CN1261806A - 聚乙二醇-干扰素α结合物治疗传染性疾病 - Google Patents
聚乙二醇-干扰素α结合物治疗传染性疾病 Download PDFInfo
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Abstract
本发明公开了对用干扰素α治疗敏感的病毒性感染,尤其是慢性丙型肝炎患者给予PEG12000-IFNα结合物的方法。
Description
相关申请的相互参照
本PCT申请对1997年4月29日提交的美国申请序号08/839,101的优先权提出了权利要求,后者是1996年11月1日提交的申请序号为08/742,305的部分继续申请,而其又是1995年11月2日提交的,临时申请序号为60/006,130的继续申请,其公开的内容全部通过引用结合于本文中。
发明背景
本发明涉及治疗病毒感染性疾病的方法,尤其是对干扰素α治疗敏感的病毒性感染的方法,本方法包括给予一定量的聚乙二醇-干扰素α结合物(polyethylene glycol-interferon alpha conjugate),在此治疗剂量下能有效地治疗病毒感染性疾病且能降低或消除通常由给予干扰素α引起的不良副作用。在本发明的优选实施方案中,平均分子量为12,000的聚乙二醇与干扰素α的结合物用于治疗慢性丙型肝炎。
干扰素是一组天然产生的小分子蛋白和糖蛋白,由大多数有核细胞在对病毒感染以及其它抗原刺激应答时分泌产生。干扰素促使细胞对抗病毒感染并对细胞表现出广泛的作用。干扰素通过与细胞膜表面的特殊受体结合而后表现出其细胞活性。与膜受体结合后,干扰素便引起一系列复杂的细胞内效应。体外研究证明,这些细胞内效应包括某些酶的减少、细胞增生的抑制、免疫调节活性如促进巨噬细胞的吞噬活性和增强淋巴细胞对靶细胞的特异的细胞毒作用以及抑制受病毒感染细胞内的病毒复制。
已知非免疫性干扰素,包括α和β干扰素,能抑制急性和慢性感染细胞中的人免疫缺陷病毒(HIV)(Poli和Fauci,1992,艾滋病研究和人体病毒。8(2):191-192)。干扰素,尤其是α干扰素,由于它们的抗病毒活性,因此在丙型肝炎病毒(HCV)有关的疾病治疗中作为治疗剂受到相当的重视。Hoofnagle等,in:Viral Hepatitis,1981,InternationalSymposium,1982,Philadelphia,Franklin Institute Press;Hoofnagle等,1986,New Eng.,J.Med.315:1575-1578;Thomson,1987,Lancet,1:539-541.Kiyosawa等,1983,in:Zuckerman,ed.,Viral Hepatitis and LiverDisease,Allen K.Liss,New York.pp.895-897;Hoofnagle等,1985,Sem.Liv.Dis.,1985,9:259-263.
慢性丙型肝炎是一种在不知不觉中缓慢进展的疾病,对生活质量有显著的影响。尽管改进了血康中血源的质量并且最近对献血者实施了HIV检测,估计因接受输血而导致的急性HCV感染率仍达5-10%(Alter等,in:Zuckerman,ed.,病毒性肝炎和肝脏疾病.Allen K.Liss,NewYork,1988.PP:537-542)。在美国,每年大约接近3百万人接受输血,这样急性丙型肝炎大约每年增加150,000人。而许多接触丙型肝炎的病人呈亚临床感染或病情轻微,约50%的患者会发展为慢性疾病状态,表现为血清转氨酶异常的波动不定以及肝组织活检可见炎症损害。据统计,这其中约有20%的患者会发展为肝硬化。Koretz etal.,1985,Gastroenterology 88:1251-1254。
已知干扰素可影响许多细胞(正常和不正常细胞)功能,包括DNA复制和RNA以及蛋白质的合成。因此,干扰素的细胞毒作用并不局限于针对肿瘤或病毒感染细胞,对正常健康细胞也有细胞毒性作用。所以,以干扰素治疗可出现不需要的副作用,特别是在需要高剂量时。使用干扰素能导致骨髓抑制,从而使得红细胞数、白细胞数和血小板数减少。高剂量的干扰素通常导致流行性感冒样症状(如发热、疲劳、头痛和发冷)、胃肠紊乱(如厌食、恶心和腹泻)、头晕和咳嗽。
干扰素α-2b在以3×106国际单位(IU)、3次/周的剂量皮下注射、连续使用24周治疗慢性丙型肝炎时是安全有效的。Causse et al.,1991,Gastroenterology 101:497-502;Davis et al.,1989,New Eng.J.Med.321:1501-1506;Marcellin et al.,1991,Hepatology,13(3):393-393.以此剂量和疗程进行治疗可减轻某些丙型肝炎患者肝脏炎症的症状和生化或组织学特征,但也可导致不需要的副作用,如流行性感冒样症状。所以,3次/周注射给予干扰素对病人是一个负担,对病人的生活质量有明显的影响。
Nieforth等人(Clin.Pharmacol.Ther.,1996,59:636-646)已报道过Roferon A以及聚乙二醇修饰RoferonA对健康志愿者的作用比较。结果表明,给予结合物(conjugates)次数不应少于2次/周,否则与未修饰的对照药物相比,治疗效果较小。
美国专利申请序号08/742,305公开了对细胞活素敏感的患者给予聚合体-细胞活素结合物的方法,但没有公开本发明的方法。
聚乙二醇对其他蛋白质的修饰已有报道。参见Fuertges et al.,1990,Journal of Controlled Release 11:139-48.其中报道了PEG-修饰的天门冬酰胺酶治疗急性淋巴母细胞白血病,PEG与腺甙脱氨酶(PEG-ADA)用于治疗ADA严重缺乏并发的免疫缺陷综合征,PEG-超氧化物歧化酶联合治疗再灌注损伤,PEG-尿酸酶用于治疗血内尿酸过多。
干扰素α治疗伴有的不需要的副作用以及每周注射三次的负担常常限制了干扰素α的治疗效果。因此,存在着一种对既维持或改进此种疗法的治疗效果,同时又减少或消除不需的副作用的治疗方法的需求。
发明概述
本发明通过提供一种治疗对干扰素α治疗敏感的疾病的方法从而满足了此种需求,通过这种方法,治疗效果得到改进,而通常与此种治疗有关的副作用则显著减少或消除。
本发明提供治疗对干扰素α治疗敏感的病毒性感染的哺乳动物的方法,包括给予哺乳动物与一定量的12000分子量的聚乙二醇结合的干扰素α(PEG12000-干扰素α),而且在此用量下能有效地治疗病毒性感染,且同时能有效地减少或消除通常与给予干扰素α有关的不良副作用。
本发明还提供一种治疗慢性丙型肝炎病毒感染的方法,包括给予感染丙型肝炎病毒的哺乳动物宿主以一定量的PEG12000-干扰素α,其能有效地治疗所述病毒感染,且同时能显著减少或消除通常与给予干扰素α有关的副作用。
发明详述
本发明涉及一种治疗对用干扰素α治疗敏感的疾病的方法,本发明意外地发现,给予12000分子量的聚乙二醇结合的干扰素α(下文指“PEG12000-IFNα”)可增强治疗效果,而大大减轻(或完全消除)通常因实施干扰素α治疗方案引起的不良副作用。特别是,已经惊奇地发现将PEG12000-IFNα-2b结合物每周一次给予慢性丙型肝炎患者,其治疗效果不变或增加,而同时大大减轻或消除了通常因实施干扰素α治疗方案引起的副作用。
通常干扰素α治疗人类HCV的剂量是3百万国际单位每周3次(“3MIU TIW”)。这种治疗方法通常导致骨髓抑制(白细胞和嗜中性细胞计数减少)。干扰素的这种剂量或更高的剂量常导致中度至严重的流行性感冒样症状,胃肠紊乱,头晕以及咳嗽;运些症状的任何一个都可能需要其他的治疗方式,或迫使病人中断或降低干扰素α的治疗剂量。
令人惊奇的是,我们发现,采用根据本发明的优选的PEG12000-IFNα-2b结合物的较高剂量和较少给药次数的方式可获得较高的治疗效果,而同时大大减轻或甚至消除了通常与干扰素α疗法有关的副作用。
“12,000分子量的聚乙二醇结合的干扰素α”和“PEG12000-IFNα”一词在本文中指的是这样的结合物,即按照国际申请序号WO95/13090的方法制备的结合物,而且这种结合物在干扰素α2a或2b的氨基基团之间有尿烷连键,且聚乙二醇的平均分子重为12000。优选的聚乙二醇-干扰素α结合物是PEG12000-干扰素α-2b。
PEG12000-IFNα-2b由将一个PEG聚合体连接到IFNα-2b分子中赖氨酸残基的ε-氨基基团上而制得。一个单独的PEG12000分子通过一个尿烷连链与一个IFNα-2b分子的自由氨基基团结合。该结合物的特征是所结合的PEG12000的分子重。PEG12000-IFNα结合物制成冻干粉用于注射。将IFNα与PEG结合的目的是通过明显延长IFNα的血浆半衰期而改善该蛋白质的传送并由此提供IFNα的延长的活性。
本文中使用的“干扰素”或“IFN”指的是一族能抑制病毒复制和细胞增生以及调节免疫应答的高度同源的种特异性蛋白质。人干扰素根据它们的细胞起源和抗原性分为三类:α-干扰素(白细胞),β-干扰素(成纤维细胞)以及γ-干扰素(B细胞)。每一类的重组物形式均已开发成功并上市出售。每一类根据抗原性或结构特征又可分为不同的亚型。通过分离并测定编码的这些肽类的DNA序列,至少已鉴别了具有不同的氨基酸序列的24种干扰素α(分成由A到H的亚型)。本申请中的“α-干扰素”、“α干扰素”、“干扰素α”以及“人白细胞干扰素”这几个术语可以互相交换使用,用来描述本组的成员。无论是天然产生的还是重组的α-干扰素,包括同源(consensus)干扰素,都可应用于本发明中。
从全血的血沉棕黄层部分分离得到人白细胞,再从中纯化干扰素α的方法在美国专利序号4,503,035中已有描述。以这种方法制备的人白细胞干扰素包含具有不同氨基酸序列的人白细胞干扰素的混合物。纯化的天然的人α-干扰素及其混合物可应用于本发明之中,它们包括但不限于得自日本Sumitomo的Sumiferon干扰素α-n1,英国Glaxo-Wellcome公司(伦敦)的Wellferon干扰素α-n1(InS),得自PurdueFrederick公司(Norwalk,CT)的Alferon干扰素α-n3。
重组DNA技术已应用于干扰素的生产,这使得某些种类的人干扰素可成功地合成,使得大规模发酵、生产、分离、纯化各种同源干扰素成为可能。以重组技术生产的干扰素仍保持了其离体和在体内的抗病毒以及免疫调节活性。重组技术还包括在重组得到的多肽上的糖基化位点上加成一个糖基。
重组DNA质粒的结构中包含着编译至少部分人白细胞干扰素的序列,在大肠杆菌E.coli中表达的具有人白细胞干扰素的免疫学或生物学活性的多肽在美国专利序号4,530,901和欧洲专利序号EP 0032 134中已有描述。美国专利序号4,414,150、4,456,748和4,678,751公开了含有不同亚型系列(如A和D、A和B、A和F)组合的杂交α-干扰素基团的构成。典型的适合应用于本发明实践中的α-干扰素包括但不限于干扰素α-2b,如得自kenilworth,N.J.的Schering公司的Intron,Hoffmann-LaRoche,Nutley,N.J.的干扰素α-2a如RoferonA。
美国专利序号4,695,623和4,897,471公开人白细胞干扰素多肽,这里指的是同源干扰素,其氨基酸序列中包含着在天然产生的干扰素α亚型多肽每个位置中的常见的主要氨基酸。
根据本发明,能够治疗的疾病一般为那些对干扰素α治疗敏感的疾病。例如,敏感的疾病包括对以干扰素α为基础的治疗的指标反应阳性和良好(这些术语为医学领域所熟知)的疾病。本发明适用于以干扰素α治疗显示出一定的效果,但却由于该治疗的副作用超过了治疗作用而不能使用干扰素的疾病。例如,由于α干扰素伴随的副作用而实际上排除了使用干扰素α治疗Epstein Barr病毒。与常规的干扰素α治疗比较,本发明的应用大大减少或消除了副作用。
能以干扰素治疗的典型疾病包括但不局限于细胞增生疾病,尤其是癌症(如绒毛细胞白血病、Kaposi’s肉瘤、慢性骨髓性白血病、多发性骨髓瘤、基底细胞癌和恶性黑色瘤、卵巢癌、皮肤T细胞淋巴瘤)和病毒性感染。不必受到限制,干扰素治疗用于抑制对干扰素敏感的病毒的复制有益的疾病。本发明可以治疗的病毒感染包括甲型肝炎、乙型肝炎、丙型肝炎,其他非甲/非乙型肝炎,疱疹病毒,Epstein Barr病毒(EBV),巨细胞病毒(CMV),单纯疱疹病毒,人疱疹病毒6型(HHV-6),乳头状瘤,痘病毒,细小核糖核酸病毒,腺病毒,鼻病毒,人T亲淋巴病毒1和2(HTLV-1/-2),人轮状病毒,狂犬病,逆病毒包括人免疫缺陷病毒(HIV),脑炎和呼吸道病毒感染。本发明的方法也可用来调节各种免疫反应。
现在有两个不同的干扰素α在美国和其他国家被批准上市,用于治疗绒毛细胞白血病,性疣,Kaposi氏肉瘤,慢性非甲或非乙型肝炎,它们是干扰素α-2b,商品名INTRONA(Schering公司,Kenilworth NJ)和干扰素α-2a,商品名是RoferonA(Hoffmann-La Roche,Nutley,NJ)。由于在所有类型的干扰素中,干扰素α-2b在全世界广泛得到批准用于治疗的慢性丙型肝炎感染,因此它也最优选用于本发明实施的慢性丙型肝炎的治疗。
慢性丙型肝炎感染患者可表现出下面的一个或多个体征或症状:(a)丙氨酸转氨酶(ALT)水平升高,(b)抗HCV抗体试验阳性,(c)HCV-RNA试验阳性,证明存在HCV,(d)具有慢性肝病的临床特征,(e)肝细胞损伤。这些标准不仅能用于诊断丙型肝炎,还能用来评价患者对药物治疗的反应。
已知血清丙氨酸转氨酶(ALT)和天门冬氨酸转氨酶升高发生于不可控制的丙型肝炎中。对治疗的完全的反应通常指的是这些酶,尤其是ALT的正常化(Davis,1989,NewEng.J.Med.321:1501-1506)。ALT在肝细胞损伤时释放出来,是HCV感染的症状。干扰素促进酶2’,5’-寡腺苷酸合成酶(2’5’OAS)的合成,从而降解病毒mRNA。Houglum,1983,临床药理学2:20-28。血清中2’5’OAS水平的提高与ALT水平的降低相吻合。
肝脏活组织样品的组织学检查可用来作为评价的第二个标准。见Knodell等,1981,Hepatology,1:431-435。其组织学活性指标(如门静脉炎症,逐渐的或bridging坏死,肝小叶损伤和纤维变性)提供了疾病状况的量化方法。
应用本发明时,优选的PEG12000-IFNα-2a或-2b结合物可给予感染丙型肝炎病毒的患者。PEG12000-IFNα-2b是最适合选用的。
用来治疗的患者选自具有抗HCV抗体的病人,且活组织检查证明是慢性活动期肝炎。每个病人以补充测定法(supplemental assay)(Ortho或Abbot)检查都是抗丙型肝炎病毒抗体(anti-HCV)阳性,以PCR检查出HCV RNA的存在,并都具有前述的肝活组织检查的慢性肝炎特征。病人年龄在18-68岁之间,且先前都没有用干扰素对丙型肝炎进行过治疗。
三个剂量的PEG12000-IFNα-2b(0.5,1.0,1.5μg/kg),每周给药一次,经过4,8和12周的治疗,结果表明其效果等于或优于干扰素α对照组3MIU TIW的抗病毒活性(以PCR测定HCV-RNA的减少水平),而同时,通常由干扰素治疗引起的副作用明显降低。
用于治疗上述任何疾病的PEG12000-IFNα结合物的给药量由聚合的结合物中的IFNα的活性决定。这个量足以明显地影响阳性临床反应而同时降低了副作用。PEG12000-IFNα-2b单一或分次剂量给予的量的范围至少为约0.25μg/kg/week。在更优选的实施方案中,给予量的范围在约0.25-2.5μg/kg/周,或0.5-1.5μg/kg/周。
以上述剂量给药可以每隔一天一次,但最好是一周一次或二次,注射给药至少要连续使用24周。
给药方法可以是通过静脉、皮下、肌内、或任何其他可以接受的全身给药方式。根据临床医生的判断,给药剂量和治疗方案取决于接受治疗患者的年龄、性别、病史、嗜中性细胞计数(如嗜中性白血球减少症的严重程度)、疾病的严重程度以及病人对局部毒性和全身性副作用的耐受性。给药剂量和频率取决于开始治疗时嗜中性细胞计数的检查结果。
对于任何一种给药途径,都可采用多次或一次给药方式。例如,当采用皮下注射给药时,若每周给予PEG12000-IFNα-2b 1.5μg/kg,则可以0.75μg/kg的剂量在0和72小时时分别给药。
为了在患者中检查HCV病毒复制对药物治疗的反应,HCV RNA可以通过血清取样测定,例如采用HCV染色体组的NS3和NS4构成基因片断衍生而来的两套引物,通过嵌套聚合酶链反应方法测定。Farci etal.,1991,New Eng.J.Med.325:98-104.Ulrich et al.,1990,J.Clin.Invest.,86:1609-1614。
可通过HCV-RNA效价的改变而测定抗病毒活性。通过将治疗结束时的效价与治疗前的HCV-RNA效价的基底测量值比较可以分析HCVRNA的数据。第4周时HCV-RNA效价的降低程度可以证明化合物是否具有抗病毒活性。Kleter et al.,1993,Antimicrob.AgentsChemother.37(3):595-97;Orito et al.,1995,J.Medical Virology,46:109-115.至少两个数量级(大于或等于2log)的变化才可看作是具有抗病毒活性的证据。
安全性和耐受性可由临床评价和白细胞以及嗜中性细胞计数的检测来决定。可通过定期的血液学参数(白细胞,嗜中性细胞,血小板和红细胞计数)监测来评定。
其他的干扰素结合物可通过将干扰素结合到一个水溶性的聚合物上获得。这样的聚合物的非限制性的例子包括其他的聚烯化氧均聚物如聚丙烯二醇,聚氧乙烯(polyoxyethylenated)多元醇,它们的共聚物或嵌段共聚物。有效的非抗原性物质如葡聚糖、聚乙烯吡咯烷酮、聚丙烯酰胺、聚乙烯醇、带糖基的聚合物及其类似物,它们作为聚烯化氧基的聚合物也可使用。这些干扰素-聚合体结合物在美国专利序号4,766,106和4,917,888、欧洲专利申请序号0 236 987和0 510 356及国际公布号WO 95/13090中都有描述。
既然聚合物的修饰可大大降低抗原的反应,外来干扰素就不需完全是自体同源的。用于制作聚合体结合物的干扰素可由哺乳动物的提取物,如人、反刍动物或牛干扰素、或重组生产的干扰素制备而得。
许多其他长效或缓释制剂可采用本领域内熟知的常规方法制备。
由一定量的起治疗作用的PEG12000-IFNα和药学上可接受的载体、调节剂、稀释剂、防腐剂和/或溶解剂混合在一起制成的常规药用组合物可应用于本发明之中。干扰素的药用组合物包含各种具有一定范围的pH和离子强度的缓中稀释剂(如Tris-HCl,醋酸盐,磷酸盐)、载体(如人血清白蛋白)、溶解剂(如吐温、聚山梨酸醋)和防腐剂(如thimerosol。苄基醇)。见例如美国专利4,496,537。
如上所述,疾病的进展及其对药物治疗的反应可通过临床检查和实验室结果来确定。本发明的治疗效果评价由上述的慢性肝炎的症状缓解的程度以及常见的干扰素的副作用(如流感样症状如发烧、头痛、发冷、肌痛、疲劳等以及与中枢神经系统有关的症状如抑郁、感觉异常、impaired concentration等)消除或减少的程度来决定。
在不背离本发明的精神和范围的情况下,本发明可作许多修改和变动,这对本领域技术人员来说应是显而易见的。本文描述的一些特殊方案仅是举例而已,本发明仅受限于本文后附的各项权利要求以及该权利要求授权保护的其等价物的全部范围。
Claims (9)
1.治疗对用干扰素α治疗敏感的病毒性感染的方法,该方法包括给予需要此种治疗的哺乳动物一定量的PEG12000-IFNα,此种用量能有效地治疗病毒感染,同时降低或消除通常与给予干扰素α有关的不良副作用。
2.治疗哺乳动物丙型病毒性肝炎的方法,该方法包括给予需要此种治疗的哺乳动物一定量的PEG12000-干扰素α,同时明显减轻或消除通常与给予干扰素α有关的不良副作用。
3.权利要求2的方法,其中所述PEG12000-IFNα是PEG12000-IFNα-2b。
4.权利要求2的方法,其中所述PEG12000-IFNα是PEG12000-IFNα-2a。
5.权利要求2的方法,其中给予PEG12000-IFNα的量至少为约0.25μg/kg/周。
6.权利要求2的方法,其中给予PEG12000-IFNα的量至少为约0.25μg/kg至1.5μg/kg/周。
7.治疗哺乳动物的丙型病毒性肝炎的方法,该方法包括给予需要此种治疗的哺乳动物至少约0.25μg/kg的PEG12000-IFNα-2b。
8.权利要求7的方法,其中每周至少给予大约0.25μg/kg的PEG12000-IFNα-2b。
9.权利要求7的方法,其中每周至少给予大约1.5μg/kg的PEG12000-IFNα-2b。
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- 1998-04-28 SK SK1491-99A patent/SK149199A3/sk unknown
- 1998-04-28 DE DE69820247T patent/DE69820247T2/de not_active Expired - Lifetime
- 1998-04-28 HU HU0003131A patent/HUP0003131A2/hu unknown
- 1998-04-28 ZA ZA983543A patent/ZA983543B/xx unknown
- 1998-04-28 EP EP98919777A patent/EP0975369B1/en not_active Expired - Lifetime
- 1998-04-28 BR BR9809425-4A patent/BR9809425A/pt not_active IP Right Cessation
- 1998-04-28 ES ES98919777T patent/ES2207830T3/es not_active Expired - Lifetime
- 1998-04-28 AT AT98919777T patent/ATE255421T1/de active
- 1998-04-28 NZ NZ500763A patent/NZ500763A/xx unknown
- 1998-04-28 IL IL13258298A patent/IL132582A0/xx unknown
- 1998-04-28 AU AU72490/98A patent/AU7249098A/en not_active Abandoned
- 1998-04-29 MY MYPI98001932A patent/MY133891A/en unknown
-
1999
- 1999-03-30 US US09/281,401 patent/US6177074B1/en not_active Expired - Lifetime
- 1999-10-28 NO NO995263A patent/NO995263L/no not_active Application Discontinuation
-
2000
- 2000-10-30 US US09/699,663 patent/US6524570B1/en not_active Expired - Lifetime
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7208167B2 (en) | 2000-08-07 | 2007-04-24 | Sciclone Pharmaceuticals, Inc. | Treatment of hepatitis C with thymosin and peptide combination therapy |
CN101700401B (zh) * | 2002-01-18 | 2013-08-14 | 比奥根艾迪克Ma公司 | 具有用于共轭生物活性化合物的部分的聚亚烷基二醇 |
WO2005077421A1 (fr) * | 2004-02-12 | 2005-08-25 | Jiangsu Hengrui Medicine Co., Ltd | Procede de preparation d'interferon alpha 1b modifie au polyethylene glycol |
CN100355784C (zh) * | 2004-02-12 | 2007-12-19 | 江苏恒瑞医药股份有限公司 | 聚乙二醇修饰α-干扰素1b的制备方法 |
Also Published As
Publication number | Publication date |
---|---|
BR9809425A (pt) | 2000-07-25 |
CA2288038A1 (en) | 1998-11-05 |
ZA983543B (en) | 1998-11-10 |
EP0975369A1 (en) | 2000-02-02 |
US5908621A (en) | 1999-06-01 |
IL132582A0 (en) | 2001-03-19 |
NZ500763A (en) | 2002-03-01 |
NO995263L (no) | 1999-12-27 |
ATE255421T1 (de) | 2003-12-15 |
HUP0003131A2 (hu) | 2001-11-28 |
DE69820247D1 (de) | 2004-01-15 |
CO4940414A1 (es) | 2000-07-24 |
PL336576A1 (en) | 2000-07-03 |
AU7249098A (en) | 1998-11-24 |
DE69820247T2 (de) | 2004-09-09 |
US6524570B1 (en) | 2003-02-25 |
EP0975369B1 (en) | 2003-12-03 |
MY133891A (en) | 2007-11-30 |
US6177074B1 (en) | 2001-01-23 |
WO1998048840A1 (en) | 1998-11-05 |
CA2288038C (en) | 2003-07-29 |
JP2001524110A (ja) | 2001-11-27 |
PT975369E (pt) | 2004-04-30 |
AR012614A1 (es) | 2000-11-08 |
NO995263D0 (no) | 1999-10-28 |
PE72799A1 (es) | 1999-08-06 |
ES2207830T3 (es) | 2004-06-01 |
DK0975369T3 (da) | 2004-04-05 |
KR20010020355A (ko) | 2001-03-15 |
SK149199A3 (en) | 2000-11-07 |
ID22977A (id) | 1999-12-23 |
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