CN101511208B - 用于在高血压前期个体和/或患有代谢综合征的个体中降低血压的方法 - Google Patents
用于在高血压前期个体和/或患有代谢综合征的个体中降低血压的方法 Download PDFInfo
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- CN101511208B CN101511208B CN2006800355712A CN200680035571A CN101511208B CN 101511208 B CN101511208 B CN 101511208B CN 2006800355712 A CN2006800355712 A CN 2006800355712A CN 200680035571 A CN200680035571 A CN 200680035571A CN 101511208 B CN101511208 B CN 101511208B
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Abstract
本发明涉及通过对哺乳动物(包括人)施用包含葡萄提取物的膳食补充剂来预防和/或治疗代谢综合征和/或包括代谢综合征的病症的方法。本发明还涉及通过对哺乳动物(包括人)施用包含葡萄提取物的膳食补充剂来治疗和/或预防高血压前期的方法。
Description
本申请要求2005年9月28日提交的美国临时申请序列号60/721,720的优先权,其通过参考整体并入本文。
技术领域
本发明涉及预防和/或治疗代谢综合征和/或包括代谢综合征的病症的方法。本发明还涉及治疗和/或预防高血压前期(pre-hypertension)的方法。这些方法包括对哺乳动物(包括人)施用包含葡萄提取物的膳食补充剂,该膳食补充剂可有效治疗高血压前期个体或患有代谢综合征和/或包括代谢综合征的病症的个体。
背景技术
血压是血流对动脉壁施加的力。正常的血压认为是收缩压120以及舒张压80。高血压是指特征为收缩压升至140及以上和/或舒张压升至90及以上的疾病。患有高血压时,总体外周血管阻力(如由于血管收缩)增加,或者心输出量增加,或者二者兼有。这些病症导致血压升高,因为血压等于流量乘以阻力。有许多因素可导致高血压,包括压力、饮食和生活方式以及肾脏疾病、激素紊乱和循环疾病。不加以治疗的高血压患者发生左心室衰竭、心肌梗死、脑出血或肾衰竭的风险很高。高血压还是中风和冠状动脉粥样硬化的风险因素。目前,高血压患者使用药物疗法进行治疗,包括使用利尿剂、β-阻断剂、ACE抑制剂、血管紧张素拮抗剂、钙通道阻断剂、α-阻断剂、α-β-阻断剂、神经系统抑制剂和血管扩张剂。
高血压前期个体分为收缩压为120至139mmHg的个体或舒张压为81至89mmHG的个体。该分类基于美国国家高血压预防、检测、评估和治疗联合委员会(Joint National Committee on Prevention,Detection,Evaluation,and Treatment of High Blood Pressure)第7次报告(JNC 7)第87页,NIH出版号No.04-5230。高血压前期个体通常不使用药物疗法治疗,而是给予健康生活方式的建议。这些建议包括维持健康体重;多锻炼身体;遵循强调水果、蔬菜和低脂肪乳制品的健康饮食计划;选择和准备含有较少钠的食品;并且即使饮用酒精饮料,也要适度。采用健康的生活方式习惯通常是有效预防和控制异常血压的第一步。
许多患有高血压的患者对胰岛素有抗性。胰岛素刺激组织摄取葡萄糖,并且其这种能力在个体间差异很大。有胰岛素抗性时,组织应答胰岛素作用的能力减弱。为补偿抗性,胰分泌更多的胰岛素。因此,胰岛素抗性个体的血浆胰岛素水平很高。有证据表明,异常血压与胰岛素抗性程度有关。发生胰岛素抗性的确切方式尚不清楚,但是相信遗传、饮食和体育锻炼水平均发挥作用。
“代谢综合征”也称为“x综合征”、“胰岛素抗性综合征”或“致命四重奏”,其特征为心血管疾病、中风和/或II型糖尿病风险因素的累积。代谢综合征可由皮质醇(一种应激激素)的过度产生而引起,其导致腹腔内的脂肪积累以及胰岛素抗性。目前不推荐患代谢性综合症的个体使用药物疗法。表征代谢综合征的风险因素包括:腹腔内脂肪组织的量增加(腹部肥胖)、胰岛素抗性以及发生糖尿病风险的提高、高胰岛素血症、高血脂水平、血压升高以及血清脂肪升高。美国国家胆固醇教育计划成人治疗组(ATP III)将代谢综合征定义为具有至少3项以下风险因素的个体:
风险因素 | 定义水平 |
腹部肥胖,以腰围给出* 男性女性 | >102cm(>40英寸)>88cm(>35英寸) |
甘油三酯 | ≥150mg/dL |
HDL胆固醇男性女性 | <40mg/Dl<50mg/dL |
血压 | ≥130/≥85mm Hg |
空腹血糖 | ≥110mg/dL |
*超重和肥胖与胰岛素抗性和代谢综合征有关。然而,与BMI升高相比,腹部肥胖与代谢风险因素更为相关。因此,推荐以简单的腰围测量确定代谢综合征的体重因素。
然而,世界卫生组织将代谢综合征定义为具有糖尿病/胰岛素抗性以及具有至少两种以下风险因素的个体:高腰/臀比;高甘油三酯或低HDL胆固醇;高血压以及高尿白蛋白排泄率。
与代谢综合征相关的病症包括II型糖尿病、异常脂蛋白血症、心肌梗死、中风及其它动脉硬化疾病以及这些疾病的风险因素,包括一般胰岛素抗性、腹内脂肪积累引起的腹部肥胖、血清脂肪和血糖升高、舒张压和/或收缩压升高以及高血压。
鼓励高血压前期个体和患有代谢综合征的个体采用健康生活方式进行治疗,包括维持健康体重;多锻炼身体以及遵循健康的饮食计划。由于不推荐这些个体使用药物疗法,那么就需要可被这些个体用作辅助疗法的包含葡萄提取物的膳食补充剂,其有效降低血压,并且不提高胰岛素抗性。
葡萄籽含有约5-8%(以重量计)的类黄酮。类黄酮构成了植物中广泛分布的一组重要的饮食多酚化合物。已在植物来源(如水果、蔬菜、豆类、坚果、种子、草本植物、香料、花)中和饮料(如茶、可可、啤酒、葡萄酒和葡萄汁)中鉴定了超过4000种化学性质独特的类黄酮。
就葡萄籽而言,术语类黄酮是指单体黄烷-3-醇,特别是(+)-儿茶素、(-)-表儿茶素和(-)-表儿茶素3-没食子酸酯。化学连接的两个或更多黄烷-3-醇单体称为原花色素或寡聚原花色素(“oligomeric proanthocyanidin,OPC”),包括原花青素和原翠雀素(prodelphinidin)。包含两个单体的OPC称为二聚体,包含三个单体的称为三聚体,包含四个单体的称为四聚体,包含五个单体的称为五聚体,等等。在实践中,寡聚体的链长为2至7(二聚体至七聚体);而多聚体代表链长大于7的组分。在大量讨论后,葡萄籽方法评估委员会(通过国家营养食品协会)一致同意将OPC定义为包含两个或更多单体的所有原花色素,其包括多聚体或缩合的鞣质。因此,葡萄提取物中的寡聚体包括如二聚体和三聚体,并且有证据表明多聚体可包含多至16个单元。
以下是原花色素的典型结构,其显示表儿荼素没食子酸酯的延伸单元和末端单元。例如,延伸单元以表儿茶素(2)和表没食子儿茶素(3)连接基团为代表。而末端单元以表儿茶素没食子酸酯(4)基团为代表。
为了使多酚化合物作为葡萄提取物用于商业用途,必须以更浓缩的形式将这些化合物从葡萄中分离出来。从完整葡萄、葡萄渣和葡萄籽中提取、纯化和浓缩多酚化合物的一般方法公开于美国专利No.6,544,581中,其通过参考并入本文。
附图说明
图1显示用本发明所使用葡萄提取物进行治疗的患有代谢综合征的个体中基线血压与收缩压下降之间的关系。
图2显示用本发明所使用葡萄提取物进行治疗的患有代谢综合征的个体中基线血压与舒张压下降之间的关系。
图3显示在用本发明所使用葡萄提取物进行治疗的患有代谢综合征的个体中氧化LDL浓度的变化。
图4显示在给予300mg本发明所使用葡萄提取物的个体中氧化LDL浓度的变化与氧化LDL基线浓度之间的关系。
发明详述
本发明提供了预防和/或治疗代谢综合征和/或包括代谢综合征的病症的方法。该方法包括对需要此治疗的哺乳动物(包括人)施用包含有效量葡萄提取物的膳食补充剂。特别地,该方法中使用的葡萄提取物在患有代谢综合征的个体中可有效降低血压和减少氧化LDL胆固醇。
本发明还提供了治疗和/或预防哺乳动物中代谢综合征的方法,其包括施用含有葡萄提取物的膳食补充剂,所述葡萄提取物包含约5-15%的单体、约5-20%的二聚体、约3-10%的三聚体、约2-10%的四聚体以及约2-10%的五聚体(以重量计)。包括单体、二聚体、三聚体、四聚体和五聚体的低分子量酚类化合物的总量约为25-50%(以重量计),优选约为25-40%(以重量计),更优选约为30-40%(以重量计),并且更优选约为25-35%(以重量计)。酚类化合物的总量约为80%(以重量计)或更多,并且优选约为90%(以重量计)或更多。
本发明还提供了预防和/或治疗高血压前期的方法。该方法包括向需要此治疗的哺乳动物(包括人)施用包含有效量葡萄提取物的膳食补充剂。特别地,该方法使用的葡萄提取物可在高血压前期个体中有效降低血压。
本发明还提供了治疗和/或预防哺乳动物中高血压前期的方法,其包括施用含有葡萄提取物的膳食补充剂,所述葡萄提取物包含约5-15%的单体、约5-20%的二聚体、约3-10%的三聚体、约2-10%的四聚体以及约2-10%的五聚体(以重量计)。包括单体、二聚体、三聚体、四聚体和五聚体的低分子量酚类化合物的总量约为25-50%(以重量计),优选约为25-40%(以重量计),更优选约为30-40%(以重量计),并且更优选约为25-35%(以重量计)。酚类化合物的总量约为80%(以重量计)或更多,并且优选约为90%(以重量计)或更多。
术语“有效量”是指葡萄提取物的量,其足以在高血压前期个体或代谢综合征个体中降低收缩压和/或舒张压之一或二者至少约2%,优选至少约5%,以及更优选至少约8%,并且无不良影响,如提高个体的胰岛素抗性。然而,适当的临床终点是高血压前期个体或代谢综合征个体的收缩压低于120mmHG。除了降低血压之外,还提出本发明使用的葡萄提取物会减少代谢综合征个体中的氧化LDL胆固醇。LDL胆固醇提高是公认的动脉粥样硬化风险因素。有强有力的证据表明,经氧化修饰的LDL起始了该病理过程的发生。因此,降低氧化LDL的浓度可以在代谢综合征个体中减少和/或预防动脉粥样硬化。
如正相高效液相层析(“HPLC”)所测定的,待用于本发明的葡萄提取物的酚谱为约5-15%的单体、约5-20%的二聚体、约4-10%的三聚体、约2-10%的四聚体以及约2-10%的五聚体(以重量计)。如Folin Ciocalteu法所测定的,本发明使用的葡萄提取物还包含约80%(以重量计)或更多、优选约90%(以重量计)或更多的总酚类化合物。如在硫解反应之后进行反相HPLC所测定的,本发明使用的葡萄提取物还包含约2%(以重量计)或更少的表儿茶素没食子酸酯末端单元,更优选约1%(以重量计)或更少。如在硫解反应之后进行反相HPLC所测定的,本发明使用的葡萄提取物还包含约12%(以重量计)或更少的表儿茶素没食子酸酯延伸单元,优选约8%(以重量计)或更少,并且更优选约5%(以重量计)或更少。
可以通过改进公开于美国专利No.6,544,581中的热水提取法来生产本发明使用的葡萄提取物,如下文所述。热水提取法(如′581专利所公开的)通常包括以下步骤。在步骤(1)中,可用热水将干燥或新鲜的葡萄籽加热足以提取大部分多酚的时间。可使用140-212的温度,优选160-212、更优选180-212,更优选190-212,时间为约1-6小时。加热时间可根据所使用温度而不同。通常,较低的温度需要较长的提取时间。在步骤(2)中,可通过流经金属筛将葡萄籽-水粗提物与用过的种子分开。然后,可冷却该提取物,并用任何适当的市售溶果胶酶(如Novo Nordisk生产的PectinexUltra SP-L)(以约为50-200ppm的浓度)进行处理,从而破坏细胞壁组分。优选地,可以在80-120温度下用酶将所述种子水提取物处理2小时。或者,可以在约40-50下用酶将所述种子的水提取物处理7-14天或更长。在步骤(3)中,可以将得到的混浊种子提取物用酸(优选无机酸,更优选硫酸)酸化至pH为约1.5-2.5,并反应约1小时至约2天。可将该酸化提取物冷却长达数周,以使高分子(包括蛋白质及其它多糖)沉降。然后,使用硅藻土过滤该冷却的酸化提取物,以得到澄清的种子提取物。也可使用其它助滤剂如珍珠岩。
可以通过在约80-120温度下用酶处理种子的水提取物4至5天来改良′581专利的步骤(2),从而生产本发明所使用的葡萄提取物。不限于任何理论地,相信在该步骤规定的温度范围中使用比′581专利中更长的持续时间是得到新葡萄提取物的原因。酶处理的时间可根据所使用的温度而不同。一般地,较低的温度需要较长的处理时间。因此,在约60-80温度下种子-水提取物可用酶处理长达2周或更长时间。
或者,可以通过以下步骤生产本发明中使用的葡萄提取物。在′581专利中步骤(1)的提取之后或者步骤(2)的果胶酶处理之后,可将所述提取物涂在细菌用琼脂平板上。孵育后可存在多种酵母、细菌和/或真菌,这取决于起始材料。这些活培养物可作为混合物分离。分离后,所述混合物即可用于后续的提取和/或果胶酶处理步骤。例如,可以用任何适当的市售溶果胶酶对种子-水提取物进行酶处理,并与分离的酵母、细菌和/或真菌混合物合并。所述合并的混合物可置于约70-100的温度下约1至10天,优选约2至5天。酶处理的时间可根据所使用的温度和接种数而不同。可如上文所述用适当的酸将得到的混浊种子提取物酸化至pH为1.5-2.5,并反应约1小时至约2天。可将该酸化提取物冷却并保存几天,以使蛋白质和多糖絮凝。然后,可以使用硅藻土将该冷却的酸化提取物过滤,从而得到澄清的种子提取物,其可以根据′581专利进一步加工以生产适于降低血压和减少氧化LDL的纯化的葡萄提取物。
将′581方法生产的葡萄提取物与包括酵母、细菌和/或真菌混合物的方法所生产的葡萄提取物相比,通过HPLC分析没食子酸的量。该分析显示,从′581方法的葡萄提取物中约50-150ppm没食子酸的值增加到使用所述混合物的本发明所使用葡萄提取物中约400-1500ppm没食子酸的值。没食子酸的增加表明,表儿荼素没食子酸酯的末端和延伸单元从原花青素上去酯化。不限于任何理论地,相信酵母、细菌和/或真菌混合物使用葡萄提取物作为底物,用于生长和产生鞣酶的酶活性,这引起原花青素的去酯化作用以及没食子酸的释放。因而,使用活酵母、细菌和/或真菌的混合物产生了本发明使用的葡萄提取物,其具有约2%(以重量计)或更少、更优选约1%(以重量计)或更少的表儿茶素没食子酸酯末端单元,以及约12%(以重量计)或更少、优选约8%(以重量计)或更少、更优选约5%(以重量计)或更少的表儿荼素没食子酸酯延伸单元。
在一个实施方案中,可以通过以下步骤生产本发明的葡萄提取物。在′581专利步骤(1)的提取之后或者步骤(2)的果胶酶处理之后,可以以约5-1000ppm的浓度添加任何适当的商品真菌鞣酶,如鞣质酰基水解酶,E.C3.1.1.20。取决于所使用鞣酶的浓度,所述混合物可反应约1小时至约2天,优选1至2天,或者直至末端单元减少至约2%或更少,优选1%或更少,延伸单元减少至8%或更少,优选约5%或更少。在足够的反应时间后,可将该提取物酸化至pH为1.5至2.5,这在40-60的较低温保存时使蛋白质和多糖絮凝。可根据′581专利将该提取物过滤至澄清并进一步加工,从而生产具有降低血压特征的葡萄提取物。
可将本发明所使用的葡萄提取物配制成膳食补充剂,包括胶囊剂、片剂、粉剂、溶液剂、凝胶剂、混悬剂、霜剂、糊剂、凝胶剂、栓剂、透皮贴剂等。可以将例如粉剂或溶液剂形式的这些膳食补充剂添加至营养品、食品和/或饮料中,以形成功能性营养品、食品和/或饮料产品。例如,可以将该膳食补充剂配制为粉剂,用于与可消费液体(如奶、果汁、水)或可消费凝胶剂或糖浆剂混合,以混入其他食用液体或食品中。可将本发明的膳食补充剂与其它食品或液体配制在一起,从而提供预称量的补充食品,如单个包装的条。可掺入本发明所使用葡萄提取物的典型食品包括乳制品(如酸乳)、谷类、面包、快餐食品、果汁及其它软饮料。可根据需要添加调味剂、粘合剂、蛋白质、复合碳水化合物、维生素、矿物质等。优选地,将该葡萄提取物配制成用于经口施用。
本发明所使用的膳食补充剂计划用于每天施用或根据需要施用。该膳食补充剂在高血压前期个体或患代谢综合征个体中预防或治疗剂量的高低将随着受治病症的严重程度和给药途径而变化。剂量(可能还有给药频率)还将根据个体的年龄、体重和应答而变化。一般而言,对于本文所述的病症来说,总日剂量范围为约50mg至约1,000mg(以葡萄提取物重量计),其以单剂量或分次剂量经口、局部或透皮给药,优选经口给药。优选的经口日剂量范围为50mg至约500mg、更优选约150mg至约300mg(以葡萄提取物重量计,即排除赋形剂和载体)。例如,胶囊剂或片剂可配制为150mg或300mg剂量,而饮料可配制为含有50mg葡萄提取物。优选将这样的给药方案维持至少一个月,更优选六个月或更长。
本发明所使用的膳食补充剂可以与可药用载体、赋形剂、维生素、矿物质和/或其它营养物混合以常规方式(例如,湿法造粒或干法造粒)配制。对于经口固体制剂(如粉剂、胶囊剂和片剂)的情况,代表性载体和赋形剂包括但不仅限于淀粉、糖、微晶纤维素、稀释剂、造粒剂、滑润剂、粘合剂、崩解剂等。
可以使用任何适当的给药途径对个体施用本发明的膳食补充剂。合适的途径包括如经口、直肠、胃肠外、静脉内、局部、透皮、皮下和肌内。尽管可以使用任何适当的给药途径来对个体提供有效量的本发明方法的葡萄提取物,但优选经口给药,包括固体剂型如片剂、胶囊剂或粉剂。还优选将所述葡萄提取物配制成用于功能性营养品、食品或饮料产品。
本发明所使用的葡萄提取物还可与其它活性剂组合,所述活性剂包括而不仅限于利尿剂、β-阻断剂、ACE抑制剂、血管紧张素拮抗剂、钙通道阻断剂、α-阻断剂、α-β-阻断剂、神经系统抑制剂、血管扩张剂、抗氧化剂。
1.葡萄提取物的表征
最近,据报道,在高血压个体中与维生素C联合使用时,葡萄籽多酚不降低收缩压,并且事实上提高收缩压。参阅Ward等“The combinationof vitamin C and grape-seed polyphenols increases blood pressure:arandomized,double-blind,placebo-controlled trial,”Journal ofHypertension 2005;23:427-434。不限于任何理论地,相信葡萄提取物的酚谱对于其在降低血压中的有效性是很重要的。Ward的研究中所评估的葡萄提取物是Vinlife,其酚谱为通过Folin Ciocalteu法测定的50.6%总酚类化合物,通过硫解反应后反相HPLC测定的11.2%表儿茶素没食子酸酯末端单元和11.8%表儿茶素没食子酸酯延伸单元,以及通过正相HPLC所测定的7.3%单体、4.4%二聚体、2.0%三聚体、1.9%四聚体和1.1%五聚体,单体至五聚体共为16.7%。
市售的葡萄籽提取物包含多种单体和原花色素。一些市售提取物的通过反相HPLC所测定的酚谱示于表1,通过正相HPLC所测定的示于表2。从这些分析来看,本发明所使用的葡萄提取物(MegaNatural-BP,目前由Polyphenols,Inc.生产)具有区别于其它葡萄提取物的3个区分因素:
1.高纯度,如通过Folin Ciocalteu法所测定的,总酚类化合物的量高于约80%(以重量计),并且更优选高于约90%(以重量计);
2.低分子量酚类化合物的量高,例如约为25-50%(以重量计),其中低分子量的酚类化合物为单体、二聚体、三聚体、四聚体和五聚体;以及
3.末端单元中表儿茶素没食子酸酯的量极低或没有,例如低于约2%,优选低于约1%,并且延伸单元中表儿茶素没食子酸酯的量较低,例如低于约12%,优选低于约5%。
同样,不限于任何理论地,相信葡萄提取物的酚谱对其在治疗或预防个体高血压前期或代谢综合征中的有效性是很重要的。特别地,相信在本发明所使用葡萄提取物的末端单元中表儿茶素没食子酸酯的缺乏和其延伸单元中少量的表儿茶素没食子酸酯以及存在较大量的低分子量化合物是血管舒张增强的原因,所述血管舒张的增强相信是下述的对患有代谢综合征和高血压前期个体的临床研究中血压下降的原因。
测定单体、寡聚体和多聚体百分比的反相HPLC方法
可使用反相HPLC分析基于280 nm处的峰面积来测定葡萄提取物中单体、寡聚体和多聚体的比例。
HPLC条件:
流动相:A:2%冰乙酸
B:80%乙腈,0.4%乙酸
梯度: 时间
(分钟) %A %B 曲线
0.00 100 0 -
3.00 100 0 6
6.00 96 4 6
15.00 90 10 6
30.00 85 15 6
50.00 77 23 6
60.00 75 25 6
66.00 70 30 6
80.00 50 50 6
83.00 20 80 6
85.00 100 0 6
105.00 100 0 6
110.00 100 0 6
(Phenomenex,Torrance,CA)
流速: 1.0mL/分钟
检测波长:280nm
温度: 30℃
注入量: 25μL
样品制备:准确称重0.1g葡萄提取物并放入100mL容量瓶中。将该样品溶解在少量甲醇中(≤5mL),必要时进行超声处理。用18兆欧的水填满体积。在注入前将该样品离心(14,000rpm,10分钟)或者通过0.45μM玻璃滤器进行过滤。基于峰面积和标准品的浓度测定单体、寡聚体和多聚体的重量百分比。
基于硫解反应之后HPLC分析来测定原花色素中末端和延伸单元的方法
硫解作用是测定葡萄提取物中原花色素平均分子大小(聚合度)和基本结构的方法。所提供的信息可表明葡萄提取物用于机体营养吸收的生物学品质。
硫解试剂:含有0.2 N HCl的甲醇中的5%苯基甲硫醇(苄硫醇)。
条件:将0.1%葡萄提取物甲醇溶液与等体积的硫解试剂混合、搅拌并在90℃加热2分钟。加水终止反应。然后,以14000rpm将反应物离心2分钟。直接通过HPLC分析上清液。
HPLC条件:
流动相: A:10%乙酸/0.1%TFA/5%乙腈/84.9%水(体积
/体积/体积/体积)
B:乙腈
梯度: 0-30分钟0-50%B
30-35分钟50-100%B
柱: 150cm×2.0mm i.d.,4μm Synergi hydro-RP 80
流速: 0.3mL/min
检测波长:HP 1100 FLD,在276nm处激发,在316nm处
发射,以及HP DAD在280nm处
温度: 30℃
注入量: 1-3μL
将待分析的葡萄提取物溶于甲醇中,与等体积的硫解试剂混合并在90℃加热2分钟。通过质谱分析法鉴定所释放的单元,并在上述条件下通过HPLC进行定量测定。通过计算所有黄烷-3-醇单元(硫醚加合物加末端单元)与末端单元的相应儿茶素、表儿茶素和表儿茶素没食子酸酯的摩尔比例来计算平均聚合度。基于表儿茶素没食子酸酯在末端单元总摩尔数中的摩尔比例来测定表儿茶素没食子酸酯末端单元的百分比,所述表儿茶素没食子酸酯末端单元包括儿茶素、表儿茶素和表儿茶素没食子酸酯。基于表儿茶素没食子酸酯硫醚加合物在延伸单元的硫醚加合物总摩尔数中的摩尔比例来测定表儿茶素没食子酸酯延伸单元的百分比,所述延伸单元硫醚加合物包括儿茶素、表儿茶素和表儿茶素没食子酸酯硫醚加合物。利用Folin Ciocalteu法以没食子酸当量(Gallic Acid Equivalent,GAE)来定量酚类化合物总量。Folin Ciocalteu分析法的更多细节参阅Waterhouse,A.L,Determination of Total Phenolics,Current Protocols in Food AnalyticalChemistry,I1.1.1-I1.1.8,Wrolstad,R.E.,Wiley,2001或者Singleton,V.L.L;Orthofer,R.;Lamuela-Raventos,R.M.“Analysis of total phenols andother oxidation substrates and antioxidants by means of Folin-CiocalteuReagent,”Methods in Enzymology 1999,299,152-178,二者均通过参考并入本文。
对原花色素进行正相HPLC分析
原花色素的HPLC分析:利用配备有自动进样器/注射器、二元梯度泵(binary pump)、柱温箱、二极管阵列检测器、荧光检测器以及用于数据收集和处理的HP ChemStation的HP 1100系列HPLC进行层析分析。在Phenomenex Luna Silica(2)柱上进行原花色素寡聚体的正相分离。
流动相: A:二氯甲烷、甲醇、水和乙酸(83∶13∶2∶2(体积/体积))
B:甲醇、水和乙酸(96∶2∶2(体积/体积))
梯度: 0-30分钟 线性0-17.6%B
30-45分钟 线性17.6-30.7%B
45-50分钟 线性30.7-87.8%B
50-60分钟 线性87.8%B
柱: Phenomenex LUNA Silica(3.0×150mm;3.0μm)
流速: 0.5mL/分钟
检测: HP 1100 FLD,在276nm处激发,在316nm处发射
温度: 25℃
注入量: 3μL
在所有的情况下,在注射之间均用相当于5mL的初始流动相将柱再次平衡。制备并分析儿茶素标准品以建立响应标准曲线,由此计算样品中原花色素的浓度。荧光检测中二聚体、三聚体、四聚体和五聚体相对于单体的响应因子报道于R.L.Prior和L.Gu,“Occurrence and biologicalsignificance of proanthocyanidins in American diet,”Phytochemistry 2005,66(18)2264-2280,其中使用分离和纯化自可可豆的标准品。这些响应因子用于计算相对于单体的二聚体、三聚体、四聚体和五聚体。
表1和表2所显示的结果使用不同方法获得,其解释了例如单体百分数的不同范围。例如,使用反相HPLC基于单体、寡聚体和多聚体的峰面积测定这三组化合物的百分比。包括了没食子酸作为单体。在正相HPLC中,使用儿茶素和表儿茶素作为标准品以测定葡萄提取物中单体、二聚体、三聚体、四聚体和五聚体的量(以重量计)。使用R.L.Prior和L.Gu所报道的二聚体、三聚体、四聚体和五聚体相对于单体的相对响应因子来计算二聚体、三聚体、四聚体和五聚体。
2.葡萄提取物对患有代谢综合征的个体中血压的影响
在24个诊断为患有代谢综合征的个体中研究本发明所使用葡萄提取物对血压的影响。该研究包括相等数量的20至50岁的男性和女性。基于由美国国家胆固醇教育计划成人治疗组III定义的标准诊断代谢综合征。每名受试者均显示至少三个以下特征:1)空腹血糖>110mg/dL,2)HDL(男性中<40mg/dL,女性中<45mg/dL),3)血压>130/85,以及4)腹部肥胖(男性>102cm,女性>88cm)。如果个体:吸烟或者从前吸烟(<3年);服用抗炎或高血压药物;或者服用非处方药抗氧化剂化合物,则排除他们。
将所述个体分组随机化(block randomize)分为三组,每组8人,并根据其分组给予以下胶囊之一。
第一组给予安慰剂胶囊
第二组给予含有150mg葡萄提取物的胶囊
第三组给予含有300mg葡萄提取物的胶囊
给所述个体足够的胶囊,以使其在接下来的28天中每天服用同样剂量一次。在该阶段结束时测量血压。在研究开始时记录12小时的动态血压,并且在四周后再次记录。该方法是非侵入性的,包括将血压袖带置于上臂。所述袖带与FDA批准的自动充气装置相连,并靠带子佩戴。
表3显示三组代谢综合征个体的血压数据。在每天接受300mg和150mg本发明所使用的葡萄提取物的个体中,收缩压和舒张压均有显著降低。在给予安慰剂的组中无显著变化。
表3.本发明所使用的葡萄提取物在代谢综合征个体血压上的结果
*p是开始和结束值相同的概率。通常认为p为0.05或更小(5%)是显著的。
基线血压与收缩压和舒张压下降之间的关系示于图1和图2。血压用mmHg表示。因为代谢综合征的诊断是基于存在所列出的三个风险因素(其中之一为血压),所以该研究不根据血压对个体进行集区随机化分组。因此,三组中的平均血压不相似(但是在窄范围内变化)。
该研究证明,日剂量150mg和300mg的本发明葡萄提取物降低代谢综合征个体的收缩压和舒张压。对于所使用的两种提取物剂量,血压降低都是统计学显著的。事实上,使用葡萄提取物观察到的血压变化与大多数临床试验中使用药物试剂所观察到的相当。
3.葡萄提取物对代谢综合征个体中氧化LDL的影响
在如上述同样的24个诊断为患有代谢综合征的个体中研究了本发明所使用的葡萄提取物对于氧化LDL的影响。在研究开始测量氧化LDL的浓度,并在治疗4周后再次测量。为了测量氧化LDL的浓度,从每名个体取血并进行分析。
三个组的氧化LDL浓度变化总结于图3。图3显示,服用安慰剂的个体的氧化LDL有轻微下降,服用150mg本发明所使用葡萄提取物的个体中氧化LDL有下降趋势,服用300mg本发明所使用葡萄提取物的个体中氧化LDL具有统计学显著的下降(p<0.05)。图4描绘了给予300mg本研究所使用葡萄提取物的个体中氧化LDL变化与氧化LDL基线浓度之间的关系。回归系数R2=0.52。图4显示,在以较高的氧化LDL水平开始治疗的个体中氧化LDL的浓度有更显著的降低。
该研究表明,本发明的葡萄提取物以日剂量150mg和300mg降低了患有代谢综合征的个体血浆中氧化LDL的浓度。另外,给予本发明所使用葡萄提取物300mg的个体的氧化LDL浓度具有统计学显著的下降。
4.葡萄提取物对于患有高血压前期的个体的影响
研究了本发明所使用的葡萄提取物对24名诊断为患有高血压前期的个体的影响。该研究包括相等数量的30至60岁之间的男性和女性。基于美国国家高血压预防、检测、评估和治疗委员会第7次报告定义的标准诊断高血压。每个受试者具有120至139mmHg的收缩压和/或81至89mmHG的舒张压。如果个体:吸烟或者从前吸烟(<3年);服用抗炎或高血压药物;或者服用非处方药抗氧化剂化合物,则排除他们。
将所述个体按性别分组随机化分为两组,每组12人,根据分组情况给予他们以下胶囊之一。
第一组给予安慰剂胶囊
第二组给予含有300mg MegaNatural-BP的胶囊
给所述个体足够的胶囊,以使其在接下来的八周中每天服用同样剂量一次。在该阶段结束时测量血压。在研究开始时记录12小时的动态血压,并且在八周后再次记录。该方法是非侵入性的,包括将血压袖带置于上臂。所述袖带与FDA批准的自动充气装置相连,并靠带子佩戴。
表4显示两组患有高血压前期的个体的血压数据。基线血压在两组之间没有显著差异。在每天接受300mg本发明所使用葡萄提取物的个体中,收缩压和舒张压均显著降低;然而,在给予安慰剂的组中无显著变化。例如,在用MegaNatural-BP治疗的组中收缩压平均降低7.2±2.5mmHg,而在安慰剂组中收缩压提高了0.03±1.5mmHg。所述数据总结于下文。数值以mmHg给出(平均值±标准差)。
*p是开始和结束时数值相同的概率。通常认为p为0.05或更小(5%)是显著的。
该研究证明,300mg日剂量的本发明葡萄提取物降低了高血压前期个体的收缩压和舒张压。血压降低是统计学显著的。事实上,使用葡萄提取物观察到的血压变化与使用药物试剂的多数临床试验中所观察到的相当。
实施例
通过参考以下实施例进一步定义本发明,所述实施例描述了用于生产葡萄提取物和制备膳食补充剂的方法。所述实施例是代表性的,它们不应理解为限制本发明的范围。
实施例1:用于生产葡萄提取物的方法
在200下用水提取干葡萄籽2小时,用金属筛将提取物与种子分开。将提取物冷却至90-100,并以200ppm的浓度加入果胶酶。将提取物分成两部分。向一部分中以1000ppm的浓度加入商品真菌鞣酶(鞣质酰基水解酶,E.C3.1.1.20)。向另一部分中以50ppm的浓度加入该鞣酶。原始提取物中没食子酸的残留浓度为117ppm,其中有18.9%的末端单元和11.1%的延伸单元。用1000ppm鞣酶处理约2小时内,没食子酸浓度升至904ppm,其中有0%末端单元和约5.5%延伸单元。用50ppm鞣酶需处理约34小时以使没食子酸到达810ppm,其中有少于1%的末端单元和少于6%的延伸单元。约2天后,将两份提取物均酸化至pH1.5至2.5,这使得蛋白质和多糖在40-60的较低温保存时发生絮凝。将提取物过滤并根据′581专利进一步加工,以产生具有降低血压和减少氧化LDL浓度特征的葡萄提取物。
实施例2:胶囊剂
实施例3:粉剂
如表4所示将MegaNatural-BP葡萄提取物与赋形剂配制成干混合物以用于饮料中,其中所述成分均干燥混合。为制备最终的饮料,将9.47g所述干混合物与500mL冷水混合并搅拌。500mL的一份中包含16卡路里。每1L的一份最终饮料中含有100mg MegaNatural-BP葡萄提取物和120mg维生素C,其ORAC值为2200TE。
ORAC代表“氧自由基吸收能力(Oxygen Radical AbsorbanceCapacity)”,以每克中毫摩尔Trolox(一种非商品化的维生素E水溶性衍生物)当量(Trolox equivalent,TE)来衡量。科学家通过该标准来测量食品和补充剂中的抗氧化活性。一份新鲜的或新烹制的水果和蔬菜提供平均为600至800 ORAC单位。已经提出,每天增加摄入具有2,000至5,000ORAC单位的食品或添加剂对健康有益。
表4
成分 | %干混合物(g) |
麦芽糖糊精 | 37.48 |
柠檬酸 | 29.99 |
混浊剂(纯胶2000)* | 5.25 |
阿斯巴甜 | 3.85 |
柠檬酸钠,FCC级 | 3.75 |
Ultra Guar** | 3.75 |
N&A桔子香精(SN313897)*** | 7.5 |
Nat FF 西番莲香精(SN 313898)*** | 4.27 |
FD&C黄#6(20∶1在麦芽糖糊精中) | 2.24 |
FD&C黄#5(20∶1在麦芽糖糊精中) | 0.75 |
维生素C | 0.64 |
MegaNatural-BP葡萄提取物(Polyphenolics,Inc.) | 0.53 |
总计 | 100 |
*可得自National Starch&Chemical Corporation,Bridgewater,NJ
**可得自P.L.Thomas&Co.,Inc.Morristown,NJ
***可得自International Flavors&Fragrances,Dayton,NJ
实施例4:饮料
如表5所示将MegaNatural-BP葡萄提取物与赋形剂配制成饮料。每8液体盎司(fl oz)的一份以下饮料中含有50mg MegaNatural-BP葡萄提取物和60mg维生素C(100%RDI)。8液体盎司的一份该饮料含有0卡路里和0.15g总碳水化合物。16液体盎司一份的ORAC值为2200TE。
表5
成分 | 重量百分比 |
水 | 99.4373 |
柠檬酸 | 0.2640 |
MegaNatural紫色颜料(Canandaigua Conc.) | 0.0528 |
Sethness-Greenleaf香精体系 | 0.0867 |
苯甲酸钠 | 0.0448 |
山梨酸钾 | 0.0448 |
维生素C | 0.0338 |
MegaNatural -BP葡萄提取物(Polyphenolics,Inc.) | 0.0211 |
阿斯巴甜 | 0.0147 |
总计 | 100.0000% |
实施例5:饮料
如表6所示将MegaNatural-BP葡萄提取物与赋形剂配制成饮料。每8液体盎司的一份以下饮料中含有50mg MegaNatural-BP葡萄提取物和60mg维生素C(100%RDI)。8液体盎司的一份该饮料含有15卡路里和4g总碳水化合物。16液体盎司一份的ORAC值为2200TE。
表6
实施例6:维生素/矿物质补充剂
表7
成分 | 每日摄取量 百分比 |
维生素A 3500IU(29%为β-胡萝卜素) | 70 |
维生素C 60mg | 100 |
维生素D 400IU | 100 |
维生素E 45IU | 150 |
维生素K 10mcg | 13 |
硫胺素1.5mg | 100 |
核黄素1.7m9 | 100 |
烟酸20mg | 100 |
维生素B63mg | 150 |
叶酸400mcg | 100 |
维生素B1225mcg | 417 |
生物素30mcg | 10 |
泛酸10mg | 100 |
钙299mg | 20 |
磷48mg | 5 |
碘150mcg | 100 |
镁100mg | 25 |
锌15mg | 100 |
硒20mg | 29 |
铜2mg | 100 |
锰2mg | 100 |
铬150mcg | 125 |
钼75mcg | 100 |
氯72mg | 2 |
钾80mg | 2 |
MegaNatural-BP葡萄提取物150mg | * |
硼150mcg | * |
镍5mcg | * |
硅2mg | * |
钒10mcg | * |
叶黄素250mcg | * |
番茄红素300mcg | * |
*无明确每日摄取量(%DV)
实施例7:维生素/矿物质补充剂
将MegaNatural-BP葡萄提取物(150mg)与表8中列出的以下成分和赋形剂在V形搅拌器中混合均匀。将混合物压制成特定重量(775mg±2%)的药片,从而形成复合维生素/矿物质补充剂。用水溶性树胶(如羟丙基甲基纤维素)透明包衣喷涂所述片剂并干燥。日剂量为每天一片。表8中配方的批次规模为500,000片。
表8
成分(测量单位) | 标签标示 | 过剩(%)* | 量/片 (ma) | 量/批 (Kg) |
维生素A棕榈酸酯500KIU/gm(IU) | 5000IU | 30 | 13.000 | 6.500 |
维生素D3850KIU/g(IU) | 400IU | 30 | 0.612 | 0.306 |
维生素E琥珀酸酯(D-a)1210IU/g(IU) | 15IU | 5 | 13.017 | 6.508 |
维生素C(mg) | 30mg | 2 | 30.600 | 15.300 |
盐酸硫胺素89.2%(mg) | 1.5mg | 2 | 1.715 | 0.858 |
核黄素(mg) | 1.7mg | 2 | 1.734 | 0.867 |
烟酰胺(mg) | 10mg | 2 | 10.200 | 5.100 |
盐酸吡哆辛82.3%(mg) | 2mg | 5 | 2.552 | 1.276 |
叶酸研制剂1.0%(mcg) | 400mcg | 25 | 50.000 | 25.000 |
维生素B-12研制剂1.0%(mcg) | 6mcg | 20 | 0.720 | 0.360 |
泛酸(泛酸钙)(mg) | 10mg | 5 | 10.500 | 5.250 |
生物素研制剂1.0%(mcg) | 30mcg | 20 | 3.600 | 1.800 |
钙(磷酸二钙)29.46%(mg) | 100mg | 0 | 344.119 | 172.060 |
磷(磷酸二钙)22.77%(mg) | 75mg | 0 | 0.000 | 0.000 |
镁(MgO)60.32%(mg) | 20mg | 0 | 33.156 | 16.578 |
锌(ZnO)80.34(mg) | 5mg | 0 | 6.224 | 3.112 |
碘(KI)76.45%(mcg) | 150mcg | 0 | 0.196 | 0.098 |
铜(葡糖酸盐)14.00%(mg) | 2mg | 0 | 14.286 | 7.143 |
锰(葡糖酸盐)12.34%(mg) | 2mg | 0 | 16.207 | 8.104 |
MegaNatura -BP葡萄提取物 | 150mg | 150.000 | 25.000 | |
微晶纤维素 | 33.750 | 16.875 | ||
交联羧甲基纤维素纳 | 20.250 | 10.125 | ||
硬脂酸 | 13.500 | 6.750 | ||
硬脂酸镁 | 5.063 | 2.531 | ||
总计 | 775.000 | 337.500 |
*为达到标示量而超过标签标示的成分量百分比
Claims (39)
1.以有效降低血压的量包含来自葡萄的多酚提取物的组合物在制备用于在有此需要的哺乳动物中治疗代谢综合征的药物中的用途,其中所述提取物包含2重量%或更少的表儿茶素没食子酸酯末端单元。
2.权利要求1的用途,其中所述多酚提取物包含总量为提取物重量25-50%的单体、二聚体、三聚体、四聚体和五聚体。
3.权利要求2的用途,其中所述提取物包含80重量%或更多的总酚类化合物。
4.权利要求3的用途,其中所述提取物包含12重量%或更少的表儿茶素没食子酸酯延伸单元。
5.权利要求1的用途,其中所述组合物中该提取物的量为50-1000mg。
6.权利要求1的用途,其中所述组合物配制成用于经口施用。
7.权利要求6的用途,其中所述组合物以选自片剂、粉剂、液体剂、胶囊剂和凝胶剂的形式施用。
8.权利要求7的用途,其中所述粉剂或液体剂用于食品或饮料产品中。
9.权利要求7的用途,其中所述粉剂或液体剂用于营养品中。
10.权利要求1的用途,其中所述哺乳动物为人。
11.以有效降低血压的量包含来自葡萄的多酚提取物的组合物在制备用于在有此需要的哺乳动物中治疗高血压前期的药物中的用途,其中所述提取物包含2重量%或更少的表儿茶素没食子酸酯末端单元。
12.权利要求11的用途,其中单体、二聚体、三聚体、四聚体和五聚体的总量为25-50重量%。
13.权利要求12的用途,其中所述提取物包含80重量%或更多的总酚类化合物。
14.权利要求13的用途,其中所述提取物包含12重量%或更少的表儿茶素没食子酸酯延伸单元。
15.权利要求11的用途,其中所述组合物中该提取物的量为50-1000mg。
16.权利要求11的用途,其中所述组合物配制成用于经口施用。
17.权利要求16的用途,其中所述组合物以选自片剂、粉剂、液体剂、胶囊剂和凝胶剂的形式施用。
18.权利要求17的用途,其中所述粉剂或液体剂用于食品或饮料产品中。
19.权利要求17的用途,其中所述粉剂或液体剂用于营养品中。
20.权利要求11的用途,其中所述哺乳动物为人。
21.以有效降低氧化LDL胆固醇的量包含来自葡萄的多酚提取物的组合物在制备用于在有此需要的哺乳动物中治疗代谢综合征的药物中的用途,其中所述提取物包含2重量%或更少的表儿茶素没食子酸酯末端单元。
22.权利要求21的用途,其中单体、二聚体、三聚体、四聚体和五聚体的总量为25-50重量%。
23.权利要求22的用途,其中所述提取物包含80重量%或更多的总酚类化合物。
24.权利要求23的用途,其中所述提取物包含12重量%或更少的表儿茶素没食子酸酯延伸单元。
25.权利要求21的用途,其中所述组合物中该提取物的量为50-1000mg。
26.权利要求21的用途,其中所述组合物配制成用于经口施用。
27.权利要求26的用途,其中所述组合物以选自片剂、粉剂、液体剂、胶囊剂和凝胶剂的形式施用。
28.权利要求27的用途,其中所述粉剂或液体剂用于食品或饮料产品中。
29.权利要求27的用途,其中所述粉剂或液体剂用于营养品中。
30.权利要求21的用途,其中所述哺乳动物为人。
31.包含来自葡萄的多酚提取物的组合物在制备用于在有此需要的哺乳动物中治疗代谢综合征的药物中的用途,所述多酚提取物包含5-15重量%的单体、5-20重量%的二聚体、3-10重量%的三聚体、2-10重量%的四聚体以及2-10重量%的五聚体,其中所述提取物包含2重量%或更少的表儿茶素没食子酸酯末端单元。
32.包含来自葡萄的多酚提取物的组合物在制备用于在有此需要的哺乳动物中治疗高血压前期的药物中的用途,所述多酚提取物包含5-15重量%的单体、5-20重量%的二聚体、3-10重量%的三聚体、2-10重量%的四聚体以及2-10重量%的五聚体,其中所述提取物包含2重量%或更少的表儿茶素没食子酸酯末端单元。
33.权利要求1的用途,其中所述多酚提取物包含5-15重量%的单体、5-20重量%的二聚体、3-10重量%的三聚体、2-10重量%的四聚体以及2-10重量%的五聚体。
34.权利要求1的用途,其中所述提取物含有400-1500ppm的没食子酸。
35.权利要求11的用途,其中所述提取物含有400-1500ppm的没食子酸。
36.权利要求21的用途,其中所述提取物含有400-1500ppm的没食子酸。
37.权利要求31的用途,其中所述提取物含有400-1500ppm的没食子酸。
38.权利要求32的用途,其中所述提取物含有400-1500ppm的没食子酸。
39.以有效降低血压的量包含来自葡萄的多酚提取物的组合物在用于制备在有此需要的哺乳动物中治疗代谢综合征的药物中的用途,其中所述提取物含有400-1500ppm的没食子酸。
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US72172005P | 2005-09-28 | 2005-09-28 | |
US60/721,720 | 2005-09-28 | ||
PCT/US2006/038344 WO2007038768A2 (en) | 2005-09-28 | 2006-09-26 | Method for lowering blood pressure in pre-hypertensive individuals and/or individuals with metabolic syndrome |
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WO2007141026A1 (en) * | 2006-06-07 | 2007-12-13 | Imagination Unlimited B.V. | Use of a polyphenol in the treatment of the metabolic syndrome and endothelial dysfunction or other vascular sequellae. |
EP1925311A1 (en) * | 2006-11-15 | 2008-05-28 | Melbrosin International Produktions und Vertriebs GmbH & Co KG | Use of a plant extract or plant juice |
EP2303252A1 (en) | 2008-05-15 | 2011-04-06 | Alois Jungbauer | Compounds for the treatment of metabolic syndrome and insulin resistance |
EA019809B9 (ru) * | 2008-11-11 | 2014-08-29 | Юнилевер Нв | Композиция черного чая |
EP2210504A1 (en) * | 2009-01-27 | 2010-07-28 | Nestec S.A. | Composition comprising chicoric acid and/or derivatives thereof |
US20140023737A1 (en) * | 2012-04-10 | 2014-01-23 | The Regents Of The University Of California | Modulation of Oxidative Stress, Inflammation, and Impaired Insulin Sensitivity with Grape seed Extract |
US9592265B2 (en) * | 2012-04-10 | 2017-03-14 | The Regents Of The University Of California | Modulation of oxidative stress, inflammation, and impaired insulin sensitivity with grape seed extract |
US9642885B2 (en) | 2012-10-16 | 2017-05-09 | Biotics Research Corporation | Blood pressure reduction with dietary supplements |
WO2014083577A2 (en) * | 2012-11-27 | 2014-06-05 | Tata Global Beverages Limited | Beverage with heart aid functional ingredients and process thereof |
FR3002453B1 (fr) * | 2013-02-28 | 2015-08-07 | Univ Bordeaux Segalen | Nouvelles combinaisons comprenant un extrait polyphenolique de marc de raisin avec un antihypertenseur et leurs utilisations |
FR3013979A1 (fr) * | 2013-12-02 | 2015-06-05 | Maximaliste Ltd | Composition comprenant des extraits de raisin tannat ou cannoneau, procede d'extraction et utilisations |
KR20170012485A (ko) | 2014-05-30 | 2017-02-02 | 샤클리 코포레이션 | 샤도네이 포도 종자 추출물 |
US10709751B2 (en) | 2014-05-30 | 2020-07-14 | Shaklee Corporation | Chardonnay grape seed extract |
CN105520930A (zh) * | 2014-09-28 | 2016-04-27 | 中国医学科学院药物研究所 | 一类黄烷化合物在预防或治疗黑色素瘤中的应用 |
EP3231421A1 (en) * | 2016-04-11 | 2017-10-18 | Greenaltech, S.L. | Uses of a carotenoid in the treatment or prevention of stress induced conditions |
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US6544581B1 (en) * | 1999-06-22 | 2003-04-08 | Canandaigua Wine Company, Inc. | Process for extraction, purification and enrichment of polyphenolic substances from whole grapes, grape seeds and grape pomace |
US20020192314A1 (en) * | 2001-03-06 | 2002-12-19 | Cho Suk H. | Dietary supplement compositions |
JP3592681B2 (ja) * | 2001-05-16 | 2004-11-24 | 花王株式会社 | 容器詰飲料 |
US7119110B2 (en) * | 2001-10-05 | 2006-10-10 | Interhealth Nutraceuticals Incorporated | Method and composition for preventing or reducing the symptoms of insulin resistance syndrome |
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US6706756B1 (en) * | 2001-11-16 | 2004-03-16 | University Of South Florida | Vasodilating compound and method of use |
US20040247714A1 (en) * | 2002-10-23 | 2004-12-09 | Suzanne Roe | Method and composition for enhancing vascular function |
WO2005122793A1 (en) * | 2004-06-18 | 2005-12-29 | Unilever N.V. | Food composition with wine extract and grape juice extract |
WO2006016383A2 (en) * | 2004-08-12 | 2006-02-16 | Re.Na.Co. S.A.S. Di Ravanello F. & C. | Natural composition |
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WO2007038768A2 (en) | 2007-04-05 |
US7651707B2 (en) | 2010-01-26 |
IL190206A0 (en) | 2009-02-11 |
RU2427382C2 (ru) | 2011-08-27 |
ES2520017T3 (es) | 2014-11-11 |
PT1942919E (pt) | 2014-10-31 |
NZ567332A (en) | 2011-05-27 |
RU2008116611A (ru) | 2009-11-10 |
CN101511208A (zh) | 2009-08-19 |
CA2623418A1 (en) | 2007-04-05 |
CA2623418C (en) | 2015-11-03 |
EP1942919A4 (en) | 2010-09-15 |
JP5230431B2 (ja) | 2013-07-10 |
EP1942919B1 (en) | 2014-08-27 |
PL1942919T3 (pl) | 2015-03-31 |
EP1942919A2 (en) | 2008-07-16 |
JP2009510118A (ja) | 2009-03-12 |
WO2007038768A3 (en) | 2009-04-16 |
US20070071841A1 (en) | 2007-03-29 |
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