CN1531432A - 伊潘立酮的新用途 - Google Patents
伊潘立酮的新用途 Download PDFInfo
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- CN1531432A CN1531432A CNA028043669A CN02804366A CN1531432A CN 1531432 A CN1531432 A CN 1531432A CN A028043669 A CNA028043669 A CN A028043669A CN 02804366 A CN02804366 A CN 02804366A CN 1531432 A CN1531432 A CN 1531432A
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- 229960003162 iloperidone Drugs 0.000 title abstract description 5
- XMXHEBAFVSFQEX-UHFFFAOYSA-N iloperidone Chemical compound COC1=CC(C(C)=O)=CC=C1OCCCN1CCC(C=2C3=CC=C(F)C=C3ON=2)CC1 XMXHEBAFVSFQEX-UHFFFAOYSA-N 0.000 title abstract description 5
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 10
- 230000008451 emotion Effects 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 6
- -1 propoxyl Chemical group 0.000 claims description 6
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 208000019022 Mood disease Diseases 0.000 abstract description 4
- 208000020925 Bipolar disease Diseases 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 17
- 238000002474 experimental method Methods 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 8
- 230000000694 effects Effects 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 208000017194 Affective disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 2
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 2
- 206010012289 Dementia Diseases 0.000 description 2
- 208000028017 Psychotic disease Diseases 0.000 description 2
- 206010041243 Social avoidant behaviour Diseases 0.000 description 2
- 229940025084 amphetamine Drugs 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 206010000117 Abnormal behaviour Diseases 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- 208000011688 Generalised anxiety disease Diseases 0.000 description 1
- 206010020651 Hyperkinesia Diseases 0.000 description 1
- 208000000269 Hyperkinesis Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 208000026725 cyclothymic disease Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000025561 forward locomotion Effects 0.000 description 1
- 208000029364 generalized anxiety disease Diseases 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 208000022610 schizoaffective disease Diseases 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4515—Non condensed piperidines, e.g. piperocaine having a butyrophenone group in position 1, e.g. haloperidol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明提供了伊潘立酮在包括双极型情感障碍在内的情感障碍的治疗中的用途。
Description
本发明涉及在下文中被称为“本发明的药物”的1-[4-[3-[4-(6-氟-1，2-苯并异噁唑-3-基)-1-哌啶基]丙氧基]-3-甲氧基苯基]乙酮(伊潘立酮)(iloperidone)和其药学可接受的酸加成盐的新的药物用途。
本发明的药物和它们的制备方法可以从例如EP402644中已知。此专利还公开了本发明药物作为抗精神病药物的用途。
根据本发明，现已令人惊讶地发现：本发明的药物可用于包括双极型情感障碍在内的情感障碍的治疗。
本发明药物在所述治疗中的活性在例如以下实验中得到证明，所述实验适合于检测具有潜在的解除行为抑制作用和/或回归社会(sociotropic)作用的药物，这种作用被认为与社会退缩(即抑郁症的首要特征)和相关的精神病状的恢复有关。
a)半封闭平台实验(The Half Enclosed Platform Test)
此实验基本上按照“精神药理学”(Psychopharmacology，1986，89：31-37)中所述的方法进行。
在于平台上进行实验的1小时前，向各个由12只雄性0F-1小鼠组成的动物组施用赋形剂或本发明物质。实验装置由一个透明的、具有25个等距离的1厘米孔的平台组成。所述平台被15厘米高、环绕半个平台的半长方形围墙等分为两半，另一半平台的边缘是敞开的。整个平台被放置在四个15厘米高的支柱上。一条线沿着平台中间从一边围墙的边缘牵至对面围墙的边缘。实验内容包括将小鼠放置在中线上，并在小鼠于平台上探察时记录小鼠的行为达5分钟，尤其是记录行为元素的频率和持续时间，并采用Kruskal-Wallis“H”检验进行统计比较，随后采用Mann-Whitney U-检验对对照组和治疗组之间进行成对比较。所引用的概率值(P≤0.05)为双尾概率。
在约0.3至约10mg/kg的口服剂量时，本发明的药物可显著地增加小鼠在开放半平台上的探察行为，如全身伸展姿势(stretched attend posture)、抬头和前倾运动(forward locomotion)，并相应地降低了小鼠在封闭半平台上的静态行为元素(如静坐、休止)的频率。
b)小鼠高脚十字迷宫模型(the Elevated Plus-maze Paradigm)
此实验基本上按照“行为药理学”(Behav.Pharmacol.，1998，8：477-496)中描述的方法进行。
在约1至约10mg/kg的口服剂量时，本发明的药物可显著地增加小鼠在开放半平台上的停留时间。这些发现与半封闭平台实验的结果一致。
c)苯异丙胺引发的运动过度实验
此实验依照Arnt J在“欧洲药理学杂志”(Eur.J.Pharmacol，283，55-62(1995))中所描述的方法进行。
经皮下施用约0.01至约10mg/kg的剂量时，本发明的药物可显著地抑制苯异丙胺引发的动物的活动。
考虑到本发明药物的解除行为抑制(类似于抗焦虑或抗抑郁的)活性和回归社会的活性，本发明药物可用于治疗包括双极型障碍在内的情感障碍，例如狂躁和抑郁性障碍、循环性情感障碍、分裂情感性障碍和行为需要稳定的过度情绪急转。此外，所述化合物可以适用于ADHD(注意力不足过动症)和与痴呆和帕金森病有关的行为障碍。如高脚十字迷宫实验所证明的：预期该化合物对焦虑症(例如广泛性焦虑，社交恐惧和广场恐惧)以及那些以社会退缩为特征的行为状态(例如孤独症和伴有突出的负性症状的精神病[青春期痴呆])有效。
对于以上提及的病症，合适的剂量将随着例如所使用的化合物、宿主、给药方式和所治疗病症的性质和严重程度而变化。但是通常在动物中获得满意结果所需的日剂量为每千克动物体重约1至约50mg。在较大的哺乳动物如人体中的日剂量取决于在不同行为障碍患者中进行的临床研究的结果，其在约1至约50mg本发明药物的范围内变化，并可以以分剂量的形式每天不超过2次方便地施用。
本发明的药物可以以任何通常的方式施用，例如通过口服(例如以片剂或胶囊的形式)或经肠道外(例如以注射溶液或悬浮液的形式)施用。
本发明还提供了包含一种本发明的药物和至少一种药物载体或稀释剂的、用于治疗情感和注意力障碍的药物组合物。这种组合物可以按照常规的方法制备。单位剂量形式可以含有例如约0.1mg至约25mg的通式I化合物。
本发明还提供了本发明的药物在制备用于治疗情感和注意力/行为障碍的药物组合物中的用途。
此外，本发明提供了在需要这种治疗的对象中治疗情感和注意力障碍的方法，其包含向所述对象施用治疗有效量的本发明药物。
Claims (4)
1.1-[4-[3-[4-(6-氟-1，2-苯并异噁唑-3-基)-1-哌啶基]丙氧基]-3-甲氧基苯基]乙酮和其药学可接受的酸加成盐用于治疗情感和注意力/行为障碍的用途。
2.包含1-[4-[3-[4-(6-氟-1，2-苯并异噁唑-3-基)-1-哌啶基]丙氧基]-3-甲氧基苯基]乙酮或其药学可接受的酸加成盐以及至少一种药物载体或稀释剂的、用于治疗情感和注意力/行为障碍的药物组合物。
3.1-[4-[3-[4-(6-氟-1，2-苯并异噁唑-3-基)-1-哌啶基]丙氧基]-3-甲氧基苯基]乙酮或其药学可接受的酸加成盐在制备用于治疗情感和注意力/行为障碍的药物组合物的用途。
4.在需要这种治疗的对象中治疗情感和注意力/行为障碍的方法，其包含向所述对象施用治疗有效量的1-[4-[3-[4-(6-氟-1，2-苯并异噁唑-3-基)-1-哌啶基]丙氧基]-3-甲氧基苯基]乙酮或其药学可接受的酸加成盐。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0102841.4 | 2001-02-05 | ||
| GBGB0102841.4A GB0102841D0 (en) | 2001-02-05 | 2001-02-05 | Organic compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1531432A true CN1531432A (zh) | 2004-09-22 |
| CN1226035C CN1226035C (zh) | 2005-11-09 |
Family
ID=9908143
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB028043669A Expired - Lifetime CN1226035C (zh) | 2001-02-05 | 2002-02-04 | 伊潘立酮的新用途 |
Country Status (21)
| Country | Link |
|---|---|
| US (4) | US20040072869A1 (zh) |
| EP (1) | EP1370262A1 (zh) |
| JP (1) | JP4278981B2 (zh) |
| KR (1) | KR100851256B1 (zh) |
| CN (1) | CN1226035C (zh) |
| AU (1) | AU2002231766B2 (zh) |
| BR (1) | BR0206918A (zh) |
| CA (1) | CA2434900C (zh) |
| CZ (1) | CZ301357B6 (zh) |
| GB (1) | GB0102841D0 (zh) |
| HU (1) | HUP0303136A3 (zh) |
| IL (3) | IL156819A0 (zh) |
| MX (1) | MXPA03006970A (zh) |
| NO (1) | NO20033163L (zh) |
| NZ (1) | NZ527111A (zh) |
| PL (1) | PL362550A1 (zh) |
| RU (1) | RU2301065C2 (zh) |
| SK (1) | SK9812003A3 (zh) |
| TW (1) | TWI322011B (zh) |
| WO (1) | WO2002064141A1 (zh) |
| ZA (1) | ZA200305331B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101822673A (zh) * | 2009-03-04 | 2010-09-08 | 北京德众万全药物技术开发有限公司 | 一种含有伊潘立酮的固体药物组合物 |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2005292246B2 (en) | 2004-09-30 | 2011-07-07 | Vanda Pharmaceuticals, Inc | Methods for the administration of iloperidone |
| US20100063093A1 (en) | 2007-03-28 | 2010-03-11 | Curt Wolfgang | Methods for the administration of iloperidone |
| RU2008150624A (ru) * | 2006-05-22 | 2010-06-27 | Ванда Фармасьютиклз, Инк. (Us) | Лечение депрессивных расстройств |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE126512T1 (de) * | 1989-05-19 | 1995-09-15 | Hoechst Roussel Pharma | N-(aryloxyalkyl)heteroarylpiperidine und - heteroarylpiperazine, verfahren zu ihrer herstellung und ihre verwendung als medikamente. |
| FR2654104B1 (fr) * | 1989-11-07 | 1992-01-03 | Adir | Nouveaux derives du 1,2-benzisoxazole, leurs procedes de preparation et les compositions pharmaceutiques qui les contiennent. |
| CA2300148C (en) * | 1997-08-11 | 2009-06-23 | University Of South Florida | Nicotine antagonists for nicotine-responsive neuropsychiatric disorders |
| US5955459A (en) * | 1997-11-26 | 1999-09-21 | Neuromedica, Inc. | Fatty acid-antipsychotic compositions and uses thereof |
| KR20010072878A (ko) * | 1998-10-16 | 2001-07-31 | 디르크 반테 | 인식을 개선하기 위한 아세틸콜린에스테라제 억제제와배합된 비정형 항정신병제 |
| EP1242058A1 (en) * | 1999-04-07 | 2002-09-25 | Pfizer Products Inc. | Use of cyp2d6 inhibitors in combination therapies |
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2001
- 2001-02-05 GB GBGB0102841.4A patent/GB0102841D0/en not_active Ceased
-
2002
- 2002-02-01 TW TW091101815A patent/TWI322011B/zh not_active IP Right Cessation
- 2002-02-04 CN CNB028043669A patent/CN1226035C/zh not_active Expired - Lifetime
- 2002-02-04 MX MXPA03006970A patent/MXPA03006970A/es active IP Right Grant
- 2002-02-04 CZ CZ20032114A patent/CZ301357B6/cs not_active IP Right Cessation
- 2002-02-04 JP JP2002563935A patent/JP4278981B2/ja not_active Expired - Lifetime
- 2002-02-04 KR KR1020037009134A patent/KR100851256B1/ko not_active IP Right Cessation
- 2002-02-04 US US10/470,499 patent/US20040072869A1/en not_active Abandoned
- 2002-02-04 EP EP02711828A patent/EP1370262A1/en not_active Withdrawn
- 2002-02-04 CA CA2434900A patent/CA2434900C/en not_active Expired - Fee Related
- 2002-02-04 SK SK981-2003A patent/SK9812003A3/sk not_active Application Discontinuation
- 2002-02-04 WO PCT/EP2002/001130 patent/WO2002064141A1/en active Application Filing
- 2002-02-04 PL PL02362550A patent/PL362550A1/xx not_active Application Discontinuation
- 2002-02-04 AU AU2002231766A patent/AU2002231766B2/en not_active Expired
- 2002-02-04 RU RU2003126175/15A patent/RU2301065C2/ru not_active IP Right Cessation
- 2002-02-04 BR BR0206918-0A patent/BR0206918A/pt not_active Application Discontinuation
- 2002-02-04 NZ NZ527111A patent/NZ527111A/en unknown
- 2002-02-04 HU HU0303136A patent/HUP0303136A3/hu unknown
- 2002-02-04 IL IL15681902A patent/IL156819A0/xx active IP Right Grant
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2003
- 2003-07-07 IL IL156819A patent/IL156819A/en not_active IP Right Cessation
- 2003-07-10 NO NO20033163A patent/NO20033163L/no not_active Application Discontinuation
- 2003-07-10 ZA ZA200305331A patent/ZA200305331B/en unknown
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2006
- 2006-05-04 US US11/418,507 patent/US20060205786A1/en not_active Abandoned
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2007
- 2007-12-21 US US11/962,893 patent/US20080103177A1/en not_active Abandoned
- 2007-12-27 IL IL188485A patent/IL188485A0/en not_active IP Right Cessation
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- 2009-01-23 US US12/358,959 patent/US20090131477A1/en not_active Abandoned
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101822673A (zh) * | 2009-03-04 | 2010-09-08 | 北京德众万全药物技术开发有限公司 | 一种含有伊潘立酮的固体药物组合物 |
| CN101822673B (zh) * | 2009-03-04 | 2013-09-18 | 北京德众万全药物技术开发有限公司 | 一种含有伊潘立酮的固体药物组合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| US20090131477A1 (en) | 2009-05-21 |
| NZ527111A (en) | 2005-05-27 |
| CZ20032114A3 (cs) | 2004-01-14 |
| EP1370262A1 (en) | 2003-12-17 |
| JP2004517959A (ja) | 2004-06-17 |
| IL156819A0 (en) | 2004-02-08 |
| NO20033163D0 (no) | 2003-07-10 |
| IL156819A (en) | 2008-03-20 |
| RU2003126175A (ru) | 2005-03-10 |
| CN1226035C (zh) | 2005-11-09 |
| SK9812003A3 (en) | 2004-04-06 |
| HUP0303136A2 (hu) | 2003-12-29 |
| AU2002231766B2 (en) | 2005-12-22 |
| US20040072869A1 (en) | 2004-04-15 |
| WO2002064141A1 (en) | 2002-08-22 |
| TWI322011B (en) | 2010-03-21 |
| CA2434900C (en) | 2010-10-05 |
| ZA200305331B (en) | 2004-05-12 |
| HUP0303136A3 (en) | 2006-05-29 |
| CA2434900A1 (en) | 2002-08-22 |
| CZ301357B6 (cs) | 2010-01-27 |
| NO20033163L (no) | 2003-07-10 |
| US20060205786A1 (en) | 2006-09-14 |
| MXPA03006970A (es) | 2003-11-18 |
| PL362550A1 (en) | 2004-11-02 |
| IL188485A0 (en) | 2008-03-20 |
| GB0102841D0 (en) | 2001-03-21 |
| US20080103177A1 (en) | 2008-05-01 |
| BR0206918A (pt) | 2004-02-03 |
| RU2301065C2 (ru) | 2007-06-20 |
| KR20030070599A (ko) | 2003-08-30 |
| KR100851256B1 (ko) | 2008-08-08 |
| JP4278981B2 (ja) | 2009-06-17 |
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