CO5690564A2 - Medicamento para tratar tejido de miocardio infartado que comprende mioblastos oseos de mamiferos geneticamente modoficados para expresar la proteina sdf-1 de mamifero - Google Patents
Medicamento para tratar tejido de miocardio infartado que comprende mioblastos oseos de mamiferos geneticamente modoficados para expresar la proteina sdf-1 de mamiferoInfo
- Publication number
- CO5690564A2 CO5690564A2 CO05015803A CO05015803A CO5690564A2 CO 5690564 A2 CO5690564 A2 CO 5690564A2 CO 05015803 A CO05015803 A CO 05015803A CO 05015803 A CO05015803 A CO 05015803A CO 5690564 A2 CO5690564 A2 CO 5690564A2
- Authority
- CO
- Colombia
- Prior art keywords
- myocardial tissue
- protein
- sdf
- express
- treatment
- Prior art date
Links
- 102100021669 Stromal cell-derived factor 1 Human genes 0.000 title abstract 5
- 101710088580 Stromal cell-derived factor 1 Proteins 0.000 title abstract 5
- 230000002107 myocardial effect Effects 0.000 title abstract 4
- 241000124008 Mammalia Species 0.000 title 2
- 229940126601 medicinal product Drugs 0.000 title 1
- 239000003814 drug Substances 0.000 abstract 5
- 239000013604 expression vector Substances 0.000 abstract 3
- 210000001519 tissue Anatomy 0.000 abstract 3
- 210000000988 bone and bone Anatomy 0.000 abstract 2
- 210000003098 myoblast Anatomy 0.000 abstract 2
- 241000701161 unidentified adenovirus Species 0.000 abstract 2
- 241000700584 Simplexvirus Species 0.000 abstract 1
- 241000700605 Viruses Species 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 102000039446 nucleic acids Human genes 0.000 abstract 1
- 108020004707 nucleic acids Proteins 0.000 abstract 1
- 150000007523 nucleic acids Chemical class 0.000 abstract 1
- 241001430294 unidentified retrovirus Species 0.000 abstract 1
- 239000013603 viral vector Substances 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/521—Chemokines
- C07K14/522—Alpha-chemokines, e.g. NAP-2, ENA-78, GRO-alpha/MGSA/NAP-3, GRO-beta/MIP-2alpha, GRO-gamma/MIP-2beta, IP-10, GCP-2, MIG, PBSF, PF-4, KC
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
-
- 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
- A61K38/18—Growth factors; Growth regulators
- A61K38/1808—Epidermal growth factor [EGF] urogastrone
-
- 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
- A61K38/193—Colony stimulating factors [CSF]
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/035—Animal model for multifactorial diseases
- A01K2267/0375—Animal model for cardiovascular diseases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2799/00—Uses of viruses
- C12N2799/02—Uses of viruses as vector
- C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
- C12N2799/022—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from an adenovirus
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Developmental Biology & Embryology (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- Cell Biology (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Virology (AREA)
- Biotechnology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
1.- El uso de un agente en la preparación de un medicamento para el tratamiento de tejido de miocardio infartado, El tejido de miocardio infartado que incluye una primera concentración de proteína SDF-1,el medicamento que es adecuado para incrementar la concentración de proteína SDF-1 en el tejido de miocardio infartado desde la primera concentración hacia la segunda concentración.2.- El medicamento de la reivindicación 1 que comprende mioblastos óseos de mamíferos modificados para expresar la proteína SDF-1 mamíferos.3.- El medicamento de la reivindicación 2, el mioblasto óseo que es genéticamente modificado con un vector de expresión, el vector de expresión incluye un ácido nucleico que codifica la proteína SDF-1 de mamíferos.4.- El medicamento de la reivindicación 3, el vector de expresión que comprende un vector viral derivado de al menos un adenovirus, virus asociado con adenovirus, virusde herpes simple, o retrovirus.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US40527402P | 2002-08-22 | 2002-08-22 | |
US10/426,712 US20040037811A1 (en) | 2002-08-22 | 2003-04-30 | Stromal cell-derived factor-1 mediates stem cell homing and tissue regeneration in ischemic cardiomyopathy |
Publications (1)
Publication Number | Publication Date |
---|---|
CO5690564A2 true CO5690564A2 (es) | 2006-10-31 |
Family
ID=31891492
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CO05015803A CO5690564A2 (es) | 2002-08-22 | 2005-02-21 | Medicamento para tratar tejido de miocardio infartado que comprende mioblastos oseos de mamiferos geneticamente modoficados para expresar la proteina sdf-1 de mamifero |
Country Status (8)
Country | Link |
---|---|
US (1) | US20040037811A1 (es) |
EP (2) | EP2520302B1 (es) |
JP (1) | JP4280708B2 (es) |
AU (1) | AU2003268131A1 (es) |
BR (1) | BRPI0313987A8 (es) |
CA (1) | CA2504019C (es) |
CO (1) | CO5690564A2 (es) |
WO (1) | WO2004017978A1 (es) |
Families Citing this family (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8147824B2 (en) | 1999-08-05 | 2012-04-03 | Athersys, Inc. | Immunomodulatory properties of multipotent adult progenitor cells and uses thereof |
US9694038B2 (en) | 2000-04-06 | 2017-07-04 | Wayne P. Franco | Combination growth factor therapy and cell therapy for treatment of acute and chronic diseases of the organs |
US20050277576A1 (en) * | 2000-04-06 | 2005-12-15 | Franco Wayne P | Combination growth factor therapy and cell therapy for treatment of acute and chronic diseases of the organs |
US20070111935A1 (en) * | 2000-04-06 | 2007-05-17 | Franco Wayne P | Combination growth factor therapy and cell therapy for treatment of acute and chronic diseases of the organs |
US10281478B2 (en) | 2000-04-06 | 2019-05-07 | Wayne P. Franco | Combination growth factor therapy and cell therapy for treatment of acute and chronic diseases of the organs |
US20050271639A1 (en) * | 2002-08-22 | 2005-12-08 | Penn Marc S | Genetically engineered cells for therapeutic applications |
AU2003290601A1 (en) * | 2002-11-05 | 2004-06-03 | The Brigham And Women's Hospital, Inc. | Mesenchymal stem cells and methods of use thereof |
ATE551066T1 (de) * | 2004-06-21 | 2012-04-15 | Cleveland Clinic Foundation | Ccr-liganden für stammzellen-homing |
US20080253996A1 (en) * | 2005-10-31 | 2008-10-16 | Laboratories Serono Sa | Use of Sdf-1 for the Treatment and/or Prevention of Neurological Diseases |
US10117900B2 (en) | 2005-11-09 | 2018-11-06 | Athersys, Inc. | MAPC treatment of brain injuries and diseases |
US11000546B2 (en) | 2005-11-09 | 2021-05-11 | Athersys, Inc. | Immunomodulatory properties of MAPCs and uses thereof |
NZ727755A (en) * | 2006-01-23 | 2023-01-27 | Abt Holding Co | Mapc therapeutics without adjunctive immunosuppressive treatment |
US7696309B2 (en) * | 2006-10-23 | 2010-04-13 | The Brigham And Women's Hospital, Inc. | Protease resistant mutants of stromal cell derived factor-1 in the repair of tissue damage |
ES2520044T3 (es) | 2007-03-30 | 2014-11-11 | The Cleveland Clinic Foundation | SDF-1 para su uso en el tratamiento de trastornos vasculares periféricos isquémicos |
WO2009079451A2 (en) | 2007-12-14 | 2009-06-25 | The Cleveland Clinic Foundation | Compositions and methods of promoting wound healing |
CA2772610C (en) | 2009-08-28 | 2018-01-23 | The Cleveland Clinic Foundation | Sdf-1 delivery for treating ischemic tissue |
US9308277B2 (en) | 2010-02-25 | 2016-04-12 | Mesoblast International Sàrl | Protease-resistant mutants of stromal cell derived factor-1 in the repair of tissue damage |
WO2011121036A2 (en) * | 2010-03-30 | 2011-10-06 | Vib Vzw | Induction of arteriogenesis using specific factors or by cell therapy with polarized myeloid cells |
WO2012048298A2 (en) | 2010-10-08 | 2012-04-12 | Caridianbct, Inc. | Methods and systems of growing and harvesting cells in a hollow fiber bioreactor system with control conditions |
WO2012094512A2 (en) * | 2011-01-05 | 2012-07-12 | The Cleveland Clinic Foundation | Myocardial tissue targeting peptides |
WO2012170495A1 (en) | 2011-06-07 | 2012-12-13 | Provasculon, Inc. | Methods for repairing tissue damage using protease-resistant mutants of stromal cell derived factor-1 |
US9617506B2 (en) | 2013-11-16 | 2017-04-11 | Terumo Bct, Inc. | Expanding cells in a bioreactor |
US11008547B2 (en) | 2014-03-25 | 2021-05-18 | Terumo Bct, Inc. | Passive replacement of media |
RU2557385C1 (ru) * | 2014-06-18 | 2015-07-20 | Общество с ограниченной ответственностью "НекстГен" | Кодон-оптимизированные последовательности и фармацевтическая композиция для восстановления кровеносных сосудов |
JP6830059B2 (ja) | 2014-09-26 | 2021-02-17 | テルモ ビーシーティー、インコーポレーテッド | スケジュール化された細胞フィーディング |
WO2017004592A1 (en) | 2015-07-02 | 2017-01-05 | Terumo Bct, Inc. | Cell growth with mechanical stimuli |
US10988731B2 (en) | 2016-04-29 | 2021-04-27 | Hope Biosciences, Llc | Formulation for storage, transportation, and delivery of protein rich conditioned medium |
US10513689B2 (en) * | 2016-04-29 | 2019-12-24 | Hope Biosciences, Llc | Culture media for multipotent stem cells |
US11111480B2 (en) | 2016-04-29 | 2021-09-07 | Hope Biosctences, Llc | Culture media for multipotent stem cells |
US10959425B2 (en) | 2016-04-29 | 2021-03-30 | Hope Biosciences, Llc | Method of banking stem cells |
US11965175B2 (en) | 2016-05-25 | 2024-04-23 | Terumo Bct, Inc. | Cell expansion |
US11104874B2 (en) | 2016-06-07 | 2021-08-31 | Terumo Bct, Inc. | Coating a bioreactor |
US11685883B2 (en) | 2016-06-07 | 2023-06-27 | Terumo Bct, Inc. | Methods and systems for coating a cell growth surface |
CN117247899A (zh) | 2017-03-31 | 2023-12-19 | 泰尔茂比司特公司 | 细胞扩增 |
US11624046B2 (en) | 2017-03-31 | 2023-04-11 | Terumo Bct, Inc. | Cell expansion |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3150340B2 (ja) | 1990-11-13 | 2001-03-26 | イムネクス コーポレイション | 二機能選択可能融合遺伝子 |
JPH09500783A (ja) | 1993-05-21 | 1997-01-28 | ターゲッティッド ジェネティクス コーポレイション | シトシンデアミナーゼ(cd)遺伝子に基づく二機能性選択融合遺伝子 |
US5602301A (en) * | 1993-11-16 | 1997-02-11 | Indiana University Foundation | Non-human mammal having a graft and methods of delivering protein to myocardial tissue |
JP3961019B2 (ja) * | 1995-02-28 | 2007-08-15 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 遺伝子転移媒介の血管形成療法 |
US5980887A (en) * | 1996-11-08 | 1999-11-09 | St. Elizabeth's Medical Center Of Boston | Methods for enhancing angiogenesis with endothelial progenitor cells |
SG117417A1 (en) * | 1998-02-06 | 2005-12-29 | Collateral Therpeutics Inc | Variants of the angiogenic factor vascular endothelial cell growth factor: vegf |
JP2002506008A (ja) * | 1998-03-09 | 2002-02-26 | セント エリザベス メディカル センター | 血管新生を調整するための組成物及び方法 |
US6358697B2 (en) * | 1999-04-21 | 2002-03-19 | Children's Hospital Medical Center | Intracellular pharmaceutical targeting |
US20020061587A1 (en) * | 2000-07-31 | 2002-05-23 | Piero Anversa | Methods and compositions for the repair and/or regeneration of damaged myocardium |
-
2003
- 2003-04-30 US US10/426,712 patent/US20040037811A1/en not_active Abandoned
- 2003-08-21 WO PCT/US2003/026013 patent/WO2004017978A1/en active Application Filing
- 2003-08-21 AU AU2003268131A patent/AU2003268131A1/en not_active Abandoned
- 2003-08-21 JP JP2004531098A patent/JP4280708B2/ja not_active Expired - Fee Related
- 2003-08-21 EP EP12164577.4A patent/EP2520302B1/en not_active Expired - Fee Related
- 2003-08-21 BR BRPI0313987A patent/BRPI0313987A8/pt not_active Application Discontinuation
- 2003-08-21 EP EP03749081A patent/EP1542701B1/en not_active Expired - Lifetime
- 2003-08-21 CA CA2504019A patent/CA2504019C/en not_active Expired - Fee Related
-
2005
- 2005-02-21 CO CO05015803A patent/CO5690564A2/es not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
EP1542701A1 (en) | 2005-06-22 |
BRPI0313987A2 (pt) | 2017-10-10 |
EP1542701A4 (en) | 2009-11-25 |
EP2520302A1 (en) | 2012-11-07 |
JP4280708B2 (ja) | 2009-06-17 |
JP2006507244A (ja) | 2006-03-02 |
EP1542701B1 (en) | 2012-07-18 |
EP2520302B1 (en) | 2016-08-17 |
BRPI0313987A8 (pt) | 2018-04-24 |
US20040037811A1 (en) | 2004-02-26 |
AU2003268131A1 (en) | 2004-03-11 |
CA2504019C (en) | 2015-06-02 |
CA2504019A1 (en) | 2004-03-04 |
WO2004017978A1 (en) | 2004-03-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CO5690564A2 (es) | Medicamento para tratar tejido de miocardio infartado que comprende mioblastos oseos de mamiferos geneticamente modoficados para expresar la proteina sdf-1 de mamifero | |
ES2167365T3 (es) | Vectores adenovirales de origen animal y utilizacion en terapia genica. | |
AR020048A1 (es) | Un polipeptido dependiente de la vitamina k, una composicion farmaceutica que lo comprende, el uso del mismo para la manufactura de un medicamento, unacido nucleico aislado que codifica a dicho polipeptido y una celula hospedante de mamifero. | |
BR9712518A (pt) | Polipeptìdeo, molécula de dna, vetor de expressão, célula hospedeira, composição farmacêutica, vacina, proteìna de fusão, processo para detectar tuberculose em um paciente, e, kit diagnóstico | |
PT693924E (pt) | Processos para administracao (in vivo) de substancias biologicas e composicoes utilizadas nestes processos | |
BR0009537A (pt) | Composições para tratamento e diagnóstico de câncer de mama e métodos para seu uso | |
AR012540A1 (es) | COMPOSICIoN FARMACÉUTICA LIOFILIZADA DE ANTICUERPOS MONOCLONALES O POLICLONALES, PROCEDIMIENTO PARA SU PRODUCCIoN | |
BR9815551A (pt) | Vacina de envoltório dimérica recombinante contra infecção flaviviral | |
BR9912653A (pt) | Vìrus de herpes atenuado, cepa de vìrus, célula dendrìtica, processo para produzir um célula, composição farmacêutica, uso de um vìrus, e, processo para executar a terapia de gene em um paciente humano ou animal ou para tratar ou prevenir uma infecção patogênica ou câncer para tratar paciente animal | |
PT915910E (pt) | Analogos de exendina, processos para a sua preparacao e medicamentos que os contem | |
SV2004001556A (es) | Preparaciones acidas de insulina con establidad mejorada | |
ES2190244T3 (es) | Uso de la hormona paratiroidea constituida por una secuencia de aminoacidos 1-34 de la hormona paratiroidea humana para reducir el riesco de fracturas oseas vertebrales y no vertebrales. | |
BR9907189A (pt) | Produtos da fração lipìdica do carotenóide de pepino do mar e métodos de uso | |
BR0110091A (pt) | Composições e processos para terapia e diagnóstico de câncer de mama | |
PE20000939A1 (es) | Formulaciones de fsh y variantes de fsh, productos y metodos | |
AR003589A1 (es) | Utilizacion de una cantidad eficaz de al menos un peptido en una composicion cosmetica o para la preparacion de un medicamento destinada paratratar la inflamacion, y un procedimiento de tratamiento cosmetico mediante una composicion cosmetica que contiene a dicho peptido. | |
ATE50260T1 (de) | Purinderivate, verfahren zu ihrer herstellung und pharmazeutische zubereitung. | |
PT1035844E (pt) | Utilizacao de poliois no combate a infeccoes por leveduras e preparacoes de poliol para a referida utilizacao | |
BR0208041A (pt) | Interferon beta modificado com imunogenicidade reduzida | |
BR0012919A (pt) | Vacina para uso na profilaxia e/ou no tratamento da sìndrome de ponto branco (white spot syndrome) em crustáceos, proteìna estrutural derivada do vìrus da sìndrome de ponto branco, sequência de ácido nucléico, uso de uma proteìna estrutural, composição farmacêutica, anticorpos, vacina ou formulação farmacêutica, e, kit diagnóstico para detecção de wssv | |
DK183389A (da) | Fremgangsmaade til fremstilling af en administrerings- og/eller doseringsform for medicinsk aktive materialer | |
CA2315277A1 (en) | Pharmaceutical compositions containing the long pentraxin ptx3 | |
ES2146214T3 (es) | Vacunas para actinobacillus pleuropneumoniae. | |
BR9813514A (pt) | Agente para tratamento de fibras queratìnicas | |
ES2279257T3 (es) | Peptido del antigeno muc-1 para el desencadenamiento de una reaccion inmune frente a celulas tumorales. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FC | Application refused |