CN1273119C - 一种包含类胡萝卜素的抗动脉粥样硬化的组合物和用于抑制ldl氧化的方法 - Google Patents
一种包含类胡萝卜素的抗动脉粥样硬化的组合物和用于抑制ldl氧化的方法 Download PDFInfo
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Abstract
一种包含抑制LDL-氧化有效量的八氢番茄红素、六氢番茄红素或其混合物的抗动脉粥样硬化的组合物和一种用于抑制动脉粥样硬化进程的方法。
Description
技术领域
本发明涉及天然产物以及用其来抑制动脉粥样硬化进程的技术领域。本发明更特别地涉及包含八氢番茄红素、六氢番茄红素或其混合物的组合物以及其用于抑制动脉粥样硬化进程的应用。
背景技术
已经知道预防LDL的氧化是抑制动脉粥样硬化中的一个重要因素。有许多抗动脉粥样硬化药,如伐他汀(vastatin)类药物,其在下文中被称为常规抗动脉粥样硬化药。此外,已经报道了某些已知是抗氧化剂的类胡萝卜素可以抑制LDL的氧化,并从而抑制了动脉粥样硬化的进程(参见例如Krinsky,N.,Free Radical Biology &Medicine,(1989)第7卷,第617-635页)。PCT/IL98/00286公开了在抑制LDL的氧化中有效并从而可以抑制动脉粥样硬化进程的具有协同作用的番茄红素和维生素E的混合物。从来没有对类胡萝卜素——八氢番茄红素和六氢番茄红素在抑制LDL-氧化中的有效性进行过评估。
动脉粥样硬化对心脏病的诱发作用是众所周知的。因此,一直需要一些可有效抑制动脉粥样硬化进程的新型组合物。
因此,本发明的目的是要提供一种新型组合物,其在抑制LDL的氧化方面十分有效,从而有效地抑制了动脉粥样硬化的进程。
本发明的另一个目的是要提供一种抑制LDL的氧化并从而可抑制动脉粥样硬化进程的方法。
随着说明书的继续,本发明的其它目的将变得显而易见。
本发明的概述
本发明提供了一种抑制动脉粥样硬化进程的方法,该方法包括给有这种需要的个体使用抗LDL-氧化有效量的八氢番茄红素、六氢番茄红素或其混合物。
本发明还提供了一种包含八氢番茄红素、六氢番茄红素或其混合物的组合物用于抑制LDL的氧化的应用。
本发明另一方面还提供了八氢番茄红素、六氢番茄红素或其混合物在制备用于抑制LDL的氧化和动脉粥样硬化进程的药物中的应用。
本发明还进一步提供了一种抗动脉粥样硬化的组合物,其包含可有效抑制LDL-氧化数量的八氢番茄红素、六氢番茄红素或其混合物。
本发明还提供了抑制LDL-氧化有效量的八氢番茄红素、六氢番茄红素或其混合物在功能性食品、饮食营养物、食品和饮料中的应用。
附图说明
图1(A),(B)-结晶的天然番茄红素和番茄油性树脂对铜离子诱导的LDL氧化的作用。
图2(A),(B)-六氢番茄红素/八氢番茄红素对铜离子诱导的LDL氧化的作用。
图3-番茄红素、维生素E、β-胡萝卜素、和六氢番茄红素/八氢番茄红素对LDL氧化的作用。
图4-番茄红素与抗氧剂组合对LDL氧化的作用。
图5-β-胡萝卜素与抗氧剂组合对LDL氧化的作用。
图6-维生素E与抗氧剂组合对LDL氧化的作用。
图7-六氢番茄红素/八氢番茄红素与抗氧剂组合对LDL氧化的作用。
图8-抗氧剂的组合对LDL氧化的作用。
图9-类胡萝卜素混合物对LDL氧化的作用。
本发明优选实施方案的详细说明
下面的说明书对本发明的实施方案进行了说明。如下的说明并不是要进行限制,应当清楚的是技术人员可以对本发明进行许多显而易见的变化。
说明了八氢番茄红素和六氢番茄红素的混合物的应用以及其单独使用其中一个时的应用。因此,涉及使用其混合物的情况也将适用于单独使用各种类胡萝卜素的情况。
在研究各种类胡萝卜素对LDL氧化的作用的同时,令人吃惊地发现八氢番茄红素、六氢番茄红素或其混合物在抑制LDL氧化时实际上比其它类胡萝卜素更有效。
根据本发明方法的特定实施方案,将至少0.2mg/天的八氢番茄红素、六氢番茄红素或其混合物给药于个体以抑制LDL在血液中的氧化并从而抑制了动脉粥样硬化的进程。在所说类胡萝卜素混合物进行给药的情况中,混合物中八氢番茄红素和六氢番茄红素的比例为约1∶20至20∶1。给药可以是一天给多个剂量或单剂量。根据本发明的方法,对给药进行调节以获得血液中八氢番茄红素、六氢番茄红素或其混合物在血液中抗LDL-氧化的有效浓度,所说的浓度为至少0.01μM。
根据本发明方法的任选实施方案,可以将八氢番茄红素、六氢番茄红素或其混合物与常规的抗动脉粥样硬化药联合给药。
根据本发明的另一个方面,其提供了一种包含抗-LDL-氧化有效量的八氢番茄红素、六氢番茄红素或其混合物的组合物。所说的组合物包含至少0.1mg八氢番茄红素、六氢番茄红素或其混合物。该组合物可以进一步包含可药用的辅剂、赋形剂和添加剂。
本发明的另一个实施方案涉及一种用于口服给药的片剂、胶囊、硬壳胶囊、软凝胶或凝胶帽形式的固体剂型,其包含至少0.1mg的八氢番茄红素、六氢番茄红素或其混合物。
根据本发明的另一个实施方案,提供了八氢番茄红素、六氢番茄红素或其混合物的应用,在该应用中其被添加到功能性食品如块状食品、饮食添加物、饮料或其它食品中以使得所说的功能性食品、饮食添加物、食品和饮料可以提供对LDL-氧化的抑制作用。根据本发明的实施方案,该功能性食品、饮食添加剂或饮料包含至少0.1mg的八氢番茄红素、六氢番茄红素或其混合物。
下面的实施例解释了获得了极大改善的优于类胡萝卜素的八氢番茄红素和六氢番茄红素对LDL氧化的抑制作用。
实施例
一般方法
将进行研究的所有化合物都溶解于THF中从而获得一种1mg/ml的储备液。在其氧化前将LDL用磷酸盐缓冲盐水(PBS)透析24时以除去可能干扰氧化的任何EDTA。在所需的天然分布下将LDL(100μg蛋白质/ml)在不存在(对照)或存在浓度逐渐增加的各种研究化合物以及包括2、3或4中组分的各种组合中进行培养。在37℃下,通过加入5μM CuSO4在2小时内来诱导LDL的氧化。通过加入1mM Na2EDTA来结束LDL的氧化并立即将其在4℃下进行冷藏。然后通过测定硫代巴比妥酸反应物质(TBARS)和所形成的脂质过氧化物(PD)来测定LDL的氧化程度。仅用THF对照LDL进行补充。
实施例1:结晶的天然番茄红素和番茄油性树脂对铜离子诱导的LDL氧化的作用:浓度研究。
用浓度增加的结晶的纯番茄红素、或用番茄油性树脂(在相等的番茄红素浓度下)在37℃下将LDL(100μg蛋白质/mL)预培养30分钟,然后将其在存在5μM CuSO4的情况下在37℃下再另外培养2小时。分别通过TBARAS(A)或脂质过氧化物(B)试验来对LDL的氧化进行测定。结果是以均值±SD的形式给出的(n=3)。加入的浓度逐渐增加的番茄红素以剂量依赖的方式中度地抑制了铜离子诱导的LDL的氧化。在使用50μmol/L的番茄红素时,在TBARS(图1A)和脂质过氧化物(图B)形成中可以分别获得最大的22%和27%的抑制。但是,向脂蛋白中加入番茄油性树脂可以在更大程度上抑制LDL的氧化(约90%的抑制),番茄红素等同物抑制TBARS(图1A)和脂质过氧化物(图B)的的IC50(将LDL氧化抑制50%所需的浓度)分别为8.0μmol/L和8.4mol/L。
实施例2:六氢番茄红素/八氢番茄红素对铜离子诱导的LDL氧化的作用:浓度研究。
正如分别通过TBARS 2(A)和通过脂质过氧化物试验2(B)所测定的那样,六氢番茄红素/八氢番茄红素剂量依赖性地抑制了CuSO4诱导的LDL的氧化。六氢番茄红素/八氢番茄红素在铜离子诱导的LDL氧化中的IC50对于TBARS形成和脂质过氧化物形成的抑制而言分别为0.25μg/ml和0.35μg/ml。
实施例3:番茄红素、维生素E、β-胡萝卜素、和六氢番茄红素/八氢番茄红素对LDL氢化的作用。
在低浓度下,其模拟的Lyc-O-Mato、番茄红素(10μg/ml)、维生素E(2.5μg/ml)和β-胡萝卜素(0.4μg/ml)的组合物不能显著影响LDL的氧化。相反,正如通过TBARS和脂质体过氧化物试验所分析的那样,六氢番茄红素/八氢番茄红素(1.2μg/ml)大体上抑制了LDL氧化,将其抑制了85-90%。
实施例4:番茄红素与抗氧化剂的组合对LDL氧化的作用。
在分别使用番茄红素(10μg/ml)与其它抗氧剂中的各种物质(在个研究中的第2化合物)的组合时,与单独使用番茄红素的作用相比,向番茄红素种加入β-胡萝卜素(0.4μg/ml)或维生素E(2.5μg/ml)分别将LDL的氧化(TBARS试验)抑制了22%和11%,而加入六氢番茄红素/八氢番茄红素(1.2μg/ml)则差不多将LDL的氧化抑制了95%。这些图4所示的结果表明,虽然作用十分微小,但是向番茄红素中加入β-胡萝卜素或维生素E有助于抑制LDL的氧化,而六氢番茄红素/八氢番茄红素(单独或与番茄红素联用)具有作为最强效的LDL氧化抑制剂的最高能力。用脂质体过氧化物试验进行的LDL氧化分析得到了类似的结果。
实施例5:β-胡萝卜素与抗氧剂组合对LDL氧化的作用。
参照图5,在单独用β-胡萝卜素作为主要的抗氧剂或将其与其它抗氧剂一起联合作为主要的抗氧剂时,与番茄红素不同,其单独或与维生素E合用时根本不会影响LDL的氧化。当将β-胡萝卜素与番茄红素联合加入时观测到了对LDL氧化(TBARS)的抑制作用,并且在将β-胡萝卜素与六氢番茄红素/八氢番茄红素一起加入时得到了对LDL氧化的最强的抑制作用(在TBARS试验中,98%的抑制)。用脂质过氧化物试验进行分析时得到了相似的结果。
实施例6:维生素E与抗氧剂组合对LDL氧化的作用。
在单独用维生素E或将其与其它抗氧剂联合作为主要的抗氧剂时,加入番茄红素而不是β-胡萝卜素时可以将LDL氧化抑制12%(TBARS试验)。向维生素E中加入六氢番茄红素/八氢番茄红素可以对LDL的氧化产生98%的抑制。正如从图6中可以看到的那样,脂质过氧化物试验得到了类似结果。
实施例7:六氢番茄红素/八氢番茄红素与抗氧剂组合对LDL氧化的作用
参照图7,发现在所检测的类胡萝卜素中六氢番茄红素/八氢番茄红素是最有效的抗氧剂,其可对LDL的氧化产生高至90%的抑制(TBARS试验)。各种其它抗氧剂的加入进一步降低了LDL的氧化,观测到在加入番茄红素时贡献最大。
实施例8:抗氧剂组合对LDL氧化的作用。
对所分析的3种抗氧剂的各种组合的作用进行了评估。仅仅当存在六氢番茄红素/八氢番茄红素部分时,在所研究的3种组合的任何一种中才可以观测到对LDL的氧化有实质性的高于90%的抑制。正如图8中TBARS和脂质过氧化物试验所示的那样,当将番茄红素、β-胡萝卜素和维生素E联用时,在不存在六氢番茄红素/八氢番茄红素的情况下,仅获得了对LDL氧化的最小抑制作用。
实施例9:类胡萝卜素混合物对LDL氧化的作用。
将Lyc-O-Mato的作用与由如下浓度的5种抗氧剂化合物的组合所制得的类胡萝卜素混合物进行了比较:番茄红素(10μg/ml)、β-胡萝卜素(0.4μg/ml)、维生素E(2.5μg/ml)和八氢番茄红素/六氢番茄红素(1.2μg/ml)。参照图9,Lyc-O-Mato在LDL的氧化中造成了约70%的抑制(TBARS试验)。该类胡萝卜素混合物对LDL氧化的抑制作用为96%(TBARS试验)。用脂质过氧化物试验获得了类似的结果。
虽然通过举例说明的方式对本发明的实施方案进行了描述,但是显然在实施本发明时显然可以对其进行修改、变化和调整,这不会脱离权利要求的主旨或超出其范围。
Claims (8)
1.包含八氢番茄红素、六氢番茄红素或其混合物的组合物在制备用于抑制LDL的氧化的药物中的应用。
2.包含八氢番茄红素、六氢番茄红素或其混合物的组合物与常规抗动脉粥样硬化剂联合用于制备抑制LDL的氧化的药物的应用。
3.八氢番茄红素、六氢番茄红素或其混合物在制备用于抑制LDL的氧化和动脉粥样硬化进程的药物中的应用。
4.如权利要求3所述的应用,其中所说的药物包含抑制LDL-氧化有效量的八氢番茄红素、六氢番茄红素或其混合物。
5.如权利要求4所述的应用,其中所说的药物包含至少0.1mg的八氢番茄红素。
6.如权利要求4所述的应用,其中所说的药物包含至少0.1mg的六氢番茄红素。
7.如权利要求4所述的应用,其中所说的药物包含至少0.1mg八氢番茄红素和六氢番茄红素的混合物。
8.如权利要求7所述的应用,其中在混合物中的八氢番茄红素和六氢番茄红素的重量比例为1∶20至20∶1。
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IL141039A (en) * | 2001-01-23 | 2006-10-31 | Lycored Natural Prod Ind Ltd | The composition for the prevention of atherosclerosis containing carotenoids and use for the preparation of drugs to inhibit LDL oxidation |
IL141038A (en) * | 2001-01-23 | 2006-10-05 | Lycored Natural Prod Ind Ltd | Use of carotenoids for the preparation of substances for the treatment of high blood pressure |
US7723327B2 (en) | 2002-07-29 | 2010-05-25 | Cardax Pharmaceuticals, Inc. | Carotenoid ester analogs or derivatives for the inhibition and amelioration of liver disease |
US7763649B2 (en) | 2002-07-29 | 2010-07-27 | Cardax Pharmaceuticals, Inc. | Carotenoid analogs or derivatives for controlling connexin 43 expression |
US20050148517A1 (en) * | 2002-07-29 | 2005-07-07 | Lockwood Samuel F. | Carotenoid ether analogs or derivatives for controlling connexin 43 expression |
US7345091B2 (en) | 2002-07-29 | 2008-03-18 | Cardax Pharmaceuticals, Inc. | Carotenoid ether analogs or derivatives for the inhibition and amelioration of disease |
US7375133B2 (en) * | 2002-07-29 | 2008-05-20 | Cardax Pharmaceuticals, Inc. | Pharmaceutical compositions including carotenoid ether analogs or derivatives for the inhibition and amelioration of disease |
US20050009788A1 (en) * | 2002-07-29 | 2005-01-13 | Lockwood Samuel Fournier | Carotenoid ester analogs or derivatives for controlling connexin 43 expression |
US7521584B2 (en) | 2002-07-29 | 2009-04-21 | Cardax Pharmaceuticals, Inc. | Carotenoid analogs or derivatives for the inhibition and amelioration of disease |
CA2564066A1 (en) * | 2004-04-14 | 2005-11-03 | Hawaii Biotech, Inc. | Carotenoid analogs or derivatives for the inhibition and amelioration of inflammation |
US20090099061A1 (en) * | 2006-01-27 | 2009-04-16 | Foss Bente J | Synthesis of carotenoid analogs or derivatives with improved antioxidant characteristics |
IL176668A0 (en) * | 2006-07-02 | 2006-10-31 | Ibr Ltd | Colorless carotenoids for skin whitening |
WO2008118862A1 (en) * | 2007-03-23 | 2008-10-02 | Cardax Pharmaceuticals, Inc. | Carotenoid analogs and derivatives for the prevention of platelet aggregation |
AU2010205367B2 (en) * | 2009-01-19 | 2015-06-18 | Lycored Ltd | Synergistic combinations of carotenoids and polyphenols |
WO2017029674A1 (en) * | 2015-08-20 | 2017-02-23 | I.B.R. Israeli Biotechnology Research Ltd. | Carotenoid compositions having antiviral activities and uses thereof |
JP2019189598A (ja) * | 2018-04-18 | 2019-10-31 | 国立大学法人京都大学 | アディポネクチン受容体作動薬及びその使用、並びにアディポネクチン受容体作動用食品組成物及びその使用 |
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AUPO693397A0 (en) | 1997-05-22 | 1997-06-12 | Betatene Limited | Carotenoid formulation |
US20040191297A1 (en) * | 1997-05-22 | 2004-09-30 | Lance Schlipalius | Carotenoid formulation |
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