CN101309678A - 用于与软骨损伤有关的应用的药物 - Google Patents
用于与软骨损伤有关的应用的药物 Download PDFInfo
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- CN101309678A CN101309678A CNA2006800426722A CN200680042672A CN101309678A CN 101309678 A CN101309678 A CN 101309678A CN A2006800426722 A CNA2006800426722 A CN A2006800426722A CN 200680042672 A CN200680042672 A CN 200680042672A CN 101309678 A CN101309678 A CN 101309678A
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Abstract
用于治疗医学关节疾病如关节病、类风湿性关节炎以及软骨损伤的物质的应用。该应用包括α-酮戊二酸、谷氨酰胺或谷氨酸、以及所述物质的盐、酰胺、二肽或三肽的应用。
Description
技术领域
本发明涉及医药组合物以及所述组合物在治疗、缓解和预防与软骨损伤相关的疾病和与它相关的疼痛、或者预防关节炎(artrose)和类风湿性关节炎和与它相关的疼痛中的应用。
背景技术
在工业世界中三个成年人中多达一个可能目前患有慢性关节症状或关节炎。最常见的症状,持续的关节疼痛,可以表现为髋痛、膝痛、手痛或腕痛、以及在身体的其它区域中的关节疼痛。所述症状造成痛苦并在人们被迫停止工作或削减工作时间时造成经济损失。医疗护理也花费不菲。显然,需要用于缓解或治疗关节症状和关节炎的经济有效的解决方案。
发明内容
本发明的具体实施方式包括包含选自由下列物质组成的组中的至少一个成员的物质在制备用于治疗或预防软骨的炎性或非炎性损伤的疾病和与上述相关的疼痛的药物制剂中的应用:α-酮戊二酸、谷氨酰胺、谷氨酸和这些酸的药用盐、α-酮戊二酸和氨基酸或二肽或三肽的酰胺、谷氨酰胺和其它氨基酸的二肽、谷氨酰胺和其它氨基酸的三肽、谷氨酸(glutamine acid)和其它氨基酸的二肽、谷氨酸和其它氨基酸的三肽和所述二肽和三肽的药用盐、α-酮戊二酸或其药用盐与至少一种氨基酸的药物学上可接受的物理状态混合物(physical mixture)。
另外的具体实施方式包括如上所述在用于治疗或预防artrose和类风湿性关节炎以及与上述相关的疼痛中的应用。
另外的具体实施方式包括如上所述在用于治疗或预防在涉及重量减轻和/或受损的营养、或胃切除术、部分(局部)胃切除术或胃囊带术(胃束带,gastric banding)的情况下的软骨损伤中的应用。
另外的具体实施方式包括如上所述在用于治疗或预防在涉及营养不良的情况下的软骨损伤中的应用。
另外的具体实施方式包括如上所述用于在上述条件下减轻与软骨损伤相关的疼痛中的应用。
另外的具体实施方式包括如上所述在用于治疗或预防与胃切除术相关的骨质疏松症中的应用。
附图说明
通过下面的借助优选的具体实施方式、实施例研究和附图的描述将进一步解释本发明,附图中:
图1是描述了饮食α-酮戊二酸盐和胃切除术对大鼠体重的影响的图;
图2示出了实验大鼠的颅骨(颅盖)的上部的四张透视照片;
图3是示出了实验大鼠的颅盖的透视照片上发现的陷窝面积(区域,范围,area)的图。
具体实施方式
因此,根据本发明的一个方面,提供了选自由下列物质组成的组中的至少一个成员在制备用于治疗或预防关节炎(artrose)、类风湿性关节炎和软骨破坏的疾病和与上述疾病相关的疼痛的药物制剂中的新应用,所述物质为:α-酮戊二酸、谷氨酰胺、谷氨酸和这些酸的药用盐、α-酮戊二酸和氨基酸或者二肽或三肽的酰胺、谷氨酰胺和其它氨基酸的二肽、谷氨酰胺和其它氨基酸的三肽、谷氨酸和其它氨基酸的二肽、谷氨酸和其它氨基酸的三肽和所述二肽和三肽的药用盐、α-酮戊二酸或其药用盐与至少一种氨基酸的药物学上可接受的物理状态混合物。
根据本发明优选的具体实施方式,使用α-酮戊二酸或其碱金属或碱土金属盐或者它们的组合。优选地,使用α-酮戊二酸钠。
根据本发明的另一方面,提供了一种用于治疗或预防哺乳动物(包括人)中选自包括artrose的组的至少一个成员的增加的疼痛的疾病的方法,该方法包括给予需要这样的治疗或预防的受治疗者有效疼痛量的选自由下列物质组成的组中的至少一种成员,所述物质为:α-酮戊二酸、谷氨酰胺、谷氨酸和这些酸的药用盐、α-酮戊二酸和氨基酸或者二肽或三肽的酰胺、谷氨酰胺和其它氨基酸的二肽、谷氨酰胺和其它氨基酸的三肽、谷氨酸和其它氨基酸的二肽、谷氨酸和其它氨基酸的三肽和所述二肽和三肽的药用盐、α-酮戊二酸或其药用盐与至少一种氨基酸的药物学上可接受的物理状态混合物。
根据这些方面的优选具体实施方式,给予α-酮戊二酸或其碱金属或碱土金属盐或者它们的组合。最优选地,给予α-酮戊二酸钠。
根据本发明所用的活性成分(有效成分,active principle)或组分(成分)的药物制剂可以给予脊椎动物,包括哺乳动物和鸟类,如啮齿动物,如小鼠、大鼠、豚鼠、或兔;鸟,如火鸡、母鸡或小鸡和其它雏鸡以及自由行走的动物;牛、马、猪或小猪以及其它农场动物、狗、猫和其它宠物,尤其是人。
可以以不同的方式进行给药,取决于要治疗的脊椎动物是什么种类、需要所述方法的脊椎动物的疾病、以及要治疗的特异性适应症(specific indication)。
在一个具体实施方式中,给药作为食物或饲料添加剂进行,如饮食添加剂和/或固体食物形式的成分和/或饮料。另外的具体实施方式可以在悬浮液或溶液中,如下面进一步描述的饮料。此外,形式可以为胶囊或片剂,如可咀嚼或可溶的,如泡腾片剂,以及粉剂和本领域技术人员已知的其它干燥形式,如丸剂,如小丸、和颗粒。
给药可以作为肠胃外、直肠或经口食物或饲料添加剂,如上所揭示的。肠道外载体包括氯化钠溶液、林格(Ringer’s)右旋糖、右旋糖和氯化钠、乳酸林格(Ringer’s)或固定油(不挥发性油)。
食物和饲料添加剂还可以被乳化。一种或多种活性治疗成分随后可以与赋形剂混合,赋形剂是药物学上可接受的并且与活性成分是相容的。合适的赋形剂是,例如,水、盐、右旋糖、甘油、乙醇等以及它们的组合。此外,如果需要,该组合物可以包含少量的辅助物质,如湿润剂或乳化剂、pH、缓冲剂,其提高了活性成分的效能。
可以供应不同形式的亲本(parental)食物或饲料添加剂,如固体食物、液体或冻干或以其他方式干燥的制剂。它可以包括各种缓冲剂(如,Tris-HCl、乙酸盐、磷酸盐)、pH和离子强度的稀释剂、添加剂如白蛋白或凝胶(明胶)以防止吸收到表面、去垢剂(如吐温20、吐温80、Pluronic F68(聚丙二醇与环氧乙烷的加聚物F68)、胆汁酸盐)、增溶剂(如甘油、聚乙二醇)、抗氧化剂(如抗坏血酸、焦亚硫酸钠)、防腐剂(如硫柳汞(工汞硫代水杨酸钠,Thimerosal)、苯甲醇、对羟基苯甲酸酯类(parabens))、膨胀物质(bulkingsubstance)或张性改性剂(如乳糖、甘露醇)、聚合物如聚乙二醇到组合物的共价连接、与金属离子络合、或物质进入或到达聚合化合物(如聚乳酸、聚乙醇酸、水凝胶等)的微粒制剂的并入、或物质到达脂质体、微乳、胶束、单层或多层泡囊、红细胞影(erythrocyteghost)、或球形体。
在一个具体实施方式中,根据本发明的方法的任何一个中,食物或饲料添加剂以饮料或它们的干燥组合物的形式给予。
饮料包括有效量的活性成分或其成分,以及营养上可接受的水溶性载体,如矿物、维生素、碳水化合物、脂肪和蛋白质。如果饮料以干燥形式提供,则所有这些组分以干燥形式供应。所提供的准备用于消费的饮料还包括水。最终的饮料溶液还可以具有受控的张性(tonicity)和酸度,如根据上面段落中的一般建议作为缓冲溶液。
pH优选在约2-5的范围内,尤其是约2-4,以防止细菌和真菌生长。也可以使用无菌饮料,其中pH为约6-8。
饮料可以单独供应或与一种或多种治疗有效的组合物结合供应。
根据另外的具体实施方式,作为用于口服和直肠应用的药物的药物制剂可以为片剂、锭剂、胶囊、粉剂、水或油状混悬剂、糖浆、酏剂、水溶液等的形式,包括活性成分或多种成分,混合有药用载体和/或添加剂,如稀释剂、防腐剂、增溶剂、乳化剂、佐剂和/或载体,在本发明披露的方法和应用中是有用的。
此外,本文所用的“药用载体”是本领域技术人员熟知的,并且可以包括,但不限于,0.01-0.05M磷酸盐缓冲液或0.8%盐水。此外,这样的药用载体可以为含水或非水溶液、悬浮液、以及乳浊液。非水溶剂的实例是丙二醇、聚乙二醇、植物油如橄榄油、以及可注射的有机酯如油酸乙酯。含水载体包括水、醇/水溶液、乳浊液或悬浮液、包括盐水和缓冲介质。肠胃外载体包括氯化钠溶液、林格右旋糖、右旋糖和氯化钠、乳酸林格或固定油。防腐剂和其它添加剂也可以存在,如,例如,抗菌剂、抗氧化剂、螯合剂、惰性气体等。
形成具有α-酮戊二酸的酰胺或具有谷氨酰胺或谷氨酸的二肽或具有谷氨酰胺和/或谷氨酸的三肽的部分的氨基酸可以为自然界中作为肽中成分存在的任何氨基酸。同样的应用于α-酮戊二酸或其盐与至少一个氨基酸的药学上可接受的物理状态混合物。优选地,所述氨基酸或酸选自由精氨酸、鸟氨酸、亮氨酸、异亮氨酸和赖氨酸组成的组。
所述氨基酸优选以它们的L-构型使用。
α-酮戊二酸与氨基酸或二肽或三肽的酰胺的实例包括,但不限于,α-酮戊二酸与选自由下列物质组成的组中的氨基酸的酰胺:谷氨酰胺、谷氨酸、精氨酸、鸟氨酸、赖氨酸、脯氨酸、异亮氨酸和亮氨酸以及α-酮戊二酸与二肽的酰胺,其中所述二肽为谷氨酰胺与谷氨酸、精氨酸、鸟氨酸、赖氨酸、脯氨酸、异亮氨酸和亮氨酸的任何一个的二肽,以及谷氨酸与精氨酸、鸟氨酸、赖氨酸、脯氨酸、异亮氨酸和亮氨酸的任何一个的二肽。
谷氨酰胺和谷氨酸与其它氨基酸的二肽和肽的实例包括上述那些,与α-酮戊二酸与二肽或三肽的酰胺有关。
α-酮戊二酸或其盐与至少一种氨基酸的物理状态混合物的实例包括,但不限于,选自由α-酮戊二酸和其钠、钾、钙和镁盐组成的组中的至少一个成员与谷氨酰胺、谷氨酸、精氨酸、鸟氨酸、亮氨酸、异亮氨酸、赖氨酸和脯氨酸以及所述氨基酸的任何组合中的任何一个的物理状态混合物。
α-酮戊二酸或其盐与所述物理状态混合物的氨基酸或多个氨基酸的摩尔比一般在1∶0.01至1∶2的限度内,优选为1∶0.1至1∶1.5,并且最优选为1∶0.2至1∶1.0。
待给予的剂量将根据待所用的活性成分或成分、待治疗的疾病、待治疗的患者的年龄、性别、体重等而变化,但一般在1至1000mg/kg体重/天的范围内,或从10至400mg/kg体重/天,优选从10至100mg/kg体重/天。
现在,将通过实施例的方式进一步示出本发明,该实施例不应被视为限制本发明的范围。
实施例
背景:手术去除胃(胃切除术,Gx)导致动物和人类中骨质疏松症。胃切除术主要影响小梁骨的结构。不清楚Gx是否也不利地影响骺板。饮食α-酮戊二酸(AKG)是羟脯氨酸(羟基脯氨酸)的前体-骨和软骨前胶原中最丰富的氨基酸。研究的目的是突出AKG对胃切除术依赖性骨/软骨损失的作用。
方法:利用40只雌性Sprague-Dawley大鼠。将20只大鼠胃切除并分成2组:Gx+AKG和Gx+安慰剂。对另外20只大鼠进行假手术(sham-operate)并分成另外的2组:Sham(假手术)+AKG和Sham(假手术)+安慰剂。在8周后,处死动物,收集颅盖、股骨和胫骨。估计右股骨和胫骨中的骨质量密度(BMD)和骨矿物浓度(BMC),并估计来自左骨的组织形态计量学(组织形态测量学,histomorphometry)。还进行了颅盖的透视法测量。
结果:饮食α-酮戊二酸揭示了对胃切除的大鼠的颅盖骨损失的强保护作用。AKG表现了对胃切除大鼠的骺板细胞、小梁骨体积和小梁形状的强抗破坏作用。
结论:AKG最小化大鼠胃切除术后发展的骨和软骨破坏。
手术去除胃导致人类、大鼠和其它实验动物中骨质减少和关节炎。胃切除术与人类中的骨质减少有关。胃功能障碍也有助于老年人中骨质减少的发展。因此,大多数研究涉及在胃切除后对患者的骨疾病处理。
胃切除术主要影响小梁骨、有时也影响皮质骨(骨皮质)、引起颅盖骨破坏的显著作用。胃切除术后皮质和小梁骨质量的减少已经在两种人类性别中报道。在胃切除术16周后胫骨和股骨中的小梁骨体积减少60%。骨损失增加了胃切除术患者中髋、椎骨和其它部位的骨折风险,其是当今严重的问题。
假定胃切除患者中的骨损失不是饮食不足(如钙)或缺乏胃酸或维生素D的结果。胃切除术后引发的骨质疏松症的机制仍是未知的。然而,假定,骨质疏松症的主要原因是骨胶原在被破骨细胞大量破坏后不能重新合成。骨前胶原的主要成分是脯氨酸-在胃肠道中经由谷氨酸盐(谷氨酸)并经由脯氨酸从AKG合成的氨基酸,其又在AKG、维生素C和Fe2+的存在下在骨前胶原中转化为羟(基)脯氨酸。最近显示AKG可以有效防止卵巢切除的大鼠和火鸡中切除神经的骨中的骨损失。考虑到上述全部,所述研究的主要目的是研究饮食AKG是否可以防止胃切除的大鼠中的骨和软骨损失。
动物和手术过程
将40只雌性Sprague-Dawley大鼠,10周大(220-230g),容纳在笼中(每个笼中2只大鼠),并给予标准大鼠食物颗粒的饮食(Lactamin,Vadstena,Sweden)和随意溶解在水中的载体或AKG(表1)。该研究持续8周。对大鼠每周进行称重。
大鼠每天饮水25至50毫升。原则上,可以认为大鼠饮水在体重的10至20%之间。
AKG组大鼠每天饮用约25ml的AKG饮品(drink)。在25ml的饮品中,存在0.36g的AKG,其给了约1至1.4g的AKG/kg大鼠体重/天。安慰剂(对照)组大鼠每天饮用约50ml的安慰剂饮品。
手术
20只大鼠被胃切除并分成2组:Gx+AKG和Gx+安慰剂(每组10只大鼠)。胃的腺部分(即,产酸部分、胃底和幽门窦)被切除,之后非腺体部分(前胃)与十二指肠首尾相连的连接。20只大鼠被假手术并分成2组:Sham(假手术)+AKG和Sham(假手术)+安慰剂(每组10只大鼠)。假手术涉及中线剖腹术、胃处理和切口闭合。通过皮下注射(50mg/kg;Parke-Davis,MorrisPlains,NJ,U.S.A)和(40mg/kg;Janssen-Cilag Pharma,Vienna,Austria)实现麻醉。通过皮下注射(0.18mg/kg;Schering-Plough,Kenilworth,NJ,U.S.A)实现镇痛。处理开始于用载体处理Sham(假手术)+安慰剂和Gx+安慰剂组,同时用AKG处理Sham(假手术)+AKG和Gx+AKG。
通过肌肉内途径每隔一周(开始于术后第一周)给Gx大鼠注射0.4mg/kg的维生素B12(1mg/ml,Dumex,Copenhagen,Denmark)以补充内因子的损失,其对于氢氧化铁聚麦芽糖复合体(50mgFe3+/ml,Vifor(International)Inc.,St.Gallen/Switzerland)(作为用于由于胃酸损失的预期的铁的不良吸收的补充)的维生素B12和20mgFe3+/kg的吸收是重要的。这些补充对于没有经历手术过程的大鼠的体重发展没有影响。
在实验过程中8只动物死亡。动物的最终数量(n)在Sham(假手术)+安慰剂中为7只,在Sham(假手术)+AKG中为10只,在Gx+安慰剂中为8只,以及在Gx+AKG组中为7只。
在如上所述麻醉下通过从腹主动脉放血处死全部大鼠。
研究通过了瑞典兰德当地动物福利委员会(Animal WelfareCommittee,Lund,Sweden)的批准。
组织收集和分析
从每个大鼠切下颅盖并通过仔细去除骨膜清除软组织。通过用浸透盐水的纱布覆盖每个颅盖避免干燥,并将它们存储在+4℃的密封容器中直到检查。每个颅盖被置于光源顶端的玻璃板上(商业荧光管),发出恒定强度的光。通过利用连接于操作显微镜(放大率×16)的相机,为所获得的透视图像照相。将图像进行由ImageJv.1.33a实施的组织形态计量学(histomor phometric)计算机分析。估计骨损失(作为观察的陷窝面积)的百分比。
收集股骨和胫骨并储存在70%的乙醇中直到进一步分析。
将乙醇固定的左股骨和胫骨在7%的硝酸(nitrogen acid)中脱钙48小时。远端股骨和近端胫骨样品(包括具有8mm的干骺端部分的骺)用于进一步组织学处理。将该样品浸入到石蜡中。股骨和胫骨样品的纵切片(6μm厚)通过自动切片机Microm HM 360切割。从1个个体的每1块骨切割20张切片(每5张后具有20μm的间隔)。在标准条件下用苏木精/伊红(曙红)将切片染色。从每个染色的切片获取显微镜图像。用于评估小梁骨的图片利用NikonEclipse E800-光学显微镜(放大率×40)和Nikon D70-数字照相机采集。对股骨和胫骨的切片的显微镜图像进行组织形态计量学计算机分析。利用ImageJ v.1.33a分析小梁。用于评估骺板的图片通过Nomarski对比技术制作并通过AXIOVERT 200 M(装备有LSM5 Pascal激光扫描头,Zeiss,放大率×100,具有514nm氩激光波长)收集。利用Analysis v.3.0分析骺板。利用AXIOVERT 200 M(装备有LSM 5 Pascal激光扫描头,Zeiss,放大率×100,具有514nm氩激光波长)的荧光模式捕获关节软骨图像。关节软骨的图片通过Zeiss LSM图像检查仪v.3.1.0.99评估。与骺板下面的小梁相关的考虑参数为:测量的小梁骨体积(BV/TV%)以获得网状骨的特征、以及小梁分形维数(Box Counting Method)。关于骺板的参数为:在包括静止区、增殖区和肥厚性软骨区的ROI(感兴趣区域)内的软骨细胞的数量。借助LSM 5 Pascal激光扫描头检测器12位(bit)灰度级作为测量规模,通过在随机选择ROI(对于每个切片相同的面积-6个圆圈,每个直径为83μm,沿着关节软骨)中的伊红染色的胶原荧光强度测量进行关节软骨的相对胶原含量的估计。对于每个切片在严格相同的标准条件下进行测量。
统计
将数据与单因素方差分析(ANOVA)、学生(student’s)t检验进行比较,并且p<0.05被认为统计上显著。
结果
在实验的最后,手术处理的动物的身体质量(body mass)比假-手术的动物少8%。在组之间没有统计上的显著性差异(图1)。
颅盖的透视
颅盖的透视表明与Sham(假手术)+安慰剂和Sham(假手术)+AKG大鼠相比,Gx+安慰剂和Gx+AKG大鼠中骨陷窝的百分数的显著增长(图2)。与Gx+安慰剂组相比,Gx+AKG大鼠也表现出陷窝的显著较低的百分数(*p=0.031)(图3)。Sham(假手术)+安慰剂和Sham(假手术)+AKG之间的差异在统计上不显著。
股骨和胫骨中的骨矿物密度(BMD)和骨矿物含量(BMC)
与Sham(假手术)+安慰剂和Sham(假手术)+AKG大鼠相比,Gx+安慰剂和Gx+AKG大鼠中BMD和BMC较低(数据未示出)。然而,Gx+AKG中的BMD倾向于比Gx+安慰剂组大(p=0.19)。
组织形态计量学
关节软骨分析
Gx+AKG组中的软骨胶原的量类似于对照(假手术)组中的量并且与Gx+安慰剂组相比明显较高(表2)。
骺板分析
骺生长板细胞的定量分析表明:与Gx+安慰剂相比,Gx+AKG组(均在股骨和胫骨中)中的细胞数量增加。此外,Gx+AKG组中的软骨细胞的数量显著大于两个Sham(假手术)组(表3、4)。
小梁骨分析
与Sham(假手术)+安慰剂和Sham(假手术)+AKG大鼠相比,Gx+安慰剂和Gx+AKG大鼠中的小梁骨体积减少。然而,Gx+AKG中小梁的面积减少小于Gx+安慰剂组(表5、6)。
骨小梁的分形维数
Gx+AKG中的分形维数类似于对照组并且高于Gx+安慰剂(表7、8)。
讨论
实验的目的是评估饮食α-酮戊二酸对由胃切除术引起的骨损失的影响。获得的数据证明假设。确实,饮食AKG防止胃切除的大鼠中的骨和软骨损失。我们的结果与最近的实验一致,表明AKG防止卵巢切除的大鼠和绝经期后的妇女中骨质疏松症的发展。
胃切除术在Gx+安慰剂中引起软骨胶原和软骨细胞损失,但是在Gx+AKG大鼠中没有引起。证明在Gx+AKG中的软骨细胞比Gx+安慰剂中多22%。这表明AKG在防止胃切除后的大鼠中的软骨细胞的损失中是有效的。分析表明AKG对骨和软骨胶原的保护作用。Gx+AKG组中胶原的量在用于实验的对照组的范围内,并且比Gx+安慰剂大鼠中高约18%。
观察到AKG对胃切除的大鼠中颅盖骨的保护性作用。来自Gx+AKG大鼠的颅盖表现出比来自Gx+安慰剂大鼠的颅盖的损伤少20%。BMD和BMC值表明:胃切除术引起Gx+安慰剂和Gx+AKG大鼠中的骨质减少,这与其它实验一致。然而,利用更敏感的组织形态计量学方法,我们表明AKG在防止GX大鼠中的骨质减少方面可能有效。
此外,表明与Gx+安慰剂动物相比,检查的小梁骨体积在Gx+AKG大鼠中减少小于38%。此外,Gx+AKG组中小梁的分形维数表现出与假手术组中几乎相同的水平。因此,α-酮戊二酸确实对骨小梁的结构的重新构建具有很大影响。
胃切除术对骨骼具有强大的破坏作用,引起骨质减少和关节病。AKG不能完全停止这些损伤,但是它的确限制骨和软骨中较大的破坏性胃切除术相关的变化并可能改善骨骼系统的重新构建。这些观察结果的含义对于人类中的临床考虑可能是重要的,例如,其中部分胃切除术被推荐用于肥胖患者中的体重减轻。所有这些患者发展了骨质减少和关节病。因此,技术人员可以推测对于这些患者饮食的AKG可以停止或限制这些破坏性骨变化。
表1.AKG和安慰剂饮品的组成
成分 | AKG(g/dm3) | 安慰剂(g/dm3) |
AKG(α-酮戊二酸) | 14.6 | 0 |
HCl盐酸 | 0 | 3.32 |
C6H12O6葡萄糖 | 30.0 | 30.0 |
C12H22O11蔗糖 | 15.0 | 15.0 |
NaOH氢氧化钠 | 3.6 | 3.6 |
KOH氢氧化钾 | 0.75 | 0.75 |
Ca(OH)2氢氧化钙 | 0.46 | 0.46 |
Mg(OH)2氢氧化镁 | 0.18 | 0.18 |
PH | 4.6 | 4.6 |
为实现每种溶液中pH相同的水平,安慰剂饮品用0.1 M HCl滴定到pH4.6(AKG饮品的pH水平)。
表2.AKG和胃切除术对关节软骨胶原相对含量的作用
处理 荧光 标准差(SD)
Gx+AKG 2363a 623
Gx+安慰剂 1928b 647
Sham+AKG 2475a 457
Sham+安慰剂 2171a 374
伴随栏中的结果给出的不同字母描述了当p<0.05时的显著性差异。
在Gx+AKG中n=7,在Gx+安慰剂中n=8,在Sham(假手术)+AKG中n=10,在Sham(假手术)+安慰剂中n=7。
表3.AKG和胃切除术对股骨骺板软骨细胞的数量的作用
处理 细胞的数量/mm2 SD
Gx+AKG 2220a 490
Gx+安慰剂 1760b 360
Sham+AKG 1890b 330
Sham+安慰剂 1850b 220
伴随栏中的结果给出的不同字母描述了当p<0.05时的显著性差异。
在Gx+AKG中n=7,在Gx+安慰剂中n=8,在Sham+AKG中n=10,在Sham+安慰剂中n=7。
表4.AKG和胃切除术对胫骨骺板软骨细胞的数量的作用
处理 细胞的数量/mm2 SD
Gx+AKG 2470a 470
Gx+安慰剂 1950b 330
Sham+AKG 1840b 410
Sham+安慰剂 2110b 340
伴随栏中的结果给出的不同字母描述了当p<0.05时的显著性差异。
在Gx+AKG中n=7,在Gx+安慰剂中n=8,在Sham+AKG中n=10,在Sham+安慰剂中n=7。
表5.α-酮戊二酸和胃切除术对股骨小梁骨体积的作用
处理 小梁的面积(%) SD
Gx+AKG 18.8a 3.7
Gx+安慰剂 11.2b 2.1
Sham+AKG 25.5c 7.8
Sham+安慰剂 24.5c 5.9
伴随栏中的结果给出的不同字母描述了当p<0.05时的显著性差异。
在Gx+AKG中n=7,在Gx+安慰剂中n=8,在Sham+AKG中n=10,在Sham+安慰剂中n=7。
表6.α-酮戊二酸和胃切除术对胫骨小梁骨体积的作用
处理 小梁的面积(%) SD
Gx+AKG 16.7a 3.4
Gx+安慰剂 10.5b 2.5
Sham+AKG 24.9c 5.3
Sham+安慰剂 21.1c 5.7
伴随栏中的结果给出的不同字母描述了当p<0.05时的显著性差异。
在Gx+AKG中n=7,在Gx+安慰剂中n=8,在Sham+AKG中n=10,在Sham+安慰剂中n=7。
表7.α-酮戊二酸和胃切除术对股骨小梁的分形维数的作用
处理 分形维数[D] SD
Gx+AKG 1.22b 0.02
Gx+安慰剂 1.19a 0.03
Sham+AKG 1.24b 0.04
Sham+安慰剂 1.25b 0.03
伴随栏中的结果给出的不同字母描述了当p<0.05时的显著性差异。
在Gx+AKG中n=7,在Gx+安慰剂中n=8,在Sham+AKG中n=10,在Sham+安慰剂中n=7。
表8.α-酮戊二酸和胃切除术对胫骨小梁的分形维数的作用
处理 分形维数[D] SD
Gx+AKG 1.22b 0.02
Gx+安慰剂 1.17a 0.02
Sham+AKG 1.22b 0.03
Sham+安慰剂 1.21b 0.04
伴随栏中的结果给出的不同字母描述了当p<0.05时的显著性差异。
在Gx+AKG中n=7,在Gx+安慰剂中n=8,在Sham+AKG中n=10,在Sham+安慰剂中n=7。
图的图注
图1.饮食α-酮戊二酸和胃切除术对大鼠体重的作用。对照组:SHAM+PLAC、GX+PLAC实验组:SHAM+AKG、GX+AKG(SHAM-假手术的大鼠、GX-胃切除的大鼠)。
图2.测试的动物的颅盖的选择的照片。对照组:SHAM+PLAC、GX+PLAC实验组:SHAM+AKG、GX+AKG(SHAM-假手术的大鼠、GX-胃切除的大鼠)。
图3.饮食α-酮戊二酸和胃切除术对颅盖的透视的作用。对照组:SHAM+PLAC、GX+PLAC实验组:SHAM+AKG、GX+AKG(SHAM-假手术的大鼠、GX-胃切除的大鼠)。
*p=0.0288
Claims (12)
1.包括选自由下列物质组成的组中的至少一个成员的物质在制备用于治疗或预防软骨或其它关节疾病的炎性或非炎性损伤的疾病的药物制剂中的应用,所述物质为:α-酮戊二酸、谷氨酰胺、谷氨酸和这些酸的药用盐、α-酮戊二酸和氨基酸或二肽或三肽的酰胺、谷氨酰胺和其它氨基酸的二肽、谷氨酰胺和其它氨基酸的三肽、谷氨酸和其它氨基酸的二肽、谷氨酸和其它氨基酸的三肽和所述二肽和三肽的药用盐、α-酮戊二酸或其药用盐与至少一种氨基酸的药物学上可接受的物理状态混合物。
2.根据权利要求1所述的应用,其中,所述至少一个成员选自由α-酮戊二酸、α-酮戊二酸的盐以及α-酮戊二酸的酰胺组成的组。
3.根据权利要求2所述的应用,其中,所述至少一个成员选自由α-酮戊二酸和α-酮戊二酸的盐组成的组。
4.根据权利要求1至3所述的应用,用于治疗或预防artrose。
5.根据权利要求1至3所述的应用,用于治疗或预防类风湿性关节炎。
6.根据权利要求1至3所述的应用,用于治疗或预防在涉及重量减轻和/或受损的营养的情况下的软骨损伤。
7.根据权利要求1至3所述的应用,用于治疗或预防在涉及胃切除术、部分胃切除术或胃囊带术的情况下的软骨损伤。
8.根据权利要求1至3所述的应用,用于治疗或预防在涉及营养不良的情况下的软骨损伤。
9.根据权利要求1至3所述的应用,用于减轻与根据权利要求1-8的疾病相关的疼痛。
10.根据前述权利要求中任一项所述的应用,其中,给予患者的剂量在所述物质的1至1000mg/kg体重/天的间隔内。
11.根据权利要求1-9所述的应用,其中,给予患者的剂量在所述物质的10至400mg/kg体重/天的间隔内。
12.根据权利要求1-9所述的应用,其中,给予患者的剂量在所述物质的10至100mg/kg体重/天的间隔内。
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