CN116440143A - 预防或治疗脂肪肝的药物组合物 - Google Patents
预防或治疗脂肪肝的药物组合物 Download PDFInfo
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- CN116440143A CN116440143A CN202310336366.5A CN202310336366A CN116440143A CN 116440143 A CN116440143 A CN 116440143A CN 202310336366 A CN202310336366 A CN 202310336366A CN 116440143 A CN116440143 A CN 116440143A
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- Prior art keywords
- liver
- mannitol
- eriodictyol
- combination
- sucralose
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- 231100000240 steatosis hepatitis Toxicity 0.000 title claims abstract description 80
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- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 6
- 210000004185 liver Anatomy 0.000 claims abstract description 111
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 33
- 230000003908 liver function Effects 0.000 claims abstract description 25
- 239000000203 mixture Substances 0.000 claims abstract description 25
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- SBHXYTNGIZCORC-ZDUSSCGKSA-N eriodictyol Chemical compound C1([C@@H]2CC(=O)C3=C(O)C=C(C=C3O2)O)=CC=C(O)C(O)=C1 SBHXYTNGIZCORC-ZDUSSCGKSA-N 0.000 claims description 62
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Abstract
本发明涉及一种预防或治疗脂肪肝的药物组合物。具体地，本发明关于一种预防或治疗脂肪肝、保护肝功能、或改善脂肪肝引起的肝病变或其他相关病症的组合物及方法。
Description
本发明是中国专利申请号为201680021216.3，发明名称为“预防或治疗脂肪肝的药物组合物”，国际申请日为2016年3月31日的进入中国的PCT专利申请的分案申请。
技术领域
本发明关于一种预防或治疗脂肪肝、保护肝功能、或改善脂肪肝引起的肝病变或其他相关病症的组合物及方法。
背景技术
肝脏是动物体消化系统的一部分，也是许多消化液制造与分泌的主要器官，肝脏亦具有吸收、代谢、清除有毒物质及免疫保护等功能。肝脏是脂肪代谢的重要器官，在脂肪类食物上的消化、吸收、分解、合成以及运输的过程中扮演着极为重要的角色。肝脏由血液中所摄取的游离脂肪酸(free fatty acid，FFA)，最终会在肝脏中合成三酸甘油脂(triglyceride，TG)并储存起来，或以极低密度脂蛋白(very low density lipoprotein,VLDL)的形式将TG转运出肝脏进入血液循环中。因此，一旦肝脏受到损伤后，将导致脂质(尤指TG)在肝细胞内异常的代谢及堆积。
正常情况下脂肪约占肝脏重量的3％，临床上所谓“脂肪肝(fatty liverdisease，FLD)”是指肝脏内的脂肪重量超过肝脏重量的5％，或肝组织切片中超过10％以上的肝细胞有脂肪空泡变现象2。脂肪肝依照病因可区分酒精性脂肪肝(alcoholic fattyliver，AFLD)、非酒精性脂肪肝疾病(non-alcohol fatty liver disease，NAFLD)或其他因素，如药物，所衍生的脂肪肝疾病，病理学外观上包括脂肪变性(fatty metamorphosis orsteatosis)、脂肪性肝炎(steatohepatitis)等表征。轻度脂肪肝是指含脂肪变性的肝细胞少于33％，中度为介于33-66％，而重度则占66％以上3,9,21。过去大都被认为脂肪肝是较良性且可逆的病症，因此较不被重视，但近年来陆续的研究发现，其严重将引发肝脏纤维化及肝硬化，甚至是肝癌，且随着肥胖人口增加，有增加的趋势。
欧美国家主要肝脏疾病是因长期饮酒过量，因此，绝大部分肝脏疾病皆因酒精伤害所致。但近15-20年，NAFLD却成为欧美国家中，肝功能异常必先考虑的病因2。Thaler曾在1962年对NAFLD有所描述，1980年Ludwig在一群肥胖女性糖尿病及高脂血症患者中，发现伴随的NAFLD中提出“非酒精性脂性肝炎”(Non-alcoholic steatohepatitis，NASH)，随后在1986年Schaffner更再次强调NASH在NAFLD病程中衍生纤维化的机制中扮演着重要的角色21；直到1998年Day发现有15-50％的NASH患者衍生不同程度的纤维化4，NAFLD才开始受到临床医师的重视。如今，除了AFLD外，在临床上NASH不仅只是NAFLD自然病程发展中的一个阶段，也由于其存在使得NAFLD不再被视为一种良性的肝脏疾病。
目前在北美、南美、日本、北欧、南欧、澳洲及中东地区的FLD研究，发现至少有10-39％的盛行率，而死后病理解剖组织病理学检查中，NAFLD盛行率约在20％上下，其中所伴随的NASH的发现率约为3-18％不等；其中肥胖者中NAFLD的盛行率则高达57-74％(是正常人的4.6倍)，其中20-25％存有NASH病变，罹患肝硬化者亦占2-3％。中国台湾地区近三十年来，由于经济环境及饮食的改善，NAFLD盛行率亦有逐年增高趋势，近年来盛行率约12-37％，与日本的9-13％相较不远，其中非肥胖者盛行率约10％，而属病态肥胖者(BMI大于30者)盛行率则高达80％15,23。
有关NAFLD致病机转，英国Day与James根据大量临床及动物实验研究提出二次打击假说(Two-hit hypothesis)，第一次打击后出现脂肪肝(fatty liver)，第二次打击后则出现脂肪性肝炎(steatohepatitis)。第一次打击肇因于肝脏内脂肪的过度堆积，原因有肥胖、高血脂症等；第二次打击则是起因于氧化压力(oxidative stress)及粒线体中活性氧物种(Reactive oxygen species,ROS)作用，造成肝细胞膜上脂质过氧化(lipidperoxidation)，释放出原发炎细胞激素及自由基，活化星状细胞(stellate cells)产生纤维化，导致肝细胞患坏死4,5,19。而NASH的致病机转主要与三酸甘油脂过氧化作用、氧化压力、ROS反应、增加肝细胞本身脂质的过氧化反应、或与细胞激素及肝脏酵素的增进，导致一系列自体免疫的相互反应有关12。
脂肪肝的形成大多是长期摄取过多动物性脂肪、蛋白质、碳水化合物，过剩的热量在体内转化成脂肪囤积起来，导致肥胖及脂肪肝。脂肪肝患者血中的GOT/GPT数值可能都正常，要正确诊断脂肪肝，必须通过腹部超音波检查，目前准确率达97％以上。
目前FLD尚无特定疗效的理想治疗药物，治疗方针主要是改善潜在危险因子或使用药物控制慢性疾病的进展为主，建议依形成脂肪肝原因对症加以治疗，如：体重过重导致的脂肪肝，须适度减轻体重；酒精性脂肪肝，需靠戒酒及摄取均衡饮食才能改善；长期接触伤害肝脏的化学物质或药物，引起的脂肪肝，则须立即停止使用这些药物；疾病引起的脂肪肝，如C型肝炎、血脂肪过高等，须针对源头着手，治疗C肝、控制血脂；若是体质因素导致三酸甘油脂太高，则无法由减肥方式改善脂肪肝。
然而，目前临床常用降低血清中的三酸甘油脂、胆固醇的药品常伴随者肝毒性(hepatotoxicity)、肌痛、肌炎、横纹肌溶解等肌肉病变(myopathy)副作用，其中降血脂药物中，肌肉毒性是最值得关注的副作用，尤以舒脂锭(Statins)发生肌肉毒性比例最高，纤维酸(Fibric acid)次之。此外，降血脂药物具有“驱脂”作用，能将血液中的脂类“驱赶”到肝脏，而肝脏内本来就已有脂肪堆积，故对大量涌入的脂类难以进行处理，脂肪便会堆积在肝脏内，使得脂肪肝更加严重。由此可知降血脂用药并不适合用于治疗FLD。
因此，仍有需要寻求一种有效的预防及治疗脂肪肝、脂肪肝引起的肝病变、保护肝功能及改善相关病症的有效成分。
发明内容
本发明提出一或多种赋形剂(包括类黄酮化合物等)具有预防或治疗脂肪肝、保护肝功能、或改善脂肪肝引起的肝病变或其他相关病症的功效，该化合物选自以下所组成的群：硫酸月桂酸钠(sodium lauryl sulfate)、薄荷醇(menthol)、三氯蔗糖(sucralose)、甘露醇(mannitol)、山梨醇(sorbitol)、糖精(saccharin)、甘油(glycerin)、苯甲酸钠(sodium benzoate)、氧化铁红(oxide red)、预糊化淀粉(pregelatinized starch)、环己烷氨基磺酸钠(sodium cyclamate)、山梨酸(sorbic acid)、柠檬油(lemon oil)、柠檬酸(citric acid)、及丁基羟基茴香醚(butylated hydroxyanisole)、枸橘苷(poncirin)、异牡荆素(isovitexin)、圣草酚(eriodictyol)、麦角固醇(ergosterol)、月桂烯(β-myrcene)、金丝桃苷(hyperoside)、儿茶素((+)-catechin)、高良姜素(galangin)、桑叶素(morin)、金松双黄酮(sciadopitysin)、香风草甙(didymin)、棉纤维素(gossypin)、木犀草素-7-葡萄糖甙(luteolin-7-Glucoside)、双氢槲皮素((+)-taxifolin)、肉桂酸(trans-cinnamic acid)、香叶木素(diosmin)、蒙花甙(linarin)、木糖醇(xylitol)、木犀草素(luteolin)、獐牙菜苦素(swertiamarin)、及其任何组合。
因此，在一方面，本发明提出所述化合物用于制备预防或治疗脂肪肝、保护肝功能、或改善脂肪肝引起的肝病变或其他相关病症的组合物的用途。本发明也提出通过投用所述化合物以预防或治疗脂肪肝、保护肝功能、或改善脂肪肝引起的肝病变或其他相关病症的方法。
在部分具体实例中，该化合物选自于以下所组成群组：硫酸月桂酸钠(sodiumlauryl sulfate)、薄荷醇(menthol)、三氯蔗糖(sucralose)、甘露醇(mannitol)、山梨醇(sorbitol)、糖精(saccharin)、甘油(glycerin)、苯甲酸钠(sodium benzoate)、氧化铁红(oxide red)、预糊化淀粉(pregelatinized starch)、环己烷氨基磺酸钠(sodiumcyclamate)、山梨酸(sorbic acid)、柠檬油(lemon oil)、柠檬酸(citric acid)、及丁基羟基茴香醚(butylated hydroxyanisole)、及其任何组合。
在部分具体实例中，该化合物选自于以下所组成群组：枸橘苷(poncirin)、异牡荆素(isovitexin)、圣草酚(eriodictyol)、麦角固醇(ergosterol)、月桂烯(β-myrcene)、金丝桃苷(hyperoside)、儿茶素((+)-catechin)、高良姜素(galangin)、桑叶素(morin)、金松双黄酮(sciadopitysin)、香风草甙(didymin)、棉纤维素(gossypin)、木犀草素-7-葡萄糖甙(luteolin-7-Glucoside)、双氢槲皮素((+)-taxifolin)、肉桂酸(trans-cinnamicacid)、香叶木素(diosmin)、蒙花甙(linarin)、木糖醇(xylitol)、木犀草素(luteolin)、獐牙菜苦素(swertiamarin)、及其任何组合。
在部分具体实例中，该化合物选自于以下所组成群组：圣草酚(eriodictyol)、甘露醇(mannitol)、薄荷醇(menthol)、三氯蔗糖(sucralose)、糖精(saccharin)、及其任何组合。
在部分具体实例中，该化合物选自于以下所组成群组：(1)糖精与甘露醇的组合、(2)薄荷醇与甘露醇的组合、(3)三氯蔗糖与甘露醇的组合、(4)圣草酚与甘露醇的组合、(5)圣草酚与三氯蔗糖、(6)薄荷醇、甘露醇、圣草酚的组合、或(7)三氯蔗糖、甘露醇、圣草酚的组合。
在部分具体实例中，此处所述的一或多种化合物与选自于以下化合物之一或多者并用：葛根素(puerarin)、根皮苷(phloridzin)、甜橙黄酮(sinensetin)、(-)-表没食子儿茶素((-)-epigallocatechin)、山柰(kaempferol)、熊果酸(ursolic acid)、水飞蓟素、(silymarin)、(+)-柠檬油精((+)-limonene)、橙皮甙(hesperidin)、(-)-表儿茶素-3-没食子酸酯((-)-epicatechin-3-gallate)、水飞蓟宾(silybin)、芒柄花黄素(formononetin)、十四烷酸乙酯(myristic acid ethyl ester)、二十碳五烯酸(eicosapentaenoic acid,EPA)、汉黄芩素(wongonin)、聚维酮K-30(povidone K-30)、原儿茶酸(protocatechuicacid)、伞形酮(umbelliferone)、橙皮(hesperitin)、去甲二氢愈创木酸(nordihydroguaiaretic acid)、新橙皮苷(neohesperidin)、柚皮苷(naringin)、(-)-表儿茶素((-)-epicatechin)、甘草甜素(glycyrrhizin)、黄芩苷(baicalin)、斛皮素(quercitrin)、及黄芩甙元(baicalein)。
在部分具体实例中，本发明的化合物可降低个体的肝脂肪含量。
在部分具体实例中，本发明的化合物可降低个体的肝细胞的脂肪含量。
在部分具体实例中，本发明的化合物可降低个体的肝损害，例如，肝组织损害或肝功能损害。
在部分具体实例中，本发明的化合物可提高个体的肝脏抗氧化活性。
在部分具体实例中，本发明的化合物可用于改善因各种原因肝脂肪累积引起的相关病症，包括但不限于，脂肪肝、急性与慢性酒精性脂肪肝、急性与慢性非酒精性脂肪肝、急性与慢性酒精性肝炎、急性与慢性非酒精性脂肪肝炎、非酒精性肝硬化、酒精性肝硬化(ICD-9-CM诊断码571.8,571.0,571.1,571.2,571.3,571.4,571.5,571.9)。
在部分具体实例中，适用于本发明的化合物的个体是脂肪肝疾病的患者或肥胖者。
在部分具体实例中，本发明的化合物可制成药物、食品添加物或健康食品。
在又一方面，本发明提供一种组合物，其包括选自于以上所述的任何两种或以上的化合物。
在部分具体实例中，本发明的组合物包括选自于以下所组成的群组的任何两种或以上的化合物：圣草酚(eriodictyol)、甘露醇(mannitol)、薄荷醇(menthol)、三氯蔗糖(sucralose)及糖精(saccharin)。
在部分具体实例中，本发明的组合物包括选自于以下所组成的群组的组合：(1)糖精与甘露醇的组合、(2)薄荷醇与甘露醇的组合、(3)三氯蔗糖与甘露醇的组合、(4)圣草酚与甘露醇的组合、(5)圣草酚与三氯蔗糖、(6)薄荷醇、甘露醇、圣草酚的组合、或(7)三氯蔗糖、甘露醇、圣草酚的组合。
无须进一步的阐述，相信本发明所属技术领域中具有通常知识者基于前述说明即可利用本发明至最广的程度。因此，可以理解以下的说明仅仅是作为示例说明之用，而非以任何方式限制其余的揭露内容。
附图说明
欲说明本发明，图式具体实施例如下。然而，应理解到，本发明未局限于所示的较佳具体实施例。在图式中：
图1显示小鼠诱导产生脂肪肝后，再依组别给予不同的试验物质治疗4周后的肝脏组织切片。
具体实施方式
除非另有指明，所有在此处使用的技术性和科学性术语具有如同本发明所属技艺中的通常技术者一般所了解的意义。
本文所使用的“一”一词，如未特别指明，是指至少一个(一个或一个以上)的数量。
本发明揭示一或多种如上所述的化合物具有降低肝脂肪含量及改善相关病症的作用。因此，本发明提供一种所述的化合物在制备预防或治疗脂肪肝、保护肝功能、或改善脂肪肝引起的肝病变或其他相关病症的组合物的用途。本发明亦提供一种预防或治疗脂肪肝、保护肝功能、或改善脂肪肝引起的肝病变或其他相关病症的方法，其包括对有需要的个体投予有效量的所述的化合物。本发明亦提供可供预防或治疗脂肪肝、保护肝功能、或改善脂肪肝引起的肝病变或其他相关病症的组合物。
本文所使用的“肝脂肪含量”是指个体内累积于肝脏的脂肪含量，包括广义的脂质，例如，三酸甘油脂(triglyceride，TG)及胆固醇等。本文所使用的“降低肝脂肪含量”通常是指使个体内的异常肝脏脂肪含量降低，也就是使异常肝脏脂肪含量减少，更特定而言，是减少至正常水平。例如，正常情况下脂肪约占肝脏重量的3％，当肝脏内的脂肪重量超过肝脏重量的5％时则属于脂肪异常累积(上述肝脏脂肪含量为相对数值且为举例说明，可能因个体族群及其他因素有所变动)。在具体态样中，本文所使用的“降低肝脂肪含量”可指使个体内的异常肝脏脂肪含量降低，例如，从肝脏重量的5％或更高降至肝脏重量的3％。标准的分析方式可用以评估肝脂肪含量，包括但不限于，超音波分析、磁振造影MRI、磁共振频谱MRS、计算机断层扫描CT、肝脏病理切片。
本文所使用的“肝功能”是指是指一个或一个以上的由肝脏执行的许多生理功能，可由许多常规的试验予以分析，例如，丙胺酸转胺酶(alanine aminotransferase，ALT)分析或天冬氨酸氨基转移酶(aspartate transaminase，AST)分析。根据本发明，所述化合物可用以保护肝功能，包括，改善肝功能或避免肝功能的损坏。
本文所使用的“肝病变”可指肝脏细胞因某些因素受伤或被破坏，因而可能导致肝脏机能受到影响。根据本发明，所述化合物可用以改善由脂肪肝所引起的肝病变。更特定而言，本文所使用的“肝损伤”是指肝脏与正常肝脏相比有组织或生化功能受损的情形。在具体态样中，本文所使用的“肝损伤”是由酒精或非酒精性因素，例如，高脂饮食或肥胖，引起的肝损伤。在具体态样中，“肝损伤”可为肝脏的组织受损，可选自以下的一或多种特征：脂肪变性(steatosis)、肝小叶发炎(lobular inflammation)、肝脏细胞气球化(hepatocyteballooning)及肝脏细胞产生泡状脂肪油滴。在具体态样中，“肝损伤”可为肝脏的生化功能受损，可由血清中的丙胺酸转胺酶(alanine aminotransferase，ALT)或天冬氨酸氨基转移酶(aspartate transaminase，AST)活性予以判断，活性越高表示肝脏的生化功能受损越严重。
本文所使用的“肝脏抗氧化活性”是指肝脏中对抗氧化压力的活性或能力。根据本发明的化合物可提高个体的肝脏抗氧化活性是指，包括但不限于，降低氧化压力或提高抗氧化系统的成员的酵素活性或含量，该等抗氧化系统的成员可为麸胱甘肽过氧化酶(glutathione peroxidase，GPx)、榖胱甘肽(glutathione，GSH)、麸胱甘肽还原酶(glutathione reductase,GRd)、及/或超氧化物歧化酶(superoxide dismutase,SOD)。
根据本发明，所述的化合物包括常用的赋形剂及生物类黄酮，可用于降低肝脂肪含量及改善相关病症。此处所述的“相关病症”包括因肝脂肪累积异常导致的病症，包括但不限于，脂肪肝、急性与慢性酒精性脂肪肝、急性与慢性非酒精性脂肪肝、急性与慢性酒精性肝炎、急性与慢性非酒精性脂肪肝炎、非酒精性肝硬化、酒精性肝硬化(ICD-9-CMDiagnosis Code 571.8,571.0,571.1,571.2,571.3,571.4,571.5,571.9)。
本文所使用的“预防”一词是指对疾病、疾病的症状或病况的预防的或防止措施，包括但不限于，施加或投予一或多种活性药剂的至可能是尚未被诊断为罹患此疾病、疾病的症状或病况，但对其易感受或有其倾向的个体，其目的在于避免、阻止或推迟此疾病、疾病的症状或病况的发生。
本文所使用的“治疗”一词是指对疾病、疾病的症状或病况的治疗措施，包括但不限于，施加或投予一或多种活性药剂至具有此疾病、疾病的症状或病况、或疾病恶化的个体，其目的在于治疗、治愈、缓解、减轻、改变、补救、改善、改进、或影响此疾病、疾病的症状或病况、疾病引发的失能、或疾病恶化。
本文所使用的“个人”或“个体”等词包括人类或非人类动物，特地而言，为哺乳类动物，例如，陪伴动物(如狗、猫等)、农场动物(如牛、绵羊、猪、马等)、或实验动物(如大鼠、小鼠、天竺鼠等)。
本文所使用的“有效量”一词是指于接受处理的个体产生所欲的生物功效或医疗效果的活性成分的量，例如，降低个体的肝脂肪含量或改善相关病症。
为达输送及吸收目的，根据本发明的治疗有效量的活性成分可与医药上可接受载体配制成适当形式的医药组合物。依据投予模式，本发明的医药组合物较佳为包含约0.1％重至约100％重的活性成分，其中百分比重是以组合物的总重量为基准计算。
本文所使用的“医药上可接受”一词是指载体与组合物的活性成分相容(不影响活性成分的作用)，且较佳为可稳定该活性成分且对于接受治疗的个体具安全性。该载体可为活性成分的稀释剂、载剂、赋形剂、或介质。适用的赋形剂的一些实例包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、无菌水、糖浆、及甲基纤维素。本组合物可额外包含润滑剂如滑石、硬脂酸镁、及矿物油；润湿剂；乳化剂及悬浮剂；防腐剂如甲基及丙基羟基苯甲酸酯；增甜剂；以及调味剂。在投予至病患后，本发明的组合物可提供活性成分快速、持续、或缓慢释放的效果
依据本发明，该组合物的形式可任何形式，例如，为片剂、丸剂、粉剂、锭剂、囊剂、扁囊剂、酏剂、悬剂、乳液、溶液、糖浆、软与硬明胶胶囊、栓剂、无菌注射液、及包装粉剂。
本发明的组合物可经由任何生理上可接受途径输送，例如，口服、非口服(如肌内、静脉、皮下、及腹腔)、经皮、栓剂、及鼻内方法。关于非口服投予，较佳为使用无菌水溶液，其可包含其他物质，如足以使溶液与血液等张的盐类或葡萄糖。水溶液可视需求适当地经缓冲(较佳为具pH值3至9)。本领域的技术人员可由习知的标准药理学技术于无菌条件下制备适合的非口服组合物。
本发明通过下面的实施例进一步的说明，下面的实施例仅提供作为示范目的，而非限制本发明。本领域的技术人员应能根据本发明了解，不脱离本发明的精神和范围，而对本发明所公开的特定具体实施例中进行许多改变，仍然能获得相同或相似的结果。
实例
1.材料方法
1.1细胞株及细胞培养基
使用人类肝癌细胞株Hep G2分析本发明的各种化合物降低脂肪含量的活性。
使用DMEM(达尔伯克氏改良伊格尔培养基，Dulbecco’s Modified Eagle’sMedium)进行后续实验，共配制编号A-F的DMEM培养液，如表1所示。
表1：编号A-F的DMEM培养液的配制
编号A-F的DMEM培养液置于2-8℃保存，实验进行前放在37℃水浴槽中温热后使用。
1.2细胞计数及存活测试
0.4％台盼兰(trypan blue)会渗入死细胞中而呈色，活细胞则因细胞膜完整，染料无法渗入而不会呈色。取100μl细胞悬浮液与100μl 0.4％台盼兰等体积混合均匀。取少许混合液(约20μl)由血球计数盘室上方凹槽中加入，盖上盖坡片于光学显微镜下观察，活细胞不染色，死细胞则为蓝色。
1.3油酸诱导HepG2细胞株形成脂肪肝细胞
将15×106的HepG2细胞株培养于编号B的DMEM培养液，在37℃，5％ CO2的培养箱中培养24小时，然后再以编号C的DMEM培养液(无血清培养液))培养24小时，最后更换为编号D的DMEM培养液(含油酸酯/白蛋白复合物)继续培养48小时，使HepG2细胞株诱导为脂肪肝细胞。
1.4脂肪肝细胞的各组处理
将HepG2细胞株分成6组，包括：(1)空白组：未作任何处理；(2)DMSO组：空白组细胞加入二甲基亚砜(dimethyl sulfoxide，DMSO)；(3)对照组：以油酸诱导形成脂肪肝细胞；(4)载体组：以油酸诱导形成的脂肪肝细胞加入DMSO；(5)阳性对照组：脂肪肝细胞加入水飞蓟素；以及(6)试验组：脂肪肝细胞加入各种本发明的化合物。
1.5细胞的三酸甘油脂(TG)的测定
各组经处理的细胞于72小时培养后，以磷酸盐缓冲液(PBS)清洗两次，之后加入0.5mL胰蛋白酶/乙二胺四乙酸(trypsin/EDTA)培养3分钟，再加入2mL的PBS将细胞刮下，移到离心管中，以超音波将细胞震碎，取20μL细胞萃取液，测细胞内蛋白质含量。TG测定是用市售组合试剂(Randox)进行。将上述所得TG含量除以蛋白质含量所得比值，即代表细胞中TG的相对含量。
1.6试验动物
选择相关规定“健康食品的护肝保健功效评估方法”规范建议采用的试验动物B6小鼠，预试验每组试验动物只数≧4只，确认试验每组试验动物只数≧12只。雄性小鼠饲养于正常明暗周期(上午7:00到下午7:00为亮期，其余为暗期)，温度23±2℃，相对湿度55±15％的动物房内，体重为18-23g，由乐斯科(中国台湾台北)购买入相关机构，动物实验遵照相关机构实验指南进行。先以一般饲料每天喂食3-5g/日，饲养1-2周观察健康状态，水则无限供应，每周记录体重一次。
1.7动物组别
将试验动物随机分组，分为空白对照组(Blank)、高脂对照组(HFD)、正向对照组(Positive control，PS)与试验组。空白对照组给予正常饲料；高脂对照组给予高脂饲料；正向对照组给予高脂饲料与管喂水飞蓟素(5mg/kg/day)；以及试验组给予高脂饲料与管喂试验化合物。
1.8.试验方法
空白对照组以正常饲料任食12周，高脂对照组、正向对照组与试验组则以高脂饲料任食12周。开始喂食8周后，空白对照组与高脂对照组每天一次管喂给予去离子水；正向对照组每天一次管喂给予水飞蓟素；试验组每天一次管喂给予试验化合物，为期4周或8周。
试验开始前及试验开始后的第8、12或16周，以脸颊或心脏采血。最后于结束时秤重后全部牺牲，以脸颊或心脏采血。小鼠血液样品在室温下放置1小时以使其凝结。再以冷冻离心机于4℃下15,700x g离心5分钟，来分离血清，然后以血液自动生化分析仪检测肝功能生化指数，包括：天冬氨酸氨基转移酶(aspartate transaminase，AST)、丙胺酸转胺酶(alanine aminotransferase，ALT)、三酸甘油脂(TG)、总胆固醇(TCHO，TC)、低密度脂蛋白胆固醇(LDL-C)及高密度脂蛋白胆固醇(HDL-C)。
此外，牺牲后的小鼠剖腹取腹部脂肪及肝脏标本，秤重后比较其脂肪重、肝重及肝重/体重比值，并将最大右叶肝割取两块约l公分立方的组织块，固定于10％的中性福尔马林(formalin)液中，石蜡包封切片后分别作H&E染色来进行组织病理学观察。另外，将其余肝脏冷冻保，检测肝脏中三酸甘油脂及总胆固醇的含量。另，利用美国食品及药物管理局及相关机构认可，推荐给临床使用的定量肝脏剩余功能的半乳糖单点测定法(GalactoseSingle Point Method)分析各组动物的肝功能，其在试验结束时，依动物体重每公斤给于0.5g半乳糖溶液(0.4g/mL)，经由静脉给药，投药完毕后60分钟以滤纸取大约0.5ml全血，评估小鼠肝功能。GSP值愈高，表示肝脏剩余功能愈差(FDA:“Guidance forIndustry:Pharmacokinetics in Patients with Impaired.Hepatic Function—StudyDesign,Data Analysis and Impact on Dosing and.Labeling.2003)。
1.9组织病理组织切片：
试验结束时，所有小鼠均予以牺牲，于最大右叶肝割取一块约l公分立方的组织块，放入10％的中性福尔马林中固定，接着以不同浓度的乙醇(30、50、70、95、99.5％)以及二甲苯(xylene)进行脱水与透明步骤，然后以热石腊溶液取代二甲苯，最后以石蜡溶液将组织进行包埋。完成的石蜡标本利用切片机切成5μm的石蜡切片，将切片沾黏在干净载玻片上，于37℃烘干后，用做进一步H&E染色。
1.10苏木紫-伊红染色(hematoxylin and eosin stain，H&E)染色法
将肝脏组织切片置入二甲苯30分钟脱蜡，再依序置于99.5、95、70、50及30％乙醇各30分钟以进行复水，再浸泡于蒸馏水10分钟后即可染色。首先浸泡苏木精30秒染细胞核，再用蒸馏水清洗数分钟，接着使用伊红染色2-5分钟，用蒸馏水清洗数分钟。完成染色过程后进行脱水流程，依序放置于50、70、95及100％酒精两次中各30秒，再以二甲苯进行透明化两次，最后以封片胶封存。
1.11组织病理学的观察
为观察肝损伤时，肝细胞的受损、脂肪堆积、坏死或是否有纤维化等变化，将肝组织做H&E染色以评估肝脂肪堆积程度。为避免观察主观上的偏差，所有的组织病理切片都是由最大右叶肝的同一位置切取下来，再去做病理染色。至于病理的半定量分析的评估，应由人医或兽医病理医师进行双盲分析确认，在不清楚本实验设计的情况下，对所有切片进行评分比较(NAS score)16，最后再以统计分析方法进行各组差异性的分析。
1.12肝脏抗氧化分析
取牺牲动物的肝组织约0.1克，以匀浆器(biomasher)离心均质10分钟，再加入9倍肝重(w/w)的缓冲液(pH 7.4，50mmol/L Tris–HCl，180mmol/L KCl)，再以试管震动机(Vortex)混匀备用。取所得的肝组织均质液样品进行各种肝抗氧化系统成员的分析，包括麸胱甘肽过氧化酶(glutathione peroxidase，GPx)、榖胱甘肽(glutathione，GSH)、麸胱甘肽还原酶(glutathione reductase,GRd)、及超氧化物歧化酶(superoxide dismutase,SOD)，相关分析方式可参见已知文献，如(相关机构公布的健康食品的护肝保健功效评估方法草案)。
1.13统计分析
所有的数据皆以平均±标准偏差(SD)表示，试验结果以单因子变异数分析(ANOVA)测试法来计算是否具有统计上的显著差异，使用社会科学统计软件包(Statistical Package of the Social Science program，Version 13,SPSS Inc.)来计算；随后使用事后比较(post hoc test)最小差异显著性(least significantdifference)方法做多重比较，以确认族群间的显著差异；族群平均的显著差异为p<0.05。
2.结果
2.1细胞实验
在细胞实验中，阳性对照组(水飞蓟素)所测出降低HepG2细胞TG含量结果如表2所示。
表2：阳性对照组的水飞蓟素降低HepG2脂肪细胞中TG含量的作用
以固定试验化合物的测试浓度，所测出降低HepG2脂肪细胞TG含量的结果如表3所示。结果显示，在固定测试浓度条件下，与对照组相比，试验化合物对HepG2细胞经诱导形成的脂肪肝细胞展现不同程度的降低肝细胞TG含量的效果。TG降低率(％)计算公式为：[1-(试验组TG含量-空白组TG含量)/(油酸诱导组TG含量-空白组TG含量)]x 100％。
表3：试验化合物可降低脂肪肝细胞的TG含量
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表3-1：来自表3的部分试验化合物可降低脂肪肝细胞的TG含量
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表3-2：来自表3的部分试验化合物(生物类黄酮)可降低脂肪肝细胞的TG含量
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表3-3：来自表3的部分试验化合物(赋形剂)可降低脂肪肝细胞的TG含量
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2.2动物实验
在动物实验中，除空白组给予正常饲料外，其余动物给予诱导脂肪肝处理，8周后，各组动物除维持给予原饲料外，再给予不同处理达4周或8周，其中，空白对照组及高脂对照组给予去离子水，正向对照组给予水飞蓟素，以及试验组给予不同试验化合物，包括葛根素、根皮苷、圣草酚、三氯蔗糖、甘露醇、糖精、橙皮、薄荷醇、或部分试验化合物的组合。
2.2.1试验化合物对动物体重、肝重、体脂肪重的影响及安全性评估
动物实验的结果显示，各组间动物的肝重、体脂肪重与体重增加量结果如表4-1与4-2。
表4-1：试验化合物的肝重、体脂肪重分析结果。
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表4-2：试验化合物的体重增加量分析结果。
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结果显示，诱导脂肪肝动物腹部脂肪重量增加，在投予单一试验化合物时，甘露醇、薄荷醇、及三氯蔗糖可显著降低动物腹部脂肪重量。
此外，试验组投予不同试验化合物后，动物无任何异常症状，试验期间无造成任何动物的死亡，试验后牺牲动物剖检，亦无观察到因试验化合物所造成的病变或临床征状的发生，故该等试验化合物安全无虞。
2.2.2试验化合物具降低肝脏脂质的作用
图1显示诱导脂肪肝小鼠，在肝门管区(包括胆管、门静脉、肝动脉)附近肝脏细胞布满许多大泡状脂肪油滴，肝细胞出现气球化，成功诱导产生脂肪肝动物模式。
动物实验的结果显示，多种试验化合物在为期4周或8周的给药期间后，显示降低动物肝脏脂质的作用。结果显示于表5-1及表5-2。
表5-1：试验化合物可降低动物的肝脏脂质(4周的给药期间)
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表5-2：试验化合物可降低动物的肝脏脂质(8周的给药期间)
结果显示，诱导脂肪肝小鼠肝脏中的三酸甘油酯及总胆固醇上升。在投予单一试验化合物时，橙皮、葛根素、圣草酚、根皮苷、甘露醇、薄荷醇、及三氯蔗糖可显著降低肝脏中的三酸甘油酯；尤其，圣草酚处理4周时，达优异效果，可降低约67％肝脏三酸甘油酯含量(p<0.005)。此外，橙皮、圣草酚、根皮苷、甘露醇、薄荷醇、三氯蔗糖、糖精可显著降低肝脏中的总胆固醇；尤其，糖精处理4周时，达优异效果，可降低约56％肝脏总胆固醇含量(p<0.005)。
在投予二种试验化合物的组合时，糖精与甘露醇的组合、薄荷醇与甘露醇的组合、三氯蔗糖与甘露醇的组合、圣草酚与甘露醇的组合、或圣草酚与三氯蔗糖的组合，可有效降低肝脏中的三酸甘油酯；尤其，薄荷醇与甘露醇的组合处理4周时，达优异效果，可降低约77％肝脏三酸甘油酯含量(p<0.005)；圣草酚与三氯蔗糖的组合处理8周时，达优异效果，可降低约78％肝脏三酸甘油酯含量(p<0.005)。此外，三氯蔗糖与甘露醇的组合、圣草酚与甘露醇的组合、或圣草酚与三氯蔗糖的组合，可显著降低肝脏中的总胆固醇；其中，圣草酚与三氯蔗糖的组合处理8周时，达优异效果，可降低约77％肝脏总胆固醇含量(p<0.005)。
在投予三种试验化合物的组合时，薄荷醇、甘露醇、圣草酚的组合、三氯蔗糖、甘露醇、圣草酚的组合，可有效降低肝脏中的三酸甘油酯；尤其，三氯蔗糖、甘露醇、圣草酚的组合处理8周时，达优异效果，可降低约79％肝脏三酸甘油酯含量(p<0.005)。此外，三氯蔗糖、甘露醇、圣草酚的组合，可显著降低肝脏中的总胆固醇。
2.2.3试验化合物具降低肝损伤的作用
2.2.3.1降低肝组织的脂肪肝及肝损伤的作用
动物实验的结果显示，多种试验化合物在为期4周的试验期间显示可降低动物的脂肪肝及肝组织损伤情形。图1显示，脂肪肝动物肝组织损伤，包括在肝门管区(包括胆管、门静脉、肝动脉)附近肝脏细胞布满许多大泡状脂肪油滴，肝细胞出现气球化。相较之下，经水飞蓟素、薄荷醇、圣草酚、或甘露醇治疗4周后，肝脏组织切片在肝脏细胞内大泡状脂肪油滴大量减少，其中，经水飞蓟素治疗的小鼠仍观察到部分小破状油滴，但经薄荷醇、圣草酚、或甘露醇治疗的小鼠的肝脏组织型态比较接近空白组，表示脂肪肝病变比较轻微。此外，NAS评分结果显示于表6。
表6：试验化合物可降低动物的肝损伤情形
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NAS(Nonalcoholic Fatty Liver Disease Activity Score)分数指的是非酒精性脂肪肝病活性分数[Hepatology.2005Jun；41(6):1313-21.]，综合评估脂肪变性(steatosis)、肝小叶发炎(lobular inflammation)及肝脏细胞气球化(hepatocyteballooning)程度，评分表如表7，分数越高表示肝损伤越严重。
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结果显示，诱导脂肪肝小鼠肝组织损伤(NAS分数上升)。在投予单一试验化合物时，圣草酚与甘露醇可显著降低肝损伤。值得注意的是，在投予二种试验化合物的组合时，薄荷醇与甘露醇的组合，达优异效果，几乎未显现肝损伤，其NAS分数与空白组相同。
2.2.3.2降低肝功能损伤的作用
动物实验的结果显示，多种试验化合物在为期4周或8周的给药期间显示可降低动物的肝功能损伤情形。结果显示于表8-1及表8-2。
表8-1：试验化合物可降低动物的肝功能损伤情形(4周的给药期间)
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表8-2：试验化合物可降低动物的肝功能损伤情形(8周的给药期间)
ALT和AST是最常用来反映肝脏生化功能损伤的酶指针。这些酶正常情况下存在于肝细胞内，当肝细胞受到破坏时便会泄露出来，血清中的ALT和AST数值上升通常可反映肝发炎及肝功能有损伤情形。
结果显示，诱导脂肪肝动物肝功能受损(ALT和AST数值上升)。在投予单一试验化合物时，橙皮、葛根素、圣草酚、根皮苷、甘露醇、薄荷醇、三氯蔗糖、及糖精均可显著降低ALT和AST数值。尤其，甘露醇处理4周时，达优异效果，可降低约64％ALT数值(p<0.005)及约60％ AST数值(p<0.005)。
在投予二种试验化合物的组合时，薄荷醇与甘露醇的组合或圣草酚与三氯蔗糖的组合可显著降低ALT数值；薄荷醇与甘露醇的组合、三氯蔗糖与甘露醇的组合、或糖精与甘露醇的组合，可显著降低AST数值。尤其，薄荷醇与甘露醇的组合处理4周时，达优异效果，可降低约76％ALT数值(p<0.005)及约62％ AST数值(p<0.005)。
在投予三种试验化合物的组合时，三氯蔗糖、甘露醇、圣草酚的组合可显著降低ALT数值(p<0.005)。
2.2.4试验化合物具提高肝脏抗氧化能力
动物实验的结果显示，多种试验化合物在为期4周的试验期间显示可提升动物肝脏抗氧化能力。结果显示于表9-1及表9-2。
表9-1：试验化合物可提升动物肝脏抗氧化能力(Gpx及GSH)
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表9-2：试验化合物可提升动物肝脏抗氧化能力(Grd及SOD)
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Gpx、GSH、Grd及SOD是常见的肝脏抗氧化系统成员，可降低肝脏的氧化压力，使肝脏免于受到氧化压力导致的伤害。Gpx、GSH、Grd及SOD的数值提高代表肝脏维持较佳的抗氧化活性。
结果显示，诱导脂肪肝小鼠动物抗氧化活性降低。在投予单一试验化合物时，橙皮、葛根素、圣草酚、根皮苷、甘露醇、三氯蔗糖均可显著提高脏抗氧化活性。尤其，甘露醇处理4周时，达优异效果，大幅提高Gpx、GSH、Grd及SOD的水平(p<0.005)。
综上，本发明所提供的化合物可降低肝脂肪含量、降低肝损伤及提高肝脏抗氧化活性。该等化合物属于低分子天然植物酚类化合物，广泛存在于蔬果、谷物、根茎、花卉、茶叶与红葡萄酒等，经动物试验确认安全无虞，具有发展成为降肝脂、改善相关病症，如脂肪肝、急性与慢性酒精性脂肪肝、急性与慢性非酒精性脂肪肝(Non-alcoholic Fatty LiverDisease,NAFLD)、急性与慢性酒精性肝炎、急性与慢性非酒精性脂肪肝炎、非酒精性肝硬化、酒精性肝硬化(ICD-9-CM Diagnosis Code571.8,571.0,571.1,571.2,571.3,571.4,571.5,571.9)等病症的保健食品或药物的潜力。
参考文献
1.Brunt EM,Janney CG,Di Bisceglie AM,Neuschwander-Tetri BA and BaconBR.
(1999)Nonalcoholic steatohepatitis:a proposal for grading and stagingthehistological lesions.Am J Gastroenterol 94:2467-2674.
2.Clark JM and Diehl AM.(2003)Nonalcoholic fatty liver disease:anunderrecognized cause of cryptogenic cirrhosis.JAMA 289:300-304.
3.Carlisle R,Galambos JT,Warren WD.(1979)The relationshipbetweenconventional liver tests,quantitative function tests,andhistopathology incirrhosis.Dig Dis Sci 24:358-362.
3.Cua IH.&George J.(2005)Non-alcoholic fatty liver disease.Hosp Med66:106-111.
4.Day CP and James OFW.(1998)Steatohepatitis:a tale of two‘hits’？
Gastroenterology 114:842-845.
5.Dowman JK,Tomlinson JW and Newsome PN.(2010)Pathogenesis ofnon-alcoholic fatty liver disease.Q J Med 103:71-83.
6.Food and Drug Administration(2003)Guidance for Industry:Pharmacokinetics inPatients with Impaired Hepatic Function:Study Design,DataAnalysis,andImpact on Dosing and Labeling.US Department of Health and HumanServices,FDA,Center for Drug Evaluation and Research,Center for BiologicsEvaluationand Research.
7.French SW.(2001)Intragastric ethanol infusion model for cellularand molecularstudies alcoholic liver disease.J Biomed Sci 8:20-27.
8.Gauthier MS,Favier R and Lavoie JM.(2006)Time course of thedevelopmentof non-alcoholic hepatic steatosis in response to high-fat diet-inducedobesity in rats.Br J Nutr 95:273-281.
9.Guo HX,Liu DH,Ma Y,Liu JF,Wang Y,Du ZY,Wang X,Shen JK and PengHL.(2009)Long-term baicalin administration ameliorates metabolic disordersandhepatic steatosis in rats given a high-fat diet.Acta Pharmacol Sin 30:1505-1512.
10.Herold C,Heinz R,Niedobitek G,Schneider T,Hahn EG,Schuppan D.(2001)
Quantitative testing of liver function in relation to fibrosis inpatients withchronic hepatitis B and C.Liver 21:260-265.
11.Hu OY,Tang HS,Chang CL.(1994)The influence of chronic lobularhepatitison pharmacokinetics of cefoperazone--a novel galactose single-pointmethod as ameasure of residual liver function.Biopharm Drug Dispos 15:563-576.
12.Hu OY,Hu TM and Tang HS.(1995)Determination of galactose inhumanblood by high-performance liquid chromatography:comparison withanenzymatic method and application to the pharmacokinetic study of galactoseinpatients with liver dysfunction.J Pharm Sci 84:231-235.
13.Hu OY,Tang HS,Sheeng TY,Chen TC and Curry SH.(1995)Pharmacokineticsof promazine in patients with hepatic cirrhosis--correlationwith a novelgalactose single point method.J Pharm Sci 84:111-114.
14.Keiding S,Johansen S,Tonnesen K.(1977)Kinetics of ethanolinhibition ofgalactose elimination in perfused pig liver.Scand J Clin LabInvest 37:487-494.15.Keiding S,Johansen S,Winkler K.(1982)Hepatic galactoseeliminationkinetics in the intact pig.Scand J Clin Lab Invest 42:253-259.
16.Knodell RG,Ishak KG,Black WC,Chen TS,Craig R,Kaplowitz N,KiernanTWand Wollman J.(1981)Formulation and application of a numerical scoringsystemfor assessing histological activity in asymptomatic chronicactivehepatitis.Hepatology 1:431–435.
17.Leclercq IA,Farrell GC and Field J.(2000)CYP2E1 and CYP4A asmicrosomalcatalysts of lipid peroxides in murine nonalcoholicsteatohepatitis.J Clin Invest105:1067-1075.
18.Lindskov J.(1982)The quantitative liver function as measured bythe galactoseelimination capacity.I.Diagnostic value and relations toclinical,biochemical,and histological findings in patients with steatosis andpatients with cirrhosis.
Acta Med Scand 212:295-302.
19.Lin SC,Lin YH,Chen CF,Chung CY and Hsu SH.(1997)Thehepatoprotectiveand therapeutic effects of propolis ethanol extract onchronic alcohol-inducedliver injuries.Am J Chin Med 25:325-332.
20.Liu CH,Huang MT and Huang PC.(1995)Sources oftriacylglycerolaccumulation in livers of rats fed a cholesterol-supplementeddiet.Lipids 30:527-531.
21.Mulhall BP,One JP and Younossi ZM.(2002)Non-alcoholic fatty liverdisease:
an overview.J Gastroenterol Hepatol 17:1130-1143.
22.Nanji AA.(2004)Another animal model for nonalcoholicsteatohepatitis:howclose to the human condition？Am J Clin Nutr 79:350-351.
23.Nistor A,Bulla A,Filip DA and Radu A.(1987)The hyperlipidemichamster as a model ofexperimental atherosclerosis.Atherosclerosis 68:159-173.
24.Sanyal AJ,Campbell-Sargent C and Mirshahi F.(2001)Nonalcoholicsteatohepatitis:association of insulin resistance andmitochondrial abnormalities.
Gastroenterology 120:1183-1192.
25 Sass DA,Chang P and Chopra,KB.(2005)Nonalcoholic fatty liverdisease:aclinical review.Dig Dis Sci 50:171-180.
26.Schaefer EJ.(1997)Effects of dietary fatty acids on lipoproteinsandcardiovascular disease risk:summary.Am J Clin Nutr 65:1655S-1656S.
27.Schaffner F and Thaler H.(1986)Nonalcoholic fatty liverdisease.Prog LiverDis 8:283-298.
28.Sullivan MP,Cerda JJ,Robbins FL,Burgin CW and Beatty RJ.(1993)Thegerbil,hamster,and guinea pig as rodent models for hyperlipidemia.LabAnimSci 43:575-578.
29.Tang HS and Hu OY.(1992)Assessment of liver function using anovelgalactose single point method.Digestion 52:222-231.
30.Tominaga K,Kurata JH and Chen YK.(1995)Prevalence of fatty liverinJapanese children and relationship to obesity.Dig Dis Sci 40:2002-2009.
31.Zhang Z,Wang H,Jiao R,Peng C,Wong YM,Yeung VS,Huang Y and ChenZY.(2009)Choosing hamsters but not rats as a model for studyingplasmacholesterol lowering activity of functional foods.Mol Nutr Food Res 53:921-930.
32.Zou Y,Li J,Lu C,Wang J,Ge J,Huang Y,Zhang L and Wang Y.(2006)
High-fat emulsion-induced rat model of nonalcoholicsteatohepatitis.Life Sci 79:1100-1107.
33.Zhang D,Xie L,Jia G,Cai S,Ji B,Liu Y,Wu W,Zhou F,Wang A,Chu L,WeiY,Liu J and Gao F.(2011)Comparative study on antioxidant capacityofflavonoids and their inhibitory effects on oleic acid-induced hepaticsteatosis invitro.Eur J Med Chem 46:4548-4558.
Claims (21)
1.一种化合物在制备降低肝脏细胞脂肪含量、降低肝脏脂肪含量、或改善脂肪肝引起的肝病变或其他相关病症的组合物的用途，其中
(i)该化合物是选自于以下所组成群组：薄荷醇(menthol)、三氯蔗糖(sucralose)、甘露醇(mannitol)、糖精(saccharin)、圣草酚(eriodictyol)、及其任何组合；或
(ii)该化合物是选自于以下所组成群组：(1)糖精与甘露醇的组合、(2)薄荷醇与甘露醇的组合、(3)三氯蔗糖与甘露醇的组合、(4)圣草酚与甘露醇的组合、(5)圣草酚与三氯蔗糖、(6)薄荷醇、甘露醇、圣草酚、及(7)三氯蔗糖、甘露醇、圣草酚的组合。
2.根据权利要求1所述的用途，其中该化合物是选自于以下所组成群组：圣草酚(eriodictyol)、甘露醇(mannitol)、薄荷醇(menthol)、三氯蔗糖(sucralose)、糖精(saccharin)、及其任何组合。
3.根据权利要求1所述的用途，其中该化合物是选自于以下所组成群组：(1)糖精与甘露醇的组合、(2)薄荷醇与甘露醇的组合、(3)三氯蔗糖与甘露醇的组合、(4)圣草酚与甘露醇的组合、(5)圣草酚与三氯蔗糖、(6)薄荷醇、甘露醇、圣草酚、及(7)三氯蔗糖、甘露醇、圣草酚的组合。
4.根据权利要求1至3中任一权利要求所述的用途，其中该化合物进一步包括硫酸月桂酸钠(sodium lauryl sulfate)、山梨醇(sorbitol)、甘油(glycerin)、苯甲酸钠(sodiumbenzoate)、氧化铁红(oxide red)、预糊化淀粉(pregelatinized starch)、环己烷氨基磺酸钠(sodium cyclamate)、山梨酸(sorbic acid)、柠檬油(lemon oil)、柠檬酸(citricacid)、丁基羟基茴香醚(butylated hydroxyanisole)、枸橘苷(poncirin)、异牡荆素(isovitexin)、麦角固醇(ergosterol)、月桂烯(β-myrcene)、金丝桃苷(hyperoside)、儿茶素((+)-catechin)、高良姜素(galangin)、桑叶素(morin)、金松双黄酮(sciadopitysin)、香风草甙(didymin)、棉纤维素(gossypin)、木犀草素-7-葡萄糖甙(luteolin-7-Glucoside)、双氢槲皮素((+)-taxifolin)、肉桂酸(trans-cinnamic acid)、香叶木素(diosmin)、蒙花甙(linarin)、木糖醇(xylitol)、木犀草素(luteolin)、獐牙菜苦素(swertiamarin)、葛根素(puerarin)、根皮苷(phloridzin)、甜橙黄酮(sinensetin)、(-)-表没食子儿茶素((-)-epigallocatechin)、山柰(kaempferol)、熊果酸(ursolic acid)、水飞蓟素、(silymarin)、(+)-柠檬油精((+)-limonene)、橙皮甙(hesperidin)、(-)-表儿茶素-3-没食子酸酯((-)-epicatechin-3-gallate)、水飞蓟宾(silybin)、芒柄花黄素(formononetin)、十四烷酸乙酯(myristic acid ethyl ester)、二十碳五烯酸(eicosapentaenoic acid,EPA)、汉黄芩素(wongonin)、聚维酮K-30(povidone K-30)、原儿茶酸(protocatechuic acid)、伞形酮(umbelliferone)、橙皮(hesperitin)、去甲二氢愈创木酸(nordihydroguaiaretic acid)、新橙皮苷(neohesperidin)、柚皮苷(naringin)、(-)-表儿茶素((-)-epicatechin)、甘草甜素(glycyrrhizin)、黄芩苷(baicalin)、斛皮素(quercitrin)、及/或黄芩甙元(baicalein)。
5.根据权利要求1至3中任一权利要求所述的用途，其中该组合物是用于降低个体的肝脂肪含量。
6.根据权利要求1至3中任一权利要求所述的用途，其中该组合物是用于降低个体的肝细胞的脂肪含量。
7.根据权利要求1至3中任一权利要求所述的用途，其中该组合物是用于降低个体的肝损害。
8.根据权利要求7所述的用途，其中该肝损害包括肝组织损害或肝功能损害。
9.根据权利要求8所述的用途，其中该肝组织损害包括以下之一或多种特征：脂肪变性(steatosis)、肝小叶发炎(lobular inflammation)、肝脏细胞气球化(hepatocyteballooning)及肝脏细胞产生泡状脂肪油滴。
10.根据权利要求1至3中任一权利要求所述的用途，其中该肝病变或其他相关病症是选自于以下所组成的群组、急性与慢性酒精性脂肪肝、急性与慢性非酒精性脂肪肝、急性与慢性酒精性肝炎、急性与慢性非酒精性脂肪肝炎、非酒精性肝硬化、及酒精性肝硬化。
11.根据权利要求1至3中任一权利要求所述的用途，其中该组合物可施用于非酒精性脂肪肝疾病的患者或肥胖者。
12.根据权利要求1至3中任一权利要求所述的用途，其中该组合物为药物。
13.一种化合物在制备降低肝脏脂肪含量、降低脂肪肝引起的肝损害、和降低脂肪肝引起的肝病变或其他相关病症的组合物的用途，其中
(i)该化合物是选自于以下所组成群组：薄荷醇(menthol)、三氯蔗糖(sucralose)、甘露醇(mannitol)、糖精(saccharin)、圣草酚(eriodictyol)、及其任何组合；或
(ii)该化合物是选自于以下所组成群组：(1)糖精与甘露醇的组合、(2)薄荷醇与甘露醇的组合、(3)三氯蔗糖与甘露醇的组合、(4)圣草酚与甘露醇的组合、(5)圣草酚与三氯蔗糖、(6)薄荷醇、甘露醇、圣草酚、及(7)三氯蔗糖、甘露醇、圣草酚的组合。
14.根据权利要求13所述的用途，其中该化合物是选自于以下所组成群组：圣草酚(eriodictyol)、甘露醇(mannitol)、薄荷醇(menthol)、三氯蔗糖(sucralose)、糖精(saccharin)、及其任何组合。
15.根据权利要求13所述的用途，其中该化合物是选自于以下所组成群组：(1)糖精与甘露醇的组合、(2)薄荷醇与甘露醇的组合、(3)三氯蔗糖与甘露醇的组合、(4)圣草酚与甘露醇的组合、(5)圣草酚与三氯蔗糖、(6)薄荷醇、甘露醇、圣草酚、及(7)三氯蔗糖、甘露醇、圣草酚的组合。
16.根据权利要求13至15中任一权利要求所述的用途，其中该化合物进一步包括硫酸月桂酸钠(sodium lauryl sulfate)、山梨醇(sorbitol)、甘油(glycerin)、苯甲酸钠(sodium benzoate)、氧化铁红(oxide red)、预糊化淀粉(pregelatinized starch)、环己烷氨基磺酸钠(sodium cyclamate)、山梨酸(sorbic acid)、柠檬油(lemon oil)、柠檬酸(citric acid)、丁基羟基茴香醚(butylated hydroxyanisole)、枸橘苷(poncirin)、异牡荆素(isovitexin)、麦角固醇(ergosterol)、月桂烯(β-myrcene)、金丝桃苷(hyperoside)、儿茶素((+)-catechin)、高良姜素(galangin)、桑叶素(morin)、金松双黄酮(sciadopitysin)、香风草甙(didymin)、棉纤维素(gossypin)、木犀草素-7-葡萄糖甙(luteolin-7-Glucoside)、双氢槲皮素((+)-taxifolin)、肉桂酸(trans-cinnamic acid)、香叶木素(diosmin)、蒙花甙(linarin)、木糖醇(xylitol)、木犀草素(luteolin)、獐牙菜苦素(swertiamarin)、葛根素(puerarin)、根皮苷(phloridzin)、甜橙黄酮(sinensetin)、(-)-表没食子儿茶素((-)-epigallocatechin)、山柰(kaempferol)、熊果酸(ursolicacid)、水飞蓟素、(silymarin)、(+)-柠檬油精((+)-limonene)、橙皮甙(hesperidin)、(-)-表儿茶素-3-没食子酸酯((-)-epicatechin-3-gallate)、水飞蓟宾(silybin)、芒柄花黄素(formononetin)、十四烷酸乙酯(myristic acid ethyl ester)、二十碳五烯酸(eicosapentaenoic acid,EPA)、汉黄芩素(wongonin)、聚维酮K-30(povidone K-30)、原儿茶酸(protocatechuic acid)、伞形酮(umbelliferone)、橙皮(hesperitin)、去甲二氢愈创木酸(nordihydroguaiaretic acid)、新橙皮苷(neohesperidin)、柚皮苷(naringin)、(-)-表儿茶素((-)-epicatechin)、甘草甜素(glycyrrhizin)、黄芩苷(baicalin)、斛皮素(quercitrin)、及/或黄芩甙元(baicalein)。
17.根据权利要求13至15中任一权利要求所述的用途，其中该肝损害包括肝组织损害或肝功能损害。
18.根据权利要求17所述的用途，其中该肝组织损害包括以下之一或多种特征：脂肪变性(steatosis)、肝小叶发炎(lobular inflammation)、肝脏细胞气球化(hepatocyteballooning)及肝脏细胞产生泡状脂肪油滴。
19.根据权利要求13至15中任一权利要求所述的用途，其中该肝病变或其他相关病症是选自于以下所组成的群组、急性与慢性酒精性脂肪肝、急性与慢性非酒精性脂肪肝、急性与慢性酒精性肝炎、急性与慢性非酒精性脂肪肝炎、非酒精性肝硬化、及酒精性肝硬化。
20.根据权利要求13至15中任一权利要求所述的用途，其中该组合物可施用于非酒精性脂肪肝疾病的患者或肥胖者。
21.根据权利要求13至15中任一权利要求所述的用途，其中该组合物为药物。
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| CN110151787A (zh) * | 2018-02-12 | 2019-08-23 | 玛旺干细胞医学生物科技股份有限公司 | 护肝组合物及其用途 |
| TWI691719B (zh) * | 2018-10-19 | 2020-04-21 | 香港商阿瓦隆 海帕波有限公司 | 半乳糖快速定量檢測系統及其應用 |
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| CN112471376A (zh) * | 2020-11-02 | 2021-03-12 | 辽宁康汇医学临床研究有限公司 | 一种防治酒精性脂肪肝的固体饮料及其制备方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| WO2015070396A1 (zh) * | 2013-11-13 | 2015-05-21 | 财团法人国防教育研究基金会 | 无肝副作用的对乙酰胺基酚新复方组合 |
Family Cites Families (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4388328A (en) * | 1981-10-15 | 1983-06-14 | Warner-Lambert Company | Sorbitol containing mixture encapsulated flavor |
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| JP4824886B2 (ja) * | 2001-09-11 | 2011-11-30 | 長岡香料株式会社 | フルクトース吸収阻害剤、組成物、および食品 |
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| JPWO2006135084A1 (ja) * | 2005-06-14 | 2009-01-08 | 学校法人 久留米大学 | 脂肪性肝炎または脂肪肝の予防または治療薬 |
| JP2007182405A (ja) * | 2006-01-10 | 2007-07-19 | Univ Kurume | 脂肪性肝疾患の改善治療薬 |
| JPWO2009028457A1 (ja) * | 2007-08-29 | 2010-12-02 | 国立大学法人信州大学 | 非アルコール性脂肪肝炎治療薬 |
| CN101744865B (zh) * | 2008-12-18 | 2012-07-25 | 山东福田药业有限公司 | 一种木糖醇护肝片的制备方法 |
| WO2010106420A1 (en) * | 2009-03-17 | 2010-09-23 | Axcan Pharma, Inc. | Method of treating nonalcoholic steatohepatitis with elevated doses of ursodeoxycholic acid |
| TR200904862A1 (tr) * | 2009-05-29 | 2010-12-21 | Sanovel İlaç San. Ve Ti̇c. A.Ş. | Sukraloz formülasyonu ve üretim prosesi |
| CN101933900A (zh) * | 2009-07-02 | 2011-01-05 | 天津瑞普生物技术股份有限公司 | 一种用于防治禽类肝病的复方制剂及其制备方法 |
| JP2011231078A (ja) * | 2010-04-30 | 2011-11-17 | Nagaoka Koryo Kk | 非アルコール性脂肪性肝疾患の予防および／または治療に有効な経口摂取用組成物 |
| AR083417A1 (es) * | 2010-10-14 | 2013-02-21 | Novartis Ag | Composiciones farmaceuticas que contienen un dgat1 inhibidor |
| CN108465110A (zh) * | 2011-04-20 | 2018-08-31 | 教育研究基金会 | 无/低副作用的抗结核病药物复方 |
| EP2606746B2 (en) * | 2011-12-22 | 2018-10-24 | International Flavors & Fragrances, Inc. | Cooling enhancing compositions |
| US20140274979A1 (en) * | 2013-03-13 | 2014-09-18 | Golden Biotechnology Corporation | Method for the treatment of fatty liver disease |
| US10441560B2 (en) * | 2013-03-15 | 2019-10-15 | Mochida Pharmaceutical Co., Ltd. | Compositions and methods for treating non-alcoholic steatohepatitis |
| EA030485B1 (ru) * | 2013-04-29 | 2018-08-31 | Харша Чигурупати | Спиртные напитки с пониженной гепатотоксичностью |
| BR112018005905B1 (pt) * | 2015-09-24 | 2023-03-21 | Sinew Pharma Inc | Composto, composição farmacêutica, e, uso de um composto |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101683351A (zh) * | 2008-09-24 | 2010-03-31 | 汪鋆植 | 根皮苷在制备保肝药物或保健食品中的用途 |
| WO2015070396A1 (zh) * | 2013-11-13 | 2015-05-21 | 财团法人国防教育研究基金会 | 无肝副作用的对乙酰胺基酚新复方组合 |
Non-Patent Citations (3)
| Title |
|---|
| TEERADATE KONGPICHITCHOKE 等: "Number of Hydroxyl Groups on the B-Ring of Flavonoids Affects Their Antioxidant Activity and Interaction with Phorbol Ester Binding Site of PKC 6 C1B Domain： In Vitro and in Silico Studies", JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, vol. 63, 24 April 2015 (2015-04-24), pages 4580 - 4586 * |
| 王悦之等: "CYP2E1 与非酒精性脂肪肝", 胃肠病学和肝病学杂志, vol. 21, no. 4, 30 April 2012 (2012-04-30), pages 384 - 386 * |
| 王颢等: "柚皮素抑制高脂饮食肥胖大鼠体重的实验研究", 中国现代医学杂志, vol. 18, no. 15, 31 August 2008 (2008-08-31), pages 2131 - 2137 * |
Also Published As
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|---|---|
| JP2021105037A (ja) | 2021-07-26 |
| TWI711464B (zh) | 2020-12-01 |
| WO2017084234A1 (zh) | 2017-05-26 |
| US10925854B2 (en) | 2021-02-23 |
| EP3391881A4 (en) | 2020-03-11 |
| CN107613968A (zh) | 2018-01-19 |
| TW201718015A (zh) | 2017-06-01 |
| JP2018534323A (ja) | 2018-11-22 |
| HK1244213A1 (zh) | 2018-08-03 |
| US20180117003A1 (en) | 2018-05-03 |
| EP3391881A1 (en) | 2018-10-24 |
| JP2023145714A (ja) | 2023-10-11 |
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