CN102905719B - 治疗复合性辐射和热损伤的方法 - Google Patents
治疗复合性辐射和热损伤的方法 Download PDFInfo
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- CN102905719B CN102905719B CN201180025747.7A CN201180025747A CN102905719B CN 102905719 B CN102905719 B CN 102905719B CN 201180025747 A CN201180025747 A CN 201180025747A CN 102905719 B CN102905719 B CN 102905719B
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Abstract
本发明提供用于治疗受到复合性全身电离辐射暴露和烧伤的对象的方法。
Description
相关申请
本发明请求2010年3月26日提交的美国临时申请序列号61/317897的优先权，其全部内容通过引用纳入本文。
美国政府资助声明
本发明在国立过敏和传染疾病研究所提供的基金号为3RC1AI080976和3RC1AI080976S1号的美国政府资助下完成。美国政府对本发明享有一定的权利。
发明背景
已知辐射延迟创伤愈合，且此效应可见于暴露在高水平辐射的个体，例如原子弹爆炸时在广岛和长崎的那些人，以及切尔诺贝利核设施发生核融毁后在切尔诺贝利及其周围的那些人。暴露于高水平电离辐射的个体不仅可能患辐射疾病，而且可能受到由爆炸和火灾导致的热诱导损伤。因此，需要用于治疗复合性辐射－热损伤对象的治疗方法。
发明概述
本发明提供用于治疗已受到复合性(i)全身电离辐射暴露及(ii)烧伤的对象的方法，所述方法包括给予所述对象治疗辐射效应和/或烧伤的有效量的肽，所述肽包括SEQ ID NO:1(Asp-Arg-Nle-Tyr-Ile-His-Pro)的肽的至少5个氨基酸，或其药用盐。在一个实施方式中，所述方法相比对照致使所述对象的存活率提高。在另一个实施方式中，所述方法相比对照致使烧伤愈合加快。在另一个实施方式中，所述对象的以下一或多个部位受到二度烧伤：躯干、背、头、手臂或腿。在另一个实施方式中，所述对象经暴露于0.2戈瑞(G)y至10Gy全身电离辐射；在另一个实施方式中，所述对象经暴露于1戈瑞(G)y至10Gy或2戈瑞(G)y至10Gy全身电离辐射。在另一个实施方式中，所述对象经暴露于至少20cGy的累积全身电离辐照。在另一个实施方式中，所述全身电离辐射选自下组：β-辐射、γ-辐射和X-射线。在另一个实施方式中，所述全身电离辐射由暴露于选自下组的辐射源引起：核武器、核能设施、计算机断层扫描设备、X-射线设备、用于骨髓移植预处理的辐射器、核能交通工具以及被放射性物质污染的环境。在另一个实施方式中，所述肽在暴露于全身电离辐射的三天内给予。在另一个实施方式中，所述肽包括SEQ ID NO:1(Asp-Arg-Nle-Tyr-Ile-His-Pro)的肽或其药用盐，或由SEQ ID NO:1(Asp-Arg-Nle-Tyr-Ile-His-Pro)的肽或其药用盐组成。
附图简述
图1.豚鼠模型中TBI剂量和烧伤尺寸对损伤区域中细胞周期蛋白阳性细胞的影响。
图2.豚鼠模型中TBI剂量和烧伤尺寸对损伤边缘的细胞周期蛋白阳性细胞的影响。
图3.经受200cGy TBI的豚鼠中NorLeu3-A(1-7)对CRBI豚鼠模型存活率的影响。
图4.NorLeu3-A(1-7))增加烧伤边缘基底角质细胞层中的增殖细胞。
图5.NorLeu3-A(1-7)增加烧伤边缘的毛囊中的增殖细胞。
图6.经受200cGy TBI后的豚鼠中NorLeu3-A(1-7)对CRBI豚鼠模型存活率的影响。
图7.经受200cGy TBI后的豚鼠中NorLeu3-A(1-7)对CRBI豚鼠模型存活率的影响。
图8.经受200cGy TBI后的豚鼠中NorLeu3-A(1-7)对CRBI豚鼠模型存活率的影响。
图9.经受200cGy TBI后的豚鼠中NorLeu3-A(1-7)对CRBI豚鼠模型存活率的影响。
图10.NorLeu3-A(1-7)减少CRBI小鼠模型(600cGy TBI后在70C烫10秒)中热损伤的真皮和皮下的细胞凋亡，而不单单是减少热损伤部位的细胞凋亡。
发明详述
本发明提供用于治疗受到复合性(i)全身电离辐射暴露和(ii)烧伤的对象的方法，所述方法包括给予所述对象治疗辐射效应和/或烧伤的有效量的肽，所述肽包括SEQ ID NO:1(Asp-Arg-Nle-Tyr-Ile-His-Pro)的肽的至少5个氨基酸或其药用盐。
已知辐射延迟创伤愈合，且其效应可见于经暴露于高水平辐射的个体，因此已表现对创伤愈合有效的化合物可能对治疗结合有全身电离辐射暴露的创伤或烧伤没有效用。发明人发现向受到复合性全身电离辐射暴露和烧伤的对象给予Nle A(1-7)，可通过提高烧伤愈合应答和提高此类患者中的整体存活率来提供意想不到的益处。
如本领域的技术人员所知，“Nle A(1-7)”是具有氨基酸序列
Asp-Arg-Nle-Tyr-Ile-His-Pro的肽。在各种实施方式中，所述肽包括以下序列或由以下
序列组成：Asp-Arg-Nle-Tyr-Ile(Nle A(1-5))(SEQ ID NO:3)、Asp-Arg-Nle-Tyr-Ile-His(Nle A(1-6))(SEQ ID NO:2)或Nle A(1-7)。
本发明适用于伴有烧伤的任何类型电离辐射暴露，例如治疗性的或意外的X-射线、γ射线或β粒子暴露。本发明所述方法适于治疗的电离辐射暴露的示例包括但不限于：临床放射治疗、使用放射性示踪剂的医疗诊断、暴露于天然存在的电离辐射源(例如铀和氡)、战时暴露(即核武器)和意外暴露(包括核能设施、医疗和研究机构中的职业照射)、计算机断层扫描设备、X-射线设备、用于骨髓移植预处理的辐射器、核能交通工具和被放射性物质污染的环境。
所述对象可以是能得益于本发明所述方法的任何合适对象。在一个实施方式中，所述对象是哺乳动物(例如人)、宠物(例如狗和猫)和牲畜，所述牲畜包括但不限于牛、绵羊、山羊、猪和鸡。
本文所述的“全身电离辐射”指暴露于影响多种器官系统的电离辐射源。
在一个实施方式中，所述对象经暴露于0.2戈瑞Gy至12Gy或更多的全身电离辐射；在另一些实施方式中，所述对象经暴露于以下剂量的全身电离辐射：1戈瑞Gy至12Gy或更高；2戈瑞Gy至12Gy或更高；0.2Gy至10Gy或更高；1Gy至10Gy或更高；2戈瑞(G)y至10Gy或更高；2.5Gy至10Gy或更高；3Gy至10Gy或更高；3.5Gy至10Gy或更高；4Gy至10Gy或更高；4.5Gy至10Gy或更高；5Gy至10Gy或更高；5.5Gy至10Gy或更高；6Gy至10Gy或更高；6.5Gy至10Gy或更高；7Gy至10Gy或更高；7.5Gy至10Gy或更高；8Gy至10Gy或更高；8.5Gy至10Gy或更高；9Gy至10Gy或更高；高于10Gy；或高于12Gy。在另一个实施方式中，所述对象受到至少20cGy的累积全身电离辐射暴露。在各种其它实施方式中，所述对象受到至少25cGy、30cGy、35cGy、40cGy、45cGy、50cGy、55cGy、60cGy、65cGy、70cGy、75cGy、80cGy、85cGy、90cGy、95cGy、100cGy或更高的累积全身电离辐射暴露。
所述烧伤可为任何严重程度的烧伤，优选任何身体部位的Ⅱ度烧伤(即二度烧伤)，所述身体部位包括但不限于躯干、背、头、手臂或腿。所述烧伤可以是任何尺寸，优选面积为至少3cm2，且更优选面积为至少4、5、6、7、8、9或10cm2。在另一个实施方式中，所述对象受到的烧伤(例如二度烧伤)超过其总的体表面积的至少10%、20%、30%、40%、50%、60%、79%或更多。
在一个优选的实施方式中，在辐射暴露的0、1、2或3天内给药。在其它优选实施方式中，所述肽以每个创伤1ug或更高剂量给予；更优选每个创伤10ug或更高剂量。在各种优选实施方式中，所述肽以10ug/cm2、50ug/天、100ug/天、200ug/cm2、250ug/天、300ug/cm2、350ug/cm2、400ug/cm2、450ug/cm2、500ug/天或更高剂量给予。
本文中所用的“治疗“或“治疗的”指达到一种或多种以下疗效：(a)降低烧伤或辐射效应的严重程度；(b)限制或防止电离辐射暴露的特征性症状的发展；(c)抑制电离辐射暴露的特征性症状恶化；(d)相比对照加速烧伤愈合；以及(e)提高存活率。辐射的生物效应取决于诸多因素，例如辐射剂量、暴露时间以及所影响的器官。暴露于全身电离辐射的效应的非限制性示例包括恶心、呕吐、腹泻、中枢神经系统功能障碍(例如认知障碍、癫痫、震颤和共济失调)、白血球减少、骨髓损伤、肠损伤、感染(细菌、病毒、真菌等)、休克、低血压、出血和死亡。
在各种实施方式中，所述肽或其药用盐的量足以提供上文所论述的剂量。在示例性的实施方式中，所述肽或其药用盐的量足以向患者提供以下剂量：0.01μg/kg至10mg/kg；0.1μg/kg至5mg/kg；0.1μg/kg至1000μg/kg；0.1μg/kg至900μg/kg；0.1μg/kg至900μg/kg；0.1μg/kg至800μg/kg；0.1μg/kg至700μg/kg；0.1μg/kg至600μg/kg；0.1μg/kg至500μg/kg；或0.1μg/kg至400μg/kg。
能与所述肽形成盐的合适的酸包括无机酸，例如盐酸、氢溴酸、高氯酸、硝酸、硫氰酸、硫酸、磷酸等；和有机酸，例如甲酸、乙酸、丙酸、乙醇酸、乳酸、丙酮酸、草酸、丙二酸、琥珀酸、马来酸、富马酸、邻氨基苯甲酸、肉桂酸、萘磺酸、对氨基苯磺酸等。能与所述肽形成盐的合适的碱包括无机碱，例如氢氧化钠、氢氧化铵、氢氧化钾等；和有机碱，例如单、二和三烷基和芳基胺(例如：三乙胺、二异丙胺、甲胺、二甲胺等)和任选取代的乙醇胺类(例如乙醇胺、二乙醇胺等)。
用于本发明所述方法的药物组合物可以固体形式(包括颗粒剂、散剂或栓剂)或液体形式(例如溶液、悬浮液或乳液)制备。所述药物组合物可以各种溶液施予。根据本发明所适用的溶液为无菌的、溶解足量Nle A(1-7)的、且对所需的施予无害。就这点而言，本发明的化合物很稳定，但可被强酸和强碱水解。本发明所述的化合物可溶于有机溶剂和pH5-8的水溶液。所述药物组合物可经过常规药物处理，例如灭菌和/或可包含常规辅料。在一个实施方式中，所述药物组合物制备用于局部皮下给药，所述肽或其盐可占0.0001%至10%w/w；在一个实施方式中，不超过5%w/w；且在另一个实施方式中，占制剂的0.01%至2%w/w。
在另一个实施方式中，所述肽或其盐制备成稳定的冻干肽制剂，所述制剂可用适合的稀释剂重构以形成本发明的适于皮下给药的重构药物组合物。当用包含防腐剂(如抑菌性注射用水)的稀释剂重构时，所述重构制剂可用作多次使用制剂。此类制剂在例如对象需要经常皮下给予肽时有用。多次使用制剂的优点在于其有助于方便患者使用、通过彻底使用小瓶内含物来减少浪费，并通过用单个小瓶包装多剂药物而使得生产商显著节约成本(降低填装和运输成本)。此类重构制剂也可适用于其它类型的非肠胃道给药。
所述肽或其盐可通过任何合适的途径给药，包括但不限于真皮、皮下、皮内、透皮(例如，通过缓释聚合物)、肌内、腹膜内、静脉内、口服、耳、硬膜外、直肠或阴道(例如通过栓剂)、以及鼻内途径、灌输或弹丸注射、或通过上皮或黏膜皮肤层吸收。在一个优选的实施方式中，所述肽或其盐通过透皮给药并配制成局部制剂，例如用羟乙基纤维素(HEC)配制。在一个实施方式中，遮蔽所述制剂以防止储存中发生降解。
对于给药，所述药物组合物通常与一种或多种适于所指示给药途径的佐剂组合。所述化合物可与以下物质混合：乳糖、蔗糖、淀粉粉末、链烷酸的纤维素酯、硬脂酸、滑石、硬脂酸镁、氧化镁、磷酸和硫酸的钠盐及钙盐、阿拉伯胶、明胶、海藻酸钠、聚乙烯吡咯烷和/或聚乙烯醇，并可制成片剂或胶囊以常规给药。或者，本发明所述的化合物可溶于盐水、水、聚乙二醇、丙二醇、羧甲基纤维素胶体溶液、羟乙基纤维素胶体溶液、乙醇、玉米油、花生油、棉籽油、麻油、黄蓍胶、和/或各种缓冲剂。药学领域中熟知其它佐剂和给药方式。载体或稀释剂可包括延时物质，例如单一的或与蜡合用的单硬脂酸甘油酯或二硬脂酸甘油酯，或本领域熟知的其它物质。在一个优选的实施方式中，所述肽或其药物组合物为局部给药。可采用能使所述肽或其药物组合物在一段时间内进入热损伤组织的任何类型局部施予方法。例如，可通过纱布绷带或带状物将水性溶液施予烧伤组织，或可配制此类溶液来获得定时灌注(使用脂质体、药膏、胶束等)。含本发明所述肽或其药物组合物的这些制剂的生产方法对本技术领域的普通技术人员是显而易见的。
所述肽或其盐可被进一步衍生以提高其半衰期，例如通过与聚乙二醇连接。所述肽或其盐可包括L-氨基酸、D-氨基酸(可在体内抗L-氨基酸特异性蛋白酶)、D-氨基酸和L-氨基酸的组合、和各种“设计者(designer)”氨基酸(如β-甲基氨基酸、Cα-甲基氨基酸和Nα-甲基氨基酸等)以赋予特定性质。合成氨基酸包括代替异亮氨酸的正亮氨酸。
另外，所述肽或其盐可含模拟肽键。例如，可引入还原肽键来形成肽，所述的肽键即为R1-CH2-NH-R2，其中R1和R2为氨基酸残基或序列。还原肽键可作为二肽亚基引入。此类多肽可抗蛋白酶活性，并在体内具有延长的半衰期。
所述肽或其盐可化学合成或重组表达，所述方法各自可用本领域的标准方法完成。
Nle A(1-7)或其盐可作为单一治疗给予或与用于治疗所讨论病状的其它药物或疗法联合给予，包括但不限于水凝胶、胶原海绵和贝卡普乐明胶(becaplermin gel)。
实施例1复合性辐射/身体损伤(CRBI)的豚鼠模型
在豚鼠中建立复合性损伤模型。所述模型的建立包括评估五个水平的全身辐射(TBI)复合2种尺寸的热损伤，以测定有最低死亡率的延迟愈合最佳组合。存在不可接受的死亡率，尤其是接受两个最高剂量TBI的较大损伤尺寸组。通过表皮基底和毛囊隆突部中细胞周期蛋白阳性细胞个数来评估TBI延迟愈合的能力。显示了第14天动物的增殖数据(图1和2)。TBI剂量为200cGy或更高时，在烧伤部位和烧伤边缘的毛囊隆突区域和基底角质细胞层的增殖细胞个数均有一致减少。由于这两种细胞群负责热损伤的上皮再形成，联同热损伤的200cGy剂量提高死亡率并降低愈合。实施例2NorLeu3-A(1-7)在CRBI模型中的效用
在后续研究中，于NorLeu3-A(1-7)剂量-反应研究中将200cGy TBI与18mm烧伤复合。热损伤当日和直至第14天的每日，将各浓度的NorLeu3-A(1-7)(0-300μg/天)施予热损伤部位(图3)。在豚鼠中施予1μg/创伤/天和以上剂量的NorLeu3-A(1-7)降低与复合伤口关联的死亡率。当NorLeu3-A(1-7)剂量为10μg/每日和以上时，烧伤边缘的基底角质细胞层中的细胞数有增长(图4)。所有剂量(除了3μg/创伤/天)的NorLeu3-A(1-7)都提高了创伤边缘毛囊隆突部的增殖细胞数(图5)。
实施例3测定豚鼠中可启动NorLeu3-A(1-7)的时间点
在该模型中进行第二个研究来评估治疗可被延迟但仍可降低死亡率的时长。在此研究中，豚鼠经受200cGy TBI，然后在2小时后经受热损伤。在第0天开始用安慰剂治疗。在第0、1、2、3或4天启动10或100μg/日的NorLeu3-A(1-7)治疗。当在第0、1、2或3天开始治疗时，存活率提高至约40-60%，而与之相对的安慰剂治疗动物中则为14％(图6-9)。然而，如果延迟至第4天才启动治疗，则疗效降低。方法
针对这些，从查尔斯河实验室(Charles Rivers Laboratory)(马萨诸塞州，查尔斯河)购得体重约500克的雄性哈特利(Hartley)豚鼠。所述豚鼠以12:12小时的明:暗周期饲养在南加州大学(USC)的动物饲养所中。使用铯137辐射器使所述动物接受200cGyTBI。1或2小时后，使所述豚鼠受到热损伤。如Rodgers等人，1997a,b,2001中所述的那样造成热损伤并实施操作后护理。简而言之，麻醉后用直径为18mm的实心黄铜棒在每个豚鼠上造成两处烧伤，所述黄铜棒已在75°C的水浴中加温。将所述黄铜棒的一端在豚鼠背上放置50秒。
用含和不含NorLeu3-A(1-7)的含2％HEC(用于局部药物施用的载体)的pH6.5的0.05mol/L磷酸缓冲剂处理每处烧伤，并分别包扎。TBI和热损伤后在如下文所述的各个时间开始治疗。
在热损伤后的第14天，使所述豚鼠安乐死，整体切除损伤区域。将所述组织置于10％缓冲福尔马林溶液中过夜。通过损伤部位的增殖细胞数来检测愈合。
用亲和素生物素(blotin)-氧化物酶偶联物法进行免疫组化染色。在PBS中进行最后一次漂洗后，将切片在含0.03%过氧化氢的0.06％3,3'-二氨基联苯胺的PBS溶液中孵育5分钟。用改进的哈里斯(Harris's)苏木精-伊红进行复染，将切片脱水，并用Permount封片剂盖片。
用奥林巴斯Vanox-S AH-2解剖显微镜和100×的放大倍数，将活检样品的每个切片分为烧伤边缘区域或实际烧伤区域。包埋烧伤边缘和烧伤的整体区域，并做组织学检测。评估每个切片中的四至六个连续中等倍数视野(mpf，100×)。以MIB-1抗体染色的细胞呈明显的褐色。对位于活检切片毛囊中的所有染色细胞计数。将载玻片上的每个切片分到单独的中等倍数视野(mpf)中来对MIB-1染色细胞计数。然后确定各视野是烧伤边缘部分还是烧伤区域本身的一部分。边缘可通过沿切片边缘表现为棕色表皮细胞的阳性染色来表明。烧伤区域可通过缺少沿边缘的棕色染色细胞来表明。在mpf放大倍数下对位于每个毛囊中的棕色细胞进行逐个计数。建立标记以移至下一个mpf，并将载玻片移至下一个相邻视野。
结果
在该模型中实施第二个研究来评估治疗可被延迟但仍可降低死亡率的时长。在该研究中，所述豚鼠经受200cGy TBI，并在2小时后经受热损伤。在第0天开始安慰剂治疗。在第0、1、2、3或4天启动10或100μg/天的NorLeu3-A(1-7)治疗。在CRBI后第0、1、2或3天开始治疗，存活提高至约40-60%，而与之相对的安慰剂治疗动物中则为14％(图7)。然而，若延迟至第4天才启动治疗，则效用降低。
实施例4
仅接受热损伤的小鼠在7％全体表面积接受10秒钟的70oC烫伤(在氯胺酮/甲苯噻嗪麻醉下)。接受复合损伤的小鼠通过铯辐射器接受6Gy剂量的全身辐射，并在2小时后接受同样的烫伤。对于所显示的数据，烫伤后立即开始治疗，并用透明伤口敷料Tegaderm包扎伤口。每日以1mg/ml的浓度对每个伤口给予100ul来进行治疗。在第7天使动物安乐死。用TUNEL实验检测真皮组织中的细胞凋亡。数据如图10所示。NorLeu3-A(1-7)提供可缓解涉及辐射的被延迟的伤口愈合的附加系统。
Claims (13)
1.由SEQ ID NO:1(Asp-Arg-Nle-Tyr-Ile-His-Pro)所示的氨基酸序列组成的肽或其药用盐在制备治疗受到复合性(i)全身电离辐射暴露和(ii)烧伤的哺乳动物的药物中的应用。
2.如权利要求1所述的应用，其特征在于，所述药物相比对照致使所述哺乳动物的存活率提高。
3.如权利要求1所述的应用，其特征在于，所述药物相比对照致使烧伤愈合加速。
4.如权利要求2所述的应用，其特征在于，所述药物相比对照致使烧伤愈合加速。
5.如权利要求1-4中任一项所述的应用，其特征在于，所述哺乳动物的一处或多处的以下部位受到二度烧伤：躯干、背、头、手臂或腿。
6.如权利要求1-4中任一项所述的应用，其特征在于，所述哺乳动物经暴露于0.2戈瑞(G)y至10Gy的全身电离辐射。
7.如权利要求1-4中任一项所述的应用，其特征在于，所述哺乳动物经暴露于1戈瑞(G)y至10Gy的全身电离辐射。
8.如权利要求1-4中任一项所述的应用，其特征在于，所述哺乳动物经暴露于2戈瑞(G)y至10Gy的全身电离辐射。
9.如权利要求1-4中任一项所述的应用，其特征在于，所述哺乳动物经暴露于至少20cGy累积全身电离辐射。
10.如权利要求1-4中任一项所述的应用，其特征在于，所述全身电离辐射选自下组：β-辐射、γ-辐射和X-射线。
11.如权利要求1-4中任一项所述的应用，其特征在于，所述全身电离辐射由暴露于选自下组的辐射源引起：核武器、核能设施、计算机断层扫描设备、X-射线设备、用于骨髓移植预处理的辐射器、核能运输工具及被放射性物质污染的环境。
12.如权利要求1-4中任一项所述的应用，其特征在于，所述肽在暴露于全身电离辐射三天内给予。
13.如权利要求1-4中任一项所述的应用，其特征在于，所述肽被配制为透皮给药的形式。
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| ES2834430T3 (es) | 2013-03-15 | 2021-06-17 | Univ Southern California | Procedimientos, compuestos y composiciones para el tratamiento de enfermedades relacionadas con la angiotensina |
| EP2968441A1 (en) | 2013-03-15 | 2016-01-20 | University of Southern California | Methods for treating multiple sclerosis |
| RU2647369C2 (ru) * | 2016-08-16 | 2018-03-15 | федеральное государственное бюджетное научное учреждение "Федеральный центр токсикологической, радиационной и биологической безопасности" (ФГБНУ "ФЦТРБ-ВНИВИ") | Способ лечения острой ожоговой токсемии организма и способ получения противоожоговой сыворотки реконвалесцентов для лечения ожоговой токсемии организма |
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| CN1706502A (zh) * | 2005-05-25 | 2005-12-14 | 中国药科大学 | 一种抗高血压核酸疫苗及其制备方法 |
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| JP3728400B2 (ja) | 1998-03-10 | 2005-12-21 | ユニヴァースティ オブ サザーン カリフォルニア | 改良型放射線治療の諸方法 |
| US7173011B2 (en) * | 2000-11-20 | 2007-02-06 | University Of Southern California | Radiation therapy methods |
| CA2367107C (en) | 1999-03-23 | 2003-10-14 | University Of Southern California | Methods for limiting scar and adhesion formation |
| US20070293458A1 (en) * | 2006-06-16 | 2007-12-20 | Ip-6 Research Inc. | Prevention of nuclear, solar, and other radiation-induced tissue damage |
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| US6455500B1 (en) * | 1998-03-10 | 2002-09-24 | University Of Southern California | Radiation therapy methods |
| CN1706502A (zh) * | 2005-05-25 | 2005-12-14 | 中国药科大学 | 一种抗高血压核酸疫苗及其制备方法 |
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Also Published As
| Publication number | Publication date |
|---|---|
| US20130123190A1 (en) | 2013-05-16 |
| CN102905719A (zh) | 2013-01-30 |
| JP2016026189A (ja) | 2016-02-12 |
| JP2013523659A (ja) | 2013-06-17 |
| EA201201338A1 (ru) | 2013-03-29 |
| WO2011120032A1 (en) | 2011-09-29 |
| EP2552469B1 (en) | 2014-09-03 |
| EP2552469A1 (en) | 2013-02-06 |
| EA022388B1 (ru) | 2015-12-30 |
| US9272013B2 (en) | 2016-03-01 |
| JP5823486B2 (ja) | 2015-11-25 |
| SG10201502348VA (en) | 2015-05-28 |
| SG184247A1 (en) | 2012-10-30 |
| KR20130066598A (ko) | 2013-06-20 |
| MX2012011036A (es) | 2013-03-18 |
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