Methods and compositions for treating diabetes, metabolic syndrome and other conditions

Abstract

Pharmaceuticals compositions comprising the 2S, 4R, ketoconazole enantiomer or its pharmaceutically acceptable salts, hydrates, and solvates, that are substantially free of the 2R, 4S ketoconazole enantiomer are useful to reduce cortisol synthese and for the treatment of type 2 diabetes, hyperglycemia, obesity, insulin resistance, dyslipidemia, hyperlipidemia, hypertension, Metabolic Syndrome, and other diseases and conditions, including but not limited to Cushing's Syndrome, depression, and glaucoma.

1 - 28 . (canceled) 
   
   
       29 . A method for treating a disease or condition associated with elevated cortisol levels or activity in a patient, said method comprising administering a therapeutically effective amount of 2S,4R ketoconazole enantiomer substantially free of the 2R,4S ketoconazole enantiomer to said patient. 
   
   
       30 . The method of  claim 29 , wherein said disease or condition is selected from the group consisting of hyperglycemia, diabetes, and insulin resistance. 
   
   
       31 . The method of  claim 30 , wherein said disease or condition is type 2 diabetes mellitus. 
   
   
       32 . The method of  claim 29 , wherein said disease or condition is Metabolic Syndrome. 
   
   
       33 . The method of  claim 29 , wherein said disease or condition is obesity. 
   
   
       34 . The method of  claim 33 , wherein said disease or condition is visceral or centripetal obesity. 
   
   
       35 . The method of  claim 29 , wherein said disease or condition is a lipid disorder selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL. 
   
   
       36 . The method of  claim 29 , wherein said disease or condition is atherosclerosis. 
   
   
       37 . The method according to  claim 29 , wherein said disease or condition is: (1) low glucose tolerance, (2) lipid disorders, (3) vascular restenosis, (4) pancreatitis, (5) abdominal obesity, (6) neurodegenerative disease, (7) retinopathy, (8) nephropathy, or (9) neuropathy. 
   
   
       38 . The method of  claim 29 , further comprising co-administering to said patient a therapeutically effective amount of a second compound selected from the group consisting of: DPP-IV inhibitors; PPAR agonists; biguanides; insulin and insulin analogs and mimetics; sulfonylureas and other insulin secretagogues; α-glucosidase inhibitors; glucagon receptor antagonists; GLP-1, GLP-1 analogs and mimetics, and GLP-1 receptor agonists; GIP, GIP analogs and mimetics, and GIP receptor agonists; PACAP, PACAP analogs and mimetics, and PACAP receptor 3 agonists; cholesterol lowering agents; HMG-CoA reductase inhibitors; sequestrants; nicotinyl alcohol, nicotinic acid and salts thereof; PPARα agonists; PPARα/γ dual agonists; inhibitors of cholesterol absorption; acyl CoA: cholesterol acyltransferase inhibitors; anti-oxidants; PPARδ agonists; antiobesity compounds; an ileal bile acid transporter inhibitor; anti-inflammatory agents excluding glucocorticoids; or protein tyrosine phosphatase-1B (PTP-1B) inhibitors. 
   
   
       39 . The method of  claim 38 , wherein the second compound is an HMG-CoA reductase inhibitor, and the disease or condition is hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia or dyslipidemia. 
   
   
       40 . The method of  claim 39 , wherein the HMG-CoA reductase inhibitor is a statin. 
   
   
       41 . The method of  claim 40 , wherein the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, itavastatin, ZD-4522, and rivastatin. 
   
   
       42 . The method of  claim 29  wherein the 2S,4R ketoconazole enantiomer is administered in combination with a cholesterol absorption inhibitor. 
   
   
       43 . The method of  claim 42 , wherein the cholesterol absorption inhibitor is ezetimibe. 
   
   
       44 . The method of  claim 39 , wherein the 2S,4R ketoconazole enantiomer and the HMG-CoA reductase inhibitor are coformulated with carrier in a single coformulation. 
   
   
       45 . The method of  claim 29 , wherein said disease or condition is depression. 
   
   
       46 . The method of  claim 29 , wherein said disease or condition is Cushing's Syndrome. 
   
   
       47 . The method of  claim 29 , wherein said disease or condition is glaucoma. 
   
   
       48 . The method of  claim 29 , wherein said disease or condition is hypertension. 
   
   
       49 . A method of reducing cortisol levels in a patient diagnosed with a condition characterized by elevated cortisol levels, comprising administering a constant daily dose of 2R4S enantiomer substantially free of the 2R,4S enantiomer, wherein the constant daily dose results in a constant exposure to 1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)-methyl]-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine (MPP) to the patient over a period of at least 14 days. 
   
   
       50 . The method of  claim 49  wherein the period of at least 14 days begins on Day 1, and the MPP has not been administered to the patient for at least 28 days prior to the administration of the 2S,4R ketoconazole enantiomer. 
   
   
       51 . The method of  claim 49  wherein the condition is hyperglycemia, diabetes or insulin resistance and the patient is not under treatment for a fungal infection. 
   
   
       52 . The method of  claim 29 , wherein said disease or condition involves impaired renal function. 
   
   
       53 . The method of  claim 29 , wherein the method results in reducing albumin leakage associated with diabetes type 2.