CN101048081B - 用于预防和治疗微量元素从消化道吸收障碍的营养性和/或药物制剂 - Google Patents
用于预防和治疗微量元素从消化道吸收障碍的营养性和/或药物制剂 Download PDFInfo
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- CN101048081B CN101048081B CN2005800372304A CN200580037230A CN101048081B CN 101048081 B CN101048081 B CN 101048081B CN 2005800372304 A CN2005800372304 A CN 2005800372304A CN 200580037230 A CN200580037230 A CN 200580037230A CN 101048081 B CN101048081 B CN 101048081B
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- glutamine
- glutamate
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- amino acid
- glu
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Abstract
本发明解决了作为刺激微量元素吸收的因素的药物制剂的问题。本发明的本质在于该制剂包含α-酮戊二酸盐或/和谷氨酰胺或/和谷氨酸盐或/和α-酮戊二酸盐的鸟氨酸、谷氨酰胺和其它氨基酸的二肽或/和谷氨酰胺和其它氨基酸的三肽或/和具有其它氨基酸的谷氨酸盐或/和α-酮戊二酸的盐或/和谷氨酰胺或/和谷氨酸盐或/和α-酮戊二酸盐的鸟氨酸、谷氨酰胺或谷氨酸盐与其它氨基酸的二肽(剂量为0.01-0.5g/kg/天，口服给予)，刺激铁、锌、铜、锰、锶、钙、磷和其它微量元素从消化道吸收入血，以确保这些化合物在人类和动物的血液中的适当的-生理-治疗水平。
Description
技术领域
本发明的目的是用于预防和治疗微量元素从消化道吸收障碍的营养性和/或药物制剂，以及作为刺激微量元素从消化道吸收入血以确保这些化合物在人类和动物血液中适当的-生理-治疗水平的因素的药物制剂的应用。
背景技术
α-酮戊二酸(AKG)(Alfa-keto-glutarate acid)，谷氨酰胺的衍生物，是Krebs循环中的关键化合物。
AKG，主要代谢循环的中间产物，通过谷氨酰胺脱氢酶复合体转化为谷氨酸(glutaminic acid)。后者在谷氨酰胺合成酶的存在下又转化为谷氨酰胺。
在借助谷氨酸盐(glutamate)脱水酶的izocitrate氧化脱羧的快速过程中，产生稳定和非毒性的AKG：
Izocitrate+NAD+→α-酮戊二酸(盐)+CO2+NADH
α-酮戊二酸(AKG)被认为是内源性合成的谷氨酰胺的足够的外源性前体，并且通过谷氨酸，其对于合成具有5-碳链的其它氨基酸(如谷氨酰胺、精氨酸、脯氨酸、组氨酸)是必要的。这些氨基酸被转化为α-谷氨酸盐，其随后被谷氨酸盐脱水酶氧化性脱氨基。AKG起源于这些反应的结果。
除了用作能量供体，α-酮戊二酸(AKG)还作为蛋白的防护性角色，不允许它们分解代谢。它作为铵离子的“清除者”起作用。在谷氨酸盐的氧化脱氨过程中(借助谷氨酸盐脱水酶)，α-氨基(残基)被转化为铵离子。AKG在有机体解毒的过程中和防止蛋白质破碎的铵离子的保持中起着重要作用。谷氨酰胺，有机体中AKG的主要前体，是肠上皮细胞的主要能量来源。它的确定的量(浓度)对于维持细胞分裂的持续率是必要的，而细胞分裂对于保持主要的吸收功能是必要的。
肠上皮细胞所用的必要的谷氨酰胺的最大部分直接起源于肠道内，但是食物和血液也是它的重要的来源。在消化道中谷氨酰胺缺乏的情况下，通过肌肉组织分解它的储备被动员。
对于具有肠功能紊乱的动物和人类以及利用谷氨酰胺的支持治疗进行了许多研究。提供给初步饥饿随后静脉内供应的大鼠的谷氨酰胺对于改善肠壁结构以及减少细菌转移到循环系统具有积极作用。还观察到谷氨酰胺在辐射和细胞毒素处理后的人类的受损肠壁中具有再生性质。
已知由肠道细菌菌群的转移引起的菌血症通常在消化道功能障碍发生时的手术后观察到。已经证明：在这样的情况下，在动物和人类中，经口或静脉内给予的谷氨酰胺具有最小化微生物转移的保护活性。通过这些观察可以得出结论：在代谢压力中，谷氨酰胺作为治疗剂的施加具有积极结果。
然而，在实际的实施中，谷氨酰胺仍然难以应用，因为其在溶液中是不稳定的并且溶解不良。
为了避免这些问题，研究人员的兴趣针对谷氨酰胺前体。
发明内容
根据本发明的营养性或/和药物制剂特征在于：其包含α-酮戊二酸(盐)(alpha-keto-glutarate)或/和谷氨酰胺或/和谷氨酸盐或/和α-酮戊二酸盐的鸟氨酸、谷氨酰胺和其它氨基酸的二肽或/和谷氨酰胺和其它氨基酸的三肽或/和具有其它氨基酸的谷氨酸盐或/和α-酮戊二酸的盐或/和谷氨酰胺或/和谷氨酸盐或/和α-酮戊二酸盐的鸟氨酸、谷氨酰胺或谷氨酸盐与其它氨基酸的的二肽(剂量为0.01-0.5g/kg/天，口服给予)，并刺激铁、锌、铜、锰、锶、钙、磷和其它微量元素从消化道吸收入血，以确保它们在人类和动物的血液中的适当的-生理-治疗水平。
如果该营养性或/和药物制剂在人类和动物的一些疾病中(尤其在贫血、产后肠郁滞、心脏功能障碍、动脉粥样硬化、手足搐搦、骨质疏松症、关节炎、肠功能障碍、肌肉功能障碍、痴呆、免疫力降低、细菌的速率(rate)增加、病毒和真菌感染、瘤和其它疾病的增加的发病率中)是治疗性和预防性的，并且还提高家畜(如猪、家禽、羊、牛、马、山羊和其它)的生产率和效率，那么它是有利的。
根据本发明的其它营养性或/和药物制剂特征在于：其包含铁(Fe)或其它二价金属离子(为营养性微量元素，剂量为0.0001-0.01g/kg/天)并且提高α-酮戊二酸盐或/和谷氨酰胺或/和谷氨酸盐或/和α-酮戊二酸盐的鸟氨酸、谷氨酰胺和其它氨基酸的二肽或/和谷氨酰胺和其它氨基酸的三肽或/和具有其它氨基酸的谷氨酸盐或/和α-酮戊二酸的盐或/和谷氨酰胺或/和谷氨酸盐或/和α-酮戊二酸盐的鸟氨酸、谷氨酰胺或谷氨酸盐与其它氨基酸的二肽吸收入血以及在肠细胞(entereocytes)中的代谢，确保它们在人类和动物的血液中的生理的-治疗-预防水平。
如果该营养性或/和药物制剂在人类和动物的一些疾病中(尤其在贫血、尤其在贫血、产后肠郁滞、心脏功能障碍、动脉粥样硬化、手足搐搦、骨质疏松症、关节炎、肠功能障碍、肌肉功能障碍、痴呆、免疫力降低、细菌的速率(rate)增加、病毒和真菌感染、瘤和其它疾病的增加的发病率中)具有治疗性和预防性的性质，并且还提高家畜(如猪、家禽、羊、牛、马、山羊和其它)的生产率和产量，那么在其它营养性或/和药物制剂中它是有用的。
根据本发明的营养性或/和药物制剂的应用特征在于：包含α-酮戊二酸盐(alpha-keto-glutarate)或/和谷氨酰胺或/和谷氨酸盐或/和α-酮戊二酸盐的鸟氨酸、谷氨酰胺和其它氨基酸的二肽或/和谷氨酰胺和其它氨基酸的三肽或/和具有其它氨基酸的谷氨酸盐或/和α-酮戊二酸的盐或/和谷氨酰胺或/和谷氨酸盐或/和α-酮戊二酸盐的鸟氨酸、谷氨酰胺或谷氨酸盐与其它氨基酸的二肽的该制剂(剂量为0.01-0.5g/kg/天，口服给予)用作铁、锌、铜、锰、锶、钙、磷和其它微量元素从消化道吸收入血的刺激剂。
根据本发明，该营养性或/和药物制剂的第一其它应用区别于它自己在于：包含α-酮戊二酸盐或/和谷氨酰胺或/和谷氨酸盐或/和α-酮戊二酸盐的鸟氨酸、谷氨酰胺和其它氨基酸的二肽或/和谷氨酰胺和其它氨基酸的三肽或/和具有其它氨基酸的谷氨酸盐或/和α-酮戊二酸的盐或/和谷氨酰胺或/和谷氨酸盐或/和α-酮戊二酸盐的鸟氨酸、谷氨酰胺或谷氨酸盐与其它氨基酸的二肽的该制剂(剂量为0.01-0.5g/kg/天)用于确保这些物质在人类和动物的血液中的适当的-生理-治疗水平，其在下面的疾病中具有治疗性和预防性性质：人类和动物中的贫血、产后肠郁滞、心脏功能障碍、动脉粥样硬化、手足搐搦、骨质疏松症、关节炎、肠功能障碍、肌肉功能障碍、痴呆、免疫力降低、细菌的速率(rate)增加、病毒和真菌感染、瘤和其它疾病的增加的发病率。
根据本发明，该营养性或/和药物制剂的第二其它应用区别于它自己在于：包含α-酮戊二酸盐或/和谷氨酰胺或/和谷氨酸盐或/和α-酮戊二酸盐的鸟氨酸、谷氨酰胺和其它氨基酸的二肽或/和谷氨酰胺和其它氨基酸的三肽或/和具有其它氨基酸的谷氨酸盐或/和α-酮戊二酸的盐或/和谷氨酰胺或/和谷氨酸盐或/和α-酮戊二酸盐的鸟氨酸、谷氨酰胺或谷氨酸盐与其它氨基酸的二肽的该制剂(剂量为0.01-0.5g/kg/天)用于提高家畜(如猪、家禽、羊、牛、马、山羊和其它)的生产率和产量。
根据本发明，该营养性或/和药物制剂的第三其它应用区别于它自己在于：包含α-酮戊二酸盐或/和谷氨酰胺或/和谷氨酸盐或/和α-酮戊二酸盐的鸟氨酸、谷氨酰胺和其它氨基酸的二肽或/和谷氨酰胺和其它氨基酸的三肽或/和具有其它氨基酸的谷氨酸盐或/和α-酮戊二酸的盐或/和谷氨酰胺或/和谷氨酸盐或/和α-酮戊二酸盐的鸟氨酸、谷氨酰胺或谷氨酸盐与其它氨基酸的二肽的该制剂(剂量为0.01-0.5g/kg/天)用于提高锰(Mn)吸收入胆汁和肝脏，这使得该制剂在人类和动物中在肝脏和消化道的其它组织的瘤的检查和诊断中作为口服对照剂的成分的应用成为可能。
根据本发明，该营养性或/和药物制剂的第四其它应用区别于它自己在于：包含作为营养微量元素的铁(Fe)或其它二价金属的离子的该制剂(剂量为0.0001-0.01g/kg/天)，提高了α-酮戊二酸盐或/和谷氨酰胺或/和谷氨酸盐或/和α-酮戊二酸盐的鸟氨酸、谷氨酰胺和其它氨基酸的二肽或/和谷氨酰胺和其它氨基酸的三肽或/和具有其它氨基酸的谷氨酸盐或/和α-酮戊二酸的盐或/和谷氨酰胺或/和谷氨酸盐或/和α-酮戊二酸盐的鸟氨酸、谷氨酰胺或谷氨酸盐与其它氨基酸的二肽吸收入血和在肠细胞(entereocytes)中的代谢，并用于在下列疾病中确保它们在人类和动物的血液中的生理-治疗-预防水平：贫血、产后肠郁滞、心脏功能障碍、动脉粥样硬化、手足搐搦、骨质疏松症、关节炎、肠功能障碍、肌肉功能障碍、痴呆、免疫力降低、细菌的速率(rate)增加、病毒和真菌感染、瘤和其它疾病的增加的发病率。
根据本发明，该营养性或/和药物制剂的第五其它应用区别于它自己在于：其包含作为营养微量元素的铁(Fe)或其它二价金属的离子(剂量为0.0001-0.01g/kg/天)，并且提高α-酮戊二酸盐或/和谷氨酰胺或/和谷氨酸盐或/和α-酮戊二酸盐的鸟氨酸、谷氨酰胺和其它氨基酸的二肽或/和谷氨酰胺和其它氨基酸的三肽或/和具有其它氨基酸的谷氨酸盐或/和α-酮戊二酸的盐或/和谷氨酰胺或/和谷氨酸盐或/和α-酮戊二酸盐的鸟氨酸、谷氨酰胺或谷氨酸盐与其它氨基酸的二肽的吸收入血和在肠细胞中的代谢，用于保护和提高家畜(如猪、家禽、羊、牛、马、山羊和其它)的生产率和产量。
按照本发明，检验了AKG对铁和其它微量元素吸收的影响。铁和其它微量元素，如锌、铜、锰对于血红蛋白、mioglobine、细胞色素、和其它酶的合成是必需的。铁和其他微量元素的吸收不良是许多疾病的主要原因，如贫血、产后肠郁滞、心脏功能障碍、动脉粥样硬化、手足搐搦、骨质疏松症、关节炎、肠功能障碍、肌肉功能障碍、痴呆、免疫力降低、细菌的速率(rate)增加、病毒和真菌感染、瘤疾病的增加的发病率。
AKG作为静脉内营养成分的影响在不同患者的临床疾病中彻底的检测。研究了具有标准组成和具有添加的支链氨基酸(BCAA)、谷氨酰胺和AKG的静脉内营养配方。证明BCAA在肠外营养中不重要，而肠外施加的谷氨酰胺和α-酮戊二酸盐提高了肌肉中组成性谷氨酰胺的水平并降低了负氮平衡。
AKG还降低了铵水平，其在医疗处理中是重要的。血液中铵(血铵，ammonaemia)的高浓度导致肝硬化；然而，这种化合物的最严重的负性活性是它对于脑的影响。铵水平的提高会导致脑水肿和昏迷。
附图说明
本发明在进行的检测的基础上以实施例进行表述：
图1-来自猪中回肠的铁(Fe)的吸收增加的图，图2-在人类中口服给予AKG后铁(Fe)吸收入血的增加，以及图3-在人类中口服给予AKG后锌(Zn)吸收入血的增加，图4-在大鼠中经肠给予AKG后锰(Mn)(μmol/kg的体重)从肠道吸收的增加。
具体实施方式
实施例I
动物
对3只重量为30-35kg的瑞典种兰德瑞斯(Swedish raceLandrace)小猪进行研究。动物来源于大学兽群(SwedishAgricultural University，Dept.of Agricultural Biosystems and Technology，Lund)。每天两次在同样的时间用标准饲料(Vaxfor，Lantmanen，Sweden)喂养小猪(上午9:00-10:00，以及下午3:00-4:00)，每日剂量为50g/kg体重。它们可随意饮水。动物被分别放在可自动调节12小时的白天和夜晚的盒子中。
手术操作
试验(experience)中所用的无菌导管和T-瘘管由具有维持的医疗标准的硅酮管制成(Dow Cornning)。
在操作前小猪禁食9-12小时。
在操作前，动物接受镇静药-azoperone(Stresnil，2mg/kg体重)。随后，进行吸入导致的全身麻醉(Fluothan，0.5-1.5vol％)。在所有动物中制备十二指肠和骨盆瘘(pelvic fistulas)并给予AKG注入。借助插入门静脉和颈总动脉的导管，收集用于随后分析的血液样品。
制备两个切口：一个10-15cm，接近右hunger fossa，第二个2-3cm，在brachial关节和下颌骨的角之间。十二指肠瘘管位置在胰管对十二指肠的开口后。骨盆T-瘘管(内径(int.diameter)3.18mm，外径(ext.diameter)4.64mm-两个瘘管)在盲肠-回肠连接的末端被引入骨盆肠(pelvic intestine)。到门静脉的导管(内径0.64mm，外径1.19mm)通过肝脏被引入并用多根缝线固定(0-2肠线，Ethicon，England)。
置于门静脉中的导管和两个肠瘘管在切口线内被引出(broughtout)身体。在颧静脉(zygomatic vein)切开后，该导管在心脏方向被引入，深度为7cm。用双结扎线(0-3硅酮，Ethicon，England)封闭该静脉并用手术针在脖子的背部引出体外。
用双层缝线封闭腹部和颈部伤口：用弯曲缝线(twisted suture)(0-0肠线，Ethicon)封闭腹膜(仅在腹部伤口内)和肌肉，用间断缝线封闭皮肤(Suturamid2-0，Ethicon)。
在操作后，小猪被置于单独的盒子内。在操作后5天中，动物每天喂养两次，它们随意饮水。该操作按照手术技术由有经验的外科医生进行。
注入/剂量
溶液1- 35.1g AKG/I pH＝5.0:0.15g/kg体重
溶液2- 5.64g FeSO4/I pH＝2.0:10mg/kg体重
溶液3- 35.1g AKG/I FeSO4/I pH＝2.0:0.15g+10mg/kg体重
上述注入，重复两次，按照“拉丁方”的规则以两天的间隔给予动物(表1)。
表1.实验(experience)设计
d-注入十二指肠
b-注入骨盆肠
5，6，7-动物数量
在注入前，动物禁食。在傍晚进食期间在下午3:00点给予日常剂量食物。
所有的注入在上午9:00开始。在注入前30分钟和注入后15、30、60和120分钟采集血液样品。
2.注入组成
结果
结果在图1和表3、4中示出。
经肠给予的AKG显著地提高了铁从肠道吸收入血(图1，表3)，FeSO4提高了AKG从肠道吸收入血(表4)。
表3
接受FeSO4和FeSO4/AKG注射到十二指肠和骨盆肠的小猪血浆中的铁浓度(μmol/l)(平均数±SD，n＝3，观察资料＝6)
表4接受FeSO4和FeSO4/AKG注射到十二指肠和骨盆肠的小猪血浆中的AKG浓度(μg/l)(平均数±SD，n＝3，观察资料＝6)
字母表示统计学上显著性差异(p<0.05)。
实施例II
对4位志愿者进行研究。
第一天，在随机化并采集最初的血液样品后，志愿者空腹饮用溶解在200ml H2O中的200mg硫酸锌-ZnS O4(S ovezink，Tika 
AB，Lund)以及剂量为200mg的甲酸亚铁-Fe(HCOO)2的片剂(Erco-Fer，Orion)。在服用药物后，志愿者立即饮用1L10％葡萄糖(在0.9％NaCl溶液中)。随后在葡萄糖饮用后30、60、120、以及180分钟采集血液样品。两天后，这些志愿者消耗相同剂量的铁和锌并且其后饮用1L的10％AKG-苏打盐溶液。
结果：结果示于图2和图3中。口服的AKG提高了人类中Fe2+和Zn2+离子从消化道吸收入血液中的量。
实施例III
对24只大鼠进行实验，大鼠在实验前整夜禁食。用氯胺酮50mg/kg(Ketalar)诱导全身麻醉。
在动物中插入到达十二指肠、空肠后部以及胆管的导管。该实验在6只动物中同时进行。
在操作后稳定30分钟的时间后，6只动物接受到达十二指肠的MnCl2，随后6只动物接受到达空肠后部的MnCl2，随后6只动物接受到达十二指肠的MnCl2外加AKG-苏打(soda salt)(剂量为0.5g/kg体重)。6只动物的最后组接受到达肠后部的加有AKG-苏打盐的MnCl2(其剂量为0.5g/kg体重)。
检测在注入后2小时收集的胆汁中以及在胆汁收集的最后后和动物安乐死后直接切碎的肝脏中的锰含量。
结果
结果表明AKG提高了锰(Mn)从空肠后部的吸收(图4)。
Claims (3)
1.α-酮戊二酸或其盐在制备营养性和/或药物制剂中的应用，其中所述制剂刺激Fe2+、和Zn2+从消化道吸收入血，并提高Mn2+从空肠后部吸收入胆汁和肝。
2.根据权利要求1所述的应用，其中所述制剂以0.01-0.5g/kg天的剂量口服给予。
3.根据权利要求1或2所述的应用，其中所述制剂进一步包含作为营养微量元素的铁(Fe)离子，剂量为0.0001-0.01g/kg/天。
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| RU2007115542A (ru) | 2008-12-10 |
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| CA2589324A1 (en) | 2006-05-04 |
| CN101048081A (zh) | 2007-10-03 |
| PL370937A1 (pl) | 2006-05-02 |
| RU2393720C2 (ru) | 2010-07-10 |
| EP1806983B1 (en) | 2008-05-14 |
| JP4960872B2 (ja) | 2012-06-27 |
| WO2006046880A1 (en) | 2006-05-04 |
| EP1806983A1 (en) | 2007-07-18 |
| KR20070117534A (ko) | 2007-12-12 |
| AU2005300125A1 (en) | 2006-05-04 |
| DE602005006831D1 (de) | 2008-06-26 |
| JP2008518002A (ja) | 2008-05-29 |
| HK1109029A1 (en) | 2008-05-30 |
| US20090238895A1 (en) | 2009-09-24 |
| AU2005300125B2 (en) | 2011-07-14 |
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