CN102058614A - 腺苷受体激动剂在治疗中的用途 - Google Patents
腺苷受体激动剂在治疗中的用途 Download PDFInfo
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Abstract
描述了式(I)化合物的用途:其中R是C1-4烷氧基和X是OH或H;用于癌,炎症,自身免疫病,缺血-再灌注损伤,癫痫,败血症,败血性休克,神经变性(包括阿尔茨海默氏病),肌肉疲劳或肌肉痛性痉挛的预防、治疗或改善。化合物在很低的剂量下有效,因此能以观察不到严重副作用的剂量给药。
Description
本申请是国际申请号为PCT/GB2004/000952、发明名称为“腺苷受体激动剂在治疗中的用途”、申请日为2004年03月05日的国际申请的分案申请。
本发明涉及腺苷受体激动剂作为治疗化合物的用途。
腺苷是无处不在的局部激素/神经递质,作用于四种已知的受体,腺苷A1,A2A,A2B,A3受体。腺苷通常起平衡组织中能量的供给与需求的作用。例如,在心脏中释放的腺苷通过A1受体在结节和心房中的介导作用,减慢心脏(Belardinelli,L & Isenberg,G Am.J.Physiol.224,H734-H737),同时地扩张冠状动脉而增加能量(亦即葡萄糖,脂肪和氧)供给(Knabb等,Circ.Res.(1983)53,33-41)。相似地,在炎症中腺苷起抑制炎症活性的作用,而在过度的神经活性的状况(例如癫痫)下,腺苷抑制神经发放(Klitgaard等,Eur J.Pharmacol.(1993)242,221-228)。这个系统,或其变体,存在于所有的组织中。
腺苷本身能用于诊断和治疗室上性心动过速。已知腺苷A1受体激动剂用作强效镇痛剂(Sawynok,J.Eur J Pharmacol.(1998)347,1-11)。已知腺苷A2A受体激动剂用作抗炎症药(例如,从US 5877180和WO 99/34804中已知)。在实验动物中,已经显示A2A受体激动剂有效对抗各种状况包括败血症,关节炎,和由肾、冠状或脑动脉闭塞引起的局部缺血/再灌注损伤。在这些情况中的共性因素是由这种受体对大多数的,如果不是所有的,炎症细胞的抑制效应引起的炎症反应的降低。
然而,无处不在的腺苷受体的分布意谓着给予腺苷受体激动剂将引起不利的副作用。这通常地妨碍以腺苷为基础的治疗的发展。选择性A1受体激动剂引起心动过缓。第一个选择性A2A受体激动剂(2-[4-(2-羧基乙基)苯乙胺]-5′-N-乙基甲酰胺腺苷,或CGS21680),作为潜在的抗高血压药在2A期临床试验中被测试。然而给药引起血压大下降和随之而来的心输出量的增加。FR 2162128公开腺苷衍生物(包括2-烷氧基腺苷衍生物,其包含不少于两个碳原子的低级烷基基团)具有降血压和冠状血管扩张活性。
Bartlett等(J.Med.Chem.1981,24,947-954)公开了1-甲基异鸟嘌呤核苷类似物的评价。这些类似物包括2-甲氧基腺苷(也被称为海绵核苷)。这个和其它的化合物在啮齿动物口服给药后测试它们的骨骼肌松弛,低体温,心血管和抗炎症的效果(抗炎症的活性由抑制角叉菜胶引起的大鼠爪水肿评定)。在大鼠中口服20mg/kg2-甲氧基腺苷使角叉菜胶引起的炎症受到25%的抑制。然而,以这个剂量给予这个化合物后也观察到平均血压(41%)和心率(25%)降低。
因此,存在一种提供可给予具有最少副作用的腺苷受体激动剂的需要。
依照本发明,在此提供下式化合物的用途:
(I)
其中R是C1-4烷氧基和X是OH;
用于制造用于预防、治疗或改善癌,炎症,自身免疫疾病,缺血-再灌注损伤,癫痫,败血症,败血性休克,神经变性(包括阿尔茨海默氏病),肌肉疲劳或肌肉痛性痉挛(尤其运动员的痛性痉挛)的药物。
依照本发明,在此也提供下式化合物的用途:
(II)
其中R是C1-4烷氧基和X是H;
用于制造用于预防、治疗或改善癌,炎症,自身免疫疾病,缺血-再灌注损伤,癫痫,败血症,败血性休克,神经变性(包括阿尔茨海默氏病),肌肉疲劳或肌肉痛性痉挛(尤其运动员的痛性痉挛)的药物。
特别地,依照本发明在此提供的式I或II化合物的用途,用于制造用于预防、治疗或改善炎症或自身免疫疾病,包括类风湿性关节炎,骨关节炎,类风湿性脊椎炎,痛风性关节炎,和其它关节炎状况,银屑病,哮喘,慢性阻塞性肺疾病,纤维化,多发性硬化症,内毒素性休克,革兰氏阴性休克,中毒性休克,出血性休克,成人呼吸窘迫综合征,脑型疟TNF-增强的HIV复制,AZT和DDI活性的TNF抑制,器官移植排斥,继发于癌的恶病质,HIV,慢性肺炎疾病,矽肺,肺肉瘤病,骨吸收疾病,再灌注损伤(包括缺血性事件,例如心肌梗塞,中风后再灌注引起的对器官的损伤),自身免疫损伤(包括多发性硬化症,急性感染性多神经炎,重症肌无力)移植物对宿主的排斥,同种异体移植排斥,归咎于感染的发热和肌痛,继发于感染或恶性肿瘤的恶病质,继发于获得性免疫缺陷综合征(AIDS)的恶病质,AIDS有关的复征(ARC),瘢痕疙瘩形成,瘢痕组织形成,局限性回肠炎病,溃疡性结肠炎和热病(pyresis),过敏性肠综合征,骨质疏松症,脑型疟,细菌性脑膜炎,两性霉素B治疗引起的不良反应,白细胞介素-2治疗引起的不良反应,OKT3治疗引起的不良反应和GM-CSF治疗引起的不良反应的药物。
特别优选式(I)或(II)的化合物是选择性腺苷A2A和/或A3受体激动剂,因为据信这样的化合物将有强的抗炎活性。选择性腺苷A2A和/或A3受体激动剂意思是指以低于激活腺苷A1受体需要的浓度(优选千分之一至五分之一)激活腺苷A2A和/或A3受体的激动剂。此外,A1受体具有的前炎症(pro-inflammatory)活性,所以关于对腺苷A2A和/或A3受体选择性的化合物,这样的作用被期望最小化。
式(I)的化合物包括:2-甲氧基腺苷,2-乙氧基腺苷,2-丙氧基腺苷,2-异丙氧基腺苷,和2-丁甲氧基腺苷。式I的优选化合物是2-甲氧基腺苷,2-乙氧基腺苷,和2-丁甲氧基腺苷。
式(II)的化合物包括:3′-脱氧-2-甲氧基腺苷,3′-脱氧-2-乙氧基腺苷,3′-脱氧-2-丙氧基腺苷,3′-脱氧-2-异丙氧基腺苷,和3′-脱氧-2-丁甲氧基腺苷。式II的优选化合物是3′-脱氧-2-丙氧基腺苷,3′-脱氧-2-异丙氧基腺苷,和3′-脱氧-2-丁甲氧基腺苷。
2-甲氧基腺苷被报道在腺苷A2A受体上具有EC50值3μM(Daly,J.W.等,(1993)Pharmacol.46,91-100)。然而,令人惊讶地,这个化合物在血浆浓度0.2μM或更小时具有显著的抗炎活性。在这些低剂量时2-甲氧基腺苷已经减少了副作用的概率和严重性。2-甲氧基腺苷能以作为抗炎剂有效的浓度给药,但这个浓度低于观察到副作用的浓度。
同样相信,式(I)的其它化合物和式(II)的化合物在低剂量时比其它腺苷受体激动剂更有效得多。因此预期式I的化合物和式II的化合物能以一种剂量有效地给药,在此剂量它们减少了副作用概率和严重性,或在此剂量没有观察到副作用。这样的化合物相对于大量的其它腺苷受体激动剂提供了显著的优点,所述其它腺苷受体激动剂仅在观察到严重副作用的相同浓度下才具有抗炎作用。
式(I)或式(II)的化合物与其它腺苷受体激动剂相比可以选择地或附加地减少副作用的概率和严重性。
给予受治疗者的式(I)或式(II)的化合物的量应该为引起的峰血浆浓度小于在pH 7.4时该化合物在腺苷受体上EC50值的量。
化合物的EC50值对不同的腺苷受体(亦即A1,A2A,A2B,A3腺苷受体)可能不同,这一点将被鉴别。给药的化合物的量应该依照该化合物对不同的受体的最低的EC50值计算。
优选峰血浆浓度是EC50值的千分之一至五分之一,或五十分之一至三分之一(更优选千分之一至二十分之一,百分之一或五十分之一至五分之一,五十分之一至十分之一,或十分之一至五分之一)。优选给药的量产生的血浆浓度被保持在pH 7.4时该化合物在腺苷受体上的EC50值的千分之一至五分之一之间,更优选在千分之一至二十分之一,或百分之一至五分之一,或五十分之一至五分之一之间,达1小时以上。
为了避免疑问,化合物的EC50值在此处被定义为化合物激发的受体响应为基线受体响应和最大受体响应之间的中间值(halfway)的浓度(当确定时,例如,使用剂量-响应曲线)。
EC50值应该在标准条件(被缓冲至pH 7.4的平衡盐溶液)下确定。关于使用分离的膜,细胞和组织的EC50测定,这将是在pH 7.4的缓冲盐溶液(例如,细胞培养基)中,例如如在Daly等的Pharmacol,(1993)46,91-100),或优选Tilburg等的(J.Med.Chem,(2002)45,91-100)。EC50还可以通过在正常健康的动物中,或甚至在正常健康动物中在正常状态(亦即氧合的血液,或氧合的等渗介质,也缓冲在pH 7.4)下灌注的组织中测量腺苷受体介导的响应进行体内测定。
选择地,给予的式(I)或式(II)的化合物的量可以是导致的峰血浆浓度为在腺苷受体上的Kd值的千分之一至二十分之一,千分之一至三分之一,更优选百分之一至五分之一,或五十分之一至十分之一的量。
化合物的Kd值对不同的腺苷受体(亦即A1,A2A,A2B,A3腺苷受体)可能不同,这一点将被鉴别。给药的化合物的量应该依照该化合物对不同的受体的最低的Kd值计算。
优选地,给予的化合物的量是导致的血浆浓度被保持在该化合物在腺苷受体上的Kd值的千分之一至五分之一之间,更优选在千分之一至二十分之一,或百分之一至五分之一,或五十分之一至五分之一之间,达至少1小时的量。
在每个受体上的化合物的Kd值应该在标准条件下使用来自内源性表达这些受体的组织或细胞的质膜,或来自转染有编码腺苷受体基因的DNA载体的细胞的质膜,作为腺苷受体的来源。选择地,使用表达腺苷受体的细胞的全细胞制备物也可以被使用,对不同受体选择性的标记配体(例如放射标记)应该在缓冲pH7.4盐溶液中(例如,Tilburg等,J.Med.Chem,(2002)45,420-429)被使用,以确定化合物在各受体上的结合亲和力和由此Kd值。
选择地,给予的式(I)或式(II)的化合物的量可以是该化合物在与给予所述化合物的受治疗者同种的动物中引起心动过缓、低血压或心动过速副作用的最小剂量的千分之一至五分之一,或五十分之一至三分之一(优选千分之一至二十之一,或百分之一或五十分之一至五分之一)的量。优选地,所述量是引起副作用的最小剂量的十分之一至五分之一。优选地,给药的量引起的血浆浓度被维持在引起所述副作用的最小剂量的千分之一至二十之一,或百分之一或五十分之一至五分之一之间达1小时以上。
选择地,给予的式(I)或式(II)的化合物的量可以是产生的血浆浓度为该化合物在与给予所述化合物的受治疗者同种的动物中引起心动过缓、低血压或心动过速副作用的最小血浆浓度的千分之一至五分之一,或五十分之一至三分之一(优选千分之一至二十之一,或百分之一或五十分之一至五分之一)的量。优选地,所述量引起的血浆浓度是引起所述副作用的最小血浆浓度的十分之一至五分之一。优选地,给药的量引起的血浆浓度被维持在引起所述副作用的最小血浆浓度的千分之一至二十之一,或百分之一或五十分之一至五分之一之间达1小时以上。
预期,给予的式(I)或式(II)的化合物的量应该是0.01至15mg/kg,例如,0.01至5或10mg/kg。所述量可以小于6mg/kg,例如0.01至2mg/kg。所述量可以是至少0.01或0.1mg/kg,例如0.1至2mg/kg,或0.2至1mg/kg。典型的量是0.2或0.6至1.2mg/kg。
对于70kg的人受治疗者,优选的剂量小于420mg,优选至少0.7mg,更优选至少3.5mg,最优选至少7mg。更优选7至70mg,或14至70mg。
上述的剂量显著低于(直到低约100倍)将预期式(I)化合物具有任何有益治疗效果所需要的量(基于海绵核苷在腺苷A2A受体上的EC50值)。
式(I)或式(II)的化合物适当的剂量将随着被治疗的受治疗者的年龄,性别,体重和状况,化合物的效能,和给药途径等而改变。适当的剂量容易地被本领域技术人员确定。
式(I)的化合物和式(II)的化合物可能特别有效用于预防、治疗或改善特殊类型的炎症,包括关节炎(特别在关节囊的关节炎),哮喘,银屑病,和肠炎。
式(I)的化合物和式(II)的化合物可能特别有效用于预防、治疗或改善类风湿性关节炎,过敏性肠综合征或骨关节炎。
依照本发明,在此还提供一种预防、治疗或改善癌,炎症,缺血-再灌注损伤,癫痫,败血症,败血性休克,神经变性(包括阿尔茨海默氏病),肌肉疲劳或肌肉痛性痉挛(尤其运动员的痛性痉挛)的方法,该方法包括给予式(I)或式(II)的化合物给需要如此预防、治疗或改善的受治疗者。
涉及式(I)化合物(特别是用于炎症的预防、治疗或改善)的本发明实施方案可以排除2-甲氧基腺苷。
式(I)或式(II)的化合物可以同或不同其它的治疗剂一起给予,例如止痛剂(例如阿片制剂,NSAIDs,大麻素类,速激肽调节剂,或缓激肽调节剂)或抗痛觉过敏剂(例如加巴喷丁,普加巴林,大麻素类,钠或钙通道调节剂,抗癫痫剂或抗抑郁药)。
一般而言,式(I)或式(II)的化合物可以使用已知的方法,在任何合适的制剂中,通过任何合适的途径给予。本发明的化合物优选口服地,肠胃外地,舌下地,透皮地,鞘内地,透粘膜地给予。其它的合适途径包括静脉内的,肌内的,皮下的,吸入的和局部的途径。当口服给予时,给予的药物的量将通常高于,比方说,静脉内给予时的量。
合适的组合物,例如用于口服给药的,包括固体单位剂量形式,和那些含液体的(例如用于注射的),例如片剂,胶囊,小瓶和安瓿,其中活性剂,经已知的方式,同生理学上可接受的赋形剂、稀释剂或载体一起组成配制。适当的稀释剂和载体是已知的,并包括,例如,乳糖和滑石粉,与适当的粘合剂等一起。
本发明化合物的单位剂量通常地包含5至500mg的活性剂。优选活性剂在药物组合物的形式中,该组合物包含活性剂和生理学上可接受的载体,赋形剂,或稀释剂。优选剂量是每千克(人)受治疗者0.1至2,例如0.5至1,代表性地约0.2或0.6mg活性剂。在这些水平,能实质上实现有效的治疗而没有相随的血压下降(例如,不超过10%)。
预期本发明的化合物优选的给药频率是每天两或三次。
本发明的化合物也用作鉴定更有效的药物,或具有进一步减少的副作用的药物的基础。
涉及式(I)化合物的本发明实施方案可以排除2-丙氧基腺苷,和/或2-异丙氧基腺苷。
涉及式(II)化合物的本发明实施方案可以排除3′-脱氧-2-甲氧基腺苷和/或3′-脱氧-2-乙氧基腺苷。
参照附图,在下面的实施例中描述本发明的实施方案,其中:
图1显示2-甲氧基腺苷抑制角叉菜胶引起的炎症,没有影响血压;
图2显示2-甲氧基腺苷(0.6mg/kg p.o.)对血压或心率没有显著的影响;和
图3显示给予2-甲氧基腺苷后血浆浓度随时间的变化。
实施例1
图1:A.2-甲氧基腺苷(62.4和624μg/kg i.p.)抑制角叉菜胶(CGN)引起的炎症,具有比得上吲哚美辛(3mg/kg,po)的效果,而没有影响血压;将角叉菜胶(2%,10微升)给予右后爪内,爪的体积由体积描记术(plethysomometry)评定。给予角叉菜胶的同时,给予2-甲氧基腺苷。2-甲氧基腺苷与吲哚美辛(Indo,3mg/kg,po)一样有效。
实施例2
图2:将可植入的无线电遥测术设备置于每组6只大鼠的腹腔内。将设备的压力导管插在腹主动脉内并在导联II位置(腹腔的左边/右肩)将两个电极埋于皮肤下。将单个鼠置于在辐射感受器(DSI)上它们自己的笼子内进行数据采集。然后评定0.6mg/kg2-甲氧基腺苷或赋形剂(p.o.)对血压的影响。A:血压;B:心率。
实施例3
2-甲氧基腺苷在腺苷A2A受体上的EC50值是900ng/ml(3μM)。图3显示了给予大鼠0.6mg/kg的2-甲氧基腺苷后血浆浓度随时间的变化。从中能看到血浆浓度维持在EC50值的2%以上超过3小时。当峰和维持的血浆浓度为低至8ng/ml时(亦即在体外确定的EC50值的2%)时,观察到抗炎效果(没有血压的变化)。如果峰血浆浓度达到900ng/ml水平(亦即EC50值)时,发生血压明显下降,它持续许多个小时。
Claims (11)
1.2-甲氧基腺苷在制造用于预防、治疗或改善炎症的药物中的用途。
2.根据权利要求1的用途,其以这样的剂量给予,在将所述剂量给予受治疗者后引起的峰血浆浓度小于在PH7.4在腺苷受体上的2-甲氧基腺苷的EC50值。
3.根据权利要求1或2的用途,其中所述受治疗者是人受治疗者。
4.根据权利要求1~3任一项所述的用途,其中所述药物用于预防、治疗或改善关节炎、肠炎、类风湿性关节炎、骨关节炎、类风湿性脊椎炎、痛风性关节炎、和其它关节炎状况、银屑病、哮喘、慢性阻塞性肺疾病、纤维化、多发性硬化症、内毒素性休克、革兰氏阴性休克、中毒性休克、出血性休克、成人呼吸窘迫综合征、脑型疟TNF-增强的HIV复制、AZT和DDI活性的TNF抑制、器官移植排斥、继发于癌的恶病质、HIV、慢性肺炎疾病、矽肺、肺肉瘤病、骨吸收疾病、包括心肌梗塞和中风后再灌注引起的对器官的损伤在内的再灌注损伤、包括多发性硬化症、急性感染性多神经炎和重症肌无力在内的自身免疫损伤、移植物对宿主的排斥、同种异体移植排斥、归因于感染的发热和肌痛、继发于感染或恶性肿瘤的恶病质、继发于获得性免疫缺陷综合征的恶病质、AIDS有关的复征、瘢痕疙瘩形成、瘢痕组织形成、局限性回肠炎、溃疡性结肠炎和热病、过敏性肠综合征、骨质疏松症、脑型疟、细菌性脑膜炎、两性霉素B治疗引起的不良反应、包括阿尔茨海默氏病的神经变性疾病、白细胞介素-2治疗引起的不良反应、OKT3治疗引起的不良反应和GM-CSF治疗引起的不良反应。
5.根据权利要求1~4任一项所述的用途,剂量导致的血浆浓度被维持在2-甲氧基腺苷在pH 7.4在腺苷受体上EC50值的千分之一和五分之一之间达1小时以上。
6.依照权利要求1至4任一项所述的用途,剂量导致的血浆浓度被维持在2-甲氧基腺苷在与给予2-甲氧基腺苷的受治疗者同种的动物中引起心动过缓、低血压或心动过速副作用的最小血浆浓度的千分之一和五分之一之间达1小时以上。
7.依照权利要求1~6任一项所述的用途,剂量是0.01至15mg/kg。
8.依照权利要求1~7任一项所述的用途,剂量是0.1至2mg/kg。
9.依照权利要求1~8任一项所述的用途,剂量是0.6至1.2mg/kg。
10.依照权利要求1~8任一项所述的用途,其中所述药物呈包含1至500mg的2-甲氧基腺苷的单位剂量形式。
11.一种呈单位剂量形式的药物组合物,它包含直到500mg的2-甲氧基腺苷和生理学上可接受的载体、赋形剂或稀释剂。
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US6004945A (en) | 1990-05-10 | 1999-12-21 | Fukunaga; Atsuo F. | Use of adenosine compounds to relieve pain |
US5677290A (en) | 1990-05-10 | 1997-10-14 | Fukunaga; Atsuo F. | Therapeutic use of adenosine compounds as surgical anesthetics |
US5683989A (en) * | 1993-12-17 | 1997-11-04 | Novo Nordisk A/S | Treatment of ischemias by administration of 2,N6 -substituted adenosines |
US5877180A (en) * | 1994-07-11 | 1999-03-02 | University Of Virginia Patent Foundation | Method for treating inflammatory diseases with A2a adenosine receptor agonists |
IT1275420B (it) | 1995-06-02 | 1997-08-05 | Schering Plough S P A | Metodo per misurare l'affinita' di legame al recettore a2a dell'adenosina di componenti di interesse farmacologico mediante l'uso del ligando triziato (3h)-sch 58261 |
JP2002500188A (ja) * | 1998-01-08 | 2002-01-08 | ザ・ユニバーシティ・オブ・バージニア・パテント・ファウンデーション | A2aアデノシンレセプター作動因子 |
US20030008841A1 (en) * | 2000-08-30 | 2003-01-09 | Rene Devos | Anti-HCV nucleoside derivatives |
GB0305149D0 (en) * | 2003-03-07 | 2003-04-09 | Cambridge Biotechnology Ltd | Compounds for the treatment of pain |
GB0305153D0 (en) | 2003-03-07 | 2003-04-09 | Cambridge Biotechnology Ltd | Identification of therapeutic compounds |
GB0305150D0 (en) * | 2003-03-07 | 2003-04-09 | Cambridge Biotechnology Ltd | Use of therapeutic compounds |
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2003
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- 2004-03-05 NZ NZ541587A patent/NZ541587A/en unknown
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- 2004-03-05 WO PCT/GB2004/000952 patent/WO2004078184A1/en active Application Filing
- 2004-03-05 US US10/547,454 patent/US7790698B2/en not_active Expired - Fee Related
- 2004-03-05 CA CA002514848A patent/CA2514848A1/en not_active Abandoned
- 2004-03-05 CN CN201010524262XA patent/CN102058614A/zh active Pending
- 2004-03-05 AU AU2004216891A patent/AU2004216891B2/en not_active Ceased
- 2004-03-05 KR KR1020057016713A patent/KR20050115895A/ko not_active Application Discontinuation
- 2004-03-05 JP JP2006505924A patent/JP2006519824A/ja not_active Ceased
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2010
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2012
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113116900A (zh) * | 2021-04-14 | 2021-07-16 | 兰州大学 | 一类核苷类似物在制备预防和/或治疗脑血管疾病药物中的应用 |
CN113116900B (zh) * | 2021-04-14 | 2022-07-08 | 兰州大学 | 一类核苷类似物在制备预防和/或治疗脑血管疾病药物中的应用 |
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NZ541587A (en) | 2008-08-29 |
EP1603576A1 (en) | 2005-12-14 |
CA2514848A1 (en) | 2004-09-16 |
JP2012111764A (ja) | 2012-06-14 |
AU2004216891B2 (en) | 2009-06-18 |
AU2004216891A1 (en) | 2004-09-16 |
US20110166093A1 (en) | 2011-07-07 |
GB0305150D0 (en) | 2003-04-09 |
NO20054475L (no) | 2005-09-27 |
JP2006519824A (ja) | 2006-08-31 |
US7790698B2 (en) | 2010-09-07 |
WO2004078184A1 (en) | 2004-09-16 |
CN1809365A (zh) | 2006-07-26 |
US20060234975A1 (en) | 2006-10-19 |
KR20050115895A (ko) | 2005-12-08 |
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