ES2554459T3 - Terapia combinada con interferón beta y andrografólidos para la esclerosis múltiple - Google Patents
Terapia combinada con interferón beta y andrografólidos para la esclerosis múltiple Download PDFInfo
- Publication number
- ES2554459T3 ES2554459T3 ES12859754.9T ES12859754T ES2554459T3 ES 2554459 T3 ES2554459 T3 ES 2554459T3 ES 12859754 T ES12859754 T ES 12859754T ES 2554459 T3 ES2554459 T3 ES 2554459T3
- Authority
- ES
- Spain
- Prior art keywords
- patients
- group
- combined therapy
- months
- multiple sclerosis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 108090000467 Interferon-beta Proteins 0.000 title abstract description 11
- 201000006417 multiple sclerosis Diseases 0.000 title abstract description 9
- 102000003996 Interferon-beta Human genes 0.000 title abstract description 6
- 238000002648 combination therapy Methods 0.000 title description 38
- 229960001388 interferon-beta Drugs 0.000 title description 4
- 230000006698 induction Effects 0.000 claims 1
- 208000016192 Demyelinating disease Diseases 0.000 abstract description 8
- 150000001875 compounds Chemical class 0.000 abstract description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract 2
- 239000001257 hydrogen Substances 0.000 abstract 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 2
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 150000001720 carbohydrates Chemical class 0.000 abstract 1
- 150000002148 esters Chemical class 0.000 abstract 1
- 125000002541 furyl group Chemical group 0.000 abstract 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 1
- 229940002612 prodrug Drugs 0.000 abstract 1
- 239000000651 prodrug Substances 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 210000000278 spinal cord Anatomy 0.000 description 14
- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical compound C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 description 13
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 description 13
- 238000011282 treatment Methods 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- 230000003902 lesion Effects 0.000 description 9
- 102000014150 Interferons Human genes 0.000 description 7
- 108010050904 Interferons Proteins 0.000 description 7
- 208000033068 episodic angioedema with eosinophilia Diseases 0.000 description 7
- 230000002757 inflammatory effect Effects 0.000 description 7
- 229940079322 interferon Drugs 0.000 description 7
- 238000011084 recovery Methods 0.000 description 7
- 206010012305 Demyelination Diseases 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 230000003210 demyelinating effect Effects 0.000 description 6
- 238000010186 staining Methods 0.000 description 6
- 102100026720 Interferon beta Human genes 0.000 description 5
- 108010005716 Interferon beta-1a Proteins 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 230000001684 chronic effect Effects 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000000926 neurological effect Effects 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 208000019505 Deglutition disease Diseases 0.000 description 3
- 206010013887 Dysarthria Diseases 0.000 description 3
- 229910052688 Gadolinium Inorganic materials 0.000 description 3
- 108010005714 Interferon beta-1b Proteins 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 239000002872 contrast media Substances 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 238000002595 magnetic resonance imaging Methods 0.000 description 3
- 230000036651 mood Effects 0.000 description 3
- 238000002610 neuroimaging Methods 0.000 description 3
- 238000009097 single-agent therapy Methods 0.000 description 3
- 230000009747 swallowing Effects 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 210000000115 thoracic cavity Anatomy 0.000 description 3
- YGCYRQKJYWQXHG-RDNQFMDVSA-N 4-[2-[(1r,4as,5r,8as)-5,8a-dimethyl-2-methylidene-5-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]-3,4,4a,6,7,8-hexahydro-1h-naphthalen-1-yl]ethyl]-2h-furan-5-one Chemical compound C([C@@]1(C)[C@H]2CCC(=C)[C@@H](CCC=3C(OCC=3)=O)[C@]2(C)CCC1)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O YGCYRQKJYWQXHG-RDNQFMDVSA-N 0.000 description 2
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 208000008238 Muscle Spasticity Diseases 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- MEEPUSVTMHGIPC-UHFFFAOYSA-N deoxyandrographiside Natural products OC1CCC2(C)C(CCC=3C(OCC=3)=O)C(=C)CCC2C1(C)COC1OC(CO)C(O)C(O)C1O MEEPUSVTMHGIPC-UHFFFAOYSA-N 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 206010016256 fatigue Diseases 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 229960004461 interferon beta-1a Drugs 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 210000000274 microglia Anatomy 0.000 description 2
- 230000002025 microglial effect Effects 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- BBGWVUQBIGGVLS-UHFFFAOYSA-N neoandrographolide Natural products CC1(COC2OC(CO)C(O)C(O)C2O)C(O)CCC3(C)C(CCC4=C(O)COC4=O)C(=C)CCC13 BBGWVUQBIGGVLS-UHFFFAOYSA-N 0.000 description 2
- YGCYRQKJYWQXHG-UHFFFAOYSA-N neoandrographoside Natural products C1CCC2(C)C(CCC=3C(OCC=3)=O)C(=C)CCC2C1(C)COC1OC(CO)C(O)C(O)C1O YGCYRQKJYWQXHG-UHFFFAOYSA-N 0.000 description 2
- 230000008447 perception Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 229940038850 rebif Drugs 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 208000018198 spasticity Diseases 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000011269 treatment regimen Methods 0.000 description 2
- 210000004885 white matter Anatomy 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 244000118350 Andrographis paniculata Species 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 206010022004 Influenza like illness Diseases 0.000 description 1
- 102100022338 Integrin alpha-M Human genes 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 108010083674 Myelin Proteins Proteins 0.000 description 1
- 102000006386 Myelin Proteins Human genes 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- ZHAFUINZIZIXFC-UHFFFAOYSA-N [9-(dimethylamino)-10-methylbenzo[a]phenoxazin-5-ylidene]azanium;chloride Chemical compound [Cl-].O1C2=CC(=[NH2+])C3=CC=CC=C3C2=NC2=C1C=C(N(C)C)C(C)=C2 ZHAFUINZIZIXFC-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229940003504 avonex Drugs 0.000 description 1
- 229940021459 betaseron Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229960003161 interferon beta-1b Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 230000001095 motoneuron effect Effects 0.000 description 1
- 210000005012 myelin Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 230000008823 permeabilization Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 230000036642 wellbeing Effects 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
- A61K38/215—IFN-beta
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Neurology (AREA)
- Zoology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Hospice & Palliative Care (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Psychiatry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161578650P | 2011-12-21 | 2011-12-21 | |
| US201161578650P | 2011-12-21 | ||
| PCT/US2012/070568 WO2013096423A1 (en) | 2011-12-21 | 2012-12-19 | Combination therapy with interferon and andrographolides for multiple sclerosis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2554459T3 true ES2554459T3 (es) | 2015-12-21 |
Family
ID=48669439
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES12859754.9T Active ES2554459T3 (es) | 2011-12-21 | 2012-12-19 | Terapia combinada con interferón beta y andrografólidos para la esclerosis múltiple |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US9060994B2 (enExample) |
| EP (1) | EP2670406B1 (enExample) |
| JP (1) | JP5936707B2 (enExample) |
| AU (1) | AU2012359081B2 (enExample) |
| BR (1) | BR112014015178A2 (enExample) |
| CA (1) | CA2853779C (enExample) |
| CL (1) | CL2014001663A1 (enExample) |
| ES (1) | ES2554459T3 (enExample) |
| RU (1) | RU2014113967A (enExample) |
| WO (1) | WO2013096423A1 (enExample) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6928963B2 (ja) * | 2016-06-08 | 2021-09-01 | イノバイオサイエンス， エルエルシー | アンドログラホリドが進化型の多発性硬化症を処置する |
| US11318153B2 (en) | 2018-06-25 | 2022-05-03 | Bialpha International Sdn. Bhd. | Method of using Neoandrographolide for lowering blood sugar, lowering blood lipid, improving liver function and improving renal function |
| CN109824655B (zh) * | 2019-04-08 | 2021-09-24 | 沈阳药科大学 | 穿心莲内酯化合物及其制备方法和用途 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1043027A1 (en) * | 1999-04-08 | 2000-10-11 | Applied Research Systems ARS Holding N.V. | Treatment of multiple sclerosis with a combination of Interferon and Growth hormone |
| US6410590B1 (en) * | 2000-02-03 | 2002-06-25 | Dr. Reddy's Research Foundation | Compounds having antitumor activity: process for their preparation and pharmaceutical compositions containing them |
| US20050181033A1 (en) | 2000-06-29 | 2005-08-18 | Dekker John P.Iii | Method for delivering interferons to the intradermal compartment |
| US20030082138A1 (en) * | 2001-09-18 | 2003-05-01 | Chiron Corporation | Methods for treating multiple sclerosis |
| KR20070026398A (ko) | 2004-02-03 | 2007-03-08 | 우니베르시다드 오스뜨랄 데 칠레 | Ｐｐａｒ-감마 수용체의 활성화에 의한 자가면역 질환 및알츠하이머병의 치료에 유용한, 천심련으로부터 추출된랍단 디테르펜을 포함하는 조성물 |
| US20050220764A1 (en) * | 2004-04-01 | 2005-10-06 | Schering Aktiengesellschaft | Higher-doses of interferon-beta for treatment of multiple sclerosis |
| US20080108641A1 (en) * | 2006-02-08 | 2008-05-08 | Ajami Alfred M | Compounds for treating inflammatory disorders, demyelinating disdorders and cancers |
| WO2011005473A2 (en) | 2009-06-22 | 2011-01-13 | Shionogi Pharma, Inc. | Methods for treating or preventing fatigue |
-
2012
- 2012-12-19 JP JP2014548825A patent/JP5936707B2/ja active Active
- 2012-12-19 RU RU2014113967A patent/RU2014113967A/ru not_active Application Discontinuation
- 2012-12-19 BR BR112014015178A patent/BR112014015178A2/pt not_active Application Discontinuation
- 2012-12-19 ES ES12859754.9T patent/ES2554459T3/es active Active
- 2012-12-19 AU AU2012359081A patent/AU2012359081B2/en active Active
- 2012-12-19 CA CA2853779A patent/CA2853779C/en active Active
- 2012-12-19 EP EP12859754.9A patent/EP2670406B1/en active Active
- 2012-12-19 US US13/984,124 patent/US9060994B2/en active Active
- 2012-12-19 WO PCT/US2012/070568 patent/WO2013096423A1/en not_active Ceased
-
2014
- 2014-06-20 CL CL2014001663A patent/CL2014001663A1/es unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CA2853779A1 (en) | 2013-06-27 |
| US9060994B2 (en) | 2015-06-23 |
| CA2853779C (en) | 2016-04-26 |
| RU2014113967A (ru) | 2016-02-10 |
| NZ625051A (en) | 2016-07-29 |
| WO2013096423A1 (en) | 2013-06-27 |
| EP2670406B1 (en) | 2015-09-02 |
| AU2012359081A1 (en) | 2014-06-05 |
| EP2670406A1 (en) | 2013-12-11 |
| EP2670406A4 (en) | 2014-05-28 |
| JP5936707B2 (ja) | 2016-06-22 |
| CL2014001663A1 (es) | 2015-02-27 |
| BR112014015178A2 (pt) | 2017-06-13 |
| AU2012359081B2 (en) | 2015-09-17 |
| US20140301981A1 (en) | 2014-10-09 |
| JP2015500880A (ja) | 2015-01-08 |
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