Reducing Nephropathy with Inhibitors of Soluble Epoxide Hydrolase and Epoxyeicosanoids

Abstract

The invention provides uses and methods for reducing nephropathy in persons with diabetes mellitus (particularly Type 2 diabetes), in persons with metabolic syndrome, in persons with triglyceride levels over 215 mg/dL, and in persons with a cholesterol level over 200 mg/dL, by administering an inhibitor of soluble epoxide hydrolase ("sEH"). Optionally, a cis-epoxyeicosantrienoic acid ("EET") can be administered with the sEH inhibitor. The invention further provides for using EETs in conjunction with one or more sEH inhibitors to reduce hypertension, and for compositions of EETs coated with a material insoluble in an acid of pH 3 but soluble in a solution with a pH of 7.4 or higher.

1 . A use of an inhibitor of soluble epoxide hydrolase (“sEH”) for the manufacture of a medicament for inhibiting development or progression of nephropathy in (a) a person with diabetes mellitus whose blood pressure is 130/80 or less, (b) a person with metabolic syndrome whose blood pressure is less than 130/85, (c) a person with a triglyceride level over 215 mg/dL, or (d) a person with a cholesterol level over 200 mg/dL. 
     
     
         2 . A use of  claim 1 , wherein said inhibitor of sEH is selected from the group consisting of 12-(3-Adamantan-1-yl-ureido)dodecanoic acid, 12-(3-Adamantan-1-yl-ureido)dodecanoic acid butyl ester, and adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}urea. 
     
     
         3 . A use of  claim 1 , wherein the medicament is a slow release formulation. 
     
     
         4 . A use of  claim 1 , wherein said medicament further comprises a cis-epoxyeicosantrienoic acid (“EET”). 
     
     
         5 . A use of  claim 10 , wherein said EET is selected from the group consisting of 14,15-EET, 8,9-EET and 11,12-EET. 
     
     
         6 . A use of  claim 10 , wherein said EET is 14R,15S-EET. 
     
     
         7 . A use of  claim 1 , wherein the person has Type 2 diabetes. 
     
     
         8 . A use of  claim 1 , wherein the person has Type 1 diabetes. 
     
     
         9 . A use of  claim 1 , wherein the person has metabolic syndrome. 
     
     
         10 . A use of  claim 1 , wherein the person has a triglyceride level over 215 mg/dL. 
     
     
         11 . A use of  claim 1 , wherein the person has a cholesterol level over 200 mg/dL. 
     
     
         12 . A use of a nucleic acid that inhibits expression of soluble epoxide hydrolase (“sEH”) for the manufacture of a medicament for inhibiting development or progression of nephropathy in (a) a person with diabetes mellitus whose blood pressure is 130/80 or less, (b) a person with metabolic syndrome whose blood pressure is less than 130/85, (c) a person with a triglyceride level over 215 mg/dL, or (d) a person with a cholesterol level over 200 mg/dL. 
     
     
         13 . A use of  claim 12 , wherein the nucleic acid is a small interfering RNA. 
     
     
         14 . A use of a cis-epoxyeicosantrienoic acid (“EET”) for the manufacture of a medicament to treat hypertension. 
     
     
         15 . A use of  claim 14 , wherein said EET is selected from the group consisting of 14,15-EET, 8,9-EET and 11,12-EET. 
     
     
         16 . A use of  claim 15 , wherein said EET is 14R,15S-EET. 
     
     
         17 . A use of  claim 14 , wherein the EET is in a material which releases the EET into the surrounding environment over time. 
     
     
         18 . A method of inhibiting progression of nephropathy in:
 (a) a person with diabetes mellitus whose blood pressure is 130/80 or less, (b) a person with metabolic syndrome whose blood pressure is less than 130/85, (c) a person with a triglyceride level over 215 mg/dL, or (d) a person with a cholesterol level over 200 mg/dL, said method comprising administering an inhibitor of soluble epoxide hydrolase (“sEH”) to said person.   
     
     
         19 . A method of  claim 18 , wherein said inhibitor of sEH is selected from the group consisting of 12-(3-Adamantan-1-yl-ureido)dodecanoic acid, 12-(3-Adamantan-1-yl-ureido)dodecanoic acid butyl ester, and adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}urea. 
     
     
         20 . A method of  claim 18 , wherein the person has Type 2 diabetes. 
     
     
         21 . A method of  claim 18 , wherein the person has Type 1 diabetes. 
     
     
         22 . A use of  claim 18 , wherein the person has metabolic syndrome. 
     
     
         23 . A use of  claim 18 , wherein the person has a triglyceride level over 215 mg/dL. 
     
     
         24 . A use of  claim 18 , wherein the person has a cholesterol level over 200 mg/dL. 
     
     
         25 . A method of  claim 18 , wherein the inhibitor of sEH is in a material which releases the inhibitor over time. 
     
     
         26 . A method of  claim 18 , further comprising administering a cis-epoxyeicosantrienoic acid (“EET”). 
     
     
         27 . A method of  claim 26 , wherein said EET is selected from the group consisting of 14,15-EET, 8,9-EET and 11,12-EET. 
     
     
         28 . A method of  claim 26 , wherein said EET is 14R,15S-EET. 
     
     
         29 . A method of  claim 26 , wherein the EET is in a material which releases the EET into its surroundings over time. 
     
     
         30 . A method of  claim 18 , wherein the inhibitor is administered orally. 
     
     
         31 . A method as in  claim 18 , wherein the inhibitor is administered in a total daily dose from about 0.001 μM/kg to about 100 mg/kg body weight of the patient. 
     
     
         32 . A method of inhibiting progression of nephropathy in (a) a person with diabetes mellitus whose blood pressure is 130/80 or less, (b) a person with metabolic syndrome whose blood pressure is less than 130/85, (c) a person with a triglyceride level over 215 mg/dL, or (d) a person with a cholesterol level over 200 mg/dL, said method comprising administering to said patient a nucleic acid which inhibits expression of a gene encoding soluble epoxide hydrolase. 
     
     
         33 . A method of  claim 32 , wherein the nucleic acid is a small interfering RNA (“siRNA”). 
     
     
         34 . A method of reducing blood pressure in a person in need thereof, said method comprising administering to said person an inhibitor of soluble epoxide hydrolase and a cis-epoxyeicosantrienoic acid (“EET”). 
     
     
         35 . A method of  claim 34 , wherein said EET is selected from the group consisting of 14,15-EET, 8,9-EET and 11,12-EET. 
     
     
         36 . A method of  claim 34 , wherein said EET is14R,15S-EET. 
     
     
         37 . A method of  claim 34 , wherein the EET is in a material which releases the EET into the surroundings over time. 
     
     
         38 . A composition comprising a cis-epoxyeicosantrienoic acid (“EET”) coated with a material insoluble in an acid of pH 3 but soluble in a solution with a pH of 7.4 or higher. 
     
     
         39 . A composition of  claim 38 , wherein said EET is selected from the group consisting of 14,15-EET, 8,9-EET and 11,12-EET. 
     
     
         40 . A composition of  claim 38 , wherein said EET is 14R,15S-EET.