Method for differentially diagnosing acth-dependent cushing's syndrome

Abstract

Applicant discloses herein methods for differentially diagnosing adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome in a patient where the differential diagnosis is between ectopic ACTH syndrome and Cushing Disease. The methods include administration of an amount of a glucocorticoid receptor antagonist (GRA) effective to increase ACTH in patients with ectopic ACTH syndrome but not in those with Cushing's Disease. Method steps may include administering a GRA dose sufficient to increase ACTH from the pituitary gland by at least two fold in persons with normal HPA function (e.g., 300 to 1500 milligrams); waiting for at least two hours; and obtaining from the patient an ACTH concentration ratio derived from the ACTH concentrations in blood samples obtained from an inferior petrosal venous sinus and from a peripheral vein. The patient is diagnosed with Cushing Disease if the ACTH concentration ratio is greater than 3.

What is claimed is: 
     
         1 . A method of obtaining a measurement indicative of differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome in a patient where the differential diagnosis is between ectopic ACTH syndrome and Cushing's disease, the method comprising the steps of:
 administering a dose of a glucocorticoid receptor antagonist (GRA) to a patient with Cushing's syndrome and an elevated ACTH level, wherein the amount of GRA administered to said patient is sufficient to increase ACTH from the pituitary gland by at least two-fold in persons with normal Hypothalamus Pituitary Adrenal (HPA) function; then,   determining the ACTH concentration ratio from venous blood samples obtained from the patient at least two hours following said GRA administration, wherein said venous blood samples are obtained from a) the left or right inferior petrosal venous sinus and from b) a peripheral vein; and   wherein an ACTH concentration ratio of greater than 3 for the ACTH concentration from an inferior petrosal venous sinus blood sample over the peripheral venous blood sample is diagnostic of Cushing's disease.   
     
     
         2 . The method of  claim 1 , wherein said GRA is administered orally. 
     
     
         3 . The method of  claim 1 , wherein said GRA is mifepristone. 
     
     
         4 . The method of  claim 1 , wherein said GRA is a compound selected from compounds comprising a heteroaryl-ketone fused azadecalin backbone, compounds comprising an octahydro fused azadecalin backbone, and compounds comprising a cyclohexyl pyrimidine backbone. 
     
     
         5 . The method of  claim 1 , wherein the amount of said GRA is an amount between 300 milligrams (mg) and 1500 mg, inclusive. 
     
     
         6 . The method of  claim 1 , wherein a first and second sampling of the ACTH 2 concentrations are taken 5-10 minutes apart from both the inferior petrosal venous sinus and 3 from a peripheral vein. 
     
     
         7 . The method of  claim 1 , comprising obtaining said venous blood samples, wherein said GRA is administered at about 11 PM the night preceding said obtaining the venous blood samples. 
     
     
         8 . The method of  claim 1 , wherein the periphery venous blood sample is a jugular venous blood sample. 
     
     
         9 . The method of  claim 1  wherein the periphery venous blood sample is an adrenal venous blood sample. 
     
     
         10 . The method of  claim 1 , wherein said administering a dose of said GRA comprises administering a plurality of daily doses of said GRA for a period of not less than 5 weeks. 
     
     
         11 . A method of obtaining a measurement indicative of differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome in a patient where the differential diagnosis is between ectopic ACTH syndrome and Cushing's disease, the method comprising the steps of:
 selecting a patient having Cushing's syndrome, said patient having hypercortisolemia and an elevated ACTH level;   determining the ACTH concentration ratio from said patient, where the patient has been administered a dose of a glucocorticoid receptor antagonist (GRA) at least two hours prior to the removal of venous samples, wherein said GRA dose is at least 300 milligrams (mg) and is no greater than 1500 mg of said GRA;   wherein the ACTH concentration ratio is derived from the ACTH concentrations in a blood sample obtained from either the left or right inferior petrosal venous sinus of the patient and from a blood sample obtained from a peripheral vein of the patient; and   wherein an ACTH concentration ratio of greater than 3 for the ACTH concentration from the inferior venous sinus blood sample over the periphery venous sinus blood sample is indicative of Cushing's disease.   
     
     
         12 . The method of  claim 11 , wherein said GRA is administered orally. 
     
     
         13 . The method of  claim 11 , wherein said GRA is mifepristone. 
     
     
         14 . The method of  claim 11 , wherein said GRA is a compound selected from compounds comprising a heteroaryl-ketone fused azadecalin backbone, compounds comprising an octahydro fused azadecalin backbone, and compounds comprising a cyclohexyl pyrimidine backbone. 
     
     
         15 . The method of  claim 11 , wherein the amount of said GRA is 300 mg or is 1500 mg. 
     
     
         16 . The method of  claim 11 , wherein a first and second sampling of the ACTH concentrations are taken 5-10 minutes apart from both the inferior petrosal venous sinus blood and a periphery venous blood sample. 
     
     
         17 . The method of  claim 11 , comprising obtaining said venous blood samples, wherein said GRA is administered at about 11 PM the night preceding said obtaining the venous blood samples. 
     
     
         18 . The method of  claim 11 , wherein the periphery venous blood sample is a jugular vein blood sample. 
     
     
         19 . The method of  claim 11  wherein the periphery venous blood sample is an adrenal vein blood sample. 
     
     
         20 . The method of  claim 11 , wherein said administering a dose of said GRA comprises administering a plurality of daily doses of said GRA for a period of not less than 5 weeks.