CN110141569B - 抗牛多杀性巴氏杆菌的药物组合物 - Google Patents
抗牛多杀性巴氏杆菌的药物组合物 Download PDFInfo
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- CN110141569B CN110141569B CN201910508854.3A CN201910508854A CN110141569B CN 110141569 B CN110141569 B CN 110141569B CN 201910508854 A CN201910508854 A CN 201910508854A CN 110141569 B CN110141569 B CN 110141569B
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- ciprofloxacin
- pasteurella multocida
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- antibacterial
- tetracycline
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Abstract
一种抗牛多杀性巴氏杆菌的药物组合物,属于药物组合物技术领域。本发明的目的是通过将三种药物进行有效合成组合药物,用于治疗牛多杀性巴氏杆菌感染的抗菌药物组合物。本发明制成有效成分是环丙沙星、硫利达嗪、四环素。本发明的药物组合物具有抗菌,消炎等临床作用,能够有效地治疗牛多杀性巴氏杆菌感染,此外,本发明的药物组合具有高效的杀菌活性且能够大幅度降低用药的计量,从而大大减少药物的毒副作用。本药物组合作用的基本机制为:通过联合抑制细菌的外输泵,以及DNA的合成和复制,从而使其具有良好的抗菌效果。进一步证明本发明药物的临床疗效和安全性。
Description
技术领域
本发明属于药物组合物技术领域。
背景技术
巴氏杆菌属为无芽孢,不运动,兼性厌氧,菌体两端常染色浓重的革兰氏染色阴性小杆菌。本属已确定的种有多杀性巴氏杆菌、嗜肺巴氏杆菌、溶血巴氏杆菌、尿巴氏杆菌和鸭疫巴氏杆菌等。多杀性巴氏杆菌是一种两段钝圆,中央微突的短杆菌或球杆菌,不形成芽胞,不运动,无鞭毛,革兰氏染色阴性的需氧兼性厌氧菌。
巴氏杆菌病(Pasteurellosis)主要由多杀性巴氏杆菌等致病菌引起的一种人畜共患的传染病。巴氏杆菌可在各种动物间互相传染,而动物咬伤也可直接使致病菌进入人体的上皮细胞,导致局部组织损伤乃至全身系统性疾病,例如人的脑膜炎、心肌炎、关节炎等多种严重的后遗症。该致病菌遍布世界各地,给养殖业造成严重的损失。近年来,国内外有关牛源巴氏杆菌耐药性研究的报道正逐渐增多,由于抗菌药物的大量不合理应用的广泛存在,导致巴氏杆菌对青霉素类、链霉素、土霉素、氨苄西林、氯霉素、磺胺类、替米考星等的耐药性正逐渐增强。因此,在对细菌耐药性研究的基础上仍需提高抗菌药物使用的合理性及规范性。
目前,牛源巴氏杆菌病的治疗主要依赖于抗生素,但随着抗生素的长期使用不可避免的出现了耐药性问题。环丙沙星的杀菌作用主要是抑制IIA型拓扑异构酶(DNA螺旋酶和拓扑异构酶IV)的表达,使得细菌的生长和DNA合成受到抑制,从而杀灭细菌。硫利达嗪在细菌中能够有效地抑制细菌的外输泵,并且能够诱导细菌细胞壁合成过程中的青霉素结合蛋白等基因发生重大变化,从而达到杀菌作用。四环素能改变细菌细胞膜的通透性,使胞内核苷酸等重要物质外漏而抑制DNA复制。为发现具有延缓或防止细菌产生耐药或/和治疗临床耐药菌感染的抗菌药物组合物,该发明专利对药物之间联合抗巴氏杆菌的作用进行了研究。
发明内容
本发明的目的是通过将三种药物进行有效合成组合药物,用于治疗牛多杀性巴氏杆菌感染的抗菌药物组合物。
本发明制成有效成分的比例是:环丙沙星:硫利达嗪:四环素=1:1:1
本发明的药物组合物作为药物在治疗牛多杀性巴氏杆菌感染中的应用。
本发明的药物组合物具有抗菌,消炎等临床作用,能够有效地治疗牛多杀性巴氏杆菌感染,此外,本发明的药物组合具有高效的杀菌活性且能够大幅度降低用药的计量,从而大大减少药物的毒副作用。本药物组合作用的基本机制为:通过联合抑制细菌的外输泵,以及DNA的合成和复制,从而使其具有良好的抗菌效果。进一步证明本发明药物的临床疗效和安全性。
附图说明
图1是将建模小鼠进行口服后对小鼠肺部载菌量进行检测结构图;
图2是病理组织学结果图。
具体实施方式
本发明制成有效成分的使用比例是:环丙沙星:硫利达嗪:四环素=1:1:1
本发明所述抗菌药物组合物中的环丙沙星,硫利达嗪,四环素均可由商业购买获得,也可按照已知的方法和技术合成制备。
本发明的药物组合物作为药物在治疗牛多杀性巴氏杆菌感染中的应用。
下面结合实例详细对本发明的药物组合物进行详细验证和说明:
选取原料药:环丙沙星,硫利达嗪,四环素。本发明的组合药物既可以原剂型单独配合给药,又可以按照比例进行掺合成一个完整的剂型进行给药;若按照比例进行掺合,则按照环丙沙星1份、硫利达嗪1份、四环素1份的剂量进行配比,制成片剂,均分为2片。本发明则最终制成片剂单独给药。
本发明药物制剂剂型可以为合剂、胶囊剂、片剂、颗粒剂、散剂和丸剂,为使上述剂型能够实现,需在制备这些剂型时加入药学可接受的辅料,例如:填充剂、崩解剂、润滑剂、助悬剂、粘合剂、甜味剂、矫味剂、防腐剂等,填充剂包括:淀粉、预胶化淀粉、乳糖、甘露醇、甲壳素、微晶纤维素、蔗糖等,崩解剂包括:淀粉、预胶化淀粉、微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙纤维素、教练羧甲基纤维素钠等,润滑剂包括:硬脂酸镁、十二烷基硫酸钠、滑石粉、二氧化硅等,助悬剂包括聚乙烯吡咯烷酮、微晶纤维素、蔗糖、琼脂、羟丙基甲基纤维素等,粘合剂包括,淀粉浆、聚乙烯吡咯烷酮、羟丙基甲基纤维素等,甜味剂包括:糖精钠、阿司帕坦、蔗糖、甜蜜素等,矫味剂包括:甜味剂及各种香精,防腐剂包括:泥泊金类、苯甲酸、苯甲酸钠、山梨酸及其盐类、苯扎溴铵、醋酸氯乙定、桉叶油等。本发明中的抗菌药物组合物可通过常用方法,如现行版《中华人民共和国药典》第二部附录的制剂通则和催福德主编的《药剂学》(人民卫生出版社,第七版)记载的剂型和方法制成上述剂型。
本发明药物组合物可根据本领域已知的方法制备。用于此目的时,如果需要,可将活性成分与一种或多种固体或液体药物赋形剂和/或辅剂结合,制成可作为兽药使用的适当施用形式或剂量形式。
本发明的药物作用机制为:环丙沙星在细菌中的作用靶点是IIA型拓扑异构酶,而II A型拓扑异构酶有DNA螺旋酶和拓扑异构酶IV两种亚型,这两种酶都是细菌生长所必须的酶,任何一种酶受到抑制都将使细菌的生长以及DNA合成受到抑制,从而杀灭细菌。硫利达嗪在细菌中能够有效地抑制细菌的外输泵,并且能够诱导细菌细胞壁合成过程中的青霉素结合蛋白(penicillin-binding proteins,PBPs)等基因发生重大变化,从而达到杀菌作用。四环素主要与细菌核蛋白体30s亚基结合,阻止蛋白质合成始动复合物,并能抑制aa-tRNA进入A位,从而抑制肽链延伸和蛋白质合成。故联合用药可低剂量有效地杀灭病原菌。
本发明以大肠埃希菌:Escherichia coli,25922(E.coli25922)为质控菌株,并以标准菌株ATCC450以及临床分离Pa菌株:Pa 01,Pa 02,Pa 03,Pa 04,Pa05,Pa 06,Pa 07,Pa 08,Pa 09,Pa 10为指示菌,采用CLSI标准方法和棋盘格实验对主药(环丙沙星)和两种辅药(硫利达嗪、四环素)三种药物进行单用和联合用药的抗菌活性测定。结果表明:(1)环丙沙星、硫利达嗪和四环素对测试牛多杀性巴氏杆菌具有显著的协同抗菌作用,联合用药较单独环丙沙星的抗菌效果提高了4-128倍,并呈现很强的抗牛多杀性巴氏杆菌活性,(2)环丙沙星、硫利达嗪和四环素联合用药时,在动物体内也产生了很强的杀菌效果。由此显示本发明提供的含有环丙沙星、硫利达嗪、四环素的抗菌药物组合物在治疗牛多杀性巴氏杆菌感染时,较药物单用环丙沙星具有以下明显的应用优点:(1)具有明显的协同增效效果:含有环丙沙星、硫利达嗪、四环素的抗菌药物组合物与单用环丙沙星相比,均可使其抗菌活性增强4-128倍,具有显著的协同增效效果;同时此抗菌药物组合物对测试菌株的最低抑菌浓度浓度范围为0.125-8μg/mL,显示很强的抗菌活性;(2)在获得相同的抗菌效果下,环丙沙星、硫利达嗪、四环素联合用药可大幅降低环丙沙星的用药剂量,从而减少了各自的毒副作用。(3)环丙沙星、硫利达嗪和四环素联合用药可显著增强机体内的杀菌效果;故本发明提供的含有环丙沙星、硫利达嗪和四环素的抗菌药物组合物具有很好的临床开发前景,可用于制备治疗牛多杀性巴氏杆菌感染的药物。
实施例1:药物组合物对牛多杀性巴氏杆菌的联合抗菌试验
一、实验材料及方法
试剂和试药:
环丙沙星(Ciprofloxacin)、硫利达嗪(Thioridazine)和四环素(Tetracyclines)购于MCE公司,纯度分别为>98.74%、>99.93%、>98%.
指示菌株:
大肠埃希菌:Escherichia coli,25922(E.coli25922);标准菌株450,临床分离Pa菌株:Pa 01,Pa 02,Pa 03,Pa 04,Pa 05,Pa 06,Pa 07,Pa 08,Pa09,Pa 010。
培养基:
BHI培养基:蛋白胨10.0g,脱水小牛脑浸粉12.5g,脱水牛心浸粉5g,氯化钠5g葡萄糖2g,磷酸氢二钠2.5g于1000mL蒸馏水中,并调节pH为7.4。将配置好的培养基121℃高压灭菌,20min后,备用。
MH培养基:混合牛肉浸膏粉2.0g,可溶性淀粉1.5g,酸水解酪蛋白1.5g,于1000mL蒸馏水中,并调节pH为7.4。将配置好的培养基121℃高压灭菌,20min后,备用。
测试样品溶液的配制:
用精密天平分别称取环丙沙星,硫利达嗪和四环素适量,加入一定量的DMSO溶解,然后用MH培养基配制成终浓度均为102.4mg/mL的测试用样品溶液(DMSO浓度小于1%)。
菌悬液的制备:
将保存于甘油中的质控菌株和指示菌株用斜面活化后,接种针挑取菌种,接种于20mL MH液体培养基中,37℃,160rpm培养24h,计数,并将菌液稀释成浓度为1×106CFU·mL-1的菌悬液供联合用药的抗菌实验测定用,菌悬液稀释后须立即使用,不可长时间放置。
药物敏感性试验:
每种抗菌药物的最低抑菌浓度(测定依照CLSI 2012标准)推荐的方法进行微量肉汤稀释法测定种抗菌药物对10株巴氏杆菌的MIC值。
联合用药的抗菌试验:
微量肉汤稀释法将环丙沙星,硫利达嗪和四环素储备液以灭菌的肉汤倍比稀释成1024-0.0078125μg/mL浓度梯度。将配好的不同浓度的两种抗菌药物按棋盘法设计两两组合加入孔平板中,每种药物各50μL,再加入100μL接种菌悬液(1×106CFU·mL-1)于恒温摇床上35℃,160rpm培养24h后,清亮孔中最小的试药浓度为该药对测试菌株的MIC。三药组合时,预先界定一种药物的浓度,另外两药进行同上的棋盘法测定。同时,每次药敏试验必须使用大肠埃希菌25922为质控菌株,只有当两者的MIC值界于标准参考值范围内,方认为试验操作准确可靠,且同时对照组的试验菌株生长良好,方可认为试验成功,结果可接受。
抑菌浓度指数(FICI):
药物间的相互作用通过分级抑菌浓度指数(FICI)进行判定。读取结果并记录单独用药时的各种抗菌药物的最低抑菌浓度(MICA 单独,MICB 单独和MICC 单独),并选择最佳组合效应时两药联用时各自的值(MICA 联合和MICB 联合和MICC 联合),以计算分级抑菌浓度FICI指数。
计算两者联用的部分抑菌浓度指数(FICI),其计算公式为:
其中,MICA 联合,MICB 联合和MICc 联合为A和B联用时最低抑菌浓度中A,B和C的浓度;MICA 单独,MICB 单独和MICc 单独即为A和B单用时各自的最低抑菌浓度;A为环丙沙星,B为硫利达嗪,C为四环素。判断两药联用效果的标准为:FICI≤0.5,协同作用;0.5<FICI≤1,相加作用;1<FICI≤4,无关作用;FICI>4,拮抗作用;三药联用效果的标准为:FICI≤1,协同作用。
二、实验结果
按上述方法,运用棋盘格法设计试验,分别测定环丙沙星,硫利达嗪和四环素的联合抗菌作用,结果表明:环丙沙星,硫利达嗪和四环素联合用药的FICIs为0.012-0.500(表1),显示:环丙沙星,硫利达嗪和四环素联合用药呈现显著的协同抗牛多杀性巴氏杆菌的作用;联合用药最低抑菌浓度时组合物中各药物的浓度为单用时最低抑菌浓度的0.125-8μg/mL,也即较单独用药的抗菌活性提高了4-128倍。
表1单用,两药组合和三药联合用药各药物的MIC
a CIP:环丙沙星,THE:硫利达嗪,TET:四环素
三、结论
由表1可知,环丙沙星,硫利达嗪和四环素联合用药具有明显的协同增效作用;联合用药的最低抑菌浓度中环丙沙星的浓度为单独用药时最低抑菌浓度的0.125-0.166倍,也即较单独用药的抗菌活性提高了4-128倍。故若达到相同的抗菌效果,联合用药可使环丙沙星的用药剂量减少为单独用药的0.125-0.166倍,从而降低药物潜在的毒副作用。同时,环丙沙星,硫利达嗪和四环素联合用药时,其对测试菌的最低抑菌浓度浓度范围为0.125-8μg/mL,显示很强的抗牛多杀性巴氏杆菌活性。由此表明:含有协同抗菌增效的环丙沙星,硫利达嗪和四环素的药物组合物具有很好的药物开发前景,可用于制备治疗牛多杀性巴氏杆菌等病原菌感染的药物。
实施例2:药物组合物给药治疗对牛多杀性巴氏杆菌小鼠肺炎模型的影响
一、实验材料及方法
试剂和试药:
环丙沙星(Ciprofloxacin)、硫利达嗪(Thioridazine)和四环素(Tetracyclines)购于MCE公司,纯度分别为>98.74%、>99.93%、>98%.
菌株:
培养基:
BHI培养基:蛋白胨10.0g,脱水小牛脑浸粉12.5g,脱水牛心浸粉5g,氯化钠5g葡萄糖2g,磷酸氢二钠2.5g于1000mL蒸馏水中,并调节pH为7.4。将配置好的培养基121℃高压灭菌,20min后,备用。
动物
SPF级BALB/C小鼠,雄性,体质量18-22g,购自长春忆思实验动物有限公司,实验室控制温度23-25℃,湿度60-70%,定时排气、换气。
方法
将保存于甘油中的质控菌株和指示菌株用斜面活化后,接种针挑取菌种,接种于5mL BHI液体培养基中,37℃,160rpm培养24h,计数,并将菌液稀释成浓度为1×105CFU·mL-1的菌悬液供小鼠建模使用。将6周龄大的体重在18-22g左右的BALB/c雄性小鼠随机分为7组:正常对照组、模型对照组、环丙沙星治疗组、三药组合治疗组,每组包含10只小鼠。小鼠通过左侧鼻孔分别接种50μL重悬过的培养至对数期的牛多杀性巴氏杆菌标准菌株和临床分离菌株,空白对照组接种等体积的PBS溶液。在用多杀性巴氏杆菌感染2h后,即进行口服给药,使用前用生理盐水进行稀释,正常对照与模型对照组分别给等体积的生理盐水,每天给药一次,共三天。
所述主药单药的剂量为:9g/kg;所述药物组合(环丙沙星:硫利达嗪:四环素)的药物剂量为:9g/kg:9g/kg:9g/kg。
检查指标与方法
(1)小鼠肺部载菌量:给药3d后,用脱颈方式将小鼠处死,在无菌条件下取其肺脏,加入预冷过的PBS溶液,置于研钵中充分研磨,然后倍比稀释接种到BHI固体平板培养基上,过夜培养直至长出肉眼可见的菌落后计数。
(2)小鼠肺部炎症的表达情况:将组织病理学检查完成的肺脏从小鼠体内取出,用10%的福尔马林溶液固定过夜。经10%EDTA脱钙液进行脱钙、梯度脱水后进行石蜡包埋。切片、HE染色。在光学显微镜下观察肺脏组织的病变程度。并对各组的病变程度进行比较。
判断标准
杀菌:联合给药组小鼠肺部载菌量较建模组显著减少,且小鼠肺部病理变化较建模组显著减轻;不杀菌:联合给药组小鼠肺部载菌量较建模组减少不明显,且小鼠肺部病理变化较建模组症状相似。
统计学分析
数据采用SPSS 17.0统计软件进行分析,计量资料采用t检验,计数资料采用χ2检验,以百分比表示,*P<0.05,#P<0.05为差异具有统计学意义。
二、结果
1、小鼠肺部载菌量:将建模小鼠进行口服后对小鼠肺部载菌量进行检测,结果如图所示,较建模组以及单独环丙沙星给药组,三药组合能够显著降低多杀性巴氏杆菌感染的小鼠的肺脏组织中CFUs含量(P<0.01)。这表明三药组合在体内也具有很强的杀菌效果,并且杀菌效果显著优于单独使用环丙沙星。
图1中:注:与空白对照组比较,*P<0.001;与ATCC450,Pa1比较,#P<0.01。
2、小鼠肺部炎症的表达情况:病理组织学结果显示,正常对照组肺泡轮廓较均匀清晰,肺泡间质明显,肺泡内无炎性细胞或渗出物;ATCC建模组以及临床菌株建模组肺组织,肺泡结构明显破坏,血管周围及肺泡间质中有大量淋巴细胞和巨噬细胞、嗜酸性粒细胞等炎性细胞浸润;而三种药物治疗组较单独环丙沙星治疗组能够显著抑制肺泡组织的破坏以及炎性细胞浸润(如图2所示)。
图2中:注:Pa1:临床分离牛多杀性巴氏杆菌,CIP:环丙沙星,THE:硫利达嗪,TET:四环素。
三、结论
这些结果表明,药物组合物在体内外均对多杀性巴氏杆菌具有显著的杀伤作用,并且杀菌效果显著好于单独使用环丙沙星;同时,本发明药物组合物(环丙沙星+硫利达嗪+四环素)低剂量就能够对牛多杀性巴氏杆菌具有显著的杀伤作用,在很大程度上减轻药物对机体的毒副作用。
Claims (2)
1.一种抗牛多杀性巴氏杆菌的药物组合物,其特征在于:制成有效成分的重量比例是:环丙沙星:硫利达嗪:四环素=1:1:1。
2.权利要求1所述的抗牛多杀性巴氏杆菌的药物组合物在制备治疗牛多杀性巴氏杆菌感染药物中的应用。
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