TW201718015A - 預防或治療脂肪肝、保護肝功能、或改善脂肪肝引起的肝病變或其他相關病症之組合物及方法 - Google Patents
預防或治療脂肪肝、保護肝功能、或改善脂肪肝引起的肝病變或其他相關病症之組合物及方法 Download PDFInfo
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- TW201718015A TW201718015A TW105110295A TW105110295A TW201718015A TW 201718015 A TW201718015 A TW 201718015A TW 105110295 A TW105110295 A TW 105110295A TW 105110295 A TW105110295 A TW 105110295A TW 201718015 A TW201718015 A TW 201718015A
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- liver
- mannitol
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- 238000000034 method Methods 0.000 title claims abstract description 18
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Abstract
本發明關於一種預防或治療脂肪肝、保護肝功能、或改善脂肪肝引起的肝病變或其他相關病症之組合物及方法。
Description
本發明關於一種預防或治療脂肪肝、保護肝功能、或改善脂肪肝引起的肝病變或其他相關病症之組合物及方法。
肝臟是動物體消化系統的一部分,也是許多消化液製造與分泌的主要器官,肝臟亦具有吸收、代謝、清除有毒物質及免疫保護等功能。肝臟是脂肪代謝的重要器官,在脂肪類食物上的消化、吸收、分解、合成以及運輸的過程中扮演著極為重要的角色。肝臟由血液中所攝取的游離脂肪酸(free fatty acid,FFA),最終會在肝臟中合成三酸甘油脂(triglyceride,TG)並儲存起來,或以極低密度脂蛋白(very low density lipoprotein, VLDL)的形式將TG轉運出肝臟進入血液迴圈中。因此,一旦肝臟受到損傷後,將導致脂質(尤指TG) 在肝細胞內異常的代謝及堆積。
正常情況下脂肪約占肝臟重量的3%,臨床上所謂「脂肪肝(fatty liver disease,FLD)」是指肝臟內的脂肪重量超過肝臟重量的5%,或肝組織切片中超過10%以上的肝細胞有脂肪空泡變現象2
。脂肪肝依照病因可區分酒精性脂肪肝(alcoholic fatty liver,AFLD)、非酒精性脂肪肝疾病(non-alcohol fatty liver disease,NAFLD)或其他因素,如藥物,所衍生的脂肪肝疾病,病理學外觀上包括脂肪變性(fatty metamorphosis or steatosis)、脂肪性肝炎(steatohepatitis)等表徵。輕度脂肪肝是指含脂肪變性的肝細胞少於33%,中度為介於33-66%,而重度則占66%以上3,9,21
。過去大都被認為脂肪肝是較良性且可逆的病症,因此較不被重視,但近年來陸續的研究發現,其嚴重將引發肝臟纖維化及肝硬化,甚至是肝癌,且隨著肥胖人口增加,有增加之趨勢。
歐美國家主要肝臟疾病係因長期飲酒過量,因此,絕大部份肝臟疾病皆因酒精傷害所致。但近15-20年,NAFLD卻成為歐美國家中,肝功能異常必先考慮的病因2
。Thaler曾在1962年對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,發現伴隨的NAFLD中提出「非酒精性脂性肝炎」(Non-alcoholic steatohepatitis,NASH),隨後在1986年Schaffner更再次強調NASH在NAFLD病程中衍生纖維化的機制中扮演著重要的角色21
;直到1998年Day發現有15-50%的NASH患者衍生不同程度的纖維化4
,NAFLD才開始受到臨床醫師的重視。如今,除了AFLD外,在臨床上NASH不僅只是NAFLD自然病程發展中的一個階段,也由於其存在使得NAFLD不再被視為一種良性的肝臟疾病。
目前在北美、南美、日本、北歐、南歐、澳洲及中東地區之FLD研究,發現至少有10-39%的盛行率,而死後病理解剖組織病理學檢查中,NAFLD盛行率約在20%上下,其中所伴隨的NASH之發現率約為3-18%不等;其中肥胖者中NAFLD的盛行率則高達57-74%(是正常人的4.6倍),其中20-25%存有NASH病變,罹患肝硬化者亦占2-3%。臺灣地區近三十年來,由於經濟環境及飲食的改善,NAFLD盛行率亦有逐年增高趨勢,近年來盛行率約12-37%,與日本的9-13%相較不遠,其中非肥胖者盛行率約10%,而屬病態肥胖者(BMI大於30者)盛行率則高達80%15,23
。
有關NAFLD致病機轉,英國Day與James根據大量臨床及動物實驗研究提出二次打擊假說(Two-hit hypothesis),第一次打擊後出現脂肪肝(fatty liver),第二次打擊後則出現脂肪性肝炎(steatohepatitis)。第一次打擊 肇因於肝臟內脂肪的過度堆積,原因有肥胖、高血脂症等;第二次打擊則是起因於氧化壓力(oxidative stress)及粒線體中活性氧物種(Reactive oxygen species, ROS)作用,造成肝細胞膜上脂質過氧化(lipid peroxidation),釋放出原發炎細胞激素及自由基,活化星狀細胞(stellate cells)產生纖維化,導致肝細胞患壞死4,5,19
。而NASH的致病機轉主要與三酸甘油脂過氧化作用、氧化壓力、ROS反應、增加肝細胞本身脂質的過氧化反應、或與細胞激素及肝臟酵素的增進,導致一系列自體免疫的相互反應有關12
。
脂肪肝的形成大多是長期攝取過多動物性脂肪、蛋白質、碳水化合物,過剩的熱量在體內轉化成脂肪囤積起來,導致肥胖及脂肪肝。脂肪肝患者血中的GOT/GPT數值可能都正常,要正確診斷脂肪肝,必須透過腹部超音波檢查,目前準確率達97%以上。
目前FLD尚無特定療效的理想治療藥物,治療方針主要是改善潛在危險因數或使用藥物控制慢性疾病的進展為主,建議依形成脂肪肝原因對症加以治療,如:體重過重導致的脂肪肝,須適度減輕體重;酒精性脂肪肝,需靠戒酒及攝取均衡飲食才能改善;長期接觸傷害肝臟的化學物質或藥物,引起的脂肪肝,則須立即停止使用這些藥物;疾病引起的脂肪肝,如C型肝炎、血脂肪過高等,須針對源頭著手,治療C肝、控制血脂;若是體質因素導致三酸甘油脂太高,則無法由減肥方式改善脂肪肝。
然而,目前臨床常用降低血清中的三酸甘油脂、膽固醇之藥品常伴隨者肝毒性(hepatotoxicity) 、肌痛、肌炎、橫紋肌溶解等肌肉病變(myopathy)副作用,其中降血脂藥物中,肌肉毒性是最值得關注的副作用,尤以舒脂錠(Statins) 發生肌肉毒性比例最高,纖維酸( Fibric acid )次之 。此外,降血脂藥物具有「驅脂」作用,能將血液中的脂類「驅趕」到肝臟,而肝臟內本來就已有脂肪堆積,故對大量湧入的脂類難以進行處理,脂肪便會堆積在肝臟內,使得脂肪肝更加嚴重。由此可知降血脂用藥並不適合用於治療FLD。
因此,仍有需要尋求一種有效的預防及治療脂肪肝、脂肪肝引起之肝病變、保護肝功能及改善相關病症之有效成分。
本發明提出一或多種賦形劑(包括類黃酮化合物等)具有預防或治療脂肪肝、保護肝功能、或改善脂肪肝引起的肝病變或其他相關病症之功效,該化合物係選自以下所組成之群:硫酸月桂酸鈉(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)、苯甲酸鈉(sodium benzoate)、氧化鐵紅(oxide red)、預糊化澱粉(pregelatinized starch)、環己烷氨基磺酸鈉 (sodium cyclamate)、山梨酸 (sorbic acid)、檸檬油 (lemon oil)、檸檬酸 (citric acid)、及丁基羥基茴香醚(butylated hydroxyanisole)、枸橘苷(poncirin)、異牡荊素(isovitexin)、聖草酚(eriodictyol)、麥角固醇(ergosterol)、月桂烯(β-myrcene)、金絲桃苷(hyperoside)、兒茶素((+)-catechin)、高良薑素(galangin)、桑葉素(morin)、金松雙黃酮(sciadopitysin)、香風草甙(didymin)、棉纖維素(gossypin)、木犀草素-7-葡萄糖甙(luteolin-7-Glucoside)、雙氫槲皮素((+)-taxifolin)、肉桂酸(trans-cinnamic acid)、香葉木素(diosmin)、蒙花甙(linarin)、木糖醇(xylitol)、木犀草素(luteolin)、獐牙菜苦素(swertiamarin)、及其任何組合。
因此,在一方面,本發明提出所述化合物用於製備預防或治療脂肪肝、保護肝功能、或改善脂肪肝引起的肝病變或其他相關病症之組合物的用途。本發明也提出藉由投用所述化合物以預防或治療脂肪肝、保護肝功能、或改善脂肪肝引起的肝病變或其他相關病症之方法。
在部份具體實例中,該化合物係選自於以下所組成群組:硫酸月桂酸鈉(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)、苯甲酸鈉(sodium benzoate)、氧化鐵紅(oxide red)、預糊化澱粉(pregelatinized starch)、環己烷氨基磺酸鈉 (sodium cyclamate)、山梨酸 (sorbic acid)、檸檬油 (lemon oil)、檸檬酸 (citric acid)、及丁基羥基茴香醚(butylated hydroxyanisole)、及其任何組合。
在部份具體實例中,該化合物係選自於以下所組成群組:枸橘苷(poncirin)、異牡荊素(isovitexin)、聖草酚(eriodictyol)、麥角固醇(ergosterol)、月桂烯(β-myrcene)、金絲桃苷(hyperoside)、兒茶素((+)-catechin)、高良薑素(galangin)、桑葉素(morin)、金松雙黃酮(sciadopitysin)、香風草甙(didymin)、棉纖維素(gossypin)、木犀草素-7-葡萄糖甙(luteolin-7-Glucoside)、雙氫槲皮素((+)-taxifolin)、肉桂酸(trans-cinnamic acid)、香葉木素(diosmin)、蒙花甙(linarin)、木糖醇(xylitol)、木犀草素(luteolin)、獐牙菜苦素(swertiamarin)、及其任何組合。
在部份具體實例中,該化合物係選自於以下所組成群組:聖草酚(eriodictyol)、甘露醇(mannitol)、薄荷醇(menthol)、三氯蔗糖(sucralose)、糖精(saccharin)、及其任何組合。
在部份具體實例中,該化合物係選自於以下所組成群組:(1)糖精與 甘露醇的組合、(2)薄荷醇與甘露醇的組合、(3)三氯蔗糖與甘露醇的組合、(4)聖草酚與 甘露醇的組合、(5)聖草酚與三氯蔗糖、(6)薄荷醇、甘露醇、聖草酚的組合、或(7)三氯蔗糖、甘露醇、聖草酚的組合。
在部份具體實例中,此處所述的一或多種化合物係與選自於以下化合物之ㄧ或多者並用:葛根素(puerarin)、根皮苷(phloridzin)、甜橙黃酮(sinensetin)、(-)-表沒食子兒茶素((-)-epigallocatechin)、山柰(kaempferol)、熊果酸(ursolic acid)、水飛薊素、(silymarin)、(+)-檸檬油精((+)-limonene)、橙皮甙(hesperidin)、(-)-表兒茶素-3-沒食子酸酯((-)-epicatechin-3-gallate)、水飛薊賓(silybin)、芒柄花黃素(formononetin)、十四烷酸乙酯(myristic acid ethyl ester)、二十碳五烯酸(eicosapentaenoic acid, EPA)、漢黃芩素(wongonin)、聚維酮K-30(povidone K-30)、原兒茶酸(protocatechuic acid)、傘形酮(umbelliferone)、橙皮(hesperitin)、去甲二氫愈創木酸(nordihydroguaiaretic acid)、新橙皮苷(neohesperidin)、柚皮苷(naringin)、(-)-表兒茶素((-)-epicatechin)、甘草甜素(glycyrrhizin)、黃芩苷(baicalin)、斛皮素(quercitrin)、及黃芩甙元(baicalein)。
在部份具體實例中,本發明的化合物可降低個體之肝脂肪含量。
在部份具體實例中,本發明的化合物可降低個體之肝細胞之脂肪含量。
在部份具體實例中,本發明的化合物可降低個體之肝損害,例如,肝組織損害或肝功能損害。
在部份具體實例中,本發明的化合物可提高個體之肝臟抗氧化活性。
在部份具體實例中,本發明的化合物可用於改善因各種原因肝脂肪累積引起的相關病症,包括但不限於,脂肪肝、急性與慢性酒精性脂肪肝、急性與慢性非酒精性脂肪肝、急性與慢性酒精性肝炎、急性與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 診斷碼571.8, 571.0, 571.1, 571.2, 571.3, 571.4, 571.5, 571.9)。
在部份具體實例中,適用于本發明的化合物的個體是脂肪肝疾病之患者或肥胖者。
在部份具體實例中,本發明的化合物可製成藥物、食品添加物或健康食品。
在又一方面,本發明提供一種組合物,其包括選自於以上所述的任何兩種或以上的化合物。
在部份具體實例中,本發明之組合物包括選自於以下所組成的群組的任何兩種或以上的化合物:聖草酚(eriodictyol)、甘露醇(mannitol)、薄荷醇(menthol)、三氯蔗糖(sucralose)及糖精(saccharin)。
在部份具體實例中,本發明之組合物包括選自於以下所組成的群組的組合:(1)糖精與 甘露醇的組合、(2)薄荷醇與甘露醇的組合、(3)三氯蔗糖與甘露醇的組合、(4)聖草酚與 甘露醇的組合、(5)聖草酚與三氯蔗糖、(6)薄荷醇、甘露醇、聖草酚的組合、或(7)三氯蔗糖、甘露醇、聖草酚的組合。
無須進一步的闡述,咸相信本發明所屬技術領域中具有通常知識者基於前述說明即可利用本發明至最廣的程度。因此,可以理解以下的說明僅僅是作為例示說明之用,而非以任何方式限制其餘的揭露內容。
除非另有指明,所有在此處使用的技術性和科學性術語具有如同本發明所屬技藝中之通常技術者一般所瞭解的意義。
本文所使用的「一」乙詞,如未特別指明,係指至少一個(一個或一個以上)之數量。
本發明係揭示一或多種如上所述的化合物具有降低肝脂肪含量及改善相關病症之作用。因此,本發明係提供一種所述之化合物在製備預防或治療脂肪肝、保護肝功能、或改善脂肪肝引起的肝病變或其他相關病症之組合物之用途。本發明亦提供一種預防或治療脂肪肝、保護肝功能、或改善脂肪肝引起的肝病變或其他相關病症之方法,其包括對有需要的個體投予有效量之所述的化合物。本發明亦提供可供預防或治療脂肪肝、保護肝功能、或改善脂肪肝引起的肝病變或其他相關病症之組合物。
本文所使用的「肝脂肪含量」是指個體內累積於肝臟的脂肪含量,包括廣義的脂質,例如,三酸甘油脂(triglyceride,TG)及膽固醇等。本文所使用的「降低肝脂肪含量」通常是指使個體內的異常肝臟脂肪含量降低,也就是使異常肝臟脂肪含量減少,更特定而言,是減少至正常水準。例如,正常情況下脂肪約占肝臟重量的3%,當肝臟內的脂肪重量超過肝臟重量的5%時則屬於脂肪異常累積(上述肝臟脂肪含量為相對數值且為舉例說明,可能因個體族群及其他因素有所變動)。在具體態樣中,本文所使用的「降低肝脂肪含量」可指使個體內的異常肝臟脂肪含量降低,例如,從肝臟重量的5%或更高降至肝臟重量的3%。標準的分析方式可用以評估肝脂肪含量,包括但不限於,超音波分析、磁振造影MRI、磁共振頻譜MRS、電腦斷層掃描CT、肝臟病理切片。
本文所使用的「肝功能」是指是指一個或一個以上的由肝臟執行的許多生理功能,可由許多常規的試驗予以分析,例如,丙胺酸轉胺酶(alanine aminotransferase,ALT)分析或天冬氨酸氨基轉移酶(aspartate transaminase,AST)分析。根據本發明,所述化合物可用以保護肝功能,包括,改善肝功能或避免肝功能的損壞。
本文所使用的「肝病變」可指肝臟細胞因某些因素受傷或被破壞,因而可能導致肝臟機能受到影響。根據本發明,所述化合物可用以改善由脂肪肝所引起的肝病變。更特定而言,本文所使用的「肝損傷」是指肝臟與正常肝臟相比有組織或生化功能受損的情形。在具體態樣中,本文所使用的「肝損傷」係由酒精或非酒精性因素,例如,高脂飲食或肥胖,引起的肝損傷。在具體態樣中,「肝損傷」可為肝臟的組織受損,可選自以下之一或多種特徵:脂肪變性(steatosis)、肝小葉發炎(lobular inflammation)、肝臟細胞氣球化(hepatocyte ballooning)及肝臟細胞產生泡狀脂肪油滴。在具體態樣中,「肝損傷」可為肝臟的生化功能受損,可由血清中的丙胺酸轉胺酶(alanine aminotransferase,ALT)或天冬氨酸氨基轉移酶(aspartate transaminase,AST)活性予以判斷,活性越高表示肝臟的生化功能受損越嚴重。
本文所使用的「肝臟抗氧化活性」是指肝臟中對抗氧化壓力的活性或能力。根據本發明的化合物可提高個體之肝臟抗氧化活性係指,包括但不限於,降低氧化壓力或提高抗氧化系統的成員之酵素活性或含量,該等抗氧化系統的成員可為麩胱甘肽過氧化酶(glutathione peroxidase,GPx)、榖胱甘肽(glutathione,GSH)、麩胱甘肽還原酶(glutathione reductase, GRd)、及/或超氧化物歧化酶(superoxide dismutase, SOD)。
根據本發明,所述的化合物包括常用的賦形劑及生物類黃酮,可用於降低肝脂肪含量及改善相關病症。此處所述的「相關病症」包括因肝脂肪累積異常導致的病症,包括但不限於,脂肪肝、急性與慢性酒精性脂肪肝、急性與慢性非酒精性脂肪肝、急性與慢性酒精性肝炎、急性與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 Code 571.8, 571.0, 571.1, 571.2, 571.3, 571.4, 571.5, 571.9)。
本文所使用的「預防」乙詞是指對疾病、疾病之症狀或病況的預防的或防止措施,包括但不限於,施加或投予一或多種活性藥劑的至可能是尚未被診斷為罹患此疾病、疾病之症狀或病況,但對其易感受或有其傾向之個體,其目的在於避免、阻止或推遲此疾病、疾病之症狀或病況的發生。
本文所使用的「治療」乙詞是指對疾病、疾病之症狀或病況的治療措施,包括但不限於,施加或投予一或多種活性藥劑至具有此疾病、疾病之症狀或病況、或疾病惡化之個體,其目的在於治療、治癒、緩解、減輕、改變、補救、改善、改進、或影響此疾病、疾病之症狀或病況、疾病引發之失能、或疾病惡化。
本文所使用的「個人」或「個體」等詞包括人類或非人類動物,特地而言,為哺乳類動物,例如,陪伴動物(如狗、貓等)、農場動物(如牛、綿羊、豬、馬等)、或實驗動物(如大鼠、小鼠、天竺鼠等)。
本文所使用的「有效量」乙詞是指於接受處理的個體產生所欲的生物功效或醫療效果的活性成分的量,例如,降低個體的肝脂肪含量或改善相關病症。
為達輸送及吸收目的,根據本發明之治療有效量之活性成分可與醫藥上可接受載體配製成適當形式之醫藥組合物。依據投予模式,本發明之醫藥組合物較佳為包含約0.1%重至約100%重之活性成分,其中百分比重係以組合物之總重量為基準計算。
本文所使用的「醫藥上可接受」乙詞是指載體與組合物之活性成分相容(不影響活性成分的作用),且較佳為可穩定該活性成分且對於接受治療之個體具安全性。該載體可為活性成分之稀釋劑、載劑、賦形劑、或介質。適用之賦形劑的一些實例包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、澱粉、阿拉伯膠、磷酸鈣、藻酸鹽、黃蓍膠、明膠、矽酸鈣、微晶纖維素、聚乙烯吡咯烷酮、纖維素、無菌水、糖漿、及甲基纖維素。本組合物可額外包含潤滑劑如滑石、硬脂酸鎂、及礦物油;潤濕劑;乳化劑及懸浮劑;防腐劑如甲基及丙基羥基苯甲酸酯;增甜劑;以及調味劑。在投予至病患後,本發明之組合物可提供活性成分快速、持續、或緩慢釋放之效果。
依據本發明,該組合物之形式可任何形式,例如,為片劑、丸劑、粉劑、錠劑、囊劑、扁囊劑、酏劑、懸劑、乳液、溶液、糖漿、軟與硬明膠膠囊、栓劑、無菌注射液、及包裝粉劑。
本發明之組合物可經由任何生理上可接受途徑輸送,例如,口服、非口服(如肌內、靜脈、皮下、及腹腔)、經皮、栓劑、及鼻內方法。關於非口服投予,較佳為使用無菌水溶液,其可包含其他物質,如足以使溶液與血液等張的鹽類或葡萄糖。水溶液可視需求適當地經緩衝(較佳為具pH值3至9)。本領域之技術人員可由習知之標準藥理學技術於無菌條件下製備適合的非口服組合物。
本發明通過下面的實施例進一步的說明,下面的實施例僅提供作為示範目的,而非限制本發明。本領域的技術人員應能根據本發明瞭解,不脫離本發明的精神和範圍,而對本發明所公開的特定具體實施例中進行許多改變,仍然能獲得相同或相似的結果。
實例
1.
材料方法
1.1
細胞株及細胞培養基
使用人類肝癌細胞株Hep G2分析本發明的各種化合物降低脂肪含量的活性。
使用DMEM(達爾伯克氏改良伊格爾培養基,Dulbecco’s Modified Eagle’s Medium)進行後續實驗,共配製編號A-F的DMEM培養液,如表1所示。
表1:編號A-F的DMEM培養液的配製
編號A-F的DMEM培養液置於2-8℃保存,實驗進行前放在37℃水浴槽中溫熱後使用。
1.2
細胞計數及存活測試
0.4% 台盼蘭(trypan blue)會滲入死細胞中而呈色,活細胞則因細胞膜完整,染料無法滲入而不會呈色。取100 μl細胞懸浮液與100 μl 0.4%台盼蘭等體積混合均勻。取少許混合液(約20 μl)由血球計數盤室上方凹槽中加入,蓋上蓋坡片於光學顯微鏡下觀察,活細胞不染色,死細胞則為藍色。
1.3
油酸誘導
HepG2
細胞株形成脂肪肝細胞
將15×106
的HepG2細胞株培養於編號B的DMEM培養液,在37℃,5% CO2
的培養箱中培養24小時,然後再以編號C的DMEM培養液(無血清培養液))培養24小時,最後更換為編號D的DMEM培養液(含油酸酯/白蛋白複合物)繼續培養48小時,使HepG2細胞株誘導為脂肪肝細胞。
1.4
脂肪肝細胞之各組處理
將HepG2細胞株分成6組,包括:(1)空白組:未作任何處理;(2)DMSO組:空白組細胞加入二甲基亞碸(dimethyl sulfoxide,DMSO);(3)對照組:以油酸誘導形成脂肪肝細胞;(4)載體組:以油酸誘導形成的脂肪肝細胞加入DMSO;(5)陽性對照組:脂肪肝細胞加入水飛薊素;以及(6)試驗組:脂肪肝細胞加入各種本發明的化合物。
1.5
細胞的三酸甘油脂(
TG
)的測定
各組經處理的細胞于72小時培養後,以磷酸鹽緩衝液(PBS)清洗兩次,之後加入0.5 mL胰蛋白酶/乙二胺四乙酸(trypsin/EDTA)培養3分鐘,再加入2 mL的PBS將細胞刮下,移到離心管中,以超音波將細胞震碎,取20 μL細胞萃取液,測細胞內蛋白質含量。TG測定是用市售組合試劑(Randox)進行。將上述所得TG含量除以蛋白質含量所得比值,即代表細胞中TG之相對含量。
1.6
試驗動物
選擇衛生署公告「健康食品之護肝保健功效評估方法」規範建議採用之試驗動物B6小鼠,預試驗每組試驗動物只數≧4只,確認試驗每組試驗動物只數≧12只。雄性小鼠飼養于正常明暗週期(上午7:00到下午7:00為亮期,其餘為暗期 ), 溫度 23±2 ℃,相對濕度55±15 % 的動物房內,體重為18-23 g, 由 樂斯科 (臺北)購買入國防動物中心, 動物實驗係遵照國衛院實驗指南進行。先以一般飼料每天餵食 3-5 g/日,飼養 1-2 周觀察健康狀態,水則無限供應,每週記錄體重一次。
1.7
動物組別
將試驗動物隨機分組,分為空白對照組(Blank)、高脂對照組(HFD)、正向對照組(Positive control,PS)與試驗組。空白對照組係給予正常飼料;高脂對照組係給予高脂飼料;正向對照組係給予高脂飼料與管喂水飛薊素(5 mg/kg/day);以及試驗組係給予高脂飼料與管喂試驗化合物。
1.8.
試驗方法
空白對照組以正常飼料任食12周,高脂對照組、正向對照組與試驗組則以高脂飼料任食12周。開始餵食8周後,空白對照組與高脂對照組每天一次管喂給予去離子水;正向對照組每天一次管喂給予水飛薊素;試驗組每天一次管喂給予試驗化合物,為期4周或8周。
試驗開始前及試驗開始後之第8、12或16周,以臉頰或心臟采血。最後于結束時秤重後全部犧牲,以臉頰或心臟采血。小鼠血液樣品在室溫下放置1小時以使其凝結。再以冷凍離心機於4oC下15,700 x g離心5分鐘,來分離血清,然後以血液自動生化分析儀檢測肝功能生化指數,包括:天冬氨酸氨基轉移酶(aspartate transaminase,AST)、丙胺酸轉胺酶(alanine aminotransferase,ALT)、三酸甘油脂(TG)、總膽固醇(TCHO,TC)、低密度脂蛋白膽固醇(LDL-C)及高密度脂蛋白膽固醇(HDL-C)。
此外,犧牲後的小鼠剖腹取腹部脂肪及肝臟標本,秤重後比較其脂肪重、肝重及肝重/體重比值,並將最大右葉肝割取兩塊約l 公分立方之組織塊,固定於10%的中性福馬林(formalin)液中,石蠟包封切片後分別作H&E 染色來進行組織病理學觀察。另外,將其餘肝臟冷凍保,檢測肝臟中三酸甘油脂及總膽固醇之含量。另,利用美國食品及藥物管理局及臺灣衛生署認可,推薦給臨床使用之定量肝臟剩餘功能的半乳糖單點測定法(Galactose Single Point Method)分析各組動物之肝功能,其係在試驗結束時,依動物體重每公斤給於0.5 g半乳糖溶液(G.S.P.® 0.4 g/mL),經由靜脈給藥,投藥完畢後60分鐘以濾紙取大約0.5ml全血,評估小鼠肝功能。GSP值愈高,表示肝臟剩餘功能愈差(FDA: “Guidance for Industry: Pharmacokinetics in Patients with Impaired. Hepatic Function—Study Design, Data Analysis and Impact on Dosing and. Labeling. 2003)。
1.9 組織病理組織切片
:
試驗結束時,所有小鼠均予以犧牲,于最大右葉肝割取一塊約l 公分立方之組織塊,放入10%的中性福馬林中固定,接著以不同濃度之乙醇(30、50、70、95、99.5%)以及二甲苯(xylene)進行脫水與透明步驟,然後以熱石臘溶液取代二甲苯,最後以石蠟溶液將組織進行包埋。完成的石蠟標本利用切片機切成5μm的石蠟切片,將切片沾黏在乾淨載玻片上,於37℃烘乾後,用做進一步H&E染色。
1.10
蘇木紫
-
伊紅染色(
hematoxylin and eosin stain
,
H&E
)染色法
將肝臟組織切片置入二甲苯30分鐘脫蠟,再依序置於 99.5、95、70、50及30 %乙醇各30分鐘以進行複水,再浸泡於蒸餾水10分鐘後即可染色。首先浸泡蘇木精30秒染細胞核,再用蒸餾水清洗數分鐘,接著使用伊紅染色2-5分鐘,用蒸餾水清洗數分鐘。完成染色過程後進行脫水流程,依序放置於 50、70、95 及100% 酒精兩次中 各30 秒,再以二甲苯進行透明化兩次,最後以封片膠封存。
1.11
組織病理學的觀察
為觀察肝損傷時,肝細胞的受損、脂肪堆積、壞死或是否有纖維化等變化,將肝組織做H&E染色以評估肝脂肪堆積程度。為避免觀察主觀上的偏差,所有的組織病理切片都是由最大右葉肝的同一位置切取下來,再去做病理染色。至於病理的半定量分析之評估,應由人醫或獸醫病理醫師進行雙盲分析確認,在不清楚本實驗設計的情況下,對所有切片進行評分比較(NAS score)16
,最後再以統計分析方法進行各組差異性的分析。
1.12
肝臟抗氧化分析
取犧牲動物的肝組織約0.1克,以勻漿器(biomasher)離心均質10分鐘,再加入9倍肝重(w/w)的緩衝液(pH 7.4,50 mmol/L Tris–HCl,180 mmol/L KCl),再以試管震動機(Vortex)混勻備用。取所得之肝組織均質液樣品進行各種肝抗氧化系統成員之分析,包括麩胱甘肽過氧化酶(glutathione peroxidase,GPx)、榖胱甘肽(glutathione,GSH)、麩胱甘肽還原酶(glutathione reductase, GRd)、及超氧化物歧化酶(superoxide dismutase, SOD),相關分析方式可參見已知文獻,如(臺灣衛生福利部公佈的健康食品之護肝保健功效評估方法草案)。
1.13
統計分析
所有的資料皆以平均±標準差(SD)表示,試驗結果以單因數變異數分析(ANOVA)測試法來計算是否具有統計上的顯著差異,使用社會科學統計套裝軟體(Statistical Package of the Social Science program ,Version 13, SPSS Inc.)來計算;隨後使用事後比較(post hoc test)最小差異顯著性(least significant difference)方法做多重比較,以確認族群間的顯著差異;族群平均之顯著差異為p
< 0.05。
2.
結果
2.1
細胞實驗
在細胞實驗中,陽性對照組(水飛薊素)所測出降低HepG2細胞TG含量結果如表2所示。 表2: 陽性對照組之水飛薊素降低HepG2脂肪細胞中TG含量之作用。
以固定試驗化合物之測試濃度,所測出降低HepG2脂肪細胞TG含量之結果如表3所示。結果顯示,在固定測試濃度條件下,與對照組相比,試驗化合物對HepG2細胞經誘導形成之脂肪肝細胞展現不同程度之降低肝細胞TG含量之效果。TG降低率(%)計算公式為:[1 - (試驗組TG含量 - 空白組TG含量) / (油酸誘導組TG含量 - 空白組TG含量)] x 100 %。
表3:試驗化合物可降低脂肪肝細胞之TG含量
表3-1:來自表3的部分試驗化合物可降低脂肪肝細胞之TG含量
表3-2:來自表3的部分試驗化合物(生物類黃酮)可降低脂肪肝細胞之TG含量
表3-3:來自表3的部分試驗化合物(賦形劑)可降低脂肪肝細胞之TG含量
2.2
動物實驗
在動物實驗中,除空白組給予正常飼料外,其餘動物給予誘導脂肪肝處理,8周後,各組動物除維持給予原飼料外,再給予不同處理達4周或8周,其中,空白對照組及高脂對照組給予去離子水,正向對照組給予水飛薊素,以及試驗組給予不同試驗化合物,包括葛根素、根皮苷、聖草酚、三氯蔗糖、甘露醇、糖精、橙皮、薄荷醇、或部分試驗化合物之組合。
2.2.1
試驗化合物對動物體重、肝重、體脂肪重的影響及安全性評估
動物實驗的結果顯示,各組間動物之肝重、體脂肪重與體重增加量結果如表4-1與4-2。
表4-1:試驗化合物之肝重、體脂肪重分析結果。
表4-2:試驗化合物之體重增加量分析結果。
結果顯示,誘導脂肪肝動物腹部脂肪重量增加,在投予單一試驗化合物時,甘露醇、薄荷醇、及三氯蔗糖可顯著降低動物腹部脂肪重量。
此外,試驗組投予不同試驗化合物後,動物無任何異常症狀,試驗期間無造成任何動物的死亡,試驗後犧牲動物剖檢,亦無觀察到因試驗化合物所造成之病變或臨床征狀的發生,故該等試驗化合物安全無虞。
2.2.2
試驗化合物具降低肝臟脂質的作用
圖1顯示誘導脂肪肝小鼠,在肝門管區(包括膽管、門靜脈、肝動脈)附近肝臟細胞佈滿許多大泡狀脂肪油滴,肝細胞出現氣球化,成功誘導產生脂肪肝動物模式。
動物實驗的結果顯示,多種試驗化合物在為期4周或8周的給藥期間後,顯示降低動物肝臟脂質的作用。結果顯示於表5-1及表5-2。
表5-1:試驗化合物可降低動物之肝臟脂質(4周的給藥期間)
表5-2:試驗化合物可降低動物之肝臟脂質(8周的給藥期間)
結果顯示,誘導脂肪肝小鼠肝臟中的三酸甘油酯及總膽固醇上升。在投予單一試驗化合物時,橙皮 、葛根素 、聖草酚、根皮苷、甘露醇、薄荷醇、及三氯蔗糖可顯著降低肝臟中的三酸甘油酯;尤其,聖草酚處理4周時,達優異效果,可降低約67 % 肝臟三酸甘油酯含量(p<0.005)。此外,橙皮 、聖草酚、根皮苷、甘露醇、薄荷醇、三氯蔗糖、糖精可顯著降低肝臟中的總膽固醇;尤其,糖精處理4周時,達優異效果,可降低約56 %肝臟總膽固醇含量(p<0.005)。
在投予二種試驗化合物之組合時,糖精與甘露醇的組合、薄荷醇與甘露醇的組合、三氯蔗糖與甘露醇的組合、聖草酚與甘露醇的組合、或聖草酚與三氯蔗糖的組合,可有效降低肝臟中的三酸甘油酯;尤其,薄荷醇與甘露醇的組合處理4周時,達優異效果,可降低約77 % 肝臟三酸甘油酯含量(p<0.005);聖草酚與三氯蔗糖的組合處理8周時,達優異效果,可降低約78 % 肝臟三酸甘油酯含量(p<0.005)。此外,三氯蔗糖與甘露醇的組合、聖草酚與甘露醇的組合、或聖草酚與三氯蔗糖的組合,可顯著降低肝臟中的總膽固醇;其中,聖草酚與三氯蔗糖的組合處理8周時,達優異效果,可降低約77%肝臟總膽固醇含量(p<0.005)。
在投予三種試驗化合物之組合時,薄荷醇、甘露醇、聖草酚的組合、三氯蔗糖、甘露醇、聖草酚的組合,可有效降低肝臟中的三酸甘油酯;尤其,三氯蔗糖、甘露醇、聖草酚的組合處理8周時,達優異效果,可降低約79 % 肝臟三酸甘油酯含量(p<0.005)。此外,三氯蔗糖、甘露醇、聖草酚的組合,可顯著降低肝臟中的總膽固醇。
2.2.3
試驗化合物具降低肝損傷的作用
2.2.3.1
降低肝組織之脂肪肝及肝損傷的作用
動物實驗的結果顯示,多種試驗化合物在為期4周的試驗期間顯示可降低動物之脂肪肝及肝組織損傷情形。圖1顯示,脂肪肝動物肝組織損傷,包括在肝門管區(包括膽管、門靜脈、肝動脈)附近肝臟細胞佈滿許多大泡狀脂肪油滴,肝細胞出現氣球化。相較之下,經水飛薊素、薄荷醇、聖草酚、或甘露醇治療4周後,肝臟組織切片在肝臟細胞內大泡狀脂肪油滴大量減少,其中,經水飛薊素治療的小鼠仍觀察到部分小破狀油滴,但經薄荷醇、聖草酚、或甘露醇治療的小鼠的肝臟組織型態比較接近空白組,表示脂肪肝病變比較輕微。此外,NAS評分結果顯示於表6。
表6:試驗化合物可降低動物之肝損傷情形
NAS (Nonalcoholic Fatty Liver Disease Activity Score)分數指的是非酒精性脂肪肝病活性分數[Hepatology. 2005 Jun;41(6):1313-21.],綜合評估脂肪變性(steatosis)、肝小葉發炎(lobular inflammation)及肝臟細胞氣球化(hepatocyte ballooning)程度,評分表如表7,分數越高表示肝損傷越嚴重。
結果顯示,誘導脂肪肝小鼠肝組織損傷(NAS分數上升)。在投予單一試驗化合物時,聖草酚與甘露醇可顯著降低肝損傷。值得注意的是,在投予二種試驗化合物之組合時,薄荷醇與甘露醇的組合,達優異效果,幾乎未顯現肝損傷,其NAS分數與空白組相同。
2.2.3.2
降低肝功能損傷的作用
動物實驗的結果顯示,多種試驗化合物在為期4周或8周的給藥期間顯示可降低動物之肝功能損傷情形。結果顯示於表8-1及表8-2。
表8-1:試驗化合物可降低動物之肝功能損傷情形(4周的給藥期間)
表8-2:試驗化合物可降低動物之肝功能損傷情形(8周的給藥期間)
ALT和AST是最常用來反映肝臟生化功能損傷的酶指針。這些酶正常情況下存在於肝細胞內,當肝細胞受到破壞時便會洩露出來,血清中的ALT和AST數值上升通常可反映肝發炎及肝功能有損傷情形。
結果顯示,誘導脂肪肝動物肝功能受損(ALT和AST數值上升)。在投予單一試驗化合物時,橙皮 、葛根素 、聖草酚、根皮苷、甘露醇、薄荷醇、三氯蔗糖、及糖精均可顯著降低ALT和AST數值。尤其,甘露醇處理4周時,達優異效果,可降低約64 % ALT數值(p<0.005)及約60% AST數值(p<0.005)。
在投予二種試驗化合物之組合時,薄荷醇與甘露醇的組合或聖草酚與三氯蔗糖的組合可顯著降低ALT數值;薄荷醇與甘露醇的組合、三氯蔗糖與甘露醇的組合、或糖精與甘露醇的組合,可顯著降低AST數值。尤其,薄荷醇與甘露醇的組合處理4周時,達優異效果,可降低約76 % ALT數值(p<0.005)及約62% AST數值(p<0.005)。
在投予三種試驗化合物之組合時,三氯蔗糖、甘露醇、聖草酚的組合可顯著降低ALT數值(p<0.005)。
2.2.4
試驗化合物具提高肝臟抗氧化能力
動物實驗的結果顯示,多種試驗化合物在為期4周的試驗期間顯示可提升動物肝臟抗氧化能力。結果顯示於表9-1及表9-2。
表9-1:試驗化合物可提升動物肝臟抗氧化能力(Gpx及GSH)
表9-2:試驗化合物可提升動物肝臟抗氧化能力(Grd及SOD)
Gpx、GSH、 Grd及SOD是常見的肝臟抗氧化系統成員,可降低肝臟的氧化壓力,使肝臟免於受到氧化壓力導致的傷害。Gpx、GSH、 Grd及SOD的數值提高代表肝臟維持較佳的抗氧化活性。
結果顯示,誘導脂肪肝小鼠動物抗氧化活性降低。在投予單一試驗化合物時,橙皮 、葛根素 、聖草酚、根皮苷、甘露醇、三氯蔗糖均可顯著提高髒抗氧化活性。尤其,甘露醇處理4周時,達優異效果,大幅提高Gpx、GSH、 Grd及SOD的水準(p<0.005)。
綜上,本發明所提供之化合物可降低肝脂肪含量、降低肝損傷及提高肝臟抗氧化活性。該等化合物屬於低分子天然植物酚類化合物,係廣泛存在於蔬果、穀物、根莖、花卉、茶葉與紅葡萄酒等,經動物試驗確認安全無虞,具有發展成為降肝脂、改善相關病症,如脂肪肝、急性與慢性酒精性脂肪肝、急性與慢性非酒精性脂肪肝(Non-alcoholic Fatty Liver Disease, NAFLD)、急性與慢性酒精性肝炎、急性與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 Code 571.8, 571.0, 571.1, 571.2, 571.3, 571.4, 571.5, 571.9)等病症之保健食品或藥物之潛力。 參考文獻 1.Brunt EM
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無
欲說明本發明,圖式具體實施例如下。然而,應理解到,本發明未局限於所示之較佳具體實施例。在圖式中:
圖1顯示小鼠誘導產生脂肪肝後,再依組別給予不同之試驗物質治療4周後之肝臟組織切片。
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Claims (34)
- 一種化合物用於製備預防或治療脂肪肝、保護肝功能、或改善脂肪肝引起的肝病變或其他相關病症之組合物的用途,其中該化合物係選自於以下所組成群組:硫酸月桂酸鈉(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)、苯甲酸鈉(sodium benzoate)、氧化鐵紅(oxide red)、預糊化澱粉(pregelatinized starch)、環己烷氨基磺酸鈉 (sodium cyclamate)、山梨酸 (sorbic acid)、檸檬油 (lemon oil)、檸檬酸 (citric acid)、及丁基羥基茴香醚(butylated hydroxyanisole)、枸橘苷(poncirin)、異牡荊素(isovitexin)、聖草酚(eriodictyol)、麥角固醇(ergosterol)、月桂烯(β-myrcene)、金絲桃苷(hyperoside)、兒茶素((+)-catechin)、高良薑素(galangin)、桑葉素(morin)、金松雙黃酮(sciadopitysin)、香風草甙(didymin)、棉纖維素(gossypin)、木犀草素-7-葡萄糖甙(luteolin-7-Glucoside)、雙氫槲皮素((+)-taxifolin)、肉桂酸(trans-cinnamic acid)、香葉木素(diosmin)、蒙花甙(linarin)木糖醇(xylitol)、木犀草素(luteolin)、獐牙菜苦素(swertiamarin)、及其任何組合。
- 根據請求項1之用途,其中該化合物係選自於以下所組成群組:硫酸月桂酸鈉(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)、苯甲酸鈉(sodium benzoate)、氧化鐵紅(oxide red)、預糊化澱粉(pregelatinized starch)、環己烷氨基磺酸鈉 (sodium cyclamate)、山梨酸 (sorbic acid)、檸檬油 (lemon oil)、檸檬酸 (citric acid)、及丁基羥基茴香醚(butylated hydroxyanisole)、及其任何組合。
- 根據請求項1之用途,其中該化合物係選自於以下所組成群組:枸橘苷(poncirin)、異牡荊素(isovitexin)、聖草酚(eriodictyol)、麥角固醇(ergosterol)、月桂烯(β-myrcene)、金絲桃苷(hyperoside)、兒茶素((+)-catechin)、高良薑素(galangin)、桑葉素(morin)、金松雙黃酮(sciadopitysin)、香風草甙(didymin)、棉纖維素(gossypin)、木犀草素-7-葡萄糖甙(luteolin-7-Glucoside)、雙氫槲皮素((+)-taxifolin)、肉桂酸(trans-cinnamic acid)、香葉木素(diosmin)、蒙花甙(linarin)、木糖醇(xylitol)、木犀草素(luteolin)、獐牙菜苦素(swertiamarin)、及其任何組合。
- 根據請求項1之用途,其中該化合物係選自於以下所組成群組:聖草酚(eriodictyol)、甘露醇(mannitol)、薄荷醇(menthol)、三氯蔗糖(sucralose)、糖精(saccharin)、及其任何組合。
- 根據請求項1之用途,其中該化合物係選自於以下所組成群組:(1)糖精與 甘露醇的組合、(2)薄荷醇與甘露醇的組合、(3)三氯蔗糖與甘露醇的組合、(4)聖草酚與 甘露醇的組合、(5)聖草酚與三氯蔗糖、(6)薄荷醇、甘露醇、聖草酚、或(7)三氯蔗糖、甘露醇、聖草酚的組合。
- 根據請求項1至5中任一項之用途,其中該化合物進一步包括葛根素(puerarin)、根皮苷(phloridzin)、甜橙黃酮(sinensetin)、(-)-表沒食子兒茶素((-)-epigallocatechin)、山柰(kaempferol)、熊果酸(ursolic acid)、水飛薊素、(silymarin)、(+)-檸檬油精((+)-limonene)、橙皮甙(hesperidin)、(-)-表兒茶素-3-沒食子酸酯((-)-epicatechin-3-gallate)、水飛薊賓(silybin)、芒柄花黃素(formononetin)、十四烷酸乙酯(myristic acid ethyl ester)、二十碳五烯酸(eicosapentaenoic acid, EPA)、漢黃芩素(wongonin)、聚維酮K-30(povidone K-30)、原兒茶酸(protocatechuic acid)、傘形酮(umbelliferone)、橙皮(hesperitin)、去甲二氫愈創木酸(nordihydroguaiaretic acid)、新橙皮苷(neohesperidin)、柚皮苷(naringin)、(-)-表兒茶素((-)-epicatechin)、甘草甜素(glycyrrhizin)、黃芩苷(baicalin)、斛皮素(quercitrin)、及/或黃芩甙元(baicalein)。
- 根據請求項6之用途,其中該組合物係用於降低個體之肝脂肪含量。
- 根據請求項6之用途,其中該組合物係用於降低個體之肝細胞之脂肪含量。
- 根據請求項6之用途,其中該組合物係用於降低個體之肝損害。
- 根據請求項9之用途,其中該肝損害包括肝組織損害或肝功能損害。
- 根據請求項6之用途,其中該組合物係用於提高肝臟抗氧化活性。
- 根據請求項6之用途,其中該肝病變或其他相關病症係選自於以下所組成的群組、急性與慢性酒精性脂肪肝、急性與慢性非酒精性脂肪肝、急性與慢性酒精性肝炎、急性與慢性非酒精性脂肪肝炎、非酒精性肝硬化、及酒精性肝硬化。
- 根據請求項1至5中任一項之用途,其中該組合物可施用於非酒精性脂肪肝疾病之患者或肥胖者。
- 根據請求1至5中任一項之用途,其中該組合物為藥物、食品添加物或健康食品。
- 一種組合物,其包括選自於以下所組成之群組的任何兩種或以上的化合物:硫酸月桂酸鈉(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)、苯甲酸鈉(sodium benzoate)、氧化鐵紅(oxide red)、預糊化澱粉(pregelatinized starch)、環己烷氨基磺酸鈉 (sodium cyclamate)、山梨酸 (sorbic acid)、檸檬油 (lemon oil)、檸檬酸 (citric acid)、丁基羥基茴香醚(butylated hydroxyanisole)、枸橘苷(poncirin)、異牡荊素(isovitexin)、聖草酚(eriodictyol)、麥角固醇(ergosterol)、月桂烯(β-myrcene)、金絲桃苷(hyperoside)、兒茶素((+)-catechin)、高良薑素(galangin)、桑葉素(morin)、金松雙黃酮(sciadopitysin)、香風草甙(didymin)、棉纖維素(gossypin)、木犀草素-7-葡萄糖甙(luteolin-7-Glucoside)、雙氫槲皮素((+)-taxifolin)、肉桂酸(trans-cinnamic acid)、香葉木素(diosmin)、蒙花甙(linarin)、異紅草素(homoorientin)、木糖醇(xylitol)、木犀草素(luteolin)、獐牙菜苦素(swertiamarin)、。
- 根據請求項15之組合物,其包括選自於以下所組成之群組的任何兩種或以上的化合物:硫酸月桂酸鈉(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)、苯甲酸鈉(sodium benzoate)、氧化鐵紅(oxide red)、預糊化澱粉(pregelatinized starch)、環己烷氨基磺酸鈉 (sodium cyclamate)、山梨酸 (sorbic acid)、檸檬油 (lemon oil)、檸檬酸 (citric acid)、及丁基羥基茴香醚(butylated hydroxyanisole)。
- 根據請求項15之組合物,其包括選自於以下所組成之群組的任何兩種或以上的化合物:枸橘苷(poncirin)、異牡荊素(isovitexin)、聖草酚(eriodictyol)、麥角固醇(ergosterol)、月桂烯(β-myrcene)、金絲桃苷(hyperoside)、兒茶素((+)-catechin)、高良薑素(galangin)、桑葉素(morin)、金松雙黃酮(sciadopitysin)、香風草甙(didymin)、棉纖維素(gossypin)、木犀草素-7-葡萄糖甙(luteolin-7-Glucoside)、雙氫槲皮素((+)-taxifolin)、肉桂酸(trans-cinnamic acid)、香葉木素(diosmin)、蒙花甙(linarin)、木糖醇(xylitol)、木犀草素(luteolin)、及獐牙菜苦素(swertiamarin)。
- 根據請求項15之組合物,其包括選自於以下所組成之群組的任何兩種或以上的化合物:、聖草酚(eriodictyol)、甘露醇(mannitol)、薄荷醇(menthol)、三氯蔗糖(sucralose)、及糖精(saccharin)。
- 根據請求項15之組合物,其包括選自於以下所組成之群組的組合:(1)糖精與 甘露醇的組合、(2)薄荷醇與甘露醇的組合、(3)三氯蔗糖與甘露醇的組合、(4)聖草酚與 甘露醇的組合、(5)聖草酚與三氯蔗糖、(6)薄荷醇、甘露醇、聖草酚、或(7)三氯蔗糖、甘露醇、聖草酚的組合。
- 根據請求項15至19中任一項之組合物,其進一步包括葛根素(puerarin)、根皮苷(phloridzin)、甜橙黃酮(sinensetin)、(-)-表沒食子兒茶素((-)-epigallocatechin)、山柰(kaempferol)、熊果酸(ursolic acid)、水飛薊素、(silymarin)、(+)-檸檬油精((+)-limonene)、橙皮甙(hesperidin)、(-)-表兒茶素-3-沒食子酸酯((-)-epicatechin-3-gallate)、水飛薊賓(silybin)、芒柄花黃素(formononetin)、十四烷酸乙酯(myristic acid ethyl ester)、二十碳五烯酸(eicosapentaenoic acid, EPA)、漢黃芩素(wongonin)、聚維酮K-30(povidone K-30)、原兒茶酸(protocatechuic acid)、傘形酮(umbelliferone)、橙皮(hesperitin)、去甲二氫愈創木酸(nordihydroguaiaretic acid)、新橙皮苷(neohesperidin)、柚皮苷(naringin)、(-)-表兒茶素((-)-epicatechin)、甘草甜素(glycyrrhizin)、黃芩苷(baicalin)、斛皮素(quercitrin)、及/或黃芩甙元(baicalein)。
- 根據請求項20之組合物,其中該化合物各自或組合係以可降低個體之肝脂肪含量或改善相關病症之有效量存在於該組合物中。
- 根據請求項20之組合物,其中該化合物各自或組合係以可降低個體之肝細胞之脂肪含量之有效量存在於該組合物中。
- 根據請求項20之組合物,其中該化合物各自或組合係以可降低個體之肝損害之有效量存在於該組合物中。
- 根據請求項23之組合物,其中該肝損害包括肝組織損害或肝功能損害。
- 根據請求項20之組合物,其中該化合物各自或組合係以可提高肝臟抗氧化活性之有效量存在於該組合物中。
- 根據請求項20之組合物,其中該化合物各自或組合係以可治療或預防脂肪肝、急性與慢性酒精性脂肪肝、急性與慢性非酒精性脂肪肝、急性與慢性酒精性肝炎、急性與慢性非酒精性脂肪肝炎、非酒精性肝硬化、及酒精性肝硬化之有效量存在於該組合物中。
- 根據請求20之組合物,其中該組合物為藥物、食品添加物或健康食品。
- 一種在有需要的個體預防或治療脂肪肝、保護肝功能、或改善脂肪肝引起的肝病變或其他相關病症之方法,其包括將有效量的化合物投用於該個體,其中該化合物係選自於以下所組成群組:硫酸月桂酸鈉(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)、苯甲酸鈉(sodium benzoate)、氧化鐵紅(oxide red)、預糊化澱粉(pregelatinized starch)、環己烷氨基磺酸鈉 (sodium cyclamate)、山梨酸 (sorbic acid)、檸檬油 (lemon oil)、檸檬酸 (citric acid)、及丁基羥基茴香醚(butylated hydroxyanisole)、枸橘苷(poncirin)、異牡荊素(isovitexin)、聖草酚(eriodictyol)、麥角固醇(ergosterol)、月桂烯(β-myrcene)、金絲桃苷(hyperoside)、兒茶素((+)-catechin)、高良薑素(galangin)、桑葉素(morin)、金松雙黃酮(sciadopitysin)、香風草甙(didymin)、棉纖維素(gossypin)、木犀草素-7-葡萄糖甙(luteolin-7-Glucoside)、雙氫槲皮素((+)-taxifolin)、肉桂酸(trans-cinnamic acid)、香葉木素(diosmin)、蒙花甙(linarin)、異紅草素(homoorientin)、木糖醇(xylitol)、犀草素(luteolin)、獐牙菜苦素(swertiamarin)、及其任何組合。
- 一種化合物用於製備降低肝脂肪含量及改善相關病症之組合物的用途,其中該化合物係選自於以下所組成群組:硫酸月桂酸鈉(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)、苯甲酸鈉(sodium benzoate)、氧化鐵紅(oxide red)、預糊化澱粉(pregelatinized starch)、環己烷氨基磺酸鈉 (sodium cyclamate)、山梨酸 (sorbic acid)、檸檬油 (lemon oil)、檸檬酸 (citric acid)、及丁基羥基茴香醚(butylated hydroxyanisole)、枸橘苷(poncirin)、異牡荊素(isovitexin)、聖草酚(eriodictyol)、麥角固醇(ergosterol)、月桂烯(β-myrcene)、金絲桃苷(hyperoside)、兒茶素((+)-catechin)、高良薑素(galangin)、桑葉素(morin)、金松雙黃酮(sciadopitysin)、香風草甙(didymin)、棉纖維素(gossypin)、木犀草素-7-葡萄糖甙(luteolin-7-Glucoside)、雙氫槲皮素((+)-taxifolin)、肉桂酸(trans-cinnamic acid)、香葉木素(diosmin)、蒙花甙(linarin)木糖醇(xylitol)、木犀草素(luteolin)、獐牙菜苦素(swertiamarin)、及其任何組合。
- 根據請求項29之用途,其中該化合物係選自於以下所組成群組:硫酸月桂酸鈉(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)、苯甲酸鈉(sodium benzoate)、氧化鐵紅(oxide red)、預糊化澱粉(pregelatinized starch)、環己烷氨基磺酸鈉 (sodium cyclamate)、山梨酸 (sorbic acid)、檸檬油 (lemon oil)、檸檬酸 (citric acid)、及丁基羥基茴香醚(butylated hydroxyanisole)、及其任何組合。
- 根據請求項29之用途,其中該化合物係選自於以下所組成群組:枸橘苷(poncirin)、異牡荊素(isovitexin)、聖草酚(eriodictyol)、麥角固醇(ergosterol)、月桂烯(β-myrcene)、金絲桃苷(hyperoside)、兒茶素((+)-catechin)、高良薑素(galangin)、桑葉素(morin)、金松雙黃酮(sciadopitysin)、香風草甙(didymin)、棉纖維素(gossypin)、木犀草素-7-葡萄糖甙(luteolin-7-Glucoside)、雙氫槲皮素((+)-taxifolin)、肉桂酸(trans-cinnamic acid)、香葉木素(diosmin)、蒙花甙(linarin)、木糖醇(xylitol)、木犀草素(luteolin)、獐牙菜苦素(swertiamarin)、及其任何組合。
- 根據請求項29之用途,其中該化合物係選自於以下所組成群組:聖草酚(eriodictyol)、甘露醇(mannitol)、薄荷醇(menthol)、三氯蔗糖(sucralose)、糖精(saccharin)、及其任何組合。
- 根據請求項29之用途,其中該化合物係選自於以下所組成群組:(1)糖精與 甘露醇的組合、(2)薄荷醇與甘露醇的組合、(3)三氯蔗糖與甘露醇的組合、(4)聖草酚與 甘露醇的組合、(5)聖草酚與三氯蔗糖、(6)薄荷醇、甘露醇、聖草酚、或(7)三氯蔗糖、甘露醇、聖草酚的組合。
- 根據請求項29至33中任一項之用途,其中該化合物進一步包括葛根素(puerarin)、根皮苷(phloridzin)、甜橙黃酮(sinensetin)、(-)-表沒食子兒茶素((-)-epigallocatechin)、山柰(kaempferol)、熊果酸(ursolic acid)、水飛薊素、(silymarin)、(+)-檸檬油精((+)-limonene)、橙皮甙(hesperidin)、(-)-表兒茶素-3-沒食子酸酯((-)-epicatechin-3-gallate)、水飛薊賓(silybin)、芒柄花黃素(formononetin)、十四烷酸乙酯(myristic acid ethyl ester)、二十碳五烯酸(eicosapentaenoic acid, EPA)、漢黃芩素(wongonin)、聚維酮K-30(povidone K-30)、原兒茶酸(protocatechuic acid)、傘形酮(umbelliferone)、橙皮(hesperitin)、去甲二氫愈創木酸(nordihydroguaiaretic acid)、新橙皮苷(neohesperidin)、柚皮苷(naringin)、(-)-表兒茶素((-)-epicatechin)、甘草甜素(glycyrrhizin)、黃芩苷(baicalin)、斛皮素(quercitrin)、及/或黃芩甙元(baicalein)。
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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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HK1244213A1 (zh) | 2018-08-03 |
CN116440143A (zh) | 2023-07-18 |
TWI711464B (zh) | 2020-12-01 |
CN107613968A (zh) | 2018-01-19 |
JP2023145714A (ja) | 2023-10-11 |
JP2021105037A (ja) | 2021-07-26 |
JP2018534323A (ja) | 2018-11-22 |
WO2017084234A1 (zh) | 2017-05-26 |
EP3391881A4 (en) | 2020-03-11 |
EP3391881A1 (en) | 2018-10-24 |
US20180117003A1 (en) | 2018-05-03 |
US10925854B2 (en) | 2021-02-23 |
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