CN111686108A - 表小檗碱在制备抗幽门螺旋杆菌感染药物中的应用 - Google Patents
表小檗碱在制备抗幽门螺旋杆菌感染药物中的应用 Download PDFInfo
- Publication number
- CN111686108A CN111686108A CN202010658035.XA CN202010658035A CN111686108A CN 111686108 A CN111686108 A CN 111686108A CN 202010658035 A CN202010658035 A CN 202010658035A CN 111686108 A CN111686108 A CN 111686108A
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- China
- Prior art keywords
- epiberberine
- helicobacter pylori
- application
- pylori infection
- antibiotic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
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- A—HUMAN NECESSITIES
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
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- 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
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
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Abstract
本发明提供表小檗碱在制备抗幽门螺旋杆菌感染药物中的应用。本发明研究发现，表小檗碱与抗生素(阿莫西林、克拉霉素、甲硝唑、呋喃唑酮、奥美拉唑中的一种或几种组合)联用时，可以显著提升抗生素的抗Hp活性，能有效缓解幽门螺杆菌耐药性问题，对于治疗耐药性或敏感性幽门螺杆菌感染导致的急、慢性胃炎、胃、十二脂肠溃疡等疾病有重要的意义。
Description
技术领域
本发明涉及表小檗碱，具体涉及表小檗碱在制备抗幽门螺旋杆菌感染药物中的应用，属于新药开发技术领域。
背景技术
幽门螺杆菌(Helicobacter Pylori，HP)是一种螺旋状或S状、微需氧的革兰氏阴性细菌，定居于人胃，引起急慢性胃炎、消化性溃疡(胃溃疡和十二指肠溃疡)、胃癌等疾病。HP在人群中的感染率非常高，在我国感染率在42－84％。这种细菌感染首先引起慢性胃炎，并导致胃溃疡和胃萎缩，严重者则发展为胃癌。幽门螺杆菌寄生在胃粘膜组织中，据统计，67％～80％的胃溃疡和95％的十二指肠溃疡是由幽门螺杆菌引起的。慢性胃炎和消化道溃疡患者的普遍症状为：食后上腹部饱胀、不适或疼痛，常伴有其他不良症状，如暖气、腹胀、反酸和食欲减退等。有些患者还可出现反复发作性剧烈腹痛、上消化道少量出血等。
临床上治疗这些疾病主要是采用抗生素杀灭Hp，由于耐药性问题，抗生素的疗效正在下降。1998年，美国FDA批准了临床上治疗Hp的“三联疗法”(三个抗生素同时使用)，但到2018《第五次全国幽门螺旋杆菌专家共识》的时候，业界普遍认为上述三联疗法疗效已经无法满足临床治疗的要求，推荐使用“四联疗法”(四个抗生素同时使用)，导致副作用越来越严重。因此，开发新的抗Hp感染的药物，成为临床上十分紧迫的问题。
发明内容
为了解决现有技术中的问题，本发明提供表小檗碱在制备抗幽门螺旋杆菌感染药物中的应用。
表小檗碱(CAS号为6873-09-2)，分子式：C20H18NO4 +，别名去氢辛乃克丁，是一种天然季铵原小檗碱型生物碱，是从黄连中提取分离得到的，在Coptisgroenlandica，Coptisjaponica，Thalictrumminus，NandChemicalbookinadomestica等植物中也含有。表小檗碱具有多种药理作用，如对细胞色素P450亚型CYP2D6较强的抑制活性，非竞争性BACE1抑制活性，抑制醛糖还原酶活性，α受体阻断作用，体外降血糖活性等。表小檗碱结构式如下：
为实现上述目的，本发明的技术方案为：
本发明提供表小檗碱在制备抗幽门螺旋杆菌感染药物中的应用。
发明人发现，有效量的表小檗碱与抗生素联用时，可以显著提升抗生素的抗Hp活性。本发明所述抗生素选自阿莫西林、克拉霉素、甲硝唑、呋喃唑酮、奥美拉唑中的一种或几种组合。
本发明提供表小檗碱与阿莫西林联合用药在制备抗幽门螺杆菌感染药物中的应用。进一步，本发明还提供药物组合物，其包含表小檗碱与阿莫西林以及药学上可接受的载体。
本发明提供表小檗碱与克拉霉素联合用药在制备抗幽门螺杆菌感染药物中的应用。进一步，本发明还提供药物组合物，其包含表小檗碱与克拉霉素以及药学上可接受的载体。
本发明提供表小檗碱与甲硝唑联合用药在制备抗幽门螺杆菌感染药物中的应用。进一步，本发明还提供药物组合物，其包含表小檗碱与甲硝唑以及药学上可接受的载体。
本发明提供表小檗碱与呋喃唑酮联合用药在制备抗幽门螺杆菌感染药物中的应用。进一步，本发明还提供药物组合物，其包含表小檗碱与呋喃唑酮以及药学上可接受的载体。
本发明提供表小檗碱与奥美拉唑联合用药在制备抗幽门螺杆菌感染药物中的应用。进一步，本发明还提供药物组合物，其包含表小檗碱与奥美拉唑以及药学上可接受的载体。
本发明药学上可接受的载体可以使用本领域已知的任何适宜载体。载体包括但不限于固体、液体或者固体和液体的混合物。载体可以采取胶囊、片剂、丸剂、粉末、锭剂、混悬剂、乳剂或糖浆剂的形式。载体可以包括充当矫味剂、润滑剂、增溶剂、助悬剂、粘合剂、稳定剂、片剂崩解剂及包封材料的物质。本文使用的短语“药学上可接受的”指在合理医学判断范围内，适用于与人类和动物的组织接触而不具有过度的毒性、刺激、过敏反应或其他问题或并发症的，与合理的受益/风险比相称的那些化合物、材料、组合物和/或剂型。
可以充当药学上可接受的载体的材料非限制性实例包括：(1)糖，例如乳糖、葡萄糖和蔗糖；(2)淀粉，例如玉米淀粉和马铃薯淀粉；(3)纤维素及其衍生物，例如羧甲基纤维素钠、乙基纤维素和乙酸纤维素；(4)粉末状西黄蓍胶；(5)麦芽；(6)明胶；(7)滑石；(8)赋形剂，例如可可脂和栓剂蜡；(9)油类，例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油；(10)二醇类，例如丙二醇；(11)多元醇类，例如甘油、山梨醇、甘露醇和聚乙二醇；(12)酯类，例如油酸乙酯和月桂酸乙酯；(13)琼脂；(14)缓冲剂，例如氢氧化镁和氢氧化铝；(15)海藻酸；(16)无热原水；(17)等渗盐水，(18)林格溶液，(19)乙醇；(20)磷酸盐缓冲液；和(21)在药物制剂中使用的其他无毒相容性物质。
如本文使用的短语“有效量”是指有效地在动物中产生一些所需作用的本发明化合物或包含本发明化合物的组合物的量。应当认识到的是，当将药剂用于达到治疗作用时，包含“有效量”的实际剂量将根据一些条件而变化，所述条件包括但不限于所治疗的特定病况、疾病的严重程度、患者的体型和健康情况、施用途径。熟练的医学从业人员可以使用医学领域熟知的方法容易地确定合适的剂量。在一些实施方式中，有效量是在有需要的受试者中有效治疗病症的量。有效量可以例如通过以相对低的量开始且随着有益作用(例如，症状减轻)的同步评价逐步递增而凭经验确定。实际有效量将使用本领域的标准方法通过剂量/应答测定来确定。
有益效果：
本发明提供表小檗碱在制备抗幽门螺旋杆菌感染药物中的应用。本发明研究发现，表小檗碱与抗生素(阿莫西林、克拉霉素、甲硝唑、呋喃唑酮、奥美拉唑中的一种或几种组合)联用时，可以显著提升抗生素的抗Hp活性，能有效缓解幽门螺杆菌耐药性问题，对于治疗耐药性或敏感性幽门螺杆菌感染导致的急、慢性胃炎、胃、十二脂肠溃疡等疾病有重要的意义。
具体实施方式
下面通过具体实施例对本发明进行具体描述，在此指出以下实施例只用于对本发明进行进一步说明，不能理解为对本发明保护范围的限制，本领域的技术熟练人员可以根据上述发明内容对本发明作出一些非本质的改进和调整。本发明所用原料及试剂均为市售产品。
实施例1表小檗碱抗Hp活性实验
①实验材料。
试验药:表小檗碱(e-BBR)，分别配制为1000ppm。
对照药物:小檗碱盐酸盐(BBR)，分别配制为1000ppm。
抗生素：阿莫西林(阿)、克拉霉素(克)、甲硝唑(甲)、左氧氟沙星(左)、呋喃唑酮(呋)、奥美拉唑(奥)，分别配置为100ppm。
②菌种：幽门螺旋杆菌(Hp，11637)
③培养基：MH肉汤，MH琼脂均为售品。
④MIC检测：按照倍半稀释法测定(中国中医基础医学杂志,2017,23(03):405-407+422)有关药物的MBC。用MH琼脂培养基取100uL浓度为3×108CFU·mL-1的幽门螺旋杆菌液，用一次性涂布器均匀涂于MH琼脂培养基上，将试验药倍比稀释成浓度400、200、100、50、25、12.5、6.25、3.1、1.56、0.78、0.39、0.198、0.099、0.050、0.025、0.0125、0.00625ug·ml-1，涂布于MH琼脂培养基上，同时以空白培养基作为对照，置三气培养箱中(85％N2，10％CO2，5％O2)培养48～72h，观察细菌生长情况，以细菌数量的最低药物浓度为最小杀菌浓度(MIC)。实验结果见表1。
表1药物对幽门螺旋杆菌(11637)的MIC(μg/mL)
| 药物 | MIC | 混合药物 | MIC | 混合药物 | MIC |
| BBR | 50 | ---- | ---- | ---- | ---- |
| e-BBR | 100 | ---- | ---- | ---- | ---- |
| 阿 | 0.05 | BBR-阿 | 50-0.05 | e-BBR-阿 | 12.5-0.0125 |
| 克 | 0.1 | BBR-克 | 50-0.10 | e-BBR-克 | 12.5-0.025 |
| 甲 | 1.56 | BBR-甲 | 50-1.56 | e-BBR-甲 | 12.5-0.39 |
| 左 | 3.1 | BBR-左 | 50-3.1 | e-BBR-左 | 25-0.78 |
| 呋 | 1.56 | BBR-呋 | 50-1.56 | e-BBR-呋 | 12.5-0.39 |
| 奥 | 100 | BBR-奥 | 50-50 | e-BBR-奥 | 25-25 |
从表1中可以看到：1)表小檗碱抗Hp的活性低于小檗碱；2)、小檗碱与抗生素联用，除对奥美拉唑有一定的协同作用以外，对其他抗生素没有任何协同作用；3)、表小檗碱与抗生素联用，具有很强的协同作用，可以显著提高抗生素的抗菌活性，同时也可以提高自身抗Hp的活性。
Claims (8)
1.表小檗碱在制备抗幽门螺旋杆菌感染药物中的应用，所述表小檗碱结构式如下：
2.表小檗碱与抗生素联合用药在制备抗幽门螺杆菌感染药物中的应用。
3.如权利要求2所述的应用，其特征在于：所述抗生素选自阿莫西林、克拉霉素、甲硝唑、呋喃唑酮、奥美拉唑中的一种或几种组合。
4.如权利要求2所述的应用，其特征在于：表小檗碱与阿莫西林联合用药在制备抗幽门螺杆菌感染药物中的应用。
5.如权利要求2所述的应用，其特征在于：表小檗碱与克拉霉素联合用药在制备抗幽门螺杆菌感染药物中的应用。
6.如权利要求2所述的应用，其特征在于：表小檗碱与甲硝唑联合用药在制备抗幽门螺杆菌感染药物中的应用。
7.如权利要求2所述的应用，其特征在于：表小檗碱与呋喃唑酮联合用药在制备抗幽门螺杆菌感染药物中的应用。
8.如权利要求2所述的应用，其特征在于：表小檗碱与奥美拉唑联合用药在制备抗幽门螺杆菌感染药物中的应用。
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