CN1604781A - 脱氧鸭嘴花碱在临床抑郁症的治疗中的应用 - Google Patents
脱氧鸭嘴花碱在临床抑郁症的治疗中的应用 Download PDFInfo
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- CN1604781A CN1604781A CNA028254031A CN02825403A CN1604781A CN 1604781 A CN1604781 A CN 1604781A CN A028254031 A CNA028254031 A CN A028254031A CN 02825403 A CN02825403 A CN 02825403A CN 1604781 A CN1604781 A CN 1604781A
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Classifications
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Abstract
脱氧鸭嘴花碱(deoxypeganine)以游离碱或酸加成盐的形式在制备用以治疗临床抑郁症，尤其是与痴呆或酒精和/或尼古丁滥用有关的抑郁症的药物中的应用。
Description
技术领域
本发明涉及一种脱氧鸭嘴花碱的应用，用于制备治疗临床抑郁症的药物，尤其是与痴呆或酒精和/或尼古丁滥用有关的抑郁症。
背景技术
根据国际疾病分类(International Classification of Diseases)(ICD-10)和美国精神疾病诊断与统计手册(American Diagnostic and StatisticsManual，DSM-IV)，单相抑郁症(相对于双极型失调，正式名称为燥狂抑郁失调)是一种综合征，其特征在于抑郁的心情，一般缺乏动力(lackof drive)和兴趣，经常同时有心神不宁、睡眠失调和社会退缩现象。有此症状的人们除了遭受自杀的风险外，抑郁症-由于治疗花费和不能工作-造成全国经济难以估计的全面性损失，例如，1990年在美国可能花费了总计约437亿美元。
到目前为止抑郁症是最常见的精神疾病。上百份大型流行病学研究概要显示有10％-25％的女性和5％-12％的男性在她/他们的一生中至少遭受一次抑郁症。在工业化国家任何时候都有约5％的人口遭受抑郁症的困扰，这里假定所有去看一般的内科医生或去医院的病人中15-25％患有抑郁症。在世界范围内，这些病人的约十分之一患有抑郁症。抑郁症是一种具有高度和进行性复发比例的疾病，而且，该比例还在不断上升。复发的几率从一次抑郁发作后的50％增加到第二次抑郁发作后的70％，再增加到第三次抑郁发作后的90％。WHO预测到2020年，全世界人口的疾病负担5.7％是由于抑郁症，抑郁症的比例仅略少于心血管病。基于上述信息，可以推算出在任何时间有1亿5千万的人遭受临床抑郁症(Mucke HAM.：Next-Generation CNS Therapeutics.Decision Resources，Inc.[Waltham，Mass.，USA]，2001)。
抑郁症、酒精滥饮和尼古丁滥用之间的三方面共病现象(comorbidity)已被许多研究所证明(参见，例如J.Hamalainen et al.；J.Epidemiol.Community Health 2001；55(8)：573-576)。外伤经历和慢性压力—两个主要的抑郁病因—也与酒精和尼古丁消耗行为的形成有较大的关联(H.J.Little，Alcohol Res.Health 2000；24(4)：215-224)。
治疗临床抑郁症最有效的药物是所谓的“三环类抗抑郁药物”-三环化合物，它同时阻断5-羟色胺和去甲肾上腺素的神经元受体，并抑制这些神经递质在各自的神经元被重吸收，因此，使它们的突触内浓度趋于正常，在抑郁的情况下该浓度会降低。三环类抗抑郁药物在当今仍被广泛地使用，虽然它们的使用会有相当大的副作用，特别是心血管方面。
选择性5-羟色胺重吸收抑制剂(SSRIs)是从大约1980年代中期开始使用。就其整个一类来看，SSRIs并不像传统的三环类抗抑郁药物那么高效，而是在1至2周的延迟后才会显示全部效果。但是，它们的副作用相对小得多，由于它们具有非常低的急性毒性，使得用SSRIs来自杀实际上是不可能的。为此，SSRIs常成为抗抑郁剂的第一选择。
但是，除了副作用以外，三环类抗抑郁剂和SSRIs在抑郁症的治疗中仍遗留有相当大的缺陷：约有30％的患者对上述两类抗抑郁剂中的任意一种在足够剂量时没有反应(所谓的难治疗的抑郁症)。而且，没有一种单一活性物质可以治疗饮酒造成的抑郁症患者，在减少酒精滥饮的同时，也能降低抑郁的程度。对于过度吸烟造成的抑郁症患者，到目前为止只有一种单一活性剂(丁氨苯丙酮(Bupropion)，GlaxoSmithKline)可用，但是，仅以两种单独的和不同剂量的药物的形式使用，其中一种(Wellbutrin)被批准仅用于治疗抑郁，另一种(Zyban)专门用于支持吸烟者的戒除治疗。
可以代替三环类抗抑郁剂和SSRIs的是单胺氧化抑制剂(MAOIs)。这是一类已知达50年的活性剂，通过抑制所有“单胺神经递质”(也就是，包括多巴胺)的降解而增加它们在大脑中的浓度。此类早期活性物质抑制两种亚型的单胺氧化酶(A和B)，部分是不可逆的方式。一方面由于对肝脏发生危害，另一方面由于产生“干酪效应(cheese effect)”(由于食物如奶酪中摄取的酪胺的降解被阻断而引发的高血压危象)，因而MAOI被放弃而使用三环类抗抑郁剂。
因此，对抗抑制剂仍然存在相当大的需求，特别是比市售的活性剂更适于治疗难以治疗的抑郁症和滥用酒精和/或尼古丁的抑郁患者的特殊情况。
发明内容
因此本发明的目的是提供一种用于治疗痴呆、特别是难治的痴呆的药物，但是，此药物比市售的活性剂更适合滥用酒精和/或尼古丁的抑郁患者的特殊情况，但没有上述所提的缺点。
具体实施方式
脱氧鸭嘴花碱(1，2，3，9-四氢吡咯并[2，1-b]喹唑啉)是一种分子式为C11H12N2的生物碱，出现在蒺藜科(Zygophyllaceae)植物中。脱氧鸭嘴花碱优选由叙利亚芸香(肉叶芸香(Peganum harmala))中分离或化学合成得到。本领域的技术人员可通过文献，特别是专利说明书得知。
德国专利DE-A19906978，相应于WO00/48582，描述了基于脱氧鸭嘴花碱的用于治疗药物成瘾和药物依赖的药物。
德国专利DE-A19906975，相应于WO00/48599，描述了脱氧鸭嘴花碱用于治疗阿尔茨海默氏痴呆症。
德国专利DE-A19906979，相应于WO00/48445，描述了基于脱氧鸭嘴花碱的用于尼古丁依赖的治疗的药物。
基于其药理学的特性，脱氧鸭嘴花碱被包括在可逆的胆碱脂酶抑制剂的组中。从这些出版物大体上可以得知脱氧鸭嘴花碱不仅可抑制乙酰胆碱脂酶，还可抑制单胺氧化酶的事实。但是，这些文件并未提供任何方式来区分这两种亚型的单胺氧化酶A和B。最重要的是，单胺氧化酶抑制经常地被描述为仅仅是一种试图加强脱氧鸭嘴花碱抑制乙酰基胆碱脂酶作用的互补作用，而乙酰基胆碱脂酶的抑制作用则被视为是最重要的。上述专利申请，举例来说，明显提及同时抑制乙酰基胆碱脂酶优点和单胺氧化酶补偿，相对于重量单位，较低的胆碱脂酶抑制作用(相对于原型有效的胆碱脂酶抑制剂毒扁豆碱)。最后，没有一篇文献提到可能在抑郁症领域的应用。
在进一步的药理学研究期间，令人惊奇地发现，脱氧鸭嘴花碱确实如上述文献所描述的能抑制乙酰胆碱酯酶，但是在体外定量的主要作用在于选择性地抑制A型单胺氧化酶(MAO-A)，同时B型酶未被明显地抑制。早期单胺氧化酶抑制剂的前述副作用可被单胺氧化酶A的选择性、可逆性抑制剂(RIMA)避免。
进一步地，发现在适当的动物实验中脱氧鸭嘴花碱显示出强烈地抗抑郁和精神运动性刺激活性，此发现与上述两个发现有关，但考虑到当前的技术水平仍完全地令人惊奇。在胆碱能活化作用的动物模式中仍没有显示出统计学的有意效果的剂量在这里已出现最大的作用。
脱氧鸭嘴花碱对于从鼠脑中(Wistar种)取得的单胺氧化酶A的抑制作用根据Medvedev等人所描述的方法(Biochem Pharmacol1994；47(2)：303-308)被测量为10nM～10μM的浓度范围内，并与作为阳性对照的氯吉兰(clorogyline)比较，在这两种情况下，都以pH7.4的20mM磷酸二氢钾缓冲液的1％二甲亚砜溶液中的95μM[3H]5-羟色胺作为底物。对于脱氧鸭嘴花碱，1.49μM的浓度就可达到半最大抑制作用(抑制度50％＝IC50)。该值几乎是在另外的体外系统中所得的对于乙酰胆碱酯酶抑制的IC50值以下10倍。相比之下，单胺氧化酶B在10μM的浓度只有10％～20％的抑制。
为了证实在体内这种MAO-A抑制作用是否是相应的，脱氧鸭嘴花碱在对大鼠的“强迫游泳试验”(R.D.Porsolt et al.，Nature 1977；266(5604)：730-732)中被测试。此模型基于所谓的“行为绝望”的行为，该行为显示动物处于它们已经知道的绝望处境中：如果它们置于装水的容器中，从该容器它们不能逃脱，一段时间后它们会放弃逃脱的努力，而只做活命最必须的游泳动作。测量动物从企图逃脱到最后这种精神消极(被认为是抑郁的替代)所花的时间，延长的活动相应于抗抑郁的作用。
在具体的情况中，从Charles River UK Ltd.获得的50只约6周的雄性大鼠(Sprague Dawley种)分成7组每组10只。第一天，适应期结束后，每只动物放入装有15cm高25℃温水的圆筒内10分钟。在此1小时后、19小时后和23小时后，分三次分别口服给药(根据不同的组)：阴性对照(水)、阳性对照(15mg/kg体重的盐酸丙咪嗪)、或剂量为1.0、2.5、7.5、15.0或22.5mg/kg体重的盐酸脱氧鸭嘴花碱。由胃管协助给药，各组的服药量为5ml/kg体重。在第三次服药后的一个小时，每只动物再被放入容器中整5分钟，并测量最小限度活动所花的时间。
有效的三环抗抑郁剂丙咪嗪，根据初步试验的结果确定在此系统中最大可达到的活性剂量为15mg/kg，与水比较丙咪嗪降低最小限度活动的时间为56.5％到58.9％。而1mg/kg剂量的脱氧鸭嘴花碱还没有效用，而2.5mg/kg剂量只有部分效用，从7.5mg/kg剂量以上的所有浓度平均能达到41.4％～44.1％的下降效力。所有这些平稳值在p＜0.01的水平上具有统计学上显著的意义。因此，对于所有的这些浓度，脱氧鸭嘴花碱的治疗的效果确实保持低于此系统可能的最大值，但使用阳性对照一半的剂量(7.5mg/kg)，就已达到了此物质的最大值(见表1)。
盐酸脱氧鸭嘴花碱在Porsolt游泳试验(大鼠，SD种)中的作用
| 处理 | 剂量(mg/kg p.o.) | 静止时间(组平均值±标准差(分钟) | 相对于对照组的变化 |
| 阴性对照组(注射用水) | --- | 3.45±0.603.38±0.60 | --- |
| 盐酸脱氧鸭嘴花碱盐酸脱氧鸭嘴花碱盐酸脱氧鸭嘴花碱盐酸脱氧鸭嘴花碱盐酸脱氧鸭嘴花碱 | 1.02.57.515.022.5 | 3.46±0.832.80±1.021.82**±0.961.98**±0.831.90**±0.591.90**±0.54 | +0.3％-18.8％-47.2％-41.4％-44.1％-43.8％ |
| 阳性对照(盐酸丙咪嗪最大有效剂量) | 15 | 1.50**±0.491.39**±0.52 | -56.5％-58.9％ |
**p＜0.01
由于这种结果原则上也可以由无抗抑郁作用的精神运动活性物质得到，同样以相同剂量范围在所谓的旷场实验(Open Field Paradigm)中检验脱氧鸭嘴花碱的效用。这里利用这样一种事实，让大鼠呆在开放的、明亮的地方会感到压力，因此如果有可能老鼠尽量避免这种环境。这种实验，同样使用Sprague-Dawley大鼠，该大鼠每天脱氧鸭嘴花碱的剂量从2.5～22.5mg/kg，持续给药2周，但是没有产生精神运动活性的指征。所以Porsolt试验的结果(7.5mg/kg p.o.的最大活性，与抗抑郁剂丙咪嗪比较)必然被认为是有意义的。
进一步的试验系统的结果更令人惊讶，其中使用脱氧鸭嘴花碱抑制乙酰胆碱酯酶的作用，由部分损毁大鼠因中枢胆碱能通路而引起的胆碱能的记忆缺失得到了补偿，这一效应在相同剂量范围内显示出明显的线性相关，口服剂量为7.5mg/kg时仍没有统计上的意义，而口服剂量为22.5mg/kg时仍没有达到其最大值。由此可以推断，在游泳试验中可观察的效应在胆碱能系统最大活性的必要剂量的小部分时达到其最大值，这一点根据现有技术发展水平还不能解释。
因此，在公认的抑郁症的动物模型中，脱氧鸭嘴花碱具有抗抑郁作用，与精神运动活性作用不同，即其他条件相同的情况下，胆碱能补偿的行为模型仍然显示出绝对地未达最佳活性的剂量，抗抑郁作用已达到最高水平。
因此，脱氧鸭嘴花碱潜在地适于作为抗抑制剂。
脱氧鸭嘴花碱可以经口服或经非肠道给药。对于口服给药，可以使用已知的给药形式，例如片剂、胶囊、糖衣片剂和锭剂。
同样适合地可以是液体或半液体剂型，例如饮液，在此情况下该药剂以溶液或悬浮形式存在。可以使用的溶剂或悬浮剂为水、水性介质或药理学上可接受的油类(植物油或矿物油)。
含有脱氧鸭嘴花碱的药物优选配制成长效药物(depot drug)，此药物能在较长的时间内以可控制方式将药物传递到体内。
此外，根据本发明脱氧鸭嘴花碱还可以直肠给药(例如通过栓剂)，吸入给药(通过吸入有特定浓度和微粒大小分布的气溶胶)，经皮给药(通过含活性剂的贴片、擦剂溶液、凝胶等)，经粘膜给药(通过口和鼻粘膜吸收具有活性剂，该活性剂通过溶解在唾液中而在口腔中释出，或通过喷射等进入鼻腔内)，通过植入导管给药(活性剂被动渗透或通过微泵等可控制地释放)，通过静脉注射、肌肉注射或皮下注射和脑心室内给药。
关于非肠道的给药，根据本发明对于脱氧鸭嘴花碱可能使用经皮或经粘膜的剂量形式有特殊的优势，最好使用如德国专利DE-A19906977所具体描述的脱氧鸭嘴花碱的粘性经皮治疗系统(膏药剂)。此种药剂能在较长时间内以可控制的方式将药物经由皮肤释放给被治疗的患者。
根据本发明，脱氧鸭嘴花碱可以以其游离碱和酸加成盐的两种形式用于治疗；优选的盐是脱氧鸭嘴花碱盐酸盐和脱氧鸭嘴花碱氢溴酸盐。此外，还可能使用其它药理上可接受的酸的盐类，例如柠檬酸盐、酒石酸盐或醋酸盐。
根据本发明用于脱氧鸭嘴花碱给药的药物制剂可以包含一个或多个下面的添加剂：
-抗氧化剂，增效剂、稳定剂；
-防腐剂；
-矫味剂；
-色素；
-溶剂，增溶剂；
-表面活性剂(乳化剂、增溶剂、润湿剂、消泡剂)；
-影响粘性和稠度的试剂，凝胶形成剂；
-吸收促进剂；
-吸附剂，湿润剂，助流剂；
-影响崩解和溶解的试剂，填充剂(膨胀剂)，胶溶剂；
-缓释剂。
此列表不是限定性的，适宜的生理上可接受的物质为本领域的技术人员所熟知。
脱氧鸭嘴花碱优选以包含该物质的比例为0.1～90wt％，特别优选2～20wt％的药物制剂的形式给药，在各种情况下活性物质以游离的脱氧鸭嘴花碱计算。根据本发明所使用的含有脱氧鸭嘴花碱的药物制剂可以另外包含添加剂，如非活性成分、赋形剂、媒介物和/或稳定剂，其量本领域的技术人员已知。
每日给药剂量优选为0.1～100mg，更优选为10～50mg。应依据个体的要求做适当地调整。
Claims (21)
1、脱氧鸭嘴花碱以游离碱或酸加成盐的形式在临床抑郁症的治疗中的应用。
2、根据权利要求1的应用，其特征在于所述抑郁症是一种难治疗的抑郁症。
3、根据上述权利要求任一项的应用，其特征在于所述抑郁症与痴呆有关。
4、根据上述权利要求任一项的应用，其特征在于抑郁症与成瘾物质或麻醉剂的滥用有关。
5、根据上述权利要求任一项的应用，其特征在于所述成瘾物质滥用为酒精和/或尼古丁滥用。
6、根据上述权利要求任一项的应用，其特征在于每日给药剂量为0.1～100mg，优选10～50mg。
7、根据上述权利要求任一项的应用，其特征在于脱氧鸭嘴花碱在药物制剂中给药，药物制剂包含该活性剂0.1～90wt％，优选2～20wt％，以游离的脱氧鸭嘴花碱计算。
8、根据权利要求7的应用，其特征在于脱氧鸭嘴花碱以具有储存作用的药物制剂给药。
9、根据权利要求7或8的应用，其特征在于脱氧鸭嘴花碱口服给药。
10、根据权利要求7或8的应用，其特征在于脱氧鸭嘴花碱经非肠道给药。
11、根据权利要求10的应用，其特征在于脱氧鸭嘴花碱经皮肤给药。
12、脱氧鸭嘴花碱以游离碱或酸加成盐的形式在制备治疗临床抑郁症的药物中的应用。
13、根据权利要求12的应用，其特征在于所述临床抑郁症是一种难治疗的抑郁症。
14、根据权利要求12或13的应用，其特征在于所述抑郁症与痴呆有关。
15、根据权利要求12至14任一项的应用，其特征在于抑郁症与成瘾物质或麻醉剂的滥用有关。
16、根据权利要求12至15任一项的应用，其特征在于所述成瘾物质滥用为酒精和/或尼古丁滥用。
17、根据权利要求12至16任一项的应用，其特征在于所述药物包含该脱氧鸭嘴花碱活性剂0.1～90wt％，优选2～20wt％，以游离的脱氧鸭嘴花碱计算。
18、根据权利要求12至17任一项的应用，其特征在于所述药物具有储存作用。
19、根据权利要求12至18任一项的应用，其特征在于所述药物为可口服给药的药物。
20、根据权利要求12至18任一项的应用，其特征在于所述药物为可经非肠道给药的药物。
21、根据权利要求12的应用，其特征在于所述药物为可经皮肤给药的药物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10163667.9 | 2001-12-21 | ||
| DE10163667A DE10163667B4 (de) | 2001-12-21 | 2001-12-21 | Verwendung von Desoxypeganin zur Behandlung der klinischen Depression |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1604781A true CN1604781A (zh) | 2005-04-06 |
| CN1283253C CN1283253C (zh) | 2006-11-08 |
Family
ID=7710660
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB028254031A Expired - Fee Related CN1283253C (zh) | 2001-12-21 | 2002-12-14 | 脱氧鸭嘴花碱在制备治疗临床抑郁症的药物中的应用 |
Country Status (30)
| Country | Link |
|---|---|
| US (1) | US20050009813A1 (zh) |
| EP (1) | EP1461042B1 (zh) |
| JP (1) | JP2005513105A (zh) |
| KR (1) | KR100614504B1 (zh) |
| CN (1) | CN1283253C (zh) |
| AR (1) | AR037967A1 (zh) |
| AT (1) | ATE404203T1 (zh) |
| AU (1) | AU2002363874B2 (zh) |
| BR (1) | BR0215306A (zh) |
| CA (1) | CA2471338C (zh) |
| CZ (1) | CZ301210B6 (zh) |
| DE (2) | DE10163667B4 (zh) |
| DK (1) | DK1461042T3 (zh) |
| EA (1) | EA006896B1 (zh) |
| ES (1) | ES2312657T3 (zh) |
| HK (1) | HK1066742A1 (zh) |
| HU (1) | HUP0402298A3 (zh) |
| IL (2) | IL162509A0 (zh) |
| MX (1) | MXPA04006125A (zh) |
| MY (1) | MY138088A (zh) |
| NO (1) | NO326446B1 (zh) |
| NZ (1) | NZ533249A (zh) |
| PL (1) | PL370315A1 (zh) |
| PT (1) | PT1461042E (zh) |
| SI (1) | SI1461042T1 (zh) |
| SK (1) | SK287152B6 (zh) |
| TW (1) | TWI241189B (zh) |
| UA (1) | UA76254C2 (zh) |
| WO (1) | WO2003053445A1 (zh) |
| ZA (1) | ZA200404053B (zh) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE521512C2 (sv) * | 2001-06-25 | 2003-11-11 | Niconovum Ab | Anordning för administrering av en substans till främre delen av en individs munhåla |
| WO2004056363A2 (en) | 2002-12-20 | 2004-07-08 | Niconovum Ab | A physically and chemically stable nicotine-containing particulate material |
| DE10354893B4 (de) * | 2003-11-24 | 2011-03-10 | Hf Arzneimittelforschung Gmbh | Verwendung von Desoxypeganin zur Behandlung schizophrener Psychosen |
| DE10354894A1 (de) * | 2003-11-24 | 2005-07-07 | Hf Arzneimittelforschung Gmbh | Orale Formulierungen des Desoxypeganins und deren Anwendungen |
| FR2865650B1 (fr) * | 2004-01-30 | 2008-06-13 | Biocortech | Utilisation du 14,15 dihydro 20,21-dinoreburnamenin14-ol pour traiter et/ou prevenir les depressions majeures et les desordres du cycle veille-sommeil |
| JP5000932B2 (ja) * | 2005-06-21 | 2012-08-15 | 日東電工株式会社 | ニコチン含有経皮吸収製剤 |
| CA2646942C (en) | 2006-03-16 | 2014-07-29 | Niconovum Ab | Improved snuff composition |
| CN101433565B (zh) * | 2008-11-26 | 2013-06-05 | 上海中医药大学 | 骆驼蓬属种子总生物碱提取物和它们的制备 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19906979B4 (de) * | 1999-02-19 | 2004-07-08 | Lts Lohmann Therapie-Systeme Ag | Verwendung von Desoxypeganin zur Behandlung der Nikotinabhängigkeit |
| DE19906977C1 (de) * | 1999-02-19 | 2000-06-15 | Lohmann Therapie Syst Lts | Desoxypeganin-TTS und seine Verwendung |
| DE19906975B4 (de) * | 1999-02-19 | 2004-04-15 | Lts Lohmann Therapie-Systeme Ag | Arzneiform zur Behandlung von Alzheimer'scher Demenz |
| DE19906978B4 (de) * | 1999-02-19 | 2004-07-08 | Lts Lohmann Therapie-Systeme Ag | Pharmazeutische Zusammensetzung enthaltend Desoxypeganin zur Behandlung der Drogenabhängigkeit |
| DE19906974C2 (de) * | 1999-02-19 | 2003-10-09 | Lohmann Therapie Syst Lts | Verwendung von Desoxypeganin zur Behandlung des Alkoholismus |
-
2001
- 2001-12-21 DE DE10163667A patent/DE10163667B4/de not_active Expired - Fee Related
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2002
- 2002-12-12 MY MYPI20024665A patent/MY138088A/en unknown
- 2002-12-14 PL PL02370315A patent/PL370315A1/xx not_active Application Discontinuation
- 2002-12-14 IL IL16250902A patent/IL162509A0/xx unknown
- 2002-12-14 PT PT02798337T patent/PT1461042E/pt unknown
- 2002-12-14 EA EA200400751A patent/EA006896B1/ru not_active IP Right Cessation
- 2002-12-14 SK SK258-2004A patent/SK287152B6/sk not_active IP Right Cessation
- 2002-12-14 MX MXPA04006125A patent/MXPA04006125A/es active IP Right Grant
- 2002-12-14 ES ES02798337T patent/ES2312657T3/es not_active Expired - Lifetime
- 2002-12-14 AU AU2002363874A patent/AU2002363874B2/en not_active Ceased
- 2002-12-14 EP EP02798337A patent/EP1461042B1/de not_active Expired - Lifetime
- 2002-12-14 CN CNB028254031A patent/CN1283253C/zh not_active Expired - Fee Related
- 2002-12-14 US US10/496,366 patent/US20050009813A1/en not_active Abandoned
- 2002-12-14 UA UA20040604815A patent/UA76254C2/uk unknown
- 2002-12-14 HU HU0402298A patent/HUP0402298A3/hu unknown
- 2002-12-14 SI SI200230755T patent/SI1461042T1/sl unknown
- 2002-12-14 JP JP2003554202A patent/JP2005513105A/ja not_active Ceased
- 2002-12-14 CA CA002471338A patent/CA2471338C/en not_active Expired - Fee Related
- 2002-12-14 KR KR1020047009851A patent/KR100614504B1/ko not_active IP Right Cessation
- 2002-12-14 DK DK02798337T patent/DK1461042T3/da active
- 2002-12-14 DE DE50212649T patent/DE50212649D1/de not_active Expired - Lifetime
- 2002-12-14 NZ NZ533249A patent/NZ533249A/en not_active IP Right Cessation
- 2002-12-14 BR BR0215306-8A patent/BR0215306A/pt not_active Application Discontinuation
- 2002-12-14 CZ CZ20040739A patent/CZ301210B6/cs not_active IP Right Cessation
- 2002-12-14 WO PCT/EP2002/014274 patent/WO2003053445A1/de active IP Right Grant
- 2002-12-14 AT AT02798337T patent/ATE404203T1/de active
- 2002-12-17 TW TW091136439A patent/TWI241189B/zh not_active IP Right Cessation
- 2002-12-20 AR ARP020105056A patent/AR037967A1/es unknown
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- 2004-06-14 NO NO20042476A patent/NO326446B1/no not_active IP Right Cessation
- 2004-06-14 IL IL162509A patent/IL162509A/en not_active IP Right Cessation
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