CN1361690A - 含必需脂肪酸和高半胱氨酸降低剂的药物组合物和营养组合物 - Google Patents
含必需脂肪酸和高半胱氨酸降低剂的药物组合物和营养组合物 Download PDFInfo
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- CN1361690A CN1361690A CN00810339A CN00810339A CN1361690A CN 1361690 A CN1361690 A CN 1361690A CN 00810339 A CN00810339 A CN 00810339A CN 00810339 A CN00810339 A CN 00810339A CN 1361690 A CN1361690 A CN 1361690A
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Abstract
本发明涉及n-6或n-3系列的至少一种必需脂肪酸、与或不与n-6或n-3系列的另外必需脂肪酸一起、与一种或多种高半胱氨酸降低剂一起的联合使用。该高半胱氨酸降低剂选自维生素B12、叶酸、与叶酸相关的具有相似生物活性的化合物和维生素B6。
Description
在过去的数十年中,收集的证据表明血液和组织的高半胱氨酸水平升高提示下列疾病的危险性增加,这些疾病为所有心血管疾病(包括冠心病、静脉和动脉血栓以及外周血管疾病)(M den Heijer等,Arterioscler ThrombVasc Biol 18:356-361,1998:M den Heijer等,Thromb Haemostas 80:874-877,1998:LM Taylor等,《血管外科杂志》(J Vasc Surgery)29:8-21,1999:NJ Wald等,Arch Intern Med 158:862-867,1998:H Refsum等,Ann RevMed 49:31-62,1998)、所有的脑血管疾病和中风(J H Yoo等,《中风》29:2478-2483,1998:CDA Stehouwer等,Arterioscler Thromb Vasc Biol1 8:1895-1901)、所有糖尿病或前驱糖尿病(胰岛素耐受或X综合征)及其各种并发症包括血管疾病、肾疾病、神经损伤和眼损伤(S Neugebauer等,Lancet352:454,1998:AK Aarsand等,国际医学杂志(J Internal Med)244:169-174,1998:EJ Giltay等,动脉粥样硬化(Atherosclerosis)139:197-198,1998:E Okada等,糖尿病护理(Diabetes Care)22:484-490,1999)、所有精神病学疾病包括抑郁症和精神分裂症(E Susser等,生物精神病学(BiolPsychiatry)44:141-143,1998;T Arinami等,美国医用遗传学杂志(Am JMed Genetics)74:526-528,1997;C Gomes-Trolin等,J Neural Trans,105:1293-1305,1998;B Regland等,J Neural Transm 98:143-152,1994;JEAlbert等,Nutrition Rev 55:145-149,1997;T Bottiglieri,Nutrition Rev 54:382-390,1996)、所有神经病学疾病包括阿耳茨海默氏病和其它痴呆(E Jensen等,Arch Gerontol Geriatr 26:215-226,1998;R Clarke等,Arch Neurol 55:1449-1455,1998;M Lehmann等,Dementia 10:12-20,1999)、多发性硬化(STFM Frequin等,J Neurol 240:305-308,1993;GA Qureshi等,BiogenicAmines 12:353-376,1996)和帕金森氏病、所有肾疾病和肾衰竭(T Tamura等,美国肾疾病杂志(Am J Kidney Dis)32:475-481,1998;A Vychytil等,Kidney Int 53:1775-1782,1998)、所有炎性疾病包括炎性肠疾病和关节炎(SL Morgan等,风湿病学杂志(J Rheumatol)25:441-446,1998;MCattaneo等,荷兰医学杂志(Netherl J Med)52:S1-61,1998)、所有眼耳疾病包括年龄相关性斑点变性、年龄相关性听觉丧失和耳鸣(DK Houston等,美国临床营养学杂志(Am J Clin Nutr)69:56471,1999)、所有癌症(DGWeir等,美国临床营养学杂志(Am J Clin Nutr)68:763-4,1998;EGiovannucci等,国际医学年刊(Ann Intern Med)129:517-524,1998)和所有一切原因的老死(EK Hoogeveen等,荷兰医学杂志(Netherlands J Med)52:S1-61,1998)。在肥胖期间且尤其是在其治疗期间高半胱氨酸水平也可升高(BF Henning等,实验医学研究(Res Exp Med)198:37-42,1998)。高半胱氨酸降低营养剂在治疗疼痛中(J Leuschner,Arzneim-Forsch 42:114115,1992)以及怀孕期间预防先天性疾病例如脊柱裂和怀孕相关的问题例如预惊厥或胎儿生长受限(M Leeda等,美国妇产科杂志(Am J ObstetGynecol)179:135-139,1998)时也很有价值。高半胱氨酸升高与疾病之间的这些广泛联系的机制还不清楚,但可能是由于某些物质对许多不同组织中的基础生化水平进行着控制。一个很肯定的候选机制是高半胱氨酸所促使的过量氧化和其代谢导致蛋白质和脂类功能的改变(PB Young等,《动脉硬化症》129:67-71,1997)。上皮尤其可能易受影响,因为上皮在身体的每一组织中均很重要,能为有关高半胱氨酸升高的病理机制提供极广泛的基础(JC Chambers等,循环(Circulation)99:1156-1160,1999)。
高半胱氨酸水平升高的主要决定因素是叶酸和维生素B12缺乏,次要的是维生素B6和具有维生素B6活性的有关物质的缺乏。高半胱氨酸主要是通过转化为蛋氨酸而进行代谢的,然后可用于制造S-腺苷-蛋氨酸,它在许多不同的基本反应中可用作甲基供体,包括调节DNA和RNA功能以及合成磷脂、神经递质和复合体糖类。高半胱氨酸向蛋氨酸的转化是蛋氨酸合成酶甲基-钴胺素催化的,该甲基-钴胺素是维生素B12的一种形式,在此反应中起重要作用。这种酶的一种必需辅因子是呈甲基-四氢叶酸形式的叶酸。在此反应过程中,甲基从5-甲基四氢叶酸转移至高半胱氨酸,这样产生四氢叶酸和蛋氨酸。因此适当摄入和吸收叶酸和维生素B12对于保持高半胱氨酸低水平和保证合适的甲基化反应是必需的。
高半胱氨酸代谢的第二途径包括在两个单独反应中转化为胱硫醚、然后转化为半胱氨酸,两者均需要维生素B6作辅因子。因此维生素B6或相关分子的不适当利用可导致高半胱氨酸水平升高。
因此高半胱氨酸代谢的最佳控制需要体内有最佳的维生素B12和B6水平,并也需要有叶酸或甲基四氢叶酸或任何其它可提供叶酸盐的相关物质的最佳水平。必须按至少2mg/天提供维生素B6,优选5mg-200mg/天。正常通过注射但可口服来提供维生素B12,即使在那些缺少从肠中有效吸收所需的胃的内在因子的患者也是如此。维生素B12的每天口服剂量至少200μg、优选500-10,000μg,这是保证那些对维生素B12不能完全正常吸收的年逾中年人体内足够的组织水平所必需的。维生素B12可以是氰钴胺或羟钴胺或任何其它维生素的生物活性形式。羟钴胺为优选形式,因为它相当稳定且不起氰化物供体的作用。应该按至少200μg/天且优选大于500μg/天的剂量提供叶酸。通过适当口服所有这三种维生素将使高半胱氨酸的升高控制到最佳效果。适合大多数人的每天合适剂量是1mg-5mg B12、优选羟钴胺,0.5-5mg叶酸,和2mg-20mg维生素B6。
必需脂肪酸(EFA)是另一类必需营养素,这样说是因为它们在体内不能制造而必须通过饮食提供。有两种类型的EFA,n-3(或ω-3)和n-6(或ω-6),它们不可互换。n-6基团的主要母体EFA是亚油酸,而n-3基团的主要母体脂肪酸是α-亚麻酸(图1)。虽然亚油酸和α-亚麻酸是饮食中最重要的EFA,但在身体中起重要作用的是其代谢产物。虽然这些代谢产物不能重新合成,但可通过图1所示的途径从母体EFA制造。根据生物学作用EFA家族中尤其重要的成员是二高γ-亚麻酸(DGLA)、花生四烯酸(AA)、二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)。
正因为高半胱氨酸水平升高与许多疾病有关,因此低水平的必需脂肪酸、尤其是低水平的代谢物DGLA、AA、EPA和DHA也与许多上述相似的疾病相关。已发现这些脂肪酸水平减少的疾病包括心血管疾病、血栓形成疾病、精神病学疾病例如精神分裂症、抑郁症和两极神经细胞疾病、炎性疾病例如各种形式的关节炎、湿疹、哮喘和炎性肠疾病、糖尿病及其并发症、肾疾病、神经变性疾病如阿耳茨海默氏疾病和其它痴呆以及帕金森氏病、肾疾病、多种癌症、以及生殖系统疾病包括男性和女性不育症以及乳房和前列腺疾病(DF Horrobin,编辑,《ω-6必需脂肪酸:病理生理学和在临床医学中的作用》(Pathophysiology and Roles in Clinical Medicine),Wiley Liss,New York,1990;DF Horrobin和CN Bennett,ProstaglandinsLeukotr Essential Fatty Acids,60:1999出版;A Leaf等,World Rev NutrDiet 83:2437,1998;DF Horrobin,Prostaglandins Leukotr Essential FattyAcids,53:385-396,1995)。
已经进行了许多研究,其中已尝试将EFA用于治疗下列疾病,包括心血管病症和脑血管病症,精神病学病症和神经病学病症,肾疾病、皮肤、关节、呼吸系统和胃肠系统的炎症,癌症和许多其它病情。已使用的EFA特别包含γ-亚麻酸(GLA)、DGLA、AA、EPA和DHA,而且包含α-亚麻酸、亚油酸和十八碳四烯酸。总的说来,这些均已显示了有益的效果,但是,这些效果也常常不及研究者所期望的那样。
许多研究还报道了患者或受治疗者的EFA水平和高半胱氨酸水平,如晚期肾疾病患者,并报道了高半胱氨酸水平与DGLA、AA、EPA和DHA水平之间存在反比关系。通过用叶酸治疗低的高半胱氨酸使这四种脂肪酸升高,其中DGLA和AA显著升高,而EPA和DHA升高不明显(S Hirose等,Jap J Nephrol 1998;40:8-16)。同样,在叶酸缺乏的大鼠中,高半胱氨酸水平升高并且同时AA、EPA和DHA的血浆水平下降,后两者显著下降(P Durand等,动脉粥样硬化(Atherosclerosis)1996;121:231-243)。在另一项研究中,母亲的血浆高半胱氨酸水平与婴儿红细胞中的脂肪酸水平相关。母亲的高半胱氨酸与婴儿DHA之间存在很强的反比关系(H Bohles等,欧洲儿科学杂志(Eur J Pediatrics)158:243-246,1999)。
本发明是基于发明人研究观察到高半胱氨酸升高与EFA尤其是AA、EPA和DHA的缺乏之间可能存在很紧密的关系。具有多个碳碳双键的EFA极易氧化。高半胱氨酸及其代谢物能促进EFA氧化而减少EFA水平。
服用EFA治疗疾病可能会由于高半胱氨酸水平高而使EFA发生氧化而被抵消,因此EFA水平的变化和EFA的治疗效果将小于所预期的。而且,由于一些氧化的EFA代谢物可能有毒,因此需要的效果可能被不希望有的结果所抵消。
同样,用叶酸、维生素B12或维生素B6来降低高半胱氨酸,无论单独或联合使用通常均具有所需的效果,但有时这些所需效果小于预期的效果。如果高半胱氨酸的某些毒性是由于EFA减少,则就可得到解释。调整高水平的高半肤氨酸可防止EFA发生破坏。然而,由于EFA在体内不能重新合成,因此控制高半胱氨酸对增加EFA供应来帮助代替已经丢失的那些EFA是没有任何用处的。
因此下列发明提供了联合使用一种或多种EFA、与一种或多种高半胱氨酸降低剂一起用于治疗各种疾病,尤其是那些在本说明书前面所讨论的疾病。优选的是,EFA制剂不含有效量的其它微营养素;该制剂的活性成分优选基本上全部由所选的EFA和高半胱氨酸减低剂组成。
高半胱氨酸降低剂优选的是选自维生素B12、叶酸、与叶酸相关的具有相似生物活性的化合物以及维生素B6。所有这四种高半胱氨酸降低剂可与EFA或其任何两种或三种一同给药。例如,叶酸和与叶酸相关的化合物一起服用可能不合适。叶酸可与维生素B12或维生素B6或两者一同给药。其它的选择是只选择一种高半胱氨酸降低剂。
用于本发明制剂中的最优选的EFA是二十碳五烯酸(EPA)和花生四烯酸(AA)。EPA可以是纯三-EPA甘油三酯的形式或更优选乙基酯。对于任何所选择EFA,该EFA可以是纯化形式或部分纯化形式,但是优选纯化形式。
本发明的制剂如所附权利要求书所述。
高半胱氨酸的降低将阻止EFA发生进行性破坏,因此服用EFA更有可能得到所需的结果。同样,EFA的供给将有助于补充由于高半胱氨酸水平高而损失的脂肪酸,这样就更加可能产生所需的降低高半胱氨酸的反应。
人奶和人工奶、蛋和其它营养全面的食物已经是天然的联合供给EFA和高半胱氨酸降低营养剂。然而,以前它们不是以药物或营养补充的剂量方式供给、也不是以可能与营养效果不同的治疗效果所需的剂量服用。尤其是,很少采用口服较高剂量的维生素B12,不论是天然的或人工的奶,还是口服或肠给药的多种营养混合物,无论哪种,所包含的维生素B12水平均不接近200μg/天。同样,这些食物含叶酸和维生素B6的量也远低于100μg叶酸/天和1.5mg维生素B6/天。
例如,最富含这些营养素的全食物奶粉每100g仅包含0.23mg维生素B6、2.0μg维生素B12和40μg叶酸[食物的组成,AA Paul和DATSouthgate,HMSO,London 1988]。100g奶粉产品有约500卡路里热量,每天不可能消耗约500g奶粉。即使这样大剂量也只能提供1.15mg维生素B6和10.0μg维生素B12。
在本发明组合物和应用中的EFA可以是能使血浆或细胞膜中的相关EFA分子的水平升高的任何形式。适合的形式包括单酸甘油酯、甘油二酯和甘油三酯,磷脂,酯的任何形式包括乙酯、丙二醇酯或任何其它适合的酯,酰胺,盐包括锂盐、钠盐和钾盐,以及任何其它化合物,这些化合物经口服、非肠道或局部给药后可提高血液或组织中有关的EFA水平。已知极适合于人或动物给药的特别合适的形式是甘油三酯和乙酯,例如GLA、DGLA、AA、EPA或DHA。EFA的服用剂量可以是10mg-100g/天,优选50mg-20g/天,最优选100mg-5g/天。可以以下列形式提供EFA,即天然油,其中除去了其它成分的部分或完全纯化的天然油,或者化学衍生的纯脂类形式或部分纯化的脂类。该制剂中的EFA成分必须包含至少5%的相关EFA或EFA衍生物,优选大于15%、最优选大于30%、50%、90%或95%。
用于本发明组合物和应用中的高半胱氨酸降低剂选自维生素B12、叶酸或与叶酸相关的具有相似生物活性的化合物、以及维生素B6。维生素B12的优选形式是羟钴胺,但可以使用氰钴胺或维生素的任何其它生物活性形式。如果用维生素B12,其剂量需要多于10μg/天。优选的剂量是每天至少200μg、更优选500-10,000μg、还优选1mg-5mg。可以使用叶酸或甲基四氢叶酸或任何可提供叶酸的其它相关物质。优选的剂量为每天至少200μg、更优选大于500μg、还优选0.5-5mg。可以使用吡哆辛形式的维生素B6。如果用维生素B6,其剂量需要至少1.5mg/天。优选的剂量为每天至少2mg、更优选5-200mg、还优选2-20mg。总的说来,优选需要至少200μg/天高半胱氨酸降低剂,无论所述的降低剂是什么。
可以将EFA和高半胱氨酸降低剂一起混合成粉末和液体,可以将它们以本领域技术人员已知的片剂、硬胶囊或软胶囊、微胶囊或任何其它适当剂型的形式一同给药。也可以将EFA和高半胱氨酸降低营养剂以单独剂型给药,但是装在一个包装中,带有两种成分的每日给药方法的说明。该制剂可包括常规的稀释剂和/或赋形剂,也可加入调味剂。
在营养用或治疗用的EFA中存在的一个问题是它们在体内容易氧化成许多产物,其中一些可能有害。人体内有一个处理此问题的抗氧化体系,但不是每个个体都具有适当的抗氧化的防卫体系。这是因为有几种主要抗氧化剂是必定会在饮食中提供的基本营养剂,但不是所有饮食都适合。因此对制剂中有一种或多种抗氧化剂是很有利的。特别有价值的抗氧化剂是任何天然或人工形式的维生素E、任何天然或人工形式的辅酶Q、任何天然或人工形式的α-硫辛酸和任何天然或人工形式的维生素C。当需要抗氧化剂成分时,可以包括这些试剂的任何一种或几种的任何组合。如果有的话,抗氧化剂的剂量优选1mg-5000mg/天。
附图说明
图1.必需脂肪酸的n-3和n-6系列
实施例
1.含500mg二十碳五烯酸乙酯或二十碳五烯酸甘油三酯、以及1mg羟钴胺、1mg叶酸和2mg吡哆辛的硬或软胶囊,每天服2-4次。
2.如实施例1的制剂,但其中首先用任何适合的微囊包封剂对二十碳五烯酸酯进行微囊包封、然后用其它成分制成片剂。
3.用于口服的溶液,其中5ml溶液中含500mg二十碳五烯酸酯衍生物、1mg叶酸、1mg羟钴胺和5mg吡哆辛以及适当的调味剂。
4.用于非肠道给药的乳液,其中将500mg二十碳五烯酸酯衍生物在10ml总体积溶液中乳化,该溶液包括1mg羟钴胺、1mg叶酸和5mg吡哆辛。
5-8.如实施例1-4所述,其中EFA选自花生四烯酸、γ-亚麻酸、二高γ亚麻酸、十八碳四烯酸、二十碳五烯酸、鲱油酸、二十二碳六烯酸、亚油酸或α-亚麻酸或它们的衍生物。
9-12.如实施例1-4所述,但其中选自1-8所列举的两种或三种EFA是一同给药的,使每个口服胶囊或片剂剂型、每5ml溶液、或每10ml非肠道乳液的EFA总量为500mg。
13-24.如实施例1-12所述,但其中所提供的唯一的高半胱氨酸降低剂成分是维生素B12。
25-36.如实施例1-12所述,但其中所提供的唯一的高半胱氨酸降低剂成分是叶酸。
37-48.如实施例1-12所述,但其中所提供的唯一的高半胱氨酸降低剂成分是维生素B6。
49-96.如实施例1-48所述,其中将选自维生素E、辅酶Q、α-硫辛酸和维生素C的一种或多种抗氧化剂加入制剂中。按1mg-5000mg/天的剂量使用维生素E、辅酶Q、α-硫辛酸和维生素C。
Claims (15)
1.一种药物制剂,含有一种或多种选自图1所示的EFA和一种或多种高半胱氨酸降低剂以及药学上可接受的赋形剂,该高半胱氨酸降低剂选自维生素B12、叶酸、与叶酸相关的具有相似的生物活性的化合物和维生素B6。
2.一种硬胶囊或软胶囊剂型的营养制剂,含有一种或多种选自图1所示EFA和一种或多种的高半胱氨酸降低剂,该高半胱氨酸降低剂选自维生素B12、叶酸、与叶酸相关的具有相似的生物活性的化合物和维生素B6。
3.一种药物或营养制剂,含有一种或多种选自图1所示的EFA和一种或多种高半胱氨酸降低剂,该高半胱氨酸降低剂选自维生素B12、叶酸、与叶酸相关的具有相似的生物活性的化合物和维生素B6,这种制剂含有200μg或更多的一种或多种高半胱氨酸降低剂。
4.根据前面任一权利要求的制剂,其中EFA为二十碳五烯酸(EPA)。
5.根据权利要求1-3任一的制剂,其中EFA为乙基酯或纯的三-EPA甘油三酯形式的二十碳五烯酸(EPA)。
6.根据权利要求1-3任一的制剂,其中EFA为花生四烯酸。
7.根据权利要求1-3任一的制剂,其中EFA为γ-亚麻酸或二高γ-亚麻酸。
8.根据权利要求1-3任一的制剂,其中EFA为二十二碳六烯酸。
9.根据前面任一权利要求的制剂,它含有两种或多种EFA。
10.根据前面任一权利要求的制剂,它含有至少5%EFA,优选大于15%EFA,很优选大于30%、大于50%、大于90%或大于95%EFA。
11.根据前面任一权利要求的制剂,它含有维生素B12,优选羟钴胺素形式作为唯一的高半胱氨酸降低剂。
12.根据权利要求1-10任一的制剂,它含有叶酸或与叶酸相关的具有相似生物活性的化合物作为唯一的高半胱氨酸降低剂。
13.根据前面任一权利要求的制剂,它是适用于口服给药的形式。
14.根据前面任一权利要求的制剂,它还进一步含有一种或多种选自天然的、合成的或半合成的维生素E、辅酶Q、α-硫辛酸和维生素C。
15.权利要求1和权利要求3-14的任一制剂用于治疗或预防下列一种或多种疾病的用途、或在生产用于治疗或预防下列一种或多种疾病的药剂中的用途:
a.任何疾病;
b.任何心血管或脑血管疾病,包括任何形式的冠状动脉粥样硬化、脑血管或末梢血管动脉粥样硬化、任何形式的心脏疾病、任何形式的脑血管疾病或中风、任何形式的末梢血管疾病和任何形式的血栓形成;
c.任何糖尿病或前驱糖尿病(X综合征)和糖尿病的任何大血管或微血管的并发症包括心血管疾病、视网膜病、肾病或神经病;
d.任何精神病,包括精神分裂症、精神分裂症型疾病和其它精神分裂症样疾病、两极性精神疾病(躁狂、或躁狂性抑郁)、任何形式的抑郁、和恐慌或焦虑疾病、睡眠障碍和社会性恐怖症;
e.任何神经学疾病或神经变性疾病,包括阿耳茨海默氏病和其它形式痴呆、帕金森氏病、多发性硬化、杭廷顿氏舞蹈病和任何形式的慢性疼痛;
f.任何肾脏疾病;
g.任何胃肠道、呼吸系统、皮肤和粘膜、或关节或任何其它组织的炎症或免疫疾病;
h.任何眼或听觉疾病,包括年龄相关性斑点变性、年龄相关性耳聋或耳鸣;
i.任何肥胖,尤其是任何肥胖的治疗方法;
j.任何癌症。
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PL (1) | PL352185A1 (zh) |
RU (1) | RU2001134300A (zh) |
SK (1) | SK332002A3 (zh) |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103432156A (zh) * | 2013-08-30 | 2013-12-11 | 深圳奥萨医药有限公司 | ω-3脂肪酸和B族维生素的药物组合物及其用途 |
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ZA200200259B (en) | 2002-12-24 |
RU2001134300A (ru) | 2003-08-27 |
AU6167800A (en) | 2001-01-30 |
CA2377502A1 (en) | 2001-01-18 |
NO20020090L (no) | 2002-01-08 |
HUP0202342A3 (en) | 2003-02-28 |
HUP0202342A2 (hu) | 2002-11-28 |
WO2001003696A1 (en) | 2001-01-18 |
NO20020090D0 (no) | 2002-01-08 |
CZ200258A3 (cs) | 2002-06-12 |
HK1042853A1 (zh) | 2002-08-30 |
JP2003504333A (ja) | 2003-02-04 |
SK332002A3 (en) | 2002-12-03 |
PL352185A1 (en) | 2003-08-11 |
TR200200045T2 (tr) | 2002-05-21 |
US20050147665A1 (en) | 2005-07-07 |
NZ516101A (en) | 2003-06-30 |
IL147556A0 (en) | 2002-08-14 |
KR20020025088A (ko) | 2002-04-03 |
CN1223346C (zh) | 2005-10-19 |
MXPA01013210A (es) | 2004-06-03 |
BR0013157A (pt) | 2002-04-02 |
EE200200021A (et) | 2003-04-15 |
EP1200085A1 (en) | 2002-05-02 |
IS6205A (is) | 2001-12-18 |
GB9916536D0 (en) | 1999-09-15 |
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