CN101646446B - Rankl产生抑制剂 - Google Patents
Rankl产生抑制剂 Download PDFInfo
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- CN101646446B CN101646446B CN2008800069226A CN200880006922A CN101646446B CN 101646446 B CN101646446 B CN 101646446B CN 2008800069226 A CN2008800069226 A CN 2008800069226A CN 200880006922 A CN200880006922 A CN 200880006922A CN 101646446 B CN101646446 B CN 101646446B
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- rankl
- inhibitor
- milk
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Abstract
通过经口摄取乳来源的碱性蛋白质，能够抑制RANKL的产生。涉及以乳来源碱性蛋白质组分为有效成分的RANKL产生抑制剂，配合了该RANKL产生抑制剂的骨代谢病用治疗剂及免疫病用治疗剂，以及特征在于配合了特定量的该RANKL产生抑制剂的、抑制RANKL产生的饮食品及饲料。它们具有显著地抑制RANKL产生的效果，能够日常摄取，且即使长期摄取安全性也高。
Description
技术领域
本发明涉及以乳来源的碱性蛋白质组分为有效成分的RANKL(Receptor Activator NF-kB Ligand，NF-kB受体活化因子配体；以下，称为RANKL)的产生抑制剂、和配合了RANKL产生抑制剂的骨代谢病用治疗剂及免疫病用治疗剂。此外，涉及特征在于配合了特定量以上的RANKL产生抑制剂的、抑制RANKL产生的饮食品及饲料。通过经口摄取乳来源的碱性蛋白质组分，能够抑制通过以往的方法不能有效调控的RANKL的产生。
背景技术
骨已知作为一种为了自身的形态变化和维持血钙浓度而常常重复形成和吸收、进行重建的动态器官。在正常的骨中，通过成骨细胞介导的骨形成和破骨细胞介导的骨吸收而保持动态平衡，然而一旦骨形成和骨吸收的平衡被破坏的话，就会形成骨质疏松症等骨代谢异常。作为骨代谢调节因子，有全身性的激素和局部性的细胞因子，通过这些调节因子而进行骨的形成和维持。
RANKL(也称为OPGL、TRANCE、或ODF)在成骨细胞、成纤维细胞等中表达，被鉴定为调节破骨细胞分化的TNF族(参照非专利文献1)，是通过与在破骨细胞前体细胞膜上表达的受体RANK结合而促进其向破骨细胞分化的分子。另外，RANKL为也可在活化T细胞中表达的分子，即使是T细胞产生的RANKL也可调节骨代谢等，这暗示骨代谢与免疫细胞功能密切相关(参照非专利文献2)。树突细胞(Dendritic Cell；以下，称为DC)是最强的抗原递呈细胞(APC)，在体内，对T细胞的抗原递呈对于一系列的免疫应答的起始是必要的。已知DC也在细胞膜上表达作为受体的RANK，可认为T细胞膜上的RANKL和DC膜上的RANK的相互作用与免疫应答有关(参照非专利文献3，4)。另外，还据称从T细胞膜上游离的可溶性RANKL调节DC的成熟化和活化(参照非专利文献5-9)。
由此，T细胞产生的RANKL不仅通过由RANK介导调节破骨细胞分化从而调控骨代谢，而且通过参与T细胞和DC的相互作用以及DC的成熟化还调控免疫系统。因此，可以期待RANKL产生抑制剂这样的药剂对RANKL-RANK信号介导的疾病，例如骨质疏松症等骨代谢病、和起因于免疫系统的异常活化的变态反应性疾病及类风湿性关节炎等免疫病的治疗和改善。
肠道是食物直接接触的器官，不仅仅是营养的吸收，而且从食物接收各种信号，再通过神经和激素将各种信号传递到身体中。此外，作为生物体防御的最前线，与以病原微生物为首的多种异物(食物、变态反应原、粘膜常驻细菌、致癌物)对峙，配备了有助于维持生物体稳态的人体最大的免疫系统。因此，如果能够从日常摄取的饮食中摄取作用于免疫系统的食品成分的话，则可以期待对于免疫病非常有效。但是，通常在骨病和免疫病的治疗中使用医药品。然而，这些物质本身为药品，安全性决不能说很高，从适合的量等问题出发，难以合理地从日常的饮食中摄取。因此，如果能够在肠道免疫系统中发挥作用，调控作为免疫活性细胞的T细胞所产生的RANKL，则可以期待通过在骨中抑制破骨细胞的分化成熟从而抑制骨吸收，骨吸收的抑制与增强骨质相关联。同样，还可以期待抑制由于异常的免疫反应而引起的变态反应等免疫病。
因此，与将RANKL产生抑制剂作为前述药物进行摄取相比，如果能够摄取可日常摄取，即使长期摄取也不会有问题，且由可以作为食品材料使用的物质获得的、作用于免疫系统的食品成分的话，则可以期待对于免疫病非常有效，强烈期望开发这种抑制剂。
目前，具有抑制T细胞的RANKL产生的作用、且可以作为食品材料使用的成分尚未被报道，本发明是新的技术。
另一方面，乳来源的碱性蛋白质组分是在乳中微量含有的多种碱性蛋白质的总称，是从脱脂乳或乳清等乳原料中提取的碱性的蛋白质组分。并且，已知该乳来源碱性蛋白质组分通过经口摄取具有骨质增强作用(参照专利文献1)。然而，关于该乳来源碱性蛋白质组分的骨质增强作用，已知的是，直接作用于破骨细胞而抑制分化增殖，关于抑制破骨细胞以外的RANKL产生，并不清楚。本发明人着眼于被认为参与骨代谢的RANKL，探索了抑制直接接触食品成分的肠道免疫细胞的RANKL产生的食品成分。
非专利文献1：Suda等，Endcr.Rev.，20：345(1999)
非专利文献2：Theil等，Annu.Rev.Immunol.，20：795(2002)
非专利文献3：Hochweller等，Eur.J.Immunol.，35：1086(2005)
非专利文献4：Williamson等，J Immunol.，169：3606(2002)
非专利文献5：Wong等，J.Exp.Med.，186：2075(1997)
非专利文献6：Wong等，J.Leukocyte Biol.，65：715(1999)
非专利文献7：Wong等，J.Biol.Chem.，272：25190-25194(1997)
非专利文献8：Josien等，J.Immunol.，162：2562(1999)
非专利文献9：Josien等，J.Exp.Med.，191：495(2000)
专利文献1：日本特开平8-151331号公报
发明内容
发明要解决的问题
本发明的课题在于提供能够日常摄取、且即使长期摄取安全性也高的、以乳来源碱性蛋白质组分为有效成分的RANKL产生抑制剂，以及具有RANKL产生抑制介导的破骨细胞分化抑制作用或树突细胞分化抑制作用、能够治疗骨病或免疫病及变态反应的配合了RANKL产生抑制剂的骨代谢病用治疗剂以及免疫病用治疗剂。此外，本发明的课题还在于提供特征在于配合了一定量的RANKL产生抑制剂的、抑制RANKL产生的饮食品及饲料。
用于解决问题的方案
本发明人等为了获得通过抑制RANKL产生而抑制破骨细胞分化或树突细胞分化的物质，对具有抑制RANKL产生的作用的物质进行了持续探索。结果发现，在乳中仅微量存在的碱性蛋白质可抑制T细胞膜上的RANKL和可溶性RANKL的产生。并且发现，能够利用该乳来源碱性蛋白质组分作为RANKL产生抑制剂的有效成分，从而完成了本发明。即，本发明为以乳来源碱性蛋白质组分为有效成分的RANKL产生抑制剂。另外，涉及配合了该RANKL产生抑制剂的骨代谢病用治疗剂及免疫病用治疗剂。此外，涉及特征在于配合了特定量的RANKL产生抑制剂的、抑制RANKL产生的饮食品及饲料。
发明的效果
通过使用本发明的以乳来源碱性蛋白质组分为有效成分的RANKL产生抑制剂，能够抑制RANKL的产生。本发明的RANKL产生抑制剂，配合了RANKL产生抑制剂的骨代谢病用治疗剂及免疫病用治疗剂，特征在于配合了RANKL产生抑制剂的、抑制RANKL产生的饮食品或饲料，它们通过抑制破骨细胞的分化而能够用于治疗骨代谢病或改善其症状等，另外通过抑制树突细胞的分化而能够用于调节免疫功能，治疗变态性疾病等与免疫功能相关的疾病或改善其症状等，是非常有用的。
附图说明
图1是示出通过抗原非特异性TCR(T细胞受体)刺激法的乳来源碱性蛋白质组分对RANKL产生量的影响的图。(实施例1、试验例1)
图2是示出通过抗原特异性TCR刺激法的乳来源碱性蛋白质组分对RANKL产生量的影响的图。(实施例1、试验例2)
具体实施方式
本发明的RANKL产生抑制剂的特征在于，其以乳来源的碱性蛋白质组分为有效成分。另外，通过配合以乳来源的碱性蛋白质组分为有效成分的RANKL产生抑制剂，抑制RANKL的产生，抑制破骨细胞的分化，从而用于治疗骨代谢病。此外，通过抑制RANKL的产生，抑制树突细胞的分化，从而调节免疫功能，用于治疗与免疫功能相关的疾病。
本发明的RANKL产生抑制剂，配合了该RANKL产生抑制剂的骨代谢病用治疗剂及免疫病用治疗剂，以及特征在于配合了特定量的RANKL产生抑制剂的、抑制RANKL产生的饮食品及饲料，作为它们的有效成分，使用以牛乳、人乳、山羊乳、羊乳等哺乳类的乳为原料的乳来源碱性蛋白质组分。
作为获得本发明的RANKL产生抑制剂的有效成分、即乳来源的碱性蛋白质组分的方法，已知有：使乳或乳来源的原料与阳离子交换体接触，使乳来源的碱性蛋白质组分吸附后，用pH超过5、离子强度超过0.5的洗脱液洗脱吸附在该阳离子交换体上的碱性蛋白质组分而获得的方法(日本特开平5-202098号公报)；使用褐藻酸凝胶而获得的方法(日本特开昭61-246198号公报)；使用无机的多孔性颗粒由乳清获得的方法(日本特开平1-86839号公报)；使用硫酸化酯化合物由乳获得的方法(日本特开昭63-255300号公报)等，本发明中能够使用由这类方法而获得的乳来源的碱性蛋白质组分。
为了获得抑制RANKL产生的效果，作为本发明的RANKL产生抑制剂、和特征在于配合了特定量的RANKL产生抑制剂的、抑制RANKL产生的饮食品的有效量，对于成人而言，以固体物质换算，期望按照20mg/天以上摄取乳来源碱性蛋白质组分。并且，RANKL产生抑制剂或配合了RANKL产生抑剂的饮食品中，以固体物质换算，期望按照10mg～100g/100g配合乳来源碱性蛋白质组分。
本发明的RANKL产生抑制剂中，可以单独使用乳来源碱性蛋白质组分，也可以与下述其他成分一起使用。根据使用目的和方法等，可以制剂成粉末状、液状、片状等形状。
将本发明的RANKL产生抑制剂制成营养组合物的形态，能够以下述蛋白质、糖类、脂质、维生素类和矿物质类等作为主要成分而构成。该具有抑制RANKL产生的效果的营养组合物也可以根据使用目的和方法等加工成粉末状、液状、片状等形状。
另外，将本发明的RANKL产生抑制剂添加到下述饮食品中，利用常规方法进行加工，还能够制成特征为配合了RANKL产生抑制剂的、抑制RANKL产生的饮食品。
在制成本发明的RANKL产生抑制剂、或者特征在于配合了RANKL产生抑制剂的、抑制RANKL产生的饮食品的情况下，作为蛋白质，可以举出酪蛋白、乳清蛋白质浓缩物(WPC)、乳清蛋白质分离物(WPI)、αs-酪蛋白、β-酪蛋白、α-乳白蛋白和β-乳球蛋白等乳蛋白质分离物，大豆蛋白质和小麦蛋白质等植物蛋白质等，此外，也可以用酸或酶处理这些蛋白质，以肽或游离氨基酸的形式使用。另外，游离氨基酸除了作为氮源之外，还能够用于赋予特定的生理作用，作为这些氨基酸，可以举出牛磺酸、胱氨酸、半胱氨酸、精氨酸、谷氨酰胺等。按照RANKL产生抑制剂和特征在于配合了RANKL产生抑制剂的、抑制RANKL产生的饮食品的固体成分计，这些蛋白质和肽或游离氨基酸优选配合5～30重量％。
作为糖类，可以举出淀粉、可溶性多糖类、糊精、蔗糖、乳糖、麦芽糖、葡萄糖等，及半乳糖基乳糖、低聚果糖、乳果糖等寡糖，或人工甜味剂等。按照RANKL产生抑制剂或特征在于配合了RANKL产生抑制剂的、抑制RANKL产生的饮食品的固体成分计，糖类优选配合40～80重量％。
作为脂质，可以举出乳脂肪、猪油、牛脂和鱼油等动物性油脂，大豆油、菜籽油、玉米油、月见草油、中链脂肪酸甘油三酯(MCT)和棉籽油等植物性油脂，以及它们的析得干性油(separated oil)、氢化油、酯交换油等。按照RANKL产生抑制剂或特征在于配合了RANKL产生抑制剂的、抑制RANKL产生的饮食品的固体成分计，脂质优选配合40重量％以下。
关于维生素类和矿物质类，只要使用基于食品卫生法的指定添加物(收录于施行规则别表第2中的食品添加物)和既存食品添加物(收录于既存添加物名簿中的食品添加物)的维生素类和矿物质类即可。作为维生素类的具体例子，可以举出维生素A、维生素B类、维生素C、维生素D、维生素E、维生素K类、叶酸、泛酸、β-胡萝卜素、烟酰胺、生物素、肌醇、胆碱等，按照RANKL产生抑制剂或特征在于配合了RANKL产生抑制剂的、抑制RANKL产生的饮食品的固体成分计，优选配合0.01～5重量％。另外，作为矿物质类的具体例子，可以举出钙、镁、钾、钠、磷、氯、铁、铜、锌、碘、锰、硒、氟、铬、钼等，按照RANKL产生抑制剂或特征在于配合了RANKL产生抑制剂的、抑制RANKL产生的饮食品的固体成分计，优选配合0.001～5重量％。
此外，作为本发明的配合了RANKL产生抑制剂的饮食品，可以举出干酪、黄油和发酵乳等乳食品，乳饮料、酸奶饮料、咖啡饮料和果汁等饮料，果冻、布丁、曲奇、饼干和威化等点心，育儿用调制乳、较大婴儿用乳(Follow-up Milk)、幼儿用饮食品、孕产妇用饮食品、病患用食品，医疗用食品、高龄者用食品、护理食品、以及冷冻食品等各种饮食品。在制造配合了RANKL产生抑制剂的饮食品时，由于乳来源碱性蛋白质组分对热比较不稳定，因此尤其是在加热杀菌的工序中，期望使用尽可能低的热历程。
接着，示出实施例和试验例，对本发明进行详细说明，这些仅仅是例示出本发明的实施方式，本发明不受其任何限制。
实施例1
(乳来源碱性蛋白质组分的制备)
用去离子水充分清洗填充有阳离子交换树脂的磺化Chitopearl(富士纺绩公司制)400g的柱(直径5cm×高度30cm)，然后以25ml/分钟的流速使401未杀菌脱脂乳(pH6.7)通过该柱。液体通过后，用去离子水充分清洗该柱，接着用含有0.7M氯化钠的0.02M碳酸缓冲液(pH7.0)清洗，之后用含有0.98M氯化钠的0.02M碳酸缓冲液(pH7.0)洗脱吸附在树脂上的乳来源碱性蛋白质组分。然后，利用反渗透(RO)膜对该洗脱液进行脱盐，浓缩后进行冻干，获得乳来源碱性蛋白质组分粉末21g，作为本发明的RANKL产生抑制剂。
[试验例1]
(通过抗原非特异性TCR刺激法的乳来源碱性蛋白质组分对RANKL产生量的影响)
利用Macs(磁性细胞分选系统，magnetic cell separationsystem)法从6-8周大小的BALB/C雄性小鼠的淋巴结中分选CD4阳性细胞。以4×106细胞/ml悬浮在RPMI1640培养基(NiproCorporation制，含有胎牛血清5％，含有青霉素-链霉素溶液(GIBCO公司制)1％；以下称为5％FCS/RPMI)中，然后，以50μl/孔接种到抗小鼠CD 3抗体包被96孔板(Becton，Dickinsonand Company制)(2×105细胞/孔)。以终浓度2.5μg/ml添加抗小鼠CD28抗体，再以终浓度0、10、100μg/ml添加实施例1中获得的乳来源碱性蛋白质组分和作为对照的牛血清白蛋白(以下，BSA)，然后在5％二氧化碳培养箱中培养。4天后回收上清，用ELISA法测定上清中的RANKL量。
测定RANKL量的结果如图1所示。在抗体带来的TCR刺激条件下培养T细胞时，培养上清中的RANKL量增加。此时，没有发现BSA的添加对RANKL产生量造成影响，但添加乳来源碱性蛋白质组分进行培养时，RANKL产生被抑制。该结果表示，在抗原非特异性TCR刺激条件下，乳来源碱性蛋白质组分直接抑制T细胞的RANKL产生。在骨形成和骨吸收的平衡病态地倾向于骨吸收的骨代谢病中，通过乳来源碱性蛋白质组分抑制T细胞和破骨细胞的RANKL-RANK信号传递的作用，显示出通过抑制破骨细胞的分化来抑制骨吸收的可能性。另外，还可以期待通过乳来源碱性蛋白质组分直接作用于产生RANKL的成骨细胞或成纤维细胞，抑制RANKL产生，从而抑制骨吸收。
[试验例2]
(通过抗原特异性TCR刺激法的乳来源碱性蛋白质组分对RANKL产生的影响)
利用Macs法从产生卵白蛋白特异性T细胞抗原受体的转基因雄性小鼠(D011.10小鼠)的淋巴组织中分选CD4阳性T细胞。以4×106细胞/ml悬浮在5％FCS/RPMI中，然后，以100μl/孔接种到48孔微孔板中(4×105细胞/孔)。利用Macs法从BALB/C雄性小鼠的淋巴集结(Peyer’s patch)细胞中分选CD11c阳性细胞(树突细胞)，以4×105细胞/ml悬浮在5％FCS/RPMI中，然后，以100μl/孔接种(2×104细胞/孔)。以终浓度0、10、100μg/ml添加实施例1中获得的乳来源碱性蛋白质组分和作为对照的BSA。再以终浓度0、100μg/ml添加卵白蛋白(以下，OVA)，在5％二氧化碳培养箱中培养。4天后回收各细胞，用PE标记抗小鼠RANKL抗体、作为针对Do11.10小鼠的TCR的特异性抗体的FITC标记抗小鼠KJ1.26抗体、和PI进行染色，通过流式细胞术法计算RANKL阳性KJ1.26阳性细胞的比例(％)。
其结果如图2所示。在没有抗原OVA刺激下，即使添加乳来源碱性蛋白质组分或BSA，也没有发现RANKL产生。另一方面，在OVA刺激下培养的话，RANKL产生会增加。可以确认，虽然BSA的添加没有影响RANKL产生，但通过乳来源碱性蛋白质组分的添加，RANKL产生被显著抑制。该结果表示，在抗原特异性TCR刺激下，乳来源碱性蛋白质组分抑制T细胞的RANKL产生。在抗原抗体反应异常活跃的免疫病中，通过乳来源碱性蛋白质组分抑制作为免疫应答的初期反应、即T细胞和树突细胞的RANKL-RANK信号的作用，抑制免疫反应，从而显示出改善变态反应和自身免疫病的可能性。
实施例2
对于实施例1中获得的乳来源碱性蛋白质粉末，利用常规方法制造表1所示组成的粉末状RANKL产生抑制剂。另外，每100g该RANKL产生抑制剂中含有4g乳来源碱性蛋白质组分。
[表1]
实施例3
(配合了RANKL产生抑制剂的饮料的制造)
如表2所示，将实施例1中获得的碱性蛋白质粉末40g溶解到用乳酸调整为pH 3.2的去离子水50L中，之后溶解砂糖1kg、香料100g，在90℃下进行15秒加热杀菌。将其以每50ml密封填充到有盖玻璃瓶中，制造特征在于配合了RANKL产生抑制剂的、抑制RANKL产生的饮料。另外，每100ml该饮料中含有80mg乳来源碱性蛋白质组分。
[表2]
实施例4
(特征在于配合了RANKL产生抑制剂的、抑制RANKL产生的饼干的制造)
制作如表3所示组成的生面团(dough)，成形后进行烘培，制造特征在于配合了RANKL产生抑制剂的、抑制RANKL产生的饼干。另外，每100g该饼干中含有100mg乳来源碱性蛋白质组分。
[表3]
实施例5
(特征在于配合了RANKL产生抑制剂的、抑制RANKL产生的饲料的制造)
使用实施例1中制备的乳来源碱性蛋白质组分粉末，以表4所示的配比将各成分搅拌均匀，制备特征在于配合了本发明的RANKL产生抑制剂的、抑制RANKL产生的饲料。每100g该饲料中含有100mg的乳来源碱性蛋白质组分。
[表4]
产业上的可利用性
本发明的以乳来源碱性蛋白质组分为有效成分的RANKL产生抑制剂、配合了RANKL产生抑制剂的骨代谢病用治疗剂及免疫病用治疗剂、以及特征在于配合了RANKL产生抑制剂的、抑制RANKL产生的饮食品或饲料，能够用于RANKL-RANK信号介导的各种疾病的治疗或症状的改善等，是非常有用的。
Claims (1)
1.以乳来源的碱性蛋白质组分为有效成分的RANKL产生抑制剂在制造免疫病用治疗剂中的用途。
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| US5230902A (en) * | 1988-04-29 | 1993-07-27 | Immunotec Research Corporation | Undenatured whey protein concentrate to improve active systemic humoral immune response |
| JPH05202098A (ja) | 1992-01-29 | 1993-08-10 | Snow Brand Milk Prod Co Ltd | 乳質原料から生理活性物質の製造法 |
| JP3112637B2 (ja) * | 1994-09-30 | 2000-11-27 | 雪印乳業株式会社 | 骨強化剤 |
| JP2974604B2 (ja) * | 1996-01-23 | 1999-11-10 | 雪印乳業株式会社 | 塩基性タンパク質組成物、塩基性ペプチド組成物及びその利用 |
| JP4647750B2 (ja) * | 2000-06-20 | 2011-03-09 | 雪印乳業株式会社 | 乳塩基性シスタチン高含有画分及びその分解物の製造法 |
| US6649590B2 (en) * | 2000-06-09 | 2003-11-18 | Snow Brand Milk Products Co., Ltd. | Method of producing fractions containing a high concentration of milk basic cystatin and decomposition products thereof |
-
2007
- 2007-03-02 JP JP2007052402A patent/JP2008214237A/ja active Pending
-
2008
- 2008-02-29 WO PCT/JP2008/053595 patent/WO2008108284A1/ja active Application Filing
- 2008-02-29 AU AU2008221993A patent/AU2008221993B2/en not_active Ceased
- 2008-02-29 CN CN2008800069226A patent/CN101646446B/zh not_active Expired - Fee Related
- 2008-02-29 KR KR1020097020047A patent/KR20090119918A/ko not_active Application Discontinuation
- 2008-02-29 CA CA002679924A patent/CA2679924A1/en active Pending
- 2008-02-29 US US12/529,660 patent/US20100099848A1/en not_active Abandoned
- 2008-02-29 EP EP08721043A patent/EP2127662A4/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004115509A (ja) * | 2002-09-05 | 2004-04-15 | Snow Brand Milk Prod Co Ltd | 破骨細胞分化抑制因子産生促進剤 |
| JP2006069995A (ja) * | 2004-09-06 | 2006-03-16 | Snow Brand Milk Prod Co Ltd | 炎症性サイトカイン産生抑制剤 |
Non-Patent Citations (4)
| Title |
|---|
| "Lactoferrin is a potent regulator of bone cell activity and increases bone formation in vivo";CORNISH J. ET AL.:;《ENDOCRINOLOGY》;20040930;第145卷(第9期);参见摘要 * |
| "Milk Gan"yu Lactoferrin no Tainai Iko to Sono Shinki Tayo Kino no Hakken";HARADA E. ET AL.:;《SHUKAN IGAKU NO AYUMI》;20060729;第218卷(第5期);参见标题 * |
| CORNISH J. ET AL.:."Lactoferrin is a potent regulator of bone cell activity and increases bone formation in vivo".《ENDOCRINOLOGY》.2004,第145卷(第9期),4366 - 4374. |
| HARADA E. ET AL.:."Milk Gan"yu Lactoferrin no Tainai Iko to Sono Shinki Tayo Kino no Hakken".《SHUKAN IGAKU NO AYUMI》.2006,第218卷(第5期),396–402. |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008108284A1 (ja) | 2008-09-12 |
| JP2008214237A (ja) | 2008-09-18 |
| AU2008221993A1 (en) | 2008-09-12 |
| CA2679924A1 (en) | 2008-09-12 |
| AU2008221993B2 (en) | 2014-02-27 |
| EP2127662A1 (en) | 2009-12-02 |
| EP2127662A4 (en) | 2011-11-09 |
| CN101646446A (zh) | 2010-02-10 |
| US20100099848A1 (en) | 2010-04-22 |
| KR20090119918A (ko) | 2009-11-20 |
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