Ketoconazole enantiomer in humans

Abstract

Treatment of patients with the 2S,4R ketoconazole enantiomer or its pharmaceutically acceptable salts, and solvates is useful for reducing systemic inflammation and cholesterol levels and improving glycemic control.

What is claimed is: 
     
         1 . A method of reducing CRP levels in a patient in need of such reduction, said method comprising administering a ketoconazole composition comprising a 2S,4R ketoconazole enantiomer substantially free of the 2R,4S ketoconazole enantiomer to said patient at a daily dose of from 100 mg to 600 mg for at least 14 days. 
     
     
         2 . The method of  claim 1  comprising identifying or diagnosing the patient as having elevated plasma CRP and in need of reduction of systemic inflammation. 
     
     
         3 . The method of  claim 2  wherein the patient has a plasma CRP level greater than 3.0 mg/L. 
     
     
         4 . The method of  claim 2  wherein the patient has a plasma CRP level greater than 5.0 mg/L. 
     
     
         5 . The method of  claim 1  wherein the patient is diabetic. 
     
     
         6 . The method of  claim 1  wherein the patient is diagnosed with metabolic syndrome. 
     
     
         7 . A method of treating a patient with a 3-hydroxy 3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor comprising coadministering the HMG CoA reductase inhibitor and a therapeutically effective amount of 2S,4R ketoconazole enantiomer substantially free of the 2R,4S ketoconazole enantiomer, wherein the dose of the HMG CoA reductase inhibitor is different from the dose indicated for the patient in the absence of 2S,4R ketoconazole enantiomer administration. 
     
     
         8 . The method of  claim 7  wherein the HMG CoA reductase inhibitor is atorvastatin. 
     
     
         9 . A method for treatment of a diabetic patient comprising:
 a) administering a therapeutically effective amount of 2S,4R ketoconazole enantiomer substantially free of the 2R,4S ketoconazole enantiomer to the patient; and   b) administering a therapeutically effective amount of a cholesterol-lowering HMG-CoA reductase inhibitor to the patient   wherein the amount of HMG-CoA reductase inhibitor administered is greater that the amount indicated for administration to the patient in the absence of administration of ketoconazole enantiomer.   
     
     
         10 . The method of  claim 9 , wherein administration of the HMG-CoA reductase inhibitor would be contraindicated in the patient in the absence of administration of the ketoconazole enantiomer. 
     
     
         11 . The method of  claim 9 , wherein the HMG-CoA reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, itavastatin, ZD-4522, and rivastatin. 
     
     
         12 . The method of  claim 11  wherein the HMG-CoA reductase inhibitor is atorvastatin. 
     
     
         13 . A method of treating a non-diabetic patient with elevated cholesterol comprising:
 (a) administering a therapeutic effective amount of 2S,4R ketoconazole enantiomer substantially free of the 2R,4S enantiomer to the patient and   (b) administering a therapeutically effective amount of a cholesterol-lowering HMG-CoA reductase inhibitor to the patient,   wherein the amount of HMG-CoA reductase inhibitor administered is greater than the amount indicated for administration to the patient in the absence of the administration of ketoconazole enantiomer.   
     
     
         14 . The method of  claim 13  wherein administration of the HMG-CoA reductase inhibitor would be contraindicated in the patient in the absence of administration of the ketoconazole enantiomer. 
     
     
         15 . The method of  claim 13  wherein the HMG-CoA reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, itavastatin, ZD-4522 and rivastatin. 
     
     
         16 . A method for treatment of a diabetic patient presenting with abnormal level of a marker of liver function, wherein said patient is in need of treatment to reduce cholesterol and/or improve glycemic control, comprising administering a therapeutically effective amount of 2S,4R ketoconazole enantiomer substantially free of the 2R,4S ketoconazole enantiomer to said patient. 
     
     
         17 . The method of  claim 16  wherein the marker is ALT, AST or AP. 
     
     
         18 . A method for treating a diabetic patient comprising administering a 2S,4R ketoconazole enantiomer substantially free of the 2R,4S ketoconazole enantiomer to said patient at a daily dose of from 100-600 mg, wherein a 14 day course of treatment results in one, more than one, or all of the following:
 a) a reduction of HbA1c levels of at least 0.3% compared to baseline;   b) a reduction of fructosamine levels of at least 10 umol/L compared to baseline;   c) a reduction of fasting blood glucose levels of at least 15 mg/dL compared to baseline;   d) a reduction of LDL cholesterol of at least 15% compared to baseline;   e) a reduction of total cholesterol of at least 25% compared to baseline; and   f) a reduction in CRP level of at least 25% compared to baseline.   
     
     
         19 . A method for treating a diabetic patient comprising administering a 2S,4R ketoconazole enantiomer substantially free of the 2R,4S ketoconazole enantiomer to said patient at a daily dose of from 100-600 mg, wherein a 120 day course of treatment results in one, more than one, or all of the following:
 a) a reduction of HbA1c levels of at least 0.8% compared to baseline;   b) a reduction of fructosamine levels of at least 40 umol/L compared to baseline;   c) a reduction of fasting blood glucose levels of at least 25 mg/dL compared to baseline;   d) a reduction of LDL cholesterol of at least 30% compared to baseline;   e) a reduction of total cholesterol of at least 40% compared to baseline; and   f) a reduction in CRP level of at least 45% compared to baseline.   
     
     
         20 . The method of  claim 18  or  19  wherein the 2S,4R ketoconazole enantiomer is administered at a daily dose of from 150 mg to 450 mg.