ES2501565T3 - Uso de epotilona D en el tratamiento de enfermedades asociadas a Tau incluyendo enfermedad de Alzheimer - Google Patents
Uso de epotilona D en el tratamiento de enfermedades asociadas a Tau incluyendo enfermedad de Alzheimer Download PDFInfo
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- ES2501565T3 ES2501565T3 ES09735906.1T ES09735906T ES2501565T3 ES 2501565 T3 ES2501565 T3 ES 2501565T3 ES 09735906 T ES09735906 T ES 09735906T ES 2501565 T3 ES2501565 T3 ES 2501565T3
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- XOZIUKBZLSUILX-SDMHVBBESA-N Epothilone D Natural products O=C1[C@H](C)[C@@H](O)[C@@H](C)CCC/C(/C)=C/C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C XOZIUKBZLSUILX-SDMHVBBESA-N 0.000 title abstract description 11
- XOZIUKBZLSUILX-UHFFFAOYSA-N desoxyepothilone B Natural products O1C(=O)CC(O)C(C)(C)C(=O)C(C)C(O)C(C)CCCC(C)=CCC1C(C)=CC1=CSC(C)=N1 XOZIUKBZLSUILX-UHFFFAOYSA-N 0.000 title abstract description 11
- XOZIUKBZLSUILX-GIQCAXHBSA-N epothilone D Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C(\C)=C\C1=CSC(C)=N1 XOZIUKBZLSUILX-GIQCAXHBSA-N 0.000 title abstract description 11
- 208000024827 Alzheimer disease Diseases 0.000 title abstract 2
- 201000010099 disease Diseases 0.000 title 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title 1
- 239000003814 drug Substances 0.000 abstract description 2
- 210000004556 brain Anatomy 0.000 description 34
- 210000004185 liver Anatomy 0.000 description 9
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 0.000 description 4
- 229960002014 ixabepilone Drugs 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 230000000717 retained effect Effects 0.000 description 4
- 229930012538 Paclitaxel Natural products 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000000149 penetrating effect Effects 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- OQUHUZWYEYDRMH-JGMJILQLSA-N (4s,7r,8r,9e,13z,16s)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(e)-1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-1-oxacyclohexadeca-9,13-diene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)\C(C)=C\CC\C(C)=C/C[C@H]1C(\C)=C\C1=CSC(C)=N1 OQUHUZWYEYDRMH-JGMJILQLSA-N 0.000 description 1
- OQUHUZWYEYDRMH-UPDIVTRLSA-N Epothilone D5 Natural products O=C1[C@H](C)[C@@H](O)/C(/C)=C\CC/C(/C)=C/C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C OQUHUZWYEYDRMH-UPDIVTRLSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- 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
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Abstract
Uso de epotilona D en la preparación de un medicamento para el tratamiento de enfermedad de Alzheimer en un paciente humano que necesita tratamiento de la misma.
Description
E09735906
10-09-2014
para animales individuales y determinando después el promedio de las proporciones; las tablas en el presente documento comunicaron los valores promedio así obtenidos.
TABLA 1
- Compuesto
- Dosis (mpk) Tiempo (hr) Conc. en plasma (nM) Conc. cerebral (nM) Proporción cerebro frente a plasma Proporción cerebro frente a hígado
- Paclitaxel
- 4 1 447 47 0,10 NQ
- 6
- 43 16 0,37 NQ
- 24
- 12 15 1,25 NQ
- Compuesto II
- 1 6 3 6,8 2,1 0,01
- 24
- 1 1,3 1,2 0,02
- Ixabepilona
- 12 0,12 11,236 579 0,05 0,05
- 0,33
- 3057 495 0,16 0,09
- 1
- 390 284 0,73 0,07
- 2
- 171 360 2,1 0,11
- 6
- 53 371 7,0 0,30
- 24
- 8 236 30 1,2
- Epotilona D
- 5 6 6 2794 470 149
- 24
- 1 2046 2046 1204
5 Observando la tabla 1, paclitaxel es pobremente penetrante en el cerebro como se evidencia por una proporción cerebro frente a plasma de 0,1 en 1 hora después de dosificación; ixabepilona es más penetrante en el cerebro que paclitaxel con una proporción cerebro frente a plasma de 0,73 a 1 hora después de dosificación (tabla 1); A tiempos de 6-24 horas después de dosificación, la proporción de cerebro frente a plasma es una reflexión tanto de la penetración cerebral intrínseca como de la retención cerebral intrínseca (semivida) en el cerebro. Los datos a 6 y 24
10 horas después de la dosificación de epotilona D muestran al menos un incremento de 60 veces en la proporción cerebro frente a plasma por encima de ixabepilona, el compuesto con la siguiente proporción cerebro frente a plasma más alta en este grupo.
Las proporciones cerebro frente a hígado no solo proporcionan una medida más singular de retención cerebral y semivida, sino que también muestran la retención selectiva comparada con tejidos periféricos. Esto es valioso 15 porque el hígado, elegido en gran parte porque está bien perfundido y tiende a tener niveles más altos que muchos otros tejidos periféricos, contiene microtúbulos donde el compuesto puede retenerse, a diferencia del plasma no celular. A diferencia de la proporción cerebro frente a plasma donde el tiempo de medida óptimo está en el intervalo de 20-60 minutos, es preferible comparar las proporciones cerebro frente a plasma a tiempos más tardíos después de la administración de la dosis (por ejemplo, 24 horas o más), cuando los niveles de plasma han disminuido 20 significativamente, permitiendo por lo tanto una medida más segura del fármaco que está específicamente retenido dentro de las células cerebrales y hepáticas. Una comparación de las proporciones cerebro frente a hígado muestra que la epotilona D está retenida alta y selectivamente en el cerebro en relación al hígado. Por ejemplo, la proporción de cerebro frente a hígado a las 24 horas de epotilona D es 1204, una proporción remarcablemente, mucho más alta comparada con las proporciones mucho menores para ixabepilona (1,2) y Compuesto II (0,02) en el mismo grupo de
25 experimentos.
En un experimento separado, se evaluaron las concentraciones en plasma y en cerebro para periodos de tiempo más largos, es decir, hasta 168 horas, tras administración de bolo IV, usando un protocolo similar al descrito anteriormente, pero con ratones transgénicos triples de mediana edad (Oddo y col., 2003), en las manos de científicos diferentes. Los resultados de este experimento se muestran a continuación en la tabla 2 y en la FIG. 10.
30
22
E09735906
10-09-2014
TABLA 4
- Compuesto
- Tiempo (hr) Conc. en plasma (nM) Conc, en cerebro (nM) Proporción Cerebro/Plasma Proporción Cerebro/Hígado
- Compuesto III
- 1 12,3 9,6 0,8 0,1
- 5
- 1,3 <LLQ (3,7 nM) NQ NQ
- 7
- 1,2 <LLQ (3,7 nM) NQ NQ
- 24
- <LLQ (0,2 nM) <LLQ (3,7 nM) NQ NQ
- Epotilona D
- 1 15,1 10,6 0,7 0,4
- 3
- 3,9 7,0 1,8 1,3
- 4
- 2,5 9,9 4,0 3,4
- 8
- 1,4 6,4 4,6 1,8
- 13
- 0,1 6,3 47,3 5,1
- 24
- 0,2 9,1 44,5 8,0
- 48
- <LLQ (0,1 nM) 5,4 NQ NQ
- 96
- <LLQ (0,1 nM) 3 NQ NQ
TABLA 5
- Compuesto
- Tiempo (hr) Conc. en plasma (nM) Conc. en cerebro (nM) Proporción Cerebro/Plasma Proporción Cerebro/Hígado
- Compuesto III
- 1 47,7 67,7 2,3 0,4
- 5
- 3,0 4,6 1,4 NQ
- 24
- 0,7 <LLQ NQ NQ
- Epotilona D
- 1 52,7 61,3 1,1 0,5
- 5
- 3,6 76,9 25,2 11,3
- 24
- <LLQ (0,5 nM) 118 NQ 18,7
5
Como se puede observar, para el Compuesto III, los niveles de tejidos de las últimas veces (es decir, después de 1 hora o más) muestran que los niveles de Compuesto III disminuyeron rápidamente en el tejido cerebral. Así, el Compuesto III tiene retención cerebral baja según se observó en la carencia de niveles cerebrales medibles a 24 horas en ambos experimentos. La dosificación oral con epotilona D reveló proporciones de cerebro frente a plasma 10 de 0,7 y 1,1 a 1 hora, reflejando buena penetración cerebral. A diferencia del Compuesto III, los niveles cerebrales de epotilona D se mantuvieron durante más de 24 horas (tablas 2, 4 y 5, figuras 9-10). La proporción cerebro frente a hígado para dosificación oral de epotilona D indica que la epotilona D está retenida selectivamente en el cerebro,
31
Claims (1)
-
imagen1
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US4772908P | 2008-04-24 | 2008-04-24 | |
| US47729 | 2008-04-24 | ||
| PCT/US2009/041634 WO2009132253A1 (en) | 2008-04-24 | 2009-04-24 | Use of epothelone d in treating tau-associated diseases including alzheimer's disease |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2501565T3 true ES2501565T3 (es) | 2014-10-02 |
Family
ID=40887113
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES09735906.1T Active ES2501565T3 (es) | 2008-04-24 | 2009-04-24 | Uso de epotilona D en el tratamiento de enfermedades asociadas a Tau incluyendo enfermedad de Alzheimer |
Country Status (25)
| Country | Link |
|---|---|
| US (3) | US20090270465A1 (es) |
| EP (1) | EP2276485B1 (es) |
| JP (1) | JP5548675B2 (es) |
| KR (1) | KR20100137576A (es) |
| CN (3) | CN104116736A (es) |
| AR (1) | AR071598A1 (es) |
| AU (1) | AU2009240538B2 (es) |
| BR (1) | BRPI0911482A2 (es) |
| CA (1) | CA2722371C (es) |
| CL (1) | CL2009000990A1 (es) |
| CY (1) | CY1115617T1 (es) |
| DK (1) | DK2276485T3 (es) |
| EA (1) | EA021758B1 (es) |
| ES (1) | ES2501565T3 (es) |
| HR (1) | HRP20140783T1 (es) |
| HU (1) | HUE024506T2 (es) |
| IL (1) | IL208926A0 (es) |
| MX (1) | MX2010011209A (es) |
| NZ (1) | NZ588555A (es) |
| PL (1) | PL2276485T3 (es) |
| PT (1) | PT2276485E (es) |
| SI (1) | SI2276485T1 (es) |
| TW (1) | TWI472329B (es) |
| WO (1) | WO2009132253A1 (es) |
| ZA (1) | ZA201007460B (es) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10022352B2 (en) | 2006-04-07 | 2018-07-17 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
| NZ571803A (en) | 2006-04-07 | 2011-12-22 | Vertex Pharma | Amide indole derivatives as modulators of ATP-binding cassette transporters |
| US7645789B2 (en) | 2006-04-07 | 2010-01-12 | Vertex Pharmaceuticals Incorporated | Indole derivatives as CFTR modulators |
| USRE50453E1 (en) | 2006-04-07 | 2025-06-10 | Vertex Pharmaceuticals Incorporated | Indole derivatives as CFTR modulators |
| US8563573B2 (en) | 2007-11-02 | 2013-10-22 | Vertex Pharmaceuticals Incorporated | Azaindole derivatives as CFTR modulators |
| EP2155197A4 (en) * | 2007-03-09 | 2011-10-12 | Link Medicine Corp | TREATMENT OF LYSOSOMAL STORAGE DISEASES |
| WO2009151683A2 (en) | 2008-03-12 | 2009-12-17 | Link Medicine Corporation | Quinolinone farnesyl transferase inhibitors for the treatment of synucleinopathies and other indications |
| MX2010011209A (es) | 2008-04-24 | 2010-11-12 | Squibb Bristol Myers Co | Uso de epotilona d en el tratamiento de enfermedades asociadas a tau incluyendo enfermedad de alzheimer. |
| US20110294794A1 (en) * | 2008-11-13 | 2011-12-01 | Link Medicine Corporation | Treatment of proteinopathies using a farnesyl transferase inhibitor |
| NZ593090A (en) | 2008-11-13 | 2013-06-28 | Link Medicine Corp | Azaquinolinone derivatives and uses thereof |
| US8802868B2 (en) | 2010-03-25 | 2014-08-12 | Vertex Pharmaceuticals Incorporated | Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxo1-5-yl)-N-(1-(2,3-dihydroxypropyl-6-fluoro-2-(1-hydroxy-2-methylpropan2-yl)-1H-Indol-5-yl)-Cyclopropanecarboxamide |
| ES2608474T3 (es) | 2010-04-22 | 2017-04-11 | Vertex Pharmaceuticals Incorporated | Proceso de producción de compuestos indol cycloalkylcarboxamido |
| US8563593B2 (en) * | 2010-06-08 | 2013-10-22 | Vertex Pharmaceuticals Incorporated | Formulations of (R)-1-(2,2-difluorobenzo[D] [1,3] dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide |
| WO2013115965A1 (en) * | 2012-01-31 | 2013-08-08 | Cerulean Pharma Inc. | Polymer-agent conjugates, particles, compositions, and related methods of use |
| SG10201708959WA (en) | 2012-07-03 | 2017-11-29 | Univ Washington | Antibodies to tau |
| WO2014014841A1 (en) | 2012-07-16 | 2014-01-23 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions of (r)-1-(2,2-diflurorbenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl) cyclopropanecarboxamide and administration thereof |
| ES2885181T3 (es) | 2014-04-15 | 2021-12-13 | Vertex Pharma | Composiciones farmacéuticas para el tratamiento de enfermedades mediadas por el regulador de la conductancia transmembrana de fibrosis quística |
| TWI734975B (zh) | 2014-06-27 | 2021-08-01 | 美商Ｃ２Ｎ醫療診斷有限責任公司 | 人類化抗-tau抗體 |
| JP6321521B2 (ja) | 2014-11-04 | 2018-05-09 | Ｗｅｌｌ Ｓｔｏｎｅ 有限会社 | タウ蛋白産生促進剤、タウ蛋白の欠乏に起因する疾患の治療薬・予防薬および治療用・予防用食品組成物 |
| BR112019000098A2 (pt) | 2016-07-14 | 2019-04-09 | Bioarctic Ab | proteína de fornecimento ao cérebro, método de tratamento e/ou profilaxia de distúrbios cerebrais em mamíferos que possuem ou encontram-se em risco de desenvolver o mencionado distúrbio e método de diagnóstico e/ou detecção de distúrbios cerebrais em mamíferos suspeitos de possuir ou que se encontram em risco de desenvolver o mencionado distúrbio |
| KR102927138B1 (ko) * | 2020-09-02 | 2026-02-12 | 베이징 바이오스타 파마슈티컬스 씨오., 엘티디. | 우티델론의 고체 경구용 제제 |
| CN113005086B (zh) * | 2021-02-01 | 2022-10-28 | 中国科学院遗传与发育生物学研究所 | 埃博霉素D和Apol8在调控神经干细胞定向神经元分化中的应用 |
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