Compositions and methods for treating nephropathy

Abstract

Activated fatty acids, pharmaceutical composition compositions including activated fatty acids, methods for using activated fatty acids to treat nephropathy, and methods for preparing activated fatty acids are provided herein.

1 . A pharmaceutical composition comprising:
 an effective amount of an activated fatty acid;   an effective amount of a secondary agent selected from a group consisting of a cytoprotective agent, an angiotensin II inhibitor, an angiotensin converting enzyme (ACE) inhibitor, and a combination thereof; and   a pharmaceutically acceptable diluent, excipient, carrier, or combination thereof.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the secondary agent is selected from a group consisting of amifostine, 2-mercaptoethane sulfonate sodium, and a combination thereof. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the secondary agent is selected from a group consisting of irbesartan, losartan, ramipril, enalapril, lisinopril, quinapril, benazepril, captopril, fosinopril, trandolapril, moexipril, perindopril, and a combination thereof. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition further comprises a second fatty acid component having a non-activated fatty acid selected from a group consisting of linoleic acid, a-linoleic acid, y-linoleic acid, oleic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and derivatives thereof. 
     
     
         5 . A method for treating a kidney injury or disease in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an activated fatty acid, a prodrug, or a metabolite thereof; and a secondary agent selected from a group consisting of a cytoprotective agent, an angiotensin II inhibitor, an angiotensin converting enzyme (ACE) inhibitor, and a combination thereof. 
     
     
         6 . The method of  claim 5 , wherein the kidney injury or disease is selected from a group consisting of acute renal failure, intravascular blood volume depletion, structural lesions of the renal arteries, drug effects on renal blood flow, renal hypoperfusion, damage to kidney tubules, damage to glomeruli, damage to interstitium, damage to vascular tissues within the kidney, kidney disease related to urinary tract obstruction, kidney stones, kidney tumor, prostatic hyperplasia, kidney strictures, drug-induced nephropathy, radiation induced nephropathy, microagiopathic hemolysis, minimal-change nephritis, hypercalcemia, hyperuricemia, lysozymuria, disseminated intravascular coagulopathy, immune complex-mediated glomerulopathy, paraprotein-related nephropathy, amyloidosis, urinary tract infections, functional abnormalities and a combination thereof. 
     
     
         7 . The method of  claim 5 , wherein the angiotensin II inhibitor is selected from a group consisting of irbesartan, losartan, and a combination thereof. 
     
     
         8 . The method of  claim 5 , wherein the angiotensin converting enzyme (ACE) inhibitor is selected from a group consisting of Ramipril, enalapril, lisinopril, quinapril, benazepril, captopril, fosinopril, trandolapril, moexipril, perindopril, and a combination thereof. 
     
     
         9 . The method of  claim 5 , wherein the activated fatty acid is an unsaturated or polyunsaturated fatty acid having an aliphatic chain comprised of 4 to 25 carbons and one or more electron withdrawing groups associated with at least one carbon-carbon double bond, the one or more electron withdrawing groups being selected from the group consisting of aldehyde (—COH), acyl (—COR), carbonyl (—CO), carboxylic acid (—COOR), ester (—COOR), halides (—Cl, —F, —Br, —I), fluoromethyl (—CFn, n=1-3), allyl fluoride (—CH=CHCH 2 F), cyano (—CN), sulfoxide (—SOR), sulfonyl (—SO 2 R), sulfonic acid (—SO 3 H), 1°, 2° and 3° ammonium (—NR 3 +), or nitro (—NO2), wherein R is a hydrogen, methyl or C2-C6 alkyl. 
     
     
         10 . The method of  claim 9 , wherein the one or more electron withdrawing groups are positioned on one of an alpha carbon, beta carbon or gamma carbon of a carbon-carbon double bond in the aliphatic chain. 
     
     
         11 . The method of  claim 5 , wherein the activated fatty acid is selected from a group consisting of nitro-linoleic acid, keto-linoleic acid, nitro-oleic acid, keto-oleic acid and a combination thereof. 
     
     
         12 . The method of  claim 5 , wherein the activated fatty acid is nitro-oleic acid. 
     
     
         13 . The method of  claim 5 , wherein the pharmaceutical composition further comprises an antioxidant, a statin, a squalene synthesis inhibitor, an azetidinone-based compound, a low-density lipoprotein (LDL) catabolism activator, a peroxisome proliferator-activated receptor (PPAR) antagonist, a PPAR agonist, an antiarrhythmic agent, a non-steroidal anti-inflammatory drug (NSAID) or a combination thereof. 
     
     
         14 . The method of  claim 5 , wherein the secondary agent is selected from a group consisting of amifostine, 2-mercapto ethane sulfonate sodium and a combination thereof. 
     
     
         15 . The method of  claim 5 , wherein the pharmaceutical composition further comprises a second fatty acid component having a non-activated fatty acid selected from a group consisting of linoleic acid, a-linoleic acid, y-linoleic acid, oleic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and derivatives thereof. 
     
     
         16 . A method of treating hypoperfusion of a kidney in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an activated fatty acid, a prodrug, or a metabolite thereof; and a secondary agent selected from a group consisting of a cytoprotective agent, an angiotensin II inhibitor, an angiotensin converting enzyme (ACE) inhibitor, and a combination thereof. 
     
     
         17 . A method of treating a functional abnormality in a urinary tract in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an activated fatty acid, a prodrug, or a metabolite thereof; and
 a secondary agent selected from a group consisting of a cytoprotective agent, an angiotensin II inhibitor, an angiotensin converting enzyme (ACE) inhibitor, and a combination thereof.   
     
     
         18 . A method of treating renal dysfunction in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an activated fatty acid, a prodrug, or a metabolite thereof; and a secondary agent selected from a group consisting of a cytoprotective agent, an angiotensin II inhibitor, an angiotensin converting enzyme (ACE) inhibitor, and a combination thereof.