CN1925849A - 用于抑制认知功能减退的组合的药物组合物 - Google Patents
用于抑制认知功能减退的组合的药物组合物 Download PDFInfo
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- CN1925849A CN1925849A CNA2004800424056A CN200480042405A CN1925849A CN 1925849 A CN1925849 A CN 1925849A CN A2004800424056 A CNA2004800424056 A CN A2004800424056A CN 200480042405 A CN200480042405 A CN 200480042405A CN 1925849 A CN1925849 A CN 1925849A
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
本发明涉及一种用于抑制认知功能减退的组合的药物组合物,包括作为A)组分的通式I的(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷或其药学可接受的酸加成盐和作为B)组分的益智药、乙酰胆碱酯酶抑制剂和/或对认知过程显示有益作用的另一种药物活性组分,与适当的惰性药物载体和/或助剂混合。根据本发明的组合的药物组合物可以特别用于治疗阿尔茨海默氏病或者显示相似症状的其它疾病、伴随智力能力障碍的疾病(例如,在精神分裂症中的心智减退)、老年人的心智减退(在老年人中的痴呆)、科萨科夫综合征、亨廷顿综合征、帕金森综合征或者由酒精中毒产生的心智减退。
Description
发明领域
本发明涉及一种用于抑制认知功能减退的组合的药物组合物
技术背景
通式
的(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷(国际非专利名称:德伦环烷)是一种用于抗焦虑的药物活性成分,其落入HU 179,174的通式中。在HU 212,574中描述了德伦环烷的制备。
德伦环烷在不同的动物焦虑和应激模型中显示出重要的作用。在Vogel惩罚性饮水试验中,德伦环烷以1到10mg/kg的剂量口服后是有效的[Gacsályi等,Receptor binding profile and anxiolyticactivity of deramciclane(EGIS-3886)in animal models,Drug Dev.Res.40:p.338-348,(1997)]。在社会相互作用模型中,在0.7mg/kg单次口服治疗后,该化合物增加了花费在社会交互作用上的时间。在亮-暗模型[Crawley,J.N.Neuropharmacological specifity of asimple model of anxiety for the behavioural actions ofbenzodiazepine,Pharmacol.Biochem.Behavior,15:p.695-699(1981)]中,证明了口服单剂量3mg/kg sc的德伦环烷是有效的。在大理石掩埋模型[Broekkamp,C.L.等,Major TranquillizersCan Be Distinguished from Minor Tranquillisers on the Basis ofEffects on Marble Burying and Swim-Induced Grooming in Mice.Eur.J.Pharmacol.126:p.223-229,(1986)]中,该分子在以10到30mg/kg口服治疗后是有效的。
其作用机理是,该化合物显著地与中枢5-HT2C和5-HT2A受体结合[Gacsalyi等,Receptor binding profile and anxiolytic activityof deramciclane(EGIS-3886)in animal models,Drug Dev.Res.40.p.338-348,(1997)]。
很多的临床研究和观测支持下列事实:以智力和心理功能减退和/或老年痴呆为特征的疾病主要伴随有情绪方面和心情的异常和无能。
作用于较高神经系统活性的认知功能的改变导致适应的无能,由此导致焦虑和/抑郁。
根据文献记载,68-71%患有阿尔茨海默氏病的患者存在焦虑的问题,而焦虑又加速了认知减退[Ferretti等,Anxiety and Alzheimer′sdisease.J.Geriatr.Psychiatry.Neurol.,Spring,14(1),52-58(2001)]。
在患有亨廷顿病的患者中,发生了较高数量的神经精神症状,其中焦虑和病理性心境恶劣是最突出的[Paulsen等,Neuropsychiatricaspects of Huntington′s disease.J.Neurol.Neurosurg.Psychiatry.,71(3),310-314,(2001)]。
在不同原因的痴呆中,用辅助药物疗法可以治疗焦虑[Rojas-Fernandez et al.,Pharmacotherapy of behavioural andpsychological symptoms of dementia.Pharmacotherapy,21(1)74-102,(2001)]。
发明简述
根据本发明提供一种用于抑制认知功能减退的组合的药物组合物,包括作为A)组分的通式I(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷或其药学可接受的酸加成盐和作为B)组分的益智药、乙酰胆碱酯酶抑制剂和/或对认知过程显示有益作用的另一种药物活性组分,与适当的惰性药物载体和/或助剂混合。
发明详述
本发明的组合的药物组合物的优点是,通过所具有的对认知功能(记忆、注意力、知觉、学习)的有益作用和同时具有对情绪方面和心情的有利影响,它可以相当大地提高被治疗患者的生活质量。本发明的组合的药物组合物的进一步优点是,被治疗的患者通常为老年人,对于他们施用几种类型的药物是有问题的。而这个问题可以通过本发明的组合的药物组合物的帮助来获得解决,其中一个单独的药物适合处理他们的情况,使患者有较好的依从性。
本发明是建立在如下认识的基础上:作为组分A)施用的通式I的德伦环烷或其适当的酸加成盐所具有的抗焦虑、抗抑郁和减少恐惧作用,和作为组分B)施用的益智药、乙酰胆碱酯酶抑制剂或对认知过程具有有益作用的其他药物所具有的作用,能增强彼此的作用。
本发明的组合的药物组合物可以应用于如下的适应症:阿尔茨海默氏病或者显示相似症状的其它疾病、伴随智力能力障碍的疾病(例如,在精神分裂症中的心智减退)、老年人的心智减退(在老年人中的痴呆)、科萨科夫综合征、亨廷顿综合征、帕金森综合征或者由酒精中毒产生的心智减退。
根据本发明的组合的药物组合物包含作为组分A)的优选是(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷-2(E)-丁烯二酸(1∶1)。
根据本发明的组合的药物组合物包含作为组分A)的特别优选的是(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷或其药学可接受的酸加成盐,其包含不高于0.2%的通式
的(1R,3S,4R)-(-)-3-[2-N,N-(二甲基氨基乙基)]-1,7,7-三甲基二环[2.2.1]庚烷-2-酮或其药学可接受的酸加成盐。
根据本发明特别优选的实施方案的组合的药物组合物包含作为组分A)的(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷-2-(E)-丁烯二酸(1∶1),其包含不高于0.2%的(1R,3S,4R)-(-)-3-[2-N,N-(二甲基氨基乙基)]-1,7,7-三甲基二环[2.2.1]庚烷-2-酮-2-(E)-丁烯二酸(1∶1)。
根据本发明的组合的药物组合物包含作为组分B)的益智药、乙酰胆碱酯酶抑制剂和/或对认知过程具有有益作用的另一种药物活性组分。
作为益智药,优选可以使用吡拉西坦、茴拉西坦、奥拉西坦或普拉西坦。
作为乙酰胆碱酯酶抑制剂,优选可以使用加兰他敏、利凡斯的明或donezepil。
作为B)组分,还可以使用长春西丁、钙拮抗剂(例如,弥新平、尼莫地平、氨氯地平、非洛地平等)或抗氧化剂(例如维生素E)。
术语“药物可接受的酸加成盐”涉及药学可接受的无机或有机酸形成的盐。对于盐的形成,可以使用例如盐酸、氢溴酸、硫酸、磷酸、乳酸、柠檬酸、酒石酸、延胡索酸、马来酸、琥珀酸、苯磺酸、对甲苯磺酸等。特别有利地,可以使用通式(I)的(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷的延胡索酸盐,即(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷-2-(E)-丁烯二酸(1∶1)。
在匈牙利专利申请HU 1559/99中描述了(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷及其药学可接受的酸加成盐,其包含不高于0.2%的通式(II)的(1R,3S,4R)-(-)-3-[2-N,N-(二甲基氨基乙基)]-1,7,7-三甲基二环[2.2.1]庚烷-2-酮或其药学可接受的酸加成盐。
根据本发明的药物组合物可以制备成制药工业常用的盖仑制剂的形式。该组合物可以是固体或者液体(例如片剂、包衣片、糖衣丸、胶囊、溶液等)。该药物组合物可以口服或胃肠外给药,优选口服。可以用制药工业中本身已知的方法来制备根据本发明的组合的药物组合物。
根据本发明的另一个方面,提供一种制备用于抑制认知功能减退的药物组合物的方法,包括将作为A)组分的(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷或其药学可接受的酸加成盐和作为B)组分的益智药、乙酰胆碱酯酶抑制剂和/或对认知过程显示有益作用的另一种药物活性组分,与惰性药物载体和/或助剂混合,并将该混合物制成盖仑制剂的形式。
根据本发明的另一个方面,提供一种组合在抑制认知功能减退中的应用,其中该组合包含作为组分A)的(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷或其药学可接受的酸加成盐和作为组分B)的益智药、乙酰胆碱酯酶抑制剂和/或对认知过程具有有益作用的另一种药物活性组分。
根据本发明的另一个方面,提供一种组合在制备用于抑制认知功能减退的药物组合物中的应用,其中该组合包含作为组分A)的(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷或其药学可接受的酸加成盐和组分B)的益智药、乙酰胆碱酯酶抑制剂和/或对认知过程具有有益作用的另一种药物活性组分。
根据本发明的另一个方面,提供一种抑制认知功能减退的方法,包括给需要治疗的患者施用药学有效量的组合,该组合包含作为组分A)的(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷或其药学可接受的酸加成盐和作为组分B)的益智药、乙酰胆碱酯酶抑制剂和/或对认知过程具有有益作用的另一种药物活性组分。
根据本发明的另一个方面,提供(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷或其药学可接受的酸加成盐在增强益智药、乙酰胆碱酯酶抑制剂和/或对认知过程具有有益作用的另一种药物活性组分的作用中的应用。
下面的实施例对本发明进行进一步的详述,但所述实施例并不是对保护的范围进行限定。
实施方案
实施例1
德伦环烷和加兰他敏的组合
优选的剂量是德伦环烷0.1到50mg/模,加兰他敏8到32mg/模。更优选的剂量是德伦环烷1到30mg/模,加兰他敏10到25mg/模。最优选的剂量是德伦环烷2到10mg/模,加兰他敏10到20mg/模。
实施例2
德伦环烷和吡拉西坦的组合
优选的剂量是德伦环烷0.1到50mg/模,吡拉西坦100到1500mg/模。更优选的剂量是德伦环烷1到30mg/模,吡拉西坦500到1200mg/模。最优选的剂量是德伦环烷2到10mg/模,吡拉西坦750到1000mg/模。
实施例3
德伦环烷和donezepil的组合
优选的剂量是德伦环烷0.1到50mg/模,donezepil 0.5到10mg/模。更优选的剂量是德伦环烷1到30mg/模,donezepil 1到10mg/模。最优选的剂量是德伦环烷2到10mg/模,donezepil 5到10mg/模。
实施例4
德伦环烷和长春西丁的组合
优选的剂量是德伦环烷0.1到50mg/模,长春西丁1到50mg/模。更优选的剂量是德伦环烷1到30mg/模,长春西丁5到40mg/模。最优选的剂量是德伦环烷2到10mg/模,长春西丁10到30mg/模。
实施例5
德伦环烷和维生素E(抗氧化剂)的组合
优选的剂量是德伦环烷0.1到50mg/模,维生素E为1到1300mg/模。更优选的剂量是德伦环烷1到30mg/模,维生素E为50到300mg/模。最优选的剂量是德伦环烷2到10mg/模,维生素E为100到300mg/模。
Claims (11)
1.一种用于抑制认知功能减退的组合的药物组合物,包括作为A)组分的通式
I的(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷或其药学可接受的酸加成盐和作为B)组分的益智药、乙酰胆碱酯酶抑制剂和/或对认知过程显示有益作用的另一种药物活性组分,与适当的惰性药物载体和/或助剂混合。
2.根据权利要求1的组合的药物组合物,用于治疗阿尔茨海默氏病或者显示相似症状的其它其它疾病、伴随智力能力障碍的疾病(例如,在精神分裂症中的心智减退)、老年人的心智减退(在老年人中的痴呆)、科萨科夫综合征、亨廷顿综合征、帕金森综合征或者由酒精中毒产生的智减退。
3.根据权利要求1或2的组合的药物组合物,包含作为A)组分的(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷-2-(E)-丁烯二酸(1∶1)。
4.根据权利要求1的组合的药物组合物,包含作为A)组分的(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷或其药学可接受的酸加成盐,其包含不高于0.2%的通式
(II)的(1R,3S,4R)-(-)-3-[2-N,N-(二甲基氨基乙基)]-1,7,7-三甲基二环[2.2.1]庚烷-2-酮或其药学可接受的酸加成盐。
5.根据权利要求4的组合的药物组合物,包含(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷-2-(E)-丁烯二酸(1∶1),其包含不高于0.2%的(1R,3S,4R)-(-)-3-[2-N,N-(二甲基氨基乙基)]-1,7,7-三甲基二环[2.2.1]庚烷-2-酮-2-(E)-丁烯二酸(1∶1)。
6.根据权利要求1到5任一项的组合的药物组合物,包含作为B)组分的吡拉西坦、茴拉西坦、奥拉西坦、普拉西坦、加兰他敏、利凡斯的明或donezepil、长春西丁、钙拮抗剂或抗氧化剂。
7.制备用于抑制认知功能减退的药物组合物的方法,包括将作为A)组分的(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷或其药学可接受的酸加成盐和作为B)组分的益智药、乙酰胆碱酯酶抑制剂和/或对认知过程显示有益作用的另一种药物活性组分,与惰性药物载体和/或助剂混合,并将该混合物制成盖仑制剂的形式。
8.一种组合在抑制认知功能减退中的应用,其中该组合包含作为组分A)的(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷或其药学可接受的酸加成盐和作为组分B)的益智药、乙酰胆碱酯酶抑制剂和/或对认知过程具有有益作用的另一种药物活性组分。
9.一种组合在制备用于抑制认知功能减退的药物组合物中的应用,其中该组合包含作为组分A)的(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷或其药学可接受的酸加成盐和作为组分B)的益智药、乙酰胆碱酯酶抑制剂和/或对认知过程具有有益作用的另一种药物活性组分。
10.一种抑制认知功能减退的方法,包括给需要该治疗的患者施用药学有效量的一种组合,该组合包含作为组分A)的(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷或其药学可接受的酸加成盐和作为组分B)的益智药、乙酰胆碱酯酶抑制剂和/或对认知过程具有有益作用的另一种药物活性组分。
11.(1R,2S,4R)-(-)-2-[N,N-(二甲基氨基乙氧基)]-2-苯基-1,7,7-三甲基二环[2.2.1]庚烷或其药学可接受的酸加成盐在增强益智药,乙酰胆碱酯酶抑制剂和/或对认知过程具有有益作用的另一种药物活性组分的作用中的应用。
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CN104173336A (zh) * | 2010-03-31 | 2014-12-03 | 重庆润泽医药有限公司 | 左旋奥拉西坦在制备预防或治疗认知功能障碍药物中的应用 |
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ES2547730T3 (es) | 2009-07-31 | 2015-10-08 | Cognition Therapeutics, Inc. | Inhibidores del deterioro cognitivo |
AU2012212219B2 (en) | 2011-02-02 | 2017-03-23 | Cognition Therapeutics, Inc. | Isolated compounds from turmeric oil and methods of use |
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CA3061787A1 (en) | 2017-05-15 | 2018-11-22 | Cognition Therapeutics, Inc. | Compositions for treating neurodegenerative diseases |
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GB8813766D0 (en) * | 1988-06-10 | 1988-07-13 | Efamol Holdings | Essential fatty acid compositions |
DE4136288A1 (de) * | 1991-11-04 | 1993-05-06 | Troponwerke Gmbh & Co Kg, 5000 Koeln, De | Kombination von calciumantagonisten mit cholinesterase-inhibitoren |
EP0813411B1 (en) * | 1995-02-15 | 2002-01-23 | Takeda Chemical Industries, Ltd. | Use of vinpocetine derivatives for inhibiting production or secretion of amyloid beta protein |
US20030077227A1 (en) * | 1997-10-01 | 2003-04-24 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing drugs for treating disorders of the central nervous system |
GB9820489D0 (en) * | 1998-09-22 | 1998-11-11 | Steiger Malcolm J | Compounds for improved treatment of parkinson's disease |
US6426097B2 (en) * | 2000-01-28 | 2002-07-30 | Herbaceuticals Inc. | Herbal supplement for cognitive related impairment due to estrogen loss |
US6335371B1 (en) * | 2000-11-28 | 2002-01-01 | Orion Corporation | Method for inducing cognition enhancement |
WO2002053147A1 (es) * | 2000-12-29 | 2002-07-11 | Osmotica Corp. | Composicion farmaceutica para el tratamiento de la enfermedad cerebrovascular cognitiva |
HUP0103017A3 (en) * | 2001-07-18 | 2004-05-28 | Egis Gyogyszergyar Nyilvanosan | Pharmaceutical composition for the treatment of diseases caused by impairment of cognitive functions and its use |
MXPA04001959A (es) * | 2001-08-30 | 2005-02-17 | Johnson & Johnson | Tratamiento de la demencia y trastornos de la memoria con anticonvulsivantes e. inhibidores de acetilcolinesterasa. |
DE20203244U1 (de) * | 2002-03-01 | 2002-05-23 | Meins Wolfgang | Pharmazeutische Zusammensetzung zur Prävention der Alzheimerdemenz |
CN100337628C (zh) * | 2002-08-07 | 2007-09-19 | 王登之 | 治疗痴呆症的尼莫地平口腔崩解片及其制备方法 |
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- 2004-03-12 CA CA002559493A patent/CA2559493A1/en not_active Abandoned
- 2004-03-12 EP EP04720092A patent/EP1727531A1/en not_active Withdrawn
- 2004-03-12 CZ CZ20060628A patent/CZ2006628A3/cs unknown
- 2004-03-12 US US10/592,461 patent/US20080021016A1/en not_active Abandoned
- 2004-03-12 MX MXPA06010384A patent/MXPA06010384A/es not_active Application Discontinuation
- 2004-03-12 EA EA200601666A patent/EA200601666A1/ru unknown
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- 2004-03-12 AU AU2004317129A patent/AU2004317129A1/en not_active Abandoned
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104173336A (zh) * | 2010-03-31 | 2014-12-03 | 重庆润泽医药有限公司 | 左旋奥拉西坦在制备预防或治疗认知功能障碍药物中的应用 |
CN104173336B (zh) * | 2010-03-31 | 2018-02-02 | 重庆润泽医药有限公司 | 左旋奥拉西坦在制备预防或治疗认知功能障碍药物中的应用 |
CN103547174A (zh) * | 2011-04-29 | 2014-01-29 | 马可·齐波利 | 食品、特别是用于人类消耗的饮料 |
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NO20064644L (no) | 2006-12-11 |
CA2559493A1 (en) | 2005-09-22 |
SK50802006A3 (sk) | 2007-03-01 |
EA200601666A1 (ru) | 2007-04-27 |
MXPA06010384A (es) | 2007-03-07 |
HRP20060326A2 (en) | 2007-02-28 |
IS8547A (is) | 2006-10-03 |
US20080021016A1 (en) | 2008-01-24 |
WO2005087212A1 (en) | 2005-09-22 |
JP2007528892A (ja) | 2007-10-18 |
EP1727531A1 (en) | 2006-12-06 |
CZ2006628A3 (cs) | 2007-01-24 |
AU2004317129A1 (en) | 2005-09-22 |
RS20060505A (en) | 2008-09-29 |
BRPI0418634A (pt) | 2007-05-29 |
IL177735A0 (en) | 2006-12-31 |
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