CN101610760A - 恶病质的治疗 - Google Patents
恶病质的治疗 Download PDFInfo
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- CN101610760A CN101610760A CNA2007800446415A CN200780044641A CN101610760A CN 101610760 A CN101610760 A CN 101610760A CN A2007800446415 A CNA2007800446415 A CN A2007800446415A CN 200780044641 A CN200780044641 A CN 200780044641A CN 101610760 A CN101610760 A CN 101610760A
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- antagonist
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- adrenaline
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Abstract
本发明提供一种防止和治疗恶病质和其它慢性疾病的方法，包括但不限于通过使用降低β－肾上腺素受体和5－HT1a受体两者的敏感性的物质，促进体重增加、减少或防止体重降低。(S)－心得乐、(S)－心得安、特他洛尔或波吲洛尔优选用于这一目的。
Description
技术领域
本发明涉及用于恶病质(Cachexia)治疗的化合物或方法的领域。
恶病质发生在许多末期疾病如癌症、心脏衰竭、慢性阻塞性肺病(COPD)、肝衰竭、肾衰竭、中风、类风湿性关节炎(rheumatoidarthritis)、重度烧伤和HIV/AIDS。其还在衰老中出现。
在重度COPD、心脏衰竭、肝衰竭和肾衰竭中，约30％的患者有恶病质；在心脏衰竭和AIDS中，该比例为近10％。
恶病质发生在约50％的所有癌症患者中，并且可以是疾病的直接结果或其治疗的结果。考虑到恶病质可以干扰放射或化学治疗并且对其的控制可以改善结果并且为患者和其家属提供康乐的感觉。
虽然还没有正式商定的定义，恶病质已被描述为一种无意识的体重降低的衰弱状态(Uomo等人，J Pancreas(Online)2006；7(2)：157-162)。Fearon等人(Am J Clin Nutr 2006；83：1345-50)陈述“患有晚期的恶病质的患者特征在于厌食症、早饱感、严重的体重降低、虚弱、贫血和水肿。……涉及到对于恶病质的新型治疗剂的批准，制定规章的权威建议重要的不只是显示改善营养状况如瘦弱的体重(LBM)的有效性还有功能状况如工作能力状况。……恶病质的不良体格功能可以涉及许多因素，包括体重降低、减少的物质供应(食物摄入)或降低的意志力(疲劳或抑郁)；其所有都涉及到，至少是部分涉及全身的炎症效应。”
虽然通常和慢性病关联，恶病质并不总是如此关联，并且还在缺少基础疾病时存在。当存在时，对基础疾病的治疗不会必然地治疗恶病质。恶病质本身在癌症(Dewys WD等人Eastern Cooperative OncologyGroup.Am J Med 1980；69：491-7)和心脏衰竭(Steinborn C，Anker SD，Basic Appl Myol 13(4)：191-201，2003)的背景下具有预后的重要性；因此独立于基础疾病而治疗恶病质具有医疗益处。恶病质不被营养介入有效地治疗，并因此与进食障碍症如厌食症不同。恶病质通常还包括不成比例地丧失肌肉，而饥饿开始是导致脂肪的丧失(Morley JE等人，Am J Clin Nutr 2006；83：735-43)。
除了体重降低，恶病质还与疲劳、衰弱、恶心、降低的工作能力状况和来源于身体形象改变的心理苦恼关联。使用过/尝试过的治疗包括妊娠素(progestins)、皮质激素(corticosteroids)、灭吐灵(metoclopramide)、大麻素类(cannabinoids)、反应停(thalidomide)、褪黑激素(melatonin)、克仑特罗(clenbuterol)、合成代谢类固醇(anabolic steroids)、omega 3脂肪酸和NSAID。
发明内容
本发明提供一种通过使用为β-肾上腺素受体和5-HT1a受体的拮抗剂或部分激动剂的化合物治疗恶病质的方法。
(S)-心得乐((S)-pindolol)、(S)-心得安((S)-propranolol)、(S)-喹酮心安((S)-carteolol)、(S)-喷布洛尔((S)-penbutolol)、(S)-心得舒((S)-alprenolol)、特他洛尔(tertatolol)、(S)-特他洛尔((S)-tertatolol)、甲吲洛尔(mepindolol)、(S)-甲吲洛尔((S)-mepindolol)、波吲洛尔(bopindolol)和(S)-波吲洛尔((S)-bopindolol)是用于这一目的的优选的化合物。(S)-心得乐是尤其优选的化合物。
根据本发明，对β-肾上腺素受体和5-HT1a受体都具有亲和力的(S)-心得乐[也称作(-)-心得乐、S(-)-心得乐、S-(-)-1-(1H-吲哚-4-基氧)-3-(1-甲基乙氨基)2-丙醇]，和(S)-心得安[也称作(-)-心得安、S(-)-心得安、(S)-1-异丙氨基-3-(1-萘氧基)-2-丙醇]，对患有恶病质的受试者具有有益的效应。
与减低血压的常规的β-阻滞剂相比，优选的化合物被认为产生减少的血压改变。优选的化合物还被认为减少疲劳。
发明详述
本发明设想作为拮抗剂或部分激动剂的与β-肾上腺素受体和5-HT1a受体相互作用的任何物质的使用。
根据EP99947762，β-肾上腺素受体拮抗剂已经被声称在恶病质的治疗中有用，其内容并入本文作为参考。本专利谈及通过使用降低交感神经系统活性的试剂治疗由于基础疾病导致的体重降低的方法。WO2006102476描述β-肾上腺素的拮抗剂和抗炎症的试剂如NSAID(非类固醇类的抗炎症试剂)的结合。心得乐和心得安的外消旋形式在这些专利中被特别地提到，虽然对映体的使用未被提到。
当在此使用，并且会被本领域的技术人员理解时，外消旋体的对映结构体形式是指基本上由单一异构体，即基本上无其它异构体，含有至少90％的这样的单一异构体，或优选地至少95％的这样的单一异构体，或更优选地至少98％的这样的单一异构体构成的组合物。
心得乐和心得安作为外消旋物用于治疗高血压和绞痛，RS心得乐和RS心得安，主要是由于它们的β-肾上腺素受体的活性。心得乐的R-形式的药理学性质与S-对映体的不同。除了对β-肾上腺素受体的亲和力，(S)-心得乐在相似的剂量范围中还有对5-HT1a的受体的亲和力。最近已经报道(WO2006030306)(S)-心得乐在大多数健康受试者中不产生血压的改变而相似剂量的外消旋心得乐具有降低舒张期血压的效果。因此，(S)-心得乐的表现不像降低血压的常规的β-阻滞剂。
(S)-心得安对映选择性地与5HT-1a受体相互作用(J.Pharm.Pharmacol.39，664-666，(1987))并且功能性测试已经确认(S)-心得安而不是(R)-心得安在背脊神经放电上阻滞了5-HT1a拮抗剂的抑制性效果(Eur J Pharmacol.1986Sep 9；128(3)：295-8)。已经在前臂血流实验中观察到(S)-心得安和(R)-心得安的不同效果(J Cardiovasc Pharmacol.1995Feb；25(2)：268-72)。
本发明使用双作用化合物而与β-肾上腺素受体和5-HT1a受体两者相互作用并且作为结果提供治疗恶病质的方法同时避免β-肾上腺素拮抗剂的共同副作用，即疲劳。在另一方面，在患有慢性疾病包括但不限于癌症、心脏衰竭、慢性阻塞性肺病(COPD)、肝衰竭、肾衰竭、中风、类风湿性关节炎、重度烧伤和HIV/AIDS的患者中，本发明使用双作用化合物而与β-肾上腺素受体和5-HT1a受体两者相互作用以促进体重增加，或降低或防止体重减少，同时避免β-肾上腺素拮抗剂的共同副作用，即疲劳。本发明设想这些受体的拮抗剂和部分激动剂。β-肾上腺素受体的部分激动剂的特征在于具有内在的拟交感神经活性。本发明的优选的具体实施方案包括异构体(S)-心得乐、(S)-心得安、(S)-喹酮心安、(S)-喷布洛尔、(S)-心得舒和外消旋特他洛尔、甲吲洛尔或波吲洛尔或其盐。本发明还设想特他洛尔、甲吲洛尔或波吲洛尔的S-对应体的使用。
β-肾上腺素受体的拮抗剂的一个副作用是疲劳。在例如癌症、心脏衰竭等的严重情况下，在作为征候的恶病质中这尤其是一个问题。例如，虽然其有被证明的死亡率方面的益处，β-肾上腺素受体的拮抗剂的治疗在心脏衰竭的患者中仍然相当地使用不足。不愿开这些试剂的处方可能是由于对它们和疲劳的症状相关联的顾虑。根据Ko等人(JAMA 2002；288：351-7)，发现在用β-肾上腺素受体的拮抗剂治疗的心脏衰竭的患者中增加15％报道的疲劳症状。
在一个方面，与只作为β-肾上腺素的拮抗剂作用的其它药物相比，在治疗恶病质中本发明的化合物特别有用，因为，例如在人类中不增加疲劳或在某些病例中可以减少，同时保持对抗恶病质的体重降低的效力。优选地，在治疗的受试者中，疲劳是减少的。
在另一方面，在无对血压的作用时，本发明的化合物对抗恶病质是有效的，例如在人类或在被治疗的受试者中。这在经常有自发的神经系统机能障碍的癌症患者的背景中是重要的。
对于癌症患者，在他们可以忍受放射或化学治疗的程度上，疲劳还可以是限制因素。因此改善疲劳可以是使得癌症治疗更有效的一种方法。本发明的化合物被设想为在治疗患有癌症疲劳的恶病质癌症患者中特别有用。
疲劳通常是普通的健康疾病。但它是最难定义的术语之一，并且是许多不同情况的症状。
美国专利6,855,729建议(S)-和R(S)-心得乐用于治疗纤维肌痛和相关的慢性疲劳症状。在这一疲劳的显示中，常规的诊断评估部不显示结构或生化异常。解释病理生理学的尝试已经产生不一致的发现结果并且已经提出大量的理论。通过比较发现与慢性疾病如心脏衰竭、癌症、COPD、肝衰竭、肾衰竭和AIDS相关联的疲劳表示至少部分与定义明确的异常相关的一种现象。
状况的病理生理异质性支持对于疲劳的一套治疗方法，其中在一种疲劳中有用的试剂不必在另一种中有用。通常对疲劳的治疗已经包括针对贫血的铁补剂、帮助睡眠呼吸暂停的药物治疗和仪器、控制血糖的药物治疗、甲状腺药物治疗、控制感染的抗生素和维生素。
虽然疲劳在癌症和心脏衰竭中是最常见的症状之一，在这一背景下几乎没有药物治疗在其治疗中是有效的。精神兴奋剂可以提供康乐的感觉、减少疲劳和增加食欲。但是，这些药物也会造成失眠、兴奋和情绪改变。大剂量和长时间使用可以造成食欲丧失、夜惊、失眠、兴奋、妄想狂行为和可能的心脏问题。
当在本发明中使用时，根据治疗反应和药学形式，(S)-心得乐的通常剂量在单个或分开的剂量中将在每天2.5mg至50mg之间。根据治疗反应和药学形式，(S)-心得安的通常剂量在单个或分开的剂量中将在每天2.5mg至100mg之间。
不同的药物包装是可能的，包括(但不限于)片剂、胶囊、口服液和悬浮液和注射液。也包括口服使用的药物配方，其中活性成分以受控和缓慢的方式被释放以便可以不频繁地使用该治疗。
本发明预期用于治疗哺乳动物，包括人类。
心得乐的治疗胃肠疾病的能力已经在美国专利5,324,783和5,403,848中描述的临床环境中被证明。
实施例
腹水肝癌Yoshida AH-130细胞(108细胞)被接种到180-200g雄性Wistar大鼠中。可选择地，动物只接受盐水注射(假的)。动物以三个一组居住。接种的第二天动物被随机分成不同的组并且然后在近17天中用安慰剂或化合物接受每天两次的治疗。研究的初始终点包括体重的评估、身体组成(有或没有肿瘤)和存活。器官重量作为次级末端在研究的末端(或在死亡后)评估。另外用Supermex系统(Muromachi，Tokyo，Japan)在笼中24h时间内，运动活性被用于评估疲劳，其中动物被单独放置(3型笼子)；缺失的数据(如果因为死亡)作为“零”活性被推算；另外实施无推算点的敏感性分析。还测量食物的摄取。
除另外声明，结果作为平均值±SEM在研究的末端而表达。剂量代表通过口腔强饲法给与的总的每日剂量。
| 安慰剂 | 比索洛尔5mg/kg/天 | 比索洛尔50mg/kg/天 | S-心得乐0.3mg/kg/天 | S-心得乐3mg/kg/天 | |
| n | 24 | 14 | 14 | 10 | 10 |
| 无肿瘤的体重(g) | 167.92±8.05 | 202.0±16.04 | 159.18±9.64 | 178.89±17.04 | 215.10±19.89 |
| 无肿瘤的体重增加(g) | -26.46±7.72 | -5.46±15.95 | -30.30±10.95 | -8.50±19.19 | 17.30±20.08 |
| 无肿瘤的无脂肪组织(g) | 132.32±6.27 | 158.10±11.86 | 124.77±7.17 | 152.37±15.47 | 171.99±15.92 |
| 无肿瘤的无脂肪组织的增加(g) | -18.45±6.11 | -1.38±11.31 | -28.96±6.64 | -1.17±15.84 | 18.90±16.06 |
| 第11天食物摄取(g) | 7.83±1.28 | 16.00±3.07 | 9.94±2.10 | 7.75±5.22 | 15.33±3.84 |
| 第11天24h运动活性 | 320±46 | 315±58 | 277±39 | 361±38 | 368±50 |
这些结果明确地显示S-心得乐在癌症恶病质的动物模型中可以减少恶病质的体重降低，同时在作为疲劳的标志的运动活性上有积极的效果，并且还减少肿瘤的重量。通过比较，关于运动活性，标准的β-肾上腺素受体阻滞剂索洛尔是中性至阴性的。
Claims (22)
1、减少哺乳动物的疲劳的联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂在治疗恶病质中的应用。
2、一种治疗恶病质的方法，该方法包括向哺乳动物使用减少疲劳的联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂的步骤。
3、减少疲劳的联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂在用于治疗恶病质的药物制备中的应用。
4、一种用于治疗恶病质的减少疲劳的联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂。
5、根据权利要求1至4中任一项所述的应用、方法或联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂，其中联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂对血压无影响。
6、根据权利要求1至5中任一项所述的应用、方法或联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂，其中联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂是(S)-心得乐、(S)-心得安、(S)-喹酮心安、(S)-喷布洛尔，(S)-心得舒、特他洛尔、(S)-特他洛尔、甲吲洛尔、(S)-甲吲洛尔、波吲洛尔或(S)-波吲洛尔或其盐。
7、根据权利要求1至5中任一项所述的应用、方法或联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂，其中联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂是(S)-心得乐。
8、根据权利要求1至5中任一项所述的应用、方法或联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂，其中联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂是甲吲洛尔或(S)-甲吲洛尔。
9、根据权利要求1至5中任一项所述的应用、方法或联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂，其中联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂是波吲洛尔或(S)-波吲洛尔。
10、根据权利要求1至9中任一项所述的应用、方法或联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂，其中恶病质是由于衰老引起的。
11、根据权利要求1至9中任一项所述的应用、方法或联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂，其中恶病质是由于癌症引起的。
12、根据权利要求1至9中任一项所述的应用、方法或联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂，其中恶病质是由于心脏衰竭引起的。
13、根据权利要求1至9中任一项所述的应用、方法或联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂，其中恶病质是由于COPD引起的。
14、根据权利要求1至9中任一项所述的应用、方法或联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂，其中恶病质是由于肝衰竭或肝硬化引起的。
15、根据权利要求1至9中任一项所述的应用、方法或联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂，其中恶病质是由于中风引起的。
16、根据权利要求1至9中任一项所述的应用、方法或联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂，其中恶病质是由于类风湿性关节炎引起的。
17、根据权利要求1至9中任一项所述的应用、方法或联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂，其中恶病质是由于重度烧伤引起的。
18、根据权利要求1至9中任一项所述的应用、方法或联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂，其中恶病质是由于肾衰竭引起的。
19、根据权利要求1至9中任一项所述的应用、方法或联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂，其中恶病质是由于HIV/AIDS引起的。
20、根据权利要求1至9中任一项所述的应用、方法或联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂，其中恶病质在无诊断的慢性疾病时被发现。
21、根据权利要求1至20中任一项所述的应用、方法或联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂，其中治疗不降低受试者的血压。
22、根据权利要求1至21中任一项所述的应用、方法或联合的β-肾上腺素拮抗剂和5-HT1a部分激动剂或拮抗剂，其中疲劳与心脏衰竭、COPD、癌症、肾衰竭、肝衰竭或AIDS相关。
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| PCT/GB2007/004644 WO2008068477A1 (en) | 2006-12-05 | 2007-12-05 | Treatment of cachexia |
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Cited By (2)
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| CN104703654A (zh) * | 2012-07-25 | 2015-06-10 | 普西奥克瑟斯医疗有限公司 | S-吲哚洛尔对于治疗恶病质和肌肉衰减症的应用 |
| CN110169962A (zh) * | 2013-03-14 | 2019-08-27 | 艾可迪迈治疗有限公司 | 用于治疗癌症的氧烯洛尔组合物 |
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| GB0907350D0 (en) | 2009-04-29 | 2009-06-10 | Myotec Therapeutics Ltd | Methods |
| US11096908B2 (en) | 2016-02-26 | 2021-08-24 | Actimed Therapeutics Ltd | S-enantiomerically enriched compositions of beta blockers for treating muscle weakness |
| GB2593902B (en) * | 2020-04-07 | 2022-04-13 | Actimed Therapeutics Ltd | Salt of a pharmaceutical compound |
| GB202114564D0 (en) | 2021-10-12 | 2021-11-24 | Actimed Therapeutics Ltd | Oral formulation |
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| US5541188A (en) * | 1987-09-15 | 1996-07-30 | The Rowett Research Institute | Therapeutic applications of beta-adrenergic agonists |
| CA1337432C (en) | 1988-03-23 | 1995-10-24 | Raymond M. Xhonneux | Method of lowering the blood pressure |
| US6545040B1 (en) * | 1988-03-23 | 2003-04-08 | Janssen Pharmaceutica N.V. | Method of lowering the blood pressure |
| CA2025398A1 (en) | 1989-09-20 | 1992-03-15 | Timothy Gerard Dinan | Diagnosis and treatment of a disorder of the gastrointestinal tract |
| US5120791A (en) | 1990-07-27 | 1992-06-09 | Lisco, Inc. | Golf ball cover compositions |
| DE69942009D1 (de) | 1998-10-15 | 2010-03-25 | Imp Innovations Ltd | Verbindungen für die behandlung von gewichtsverlust |
| EE200200425A (et) * | 2000-01-31 | 2003-10-15 | Pfizer Products Inc. | Selektiivsete PDE4 isosüümide inhibiitoritena kasulikud nikotiinamiidi bensokondenseerunud heterotsüklüülderivaadid |
| AR030414A1 (es) * | 2000-04-03 | 2003-08-20 | Astrazeneca Ab | Combinacion farmaceutica que comprende un beta bloqueante y un inhibidor de hmg-coa reductasa , formulacion farmaceutica, equipo transportable de partes , uso de esta combinacion y de esta formulacion para preparar medicamentos |
| WO2003065970A2 (en) * | 2001-02-20 | 2003-08-14 | Royal College Of Surgeons Ie | Treatment of fibromyalgia and related fatigue syndromes using pindolol |
| US6670140B2 (en) * | 2001-03-06 | 2003-12-30 | The Procter & Gamble Company | Methods for identifying compounds for regulating muscle mass or function using corticotropin releasing factor receptors |
| AU2005283829A1 (en) | 2004-09-17 | 2006-03-23 | Neurocure Ltd | Pindolol for the treating premenstrual syndrome and premenstrual dysphoric disorder |
| CA2580694A1 (en) | 2004-09-23 | 2006-03-30 | Alexander Michalow | Methods for regulating neurotransmitter systems by inducing counteradaptations |
| EP2374458A1 (en) * | 2005-03-21 | 2011-10-12 | Vicus Therapeutics SPE 1, LLC | Combination of an ACE inhibitor and an NSAID for use in ameliorating cachexia/SIRS |
| US8080528B2 (en) * | 2005-12-22 | 2011-12-20 | The Releef Initiative | Compositions and methods for treatment of cachexia |
| JP2009528289A (ja) | 2006-02-27 | 2009-08-06 | ミシャロウ、アレクサンダー | 対抗適応を誘発することにより神経伝達物質系を調節する方法 |
| JP5337040B2 (ja) | 2006-11-09 | 2013-11-06 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Ｓｇｌｔ−２インヒビターとの組み合わせ治療及びそれらの医薬組成物 |
| CA2721739C (en) | 2007-04-24 | 2016-08-23 | Acacia Pharma Limited | Drug combination and its use in the treatment of muscle loss |
| EP3028743A3 (en) | 2008-03-05 | 2017-01-25 | Vicus Therapeutics, LLC | Compositions for mucositis and oncology therapies |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104703654A (zh) * | 2012-07-25 | 2015-06-10 | 普西奥克瑟斯医疗有限公司 | S-吲哚洛尔对于治疗恶病质和肌肉衰减症的应用 |
| CN110169962A (zh) * | 2013-03-14 | 2019-08-27 | 艾可迪迈治疗有限公司 | 用于治疗癌症的氧烯洛尔组合物 |
| US11433036B2 (en) | 2013-03-14 | 2022-09-06 | Actimed Therapeutics Limited | Oxprenolol compositions for treating cancer |
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| AU2007330607B2 (en) | 2013-02-07 |
| EP2359822B1 (en) | 2016-08-03 |
| RU2009125548A (ru) | 2011-01-20 |
| EP2094254A1 (en) | 2009-09-02 |
| BRPI0720114A2 (pt) | 2014-04-15 |
| PL2094254T3 (pl) | 2011-12-30 |
| AU2007330607A1 (en) | 2008-06-12 |
| ES2395244T3 (es) | 2013-02-11 |
| CA2671622C (en) | 2015-01-27 |
| EP2359822A1 (en) | 2011-08-24 |
| WO2008068477A1 (en) | 2008-06-12 |
| DK2094254T3 (da) | 2011-10-03 |
| JP5166437B2 (ja) | 2013-03-21 |
| EP2094254B1 (en) | 2011-06-22 |
| CA2671622A1 (en) | 2008-06-12 |
| PT2094254E (pt) | 2011-09-19 |
| ZA200904704B (en) | 2010-05-26 |
| US8716325B2 (en) | 2014-05-06 |
| GB0624282D0 (en) | 2007-01-10 |
| JP2010511685A (ja) | 2010-04-15 |
| CN101610760B (zh) | 2012-09-26 |
| RU2485950C2 (ru) | 2013-06-27 |
| BRPI0720114A8 (pt) | 2016-01-19 |
| ATE513543T1 (de) | 2011-07-15 |
| US20100292270A1 (en) | 2010-11-18 |
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