CN100486601C - 鬼针草醇提取物在制备防治非酒精性脂肪肝药物中的应用 - Google Patents
鬼针草醇提取物在制备防治非酒精性脂肪肝药物中的应用 Download PDFInfo
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- CN100486601C CN100486601C CN 200510097344 CN200510097344A CN100486601C CN 100486601 C CN100486601 C CN 100486601C CN 200510097344 CN200510097344 CN 200510097344 CN 200510097344 A CN200510097344 A CN 200510097344A CN 100486601 C CN100486601 C CN 100486601C
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- alcohol extract
- fatty liver
- herb
- alcoholic fatty
- liver
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Abstract
本发明涉及鬼针草醇提取物在制备防治非酒精性脂肪肝药物中的新用途。鬼针草醇提取物是从中药材鬼针草中提取的有效成分,可明显降低高脂饮食脂肪肝动物模型和药物中毒性脂肪肝动物模型中的脂质,对脂肪肝模型中的肝细胞有保护作用。用于预防或治疗非酒精性脂肪肝采用口服给药,服用方便,毒副作用小,长期服药无危害。
Description
技术领域
本发明涉及鬼针草醇提取物的新用途,尤其涉及鬼针草醇提取物在制药领域中的用途,确切的说是在制备防治非酒精性脂肪肝药物中的用途。
背景技术
鬼针草又名婆婆针、鬼杈草、小鬼针、粘身草等,其药用历史悠久,始载于唐·陈藏器《本草拾遗》,谓:“鬼钗草,味苦平,无毒,主蛇及蜘蛛咬,杵碎傅之,亦杵绞汁服。生地畔,有桠,方茎,子作钗脚,着人如衣针,北方呼之为鬼针。”鬼针草类药材全草均可用药,味苦性平而无毒,具有清热解毒,散瘀消肿等功效,主治疟疾、腹泻、痢疾、肝炎、急性肾炎、胃痛、噎膈、肠痈、咽喉肿痛、跌打损伤、蛇虫咬伤等。为了更好的认识和了解这一自然资源,更好的开发与利用,现将鬼针草的研究与开发现状综述如下。
鬼针草为菊科(Compositae)管状花亚科鬼针草属(Bidens L.)植物为一年生草本,其药材资源非常丰富,主要分布于我国东北、河北、山东、山西、河南、江苏、云南、四川、两广等地,生于水边、河岸、湿地、荒地及山坡等处,极易采集。
鬼针草的化学成分:
鬼针草所含化学成分种类较多,文献报道曾从该植物中分离得到挥发油类、甾醇、查耳酮、橙酮、聚乙炔类等,其活性成分以聚乙炔类和黄酮类成分为主。已分离出多种聚乙炔类成分。乙醇提取物的正丁醇部分鉴定出4个黄酮成分,为金丝桃甙(hyperoside)、奥卡宁(okanin)、异奥卡宁-7-0-葡萄糖甙和海生菊甙(maritimein)。鬼针草各部位中黄酮类成分有较大差异,在花果期,叶和花序中总黄酮含量较高(分别为6.67%和6.68%),茎枝中含量较低(0.89%)。叶中分离鉴定了21种挥发性成分,主要为脂肪烷和脂肪酸类,另外含少量的醛、酮烯、腈、胺及呋喃类成分;其中脂肪类化合物占相当比例。分离出的4种酚酸类成分,经理化测试及光谱分析,分别鉴定为水杨酸、原儿茶酸、没食子酸、脂肪酸类化合物。还有甾体类化合物如菠甾醇、胡萝卜苷,谷甾醇、豆甾醇-3-O-β-D-葡萄糖苷。
鬼针草含有丰富的氨基酸,如天冬氨酸、苏氨酸、丝氨酸、谷氨酸、丙氨酸、缬氨酸、异亮氨酸、脯氨酸、酪氨酸、赖氨酸等17种氨基酸,其中8种为人体必需氨基酸,总蛋白质157.89g/kg,总游离氨基酸含量达139.89g/kg,必需氨基酸总量57.09g/kg。鬼针草所含氨基酸与传统名贵药材亚香棒虫草、冬虫夏草相比,在种类上多了胱氨酸,在含量上脯氨酸、谷氨酸高于两者,其他氨基酸含量相当
另外鬼针草中还含有11种人体必需微量元素,测定结果表明,Mg含量最高,P、Fe、Ca含量较高,Cu、Zn次之,Mn、Co、Ni、Mo、Cr含量最低,鬼针草中含有丰富的P,是其调节神经、催眠、镇静等作用的内在原因。
维生素在鬼针草中也有分布,如维生素B1、维生素B2、β-胡萝卜素。
鬼针草药材资源丰富,药用历史悠久,在民间验方中有小人参之称。其生物活性多样,且作用温和持久,具有较高的药用价值,尤其对消化系统、中枢神经系统及心血管系统显示较强的药理作用。近年来对鬼针草药材进行了一些开发和利用,目前国内的鬼针草产品有悦年片、鬼针草口服液、鬼针草保健冲剂等,但也仅限于防治高血压等心血管疾病,还未见对鬼针草醇提取物在制备防治非酒精性脂肪肝药物方面的报道。
发明内容
本发明的目的是提供鬼针草醇提取物的新用途,即在制药中的新应用。
实际上,本发明提供了鬼针草醇提取物在制备预防或治疗非酒精性脂肪肝的药物中的应用。
近年来,随着我国人民物质生活的不断提高,非酒精性脂肪肝(NASH)的发病率逐年上升,在某些地区非酒精性脂肪肝NASH已超过病毒性肝炎而成为第一大肝病。非酒精性脂肪肝NASH是一类与酒精性肝病相似的肝脏组织学改变,但无过量饮酒史(摄入酒精<40g/d)的临床病理综合征,通常原发于与胰岛素抵抗相关的肥胖、II型糖尿病、高脂血症、高血压等代谢紊乱。既往认为,脂肪肝为良性病变,不会发展为肝纤维化、肝硬化,但大量临床肝活检研究证实,非酒精性脂肪肝NASH在脂肪性肝炎的基础上约40%-50%会发展为肝纤维化,15%-20%可发展为肝硬化,甚至会导致肝细胞癌的发生。因此NASH的积极防治可阻止慢性肝病的进展,改善NASH患者的预后。
目前临床上用于治疗非酒精性脂肪肝NASH的措施主要包括(1)去除病因和诱因;(2)控制饮食;(3)运动疗法;(4)药物干预等。近年来治疗NASH的药物发展很快,其主要治疗药物有:
A、针对改善胰岛素抵抗,增加胰岛素敏感的药物。如二甲双呱,能明显改善患者的糖耐量和高胰岛素血症,降低血浆游离脂肪酸和血浆甘油三酯水平。其主要不良反应是消化道症状,有心、肾功能障碍的老年患者有发生乳酸中毒的危险,目前尚无随机双盲对照实验研究证实该药可以安全用于治疗非酒精性脂肪肝。
B、抑制过氧化作用药物。如维生素类,主要通过抑制过氧化自由基的形成,防止细胞受损,但维生素A、E均属于脂溶性维生素,大剂量补充易产生蓄积中毒而加重肝损害。
C、针对高脂血症的药物,但许多降血脂药可促进血脂更集中于肝脏进行代谢,反而可能促进脂质在肝内的蓄积,并进一步损害肝功能。
D、熊去氧胆酸,能够降低非酒精性脂肪肝患者血清酶水平,但是不能改变肝脏脂肪沉积。
总的来说,虽然目前有大批治疗非酒精性脂肪肝的药物,但是尚缺乏安全有效、作用肯定的药物供临床使用。因此,积极寻找具有保肝、降血脂、抗脂肪肝的药物是非常必要的,而发挥中医药治疗的优势尤为重要。中医药治疗慢性脂肪性肝疾患的最大优点是副作用小,且在治疗的同时,对其相关联疾病如肥胖、高脂血症、高血压、糖尿病等有一定的治疗作用,故具有广阔的应用和开发前景。
根据传统中医理论,大多数慢性肝病患者的中医辩证诊断证型为肝郁脾虚证及淤血阻络证,相应的治疗应为益气养血,活血化瘀,舒肝健脾。本发明遵循这一治疗原则,基于长期治疗经验,发现鬼针草具有清热解毒,散瘀消肿等功效,不仅具有抗高血压、降血糖等作用,而且对非酒精性脂肪肝也有很好的治疗作用,为将其开发成对肝病作用的有效药物提供非常珍贵的依据。我们提取其有效部位,通过动物实验证实其有显著的防治非酒精性脂肪肝的作用。
为了更好地理解本发明的实质,下面将用鬼针草醇提取物的药理实验及结果来说明其在防治非酒精性脂肪肝药物中的应用。
鬼针草醇提取物防治非酒精性脂肪肝试验如下:
(一)鬼针草醇提取物的制备
取鬼针草生药粉碎,40-80%的乙醇回流提取2-3次,提取液合并,回收乙醇,减压浓缩得浸膏。浸膏水溶,静置,过滤,澄清液上树脂柱,水洗后收集40-95%乙醇洗脱部分,回收乙醇,减压浓缩,干燥即得鬼针草醇提取物。该醇提取物为黄绿色粉末,具有芳香味,易潮解;其主要成分为总黄酮,含量为20-60%。该醇提取物可加入相应辅料,制成片剂、胶囊、缓释片、滴丸、冲剂、微粒剂,并进一步纯化制成针剂。
(二)实验
1.鬼针草醇提取物对四氯化碳致小鼠急性化学性肝损伤的保护作用
(1)材料及试剂:鬼针草醇提取物;0.1% CCl4;联苯双酯;ALT,AST试剂盒:南京建成生物技术公司;昆明种雄性小鼠60只,体重18-22g,由安徽医科大学动物实验中心提供。
(2)方法:正常小鼠60只随机分6组,灌胃给药(鬼针草醇提取物80mg/kg、160mg/kg、320mg/kg,阳性药对照组联苯双酯100mg/kg)或等体积生理盐水(正常对照、模型),每天2次,连续7d,于末次给药后2h,正常对照组ip10ml/kg花生油,其余5组均ip0.1%CCl410ml/kg,禁食16h后自小鼠后眼眶静脉从取血,测定血清ALT,AST活性,并取肝脏左叶同一部位,固定,做病理切片,进行肝脏病理组织学HE染色检查,结果以光镜下肝脏病理损伤程度评分和病理照片作为标准。
肝组织病变程度分级方法:光镜下检查,按肝脏坏死程度分为5级:
0级,正常或肝脏有轻微变性,肝细胞无坏死;
I级,点状坏死,坏死占肝小叶<1/4;
II级,点灶状坏死,坏死占肝小叶1/4-1/3;
III级,灶状坏死,坏死占肝小叶<1/2;
IV级,片状坏死,坏死占肝小叶>1/2
(3)结果:表1结果表明,CCl4显著升高小鼠血清中ALT、AST活性,而鬼针草醇提取物显著降低CCl4致急性化学性肝损伤小鼠血清中过高的ALT、AST活性。
表1鬼针草总黄酮对小鼠血清中ALT、AST的影响(n=10,x±s)
**p<0.01与对照组相比;##p<0.01与模型组相比
表2结果显示,模型组肝组织可见炎症细胞浸润,出现不同程度的坏死。鬼针草醇提取物可明显减轻肝脏炎症细胞浸润和坏死。
表2鬼针草醇提取物对CCl4致急性化学性肝损伤小鼠病理组织学的影响
1、鬼针草醇提取物对大鼠高脂血症性脂肪肝的治疗作用
(1)材料与试剂:
SD大鼠66只,雌雄各半,体重180-200g,由安徽医科大学实验动物中心提供;鬼针草醇提取物;东宝肝泰片(上海九福药业有限公司);TG、TC、HDL-C测定试剂盒购自北京福瑞生物工程公司;ALT、MDA、SOD、GLU、FFA测定试剂盒购自南京建成生物工程研究所;
脂肪乳剂的制备:取猪油25g加入200mL的烧杯里,加热搅拌,加入10g胆固醇,溶化,再加入1g丙赛优,充分搅匀,然后加入25mL吐温80,制成油相。同时在另一烧杯中加入30mL蒸馏水和1-2丙二醇20mL,加热,然后加入2g脱氧胆酸钠,充分搅拌直到完全溶解,制成水相。然后将水相加入油相,充分混匀,即制成脂肪乳剂,使用前37℃水浴加热。
(2)方法:
SD大鼠在实验室饲养一周后,随机分为2组:正常组(n=12)、脂肪乳剂组(n=54)。脂肪乳剂组每天给予脂肪乳剂灌胃,同时正常组给予等体积CMC-Na。3W后,断尾取血测定TG,脂肪乳剂组取50只按血脂水平分为东宝肝泰组、鬼针草醇提取物(320、160、80mg·kg-1)组、模型组,除对照组和模型组给予等体积CMC-Na,其它各组分别给予相应药物。给药3周后处死动物,取出血清和肝脏,测定血清TG、TC、HDL-C、ALT、MDA、SOD、FFA和肝匀浆TG、MDA、SOD。
(3)结果
造摸3周时,脂肪乳剂组血脂已显著升高。从表3可见造摸6周时模型组血清TC和TG均显著高于对照组;与模型组相比,东宝肝泰组和鬼针草总黄酮组血清TG明显降低,血清HDL-C升高。表4血清ALT、S0D、MDA、FFA的变化中可见,与对照组相比,模型组ALT、FFA、MDA明显升高;与模型组相比,东保肝泰组和鬼针草醇提取物组FFA、MDA、ALT明显下降。表5可见肝匀浆中与对照组相比,模型组TG、MDA显著升高,SOD则降低;与模型组相比,东宝肝泰组和鬼针草醇提取物组能降低TG,MDA,鬼针草醇提取物组还能升高SOD。由此表明鬼针草醇提取物具有明显的抗大鼠高脂血症性脂肪肝的作用。
表3 第6周时各组血清脂质变化(x±s,n=10)
*p<0.05,**p<0.01与对照组相比;#p<0.05,##p<0.01与模型组相比
表4 各组血清ALT、MDA、SOD、FFA的变化(x±s,n=10)
*p<0.05,**p<0.01与对照组相比;#p<0.05,##p<0.01与模型组相比
表5 各组肝匀浆中TG、MDA、SOD的变化(x±s,n=10)
*p<0.05,**p<0.01与对照组相比;#p<0.05,##p<0.01与模型组相比
2、鬼针草醇提取物对乙硫氨酸致大鼠脂肪肝的影响
(1)方法:取SD大鼠66只,雌雄各半,体重为180-200g,分为6组,即空白对照组和模型组(灌胃给予等体积CMC-Na)、东宝肝泰组、鬼针草醇提取物(320、160、80mg·kg-1)。从试验第1天起,每天灌胃给药一次,连续给药3天,实验第4天起,除空白对照组外,其余5组分别按0.25g/kg体重灌胃给予乙硫氨酸一次,随后,按前法每12h给药一次,共4次。给予乙硫氨酸后48h,取血测定TC、TG和肝匀浆TC、TG。
(2)结果:
表6 鬼针草醇提取物对乙硫氨酸致大鼠脂肪肝的影响(x±s)
*p<0.05,**p<0.01与模型组相比
由表6结果可见鬼针草醇提取物可明显降低总胆固醇和甘油三酯含量,具有一定的抗乙硫氨酸致脂肪肝的作用。
上述实验结果表明,本发明具有几个方面的优点:
1、本发明鬼针草醇提取物是从中药材鬼针草中提取的有效成分,可明显降低高脂饮食脂肪肝动物模型和药物中毒性脂肪肝动物模型中的脂质,对脂肪肝模型中的肝细胞有保护作用;发掘了鬼针草醇提取物新的药用前景,开拓了一个新的药用领域;
2、本发明的鬼针草醇提取物采用口服给药,服用方便,毒副作用小,长期服药无危害;
3、本发明鬼针草醇提取物的原药资源非常丰富,具有良好的社会和经济效益;
4、本发明的鬼针草醇提取物适用于非酒精性脂肪肝,作用于多个环节,疗效确切;
5、本发明为将鬼针草进一步开发成新药提供了强有力的基础。
具体实施方式
下面结合实施例对本发明作进一步地描述。
实施例1:
称取鬼针草生药10kg,粉碎后加入80%乙醇100L,热回流提取2次,每次1h,合并提取液,回收乙醇,减压浓缩得浸膏。浸膏水溶,静置,过滤,澄清液上大孔树脂柱,水洗后收集80%乙醇洗脱部分。回收乙醇,减压浓缩,干燥即得鬼针草醇提取物。该醇提取物为黄绿色粉末,具有芳香味,易潮解;其主要成分为总黄酮,含量为20-60%。该醇提取物可加入相应辅料,制成片剂、胶囊、缓释片、滴丸、冲剂、微粒剂,并进一步纯化制成针剂。
鬼针草醇提取物临床推荐剂量:300-1200mg/天,口服,一日三次。
Claims (1)
1、鬼针草醇提取物在制备防治非酒精性脂肪肝药物中的应用,其特征在于:总黄酮含量为20-60%的鬼针草总黄酮在制备防治非酒精性脂肪肝药物中的应用。
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中医药治疗脂肪肝的临床与实验研究进展. 刘锋,陈钢.安徽中医学院学报,第23卷第3期. 2004 |
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