CN1863464A - 维持口腔健康的组合物及方法 - Google Patents
维持口腔健康的组合物及方法 Download PDFInfo
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- CN1863464A CN1863464A CNA2004800294851A CN200480029485A CN1863464A CN 1863464 A CN1863464 A CN 1863464A CN A2004800294851 A CNA2004800294851 A CN A2004800294851A CN 200480029485 A CN200480029485 A CN 200480029485A CN 1863464 A CN1863464 A CN 1863464A
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Abstract
本发明提供的组合物包含一或多种分离的乳酸脱氢酶缺乏的变异链球菌菌株和一或多种分离的口腔链球菌菌株和/或者一或多种分离的乳房链球菌菌株。本发明的组合物通过例如治疗和/或预防一或多种龋齿、牙周炎和/或其他口腔疾病或创伤的症状,对于维持口腔健康是有用的。
Description
优先权
本申请要求2003年8月11日提交的美国临时专利申请序号60/494,169的权益。
发明背景
龋齿的特征在于牙齿的无机部分的溶解,这可导致牙齿疼痛和丧失活力,迫使人们作出补牙或拔牙的花费。在美国龋齿影响50%的年龄5-9岁的儿童、67%的年龄12-17岁的青少年和94%的年龄≥18岁的成年人(Morbidity and Mortality Weekly Reports 51:144-147,2002)。清洁的牙齿不会腐蚀;然而即使用力的清洗也难以使牙齿保持充分的清洁。已经发展了各种各样的方法来预防或减缓龋齿的发生,包括例如给饮用水添加氟化钠、氟硅酸钠或氢氟硅酸,以及给局部用制剂包括牙膏(dentifrices)和口腔清洗剂(mouthrinses)添加氟化钠或氟化亚锡。也已经应用通过以聚合材料或密封剂(sealants)包封牙齿的方法来预防龋蚀;然而这些技术花费很高,也可能需要以磷酸刻蚀牙齿,且也可能只对还没有发生龋蚀的幼儿有作用。抗菌剂,包括抗生素,也已经被推荐为一种对于龋齿的治疗。抗生素杀灭在口腔中负责产酸的细菌如变异链球菌(streptococcus mutans),但抗生素在杀灭口腔中的细菌时不是选择性的,它们同时也杀灭了存在于口腔中的有益的细菌。这可导致在口腔中的微生物不均衡,从而导致严重的后果。因此,在本领域中需要治疗和预防龋齿的更有效的方法。
伴放线放线杆菌(Actinobacillus actinomycetemcomitans)(Aa)是早发性牙周炎包括局限型和泛发型青春期前的牙周炎、局限型和泛发型青少年牙周炎和快速进展型或难治性成人牙周炎的主要的病原体。破坏性的牙周病的最终的有害影响是牙齿的丧失。美国的一项全国调查显示局限型青少年牙周炎的患病率(prevalence)是0.53%,而泛发型青少年牙周炎的患病率是0.13%。Loe & Brown,J.Periodontol.62:608-616(1991)。许多研究的发现支持以下结论:早发性疾病在其他工业化国家中是相似的,而在发展中国家中更频发。Loe & Brown,J.Periodontol.62:608-616(1991)。
另外,某些类型的成人牙周炎,一般说来是影响超过半数成年人群的极常见疾病,很可能是由口腔固有的一组选择的微生物所引起的。这些微生物包括Aa、牙龈卟啉单胞菌(Porphyromonasgingivalis)、中间普雷沃氏菌(Prevotella intermedia)、福赛斯拟杆菌(Bacteroides forsythus)、齿垢密螺旋体(Treponema denticola)、直肠弯曲杆菌(Campylobacter rectus)和腐蚀艾肯菌(Eikenella corrodens)。
对于治疗各型牙周炎可应用抗生素的、手术的和机械的疗法,但都比不上预防其发生。已经广泛地应用四环素来治疗早发性牙周炎。然而,还有一种担心,涉及产生四环素抗药性菌株以及其他病原微生物过度生长的可能性。考虑到牙周病的发生率,在本领域中需要安全的预防和治疗策略。根据最近的关于牙周感染作为对于全身疾病(例如冠心病)的危险因素的可能作用的关注,牙周病的控制也非常重要。因此,治疗和预防早发性牙周炎、局限型和泛发型青少年牙周炎和快速进展型或难治性成人牙周炎的方法也是本领域需要的。
发明概述
本发明提供维持口腔健康,例如治疗和/或预防牙周炎、龋齿、在口腔中念珠菌属(Candida)或真菌的过度生长、口臭、口腔干燥导致的龋齿、口腔细菌传染或疾病,以及口腔外伤的方法和组合物。在一个实施方案中,本发明提供用于维持口腔健康的益生菌(Probiotics)。
益生菌是有生机的单独的或者混合培养的微生物,作用于动物或者人时可通过改善其固有的微生物丛(microflora)的性质而对其宿主产生有益的作用。传统上,益生菌的应用集中于胃肠健康的常规范畴,但已经有人建议应用有益的生物体来预防或治疗其他疾病,包括应用于保持阴道和泌尿道的健康的途径。在本发明中应用益生菌来维持口腔健康。
本发明的一个实施方案提供一种组合物,它包含一或多种分离的口腔链球菌(Streptococcus oralis)菌株和/或一或多种乳房链球菌(S.uberis)菌株,结合一或多种分离的乳酸脱氢酶缺乏的变异链球菌(mutans streptococcus)菌株。变异链球菌菌株可以是一或多种LDH缺乏的鼠链球菌(S.rattus)、大鼠链球菌(S.cricetus)、变异链球菌、表兄链球菌(S.sobrinus)、汗毛链球菌(S.downeii)、猕猴链球菌(S.macacae)和野生链球菌(S.ferus)菌株。所述组合物还可包含一种载体。变异链球菌菌株可以是天然存在的或经遗传学修饰的乳酸脱氢酶缺乏的菌株。变异链球菌菌株可以是例如鼠链球菌菌株JH145。口腔链球菌菌株可以是例如口腔链球菌菌株KJ3或者KJ3sm。乳房链球菌菌株可以是例如乳房链球菌菌株KJ2或者KJ2sm。
本发明的另一实施方案提供一种食品组合物,它包含一或多种分离的口腔链球菌菌株和/或一或多种分离的乳房链球菌菌株,以及一或多种分离的变异链球菌菌株,其中变异链球菌菌株是乳酸脱氢酶缺乏的。
本发明的另一个实施方案还提供一种牙膏、口香糖、锭剂、口腔清洗剂或者局部用药物(topical agent)组合物,其包含一或多种分离的口腔链球菌菌株和/或一或多种分离的乳房链球菌菌株,以及一或多种分离的变异链球菌菌株,其中变异链球菌菌株是乳酸脱氢酶缺乏的。
本发明的又一个实施方案提供一种维护受治疗者的口腔健康的方法,它包括将一种组合物给药于受治疗者的口腔,该组合物包含一或多种分离的口腔链球菌菌株和/或一或多种分离的乳房链球菌菌株以及一或多种分离的变异链球菌菌株,其中变异链球菌菌株是乳酸脱氢酶缺乏的。可以将组合物以大约一天一次、大约一周一次或者大约一月一次给予受治疗者。受治疗者可以是哺乳动物,例如人。维持口腔健康可以包括以下疾病的治疗、预防或者治疗和预防两者:牙周病、龋齿、念珠菌属或者真菌的过度生长、口臭、口腔干燥导致的龋齿或者牙周病、口腔的细菌感染或者疾病、口腔的创伤或其组合。
本发明甚至还有一个实施方案提供一种用治疗有效的细菌非持续地定居(colonizing)于受治疗者的口腔的方法,它包括给予受治疗者的口腔包含一或多种分离的口腔链球菌菌株和/或一或多种分离的乳房链球菌菌株和一或多种分离的变异链球菌菌株,其中变异链球菌菌株是乳酸脱氢酶缺乏的。受治疗者可以是哺乳动物,例如人。
因此,本发明提供维持口腔健康的方法和组合物,包括预防和/或治疗例如龋齿、牙周病、念珠菌属或者真菌过度生长、口臭,或者口腔干燥导致的龋齿或者牙周病、口腔的细菌感染或者疾病、口腔的创伤或其组合。
图的简述
图1显示每日以JH 145给药治疗的结果
图2A-C显示变异链球菌JH 145 ldh基因与变异链球菌BHT-2ldh基因的比较和对应的蛋白序列。
发明详述
可将益生菌定义为为了有益于宿主的健康,而给予足够数量的活的微生物。虽然起初是为了“肠道健康”而发展的,但是现在正在研究益生菌对于免疫系统的调节、阴道和泌尿道健康、变态反应、炎性疾病以及高血压的影响。细菌是人类的的正常栖居者,而且口腔提供了超过300种微生物的生态小环境(ecological niche)。合乎逻辑地,微生物的相互作用在控制菌斑的生态学方面有极大的重要性,且因此结果为:口腔健康或疾病。一种预防的途径是助长保护性菌种的定居和生长或者是有利于健康的平衡的微生物丛的形成。有益的效果可包括特异性酶或者代谢物的产生,或者益生菌生物体还可以引起身体产生有益的作用。还可以通过养分或者附着部位的竞争而抑制病原微生物的定居或者过度生长(outgrowth),从而得到有益的效果。
本发明提供对于维持口腔健康的组合物、治疗体系和方法,包括例如治疗和/或预防在受治疗者中的龋齿、牙周炎、口腔细菌感染和疾病、口腔创伤、念珠菌属或者真菌过度生长、口臭或者口腔干燥引起的龋齿或者牙周病、伤口愈合的促进或其组合。本发明的一种组合物包含治疗有效量的一或多种分离的变异链球菌的LDH缺乏菌株与治疗有效量的一或多种分离的口腔链球菌菌株和/或一或多种分离的乳房链球菌菌株的组合产品。
口腔链球菌和乳房链球菌
口腔链球菌(以前称为II型血链球菌(S.sanguis Type II))和乳房链球菌是在维持组成牙周菌丛的微生物的正常的、健康的平衡的重要组成部分。参见Socransky等,Oral Microbiol.Immunol.3:1-7(1988);Hillman和Shivers,Arch.Oral.Biol.,33:395-40l(1988);Hillman等,Arch.Oral.Biol.,30:791-795(1985)。口腔链球菌产生过氧化氢,其可抑制牙周的病原体例如伴放线放线杆菌(Aa)、福赛斯拟杆菌(Bacteroides forsythus)和中间普雷沃氏菌(P.intermedia)。因此,口腔链球菌和乳房链球菌可用于维持口腔健康。本发明的组合物包含一或多种分离的口腔链球菌菌株例如ATCC 35037、ATCC 55229、ATCC 700233、ATCC 700234和ATCC 9811。其他的口腔链球菌菌株包括KJ3和KJ3sm。KJ3sm是天然存在的KJ3的遗传学变种,对链霉素有抗药性。该链霉素抗药性是有利的,因为它提供了容易地分离该细菌的标记。此外,链霉素抗药性菌株稍微减毒的,在口腔中不能像野生型菌株那样生存时间长。在目标是使该细菌非长期定居于动物的口腔时,这种性质是有用的。
已经发现在菌斑中的乳房链球菌与牙周的健康有关,特别是由于其干扰牙周的病原体如牙龈卟啉单胞菌直肠弯曲杆菌和腐蚀艾肯菌的定居。本发明的组合物可包含一或多种分离的乳房链球菌菌株,例如ATCC 13386、ATCC 13387、ATCC 19435、ATCC 27958、ATCC35648、ATCC 700407、ATCC 9927、菌株KJ2或者菌株KJ2sm。KJ2sm是KJ2的天然存在的遗传学变种。即具有链霉素抗药性且提供与口腔链球菌的链霉素抗药性菌株相同的优点。一或多种分离的口腔链球菌菌株或者一或多种分离的乳房链球菌菌株,或者两者,均可被用于本发明的组合物和方法中。
变异链球菌
本发明的组合物包含一或多种分离的变异链球菌菌种(bacteriaspecies),其缺乏乳酸的产生。这些菌株包括例如鼠链球菌、大鼠链球菌、变异链球菌、表兄链球菌、汗毛链球菌、猕猴链球菌和野生链球菌。本发明的变异链球菌菌株基本不产生L(+)乳酸脱氢酶(LDH)。这样的菌株被定义为LDH缺乏菌株。变异链球菌LDH缺乏菌株产生的乳酸比变异链球菌野生型菌株减少75%、80%、90%、95%、98%、99%或者100%。变异链球菌的LDH缺乏菌株可以是天然存在的变异链球菌菌株或者经遗传学修饰的变异链球菌菌株。LDH缺乏的变异链球菌可在口腔中与病原菌例如变异链球菌(一种主要的龋齿的病原体)竞争和/或代替所述病原菌。当在口腔中作为益生菌给药时,变异链球菌的LDH缺乏菌株将与变异链球菌竞争一样的营养、定居位置等。因此,变异链球菌的LDH缺乏菌株可用于例如预防和/或治疗龋齿。LDH缺乏的变异链球菌菌株是非病原性的,它可改变口腔微环境以防止病原微生物的定居或者过度生长,和/或将病原微生物从病原体本属于宿主的自然菌丛的口腔中替换出来。
LDH缺乏的变异链球菌菌株的例子包括例如鼠链球菌JH145(ATCC 31377)(一种自生的,天然存在的LDH缺乏的突变株)(参见图2A-CJH145突变株的LDH核苷酸和多肽序列)和JH140(ATCC31341)(一种化学修饰的LDH缺乏的突变株)。参见例如Stanshenko和Hillman,在大鼠中以LDH缺乏的鼠链球菌突变株感染后的菌斑微生物丛(Microflora of plaque in rats following infection with an LDH-deficient mutants of Streptococcus rattus),Caries Res.23:375-377(1989);Hillman,变异链球菌的乳酸脱氢酶突变株:分离和初步的鉴定(Lactatedehydrogenase mutant of Streptococcus mutans:Isolation and preliminary)Infect.Immun.21:206-212(1978);还参见Abhyankar等,血清型c变异链球菌可突变(mutatable)至乳酸脱氢酶缺乏(Serotype cStreptococcus mutans mutatable to lactate dehydrogenase deficiency)。JDent Res 1985 Nov;64(11):1267-71。
可应用例如化学的或者物理的诱变技术,从一种变异链球菌菌株得到变异链球菌的LDH缺乏菌株。经应用这些技术诱变的株被认为是遗传学修饰的株。例如,一种变异链球菌菌株可经受诱变剂例如亚硝酸、蚁酸、硫酸氢钠、紫外线、类碱基诱变剂包括例如5-溴基-脱氧尿苷(5BU)、烷化剂(alkylators)例如甲磺酸乙酯(EMS)、甲磺酸甲酯(MMS)、硫酸二乙酯(DES)和亚硝基胍(NTG,NG,MNNG)的处理。参见例如,体外诱变方案(In Vitro Mutagenesis Protocols),Braman,Ed.,Humana Press,2002。
可以应用以下公开的方法制备天然存在的、自生的变异链球菌的LDH缺乏菌株:例如Hillman,变异链球菌的乳酸脱氢酶突变株:分离和初步的鉴定(Lactate dehydrogenase mutants of streptococcusmutans:isolation and preliminary characterization)。Infect Immun.21:206-212(1978)。自生的LDH缺乏的突变株以大约10-5的频率发生。参见Johnson等,变异链球菌的乳酸脱氢酶突变株在人体外和在大鼠体内导致龋齿的可能性(Cariogenic potential in vitro in man and invivo in the rat of lactate dehydrogenase mutants of Streptococcusmutans)。Arch.Oral Biol.25:707-713(1980)。
可通过将它们平皿培养于葡萄糖四唑翁培养基上,而将天然存在的、自生的变异链球菌的LDH缺乏菌株与产LDH变异链球菌菌株区别开来。在葡萄糖四唑翁培养基上,与亲代菌株相比较,LDH缺乏的变异链球菌菌落将是鲜红色而且在尺寸上相对较大,而前者是白色且在尺寸上相对较小。可将天然存在的、自生的变异链球菌的LDH缺乏菌株用于本发明的组合物中。
已经分离出LDH缺乏的鼠链球菌菌株。简言之,将鼠链球菌BHT-2的培养物在Todd Hewitt肉汤培养基中生长过夜至饱和,然后将稀释的样品涂敷于葡萄糖四唑翁培养基,每皿给予大约300个菌落。在此培养基上,野生型、产酸的菌落是白色的。LDH缺乏的突变株是鲜红色的。鼠链球菌JH145是在筛选的大约100,000个白色菌落中的一个红色的菌落。鼠链球菌JH145因此是一个天然存在的LDH缺乏的突变株。
变异链球菌LDH缺乏菌株,例如鼠链球菌BHT-2的LDH缺乏突变株,在葡萄糖及其他糖或者多元醇存在下培养时,产生较少总数的可滴定的酸,在葡萄糖存在下,在静置和生长培养基中培养时生成实质上较少的乳酸,当在蔗糖存在下生长时,可更好地粘附到羟基磷灰石上而且聚集更多的菌斑。可根据Brown和Wittenberger(J.Bacteriol.110:604,1972)所述分析LDH活性。
终点pH值可通过在包含1%葡萄糖的Todd-Hewitt肉汤培养基的次代培养株(1∶100)而测定。在37℃下在candle jars中培养48小时后,可测定培养物在580nm的吸光度和pH值。培养物的乳酸浓度可通过气-液相色谱测定。参见Salanitro和Muirhead,在发酵培养基中短链一元羧酸和二羧酸的气相色谱分析的定量法(Quantitativemethod for the gas chromatographic analysis of short-chainmonocarboxylic and dicarboxylic acids in fermentation media)Appl.Microbiol.29:374-381(1975);Hillman等,变异链球菌的野生型和乳酸脱氢酶缺乏的突变株的3-羟基-2-丁酮的生产(Acetoin production bywild-type strains and a lactate dehydrogenase-deficient mutant ofStreptococcus mutans)。Infect.Immun.55:1399-1402(1987)。
此外,任何为本领域技术人员所知的遗传修饰技术均可用于从产LDH的变异链球菌亲代菌株而产生变异链球菌的LDH缺乏菌株。例如,可以将LDH基因或者LDH基因的一部分缺失或者诱变处理,包括例如应用插入诱变技术。其他的诱变技术包括例如源重组、递归序列重组(recursive sequence recombination)、寡核苷酸指导的诱变、位置指导的诱变、易错聚合酶链反应、硫代磷酸化(phosphothioate)修饰的DNA诱变、含尿嘧啶模板诱变、缺口双链体诱变、点错配修复诱变(point mismatch repair mutagenesis)、修复缺失型宿主菌株诱变(repair-deficient host strain mutagenesis)、辐射所致的诱变、缺失诱变、限制-选择诱变(restriction-selection mutagenesis)、限制-提纯诱变(restriction-purification mutagenesis)、位点饱和诱变(site saturationmutagenesis)、整体诱变(ensemble mutagenesis)、递归的整体诱变和嵌合核酸产生(creation)。因此,任何可以使得LDH基因失能的遗传修饰技术均可用于产生变异链球菌的LDH缺乏菌株。
在本发明的一个实施方案中,LDH缺乏菌株,无论天然存在的或者是遗传学修饰的突变株,均有少于10-7的逆转频率和产生少于10%的亲代水平的乳酸脱氢酶活性。
本发明的组合物
本发明的组合物包含一或多种分离的变异链球菌突变株株以及与之组合的一或多种分离的口腔链球菌菌株,或者一或多种分离的乳房链球菌菌株,或者一或多种分离的口腔链球菌菌株和一或多种分离的乳房链球菌菌株两者,其中变异链球菌菌株是乳酸脱氢酶(LDH)缺乏的。LDH缺乏的变异链球菌与口腔链球菌和/或乳房链球菌的组合产品提供了一个有意义的实用的优点,即该组合产品可用于预防和治疗例如龋齿和牙周炎两者。龋齿和/或牙周炎的治疗意味着龋齿和/或牙周炎的一或多种症状的持久的或者暂时的缓解、减轻、阻止或者改善。本发明的组合物和方法还可以用来治疗或者预防念珠菌属或者真菌由于例如抗生素治疗而在口腔中的过度生长,治疗或者预防口臭(口腔气味不佳),以及治疗或者预防与口腔干燥(口干)相关的龋齿和/或牙周炎,治疗或者预防口腔细菌感染或者疾病,治疗或者预防口腔创伤及其组合。
本发明的变异链球菌、口腔链球菌和/或乳房链球菌菌株可以任何治疗有效的比例存在。治疗有效的意指持久地或者暂时地有效缓解、减轻、阻止和/或改善龋齿、牙周炎、细菌感染或者疾病、口腔创伤、念珠菌属或者真菌过度生长、口臭或者口腔干燥引起的龋齿或者牙周病或其组合的一或多种症状。治疗有效的也意指有效地促进口腔中的伤口愈合。
本发明的细菌菌株还可包含药学上可接受的或者营养学上可接受的载体。该载体与其给予的受治疗者的口腔是生理学相容的。载体可由固体基的、干的材料组成,用于配制成片剂、胶囊、锭剂或者粉末形式。载体还可以由液体或者凝胶基材料组成,用于配制成液体、凝胶和口香糖形式。
适当的液体或者凝胶基载体包括但是不局限于:水、生理盐水溶液、脲、醇及其衍化物,以及二醇(如乙二醇或者丙二醇)。本发明的组合物还可以包含天然的或者合成的调味剂以及食品级的着色剂,所有这些均应适于维持本发明的细菌菌株的生存能力。还可以向本发明的组合物中加入增稠剂例如玉米淀粉、瓜尔胶、聚羧乙烯(carbopol)以及黄原胶。
调味剂和/或着色剂也可以被包括在载体中。本发明的组合物还可以包含增塑剂例如甘油或者聚乙二醇。载体的成分可以改变,只要它不明显干扰本发明的细菌菌株的治疗活性。
组合物可以以适合口腔给予的各种的方式配制,例如液体、干的丸块、牙膏、漱口剂、口腔清洗剂、液体悬浮液、局部用药物(topicalagent)、粉状食品添加剂、糊剂、凝胶、固体食物、包装食品、糯米纸囊剂(wafer)、锭剂、口香糖等。其他制剂对本领域技术人员来说应是显而易见的。本发明的组合物可包含营养添加剂成分以及可包含任何的各种各样的熟知的营养剂,包括维生素、矿物质、必需的以及非必需的氨基酸、碳水化合物、脂质、食物、营养添加剂等。
本发明的细菌可以在例如发酵罐中制备。细菌可以从发酵罐中收获并且可以例如被浓缩。本发明的细菌可以在应用前通过例如脱水或者喷雾干燥而制备。喷雾干燥通常包括将细菌的悬浮液喷雾到一容器中并且置于热空气流下。细菌还可以在应用前以微囊包裹(参见例如,美国专利号6,251,478)、冷冻干燥,或者通过用保护性物质例如脂质材料,如三酰甘油、蜡、有机酯、豆油、棉子油、棕榈油以及长链脂肪酸和醇的酯包被来制备。
维持口腔健康的方法
可以定居于动物的口腔的病原性细菌,例如变异链球菌和伴放线放线杆菌,可以通过将组合物给予到口腔来抑制和/或控制,所述组合物包含一或多种变异链球菌的LDH缺乏菌株和一或多种分离的口腔链球菌菌株,或者一或多种分离的乳房链球菌菌株,或者一或多种分离的口腔链球菌菌株和一或多种分离的乳房链球菌菌株两者。可以将组合物给予受治疗者例如动物的口腔,所述动物包括哺乳动物,例如人、非人灵长类动物、狗、猫、大鼠、小鼠、马、羊或者兔子。本发明的细菌菌株可以形成至少一部分短暂的或者固有的口腔菌丛,并且在口腔中表现出有益的预防和/或治疗效果。
本发明提供治疗、预防或者治疗和预防以下病症的方法:龋齿、牙周炎、念珠菌属或者真菌过度生长、口臭,或者口腔干燥引起的龋齿或者牙周病、口腔细菌感染或者疾病、口腔创伤或其组合,该方法包括将本发明的组合物给予受治疗者的口腔。牙周炎包括例如早发性牙周炎、局限型和泛发型青少年牙周炎以及快速进展型或者难治性成人牙周炎。组合物以大约一天一次、大约一周一次或者大约一月一次给予受治疗者。
本发明的组合物可以以例如食品、水、牙膏、凝胶、糊剂、乳剂、气溶胶喷雾剂、口香糖、锭剂、片剂、胶囊或者液体悬浮液经口给予。细菌也可以配制到食品、水、凝胶或者其他载体中或者可以是一种在使用前由使用者加入到载体中的组合物。
本发明的一个实施方案提供以治疗有效量的细菌非持续地定居于受治疗者的口腔中的方法,它包括将包含一或多种分离的口腔链球菌菌株和/或乳房链球菌菌株以及一或多种分离的变异链球菌生物体的组合产品给予受治疗者的口腔,其中变异链球菌生物体是乳酸脱氢酶缺乏的。本发明的一个实施方案中,给予的细菌菌株并非持久地定居于口腔中,而是在给予所述细菌后,所述菌株在口腔中存在大约1天、大约1周、大约2周、大约3周、大约1月、大约2月或者大约3月。任选地,细菌可以持久地和持续地定居于受治疗者的口腔中。
本发明的组合物可以以以下剂量给药:大约1×103、l×105、1×107、l×109或l×1011个活菌的菌落形成单位(CFU)。每天可给予一个、二个或更多个剂量,持续大约1周、大约2周、大约1月、大约2月、大约3月、大约一年或更久。任选地,剂量可以以大约隔日一次、大约一周一次、大约一月一次或者大约每年一次给予。
实施例1
维持口腔健康的变异链球菌
每日用JH145治疗,因为竞争养分、附着位点及其他因素导致固有的变异链球菌的水平的减少。固有的变异链球菌的水平的降低促进口腔健康,因为该微生物与龋齿密切相关。
通过微量移液管将包含大约每毫升1010个细胞的100微升悬浮液移液至72只刚断奶的(24日龄)Sprague-Dawley大鼠的口中,而使其感染变异链球菌菌株NG8。在随后的日子里将感染方式重复两次。给动物喂养TD 80406食物(Harlan Teklad),并且随意地饮水,隔离笼养。允许NG 8自行生长(establish itself)4周。将动物随机分成6组,每组12只,并且每天进行如下治疗,持续16周:
a.使用微量移液管使第1组的动物接受包含每毫升1010个细胞的100微升JH145的悬浮液。
b.使用微量移液管使第2组的动物接受包含每毫升109个细胞的100微升JH145的悬浮液。
c.使用微量移液管使第3组的动物接受包含每毫升108个细胞的100微升JH145的悬浮液。
d.使用微量移液管使第4组的动物接受包含每毫升107个细胞的100微升JH145的悬浮液。
e.使用微量移液管使第5组的动物接受包含每毫升106个细胞的100微升JH145的悬浮液。
f.对在第6组的动物进行伪处理。
棉签每周一次对菌斑和唾液进行取样,将样品接种于变异链球菌筛选/选择培养基上,以选择性地培养NG 8(白色菌落)和JH145(红色菌落)。将NG 8的水平作为时间函数绘图。参见图1。
在9周期间,用单因素方差分析(ANOVA)检验6组之间的差异(即5个治疗组和1个对照组),结果显示有意义的组间效应(group effect),F(5,63)=5.53,p<.001。对于该分析的效应大小(ES=.31)和观测强度(observed power)(Φ=.99)显示有足够量的强度来发现组间的这种小的效应。随后的Bonferroni修正的t检验(p=.01)是应用预先计划的比较(priori planned comparisons)进行的,其测试各治疗组与对照组的比较。这些分析显示,相对于对照组来说,治疗组1-4显示变异链球菌NG 8表达的显著减少,t′s(1,21)≥2.7,p≤.01。
因此,每天以>106个细胞的JH145治疗的大鼠导致固有的变异链球菌水平的减少。随之将减少龋齿的危险并且改善口腔健康。治疗效果在病人中可能明显更好,在每次治疗中,他们将在其口腔中保持并漱动(swish)益生菌30到60秒钟。相对于很快吞下益生菌制剂的大鼠,人的牙齿暴露于JH145相对较久,应该能够增加其与固有的变异链球菌竞争的机会,从而改善效果。可进行关于人的研究,以证实每天接受变异链球菌例如鼠链球菌JH145(ldh,str)的悬浮液,可导致减少固有的变异链球菌菌株数量,而中止这种暴露可导致鼠链球菌JH145的最终清除,从而使固有的变异链球菌回到原有的水平。可测定固有的变异链球菌的基线水平。可将日剂量的鼠链球菌JH145给予受治疗者的口腔。可每周将受治疗者的口腔菌丛采样,监测野生型变异链球菌和鼠链球菌JH145水平,直到观察到野生型变异链球菌水平减少。中止给予鼠链球菌JH145剂量,并且每周对口腔菌丛采样,以跟踪鼠链球菌JH145水平的减少和野生型变异链球菌水平的增加。
维持牙周健康的口腔链球菌和乳房链球菌
可进行人的研究以检验每天暴露于口腔链球菌(str)和/或乳房链球菌的悬浮液时,可导致固有的牙周病原(periodontopathic)菌种和生龋齿的菌种数量的减少,以及中止治疗后导致口腔链球菌和/或乳房链球菌益生菌菌株的最终消除,并使牙周病菌种和生龋齿的菌种回到原有的水平。
例如,可测定病人的唾液中的4种牙周病细菌的基线水平。可将日剂量的口腔链球菌和/或乳房链球菌给予病人的口腔。可每周对病人的口腔菌丛采样以监测病原体和口腔链球菌和/或乳房链球菌水平,直到观察到一或多种病原体水平的减少。停止给予口腔链球菌和/或乳房链球菌的剂量,并且每周对病人的口腔菌丛采样以追踪口腔链球菌和/或乳房链球菌水平的减少以及病原体水平的相应增多。
最后,可进行人的研究和动物研究,以检验每天暴露于一或多种分离的口腔链球菌(str)和/或乳房链球菌菌株于一或多种分离的变异链球菌的LDH缺乏菌株的组合的悬浮液时,可导致的固有的牙周病菌种数量的减少,而且中止治疗后益生菌菌株会最终消除,以及牙周病菌种返回到原有的水平。
全部的专利、专利申请及本文中无论何处所引用的其他科学或技术著作,在这里通过引用全文结合到本文中。在此处适当地举例描述的本发明可在缺少没有在此处具体公开的任何成分或者限定下实施。因此,例如在本文的各种情况下,术语“包含(comprising)”、“基本上由...组成(consisting essentially of)”和“由...组成(consistingof)”中的任一个都可以用其他两个术语中任何一个替换。已经使用的术语和措辞用作本说明书的术语且不作为限定,并且在使用这样的术语和措辞时,无意排除任何显示和描述的特征或其部分的等同替换,但是应该认识到,在本发明的权利要求范围内,各种修饰是可能的。因此,应该理解,虽然本发明已经通过实施方案被具体公开,对此处公开的概念的任选的特征、修饰和变化对于本领域技术人员来说可以是显而易见的,并且这样的修改和变化,正如在说明书和所附的权利要求所定义的那样,被认为是在本发明的范围之内。
此外,本发明的特征或者方面是依据Markush分组(Markush group)或其他的备选分组进行描述的,本领域技术人员应该认识到,本发明也因此可按照Markush分组和其它组别的任何单个成员或者亚组成员来描述。
Claims (23)
1.一种组合物,它包含:
(a)一或多种分离的口腔链球菌(streptococcus oralis)菌株,或者一或多种分离的乳房链球菌(streptococcus uberis)菌株,或者一或多种分离的口腔链球菌菌株和一或多种分离的乳房链球菌菌株;以及
(b)一或多种分离的变异链球菌(mutans streptococcus)菌株,其中所述变异链球菌菌株是乳酸脱氢酶缺乏的。
2.权利要求1的组合物,它还包含载体。
3.权利要求1的组合物,其中所述变异链球菌菌株选自鼠链球菌(S.rattus)、大鼠链球菌(S.cricetus)、变异链球菌(S.mutans)、表兄链球菌(S.sobrinus)、汗毛链球菌(S.downeii)、猕猴链球菌(S.macacae)和野生链球菌(S.ferus)。
4.权利要求1的组合物,其中所述变异链球菌菌株是鼠链球菌菌株JH145。
5.权利要求1的组合物,其中所述变异链球菌菌株是天然存在的的乳酸脱氢酶缺乏的突变株。
6.权利要求1的组合物,其中所述口腔链球菌菌株是口腔链球菌菌株KJ3sm或KJ3。
7.权利要求1的组合物,其中所述乳房链球菌菌株是乳房链球菌菌株KJ2sm或菌株KJ2。
8.权利要求1的组合物,其中所述变异链球菌菌株是遗传学修饰的乳酸脱氢酶缺乏的菌株。
9.一种食品组合物,它包含:
(a)一或多种分离的口腔链球菌菌株,或者一或多种分离的乳房链球菌菌株,或者一或多种分离的口腔链球菌菌株和一或多种分离的乳房链球菌菌株;以及
(b)一或多种分离的变异链球菌菌株,其中所述变异链球菌菌株是乳酸脱氢酶缺乏的。
10.权利要求9的食品组合物,其中所述变异链球菌菌株选自鼠链球菌、大鼠链球菌、变异链球菌、表兄链球菌、汗毛链球菌、猕猴链球菌和野生链球菌。
11.权利要求9的食品组合物,其中所述变异链球菌菌株是天然存在的乳酸脱氢酶缺乏的突变株。
12.权利要求9的食品组合物,其中所述变异链球菌菌株是遗传学修饰的乳酸脱氢酶缺乏的菌株。
13.一种牙膏、口腔清洗剂、口香糖、锭剂或局部用药物组合物,它包含:
(a)一或多种分离的口腔链球菌菌株,或者一或多种分离的乳房链球菌菌株,或者一或多种分离的口腔链球菌菌株和一或多种分离的乳房链球菌菌株;以及
(b)一或多种分离的变异链球菌菌株,其中所述变异链球菌菌株是乳酸脱氢酶缺乏的。
14.权利要求13的组合物,其中所述变异链球菌菌株选自鼠链球菌、大鼠链球菌、变异链球菌、表兄链球菌、汗毛链球菌、猕猴链球菌和野生链球菌。
15.权利要求13的组合物,其中所述变异链球菌菌株是天然存在的乳酸脱氢酶缺乏的突变株。
16.权利要求13的食品组合物,其中所述变异链球菌菌株是遗传学修饰的乳酸脱氢酶缺乏的菌株。
17.一种维持受治疗者的口腔健康的方法,该方法包括将权利要求1的组合物给予受治疗者的口腔。
18.权利要求17的方法,其中所述受治疗者是哺乳动物。
19.权利要求17的方法,其中所述组合物以大约一天一次、大约一周一次或大约一月一次给予受治疗者。
20.权利要求17的方法,其中维持口腔健康包括对以下疾病的治疗、预防或治疗和预防两者:牙周炎、龋齿、念珠菌属(candida)或真菌过度生长、口臭、口腔干燥引起的龋齿或牙周病、口腔细菌感染、口腔细菌疾病、口腔创伤或其组合。
21.一种以治疗有效的细菌非持续地定居于受治疗者的口腔的方法,该方法包括将一种组合产品给予受治疗者的口腔,所述组合产品包含:
(a)一或多种分离的口腔链球菌菌株,或者一或多种分离的乳房链球菌菌株,或者一或多种分离的口腔链球菌菌株和一或多种分离的乳房链球菌菌株;以及
(b)一或多种分离的变异链球菌菌株,其中所述变异链球菌菌株是乳酸脱氢酶缺乏的。
22.权利要求21的方法,其中所述组合产品以大约一天一次、大约一周一次或大约一月一次给予所述受治疗者。
23.权利要求21的方法,其中所述受治疗者是哺乳动物。
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102123693A (zh) * | 2008-06-13 | 2011-07-13 | 奥洁克公司 | 产过氧化氢细菌用于牙齿增白的用途 |
CN105687108A (zh) * | 2008-06-13 | 2016-06-22 | 奥洁克公司 | 产过氧化氢细菌用于牙齿增白的用途 |
US11096770B2 (en) | 2008-06-13 | 2021-08-24 | ProBiora Health, LLC | Use of hydrogen peroxide-producing bacteria for tooth whitening |
US11564785B2 (en) | 2008-06-13 | 2023-01-31 | ProBiora Health, LLC | Hydrogen peroxide-producing bacterial composition |
CN103282774A (zh) * | 2010-12-28 | 2013-09-04 | 狮王株式会社 | 口腔状态的判定方法及其所使用的分析用具、装置以及程序 |
CN103282774B (zh) * | 2010-12-28 | 2015-08-05 | 狮王株式会社 | 口腔状态的判定方法及其所使用的分析用具、装置以及程序 |
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KR20060056985A (ko) | 2006-05-25 |
PL1659885T3 (pl) | 2013-06-28 |
US20150050221A1 (en) | 2015-02-19 |
NZ545730A (en) | 2009-08-28 |
AU2004266615B2 (en) | 2008-07-17 |
ES2403053T3 (es) | 2013-05-13 |
JP2012046528A (ja) | 2012-03-08 |
US9962330B2 (en) | 2018-05-08 |
US20180296465A1 (en) | 2018-10-18 |
US10688038B2 (en) | 2020-06-23 |
US20110123461A1 (en) | 2011-05-26 |
CA2535764A1 (en) | 2005-03-03 |
US20220347088A1 (en) | 2022-11-03 |
KR101176660B1 (ko) | 2012-08-23 |
US11364194B2 (en) | 2022-06-21 |
US20200315952A1 (en) | 2020-10-08 |
WO2005018342A1 (en) | 2005-03-03 |
WO2005018342A8 (en) | 2006-03-30 |
EP1659885B1 (en) | 2013-01-16 |
AU2004266615A1 (en) | 2005-03-03 |
DK1659885T3 (da) | 2013-04-02 |
JP2007502280A (ja) | 2007-02-08 |
CN102389390A (zh) | 2012-03-28 |
US7931892B2 (en) | 2011-04-26 |
US8865156B2 (en) | 2014-10-21 |
CA2535764C (en) | 2012-01-24 |
US20060246015A1 (en) | 2006-11-02 |
EP1659885A1 (en) | 2006-05-31 |
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