JP5290163B2 - 薬剤、方法および使用 - Google Patents
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- JP5290163B2 JP5290163B2 JP2009514867A JP2009514867A JP5290163B2 JP 5290163 B2 JP5290163 B2 JP 5290163B2 JP 2009514867 A JP2009514867 A JP 2009514867A JP 2009514867 A JP2009514867 A JP 2009514867A JP 5290163 B2 JP5290163 B2 JP 5290163B2
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/23—Luteinising hormone-releasing hormone [LHRH]; Related peptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
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| CN101864398B (zh) * | 2009-09-03 | 2012-11-14 | 李吉祐 | 一种抗促性腺激素释放激素受体的单克隆抗体与应用 |
| US20120004182A1 (en) * | 2010-07-02 | 2012-01-05 | Carsten Gruendker | Pharmaceutical compositions and methods for induction and enhancement of apoptosis in tumor cells |
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| WO2016065052A1 (en) | 2014-10-22 | 2016-04-28 | Extend Biosciences, Inc. | Insulin vitamin d conjugates |
| US9789197B2 (en) | 2014-10-22 | 2017-10-17 | Extend Biosciences, Inc. | RNAi vitamin D conjugates |
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| US9526768B2 (en) | 2014-11-13 | 2016-12-27 | Jennifer Mai | Compositions for the treatment of cancer |
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| WO2018134370A1 (en) * | 2017-01-20 | 2018-07-26 | Immune System Regulation Holding Ab | Novel compounds (immunorhelins) |
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| JP2025534350A (ja) | 2022-09-30 | 2025-10-15 | エクステンド バイオサイエンシズ インコーポレーテッド | 長時間作用型副甲状腺ホルモン |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2029018A1 (en) | 1989-11-01 | 1991-05-02 | Robert P. Millar | Analogues of gonadotropin releasing hormone |
| PT769956E (pt) * | 1994-07-22 | 2000-07-31 | Hampton Roads Medical College | Utilizacao de antagonistas de gnrh para a preparacao de medicamentos para o tratamento de condicoes dependentes de gonado-esteroides |
| US6664369B1 (en) * | 1994-08-10 | 2003-12-16 | Creighton University | GnRH analogues with antitumour effects and pharmaceutical compositions thereof |
| CN1179181A (zh) * | 1995-02-10 | 1998-04-15 | 萨斯喀彻温大学 | GnRH－白细胞毒素嵌合体 |
| DE69737635T2 (de) * | 1996-08-30 | 2008-01-03 | Peptech Ltd., North Ryde | Formulierung zur verzögerten Freisetzung von Peptidagonisten und -analoga des GnRH |
| GB2343182A (en) | 1998-10-27 | 2000-05-03 | Ferring Bv | Use of GnRH-II and analogues thereof for the treatment of osteoporosis |
| GB2344287A (en) | 1998-12-03 | 2000-06-07 | Ferring Bv | Controlled release pharmaceutical formulation |
| US6323179B1 (en) | 1999-10-15 | 2001-11-27 | Theresa Siler-Khodr | Chicken GNRH analogs and uses thereof in regulation of fertility and pregnancy |
| US7109171B2 (en) | 2000-02-28 | 2006-09-19 | Praecis Pharmaceuticals Inc. | Methods for treating FSH related conditions with GnRH antagonists |
| US7834141B1 (en) | 2000-03-31 | 2010-11-16 | Theresa Siler-Khodr | Non-mammalian GnRH analogs and uses thereof in tumor cell growth regulation and cancer therapy |
| US20040152639A1 (en) | 2001-08-28 | 2004-08-05 | Siler-Khodr Theresa M. | Non-mammalian GnRH analogs and uses thereof in regulation of fertility and pregnancy |
| WO2003093304A1 (en) | 2002-05-03 | 2003-11-13 | Neurogenex Co., Ltd. | Agonists and antagonists of gonadotropin-releasing hormone-2, and use thereof |
| GB2397649B (en) * | 2002-07-22 | 2005-12-21 | Ardana Bioscience Ltd | Screening method and anti-tumor drug candidate obtained therefrom |
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| US9388216B2 (en) | 2016-07-12 |
| CN102977188A (zh) | 2013-03-20 |
| EP2029618B1 (en) | 2015-08-12 |
| JP2009539952A (ja) | 2009-11-19 |
| EP2029618A2 (en) | 2009-03-04 |
| GB0616111D0 (en) | 2006-09-20 |
| WO2007144554A3 (en) | 2008-02-14 |
| US20100234303A1 (en) | 2010-09-16 |
| CN102977188B (zh) | 2015-07-15 |
| CN101553500B (zh) | 2014-01-01 |
| CN101553500A (zh) | 2009-10-07 |
| WO2007144554A2 (en) | 2007-12-21 |
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