MX2011006527A - Agentes medicinales unidos a dipeptido. - Google Patents
Agentes medicinales unidos a dipeptido.Info
- Publication number
- MX2011006527A MX2011006527A MX2011006527A MX2011006527A MX2011006527A MX 2011006527 A MX2011006527 A MX 2011006527A MX 2011006527 A MX2011006527 A MX 2011006527A MX 2011006527 A MX2011006527 A MX 2011006527A MX 2011006527 A MX2011006527 A MX 2011006527A
- Authority
- MX
- Mexico
- Prior art keywords
- dipeptide
- medicinal agents
- linked
- physiological conditions
- compounds
- Prior art date
Links
- 108010016626 Dipeptides Proteins 0.000 title abstract 6
- 239000003795 chemical substances by application Substances 0.000 abstract 4
- 150000001875 compounds Chemical class 0.000 abstract 2
- 230000004962 physiological condition Effects 0.000 abstract 2
- 229940079593 drug Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 239000007972 injectable composition Substances 0.000 abstract 1
- 229920000642 polymer Polymers 0.000 abstract 1
- 229940002612 prodrug Drugs 0.000 abstract 1
- 239000000651 prodrug Substances 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
Classifications
-
- 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
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Transplantation (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13922708P | 2008-12-19 | 2008-12-19 | |
| PCT/US2009/068711 WO2010080605A1 (en) | 2008-12-19 | 2009-12-18 | Dipeptide linked medicinal agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MX2011006527A true MX2011006527A (es) | 2011-08-17 |
Family
ID=42316744
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MX2011006527A MX2011006527A (es) | 2008-12-19 | 2009-12-18 | Agentes medicinales unidos a dipeptido. |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US20110237493A1 (enExample) |
| EP (1) | EP2376098A4 (enExample) |
| JP (2) | JP2012512898A (enExample) |
| KR (1) | KR20110114568A (enExample) |
| CN (1) | CN102300580A (enExample) |
| AU (1) | AU2009335711A1 (enExample) |
| CA (1) | CA2747195A1 (enExample) |
| IL (1) | IL213341A0 (enExample) |
| MX (1) | MX2011006527A (enExample) |
| PE (1) | PE20120331A1 (enExample) |
| RU (1) | RU2578591C2 (enExample) |
| SG (1) | SG172290A1 (enExample) |
| WO (1) | WO2010080605A1 (enExample) |
Families Citing this family (42)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2913805A1 (en) | 2005-11-07 | 2007-05-18 | Indiana University Research And Technology Corporation | Glucagon analogs exhibiting physiological solubility and stability |
| CN101578102B (zh) | 2007-01-05 | 2013-07-17 | 印第安纳大学研究及科技有限公司 | 在生理性pH缓冲液中显示增强的溶解性的胰高血糖素类似物 |
| NZ578948A (en) | 2007-02-15 | 2012-03-30 | Univ Indiana Res & Tech Corp | Glucagon/glp-1 receptor co-agonists |
| WO2009058734A1 (en) | 2007-10-30 | 2009-05-07 | Indiana University Research And Technology Corporation | Compounds exhibiting glucagon antagonist and glp-1 agonist activity |
| CA2707861A1 (en) | 2007-10-30 | 2009-05-07 | Indiana University Research And Technology Corporation | Glucagon antagonists |
| US20110065633A1 (en) | 2008-01-30 | 2011-03-17 | Indiana University Research And Technology Corporation | Ester-based peptide prodrugs |
| CA2728284C (en) | 2008-06-17 | 2019-09-10 | Richard D. Dimarchi | Glucagon/glp-1 receptor co-agonists |
| TWI541023B (zh) | 2008-06-17 | 2016-07-11 | 印第安納大學科技研究公司 | 在生理ｐｈ緩衝液中呈現增強之溶解度及穩定性之升糖激素類似物 |
| ES2558842T3 (es) | 2008-06-17 | 2016-02-09 | Indiana University Research And Technology Corporation | Agonistas mixtos a base de GIP para el tratamiento de trastornos metabólicos y obesidad |
| EP2376097A4 (en) | 2008-12-19 | 2012-10-03 | Univ Indiana Res & Tech Corp | PEPTIDE PRODRUGS OF AMIDE-BASED GLUCAGON SUPERFAMILY |
| US8697632B2 (en) | 2008-12-19 | 2014-04-15 | Indiana University Research And Technology Corporation | Amide based insulin prodrugs |
| JP5789515B2 (ja) | 2008-12-19 | 2015-10-07 | インディアナ ユニバーシティー リサーチ アンド テクノロジー コーポレーションＩｎｄｉａｎａ Ｕｎｉｖｅｒｓｉｔｙ Ｒｅｓｅａｒｃｈ Ａｎｄ Ｔｅｃｈｎｏｌｏｇｙ Ｃｏｒｐｏｒａｔｉｏｎ | インスリン類似体 |
| WO2010148089A1 (en) | 2009-06-16 | 2010-12-23 | Indiana University Research And Technology Corporation | Gip receptor-active glucagon compounds |
| WO2011075393A2 (en) | 2009-12-18 | 2011-06-23 | Indiana University Research And Technology Corporation | Glucagon/glp-1 receptor co-agonists |
| KR20120123443A (ko) | 2010-01-27 | 2012-11-08 | 인디애나 유니버시티 리서치 앤드 테크놀로지 코퍼레이션 | 대사 장애 및 비만 치료용 글루카곤 길항제-ｇｉｐ 항진제 콘쥬게이트 |
| ES2661228T3 (es) | 2010-05-13 | 2018-03-28 | Indiana University Research And Technology Corporation | Péptidos de la superfamilia de glucagón que muestran actividad de receptor nuclear de hormona |
| RU2012153753A (ru) | 2010-05-13 | 2014-06-20 | Индиана Юниверсити Рисерч Энд Текнолоджи Корпорейшн | Пептиды глюкагонового суперсемейства, обладающие активностью в отношении сопряженных с g-белком рецепторов |
| JP5969469B2 (ja) | 2010-06-16 | 2016-08-17 | インディアナ ユニバーシティー リサーチ アンド テクノロジー コーポレーションＩｎｄｉａｎａ Ｕｎｉｖｅｒｓｉｔｙ Ｒｅｓｅａｒｃｈ Ａｎｄ Ｔｅｃｈｎｏｌｏｇｙ Ｃｏｒｐｏｒａｔｉｏｎ | インスリン受容体に対して高い活性を示す単鎖インスリンアゴニスト |
| CA2803164C (en) | 2010-06-24 | 2018-08-21 | Indiana University Research And Technology Corporation | Amide-based insulin prodrugs |
| KR20130083843A (ko) * | 2010-06-24 | 2013-07-23 | 인디애나 유니버시티 리서치 앤드 테크놀로지 코퍼레이션 | 디펩티드 연결된 약제 |
| US8778872B2 (en) | 2010-06-24 | 2014-07-15 | Indiana University Research And Technology Corporation | Amide based glucagon superfamily peptide prodrugs |
| NZ612297A (en) | 2010-12-22 | 2015-10-30 | Univ Indiana Res & Tech Corp | Glucagon analogs exhibiting gip receptor activity |
| CN103857408B (zh) | 2011-06-22 | 2017-04-12 | 印第安那大学科技研究公司 | 胰高血糖素/glp‑1受体协同激动剂 |
| JP6184404B2 (ja) | 2011-06-22 | 2017-08-23 | インディアナ ユニヴァーシティ リサーチ アンド テクノロジー コーポレイション | グルカゴン／ｇｌｐ−１レセプターコアゴニスト |
| BR112014007124A2 (pt) * | 2011-11-17 | 2017-06-13 | Univ Indiana Res & Tech Corp | superfamília de peptídeos gluxagon que exibem atividade no receptor glicocorticóide |
| CN104114183A (zh) | 2011-12-20 | 2014-10-22 | 印第安纳大学研究及科技有限公司 | 用于治疗糖尿病的基于ctp的胰岛素类似物 |
| CN103172726B (zh) * | 2011-12-22 | 2017-06-13 | 杭州淳泰科技有限公司 | 胰泌素类似物及其制备方法和用途 |
| ES2810153T3 (es) | 2012-03-01 | 2021-03-08 | Novo Nordisk As | Profármacos de GLP-1 |
| ES2602486T3 (es) | 2012-06-21 | 2017-02-21 | Indiana University Research And Technology Corporation | Análogos de glucagón que muestran actividad de receptor de GIP |
| CN108383902A (zh) | 2012-09-26 | 2018-08-10 | 印第安纳大学研究及科技有限公司 | 胰岛素类似物二聚体 |
| JP6538645B2 (ja) | 2013-03-14 | 2019-07-03 | インディアナ ユニバーシティー リサーチ アンド テクノロジー コーポレーションＩｎｄｉａｎａ Ｕｎｉｖｅｒｓｉｔｙ Ｒｅｓｅａｒｃｈ Ａｎｄ Ｔｅｃｈｎｏｌｏｇｙ Ｃｏｒｐｏｒａｔｉｏｎ | インスリン‐インクレチン複合物 |
| WO2015081891A1 (en) | 2013-12-06 | 2015-06-11 | Baikang (Suzhou) Co., Ltd | Bioreversable promoieties for nitrogen-containing and hydroxyl-containing drugs |
| CN108271356A (zh) | 2014-09-24 | 2018-07-10 | 印第安纳大学研究及科技有限公司 | 肠降血糖素-胰岛素缀合物 |
| EP3197912B1 (en) | 2014-09-24 | 2023-01-04 | Indiana University Research & Technology Corporation | Lipidated amide-based insulin prodrugs |
| SI3464336T1 (sl) | 2016-06-01 | 2022-06-30 | Athira Pharma, Inc. | Spojine |
| CA3183120A1 (en) * | 2020-05-26 | 2021-12-02 | Indiana University Research And Technology Corporation | Pth analogs for the treatment of hypoparathyroidism |
| AU2021312323A1 (en) | 2020-07-22 | 2023-02-02 | Novo Nordisk A/S | Co-agonists at GLP-1 and GIP receptors suitable for oral delivery |
| JP7484018B2 (ja) | 2020-11-06 | 2024-05-15 | ノヴォ ノルディスク アー／エス | Ｇｌｐ－１プロドラッグおよびその使用 |
| WO2023012263A1 (en) | 2021-08-04 | 2023-02-09 | Novo Nordisk A/S | Solid oral peptide formulations |
| TW202330584A (zh) | 2022-01-20 | 2023-08-01 | 丹麥商諾佛 儂迪克股份有限公司 | 前藥及其用途 |
| US20250304645A1 (en) | 2022-05-10 | 2025-10-02 | Novo Nordisk A/S | Prodrugs of GLP-1 Polypeptide and Uses Thereof |
| TW202421645A (zh) | 2022-11-25 | 2024-06-01 | 丹麥商諾佛 儂迪克股份有限公司 | 如ｇｌｐ—１之肽治療劑的口服投與 |
Family Cites Families (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3740385A (en) * | 1970-05-07 | 1973-06-19 | M Ondetti | N-terminal derivatives of secretin |
| DK119785D0 (da) * | 1985-03-15 | 1985-03-15 | Nordisk Gentofte | Insulinpraeparat |
| US4741897A (en) * | 1986-07-08 | 1988-05-03 | Baxter Travenol | Thyroxine analogs and reagents for thyroid hormone assays |
| US5545618A (en) * | 1990-01-24 | 1996-08-13 | Buckley; Douglas I. | GLP-1 analogs useful for diabetes treatment |
| DE19828113A1 (de) * | 1998-06-24 | 2000-01-05 | Probiodrug Ges Fuer Arzneim | Prodrugs von Inhibitoren der Dipeptidyl Peptidase IV |
| US20030236190A1 (en) * | 1998-09-02 | 2003-12-25 | Renuka Pillutla | Isulin and IGF-1 receptor agonists and antagonists |
| ATE272650T1 (de) * | 1999-03-29 | 2004-08-15 | Uutech Ltd | Analoge des magensaft inhibierenden peptides und ihre verwendung für die behandlung von diabetes |
| AUPQ661800A0 (en) * | 2000-03-31 | 2000-05-04 | Metabolic Pharmaceuticals Limited | Insulin-potentiating compounds |
| US6967202B2 (en) * | 2000-08-04 | 2005-11-22 | Dmi Biosciences, Inc. | Method of synthesizing diketopiperazines |
| US7052686B2 (en) * | 2000-09-29 | 2006-05-30 | Schering Corporation | Pegylated interleukin-10 |
| EP1243276A1 (en) * | 2001-03-23 | 2002-09-25 | Franciscus Marinus Hendrikus De Groot | Elongated and multiple spacers containing activatible prodrugs |
| ES2464532T3 (es) * | 2001-04-19 | 2014-06-03 | The Scripps Research Institute | Métodos y composiciones para la producción de pares ortogonales de ARNt-aminoacil-ARNt sintetasa |
| WO2003020201A2 (en) * | 2001-08-28 | 2003-03-13 | Eli Lilly And Company | Pre-mixes of glp-1 and basal insulin |
| US7238656B2 (en) * | 2001-08-29 | 2007-07-03 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Protective factors against inflammation, burns and noxious stimuli |
| AU2002346490A1 (en) * | 2001-12-20 | 2003-07-09 | Eli Lilly And Company | Insulin molecule having protracted time action |
| FR2842209B1 (fr) * | 2002-07-09 | 2007-11-23 | Nouvelle protease aspartique dite saspase et son utilisation dans le domaine cosmetique et therapeutique | |
| US7557183B2 (en) * | 2003-03-19 | 2009-07-07 | Eli Lilly And Company | Polyethylene glycol linked GLP-1 compounds |
| WO2004089280A2 (en) * | 2003-04-08 | 2004-10-21 | Yeda Research And Development Co. Ltd. | Reversible pegylated drugs |
| GB0310593D0 (en) * | 2003-05-08 | 2003-06-11 | Leuven K U Res & Dev | Peptidic prodrugs |
| EP1670515A2 (en) * | 2003-09-19 | 2006-06-21 | Novo Nordisk A/S | Albumin-binding derivatives of therapeutic peptides |
| US20050187147A1 (en) * | 2003-09-22 | 2005-08-25 | Newman Michael J. | Compositions and methods for increasing drug efficiency |
| US8263545B2 (en) * | 2005-02-11 | 2012-09-11 | Amylin Pharmaceuticals, Inc. | GIP analog and hybrid polypeptides with selectable properties |
| EP1929030A2 (en) * | 2005-09-08 | 2008-06-11 | Shire LLC | Prodrugs of t3 and t4 with enhanced bioavailability |
| AU2007227202B2 (en) * | 2006-03-21 | 2013-08-22 | Amylin Pharmaceuticals, Llc | Peptide-peptidase inhibitor conjugates and methods of using same |
| KR20090060294A (ko) * | 2006-09-08 | 2009-06-11 | 암브룩스, 인코포레이티드 | 변형된 인간 혈장 폴리펩티드 또는 Ｆｃ 스캐폴드 및 그의 용도 |
| DE102006052755A1 (de) * | 2006-11-08 | 2008-05-15 | N-Zyme Biotec Gmbh | Michaelsysteme als Transglutaminaseinhibitoren |
| NZ578948A (en) * | 2007-02-15 | 2012-03-30 | Univ Indiana Res & Tech Corp | Glucagon/glp-1 receptor co-agonists |
| US20110065633A1 (en) * | 2008-01-30 | 2011-03-17 | Indiana University Research And Technology Corporation | Ester-based peptide prodrugs |
| EP2376097A4 (en) * | 2008-12-19 | 2012-10-03 | Univ Indiana Res & Tech Corp | PEPTIDE PRODRUGS OF AMIDE-BASED GLUCAGON SUPERFAMILY |
-
2009
- 2009-12-18 JP JP2011542481A patent/JP2012512898A/ja not_active Withdrawn
- 2009-12-18 EP EP09837981.1A patent/EP2376098A4/en not_active Withdrawn
- 2009-12-18 MX MX2011006527A patent/MX2011006527A/es active IP Right Grant
- 2009-12-18 US US13/130,963 patent/US20110237493A1/en not_active Abandoned
- 2009-12-18 WO PCT/US2009/068711 patent/WO2010080605A1/en not_active Ceased
- 2009-12-18 CN CN2009801518123A patent/CN102300580A/zh active Pending
- 2009-12-18 SG SG2011045275A patent/SG172290A1/en unknown
- 2009-12-18 KR KR1020117016192A patent/KR20110114568A/ko not_active Ceased
- 2009-12-18 AU AU2009335711A patent/AU2009335711A1/en not_active Abandoned
- 2009-12-18 CA CA2747195A patent/CA2747195A1/en not_active Abandoned
- 2009-12-18 RU RU2011129764/04A patent/RU2578591C2/ru not_active IP Right Cessation
- 2009-12-18 PE PE2011001237A patent/PE20120331A1/es not_active Application Discontinuation
-
2011
- 2011-06-02 IL IL213341A patent/IL213341A0/en unknown
-
2015
- 2015-09-14 JP JP2015181062A patent/JP2016028082A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JP2012512898A (ja) | 2012-06-07 |
| CN102300580A (zh) | 2011-12-28 |
| EP2376098A4 (en) | 2014-06-11 |
| IL213341A0 (en) | 2011-07-31 |
| CA2747195A1 (en) | 2010-07-15 |
| PE20120331A1 (es) | 2012-04-14 |
| RU2011129764A (ru) | 2013-01-27 |
| RU2578591C2 (ru) | 2016-03-27 |
| KR20110114568A (ko) | 2011-10-19 |
| WO2010080605A1 (en) | 2010-07-15 |
| SG172290A1 (en) | 2011-07-28 |
| AU2009335711A1 (en) | 2010-07-15 |
| US20110237493A1 (en) | 2011-09-29 |
| JP2016028082A (ja) | 2016-02-25 |
| EP2376098A1 (en) | 2011-10-19 |
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