CA2791081C - Treatment for pulmonary hypertension - Google Patents
Treatment for pulmonary hypertension Download PDFInfo
- Publication number
- CA2791081C CA2791081C CA2791081A CA2791081A CA2791081C CA 2791081 C CA2791081 C CA 2791081C CA 2791081 A CA2791081 A CA 2791081A CA 2791081 A CA2791081 A CA 2791081A CA 2791081 C CA2791081 C CA 2791081C
- Authority
- CA
- Canada
- Prior art keywords
- treprostinil
- oral
- therapeutic agent
- pulmonary hypertension
- inhaled
- 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
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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
- A61K31/5585—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin
-
- 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
- A61K31/343—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 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- 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
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
-
- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5578—Eicosanoids, e.g. leukotrienes or prostaglandins having a pentalene ring system, e.g. carbacyclin, iloprost
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pulmonology (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Otolaryngology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2892104A CA2892104C (en) | 2010-03-15 | 2011-03-14 | Treatment for pulmonary hypertension |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US28265910P | 2010-03-15 | 2010-03-15 | |
| US61/282,659 | 2010-03-15 | ||
| PCT/US2011/028390 WO2011115922A1 (en) | 2010-03-15 | 2011-03-14 | Treatment for pulmonary hypertension |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2892104A Division CA2892104C (en) | 2010-03-15 | 2011-03-14 | Treatment for pulmonary hypertension |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2791081A1 CA2791081A1 (en) | 2011-09-22 |
| CA2791081C true CA2791081C (en) | 2015-08-25 |
Family
ID=43858371
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2791081A Active CA2791081C (en) | 2010-03-15 | 2011-03-14 | Treatment for pulmonary hypertension |
| CA2892104A Active CA2892104C (en) | 2010-03-15 | 2011-03-14 | Treatment for pulmonary hypertension |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2892104A Active CA2892104C (en) | 2010-03-15 | 2011-03-14 | Treatment for pulmonary hypertension |
Country Status (8)
| Country | Link |
|---|---|
| US (2) | US8609728B2 (https=) |
| EP (2) | EP2547341B1 (https=) |
| JP (4) | JP5681276B2 (https=) |
| KR (3) | KR20150027846A (https=) |
| CN (1) | CN102883722B (https=) |
| CA (2) | CA2791081C (https=) |
| ES (2) | ES2611187T3 (https=) |
| WO (1) | WO2011115922A1 (https=) |
Families Citing this family (30)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101903324B (zh) | 2007-12-17 | 2013-07-03 | 联合治疗公司 | 一种制备Remodulin中的活性成分曲前列素的改良方法 |
| ES2611187T3 (es) | 2010-03-15 | 2017-05-05 | United Therapeutics Corporation | Tratamiento para hipertensión pulmonar |
| JP6046034B2 (ja) | 2010-06-03 | 2016-12-14 | ユナイテッド セラピューティクス コーポレイション | トレプロスチニルの製造 |
| US20130345471A1 (en) | 2011-03-02 | 2013-12-26 | United Therapeutics Corporation | Synthesis of intermediate for treprostinil production |
| US9387214B2 (en) | 2012-01-13 | 2016-07-12 | United Therapeutics Corporation | Method of identifying therapies for pulmonary hypertension |
| JP2016517410A (ja) | 2013-03-14 | 2016-06-16 | ユナイテッド セラピューティクス コーポレイション | トレプロスチニルの固体形態 |
| CN109608326A (zh) | 2013-03-15 | 2019-04-12 | 联合治疗公司 | 曲前列环素的盐 |
| JP6263604B2 (ja) | 2013-03-25 | 2018-01-17 | ユナイテッド セラピューティクス コーポレイション | チオールリンカーを持つ、ペグ化型のプロスタサイクリン化合物の製造方法 |
| ES2860975T3 (es) | 2013-10-25 | 2021-10-05 | Insmed Inc | Compuestos de prostaciclina |
| US20160317542A1 (en) | 2013-12-09 | 2016-11-03 | Respira Therapeutics, Inc. | Pde5 inhibitor powder formulations and methods relating thereto |
| ES2908142T3 (es) | 2014-06-13 | 2022-04-27 | United Therapeutics Corp | Formulaciones de treprostinil |
| US9593061B2 (en) | 2014-10-20 | 2017-03-14 | United Therapeutics Corporation | Synthesis of intermediates for producing prostacyclin derivatives |
| AU2015349969B2 (en) | 2014-11-18 | 2020-02-06 | Insmed Incorporated | Methods of manufacturing treprostinil and treprostinil derivative prodrugs |
| DK3496739T3 (da) | 2016-07-15 | 2021-05-10 | Acceleron Pharma Inc | Sammensætninger omfattende actriia-polypeptider til brug i behandlingen af pulmonal hypertension |
| JP7220650B2 (ja) | 2016-09-26 | 2023-02-10 | ユナイテッド セラピューティクス コーポレイション | トレプロスチニルプロドラッグ |
| MX2019006938A (es) | 2016-12-14 | 2019-09-06 | Respira Therapeutics Inc | Metodos y composiciones para trataminto de hipertension pulmonar y otros trastornos del pulmon. |
| KR20190030805A (ko) * | 2017-09-14 | 2019-03-25 | 경상대학교산학협력단 | 폐고혈압 예방 또는 치료용 흡입제, 및 이의 투여방법 |
| HU231296B1 (hu) * | 2018-03-09 | 2022-09-28 | Chinoin Zrt | Eljárás treprostinil-dietanol-amin só B polimorf formájának előállítására |
| ES2976468T3 (es) | 2018-09-18 | 2024-08-01 | Lilly Co Eli | Sal de treprostinil erbumina |
| CN114072136B (zh) | 2019-04-29 | 2024-11-29 | 英斯梅德股份有限公司 | 曲前列素前药的干粉组合物及其使用方法 |
| TWI757739B (zh) | 2019-05-14 | 2022-03-11 | 國邑藥品科技股份有限公司 | 包含弱酸藥物之醫藥組成物及其用途 |
| EP4017588A1 (en) | 2019-08-23 | 2022-06-29 | United Therapeutics Corporation | Treprostinil prodrugs |
| JP2023523557A (ja) | 2020-04-17 | 2023-06-06 | ユナイテッド セラピューティクス コーポレイション | 間質性肺疾患の治療における使用のためのトレプロスチニル |
| US20230174620A1 (en) | 2020-04-28 | 2023-06-08 | Acceleron Pharma Inc. | Actrii proteins and use in treating post-capillary pulmonary hypertension |
| IL298591A (en) | 2020-06-09 | 2023-01-01 | United Therapeutics Corp | Pomeryl dictopiperidine prodrugs of treprostinil |
| KR20250133451A (ko) | 2020-12-14 | 2025-09-05 | 유나이티드 쎄러퓨틱스 코포레이션 | 트레프로스티닐 프로드러그로 질환을 치료하는 방법 |
| JP2024510930A (ja) | 2021-03-03 | 2024-03-12 | ユナイテッド セラピューティクス コーポレイション | トレプロスチニル及びそのプロドラッグの乾燥粉末組成物、及び、さらに(e)-3,6-ビス[4-(n-カルボニル-2-プロペニル)アミドブチル]-2,5-ジケトピペラジン(fdkp)を含む乾燥粉末組成物 |
| WO2023154705A1 (en) | 2022-02-08 | 2023-08-17 | United Therapeutics Corporation | Treprostinil iloprost combination therapy |
| EP4516297A4 (en) | 2022-04-29 | 2026-02-25 | Zhaoke pharmaceutical guangzhou co ltd | Treprostinil Gentle Inhalation Mist |
| EP4652151A1 (en) | 2023-01-19 | 2025-11-26 | United Therapeutics Corporation | Treprostinil analogs |
Family Cites Families (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4306075A (en) | 1980-03-28 | 1981-12-15 | The Upjohn Company | Composition and process |
| GB8814438D0 (en) | 1988-06-17 | 1988-07-20 | Wellcome Found | Compounds for use in medicine |
| GB9011588D0 (en) | 1990-05-24 | 1990-07-11 | Wellcome Found | Prostaglandin analogues for use in medicine |
| GB9311920D0 (en) * | 1993-06-09 | 1993-07-28 | Pfizer Ltd | Therapeutic agents |
| KR100638684B1 (ko) | 1997-11-14 | 2006-10-27 | 유나이티드 세러퓨틱스 코오포레이션 | 말초 혈관 질환의 치료를 위한 9-데옥시-2',9-알파-메타노-3-옥사-4,5,6-트리노르-3,7-(1',3'-인터페닐렌)-13,14-디하이드로-프로스타글란딘 에프1의 용도 |
| US6521212B1 (en) | 1999-03-18 | 2003-02-18 | United Therapeutics Corporation | Method for treating peripheral vascular disease by administering benzindene prostaglandins by inhalation |
| US6803386B2 (en) | 2002-01-16 | 2004-10-12 | United Therapeutics Corporation | Prostacyclin derivative containing compositions and methods of using the same for the treatment of cancer |
| ES2622471T5 (es) | 2003-05-22 | 2020-07-23 | United Therapeutics Corp | Compuestos y procedimientos para la administración de análogos de prostaciclina |
| ATE441418T1 (de) | 2003-12-16 | 2009-09-15 | United Therapeutics Corp | Verwendung von treprostinil zur verbesserung der nierenfunktion |
| DE602004028155D1 (de) | 2003-12-16 | 2010-08-26 | United Therapeutics Corp | Verwendung von treprostinil zur behandlung von ischämischen läsionen |
| WO2005099680A2 (en) | 2004-04-12 | 2005-10-27 | United Therapeutics, Inc. | Use of treprostinil to treat neuropathic diabetic foot ulcers |
| EP2026816B1 (en) * | 2006-05-15 | 2018-10-24 | United Therapeutics Corporation | Treprostinil administration using a metered dose inhaler |
| US20090036465A1 (en) | 2006-10-18 | 2009-02-05 | United Therapeutics Corporation | Combination therapy for pulmonary arterial hypertension |
| JP2010518122A (ja) * | 2007-02-09 | 2010-05-27 | ユナイテッド セラピューティクス コーポレーション | 間質性肺疾患および喘息のためのトレプロスチニル処置 |
| CN103181893A (zh) | 2007-09-07 | 2013-07-03 | 联合治疗公司 | 针对革兰氏阴性细菌具有选择性杀菌活性的缓冲液及其使用方法 |
| CA2723540C (en) | 2008-05-08 | 2016-01-05 | United Therapeutics Corporation | Treprostinil monohydrate |
| CN102164487A (zh) | 2008-09-25 | 2011-08-24 | 阿拉迪姆公司 | 曲前列素的深肺部递送 |
| US8349892B2 (en) | 2009-05-07 | 2013-01-08 | United Therapeutics Corporation | Solid formulations of prostacyclin analogs |
| ES2611187T3 (es) | 2010-03-15 | 2017-05-05 | United Therapeutics Corporation | Tratamiento para hipertensión pulmonar |
| US20120010159A1 (en) | 2010-07-09 | 2012-01-12 | United Therapeutics Corporation | Combination therapies with cox-2 inhibitors and treprostinil |
-
2011
- 2011-03-14 ES ES11711190.6T patent/ES2611187T3/es active Active
- 2011-03-14 WO PCT/US2011/028390 patent/WO2011115922A1/en not_active Ceased
- 2011-03-14 JP JP2013500129A patent/JP5681276B2/ja active Active
- 2011-03-14 KR KR1020157004406A patent/KR20150027846A/ko not_active Ceased
- 2011-03-14 ES ES16182514T patent/ES2790859T3/es active Active
- 2011-03-14 KR KR1020127026242A patent/KR101508047B1/ko active Active
- 2011-03-14 KR KR1020167031528A patent/KR20160132501A/ko not_active Ceased
- 2011-03-14 EP EP11711190.6A patent/EP2547341B1/en active Active
- 2011-03-14 CN CN201180023177.8A patent/CN102883722B/zh active Active
- 2011-03-14 CA CA2791081A patent/CA2791081C/en active Active
- 2011-03-14 EP EP16182514.6A patent/EP3108888B1/en active Active
- 2011-03-14 CA CA2892104A patent/CA2892104C/en active Active
- 2011-03-14 US US13/047,033 patent/US8609728B2/en active Active
-
2013
- 2013-05-22 US US13/899,734 patent/US8969409B2/en active Active
-
2015
- 2015-01-08 JP JP2015002312A patent/JP2015129129A/ja active Pending
-
2016
- 2016-03-16 JP JP2016052406A patent/JP2016153413A/ja not_active Withdrawn
-
2018
- 2018-05-08 JP JP2018089769A patent/JP2018135383A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| EP2547341A1 (en) | 2013-01-23 |
| CN102883722A (zh) | 2013-01-16 |
| CA2892104A1 (en) | 2011-09-22 |
| JP5681276B2 (ja) | 2015-03-04 |
| KR20130038835A (ko) | 2013-04-18 |
| US8609728B2 (en) | 2013-12-17 |
| JP2016153413A (ja) | 2016-08-25 |
| US20130253049A1 (en) | 2013-09-26 |
| JP2013522303A (ja) | 2013-06-13 |
| KR20160132501A (ko) | 2016-11-18 |
| CN102883722B (zh) | 2014-11-05 |
| EP3108888A1 (en) | 2016-12-28 |
| US20110224236A1 (en) | 2011-09-15 |
| WO2011115922A1 (en) | 2011-09-22 |
| ES2611187T3 (es) | 2017-05-05 |
| KR20150027846A (ko) | 2015-03-12 |
| EP3108888B1 (en) | 2020-02-12 |
| CA2791081A1 (en) | 2011-09-22 |
| JP2018135383A (ja) | 2018-08-30 |
| US8969409B2 (en) | 2015-03-03 |
| CA2892104C (en) | 2016-08-30 |
| EP2547341B1 (en) | 2016-09-14 |
| ES2790859T3 (es) | 2020-10-29 |
| KR101508047B1 (ko) | 2015-04-06 |
| JP2015129129A (ja) | 2015-07-16 |
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