CN113398110A - 一种脱落酸在制备治疗和/或改善多囊卵巢综合征的产品及用途 - Google Patents
一种脱落酸在制备治疗和/或改善多囊卵巢综合征的产品及用途 Download PDFInfo
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- CN113398110A CN113398110A CN202110806991.2A CN202110806991A CN113398110A CN 113398110 A CN113398110 A CN 113398110A CN 202110806991 A CN202110806991 A CN 202110806991A CN 113398110 A CN113398110 A CN 113398110A
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- abscisic acid
- polycystic ovary
- ovary syndrome
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Abstract
本发明公开了一种脱落酸在制备治疗和/或改善多囊卵巢综合征的产品及用途,提供了脱落酸在制备治疗和/或改善多囊卵巢综合征中高雄激素血症、胰岛素抵抗及炎症的药物中的应用,以及一种改善多囊卵巢综合征的食品及其用途,为治疗和改善多囊卵巢综合征高雄激素血症及胰岛素抵抗等代谢问题提供了最佳药物,也为治疗多囊卵巢综合征这一临床难题提供一种有效、安全的有效手段。
Description
技术领域
本发明是一种脱落酸在制备治疗和/或改善多囊卵巢综合征的产品及用途,具体涉及脱落酸在制备治疗和/或改善多囊卵巢综合征高雄激素血症及胰岛素抵抗等代谢问题的产品及用途,属于医药技术领域。
背景技术
囊卵巢综合征(Polycystic ovary syndrome,PCOS)是一种以高雄激素血症、排卵障碍、卵巢多囊样改变为特征的生殖内分泌疾病,青春期和育龄期女性发病率较高。据统计,超过50%的PCOS患者存在不同程度的胰岛素抵抗,且PCOS患者及其后代罹患糖尿病、高脂血症、高血压和冠心病等慢性疾病及子宫内膜癌、卵巢癌和乳腺癌等恶性肿瘤的风险均显著增加。其发病机制复杂,通常认为遗传因素与非遗传因素在其发病过程中均起重要作用。
目前,多囊卵巢综合征药物治疗包括口服短效避孕药如达英-35、优思明、优思悦等,以及二甲双胍等胰岛素增敏剂等药物治疗,口服短小避孕药可在一定程度上调节月经周期,降低雄激素等作用,但是由于其避孕的作用机制,导致有生育需求的多囊卵巢综合征女性无法使用。而二甲双胍虽作为一类胰岛素增敏剂,在有胰岛素抵抗、肥胖的患者中被广泛使用,但更多的多囊卵巢综合征患者并无胰岛素抵抗、肥胖等问题,因为无药物使用适应症,并且二甲双胍无降低雄激素等作用,而存在较为严重且广泛的副作用,如腹泻、呕吐、恶心、腹痛等不适,导致患者的服药依从性较差。
基于目前多囊卵巢综合征现有的治疗药物均存在相应技术缺点,亟待开发更为适宜的药物。例如:公开号为CN103156835A的发明专利公开的一种治疗多囊卵巢综合症PCOS与糖代谢异常并存疾病的药物。该药物主要由十六碳酸、十六碳一烯酸、9-十八碳烯酸和9,12,15-十八碳三烯酸等四种脂肪酸组成,可有效减少胰岛素受体底物(IRS)蛋白的水平而抑制葡萄糖的去路,增加胰岛素受体活性时间并增加胰岛素水平,并使胰岛素敏感性增加而有助于降低胰岛素抵抗程度。并能有效抑制雄激素受体激活雌激素受体而有效降低血清雄激素水平。对自主调节性腺轴、免疫轴、神经内分泌轴等调节功能方面具有细胞因子信号转导负调控的作用。而具有改善调治卵巢排卵功能障碍-多囊卵巢综合症(PCOS)与糖代谢异常的疾病的功能。
又如:公开号为CN103285022A的发明专利公开的一种用于制备治疗多囊卵巢综合征的中药单体组合物。该专利采用隐丹参酮、黄苓苷、槲皮素三种药物的联合应用,可以通过调节雄激素合成代谢过程中相关基因的表达,抑制雄激素的合成,最终达到治疗多囊卵巢综合征的效果。以及公开号为CN108542907A的发明专利公开的一种茯苓酸或茯苓酸衍生物用于制备治疗多囊卵巢综合症药物的应用及药物制剂。茯苓酸作为中药中提取分离的化合物,可用于改善由DHEA诱导的小鼠PCOS疾病,可以抑制炎症及缓解PCOS小鼠胰岛素抵抗,从而抑制颗粒细胞的损伤,抑制卵母细胞氧化及调亡,间接提高多囊卵巢综合征小鼠卵母细胞质量,因此,对治疗多囊卵巢综合症具有较好的效果。
在临床医疗中,如何有效的对PCOS患者进行治疗一直是业内难点,虽然上述专利药物从安全和无毒副作用的目的出发,通过药物来降低多囊卵巢综合征血清雄激素水平、改善糖代谢紊乱以及降低炎症水平,以达到治疗多囊卵巢综合征的作用。但为了更好的促进PCOS患者临床治疗的可行性,满足各年龄阶段多囊卵巢综合征患者治疗的需求和目的,针对PCOS患者治疗的药物研发仍在继续,以期找到更适宜的治疗药物。
脱落酸(Abscisic acid,ABA)是一种抑制生长的植物激素,广泛存在于高等植物中,是植物五大天然生长调节剂之一,可促进植物平衡吸收水、肥和协调体内代谢的能力,同时有效激活植物体内抗逆免疫系统,是所有绿色植物均含有的天然产物,对人畜无毒害、无刺激性,是一种高效的、天然绿色植物生长活性物质。
近年来的研究结果表明,脱落酸在哺乳动物的各组织细胞中广泛存在[1],ABA 对免疫系统、心血管细胞、干细胞和糖尿病等有广泛的调节作用[2]。这些研究使人们对ABA作为生物界通用的信号因子和作为多种疾病的治疗药物产生了广泛的兴趣。然而,ABA在动物中的研究还处在起始阶段,进一步深入研究ABA在动物体内的作用与作用机制以及ABA 的生物合成与代谢等,具有重要的理论意义和潜在的应用价值。
参考文献:
[1] Mirko Magnone;et al. Abscisic Acid: A Conserved Hormone in Plantsand Humans and a Promising Aid to Combat Prediabetes and the MetabolicSyndrome. Nutrients,2020,12,1724。
[2] Laurens Lievens; et al. Abscisic Acid as Pathogen Effector andImmune Regulator. Impaired Increase of Plasma Abscisic Acid in Response toOral Glucose Load in Type 2 Diabetes and in Gestational Diabetes. 2015,10.1371; Laura Sturla; et al. Binding of abscisic acid to human LANCL2.2011.10.079。
发明内容
本发明的目的是克服治疗多囊卵巢综合征的瓶颈,提供脱落酸在制备治疗和/或改善多囊卵巢综合征的产品及用途,具体涉及一种治疗和/或改善多囊卵巢综合征的药物及其用途以及一种改善多囊卵巢综合征的食品及其用途,提供了治疗和改善多囊卵巢综合征高雄激素血症及胰岛素抵抗等代谢问题的最佳药物,从而为治疗多囊卵巢综合征这一临床难题提供一种有效、安全的有效手段。
本发明通过下述技术方案实现:脱落酸在制备治疗和/或改善多囊卵巢综合征的产品中的用途,所述脱落酸在制备治疗和/或改善多囊卵巢综合征中高雄激素血症、胰岛素抵抗及炎症的药物中的应用。
一种治疗和/或改善多囊卵巢综合征的药物,包括以下特征:
A.含有脱落酸;
B.所述药物中,脱落酸的使用剂量为0.125微克/Kg体重;
C.所述药物中,还包括药学上可接受的载体或辅料,所述载体包括但不限于微囊、微球、纳米粒、脂质体,所述辅料包括但不限于淀粉、糊精、乳糖、硬脂酸镁。
所述药物的剂型选自胶囊剂、片剂、颗粒剂、散剂、肠溶制剂中的任一种。
所述药物用于治疗和/或改善多囊卵巢综合征中的高雄激素血症、胰岛素抵抗及炎症。
脱落酸在制备改善多囊卵巢综合征的产品中的用途,所述脱落酸在制备改善多囊卵巢综合征中高雄激素血症、胰岛素抵抗及炎症的食品中的应用。
一种改善多囊卵巢综合征的食品,包括以下特征:
A.含有脱落酸;
B.所述食品中,脱落酸的使用量为0.125微克/Kg体重;
C.所述食品中,还包括其他不影响脱落酸有效性的食品添加剂或辅料,所述食品添加剂包括但不限于柠檬黄、日落黄、安赛蜜或三氯蔗糖,所述辅料包括但不限于淀粉、糊精、乳糖、硬脂酸镁。
所述食品用于改善多囊卵巢综合征中的高雄激素血症、胰岛素抵抗及炎症。
本发明与现有技术相比,具有以下优点及有益效果:
目前临床中发现多囊卵巢综合征患者同时存在有肥胖、雄激素水平升高,胰岛素抵抗,糖耐量异常,肥胖等问题。本发明通过脱落酸(ABA)在多囊卵巢综合征药物中应用,提供了一种可治疗和改善多囊卵巢综合征中高雄激素血症、胰岛素抵抗及炎症的药物。经试验证明,脱落酸可以降低多囊卵巢综合征体重及雄激素水平,同时还可以改善血糖及胰岛素等代谢紊乱的问题。由于脱落酸广泛存在于较多日常果蔬中,是其提取物,其安全并且无副作用,适用于各年龄阶段多囊卵巢综合征患者,特别是备孕期及妊娠期妇女,为多囊卵巢综合征治疗及饮食指导提供新的思路。
附图说明
图1为PCOS大鼠模型的动情周期图。
图2为PCOS大鼠模型的卵巢图。
图3为PCOS大鼠模型的体重变化图。
图4为PCOS大鼠模型的血清性激素变化图。
图5为PCOS大鼠模型的卵巢HE染色图。
图6为对照组、PCOS组以及PCOS+ABA组的大鼠体重变化图。
图7为对照组、PCOS组以及PCOS+ABA组的大鼠睾酮变化图。
图8为对照组、PCOS组以及PCOS+ABA组的大鼠血糖变化图。
图9为对照组、PCOS组以及PCOS+ABA组的大鼠大鼠血清IL-17,MCP-1以及TNF-α变化图。
具体实施方式
下面将本发明的发明目的、技术方案和有益效果作进一步详细的说明。
应该指出,以下详细说明都是示例性的,旨在对所要求的本发明提供进一步的说明,除非另有说明,本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
囊卵巢综合征(PCOS)是一种临床表现复杂、以稀发/无排卵、高雄激素和卵巢多囊样改变为主要特征的内分泌及生殖功能障碍性疾病。现有研究表明,PCOS疾病的发生不仅受多个致病基因的影响,同时还受环境因素影响,因此,存在着基因-基因、基因-环境间的相互作用。由于现有采用口服短效避孕药、二甲双胍等胰岛素增敏剂等药物治疗PCOS疾病存在较为严重的副作用,且对有生育需求的多囊卵巢综合征女性极不友好,因此,为更好的满足目前各年龄阶段多囊卵巢综合征患者,尤其是备孕期及妊娠期妇女,亟待开发出一种安全、无毒副作用的口服药物。
本发明通过对植物激素进行研究发现,植物激素对睾丸激素过高或雌激素水平过低的女性具有治疗作用,因此,在一定程度上能够改善患者的生育能力。例如:公开号为CN101163521A的发明专利公开的一种增强动物生育能力的方法,通过给动物饲喂一定量的天然存在的免疫增强成分,如吲哚-3-乙酸、细胞分裂素、赤霉素、赤霉酸、乙烯、脱落酸、油菜素类固醇、茉莉酸和水杨酸等,因其对免疫系统的调节作用可以改善动物的生育能力并提高其怀孕的几率。但由于PCOS是一类较复杂的综合症候群,植物激素虽然能够调节雌激素水平,但是否能够改善PCOS的其他症状并适用于各年龄阶段多囊卵巢综合征患者使用,难以预计。因此,本发明希望从植物激素中找到一种即能降低PCOS患者雄激素水平、改善PCOS患者糖代谢紊乱及炎症水平的有效成分,还要具备用药安全性、无毒副作用,且适用于各年龄阶段多囊卵巢综合征患者,特别是备孕期及妊娠期妇女。
下面以几个典型实施例来列举说明本发明的具体实施方式,当然,本发明的保护范围并不局限于以下实施例。
实施例1:
本实施例是一种治疗和/或改善多囊卵巢综合征的药物。
该药物为采用脱落酸作为有效成分或有效成分之一的产品,用于治疗和/或改善多囊卵巢综合征中的高雄激素血症、胰岛素抵抗及炎症。该药物包括以下特征:
A.含有脱落酸;
B.所述药物中,脱落酸的使用剂量为0.125微克/Kg体重;
C.所述药物中,还包括药学上可接受的载体(如微囊、微球、纳米粒、脂质体)或辅料(如淀粉、糊精、乳糖、硬脂酸镁)。
使用时,可制备成胶囊剂、片剂、颗粒剂、散剂或肠溶制剂,供多囊卵巢综合征患者服用,对各年龄阶段的多囊卵巢综合征患者均具有降低PCOS患者雄激素水平、改善PCOS患者糖代谢紊乱及炎症水平的作用。
例如在一个具体的实施例中,将脱落酸与适当比例的淀粉混合,按单位剂量装入大小合适的胶囊中制得胶囊剂,每个胶囊剂中保证脱落酸的使用剂量为0.125微克/Kg体重,或者是0.125微克/Kg体重的整数分之一,便于患者按剂量进行服用。
实施例2:
本实施例是一种改善多囊卵巢综合征的食品。
该食品为采用脱落酸作为有效成分或有效成分之一的产品,用于改善多囊卵巢综合征中的高雄激素血症、胰岛素抵抗及炎症。该食品包括以下特征:
A.含有脱落酸;
B.所述食品中,脱落酸的使用量为0.125微克/Kg体重;
C.所述食品中,还包括其他不影响脱落酸有效性的食品添加剂(如柠檬黄、日落黄、安赛蜜或三氯蔗糖)或辅料(如淀粉、糊精、乳糖、硬脂酸镁)。
使用时,可制备成糖果、饮料等,供多囊卵巢综合征患者服用,对各年龄阶段的多囊卵巢综合征患者均具有降低PCOS患者雄激素水平、改善PCOS患者糖代谢紊乱及炎症水平的作用。
例如在一个具体的实施例中,将脱落酸与适当比例的糊精、乳糖、柠檬黄混合均匀后,压片制成糖果,每片糖果中保证脱落酸的使用剂量为0.125微克/Kg体重,或者是0.125微克/Kg体重的整数分之一,便于患者按剂量进行服用。
实施例3:
本实施例通过PCOS大鼠模型造模前后灌胃脱落酸,观察脱落酸对多囊卵巢综合征中高雄激素血症、胰岛素抵抗及炎症水平的治疗和/改善作用。
一、实验材料
实验用动物:21日龄雌性Wistar大鼠。
实验用药物:脱落酸。
二、试验方法
1. 构建PCOS大鼠模型
选取45只21日龄雌性Wistar大鼠,随机挑选30只作为PCOS模型组并于颈背部皮下埋置来曲唑(Letrozole)缓释剂,随机挑选15只作为Control组于颈背部皮下埋置安慰剂,通过测量周体重、观测动情周期、性激素水平、IPGTT试验、血清空腹胰岛素水平并计算稳态模型胰岛素抵抗指数(HOMA-IR)筛选出PCOS-IR大鼠模型(PCOS大鼠出现胰岛素抵抗但无糖耐量受损或 2 型糖尿病),两组大鼠随机挑选5只处死并取卵巢行形态学检查,证实PCOS模型组大鼠有符合多囊卵巢综合征的形态学改变。
A. PCOS大鼠排卵发育情况
通过显微镜观察PCOS组大鼠的阴道涂片结果,记录各组大鼠动情周期等数据,采用EXCEL方法绘制大鼠动情周期图进行比对。如图1所示,对照组雌鼠动情周期为4-5天,PCOS组大鼠大部分时间处于动情间期,提示无排卵。
B. PCOS大鼠卵泡发育情况
采用相机拍摄得到大鼠卵巢图进行比对。如图2所示,对照组卵巢周边脂肪组织少,卵巢表面色泽较红润,而PCOS组雌鼠卵巢被大量脂肪组织包裹,卵巢表面较苍白,可见包膜下扩张的卵泡,符合PCOS卵巢改变。
C. PCOS大鼠体重情况
通过体重计测量大鼠体重等数据,采用 Prism 方法绘制的大鼠体重变化图进行比对,如图3所示, PCOS大鼠的体重较对照组大鼠显著增加,差异有统计学意义。
D. PCOS大鼠性激素变化情况
通过高效液相色谱法(HPLC)检测大鼠睾酮(T)、孕酮(P)雌二醇(E2)水平,ELISA试验测定黄体生成素(LH)、卵泡刺激素(FSH)水平等数据,采用 Prism 方法绘制血清性激素变化图进行比对。如图4所示,PCOS大鼠血清睾酮(T)、雌二醇(E2)以及黄体生成素(LH)明显升高,卵泡刺激素(FSH)及孕酮(P)明显降低,有统计学差异。
E. PCOS大鼠卵巢周期情况
采用大鼠卵巢组织切片苏木精-伊红染色(HE)方法得到大鼠卵巢HE染色图进行比对。如图5所示,对照组镜下见各期卵泡,颗粒细胞形态完整,排列整齐,卵泡膜细胞、间质细胞未见增生,而PCOS组雌鼠卵泡多呈囊状,卵泡内卵母细胞消失或放射冠消失,卵泡膜细胞、间质细胞增生。
由上述图1至图5可以知道,PCOS大鼠无排卵或卵泡发育障碍,动情周期紊乱,体重明显增加,性激素紊乱等问题。
F. PCOS大鼠胰岛素及血糖代谢情况
采用酶联免疫吸附试验(ELISA试验)检测空腹胰岛素水平,采用Roche血糖仪检测空腹血糖水平。如下表1所示,PCOS大鼠的空腹胰岛素水平增加,出现胰岛素抵抗的代谢问题。
表1 PCOS大鼠出现胰岛素及血糖异常的代谢问题。
2.脱落酸对PCOS大鼠前后体重的影响
用脱落酸灌胃PCOS大鼠后,通过体重计测量大鼠体重,观察对照组、PCOS组以及PCOS+ABA组的大鼠体重变化,采用Prism软件制图,得到各组大鼠体重变化图。如图6所示,PCOS+ABA组大鼠体重变化最大,由此可以证明,脱落酸可以显著降低PCOS大鼠的体重。
3.脱落酸对PCOS大鼠前后雄激素水平的影响
采用高效液相色谱法(HPLC)检测脱落酸灌胃PCOS大鼠前后的雄激素水平,观察对照组、PCOS组以及PCOS+ABA组的大鼠睾酮变化,采用Prism软件制图,得到各组大鼠睾酮变化变化图。如图7所示,脱落酸可以显著降低PCOS大鼠的血清睾酮水平。
4. 脱落酸对PCOS大鼠前后血糖水平的影响
采用Roche血糖仪检测脱落酸灌胃PCOS大鼠前后的血糖水平,观察对照组、PCOS组以及PCOS+ABA组的大鼠血糖变化,采用Prism软件制图,得到各组大鼠血糖变化图。如图8所示,脱落酸灌胃后,PCOS大鼠血糖水平明显下降。
5. 脱落酸对PCOS大鼠前后炎症相关因子(IL-17,MCP-1,以及TNF-α)水平的影响
采用酶联免疫吸附测定法(Elisa)检测脱落酸灌胃PCOS大鼠前后炎症相关因子水平,观察对照组、PCOS组以及PCOS+ABA组的大鼠血清IL-17,MCP-1以及TNF-α变化,采用Prism软件制图,得到各组大鼠炎症因子变化图。如图9所示,脱落酸灌胃后,PCOS大鼠的炎症因子IL-17,MCP-1,以及TNF-α的表达水平明显下降。
以上所述,仅是本发明的较佳实施例,并非对本发明做任何形式上的限制,凡是依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化,均落入本发明的保护范围之内。
Claims (7)
1.脱落酸在制备治疗和/或改善多囊卵巢综合征的产品中的用途,其特征在于:所述脱落酸在制备治疗和/或改善多囊卵巢综合征中高雄激素血症、胰岛素抵抗及炎症的药物中的应用。
2.一种治疗和/或改善多囊卵巢综合征的药物,其特征在于:包括以下特征:
A.含有脱落酸;
B.所述药物中,脱落酸的使用剂量为0.125微克/Kg体重;
C.所述药物中,还包括药学上可接受的载体或辅料,所述载体包括但不限于微囊、微球、纳米粒、脂质体,所述辅料包括但不限于淀粉、糊精、乳糖、硬脂酸镁。
3.根据权利要求2所述一种治疗和/或改善多囊卵巢综合征的药物,其特征在于:所述药物的剂型选自胶囊剂、片剂、颗粒剂、散剂、肠溶制剂中的任一种。
4.根据权利要求2所述一种治疗和/或改善多囊卵巢综合征的药物,其特征在于:所述药物用于治疗和/或改善多囊卵巢综合征中的高雄激素血症、胰岛素抵抗及炎症。
5.脱落酸在制备改善多囊卵巢综合征的产品中的用途,其特征在于:所述脱落酸在制备改善多囊卵巢综合征中高雄激素血症、胰岛素抵抗及炎症的食品中的应用。
6.一种改善多囊卵巢综合征的食品,其特征在于:包括以下特征:
A.含有脱落酸;
B.所述食品中,脱落酸的使用量为0.125微克/Kg体重;
C.所述食品中,还包括其他不影响脱落酸有效性的食品添加剂或辅料,所述食品添加剂包括但不限于柠檬黄、日落黄、安赛蜜或三氯蔗糖,所述辅料包括但不限于淀粉、糊精、乳糖、硬脂酸镁。
7.根据权利要求6所述的一种改善多囊卵巢综合征的食品,其特征在于:所述食品用于改善多囊卵巢综合征中的高雄激素血症、胰岛素抵抗及炎症。
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