Methods for the treatment of tinnitus induced by cochlear excitotoxicity

Abstract

The invention relates to methods for the prevention and/or treatment of tinnitus induced by cochlear excitotoxicity. In these methods, a pharmaceutical composition comprising an NMDA receptor antagonist is administered to an individual in need of such treatment by appropriate devices and/or formulations for local administration to the inner ear. The tinnitus to be prevented and/or treated may be provoked by acoustic trauma, presbycusis, ischemia, anoxia, treatment with one or more ototoxic medications, sudden deafness, or other cochlear excitotoxic-inducing occurrence. The invention also relates to method for the identification of compounds effective in the treatment and prevention of tinnitus by a novel screening method incorporating an electrophysiological test method.

1 . A method for treating tinnitus induced by cochlear excitotoxicity in a human, the method comprising administering to a human a therapeutically effective amount of a pharmaceutical composition comprising an NMDA receptor antagonist, effective to suppress or reduce NMDA receptor mediated aberrant activity of the auditory nerve in a human in need of such treatment.  
     
     
         2 . A method for preventing tinnitus induced by cochlear excitotoxicity in a human, the method comprising administering to a human a therapeutically effective amount of a pharmaceutical composition comprising an NMDA receptor antagonist, effective to prevent NMDA receptor mediated aberrant activity of the auditory nerve in a human in need of such treatment.  
     
     
         3 . The method of claims  1  or  2  wherein the NMDA receptor antagonist is selected from the group consisting of ketamine, 7-chlorokynurenate, D-AP5, MK 801 and gacyclidine.  
     
     
         4 . The method of claims  1  or  2  wherein the cochlear excitotoxicity is provoked by an occurrence selected from the group consisting of acoustic trauma, presbycusis, ischemia, anoxia, treatment with one or more ototoxic medications, and sudden deafness.  
     
     
         5 . The method of claims  1  or  2  wherein the pharmaceutical composition is administered topically via the round window membrane or the oval window membrane to the inner ear.  
     
     
         6 . The method of claims  1  or  2  wherein the pharmaceutical composition is administered topically by means of invasive drug delivery techniques to the inner ear.  
     
     
         7 . The method of  claim 4  wherein the cochlear excitotoxicity is characterized as acute.  
     
     
         8 . The method of  claim 4  wherein the cochlear excitotoxicity is characterized as repeated.  
     
     
         9 . The method of  claim 4  wherein the cochlear excitotoxicity is characterized as prolonged or chronic.  
     
     
         10 . An electrophysical method for identifying compounds effective in the treatment of tinnitus, said method comprising: 
 a) providing: i) an animal exhibiting tinnitus as is indicated by an ensemble spontaneous activity (ESA) with a spectral peak centered at about 200 to 250 Hz and ii) a test compound;    b) administering said test compound to said animal, and;    c) measuring the ESA of the animal to determine if tinnitus is reduced wherein the reduction of the spectral peak at about 200 to 250 Hz is indicative of whether tinnitus is reduced or eliminated.    
     
     
         11 . The method of  claim 10 , wherein said tinnitus is induced by exposure of the animal to acoustic trauma.  
     
     
         12 . The method of  claim 11 , wherein said acoustic trauma results in cochlear excitotoxicity.  
     
     
         13 . The method of  claim 12 , wherein said cochlear excitotoxicity is induced through exposure of the animal to a noise of sufficient intensity, frequency and duration to result in cochlear tinnitus.  
     
     
         14 . The method of  claim 10 , wherein said reduction in the spectral peak at about 200 to 250 Hz is compared in relation to the ear of an untreated animal exhibiting tinnitus.  
     
     
         15 . The method of  claim 10 , wherein said administration of said test compound comprises the application of the test compound to the round window membrane or inner ear.  
     
     
         16 . The method of  claim 14 , wherein said reduction in the spectral peak at about 200 to 250 Hz is compared in relation to an untreated ear exhibiting tinnitus on the same animal.  
     
     
         17 . The method of  claim 1 , wherein the test compound is an NMDA receptor antagonist.  
     
     
         18 . An electrophysical method for identifying compounds effective in the prevention of tinnitus, said method comprising: 
 a) providing: i) a test animal, ii) a control animal and iii) a test compound;    b) administering said test compound to said test animal, and;    c) exposing said test animal and said control animal to conditions capable of inducing tinnitus;    d) measuring the ESA of the test and control animals to determine if tinnitus is reduced wherein the reduction of the spectral peak at about 200 to 250 Hz of the test animal as compared to the control animal is indicative of the reduction of tinnitus.    
     
     
         19 . The method of  claim 18 , wherein said conditions capable of inducing tinnitus comprise exposing the animal to acoustic trauma.  
     
     
         20 . The method of  claim 19 , wherein said acoustic trauma results in cochlear excitotoxicity.  
     
     
         21 . The method of  claim 20 , wherein said cochlear excitotoxicity is induced through exposure of the animal to a noise of sufficient intensity, frequency and duration to result in cochlear tinnitus.