CN108165505A - 用于治疗关节炎的益生菌及其医药组合物 - Google Patents
用于治疗关节炎的益生菌及其医药组合物 Download PDFInfo
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Abstract
本发明涉及一种益生菌TCI633及其在用于制备治疗关节炎或减缓关节炎疼痛的医药方面的用途,和在用于制备增加软骨细胞或保护软骨细胞的医药方面的用途;该益生菌TCI633保藏于德国微生物保藏中心,保藏号为DSM 28121;本发明还涉及一种用于治疗关节炎的医药组合物,其包含益生菌TCI633和药学上可接受的载体;该医药组合物,对于骨关节炎具有显著的治疗效果,对于关节组织被破坏也具有减缓的作用。
Description
技术领域
本发明涉及一种新的益生菌TCI633,含有该益生菌的用于治疗关节炎医药组合物,以及该益生菌在用于制备治疗关节炎或减缓关节炎疼痛的医药方面的用途,和在用于制备增加软骨细胞或保护软骨细胞的医药方面的用途,属于生物医药领域。
背景技术
临床上,关节炎大致可分为骨关节炎、类风湿性关节炎、痛风性关节炎、细菌性关节炎等,每一类型关节炎的症状及好发部位皆不尽相同,而骨关节炎则是其中最常见的一种。骨关节炎是一种退化性的关节疾病,患者的关节软骨受到侵害,除造成患者疼痛外,也有僵硬、肿胀与变形等症状,此症状若持续进行,还可能造成患者行动困难而需要拐杖或轮椅的协助。
一般情形下,骨关节炎主要损伤经常活动以及需要负重的关节,例如膝关节、髋关节、手指指间关节、腰椎及颈椎等。骨关节炎的治疗方式,起初多采非手术性的治疗,包括:药物治疗、复健治疗或施打玻尿酸。若仍无法以上述方式减缓患者的症状时,才以手术作为治疗的手段。
在药物治疗方面,可使用类固醇药物,其止痛效果快速而显著,但它的副作用也相当大,例如会产生骨质疏松症、伤口不易愈合、皮肤变薄、上消化道出血等,甚至会加重高血压、糖尿病的病情,因此,目前大多数的情况都已停止使用,但对于某些类风湿性关节炎、红斑性狼疮、僵直性脊椎炎或脊椎外伤患者而言,仍需使用类固醇以缓解病情。可取代类固醇药物的药物有非类固醇抗炎药与葡萄糖胺。目前,非类固醇抗炎药的使用相当普遍,止痛效果也都不错,但长期使用仍有副作用,例如消化性溃疡、下肢水肿、肾脏功能的损伤等,故在使用上也需相当注意。此外,由于葡萄糖胺可刺激关节内的软骨细胞合成醣蛋白,又同时具有消炎止痛的效果、无非类固醇抗炎药的副作用,许多患者也使用此种方式治疗,但由于其剂量以及吸收能力的差异,葡萄糖胺对于许多患者并无明显的效果。
另一方面,则可在关节腔内注射玻尿酸,当作一种润滑剂以帮助关节活动而减缓症状。玻尿酸虽可抑制一些发炎反应,但对于疼痛减缓的功效却是有限,其虽然没有副作用,但在体内,只要数星期就会被人体吸收,持久性不高。
当前述非手术治疗方式都无法改善患者症状并减轻痛楚时,只能进行以侵入式的手术治疗,例如利用关节镜手术,清除关节腔内的异物或对受损的软骨进行修补,但其对于关节受损已经相当严重的患者而言效果极其有限。若是直接更换以人工关节,虽可避免发炎、减少疼痛,但人工关节也有其使用寿命,若使用较长寿命的纯金属或陶瓷,则需高额的费用。
因此,若能发现一种药物及其医药组合物,没有副作用,而且可持续产生作用,特别是能够缓解患者的疼痛,且能以最经济、无须经手术治疗的方式达到治疗关节炎的功效,将是关节炎患者的一大福音。
发明内容
为解决上述技术问题,本发明提供了一种益生菌TCI633,该益生菌 TCI633保藏于布达佩斯条约承认的生物材料样品国际保藏单位“德国微生物保藏中心(DeutscheSammlung von Mikroorganismen und Zellkulturen GmbH, DSMZ)”,保藏号为DSM 28121。
本发明另一方面提供了一种用于治疗关节炎的医药组合物,所述医药组合物包含如上述的益生菌TCI633。
优选的,所述医药组合物包含有效剂量的如上述的益生菌TCI633和药学上可以接受的载体。
本发明再一方面提供了上述的益生菌TCI633在用于制备治疗关节炎或减缓关节炎疼痛的医药方面的用途。
本发明还一方面提供了上述的益生菌TCI633在用于制备增加软骨细胞或保护软骨细胞的医药方面的用途。
本发明的益生菌TCI633及其医药组合物可以用于治疗关节炎或减缓关节炎疼痛,具有增加软骨细胞或保护软骨细胞方面的功能,没有副作用,而且可持续产生作用,特别是能够缓解患者的疼痛,且能以最经济、无须经手术治疗的方式达到治疗关节炎的功效,为未来关节炎药物提供了一个新的发展方向。
附图说明
图1为本发明实施例中益生菌TCI633的不同剂量对于ACLT诱发后腿负重分布改变的比较结果图;
图2为本发明实施例中益生菌TCI633的不同剂量对于温度感觉异常影响的比较结果图;
图3为本发明实施例中益生菌TCI633的不同剂量对于ACLT诱发机械性触觉过敏影响的比较结果图;
图4为本发明实施例中益生菌TCI633的不同剂量对于ACLT诱发膝关节肿胀影响的比较结果图;
图5为本发明实施例中益生菌TCI633的不同剂量对于体重变化的比较结果图;
图6为本发明实施例中益生菌TCI633的不同剂量对于膝关节滑膜组织发炎影响的组织解剖图;
图7为本发明实施例中益生菌TCI633的不同剂量对于膝关节骨头组织影响的组织解剖图;
图8为本发明实施例中益生菌TCI633的不同剂量对于膝关节软骨组织影响的组织解剖图;
图9为本发明实施例中利用国际骨关节炎研究学会评估分数系统评估益生菌TCI633的不同剂量对于膝关节软骨组织影响的比较结果图。
具体实施方式
以下将结合附图所示的具体实施方式对本发明进行详细描述。但这些实施方式并不限制本发明,本领域的普通技术人员根据这些实施方式所做出的结构、方法、或功能上的变换均包含在本发明的保护范围内。
现在将参考附图更全面地描述示例实施方式。然而,示例实施方式能够以多种形式实施,且不应被理解为限于在此阐述的实施方式;相反,提供这些实施方式使得本发明将全面和完整,并将示例实施方式的构思全面地传达给本领域的技术人员。
定义
本文所称的术语“有效剂量”是指能持续减轻关节炎的症状和/或征象(诸如疼痛及关节僵硬)的剂量。
在本案所称的术语“治疗”是指一种能减轻或延缓关节炎的一种或多种影响、或症状的方法。治疗也是指一种能减轻基础病因而非仅症状的方法。
益生菌的培养
本发明的益生菌新菌株命名为TCI633,属嗜热链球菌(Streptococcusthermophilus),是从人类健康的母乳中分离。该益生菌TCI633于2013年12 月2日保藏于布达佩斯条约承认的生物材料样品国际保藏单位“德国微生物保藏中心(Deutsche Sammlungvon Mikroorganismen und Zellkulturen GmbH, DSMZ)”,地址:Leibniz InstituteDSMZ-German Collection of Microorganisms and Cell cultures Inhoffenstraβe 7B38124Braunschweig Germany(德国不伦瑞克市德国莱布尼茨DSMZ微生物和细胞培养物保藏中心,38124),保藏号为DSM 28121。
关于益生菌TCI633的培养,可将保存于甘油的菌株,接种在MRS培养基(1%,v/v)上培养16至24小时,之后将菌株转移至含有20g/L至60g/L 葡萄糖、5g/L至30g/L蔗糖、10g/L至20g/L酵母菌萃取物5g/L至10g/L 蛋白胨(peptone)、2.5g/L至8g/L磷酸氢二钾(K2HPO4)、1g/L至2g/L氯化钠(NaCL)及0.5g/L至1.2g/L七水硫酸镁(MgSO4 7H2O)的培养基中,再于37℃下培养48小时后备用。
动物模式的建立
本发明实施例中,实验所用的雄性大鼠(Wistar rat,8周龄)系购自乐斯科生物科技股份有限公司(Taipei,Taiwan),饲养于中山大学海洋生物科技暨资源学海洋药物前临床测试核心实验室。其光周期控制在12小时光照 12小时黑暗周期,而动物房的湿度(50~55%)与温度(24±1℃)皆受空调系统控制,先经过约10天的训养期。进行实验时,大鼠体重约300±10公克重(9-10周龄)。所有模式建立手术与灌食动作均在2.5%异氟烷(isoflurane, Catalog No.08547,Panion&BF Biotech Inc.,Taoyuan,Taiwan)麻醉下进行。所有动物实验的操作和使用均遵照美国生理学协会动物照护和使用指导原则(GuidingPrinciples in the Care and Use of Animals of the American Physiology Society)并同时在中国台湾中山大学动物照护及使用委员会(Institutional animal care anduse committee of National Sun Yat-sen university)的允许下进行。
动物模式中,大鼠前十字韧带切除骨关节炎模式(anterior cruciate ligamenttransected,以下称ACLT)是仿照Stoop等人于2001所发表的论文与Yang等人于2014所发表的论文中方法进行(Stoop et al.,2001;Yang et al., 2014)。在进行动物行为基础值(baseline)测量后,大鼠进行麻醉后将双膝部位剃毛,并以酒精消毒处理后再从内侧髌骨旁切入,打开膝部关节囊后,将髌骨向外脱臼,使膝部置于完全屈曲状态,得以露出前十字韧带。利用尖刀片将前十字韧带中段切除,并以前拖曳测验(anterior draw test)来判断是否切除足够,确认完全切除后,进行手术缝合;而控制组则是只打开膝部的关节囊,不切除前十字韧带(Stoop,et al.,2001)。手术后注射cefazolin(20 mg/kg)以防伤口感染,并将大鼠放回鼠笼使其自由活动八周。其中每周进行动物行为测试,以确认疼痛与发炎肿胀行为正常组有显著差异,再施以益生菌治疗。
动物实验分为以下五组:
a.控制组(control),为一般正常大鼠,其膝关节被打开,但未诱发关节炎;
b.前十字韧带切除组(ACLT):于手术诱发后第8至20周,每天口服给予赋形剂;
c.ACLT+TCI633(5x1011CFU/公斤/天)组:于手术诱发后第8至20周,每天口服给予TCI633(5x1011CFU/公斤/天);
d.ACLT+TCI633(5x1010CFU/公斤/天)组:于手术诱发后第8至20 周,每天口服给予TCI633(5x1010CFU/公斤/天);以及
e.ACLT+(TCI633 5x109CFU/公斤/天)组:于手术诱发后第8至20周,每天口服给予TCI633(5x109CFU/公斤/天)。
医药组成物的制备
准备益生菌TCI633及赋形剂(由台湾第一新药股份有限公司提供)。其中,控制组仅口服喂食赋形剂加水,作为空白溶剂组别,而益生菌TCI633 三种剂量组别(前述第c-e组),皆利用TCI633加水进行口服喂食。
益生菌也可以和药学上可接受的载剂混合,以制备成溶液、悬浮液、乳剂、粉末、锭剂、丸剂、糖浆、口含锭、片剂、口嚼胶或胶囊的剂型。
数据分析
以下所有实施例的实验所得数据的呈现上皆以mean±SEM程序表示。两组间数据比较,依照t检定方法进行统计分析。多组间数据比较,则利用单因子变异数分析(one-wayanalysis of variance,ANOVA)进行数据统计分析其各组间的差异性,同时根据Duncan'sMethod进行多重组间差异性比较。当P值小于0.05时,表示有显著差异,进行统计分析。
实施例1后脚负重分布改变(weight bearing)
前十字韧带切除(ACLT)后导致退化关节的脚和对侧控制组的脚的负重分布改变代表了骨关节炎的疼痛指标之一(Bove et al,2006)。双足平衡测痛仪(Dual ChannelWeight Averager,Singa Technology Corporation,Taiwan)可用来测试大白鼠左右后脚施力的重量。将大白鼠置于一有坡度的管道内,左右脚站立于可分别测量左右脚施重的分离量秤上,待大鼠姿势稳定及静置稳定后,按下仪器测量键,纪录三秒后的数据,结果以正常肢(左脚)减去受伤肢(右脚)的两脚负重差值计算(Fernihough,et al.,2004),在动物行为基础值测量与前十字韧带切除手术后第1到第24周,每周测定一次,其结果如图1所示。
由图1可知,在ACLT诱发后腿负重分布改变方面,ACLT组与控制组相比较,于第1周至第24周后脚负重分布改变有显著上升的差异。在诱发关节炎模式后,ACLT+TCI633(5x1011CFU/公斤/天)组与ACLT组比较上,于第9周至第24周其后脚负重分布改变有显著下降的差异。在ACLT+TCI633 (5x 1010CFU/公斤/天)组与ACLT组比较上,于第10周至第24周其后脚负重分布改变有显著下降的差异。在ACLT+TCI633(5x 109CFU/公斤/天) 组与ACLT组比较上,于第13周至第19周与第22周其后脚负重分布改变有显著下降的差异。其中于第9周至第24周时,后脚负重分布改变在 ACLT+TCI633(5x 1010CFU/公斤/天)和ACLT+TCI633(5x1011CFU/公斤 /天)组与ACLT+TCI633(5x 109CFU/公斤/天)比较下,越有显著下降的差异。因此,综合以上结果可确认,益生菌TCI633对于ACLT诱发后脚负重分布改变有显著改善的效果,同时呈现剂量依赖效应。而在停止喂食TCI633 后,如表1所示,在ACLT+TCI633各组对后脚负重分布改变行为止痛效果百分比(%)有趋向减缓的趋势。
表1
实施例2温度感觉异常测试(thermal hyperalgesia)
温度感觉异常测试是仿照Hargreaves等人于1988年所建立的方式以低能量的放射性热光源照射动物脚掌量取其退缩时间。热觉过敏行为是以热足板法(plantar test)进行分析。热源刺激仪器(Plantar Stimulator Analgesia Meter) (Life IITC Model 390,Woodland Hills,CA,USA.)热源设定强度为25,为了避免大白鼠脚掌组织因长时间受到热源伤害,故设定照射30秒为截止时间点 (Hargreaves et al.,1988)。将大鼠置于压克力玻璃平台上,利用热源刺激大白鼠后脚掌中间位置,观察并记录其脚掌何时举离台面,在动物行为基础值测量与前十字韧带切除手术后第1到第24周,每周测定一次,其结果如图2所示。
由图2可知,ACLT组与控制组(control,正常组)相比较,第0周至第24周后无显著改变温度感觉异常的差异。在诱发关节炎模式后, ACLT+TCI633三组与ACLT组比较上亦无显著改变温度感觉异常的差异。因此,总合以上结果可以确认,益生菌TCI633对于手术后诱发骨关节炎上无显著改变温度感觉异常的差异,其数值呈现与控制组相似。而在停止喂食益生菌TCI633后亦无显著的影响。
实施例3机械性触觉过敏(mechanical allodynia)
依据Chaplan等人于1994年所发表论文中的方法,评估益生菌TCI633 对于ACLT诱发机械性触觉过敏的影响。将大鼠置于铁丝网上的褐色压克力盒内竟置15分中使大鼠适应。以凡芙瑞丝(Von Frey filaments,Stoelting,Wood Dale,IL,USA)由下往上对大鼠后脚掌施垂直加压力,从1g开始逐渐增加压力克数直到大鼠产生缩脚行为,并纪录其压力数值作为缩足阈值。每次施加压力最多持续5秒,并重复测量3次以确保数据准确性,且每次刺激间隔15 秒以上(Chaplan et al.,1994),其结果如图3所示。
由图3可知,ACLT组与控制组(control,正常组)相比较,于第6周至第24周其缩足反应阈值有显著下降的差异。在诱发关节炎模式后,在 ACLT+TCI633(5x 1011CFU/公斤/天)组与ACLT组比较上,于第9周至第 24周其缩足反应阈值有显著上升的差异。在ACLT+TCI633(5x 1010CFU/ 公斤/天)组与ACLT组比较上,于第9周至第23周其缩足反应阈值有显著上升的差异。在ACLT+TCI633(5x 109CFU/公斤/天)组与ACLT组比较上,于第13周至第22周其缩足反应阈值有显著上升的差异。其中于第9周至第 22周时,缩足反应阈值在ACLT+TCI633(5x 1010CFU/公斤/天)和 ACLT+TCI633(5x 1011CFU/公斤/天)组与ACLT+TCI633(5x109CFU/公斤/天)比较下,越有显著下降的作用。因此,总合以上结果可以确认,益生菌TCI633对于ACLT诱发机械性触觉过敏有显著改善的效果,同时呈现剂量依赖效应。而在停止喂食TCI633(第21周至第24周)后,如表2所示,在ACLT+TCI633各组对机械性触觉过敏行为止痛效果百分比(%)有趋向减缓的趋势。
表2
实施例4膝关节宽度肿胀的测量(knee swelling)
在前十字韧带切除手术前(basline)和手术后第1到第24周的膝部关节宽度变化每周测定一次,以评估膝部发炎情形。将大鼠以2.5%isofurane麻醉后,以游标尺(calipers,AA847R,Aesculap,AG&CO,KG,German)测量大鼠左右膝部宽度,观测其左右脚膝关节宽度,并详加纪录改变情形(Yang et al.,2014)。结果以受伤肢(右脚)减去正常肢(左脚)的两脚膝关节宽度差值作为计算,如图4所示。
由图4可知,ACLT组与控制组(control)相比较,于第1周至第24周在左右膝关节宽度差异有显著上升的差异。在诱发关节炎模式后, ACLT+TCI633(5x 1011CFU/公斤/天)组与ACLT组比较上,于第9周至第 24周其左右膝关节宽度差异有显著下降的差异。在ACLT+TCI633(5x 1010 CFU/公斤/天)组与ACLT组比较上,于第8周至第11周和第14周到第22 周其左右膝关节宽度差异有显著下降的差异。在ACLT+TCI633(5x 109CFU/ 公斤/天)组与ACLT组比较上,于第13周至第22周其左右膝关节宽度差异有显著下降的差异。其中于第8周至第22周时,左右膝关节宽度差异在 ACLT+TCI633(5x 1010CFU/公斤/天)和ACLT+TCI633(5x1011CFU/公斤 /天)组与ACLT+TCI633(5x 109CFU/公斤/天)比较下,越有显著下降的差异。因此,总合以上结果可以确认,益生菌TCI633对于ACLT诱发左右膝关节宽度差异有显著改善的效果,同时呈现剂量依赖效应。而在停止喂食 TCI633后,如表3所示,在ACLT+TCI633各组对膝关节肿胀的抑制效果百分比(%)有趋向减缓的趋势。
表3
实施例5体重的测量
在前十字韧带切除手术前(basline)和手术后第1到第24周的每周测定一次大鼠体重,其结果如图5所示。
由图5可知,ACLT组与控制组(control,正常组)相比较,于第0周至第24周的体重变化无显著影响,且呈现随时间增加体重的趋势。在诱发关节炎模式后,ACLT+TCI633(5x1011CFU/公斤/天)组与ACLT组比较上,于第0周至第24周的体重变化无显著影响,且亦呈现随时间增加体重的趋势。在ACLT+TCI633(5x 1010CFU/公斤/天)组与ACLT组比较上,于第8周与第11周至第24周其体重增加有显著较少的趋势。在ACLT+TCI633(5x 109 CFU/公斤/天)组与ACLT组比较上,于第8周与第10周至第24周其体重增加有显著较少的趋势。因此,总合以上结果可以确认,益生菌TCI633对于ACLT模式中体重变化中,在ACLT+TCI633(5x 1010和5x 109CFU/公斤 /天)组对于体重增加有显著减缓的作用。
实施例6病理切片观察
样品收集固定
于前述完成动物行为测试后进行人道牺牲。利用2.5%异氟烷深度麻醉后借由手术器械打开大鼠胸部后,以灌流针头由心脏底部插至左大动脉固定针头后,将存放在4℃每只大白鼠600ml的4%磷酸盐缓冲溶液(phosphate buffered saline,PBS)(137mM NaCl,2.68mM KCl,10mM Na2HPO4,1.76mM KH2PO4,Ph=7.2)含有肝素(heparin)(0.2U/ml)缓缓注入大白鼠体内,并透过剪破的右心房流出,以达到全身血液置换的流成。随后以4℃的4%三聚甲醛(paraformaldehyde)灌流,透过三聚甲醛固定大白鼠身体组织,最后在以手术器械取下大白鼠膝盖组织,放置于10%中性福马林固定液中,并存放在4℃环境下固定3-4天,其间每两天更换中性福马林确以保固定效果。而后将已固定后的组织更换放置脱钙液(100g乙二胺四醋酸二钠, E.D.T.A..2Na/1000ml PBS)中,置于在室温下,并每两天更换一次脱钙液,以达到脱钙的效果,维持2-3周脱钙时间。将已固定、脱钙的组织放置包埋盒中,以组织自动脱水处理机(Tissue-Tek,Sakura Finetek Japan Co.,Ltd,Japan) 进行依序为35%酒精、75%酒精、85%酒精、85%酒精、95%酒精、95%酒精、100%酒精、l00%酒精、90%xyline/酒精、100%xyline、软蜡、硬蜡共18个小时的程序,行组织脱水与渗蜡的步骤,再应用石蜡组织包埋机(CSA Embedding Center EC780-1;EC780-2)将组织进行包埋成蜡块后,以石蜡切片机(Microm,HM340E,USA)进行厚度为1μm组织切片后,进以利用紫苏-伊红(hematoxylin-eosin staining)和番红-快速绿(Safranin O/Fast green staining)染色方法进行组织切片染色。将完成样本玻片置于光学显微镜(DM 6000,Leica Inc,Germany),利用显微镜数位影像输出系统(idea SPOT, Diagncstic instruments Inc.U.S.A.)拍摄和纪录切片结果并针对切片进行分析,其结果如图6~8所示。
评估益生菌TCI633对于膝关节滑膜组织发炎的影响
如图6所示,在大鼠接受前十字韧带切处手术后,与控制组比较上,于第24周可明显观察到在滑膜组织中发炎性血球浸润、组织增生和组织肥大的现象。在治疗组部份,在ACLT+TCI633(5x 109CFU/公斤/天)也可观察到相似于ACLT组的现象。在ACLT+TCI633(5x1011CFU/公斤/天)和 ACLT+TCI633(5x 1010CFU/公斤/天)组中,其可观察较轻微发炎性血球浸润,同时有效改善前十字韧带切处手术造成的组织增生和组织肥大的现象。因此,总合以上结果可以确认,益生菌TCI633对于ACLT模式中,在 ACLT+TCI633(5x 1011CFU/公斤/天)和ACLT+TCI633(5x 1010CFU/公斤 /天)组对于滑膜组织发炎有显著减缓的作用。
评估益生菌TCI633对于膝关节软骨组织的影响
利用紫苏-伊红染色方式分析如图7所示,在大鼠接受前十字韧带切处手术后,与控制组比较上,于第24周可明显观察到软骨厚度与表层软骨细胞破损的现象。在治疗组部份,在ACLT+TCI633三个组别与ACLT组比较上,均可观察到骨头组织表层呈现不规则的现象。在ACLT+TCI633(5x 1010CFU/ 公斤/天)组则可观察到软骨表面些许不平整,而ACLT+TCI633(5x 1011CFU/ 公斤/天)组可观察到与正常组较相近的软骨组织。因此,总合以上结果可以确认,益生菌TCI633对于ACLT模式中,在ACLT+TCI633(5x 1011CFU/ 公斤/天)和ACLT+TCI633(5x 1010CFU/公斤/天)组对骨头组织有显著减缓损坏的作用。
评估益生菌TCI633对于膝关节软骨组织的影响
其结果如图8所示,在大鼠接受前十字韧带切处手术后,与正常组比较上,于第24周可明显观察到到软骨组织表面破损、软骨细胞减少与软骨层染色讯号(红色)强度下降的情形。在ACLT+TCI633三个组别与ACLT组比较上,均可观察到骨头组织有较轻微的软骨组织表面不规则和软骨层染色讯号强度下降的情形。
另一方面,由图7及8结果所示,可知位于软骨组织中的软骨细胞数量在有使用TCI633的组别中明显高于ACLT的软骨细胞数量,因此益生菌 TCI633具有增加/保护软骨细胞的功效。
此外,利用国际骨关节炎研究学会评估分数系统(OARSI score)评估益生菌TCI633对于膝关节软骨组织的影响,其结果如图9所示。评分时,同时采用OARSI的分级和骨关节炎恢复的阶段进行半定量评估,其中包含六个级分(six histological grades)和四个阶段(four histological stages)。总分为不同级分乘上不同阶段,因此总分范围由1分(normal articular cartilage)至 24分(no repair)(Pritzker et al.,2006)。由图9可知,大鼠接受前十字韧带切除手术在第24周后,其ACLT组与控制组相比较,分数有显著增加的情形。在给予益生菌TCI633的治疗组与ACLT组相比较下,其评估分数有显著下降的情形。同时在给予ACLT+TCI633(5x 1011CFU/公斤/天)和 ACLT+TCI633(5x 1010CFU/公斤/天)组其评估分数与ACLT+TCI633(5x 109 CFU/公斤/天)组比较下,有显著下降的情形。因此,总合以上结果可以确认,益生菌TCI633对于ACLT模式中,在ACLT+TCI633(5x 1011CFU/公斤/天) 和ACLT+TCI633(5x 1010CFU/公斤/天)组对膝关节软骨组织有显著减缓损坏的作用。
综合以上结果,口服益生菌TCI633三种剂量(5x1011,5x1010,5x109CFU/ 公斤/天),对于骨关节炎的治疗效果上,与ACLT组别相比较,对于机械性触觉过敏、后脚负重分布改变和膝关节肿胀上均有显著的治疗的效果。同时利用组织学和国际骨关节炎研究学会评估分数系统进行分析上,益生菌 TCI633对于骨关节炎可有效减缓关节组织被破坏的作用。
应当理解,虽然本说明书按照实施方式加以描述,但并非每个实施方式仅包含一个独立的技术方案,说明书的这种叙述方式仅仅是为清楚起见,本领域技术人员应当将说明书作为一个整体,各实施方式中的技术方案也可以经适当组合,形成本领域技术人员可以理解的其他实施方式。
上文所列出的一系列的详细说明仅仅是针对本发明的可行性实施方式的具体说明,它们并非用以限制本发明的保护范围,凡未脱离本发明技艺精神所作的等效实施方式或变更均应包含在本发明的保护范围之内。
Claims (5)
1.一种益生菌TCI633,该益生菌TCI633保藏于布达佩斯条约承认的生物材料样品国际保藏单位“德国微生物保藏中心(Deutsche Sammlung von Mikroorganismen undZellkulturen GmbH,DSMZ)”,保藏号为DSM 28121。
2.一种用于治疗关节炎的医药组合物,其特征在于:所述医药组合物包含如权利要求1所述的益生菌TCI633。
3.一种如权利要求2所述的医药组合物,其特征在于:所述医药组合物包含有效剂量的如权利要求1所述的益生菌TCI633和药学上可以接受的载体。
4.如权利要求1所述的益生菌TCI633在用于制备治疗关节炎或减缓关节炎疼痛的医药方面的用途。
5.如权利要求1所述的益生菌TCI633在用于制备增加软骨细胞或保护软骨细胞的医药方面的用途。
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