CN114588154A - 用于治疗水肿的组合物和方法 - Google Patents
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- CN114588154A CN114588154A CN202210078205.6A CN202210078205A CN114588154A CN 114588154 A CN114588154 A CN 114588154A CN 202210078205 A CN202210078205 A CN 202210078205A CN 114588154 A CN114588154 A CN 114588154A
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Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
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| US201562112273P | 2015-02-05 | 2015-02-05 | |
| US62/112,273 | 2015-02-05 | ||
| PCT/US2016/016680 WO2016127013A1 (en) | 2015-02-05 | 2016-02-05 | Compositions and methods for treatment of edema |
| CN201680016894.0A CN107427007B (zh) | 2015-02-05 | 2016-02-05 | 用于治疗水肿的组合物和方法 |
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| WO2016127013A1 (en) * | 2015-02-05 | 2016-08-11 | Memorial Sloan Kettering Cancer Center | Compositions and methods for treatment of edema |
| CA3033863C (en) * | 2016-08-18 | 2021-09-14 | Memorial Sloan Kettering Cancer Center | Inhibition of sphingosine 1-phosphate receptor for treatment and prevention of lymphedema |
| EP4603148A3 (en) * | 2018-09-14 | 2025-10-29 | Puretech Lyt 100, Inc. | Deuterium-enriched pirfenidone and methods of use thereof |
| AU2019375206A1 (en) * | 2018-11-05 | 2021-06-24 | Apramitha Innovations Private Limited | Teriflunomide topical pharmaceutical compositions |
| CA3175866A1 (en) * | 2020-03-18 | 2021-09-23 | Puretech Lyt 100, Inc. | Methods of treating lymphedema with deupirfenidone |
| CN112642065B (zh) * | 2020-12-28 | 2022-08-02 | 锐可医疗科技(上海)有限公司 | 激光治疗仪及存储介质 |
| WO2024059336A1 (en) * | 2022-09-18 | 2024-03-21 | Memorial Sloan Kettering Cancer Center | Inhibition of protease-activated receptor 2 (par2) pathway for treatment and prevention of lymphedema |
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|---|---|---|---|---|
| CN102209543A (zh) * | 2008-11-10 | 2011-10-05 | 英特芒尼公司 | 用于具有非典型肝功能的患者的吡非尼酮治疗 |
| US20110288134A1 (en) * | 2008-10-29 | 2011-11-24 | Pacific Therapeutics Ltd. | Composition and method for treating fibrosis |
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| US20050158371A1 (en) * | 2002-02-12 | 2005-07-21 | Sumitomo Pharmaceuticals Co., Ltd. | Novel external agent |
| US7232828B2 (en) * | 2002-08-10 | 2007-06-19 | Bethesda Pharmaceuticals, Inc. | PPAR Ligands that do not cause fluid retention, edema or congestive heart failure |
| JPWO2005011669A1 (ja) * | 2003-08-05 | 2006-09-14 | 大日本住友製薬株式会社 | 経皮投与用医薬組成物 |
| CA2644311C (en) * | 2006-03-01 | 2012-07-10 | Tristrata, Inc. | Composition and method for topical treatment of tar-responsive dermatological disorders |
| ES2563288T3 (es) * | 2006-03-23 | 2016-03-14 | Santen Pharmaceutical Co., Ltd | Rapamicina en dosis bajas para el tratamiento de enfermedades relacionadas con la permeabilidad vascular |
| JP5213852B2 (ja) * | 2006-06-15 | 2013-06-19 | シャンハイ ゲノミックス インク | 放射線肺障害の予防及び治療のためのピリドン系誘導体の使用 |
| MX337408B (es) * | 2007-03-22 | 2016-03-03 | Berg Llc | Formulaciones topicas que tienen biodisponibilidad aumentada. |
| CN102307475A (zh) * | 2009-02-04 | 2012-01-04 | 彼帕科学公司 | 用与生长因子抑制剂组合的parp抑制剂治疗肺癌 |
| DE102010015143A1 (de) * | 2010-04-16 | 2011-10-20 | Cts Chemical Industries Ltd. | Stabile flüssige ölige gebrauchsfertige Formulierungen, Herstellung davon und Verwendung davon |
| WO2016127013A1 (en) * | 2015-02-05 | 2016-08-11 | Memorial Sloan Kettering Cancer Center | Compositions and methods for treatment of edema |
| US10292961B2 (en) * | 2015-07-15 | 2019-05-21 | Hangzhou Dac Biotech Co., Ltd. | Disulfur bridge linkers for conjugation of a cell-binding molecule |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110288134A1 (en) * | 2008-10-29 | 2011-11-24 | Pacific Therapeutics Ltd. | Composition and method for treating fibrosis |
| CN102209543A (zh) * | 2008-11-10 | 2011-10-05 | 英特芒尼公司 | 用于具有非典型肝功能的患者的吡非尼酮治疗 |
Non-Patent Citations (1)
| Title |
|---|
| NICHOLAS W. CLAVIN: "TGF-β1 is a negative regulator of lymphatic regeneration during wound repair", AJP - HEART AND CIRCULATORY PHYSIOLOGY, vol. 295, pages 2113 * |
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| US20230241043A1 (en) | 2023-08-03 |
| JP6704403B2 (ja) | 2020-06-03 |
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| AU2020201161B2 (en) | 2021-07-15 |
| JP2018504436A (ja) | 2018-02-15 |
| US20250235436A1 (en) | 2025-07-24 |
| CN107427007A (zh) | 2017-12-01 |
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| WO2016127013A1 (en) | 2016-08-11 |
| CN107427007B (zh) | 2022-02-11 |
| EP3253211B1 (en) | 2025-06-11 |
| EP3253211A4 (en) | 2018-10-31 |
| US10874651B2 (en) | 2020-12-29 |
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