CN103083310B - 木犀草素在制备抗卵巢衰老药物中的应用 - Google Patents
木犀草素在制备抗卵巢衰老药物中的应用 Download PDFInfo
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Abstract
本发明公开了木犀草素在制备抗卵巢衰老药物中的应用。木犀草素可治疗多种卵巢衰退疾病，如多囊卵巢综合征、功能失调性子宫出血、卵巢早衰或绝经期综合征等具有显著效果。本发明是将木犀草素制成用于治疗卵巢衰退疾病的口服给药、经皮给药或注射给药。
Description
技术领域
本发明涉及木犀草素的医药用途，即木犀草素在有效治疗多种卵巢衰退疾病药物中的应用。
背景技术
卵巢衰老是一个多因素相互作用、逐渐累积的复杂的生物过程。随着年日逝去卵泡不断消耗，卵泡数目下降是卵巢衰老的主因；而机体内代谢产物堆积卵巢内微环境改变，如自由基、糖基化终末产物对卵泡的损伤，及线粒体DNA突变、端粒缩短等因素的不断累积，剩余卵泡的质量也同时降低；卵巢中一系列基因的表达与功能改变，以及H-P-O轴(Hypothalamus-Pituitary-Ovary Axis，下丘脑-垂体-卵巢轴)激素的分泌精密调控卵巢的功能。卵巢功能衰退即卵巢衰老，以绝经为表现，40岁以前绝经称为卵巢早衰(Premature Ovarian Failure，POF)，即病理性卵巢衰老。卵巢功能衰退可引发卵巢功能紊乱性疾病(如多囊卵巢综合征、功能失调性子宫出血等)，继而衰竭引发围绝经期综合征，这些疾病相继出现各器官系统衰老性疾病：循环系统里冠心病、脑血管病发生率明显提高，中枢神经系统中易发早老性痴呆、抑郁症，由于钙流失急剧增加而骨质疏松症高发等等。近年来，随着生活节奏加快和学习压力过大，发生在妇女中的卵巢衰退疾病相关疾病已有明显增加的趋势。由于每个家庭都有青年、中年或老年妇女，因此卵巢衰老产生的上述疾病已成为普遍关心的社会问题，对该病的研究已成为国内外生殖发育界的热点和难点。
目前国内外研究多认为卵巢衰老与遗传、免疫、代谢、病毒感染以及医源性等因素有关。概括为以下几个方面：1染色体核型异常，通过对染色体异常卵巢衰老患者的研究法相，一些证候基因主要集中在X染色体和常染色体上，染色体核型的异常多少与家族遗传有关，另外环境因素引起的基因突变也是引起此病症的关键因素。2免疫性因素，可能与细胞因子诱导颗粒细胞及黄体细胞，主要是组织相容性复合物(MHC)类抗原表达，诱发机体的自身免疫反应，使颗粒细胞及卵泡受到破坏有关。此外，还有认为卵巢功能衰退与卵巢自身抗体的产生以及合并其他内分泌腺体或系统的自身免疫性疾病，如自身免疫性甲状腺炎、系统性红斑狼疮、重症肌无力、甲状旁腺功能衰退、类风湿性关节炎、特发性血小板减少性紫癜、糖尿病等有关。3促性腺激素及其受体异常，促性腺激素FSH、LH及其受体(FSHR、LHR)的传导缺陷可引起卵巢功能衰退。4酶缺乏可引起半乳糖血症，半乳糖血症与卵巢功能衰退发生有关。半乳糖可以直接损害卵母细胞，其代谢产物又可对卵巢实质产生损害，半乳糖分子的渗入还可改变促性腺激素的活性，从而引起卵巢卵泡的耗竭。5卵巢破坏因素，随着女性社会活动的日益频繁，无意长期接触反射线刺激，或因工作、疾病、意外事故接受大剂量或长时期的放射线，均可破坏卵巢。6其它相关高危因素，吸烟、抑郁、长期大量接触外源性E2和未产妇与卵巢衰退有密切的关系。而重金属类环境激素对卵巢功能衰退的影响研究还是空白，随着我国经济的高速发展，这类环境因素将对我国人民生殖健康会产生长远的不利影响。
激素替代治疗(Hormone replacement therapy，HRT)是目前现代医学治疗卵巢衰老相关症状和疾病的重要方法，但现有研究明显表明其具有多种副作用和远期致癌性，使其临床应用受到明显的限制。对应此状态，在中国遵循传统中医理论，主张“补肾益阴、疏肝养血”而延缓卵巢衰老，采用中药方剂治疗，但目前在还没有搞清其病因、病理的情况下，存在着乱用药、乱治疗的误区，且复方药物治疗存在有效物质基础不清，作用机制不明的缺陷，无法使中医中药走向现代化，走向国际化。
木犀草素(Luteolin)是一种天然黄酮类化合物，广泛存在于金银花、菊花、荆芥、白毛夏枯草、洋蓟、紫苏属、黄芩属等天然药材中，以及芽甘蓝、洋白菜、菜花、甜菜、椰菜、胡萝卜、芹菜、甜椒、辣椒、落花生等蔬菜果实中，其它如橄榄油和红酒等植物产品以及野凤仙花、百里香草、唇形科植物全叶青兰草、筋骨草中。木犀草素为黄色针状结晶，分子式：C15H10O6，分子量：286.23，熔点330℃，其结构如式I，具有多种药理活性，如消炎、抗过敏、抗肿瘤、抗菌、抗病毒等，临床主要用于止咳、祛痰、消炎、治疗心血管疾病、治疗“肌萎缩性脊髓侧索硬化症”，SARS，肝炎等，是一种重要的天然产物。目前尚未有报道将木犀草素用于制备抗卵巢衰老药物中的应用。
发明内容
本发明所要解决的技术问题是提供木犀草素在制备抗卵巢衰老药物中的应用。所述的木犀草素(Luteolin)具有如下结构：
本发明涉及木犀草素(Luteolin)抗卵巢衰老疾病的应用，特别是对多囊卵巢综合征、功能失调性子宫出血、卵巢早衰或绝经期综合征等疾病等具有显著的疗效，并且在用于上述用途时具有使用安全和可长期服用等特点。因此，木犀草素可在制备抗卵巢衰老药物中应用，该药物具有治疗多种卵巢衰退疾病的用途。
木犀草素可来源于市售或采用现有技术制备得到。
本发明应用的木犀草素可以和药学上允许的任意一种辅料或药物赋形剂制成药物，其制剂可以是药学上允许的任意一种剂型，包括但不限于液体制剂、颗粒剂、片剂、冲剂、软胶丸、软胶囊、滴丸剂、软膏剂或注射剂。
本发明提供的药物，其给药形式主要包括口服给药、经皮给药或注射给药。
本发明中木犀草素的给药量，因患者的状态、体重、给药方式等不同而异，其特征是所述药物含有1-1000mg的木犀草素和药用载体。
与现有技术比较本发明的有益效果：木犀草素对离体卵巢颗粒细胞具有显著的增殖作用，能显著提高离体卵巢颗粒细胞的雌孕激素分泌水平，能显著增加自然衰老大鼠雌孕激素的分泌，能降低多囊卵巢综合征模型鼠FSH、LH、T水平，能对环磷酰胺所致卵巢早衰大鼠有性激素调节作用。因此，木犀草素可在制备抗卵巢衰老药物中应用，特别是在制备抗卵巢衰老症状为卵巢早衰及卵巢抵抗综合征的药物中应用。本发明为木犀草素提供了临床新用途，扩大了其应用范围。
具体实施方式
以下将结合具体实施例对本发明做进一步阐述，这些实例仅用于说明目的，而不用于限制本发明范围。本发明的实验动物，购自中国人民解放军军事医学科学院实验动物中心(生产许可证号：SCXK(军)2007-004)，选用临床有较好疗效的戊酸雌二醇做阳性对照。木犀草素对照品(批号：111520-200504)购于中国药品生物制品检定所，纯度≥98％，溶于水配制成给药浓度。
[实施例一]木犀草素对离体卵巢颗粒细胞的增殖作用(MTT法)
取22-27日龄雌性大鼠，常规饲养48h后颈椎脱臼法处死，无菌摘取大鼠的双侧卵巢，将卵巢破碎使颗粒细胞释放，用2mL含青霉素和链霉素的DMEM-F12培养液中稀释，并轻轻吹打，使其分散成单个细胞。离心过滤收集颗粒细胞。将一定浓度细胞悬液接种于24孔板，每孔80μl，每孔再加120μl培养液调整细胞密度至200μl/孔，每组设6个平行孔。将其置于5％CO2培养箱中培养24h。取CO2培养箱内培养了24h的颗粒细胞悬液，每孔先后加入造模浓度氯化镉和不同浓度木犀草素样品(1.0mg·mL-1、0.1mg·mL-1、0.01mg·mL-1)，平行设定正常对照组(生理盐水)和模型组(氯化镉和生理盐水)。常规培养20h后于每孔中加入MTT溶液(5mg·mL-1)20μL继续培养4h，每孔加入80μL的三联液，过夜培养，选择570nm波长，在酶联免疫检测仪上测定各孔吸光度，结果见表1。结果显示模型组与正常对照组均有显著性差异(p＜0.01)，阳性药、不同剂量木犀草素作用后离体卵巢颗粒细胞增殖效果均与模型组有显著性差异(均p＜0.01)。
表1木犀草素对离体卵巢颗粒细胞的增殖作用
*P＜0.05，**P＜0.01vs模型组.ΔP＜0.05，ΔΔP＜0.01vs正常对照组
[实施例二]木犀草素对离体卵巢颗粒细胞的雌孕激素分泌作用(放射免疫法)
取22-27日龄雌性大鼠，常规饲养48h后颈椎脱臼法处死，无菌摘取大鼠的双侧卵巢，将卵巢破碎使颗粒细胞释放，用2ml含青霉素和链霉素的DMEM-F12培养液中稀释，并轻轻吹打，使其分散成单个细胞。离心过滤收集颗粒细胞。将一定浓度细胞悬液接种于24孔板，每孔80μl，每孔再加120μl培养液调整细胞密度至200μl/孔，每组设6个平行孔。将其置于5％CO2培养箱中培养24h。取CO2培养箱内培养了24h的颗粒细胞悬液，每孔先后加入造模浓度氯化镉和不同浓度木犀草素样品，平行设定正常对照组(生理盐水)和模型组(氯化镉和生理盐水)。将其置于5％CO2培养箱中培养24h。离心取其细胞上清液，用放免试剂盒测定E2、P的含量，结果见表2。结果显示模型组与正常对照组均有显著性差异(p＜0.01)，阳性药、不同剂量木犀草素作用后离体卵巢颗粒细胞雌孕激素分泌水平比模型组均有提高，有显著性差异(p＜0.01)。
表2木犀草素对离体卵巢颗粒细胞的雌孕激素分泌作用
*P＜0.05，**P＜0.01vs模型组.ΔP＜0.05，ΔΔP＜0.01vs正常对照组
[实施例三]木犀草素对自然衰老大鼠雌孕激素分泌的影响(放射免疫法)
采用自然衰老的早老模型。选取14月龄雌性SD大鼠，体重(270±30)g，动物适应性喂养一周后，做阴道细胞学涂片，连续观察4个动情周期，以阴道细胞学表现动情周期延长、之后持续动情、反复假妊娠细胞相时，作为雌性老龄模型成功。将自然衰老大鼠随机分为模型组、木犀草素(10mg/kg、30mg/kg、50mg/kg)组及阳性药组，每组各10只，另取4月龄雌性大鼠11只为正常对照组，每天灌胃1次，正常对照组和模型组给予等容积生理盐水，连续给药30天后，给药前及末次给药后从大鼠眼眶静脉丛取血，离心，取血清，用放射免疫法分别测定血清中雌激素和孕酮的含量，结果见表3。结果显示模型组与正常对照组均有显著性差异(p＜0.01)，灌服阳性药、木犀草素(高中低剂量)30天后雌孕激素均与模型组有显著性差异(p＜0.01)。
表3木犀草素组和对照组雌孕激素水平的比较
*P＜0.05，**P＜0.01vs模型组.ΔP＜0.05，ΔΔp＜0.01vs正常对照组
[实施例四]木犀草素对多囊卵巢综合征模型大鼠的影响
24d龄未成年SD雌性大鼠，体重30-40g，0.5mg18-甲基炔诺酮日1次皮下注射，在27d龄时，加用HCG1.5IU日2次皮下注射，共注射21d。造模成功后，随机分为模型组、样品(高中低剂量)组及阳性药组(二甲双胍0.018g/d)，每组各10只，另取45d龄SD雌性大鼠10只为正常对照组，每天灌胃1次，正常对照组和模型组给予等容积生理盐水，连续给药15天后，末次给药后取血检测血清中FSH、LH、T浓度，结果见表4。结果显示模型组与正常对照组均有显著性差异(p＜0.01)，灌服阳性药、木犀草素(高中低剂量)15天后FSH、LH、T水平均与模型组有不同显著性的差异。
表4木犀草素组和对照组血清中FSH、LH、T浓度的比较
*P＜0.05，**P＜0.01vs模型组.ΔP＜0.05，ΔΔP＜0.01vs正常对照组
[实施例五]木犀草素对卵巢早衰大鼠性激素水平的影响
采用9d龄SD雌性大鼠，连续腹腔注射14天环磷酰胺8mg/(kg·d)造模。造模成功后，随机分为模型组、样品(高中低剂量)组及阳性药组(倍美力0.075mg/kg)，每组各10只，另取23d龄SD雌性大鼠10只为正常对照组，每天灌胃1次，正常对照组和模型组给予等容积生理盐水，连续给药35天后，末次给药后取血检测血清中FSH、E2浓度，结果见表5。结果显示模型组与正常对照组均有显著性差异(p＜0.01)，灌服阳性药、木犀草素(高中剂量)35天后FSH、E2水平均与模型组有不同显著性的差异。
表5木犀草素组和对照组血清中FSH、E2浓度的比较
*P＜0.05，**P＜0.01vs模型组.ΔP＜0.05，ΔΔP＜0.01vs正常对照组
[实施例六]木犀草素胶囊
木犀草素100g，淀粉80g，羧甲基淀粉钠24g，糊精17g，70％乙醇适量，制成1000粒(每粒含木犀草素100mg)。
[实施例七]木犀草素胶囊
木犀草素15g，淀粉10g，羧甲基淀粉钠4g，糊精12g，70％乙醇适量，制成1000粒(每粒含木犀草素15mg)。
[实施例八]木犀草素片
木犀草素1000g，乳糖55g，可压性淀粉15g，羟丙纤维素10g，硬脂酸镁5g，70％乙醇适量，制成1000片(每片含木犀草素1000mg)。
[实施例九]木犀草素颗粒剂
木犀草素6g，乳糖粉800g，硬脂酸镁194g，70％乙醇适量，制成1000克颗粒(每g颗粒制中含木犀草素6mg)。
[实施例十]木犀草素软胶囊
木犀草素20g，大豆油10g，明胶5g，甘油5g，蒸馏水7g，制成1000粒(每粒含木犀草素20mg)。
[实施例十一]木犀草素乳膏
木犀草素1g，硬脂酸100g，十六醇20g，单硬脂酸甘油酯10g，液体石腊10g，羟苯甲酯0.8g，羟苯丁酯0.2g，甘油140g，氢氧化钾5g，乙醇10g，蒸馏水加至1000g。
[实施例十二]木犀草素乳膏
木犀草素0.5g，硬脂酸100g，十六醇20g，单硬脂酸甘油酯10g，液体石腊10g，羟苯甲酯0.8g，羟苯丁酯0.2g，甘油140g，氢氧化钾5g，乙醇10g，蒸馏水加至1000g。
[实施例十三]木犀草素凝胶
木犀草素0.5g，PEG400450g，己二醇80g，吐温8020g，卡波姆30g，乙醇胺6ml，苯甲醇10g，蒸馏水加至1000g。
[实施例十四]木犀草素注射液
木犀草素25.0g，溶于1000ml注射用水中，充分搅拌溶解，补加注射用水至2000ml，加入针用活性碳2.5g，加热至60℃搅拌30分钟，碳棒过滤，滤液经0.25μm微孔滤膜过滤除菌，分装于1000支西林瓶中，装量2.0ml/支，封口，灭菌，即得。
Claims (5)
1.木犀草素在制备抗卵巢衰老药物中的应用。
2.根据权利要求1的应用，其特征在于所述的卵巢衰老症状为多囊卵巢综合征、功能失调性子宫出血、卵巢早衰或绝经期综合征。
3.根据权利要求1所述应用，其特征是所述药物含有1-1000mg的木犀草素和药用载体。
4.根据权利要求1所述应用，其特征是所述药物的剂型为药学上认可的任何一种剂型。
5.根据权利要求4所述应用，其特征是所述药物的剂型包括颗粒剂、片剂、冲剂、软胶囊、滴丸剂、软膏剂或注射剂。
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| Antifertility and hormonal properties of flavones of Striga orobanchioides;Shivayogi P.Hiremath等;《European Journal of Phaimacology》;20001231;第391卷(第1－2期);第335－338页 * |
| Shivayogi P.Hiremath等.Antifertility and hormonal properties of flavones of Striga orobanchioides.《European Journal of Phaimacology》.2000,第391卷(第1－2期),第193－197页. |
| 木犀草素的药理活性研究;李星霞等;《中国药房》;20071231;第18卷(第18期);第1421－1424页 * |
| 李星霞等.木犀草素的药理活性研究.《中国药房》.2007,第18卷(第18期),第1421－1424页. |
| 蔡际群.雌激素类药和雌激素拮抗药.《药物治疗与疾病》.上海科学技术出版社,2008,第335－338页. * |
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