WO2015039442A1 - 黄芩苷在制备治疗急性溶血性尿毒综合征药物中的应用 - Google Patents

黄芩苷在制备治疗急性溶血性尿毒综合征药物中的应用 Download PDF

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WO2015039442A1
WO2015039442A1 PCT/CN2014/076442 CN2014076442W WO2015039442A1 WO 2015039442 A1 WO2015039442 A1 WO 2015039442A1 CN 2014076442 W CN2014076442 W CN 2014076442W WO 2015039442 A1 WO2015039442 A1 WO 2015039442A1
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baicalin
uremic syndrome
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hemolytic uremic
shiga toxin
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邓旭明
饶子和
董靖
杨诚
牛效迪
李雪梅
陈瑜涛
王权
王大成
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吉林大学
天津市国际生物医药联合研究院
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Publication of WO2015039442A1 publication Critical patent/WO2015039442A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • baicalin in the preparation of drugs for treating acute hemolytic uremic syndrome
  • the present invention relates to the application of baicalin in the preparation of a medicament for treating acute hemolytic uremic syndrome, and belongs to the field of medicine.
  • Baicalin is a flavonoid compound isolated from the root of Astragalus membranaceus. It has obvious antifungal activity, especially for yeast fungi, and the minimum inhibitory concentration (MIC) is 70-100. Between g/ml. However, no reports of baicalin for the treatment of acute hemolytic uremic syndrome caused by Escherichia coli have been reported.
  • Acute hemolytic uremic syndrome is usually a kidney injury caused by type II Shiga toxin secreted by Escherichia coli, which is usually a serious complication. It is usually more common in the elderly and children, and the mortality rate is extremely high. In recent years, due to the large number of antibiotics, the number of Escherichia coli resistant strains has increased. Clinically, the treatment of E. coli infection is facing severe challenges. Usually, antibiotics can promote the secretion of drug-resistant Escherichia coli type II Shiga toxin. Lead to further aggravation of the disease. Therefore, it is extremely urgent to find new and safe therapeutic drugs.
  • Baicalin is a component derived from traditional Chinese medicinal materials such as Astragalus membranaceus, Wood Butterfly, etc.
  • the present invention confirmed the acute hemolytic effect of baicalin on Escherichia coli type II Shiga toxin, especially resistant Escherichia coli type II Shiga toxin.
  • Uremic syndrome has a good therapeutic effect.
  • baicalin has a good therapeutic effect on acute hemolytic uremic syndrome caused by Escherichia coli type II Shiga toxin.
  • acute hemolytic uremic syndrome caused by drug-resistant Escherichia coli type II Shiga toxin has a better therapeutic effect.
  • the invention also provides the application of baicalin in the preparation of a medicament for treating acute hemolytic uremic syndrome.
  • the technical solution of the present invention preferably uses the baicalin in the preparation of an acute hemolytic uremic syndrome drug caused by Escherichia coli type II Shiga toxin.
  • the present invention can prepare baicalin and pharmaceutically acceptable adjuvants in various dosage forms.
  • the medicament of the present invention includes any dosage form that is pharmaceutically acceptable.
  • baicalin is preferably prepared into a dosage form such as an injection, a capsule, a tablet, a powder injection or the like.
  • baicalin binds to the Stx2 A subunit enzyme activity center (left panel shows the binding of baicalin to Stx2, and the right panel shows the binding site of baicalin to Stx2).
  • Figure 2. Free energy contribution analysis of the complex system (the horizontal axis is the amino acid species, the vertical axis is the free energy change; Etotal is the total binding energy, E vdw is the van der Waals force, 16 is the electrostatic force, and E SQl is the non-polar solvation can) .
  • Figure 3 Free energy contribution analysis of the complex system (the horizontal axis is the amino acid species, the vertical axis is the free energy change; Etotal is the total binding energy, E vdw is the van der Waals force, 16 is the electrostatic force, and E SQl is the non-polar solvation can) .
  • Baicalin induces the formation of multimers of the ricin A subunit.
  • Figure 4. Effect of baicalin on survival rate of acute uremic syndrome in mice (abscissa is observation time, ordinate is survival rate, d is in days, PBS is negative control group, Stx is infection unadministered group, Stx +BAI is the administration group).
  • Figure 5. Renal histopathological changes in mice with acute uremic syndrome after baicalin injection (PBS as a negative control group, Stx as an uninfected group, and Stx+BAI as a drug-administered group).
  • baicalin can bind to the active pocket of type II Shiga toxin, thereby inhibiting the activity of its activity, by decomposing the complex system.
  • Free energy it is found that the amino acids that contribute to the free energy of the complex system are
  • mice Male, 18-22 g were anesthetized with ether, and the purified type II Shiga toxin protein was administered intraperitoneally. The mice lay flat until they awoke, and a mouse model of acute hemolytic uremic syndrome was established. The survival rate test, the pathology test, and the renal function evaluation test were administered with 50 ng of purified type II Shiga toxin protein.
  • the protection rate test was divided into three groups, 20 BALB/C male mice in each group, sterile PBS as the negative control group, Stx as the infection-untreated group, and Stx+BAI as the treatment group.
  • the mice in the drug-administered group were injected with 200 mg/kg of baicalin 2 hours after the injection of type II Shiga toxin protein, and were administered once every 6 hours for 96 hours.
  • Positive control group (Stx group) was given 100 ⁇ after injecting toxin
  • the bacteria PBS the survival rate was counted.
  • the results showed that after treatment with baicalin, the survival rate of acute hemolytic uremic syndrome in mice was significantly improved, as shown in Fig. 4.
  • mice in the drug-administered group were injected with 200 mg/kg of baicalin 2 hours after the injection of type II Shiga toxin protein, and were administered once every 6 hours for 72 hours.
  • the positive control group (Stx group) was given sterilized PBS with ⁇ , 10 mice in each group. After 72 hours of infection, the mice were anesthetized and sacrificed for kidney pathological examination to observe the pathological changes.
  • the test was divided into three groups, 20 BALB/C male mice in each group, sterile PBS as negative control group, Stx as infection untreated group and Stx+BAI as treatment group.
  • the mice in the drug-administered group were injected with 200 mg/kg of baicalin 2 hours after the injection of type II Shiga toxin protein, and were administered once every 6 hours for 72 hours.
  • the positive control group (Stx group) was given sterilized PBS of ⁇ , 10 mice per group.
  • the improvement of renal function of baicalin was evaluated by evaluating the content of creatinine and urea nitrogen in the serum of mice.

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  • Life Sciences & Earth Sciences (AREA)
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  • Urology & Nephrology (AREA)
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Abstract

黄芩苷在制备治疗急性溶血性尿毒综合征的药物中的应用。

Description

黄芩苷在制备治疗急性溶血性尿毒综合征药物中的应用
技术领域 本发明涉及黄芩苷在制备治疗急性溶血性尿毒综合征药物中的应用， 属于医药领域。 背景技术 黄芩苷（Baicalin)是从黄芩根中提取分离出来的一种黄酮类化合物， 具有明显的抗真菌 活性， 尤其对酵母型真菌具选择性作用， 最低抑菌浓度（MIC)在 70-100 g/ml 之间。但未见 黄芩苷用于治疗由大肠杆菌引起的急性溶血性尿毒综合征的报道。 急性溶血性尿毒综合征通常是由大肠杆菌分泌的 II型志贺毒素引起的肾脏损伤， 通常是 严重的并发症， 一般在老年人和儿童较容易发病， 病死率极高。 近年来由于抗生素的大量使 用导致大肠杆菌耐药菌株越来越多， 临床上对大肠杆菌感染的治疗面临严峻的挑战， 而通常 抗生素能够促进耐药性大肠杆菌 II型志贺毒素的分泌， 进而导致疾病的进一步加重。 因此， 寻找新型、 安全的治疗药物迫在眉睫。 黄芩苷是来源于我国传统中药材黄芩、 木蝴蝶等的成 分， 本发明研究证实了黄芩苷对大肠杆菌 II型志贺毒素， 尤其是耐药性大肠杆菌 II型志贺毒 素引起的急性溶血性尿毒综合征具有较好的治疗效果。
发明内容 黄芩苷的分子结构如下:
Figure imgf000002_0001
本发明发现了黄芩苷对大肠杆菌 II型志贺毒素引起的急性溶血性尿毒综合征具有较好的 治疗效果。 尤其是耐药性大肠杆菌 II型志贺毒素引起的急性溶血性尿毒综合征具有更好的治 疗效果。
本发明同时提供了黄芩苷在制备治疗急性溶血性尿毒综合征药物中的应用。
本发明技术方案优选黄芩苷在制备由大肠杆菌 II型志贺毒素引起的急性溶血性尿毒综合 征药物中的应用。 本发明可将黄芩苷和药学上可接受的辅料制备成各种剂型。 本发明所述药物， 包括药学 上可接受的任何剂型。
本发明优选将黄芩苷制备成注射剂、 胶囊、 片剂、 粉针剂等剂型。
本发明与用抗生素治疗相比较， 使用黄芩苷治疗具有无耐药性， 治愈率高的优点。 附图说明 图 1. 分子对接发现黄芩苷结合于 Stx2 A亚基酶活性中心（左图为黄芩苷与 Stx2的结合方式， 右图为黄芩苷与 Stx2的结合位点）。 图 2. 复合物体系自由能贡献分析 （横轴为氨基酸种类， 纵轴为自由能变化； Etotal为总结合 能， Evdw为范德华力， 16为静电作用力， ESQl为非极性溶剂化能） 。 图 3. 黄芩苷诱导蓖麻毒素 A亚基形成多聚体。 图 4. 黄芩苷对小鼠急性尿毒综合征存活率的影响 （横坐标为观察时间， 纵坐标为存活率， d 的单位为天， PBS为阴性对照组， Stx为感染未给药组， Stx+BAI为给药组）。 图 5. 注射黄芩苷后急性尿毒综合征小鼠肾脏病理组织学变化 （PBS为阴性对照组， Stx为感 染未给药组， Stx+BAI为给药组）。 图 6. 黄芩苷对急性尿毒综合征小鼠肾功能的影响 （横坐标为处理方式， 纵坐标为浓度， Con 为阴性对照组， Stx+BAI为给药组， Stx为感染未给药组）。 具体实施方式 通过对 Hela细胞的保护作用以及小鼠性溶血性尿毒综合征模型证实了黄芩苷治疗 II型志 贺毒素感染的作用。
1.黄苓苷对 Hela细胞的保护作用 将培养的 Hela细胞以每孔 15000个细胞铺到 96孔细胞培养板中，培养 24小时完全贴壁后每 孔加入纯化的 II型志贺毒素 50pg， 并加入不同梯度的黄芩苷溶液， 置于 C02培养箱中培养 72小 时后离心去除细胞培养液上清检测其乳酸脱氢酶释放量， 通过乳酸脱氢酶释放评价其对细胞 的保护作用。结果显示黄芩苷能显著抑制 II型志贺毒素导致的 Hela细胞毒性作用， 并呈现剂量 依赖性。 加入不同浓度的黄芩苷后 Hela细胞的存活率如下表 1 : 表 1.黄芩苷对 II型志贺毒素导致的 Hela细胞毒性的抑制作用
黄芩苷 （ g/ml ) 存活率 （％)
0 24.34
4 38.63
8 50.22
16 57.14
32 75.14
2.黄芩苷抗 II型志贺毒素机制分析及靶点确证 应用分子模拟和对接发现黄芩苷能结合到 II 型志贺毒素的活性口袋中， 从而抑制了其 活性的发挥， 通过分解复合物体系的自由能， 发现对复合物体系自由能贡献较大的氨基酸是
77位酪氨酸和 204位精氨酸。进一步将得到的数据应用点突变技术和荧光淬灭技术进行验证， 结果发现计算机模拟结果和验证结果一致。 黄芩苷结合到 II型志贺毒素的 77和 204位的氨 基酸导致其失去酶活性从而抑制了其活性作用的发挥， 黄芩苷与 II型志贺毒素结合位点见图 1， 结合能分析见图 2。
3.结构生物学靶点确证 本研究得到了 II型志贺毒素结构和功能类似蛋白蓖麻毒素 A亚基的晶体，并解析了蓖麻 毒素 A亚基和黄芩苷复合物的晶体结构，通过结构分析发现黄芩苷促使蓖麻毒素 A亚基形成 多聚体而失去活性（附图 3 )，黄芩苷与蓖麻毒素 A亚基的结合位点为 R189, T190, R193, Y194, R235和 R258; 通过序列比对发现， 黄芩苷与 II型志贺毒素的结合位点为 R179, Q180, S183, E184禾 P V218。
4. 小鼠急性溶血性尿毒综合征实验治疗学研究
4.1 小鼠急性溶血性尿毒综合征模型
BALB/C小鼠 （雄性， 18-22g) 经乙醚麻醉后， 经腹腔给予纯化的 II型志贺毒素蛋白， 小 鼠平躺直至苏醒， 建立小鼠急性溶血性尿毒综合征模型。 存活率试验、 病理学试验及肾功能 评价试验给予 50ng纯化的 II型志贺毒素蛋白。
4.2 保护率试验
保护率试验分为三组， 每组 20只 BALB/C雄性小鼠， 灭菌 PBS为阴性对照组， Stx为感 染未给药组， Stx+BAI为治疗组。给药组小鼠在注射 II型志贺毒素蛋白 6h后皮下注射 200mg/kg 的黄芩苷， 每 6h给药一次， 共给药 96h。 阳性对照组 （Stx组） 注射毒素后给予 100 μΐ的灭 菌 PBS， 统计其存活率。 结果表明， 经黄芩苷处理后， 显著提高小鼠急性溶血性尿毒综合征 的存活率， 见图 4。
4.3 病理组织学实验 试验分为三组， 每组 20只 BALB/C雄性小鼠， 灭菌 PBS为阴性对照组， Stx为感染未给药组， Stx+BAI 为治疗组。 给药组小鼠在注射 II型志贺毒素蛋白 6h后皮下注射 200mg/kg的黄芩苷， 每 6h给药一 次， 共给药 72h。 阳性对照组 （Stx组） 给与 ΙΟΟ μΙ的灭菌 PBS， 每组 10只小鼠， 感染 72小时后 将小鼠麻醉致死取肾脏做病理切片观察其病理变化。结果发现， 阳性对照组小鼠肾脏有出血， 肾小管上皮细胞有大量细胞脱落， 肾小球消失； 而给药组肾组织仅有少量出血， 与正常组小 鼠比较无明显差异； 见图 5。
4.4 肾功能评价试验 试验分为三组， 每组 20只 BALB/C雄性小鼠， 灭菌 PBS为阴性对照组， Stx为感染未给药组， Stx+BAI 为治疗组。 给药组小鼠在注射 II型志贺毒素蛋白 6h后皮下注射 200mg/kg的黄芩苷， 每 6h给药一 次， 共给药 72h。 阳性对照组 （Stx组） 给与 ΙΟΟ μΙ的灭菌 PBS， 每组 10只小鼠。 通过评价小鼠 血清中肌酐、 尿素氮的含量来评价黄芩苷对模型小鼠肾功能的改善。 结果发现， 给药组肌酐、 尿素氮含量与阴性对照组小鼠比较无显著差异 (P>0.05)，而阳性组小鼠与阴性组则差异极显著 (P<0.01)， 见图 6。

Claims

权 利 要 求 书
1. 黄芩苷在制备治疗急性溶血性尿毒综合征药物中的应用。
2. 如权利要求 1所述的应用， 其中所述急性溶血性尿毒综合征是由大肠杆菌 II 型志贺毒素引起的。
3. 如权利要求 1或 2所述的应用， 其特征在于， 所述药物为药学上可接受的任 何剂型。
4. 如权利要求 3所述的应用， 其特征在于， 所述剂型选自注射液、 胶囊、 片剂 或粉针剂。
PCT/CN2014/076442 2013-09-18 2014-04-29 黄芩苷在制备治疗急性溶血性尿毒综合征药物中的应用 WO2015039442A1 (zh)

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CN1511540A (zh) * 2002-12-24 2004-07-14 山东绿叶天然药物研究开发有限公司 黄芩苷在制备治疗或预防口腔溃疡药物中的应用
CN103622984A (zh) * 2013-09-18 2014-03-12 吉林大学 黄芩苷在制备治疗急性溶血性尿毒综合征药物中的应用

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