CN107802651A - 灭活乳酸菌在防治病毒性疾病药物中的应用 - Google Patents
灭活乳酸菌在防治病毒性疾病药物中的应用 Download PDFInfo
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Abstract
本发明涉及一种灭活乳酸菌在制备防治病毒性疾病药物中的用途,属于生物医药领域。这种药物的主要成分是灭活乳酸菌,可以通过将活的乳酸菌经过常规方法灭活制备。灭活乳酸菌静脉给药可以用于人或动物的各种病毒性疾病的预防、治疗或辅助治疗,具有广阔的应用前景。
Description
技术领域
本发明属于生物医药领域,尤其涉及灭活乳酸菌在防治病毒性疾病中的新用途。
背景技术
病毒性疾病严重地威胁着人类和动物健康。在人医临床上,发生的病毒性疾病种类较多,如艾滋病、病毒性肝炎、流行性感冒、流行性乙型脑炎、非典型肺炎、埃博拉病毒病、登革热、病毒性出血热、轮状病毒腹泻、带状疱疹、手足口病、流行性腮腺炎等。曾由甲型流感病毒、SARS病毒和埃博拉病毒等引发的烈性传染病导致大量人员死亡。此外一些慢性传染病如艾滋病、乙型肝炎等目前仍很难治愈。在兽医临床上,发生的马传染性贫血病、牛***、羊小反刍兽疫、猪瘟、禽流感等各种病毒病对畜禽养殖业造成了巨大危害;宠物发生的犬瘟热、细小病毒病常引起犬死亡。目前应对病毒性疾病常采用接种疫苗和药物防治的方法。由于病毒不断变异,疫苗防控也往往失效,另外,一些新的传染病突然爆发,尚无疫苗可控。
目前使用的抗病毒药物有利巴韦林、金刚烷胺、奥司他韦、吗啉双胍、伐昔洛韦、阿糖腺苷、拉米夫定等,长期大量地使用抗病毒药也会使病毒产生耐药性,如一些流感病毒对金刚烷胺产生了耐药性。抗病毒中药临床应用也较为广泛,如双黄连口服液、清开灵颗粒、银翘散、蒲地蓝片等,中药抗病毒虽疗效确切,但有时也很难达到理想效果。其他种类的抗病毒药还有一些抗体类,如抗血清、丙种免疫球蛋白、卵黄抗体等。另外,一些免疫增强剂也常用于病毒病的辅助治疗,如黄芪多糖、转移因子、干扰素等。虽然目前用于防治病毒病药物的种类不少,但由于一些病毒致病力强而且容易变异和产生耐药性,防治难度较大,因此寻找新型的抗病毒药物非常重要。
本发明发现将灭活的乳酸菌进行静脉给药,对病毒性疾病防治非常有效,未来具有广阔的应用前景。目前尚无将灭活乳酸菌静脉给药用于防治病毒性疾病的相关报道。
发明内容
本发明提供了一种全新的可以用于病毒性疾病防治的灭活乳酸菌静脉注射剂,这种药物的主要成分为灭活的乳酸菌,该药物静脉给药可以有效防治病毒性疾病。
灭活乳酸菌在制备防治病毒性疾病药物中的用途,对所述的灭活乳酸菌进行革兰氏染色,在油镜下观察,灭活乳酸菌保持完整菌体形态,药物的给药方式为注射给药。所述的保持完整菌体形态是指与灭活前活菌菌体的轮廓和形态基本一致。所说的基本一致实质上是指乳酸菌灭活过程中菌体细胞壁可能会出现轻微变化,比如部分表面成分的流失,但这种变化微乎其微或很少发生。
所述的每单位剂量药物中包含灭活乳酸菌完整菌体数量为105—1012个。
所述的注射给药为静脉注射给药。利用高温高压灭活、紫外线灭活、化学试剂灭活或辐射灭活中的任一种灭活方法得到所述灭活乳酸菌。
用于本发明制备灭活乳酸菌静脉注射剂的乳酸菌种类包括:(1)乳杆菌属:德氏乳杆菌(L.delbrueckii)、保加利亚乳杆菌(L.bulgaricus)、瑞士乳杆菌(L.helviticus)、嗜酸乳杆菌(L.acidophlus)、格氏乳杆菌(L.gasseri)、唾液乳杆菌(L.salivarius)、植物乳杆菌(L.plantarum)、罗伊氏乳杆菌(L.reuteri)、短乳杆菌(L.brevis)、干酪乳杆菌(L.casei)、发酵乳杆菌(L.fementi)等;(2)片球菌属:如乳酸片球菌(P.acidi1actic)、戊糖片球菌(P.pentasiaceus)、小片球菌(P.parvulus)等;(3)明串球菌属:肠膜明串球菌(L.mesenteroides)及其乳脂亚种(L.cremoris)和葡聚糖亚种(Leuc.dextranicun)、乳酸明串球菌(L.lactis)、酒明串球菌(L.oenos)等;(4)肠球菌属:屎肠球菌(E.faecium)、粪肠球菌(E.faecalis)等;(5)乳球菌属:乳酸乳球菌乳酸亚种(L.lactis subsp.lactis)、乳酸乳球菌乳脂亚种(L.lactis subsp.cremoris)、乳酸乳球菌叶蝉亚种(L.lactissubsp.hordniae)等;(6)链球菌属:乳酸链球菌(S.lactis)、丁二酮乳酸链球菌(S.diacetilactis)、乳酪链球菌(S.creamoris)、嗜热乳链球菌(S.thermophilus)等;(7)双歧杆菌属:两歧双歧杆菌(B.bifidum)、长双歧杆菌(B.longum)、短双歧杆菌(B.breve)、婴儿双歧杆菌(B.infantis)、青春双歧杆菌(B.adolescentis)、动物双歧杆菌(B.animalis)等;(8)其他种属的乳酸菌。
优选的,乳酸菌选自乳酸乳球菌乳酸亚种(拉丁名称:Lactococcus lactissubsp.Lactis,保藏编号:CICC 6246)、植物乳杆菌植物亚种(拉丁名称:Lactobacillusplantarum subsp.Plantarum,保藏编号:CICC 6240)、长双歧杆菌(拉丁名称:Bifidobacterium longum,保藏编号:CICC 6196)、短乳杆菌(拉丁名称:Lactobacillusbrevis,保藏编号:CICC 6239)、屎肠球菌(拉丁名称:Enterococcus faecium,保藏编号:CICC 6049)。
用于本发明的制备灭活乳酸菌静脉给药的剂型包括:粉针剂、混悬注射剂等各种剂型。用于本发明的灭活乳酸菌静脉注射剂的给药方式包括:静脉推注和静脉滴注等。
本发明采用常规方法灭活了屎肠球菌,发现灭活的屎肠球菌仍然可以进行革兰氏染色,油镜下观察灭活的屎肠球菌与活的屎肠球菌保持一致的菌体轮廓和形态。然后对灭活屎肠球菌生理盐水混悬液进行离心,弃上清留沉淀,提取DNA,采用PCR技术仍可以扩增出16S rDNA基因片段,通过测序还可以进行乳酸菌种类鉴别。进一步研究发现,将灭活屎肠球菌对小鼠尾静脉给药,可以有效地降低流感病毒PR8株感染小鼠的死亡数;灭活屎肠球菌静脉给药还可以显著降低新城疫感染鸡的死亡数;灭活植物乳杆菌植物亚种静脉给药还可以有效地防治猪蓝耳病的发生。以上说明灭活乳酸菌静脉给药可以用于病毒性疾病的防治。
本发明的灭活乳酸菌静脉注射剂经静脉给药可以用于各种病毒性疾病的防治,包括:(1)人的各种病毒性疾病,如艾滋病、病毒性肝炎、流行性感冒、流行性乙型脑炎、非典型肺炎、埃博拉病毒病、登革热、病毒性出血热、轮状病毒腹泻、带状疱疹、手足口病、流行性腮腺炎、麻疹、风疹、腺病毒病等;(2)家畜的各种病毒病,如猪瘟、猪繁殖与呼吸综合征、猪圆环病毒病、猪细小病毒病、猪伪狂犬、猪传染性胃肠炎、猪流行性腹泻、猪日本脑炎、猪水疱性病、猪流感、猪痘、***、牛呼吸道合胞体病毒病、牛传染性鼻气管炎、牛病毒性腹泻、牛副流感、牛轮状病毒病、羊痘病毒病、小反刍兽疫、马流感、马传染性贫血病等;(3)家禽的各种病毒病,如禽流感、鸡新城疫、鸡传染性法氏囊病、鸡传染性支气管炎、鸡传染性喉气管炎、鸡痘、鸡马立克氏病、鸭瘟、鸭病毒性肝炎、鸭副黏病毒病、鸭黄病毒病、鸭细小病毒病、小鹅瘟、鹅副黏病毒病等;(4)宠物的各种病毒病,如犬瘟热、犬细小病毒病、犬传染性肝炎、狂犬病、猫瘟热等。
静脉注射灭活乳酸菌防治病毒性疾病的机制目前尚不完全清楚,推测可能的机制是:灭活乳酸菌静脉给药,可能与病毒发生相互作用,阻断病毒感染组织器官;也可能灭活乳酸菌静脉给药后经机体代谢产生了抗病毒物质;或者灭活乳酸菌静脉给药后可激活机体免疫***,间接发挥抗病毒作用等。
具体实施方式
实施例1
将屎肠球菌(购于中国工业微生物菌种保藏管理中心,拉丁名称:Enterococcusfaecium,保藏编号:CICC 6049)接种于MRS培养基,于37℃温箱培养24小时,然后3000转离心5分钟,去除上层培养液保留沉淀,加入无菌生理盐水清洗沉淀,离心5分钟,重复清洗3次后,加入无菌生理盐水,与沉淀混匀。取一定量的屎肠球菌生理盐水混悬液,于分光光度计690nm处测量其OD值,当用无菌生理盐水稀释的最终浓度的OD值为0.38时,将该稀释浓度的屎肠球菌生理盐水混悬液作为1倍(1×)浓度,经过THOMA细菌计数板进行细菌计数测定该浓度下每mL混悬液中含有约108个屎肠球菌菌体。取少量的1×浓度的屎肠球菌生理盐水混悬液,进行革兰氏染色,在油镜下观察活菌的形态。此后将配制好的1×浓度的屎肠球菌生理盐水混悬液于121℃、压力0.12MPa,灭活15min,得到灭活屎肠球菌混悬液,取少量混悬液进行革兰氏染色,在油镜下观察灭活菌体的形态,发现灭活乳酸菌保持完整菌体形态,与其灭活前活菌菌体轮廓和形态一致,细菌计数发现灭活前后菌体数量没有明显变化。
实施例2
将屎肠球菌(购于中国工业微生物菌种保藏管理中心,拉丁名称:Enterococcusfaecium,保藏编号:CICC 6049)接种于MRS培养基,于37℃温箱培养24小时,然后3000转离心5分钟,去除上层培养液保留沉淀,加入0.9%无菌生理盐清洗沉淀,离心5分钟,重复清洗3次后,加入适量0.9%无菌生理盐水,与沉淀混匀。取一定量的乳酸菌混悬液,于分光光度计690nm处测量其OD值,当用灭菌生理盐水稀释的最终浓度的OD值为0.38时,将这样稀释浓度的乳酸菌混悬液作为1倍(1×)浓度。以此为依据,对含有乳酸菌生理盐水进行不同倍数的生理盐水稀释,便可以得到5×、1×和0.2×浓度的乳酸菌混悬液。此后分别将配制好的5×、1×和0.2×浓度的屎肠球菌混悬液于121℃、压力0.12MPa,灭活15min,得到5×、1×和0.2×浓度的灭活屎肠球菌混悬液药品。检测混悬液对流感病毒PR8株感染小鼠死亡数的影响。实验选用18-22g清洁级昆明种小白鼠分为正常对照组、PR8株模型组(即流感病毒PR8株感染小鼠模型组)和高、中、低三个剂量的灭活屎肠球菌给药组。每组30只小鼠,雌雄各半。高、中、低三个剂量的灭活乳酸菌组分别尾静脉注射5×、1×和0.2×浓度的灭活屎肠球菌静脉注射剂;正常对照组和PR8株模型组尾静脉注射无菌生理盐水,各组给药体积均为0.1mL/10g。各组小鼠于给药1次后间隔24小时,除正常对照组外,其他各组小鼠在***轻度麻醉下于鼻腔内接种含流感病毒PR8株的鸡胚尿囊液,每只0.05mL,使流感病毒PR8株感染小鼠。此后观察记录10天内各组小鼠死亡数。采用SPSS 11.5软件对实验数据进行卡方检验,结果见表1。由表1可知,高、中剂量的灭活屎肠球菌给药组与PR8株模型组比较,均可以极显著降低了小鼠死亡数,而低剂量给药组与PR8株模型组比较,可以显著降低小鼠死亡数。以上说明灭活屎肠球菌注射剂可以用于防治病毒性疾病。
表1灭活屎肠球菌静脉给药对流感病毒PR8株感染小鼠的影响结果
注:**表示与正常对照组比较差异极显著P<0.01,*表示与正常对照常组比较差异显著P<0.05;△△表示与PR8株模型组比较差异极显著P<0.01,△表示与PR8株模型组比较差异显著P<0.05。
实施例3
根据实施例2的方法和所用灭活屎肠球菌制备10×浓度的灭活屎肠球菌混悬液,研究灭活屎肠球菌给药对鸡新城疫的防治作用。选用10日龄白羽肉鸡随机分为新城疫对照组、灭活屎肠球菌高剂量组和灭活屎肠球菌低剂量组,每组30只。高剂量和低剂量灭活屎肠球菌组的给药剂量分别是翅下静脉注射10×的灭活屎肠球菌生理盐水混悬液0.05mL/只和0.1mL/只。新城疫对照组翅下静脉注射生理盐水。对鸡翅下静脉注射给药24小时后攻毒,每组鸡肌肉注射含有新城疫病毒的尿囊液0.2mL。连续观察5天,记录死亡数。采用SPSS 11.5软件对数据进行卡方检验,结果见表2。由表2可知,高剂量的灭活屎肠球菌静脉给药可以显著降低鸡的死亡数,说明灭活乳酸菌可以用于制备家禽病毒性疾病药物。
表2灭活屎肠球菌静脉给药对鸡新城疫的防治结果
注:**表示与新城疫对照组比较差异极显著P<0.01,*表示与新城疫对照组比较差异显著P<0.05。
实施例4
将植物乳杆菌植物亚种(购于中国工业微生物菌种保藏管理中心,拉丁名称:Lactobacillus plantarum subsp.Plantarum,保藏编号:CICC 6240)根据实施例2方法制备10×浓度的灭活植物乳杆菌植物亚种混悬液,检测灭活植物乳杆菌植物亚种给药对猪蓝耳病的防治作用。购买16头健康猪随机分为正常组、蓝耳病模型组、预防给药组和治疗给药组,每组4头。采用每头猪耳后肌肉注射蓝耳病病毒液2mL,制备猪蓝耳病模型。预防给药组的猪耳静脉注射10×浓度的灭活植物乳杆菌植物亚种混悬液1mL,第二天进行攻毒制备蓝耳病模型;治疗给药组的猪在攻毒制备蓝耳病模型后的当天耳静脉注射10×浓度的灭活植物乳杆菌植物亚种混悬液1mL,蓝耳病模型组在猪攻毒制备蓝耳病模型后的当天耳静脉注射1mL无菌生理盐水。正常组猪耳静脉注射1mL无菌生理盐水。此后观察了10天猪的采食量和外观变化,结果见表3。蓝耳病模型组的4头猪均发病,表现为炸毛消瘦,采食量明显下降;治疗给药组的4头猪均发病,也表现为炸毛消瘦,采食量下降;而预防给药组4头猪均无发病症状,即无炸毛消瘦现象,食量较正常组慢,但采食量没有下降。以上说明,灭活植物乳杆菌植物亚种制成的注射剂可以有效地防治猪蓝耳病的发生。
表3灭活植物乳杆菌植物亚种静脉给药对蓝耳病发病的影响
Claims (10)
1.灭活乳酸菌在制备防治病毒性疾病药物中的用途,其特征在于,对所述的灭活乳酸菌进行革兰氏染色,在油镜下观察,灭活乳酸菌保持完整菌体形态,药物的剂型为混悬液或粉针剂,给药方式为注射给药。
2.根据权利要求1的用途,其特征在于,所述的乳酸菌选自乳杆菌属、肠球菌属、乳球菌属、双歧杆菌属、明串球菌属、链球菌属。
3.根据权利要求1所述的用途,其特征在于,所述乳酸菌选自乳酸乳球菌乳酸亚种(拉丁名称:Lactococcus lactis subsp.Lactis,保藏编号:CICC 6246)、植物乳杆菌植物亚种(拉丁名称:Lactobacillus plantarum subsp.Plantarum,保藏编号:CICC 6240)、长双歧杆菌(拉丁名称:Bifidobacterium longum,保藏编号:CICC 6196)、短乳杆菌(拉丁名称:Lactobacillus brevis,保藏编号:CICC 6239)、屎肠球菌(拉丁名称:Enterococcusfaecium,保藏编号:CICC 6049)。
4.如权利要求1所述的用途,其特征在于,灭活乳酸菌为一种或两种以上灭活乳酸菌混合物。
5.根据权利要求1的用途,其特征在于,利用高温高压灭活、紫外线灭活、化学试剂灭活或辐射灭活中的任一种灭活方法得到所述灭活乳酸菌。
6.根据权利要求1所述的用途,其特征在于,所述注射给药为静脉注射给药。
7.根据权利要求6所述的用途,其特征在于,注射给药时,每ml剂量药物中包含灭活乳酸菌完整菌体数量为105—1012个。
8.根据权利要求7所述的用途,其特征在于,所述的药物按照如下方法制备得到:将乳酸菌进行常规液体培养基培养12-36小时后,3000-5000转离心保留沉淀,再将沉淀充分清洗后,配制成所需浓度混悬液,于120-122℃、压力0.1-0.2MPa,灭活15-30min得到灭活乳酸菌注射剂。
9.根据权利要求1-8任一项所述的用途,其特征在于,所述的病毒性疾病包括艾滋病、病毒性肝炎、流行性感冒、流行性乙型脑炎、非典型肺炎、埃博拉病毒病、登革热、病毒性出血热、轮状病毒腹泻、带状疱疹、手足口病、流行性腮腺炎、麻疹、风疹、腺病毒病、猪瘟、猪繁殖与呼吸综合征、猪圆环病毒病、猪细小病毒病、猪伪狂犬、猪传染性胃肠炎、猪流行性腹泻、猪日本脑炎、猪水疱性病、猪流感、猪痘、***、牛呼吸道合胞体病毒病、牛传染性鼻气管炎、牛病毒性腹泻、牛副流感、牛轮状病毒病、羊痘病毒病、小反刍兽疫、马流感、马传染性贫血病。
10.根据权利要求1-8任一项所述的用途,其特征在于,所述病毒性疾病包括禽流感、鸡新城疫、鸡传染性法氏囊病、鸡传染性支气管炎、鸡传染性喉气管炎、鸡痘、鸡马立克氏病、鸭瘟、鸭病毒性肝炎、鸭副黏病毒病、鸭黄病毒病、鸭细小病毒病、小鹅瘟、鹅副黏病毒病、犬瘟热、犬细小病毒病、犬传染性肝炎、狂犬病、猫瘟热。
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