ES2521519T9 - Tratamiento de fenómenos fantasma - Google Patents

Tratamiento de fenómenos fantasma Download PDF

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Publication number
ES2521519T9
ES2521519T9 ES10158404.3T ES10158404T ES2521519T9 ES 2521519 T9 ES2521519 T9 ES 2521519T9 ES 10158404 T ES10158404 T ES 10158404T ES 2521519 T9 ES2521519 T9 ES 2521519T9
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bdnf
signal transduction
transduction cascade
phantom
antagonist
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ES10158404.3T
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ES2521519T3 (es
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Dr. Marlies Knipper
Dr. Lukas Rüttiger
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Otolanum AG
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Otolanum AG
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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
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • 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
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • 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
    • A61K9/0046—Ear
    • 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
    • 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
    • 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
    • A61P27/16—Otologicals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Description

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E10158404
26-03-2015
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(figura 5A, izquierda), del exón III de BDNF (figura 5B, izquierda) y del exón IV de BDNF (figura 5C, izquierda).
Mientras que en la cóclea se detectaron distintos patrones de activación con dosificaciones diferentes y productos de transcripción de BDNF diferentes, el efecto de disminución en caso de concentraciones superiores no era tan claro en la corteza auditiva (figuras 5A-C). Mediante análisis densitométrico se confirmó que se produce una disminución significativa de la expresión del exón IV de BDNF (49  12%, n = 8, p < 0,05) y de c-fos (69  11%, n = 8, p < 0,05).
Los inventores han examinado en otro experimento si el fenómeno del aumento de la expresión del BDNF detectado por primera vez en el tinnitus agudo se puede eliminar utilizando israpidina, un antagonista del canal de Ca++ de tipo L, el cual influye sobre el receptor BDNF de la cascada de transducción de señales conectada en serie.
Para ello, 22 horas antes de la toma del tejido se administraron 10 µl de una solución de cloruro sódico al 0,9% (figura 6A, solución salina) y 10 µl de una solución de israpidina 10 mM (figura 6B, israpidina) localmente en el nicho de la ventana redonda, es decir, delante de la membrana de la ventana redonda. Tres horas antes de la toma de tejido de la cóclea se inyectó sistémicamente un volumen idéntico de la solución de cloruro sódico (C) o 350 mg de salicilato por kg de peso corporal (Scy). Después de la toma del tejido se analizó la expresión de BDNF en los dos ensayos.
En la figura 6 se muestra la expresión del exón IV de BDNF bajo las condiciones arriba mencionadas. Como ya se ha indicado, el salicilato produce un aumento de la expresión del BDNF en las neuronas cocleares (figura 6A, pista derecha), mientras que dicho aumento de la expresión del BDNF se inhibe en el ensayo realizado idénticamente en el grupo de animales a los que se les había administrado isradipina en lugar de cloruro sódico.
El experimento anteriormente descrito y representado en la figura 6 también se llevó a cabo bajo condiciones idénticas con un antagonista del canal de Ca++ de tipo L: nifedipina. En este caso también se detectó un efecto inhibidor del aumento de la expresión del BDNF en las neuronas cocleares después de la inducción del tinnitus agudo, aunque menos intenso que en el caso de la israpidina (datos no mostrados).
Los inventores también han investigado si el aumento de la expresión del BDNF que acompaña al tinnitus agudo se puede inhibir mediante la administración de agonistas del receptor GABA, el cual interactúa en serie con la cascada de transducción de señales, tales como benzodiazepinas. Como ya se ha descrito anteriormente, a ratas hembra se les administraron cantidades crecientes de salicilato (Scy) localmente en el nicho de la ventana redonda. Como ya se esperaba por los experimentos arriba descritos, se observó un aumento de la expresión del producto de transcripción del exón IV de BDNF en las neuronas cocleares y una disminución de la expresión de la proteína citoesquelética dependiente de la actividad Arc en la corteza auditiva. La figura 7A muestra el resultado de una RT-PCR representativa para n = 3 con resultados comparables.
En otro ensayo experimental, a las ratas se les administraron sistémicamente 350 mg/kg de salicilato. Como muestra la figura 7A en relación con la administración local en la ventana redonda, la administración sistémica de salicilato también conduce a un aumento de la expresión del exón IV de BDNF (figura 7B, arriba) y, conforme a lo esperado, del c-fos (figura 7C, arriba) en las neuronas cocleares, mientras que en la corteza auditiva primaria se puede observar una disminución de la expresión de Arc (figura 7B, abajo) y del exón IV de BDNF (no mostrado) y ocasionalmente del c-fos (figura 7C, abajo).
Dos horas y media después de la inducción del tinnitus agudo por la inyección de 350 mg/kg de salicilato, los animales recibieron una administración sistémica de midazolam (Dormicum, Roche, Grenzach-Wyhlen, Alemania) (0,5 mg/kg de peso corporal) y después de la extracción del órgano se analizó la expresión génica con ayuda de una RT-PCR. Se comprobó que el midazolam (MDZ) conduce a una reducción significativa del efecto del salicilato en la expresión del exón IV de BDNF (n = 7) en las neuronas cocleares y de Arc en la corteza auditiva (figura 7B, barra derecha, n = 12), pero la expresión de c-fos permanece inalterable (figura 7C, barra derecha, n = 7 a 12). La evaluación estadística se llevó a cabo mediante un Test-T de Student; * = p < 0,05.
En otro experimento, correspondiente al anterior, se administró un agonista del receptor GABA pero no sistémicamente, sino localmente en el nicho de la ventana redonda, bajo condiciones por lo demás idénticas. En este experimento se comprobó que el aumento de la expresión del exón IV de BDNF en las neuronas cocleares relacionado con el tinnitus agudo se inhibía de forma todavía más intensa y que los efectos en la expresión del exón IV de BDNF en la corteza auditiva se reducían claramente.
Por consiguiente, la administración local de un antagonista de BDNF elimina la regulación errónea patológica de la expresión del BDNF en el caso del tinnitus agudo. Por consiguiente, los inventores han podido
E10158404
26-03-2015
demostrar que los antagonistas de BDNF según la invención son sustancias que en principio son adecuadas para el tratamiento del tinnitus agudo.
Los inventores han podido demostrar por primera vez que el tinnitus agudo se puede tratar eficazmente con sustancias que bloquean o inhiben los receptores BDNF o que interactúan aguas abajo con la cascada de transducción de señales del BDNF o que la inhiben.

Claims (1)

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ES10158404.3T 2005-01-25 2006-01-19 Tratamiento de fenómenos fantasma Active ES2521519T3 (es)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005004343A DE102005004343A1 (de) 2005-01-25 2005-01-25 Behandlung von Phantomphänomenen
DE102005004343 2005-01-25

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ES2521519T3 ES2521519T3 (es) 2014-11-12
ES2521519T9 true ES2521519T9 (es) 2015-04-07

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US (4) US20080255096A1 (es)
EP (2) EP2196199B9 (es)
AT (1) ATE462422T1 (es)
CY (1) CY1115638T1 (es)
DE (2) DE102005004343A1 (es)
DK (2) DK1843757T3 (es)
ES (2) ES2343691T3 (es)
PL (2) PL2196199T3 (es)
PT (2) PT2196199E (es)
SI (2) SI1843757T1 (es)
WO (1) WO2006079476A1 (es)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
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DE102007063210A1 (de) 2007-12-20 2009-06-25 Eberhard-Karls-Universität Tübingen Universitätsklinikum Arzneimittel zur Behandlung von Phantomphänomenen
ES2862673T3 (es) 2011-12-12 2021-10-07 Zilentin AG Tratamiento del tinnitus mediante la modulación del cotransportador de cloruro NKCC1 en el sistema auditivo
US10066229B2 (en) * 2015-07-28 2018-09-04 Otonomy, Inc. Treatment using truncated Trk B and Trk C antagonists
US10071083B2 (en) 2017-02-03 2018-09-11 Ovid Therapeutics Inc Use of gaboxadol in the treatment of tinnitus
GB2571696B (en) 2017-10-09 2020-05-27 Compass Pathways Ltd Large scale method for the preparation of Psilocybin and formulations of Psilocybin so produced
US10765666B2 (en) 2018-09-20 2020-09-08 Ovid Therapeutics Inc Use of gaboxadol for the treatment of Tourette syndrome, tics and stuttering
US11690829B2 (en) 2018-12-17 2023-07-04 Ovid Therapeutics Inc. Use of gaboxadol for the treatment of non-24 hour sleep-wake disorder
WO2020212948A1 (en) 2019-04-17 2020-10-22 Compass Pathfinder Limited Methods of treating neurocognitive disorders, chronic pain and reducing inflammation

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Publication number Publication date
CY1115638T1 (el) 2017-01-04
DE102005004343A1 (de) 2006-08-10
EP1843757B1 (de) 2010-03-31
PT2196199E (pt) 2014-09-09
US20120302554A1 (en) 2012-11-29
SI1843757T1 (sl) 2010-09-30
WO2006079476A1 (de) 2006-08-03
DE502006006576D1 (de) 2010-05-12
EP2196199B1 (de) 2014-08-13
ATE462422T1 (de) 2010-04-15
EP1843757A1 (de) 2007-10-17
DK2196199T3 (da) 2014-11-03
DK1843757T3 (da) 2010-07-26
EP2196199B8 (de) 2014-09-24
US20150099742A1 (en) 2015-04-09
PT1843757E (pt) 2010-07-06
ES2343691T3 (es) 2010-08-06
EP2196199B9 (de) 2014-12-31
SI2196199T1 (sl) 2014-12-31
US20170072007A1 (en) 2017-03-16
PL2196199T3 (pl) 2015-01-30
EP2196199A1 (de) 2010-06-16
ES2521519T3 (es) 2014-11-12
PL1843757T3 (pl) 2010-09-30
US20080255096A1 (en) 2008-10-16

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