CN1322209A - 由柑桔属果皮衍生的作为胶原诱发性血小板聚集抑制剂的类黄酮化合物 - Google Patents
由柑桔属果皮衍生的作为胶原诱发性血小板聚集抑制剂的类黄酮化合物 Download PDFInfo
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- CN1322209A CN1322209A CN99811887A CN99811887A CN1322209A CN 1322209 A CN1322209 A CN 1322209A CN 99811887 A CN99811887 A CN 99811887A CN 99811887 A CN99811887 A CN 99811887A CN 1322209 A CN1322209 A CN 1322209A
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- flavonoids
- platelet aggregation
- collagen
- citrus peels
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
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Abstract
本发明涉及由柑桔属果皮衍生的类黄酮化合物在抑制哺乳动物的胶原诱发性血小板聚集中的应用。
Description
发明领域
本发明涉及由柑桔属果皮衍生的类黄酮化合物在哺乳动物中用于抑制胶原诱发性血小板聚集的应用。类黄酮化合物可以以药物组合物或食品组合物的形式施用给所述哺乳动物。
发明背景
若干种因子如胶原、二磷酸腺苷(ADP)、凝血酶、肾上腺素、瑞斯托菌素和花生四烯酸可以在血管上引起血小板聚集。譬如，当血管的上皮细胞受到损害时，上皮细胞下面的胶原暴露在血流下并且激活血小板。血小板的活化引发了反应级联，导致血栓形成和血小板聚集在血管上。这些可能诱发严重的循环性疾病，例如血栓形成、粥样硬化、脑中风和冠状动脉血栓栓塞。
迄今为止，为了预防此类血小板聚集业已开发出多种药物，例如血栓烷A2抑制剂，PGG/H合酶抑制剂、血管烷合酶抑制剂、血栓烷A2受体拮抗剂、噻氯匹定、GP Hb-IHa抑制剂和5-羟色胺拮抗剂。然而，这些药物对内部器官表现出多种不利副作用和致出血性能。
噻氯匹定及其类似物如氯吡格雷选择性抑制体内ADP诱发的血小板聚集，并由此有效治疗暂时性缺血性脑中风和外周动脉或缺血性心脏疾病(Hass，W.K.等人，
新英格兰医学杂志，
21，501(1989)；和Easton，J.D.，
药物，
42，39(1991))。然而，据报道这些药物具有有害副作用，例如脊髓抑制，增高总胆甾醇水平，腹泻，发疹和嗜中性白细胞减少症((McTavish，E.等人，
药物，
40，238(1990))；Hass，W.K.等人，同上；和Dunn C.D.R.，原稿报导(Scrip.Reports)
中风：趋势、治疗和市 场，PJB出版有限公司，133-139(1995))。
所以，仍然需要开发出对胶原诱发性血小板聚集具有高选择性抑制活性而且无发生有害副作用的血小板聚集抑制剂。
已知由柑桔属果皮提取出的类黄酮化合物如柚皮苷、柚皮素、桔皮苷和橙皮素(hesperetin)具有改善脂质代谢预防心血管疾病的作用，以及抗癌作用和抗病毒活性。特别是，迄今已报导桔皮苷和橙皮素都具有增强毛细血管、降低通透性、抗炎、抗病毒、降血压和降低胆甾醇的作用(Meyer，O.C.，
脉管学(Angiology)，
45，579-584(1994)；Struckmann，J.R.等人，
脉管学，
45，419-428(1994)；Matsubara，Y.等人，日本有机合成化学协会杂志(Japan Organic Synthesis Chem.Association Journal)，
52，318-327(1884，.3)；Galati，E.M.等人，
药理学(Farmaco.)，51(3)，219-221(1996，3)；Monforte，M.T.等人，
药理学，50(9)，595-599(1995，9)；JP 95-86929；JP 95-86930；Galati，E.M.等人，药理学，
40(11)，709-712(1994，11))。此外，有报导称，柚皮苷和柚皮素具有抗癌、抗溃疡和降胆甾醇作用(Monforte，M.T.等人，药理学，50(9)，595-599(1995，9)；JP 95-86929；JP 95-86930；Felicia，V.等人，
营养与癌症(Nutr.Cancer)，
26，167-181(1996)；EP 0352147A2(1990.1.24)；和Martin，M.J.等人，
药理学，
49，144-150(1994))。
另据报导，柚皮素抑制花生四烯酸诱发的血小板聚集(Corcazier，E.等人，
生物化学和生物物理学报，
835，315-321(1985))。
然而，迄今还未报导由柑桔属果皮获得的类黄酮化合物对于胶原诱发性血小板聚集的选择性抑制作用。
发明概述
所以，本发明的一个主要目的是提供胶原诱发性血小板聚集的抑制剂。
根据本发明，提供了由柑桔属果皮衍生的类黄酮化合物在抑制胶原诱发性血小板聚集中的应用。发明详述
按照本发明，由柑桔属果皮衍生的类黄酮化合物可以以药物组合物或食品组合物的形式给予哺乳动物。
所述柑桔属可以是柑橘、橙子、柠檬、葡萄柚或枳(
poncirus trifoliata)。
由柑桔属果皮衍生的类黄酮化合物包括柚皮苷、柚皮素、桔皮苷和橙皮素。也可以按照Zemplen.Bognar
Ber.，
75，1043(1943)和Seka，Prosche，
Monatsh，
69，284(1936)所述方法合成这些类黄酮化合物。此外，柚皮素和橙皮素分别可以通过水解柚皮苷和桔皮苷来制备。
类黄酮化合物对胶原诱发性血小板聚集和血栓形成具有选择性抑制活性。
此外，尽管其功效很强，但类黄酮化合物在动物试验中显示出低毒性或促有丝分裂性。具体而言，当以1,000mg/kg的剂量经口服给予小鼠时，类黄酮化合物无毒性，该剂量相当于3-10g/kg体重的口服给药剂量。而且，类黄酮化合物对肝功能无副作用。
本发明还提供用于抑制胶原诱发性血小板聚集的药物组合物，该组合物含有有效量的由柑桔属果皮衍生的类黄酮作为活性成分以及药学可接受赋形剂、载体或稀释剂。
所述药物制剂可以利用任何常规方法制备。在制剂的制备中，适宜将活性成分与载体混合或用载体稀释，或包封在载体中，载体可以是胶囊、小药囊或其他容器的形式。当载体起稀释剂的作用时，它可以是固体、半固体或液体物质，作用是充当活性成分的载体、赋形剂或介质。所以，制剂可以是片剂、丸剂、散剂、药囊、酏剂、混悬剂、乳剂、溶液、糖浆剂、气溶胶、软和硬明胶胶囊、灭菌可注射溶液、灭菌包装散剂等的形式。
适用的载体、赋形剂和稀释剂例如是：乳糖、葡萄糖、蔗糖、甘露糖醇、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、硬脂酸镁和矿物油。制剂可以另外含有填充剂、抗凝集剂、润滑剂、湿润剂、矫味剂、乳化剂、防腐剂恩公。可以利用所属领域已知的方法将本发明的组合物配制为在给予哺乳动物后快速、长效或延迟释放活性成分。
本发明的药物制剂可以经多种途径给药，其中包括口服、经皮、皮下、静脉内和肌肉内引入。在人的情况中，类黄酮化合物的典型日剂量可以是约0.5-100mg/kg体重，优选2-10mg/kg体重，并且可以以单剂量给药或分成多剂量给药。但应理解，活性成分的实际给药量应该根据多种相关因素而定，其中包括被治疗的病症、选择的给药途径、患者个体的年龄、性别和体重和患者症状的严重程度；所以，上述剂量应不以任何方式局限在本发明的范围内。
此外，可以将类黄酮化合物掺混在食品中作为添加剂或食品强化剂，用于抑制胶原诱发性血小板聚集。所以，本发明海提供一种用于一种胶原诱发性血小板聚集的食品组合物，其中含有有效量的所述类黄酮化合物。所述食品是指：肉；巧克力；快餐；甜食；比萨饼；由谷粉制成的食品，例如面包、蛋糕、苏打饼干、曲奇、饼干、面条等；树胶；奶制品，连日牛奶、乳酪、酸乳酪和冰淇淋；汤；肉汤；糊制品、番茄酱和调味汁；复合维生素；和多种保健食品。在这样的情况中，类黄酮化合物在食品中的含量可以是0.1-50％(重量)。
如上所述，黄酮可以用作有效、无毒的用于抑制胶原诱发性血小板聚集的药剂。下列实施例进一步说明本发明但不限定本发明的范围。
此外，下面给出的固体在固体混合物中、液体在液体混合物中、固体在液体中的百分比分别是基于重量/重量、体积/体积和重量/体积，并且所有反应是在室温下进行，除非另外具体说明。实施例1：类黄酮化合物在血小板聚集抑制中的活性
根据O’Brein(O’Brein JR.，
临床病理学杂志(J.Clin.Pathol.)，
15，452(1962))和Aok(Aok，H.等人，
麻醉学，
88，362(1998))所述方法，柑桔属果皮类黄酮化合物对于血小板聚集的抑制活性测定如下。
将9ml人血加入1ml的3.8％柠檬酸钠中并且令该混合物在1000rpm下离心10分钟。上清液用磷酸盐缓冲盐水(PBS)稀释至浓度为20000-400000血小板/mm3。分别将450μl的稀释血浆置于比色杯中，并且将5ul的黄酮溶液加入其中，除对照比色杯以外，所述黄酮溶液中柚皮苷、柚皮素、桔皮素和橙皮素溶解在二甲基亚砜中浓度为10mg/l。使该混合物在37℃下于血小板凝集仪(血小板aggrecoder II，PA-3220，Chronolog，U.S.A.)中加热3分钟。此后，向其中加入50ul促聚集溶液，即2mg/ml胶原溶液，100uM ADP，200uM肾上腺素或15mg/ml瑞斯托菌素。所得混合物在37℃下反应3分钟。随后测定它们的光密度。利用无血小板血浆测定出基线。
所以，柚皮苷、柚皮素、桔皮素和橙皮素均对胶原诱发性血小板聚集表现出抑制活性，但同时它们不抑制任何ADP-、肾上腺素-和瑞斯托菌素诱发的血小板聚集。柚皮苷、柚皮素、桔皮素和橙皮素分别抑制了59-85％、30-87％、59-93％和15-93％的胶原诱发性血小板聚集。这些结果表明，由柑桔属果皮衍生的类黄酮化合物选择性抑制胶原诱发性血小板聚集。实施例2：柑桔属果皮衍生的类黄酮化合物的口服给药毒性
在温度22±1℃、湿度55±5％和光周期12L/12D的条件下饲养各重约34-38g的7-8周龄、特定无病原体ICR雌性小鼠(8头)。将饲料(Cheiljedang Co.，小鼠和大鼠饲料)和水灭菌并且给小鼠喂食。
将柑桔属果皮衍生的类黄酮化合物柚皮苷或桔皮苷溶解在0.5％吐温80中至浓度为100mg/ml，该溶液经口服给予小鼠，给药量是0.2ml/20g小鼠体重。该溶液施用一次并且按照下列计划表观察10天副作用或死亡的迹象：给药后1、4、8和12小时，每12小时后。每天记录小鼠的体重变化以检查柑桔属果皮衍生类黄酮化合物的影响。此外，在第10天，处死小鼠并且目测检查内脏器官。
全部小鼠在第10天时都存在，并且柑桔属果皮衍生的类黄酮化合物在1000mg/kg的剂量下不具有毒性。尸体解剖显示，小鼠未恶化出现任何病理性异常，而且在10天的试验期间没有观察到体重减轻。因此，当经口服给予哺乳动物时，柑桔属果皮衍生的类黄酮化合物无毒。实施例3：含有柑桔属果皮衍生类黄酮化合物的药物制剂
采用下列组分制备硬明胶胶囊：
含量
(mg/胶囊)活性成分 200(柚皮苷、柚皮素、桔皮素或橙皮素)维生素C 100干燥淀粉 180硬脂酸镁 20总量 500mg实施例4：含有柑桔属果皮衍生类黄酮化合物的食品
含有柑桔属果皮类黄酮化合物的食品制备如下。
(1)番茄酱和调味汁
将柚皮苷、柚皮素、桔皮素或橙皮素以0.01-5(重量)％的量加入番茄酱或调味汁，获得保健番茄酱或调味汁。
(2)小麦面粉食品的制作
以0.01-5％(重量)的量将柚皮苷、柚皮素、桔皮素或橙皮素加入小麦面粉中，并且利用该混合物制成面包、蛋糕、曲奇、苏打饼干和面条，得到保健食品。
(3)汤和肉汁的制作
以0.01-5％(重量)的量将柚皮苷、柚皮素、桔皮素或橙皮素加入汤和肉汤中，得到保健汤和肉汤。
(4)以0.01-5％(重量)的量将柚皮苷、柚皮素、桔皮素或橙皮素加入碎牛肉中得到保健牛肉粉。
(5)乳制品的制作
以0.01-5％(重量)的量将柚皮苷、柚皮素、桔皮素或橙皮素加入牛奶中并且利用这种牛奶生产多种乳制品，例如奶油和冰淇淋。
然而，在乳酪的生产情况中，将柚皮苷、柚皮素、桔皮素或橙皮素加入凝固乳蛋白中；并且在生产酸乳酪的情况中，将柚皮苷、柚皮素、桔皮素或橙皮素加入发酵后获得的凝固乳蛋白中。
尽管本发明利用上述具体实施例进行描述，但是应理解，所属领域普通技术人员可以进行多种改进和变化，这些也属于本发明的范围内，本发明的范围如所附权利要求书限定。
Claims (7)
1.由柑桔属果皮衍生的类黄酮化合物在抑制哺乳动物的胶原诱发性血小板聚集中的应用。
2.权利要求1的应用，其中所述类黄酮化合物是柚皮苷、柚皮素、桔皮苷或橙皮素。
3.权利要求1的应用，其中所述柑桔属是柑橘、橙子、柠檬、葡萄柚或枳。
4.权利要求1的应用，其中哺乳动物是人。
5.权利要求1的应用，其中类黄酮化合物是以药物组合物或食品组合物的形式给药。
6.权利要求5的应用，其中在药物组合物中含有的类黄酮化合物的有效量是0.5-100mg/kg体重/天。
7.权利要求5的应用，其中在食品组合物中的类黄酮化合物的含量是0.1-50mg/kg体重/天。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/KR1999/000464 WO2001014396A1 (en) | 1999-08-19 | 1999-08-19 | Flavonoids derived from citrus peels as collagen-induced platelet aggregation inhibitor |
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| CN1322209A true CN1322209A (zh) | 2001-11-14 |
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ID=19570985
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99811887A Pending CN1322209A (zh) | 1999-08-19 | 1999-08-19 | 由柑桔属果皮衍生的作为胶原诱发性血小板聚集抑制剂的类黄酮化合物 |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1123304B1 (zh) |
| JP (1) | JP2003507486A (zh) |
| CN (1) | CN1322209A (zh) |
| CA (1) | CA2345618A1 (zh) |
| DE (1) | DE69911987T2 (zh) |
| WO (1) | WO2001014396A1 (zh) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005272456A (ja) * | 2004-02-24 | 2005-10-06 | Takara Shuzo Co Ltd | 血糖値降下剤又は便通改善剤 |
| NZ532666A (en) * | 2004-04-30 | 2008-03-28 | Ind Res Ltd | A method of promoting angiogenesis, or treating a disease or disorder where it is desirable to promote angiogenesis, comprising administering a therapeutically effective amount of an angiogenesis promoting extract of the skin of a citrus fruit to a non-human animal |
| KR100702567B1 (ko) * | 2004-06-09 | 2007-04-02 | 퓨리메드 주식회사 | 심근경색 발작 후 회복을 위한 지각 추출물 및 이를 함유하는 약학적 조성물과 건강 식품 |
| EP2368442B1 (en) | 2005-07-27 | 2014-12-17 | Symrise AG | Use of hesperetin for enhancing the sweet taste |
| JP2008297279A (ja) * | 2007-06-01 | 2008-12-11 | Kao Corp | 血管内皮機能改善剤 |
| JP2009234924A (ja) * | 2008-03-25 | 2009-10-15 | Kinji Ishida | 免疫回復剤及びそれを含有する飼料組成物 |
| JP2009234926A (ja) * | 2008-03-25 | 2009-10-15 | Kinji Ishida | 副腎肥大抑制剤及びそれを含有する飼料組成物又は治療用組成物 |
| WO2015199169A1 (ja) * | 2014-06-27 | 2015-12-30 | 国立大学法人九州大学 | カテキンの機能性増強法 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4842859A (en) * | 1986-09-08 | 1989-06-27 | Yaguang Liu | Pharmaceutical compositions for reducing hyperlipidemia and platelet-aggregation |
| EP0577143B1 (de) * | 1992-07-03 | 1999-01-27 | ALFATEC-PHARMA GmbH | Feste und flüssige Lösungen von Flavonoiden |
| JP4295840B2 (ja) * | 1997-12-09 | 2009-07-15 | 株式会社林原生物化学研究所 | 血行改善剤 |
-
1999
- 1999-08-19 CA CA002345618A patent/CA2345618A1/en not_active Abandoned
- 1999-08-19 JP JP2001518726A patent/JP2003507486A/ja active Pending
- 1999-08-19 EP EP99938643A patent/EP1123304B1/en not_active Expired - Lifetime
- 1999-08-19 WO PCT/KR1999/000464 patent/WO2001014396A1/en active IP Right Grant
- 1999-08-19 CN CN99811887A patent/CN1322209A/zh active Pending
- 1999-08-19 DE DE69911987T patent/DE69911987T2/de not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| EP1123304A1 (en) | 2001-08-16 |
| DE69911987D1 (de) | 2003-11-13 |
| CA2345618A1 (en) | 2001-03-01 |
| JP2003507486A (ja) | 2003-02-25 |
| EP1123304B1 (en) | 2003-10-08 |
| WO2001014396A1 (en) | 2001-03-01 |
| DE69911987T2 (de) | 2004-07-29 |
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