PT1399143E - Utilização da acetil-l-carnitina na preparação de um medicamento para tratar a anedonia - Google Patents
Utilização da acetil-l-carnitina na preparação de um medicamento para tratar a anedonia Download PDFInfo
- Publication number
- PT1399143E PT1399143E PT02741156T PT02741156T PT1399143E PT 1399143 E PT1399143 E PT 1399143E PT 02741156 T PT02741156 T PT 02741156T PT 02741156 T PT02741156 T PT 02741156T PT 1399143 E PT1399143 E PT 1399143E
- Authority
- PT
- Portugal
- Prior art keywords
- stress
- carnitine
- acetyl
- quot
- mice
- Prior art date
Links
- 208000007415 Anhedonia Diseases 0.000 title claims abstract description 13
- 239000003814 drug Substances 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- RDHQFKQIGNGIED-MRVPVSSYSA-N O-acetyl-L-carnitine Chemical compound CC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C RDHQFKQIGNGIED-MRVPVSSYSA-N 0.000 title claims description 73
- 229940079593 drug Drugs 0.000 title description 8
- 238000011282 treatment Methods 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- -1 alkanoyl L-carnitine Chemical compound 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims description 16
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 8
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 4
- 229940095064 tartrate Drugs 0.000 claims description 4
- XOAAWQZATWQOTB-UHFFFAOYSA-M 2-aminoethanesulfonate Chemical compound NCCS([O-])(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-M 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 229940009098 aspartate Drugs 0.000 claims description 2
- 229960005336 magnesium citrate Drugs 0.000 claims description 2
- 235000002538 magnesium citrate Nutrition 0.000 claims description 2
- 239000004337 magnesium citrate Substances 0.000 claims description 2
- 229940095060 magnesium tartrate Drugs 0.000 claims description 2
- MUZDLCBWNVUYIR-ZVGUSBNCSA-L magnesium;(2r,3r)-2,3-dihydroxybutanedioate Chemical compound [Mg+2].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O MUZDLCBWNVUYIR-ZVGUSBNCSA-L 0.000 claims description 2
- QUIOHQITLKCGNW-TYYBGVCCSA-L magnesium;(e)-but-2-enedioate Chemical compound [Mg+2].[O-]C(=O)\C=C\C([O-])=O QUIOHQITLKCGNW-TYYBGVCCSA-L 0.000 claims description 2
- YZURQOBSFRVSEB-UHFFFAOYSA-L magnesium;2-aminoethanesulfonate Chemical compound [Mg+2].NCCS([O-])(=O)=O.NCCS([O-])(=O)=O YZURQOBSFRVSEB-UHFFFAOYSA-L 0.000 claims description 2
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 229940066528 trichloroacetate Drugs 0.000 claims description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 2
- PLSARIKBYIPYPF-UHFFFAOYSA-H trimagnesium dicitrate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PLSARIKBYIPYPF-UHFFFAOYSA-H 0.000 claims description 2
- NDVRKEKNSBMTAX-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;phosphoric acid Chemical compound OP(O)(O)=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O NDVRKEKNSBMTAX-BTVCFUMJSA-N 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims 1
- 229960004203 carnitine Drugs 0.000 claims 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims 1
- 229960001231 choline Drugs 0.000 claims 1
- 235000002906 tartaric acid Nutrition 0.000 claims 1
- 239000011975 tartaric acid Substances 0.000 claims 1
- 229960001367 tartaric acid Drugs 0.000 claims 1
- 230000035882 stress Effects 0.000 description 71
- 241000699670 Mus sp. Species 0.000 description 60
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 54
- 230000037326 chronic stress Effects 0.000 description 44
- 241001465754 Metazoa Species 0.000 description 33
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 31
- 229960004801 imipramine Drugs 0.000 description 31
- 230000000694 effects Effects 0.000 description 29
- 229960003638 dopamine Drugs 0.000 description 27
- 238000012360 testing method Methods 0.000 description 21
- 238000012549 training Methods 0.000 description 20
- 235000009499 Vanilla fragrans Nutrition 0.000 description 17
- 244000263375 Vanilla tahitensis Species 0.000 description 17
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 17
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 16
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 15
- 229960002464 fluoxetine Drugs 0.000 description 15
- 238000000034 method Methods 0.000 description 11
- 239000008188 pellet Substances 0.000 description 11
- 210000004556 brain Anatomy 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- 235000012054 meals Nutrition 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 229960003920 cocaine Drugs 0.000 description 8
- 230000015883 synaptic transmission, dopaminergic Effects 0.000 description 8
- 230000001154 acute effect Effects 0.000 description 5
- 230000003042 antagnostic effect Effects 0.000 description 4
- 230000036528 appetite Effects 0.000 description 4
- 235000019789 appetite Nutrition 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000006735 deficit Effects 0.000 description 4
- 210000001009 nucleus accumben Anatomy 0.000 description 4
- 239000000935 antidepressant agent Substances 0.000 description 3
- 230000003542 behavioural effect Effects 0.000 description 3
- 239000000385 dialysis solution Substances 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 238000002483 medication Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 229940005513 antidepressants Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 230000001722 neurochemical effect Effects 0.000 description 2
- 210000002442 prefrontal cortex Anatomy 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 1
- QWJSAWXRUVVRLH-LREBCSMRSA-M 2-hydroxyethyl(trimethyl)azanium;(2r,3r)-2,3,4-trihydroxy-4-oxobutanoate Chemical compound C[N+](C)(C)CCO.OC(=O)[C@H](O)[C@@H](O)C([O-])=O QWJSAWXRUVVRLH-LREBCSMRSA-M 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229960001009 acetylcarnitine Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002197 limbic effect Effects 0.000 description 1
- 210000003715 limbic system Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- QSLMDECMDJKHMQ-GSXCWMCISA-N maprotiline Chemical compound C12=CC=CC=C2[C@@]2(CCCNC)C3=CC=CC=C3[C@@H]1CC2 QSLMDECMDJKHMQ-GSXCWMCISA-N 0.000 description 1
- 229960004090 maprotiline Drugs 0.000 description 1
- 238000001690 micro-dialysis Methods 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 238000001671 psychotherapy Methods 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000000862 serotonergic effect Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 235000000891 standard diet Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Emergency Medicine (AREA)
- Pain & Pain Management (AREA)
- Gynecology & Obstetrics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2001RM000292A ITRM20010292A1 (it) | 2001-05-29 | 2001-05-29 | Uso dell'acetil l-carnitina per la preparazione di un medicamento peril trattamento dell'anedonia. |
| IT2001RM000319A ITRM20010319A1 (it) | 2001-06-08 | 2001-06-08 | Uso di una alcanoil l-carnitina per la preparazione di un medicamentoper il trattamento dell'anedonia. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PT1399143E true PT1399143E (pt) | 2007-01-31 |
Family
ID=26332845
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PT02741156T PT1399143E (pt) | 2001-05-29 | 2002-05-24 | Utilização da acetil-l-carnitina na preparação de um medicamento para tratar a anedonia |
Country Status (16)
| Country | Link |
|---|---|
| US (2) | US20040171685A1 (enExample) |
| EP (1) | EP1399143B1 (enExample) |
| JP (1) | JP2004532867A (enExample) |
| KR (1) | KR20040003031A (enExample) |
| AT (1) | ATE345124T1 (enExample) |
| CA (1) | CA2448246A1 (enExample) |
| CZ (1) | CZ20033222A3 (enExample) |
| DE (1) | DE60216090T2 (enExample) |
| DK (1) | DK1399143T3 (enExample) |
| ES (1) | ES2275881T3 (enExample) |
| HU (1) | HUP0400007A2 (enExample) |
| MX (1) | MXPA03010920A (enExample) |
| PL (1) | PL367628A1 (enExample) |
| PT (1) | PT1399143E (enExample) |
| SK (1) | SK15862003A3 (enExample) |
| WO (1) | WO2002096411A1 (enExample) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITRM20020620A1 (it) * | 2002-12-13 | 2004-06-14 | Sigma Tau Ind Farmaceuti | Uso delle carnitine per la prevenzione e/o il trattamento dei disturbi causati dall'andropausa. |
| WO2023084531A1 (en) * | 2021-11-12 | 2023-05-19 | Celagenex Research (India) Pvt. Ltd. | A synergistic composition for activating intracellular secondary messenger(camp) pathway |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4346107A (en) * | 1979-02-12 | 1982-08-24 | Claudio Cavazza | Pharmaceutical composition comprising acyl-carnitine for the treatment of impaired cerebral metabolism |
| IT1291930B1 (it) * | 1997-06-18 | 1999-01-21 | Sigma Tau Ind Farmaceuti | Composizione riequilibratrice delle turbe dell'umore in individui sani |
-
2002
- 2002-05-24 ES ES02741156T patent/ES2275881T3/es not_active Expired - Lifetime
- 2002-05-24 DE DE60216090T patent/DE60216090T2/de not_active Expired - Fee Related
- 2002-05-24 DK DK02741156T patent/DK1399143T3/da active
- 2002-05-24 PT PT02741156T patent/PT1399143E/pt unknown
- 2002-05-24 WO PCT/IT2002/000339 patent/WO2002096411A1/en not_active Ceased
- 2002-05-24 HU HU0400007A patent/HUP0400007A2/hu unknown
- 2002-05-24 CA CA002448246A patent/CA2448246A1/en not_active Abandoned
- 2002-05-24 US US10/478,998 patent/US20040171685A1/en not_active Abandoned
- 2002-05-24 AT AT02741156T patent/ATE345124T1/de not_active IP Right Cessation
- 2002-05-24 KR KR10-2003-7015576A patent/KR20040003031A/ko not_active Ceased
- 2002-05-24 CZ CZ20033222A patent/CZ20033222A3/cs unknown
- 2002-05-24 JP JP2002592921A patent/JP2004532867A/ja active Pending
- 2002-05-24 PL PL02367628A patent/PL367628A1/xx unknown
- 2002-05-24 MX MXPA03010920A patent/MXPA03010920A/es active IP Right Grant
- 2002-05-24 SK SK1586-2003A patent/SK15862003A3/sk unknown
- 2002-05-24 EP EP02741156A patent/EP1399143B1/en not_active Expired - Lifetime
-
2005
- 2005-12-20 US US11/311,406 patent/US20060148896A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| KR20040003031A (ko) | 2004-01-07 |
| MXPA03010920A (es) | 2004-02-27 |
| ATE345124T1 (de) | 2006-12-15 |
| PL367628A1 (en) | 2005-03-07 |
| US20040171685A1 (en) | 2004-09-02 |
| SK15862003A3 (sk) | 2004-06-08 |
| HUP0400007A2 (hu) | 2004-04-28 |
| DE60216090D1 (de) | 2006-12-28 |
| DE60216090T2 (de) | 2007-05-31 |
| DK1399143T3 (da) | 2007-03-26 |
| EP1399143B1 (en) | 2006-11-15 |
| CZ20033222A3 (cs) | 2004-06-16 |
| CA2448246A1 (en) | 2002-12-05 |
| EP1399143A1 (en) | 2004-03-24 |
| WO2002096411A1 (en) | 2002-12-05 |
| ES2275881T3 (es) | 2007-06-16 |
| US20060148896A1 (en) | 2006-07-06 |
| JP2004532867A (ja) | 2004-10-28 |
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