CN115697362A - 用于治疗b族链球菌(gbs)感染的组合物 - Google Patents
用于治疗b族链球菌(gbs)感染的组合物 Download PDFInfo
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- CN115697362A CN115697362A CN202180039604.5A CN202180039604A CN115697362A CN 115697362 A CN115697362 A CN 115697362A CN 202180039604 A CN202180039604 A CN 202180039604A CN 115697362 A CN115697362 A CN 115697362A
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- lactobacillus
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- lactoferrin
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Abstract
本发明涉及细菌感染领域,具体涉及怀孕期间和之后的B族链球菌(GBS)感染。本发明涉及包括嗜酸乳杆菌菌株、鼠李糖乳杆菌菌株和乳铁蛋白的组合物在预防性和/或治愈性治疗B族链球菌(GBS)感染中的用途。
Description
技术领域
本发明涉及细菌感染领域,具体涉及怀孕期间和之后的B族链球菌(GBS)感染。
本发明涉及包括嗜酸乳杆菌(Lactobacillus acidophilus)菌株、鼠李糖乳杆菌(Lactobacillus rhamnosus)菌株和乳铁蛋白的组合物在预防性和/或治愈性治疗B族链球菌(Group-B Streptococcus,GBS)感染中的用途。
背景技术
无乳链球菌(Streptococcus agalactiae)或B族链球菌(GBS)是全球母亲和新生儿发病率和死亡率的重要原因。胃肠道代表了GBS的天然储库,该细菌可以从其中移动并定殖在阴道中。在美国进行的研究表明,10-35%的孕妇是无症状的GBS携带者。定殖可能是偶然的、长期的或间歇的事件。新生儿感染最重要的危险因素是在分娩期间和胎儿通过产道后,母亲的泌尿生殖道中存在病原体细菌。或者,在胎膜破裂后,病原体细菌可以到达羊水的上行通道,尽管后者事件对于细菌的定殖不是必需的。
关于晚期新生儿感染的发病机制,假定传播是水平的。在引起感染的因素中,与母亲的密切接触、母乳喂养和医院传播都可能被提及。
与母亲的泌尿生殖道和胃肠道中GBS的存在相关的主要问题表现为无症状的定殖。事实上,无症状的菌尿症经常在怀孕期间发现。在无症状的形式中,孕妇的临床表现包括绒毛膜羊膜炎、膀胱炎、肾盂肾炎和发热性菌血症,以及产褥期的发热和子宫内膜炎。此外,该病原体可能与产程延长、胎膜早破(PROM)和早产(PPT)相关。在较少见的情况下,它与剖腹产后的手术伤口感染、盆腔脓肿、盆腔脓毒性血栓性静脉炎和骨髓炎有关。
在出生时,50-65%的新生儿在外耳道、咽、脐和肛门直肠道显示来自定殖母亲的GBS。
大约98%的显示出定殖迹象的新生儿不发生感染;然而,这种感染发生在1-2%的案例中。
GBS可导致两种不同的临床表现:早期和晚期新生儿感染。第一种(早期感染)发生在出生后7天内,其主要症状是呼吸窘迫。肺炎和败血症是最常见的临床表现,而5-10%的新生儿显示脑膜炎。早产儿在早期有10倍概率发生感染。
晚期感染发生在出生后第7天至3个月之间。这类患者通常是早产儿,并在许多情况下患有脑膜炎、败血症和骨关节感染。在由GBS引起的脑膜炎中幸存的新生儿,超过20%出现永久性神经损伤,例如感音神经性耳聋、精神发育迟滞、皮质性盲。美国的死亡率在过去30年间显著下降:从1970年的50%下降至1990年的6%;来自疾病预防控制中心(CDC)的最新数据显示更低的死亡率。
对孕妇的诊断通过以下方式进行:
——用于从阴道或肛门直肠拭子中寻找病原体细菌的培养试验;
——尿液培养测试。
对新生儿的诊断通过以下方式进行:
——用于从鼻咽或耳拭子中寻找病原体细菌的培养试验;
——血培养;
——脑脊液检查。
如今,降低早期新生儿感染发生率的最有效方法是对孕妇进行筛查以识别病原体细菌(无任何症状)和产时抗生素治疗。后者似乎是预防母亲并发症、感染和新生儿事件的最佳方式。可在怀孕35至37周期间基于培养筛查进行,或考虑产前或产时的风险因素,例如:
——怀孕35-37周期间的阴道直肠定殖;
——早产;
——在没有拭子结果的情况下,考虑病史,具体为:早产(<37周)、未足月胎膜早破(pPROM)、胎膜早破(PROM)超过18小时、分娩期间发烧(>38℃或100℉)、之前分娩的新生儿GBS阳性、母亲尿液培养GBS阳性。
怀孕期间、分娩前口服抗生素的治疗仅适用于尿液样本中GBS领先的情况,而GBS引起的阴道炎不是该治疗的指征。
产时预防必须在分娩前每4小时施用青霉素或氨苄青霉素。对有感染风险新生儿的抗生素治疗必须仅在诊断出感染和感染临床表现之后进行。
目前还没有针对GBS感染的疫苗。
鉴于目前缺乏可以避免母亲和新生儿并发症和感染的GBS治疗方法,人们越来越感觉到开发替代治疗方法的需要和重要性,以在怀孕和分娩期间替代抗生素治疗的使用。
发明内容
本发明的根本问题是提供用于预防和治疗B族链球菌感染的可用治疗方法。
通过本发明的发现解决了该问题,通过在预防性和/或治愈性治疗B族链球菌感染中使用包括嗜酸乳杆菌(Lactobacillus acidophilus)菌株、鼠李糖乳杆菌(Lactobacillus rhamnosus)菌株和乳铁蛋白(lactoferrin)的组合物。
如将在本发明的详细描述中进一步描述的,本发明的组合物具有允许在不使用抗生素的情况下治疗无乳链球菌(Streptococcus agalactiae)感染的优点。
附图说明
本发明的特征和优点将从以下报告的详细描述、出于说明性和非限制性目的给出的实施例,以及附图1和2中变得显而易见,其中:
图1A、1B和1C:图中显示了用嗜酸乳杆菌、鼠李糖乳杆菌、两种乳杆菌的混合物,以及与乳铁蛋白(在0.1至10mg/ml的范围内)组合的混合物进行不同处理后对GBS(106CFU)的生长抑制。如实施例7所描述的,以107CFU使用两种乳杆菌菌株(嗜酸乳杆菌LMG S-29159和鼠李糖乳杆菌SD5675)。图1A、1B和1C分别显示了6、12和24小时后对GBS的生长抑制。
图2:图中显示了在乳铁蛋白(Lf)存在下GBS的生长。
具体实施方式
本发明涉及包括嗜酸乳杆菌菌株、鼠李糖乳杆菌菌株和乳铁蛋白的组合物,其用于预防性和/或治愈性治疗B族链球菌(GBS)感染。包括嗜酸乳杆菌菌株、鼠李糖乳杆菌菌株和乳铁蛋白的组合物适用于制备用于预防性和/或治愈性治疗B族链球菌(GBS)感染的药物。
乳杆菌,例如嗜酸乳杆菌和鼠李糖乳杆菌,当以足够的量施用时,这些微生物对人类健康发挥多种有益作用。由于这个原因,它们被认为是益生菌。
乳杆菌属(Lactobacillus spp.)是在健康阴道生态系统中占优势的微生物种类代表。乳杆菌通过产生能够防止病原微生物生长的抗微生物物质来平衡不同的细菌种群,从而有助于阴道的内环境稳定。此外,它们还产生乳酸,乳酸保持阴道生理性的低pH值,从而有助于健康的阴道环境。在阴道生态系统中微生物组成的改变与一些不良的健康结果有关,例如细菌性阴道病(BV)和需氧菌性阴道炎(AV)。
乳铁蛋白(Lf)是大多数外分泌生物液体(包括眼泪、乳汁、唾液和阴道分泌物)的安全天然组分,其作为可能的治疗剂而值得关注。Lf是约80kDa的铁结合多功能糖蛋白,其构成先天免疫系统的主要免疫调节组分之一。科学文献中描述的Lf的其它生物活性包括对抗多种多样的病原性细菌、真菌、原生动物和病毒的抗微生物活性,以及抗炎和铁载体活性。与其他的乳汁糖缀合物一样,Lf作为可溶性受体模拟物发挥作用,抑制病原体结合至粘膜细胞表面。尽管Lf具有以上提到的广谱抗微生物和免疫调节活性,但对于Lf调节阴道细菌生长的能力却知之甚少。
不受任何理论的束缚,负责预防女性GBS感染的作用机制是由于本发明组合物在肠道中的抗微生物作用而产生的直接作用。事实上,肠道代表了许多引起人类疾病的病原体微生物的储库,例如下泌尿生殖道感染。我们的组合物能够显著减少GBS的增殖,由此减少其在下泌尿生殖道的迁移和定殖。
在我们之前的实验研究中,我们发现乳杆菌的组合(即嗜酸乳杆菌和鼠李糖乳杆菌)通过抑制某些特定病原体和条件致病菌的增殖和生长而发挥抗微生物作用。具体地,我们发现益生菌组合对金黄色葡萄球菌(Staphylococcus aureus)和大肠杆菌(Escherichiacoli)具有显著的诱导作用,金黄色葡萄球菌和大肠杆菌被认为是引起下尿路感染的最常见原因。相反,对于这种复合物对GBS的影响,却一无所知。
基于以上提到的证据,我们研究了选择的乳杆菌,主要是嗜酸乳杆菌和鼠李糖乳杆菌,单独或组合,以及存在或不存在Lf(优选牛乳铁蛋白)时,对GBS生长和增殖影响的能力。
令人惊讶的是,发明人发现当在组合物中将嗜酸乳杆菌菌株、鼠李糖乳杆菌菌株和乳铁蛋白组合在一起时,该组合物对GBS具有协同作用。
图1和图2中所示以及实施例7中所描述的结果表明,无论是嗜酸乳杆菌还是鼠李糖乳杆菌,无论是单独还是组合,孵育6小时后均不能抑制GBS的生长。对于嗜酸乳杆菌,12小时后可以观察到轻微的抑制,而单独的乳铁蛋白在任何孵育时间下均没有产生显著的抑制作用。
图1和2的结果是用嗜酸乳杆菌菌株LMG S-29159和鼠李糖乳杆菌菌株SD5675获得的。
然而,本领域普通技术人员已知,通过使用嗜酸乳杆菌和鼠李糖乳杆菌的不同菌株可以获得相同的结果,因为不同的细菌菌株通常可能具有非常谨慎的遗传变异,并且同时具有相同的活性。技术人员还知道,相同的细菌菌株可能具有不同的保藏号和/或不同的商品名称。
发明人惊讶地发现,通过来源于嗜酸乳杆菌La-14菌株的嗜酸乳杆菌菌株(例如嗜酸乳杆菌L MGS-29159和嗜酸乳杆菌GLA-14),允许获得具有本发明所描述作用的组合物。
具体地,通过比较16s rRNA基因序列可以鉴定出具有令人惊讶的活性的嗜酸乳杆菌。
SEQ ID NO:1描述了来自嗜酸乳杆菌L MGS-29159、嗜酸乳杆菌La-14和嗜酸乳杆菌GLA-14的16s区域的500个碱基对区域:
TGGAGAGTTTGATCCTGGCTCAGGACGAACGCTGGCGGCGTGCCTAATACATGCAAGTCGAGCGAGCTGAACCAACAGATTCACTTCGGTGATGACGTTGGGAACGCGAGCGGCGGATGGGTGAGTAACACGTGGGGAACCTGCCCCATAGTCTGGGATACCACTTGGAAACAGGTGCTAATACCGGATAAGAAAGCAGATCGCATGATCAGCTTATAAAAGGCGGCGTAAGCTGTCGCTATGGGATGGCCCCGCGGTGCATTAGCTAGTTGGTAGGGTAACGGCCTACCAAGGCAATGATGCATAGCCGAGTTGAGAGACTGATCGGCCACATTGGGACTGAGACACGGCCCAAACTCCTACGGGAGGCAGCAGTAGGGAATCTTCCACAATGGACGAAAGTCTGATGGAGCAACGCCGCGTGAGTGAAGAAGGTTTTCGGATCGTAAAGCTCTGTTGTTGGTGAAGAAGGATAGAGGTAGTAACTGGCCTTTATTTGACGGTAATCAACCAGAAAGTCACGGCTAACTACGTGCCAGCAGCCGCGGTA。
鼠李糖乳杆菌和乳铁蛋白与嗜酸乳杆菌菌株的任何组合允许获得根据权利要求1使用的组合物,该嗜酸乳杆菌菌株具有以下16s rRNA基因序列,该16s rRNA基因序列具有与SEQ ID NO:1的序列具有90%、95%、96%、97%、98%、99%或100%同一性的16s区域。
在优选的方面,本发明提供了组合物的用途,该组合物包括嗜酸乳杆菌菌株,其中所述嗜酸乳杆菌菌株具有与SEQ ID NO:1的序列具有至少95%同一性的16s区域。
然而,当组合在一起时,乳杆菌菌株的抑制作用产生得更强且出现得更早,并且当与Lf组合时显著增强,突出了协同作用。
在优选的方面,本发明提供了组合物的用途,该组合物包括嗜酸乳杆菌菌株、鼠李糖乳杆菌菌株和乳铁蛋白,其中所述嗜酸乳杆菌菌株和所述鼠李糖乳杆菌菌株的总浓度各自彼此独立地在107至1012CFU/剂量的范围内,优选为109CFU/剂量。
在另一个方面,在本发明的组合物中,嗜酸乳杆菌菌株选自以保藏号SD5212(美国典型培养物保藏中心或ATCC)和保藏号LMG S-29159(比利时微生物协调保藏中心或比利时根特大学BCCM/LMG)保藏的嗜酸乳杆菌(相当于嗜酸乳杆菌La-14和嗜酸乳杆菌GLA-14),以及属于相同物种的其它乳酸菌,例如但不限于嗜酸乳杆菌NCFM、嗜酸乳杆菌La-5、嗜酸乳杆菌Lafti L-10、嗜酸乳杆菌W22和嗜酸乳杆菌BIFOLAC 5的菌株,鼠李糖乳杆菌菌株选自以保藏号SD5675保藏的鼠李糖乳杆菌(ATCC,相当于鼠李糖乳杆菌HN001),以及属于相同物种的其它乳酸菌,例如但不限于鼠李糖乳杆菌Lr-32、鼠李糖乳杆菌GG、鼠李糖乳杆菌GR-1和鼠李糖乳杆菌SP-1的菌株。
在优选的方面,在本发明的组合物中,嗜酸乳杆菌菌株是以保藏号LMG S-29159保藏的嗜酸乳杆菌,所述鼠李糖乳杆菌菌株是以保藏号SD5675保藏的鼠李糖乳杆菌。
在更优选的方面,在本发明的组合物中,嗜酸乳杆菌菌株具有与SEQ ID NO:1的序列具有至少90%、95%、96%、97%、98%或99%同一性的16s区域,更优选地该16s区域为SEQ ID NO:1。
在另一方面,在本发明的组合物中,所述乳铁蛋白优选为牛乳铁蛋白,所述乳铁蛋白的总浓度在5mg/剂量至300mg/剂量的范围内,优选为50m g/剂量。
根据另一方面,所描述的发明提供了组合物的用途,该组合物包括嗜酸乳杆菌菌株、鼠李糖乳杆菌菌株和乳铁蛋白,所述组合物可以还包括至少一种额外的组分,其选自矿物质、维生素、益生菌、益生元、蛋白质或其任何混合物。
优选地,所述矿物质选自钙、磷、铜、镁、钾、铁、硒、钠、锌、锰、氯化物和碘;所述维生素选自维生素A、维生素B1(硫胺素)、维生素B2(核黄素)、维生素B3(烟酸)、维生素B6、维生素B8(生物素)、维生素B12、维生素C、维生素D、维生素E和叶酸;所述益生菌是双歧杆菌或乳酸菌,选自保加利亚乳杆菌(Lactobacillus bulgaricus)、干酪乳杆菌(Lactobacilluscasei)、双歧乳杆菌(Lactobacillus bifidus)、罗伊氏乳杆菌(Lactobacillus reuteri)、卷曲乳杆菌(Lactobacillus crispatus)、加氏乳杆菌(Lactobacillus gasseri)、植物乳杆菌(Lactobacillus plantarum)、詹氏乳杆菌(Lactobacillus jensenii)、德氏乳杆菌(Lactobacillus delbrueckii)、发酵乳杆菌(Lactobacillus fermentum)、惰性乳杆菌(Lactobacillus iners)、瑞士乳杆菌(Lactobacillus helveticus);所述蛋白质选自乳清和酪蛋白。
在更优选的方面,本发明涉及组合物的用途,该组合物包括107至1012CFU/剂量范围内的嗜酸乳杆菌、107至1012CFU/剂量范围内的鼠李糖乳杆菌、5mg/剂量至300mg/剂量范围内的乳铁蛋白和药学上可接受的赋形剂。
此类药学上可接受的赋形剂可以为但不限于羟丙基甲基纤维素、淀粉、硬脂酸镁和二氧化硅。本领域普通技术人员知晓其它可以用于制备根据实施例的组合物的赋形剂。
在另一方面,包括嗜酸乳杆菌菌株和鼠李糖乳杆菌菌株的组合物可以以107至1012CFU/剂量的日剂量使用,优选以109CFU/剂量的日剂量使用,其中嗜酸乳杆菌与鼠李糖乳杆菌的比例在20∶1至2∶1之间,优选4∶1,并且嗜酸乳杆菌的量总是高于鼠李糖乳杆菌。
乳铁蛋白,优选为牛乳铁蛋白,可以以5mg/剂量至300mg/剂量的日剂量使用,优选以50mg/剂量的日剂量使用。
该剂量用于我们正在进行的多中心临床试验,其中410名孕妇根据治疗方法随机分为2组(试验组(verum)或安慰剂组)。她们将在怀孕32至37周期间每天服用一粒制剂胶囊。每粒胶囊包含5×109CFU的乳杆菌混合物(即嗜酸乳杆菌和鼠李糖乳杆菌)和50mg乳铁蛋白。在优选的方面,根据本发明使用的组合物用于口服施用,其中所述组合物为固体、液体形式,该组合物的形式选自片剂、胶囊、粉末、颗粒、可溶棒、液体悬浮液。
本文所描述的组合物有利地用于预防和/或治疗在怀孕期间或之后发生的B族链球菌(GBS)感染。
如上文所描述和如以下权利要求部分所要求的本发明的各种实施例和方面,在以下实施例中得到实验支持。
实施例
现参考以下实施例,其与上述描述一起阐释本发明的一些实施方案。
实施例1
根据本发明组合物的制备(胶囊)
根据本发明的组合物通过在湿度控制在20-30%范围内的车间中称重每种原料来制备,原料为嗜酸乳杆菌、鼠李糖乳杆菌、乳铁蛋白、脂肪酸镁盐和二氧化硅。在此之后,将每种成分过筛并引入混合机中,在氮气存在下混合,以便尽可能多地除去氧气。将混合物(粉末)装入胶囊机的料斗中,用于在受控的环境条件(温度和湿度)下生产HPMC胶囊。灌装后,将胶囊输送到发泡机,用于在铝/铝(alu/alu)泡罩或合适的广口瓶中进行初步包装。
组成:
乳铁蛋白54.3mg,
嗜酸乳杆菌+鼠李糖乳杆菌:5×109CFU,
羟丙基甲基纤维素80mg,
淀粉53.6mg,
脂肪酸镁盐5mg,
二氧化硅3.7mg。
实施例2
根据本发明组合物的制备(包衣片剂1g)
乳铁蛋白60mg,
嗜酸乳杆菌20×109,
鼠李糖乳杆菌5×109,
磷酸钙300mg,
微晶纤维素150mg,
脂肪酸镁盐10mg,
二氧化硅5mg,
包衣剂50mg,
不同粘度的羟丙基甲基纤维素(200mg)和甲基纤维素(125mg)的混合物。
实施例3
根据本发明组合物的制备(小袋2g)
乳铁蛋白100mg,
嗜酸乳杆菌10×109,
鼠李糖乳杆菌2×109,
麦芽糊精1780mg,
二氧化硅20mg。
实施例4
根据本发明组合物的制备(口服棒包装——即用型1.5g)
乳铁蛋白50mg,
嗜酸乳杆菌15×109,
鼠李糖乳杆菌5×109,
低聚果糖1000mg,
山梨醇335mg,
Biossido di silicio 15mg。
实施例5
根据本发明组合物的制备(油中悬浮液10ml)
乳铁蛋白30mg,
嗜酸乳杆菌6×109,
鼠李糖乳杆菌3×109,
葵花籽油加至10mL,
脂肪酸单甘油二酯5mg,
维生素E15mg。
实施例6
根据本发明组合物的制备(液体悬浮液)
小瓶10mL;
塞(Plug):乳铁蛋白25mg;乳杆菌混合物15×109(嗜酸乳杆菌;鼠李糖乳杆菌)75mg,二氧化硅5mg;
小瓶:水、果糖、山梨酸钾、苯甲酸钠、香料、柠檬酸。
实施例7
本发明组合物的体外活性分析:液体共培养试验。
通过液体共培养试验评估嗜酸乳杆菌和鼠李糖乳杆菌,单独以及与乳铁蛋白组合,干扰GBS生长的能力。
将乳杆菌菌株(嗜酸乳杆菌LMG S-29159和鼠李糖乳杆菌SD5675)储存在-80℃的牛乳酵母提取物(milk yeast extract,MYE)中。
在实验之前,将每种菌株从冷冻的原种培养物转移至MRS(De Man RugosaSharpe)肉汤中,在37℃下以非搅拌条件培养。
在脑心浸液(Brain Heart Infusion,BHI)肉汤中培养无乳链球菌。
通过在模拟生殖道分泌物的限定培养基(Defined Medium Simulating GenitalTract Secretions,DMSGTS)(能够维持益生菌和病原体的生长)中培养不同浓度的益生菌菌株(107和108cfu/mL),单独或组合,与不同浓度(106和107cfu/mL)的目标病原体来进行共培养试验。益生菌菌株单独进行测试以及与乳铁蛋白进行组合测试,乳铁蛋白的最终浓度如下:0.1-1-5-10mg/ml。
对照通过培养仅有细菌的DMSGTS来进行。
为了检查病原体是否被抑制或杀灭,将0.05mL共培养悬浮液稀释并接种在特定的琼脂培养基上。在37℃下孵育6-24h后,评估细菌的生长。没有生长解释为具有杀微生物活性(100%抑制)。
对于不成对的数据,通过学生T检验(Student’s t-test)进行统计分析。数据以平均值和标准偏差(SD)来表示,P值<0.05被认为是显著的。
结果
用嗜酸乳杆菌LMG S-29159和鼠李糖乳杆菌SD5675进行的实验结果如图1和2中所示。
当单独测试时,乳杆菌显示出对GBS生长的不同作用。具体地,嗜酸乳杆菌在与病原体细菌培养12小时后引起轻微的生长抑制。相反,无论在6小时还是12小时后,鼠李糖乳杆菌均没有减少细菌的生长,而在24小时后显示出轻微的抑制。乳铁蛋白没有显著影响GBS的生长(图2)。令人惊讶的是,当Lf加入到乳杆菌混合物中时,复合物发挥出更明显的抑制,这在培养6小时后已经非常显著。
这种作用不依赖于初始的益生菌数目(107和108cfu/ml均获得了类似的结果)。
结论
图1和图2所示的结果清楚地证明了根据本发明的组合物(两种乳杆菌(嗜酸乳杆菌LMG S-29159和鼠李糖乳杆菌SD5675)与乳铁蛋白组合的制剂)用于预防和减少GBS病原体细菌生长的功效。
培养6小时后,无论是单独的嗜酸乳杆菌或鼠李糖乳杆菌,还是组合的嗜酸乳杆菌与鼠李糖乳杆菌,均不能抑制GBS的生长。对于嗜酸乳杆菌,12小时后可以观察到轻微的抑制,而单独的乳铁蛋白在任何培养时间下均没有发挥显著的抑制作用。
令人惊讶的是,乳铁蛋白增强了乳杆菌组合的作用,突出了协同作用。
考虑到GBS是在孕妇和主要是新生儿中引起严重病症的最常见和致病的细菌之一,本发明的组合物可以代表用于预防和治疗怀孕期间GBS感染的潜在替代方法。
实施例8
正在进行的临床研究
多中心、双盲、随机、安慰剂对照的临床试验正在进行中,以评估根据本发明的组合物在预防孕妇GBS感染中的功效。
本研究将在获得各研究点独立伦理委员会的书面批准并与意大利卫生部(Italian Ministry of Health)沟通后才会开始。该试验将根据赫尔辛基宣言(Declaration of Helsinki)(巴西,福塔莱萨,2013年10月)和良好临床实践(Goodclinical practice)进行。
将招募410名孕妇(怀孕32至37周),并根据治疗方法随机分为2组(试验组(verum)或安慰剂组)。招募将在摩德纳大学(University of Modena)(协调员)、米兰大学(University of Milan)和雷焦艾米里亚大学(University of Reggio Emilia)进行。
以下所有女性将可被招募:如果她们是成年人(>18岁),怀孕并具有低的产科风险,其直肠-阴道拭子为GBS阳性;怀孕周数在33周内并预测将阴道分娩。
排除标准包括:尿液为GBS阳性的孕妇;之前分娩的婴儿有早期败血症的妇女;招募前一个月使用抗生素;无法理解研究和签署知情同意书。
主要终点是产前筛查(35-37周)时GBS定殖孕妇(携带者)的比例。
次要终点包括分娩期间接受抗生素治疗的女性比例;胎膜早破的女性比例;5分钟的阿普加评分(Apgar score)>8;新生儿在出生后首48小时内接受抗生素的比例;新生儿患有早期GBS败血症的比例;以及研究产品/安慰剂的安全性和耐受性。
治疗包括从怀孕第32至37周每天口服施用1粒胶囊的研究产品(两种乳杆菌和乳铁蛋白的组合)或安慰剂。每粒verum胶囊含有5×109CFU的乳杆菌(即嗜酸乳杆菌和鼠李糖乳杆菌)和50mg乳铁蛋白。
在研究过程中,将根据当前的临床实践从每位女性处采集直肠和阴道拭子进行GBS分析。分娩后将进行随访,以评估新生儿的GBS定殖情况。
此外,在每个中心20名女性的亚组中,将在第35-37周的评估期间收集额外的阴道拭子。它将用于证明研究产品中包含的2种乳杆菌菌株的阴道定殖,并通过分子方法(从拭子中提取和分离细菌的DNA;16S rDNA测序;RT-PCR分析)以评估阴道微生物群和细胞因子谱。
将通过记录不良事件来评估安全性。
所有数据将以绝对或相对频率显示。主要和次要终点将使用双尾Z检验在2个研究组之间进行比较。
从以上描述和以上所述的实施例中,根据本发明描述和获得的组合物所取得的优点是显而易见的。
序列表
<110> 吉勒皮股份公司(GIELLEPI S.P.A.)
<120> 用于治疗B族链球菌(GBS)感染的组合物
<130> P22JM1WN00881IT
<150> EP20170598.5
<151> 2020-04-21
<160> 1
<170> BiSSAP 1.3.6
<210> 1
<211> 550
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 来自16s rRNA基因的区域
<400> 1
tggagagttt gatcctggct caggacgaac gctggcggcg tgcctaatac atgcaagtcg 60
agcgagctga accaacagat tcacttcggt gatgacgttg ggaacgcgag cggcggatgg 120
gtgagtaaca cgtggggaac ctgccccata gtctgggata ccacttggaa acaggtgcta 180
ataccggata agaaagcaga tcgcatgatc agcttataaa aggcggcgta agctgtcgct 240
atgggatggc cccgcggtgc attagctagt tggtagggta acggcctacc aaggcaatga 300
tgcatagccg agttgagaga ctgatcggcc acattgggac tgagacacgg cccaaactcc 360
tacgggaggc agcagtaggg aatcttccac aatggacgaa agtctgatgg agcaacgccg 420
cgtgagtgaa gaaggttttc ggatcgtaaa gctctgttgt tggtgaagaa ggatagaggt 480
agtaactggc ctttatttga cggtaatcaa ccagaaagtc acggctaact acgtgccagc 540
agccgcggta 550
Claims (13)
1.一种组合物,其包括嗜酸乳杆菌菌株、鼠李糖乳杆菌菌株和乳铁蛋白,所述组合物用于预防性和/或治愈性治疗B族链球菌(GBS)感染,其中所述B族链球菌(GBS)感染发生在怀孕期间或之后。
2.根据权利要求1所用的组合物,其中所述嗜酸乳杆菌菌株和所述鼠李糖乳杆菌菌株的总浓度各自彼此独立地在107至1012CFU/剂量的范围内,优选为109CFU/剂量。
3.根据权利要求1或2中任一项所用的组合物,其中所述嗜酸乳杆菌菌株选自以保藏号SD5212和LMG S-29159保藏的嗜酸乳杆菌、嗜酸乳杆菌NCFM、嗜酸乳杆菌La-5、嗜酸乳杆菌Lafti L-10、嗜酸乳杆菌W22和嗜酸乳杆菌BIFOLAC 5。
4.根据权利要求1至3中任一项所用的组合物,其中所述鼠李糖乳杆菌菌株选自以保藏号SD5675保藏的鼠李糖乳杆菌、鼠李糖乳杆菌Lr-32、鼠李糖乳杆菌GG、鼠李糖乳杆菌GR-1和鼠李糖乳杆菌SP-1。
5.根据权利要求1至4中任一项所用的组合物,其中所述嗜酸乳杆菌菌株具有与SEQIDNO:1的序列具有至少95%同一性的16s区域。
6.根据权利要求1至5中任一项所用的组合物,其中所述嗜酸乳杆菌菌株以保藏号LMGS-29159保藏,所述鼠李糖乳杆菌菌株以保藏号SD5675保藏。
7.根据权利要求1至6中任一项所用的组合物,其中所述乳铁蛋白优选为牛乳铁蛋白,所述乳铁蛋白的总浓度在5mg/剂量至300mg/剂量的范围内,所述乳铁蛋白的总浓度优选为50mg/剂量。
8.根据权利要求1至7中任一项所用的组合物,其还包括至少一种额外的组分,所述额外的组分选自矿物质、维生素、益生菌、益生元、蛋白质或其任何的混合物。
9.根据权利要求8所用的组合物,其中所述矿物质选自钙、磷、铜、镁、钾、铁、硒、钠、锌、锰、氯化物和碘;所述维生素选自维生素A、维生素B1(硫胺素)、维生素B2(核黄素)、维生素B3(烟酸)、维生素B6、维生素B8(生物素)、维生素B12、维生素C、维生素D、维生素E和叶酸;所述益生菌选自双歧杆菌或乳酸菌,所述乳酸菌选自保加利亚乳杆菌、干酪乳杆菌、双岐乳杆菌、罗伊氏乳杆菌、卷曲乳杆菌、加氏乳杆菌、植物乳杆菌、詹氏乳杆菌、德氏乳杆菌、发酵乳杆菌、瑞士乳杆菌、惰性乳杆菌;所述蛋白质选自乳清和酪蛋白。
10.根据权利要求1至9中任一项所用的组合物,其包括107至1012CFU/剂量范围内的嗜酸乳杆菌、107至1012CFU/剂量范围内的鼠李糖乳杆菌、5mg/剂量至300mg/剂量范围内的乳铁蛋白和药学上可接受的赋形剂。
11.根据权利要求1至10中任一项所用的组合物,其中所述组合物以107至1012CFU/剂量的日剂量与乳铁蛋白组合使用,优选地所述组合物以109CFU/剂量的日剂量与乳铁蛋白组合使用,所述乳铁蛋白为5mg/剂量至300mg/剂量,优选地所述乳铁蛋白为50mg/剂量。
12.根据权利要求1至11中任一项所用的组合物,其中所述组合物用于口服施用。
13.根据权利要求1至12中任一项所用的组合物,其中所述组合物为固体、液体或半液体的形式,所述形式选自片剂、胶囊、粉末、颗粒、可溶棒、液体悬浮液。
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PCT/EP2021/060394 WO2021214139A1 (en) | 2020-04-21 | 2021-04-21 | Composition for use in the treatment of group-b streptococcus (gbs) infections |
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