CN1124134C - 柚苷和柚苷配基作为肝病的预防或治疗剂的应用 - Google Patents
柚苷和柚苷配基作为肝病的预防或治疗剂的应用 Download PDFInfo
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- CN1124134C CN1124134C CN98810708A CN98810708A CN1124134C CN 1124134 C CN1124134 C CN 1124134C CN 98810708 A CN98810708 A CN 98810708A CN 98810708 A CN98810708 A CN 98810708A CN 1124134 C CN1124134 C CN 1124134C
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- naringin
- naringenin
- cholesterol
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Abstract
本发明涉及柚苷和柚苷配基在哺乳动物中抑制酰基CoA-胆固醇-O-酰基转移酶(ACAT)的活性、抑制巨噬细胞-脂质复合物在动脉壁上的累积、以及预防或治疗肝病的应用。
Description
发明领域
本发明涉及柚苷和柚苷配基在哺乳动物中抑制酰基CoA-胆固醇-O-酰基转移酶(ACAT)的活性、抑制巨噬细胞-脂质复合物在动脉壁上的累积、以及预防或治疗肝病的应用。
发明背景
近些年来，冠状心血管循环疾病，例如动脉粥样硬化和高胆固醇血症，已逐渐成为主要的致死原因。已有报道称，血浆胆固醇浓度增高导致脂肪、巨噬细胞和泡沫细胞沉积在血管壁上，此等沉积则导致斑块形成，并由此引发动脉粥样硬化(Ross，R.，Nature，362，801-809(1993))。降低血浆胆固醇浓度的方法之一是饮食料法，以降低胆固醇和脂质的摄入。另一种方法是通过抑制其中所涉及的酶来抑制胆固醇的吸收。
酰基CoA-胆固醇-O-酰基转移酶(ACAT)促进血液中胆固醇的酯化。泡沫细胞是在ACAT的作用下形成的，并包含大量的由低密度脂蛋白携带的胆固醇酯。泡沫细胞在动脉壁上的形成随ACAT的活性而增加，因此ACAT的抑制剂也可以是防止动脉粥样硬化的药剂。另外，已有人报道LDL-胆固醇的血浓可通过抑制ACAT的活性来降低(Witiak，D.T.和D.R.Feller(eds.)，Anti-Lipidemic Drugs：Medicinal，Chemical and Biochemical Aspects，Elsevier，pp 159-195(1991))。
另一方面，由于过度摄入酒精或具有高脂质含量的食品、或者感染肝炎B或C病毒有可能发生肝功能的损坏，并有可能发展为肝炎、肝硬变或肝癌。具体而言，过量摄入含脂肪的食品和酒精导致脂肪肝，其中在肝组织中沉积了大量的脂质类物质，而且血清GOT(谷氨酸-草酰乙酸转氨酶)、GPT(谷氨酸-丙酮酸转氨酶)和γ-GTP(γ-谷氨酰基转肽酶)升高(T.Banciu等人，Med.Inteme.，20，69-71(1982)；以及A.Par等人，Acta.Med.Acad.Sci.Hung.，33，309-319(1976))。
已进行了许多努力来研制可以抑制ACAT活性的药物；其结果是已有几种从各种微生物的培养物中分离出的化合物。此等化合物的例子包括从Aspergillus fumigatus的培养物中分离出的pyripyropenes(S.Omura等人，J.Antibiotics，46，1168-1169(1993)；以及从Pseudomonas sp.中分离出的Acaterin(S.Nagamura等人，J.Antibiotics，45，1216-1221(1992))。
另外，作为高胆固醇血症的治疗剂，Merck Co.，USA已研制并销售称为Lovastatin的HMG-CoA还原酶抑制剂。但是，已知该药物会诱发肝脏中肌酸激酶增加的副作用。
因此，仍有必要继续研制无毒性的ACAT和巨噬细胞-脂质复合物在动脉上皮上累积的抑制剂、以及肝病预防或治疗剂。
本发明的发明者努力由天然物质研制新型且强效的ACAT抑制剂、巨噬细胞-脂质复合物累积抑制剂以及肝病治疗剂，其结果是发现柚苷或柚苷配基具有强效ACAT抑制活性、巨噬细胞-脂质复合物累积抑制活性、以及对肝病的预防或治疗活性。
柚苷(C27H32O14，M.W.：580.53)和柚苷的配基——柚苷配基(C15H12O5，M.W：272.25)是存在于柠檬、葡萄柚、柑桔、枸橼和橙中的生物类黄酮(Horowitz，Gentili，Tetrahedron，19，773(1963))。
已有报道称，柚苷或柚苷配基具有抗癌、抗病毒和降低胆固醇的活性(Monforte，M.T.等人，Farmaco.，50(9)，595-599(1995，Sep.)；JP95-86929；JP 95-86930；Felicia，V.等人，J.Med.Virol.，15，71-79(1985)；EP 0352147 A2(1990.1.24)；以及Martin，M.J.等人，Pharmacal.，49，144-150(1994))。
另外，柚苷已被用作苦味剂、甜味剂或口香糖基质。
但是，目前尚没有人报道柚苷或柚苷配基的ACAT抑制活性、巨噬细胞-脂质复合物累积抑制活性、以及对肝病的预防或治疗活性。
发明简述
因此，本发明的目的是提供柚苷或柚苷配基抑制哺乳动物中ACAT活性的新用途。
本发明的另一个目的是提供柚苷或柚苷配基抑制哺乳动物中巨噬细胞-脂质复合物在动脉内皮壁上累积的新用途。
本发明的再一个目的是提供柚苷或柚苷配基预防或治疗哺乳动物中肝病的新用途。
附图简述
参考以下附图及描述，本发明的上述和其他目的及优点将更为显而易见，在附图中：
图1A、1B和1C显示了分别给药1％胆固醇、1％胆固醇及1mg/kgLovastatin、以及1％胆固醇及0.1％柚苷的兔动脉；以及
图2A、2B和2C代表分别给药1％胆固醇、1％胆固醇及1mg/kgLovastatin、以及1％胆固醇及0.1％柚苷的兔肝脏的显微特征。
发明详述
根据本发明的一个方面，其提供柚苷或柚苷配基抑制哺乳动物中酰基CoA-胆固醇-O-酰基转移酶(ACAT)活性的新用途。
根据本发明的另一个方面，其提供柚苷或柚苷配基抑制哺乳动物中巨噬细胞-脂质复合物在动脉内皮壁上累积的新用途。
根据本发明的再一个方面，其提供柚苷或柚苷配基预防或治疗哺乳动物中肝病的新用途。
柚苷和柚苷配基可从桔属植物的皮中提取，或者根据Zemplen，Bognar(Ber.，75，1043(1943))和Seka，Prosche(Monatsh.，69，284(1936))描述的方法来合成。另外，柚苷配基可通过水解柚苷来制得。
柚苷或柚苷配基在0.1mg/kg/天或更高的剂量时对ACAT活性和巨噬细胞-脂质复合物在动脉内皮壁上的累积具有抑制作用，而且对肝病具有预防和治疗作用，所述抑制作用随剂量而增加。
而且，尽管有强的效力，但柚苷或柚苷配基在鼠实验中几乎没有表现出毒性或促有丝***性。更具体而言，当以1000mg/kg的剂量给鼠口服给药时，柚苷或柚苷配基没有产生毒性，对于50kg重的人来说，上述剂量相当于口服给药50-100g柚苷或柚苷配基/kg体重。另外，柚苷和柚苷配基对肝功能没有副作用。
本发明还提供用于抑制ACAT活性和巨噬细胞-脂质复合物在动脉内皮壁上累积、以及预防或治疗肝病的药物组合物，该组合物包括柚苷或柚苷配基作为活性成分以及药物学上可接受的赋形剂、载体或稀释剂。
可根据任何常规方法来制备药物制剂。在制备制剂时，活性成分优选与载体混合或用载体稀释，或者包封在胶囊、小药囊或其他容器之形式的载体中。如果载体为稀释剂，其可为固体、半固体或液体物质，作为活性成分的载体、赋形剂或介质。因此，制剂可为片剂、丸剂、粉末、小药囊剂、甘香酒剂、混悬剂、乳剂、溶液、糖浆、气雾剂、软和硬明胶胶囊、无菌注射液、无菌包装的粉末等剂型。
合适的载体、赋形剂和稀释剂的例子是乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、***树胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石粉、硬脂酸镁和矿物油。药物制剂可另外包括填料、抗附聚剂、润滑剂、润湿剂、调味剂、乳化剂、防腐剂等。本发明的组合物可用任何本领域已知的方法配制成在给药于哺乳动物后快速、持续或延迟释放活性成分的制剂。
本发明的药物制剂可通过各种途径给药，包括口服、透皮、皮下、静脉和肌肉给药。对于人，柚苷或柚苷配基的典型日剂量是约0.1-100mg/kg体重，优选为3-10mg/kg，而且该剂量可以单剂量或多份剂量给药。
但应理解的是，实际给药的活性成分的量应根据各种相关因素来确定，所述因素包括待治疗的疾病、所选择的给药途径、每个患者的年龄、性别和体重、以及患者症状的严重程度；因此，上述剂量绝不是用于限制本发明的范围。
另外，柚苷或柚苷配基可掺入在食品或饮料中，作为添加剂或食物增补剂，用于抑制ACAT活性、抑制巨噬细胞-脂质复合物在动脉内皮上的累积和/或预防或治疗肝病。食品或饮料可包括肉食；汁液如蔬菜汁(例如胡萝卜汁和番茄汁)和果汁(例如橙汁、葡萄汁、菠萝汁、苹果汁和香蕉汁)；巧克力；小吃；糖果；意大利馅饼；由谷粉制成的食品，如面包、蛋糕、苏打饼干、曲奇饼干、饼干、面条等；口香糖；乳制品，如牛奶、乳酪、酸奶和冰淇淋；汤；肉汤；稀粥、番茄沙司和调味汁；茶；酒精饮料；碳酸饮料如开口可乐和百事可乐；维生素复合物；以及各种保健食品。
在此情况下，食品或饮料中的柚苷或柚苷配基含量可在0.01-5％重量之间。具体而言，每1000ml根据本发明的饮料可包含200-10000mg的柚苷或柚苷配基。
如上所述，柚苷或柚苷配基可用作有效抑制ACAT活性、抑制巨噬细胞-脂质复合物在动脉内皮上累积、和/或预防或治疗肝病的非毒性药物。
以下实施例用于进一步阐明本发明，而不是限制其范围。
另外，以下固体混合物中之固体、液体中之液体、以及液体中之固体的百分比分别是以wt/wt、vol/vol和wt/vol计算，而且所有的反应都是在室温下进行，除非另有说明。实施例1：从桔皮中提取柚苷
在室温下干燥柑桔(Cheju Island，Korea)、枸橼(Jeollanamdo，Korea)以及橙、葡萄柚和柠檬(California，CA，USA)的皮，然后粉碎成粒径为100-200μm的粉末。在500mg的上述各桔皮粉末中分别加入50ml的甲醇，然后在水浴中于50℃下提取6小时。冷却所得到的提取物，然后过滤，在滤液中添加甲醇至50ml的体积。
为证实如上制得的提取物中柚苷的含量，对0.5μl所述提取物进行高效液相色谱(HPLC)分析，其中使用Lichrosorb RP-8柱(5μm，4×250mm)，所述色谱柱用37％甲醇预平衡并保持在30℃下。提取物用37％甲醇以1.0ml/min的流速洗脱。将柚苷(Sigma Chemical Co.，USA)溶解在甲醇中，使得最终浓度分别为0.1、0.2、0.3、0.4、和0.5mg/ml，由此制备标准溶液，然后在相同的条件下进行HPLC分析。在280nm下用UV-VIS分光光度计检测洗脱液，并通过比较桔皮提取物和标准溶液的HPLC曲线面积来计算柚苷的含量。各种桔皮提取物中的柚苷含量(％)见表I所示。
表I
实施例2：口服给药柚苷或柚苷配基的毒性
| 柚苷(％) | |
| 橙 | 痕量 |
| 柠檬 | 痕量 |
| 柑桔 | 痕量 |
| 葡萄柚 | 4.70 |
| 枸橼 | 0.80 |
在22±1℃的温度、55±5％的湿度和光照周期12L/12D的条件下，饲养7-8周龄、无特定病原的ICR雌鼠(6只)和雄鼠(6只)，雌鼠重量在25-29g，雄鼠重量在34-38g。将饲料(Cheiljedang Co.，鼠饲料)和水消毒，然后喂给小鼠。
将柚苷或柚苷配基溶解在0.5％Tween 80中，至浓度为100mg/ml，然后将该溶液口服给药至小鼠，用量为0.2ml/20g小鼠体重。给药所述溶液后，按以下程序观察小鼠10天并记录副作用或死亡现象：给药后1、4、8和12小时，以后则每隔12小时观察。每天记录小鼠体重变化，以检查柚苷或柚苷配基的作用。另外，在第10天时，将小鼠处死，并肉眼检查内部器官。
在第10天时所有小鼠都存活，而且1000mg/kg剂量的柚苷或柚苷配基没有毒性。尸检结果是，小鼠没有形成任何病理非正常性，而且在10天的检查期间没有观察到体重减轻。因此，可得出以下结论：桔柚苷或柚苷配基在口服给药于动物时没有毒性。实施例3：向动物给药柚苷或柚苷配基
随机将体重为90-110g的30只4周龄Sprague-Dawley大鼠(Taihanlaboratory animal center，Korea)平均分成3个饮食组。三个组的大鼠分别用三种不同的高胆固醇食物喂养，即包含1％胆固醇的AIN-76实验室动物饲料(ICN Biochemicals，Cleveland，OH，USA)(对照组)，以及1％胆固醇加0.1％柚苷或柚苷配基。三个组所用饲料的成分见下表II。
表II
| 饲料成分 | 对照组 | 柚苷组 | 柚苷配基组 |
| 酪蛋白 | 20 | 20 | 20 |
| D，L-蛋氨酸 | 0.3 | 0.3 | 0.3 |
| 玉米淀粉 | 15 | 15 | 15 |
| 蔗糖 | 49 | 48.9 | 48.9 |
| 纤维素粉末*1 | 5 | 5 | 5 |
| 矿物质混合物*1 | 3.5 | 3.5 | 3.5 |
| 维生素混合物*1 | 1 | 1 | 1 |
| 重酒石酸胆碱 | 0.2 | 0.2 | 0.2 |
| 玉米油 | 5 | 5 | 5 |
| 胆固醇 | 1 | 1 | 1 |
| 柚苷*2 | 0.1 | ||
| 柚苷配基*2 | - | - | 0.1 |
| 总计 | 100 | 100 | 100 |
*1：从TEKLAD Premier Co.(Madison，WI，U.S.A.)购得
*2：从Sigma Chemical Co.(St.Louis，MO，U.S.A.)购得
无限制地用具体饲料和水喂养大鼠共6周，每日记录摄取量，然后每7天称重，并分析记录数据。所有大鼠都显示正常的生长速度，而且三个组之间在食物摄取量和体重增加方面没有显著差异。实施例4：血浆中总胆固醇、HDL-胆固醇和中性脂质含量的测定
以下测定向大鼠给药柚苷或柚苷配基对血浆胆固醇和中性脂质含量的影响。
从上三个组的大鼠中采取血样，并用包含葡萄糖硫酸酯的HDL-胆固醇试剂(Sigma Chemical Co.，Cat.No.352-3)从中分离血浆HDL成分。用Sigma Diagnostic Kit Cat.No.352-100(Sigma Chemical Co.，USA)测定总胆固醇和HDL-胆固醇浓度(Allain et al.，Clin.Chem.，20，470-475(1974))。用Sigma Diagnostic Kit Cat.No.339-50(SigmaChemical Co.，USA)测定中性脂质浓度(Bucolo，G.和David，H.，Clin.Chem.，19，476-482(1973))。结果见表III，其中，与对照组大鼠相比，柚苷和柚苷配基饲养组中大鼠的总血浆胆固醇浓度分别下降32％和18％。
表III
| 组脂质浓度 | 对照组 | 柚苷组 | 柚苷配基组 |
| 总胆固醇(mg/dl) | 147.8±34.8 | 100.8±16.1 | 120.9±25.9 |
| HDL-胆固醇(mg/dl) | 22.2 | 24.0 | 23.4 |
| HDL-胆固醇/总胆固醇(％) | 15.7±5.3 | 23.9±7.6 | 20.8±9.1 |
| TG(mg/dl) | 99.2±18.9 | 86.7±14.6 | 103.4±18.2 |
TG：甘油三酯实施例5：柚苷和柚苷配基在ACAT抑制中的活性(步骤1)制备微粒体
为确定用柚苷或柚苷配基饲养大鼠对ACAT活性的作用，从肝组织中制备微粒体作为酶源。
首先，将实施例3中的三组大鼠断头处死，并取出肝脏。分别将1g肝脏在5ml匀浆介质(50mM KH2PO4(pH7.4)，0.1 MEDTA，2mMβ-巯基乙醇)中均化。在4℃、3000×g下离心所述匀浆10分钟，然后在40℃、15000×g下离心所得到的上清液15分钟，由此得到上清液。将上清液放入超离心管(Beckman)中，并在100000×g、4℃下离心1小时，以得到微粒体沉淀物，然后将该沉淀物悬浮在3ml的匀浆介质中，并在4℃、100000×g下离心1小时。将由此得到的沉淀物悬浮在1ml匀浆介质中。用Lowry法测定所得悬浮液中蛋白质的含量，然后调节至4-8mg/ml。将所得悬浮液储存在深冷冻机(Biofreezer，Forma Scientific Inc.)中(步骤2)ACAT实验
在丙酮中将6.67μl的1mg/ml胆固醇丙酮溶液与6μl的10％TritonWR-1339(Sigma Co.)混合，然后通过使用氮气进行蒸发来除去丙酮。在所得的混合物中添加蒸馏水，其量是将胆固醇的浓度调节为30mg/ml。
在10μl得到的胆固醇水溶液中添加10μl的1M磷酸二氢钾(pH7.4)、5μl的0.6mM牛血清白蛋白(BSA)、10μl的步骤1中制得的微粒体溶液和55μl的蒸馏水(总共90μl)。在水浴中于37℃下预温育该混合物30分钟。
将10μl(1-14C)油酰-CoA溶液(0.05μCi，最终浓度10μM)添加至经预温育的混合物中，在水浴中于37℃下温育所得的混合物30分钟。在该混合物中添加500μl的异丙醇∶庚烷混合物(4∶1 v/v)、300μl的庚烷和200μl的0.1M磷酸二氢钾(pH7.4)，然后使用vortex剧烈搅拌混合物，并在室温下静置2分钟。
将200μl所得的上清液放入闪烁瓶中，并在其中添加4ml的闪烁液(Lumac)。用1450 Microbeta液体闪烁计数器(Wallacoy，Finland)对混合物进行放射活性分析。以每mg蛋白每分钟合成的胆固醇油酸酯的pmol数(pmoles/min/mg蛋白)计算ACAT活性。结果见表IV。
表IV
| 组 | ACAT活性(pmol/min/mg蛋白) | 对ACAT活性的抑制百分数 |
| 对照组 | 806.2±105.2 | 0 |
| 0.1％柚苷组 | 643.5±80.7 | 20.2 |
| 0.1％柚苷配基组 | 666.3±65.3 | 17.4 |
从表IV的结果可以看出，柚苷和柚苷配基组大鼠中ACAT活性分别低于对照组20.2％和17.4％。实施例6：在柚苷和柚苷配基饲养动物中对由巨噬细胞-脂质复合物导致的斑块形成的抑制作用(步骤1)向动物给药柚苷和柚苷配基
在20±2℃的温度、55±5％的相对湿度和光照周期12L/12D的条件下，饲养24只重量分别为2.5-2.6kg的3月龄新西兰白兔(YeonamHorticulture and Animal Husbandry College，Korea)。将上述兔子分为4个组，然后向4个组的兔子饲养4种不同的饲料，即分别是：包含1％胆固醇的RC4饲料(Oriental Yeast Co.，Japan)(对照组)；1％胆固醇及1mg/kg Lovastatin(Merck，USA)(对比组)；1％胆固醇及0.1％柚苷；以及1％胆固醇及0.1％柚苷配基。RC4饲料包含7.6％水分、22.8％粗蛋白、2.8％粗脂肪、8.8％粗灰、14.4％粗纤维素和43.6％可溶性无氮物质。兔子饲养6周，并可自由摄取饲料和水。(步骤2)分析动物动脉中的脂肪条纹
将步骤1中饲养的兔子杀死，然后切开胸部。由主动脉阀上1cm的部位开始向下切除长度约为5cm的主动脉，然后除去主动脉周围的脂肪。沿纵轴中间切开主动脉，并钉在板上。对湿的动脉进行照相，然后如下根据Esper，E.等人的方法(J.Lab.Clin.Med.，121，103-110(1993))对脂肪条纹进行染色。
用无水丙二醇在2分钟内洗涤一部分经切可的主动脉3次，然后用Oil Red O(ORO，Sigman Co.)的丙二醇饱和溶液染色30分钟。之后，用85％丙二醇溶液在3分钟内洗涤主动脉2次，以除去残留的染色溶液，再用生理盐水洗涤。对主动脉进行照相，并跟踪照相。用图象分析仪(LEICA，Q-600，Germany)测定染色区域(脂肪条纹区域)的面积，并计算与总主动脉面积的比例(％)。
另一方面，根据苏木精-曙红(H&E)和Masson′s三色染色法对主动脉的其他部分进行染色，然后在显微镜下观察，以证实巨噬细胞-脂质复合物是否累积在内膜、管腔中部、弹性层和中层。
另外，从兔子中采取血样，并根据与实施例4相同的方法测定总胆固醇和甘油三酯。
结果见表V所示。
表V
| 饲料组 | 总胆固醇(mg/dl) | 甘油三酯(mg/dl) | M-L*复合物面积(％) |
| 对照 | 1143 | 56 | 35 |
| 1mg/kg Lovastatin组 | 1210 | 66 | 5 |
| 0.1％柚苷组 | 1367 | 72 | 12 |
| 0.1％柚苷配基组 | 1350 | 70 | 13 |
*M-L复合物：巨噬细胞-脂质复合物
由表V可以看出，与对照组相比，1mg/ml Lovastatin、0.1％柚苷和0.1％柚苷配基组中累积在动脉内皮上的巨噬细胞-脂质复合物面积显著降低。因此，证实柚苷和柚苷配基可抑制巨噬细胞-脂质复合物在动脉内皮上的累积。具体而言，明显可以看出，在高于1100mg/dl的胆固醇血液浓度时柚苷和柚苷配基对巨噬细胞-脂质复合物的累积具有抑制活性，所述胆固醇浓度大大高于正常兔子的浓度，即、约50mg/dl。该结果提示有新的机制防止动脉粥样硬化的开始，这与HMG-CoA还原酶抑制剂阻断胆固醇合成、ACAT抑制剂阻断胆固醇吸收、或者CETP抑制剂阻断胆固醇转移不同。
图1A、1B和1C显示了分别给药1％胆固醇(对照组)；1％胆固醇及1mg/kg Lovastatin(对比组)；和1％胆固醇及0.1％柚苷的兔子的动脉。如图1A、1B和1C所示，在给药1％胆固醇的兔子的动脉内皮上观察到厚层的巨噬细胞-脂质复合物，而在给药1％胆固醇及1mg/kg Lovastatin、和1％胆固醇及0.1％柚苷的兔子的动脉内皮上几乎没有或者仅观察到较薄层的巨噬细胞-脂质复合物。
因此，可以得出以下结论：柚苷和柚苷配基可强烈地抑制巨噬细胞-脂质复合物在动脉内皮上的累积。实施例7：柚苷对肝病的预防(步骤1)向鼠给药柚苷
随机将20只重量为约90-110g的Sprague-Dawley大鼠(TaihanLaboratory Animal Center，Korea)平均分为二个饲料组。这2个组的大鼠分别喂以2种不同的高胆固醇饲料，即、包含1％胆固醇的AIN-76实验室动物饲料(ICN Biochemicals，Clevand，OH，USA)(对照组)；以及1％胆固醇及0.02％柚苷。2个组的饲料的组成见表VI所示。
表VI
| 饲料组成分 | 对照组 | 0.02％柚苷组 |
| 酪蛋白 | 20 | 20 |
| D，L-蛋氨酸 | 0.3 | 0.3 |
| 玉米淀粉 | 15 | 15 |
| 蔗糖 | 39 | 38.98 |
| 纤维素粉末*1 | 5 | 5 |
| 矿物质混合物*1 | 3.5 | 3.5 |
| 维生素混合物*1 | 1 | 1 |
| 重酒石酸胆碱 | 0.2 | 0.2 |
| 脂肪 | 15 | 15 |
| 胆固醇 | 1 | 1 |
| 柚苷*2 | - | 0.02 |
| 总计 | 100 | 100 |
*1：购自于TEKLAD Premier Co.(Madison，WI，USA)
*2：购自于Sigma Chemical Co.(St.Louis，MO，USA)
无限制地用具体饲料和水喂养大鼠共6周，每日记录摄取量，然后每7天称重，并分析记录数据。所有大鼠都显示正常的生长速度，而且二个组之间在食物摄取量和体重增加方面没有显著差异。(步骤2)测定血清GOT和GPT浓度
如下测定给药柚苷对鼠肝功能的作用。
从2个组的鼠中采取血液，然后根据Reitman和Frankel的方法(Reitman，S.和J.S.Frankel，Am.J.Clin.Pathol.，28，56(1956))测定血清GOT(谷氨酸-草酰乙酸转氨酶)和GPT(谷氨酸-丙酮酸转氨酶)。GOT和GPT是在肝脏和心脏中合成的，并在这些器官被损坏时释放在血液中。因此，GOT和GPT是肝功能的代表性指标，而高血清GOT和GPT浓度代表肝脏受到严重损伤。
结果显示，柚苷组的GOT和GPT浓度较对照组的分别低约30％和10％。(步骤3)使用兔子的实验
重复步骤1中的相同步骤，但使用30只重量分别为约2.5-2.6kg的3月龄新西兰白兔(Yeonam Horticulture and Animal Husbandry College，Korea)代替鼠，然后用3种不同的饲料分别喂养所述兔子，即、包含1％胆固醇的RC4饲料(对照组)；1％胆固醇及1mg/kg Lovastatin(对比组)；以及1％胆固醇及0.1％柚苷。
之后，从兔子中分离肝脏，并如下所述进行组织病理学观察。
肌肉注射***(75mg/kg)麻醉兔子，然后切开腹部。肉眼观察肝脏硬化的颜色和程度，并将从兔中分离的肝脏用10％中性缓冲***固定24小时以上。用水充分洗涤经固定的肝脏，分步用70％、80％、90％和100％乙醇脱水，然后嵌在石蜡中。用切片机将嵌入的肝脏切成4μm的厚度，并用苏木精和曙红染色。用二甲苯使经染色的肝脏样品呈透明状，用permount固定，然后用显微镜观察，以证实损伤的存在。
图2A、2B和2C分别代表了给药1％胆固醇(对照组)、1％胆固醇及1mg/kg Lovastatin(对比组)、和1％胆固醇及0.1％柚苷的兔子肝脏的显微特征。如图2A和2B所示，对照组和对比组的肝细胞为不规则地排列并增大，而且其中沉积大量的脂肪。相反地，如图2C所示，柚苷组的肝细胞为正常，而且没有观察到脂肪的沉积。该结果表明，柚苷强烈地抑制脂肪肝的发生，而且对肝细胞没有毒副作用。(步骤4)使用人的实验
以10mg/kg的剂量向一位55岁的男人给药柚苷共68天，并分别在开始给药之前(第0天)以及给药后的45和68天(第45和68天)时测定GOT、GPT和γGTP。其结果是，与第0天时的相比，第45和68天时的血清GOT浓度分别降低17％。与第0天时的相比，第45和68天时的血清GPT浓度分别降低15％和19％。而且，与第0天时的相比，第45和68天时的血清γGTP浓度分别降低25％和51％。令人惊奇的是，与第0天时的相比，血清γGTP浓度在第68天时降低50％以上。该结果表明，柚苷或柚苷配基对肝病如肝炎、脂肪肝和酒精性脂肪肝具有强效的肝保护活性。
另一方面，以6mg/kg的每日剂量向一位56岁的男性口服给药柚苷共30天，该男性每天习惯性地饮用100cc的酒精饮料，然后在给药之前(第0天)和给药之后30天(第30天)测定血清γGTP浓度。
其结果是，第0天时的初始血清γGTP浓度为129IU/1，而第30天时的浓度降低至69IU/1，达到了正常范围。该结果证实柚苷或柚苷配基对预防酒精性脂肪肝和肝硬变具有高活性。实施例9：包含柚苷或柚苷配基的食品
如下制造包含柚苷或柚苷配基的食品。
(1)制造番茄沙司和调味汁
将柚苷或柚苷配基添加至番茄沙司或调味汁中，其量为0.01-5wt％，以得到更有益于健康的番茄沙司或调味汁。
(2)制造小麦粉食品
将柚苷或柚苷配基添加至小麦粉食品中，其量为0.01-5wt％，并使用该混合物制造面包、蛋糕、曲奇饼干、苏打饼干、和面条，以得到更有益于健康的食品。
(3)制造汤和肉汁
将柚苷或柚苷配基添加至汤和肉汁中，其量为0.01-5wt％，以得到更有益于健康的汤和肉汁。
(4)制造牛肉末
将柚苷或柚苷配基添加至牛肉末中，其量为0.01-5wt％，以得到更有益于健康的牛肉末。
(5)制造乳制品
将柚苷或柚苷配基添加至牛奶中，其量为0.01-5wt％，然后使用该牛奶制造各种乳制品如黄油和冰淇淋。
但是，在制造乳酪时，将柚苷或柚苷配基添加至凝聚乳蛋白中；而在制造酸奶时，则将柚苷或柚苷配基添加至发酵后得到的凝聚乳蛋白中。实施例10：包含柚苷或柚苷配基的饮料
(1)制造蔬菜汁
将200-10000mg柚苷或柚苷配基添加至1000ml番茄或胡萝卜汁中，以制得更有益于健康的蔬菜汁。
(2)制造果汁
将200-10000mg柚苷或柚苷配基添加至1000ml苹果或葡萄汁中，以制得更有益于健康的果汁。
(3)制造碳酸饮料
将200-10000mg柚苷或柚苷配基添加至1000ml可口可乐或百事可乐中，以制得更有益于健康的碳酸饮料。
虽然已参考上述具体实施方案对本发明进行了描述，但应认识到，本领域技术人员在本发明的范围内还可进行各种改进和变化，而本发明的范围为以下权利要求书所限定。
Claims (8)
1、柚苷或柚苷配基在制备用于预防或治疗哺乳动物之脂肪肝的组合物中的应用。
2、如权利要求1所述的应用，其中，所述哺乳动物是人。
3、如权利要求1所述应用，其中，所述组合物选自于以下组中：药物组合物、食品组合物和饮料组合物。
4、如权利要求3所述的应用，其中，在食品组合物中包含的柚苷或柚苷配基的含量为0.01-5重量％。
5、如权利要求3所述的应用，其中，所述食品组合物是肉食、巧克力、小吃、糖果、意大利馅饼、由谷粉制成的食品、口香糖、乳制品、汤、肉汤、稀粥、番茄沙司、调味汁、维生素复合物、或保健食品。
6、如权利要求5所述的应用，其中，所述由谷粉制成的食品是面包、蛋糕、苏打饼干、曲奇饼干、饼干、或面条。
7、如权利要求3所述的应用，其中，所述饮料组合物是乳制品、蔬菜汁、果汁、茶、酒精饮料或碳酸饮料
8、如权利要求3所述的应用，其中，在饮料组合物中的柚苷或柚苷配基含量为每1000ml饮料200-10000mg。
Applications Claiming Priority (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019970055579A KR19990034090A (ko) | 1997-10-28 | 1997-10-28 | 나린진 또는 나린제닌을 포함하는 아실 코에이: 콜레스테롤-오르토-아실트랜스퍼레이즈 저해제 조성물 |
| KR55579/1997 | 1997-10-28 | ||
| KR10889/1998 | 1998-03-28 | ||
| KR1019980010889A KR19990076179A (ko) | 1998-03-28 | 1998-03-28 | 나린진을 포함하는 간 질환의 예방 및 치료용 조성물 |
| KR11450/1998 | 1998-04-01 | ||
| KR1019980011450A KR19990079062A (ko) | 1998-04-01 | 1998-04-01 | 나린진 또는 나린제닌을 포함하는 동맥경화증 예방 및 치료용조성물 |
| KR1019980012411A KR19990079683A (ko) | 1998-04-08 | 1998-04-08 | 감귤류의 과피 분말 또는 과피 추출물을 포함하는 기능성 건강식품 |
| KR12411/1998 | 1998-04-08 | ||
| KR13283/1998 | 1998-04-14 | ||
| KR1019980013283A KR19990080214A (ko) | 1998-04-14 | 1998-04-14 | 감귤류의 과피 추출물을 포함하는 건강개선용 기능성 음료 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1278171A CN1278171A (zh) | 2000-12-27 |
| CN1124134C true CN1124134C (zh) | 2003-10-15 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98810708A Expired - Fee Related CN1124134C (zh) | 1997-10-28 | 1998-10-20 | 柚苷和柚苷配基作为肝病的预防或治疗剂的应用 |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US6165984A (zh) |
| EP (1) | EP1032381B1 (zh) |
| JP (1) | JP2001520992A (zh) |
| CN (1) | CN1124134C (zh) |
| CA (1) | CA2307891A1 (zh) |
| DE (1) | DE69817862T2 (zh) |
| WO (1) | WO1999021548A1 (zh) |
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| US20040033480A1 (en) * | 2002-08-15 | 2004-02-19 | Wong Norman C.W. | Use of resveratrol to regulate expression of apolipoprotein A1 |
| ATE439848T1 (de) * | 2003-01-21 | 2009-09-15 | Wei-Wei Su | Verwendung von naringenin, naringin und salzen daraus als schleimlíser bei der behandlung von husten sowie zusammensetzungen daraus |
| WO2004064848A1 (fr) * | 2003-01-21 | 2004-08-05 | Wei-Wei Su | Utilisation de naringenine, de naringine et de leurs sels en tant qu'expectorants dans le traitement de la toux et compositions correspondantes |
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| US7846915B2 (en) * | 2004-10-20 | 2010-12-07 | Resverlogix Corporation | Stilbenes and chalcones for the prevention and treatment of cardiovascular diseases |
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| US20090118361A1 (en) * | 2006-05-17 | 2009-05-07 | Arkray, Inc. | Suppressor of expression of mcp-1, and ameliorating agent for inflammatory disease, pharmaceutical, supplement, food, beverage or food additive using the suppressor |
| CN101641339B (zh) | 2007-02-01 | 2013-07-17 | 雷斯韦洛吉克斯公司 | 用于预防和治疗心血管疾病的化合物 |
| US9314048B2 (en) | 2007-03-14 | 2016-04-19 | The Concentrate Manufacturing Company Of Ireland | Beverage products with non-nutritive sweetener and bitterant |
| KR101629356B1 (ko) | 2008-06-26 | 2016-06-13 | 리스버로직스 코퍼레이션 | 퀴나졸리논 유도체의 제조방법 |
| AU2010204106B2 (en) | 2009-01-08 | 2014-05-08 | Resverlogix Corp. | Compounds for the prevention and treatment of cardiovascular disease |
| MX2021012876A (es) | 2009-03-18 | 2022-06-23 | Resverlogix Corp | Nuevos agentes anti-inflamatorios. |
| ES2821018T3 (es) | 2009-04-22 | 2021-04-23 | Resverlogix Corp | Nuevos agentes antiinflamatorios |
| PT2515646T (pt) | 2009-11-02 | 2017-03-28 | Meda Ab | Composições que compreendem extractos que contêm flavonóides de plantas do género citrus e/ou flavonóides citrus isolados e agentes surfactantes catiónicos especificos, e para utilizar a referida composição como um agente para tratar infestações com piolho da cabeça |
| PT2773354T (pt) | 2011-11-01 | 2019-07-17 | Resverlogix Corp | Formulações orais de libertação imediata para quinazolinonas substituídas |
| US9073878B2 (en) | 2012-11-21 | 2015-07-07 | Zenith Epigenetics Corp. | Cyclic amines as bromodomain inhibitors |
| WO2014080291A2 (en) | 2012-11-21 | 2014-05-30 | Rvx Therapeutics Inc. | Biaryl derivatives as bromodomain inhibitors |
| AU2013365926B9 (en) | 2012-12-21 | 2019-01-17 | Zenith Epigenetics Ltd. | Novel heterocyclic compounds as bromodomain inhibitors |
| JP6429898B2 (ja) * | 2014-05-04 | 2018-11-28 | フイルメニツヒ ソシエテ アノニムＦｉｒｍｅｎｉｃｈ Ｓａ | フレーバー付きの食品製品および飲料製品 |
| US10111885B2 (en) | 2015-03-13 | 2018-10-30 | Resverlogix Corp. | Compositions and therapeutic methods for the treatment of complement-associated diseases |
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- 1998-10-20 CA CA002307891A patent/CA2307891A1/en not_active Abandoned
- 1998-10-20 EP EP98951776A patent/EP1032381B1/en not_active Expired - Lifetime
- 1998-10-20 JP JP2000517706A patent/JP2001520992A/ja active Pending
- 1998-10-20 DE DE69817862T patent/DE69817862T2/de not_active Expired - Fee Related
- 1998-10-20 WO PCT/KR1998/000323 patent/WO1999021548A1/en active IP Right Grant
- 1998-10-20 CN CN98810708A patent/CN1124134C/zh not_active Expired - Fee Related
- 1998-10-28 US US09/181,393 patent/US6165984A/en not_active Expired - Fee Related
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Also Published As
| Publication number | Publication date |
|---|---|
| EP1032381B1 (en) | 2003-09-03 |
| CA2307891A1 (en) | 1999-05-06 |
| DE69817862T2 (de) | 2004-07-15 |
| EP1032381A1 (en) | 2000-09-06 |
| DE69817862D1 (de) | 2003-10-09 |
| WO1999021548A1 (en) | 1999-05-06 |
| CN1278171A (zh) | 2000-12-27 |
| US6165984A (en) | 2000-12-26 |
| JP2001520992A (ja) | 2001-11-06 |
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