CN103006846A - 清开灵在制备抗多重耐药菌药物中的应用 - Google Patents
清开灵在制备抗多重耐药菌药物中的应用 Download PDFInfo
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- 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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- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
本发明涉及清开灵在制备抗多重耐药菌药物中的应用。清开灵对含NDM-1耐药基因多重耐药菌，乙酸钙不动杆菌（Acinetobactercalcoaceticus）、鲍曼不动杆菌（Acinetobacterbaumannii ）和含NDM-1耐药基因大肠杆菌（Escherichiacoli）具有抑制作用。另外，清开灵注射液与20种临床上常用抗生素联用，对乙酸钙不动杆菌、含NDM-1耐药基因大肠杆菌和嗜麦芽寡养窄食单胞菌（Stenotrophomonasmaltophilia）也有抑制作用。因此，清开灵可用于单独使用或者联合抗生素用于治疗和/或预防含NDM-1耐药基因细菌引起的疾病。
Description
技术领域
本发明涉及清开灵的一种新的医药用途，具体地说是在制备抗多重耐药菌药物中的应用。
背景技术
多重耐药菌（multiple resistant bacteria）是指有多重耐药性的病原菌，即一种微生物对三类（比如氨基糖苷类、红霉素、β－内酰胺类）或三类以上抗生素同时耐药。其中最为多见的是NDM-1、MDR-TB、MDR-MRSA以及常在ICU中出现的鲍曼不动杆菌和铜绿假单胞菌。NDM-1（New Delhi metallo-β-lactamase-1，新德里金属β-内酰胺酶），又名NDM-1细菌，是一种耐碳青霉烯类的酶。NDM-1基因常由质粒携带，但也整合在细菌的染色体上，易于在不同的菌株间传播和扩散，NDM-1编码的蛋白单体分子量为28kDa，它的序列和其他MBL的序列相似性很低。NDM-1主要分布在肠杆菌科和鲍曼不动杆菌中，携带NDM-1的细菌不但包括条件致病菌，也包括致病菌，如常见的志贺氏菌、霍乱、绿脓假单胞杆菌等。它具有高度耐药性，几乎可以水解临床常用的一线抗菌药物，包括β-内酰胺类、碳青霉烯类、氟喹诺酮类、氨基糖苷等。长期以来，抗生素药物的滥用，是催生多重耐药菌的重要原因。目前，多重耐药菌感染呈现出增长趋势，但抗菌药物选择方案却很少，因此重耐药菌感染已成为全球性棘手问题。
清开灵是经典方安宫牛黄丸的改良制剂，具有清热解毒、化痰通络、醒神开窍之功能。临床上主要用于外感风热、火毒内盛所致高热不退、烦躁不安、咽喉肿痛、舌质红绛、苔黄、脉数者以及上呼吸道感染，病毒性感冒，急性化脓性扁桃体炎，急性咽炎，急性气管炎，高热等病症。在科研人员的不断努力下，人们发明了清开灵制剂更多的新的医药用途功。如，CN1518992A公开了清开灵制剂在治疗多发性硬化等疾病的新用途；CN1475264A公开了清开灵制剂在改善急性呼吸窘迫综合征肺泡渗出、改善肺间质损害肺微循环障碍导致低血氧分压和/或低血氧饱和度病理状态的新用途；CN100998670A公开了清开灵制剂在治疗缺血性脑血管疾病中的新用途；CN101385796A公开了清开灵制剂改善认知功能障碍预防及治疗老年痴呆症的新用途；CN101244137A公开了清开灵制剂治疗肺炎及高热、低热不退、炎症性眼病的新用途。
发明内容
本发明的目的就是要开发清开灵的新医药用途，同时为临床提供一种可有效拮抗多重耐药菌的药物。
本发明的发明人经长期研究发现清开灵对含NDM-1耐药基因细菌具有显著地抑制作用。从而发明了清开灵的一种新的医药用途，即完成了清开灵在制备抗多重耐药菌药物中的应用。
本发明中所述清开灵包括有清开灵软胶囊、清开灵滴丸、清开灵注射剂、清开灵胶囊等剂型。清开灵是由板蓝根（十字花科植物菘蓝Isatis indigotica Fort.的干燥根）、金银花（忍冬科植物忍冬Lonicera japonica Thunb.、红腺忍冬Lonicera hypoglauca Miq.、山银花Loniceraconfusa DC.或毛花柱忍冬Lonicera dasystyla Rehd.的干燥花蕾或带初开的花）、栀子（茜草科植物栀子Gardenia jasminoides Ellis的干燥成熟果实）、黄芩苷（唇形科植物黄芩Scutellariabaicalensis Georgi的干燥根的提取物）、胆酸、珍珠母、猪去氧胆酸和水牛角为原料药制成。
本发明中所述的多重耐药菌是指含有NMD-1基因的多重耐药菌，包括乙酸钙不动杆菌（Acinetobacter calcoaceticus）、鲍曼不动杆菌（Acinetobacter baumannii，A.baumannii）、嗜麦芽寡养窄食单胞菌（Stenotrophomonas maltophilia）或含NDM-1耐药基因大肠杆菌（Escherichia coli）。
上述含NDM-1耐药基因检测菌株为革兰氏阴性菌，具有较强的致病性和抗生素耐药性。其中，乙酸钙不动杆菌和鲍曼不动杆菌可引起肺部感染、伤口及皮肤感染、泌尿生殖系统感染、菌血症菌血症、脑膜炎等，麦芽寡养窄食单胞菌能引起严重的呼吸系统感染等，含NDM-1耐药基因大肠杆菌可引发对肠道感染且对抗生素具有抗药性。
本发明的研究结果发现，清开灵制剂对上述含NDM-1基因耐药细菌具有显著抑制作用，且与浓度正比。最小抑菌浓度分别是乙酸钙不动杆菌1.588g/ml（以总生计算）、鲍曼不动杆菌1.588g/ml、含NDM-1耐药基因大肠杆菌0.744g/ml。这为临床治疗多重耐药菌感染症提供了新的用药选择，也为清开灵制剂增加了一种新临床适应症。
更进一步地，本发明还提供了清开灵在制备治疗和/或预防乙酸钙不动杆菌引起的疾病的药物中的应用。
更进一步地，本发明还提供了清开灵制备治疗和/或预防嗜麦芽寡养窄食单胞菌引起的疾病的药物中的应用。
更进一步地，本发明还提供了清开灵在制备治疗和/或预防鲍曼不动杆菌引起的疾病的药物中的应用。
更进一步地，本发明还提供了治疗和/或预防含NDM-1耐药基因大肠杆菌引起的疾病的药物中的应用。
本发明所述清开灵制剂可用于治疗上述由含NDM-1耐药基因多重耐药细菌引发的感染疾病，如NDM-1耐药基因多重耐药细菌引发的肠道感染、呼吸系统感染、伤口及皮肤感染、泌尿生殖系统感染、菌血症菌血症、脑膜炎等，尤其是适用于治疗是由乙酸钙不动杆菌、鲍曼不动杆菌、嗜麦芽寡养窄食单胞菌或含NDM-1耐药基因大肠杆菌引发的各种感染性疾病。
清开灵注射液在作为本发明的用途使用时，其具体用量可根据临床实验以及患者的具体情况确定，也可参照清开灵注射液普通给药剂量的3-5倍量给药。
清开灵制剂还可以与抗生素联合用于抗含NDM-1耐药基因细菌，如乙酸钙不动杆菌、含NDM-1耐药基因大肠杆菌或嗜麦芽寡养窄食单胞菌。其中，所述的抗生素包括，但不限于，亚胺培南、美洛培南、青霉素G、庆大霉素、替卡西林/克拉、环丙沙星、妥布霉素、头孢它定、美洛西林、万古霉素、多四环素、替考拉宁、左氧氟沙星、哌拉西林、头孢克肟、氨苄西林、磺胺嘧啶/甲氧苄啶、咪唑环素、氨曲南、红霉素等常用抗生素。并且，将这种联合用药也包含在本发明的保护范围内。
本发明的研究结果表明，清开灵注射液与上述20种临床上常用抗生素联用对乙酸钙不动杆菌乙酸钙不动杆菌、含NDM-1耐药基因大肠杆菌和嗜麦芽寡养窄食单胞菌（Stenotrophomonas maltophilia）也有抑制作用，且较单独使用抗生素效果好，尤其是对乙酸钙不动杆菌。这将为临床治疗提供可行性。
具体实施方案
以下通过实施例和试验例来进一步阐述本发明所述药物的有益效果。
本药效学试验所采用的检测菌株：乙酸钙不动杆菌（Acinetobacter calcoaceticus，A.calcoaceticus）、鲍曼不动杆菌（Acinetobacter baumannii，A.baumannii）和嗜麦芽寡养窄食单胞菌（Stenotrophomonas maltophilia，S.maltophilia），均含有blaNDM-1耐药基因；pGEX-4T-NDM1-DH5α是含NDM-1重组质粒的大肠杆菌（Escherichia coli）；pGEX-4T-NDM-1-BL21（在大肠杆菌BL21中表达NDM-1）是含NDM-1重组质粒的大肠杆菌（Escherichia coli），其质粒上带有GST标签。上述菌株均由中国人民解放军疾病预防控制所提供。
本药效学试验所采用的检测样品：市售清开灵注射液（规格10ml/支，生药量0.372g/ml），由神威药业有限公司生产。
试验例1
清开灵注射液对含NDM-1耐药基因多重耐药菌抑菌效果检测
将清开灵注射液原液浓缩至1、2、3、4、5和6倍浓度，制成清开灵注射液浓缩物，与原液一起作为检测样品，备用。
将3株含NDM-1耐药基因多重耐药菌乙酸钙不动杆菌、鲍曼不动杆菌、大肠杆菌pGEX-4T-NDM-1-BL21作为原始菌，以1%量接种于5mL的含32ug/ml亚胺培南的LB液体培养基中，在37℃、12h左右，活化两代，进行菌株活化处理，制备检测用菌株，备用。
采用K-B法进行检测。将3种活化二代的检测菌株（鲍曼不动杆菌、乙酸钙不动杆菌、大肠杆菌pGEX-4T-NDM-1-BL2）的菌悬液（摇床培养6h左右）分别混于LB琼脂培养基中，混匀倒板，打孔后，制成含测试菌的琼脂平板；分别将50uL和100uL的不同浓度的清开灵注射液（原液，1-6倍浓度的浓缩液）接入孔中进行抑菌实验，接种好后置37℃孵育16-18h左右，观察各平板菌株生长结果，并以不含菌株的平板作对照。在孔周围抑菌浓度范围内的细菌的生长被抑制，会形成透明的抑菌圈。抑菌圈的大小反映测试菌对测定药物的敏感程度，并与该药对测试菌的MIC呈负相关。
实验显示：清开灵注射液原液对三株菌没有抑菌效果，随着浓度浓缩倍数的增加抑菌效果明显，并且抑菌圈也逐渐增大。清开灵注射液浓度浓缩2倍后50ul的量对耐药菌pGEX-4T-NDM-1-BL2有抑制效果，随着浓度的增加，抑菌效果更明显；浓缩4倍的样品50ul量对鲍曼不动杆菌和乙酸钙不动杆菌菌株均有抑菌效果，浓缩倍数越高抑菌圈越明显，接种100ul量与50ul量抑菌效果没有明显差别。结果表明：清开灵注射液原液浓缩后，对三株含NDM-1耐药基因多重耐药菌均有抑菌效果，且随着浓度倍数的增加，抑菌效果更明显。
实施例1
清开灵注射液与抗生素联合用药对含NDM-1耐药基因多重耐药菌抑菌效果检测
将清开灵注射液（神威药业有限公司，规格10ml/支，水浴50℃左右）加入已加热溶解，并在45~50℃水浴中平衡的MH琼脂培养基中，充分混匀倾倒灭菌平皿，琼脂厚度3~4mm，配制成50%的含药琼脂平板，备用。
采用K-B法进行检测。将活化的含NDM-1基因多重耐药菌（乙酸钙不动杆菌、pGEX-4T-NDM1-DH5α、嗜麦芽寡养窄食单胞菌）检测菌株的菌悬液分别涂于MH含药平板上和不含药平板上，然后将20种含有定量临床抗生素（见表1）的纸片分别睡帖在已接种测试菌的两种琼脂平板上，接种好后置37℃孵育16-18h左右，观察各菌株生长结果，并以不含药物的平板作对照。在纸片周围抑菌浓度范围内的细菌的生长被抑制，形成透明的抑菌圈。抑菌圈的大小反映测试菌对测定药物的敏感程度，并与该药对测试菌的MIC呈负相关。
20种临床抗生素的药敏纸片周围在不含清开灵注射液的平板上绝大部分出现明显的抑菌圈，而在含药平板上抑菌圈明显增大，各药抑菌圈直径明显大于对照平板（见表1）。实验结果表明，联合用药对表1中含NDM-1基因多重耐药菌的抑菌效果明显。
表1抗生素与清开灵注射液是否联合用药对含NDM-1耐药基因菌株的抑菌效果差异比较
注：“+”为抗生素与清开灵注射液连用，“-”为抗生素未与清开灵注射液连用；>表示抑菌圈超出测量范围。
Claims (6)
1.清开灵在制备治疗和\或预防多重耐药菌引起的疾病的药物中的应用。
2.清开灵在制备治疗和\或预防含NDM-1耐药基因细菌引起的疾病的药物中的应用。
3.清开灵在制备治疗和\或预防乙酸钙不动杆菌引起的疾病的药物中的应用。
4.清开灵在制备治疗和\或预防鲍曼不动杆菌引起的疾病的药物中的应用。
5.清开灵在制备治疗和\或预防嗜麦芽寡养窄食单胞菌引起的疾病的药物中的应用。
6.清开灵在制备治疗和\或预防含NDM-1耐药基因大肠杆菌引起的疾病的药物中的应用。
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