CN106344596A - 鞣酸在制备保护心肌作用药物中的应用 - Google Patents
鞣酸在制备保护心肌作用药物中的应用 Download PDFInfo
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- CN106344596A CN106344596A CN201610755241.6A CN201610755241A CN106344596A CN 106344596 A CN106344596 A CN 106344596A CN 201610755241 A CN201610755241 A CN 201610755241A CN 106344596 A CN106344596 A CN 106344596A
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- tannic acid
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7024—Esters of saccharides
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
鞣酸在制备保护心肌作用药物中的应用，涉及鞣酸的新用途技术领域。鞣酸在制备保护心肌作用药物中的应用。作为抗氧化应激、抗炎和抗凋亡作用达到多靶点治疗心脏毒性的药物的应用。本发明开发了多元酚类化合物鞣酸的新的药物用途。
Description
技术领域
本发明涉及鞣酸的新用途，具体地说是鞣酸在制备具有保护心肌作用药物的用途。
背景技术
鞣酸(tannic acid)，又名单宁酸，是一类比较复杂的多元酚类化合物，广泛存在于植物界，亦是一种食品添加剂，在许多平常的食物如茶、咖啡、坚果、豆类、葡萄及未成熟的水果中均发现含有鞣酸；约70％以上的中草药含有鞣质类化合物，如五倍子、地榆、肉桂、大黄、仙鹤草等。
阿霉素属蒽醌类抗生素，具有抗瘤谱广、作用强的特点，己在临床上广泛用于治疗多种恶性肿瘤。然而，阿霉素具有严重的心脏毒性作用，主要表现为用药早期出现各种心律失常，晚期出现剂量依赖性、充血性心力衰竭，而且一旦出现充血性心力衰竭，其病死率可达30％-50％，这在一定程度上限制了阿霉素的大剂量长期应用。阿霉素与心肌组织的亲和力明显高于其他组织，使得心肌组织更易受到阿霉素的损害。阿霉素在心肌细胞中产生的氧自由基(如OH、H2O2)作用于细胞膜及各种细胞器膜上的磷脂中的多价不饱和脂肪酸，形成脂质自由基，引发脂质过氧化反应，使膜的结构发生改变、扭曲，并影响膜上功能蛋白质的位置及构型，最终导致膜的完整性遭到破坏，膜的流动性降低，通透性增加，容量调节功能及离子转运功能障碍。
鞣酸本身具有多羟基结构，具有很强的还原性，所以有较强的自由基清除作用，同时鞣酸有多个羟基可与许多金属离子(如二价铁离子、二价铜离子等金属离子)络合，这些金属离子被络合后，便不能产生启动脂肪过氧化的羟基自由基或使其不能分解脂质过氧化产生的过氧化氢，从而抑制自由基的产生。而人体内的氧化反应主要是由自由基引起的，过多的自由基会攻击机体的生物膜，对机体的组织和细胞造成损害，产生各种各样的炎症反应和心血管疾病。据报道，饮食摄入多元酚与降低血压和降低心血管发病率有关，但其心脏保护机制仍不清楚。
发明内容
本发明的目的就是提供一种保护心脏的药物，该药物能够减轻阿霉素诱导的心脏毒性，起到心肌保护作用。
本发明的目的是这样实现的：
本发明提供了一种多元酚类化合物鞣酸的新用途，即鞣酸在制备保护心肌作用药物中的应用，作为抗氧化应激、抗炎和抗凋亡作用达到多靶点治疗心脏毒性的药物的应用，尤其治疗阿霉素诱导的心脏毒性的药物的应用。
进一步多元酚类化合物鞣酸的新用途，即鞣酸在制备保护心肌构架作用药物中的应用。
进一步多元酚类化合物鞣酸的新用途，即鞣酸在制备维持过氧化氢酶(CAT)、谷胱甘肽过氧化物酶(GSH-Px)作用药物中的应用。
进一步多元酚类化合物鞣酸的新用途，即鞣酸在制备提高丙二醛(MDA)、超氧化物歧化酶(SOD)水平作用药物中的应用。
进一步多元酚类化合物鞣酸的新用途，即鞣酸在制备提高一氧化氮(NO)水平作用药物中的应用。
进一步多元酚类化合物鞣酸的新用途，即鞣酸在制备降低c-fos、c-jun、肿瘤坏死因子-α(TNF-α)和白介素-1β(IL-1β)的表达量药物中的应用。
进一步多元酚类化合物鞣酸的新用途，即鞣酸在制备降低细胞凋亡相关因子bax、caspase-3和NF-κB表达量水平，提高bcl-2表达量水平药物中的应用。
本发明提供的鞣酸作为制备心脏保护药，与药学上允许使用的载体或稀释剂混合，制备成药物制剂，作为制备抑制阿霉素诱导的心肌细胞氧化应激反应、炎症反应和心肌细胞凋亡的药物的应用，可保护心肌细胞。
本发明所述化合物均可从商业渠道获得。
本发明所指药学上可以接受的载体或稀释剂，可选自药物制剂中常用的赋形剂、辅料或溶剂。如乳糖、蔗糖、糊精、滑石粉、明胶、琼脂、果胶、阿拉伯树胶、硬脂酸镁、硬脂酸、纤维素的低级烷基醚、玉米淀粉、马铃薯淀粉、树胶、糖浆、花生油、橄榄油、磷脂、脂肪酸、脂肪酸胺、单硬脂酸甘油脂或二硬脂酸甘油脂、着色剂、矫味剂、防腐剂、水、乙醇、丙醇、生理盐水、葡萄糖溶液等等。
本发明提供的鞣酸作为心脏保护药的具体制备方法可按照制剂常规进行。如可以本发明所述化合物作为活性成份，与水、蔗糖、山梨醇糖、果糖等制备成口服液体制剂；也可以乳糖、葡萄糖、蔗糖、甘露醇糖等为赋形剂，以淀粉等为崩解剂，以硬脂酸、滑石粉等为润滑剂，明胶、聚乙烯醇为结合剂制备成片剂或胶囊剂；还可与生理盐水、葡萄糖溶液或盐水与葡萄糖组成的混合载体制备成注射液。还可制成无菌粉针剂以及各种缓释剂、混悬剂、乳剂等等。
附图说明
图1鞣酸的化学结构式图
图2鞣酸对心脏组织病理学变化的影响：其中，
图2A空白组大鼠心脏组织的病理切片图(400×)；
图2B阿霉素模型组(10mg/kg)大鼠心脏组织的病理切片图(400×)；
图2C卡托普利组(30mg/kg)大鼠心脏的病理切片图(400×)；
图2D鞣酸低剂量组(20mg/kg)大鼠心脏的病理切片图(400×)；
图2E鞣酸高剂量组(40mg/kg)大鼠心脏的病理切片图(400×)；
图3鞣酸对丙二醛(MDA)、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、谷胱甘肽过氧化物酶(GSH-Px)的调节作用：其中，
图3A鞣酸降低MDA含量的统计图；
图3B鞣酸增大GSH-Px活性的统计图；
图3C鞣酸增大SOD活性的统计图；
图3D鞣酸增大CAT活性的统计图；
图4鞣酸对阿霉素致大鼠心肌损伤一氧化氮(NO)、内皮素-1(ET-1)的调节作用：其中，
图4A鞣酸抑制ET-1的统计图；
图4B鞣酸增大NO的统计图；
图5鞣酸对肿瘤坏死因子-α(TNF-α)和白介素-1β(IL-1β)的表达调节作用。其中，
图5A鞣酸对阿霉素致大鼠心肌损伤免疫组化切片图(400×)；
图5B鞣酸抑制IL-1β的统计图；
图5C鞣酸抑制TNF-α的统计图；
图6鞣酸对c-fos，c-jun的表达调节作用。其中，
图6A鞣酸对阿霉素致大鼠心肌损伤免疫组化切片图(400×)；
图6B鞣酸抑制c-fos的统计图；
图6C鞣酸抑制c-jun的统计图；
图7鞣酸对bax/bcl-2，caspase-3表达水平的影响。其中，
图7A鞣酸降低caspase-3表达的Western blot条带；
图7B鞣酸降低caspase-3表达的统计图；
图7C鞣酸降低bax/增大bcl-2表达的Western blot条带；
图7D鞣酸增大bcl-2表达的统计图；
图7E鞣酸降低bax表达的统计图；
图8鞣酸对NF-κB(p65)表达水平的影响。其中，
图8A鞣酸降低NF-κB(p65)表达的Western blot条带；
图8B鞣酸降低NF-κB(p65)表达的统计图。
具体实施方式
下面结合实施例对本发明作进一步说明，但本发明不限于以下实施例。
实施例1鞣酸对阿霉素所致心肌损伤的保护作用
材料与方法：
1.1实验动物
纯种清洁级SD大鼠60只，体重180-220g，购自河北医科大学实验动物中心。
1.2实验用药物
鞣酸(Tannic acid，TA)购自Sigma Chemicals(St.Louis,MO,USA)。
阿霉素(Doxorubicin，DOX)购自Sigma Chemicals(St.Louis,MO,USA)。
卡托普利(Captoril，CAP)购自黄海制药公司(Shanghai，China)。
1.3模型制备
实验动物常规观察1周后随机分为5组，每组各112只。分别为空白对照组(CONT)、DOX模型对照组(10mg/kg，DOX)、TA低剂量组(20mg/kg，TAL)、TA高剂量组(40mg/kg，TAH)和CAP阳性药对照组(30mg/kg，CAP)。各组大鼠称重后，CONT及DOX模型对照组每天灌胃生理盐水1ml/100g，TAL、TAH和CAP阳性药对照组分别灌胃20mg/kg TA，40mg/kg TA和30mg/kg CAP，连续6天。第4天除CONT组外其余各组于腹腔注射DOX(10mg/kg)，复制大鼠DOX诱导心肌损伤模型。
1.4检测指标
1.4.1生物化学方法测定氧化应激及器官功能相关因子：乳酸脱氢酶(LDH)，肌酸激酶(CK)，肌酸激酶同工酶(CK-MB)，丙二醛(MDA)，一氧化氮(NO)和内皮素-1(ET-1)、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、谷胱甘肽过氧化物酶(GSH-Px)。
1.4.2病理学指标：光镜观察心脏组织病理学变化。
1.4.3Western blot测定细胞凋亡相关因子(bax/bcl-2，NF-κB(p65)，caspase-3)表达水平。
1.4.4免疫组化测定c-fos，c-jun，肿瘤坏死因子-α(TNF-α)和白介素-1β(IL-1β)的表达。1.5统计处理
实验数据以均数±标准差表示，P<0.05具有统计学意义。
2结果
2.1TA对DOX造成的心脏毒性指数的影响
与CONT组对比，阿霉素中毒导致体重下降但无统计学意义，但血清标志物如LDH，CK，CK-MB在DOX组中显著上升(P<0.01)。与DOX组相比，TA各组显著降低LDH，CK，CK-MB水平(P<0.05or P<0.01)(详见表1)。
2.1DOX诱导的心肌损伤的组织病理学检查
大鼠心脏组织在光镜下检查发现，CONT组大鼠心肌细胞均表现为正常心肌细胞结构和分布(详见图2A)，而DOX模型对照组则表现为肌原纤维和波纹纤维的损失(图2B)。与之相反的是经过各浓度TA组(20mg/kg，40mg/kg)治疗，大鼠心脏保留了正常的心肌构架(详见图2D，2E)。
2.2TA对MDA、SOD、CAT和GSH-Px的影响
与CONT组比较，DOX组显著降低CAT和GSH-Px水平(P<0.001)，而在TAL和TAH组中，CAT和GSH-Px水平接近正常。SOD活性在DOX组显著降低，而MDA含量则显著上升，而在TAL和TAH组中SOD和MDA指标水平与在DOX组中截然相反(详见图3)。
2.3TA对NO和ET-1的影响
与CONT组比较，DOX组显著降低ET-1水平，显著降低NO水平(P<0.001)。ET-1在CAP组中水平比在DOX组低而NO则相反(P<0.01)。ET-1在TAL和TAH组中水平比在DOX组低而NO则相应升高(P<0.01)(详见图4)。2.4TA对TNF-α和IL-1β表达的影响
与CONT组比较，心肌组织中DOX组TNF-α和IL-1β表达量显著增加，CAP组和TA各组则显著降低TNF-α和IL-1β表达量(详见图5)。
2.4TA对c-fos和c-jun表达的影响
与CONT组比较，心肌组织中DOX组c-fos和c-jun表达量显著增加，CAP组和TA各组则显著降低c-fos和c-jun表达量(详见图6)。
2.5TA对bax，bcl-2和caspase-3表达的影响
与CONT组相比较，DOX组bax，caspase-3表达显著增加(P<0.01)，而bcl-2的表达显著降低(P<0.01)。与之相反，TA组的bax，caspase-3表达显著降低(P<0.01)，而bcl-2的表达显著增加(P<0.01or P<0.05)(详见图7)。
2.5TA对NF-κB(p65)表达的影响
与CONT组相比较，DOX组NF-κB(p65)表达显著增加(P<0.01)。与之相反，TA组的NF-κB(p65)表达显著降低(P<0.01)(详见图8)。
本实验结果显示，TA能够显著改善DOX对心肌的毒性作用。TA使LDH、CK、CK-MB值下降至正常水平。作为氧化应激指标，TA能增加SOD、CAT、GSH-Px抗氧化物的活性并降低MDA水平。此外，DOX还能够通过增加促炎细胞因子水平如TNF-α，IL-1β，ET-1，NO和NF-κB引起炎症反应，而TA能够显著抑制这些炎症反应，同时TA还能抑制c-fos，c-jun，Caspase-3和Bax的过度表达而上调Bcl-2的表达达到抑制DOX诱导的凋亡现象。综上所述，本实验结果提示TA能够通过抗氧化、抗炎、抗凋亡作用抑制DOX诱导的心肌毒性。
实施例2制备口服片剂
按照本领域已知的方法制备片剂，每片含有下述成分：
表1鞣酸对阿霉素造成的心脏毒性指数的影响
以上实施例是为了更详细地说明本发明，但它不以任何形式限制本发明。
Claims (10)
1.一种多元酚类化合物鞣酸的用途，其特征在于，鞣酸在制备保护心肌作用药物中的应用。
2.按照权利要求1所述的一种多元酚类化合物鞣酸的用途，其特征在于，作为抗氧化应激、抗炎和抗凋亡作用达到多靶点治疗心脏毒性的药物的应用。
3.按照权利要求2所述的一种多元酚类化合物鞣酸的用途，其特征在于，治疗阿霉素诱导的心脏毒性的药物的应用。
4.按照权利要求3所述的一种多元酚类化合物鞣酸的用途，其特征在于，鞣酸在制备保护心肌构架作用药物中的应用。
5.按照权利要求3所述的一种多元酚类化合物鞣酸的用途，其特征在于，鞣酸在制备维持过氧化氢酶(CAT)、谷胱甘肽过氧化物酶(GSH-Px)作用药物中的应用。
6.按照权利要求3所述的一种多元酚类化合物鞣酸的用途，其特征在于，鞣酸在制备提高丙二醛(MDA)、超氧化物歧化酶(SOD)水平作用药物中的应用。
7.按照权利要求3所述的一种多元酚类化合物鞣酸的用途，其特征在于，鞣酸在制备提高一氧化氮(NO)水平作用药物中的应用。
8.按照权利要求3所述的一种多元酚类化合物鞣酸的用途，其特征在于，鞣酸在制备降低c-fos、c-jun、肿瘤坏死因子-α(TNF-α)和白介素-1β(IL-1β)的表达量药物中的应用。
9.按照权利要求3所述的一种多元酚类化合物鞣酸的用途，其特征在于，鞣酸在制备降低细胞凋亡相关因子bax、caspase-3和NF-κB表达量水平，提高bcl-2表达量水平药物中的应用。
10.按照权利要求1所述的一种多元酚类化合物鞣酸的用途，其特征在于，鞣酸作为制备心脏保护药活性成分，与药学上允许使用的载体或稀释剂混合，制备成药物制剂。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019182279A1 (ko) * | 2018-03-22 | 2019-09-26 | 한국화학연구원 | 탄닌산을 포함하는 심장 표적화제 |
-
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Non-Patent Citations (2)
| Title |
|---|
| HU X等: "Cardioprotective Effects of Tannic Acid on Isoproterenol-Induced Myocardial Injury in Rats:Further Insight into ‘French Paradox’", 《PHYTOTHERAPY RESEARCH PTR》 * |
| TIKOO K等: "Tannic acid ameliorates doxorubicin-induced cardiotoxicity and potentiates its anti-cancer activity: Potential role of tannins in cancer chemotherapy", 《TOXICOLOGY AND APPLIED PHARMACOLOGY》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019182279A1 (ko) * | 2018-03-22 | 2019-09-26 | 한국화학연구원 | 탄닌산을 포함하는 심장 표적화제 |
| CN111971067A (zh) * | 2018-03-22 | 2020-11-20 | 韩国化学研究院 | 含有单宁酸的心脏靶向剂 |
| US11446384B2 (en) | 2018-03-22 | 2022-09-20 | Korea Research Institute Of Chemical Technology | Agent for targeting heart comprising tannic acid |
| CN111971067B (zh) * | 2018-03-22 | 2023-09-08 | 韩国化学研究院 | 含有单宁酸的心脏靶向剂 |
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