CN111012822A - 冠心丹参方在治疗糖尿病肾病中的应用 - Google Patents
冠心丹参方在治疗糖尿病肾病中的应用 Download PDFInfo
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Abstract
本申请提供了包括丹参、三七、降香油的冠心丹参复方制剂在制备预防和治疗糖尿病肾病药物中的应用。研究表明,冠心丹参复方制剂能改善糖尿病小鼠胰岛素耐量和血液相关指标,逆转糖尿病造成的肾脏抗氧化能力降低,减轻肾脏病理损伤,上调抗氧化应激蛋白Nrf2、HO‑1的表达。
Description
技术领域
本申请属于中药复方制剂领域和糖尿病并发症治疗领域,具体地,本申请提供了冠心丹 参复方制剂在制备预防和治疗糖尿病肾病的药物中的应用。
背景技术
糖尿病肾病是糖尿病人重要的合并症之一,据研究其发病机制可能与遗传、肾脏血流异 常、高血糖损伤、血管活性物质代谢异常相关,确切病因尚不确定,相应疗效确切的治疗手 段也较为匮乏;糖尿病肾病是导致终末期肾病的第二原因,比其它肾脏疾病的治疗更加棘手。 糖尿病肾病的发病机制和治疗药物一直是临床和基础研究的热点课题。
冠心丹参方是临床治疗冠心病常用中药复方,由丹参、三七和降香油组成,已知具有活 血化瘀、理气止痛的功效,主治气滞血瘀型冠心病,长期临床实践证明其安全有效。以冠心 丹参方为基础开发的现代剂型如冠心丹参片、冠心丹参胶囊等疗效显著,广泛用于冠心病的 预防和治疗。但是冠心丹参方是否对糖尿病肾病具有保护作用尚需进一步的验证,并且其具 体保护机制更尚不明确,冠心丹参方用途的进一步的开发与临床应用仍然有待扩展。
发明内容
一方面,本申请提供了冠心丹参复方制剂在制备预防和治疗糖尿病肾病的药物中的应 用。
进一步地,所述冠心丹参复方制剂由包括丹参提取物、三七提取物、降香油提取物的的 原料制成。
进一步地,所述冠心丹参复方制剂为包括但不限于注射剂、混悬剂、糖浆剂的液体制剂、 或者包括但不限于颗粒剂、片剂、胶囊、丸剂、粉针剂、滴丸剂型的固体剂型。
进一步地,冠心丹参复方制剂为滴丸剂。
进一步地,所述冠心丹参复方制剂中丹参提取物、三七提取物、降香油提取物配比为 40-80mg:15-35mg:10-20μL
进一步地,所述冠心丹参复方制剂中丹参提取物、三七提取物、降香油提取物配比为: 65mg:24.3mg:14.25μL。
进一步地,所述应用包括提高肾脏的抗氧化应激能力。
进一步地,所述提高肾脏的抗氧化应激能力包括提高Nrf2、HO-1表达。
进一步地,将冠心丹参复方制剂与其他治疗肾病的药物或治疗联合使用。
除上面所列剂型外,冠心丹参复方制剂还可以为临床上任何可接受的剂型形式,包括口 服及肠胃外给药形式的各种剂型。除了丹参提取物、三七提取物、降香油提取物外,本申请 的冠心丹参复方制剂中还可以根据剂型的需要包含各种药学可接受的辅料,包括但不限于包 衣材料、溶剂、增溶剂、粘合剂、稳定剂、抗氧化剂、pH调节剂、矫味剂,这些辅料成分 本领域技术人员可以根据药剂学常识选用。
本发明所针对的糖尿病肾病是指由于糖尿病微血管病症引起的肾脏疾病,症状包括蛋白 尿、水肿、高血压等。
本发明所制备的治疗肾病的药物中还可以含有其他已知和未知的治疗肾病的药物或者 将本发明所制备的治疗肾病的药物与此类药物或治疗联用,此类药物包括但不限于控制血糖 的药物如二甲双胍、各种胰岛素;此类治疗包括但不限于透析、肾移植等。
附图说明
图1冠心丹参方对糖尿病小鼠胰岛素耐量的影响,(A)注射胰岛素后不同时间血糖,(B) 曲线下面积;**p<0.01vs Control,#p<0.05或##p<0.01vs Model;
图2冠心丹参方对糖尿病小鼠血清LDH、血脂四项含量的影响。(A-D)血清胆固醇、甘 油三酯、高密度脂蛋白和低密度脂蛋白水平,(B)血清LDH水平;**p<0.01vs Control,#p<0.05或##p<0.01vs Model;
图3试剂盒检测冠心丹参方对糖尿病小鼠肾脏抗氧化能力的影响。(A)肾组织内LDH 水平,(B)肾组织内MDA水平,(C)肾组织内GSH-Px水平;*p<0.05,**p<0.01,***p<0.001;
图4冠心丹参方对糖尿病小鼠肾脏病理的影响;
图5冠心丹参方对糖尿病小鼠包括肾脏在内不同脏器的抗氧化应激蛋白表达的影响,右 为肾组织内ER、Nrf2和HO-1的表达及其定量分析,**p<0.01vs Control,#p<0.05或##p <0.01vs Model。
具体实施方式
实施例1冠心丹参方药物的配制和基本实验方案
冠心丹参方包括丹参、三七和降香油均购自中发实业集团业锐药业,冠心丹参复方制剂 中丹参提取物、三七提取物、降香油提取物配比为:65mg:24.3mg:14.25μL。
10只8周龄的db/m和60只先天性2型糖尿病db/db小鼠购自南京大学模式动物研究中心,饲养于中国医学科学院药用植物研究所SPF级动物房。适应性饲养8周后分成七组 (n=10):(1)db/m对照组,(2)db/db模型组,(3)db/db+二甲双胍组(140mg/kg/day), (4)db/db+缬沙坦(48mg/kg/day),(5)冠心丹参方高剂量组(丹参1.81g/kg,三七 1.81g/kg,降香15.88μL/kg),(6)冠心丹参方中剂量组(高剂量组的一半剂量),(7)冠 心丹参方低剂量组(高剂量组的四分之一剂量),各组小鼠每天灌胃给药,连续给药10周, 对照和模型组给予同体积的蒸馏水。
实施例2:冠心丹参方对糖尿病小鼠胰岛素耐量的影响
给药10周后,小鼠禁食8小时,腹腔注射胰岛素1U/kg,分别剪尾检测 0,30,60,90,120min小鼠血糖,计算曲线下面积。如图1所示,模型组小鼠胰岛素耐量降低, 冠心丹参方能显著改善糖尿病小鼠胰岛素耐量。
实施例3:冠心丹参方对糖尿病小鼠血清LDH、血脂四项含量的影响
给药10周后,小鼠隔夜禁食,摘眼球取血,常温放置30min后3000r/min离心10min,取血清,全自动生化仪检测LDH、TG、CHO、HDL、LDL水平。如图2所示,模型组LDH、TG、 CHO、HDL、LDL水平均上升,冠心丹参方给药后可显著降低糖尿病小鼠血清LDH、TG、CHO、 HDL、LDL水平。
实施例4:冠心丹参方对糖尿病小鼠肾脏抗氧化能力的影响
给药10周后,脱颈处死小鼠,取肾脏,生理盐水洗净后100mg组织900μl生理盐水研磨肾脏组织,匀浆后4℃,3000r/min离心10min取上清测试剂盒。如图3所示,糖尿病小 鼠肾脏MDA、LDH水平上升,GSH-px水平降低,而冠心丹参方显著逆转糖尿病造成的肾脏抗 氧化能力降低。
实施例5:冠心丹参方对糖尿病小鼠肾脏病理的影响
给药10周后,脱颈处死小鼠,取肾脏,福尔马林固定,切片,HE染色。如图4所示, 与正常对照组相比,模型组小鼠肾脏出现间质炎症细胞浸润,肾小管上皮细胞肿胀,肾间质纤维细胞增生,冠心丹参方处理可以减轻糖尿病小鼠肾损伤。
实施例6:Western blot检测冠心丹参方对糖尿病小鼠肾脏抗氧化应激蛋白表达的影响
给药10周后,脱颈处死小鼠,取肾脏,生理盐水洗净后100mg组织加入1ml裂解液裂解组织。裂解终止后,将裂解液在4℃、12 000×g离心30min,收集上清液用于蛋白表达 分析。采用BCA蛋白定量法确定蛋白浓度,然后10%SDA-PAGE电泳分离。电泳完毕后,将 蛋白转移至NC膜上,用丽春红染色观测蛋白转移是否完全,TBST脱色后用脱脂牛奶室温封 闭:3h。分别加入相应的一抗抗体(Nrf2、HO-1、GAPDH),4℃孵育过夜。TBST洗涤后,加 入HRP标记的二抗,室温孵育1.5h,TBST洗涤后采用化学发光法检测蛋白的变化。
如图5所示,与空白对照组相比,模型组显著抑制抗氧化应激蛋白Nrf2、HO-1的表达; 而给予冠心丹参方孵育后,可显著上调该蛋白表达,从而恢复抗氧化应激功能。
发明人在研究中通过对糖尿病db/db小鼠给予冠心丹参方治疗,发现冠心丹参方能改善 糖尿病小鼠胰岛素耐量;通过体外实验探究冠心丹参方对糖尿病肾病的保护作用;同时进一 步探究冠心丹参方发挥上述保护作用的作用机制。以具体实验资料和理论分析证明了冠心丹 参方对糖尿病肾病的确切疗效,进一步扩展了其用途。
Claims (13)
1.冠心丹参复方制剂在制备预防和治疗糖尿病肾病的药物中的应用。
2.根据权利要求1所述的应用,其中所述冠心丹参复方制剂由包括丹参提取物、三七提取物、降香油提取物的原料制成。
3.根据权利要求1或2所述的应用,其中所述冠心丹参复方制剂为选自注射剂、混悬剂、糖浆剂的液体制剂,或者选自颗粒剂、片剂、胶囊、丸剂、粉针剂、滴丸剂型的固体剂型。
4.根据权利要求3所述的应用,其中冠心丹参复方制剂为滴丸剂。
5.根据权利要求2-4任一项所述的应用,其中所述冠心丹参复方制剂中丹参提取物、三七提取物、降香油提取物配比为40-80mg:15-35mg:10-20μL。
6.根据权利要求5所述的应用,其中所述冠心丹参复方制剂中丹参提取物、三七提取物、降香油提取物配比为:65mg:24.3mg:14.25μL。
7.根据权利要求3-6任一项所述的应用,其中所述冠心丹参复方制剂中根据剂型的需要包含药学可接受的辅料。
8.根据权利要求7所述的应用,所述辅料选自包衣材料、溶剂、增溶剂、粘合剂、稳定剂、抗氧化剂、pH调节剂、矫味剂。
9.根据权利要求1-8任一项所述的应用,其中所述应用包括提高肾脏的抗氧化应激能力。
10.根据权利要求9所述的应用,所述提高肾脏的抗氧化应激能力包括提高Nrf2、HO-1表达。
11.根据权利要求1-10任一项所述的应用,其中所述糖尿病肾病为糖尿病引起的,有蛋白尿、水肿或高血压症状的肾脏疾病。
12.根据权利要求1-11任一项所述的应用,其中将冠心丹参复方制剂与其他治疗肾病的药物或治疗联合使用。
13.根据权利要求12的所述应用,其中其他治疗肾病的药物或治疗可选二甲双胍、胰岛素、透析、肾移植。
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