CN1106840C - 作为3－羟基－3－甲基戊二酰辅酶A(HMG－CoA)还原酶抑制剂的柚皮苷和柚苷配基 - Google Patents

作为3－羟基－3－甲基戊二酰辅酶A(HMG－CoA)还原酶抑制剂的柚皮苷和柚苷配基 Download PDF

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CN1106840C
CN1106840C CN97198802A CN97198802A CN1106840C CN 1106840 C CN1106840 C CN 1106840C CN 97198802 A CN97198802 A CN 97198802A CN 97198802 A CN97198802 A CN 97198802A CN 1106840 C CN1106840 C CN 1106840C
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卜成海
孙光熙
郑泰淑
权柄穆
金永国
崔度一
金成郁
裴基焕
朴镛福
崔明淑
黄仁奎
文锡植
权容国
安贞娥
李恩淑
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Abstract

本发明涉及一种用于抑制哺乳动物中3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶活性的药物组合物，其包括有效量之作为活性成分的柚皮苷或柚苷配基以及药物学上可接受的载体。本发明还涉及用于抑制哺乳动物中3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶活性的食品或饮料组合物，其包括有效量的柚皮苷或柚苷配基。

Description

作为3-羟基-3-甲基戊二酰辅酶A(HMG-CoA) 还原酶抑制剂的柚皮苷和柚苷配基
发明领域
本发明涉及抑制哺乳动物中3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶活性的药物组合物，该组合物包括有效量之作为活性成分的柚皮苷或柚苷配基以及药物学上可接受的载体，本发明还涉及用于抑制HMG-CoA还原酶活性的食品或饮料组合物，该组合物包含有效量的柚皮苷或柚苷配基。
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。另一种方法是降低在肝脏中进行的胆固醇的生物合成速率。已有报道称，高胆固醇血症可通过抑制HMG-CoA还原酶并由此降低胆固醇的生物合成速率来有效地治疗，所述HMG-CoA还原酶介导3，5-二羟基-3-甲基戊酸的合成，该化合物是甾醇或类异戊二烯之生物合成中的中间体(Cardiovascular Pharmacology，William W.Parmley and Kanu Chatterjee Ed.，Wolfe Publishing，pages 8.6-8.7，1994)。
因此，已进行了许多努力来研制可以抑制HMG-CoA还原酶的药物；其结果是已有几种从Penicillium sp.和Aspergillus sp.得到的化合物进入市场销售。具体而言，Merck Co.，USA研制的Lovastatin和Simvastatin以及Sankyo Co.，Japan研制的Pravastatin已在市场上销售(C.D.R.Dunn，Stroke：Trends，Treatment and Markets，SCRIPT Report，PJB Publications Ltd.，1995)。但是，这些药物非常昂贵，而且已知长期给药会诱发肝脏中肌酸激酶增加的副作用。因此，仍有必要继续研制价格低廉而且无毒性的HMG-CoA还原酶抑制剂。
柚皮苷和柚皮苷的糖苷配基--柚苷配基是在柠檬、葡萄柚、柑桔和橙(甜橙，Citrus sinensis)中发现的黄酮类似物，而且它们具有以下结构(Horowitz，Gentili，Tetrahedron，19，773(1963))： 柚苷配基
柚皮苷已被用作苦味剂、发汗剂(sweater)或口香糖基质。但是，尚没有报道称柚皮苷或柚苷配基具有HMG-CoA还原酶抑制剂的活性。
发明简述
因此，本发明的目的是提供一种用于抑制哺乳动物中HMG-CoA还原酶活性的药物组合物。
本发明的另一个目的是提供一种用于抑制哺乳动物中HMG-CoA还原酶活性的食品或饮料组合物。
根据本发明的一个方面，其提供一种用于抑制哺乳动物中3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶之活性的药物组合物，该组合物包括有效量之作为活性成分的柚皮苷或柚苷配基以及药物学上可接受的载体。发明详述
本发明提供一种用于抑制HMG-CoA还原酶活性的药物组合物，该组合物包括作为活性成分的柚皮苷或柚苷配基以及药物学上可接受的赋形剂、载体或稀释剂。
柚皮苷和柚苷配基可从柑桔属植物的皮中提取，或者根据Rosenmund(Rosenmund，Ber.，61，2608(1958))和Zemplen，Bognar(Ber.，75，648(1942))描述的方法进行合成。而柚苷配基则可通过水解柚皮苷来制备。
柚皮苷或柚苷配基在0.05mg/kg/天或更高的剂量时对HMG-CoA还原酶具有抑制作用，该抑制作用随剂量而增高。
而且，尽管有强的效力，但柚皮苷和柚苷配基在鼠实验中几乎没有表现出毒性或促有丝分裂性。更具体而言，当以1000mg/kg的剂量给鼠口服给药时，柚皮苷没有产生毒性，对于50kg重的人来说，上述剂量相当于口服给药50-100g柚皮苷/kg体重。另外，柚皮苷和柚苷配基对肝功能没有副作用。
可使用上述组合物根据任何常规方法来制备药物制剂。在制备制剂时，柚皮苷或柚苷配基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、阿拉伯树胶、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，柚皮苷或柚苷配基的典型日剂量是约0.05-300mg/kg体重，优选为0.5-30mg/kg，而且该剂量可以单剂量或多份剂量给药。但是应理解到，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，柚皮苷和柚苷配基可掺入在食品或饮料中，用于抑制HMG-CoA还原酶活性。因此，本发明还提供用于抑制HMG-CoA还原酶活性的食品或饮料组合物，该组合物包括有效量的柚皮苷或柚苷配基。
如上所述，柚皮苷或柚苷配基可用作有效抑制HMG-CoA还原酶活性的非毒性药物。
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：向动物给药柚皮苷和柚苷配基
随机将体重为90-11g的30只4周龄Sprague-Dawley小鼠(Taihanlaboratory animal center，Korea)平均分成3个组。三个组的小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)、1％胆固醇加0.1％柚皮苷(柚皮苷组)、以及1％胆固醇加0.1％柚苷配基(柚苷配基组)。三个组所用饲料的成分见下表I。
                         表I
饲料成分     对照组     柚皮苷组 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
柠檬酸胆碱     0.2     0.2     0.2
玉米油     5     5     5
胆固醇     1     1     1
柚皮苷*2     0.1
柚苷配基*2     0.1
总计     100     100     100
*1：从TEKLAD Premier Co.(Madison，WI，USA)购得*2：购自Sigma Chemical Company(St.Louis，MO，USA)
无限制地用具体饲料和水喂养小鼠共6周，每日记录摄取量，然后每7天称重，并分析记录数据。所有小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2：血浆中总胆固醇、HDL-胆固醇和中性脂质含量的测定
以下测定向小鼠给药柚皮苷和柚苷配基对血浆胆固醇和中性脂质含量的影响。
从上三个组的小鼠中采取血样，并用包含葡萄糖硫酸酯的HDL-胆固醇试剂(Sigma Chemical Co.，Cat.No.352-2)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.And David，H.，Clin.Chem.，19，476-482(1973))。结果见表II，其中，与对照组小鼠相比，柚皮苷饲养组中小鼠的总血浆胆固醇浓度下降32％，而柚苷配基饲养组中小鼠的总血浆胆固醇浓度下降18％。
                                 表II
 组    对照组     柚皮苷组     柚苷配基组
 总-C(mg/dl)    147.8±34.8     100.8±16.1     120.9±25.9
 HDL-C(mg/dl)    22.2     24.0     23.4
 HDL-C/总-C(％)    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
*总-C：总-胆固醇*HDL-C：HDL-胆固醇*TG：甘油三酯实施例3：柚皮苷和柚苷配基在HMG-CoA抑制中的活性(步骤1)制备微粒体
为确定用柚皮苷和柚苷配基饲养小鼠对HMG-CoA还原酶活性的作用，从肝组织中制备微粒体作为酶源，所述还原酶是调节肝脏中胆固醇之生物合成的酶。
首先，将上述三组小鼠断头处死，取出肝脏，并立即放置在冰冷却的匀浆介质(50mM KH2PO4(pH7.0)，0.2M蔗糖，2mM二硫苏糖醇(DTT))中。在匀浆介质(2ml介质/g肝脏)中用Waring混合器(三冲程的Potter-Elvehjem型玻璃匀浆器，带有一个马达驱动的Teflon研杵)使肝脏匀浆15秒。在15000×g下离心匀浆10分钟，由此得到的上清液在100000×g下离心75分钟，得到微粒体沉淀，然后将该沉淀重新悬浮在包含50mM EDTA的匀浆介质中，然后在100000×g下离心60分钟。用包含微粒体的上清液作为酶源。(步骤2)HMG-CoA还原酶实验
如下根据Shapiro等人的方法(Biochemical et Biophysica Acta，370，369-377(1974))使用[14C]HMG-CoA测定HMG-CoA还原酶的活性。
在37℃下活化含微粒体之上清液(步骤1中得到的)中的酶30分钟。在反应试管中加入20μl的HMG-CoA还原酶实验缓冲液(0.25MKH2PO4(pH7.0)，8.75mM EDTA，25mM DTT，0.45M KCl和0.25mg/mlBSA)、5μl的50mM NADPH、5μl的[14C]HMG-CoA(0.05μCi/试管，最终浓度120μM)和10μl之经活化的微粒体酶(0.03-0.04mg)，然后混合物在37℃下培育该混合物30分钟。在该混合物中加入10μl的6M盐酸，由此使反应停止，然后在37℃下培育该混合物15分钟，使产物(甲羟戊酸)完全内酯化。在10000×g下离心1分钟，由此除去沉淀物，然后将上清液用在硅胶60G TLC板(Altech，Inc.，Newark，USA)上，并用苯：丙酮(1∶1，v/v)展开。用一次性载玻片刮下Rf值在0.65-0.75之间的区域，并用1450 Microbeta液体闪烁计数器(Wallacoy，Finland)进行放射活性实验。以pmol合成的甲羟戊酸/分钟/mg蛋白计算酶活性。结果见表III。
                           表III
    组   对照组   柚皮苷组   柚苷配基组
HMG-CoA还原酶活性(pmol/min/mg蛋白)  147±12.5   111.1±14   101.4±7.3
从表III的结果可以看出，对照组小鼠具有相对较高的HMG-CoA还原酶活性，而柚皮苷饲养组和柚苷配基饲养组小鼠中观察到的HMG-CoA活性则分别低于对照组25％和31％。实施例4：口服给药柚皮苷的毒性
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(8只)和雄鼠(8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。
将柚皮苷溶解在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，以检查柚皮苷的作用。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剂量的柚皮苷没有毒性。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：柚皮苷在口服给药动物时没有毒性。
以下制剂实施例仅用于说明本发明，而绝不是限制本发明的范围。制剂实施例
使用以下成分制备硬明胶胶囊：
                                  量(mg/胶囊)活性成分(柚皮苷)                      20干燥淀粉                              160硬脂酸镁                              20总计                                  200mg
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 (2)

1.柚皮苷或柚苷配基在制备用于抑制哺乳动物的3-羟基-3-甲基戊二酰基CoA还原酶活性的组合物中的用途。
2.如权利要求1所述的用途，其中所述组合物选自药物组合物、食品组合物和饮料组合物。
CN97198802A 1996-10-14 1997-10-13 作为3－羟基－3－甲基戊二酰辅酶A(HMG－CoA)还原酶抑制剂的柚皮苷和柚苷配基 Expired - Fee Related CN1106840C (zh)

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Families Citing this family (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6239114B1 (en) * 1997-09-26 2001-05-29 Kgk Synergize Compositions and methods for treatment of neoplastic diseases with combinations of limonoids, flavonoids and tocotrienols
EP1032381B1 (en) * 1997-10-28 2003-09-03 Korea Institute Of Science And Technology Naringin and naringenin as preventive or treating agent for hepatic diseases
WO2000023073A1 (en) * 1998-10-20 2000-04-27 Korea Institute Of Science And Technology Bioflavonoids as plasma high density lipoprotein level increasing agent
JP2002535410A (ja) * 1999-01-27 2002-10-22 ザィエリンスキ，ラブラトリー 高められたバイオアベイラビリティーを有するヘスペレチンプロフォーム
US6797300B2 (en) * 1999-03-23 2004-09-28 Alejandro Mendez Composition for preserving fresh cut flowers, fresh fruits and vegetables without the use of refrigeration
US20050037116A1 (en) * 1999-03-23 2005-02-17 Alejandro Mendez Synthetic solution for preserving fresh flowers, fruits, and vegetables without the use of refrigeration, and method of producing same
US6123968A (en) * 1999-03-23 2000-09-26 Mendez; Alejandro Composition for extending shelf life for fresh fruits and vegetables without the use of refrigeration
KR100314668B1 (ko) * 1999-05-26 2001-11-17 은종방 감귤과피에서 펙틴과 헤스페리딘의 연속추출방법
US6426362B1 (en) 1999-10-08 2002-07-30 Galileo Laboratories, Inc. Formulations of tocopherols and methods of making and using them
US20020006953A1 (en) * 1999-11-05 2002-01-17 Carla R. McGill Modification of cholesterol concentrations with citus phytochemicals
WO2002026047A1 (en) * 2000-09-25 2002-04-04 Alejandro Mendez Composition for preserving fruits and vegetables, method of making said composition, and method of using said composition without refrigeration
AU2001232182A1 (en) * 2001-01-15 2002-07-24 Kgk Synergize Compositions and methods for regulating lipoproteins and hypercholesterolmia with limonoids flavonoids and tocotrienols
DE10122898A1 (de) * 2001-05-11 2002-11-14 Haarmann & Reimer Gmbh Verwendung von Hydroxyflavanonen zur Maskierung des bitteren Geschmacks
US8337914B2 (en) * 2002-02-27 2012-12-25 Access Business Group International Llc Dietary food supplement containing natural cyclooxygenase inhibitors and methods for inhibiting pain and inflammation
US20030170327A1 (en) * 2002-03-05 2003-09-11 Dahl Eva Marie Vitamin and zinc monomethionine compositions
KR20030082219A (ko) * 2002-04-17 2003-10-22 한국생명공학연구원 플라바논 에스테르 유도체 및 이를 포함하는 혈중 지질농도 관련 질환의 예방 및 치료용 조성물
FR2841472B1 (fr) * 2002-06-28 2006-02-24 Agronomique Inst Nat Rech Composition nutritionnelle ou therapeutique contenant le compose hesperidine ou l'un de ses derives
KR100479736B1 (ko) * 2002-06-28 2005-03-30 (주)바이오뉴트리젠 천연 식물체 유래의 혼합분말 또는 추출물을 포함하는 지방간 예방용 식품
US7867525B2 (en) * 2002-08-14 2011-01-11 Bionutrigen Co., Ltd. Powder or extracts of plant leaves with anti-obesity effects and anti-obesity food comprising them
US20050080021A1 (en) * 2002-08-15 2005-04-14 Joseph Tucker Nitric oxide donating derivatives of stilbenes, polyphenols and flavonoids for the treatment of cardiovascular disorders
US20040033480A1 (en) * 2002-08-15 2004-02-19 Wong Norman C.W. Use of resveratrol to regulate expression of apolipoprotein A1
US20050080024A1 (en) * 2002-08-15 2005-04-14 Joseph Tucker Nitric oxide donating derivatives for the treatment of cardiovascular disorders
JP2005130811A (ja) * 2003-10-31 2005-05-26 Yutaka Miyauchi 柑橘類の果皮を原材料とする液状飲用物
JP2005137204A (ja) * 2003-11-04 2005-06-02 Yutaka Miyauchi 液状飲用物
KR100702567B1 (ko) * 2004-06-09 2007-04-02 퓨리메드 주식회사 심근경색 발작 후 회복을 위한 지각 추출물 및 이를 함유하는 약학적 조성물과 건강 식품
JP4745764B2 (ja) * 2004-09-09 2011-08-10 花王株式会社 Ａｍｐｋ活性化剤
CN1760363B (zh) * 2004-10-14 2010-04-28 蒋继宏 杜仲3-羟基-3-甲基戊二酰辅酶a还原酶蛋白编码序列
EP1838296B1 (en) 2004-10-20 2012-08-08 Resverlogix Corp. Flavanoids and isoflavanoids for the prevention and treatment of cardiovascular diseases
GB2423928B (en) * 2004-11-16 2008-04-09 Efflux Technology Inc Methods and compositions for treating pain
US20070087977A1 (en) * 2004-11-16 2007-04-19 Wendye Robbins Methods and compositions for treating pain
EP2368442B1 (en) 2005-07-27 2014-12-17 Symrise AG Use of hesperetin for enhancing the sweet taste
CA2617213C (en) * 2005-07-29 2014-01-28 Resverlogix Corp. Pharmaceutical compositions for the prevention and treatment of complex diseases and their delivery by insertable medical devices
WO2007150063A2 (en) * 2006-06-23 2007-12-27 Cargill Incorporated Compositions for lowering blood serum cholesterol and use in foods, beverages, and health supplements
SI2118074T1 (sl) 2007-02-01 2014-05-30 Resverlogix Corp. Spojine za preprečevanje in zdravljenje kardiovaskularnih bolezni
JP2009256256A (ja) * 2008-04-18 2009-11-05 Kyushu Univ 組成物及び飲食品
PL2346837T3 (pl) 2008-06-26 2015-07-31 Resverlogix Corp Sposoby wytwarzania pochodnych chinazolinonu
US8952021B2 (en) 2009-01-08 2015-02-10 Resverlogix Corp. Compounds for the prevention and treatment of cardiovascular disease
CN105859639A (zh) 2009-03-18 2016-08-17 雷斯韦洛吉克斯公司 新的抗炎剂
SI2421533T1 (sl) 2009-04-22 2019-01-31 Resverlogix Corp. Nova protivnetna sredstva
US8323513B2 (en) * 2009-07-28 2012-12-04 Cp Kelco Aps Dewatering biomass material comprising polysaccharide, method for extracting polysaccharide from biomass material, and dewatered biomass material
US8877221B2 (en) 2010-10-27 2014-11-04 Warsaw Orthopedic, Inc. Osteoconductive matrices comprising calcium phosphate particles and statins and methods of using the same
US9107983B2 (en) 2010-10-27 2015-08-18 Warsaw Orthopedic, Inc. Osteoconductive matrices comprising statins
KR101444698B1 (ko) * 2010-12-30 2014-10-07 주식회사 엘지생명과학 위장관 운동 장애 질환의 개선, 치료 및 예방용 조성물
US9499640B2 (en) 2011-01-21 2016-11-22 Cp Kelco Aps Preservation of biomass material comprising polysaccharide and method for extracting polysaccharide from preserved biomass material
US9308190B2 (en) 2011-06-06 2016-04-12 Warsaw Orthopedic, Inc. Methods and compositions to enhance bone growth comprising a statin
CN103945848B (zh) 2011-11-01 2016-09-07 雷斯韦洛吉克斯公司 被取代的喹唑啉酮的口服即释制剂
WO2014080290A2 (en) 2012-11-21 2014-05-30 Rvx Therapeutics Inc. Cyclic amines as bromodomain inhibitors
WO2014080291A2 (en) 2012-11-21 2014-05-30 Rvx Therapeutics Inc. Biaryl derivatives as bromodomain inhibitors
CA2895905A1 (en) 2012-12-21 2014-06-26 Zenith Epigenetics Corp. Novel heterocyclic compounds as bromodomain inhibitors
CN103304610A (zh) * 2012-12-24 2013-09-18 李玉山 一种甲基橙皮苷的制备工艺
EA201591476A1 (ru) 2013-02-06 2016-02-29 Университет Брандайс Лечение повреждений днк и митохондриальной дисфункции с применением сока плодов масличной пальмы
CN103263427A (zh) * 2013-05-07 2013-08-28 浙江大学 新橙皮苷在制备防治高脂血症药物中的应用
US9132117B2 (en) 2013-06-17 2015-09-15 Kgk Synergize, Inc Compositions and methods for glycemic control of subjects with impaired fasting glucose
TWI634886B (zh) * 2014-08-22 2018-09-11 財團法人國防教育研究基金會 Compound composition for liver-free side effects with reduced liver fat for treating symptoms of non-alcoholic fatty liver disease (NAFLD)
JO3789B1 (ar) 2015-03-13 2021-01-31 Resverlogix Corp التراكيب والوسائل العلاجية المعتمدة لمعالجة الامراض المتعلقة بالمتممة
KR102139253B1 (ko) * 2018-05-04 2020-07-29 (주)노아스 시트러스 과피 추출물을 포함하는 카페인에 의한 수면장애 개선용 조성물
KR102113583B1 (ko) * 2019-10-25 2020-05-21 경희대학교 산학협력단 레몬 추출물 및 오렌지 추출물을 포함하는 카페인에 의한 수면장애 개선용 조성물
EP4247399A1 (en) * 2020-11-20 2023-09-27 Esserre Pharma Srl Composition comprising natural extracts and uses thereof
CN115896201B (zh) * 2023-01-09 2023-05-26 成都欧康医药股份有限公司 一种4-甲氧基-3,5`,7`-三羟基黄烷酮的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0185117A1 (de) * 1984-12-21 1986-06-25 IPEX Getränke-Herstellungs- und Vertriebsgesellschaft mbH Getränk
JPS63104920A (ja) * 1986-10-21 1988-05-10 Tsumura & Co アルド−スリダクタ−ゼ阻害剤
US5145839A (en) * 1988-06-23 1992-09-08 Mirko Beljanski Pharmaceutical composition and method of use
JP2003154569A (ja) * 2001-10-16 2003-05-27 Ralph Peter Hegler 波形プラスチックパイプの製造装置

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1179019A (en) * 1967-05-23 1970-01-28 Produits Chimique Soc Et Polynicotinic Esters of Flavonoids
US4277464A (en) * 1975-09-19 1981-07-07 General Foods Corporation Preventing tooth demineralization using aspartame
JPS54154569A (en) * 1978-05-20 1979-12-05 Lotte Co Ltd Chewing gum for sports
US4497842A (en) * 1982-01-18 1985-02-05 Ehrlich Joseph R Beverages obtained from alcoholic treatment of roasted citrus fruit peels
US4497838A (en) * 1982-02-17 1985-02-05 Tropicana Products, Inc. Process for the production of useful products from orange peel
JPS60214858A (ja) * 1984-04-09 1985-10-28 Toshio Horiuchi 血糖改善食品
DE3879688T2 (de) * 1987-12-10 1993-07-01 Tsumura & Co Anti-retrovirales arzneimittel.
EP0347864A3 (en) * 1988-06-24 1992-04-01 Andries Johannes Cornelus Strydom Anti-atherogenic agents
US4997658A (en) * 1988-11-21 1991-03-05 Merck & Co., Inc. Method for enhancing the lowering of plasma cholesterol levels
JPH03275625A (ja) * 1990-03-23 1991-12-06 Nippon Oil & Fats Co Ltd 制癌剤およびその製造法
JPH04295428A (ja) * 1991-03-22 1992-10-20 Dai Ichi Seiyaku Co Ltd 抗アレルギー剤
JPH04346933A (ja) * 1991-05-24 1992-12-02 Pokka Corp 虫歯菌、歯周病原菌増殖阻害剤
JP3159509B2 (ja) * 1992-03-30 2001-04-23 サンスター株式会社 プロテアーゼ阻害剤
AU6666594A (en) * 1993-04-20 1994-11-08 Procter & Gamble Company, The Methods of using hesperetin for sebum control and treatment of acne
JPH0725761A (ja) * 1993-07-09 1995-01-27 Kureha Chem Ind Co Ltd 軟骨保護剤
WO2000023073A1 (en) * 1998-10-20 2000-04-27 Korea Institute Of Science And Technology Bioflavonoids as plasma high density lipoprotein level increasing agent

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0185117A1 (de) * 1984-12-21 1986-06-25 IPEX Getränke-Herstellungs- und Vertriebsgesellschaft mbH Getränk
JPS63104920A (ja) * 1986-10-21 1988-05-10 Tsumura & Co アルド−スリダクタ−ゼ阻害剤
US5145839A (en) * 1988-06-23 1992-09-08 Mirko Beljanski Pharmaceutical composition and method of use
JP2003154569A (ja) * 2001-10-16 2003-05-27 Ralph Peter Hegler 波形プラスチックパイプの製造装置

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