CN108685933B - 改善猪免疫抑制状态的中药成分方剂及其制备方法和应用 - Google Patents
改善猪免疫抑制状态的中药成分方剂及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于含有来自藻类、苔藓、真菌或植物或其派生物,例如传统草药的未确定结构的药物制剂技术领域,公开了一种改善猪免疫抑制状态的中药成分方剂及其制备方法和应用,柯里拉京、虫草素、淫羊藿苷和芍药苷的质量配比比例为1‑4:1‑4:1‑4:1‑4。将柯里拉京、虫草素、淫羊藿苷和芍药苷按质量比1‑4:1‑4:1‑4:1‑4,加生理盐水制成总浓度为2mg/mL的药液。本发明能有效提升动物特异性的抗体效价,降低病毒载量,增强免疫细胞和免疫介质的数量与活性,促进免疫器官的生长发育,全面增强动物免疫功能和防御疾病的能力,克服了疫苗、化药、抗生素的毒副作用与食品安全隐患,研发前景乐观,临床应用广阔。
Description
技术领域
本发明属于含有来自藻类、苔藓、真菌或植物或其派生物,例如传统草药的未确定结构的药物制剂技术领域,尤其涉及一种改善猪免疫抑制状态的中药成分方剂及其制备方法和应用。
背景技术
目前,业内常用的现有技术是这样的:目前我国养猪生产面临着日趋严峻的疫病威胁,发病情况复杂多变,生产风险与日俱增,控制成本显著提高,经济损失无法估量。其重要原因在于猪群中普遍存在免疫抑制性疾病。猪免疫抑制性疾病是通过损伤免疫组织,影响细胞活性,干扰抗原递呈,抑制抗体形成等途径,导致机体抗病能力显著下降的一类疾病,同时也是当前疫苗免疫失败与诱发混合感染的重要因素。免疫抑制的两种主要表现形式可以概括为“一高一低”,即机体对疾病的易感性增高和对疫苗的应答性降低。由于免疫抑制性疾病常以亚临床感染的形式出现,易被忽视,因此,必须加强对免疫抑制性疾病的重视,并做好防控工作。猪群中普遍存在的免疫抑制性疾病包括猪圆环病毒2型感染、猪繁殖与呼吸综合征、猪瘟、猪支原体肺炎、猪伪狂犬、猪附红细胞体等疫病。病原体在传染的过程中,会遇到三道防御机制,即上皮防御机制、非特异性防御机制、特异性防御机制。这三道互相补充、相互协作,共同构成机体完整的免疫功能系统,维持机体的健康。当机体受到病原体侵入时,会调动这三方面的防御机制。猪是否发病取决于其综合防御机能的强弱,也就是抗病力水平的高低。抗病力主要受先天免疫和后天免疫影响:先天免疫快速,无特异性,是防御的第一线,主要与嗜中性细胞、巨噬细胞、自然杀伤细胞、补体、干扰素、溶菌酶及急性蛋白因子有关;后天免疫(获得性免疫)是特异性的,由抗原递呈细胞、T淋巴细胞和B淋巴细胞及各种细胞因子(cytokines)共同作用而产生。猪圆环病毒(Porcine circovirus,PCV)是迄今发现的一种最小的动物病毒。现已知PCV有两个血清型,PCV1为非致病性的病毒。PCV2为致病性的病毒,它是断奶仔猪多系统衰竭综合征(porcine multi-systemicwasting syndrome,PMWS)的主要病原。PCV2感染可造成猪体内Th1/Th2免疫应答的失衡,这可能是PCV2对猪产生免疫抑制的分子机制之一。PCV2诱导的Th1类和Th2类细胞因子间可以进行相互调节,表现为交互抑制作用。PCV2能引起细胞的凋亡,且使B细胞和T细胞的机能下降,从而使感染猪不能产生有效的免疫应答。PCV2感染引起的淋巴滤泡破坏和白细胞数量减少导致了猪的免疫抑制。淋巴枯竭的严重性与PCV2抗原在感染组织中检测到的数量积极相关。PCV2在淋巴组织中感染和复制能破坏淋巴滤泡的结构,导致淋巴枯竭,随后淋巴组织中淋巴细胞由组织细胞代替。猪繁殖与呼吸综合征(Porcine reprodutive andrespratory syndrome,PRRS)是由冠状病毒科动脉炎病毒属的PRRSV引起的一种猪繁殖和呼吸发生障碍的传染病。本病以妊娠母猪死胎、流产、木乃伊胎、弱仔及仔猪呼吸道症状和高死亡率等为特征。PRRSV感染早期可以诱导受感染猪外周血单核细胞和肺泡巨噬细胞的细胞凋亡,此凋亡可能是导致PRRSV相关病变及免疫抑制的重要机制;PRRSV感染猪肺泡巨噬细胞早期细胞凋亡的表达率在病毒感染后24h达到高峰,随后逐渐下降。由于淋巴结、淋巴小结和副皮质区及脾白髓都受到了广泛性的破坏,致使机体的体液免疫和细胞免疫能力降低。仔猪感染PRRSV病毒后淋巴细胞各亚群的比例下降可能会抑制机体对其它病原体的免疫反应,扁桃体的细胞比例变化有利于其它呼吸道病原体的混合感染或继发感染。应用中药调节机体免疫功能和防治疫病在我国已有数千年的历史,并以确切的疗效和较低的毒副残留及抗药性而广受欢迎。我国拥有丰富的中草药资源,应加速对其的研究与开发,打造具有中国特色的品牌。这对解决长期困扰养殖业发展的抗生素残留问题,发展绿色畜牧业,满足人们对食品安全的需求,增强我国动物性产品在国际市场的竞争力,都具有重要的经济意义和社会效益。但传统中药材在加工、使用、存贮、运输等诸多环节存有不便。中药现代化便是把中药中的活性成分一一分离出来进行研究。PCV2和PRRSV感染造成兽医临床上最为常见和典型的免疫抑制性疾病,这直接导致在疾病诊治过程中使用大量药物,造成病原微生物的耐药性日新月异;同时动物机体的特异性和非特异性免疫力下降,对各种疫苗无法应答,或产生的抗体效价低下,造成低致病力的病原体或弱毒疫苗也可能感染猪体发病;更为严重的是由PCV2和PRRSV等所带来的混合感染,使疾病更为复杂,有时会造成新的综合征,甚至达到难以控制的程度,给养猪生产造成巨大的经济损失,同时带来公共卫生安全隐患。
综上所述,现有技术存在的问题是:现有的PCV2和PRRSV感染的治疗方法导致在疾病诊治过程中使用大量药物,造成病原微生物的耐药性日新月异;同时动物机体的特异性和非特异性免疫力下降,对各种疫苗无法应答,或产生的抗体效价低下,造成低致病力的病原体或弱毒疫苗也可能感染猪体发病;更为严重的是由PCV2和PRRSV等所带来的混合感染,使疾病更为复杂,有时会造成新的综合征,甚至达到难以控制的程度,给养猪生产造成巨大的经济损失,同时带来公共卫生安全隐患。
解决上述技术问题的难度和意义:本发明通过大量实验发现柯里拉京等中药成分联用具有解除免疫抑制和调节免疫功能的作用,现有技术没有公开过该中药成分方剂具有解除免疫抑制和调节免疫功能的作用,也没有将该中药成分方剂作为饲料添加剂替代抗生素应用于畜禽养殖中,基于此,做出本申请。
发明内容
针对现有技术存在的问题,本发明提供了一种改善猪免疫抑制状态的中药成分方剂及其制备方法和应用。
本发明是这样实现的,一种改善猪免疫抑制状态的中药药物,所述改善猪免疫抑制状态的中药药物由柯里拉京、虫草素、淫羊藿苷、芍药苷组成;柯里拉京、虫草素、淫羊藿苷和芍药苷的质量配比比例为1-4:1-4:1-4:1-4。
本发明的另一目的在于提供一种所述的改善猪免疫抑制状态的中药药物的制备方法,所述改善猪免疫抑制状态的中药药物的制备方法包括:将柯里拉京、虫草素、淫羊藿苷和芍药苷按质量比1-4:1-4:1-4:1-4,加生理盐水制成总浓度为2mg/mL的药液。
本发明的另一目的在于提供一种由所述改善猪免疫抑制状态的中药药物得到的中药方剂。
本发明的另一目的在于提供一种所述改善猪免疫抑制状态的中药成分方剂在改善猪免疫抑制状态中的应用。
本发明的另一目的在于提供一种所述的改善猪免疫抑制状态的中药成分方剂制备的注射剂。
综上所述,本发明的优点及积极效果为:柯里拉京是一种含多酚羟基的糖苷,能够抑制促凋亡因子的释放来上调免疫应答。虫草素为含氮配糖体的核酸衍生物,属嘌吟类生物碱,是一种核甙类新药,它能够诱导调节性T细胞增殖,提高机体单核巨噬细胞系统的吞噬功能。淫羊藿苷能增强机体非特异性免疫功能和细胞免疫功能,调节体液免疫功能。芍药苷对脾淋巴细胞增殖反应有诱导作用,并且能使AA大鼠大量低下的脾淋巴细胞增殖反应恢复和接近正常水平,表明芍药苷具有浓度和机能依赖性的双向免疫调节作用。本发明通过大量实验发现柯里拉京等中药成分联用具有解除免疫抑制和调节免疫功能的作用,现有技术中没有公开过该中药成分方剂具有解除免疫抑制和调节免疫功能的作用。
本发明能有效提升动物特异性的抗体效价,降低病毒载量,增强免疫细胞和免疫介质的数量与活性,促进免疫器官的生长发育,全面增强动物免疫功能和防御疾病的能力,克服了疫苗、化药、抗生素的毒副作用与食品安全隐患,研发前景乐观,临床应用广阔。
附图说明
图1是本发明实施例提供的改善猪免疫抑制状态的中药成分方剂的制备方法流程图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
本发明旨在解决现有的PCV2和PRRSV感染的治疗方法导致在疾病诊治过程中使用大量药物,造成病原微生物的耐药性日新月异;同时动物机体的特异性和非特异性免疫力下降,对各种疫苗无法应答,或产生的抗体效价低下,造成低致病力的病原体或弱毒疫苗也可能感染猪体发病;更为严重的是由PCV2和PRRSV等所带来的混合感染,使疾病更为复杂,有时会造成新的综合征,甚至达到难以控制的程度,给养猪生产造成巨大的经济损失,同时带来公共卫生安全隐患的问题;中药成分方剂能有效提升动物特异性的抗体效价,降低病毒载量,增强免疫细胞和免疫介质的数量与活性,促进免疫器官的生长发育,全面增强动物免疫功能和防御疾病的能力,克服了疫苗、化药、抗生素的毒副作用与食品安全隐患,研发前景乐观,临床应用广阔,以解决上述现有技术存在的问题。
下面结合附图对本发明的应用原理作详细的描述。
本发明实施例提供的改善猪免疫抑制状态的中药成分方剂由柯里拉京、虫草素、淫羊藿苷和芍药苷组成;柯里拉京、虫草素、淫羊藿苷和芍药苷的质量配比比例为1-4:1-4:1-4:1-4。
本发明实施例提供的改善猪免疫抑制状态的中药成分方剂的药液对猪进行肌肉注射,每天一次,每次2ml,持续1周即可。
如图1所示,本发明实施例提供的改善猪免疫抑制状态的中药成分方剂的制备方法包括以下步骤:
S101:按照质量比准备柯里拉京、虫草素、淫羊藿苷和芍药苷;
S102:将柯里拉京、虫草素、淫羊藿苷和芍药苷按质量比1-4:1-4:1-4:1-4,加生理盐水制成总浓度为2mg/mL的药液。
下面结合实验对本发明的应用原理作进一步的描述。
实验1
中国食品药品检定研究院购得的柯里拉京、虫草素、淫羊藿苷和芍药苷按质量比1:1:1:1,加生理盐水制成总浓度为2mg/mL的药液,进行仔猪体内实验。
40头健康普通级“杜×大×长”三元杂交断奶仔猪,50日龄,购自南京农业大学江浦实验猪场。适应环境后随机分为4组,每组10头,公母各半。PCV2组和治疗组以107TCID50/mL的PCV2AH株攻毒,每头颈部肌肉注射2.0mL,1次,同时滴鼻2.0mL,1次。空白组和药物对照组不进行攻毒。各组隔离饲养2周。于实验的第三周第1d治疗组和药物对照组对侧颈部肌肉注射该中药成分复方液每天1次,每次2.0mL,持续1周。空白组和PCV2组不进行颈部肌肉注射该中药成分方剂。实验总周期为4周。
实验最后1d仔猪清晨空腹前腔静脉采血,酶联免疫吸附法检测血清中PCV2的抗体水平,实时荧光定量PT-PCR法检测血清中PCV2的抗原含量。结果发现,PCV2组的PCV2抗体水平OD值为0.289,治疗组的PCV2抗体水平OD值为0.443,两者差异极显著,空白组的PCV2抗体水平OD值为0.072,药物对照组的PCV2抗体水平OD值为0.079。PCV2组的抗原含量为6.88(lg)/μL,治疗组的抗原含量为4.05(lg)/μL,两者差异极显著,空白组和药物对照组的PCV2抗原均未检测到。实验表明,该中药成分方剂可以大幅上调仔猪PCV2的抗体水平,特异性的中和、消灭PCV2病原,从而增强机体免疫功能,预防疫病的发生。同时显著降低机体内的病毒含量,抑制病毒血症的产生,具有明显的抗PCV2病毒作用。
实验最后1d仔猪清晨空腹前腔静脉采血,全自动生化分析仪检测机体中IgG、IgM、白蛋白(ALB)和球蛋白(GLO)的水平。结果发现PCV2组的IgG水平为1.22mg/mL,治疗组的IgG水平为1.87mg/mL,两者差异极显著,空白组的IgG水平为1.39mg/mL,药物对照组的IgG水平为1.56mg/mL。PCV2组的IgM水平为0.54mg/mL,治疗组的IgM水平为0.91mg/mL,两者差异极显著,空白组的IgM水平为0.58mg/mL,药物对照组的IgM水平为0.73mg/mL。PCV2组的血清ALB含量为30.4g/L,治疗组的ALB含量为38.8g/L,两者差异显著,空白组的ALB含量为32.7g/L,药物对照组的ALB含量为35.6g/L。PCV2组的血清GLO含量为30.1g/L,治疗组的GLO含量为37.2g/L,两者差异极显著,空白组的GLO含量为32.5g/L,药物对照组的GLO含量为36.1g/L。实验表明,该中药成分方剂能大幅上调仔猪血清中IgG的水平,从而提高防病抗病能力。同时还能显著提高IgM水平,影响体液免疫反应。白蛋白作为一种贮存蛋白质,可随时修补组织和提供能量。该中药成分方剂能显著上调ALB水平,增加机体肝脏代谢功能。同时还能显著提高GLO水平,增强机体免疫功能。
实验最后1d仔猪清晨空腹前腔静脉采血,酶联免疫吸附法检测血清中IL-4、IL-10、IL-2和IFN-γ的含量。结果发现,PCV2组的IL-4含量为88.3pg/mL,治疗组的IL-4含量为56.1pg/mL,两者差异极显著,空白组的IL-4含量为82.0pg/mL,药物对照组的IL-4含量为79.8pg/mL。PCV2组的IL-10含量为144.0pg/mL,治疗组的IL-10含量为119.3pg/mL,两者差异极显著,空白组的IL-10含量为134.5pg/mL,药物对照组的IL-10含量为128.1pg/mL。PCV2组的IL-2含量为237.3pg/mL,治疗组的IL-2含量为311.4pg/mL,两者差异极显著,空白组的IL-2含量为226.5pg/mL,药物对照组的IL-2含量为287.7pg/mL。PCV2组的IFN-γ含量为174.6pg/mL,治疗组的IFN-γ含量为241.2pg/mL,两者差异极显著,空白组的IFN-γ含量为155.5pg/mL,药物对照组的IFN-γ含量为193.9pg/mL。实验表明,该中药成分方剂能显著下调IL-4和IL-10水平,减弱静止性Th0细胞向Th2方向分化,抑制Th2效应,从而解除机体免疫耐受情况;同时该中药成分方剂能显著上调IL-2和IFN-γ水平,促进静止性Th0细胞向Th1方向分化,增强Th1效应,从而改善机体免疫抑制状态。
实验2
中国食品药品检定研究院购得的柯里拉京、虫草素、淫羊藿苷和芍药苷按质量比1:1:1:1,加生理盐水制成总浓度为2mg/mL的药液,进行仔猪体内实验。
40头健康普通级“杜×大×长”三元杂交断奶仔猪,50日龄,购自南京农业大学江浦实验猪场。适应环境一周后,随机分为4组,每组10头,公母各半。空白组和PRRSV组不进行颈部肌肉注射该中药成分复方液。PRRSV组和治疗组以106TCID50/mL的PRRSV SH株攻毒,每头颈部肌肉注射2.0mL,1次,同时滴鼻2.0mL,1次,然后隔离饲养2周。于实验的第三周第1d治疗组和药物对照组肌肉注射该中药成分复方液每天1次,每次2.0mL,持续1周。实验总周期为4周。
实验最后1d仔猪清晨空腹前腔静脉采血,间接ELISA法测定各组血清中特异性抗体的活性,用免疫球蛋白ELISA试剂盒测定IgG、IgM、IgA含量。结果发现,PRRSV组的血清抗体OD值为0.519,治疗组的血清抗体OD值为0.703,两者差异显著,空白组的血清抗体OD值为0.388,药物对照组的血清抗体OD值为0.495。PRRSV组的IgG水平为498.3mg/L,治疗组的IgG水平为671.2mg/L,两者差异极显著,空白组的IgG水平为402.1mg/L,药物对照组的IgG水平为513.6mg/L。PRRSV组的IgM水平为230.7mg/L,治疗组的IgM水平为407.5mg/L,两者差异极显著,空白组的IgM水平为200.8mg/L,药物对照组的IgM水平为303.1mg/L。PRRSV组的IgA水平为46.6mg/L,治疗组的IgA水平为72.3mg/L,两者差异极显著,空白组的IgA水平为44.5mg/L,药物对照组的IgA水平为60.5mg/L。实验表明,该中药成分方剂能大幅上调仔猪血清中特异性PRRSV的抗体水平,及非特异性免疫球蛋白IgG、IgM、IgA的含量,从而改善机体免疫抑制状态,提高动物体液免疫功能。
实验最后1d仔猪清晨空腹前腔静脉采EDTA-Na抗凝血2mL/头,用于检测淋巴细胞亚群。结果发现,PRRSV组的CD3+细胞亚群比例为73.56,治疗组的CD3+细胞亚群比例为54.19,两者差异极显著,空白组的CD3+细胞亚群比例为55.82,药物对照组的CD3+细胞亚群比例为66.17。PRRSV组的CD4+细胞亚群比例为13.36,治疗组的CD4+细胞亚群比例为24.48,两者差异极显著,空白组的CD4+细胞亚群比例为25.11,药物对照组的CD4+细胞亚群比例为22.18。PRRSV组的CD8+细胞亚群比例为29.97,治疗组的CD8+细胞亚群比例为45.31,两者差异极显著,空白组的CD8+细胞亚群比例为40.09,药物对照组的CD8+细胞亚群比例为33.05。CD3T淋巴细胞的数量直接反映了外周免疫器官中总T细胞数量水平。CD4T细胞具有辅助性T细胞的功能,能诱导和增强免疫应答,激活各种免疫细胞(包括直接激活B细胞的增值与分泌抗体)。CD8T细胞代表着细胞毒性T细胞或抑制性T细胞的一个功能亚群,对消除细胞内源起重要作用。免疫抑制主要表现为CD4数量减少,CD8数量相对增多。实验表明,该中药成分方剂能增强动物机体细胞免疫功能,改善免疫抑制。
实验最后1d仔猪清晨空腹前腔静脉采肝素抗凝血2mL/头,用于检测淋巴细胞转化率。无菌取脾脏,用于检测脾脏淋巴细胞凋亡率。结果发现,PRRSV组的淋巴细胞转化率值为1.19,治疗组的转化率值为1.78,两者差异极显著,空白组的转化率值为1.23,药物对照组的转化率值为1.48。PRRSV组的凋亡率值为22.59,治疗组的凋亡率值为12.17,两者差异极显著,空白组的凋亡率值为15.18,药物对照组的凋亡率值为14.73。PRRSV组的NK细胞值(%)为21.2,治疗组的NK细胞值(%)为29.7,两者差异极显著,空白组的NK细胞值(%)为22.2,药物对照组的NK细胞值(%)为25.4。实验表明,该中药成分方剂可以大幅上调仔猪淋巴细胞转化率,通过促进猪体内细胞免疫功能,从而增强机体非特异性免疫。同时显著降低脾脏淋巴细胞的凋亡率,减少免疫抑制的直接损害。NK细胞是目前公认的免疫监视系统中最理想的效应细胞,本实验结果表明,该中药成分方剂能够增加NK细胞的数量,使整体免疫水平提高。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (4)
1.一种改善猪免疫抑制状态的中药药物,其特征在于,所述改善猪免疫抑制状态的中药药物由柯里拉京、虫草素、淫羊藿苷、芍药苷组成;柯里拉京、虫草素、淫羊藿苷和芍药苷的质量配比比例为1-4:1-4:1-4:1-4。
2.一种如权利要求1所述的改善猪免疫抑制状态的中药药物的制备方法,其特征在于,所述改善猪免疫抑制状态的中药药物的制备方法包括:将柯里拉京、虫草素、淫羊藿苷和芍药苷按质量比1-4:1-4:1-4:1-4,加生理盐水制成总浓度为2mg/mL的药液。
3.一种由权利要求1所述改善猪免疫抑制状态的中药药物得到的中药方剂,其特征在于,所述中药方剂为:由柯里拉京、虫草素、淫羊藿苷和芍药苷按质量比1:1:1:1,加生理盐水制成总浓度为2mg/mL的药液。
4.一种如权利要求3所述的改善猪免疫抑制状态的中药成分方剂制备的注射剂。
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