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WO2005049042A1 - Combinaisons comprenant des antagonistes du recepteur ampa, utilisees dans le traitement du tinnitus - Google Patents

Combinaisons comprenant des antagonistes du recepteur ampa, utilisees dans le traitement du tinnitus Download PDF

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Publication number
WO2005049042A1
WO2005049042A1 PCT/EP2004/012263 EP2004012263W WO2005049042A1 WO 2005049042 A1 WO2005049042 A1 WO 2005049042A1 EP 2004012263 W EP2004012263 W EP 2004012263W WO 2005049042 A1 WO2005049042 A1 WO 2005049042A1
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WO
WIPO (PCT)
Prior art keywords
tinnitus
aliphatic
combination according
treatment
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2004/012263
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English (en)
Inventor
Kurt LINGENHÖHL
Silvio Ofner
Mary Ann Karolchyk
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis Pharma GmbH Austria
Novartis AG
Original Assignee
Novartis Pharma GmbH Austria
Novartis AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis Pharma GmbH Austria, Novartis AG filed Critical Novartis Pharma GmbH Austria
Publication of WO2005049042A1 publication Critical patent/WO2005049042A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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

Definitions

  • the present invention relates to combinations suitable for the treatment of neurological disorders, in particular tinnitus.
  • Tinnitus is the medical term for roaring, buzzing, clicking, whistling, hissing, or high pitched ringing in the ears or inside the head. Tinnitus may be constant or occur intermittently in one or both ears. Although there are many theories about how tinnitus occurs, there is no scientific consensus to its origin. Some causes of tinnitus result from a blow to the head, large doses of aspirin, anemia, noise exposure, stress, impacted wax, hypertension and certain types of medications and tumors.
  • the effect of a combination which comprises at least one AMPA receptor antagonist and at least one compound selected from the group consisting of anti-anxiety drugs, antidepressants, antihistamines, anticonvulsants, vasodilators, zinc salts and anesthetics is greater than the additive effect of the combined drugs.
  • the combinations disclosed herein can be used to treat tinnitus which is refractory to monotherapy employing one of the combination partners alone.
  • the invention relates to a combination, such as a combined preparation or pharmaceutical composition, which comprises at least one AMPA receptor antagonist and at least one compound selected from the group consisting of anti-anxiety drugs, antidepressants, antihistamines, anticonvulsants, vasodilators, zinc salts and anesthetics, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.
  • a combination such as a combined preparation or pharmaceutical composition, which comprises at least one AMPA receptor antagonist and at least one compound selected from the group consisting of anti-anxiety drugs, antidepressants, antihistamines, anticonvulsants, vasodilators, zinc salts and anesthetics, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.
  • AMPA receptor antagonists as used herein includes, but is not limited to the quinoxaline-dione aminoalkylphosphonates of formula I
  • R-i represents hydroxy or an aliphatic, aryl aliphatic or aromatic group
  • X represents an aliphatic, cycloaliphatic, cycloaliphatic aliphatic, aryl aliphatic, heteroaryl aliphatic or aromatic group
  • R 2 represents hydrogen or an aliphatic or aryl aliphatic group, alk stands for C1-C7alkylene, and
  • R 3 , R and R 5 represent independently of each other hydrogen, C1-C7alkyl, halogen, trifluoromethyl, cyano or nitro, and wherein the radicals have the meanings as defined in WO 98/17672.
  • AMPA receptor antagonists include also, EGIS 8332 (7-acetyl-5-(4-aminophenyl)-8,9- dihydro-8-methyl-7H-1 ,3-dioxolo[4,5-h][2,3]benzodiazepine-8-carbonitrile), GYKI 47261 (4- (7-chloro-2-methyl-4H-3,1O,10a-triaza-benzo[f]azulen-9-yl)-phenylamine), irampanel (BUR 561; N,N-dimethyl-2-[2-(3-phenyl-1 ,2,4-oxadiazol-5-yl)phenoxy]ethanamine), KRP 199 (7-[4- [[[[[(4-carboxyphenyl)-amino]carbonyl]oxy]methyl]-1H-imidazoI-1-yl]-3,4-dihydro-3-oxo-6- (trifluoromethyl)-2-quinoxalinecarboxy
  • YM90K (6-imidazol-1-yl-7-nitro-1,4- dihydro-quinoxaline-2,3-dione), S-34730 (7-chloro-6-sulfamoyl-2-(1 H)-quinolinone-3- phosphonic acid), Zonampanel (YM-872; (7-imidazol-1-yl-6-nitro-2,3-dioxo-3,4-dihydro-2H- quinoxalin-1-yl)-acetic acid), GYKI-52466 (4-(8-methyl-9H-1,3-dioxa-6,7-diaza- cyclohepta[f]inden-5-yl)-phenylamine), ZK-200775 (MPQX, (7-morpholin-4-yl-2,3-dioxo-6- trifluoromethyl-3,4-dihydro-2H-quinoxalin-1-ylmethyl)-phosphonic acid), CP-4650
  • anti-anxiety drug includes, but is not limited to alprazolam.
  • antitriptyline N- methyl-3-(10, 11 -dihydro-5H-dibenzo[a,d]cyclohepten-5-yliden)propylamine.
  • anticonvulsants includes, but is not limited to oxcarbazepine.
  • vasodilators as used herein includes, but is not limited to pentoxifylline.
  • zinc salts as used herein includes, but is not limited to zinc sulfate.
  • Topiramate can be administered, e.g., in the form as marketed, e.g. under the trademark TopamaxTM.
  • the compounds of formula I as well as their production process and pharmaceutical compositions thereof are known, e.g., from WO 98/17672.
  • Alprazolam can be administered, e.g., in the form as marketed, e.g. under the trademark XanaxTM.
  • Nortriptyline can be administered, e.g., in the form as marketed, e.g. under the trademark NortrilenTM.
  • Oxcarbazepine can be administered, e.g., in the form as marketed, e.g. under the trademark TrileptalTM.
  • Lidocaine can be administered in the form of its hydrochloride, e.g., in the form as marketed as injection solution, e.g. under the trademark HeweneuralTM.
  • zinc sulfate can be administered, e.g., in the form as marketed, e.g. under the trademark Zink-SandozTM.
  • Pentoxifyllin can be administered, e.g., in the form as marketed, e.g. under the trademark TrentalTM.
  • a combined preparation defines especially a "kit of parts" in the sense that the first and second active ingredient as defined above can be dosed independently or by use of different fixed combinations with distinguished amounts of the ingredients, i.e., simultaneously or at different time points.
  • the parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • the time intervals are chosen such that the effect on the treated disease in the combined use of the parts is larger than the effect which would be obtained by use of only any one of the active ingredients.
  • the ratio of the total amounts of the active ingredient 1 to the active ingredient 2 to be administered in the combined preparation can be varied, e.g., in order to cope with the needs of a patient sub-population to be treated or the needs of the single patient which different needs can be due to age, sex, body weight, etc. of the patients.
  • there is at least one beneficial effect e.g., a mutual enhancing of the effect of the first and second active ingredient, in particular a synergism, e.g. a more than additive effect, additional advantageous effects, less side effects, a combined therapeutically effect in a non-effective dosage of one or both of the first and second active ingredient, and especially a strong synergism the first and second active ingredient.
  • references to the active ingredients are meant to also include the pharmaceutically acceptable salts. If these active ingredients have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center.
  • the active ingredients having an acid group (for example COOH) can also form salts with bases.
  • the active ingredient or a pharmaceutically acceptable salt thereof may also be used in form of a hydrate or include other solvents used for crystallization.
  • a pharmaceutical combination which comprises at least one AMPA receptor antagonist and at least one compound selected from the group consisting of anti-anxiety drugs, antidepressants, antihistamines, anticonvulsants, vasodilators, zinc salts and anesthetics, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, if at least one salt-forming group is present, will be referred to hereinafter as a COMBINATION OF THE INVENTION.
  • the pharmacological activity of a COMBINATION OF THE INVENTION may, for example, be evidenced in preclinical studies known as such, e.g., the methods described herein.
  • the activity in tinnitus of the COMBINATION OF THE INVENTION can be shown in standard tests, e.g. in the salicylate-induced tinnitus model.
  • the pharmacological activity of a COMBINATION OF THE INVENTION may, for example, be demonstrated in a clinical study.
  • Such clinical studies are preferably randomized, double-blind, clinical studies in patients with tinnitus.
  • Such studies demonstrate, in particular, the synergism of the active ingredients of the COMBINATIONS OF THE INVENTION.
  • the studies are, in particular, suitable to compare the effects of a monotherapy using the active ingredients and a COMBINATION OF THE INVENTION.
  • a further benefit is that lower doses of the active ingredients of the COMBINATION OF THE INVENTION can be used, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side effects. This is in accordance with the desires and requirements of the patients to be treated.
  • the COMBINATIONS OF THE INVENTION can be used, in particular, for the treatment of tinnitus which is refractory to monotherapy.
  • the AMPA receptor antagonists used in the present invention are competitive AMPA receptor antagonists.
  • the COMBINATION OF THE INVENTION comprises an AMPA receptor antagonist, which is a quinoxalinedione aminoalkylphosphonate, in particular a quinoxalinedione aminoalkylphosphonate of formula I
  • Ri represents hydroxy or an aliphatic, aryl aliphatic or aromatic group
  • X represents an aliphatic, cycloaliphatic, cycloaliphatic aliphatic, aryl aliphatic, heteroaryl aliphatic or aromatic group
  • R 2 represents hydrogen or an aliphatic or aryl aliphatic group, alk stands for C1-C7alkylene, and
  • R 3 , R and R 5 represent independently of each other hydrogen, C1-C7alkyl, halogen, trifluoromethyl, cyano or nitro, and wherein the radicals have the meanings as defined in WO 98/17672.
  • the COMBINATION OF THE INVENTION comprises an AMPA receptor antagonist which is a compound of formula I, wherein R-i represents hydroxyl, X represents methylene, R 2 represents hydrogen, alk stands for methylene, R 3 and R 5 represent hydrogen, and R-t represents nitro or a salt thereof, i.e. is ⁇ [(7-Nitro-2,3-dioxo-1 ,2,3,4- tetrahydro-quinoxalin-5-ylmethyl)-amino]-methyl ⁇ -phosphonic acid or a salt thereof (cf. WO 97/08155, Example 57, 1st entry, and WO 98/17672, Example 12, 4th entry).
  • the AMPA receptor antagonists is selected from EGIS 8332 (7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1 ,3- dioxolo[4,5-h][2,3]benzodiazepine-8-carbonitrile), GYKI 47261 4-(7-chloro-2-methyl- 4H-3,10,10a-triaza-benzo[f]azulen-9-yl)-phenylamine), irampanel (BUR 561 ; N,N- dimethyl-2-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy]ethanamine), KRP 199 (7-[4- [[[[[(4-carboxyphenyl)-amino]carbonyl]oxy]methyl]-1 H-imidazol-1 -yl]-3,4-dihydro-3-oxo- 6-(trifluoromethyl)-2-
  • YM90K (6-imidazol-1-yl-7-nitro-1 ,4-dihydro-quinoxaline-2,3-dione), S-34730 (7-chloro-6-sulfamoyl-2-(1H)-quinolinone-3-phosphonic acid), Zonampanel (YM-872; (7-imidazol-1-yl-6-nitro-2,3-dioxo-3,4-dihydro-2H-quinoxalin-1-yl)-acetic acid), GYKI- 52466 (4-(8-methyl-9H-1 ,3-dioxa-6,7-diaza-cyclohepta[f]inden-5-yl)-phenylamine), ZK- 200775 (MPQX, (7-morpholin-4-yl-2,3-dioxo-6-trifluoromethyl-3,4-dihydro-2H- quinoxalin-1-ylmethyl)-phosphonic acid), CP
  • It is one objective of this invention to provide a pharmaceutical composition comprising a quantity, which is jointly therapeutically effective against tinnitus, comprising at least one AMPA antagonist and at least one compound selected from the group consisting of anti- anxiety drugs, antidepressants, antihistamines, anticonvulsants, vasodilators, zinc salts and anesthetics, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier.
  • the first and second active ingredient can be administered together, one after the other or separately in one combined unit dosage form or in two separate unit dosage forms.
  • the unit dosage form may also be a fixed combination.
  • compositions according to the invention can be prepared in a manner known per se and are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals (warm-blooded animals), including man, comprising a therapeutically effective amount of at least one pharmacologically active ingredient, alone or in combination with one or more pharmaceutically acceptable carries, especially suitable for enteral or parenteral application or local application into the ear showing the tinnitus.
  • enteral such as oral or rectal
  • parenteral administration to mammals warm-blooded animals
  • mammals warm-blooded animals
  • the preferred route of administration of the dosage forms of the present invention is orally.
  • the novel pharmaceutical composition contain, for example, from about 10 % to about 100 %, preferably from about 20 % to about 60 %, of the active ingredients.
  • Pharmaceutical preparations for the combination therapy for enteral or parenteral administration are, for . example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, and furthermore ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar- coating, dissolving or lyophilizing processes. It will be appreciated that the unit content of active ingredient or ingredients contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount can be reached by administration of a plurality of dosage units.
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils or alcohols; or carriers such as starches, sugars, microcristalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed.
  • Unit dosage forms may contain, for example, from about 2.5 mg to about 500 mg of the active ingredients.
  • the present invention relates to the use of a COMBINATION OF THE INVENTION for the preparation of a medicament for the treatment of tinnitus.
  • the present invention provides a method of treating a warm-blooded animal having tinnitus_comprising administering to the animal a COMBINATION OF THE INVENTION in a quantity which is jointly therapeutically effective against tinnitus_and in which the compounds can also be present in the form of their pharmaceutically acceptable salts.
  • the present invention provides a commercial package comprising as active ingredients COMBINATION OF THE INVENTION, together with instructions for simultaneous, separate or sequential use thereof in the treatment of tinnitus.
  • a therapeutically effective amount of each of the active ingredients of the COMBINATION OF THE INVENTION may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination.
  • the method of treatment of tinnitus according to the invention may comprise (i) administration of the first active ingredient in free or pharmaceutically acceptable salt form and (ii) administration of the second active ingredient in free or pharmaceutically acceptable salt form, simultaneously or sequentially in any order, in jointly therapeutically effective amounts, preferably in synergistically effective amounts, e.g. in daily dosages corresponding to the amounts described herein.
  • the individual active ingredients of the COMBINATION OF THE INVENTION can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • administering also encompasses the use of a pro-drug of an active ingredient that convert in vivo to the active ingredient.
  • the instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
  • the COMBINATION OF THE INVENTION is used for the treatment of treatment of tinnitus which is refractory to monotherapy.
  • the effective dosage of each of the active ingredients employed in the COMBINATION OF THE INVENTION may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the severity of the condition being treated.
  • the dosage regimen the COMBINATION OF THE INVENTION is selected in accordance with a variety of factors including the route of administration and the renal and hepatic function of the patient.
  • a physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the single active ingredients required to prevent, counter or arrest the progress of the condition.
  • Optimal precision in achieving concentration of the active ingredients within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the active ingredients' availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of the active ingredients.
  • Topiramate may be administered to an adult patient in a total daily dosage of between about 250 to about 500 mg.
  • ⁇ [(7-Nitro-2,3-dioxo-1 ,2,3,4-tetrahydro-quinoxalin-5-ylmethyl)-amino]-methyl ⁇ -phosphonic acid may be administered to a patient in a total daily dosage of about 60 to about 400 mg.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des combinaisons appropriées pour traiter des troubles neurologiques, notamment le tinnitus. Lesdites combinaisons comprennent au moins un antagoniste du récepteur AMPA et au moins un composé sélectionné dans le groupe comprenant des médicaments anxiolytiques, des antidépresseurs, des antihistaminiques, des anticonvulsifs, des vasodilatateurs, des sels de zinc et des anesthésiques.
PCT/EP2004/012263 2003-10-30 2004-10-29 Combinaisons comprenant des antagonistes du recepteur ampa, utilisees dans le traitement du tinnitus Ceased WO2005049042A1 (fr)

Applications Claiming Priority (2)

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GB0325390.3 2003-10-30
GBGB0325390.3A GB0325390D0 (en) 2003-10-30 2003-10-30 Organic compounds

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WO2005049042A1 true WO2005049042A1 (fr) 2005-06-02

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PCT/EP2004/012263 Ceased WO2005049042A1 (fr) 2003-10-30 2004-10-29 Combinaisons comprenant des antagonistes du recepteur ampa, utilisees dans le traitement du tinnitus

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020086149A1 (fr) 2018-10-26 2020-04-30 University Of South Florida Médicament pour le traitement de l'acouphène

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998017672A1 (fr) * 1996-10-24 1998-04-30 Novartis Ag Acides aminoalcanophosphoniques substitues
WO1998038173A1 (fr) * 1997-02-28 1998-09-03 Pfizer Products Inc. Atropisomeres de 3-aryl-4(3h)-quinazolinones et leur utilisation comme antagonistes des recepteurs de l'ampa
WO2003092701A2 (fr) * 2002-04-30 2003-11-13 Novartis Ag Utilisation d'acides amino-alcane-phosphoniques substitués

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998017672A1 (fr) * 1996-10-24 1998-04-30 Novartis Ag Acides aminoalcanophosphoniques substitues
WO1998038173A1 (fr) * 1997-02-28 1998-09-03 Pfizer Products Inc. Atropisomeres de 3-aryl-4(3h)-quinazolinones et leur utilisation comme antagonistes des recepteurs de l'ampa
WO2003092701A2 (fr) * 2002-04-30 2003-11-13 Novartis Ag Utilisation d'acides amino-alcane-phosphoniques substitués

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DENK D M ET AL: "Caroverine in tinnitus treatment. A placebo-controlled blind study.", ACTA OTO-LARYNGOLOGICA. NOV 1997, vol. 117, no. 6, November 1997 (1997-11-01), pages 825 - 830, XP009043354, ISSN: 0001-6489 *
SANCHEZ T G ET AL: "An evaluation of tinnitus treatment", EXPERT OPINION ON THERAPEUTIC PATENTS 2000 UNITED KINGDOM, vol. 10, no. 12, 2000, pages 1911 - 1917, XP002316994, ISSN: 1354-3776 *
SEIDMAN M D ET AL: "Alternative medications and other treatments for tinnitus: Facts from fiction", OTOLARYNGOLOGIC CLINICS OF NORTH AMERICA 2003 UNITED STATES, vol. 36, no. 2, 2003, pages 359 - 381, XP009043380, ISSN: 0030-6665 *
SEIDMAN M D: "Glutamate antagonists, steroids, and antioxidants as therapeutic options for hearing loss and tinnitus and the use of an innear ear drug delivery system", INTERNATIONAL TINNITUS JOURNAL 1998 UNITED STATES, vol. 4, no. 2, 1998, pages 148 - 154, XP009043381, ISSN: 0946-5448 *
SIMPSON J J ET AL: "Recent advances in the pharmacological treatment of tinnitus", TRENDS IN PHARMACOLOGICAL SCIENCES, ELSEVIER TRENDS JOURNAL, CAMBRIDGE, GB, vol. 20, no. 1, January 1999 (1999-01-01), pages 12 - 18, XP004156960, ISSN: 0165-6147 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020086149A1 (fr) 2018-10-26 2020-04-30 University Of South Florida Médicament pour le traitement de l'acouphène
EP3870159A4 (fr) * 2018-10-26 2022-08-17 University of South Florida Médicament pour le traitement de l'acouphène
US12194026B2 (en) 2018-10-26 2025-01-14 University Of South Florida Drug for treating tinnitus

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