CN112999234A - 一种黄酮类化合物的应用和溃疡性结肠炎的预防药物 - Google Patents
一种黄酮类化合物的应用和溃疡性结肠炎的预防药物 Download PDFInfo
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- CN112999234A CN112999234A CN202110143415.4A CN202110143415A CN112999234A CN 112999234 A CN112999234 A CN 112999234A CN 202110143415 A CN202110143415 A CN 202110143415A CN 112999234 A CN112999234 A CN 112999234A
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本申请属于医药技术领域,尤其涉及一种黄酮类化合物的应用和溃疡性结肠炎的预防药物。本申请第一方面公开了黄酮类化合物在制备预防溃疡性结肠炎药物中的应用;本申请第二方面公开了黄酮类化合物在制备治疗溃疡性结肠炎药物中的应用;所述黄酮类化合物具有式Ⅰ的结构;本申请第三方面公开了一种溃疡性结肠炎的预防药物,包括具有式Ⅰ所述结构的黄酮类化合物以及药学上可接受的辅料。本申请提供了一种黄酮类化合物的应用和溃疡性结肠炎的预防药物,用于解决现有技术中防治溃疡性结肠炎的药物存在的特异性差、副作用大的技术缺陷。
Description
技术领域
本申请属于医药技术领域,尤其涉及一种黄酮类化合物的应用和溃疡性结肠炎的预防药物。
背景技术
溃疡性结肠炎是一种炎症性肠病,是一种原因不明的慢性非特异性自身免疫性疾病,与遗传、免疫、感染、环境等多种因素有关,其主要症状为腹泻、粘液脓血便、腹痛和里急后重等,主要病理特点为结肠粘膜慢性炎症及溃疡形成,无法治愈,跟克罗恩病同为两种典型的炎症性肠病。溃疡性结肠炎在我国的发病率也呈逐年增高的趋势。本病治愈难度大,且愈后又常易复发,已被世界卫生组织列为现代难治病之一。
现有技术主要关注急性肠炎,但是溃疡性结肠炎相关研究仍有待进一步发展。溃疡性结肠炎和急性肠炎这两个病症都能造成严重的腹泻,因为这个相似点,很多人会把它们搞混。实际上溃疡性结肠炎和急性肠炎的外在表现,发生时间和病发范围都有一定的区别。溃疡性结肠炎和急性肠炎这两种疾病的病因不同,治疗方式也是不同。1、外在表现。自身免疫功能与溃疡性结肠炎有很大关系,主要是免疫因素导致结肠黏膜损伤,出现溃疡,从而引起粘连性的血便,腹泻,便秘并伴随阵发性结肠痛,便后可得到一定的缓解。溃疡性结肠炎一般以腹泻为主要表现,而急性肠炎一般是以恶心呕吐为主要表现,另外还会伴随腹泻、腹痛、发热以及全身酸痛等症状。2、发生时间。除了极少数溃疡性结肠炎病发急剧之外,一般发病都是比较迟缓,多呈慢性、迁延性、反复发作性。而急性肠炎一般病发突然。一般溃疡性结肠炎的发生并沒有特殊的时间规律性。急性肠炎一般多在夏天秋天会突然病发,主要是因为细菌的大量繁殖而造成。3、病发范围。溃疡性结肠炎大规模,大范围爆发的状况是比较罕见的,一般不会发生传染的现象。而急性肠炎可能会造成大规模,大范围的群体病发,如果是由食材,病毒感染或者是有害化学物质造成的急性肠炎,就有很大的概率发生群体病发。
溃疡性结肠炎难以治愈,针对此病的特异性药物较少,当前临床上在治疗溃疡性结肠炎常规药物有三类:氨基水杨酸类、类固醇糖皮质激素及免疫抑制剂,这些药物效果都不够理想,且副作用较大。氨基水杨酸类药物及皮质类固醇激素是目前治疗溃疡性结肠炎的主要方法,但这些非特异性抗炎和免疫抑制药物,只能暂时控制和缓解症状,很难完全治愈或阻止炎症复发,不能从根本上治愈该病,长期应用不良反应增多,停药后容易复发(1年复发率大于50%),部分激素耐药或抵抗的顽固性患者效果更不理想,严重危害患者的健康。因此,必须寻找新的更加特异的预防和治疗方法。
发明内容
有鉴于此,本申请公开了一种黄酮类化合物的应用和溃疡性结肠炎的防治药物,能有效、安全的预防和治疗溃疡性结肠炎。
本申请第一方面公开了黄酮类化合物在制备预防溃疡性结肠炎药物中的应用;
所述黄酮类化合物具有式Ⅰ的结构;
本申请第二方面公开了黄酮类化合物在制备治疗溃疡性结肠炎药物中的应用;
所述黄酮类化合物具有式Ⅰ的结构;
另一些实施例中,所述黄酮类化合物的用量为2.0~30.0mg/Kg/天。
另一些实施例中,所述黄酮类化合物的用量为2.0mg/Kg/天。
另一些实施例中,所述黄酮类化合物包括在三七叶或三七药渣中提取获得。
另一些实施例中,所述提取方法包括水提法、醇提法、碱提酸沉法、微波辅助提取法、超声波提取法、超临界流体提取法或超滤法中的一种。
本申请第三方面公开了一种溃疡性结肠炎的预防药物,包括具有式Ⅰ所述结构的黄酮类化合物以及药学上可接受的辅料。
另一些实施例中,所述溃疡性结肠炎的防治药物为片剂、胶囊剂、颗粒剂、丸剂、散剂、膏剂、粉剂或口服液体剂。
另一些实施例中,所述药学上可接受的辅料为水、乙醇、淀粉、糖粉、糊精、乳糖、可压性淀粉、微晶纤维素、无机盐、甘露醇、淀粉浆、羧甲基纤维素钠、甲基纤维素、乙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、 CMS-Na、L-HPC、交联PVP、CCNa、硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、PEG、月桂醇硫酸镁、乳糖、玉米淀粉、碳酸钙、磷酸钙、十二烷基硫酸钠、吐温-80、硼酸、硬脂酸、氯化钠、苯甲酸钠、醋酸钠、聚乙二醇、液体石蜡、磷酸氢钙、磷酸二氢钙、乳糖、预胶化淀粉、聚维酮、枸橼酸、聚山梨酯80、石蜡、氢化植物油、甘氨酸、CAP、AEA、丙烯酸树脂、环糊精、阿拉伯胶、明胶、海藻酸钠中的一种或多种。
本申请的式Ⅰ的黄酮类化合物具有良好的预防和治疗溃疡性结肠炎的功效,可用于制备溃疡性结肠炎的防治药物;式Ⅰ的黄酮类化合物因糖链的特性,具有非常好的水溶性,使其在肠道能够缓慢释放,因此具有更高的生物利用度。从本申请实施数据可知,本申请式Ⅰ的黄酮类化合物与DSS共同作用小鼠后,明显缓解了体重下降和结肠变短,DAI评分更低,死亡率下降;还表现出较少的炎性细胞浸润,完整的结肠结构,较少的粘膜损伤安全性强,组织学评分更低。可见,本申请的式Ⅰ的黄酮类化合物具有显著的防治溃疡性肠道炎症效果,且易坚持,能够长期使用,因此在避免不良反应的同时,能够长期使用,防治病情反复。
附图说明
为了更清楚地说明本申请实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1为本申请实施例的黄酮类化合物的结构式示意图;
图2为本申请实施例提供的构建小鼠模型的喂养过程示意图;
图3为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的体重变化;
图4为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的体重指数变化曲线;
图5为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的体重变化评分;
图6为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的粪便粘稠度评分;
图7为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的血便评分;
图8为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的炎症指数、上皮损伤指数、隐窝萎缩指数、非典型性增生指数以及受非典型性增生影响的区域指数评分;
图9为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的DAI评分曲线;
图10为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的结肠实拍比较;
图11为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的结肠长度统计;
图12为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的死亡率统计;
图13为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的组织病理性分析;
图14为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的组织学评分。
具体实施方式
本申请提供了一种黄酮类化合物的应用和溃疡性结肠炎的预防药物,用于解决现有技术中防治溃疡性结肠炎的药物存在的特异性差、副作用大的技术缺陷。
下面将对本申请实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本申请一部分实施例,而不是全部的实施例。基于本申请中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本申请保护的范围。
其中,以下实施例所用原料或实际均为市售或自制。
本申请实施例的黄酮类化合物结构式如图1所示,购于阿拉丁公司,CAS 编号为74639-14-8,以下实施例将式Ⅰ的黄酮类化合物命名为LA。
本申请实施例采用硫酸葡糖钠盐(葡聚糖硫酸钠),英文Dextran Sulfate SodiumSalt,缩写DSS,是葡聚糖的聚阴离子衍生物,由葡聚糖和氯磺酸的酯化反应形成。DSS是最常用的诱导溃疡性结肠炎的化学试剂。
实施例1
本申请实施例提供了构建DSS组和LA+DSS组试验,包括:
将6~8周龄SPF级雄性小鼠10只C57BL/6实验动物小鼠,随机分成两组,分别标记为DSS组和LA+DSS组,图2为本申请实施例提供的构建小鼠模型的喂养过程示意图,如图2所示,DSS组为在0~7天每天让小鼠饮用含有3%(W/V)的DSS水溶液,在8~10天每天让小鼠饮用正常水,同时,在 0~10天每天灌胃100μl饮用水(阴性对照),诱导小鼠溃疡性结肠炎;LA+DSS 组为在0~7天让小鼠饮用含有3%(W/V)的DSS水溶液,在8~10天让小鼠饮用正常水,同时,在0~10天每天灌胃100μl含LA(2mg/ml)的水溶液。
实施例2
本申请实施例提供了采用式Ⅰ的黄酮类化合物作用DSS模型后测定其体重改变、死亡率、结肠长度、疾病活动指数(DAI)得分和H&E染色试验,包括:
在0~10天每天记录DSS组小鼠和LA+DSS组小鼠的病理特征(体重变化、粪便粘稠度、便血),进行DAI打分,DAI打分如表1所示。
表1
scoring system for disease acticity index(DAI)疾病活动指数评分系统
观察并记录小鼠死亡状况,作图分析两组小鼠死亡率。
第11天杀死小鼠后测量小鼠结肠长度。
基于发炎、上皮破损、隐窝萎缩、非典型性增生、受影响的区域大小等参数进行组织病理学打分(总分值0-20),评分细则如表2所示。
表2评分细则
结果如图3~图14所示,图3为本申请实施例提供的DSS组小鼠和 LA+DSS组小鼠的体重变化;图4为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的体重指数变化曲线;图5为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的体重变化评分;图6为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的粪便粘稠度评分;图7为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的血便评分;图8为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的炎症指数、上皮损伤指数、隐窝萎缩指数、非典型性增生指数以及受非典型性增生影响的区域指数评分。图9为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的DAI评分曲线;图10为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的结肠实物比较;图11为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的结肠长度统计;图12为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的死亡率统计;图13为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的组织病理性分析;图14为本申请实施例提供的DSS组小鼠和LA+DSS组小鼠的组织学评分。
从图3~图7可知,本申请式Ⅰ的黄酮类化合物与DSS共同作用小鼠后,相对于DSS组小鼠,明显缓解了体重下降,体重变化评分、粪便粘稠度评分、血便评分、炎症指数、上皮损伤指数、隐窝萎缩指数、非典型性增生指数以及受非典型性增生影响的区域指数评分更低。
从图8~图14可知,本申请式Ⅰ的黄酮类化合物与DSS共同作用小鼠后,相对于DSS组小鼠,LA+DSS组小鼠明显缓解了体重下降的趋势和结肠变短的趋势,LA+DSS组小鼠的DAI评分更低,且LA+DSS组小鼠的死亡率下降;通过H&E染色进行组织病理学分析可知,DSS组小鼠隐窝丢失,单核细胞浸润,严重的粘膜损伤,而LA+DSS组小鼠表现出较少的炎性细胞浸润,完整的结肠结构,较少的粘膜损伤;因此,LA+DSS组小鼠组织学评分更低。说明本申请式Ⅰ的黄酮类化合物具有显著的防治溃疡性肠道炎症效果,不良反应少且安全性高,可以用作预防,可以长期使用。
综上所述,从上述实施例的数据可知,本申请式Ⅰ的黄酮类化合物与DSS 共同作用小鼠后,明显缓解了体重下降和结肠变短,DAI评分更低,死亡率下降;还表现出较少的炎性细胞浸润,完整的结肠结构,较少的粘膜损伤安全性强,组织学评分更低。可见,本申请的式Ⅰ的黄酮类化合物具有显著的防治溃疡性肠道炎症效果,安全性高,且易坚持,能够长期使用,因此在避免不良反应的同时,能够长期使用,防治病情反复。
以上所述仅是本申请的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本申请原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本申请的保护范围。
Claims (9)
3.根据权利要求1或2所述的应用,其特征在于,所述黄酮类化合物的用量为2.0~30.0mg/Kg/天。
4.根据权利要求1或2所述的应用,其特征在于,所述黄酮类化合物的用量为2.0mg/Kg/天。
5.根据权利要求1或2所述的应用,其特征在于,所述黄酮类化合物包括在三七叶或/和三七药渣中提取获得。
6.根据权利要求5所述的应用,其特征在于,所述提取方法包括水提法、醇提法、碱提酸沉法、微波辅助提取法、超声波提取法、超临界流体提取法或超滤法中的一种。
7.一种溃疡性结肠炎的预防药物,其特征在于,包括具有式Ⅰ所述结构的黄酮类化合物以及药学上可接受的辅料。
8.根据权利要求7所述的溃疡性结肠炎的预防药物,其特征在于,所述溃疡性结肠炎的防治药物为片剂、胶囊剂、颗粒剂、丸剂、散剂、膏剂、粉剂或口服液体剂。
9.根据权利要求7所述的溃疡性结肠炎的预防药物,其特征在于,所述药学上可接受的辅料为水、乙醇、淀粉、糖粉、糊精、乳糖、可压性淀粉、微晶纤维素、无机盐、甘露醇、淀粉浆、羧甲基纤维素钠、甲基纤维素、乙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、CMS-Na、L-HPC、交联PVP、CCNa、硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、PEG、月桂醇硫酸镁、乳糖、玉米淀粉、碳酸钙、磷酸钙、十二烷基硫酸钠、吐温-80、硼酸、硬脂酸、氯化钠、苯甲酸钠、醋酸钠、聚乙二醇、液体石蜡、磷酸氢钙、磷酸二氢钙、乳糖、预胶化淀粉、聚维酮、枸橼酸、聚山梨酯80、石蜡、氢化植物油、甘氨酸、CAP、AEA、丙烯酸树脂、环糊精、阿拉伯胶、明胶和海藻酸钠中的一种或多种。
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CN115487177A (zh) * | 2022-08-15 | 2022-12-20 | 四川大学华西医院 | 一种黄酮类化合物用于治疗溃疡性结肠炎的新用途 |
CN115487177B (zh) * | 2022-08-15 | 2023-11-24 | 四川大学华西医院 | 一种黄酮类化合物用于治疗溃疡性结肠炎的新用途 |
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