CN108434432B - 一种柴胡桂枝汤的制药用途 - Google Patents
一种柴胡桂枝汤的制药用途 Download PDFInfo
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- CN108434432B CN108434432B CN201810650922.5A CN201810650922A CN108434432B CN 108434432 B CN108434432 B CN 108434432B CN 201810650922 A CN201810650922 A CN 201810650922A CN 108434432 B CN108434432 B CN 108434432B
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Abstract
本发明涉及柴胡桂枝汤联合替加环素在治疗或预防肺炎的作用,尤其是在治疗白细胞减少性鲍曼不动杆菌肺炎中的作用,采用白细胞减少性鲍曼不动杆菌肺炎大鼠模型,为临床治疗鲍曼不动杆菌感染提供参考。
Description
技术领域
本发明属于药物领域,具体涉及一种柴胡桂枝汤的制药用途。
背景技术
近年来细菌耐药问题日益严重,鲍曼不动杆菌作为“ESKAPE”六种多重耐药菌之一,有强大的获得耐药性和克隆传播能力,身体较弱的老年人及机体免疫状态低下患者容易感染发生耐药[1,2],已成为我国院内感染最重要的病原菌之一[3]。西医药治疗细菌感染多从抗菌单方面出发,使用多种抗生素进行杀菌抑菌,但感染情况并未完全控制,且耐药问题日益严重,存在一定的局限性[4]。中医治疗细菌感染性疾病不仅着眼于疾病本身,且强调患者自身正气的强弱与疾病的关系,认为“正气存内则邪不可干”,内因是根本,不是单纯的抗菌 [5,6]。古代文献并无鲍曼不动杆菌感染的相关报道,其感染以发热或寒热往来、咳嗽、胸痛、气急及血性痰,或者出现头痛、呕吐、局部感染的特点,临床缓解慢、病程长,多见于老年患者、素体虚弱或者危重疾病及机体抵抗力弱的患者。
柴胡桂枝汤出自《伤寒论》146条,为张仲景创立的经典方剂。由小柴胡汤和桂枝汤加减而来,小柴胡汤具有寒温并用、升降协调,攻补兼施作用。桂枝汤具有辛甘合用、一开一敛、外调营卫、内补脾胃的作用。二方相合,既能调理营卫气血,又能和解表里,疏肝利胆,达到扶正祛邪之目的[7,8],因此柴胡桂枝汤正适合此证。另外,从中医角度讲,临床发现“阳虚体质”容易感染耐药菌,口服温阳升阳之方,病情容易得到控制[9]。中医所谓“阳虚体质”与西医免疫功能低下有相似之处,提高机体的免疫功能对清除耐药菌感染有一定积极意义,现代药理学研究显示柴胡桂枝汤可增强正常小鼠迟发型变态反应,对于正常小鼠的免疫功能激活具有正向作用[10]。
本发明涉及柴胡桂枝汤联合替加环素在治疗或预防肺炎的作用,尤其是在治疗白细胞减少性鲍曼不动杆菌肺炎中的作用,采用白细胞减少性鲍曼不动杆菌肺炎大鼠模型,为临床治疗鲍曼不动杆菌感染提供参考。
发明内容
本发明涉及一种柴胡桂枝汤的制药用途。
本发明涉及一种柴胡桂枝汤的制药用途,其特征在于,制成组合,其中含有柴胡桂枝汤、替加环素。
本发明涉及一种柴胡桂枝汤的制药用途,其特征在于:
制成组合,其中含有柴胡桂枝汤10-50g、替加环素9-20mg;
柴胡桂枝汤制备方法:称取桂枝、黄芩、人参、芍药、生姜各63g,柴胡168g,半夏87g,甘草42g,大枣244g,8倍量水充分润湿,放置浸泡30min,加热煮沸后煎煮30 min,趁热3层纱布过滤,滤渣加6倍量水回流提取20min,滤过,合并滤液,浓缩至 750ml,得浓度为1.14g/ml药液,冷藏备用。
本发明甘草优选为炙甘草,桂枝优选为去皮桂枝。
本发明涉及一种柴胡桂枝汤的制药用途,其特征在于,
制成组合,其中含有柴胡桂枝汤11.2g、替加环素9mg;
柴胡桂枝汤制备方法:称取桂枝、黄芩、人参、芍药、生姜各63g,柴胡168g,半夏87g,甘草42g,大枣244g,8倍量水充分润湿,放置浸泡30min,加热煮沸后煎煮30 min,趁热3层纱布过滤,滤渣加6倍量水回流提取20min,滤过,合并滤液,浓缩至 750ml,得浓度为1.14g/ml药液,冷藏备用。
本发明涉及一种柴胡桂枝汤的制药用途,其特征在于:
制成组合,其中含有柴胡桂枝汤的冻干粉0.1-0.5g、替加环素9mg;
柴胡桂枝汤制备方法:称取桂枝、黄芩、人参、芍药、生姜各63g,柴胡168g,半夏87g,甘草42g,大枣244g,8倍量水充分润湿,放置浸泡30min,加热煮沸后煎煮30 min,趁热3层纱布过滤,滤渣加6倍量水回流提取20min,滤过,合并滤液,浓缩至 750ml,得浓度为1.14g/ml药液,冷藏备用;
组合是将柴胡桂枝汤的冻干粉与替加环素放置于一个包装中,包装不限于一个盒子、一个瓶子中,一个包装袋中。
柴胡桂枝汤的冻干粉:柴胡桂枝汤冷冻干燥得到冻干粉。
本发明涉及一种柴胡桂枝汤的制药用途,其特征在于:
制成组合物,由如下组分组成:柴胡桂枝汤的冻干粉0.1-0.5g、替加环素9mg;
柴胡桂枝汤制备方法:称取桂枝、黄芩、人参、芍药、生姜各63g,柴胡168g,半夏87g,甘草42g,大枣244g,8倍量水充分润湿,放置浸泡30min,加热煮沸后煎煮30 min,趁热3层纱布过滤,滤渣加6倍量水回流提取20min,滤过,合并滤液,浓缩至 750ml,得浓度为1.14g/ml药液,冷藏备用;
柴胡桂枝汤的冻干粉:柴胡桂枝汤冷冻干燥得到冻干粉;
组合物是将柴胡桂枝汤的冻干粉与替加环素进行组合,方法不限于混合、混匀、分散。
本发明涉及一种柴胡桂枝汤的制药用途,其特征在于:
制成组合物,由如下组分组成:柴胡桂枝汤的冻干粉0.1-0.5g、替加环素9mg;
柴胡桂枝汤的冻干粉的制备方法:冷藏备用的柴胡桂枝汤0.5-10g;加入1.0-10.0g谷氨酸,加入1-30.0g乳糖,加入注射用水,加热溶解,稀释至50-5000ml,过滤、滤液超滤,分装、冷冻干燥,完毕后压盖;制成1000只;上述冷冻干燥分为四个阶段:(1)预冻5小时,温度在-45℃;(2)减压干燥10小时,温度在-30℃;(3)升温干燥5小时,温度在-10℃;(4)二次升温干燥4小时,温度在25℃。
将柴胡桂枝汤的冻干粉与替加环素进行组合,方法不限于混合、混匀、分散。
本发明的一种柴胡桂枝汤的制药用途,用于制备治疗或预防肺炎的组合物。
本发明的一种柴胡桂枝汤的制药用途,用于制备治疗或预防耐药鲍曼不动杆菌感染肺炎的组合物。
本发明的一种柴胡桂枝汤的制药用途,用于制备治疗或预防白细胞减少性鲍曼不动杆菌肺炎的组合物。
分析以上实验结果,可以得出柴胡桂枝汤联合替加环素在干预白细胞减少性耐药鲍曼不动杆菌肺炎中有一定的效果,可以减慢大鼠体重下降速度,延长生存时间,减轻大鼠肺组织的炎症损伤且有一定的杀菌或抑菌作用。以上各指标均显示替加环素与柴胡桂枝汤联合使用干预效果最好,分析其原因可能与柴胡桂枝汤发挥扶正,祛邪加强替加环素干预鲍曼不动杆菌肺炎的效果有关。大鼠血清中TNF-α,IL-2,IL-6的含量测定结果显示,模型组含量显著高于空白对照组,治疗组含量均有所下降,且替加环素联合柴胡桂枝汤组下降最为明显,证明治疗组均可减少各炎症因子的表达,抑制感染大鼠的炎症反应,降低免疫损伤,且联合用药效果最好。
当前西医药治疗鲍曼不动杆菌感染多从抗菌单方面出发,使用多种抗生素进行杀菌抑菌,但感染情况并未完全得到控制,并且造成对各种抗菌药物的敏感性日益减弱,存在一定的局限性,中医药从机体本身和细菌两个方面入手,一方面抑制或杀灭细菌,另一方面提高机体自身免疫力,减轻细菌感染对机体的影响。该研究结果表明,柴胡桂枝汤对治疗鲍曼不动杆菌肺炎有一定的效果,且联合替加环素治疗效果最佳,提示柴胡桂枝汤不但具有杀菌或抑菌效果,还可能通过提高机体自身免疫力以增强替加环素的干预效果。这给鲍曼不动杆菌的临床治疗提供一个新思路,即中西药联合治疗,杀菌的同时提高自身免疫力,并以期减少抗生素的使用剂量,减少细菌耐药的发生。该研究意义深远,后期应进行更深入的研究验证柴胡桂枝汤在治疗耐药鲍曼不动杆菌中发挥的重要作用。
本发明探讨柴胡桂枝汤联合替加环素对大鼠白细胞减少性耐药鲍曼不动杆菌感染肺炎的干预作用。方法实验分组:空白组,模型组,替加环素(9mg/kg)组,柴胡桂枝杨(11.2g/kg)组,柴胡桂枝汤(11.2g/kg)联合替加环素(9mg/kg)组除空白组外其他各组建立耐药鲍曼不动杆菌肺炎大鼠模型,给药后观察大鼠体重变化,生存时间,采用HE染色观察肺组织病理改变,检测血清中炎症因子TNF-α,IL-2,IL-6含量变化,肺组织中NF-κB -p65和TLR-4蛋白表达情况等指标考察柴胡桂枝汤联合替加环素对鲍曼不动杆菌肺炎的干预作用。
结果:柴胡桂枝汤联合替加环素组大鼠体重下降较模型组缓慢,存活时间长,死亡率低;大鼠肺组织病理切片显示模型组大鼠肺泡腔隙变小、消失,广泛肺泡上皮细胞变性、坏死,联合组大鼠肺组织损伤较轻,部分肺泡上皮细胞变性、坏死;肺组织细菌培养结果显示联合组细菌数量低于模型组p<0.01,差异极具统计学意义;联合组大鼠血清中TNF-α的含量低于模型组p<0.05,有显著性差异。联合组血清中IL-2和IL-6的含量低于模型组 p<0.05,有显著性差异。联合组大鼠肺组织中P65表达量低于模型组p<0.05,有显著性差异。
实验结果显示模型组NF-KB-P65入核阳性表达显著高于正常组,说明在造模过程中激活了NF-KB免疫炎症通路,产生了免疫损伤,释放了炎症因子TNF-α,IL-2及IL-6。且柴胡桂枝汤联合替加环素治疗可有效降低NF-KB-P65入核,减少炎症因子的释放,抑制免疫反应,降低免疫损伤。该结果从炎症通路及作用机制方面验证了柴胡桂枝汤联合替加环素干预耐药鲍曼不动杆菌肺炎的效果,为进行更深入的研究奠定基础。
研究结果显示柴胡桂枝汤联合替加环素干预鲍曼不动杆菌肺炎有一定效果,该研究结果可为临床治疗鲍曼不动杆菌感染提供参考。
附图说明
图1:大鼠生存率
图2:大鼠肺组织病理改变,HE染色(×200)
图3:大鼠NF-κB-p65和TLR-4表达情况
图4:免疫组化表征NF-KB-P65入核情况具体实施例
实施例1:柴胡桂枝汤治疗或预防肺炎的实验方案
1.1试验药物
桂枝,批号:16092701,产地:广东,经首都医科大学附属北京友谊医院中药剂科主任赵奎君教授鉴定为樟科植物肉桂Cirmarnomum cassia Presl的干燥嫩枝;
甘草,批号:16062303,产地:内蒙古,经赵奎君教授鉴定为豆科植物甘草Glycyrrhiza uralensis Fisch的干燥根和根茎的炮制品;
黄芩,批号:17050801,产地:山西,经赵奎君教授鉴定为为唇形科植物黄芩Scutellaria baicalensis Georgi的干燥根;
柴胡,批号:16111801,产地:陕西,经赵奎君教授鉴定为伞形科植物柴胡BupleurumchinenseDC.或狭叶柴胡Bupleurum scorzonerifolium Willd.的干燥根;
大枣,批号:16080304,产地:山西,经赵奎君教授鉴定为鼠李科植物枣Ziziphusjujuba Mill的干燥成熟果实;
半夏,批号:16040501,产地:甘肃,经赵奎君教授鉴定为天南星科植物半夏Pinellia ternata(Thunb.)Breit.的干燥块茎,
白芍,批号:17042502,产地:河南,经赵奎君教授鉴定为毛莨科植物芍药Paeonialactiflora Pall的干燥根;
人参,批号17041503,产地:山西,经赵奎君教授鉴定为五加科植物人参Panaxginseng C.A.Mey.的干燥根和根茎,
以上药材皆购于盛世百草药业有限公司。
柴胡桂枝汤制备方法:称取桂枝、黄芩、人参、芍药、生姜各63g,柴胡168g,半夏87g,甘草42g,大枣244g,8倍量水充分润湿,放置浸泡30min,加热煮沸后煎煮30 min,趁热3层纱布过滤,滤渣加6倍量水回流提取20min,滤过,合并滤液,浓缩至 750ml,得浓度为1.14g/ml药液,冷藏备用。
1.2动物与菌株
动物:雌性SD大鼠,SPF级,140-210g,购于北京华阜康生物科技股份有限公司,动物合格证号11401300055117饲养于首都医科大学附属北京友谊医院实验动物中心,实验室合格证号:SYXK(京)2017-0019,分笼饲养,自由饮水及进食。室温(25±2)℃,通风良好、环境安静,室内保持12h照明,12h黑暗,并定期用紫外灯光消毒。
菌株:由北京友谊医院检验科提供,临床分离的耐药鲍曼不动杆菌菌株,采用VITEK2 compact系统对病原菌进行鉴定及最小抑菌浓度测定(MIC),并根据美国临床实验室标准化协会(CLSI)2017年M100-S27标准判定细菌耐药性,测试抗菌药物、MIC及结果。结果显示该菌株为多药耐药(MDR)鲍曼不动杆菌,其中替加环素最小抑菌浓度为4μg/ml,已达中介,属替加环素非敏感菌株,临床剂量的替加环素无法完全清除该菌株。
最小抑菌浓度结果
1.3试剂 环磷酰胺(Sigma公司,批号6055-19-2)、地塞米松(Sigma公司,批号50-02-2)、替加环素(浙江海正药业股份有限公司,批号:81607191)、水合氯醛(北京百灵威科技有限公司,批号302-17-0)、哥伦比亚血琼脂培养基(梅里埃生物制品有限公司批号:1005734760)。
1.4仪器 IX71型倒置显微镜(日本Olympus公司),恒温二氧化碳培养箱(美国NAPCO公司);IKA T10高速组织匀浆机,德国;无菌操作台;eppendorf 5424R小型冷冻高速离心机离心机,德国;酶标仪(Molecular Devices);Leica 2016石蜡切片机(上海莱卡仪器有限公司)。
1.5方法
1.5.1动物分组方法
SD雌性大鼠正常喂养1周后,随机分为5组,每组10只,分别为:A.正常对照组、B.模型对照组、C.替加环素组(9mg/kg)、D.柴胡桂枝汤组(11.2g/kg;采用人与大鼠给药剂量方法折算出大鼠给药的等效剂量,11.2g/kg为2倍等效剂量)、E.柴胡桂枝汤(11.2g/kg) 联合替加环素组(9mg/kg)。
1.5.2动物造模及给药方法
所有动物造模前称重,实验开始第一天除A组外,其他组大鼠腹腔注射环磷酰胺30mg/kg,肌肉注射地塞米松60mg/kg,使大鼠白细胞减少,形成免疫抑制,A组给予等量生理盐水。第四天重复第一天操作。第五天所有动物均采用异氟烷麻醉,将大鼠抓持后头部伸入装有异氟烷棉球的50ml离心管中,待大鼠眨眼反射消失后,迅速用皮筋把大鼠的四肢和牙齿固定于固定台上,用止血钳将大鼠的舌拉出,固定于口外。用小儿喉镜提供光源,长叶鼻镜暴露声门,迅速用带导丝的导管缓缓插入大鼠气管,待插入适当(0.5cm左右)的深度后,缓慢地拔出导丝,用注射器把已准备好的鲍曼不动杆菌菌悬液0.1ml(1.2×109CFU/ml) 经导管注入大鼠气管,然后注入少量空气,使菌悬液尽可能全部进入大鼠气管。立即竖立固定台,使大鼠保持直立位约20s,并左右摇晃固定台,保证菌液均匀分布于两肺。对照组用同法注入等量的无菌生理盐水[12]。第六天开始给药治疗,C组给予替加环素9mg/kg灌胃, D组给予柴胡桂枝汤11.2g/kg灌胃,E组给予替加环素9mg/kg灌胃,柴胡桂枝汤11.2g/kg 灌胃,A组和B组给予等量生理盐水灌胃。
1.5.3指标检测方法
外观指标 造模前、造模后和给药后分别观察大鼠精神及活动状况,记录外观状态及体重。
生存率 生存率自实验第一天起到实验结束,记录大鼠死亡时间计算生存率。
病理学指标 连续给药一周,给药结束后各组大鼠无菌条件下麻醉解剖取血,将整肺取出。右下肺叶置于甲醛固定,待行石蜡切片常规作苏木精一伊红一染色行病理学检查。
肺组织细菌培养 左上肺叶称重后每0.1g加0.9ml生理盐水,组织匀浆机研磨,取100μL 经系列稀释后接种于LB培养基培养16h后行菌落计数,继而计算出每克肺组织的细菌含量[13]。
血清中细胞因子测定 TNF-α、IL-2、IL-6含量用ELISA试剂盒测定,具体步骤按试剂盒说明书进行操作。
肺组织中蛋白的表达情况 肺组织经匀浆处理、灌胶、上样、转膜、免疫反应、化学发光等步骤,最后得到凝胶图像扫描分析。
免疫组化染色 大鼠肺组织按常规包埋、切片。采用S-P法检测大鼠肺组织中核因子NF-κB p65蛋白表达。肺组织用中性甲醛固定24h后,脱水、浸蜡、包埋、切片,二甲苯脱蜡,梯度酒精水化,然后采用复合消化液和抗原修复液进行抗原修复,PBS洗3 次,用3%H2O2溶液孵育10min,滴加1∶200浓度的兔抗鼠NF-κB p65单克隆抗体, 4℃过夜,PBS洗3次,滴加聚合HRP标记抗兔IgG 37℃孵育50min,PBS冲洗, DAB显色,常规脱水,用中性树胶封片。每张切片在高倍镜下(400×)随机选取4个视野,以出现棕黄色染色为阳性信号,检测NF-κB-p65积分光密度,以均值表示每个标本积分光密度[14]。
2结果
2.1大鼠精神活动状况及体重变化
大鼠免疫抑制后,表现为弓背、反应迟钝、毛发竖立、光泽度较差易脱落。接种鲍曼不动杆菌后大鼠进食减少、嗜睡、呼吸缓慢,部分老鼠口、鼻、肛门周围有出血。给药期间观察大鼠状态,空白组大鼠饮食、活动正常,毛发有光泽,模型组与各给药组大鼠活动、饮食均减少,毛发竖立,失去光泽,与模型组比,替加环素组(9mg/kg)、和柴胡桂枝汤组 (11.2g/kg)大鼠状态无明显差别,柴胡桂枝汤(11.2g/kg)联合替加环素组(9mg/kg)组状态稍好,证明联合治疗组效果较明显。
除A组正常对照组外,其他组大鼠体重均下降。且治疗组大鼠均较模型组大鼠体重下降相对缓慢,联合组下将最慢,证明治疗组均有效,且柴胡桂枝汤(11.2g/kg)联合替加环素 (9mg/kg)组效果最明显。
2.2生存率 自造模开始至大鼠处死前为止统计大鼠生存率,绘制生存曲线见图1.
实验开始第10天即给药第4天,空白组生存率为1,模型组0.7,替加环素组(9mg/kg) 组和柴胡桂枝汤(11.2g/kg)组均为0.6,柴胡桂枝汤(11.2g/kg)联合替加环素(9mg/kg)组为0.8;实验开始第13天即给药第7天,空白组生存率为1,模型和替加环素组均为0.5,柴胡桂枝汤组和联合组均为0.6,联合组在延长大鼠生存时间,降低死亡率方面有一定效果。
分析各组大鼠生存曲线得出,联合组比模型组大鼠生存时间长,死亡率低,证明柴胡桂枝汤联合替加环素在干预白细胞减少性鲍曼不动杆菌肺炎中有一定效果,可延长大鼠的生存时间。
图1.大鼠生存率,其中:A.空白组B.模型组C.替加环素组D.柴胡桂枝汤组E.柴胡桂枝汤(11.2g/kg)联合替加环素(9mg/kg)组
2.3病理学指标
分析大鼠肺组织切片(图2)得出,除A空白组外,其他四组均有炎症细胞渗出,且间质水肿,增宽。
B模型组最严重,肺泡腔隙变小,消失,如箭头所示。广泛肺泡上皮细胞变性、坏死如红色箭头所示,支气管周围可见蛋白样物质,如箭头所示,C、D、E三个治疗组与模型组相比,肺泡腔隙变小如黑色箭头所示,但程度较小,部分肺泡上皮细胞变性、坏死,如箭头所示,且柴胡桂枝汤(11.2g/kg)联合替加环素(9mg/kg)组相对变化最小,证明柴胡桂枝汤联合替加环素在干预鲍曼不动杆菌肺炎中较替加环素单用效果好,在一定程度上减轻鲍曼不动杆菌对肺组织的侵害。
图2.大鼠肺组织病理改变,HE染色(×200),其中:A.空白组B.模型组C.替加环素组 D.柴胡桂枝汤组E.柴胡桂枝汤(11.2g/kg)联合替加环素(9mg/kg)组
2.4肺组织细菌培养 各组大鼠肺组织细菌培养结果推算得每克肺组织所含细菌数(细菌含量),相对细菌数=每只大鼠细菌含量/模型组细菌含量的均值。
分析各组大鼠细菌培养结果(表)可以得出,空白组培养结果为阴性,模型组及各给药组培养结果均为阳性,给药治疗组细菌数量均比模型组低,替加环素(9mg/kg)组与模型组相比P<0.05,差异有统计学意义;
柴胡桂枝汤(11.2g/kg)和柴胡桂枝汤(11.2g/kg)联合替加环素(9mg/kg)组与模型组相比 P<0.01,差异极具统计学意义。
柴胡桂枝汤可有效抑制细菌生长或具有杀菌效果,且柴胡桂枝汤与替加环素联合使用较两药单独使用效果好。
注:与模型组比,*P<0.05,**P<0.01
2.5柴胡桂枝汤对SD大鼠血清中TNF-α,IL-2,IL-6含量的影响
大鼠造成耐药鲍曼不动杆菌肺炎模型后,连续给药7天血清中组大鼠血清中TNF-α,
IL-2,IL-6的含量变化结果。
注:与空白组比,*P<0.05,**P<0.01,与模型组比,△P<0.05,△△P<0.01
模型组大鼠血清中TNF-α,IL-2,IL-6的含量均显著高于空白对照组,柴胡桂枝杨(11.2g/kg)组,替加环素(9mg/kg)组,
柴胡桂枝汤(11.2g/kg)联合替加环素(9mg/kg)组大鼠血清中TNF-α的含量与模型组相比均有降低,其中联合组与模型组比有显著性差异。对于IL-2和IL-6的含量,给药组均比模型组有所降低,其中柴胡桂枝汤组和联合组与模型组相比有显著性差异,联合组效果较好。
2.6柴胡桂枝汤对耐药鲍曼不动杆菌肺炎大鼠肺组织中NF-κB-p65和TLR-4表达的影响
Western blot实验结果显示,模型组大鼠TLR-4灰度值比值与空白组无显著性差异,治疗组与模型组无显著性差异,证明大鼠感染耐药鲍曼不动杆菌肺炎时对TLR-4的表达量无显著影响。
模型组大鼠P65灰度值比值与空白组相比有显著性差异,造模过程使P65表达量发生明显改变。给药组比值均有所下降,但替加环素(9mg/kg)组和柴胡桂枝汤(11.2g/kg)组与模型组相比无显著性差异,柴胡桂枝汤(11.2g/kg)联合替加环素(9mg/kg)组与模型组相比有显著性差异。
注:与空白组比,*P<0.05,**P<0.01,与模型组,△P<0.05,△△P<0.01
图3大鼠NF-κB-p65和TLR-4表达情况,其中:A.空白组B.模型组C.替加环素组 D.柴胡桂枝汤组E.柴胡桂枝汤(11.2g/kg)联合替加环素(9mg/kg)组
2.7免疫组化表征NF-KB-P65入核情况
免疫组化检测发现,正常组大鼠肺组织仅少量细胞胞质内可见黄色颗粒,模型组胞质胞核均可见棕黄色和褐色颗粒,各治疗组与模型组相比细胞核内棕黄色和褐色颗粒均有明显减少,结果见图4;
分析各组大鼠NF-KB-P65阳性表达光密度值,模型组(B)NF-KB-P65入核阳性表达显著高于正常组,
说明在造模过程中激活了NF-KB免疫炎症通路,产生了免疫损伤,释放了上述免疫炎症因子,替加环素(9mg/kg)组(C),柴胡桂枝汤(11.2g/kg)组(D)和柴胡桂枝汤(11.2g/kg) 联合替加环素(9mg/kg)组(E)在治疗过程中抑制NF-KB-P65入核,阻止了炎症反应;
且柴胡桂枝汤组和联合组与模型组相比有显著性差异,联合组入核最少,证明柴胡桂枝汤(11.2g/kg)联合替加环素(9mg/kg)组效果最好。
图4免疫组化表征NF-KB-P65入核情况,其中:A.空白组B.模型组C.替加环素组D.柴胡桂枝汤组E.柴胡桂枝汤(11.2g/kg)联合替加环素(9mg/kg)组
注:与空白组比,*P<0.05,**P<0.01,与模型组,△P<0.05,△△P<0.01
具体实施方式
实施例1一种柴胡桂枝汤的制药用途
一种药物包装组合,其中含有柴胡桂枝汤11.2g、替加环素9mg;
柴胡桂枝汤制备方法:称取桂枝、黄芩、人参、芍药、生姜各63g,柴胡168g,半夏87g,甘草42g,大枣244g,8倍量水充分润湿,放置浸泡30min,加热煮沸后煎煮30 min,趁热3层纱布过滤,滤渣加6倍量水回流提取20min,滤过,合并滤液,浓缩至 750ml,得浓度为1.14g/ml药液,冷藏备用。
实施例2一种柴胡桂枝汤的制药用途
一种药物包装组合,其中含有柴胡桂枝汤的冻干粉0.1g、替加环素9mg;
柴胡桂枝汤制备方法:称取桂枝、黄芩、人参、芍药、生姜各63g,柴胡168g,半夏87g,甘草42g,大枣244g,8倍量水充分润湿,放置浸泡30min,加热煮沸后煎煮30 min,趁热3层纱布过滤,滤渣加6倍量水回流提取20min,滤过,合并滤液,浓缩至 750ml,得浓度为1.14g/ml药液,冷藏备用;
柴胡桂枝汤的冻干粉的制备方法:冷藏备用的柴胡桂枝汤10g;加入1.0g谷氨酸,加入5.0g乳糖,加入注射用水,加热溶解,稀释至1000ml,过滤、滤液超滤,分装、冷冻干燥,完毕后压盖;制成1000只;上述冷冻干燥分为四个阶段:(1)预冻5小时,温度在-45℃;(2)减压干燥10小时,温度在-30℃;(3)升温干燥5小时,温度在-10℃; (4)二次升温干燥4小时,温度在25℃。
包装是一个盒子中放置两个包装袋,一个包装袋中放置柴胡桂枝汤的冻干粉、一个包装袋中放置替加环素。
实施例3一种柴胡桂枝汤的制药用途
一种药物组合物,其中含有柴胡桂枝汤的冻干粉0.1g、替加环素9mg;
柴胡桂枝汤制备方法:称取桂枝、黄芩、人参、芍药、生姜各63g,柴胡168g,半夏87g,甘草42g,大枣244g,8倍量水充分润湿,放置浸泡30min,加热煮沸后煎煮30 min,趁热3层纱布过滤,滤渣加6倍量水回流提取20min,滤过,合并滤液,浓缩至 750ml,得浓度为1.14g/ml药液,冷藏备用;
柴胡桂枝汤的冻干粉的制备方法:冷藏备用的柴胡桂枝汤10g;加入1.0g谷氨酸,加入5.0g乳糖,加入注射用水,加热溶解,稀释至1000ml,过滤、滤液超滤,分装、冷冻干燥,完毕后压盖;制成1000只;上述冷冻干燥分为四个阶段:(1)预冻5小时,温度在-45℃;(2)减压干燥10小时,温度在-30℃;(3)升温干燥5小时,温度在-10℃; (4)二次升温干燥4小时,温度在25℃。
药物组合物是将柴胡桂枝汤的冻干粉和替加环素按照比例混匀。
实施例4一种柴胡桂枝汤的制药用途
一种药物包装组合,其中含有柴胡桂枝汤的冻干粉0.1g、替加环素的冻干粉9mg;
柴胡桂枝汤制备方法:称取桂枝、黄芩、人参、芍药、生姜各63g,柴胡168g,半夏87g,甘草42g,大枣244g,8倍量水充分润湿,放置浸泡30min,加热煮沸后煎煮30 min,趁热3层纱布过滤,滤渣加6倍量水回流提取20min,滤过,合并滤液,浓缩至 750ml,得浓度为1.14g/ml药液,冷藏备用;
柴胡桂枝汤的冻干粉的制备方法:冷藏备用的柴胡桂枝汤10g;加入1.0g谷氨酸,加入5.0g乳糖,加入注射用水,加热溶解,稀释至1000ml,过滤、滤液超滤,分装、冷冻干燥,完毕后压盖;制成1000只;上述冷冻干燥分为四个阶段:(1)预冻5小时,温度在-45℃;(2)减压干燥10小时,温度在-30℃;(3)升温干燥5小时,温度在-10℃; (4)二次升温干燥4小时,温度在25℃。
替加环素的冻干粉的制备方法:替加环素10g;加入1.0g谷氨酸,加入5.0g甘露醇,加入注射用水,加热溶解,稀释至1000ml,过滤、滤液超滤,分装、冷冻干燥,完毕后压盖;制成1000只;上述冷冻干燥分为四个阶段:(1)预冻5小时,温度在-45℃;(2) 减压干燥10小时,温度在-30℃;(3)升温干燥5小时,温度在-10℃;(4)二次升温干燥4小时,温度在25℃。
包装是一个盒子中放置两个包装袋,一个包装袋中放置柴胡桂枝汤的冻干粉、一个包装袋中放置替加环素的冻干粉。
实施例5一种柴胡桂枝汤的制药用途
一种药物组合物,其中含有柴胡桂枝汤的冻干粉0.1g、替加环素的冻干粉9mg;
柴胡桂枝汤制备方法:称取桂枝、黄芩、人参、芍药、生姜各63g,柴胡168g,半夏87g,甘草42g,大枣244g,8倍量水充分润湿,放置浸泡30min,加热煮沸后煎煮30 min,趁热3层纱布过滤,滤渣加6倍量水回流提取20min,滤过,合并滤液,浓缩至 750ml,得浓度为1.14g/ml药液,冷藏备用;
柴胡桂枝汤的冻干粉的制备方法:冷藏备用的柴胡桂枝汤10g;加入1.0g谷氨酸,加入5.0g乳糖,加入注射用水,加热溶解,稀释至1000ml,过滤、滤液超滤,分装、冷冻干燥,完毕后压盖;制成1000只;上述冷冻干燥分为四个阶段:(1)预冻5小时,温度在-45℃;(2)减压干燥10小时,温度在-30℃;(3)升温干燥5小时,温度在-10℃; (4)二次升温干燥4小时,温度在25℃。
替加环素的冻干粉的制备方法:替加环素10g;加入1.0g谷氨酸,加入5.0g甘露醇,加入注射用水,加热溶解,稀释至1000ml,过滤、滤液超滤,分装、冷冻干燥,完毕后压盖;制成1000只;上述冷冻干燥分为四个阶段:(1)预冻5小时,温度在-45℃;(2) 减压干燥10小时,温度在-30℃;(3)升温干燥5小时,温度在-10℃;(4)二次升温干燥4小时,温度在25℃。
药物组合物是将柴胡桂枝汤的冻干粉和替加环素的冻干粉按照比例混匀。
实施例6一种柴胡桂枝汤的制药用途的分析方法
取实施例5粉末0.01g,加乙醇10ml,密塞,冷浸20min,时时振摇,滤过,滤液作为供试溶液。另取桂皮醛对照品,加乙醇制成每1ml含1μl的溶液,作为对照品溶液。
吸取供试品溶液10μl,对照品溶液2μl,分别点于同一硅胶G薄层板上,以石油醚(60-90℃)-乙酸乙酯(10:1)为展开剂,展开,取出,晾干,喷2%二硝基苯肼试液。供试品色谱中,在与对照品色谱相应的位置上,显相同的橙红色斑点。
参考文献
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Claims (1)
1.一种柴胡桂枝汤的制药用途,其特征在于,
用于制备治疗或预防耐药鲍曼不动杆菌感染肺炎的组合物;
由柴胡桂枝汤11.2g、替加环素9mg制成;
柴胡桂枝汤制备方法:称取桂枝、黄芩、人参、芍药、生姜各63g,柴胡168g,半夏87g,甘草42g,大枣244g,8倍量水充分润湿,放置浸泡30min,加热煮沸后煎煮30min,趁热3层纱布过滤,滤渣加6倍量水回流提取20min,滤过,合并滤液,浓缩至750ml,得浓度为1.14g/ml药液,冷藏备用。
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CN103040804A (zh) * | 2012-12-19 | 2013-04-17 | 程新明 | 去甲汉黄芩素及其在制备治疗鲍曼不动杆菌感染的药物中的应用 |
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CN103040804A (zh) * | 2012-12-19 | 2013-04-17 | 程新明 | 去甲汉黄芩素及其在制备治疗鲍曼不动杆菌感染的药物中的应用 |
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