositions nutritionnelles carencees en methionine destinees a inhiber le developpement et la dissemination des tumeurs malignes chez les mammiferes |
US4988724A (en) * | 1988-12-09 | 1991-01-29 | Board Of Regents, The University Of Texas System | Methods and improved formulations for the determination and treatment of malignant disease in patients |
WO1993005780A1 (en) * | 1991-09-27 | 1993-04-01 | Board Of Regents, The University Of Texas System | Amino acids containing parenteral formulations for the treatment of hypotension and related pathologies |
US5571783A (en) * | 1993-03-09 | 1996-11-05 | Clintec Nutrition Company | Composition and method for treating patients with hepatic disease |
-
1996
- 1996-02-22 AU AU48795/96A patent/AU710527B2/en not_active Ceased
- 1996-02-22 JP JP8525404A patent/JPH11501301A/ja active Pending
- 1996-02-22 AT AT96904849T patent/ATE191615T1/de not_active IP Right Cessation
- 1996-02-22 ES ES96904849T patent/ES2145997T3/es not_active Expired - Lifetime
- 1996-02-22 PT PT96904849T patent/PT810829E/pt unknown
- 1996-02-22 PL PL96321238A patent/PL182205B1/pl unknown
- 1996-02-22 EP EP96904849A patent/EP0810829B1/en not_active Expired - Lifetime
- 1996-02-22 CZ CZ972667A patent/CZ266797A3/cs unknown
- 1996-02-22 BR BR9607336A patent/BR9607336A/pt not_active Application Discontinuation
- 1996-02-22 DK DK96904849T patent/DK0810829T3/da active
- 1996-02-22 CN CN96192066A patent/CN1175887A/zh active Pending
- 1996-02-22 CA CA002210499A patent/CA2210499A1/en not_active Abandoned
- 1996-02-22 DE DE69607750T patent/DE69607750T2/de not_active Expired - Fee Related
- 1996-02-22 KR KR1019970705835A patent/KR19980702436A/ko not_active Application Discontinuation
- 1996-02-22 HU HU9800049A patent/HUP9800049A3/hu unknown
- 1996-02-22 WO PCT/EP1996/000739 patent/WO1996025861A1/en not_active Application Discontinuation
-
1997
- 1997-06-25 FI FI972744A patent/FI972744A/fi unknown
- 1997-08-22 NO NO973884A patent/NO973884L/no not_active Application Discontinuation
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101472612B (zh) * | 2006-06-14 | 2011-06-08 | 纽崔西亚公司 | 包含甘氨酸和乳铁蛋白的抗炎组合物及其应用 |
CN108348493A (zh) * | 2015-10-02 | 2018-07-31 | 荷兰纽迪希亚公司 | 甘氨酸用于过敏性患者的耐受性诱导 |
CN108348493B (zh) * | 2015-10-02 | 2022-03-29 | 荷兰纽迪希亚公司 | 甘氨酸用于过敏性患者的耐受性诱导 |
Also Published As
Publication number | Publication date |
---|---|
EP0810829B1 (en) | 2000-04-12 |
CA2210499A1 (en) | 1996-08-29 |
CZ266797A3 (cs) | 1998-03-18 |
ES2145997T3 (es) | 2000-07-16 |
PL182205B1 (pl) | 2001-11-30 |
NO973884D0 (no) | 1997-08-22 |
NO973884L (no) | 1997-10-17 |
PT810829E (pt) | 2000-08-31 |
PL321238A1 (en) | 1997-11-24 |
DE69607750D1 (de) | 2000-05-18 |
HUP9800049A2 (hu) | 1998-05-28 |
ATE191615T1 (de) | 2000-04-15 |
WO1996025861A1 (en) | 1996-08-29 |
BR9607336A (pt) | 1997-11-25 |
HUP9800049A3 (en) | 1999-01-28 |
EP0810829A1 (en) | 1997-12-10 |
JPH11501301A (ja) | 1999-02-02 |
DE69607750T2 (de) | 2000-08-31 |
MX9706140A (es) | 1997-11-29 |
DK0810829T3 (da) | 2000-08-28 |
AU4879596A (en) | 1996-09-11 |
KR19980702436A (ko) | 1998-07-15 |
FI972744A0 (fi) | 1997-06-25 |
AU710527B2 (en) | 1999-09-23 |
FI972744A (fi) | 1997-08-22 |
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