CN1098624A - 用于预防酒精中毒的药物制剂及其制备方法 - Google Patents
用于预防酒精中毒的药物制剂及其制备方法 Download PDFInfo
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- CN1098624A CN1098624A CN94104765A CN94104765A CN1098624A CN 1098624 A CN1098624 A CN 1098624A CN 94104765 A CN94104765 A CN 94104765A CN 94104765 A CN94104765 A CN 94104765A CN 1098624 A CN1098624 A CN 1098624A
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Abstract
本发明叙述了用作食品、软饮料、维生素等的添
加剂的含有L-天冬氨酸盐或L-天冬酰胺的组合
物。本发明也提供了预防人体受治疗者酒精中毒的
方法。
Description
本发明涉及含有L-天冬氨酸盐(以后简称“ASP”)或L-天冬酰胺(以后简称“ASN”)的药物制剂以及它们的制备方法。更具体地说,本发明涉及可用于加入食品、食品添加剂、软饮料或维生素的含有ASP或ASN的药物组合物;ASP化合物或ASN化合物;用于预防人酒精中毒的给药方法(对人每天每千克体重给药约0.001~0.4g ASP或ASN);以及制备这类组合物的方法。
ASP和ASN已从天然物质中或由合成方法获得。以前在先有技术中已公开了以少量加入的所述ASP或ASN被广泛地用作食品添加剂。但是,对人给药大量的ASP或ASN可预防酒精中毒却是未知的。
已有建议提示促进乙醇氧化作用或阻断乙醇的细胞毒性的途径。例如长期以来认为,果糖具有通过下述机理促进乙醇氧化的潜能:首先是果糖经果糖激酶的作用被转化成果糖1-磷酸盐,同时将ATP转变成ADP,随之ADP被转移到线粒体中,并在此促进氧吸收和NADH的再氧化作用(Crownover等,1986,Scholz & Nohl 1976,Ylikari等,1971)。但是有关果糖对乙醇氧化作用的功效,仍然是有争论的(Berry & Kun1978)。
在另一个例子中,已报道咪唑并二氮杂
类化合物R015-4513(8-叠氮基-5,6-二氢-5-甲基-6-氧代-4H-咪唑并[1,5-1][1,4]苯并二氮杂
-3-羧酸乙酯)具有作为特异性乙醇拮抗剂作用(Lister & Nutt 1987,Hoffman等1987)。从R015-4513在突触体中逆转乙醇对GABA介导的Cl-流动的促进作用中的活性,已经注意到R015-4513的特异性生化作用(Suzdak等,1986)。已经观察到R015-4513对酒精诱导的行为紊乱的治疗作用。但是,R015-4513的毒性作用仍然限制了它的普遍应用(Corda等,1989)。此外据报道,GABA拮抗剂、5-羟色胺吸收抑制剂、a-肾上腺素能受体拮抗剂、锂离子(Lithium)、咖啡因、甲状腺激素释放激素(TRH)和高压氧具有逆转(至少部分地逆转)某些酒精行为作用的潜能(Lister & Nutt 1987,Judd & Huey 1984,Mezey 1976,Nuotto等 1982,Menon & Kodama 1985,Alkana等1977,Alkana & Malcom1982)。但是,大多数所建议的药品对乙醇的血液含量或对它的代谢转换均没有显著的影响。
另一方面,有关肝功能和乙醇代谢的许多报道已经公开于下列文献中:Pettersson G.(1987),“Liver alcohol dehydrogenase”,CRC-Crit-Rev.21(4),349~89;Gianoulakis C.(1989),“The effect of alcohol on the biosynthesis and regulation of opioid peptides”,Experientia 45(5),428~35;Hoekn,J.B等(1992),“Ethanol and signal transduction in the liver”,FASEB-J.6(7),2386-96;Mitchell MC和Herlong HF(1986),“Alcoholand nutrition,Caloric Value,bioenergetics and relationship to liver damage”,Ann.Rev.Nutr.6(4),457-74;Gellert J和Teschke,R.(1988),“The biochemistry of alcohol metabolism”,Z.Gastroenterol.26(suppl 3)22-7;以及Principles of Biochemistry(1993),(Lehninger,Nelson,Cox)3rd ed.,Chap.18,pp.9542~597,Worth Publishers.
美国专利第5,102,910号公开了用作肝功能驱动剂的含有以下成分的药物组合物:(a)L-天冬氨酸,(b)L-半胱氨酸,(c)L-谷氨酸,(d)硒酸钠,和(e)乙酸锌或硫酸锌。但是,该专利既未公开其特异性机理,也未公开有关体外或体内试验的资料。
因此,本发明的一个目的是提供用于加到食品、食品添加剂、软饮料、维生素等中,以预防酒精中毒的含有L-天冬氨酸盐或L-天冬酰胺的药物制剂,以及它们的制备方法。
本发明的另一目的是提供用于预防酒精中毒的作为固体、液体或粉末状制剂的含有ASP或ASN的药用化合物,以及它们的制备方法。
本发明的又一目的是提供用于预防酒精中毒的方法,该方法包括对人按0.001g~0.4g/kg/天的剂量给药ASP或ASN。
本发明的再一目的是提供用于降低、减轻或预防肝损伤、组织损伤和智能或协调变化的方法,该方法包括对人按0.001~0.4g/kg/天的剂量给药ASP或ASN。
本发明的其他目的和另外的应用范围从下面给出的详细描述中将变得很明显。但是,应该明白,在阐述本发明的优选实施方案时,只是通过举例的方式给出详细的说明和特定的实施例,因为本领域技术人员根据这些详细的说明,将会明白在本发明的精神实质和范围内进行的各种变化和改良。
从以下给出的详细说明和仅以举例方式给出的附图将使人们更充分地了解本发明,因此以下的说明和附图并不限制本发明。
按照本发明,图1表示乙醇代谢转换的途径。
按照本发明,图2表示通过苹果酸盐-天冬氨酸盐互变机制,胞液中烟酰胺腺嘌呤二核苷酸(以下简称“NAD”)的代谢再生系统。
按照本发明,图3表示饮用酒精后并用ASP处理后血液乙醇含量的变化,也给出了未用ASP处理的对照受治疗者的血液乙醇的含量。
按照本发明,图4表示ASP和ASN对人体内乙醇(血液乙醇含量)的药物动力学的影响。
按照本发明,图5表示ASP和ASN对人体内乙醇(血液乙醛含量)的药物动力学的影响。
按照本发明,图6表示由于给予ASP而在哺乳动物肝细胞瘤细胞(FT02B)中引起的对乙醇毒性的抗性;以0.005、0.05或0.5mM的浓度加入ASP。
按照本发明,图7表示由于给予ASN而在哺乳动物肝细胞瘤细胞中引起的对乙醇毒性的抗性;以0.005、0.05或0.5mM的浓度加入ASN。
如图1-7所示,本发明提供了用于预防酒精中毒的药物制剂,含有L-天冬氨酸盐或L-天冬酰胺的该药物制剂以其大剂量包含在食品、食品添加剂、软饮料、维生素及许多类型的药物制剂中。该类药物制剂可以采用供人口服、注射或腹膜内给药的形式。
本发明化合物或组合物可以以粒剂、片剂、丸剂、胶囊剂、液体、粉剂等剂型供口服给药,并且可以悬浮液剂、液体、乳剂、安瓿、注射液或上述制剂的结合形式供非经胃肠道给药。作为在组合物中使用的大多数类型采用的是固体、半固体、液体或粉剂的形式。所述组合物包括水、苏打水、维生素、糖、盐类、汤、肉、氨基酸类、水果、农作物、蔬菜、鱼、海洋植物、有机酸类等,或者是并用其中两种或多种的组合物。
按照本发明,ASP或ASN在组合物中的比例约为0.1~100%(重量),优选0.2~10%(重量)。当组合物为液体形式如汤、软饮料或重新组成的饮料(例如GatoradeTM)时,它含有0.1~10.0%(重量),优选0.2~1.0%(重量)的ASP或ASN。此外,它同时还包括0.1~10.0%(重量),优选1-5%(重量)的其他氨基酸、糖(例如蔗糖、乳糖、葡萄糖、低聚糖、卡哈苡苷等)、有机酸类或维生素。它还可以选择性地含有0~0.1M,优选0.02~0.04M的电解质混合物,例如可溶性钠盐或钾盐(NaCl,KCl等)。
如果配制成胶囊剂或片剂形式,本发明组合物可以含有0.2~90%(重量),优选30~50%(重量)的ASP或ASN,而其余的成分包含维生素、氨基酸类、糖、有机酸类等。
按照本发明,下面表1表示对于L-天冬氨酸盐或L-天冬酰胺的附加任选成分。
表1
对于ASP或ASN的附加任选成分
成分 常用含量 优选含量
ASP或ASN 0.2-100重量% 30-50重量%
氨基酸类 q.s. q.s.
人造调味品 q.s. q.s.
天然调味品 q.s. q.s.
糖 q.s. q.s.
维生素 q.s. q.s.
色素 q.s. q.s.
其中q.s.表示适量。
本发明可以预防、减轻或解除人由于饮用酒精而引起的肝损伤、其他组织损伤以及智能或协调的变化,或其他与醉酒有关的行为变化。
一般被广泛接受的是,乙醇通过三条独立的代谢途径氧化为乙醛,例如乙醇脱氢酶(以下简称“ADH”)、细胞色素P450系统(下简称“MEOS”)和过氧化氢酶。如图1所示,乙醇氧化作用的核心和主要的机理是以烟酰胺腺嘌呤二核苷酸(以下简称“NAD”)作为辅助因子的ADH所催化的反应。ADH活性主要位于肝细胞的细胞溶质中,但是在其他组织中(特别是胃肠道中)也发现有ADH活性。而且一般来讲,由ADH催化的从乙醇变为乙醛的代谢转换伴有NAD还原为还原型烟酰胺腺嘌呤二核苷酸(以下简称“NADH”)的反应。
关于非-ADH介导的乙醇的代谢过程,过氧化氢酶和MEOS的相对贡献尚有争议。由于以烟酰胺腺嘌呤二核苷酸磷酸(以下简称“NADPH”)作为辅助因子氧化乙醇和其他伯醇的、依赖细胞色素P450的单氧合酶是可以诱生的,并且对乙醇具有较高的Km,因此MEOS可能对慢性嗜酒者和具有较高乙醇浓度的情况起较大的作用。一般来讲,最近对MEOS的兴趣是由于其在致癌物和药物的异生物质激活中的作用而产生的。另一种非-ADH的乙醇氧化活性(由过氧化氢酶所引起)是依赖于H2O2的可得性,并且认为在大脑中起相当重要的作用。
由乙醇随后生成的乙醛是非常有毒的,应该被立即除去,对此乙醛脱氢酶(以下简称“ALDH”)负有完全责任。为了使乙醛转变为乙酸盐,需要伴随NAD的还原。因此,在乙醇通过乙醛连续代谢转化为乙酸盐的过程中,细胞的NAD/NADH的状态非常重要。
因此,通过ADH和ALDH催化的乙醇氧化作用消耗了胞质中的NAD,并且随之使细胞内NAD/NAD比率降低。胞液中NAD/NADH比率降低可以引起许多生物化学变化和组织损伤。由于细胞溶质中NAD依赖性脱氢酶的所有反应均受到了影响,该比率的改变导致乳酸盐产量的增加和δ-氨基乙酰丙酸合成,并导致雄性激素分解代谢增加和乙醛累积,同时引起葡糖异生作用、半乳糖氧化作用和柠檬酸循环活性等降低。
此外,通过细胞内信息转导系统、脂肪酸和蛋白质的生物合成和降解作用以及与几种功能蛋白质直接的相互作用,乙醇及其代谢产物对肝脏、大脑和性腺有它们自己的生物学作用。在大多数情况下,由乙醇所引起的这些生物学作用对组织是有害的。因此,如果有任何生物化学方法以促进乙醇完全氧化为乙酸盐,那么该方法将可以减少乙醇或乙醛的细胞内含量,并可以直接或间接地预防乙醇引起的许多类型的细胞损伤。
乙醇的代谢作用是多种多样的,可以直接由乙醇和乙醛引起,或者间接地由乙醇氧化作用所导致的胞液的NAD/NADH比率紊乱引起。为了维持细胞的自身稳定和保护细胞免受乙醇的损伤,本领域技术人员认为,细胞可以通过加强NAD再生能力来加速乙醇的代谢消除。
由于大多数脱氢酶是NAD依赖性的,因此存在许多NAD再生系统。为此,脱氢酶的活化可以通过调节分子或通过加入底物进行试验。在本发明中,考虑了通过刺激NAD再生来激活ADH的后一方式。此外,来自外源途径的底物在体内的可得性,引导本发明人去分析乳酸脱氢酶(LDH)和苹果酸脱氢酶(MDH)。虽然a-酮酸可能不进入细胞,但是它们的前体如天冬氨酸盐或丙酸可以容易地被吸收到细胞内,并在细胞内进行有效的转氨作用变成相应的a-酮酸(图1)。通过特异性脱氢酶的作用,可以使丙酮酸盐和草酰乙酸盐分别被还原为乳酸盐和苹果酸盐,同时由NADH再生NAD。结果,再循环的NAD可以用于进一步的乙醇的氧化。用于乙醇氧化作用的NAD/NADH再循环中涉及的所有酶,例如ADH、乳酸脱氢酶(以下简称“LDH”)、谷氨酸丙酮酸转氨酶(以下简称“GPT”)、苹果酸脱氢酶(以下简称“MDH”)和谷氨酸-草酰乙酸转氨酶(以下简称“GOT”)均具有接近平衡的工作特征。即这些酶的活性由质量作用定律控制,并且取决于底物的浓度。这种平衡酶的特征在缓和代谢紊乱和迅速协调细胞功能方面十分有益,而无需消耗能量或动用复杂的变构调节系统。
通过加入天冬氨酸盐或丙氨酸可以在GOT/MDH偶联系统或在GPT/LDH偶联系统中观察到NAD的以化学计量比再循环。还发现ADH/MDH/GOT酶或ADH/LDH/GPT酶的双偶联系统可以有效地在乙醇氧化为乙醛中起作用,这两个系统在功效方面几乎是类似的,但是,在生物学上的重要性方面,在用于体内乙醇氧化作用时,ADH/MDH/GOT系统是较好的。通过已知的用于NAD/NADH传递的苹果酸盐-天冬氨酸盐互变机制,MDH/GOT偶联系统在胞液和线粒体之间进行良好的平衡(图2)。此外,细胞内GOT的活性明显高于GPT,这表明MDH/GOT偶联系统对于NAD再生具有比LDH/GPT系统更高的功效。在线粒体中,被传递的NADH可以容易地用于氧化磷酸化作用,这可以加强被乙醇扰乱的柠檬酸循环活性。因此,由ADH/MDH/GOT系统催化的乙醇氧化作用所得的产物苹果酸盐可以容易地被吸收到线粒体中,而没有任何代谢后遗症。由该循环再生的NAD通过醛脱氢酶(以下简称“ALDH”)的作用,可以加速乙醛被氧化成乙酸盐,因为ALDH也是NAD依赖性的。
因此,通过天冬氨酸盐的富集作用产生的苹果酸盐-天冬氨酸盐互变机制的加强,可以促进NAD再生循环,这可加速细胞内的乙醇完全被氧化为乙酸盐。该机制有助于在饮酒之后降低组织中乙醇的含量,并有助于预防由于乙醇和乙醛或者由于细胞的NAD/NADH比率降低所引起的酒精损伤。为此,在本发明中开发了恢复被降低了的细胞的NAD/NADH比率的方法,其方法是:通过乙醇的代谢降解,加速乙醇和乙醛的代谢,缩短它们在组织中停留的时间,或者是通过其他方法,例如由于持久性训练产生的乳酸盐积累。因此,本发明的下述目的已经达到,即预防或解除组织损伤,由NAD/NADH比率变化所引起的代谢失去平衡,以及预防、减轻或解除由于长期酒精中毒所引起的疾病(包括肝病、精神障碍和行为失调)。为了调节NAD/NADH的比率,可通过苹果酸盐-天冬氨酸盐互变机制加强前述的MDH/GOT偶联系统,这是由于相应的组织胞液中大量的转氨酶将促进天冬氨酸盐的转氨作用而提供草酰乙酸盐。即由于NAD和NADH不能直接地越过细胞膜转移,因此细胞内NAD和NADH的调节,需由a-酮戊二酸盐和苹果酸盐以及谷氨酸盐和天冬氨酸盐越过线粒体膜的往复传递来实现。
在苹果酸盐-天冬氨酸盐互变机制中,草酰乙酸盐不能越过线粒体膜扩散,而天冬氨酸盐可通过谷氨酸盐-天冬氨酸盐传递载体和苹果酸盐-a-酮戊二酸盐传递载体以化学计量比循环。并且在胞质中,天冬氨酸盐还通过转氨酶的作用与a-酮戊二酸盐反应,以生成草酰乙酸盐和谷氨酸盐,因此生成的草酰乙酸盐通过苹果酸脱氢酶的作用氧化NADH为NAD,同时使草酰乙酸盐还原为苹果酸盐。该途径对再生于胞质中耗竭的NAD是十分重要的,并且苹果酸盐被吸收进入线粒体,随之被转变为草酰乙酸盐或天冬氨酸盐或者用于三羧酸循环,因为用于该途径的天冬氨酸氨基转移酶或MDH大量地存在于组织中,并且具有平衡酶的特征,因此酶反应速率主要由大量底物进行调节。
在本发明中,通过利用组织的生物化学特性,MDH/GOT偶联系统和苹果酸盐-天冬氨酸盐互变机制被用作补充由于乙醇代谢或者任何其他代谢紊乱而耗竭的NAD的一种手段,并且由于提高了细胞内草酰乙酸盐的浓度而增进了MDH活性,使多次产生的NADH更容易被转变为NAD。但是,由于草酰乙酸盐不容易越过细胞膜转移,因此通过大量地存在于组织中的天冬氨酸基转移酶的作用并加入可转移的天冬氨酸盐,可以使天冬氨酸盐容易地被转变为草酰乙酸盐,从而间接地使草酰乙酸盐的浓度升高。显然,加入天冬氨酸盐可以加速乙醇氧化作用。而且在本发明中,加入在人体内可产生天冬氨酸盐的天冬酰胺可以得到与加入天冬氨酸盐类似的作用,因为天冬酰胺在肠的上皮被吸收,并且通过天冬酰胺酶的作用直接被转变为天冬氨酸盐。
在本发明中,对用乙醇单独处理组和同时用乙醇和天冬氨酸盐(或天冬酰胺)处理组在不同时间内的血液乙醇含量进行了比较。结果是,由于用天冬氨酸盐或天冬酰胺处理使NAD再生增加并加速乙醇的代谢转变,从而降低了血液乙醇含量。该作用可以用于细胞代谢平衡以及由酒精或任何其他方式所引起的各种疾病以及精神障碍和行为失调。在类似试验中通过给动物腹膜内注射给药,本发明得到了显著的效果。
试验实施例1
饮用酒精试验
1、实验材料
所用酒精为Johnny Walker威士忌酒(黑标签)(86标准酒精度(proof)),并应用天冬氨酸钠(由日本Tanabe公司制造)。采用无任何特殊病史特别是肝功能检查无异常征兆的年龄20岁出头的健康人作为实验对象。用气相色谱法测定血液乙醇浓度。
2、实验方法
5名实验对象各自饮用120ml威士忌酒(86标准酒精度)之后,在1小时和3小时后分别采集2ml血样测定血液乙醇含量。第一次实验之后3天,让这同一批人饮用酒精并同时服用5克天冬氨酸盐胶囊,用上述同样方法测定血液乙醇含量。并且在饮酒1小时后,对每个实验对象进行简要的身体平衡试验。身体平衡试验重复进行3次。这种身体平衡试验按下法进行:使受试者沿直线向一个方向行走,行走距离为3m,同时两臂伸向两边。偏离直线路径15cm宽表示异常表现。
3、给药天冬氨酸盐引起的血液乙醇含量改变
如表2和图3所示,与乙醇单独处理组比较,乙醇和L-天冬氨酸盐处理组在饮酒1小时之后,显示出血液乙醇浓度降低55%以上(P<0.05)(降低至0.01~0.04g/dL)的作用。在3小时之后,在两组中血液乙醇含量相等。这可以解释为该作用(给药L-天冬氨酸盐降低了血液乙醇浓度)是由于给药L-天冬氨酸盐加速乙醇的代谢,并且继而通过加强NAD的再生性促进了乙醇氧化作用的结果,详见表2。
表2
饮用酒精之后,通过给药ASP引起的血液乙醇含量变化
饮酒后 乙醇单独处理 乙醇和ASP处理
的时间 组(5人)(g/dl) 组(4人)(g/dl)
1小时 0.055±0.010 0.025±0.010
3小时 0.024±0.007 0.018±0.017
其中饮用的酒精量为120ml(86标准酒精度的威士忌酒),ASP的给药量为5g粉剂。
4、饮酒后给药ASP引起的身体平衡指数的变化
饮用酒精1小时之后分析身体平衡指数表明,由于给药天冬氨酸盐降低了血液乙醇含量,结果改善了由乙醇诱发的行为失调(表3)。在乙醇单独处理组中,差错率为53%,而在乙醇和天冬氨酸盐处理组中差错率仅为26%。也就是说给药ASP使身体平衡改善49%,详见表3。
表3 饮酒后给药ASP对身体平衡指数的影响
实验组 | 乙醇单独处理组 | 乙醇和ASP处理组 |
身体平衡差错率 | 8/15(53%) | 4/15(26%) |
试验实施例2
腹膜内注射乙醇
1、实验材料和方法
在实验中应用重200g的Sprague-Dawley大白鼠。本实验中应用的所有试剂均为分析级的。L-天冬氨酸盐为日本Tanabe公司的产品,将该产品溶于无菌水中以配成适当的浓度,调节溶液的酸性至PH7.4并过滤。
乙醇经腹膜内注射。将大白鼠分成5组,每组5只。第一组为未经处理的对照组。另外的3组接受2ml 50%乙醇。乙醇处理组中的第一组不接受另外的处理(仅给予乙醇),第二乙醇处理组用低剂量的天冬氨酸盐(0.75ml 3.45M ASP)处理,第三乙醇处理组同时接受高剂量的天冬氨酸盐(2ml 3.45M ASP)。第5组大白鼠仅给予大剂量天冬氨酸盐。每组每天如上处理1次,连续5天,在第6天检查大白鼠的身体状况,然后活杀。取出肝组织并进行病理和组织学检查。
2、给药天冬氨酸盐可改善腹膜内注射乙醇引起的影响
组织学检查发现,ASP可以抑制由于直接的腹膜内注射乙醇所引起的炎症(见表4)。在仅给予乙醇的大白鼠中观察到腹部炎症和腹腔中组织粘连。而在除给予乙醇之外还给予ASP或ASN的动物中,这些影响明显地减少。
表4 给药ASP对腹膜内注射 乙醇所产生的症状的影响
组 | 粘连 | 肝炎症 |
对照组 | - | - |
乙醇单独处理组 | +++ | +++ |
乙醇和低剂量ASP组 | ++ | + |
乙醇和高剂量ASP组 | + | + |
高剂量ASP单独处理组 | + | - |
实验实施例3
给药L-天冬氨酸盐和天冬酰胺对乙醇代谢的影响
1、材料和方法
为了试验给药L-天冬氨酸盐或天冬酰胺对人体乙醇代谢的影响,按下法试验血液乙醇浓度以及血液乙醛浓度随时间的变化:6名健康成年人分别服用120ml威士忌酒(86标准酒精度)和5g L-天冬氨酸盐或天冬酰胺。每小时用肝素处理的针管采集1ml血样,分别置于含有EDTA的小瓶中。在第二天用气相色谱法检测血液中乙醇和乙醛浓度。
2、结果
L-天冬氨酸盐可将血液乙醛浓度降低36%以上,天冬酰胺可将血液乙醛浓度降低30%以上。该结果在统计学上是有意义的。因此,本试验表明,给药L-天冬氨酸盐或天冬酰胺可用于预防酒精中毒(请见表5和图4及图5)。
表5 给药天冬氨酸盐和天冬酰胺对乙醇代谢的影响
组 | 天冬氨酸盐处理组 | 天冬酰胺处理组 |
血液乙醇含量的降低 | -10.79% | -14.65% |
血液乙醛含量的降低 | -36.14% | -30.16% |
(仅饮用酒精对照组的百分率)
试验实施例4
天冬氨酸盐和天冬酰胺对细胞系酒精中毒的影响
1、材料和方法
进行MTT试验,以便分析在体外给予乙醇对哺乳动物细胞的影响,以及天冬氨酸盐或天冬酰胺对乙醇中毒的影响。将哺乳动物肝细胞瘤细胞系FT02B置于培养基中培养,其中DMEM与Ham'sF12培养基以相等的量混合并加入5%小牛血清和胎牛血清。细胞于5% CO2和95%空气中于37℃保温。将细胞分配到96孔检测板中,每孔5×103个细胞。将各自不同浓度的乙醇,或乙醇加天冬氨酸盐,或乙醇加天冬酰胺分别加到各孔中。培养4天之后,利用通过加入MTT(溴化3-(4,5-二甲基-噻唑-2-基)-2,5-二苯基四唑鎓)和二甲基亚砜引起的颜色反应,用ELISA板读数器测量在540nm处的吸收率,以便计数存活细胞的数目。测定在各个条件下(乙醇,乙醇+ASP,乙醇+ASN)的IC50(细胞毒性指数),与不加乙醇、不加ASP(或ASN)的对照培养物相比较,以能保持50%细胞存活的乙醇浓度来测定。
2、实验测定结果
天冬氨酸盐对乙醇的细胞毒性的改善作用是与剂量有关的。天冬酰胺也表现出这种作用,尽管与天冬氨酸盐相比它的作用较弱(见图6和7)。
下面叙述制备实施例,其中将天冬氨酸盐和天冬酰胺加到食品、饮料或维生素等中或者与这些物质同时分别应用。
制备实施例1
将天冬氨酸盐或天冬酰胺按0.2~5%(重量)溶于软饮料如可口可乐中。
制备实施例2
将天冬氨酸盐或天冬酰胺按0.2~5%(重量)溶于运动饮料如GatoradeTM中。
制备实施例3
将天冬氨酸盐或天冬酰胺按0.5~1.5%(重量)加到由蔬菜(如龙须菜、豆芽)制得的汤,以及水果(如梨、桃、苹果)的汁液或浸膏中。
制备实施例4
将天冬氨酸盐或天冬酰胺加到维生素粗品中,或者与该维生素粗品混合,以便制成片剂或胶囊剂的形式,其中天冬氨酸盐或天冬酰胺占10~50%(重量)。
制备实施例5
将天冬氨酸盐或天冬酰胺与一种或二种另外的氨基酸、柠檬酸或糖混合,以便制成片剂或胶囊剂的形式,其中天冬氨酸盐或天冬酰胺占0.1~90%,优选0.1~50%,最优选0.1~10%(重量)。
制备实施例6
将天冬氨酸盐或天冬酰胺与一种或二种其他氨基酸混合,或与维生素混合,以便制成ASP或ASN占0.5~5%(重量)的用于静脉注射的溶液剂。
制备实施例7
将干鱼如鱿鱼、干绿鳕等浸泡在含10~90%(重量)加味的天冬氨酸盐或天冬酰胺溶液中,并干燥以用作调味品。
制备实施例8
在小吃(如脆饼)的制备中,将与面粉重量相比占0.1~10%(重量)的天冬氨酸盐或天冬酰胺加入,或与之混合,然后油炸制作小吃。
显然,上面叙述的本发明可以按许多方式进行改变。不要把这些改变看作是偏离本发明的精神实质和范围,对本领域技术人员来讲显而易见的所有这些改良均包括在如以下权利要求书所述的本发明的范围内。
Claims (20)
1、用于预防酒精中毒的包含有效量的L-天冬氨酸盐或L-天冬酰胺的药物制剂。
2、权利要求1所述的药物制剂,其中所述有效量约为0.001~0.4g/kg/天。
3、权利要求1所述的药物制剂,其中所述有效量约为0.001~0.4g/kg/天。
4、权利要求1所述的药物制剂,其中将所述L-天冬氨酸盐或L-天冬酰胺与选自水、苏打水、维生素、糖、盐类、汤、肉、氨基酸类、水果、农作物、蔬菜、鱼、海洋植物和有机酸类的食品混合。
5、权利要求4所述的药物制剂,其中所述汤选自豆芽汤、龙须菜汤和鱼汤。
6、权利要求4所述的药物制剂,其中所述的氨基酸类选自异亮氨酸、亮氨酸、缬氨酸和牛磺酸。
7、权利要求4所述的药物制剂,其中所述的水果选自梨、桃、苹果、无花果、草莓、菠萝,柑橘和李子。
8、权利要求4所述的药物制剂,其中所述的农作物和蔬菜选自豆、绿豆芽、菜豆、花生、龙须菜、葫芦、南瓜、莲根、红甜菜、甘薯和马铃薯。
9、权利要求4所述的药物制剂,其中所述的鱼和海洋植物选自甘紫菜、棕海藻、大型褐藻、鱿鱼和干绿鳕。
10、权利要求4所述的药物制剂,其中所述的有机酸类选自柠檬酸、苹果酸、琥珀酸和酒石酸。
11、权利要求1所述的药物制剂,其中将L-天冬氨酸盐或L-天冬酰胺配制成注射剂注入人体组织,人体组织选自肌肉、皮下组织和血液。
12、用于预防酒精中毒的含有L-天冬氨酸盐或L-天冬酰胺的组合物,所述的L-天冬氨酸盐或L-天冬酰胺占其组合物重量的约0.1~90%(重量)。
13、权利要求12所述的组合物,其中将所述的组合物配制成含有约0.1~10%(重量)L-天冬氨酸盐或L-天冬酰胺的液体。
14、权利要求12所述的组合物,其中将所述的L-天冬氨酸盐或L-天冬酰胺与食品混合,所述食品选自水、苏打水、维生素、糖、盐类、汤、肉、氨基酸类、水果、农作物、蔬菜、鱼、海洋植物和有机酸类。
15、预防人体受治疗者酒精中毒的方法,该方法包含给人按0.001~0.4g/kg/天的剂量范围给药L-天冬氨酸盐或L-天冬酰胺以预防饮用酒精之后酒精中毒。
16、权利要求15所述的方法,其中所述的剂量范围为0.01~0.4g/kg/天。
17、权利要求15所述的方法,其中将L-天冬氨酸盐或L-天冬酰胺注入选自肌肉、皮下组织和血液的人体组织中。
18、权利要求15所述的方法,其中将所述的L-天冬氨酸盐或L-天冬酰胺与食品混合,所述食品选自水、苏打水、维生素、糖、盐类、汤、肉、氨基酸类、水果、农作物、蔬菜、鱼、海洋植物和有机酸类。
19、权利要求18所述的方法,其中存在的所述L-天冬氨酸盐或L-天冬酰胺的含量为0.1~10%(重量)。
20、权利要求15所述的方法,其中所述L-天冬氨酸盐或L-天冬酰胺的量在给药组合物中占6~46%(重量)。
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KR1019930026324A KR970008105B1 (ko) | 1993-06-28 | 1993-12-03 | L-아스파테이트 또는 아스파라긴을 유효성분으로 함유하는 알콜성 장해 보호제 및 그의 제조방법 |
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EP (1) | EP0631778A1 (zh) |
JP (1) | JPH0753366A (zh) |
KR (1) | KR970008105B1 (zh) |
CN (1) | CN1098624A (zh) |
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KR20020088734A (ko) * | 2001-05-21 | 2002-11-29 | 엄경용 | 숙취 해소용 조성물 |
JPWO2006061992A1 (ja) * | 2004-12-10 | 2008-06-05 | 味の素株式会社 | 肝疾患予防・治療用組成物 |
JP2007020432A (ja) * | 2005-07-13 | 2007-02-01 | Asahi Breweries Ltd | アルコール代謝促進飲料 |
US7565555B2 (en) * | 2005-11-23 | 2009-07-21 | Cisco Technology, Inc. | Uninterruptible power supply resource sharing for multiple power sourcing equipment network devices |
JPWO2007142297A1 (ja) * | 2006-06-09 | 2009-10-29 | 味の素株式会社 | 肝疾患予防・治療用組成物 |
IT1395957B1 (it) * | 2009-05-19 | 2012-11-02 | Pharmaguida S R L | Uso di una combinazione di d-aspartato e l-aspartato per il trattamento della infertilita' maschile. |
JP6423717B2 (ja) * | 2012-05-07 | 2018-11-14 | 株式会社明治 | 非糖質性エネルギー産生増強剤 |
US9161957B2 (en) * | 2012-08-03 | 2015-10-20 | Life Well Lived, Llc | Compositions and methods for reducing blood alcohol content |
WO2015008101A1 (en) | 2013-07-15 | 2015-01-22 | Schaumlöffel Rolf A | Composition of a drink for enhanced reduction of blood alcohol level |
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US3009859A (en) * | 1958-07-22 | 1961-11-21 | Laborit Henri | Potassium aspartate and magnesium aspartate fatigue-recovery promoting process and compositions |
GB949076A (en) * | 1961-08-10 | 1964-02-12 | Wesley Gale Irons | Preparation of polypeptide derivatives |
GB1066084A (en) * | 1963-05-08 | 1967-04-19 | Kyowa Hakko Kogyo Kk | Improved alcoholic beverages |
GB1068478A (en) * | 1963-07-30 | 1967-05-10 | Kyowa Hakko Kogyo Kk | Increasing amino-acid content of food |
RO55542A2 (zh) * | 1971-02-27 | 1973-09-20 | ||
CA1057568A (en) * | 1974-06-10 | 1979-07-03 | General Foods Corporation | Soluble sweetening composition and method |
FR2310708A1 (fr) * | 1975-05-16 | 1976-12-10 | Sopharga Lab | Nouvelles boissons sans alcools |
US4479974A (en) * | 1982-10-19 | 1984-10-30 | General Foods Corporation | Amino acids as dry beverage mix ingredients |
GB8325627D0 (en) * | 1983-09-24 | 1983-10-26 | Scras | Therapeutic compositions |
US4913923A (en) * | 1984-09-12 | 1990-04-03 | Firmenich Sa | Process for improving or modifying the taste and aroma of citrus fruit compositions |
US4738856A (en) * | 1985-05-13 | 1988-04-19 | Nutrition Technologies, Inc. | Beverage and method for making a beverage for the nutritional supplementation of calcium in humans |
US4997672A (en) * | 1987-03-10 | 1991-03-05 | Virginia Commonwealth University | Salt taste enhancer |
EP0336960A4 (en) * | 1987-10-19 | 1990-02-20 | Joseph A Haklitch | DETOXIDATION ADDITIVES FOR FOODSTUFFS. |
IT1219919B (it) * | 1988-04-11 | 1990-05-24 | Foscama Biomed Chim Farma | Impiego del fruttosio-1,6-difosfato nel trattamento della intossicazione alcolica acuta e dell' etilismo cronico e composizioni farmaceutiche relative |
US4992282A (en) * | 1989-05-08 | 1991-02-12 | The Procter & Gamble Company | Stable nutritional vitamin and mineral supplemented beverage |
AT394493B (de) * | 1989-05-11 | 1992-04-10 | Homosan Ag | Pharmazeutisches praeparat zur behandlung von lebererkrankungen |
HU207800B (en) * | 1990-05-10 | 1993-06-28 | Andras Sikter | Process for producing composition for improving condition and for treating different illnesses |
US5176934A (en) * | 1991-12-12 | 1993-01-05 | Kraft General Foods, Inc. | Seasoned food product with a salt enhancer |
US5145707A (en) * | 1991-12-12 | 1992-09-08 | Kraft General Foods, Inc. | Salt enhancer |
KR930012028A (ko) * | 1991-12-19 | 1993-07-20 | 박용성 | 생약제제 |
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- 1994-02-18 JP JP6021537A patent/JPH0753366A/ja active Pending
- 1994-02-25 TW TW083101619A patent/TW278035B/zh active
- 1994-03-30 BR BR9401354A patent/BR9401354A/pt not_active Application Discontinuation
- 1994-05-02 CN CN94104765A patent/CN1098624A/zh active Pending
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TW278035B (zh) | 1996-06-11 |
KR950000143A (ko) | 1995-01-03 |
BR9401354A (pt) | 1995-03-07 |
EP0631778A1 (en) | 1995-01-04 |
KR970008105B1 (ko) | 1997-05-21 |
US5389359A (en) | 1995-02-14 |
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