Medicament and method of diagnosis

Abstract

Disclosed is a diagnostic test to determine suitable therapeutic intervention of subjects suffering from subclinical Cushing's syndrome [SCS] and also agents that antagonise the action of cortisol or inhibit excess cortisol production in the treatment of conditions such as SCS in the presence of an adrenal incidentaloma.

1 . A pharmaceutical composition comprising: a glucocorticoid receptor antagonist, an inhibitor of adrenal steroidogenesis and a pharmaceutical excipient. 
     
     
         2 . A method of treating subclinical Cushing's syndrome in a subject comprising administering to the subject either (a) an effective amount of an agent that inhibits the synthesis or activity of cortisol; or (b) an effective amount of a glucocorticoid receptor antagonist and an inhibitor of adrenal steroidogenesis, thereby treating the subclinical Cushing's syndrome. 
     
     
         3 . A method of treating an adrenal incidentaloma in a subject comprising administering to the subject an effective amount of (a) an agent that inhibits the synthesis or activity of cortisol; or (b) an effective amount of a glucocorticoid receptor antagonist and an inhibitor of adrenal steroidogenesis, thereby treating the adrenal incidentaloma. 
     
     
         4 . A method to determine a suitable treatment regime for a subject suffering from or having a pre-disposition to subclinical Cushing's syndrome or adrenal incidentaloma, said method comprising:
 i) determining the level of cortisol in a sample from the subject and comparing said level to control cortisol levels as a measure of subclinical Cushing's syndrome;   ii) administering to the subject an effective amount of at least one agent that inhibits the synthesis or activity of cortisol; and   iii) analyzing the improvement of hypertension and/or glucose metabolism and/or osteoporosis in said subject as a measure of the response of the subject to the administration of the agent, to determine an improvement or not of the subject's condition and define a suitable treatment regime.   
     
     
         5 . The method according to  claim 4  wherein an improvement in the subject's condition indicates the subject can be treated by surgical intervention. 
     
     
         6 . The method according to  claim 4  wherein, if the subject's condition does not improve, the subject is administered an alternative treatment regimen comprising symptomatic treatment for hypertension and/or glucose metabolism impairment and/or osteoporosis. 
     
     
         7 . The method according to  claim 5  wherein said surgical intervention is adrenalectomy. 
     
     
         8 . The method according to  claim 4  wherein said agent is a glucocorticoid receptor antagonist. 
     
     
         9 . The method according to  claim 8  wherein said glucocorticoid receptor antagonist is selected from the group as illustrated in  FIG. 1 . 
     
     
         10 . The method according to  claim 8  wherein said glucocorticoid receptor antagonist is mifepristone. 
     
     
         11 . The method according to  claim 4  wherein said agent is a non-steroidal glucocorticoid receptor antagonist. 
     
     
         12 . The method according to  claim 11  wherein said non-steroidal glucocorticoid receptor antagonist is selected from the group consisting of: N-(2-[4,4′,441-trichlorotrityl]oxyethyl)morpholine; 1-(2[4,4′,4″-trichlorotrityl]oxyethyl)-4-(2-hydroxyethyl)piperazine dimaleate; N-([4,4′,4″]-trichlorotrityl)imidazole; 9-(3-mercapto-1,2,4-triazolyl)-9-phenyl-2,7-difluorofluorenone; 1-(2-chlorotrityl)-3,5-dimethylpyrazole; 4-(morpholinomethyl)-A-(2-pyridyl)benzhydrol; 5-(5-methoxy-2-(N-methylcarbamoyl)-phenyl)dibenzosuberol; N-(2-chlorotrityl)-L-prolinol acetate; 1-(2-chlorotrityl)-1,2,4-triazole; 1,S-bis(4,4′,4″-trichlorotrityl)-1,2,4-triazole-3-thiol; 4-α-S)-Benzyl-2(R)-chloroethynyl-1,2,3,4,4-α-9,10,10-α-(R)-octahydro-phenanthrene-2,7-diol (“CP 394531”), 4-α(S)-Benzyl-2(R)-prop-1-ynyl-1,2,3,4,4-α,9,10,10-α-(R)-octahydro-phenanthrene-2,7-diol (“CP-409069”), trans-(1R,2R)-3,4-dichloro-N-methyl-N-[2-1 pyrrolidinyl)cyclohexyl]benzeneacetamide, bremazocine, ethylketocyclazocine and naloxone. 
     
     
         13 . The method according to  claim 11  wherein said non-steroidal glucocorticoid antagonist is represented by formula I: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is H and R 2  is H or Cl, 
         or R 1  is o-chloro or m-chloro and R 2  is H. 
       
     
     
         14 . The method according to  claim 8  wherein said glucocorticoid receptor antagonist is an azadecalin. 
     
     
         15 . The method according to  claim 14  wherein said azadecalin antagonist is represented by formula II: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is F and R 2  is pyrrolidine, 
         or R 1  is t-butyl and R 2  is selected from the group consisting of H, a phenyl group, and —CH 2 —O—CH 3 . 
       
     
     
         16 . The method according to  claim 4  wherein said agent is an inhibitor of adrenal steroidogenesis. 
     
     
         17 . The method according to  claim 16  wherein said inhibitor of adrenal steroidogenesis is selected from the group consisting of: ketoconazole, metyrapone, aminoglutethimide, trilostane, etomidate, epostane, thiopentone and ketotrilostane. 
     
     
         18 . The method according to  claim 17  wherein said inhibitor of adrenal steroidogenesis is ketoconazole or metyrapone. 
     
     
         19 . The method according to  claim 4  wherein said agent is a combination of agents that inhibit the synthesis or activity of cortisol. 
     
     
         20 . The method according to  claim 19  wherein said combination is a glucocorticoid receptor antagonist and an inhibitor of adrenal steroidogenesis.