CN101232822A - 用于减缓乙醇代谢和用于降低乙醇诱导的疾病风险的组合物 - Google Patents
用于减缓乙醇代谢和用于降低乙醇诱导的疾病风险的组合物 Download PDFInfo
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Abstract
本发明涉及物质组合物，特别是分别涉及食品组合物、饮食或食品添加剂、和药物组合物。该物质组合物降低神经病变、包括迟发性阿尔茨海默病的神经退行性疾病和癌症的风险，特别是药物和/或乙醇诱导的所述疾病的风险，所述癌症特别是胰腺癌、食管癌、口咽癌、肝癌、结肠直肠癌、肺癌和/或乳腺癌。在这方面，本发明也涉及物质组合物，特别是分别涉及食品组合物、饮食或食品添加剂、和药物组合物，所述组合物支持和/或减缓人体内乙醇的降解过程。
Description
本发明涉及物质组合物，特别是分别涉及食品组合物、饮食或食品添加剂、和药物组合物。该物质组合物降低神经病变、包括迟发性阿尔茨海默病的神经退行性疾病和癌症的风险，特别是药物和/或乙醇诱导的所述疾病的风险，所述癌症特别是胰腺癌、食管癌、口咽(oropharyngolaryngeal)癌、肝癌、结肠直肠癌、肺癌和/或乳腺癌。在这方面，本发明也涉及物质组合物，特别是分别涉及食品组合物、饮食或食品添加剂、和药物组合物，所述组合物支持和/或减缓人体内乙醇的降解过程。
本发明特别解决了快速乙醇降解，即乙醇代谢后乙醛的累积问题，其可能在大多数非白人(Non-Caucasian)型基因结构的人中发生。
认为饮用含酒精饮料与增加神经病变的风险有关。乙醇诱导脑和神经系统的许多作用，其导致行为、运动协调的改变，且极端情况，导致脑损伤。特别是，在酒精中毒患者中通常能观察到周围神经多神经病。一种可能的乙醇作用的中介是乙醛，一种高毒性的乙醇代谢物。乙醛是高活性分子，其具有氧化活性且具有细胞毒性效应，且使细胞中的蛋白改性，导致其机能障碍。
也认为饮用含酒精饮料与增加神经退行性疾病的风险有关。这些疾病认为是由神经元细胞中的包涵体的沉积、且最终细胞的消失引起的。由氧化剂如活性氧簇引起的氧化应激和随后的脂质过氧化，据报道是在神经退行性疾病发病机理中起到重要作用，所述疾病包括阿尔茨海默病、帕金森疾病和脑缺血。因此乙醛被认为是几种乙醇诱导的神经元变化的原因。乙醛也被认为是在乙醇相关的癌症发生中起到关键作用，因为其在实验室动物中已确认的DNA损伤作用(单链和双链断裂)和致癌性。
也认为饮用含酒精饮料与增加某些癌症的风险有关，包括胰腺癌、肝癌、结肠直肠癌、肺癌、乳腺癌、食管癌和口咽癌。认为乙醇消耗与增加的食管癌和口咽癌风险的相关性是明显的，至少从表明乙醇本身和/或其代谢物具有致癌潜力的流行病学研究中可以看出。
而且，女性饮酒者增加的雌激素水平看来是产生乳腺癌的重要机理。一种可能的增加雌激素的机理是饮酒后过量产生的乙酸转变为类固醇。乙醛对于乙醇诱导的乳腺癌的可能作用看起来是明显的。
一份最近的文件(Lancet Oncol 7：149-156，2006)讨论了乙醇消耗和结肠直肠癌和肺癌风险的关系。
乙醇吸收进体内通过其主要是在肝中的氧化被消除。乙醇(CH3CH2OH)首先通过醇脱氢酶(ADH)代谢为乙醛(CH3CHO)，然后乙醛(CH3CHO)进一步通过醛脱氢酶(ALDH)、主要是肝醛脱氢酶2(ALDH2)，代谢为乙酸(CH3COOH)。
CH3CH2OH+NAD→CH3CHO+NADH+H+
CH3CHO+NAD+H2O→CH3COOH+NADH+H+
乙醇代谢中产生的大部分乙醛通过ALDH2-低Km的ALDH，迅速消除。ALDH存在多型亚型，且2型ALDH(ALDH2)具有最低的亲和常数(Km)，是乙醛氧化的最重要的酶。突变体等位基因，ALDH2*2，在活性ALDH2*1基因的外显子12中具有单点突变(G→A)。该突变导致在氨基酸位487的谷氨酸(Glu)被赖氨酸(Lys)取代。因此ALDH2*2编码该催化非活性的亚单元并以显性负型作用。具有杂合ALDH2*1/2*2基因型的个体与具有正常纯合ALDH2*1/2*1基因型的相比仅具有6％的活性。ALDH2*2等位基因的分布按种族改变：在东亚普遍，但在白人(Caucasians)和非洲人中没有发现，其具有活性ALDH2*1等位基因。40-50％的东亚人具有非活性ALDH2*2等位基因。饮用少量乙醇(0.1g/kg体重)后ALDH2*1/2*2杂合子和ALDH2*2/2*2纯合子的血液乙醛浓度的平均峰值分别是饮用适量乙醇(0.8g/kg体重)后ALDH2*1/2*1纯合子中的5倍和18倍。在给予乙醇的ALDH2*1/2*2杂合子的唾液中的乙醛量增加，且当活性ALDH2*1/2*1纯合子的乙醇氧化被ALDH抑制剂4-甲基吡唑抑制时，乙醛量降低。因此，在具有ALDH2*2等位基因的个体中乙醛氧化显著地减弱。
ALDH2活性的缺失与增加的癌症风险有关，且因此乙醛被认为是致癌物。事实上，乙醛可以损伤培养的肝细胞并导致继发性过度增生。
同样明显的是ALDH2缺失与增加的多神经病和迟发性阿尔茨海默病风险有关。而且，具有低活性ALDH2*2等位基因的日本酒精中毒患者的感觉传导时间明显长于活性ALDH2*1/2*1纯合子的，表明前者的外周神经元的机能异常。该实验神经元细胞系统(其中ALDH通常是非活性的)变得对于外源增加的醛代谢产物高度易损，表明乙醛引起的氧化应激显著地损伤了神经元细胞。这些结果共同表明乙醛引起的氧化应激可损伤线粒体能量生产并使神经元细胞中的蛋白改性，导致形成改性蛋白的沉积。这些变化进一步损伤细胞功能并最终引起细胞死亡。因此，乙醛与多神经病和/或神经退行性疾病如迟发性阿尔茨海默病密切相关。
同样认为ALDH2缺失与增加的乳腺癌风险有关。乙醛具有亲脂性特性并在脂肪组织中蓄积。乳腺富含在脂肪和其它亲脂组织中。由此得出结论饮用含酒精饮料与增加乳腺癌的风险相关。因此，也认为乙醛对于乙醇诱导的乳腺癌的可能作用。
对于肝癌，已知肝炎病毒(HV)，尤其是HVB和HVC，增加肝癌的风险。然而，认为流行病学研究支持ALDH2缺失也与具有或没有肝炎病毒的酒精饮用者增加肝癌风险有关。这支持了以下观点，即，乙醛与饮酒者肝细胞的癌发生紧密相关。
此外，明显地含酒精饮料对人致癌且因此涉及口腔癌、咽腔癌、喉癌和食道癌。特别是，看起来ALDH2缺失也与增加口腔癌、咽腔癌、喉癌和食道癌的风险相关。饮酒后，这些上消化道中的上皮细胞不仅被从血液扩散的乙醛而且被唾液腺分泌出的乙醛侵袭，尤其是在具有ALDH2*2等位基因的人中。饮酒后不仅在ALDH2*1/2*1纯合子而且在ALDH2*1/2*2杂合子中，本发明的添加剂混合物加速乙醇和乙醛的消失。本发明的添加剂有效地加速乙醇代谢，且期望地抑制乙醛从唾液腺分泌。因此，本发明的添加剂可以用来减少口腔癌、咽腔癌、喉癌和食道癌的风险。
在日本男性慢性胰腺炎中，酒精性胰腺炎是最常见类型(68.5％)。慢性胰腺炎表明是胰腺癌的危险因素。而吸烟是产生胰腺癌的已证明的风险因素，看起来ALDH2缺失增加了吸烟者胰腺癌的风险，且认为乙醇增加了吸烟者胰腺癌的风险。这些资料集中表明乙醇，更可能是其代谢物乙醛，参与了胰腺细胞的癌发生。
看起来ALDH2缺失也与增加胰腺癌风险相关。饮酒后，在这些上消化道中的上皮细胞不仅被从血液扩散的乙醛而且被唾液腺分泌出的乙醛侵袭，尤其是在具有ALDH2*2等位基因的人中。
因此，本发明的目的之一是提供有效减少乙醇诱导的疾病的组合物。
该目的被权利要求中定义的主题所解决。
以下图是本说明书的一部分，且包含这些图以说明本发明的某些方面。通过将图与本文详述的具体实施方案结合参考可更好理解本发明。
图1显示本发明的组合物对乙醇增加的RPMI4788转移的作用。ETOH指乙醇；SUP指本发明的组合物；4788指RPMI4788细胞。
图2显示本发明的组合物对血液乙醇含量的作用。SUP指本发明组合物。
图3显示本发明的组合物对乙醛含量的作用。SUP指本发明组合物。
图4显示本发明组合物与Amino de Kanpai相比较对血液乙醇含量的作用。SUP指本发明的组合物。
在此使用的术语“神经病变”，指神经系统神经元的任何疾病或异常。具体地“神经病变”指外周神经系统的疾病，影响除了脑和脊髓外的任何神经。神经病变的非限制性实例为酒精性多发性神经病，其特征为麻木，感觉异常-称为感觉迟钝，和异常性疼痛-其或者自发产生或者由对外部刺激的反应产生，和一种疼痛的特殊形式-称为神经性疼痛或神经痛。
在此使用的术语“神经退行性疾病”，指的是由神经元退化引起的神经系统的任何疾病或异常，其包括神经元的死亡和神经递质的功能损失。神经退行性疾病的非限制性实例为阿尔茨海默病和帕金森疾病。
在此使用的术语“食物组合物”指的是任何种类的可食用的和/或可饮用的组合物，在食用或饮用该各种组合物中不会引起毒性症状。
在此使用的术语“添加剂”、“食品添加剂”或“食品添加剂”指的是除了每天餐饮之外或在餐饮之间服用的组合物。
在此使用的术语“迟发性阿尔茨海默病”指的是老年人阿尔茨海默病的发生，特别是65岁或更老的人。
在此使用的术语“面红综合征”指的是饮酒后面红。面红是饮酒后与面、颈和肩的红斑(由毛细管扩大引起的红化)相关的。饮酒后的面红经常与一系列症状相关：头晕、恶心、头疼、增加的脉搏、偶发性极端困倦和偶发性皮肤肿胀和发痒。这些症状共同称为“面红综合征”或“亚洲型面红”。
在此使用的术语“口咽癌”指的是源自口腔、咽、喉或食管上端的癌症。在该区域的癌症早期，可以确定起源。然而，经常该区域的癌症发现于后侵袭期，且不能确定起源。因此，从该起源发生的癌症共同称为“口咽癌”。
在此使用的术语“剂型”(dosage form)”指的是一次服用的一定量的药物，任选在规则的间隔间。
根据本发明，所述目的通过包含以下物质的物质组合物实现：
葡萄糖、维生素C、L-谷氨酰胺和/或L-谷氨酸、半胱氨酸、核黄素、琥珀酸、富马酸、辅酶Q10和烟酸。
本发明的组合物减少其活性或抑制特定醇脱氢酶，即ADH3的产生，以使乙醛的产生和乙醇代谢过程变缓，且人体负载的乙醇诱导的峰降低。而且，醛脱氢酶ALDH2增强，从而支持了乙醛代谢。
本发明的物质组合物加速饮酒后乙醇和乙醛的消失。该组合物优选在ALDH2*1/2*1纯合子和ALDH2*1/2*2杂合子受试者中有活性。本发明的组合物有效地加速乙醇代谢和抑制乙醛从唾液腺分泌。因此，本发明的组合物可用于减少神经病变、神经退行性疾病例如迟发性阿尔茨海默病、和癌症特别是胰腺癌、食管癌、口咽癌、结肠直肠癌、肺癌、肝癌和乳腺癌的风险。
通过降低过量乙醛进入血流的峰值，从而降低重要器官和人体功能损伤的风险，本发明的组合物降低几种癌症的风险，如胰腺癌、食管癌、口咽癌、结肠直肠癌、肺癌、肝癌和/或乳腺癌。
通过降低饮酒后血液乙醛浓度，本发明的组合物降低胰腺癌风险，优选对于具有吸烟习惯的饮酒者，特别是具有ALDH2*2等位基因的。
通过由激活三羧酸(TCA)循环和电子传递体系消除乙酸，且因此通过阻止包括雌激素的类固醇合成，本发明的组合物降低乳腺癌和肝癌的风险，优选对于饮酒者，尤其是具有ALDH2*2等位基因的。
本发明的物质组合物包含几种物质，它们是酒精性神经病患者经常缺失的物质。因此该组合物能有效减少面红综合征、减少头痛的可能和帮助避免或减轻乙醇诱导的第二天的宿醉。该组合物中包含的烟酸部分(维生素B3)起到烟酰胺腺嘌呤二核苷酸(NAD)的作用，其对醇脱氢酶(ADH)和醛脱氢酶(ALDH)的辅酶有效。提供该维生素以加速乙醇代谢。
根据一特别优选的实施方案，该组合物也包含泛酸，特别是在约1至约5mg的范围内。泛酸起辅酶A(CoA)的作用，认为需要它以代谢乙酸。乙酸在与CoA结合形成乙酰CoA中被激活，其在TCA循环中代谢。以酶的观点，消除产物(乙酸)能有效加速底物(乙醛)的代谢。
优选该组合物应在饮酒约5分钟前服用，且若饮酒量高，再在饮酒同时服用一次。服用者服用该组合物的量应为饮用的酒中包含的乙醇量的约70至120％的范围内。标准剂量可包括约10.0g葡萄糖、1.0g维生素C、1.5g的L-谷氨酰胺和/或L-谷氨酸、500mg半胱氨酸、40mg核黄素、100mg琥珀酸、100mg富马酸、60mg辅酶Q10和约10mg烟酸(维生素B3)。优选该组合物成分的比例定义为上述比例。总剂量可根据饮酒者的体重改变。
本发明的组合物目的是防止过量乙醛进入线粒体基质且以抑制ALDH的酶活性的自阻断，且从而促进乙醛的分解。
因此，与乙醇消耗有关的生理学风险可通过使用本发明的组合物显著地减少，因为饮酒后该组合物以协同方式促进早期乙醛量的减少，并同时提供关于抑制自由基产生的保护效应。
如果该组合物要以食物组合物或食品添加剂给予，优选以如下形式，优选以一种开胃酒成分的形式，使得该食物组合物在餐厅或酒吧内在饮酒之前服用。该食物组合物或食品添加剂优选以以下方式构成，其中该食物组合物或食品添加剂的剂型为片剂的形式。将所述片剂定形和形成所需的尺寸，以使得所述片剂易于吞服。优选所述片剂为一个剂型(dosage)包含多个那样片剂的形式。这些片剂可装在剂型容器(dosage receptacle)中，该容器中包含多个这种片剂。该食物组合物可以以小片或小球的形式，并将所述小片或小球保存在小管中，而服用者服用的食物组合物的体积可根据要饮用的酒精的体积来确定。该组合物或食品添加剂还可以是类似于方糖或以冻干粉末(cryopower)的形式。可将该组合物或食品添加剂被分隔到单独的亚单元。可以提供一种单元，例如包含维生素C部分、半胱氨酸、核黄素、琥珀酸、富马酸和辅酶Q10的胶囊，同时将大多数的葡萄糖部分放在单独的单元、胶囊、片剂等中。可以以合适的量添加其它物质如果汁提取物、姜黄、丹宁、三七粉和长春花。也可添加乌龙茶、芦荟和螺旋水藻。该组合物或食品添加剂还可以是液体形式，特别是糖浆型液体。可以小瓶的软饮料(soft drink)形式提供该食物组合物。
对于体重约80kg的人，优选剂型包含约75％的葡萄糖部分。这种剂型降解了约18ml乙醇，从而提供了相当的缓解。
该组合物优选由以下方式构成，其中该组合物的剂型包含约75.2质量％的葡萄糖部分，即在13.3g的剂量中葡萄糖量在7.2至12.8g范围，优选10.0g。
该组合物优选由以下方式构成，其中该组合物的剂型包含约7.5质量％的维生素C部分，即在13.3g的剂量中维生素C量在0.78至1.18g范围，优选1.0g。
该组合物优选由以下方式构成，其中该组合物的剂型包含约11.27质量％的L-谷氨酰胺和/或L-谷氨酸部分，即在13.3g的剂量中所述L-谷氨酰胺和/或L-谷氨酸部分量在1.23至1.7g范围，优选1.5g。
该组合物优选由以下方式构成，其中该组合物的剂型(a dosage of same)包含约3.76质量％的半胱氨酸部分，即在13.3g的剂量中所述半胱氨酸部分量在460至540mg范围，优选500mg。
该组合物优选由以下方式构成，其中该组合物的剂型包含约0.30质量％的核黄素部分，即在13.3g的剂量中所述核黄素量在32至48mg范围，优选40mg。
该组合物优选由以下方式构成，其中该组合物的剂型包含约0.752质量％的琥珀酸部分，即在13.3g的剂量中所述琥珀酸量在90至110mg范围，优选100mg。
该组合物优选由以下方式构成，其中该组合物的剂型包含约0.752质量％的富马酸部分，即在13.3g的剂量中所述富马酸量在90至110mg范围，优选100mg。
该组合物优选由以下方式构成，其中该组合物的剂型包含约0.451质量％的辅酶Q10部分，即在13.3g的剂量中所述辅酶部分在50至70mg范围，优选60mg。
该组合物优选由以下方式构成，其中该组合物的剂型在13.3g的剂量中包含约1至20mg，优选15mg的烟酸部分。
更优选该组合物的各成分除了烟酸外为约0.01至约100g，优选约0.05至50g，其中烟酸在约1至20mg的范围。
据信该组合物能提供以下的效果：
1.首先，通过减缓乙醇氧化过程而减少乙醇代谢为乙醛，以防止乙醛的蓄积。
2.刺激ALDH的活性并消除其酶活性的任何阻断。
3.加速乙醛至乙酸的反应并进一步在柠檬酸循环中分解。
4.提高饮酒者的抗氧化剂含量，所述抗氧化剂特异地对抗乙醛的毒性作用。
据信第一个效果将通过服用大剂量的糖(葡萄糖)实现。
使用将乙醇转化为乙醛的相同胞质NAD池(NAD pool)，将葡萄糖在肝细胞的胞质中快速氧化。因为胞质NAD的量是有限的且只能从NADH+H+恒定再生，大大少于乙醛蓄积。
认为第二个成就也将通过服用大剂量的葡萄糖实现。葡萄糖增加ADH及ALDH的酶活性。当大量葡萄糖负荷出现于肝细胞的细胞溶质中，则乙醛不可能达到能导致ALDH失活或线粒体损伤的含量。
认为第三个成就通过以下实现：
a)通过加速电子转运通过线粒体内膜从而加速从NADH+H+再氧化至NAD，
b)加速Krebs循环，认为通过掺入辅酶Q10和核黄素实现。
核黄素将会快速转化为FMN，其与辅酶Q10一起是线粒体基质中决定NADH+H+至NAD+再氧化速度的物质。当乙醛代谢为乙酸时需要NAD+。在该反应中NAD转化为NADH+H+。因为在线粒体基质中可用的NAD是有限的，所以NADH+H+必须再转化为NAD以再用于乙醛分解。该反应仅仅是可能的，因为FMN和辅酶Q10吸收NADH+H+的电子并使电子往返于线粒体膜。可用的FMN和辅酶Q10越多，该过程越快，且因为更多的NAD可用从而加速乙醛的代谢。
已知人体内的辅酶Q10随着年龄增加而减少。
Krebs(柠檬酸)循环的激活通过掺入琥珀酸和富马酸实现。两种物质都激活柠檬酸循环的下半部分从而激活线粒体中的需氧氧化过程。人体吸收后L-谷氨酸迅速转化为L-谷氨酰胺，且L-谷氨酰胺有助于加速线粒体细胞溶质苹果酸/天冬氨酸往返支路，其在乙醛引起的中毒过程中起关键作用。它也通过防止琥珀酸脱氢酶的草酸和乙酸抑制加速琥珀酸盐氧化过程。
第四个成就，提高抗氧化剂含量，是通过掺入半胱氨酸、维生素C和L-谷氨酰胺和/或L-谷氨酸来实现。半胱氨酸和维生素C能提供强抗氧化作用。人体转换半胱氨酸为谷胱甘肽，其特别对抗乙醛的毒性作用。为达到谷胱甘肽的最佳含量并避免半胱氨酸转化为胱氨酸，重要的是将半胱氨酸与谷氨酰胺结合并给予半胱氨酸两倍的维生素C。
通过给予上述物质，饮酒后的乙醛量将会被明显减少且面红综合征至少减少。其它已知的乙醛的副作用如头痛和宿醉也应消失。
因此，本发明涉及通过在人体内减缓有关乙醇代谢的乙醇降解过程从而降低乙醇诱导的神经病变、包括迟发性阿尔茨海默病的神经退行性疾病和癌症的风险的组合物，所述癌症特别是食管癌、口咽癌、结肠直肠癌、肺癌、肝癌、乳腺癌和/或胰腺癌。本发明的组合物包含生理相关量的以下物质：烟酸(维生素B3)、葡萄糖、维生素C、L-谷氨酰胺和/或L-谷氨酸、半胱氨酸、核黄素、琥珀酸、富马酸和辅酶Q10。
而且，本发明的组合物可用作药物。该药物或药品可分别用于例如制备治疗和/或预防癌症的药物。通过非限制性实施例的方式，这些癌症可选自乳腺癌、肝癌、胰腺癌、食管癌、结肠直肠癌、肺癌和口咽癌。
另一个实施方案，通常本发明组合物也可用于制备预防瘤转移的药物。
另一个实施方案，本发明组合物也可用于制备治疗和/或预防神经病变以及治疗和/或预防神经退行性疾病的药物，特别是迟发性阿尔茨海默病。
另一个实施方案，本发明组合物也可用于制备治疗和/或预防宿醉、面红综合征、头痛和/或乙醇中毒的药物。
另一个实施方案，本发明组合物以片剂的形式存在。另一个实施方案，一次剂量(a dose of)的本发明的组合物的包含多个小片剂或胶囊。具体地，所述片剂或胶囊可包含在一个剂型容器(dosage receptacle)内。另一个实施方案，本发明组合物是方糖形式。另一个实施方案，本发明组合物是冻干粉末(cryopower)的形式。另一个实施方案，本发明组合物是小饮料单元形式。另一个实施方案，本发明组合物是糖浆形式。
本发明另一方面涉及用于减少乙醇诱导的神经病变和/或包括迟发性阿尔茨海默病的神经退行性疾病、食管癌、口咽(oropharyngolaryngeal)癌、乳腺癌、肝癌、肺癌、结肠直肠癌和/或胰腺癌的风险的组合物、食物或食品添加剂和药物组合物，所述组合物包含用于影响乙醇降解过程特别是关于人体内乙醇的代谢的烟酸，和物质，特别是上述物质，其在人体内提供以下作用：-首先通过减缓乙醇氧化成乙醛减少乙醇代谢，以防止乙醛蓄积；-刺激ALDH的活性并避免任何其酶活性的阻断；-加速乙醛至乙酸的反应并进一步在柠檬酸循环中分解； -增加饮酒者的抗氧化剂含量，其特别对抗乙醛的毒性作用。
如上所述，本发明涉及一种组合物，其包含烟酸(维生素B3)、葡萄糖、维生素C、L-谷氨酰胺和/或L-谷氨酸、半胱氨酸、核黄素、琥珀酸、富马酸和辅酶Q10。如上所述，存在该组合物的各种实施方案。
实施例
实施例1：添加剂溶液和动物
除了辅酶Q10外的添加剂的成分购自Sigma Aldrich Japan(东京，日本)。10g葡萄糖、1.0g维生素C、1.5g的L-谷氨酰胺、500mg半胱氨酸、40mg核黄素、100mg琥珀酸、100mg富马酸和10mg烟酸溶于100ml蒸馏水(添加剂溶液)。100mg辅酶Q10(Jarrow Formulas，洛杉矶，CA，USA)溶于14ml麻油中。
购买BALB/cA-jcl-nu/nu型的雄性、6周龄裸小鼠(Clea Japan Inc.静冈，日本)，并在研究前使其适应环境一周。在实验过程中，小鼠保持在温度23℃、50％湿度和无特异病原体(SPF)条件下。
实施例2：细胞株和转移实验
源自人结肠直肠癌的RPMI4788细胞在裸小鼠中产生肺转移(Moore GE&Koike A(1964)，Cancer January，17：11-20；Kondo H.等人(1987)，Jpn J CancerRes(Gann)78，12：1400-1408)。该细胞株于37℃、100％湿度、5％CO2和95％空气的环境中传代培养于组织培养瓶中，该培养瓶含有RPMI1640溶液的培养基(Nikken Biomedical Laboratory，京都，日本)，并补充有10％胎牛血清(FBS)(Hyclone Laboratories Inc.Logan，UT)。通过0.02％的EDTA分离培养的细胞之后，使用0.01M的PBS制备细胞悬浮液；台盼蓝染色确定细胞存活率超过98％。
为产生肺转移，裸小鼠于尾静脉注射5×104/0.1ml的细胞悬浮液。注射28天后，计数所有肺表面上的转移瘤。该肺用10％中性甲醛固定并包埋于石蜡。用Hematoxylin-Eosin染色切片并作组织学检查。
为检测添加剂，320μl添加剂溶液和50μl溶于麻油的辅酶Q10通过口金属管对每个小鼠灌胃给药。为检测添加剂+EtOH的作用，给予添加剂1小时后，7.0ml/kg的乙醇注射到腹膜腔。注射乙醇1小时后，5×104/100μl的RPMI4788细胞注射于尾静脉。细胞注射28天后处死裸小鼠并计数肺表面的转移瘤。
这些实验的结果示于表1。
表1
| 实验 | 肺表面的转移瘤数 | |||
| 4788(对照) | ETOH+4788 | SUP+4788 | SUP+ETOH++4788 | |
| 14 | 48 | 28 | 49 | |
| 27 | 70 | 24 | 46 | |
| 31 | 64 | 54 | 80 | |
| 61 | 68 | 28 | 66 | |
| 41 | 75 | 40 | 46 | |
| 82 | 58 | 34 | 21 | |
| 37 | 69 | 45 | 64 | |
| 9 | 62 | 67 | 79 | |
| 16 | 18 | 21 | 9 | |
| 14 | 19 | 13 | 11 | |
| 14 | 21 | 15 | 12 | |
| 12 | 24 | 13 | 14 | |
| 16 | 19 | 11 | 16 | |
| 16 | 20 | 17 | 14 | |
| 17 | 21 | 16 | 15 | |
| 18 | 20 | 17 | 14 | |
总量 425 676 443 556
平均 26.6 42.25 27.7 34.75
减去4788 0 251 18 131
52.20％
进行两组独立的各自具有8只小鼠的实验。肺表面的平均转移瘤，对照中(仅4788细胞)：26.6，乙醇+4788细胞：42.25，添加剂+4788细胞：27.7，添加剂+乙醇+4788细胞：34.75。这些结果表明本发明的添加剂没有影响4788细胞株的转移潜能。乙醇增加约60％的4788细胞株的转移潜能。添加剂减少由乙醇增加的转移的一半。乙醇+4788细胞和添加剂+乙醇+4788细胞组之间的差异通过t-检验是显著的(P＝0.03)。
实施例3：NK-活性
使用短期51Cr-释放检测确定自然杀伤细胞(NK)的细胞毒活性。小鼠分成以下3组：对照组、乙醇给药组以及添加剂和乙醇给药组。给予乙醇24小时后，分离裸小鼠的脾细胞作为单细胞悬浮液。通过在3 7℃与200μCi的51Cr孵育2小时标记靶YAC-1细胞(1×107)。清洗然后在37℃孵育2小时之后，细胞添加RPMI1640培养基中。20μl标记的靶细胞和100μl效应细胞以不同的效应细胞/靶细胞的比例混合于96孔微量滴定板中(SumitomoBakelite Co.Lt d.东京，日本)。孵育4小时后，离心该板并通过γ计数器测量上清液的放射性。细胞毒性的百分比计算为(试验组释放-自发释放/总释放-自发释放)。该结果的统计学分析通过t2检验进行，且定义p＜0.5为显著水平。该实验结果示于下表2。
表2
| 自发释放 | 51Cr总51Cr释放 | 对照 | EtOH | 添加剂+EtOH | |
| 平均含量NK活性％对照％增加NK | 264.3 | 2966.3 | 930.624.60％ | 568.611.20％45.5％ | 771.818.70％55.9 |
因此，乙醇减少对照裸小鼠的NK活性至45.5％，且这种作用如之前很多文献报导的由乙醛诱导。添加剂增加55.9％的NK活性，这种活性由乙醇降低。类似人，添加剂可减少裸小鼠中的乙醛，和NK活性。
实施例4：添加剂制备、人志愿者和乙醇
除了辅酶Q10外的添加剂的成分购自Sigma Aldrich Japan(东京，日本)。AQUAQ10P40(Nissin Pharma.东京，日本)用作辅酶，其为Q10为粉末形式且包含40％的辅酶Q10的。混合1g维生素C、1.5g的L-谷氨酸、500mg半胱氨酸、40mg核黄素、100mg琥珀酸、100mg富马酸、10mg烟酸和250mgAQUAQ10P40(相当于100mg准确量的辅酶Q10)。添加剂混合物饮用前溶于100ml水。
四个健康成人志愿者(两男两女，年龄26-48)经允许消耗乙醇并采血。使用含有12.5％乙醇的400ml红酒作为乙醇，且该量实际相当于50g乙醇。从实验开始第一个30分钟期间内给予红酒。在不同日期检测对照和添加剂研究。
实施例5：取血样和血液乙醇和乙醛的测量
血液样品在以下4个时间采取：乙醇给予之前(0)和乙醇给予30、60和90分钟之后(30，60，90分钟)。给予之前20分钟口服添加剂和100ml水。为测量乙醇，全血于4℃储存在肝素包被的管中。为测量乙醛，血样品通过肝素包被的管在1500rpm立即离心10分钟，血清于-80℃冷冻。通过bic药物实验室公司BML，INC.(Shibyya-ku，东京，日本)测量乙醇和乙醛。通过t2检验进行结果的统计分析，且定义p＜0.5为显著水平。该血液乙醇实验的结果如下表3所示。
表3
添加剂对人血乙醇的作用
| 时间无SUP有SUP | 000 | 30分钟83.7524.75 | 60分钟80.7550.75 | 90分钟70.2545 |
(示出的数据是4个样品的平均值.mg/dl)
在给予乙醇后，该添加剂(本发明组合物)与在时间点30，60和90分钟的对照相比减少了血液乙醇量。在对照和添加剂研究之间在60分钟和90分钟时观察到显著差异(P＜0.05)。
血液乙醛实验的结果示于下表4。
表4
添加剂对人血乙醛的作用
| 时间无SUP有SUP | 000 | 30分钟2.1250.575 | 60分钟1.650.475 | 90分钟1.70.475 |
(示出的数据是4个样品的平均值.μM)
在给予乙醇后，该添加剂(本发明组合物)与在时间点30，60和90分钟的对照相比保持低血液乙醛量。在对照和添加剂研究之间在30、60和90分钟时观察到显著差异(P＜0.05)。
实施例6：本发明组合物和Amino de Kanpai的比较
Amino de Kanpai是Ajinomoto(东京，日本)的产品，其从2006年3月在日本市场销售，其包含1.4g谷氨酰胺和1.4g丙氨酸。Ajinomoto以用作人体的乙醇减少组合物销售Amino de Kanpai。而且，该组合物应减少乙醇引起的头痛和不适。在这些实验中，除了参与的三个志愿者以及一部分Amino de Kanpai(3.0g)在给予乙醇之前20分钟给予外，所有实验条件与上述实施例4和5的条件相同。服用Amino de Kanpai的血液乙醇量的结果和对照和添加剂(SUP：本发明组合物)的相应数据如下表5所述。
表5
本发明和Amino de Kanpai组合物的比较
| 时间 | 0 | 30分钟 | 60分钟 | 90分钟 |
| 对照有Amino de Kanpai有SUP | 000 | 57.658.326 | 797154.3 | 706148.3 |
(示出的数据是3个样品的平均值.mg/dl)
Amino de Kanpai与对照相比显示轻微的乙醇减少作用。Amino deKanpai在90分钟的乙醇减少率为12.8％，而SUP为31％。通过t2检验在Amino de Kanpai和对照之间没有显著差异。
Claims (17)
1.包含烟酸、葡萄糖、维生素C、L-谷氨酰胺和/或L-谷氨酸、半胱氨酸、核黄素、琥珀酸、富马酸和辅酶Q10的组合物。
2.根据权利要求1的组合物，其中该组合物另外包含泛酸。
3.根据权利要求1或2的组合物，其中该组合物包含约75.2质量％的葡萄糖部分。
4.根据前述权利要求任一项的组合物，其中该组合物包含约7.5质量％的维生素C部分。
5.根据前述权利要求任一项的组合物，其中该组合物包含约11.28质量％的L-谷氨酰胺和/或L-谷氨酸部分。
6.根据前述权利要求任一项的组合物，其中该组合物包含约3.76质量％的半胱氨酸部分。
7.根据前述权利要求任一项的组合物，其中该组合物包含约0.3质量％的核黄素部分。
8.根据前述权利要求任一项的组合物，其中该组合物包含约0.752质量％的琥珀酸部分。
9.根据前述权利要求任一项的组合物，其中该组合物包含约0.752质量％的富马酸部分。
10.根据前述权利要求任一项的组合物，其中该组合物包含约0.45 1质量％的辅酶Q10部分。
11.根据前述权利要求任一项的组合物，其作为药物。
12.根据权利要求1-10任一项的组合物在制备用于治疗和/或预防癌症、肿瘤转移、神经病变、神经退行性疾病、宿醉综合征、面红综合征、头痛和/或酒精中毒的药物中的用途。
13.根据权利要求12的用途，其中所述癌症选自乳腺癌、肝癌、结肠直肠癌、肺癌、胰腺癌、食管癌和口咽癌。
14.根据权利要求12的用途，其中所述神经退行性疾病为阿尔茨海默病，特别是迟发性阿尔茨海默病。
15.根据权利要求1-10任一项的组合物，其中所述组合物以冻干粉末、液体，特别是以小饮料单元或糖浆的剂型存在。
16.根据权利要求15的组合物，其中该剂型特别为片剂形式或方糖型形式或包含多个小片或胶囊的剂型。
17.根据权利要求16的组合物，其中该片或胶囊存在于剂型容器中。
Applications Claiming Priority (24)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05016568 | 2005-07-29 | ||
| EP05016564.6 | 2005-07-29 | ||
| EP05016563.8 | 2005-07-29 | ||
| EP05016563 | 2005-07-29 | ||
| EP05016566.1 | 2005-07-29 | ||
| EP05016567.9 | 2005-07-29 | ||
| EP05016566 | 2005-07-29 | ||
| EP05016567 | 2005-07-29 | ||
| EP05016564 | 2005-07-29 | ||
| EP05016565.3 | 2005-07-29 | ||
| EP05016565 | 2005-07-29 | ||
| EP05016568.7 | 2005-07-29 | ||
| EPPCT/EP2005/009151 | 2005-08-24 | ||
| EPPCT/EP2005/009153 | 2005-08-24 | ||
| EPPCT/EP2005/009148 | 2005-08-24 | ||
| EPPCT/EP2005/009150 | 2005-08-24 | ||
| EPPCT/EP2005/009147 | 2005-08-24 | ||
| PCT/EP2005/009153 WO2007016955A1 (en) | 2005-07-29 | 2005-08-24 | Alcohol metabolism moderating composition |
| PCT/EP2005/009150 WO2007016952A1 (en) | 2005-07-29 | 2005-08-24 | Composition for reducing the risk of alcohol induced esophagenal and oropharyngolaryngeal cancer |
| EPPCT/EP2005/009152 | 2005-08-24 | ||
| PCT/EP2005/009148 WO2007016950A1 (en) | 2005-07-29 | 2005-08-24 | Composition for reducing the risk of alcohol induced neurodegenerative disease |
| EPPCT/EP2005/009149 | 2005-08-24 | ||
| PCT/EP2005/009147 WO2007016949A1 (en) | 2005-07-29 | 2005-08-24 | Composition for reducing the risc of alcohol induced neuropathy |
| PCT/EP2006/007466 WO2007017139A1 (en) | 2005-07-29 | 2006-07-27 | Composition for moderating alcohol metabolism and for reducing the risk of alcohol induced diseases |
Publications (2)
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| CN101232822B CN101232822B (zh) | 2012-11-14 |
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| AT (1) | ATE554663T1 (zh) |
| AU (1) | AU2006278823B2 (zh) |
| CA (1) | CA2611389C (zh) |
| CY (1) | CY1113015T1 (zh) |
| DK (1) | DK1909600T3 (zh) |
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| SI (1) | SI1909600T1 (zh) |
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| CN104053368A (zh) * | 2011-11-15 | 2014-09-17 | 蒂马基金会 | 抵御细胞损伤效应的组合物 |
| CN104780782A (zh) * | 2012-07-09 | 2015-07-15 | 诺格罗有限责任公司 | 使用膳食补充剂预防酒精反应 |
| CN109125310A (zh) * | 2018-11-06 | 2019-01-04 | 河北工业大学 | 琥珀酸在抑制Kv10.1离子通道活性中的应用和药物 |
| CN110339233A (zh) * | 2019-04-01 | 2019-10-18 | 山东济世药业有限公司 | 一种用于防治酒精性肝损伤的组合物及其制备方法和用途 |
| CN114053312A (zh) * | 2012-08-03 | 2022-02-18 | 卓越人生有限责任公司 | 用于降低血液酒精含量的组合物和方法 |
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| US8633192B2 (en) | 2006-12-15 | 2014-01-21 | Tima Foundation | Compositions and uses thereof |
| EA016926B1 (ru) * | 2006-12-15 | 2012-08-30 | Тима Фаундейшн | Композиции для профилактики и лечения гипергликемии |
| EP2057905A1 (en) * | 2007-11-12 | 2009-05-13 | TIMA Foundation | Composition for moderating Triglyceride and Cholesterol Levels |
| US8440632B2 (en) * | 2008-01-24 | 2013-05-14 | Raptor Therapeutics Inc. | Protopanaxadiol-type ginsenoside compositions and uses thereof |
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| KR20110115862A (ko) * | 2010-04-16 | 2011-10-24 | 씨제이제일제당 (주) | 숙취 해소 및 예방용 조성물과 이를 이용한 음주전 후 숙취해소용 음료 |
| WO2012095509A1 (en) * | 2011-01-14 | 2012-07-19 | Tima Foundation | Composition for accelerating alcohol metabolism and for reducing the risk of alcohol induced diseases |
| CN103608323B (zh) * | 2011-04-04 | 2016-08-17 | 博格有限责任公司 | 治疗中枢神经系统肿瘤的方法 |
| DE102011001768A1 (de) * | 2011-04-04 | 2012-10-04 | Gunnar Frank | Präparat oder Nahrungsergänzungsmittel |
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| EP2782583B1 (en) * | 2011-11-22 | 2019-09-25 | The John Hopkins University | Methods and compositions for reducing alcohol toxicity |
| RU2678198C2 (ru) * | 2013-11-06 | 2019-01-24 | Салим ДЖАРРУДЖ | Композиция и способы повышения скорости метаболизма алкоголя и предупреждения симптомов похмелья |
| WO2016072496A1 (ja) | 2014-11-07 | 2016-05-12 | 株式会社ニチレイバイオサイエンス | アルコール代謝促進剤 |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104053368A (zh) * | 2011-11-15 | 2014-09-17 | 蒂马基金会 | 抵御细胞损伤效应的组合物 |
| CN104053368B (zh) * | 2011-11-15 | 2017-03-15 | 蒂马基金会 | 抵御细胞损伤效应的组合物 |
| CN104780782A (zh) * | 2012-07-09 | 2015-07-15 | 诺格罗有限责任公司 | 使用膳食补充剂预防酒精反应 |
| CN114053312A (zh) * | 2012-08-03 | 2022-02-18 | 卓越人生有限责任公司 | 用于降低血液酒精含量的组合物和方法 |
| CN109125310A (zh) * | 2018-11-06 | 2019-01-04 | 河北工业大学 | 琥珀酸在抑制Kv10.1离子通道活性中的应用和药物 |
| CN110339233A (zh) * | 2019-04-01 | 2019-10-18 | 山东济世药业有限公司 | 一种用于防治酒精性肝损伤的组合物及其制备方法和用途 |
| CN110339233B (zh) * | 2019-04-01 | 2021-10-19 | 山东济世药业有限公司 | 一种用于防治酒精性肝损伤的组合物及其制备方法和用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR101562271B1 (ko) | 2015-10-21 |
| US20140105877A1 (en) | 2014-04-17 |
| EA200800427A1 (ru) | 2008-06-30 |
| WO2007017139A1 (en) | 2007-02-15 |
| PL1909600T3 (pl) | 2012-09-28 |
| EP1909600A1 (en) | 2008-04-16 |
| AU2006278823B2 (en) | 2011-05-12 |
| UA94713C2 (uk) | 2011-06-10 |
| DK1909600T3 (da) | 2012-07-30 |
| KR20080033899A (ko) | 2008-04-17 |
| HK1117709A1 (en) | 2009-01-23 |
| KR20130137719A (ko) | 2013-12-17 |
| US20090054351A1 (en) | 2009-02-26 |
| US8580750B2 (en) | 2013-11-12 |
| CA2611389C (en) | 2015-02-17 |
| CN101232822B (zh) | 2012-11-14 |
| JP5371428B2 (ja) | 2013-12-18 |
| EA012753B1 (ru) | 2009-12-30 |
| KR101487848B1 (ko) | 2015-02-03 |
| JP5785581B2 (ja) | 2015-09-30 |
| CA2611389A1 (en) | 2007-02-15 |
| US9402849B2 (en) | 2016-08-02 |
| AU2006278823A1 (en) | 2007-02-15 |
| EP1909600B1 (en) | 2012-04-25 |
| HRP20120489T1 (hr) | 2012-07-31 |
| ATE554663T1 (de) | 2012-05-15 |
| SI1909600T1 (sl) | 2012-07-31 |
| CY1113015T1 (el) | 2016-04-13 |
| JP2009516639A (ja) | 2009-04-23 |
| PT1909600E (pt) | 2012-07-24 |
| JP2013189437A (ja) | 2013-09-26 |
| ES2386460T3 (es) | 2012-08-21 |
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