Reduction in complement activation and inflammation during tissue injury by carotenoids, carotenoid analogs, or derivatives thereof

Abstract

Administering water-soluble or dispersible synthetic analogs or derivatives of astaxanthin, lutein, zeaxanthin, or lycophyll and/or other carotenoids to a subject may reduce some of the adverse effects of inflammation in a body organ or tissue. The analogs or derivatives may be incorporated into pharmaceutical, over-the-counter, or nutraceutical preparations. Administration of the analogs or derivatives described herein may reduce deposition of inflammatory mediators such as C-reactive protein, complement system proteins or the membrane attack complex (MAC) in tissues. Reduced deposition of these molecules in tissues may reduce cell damage and/or lysis in the tissues.

1 . A method of preventing, inhibiting or reducing tissue damage associated with an inflammatory response in a subject comprising administering to a subject who would benefit from such treatment a prophylactically or therapeutically effective amount of a pharmaceutically acceptable formulation comprising a synthetic carotenoid analog or a carotenoid derivative having the structure;  
     
       
         
         
             
             
         
       
       where each R 3  is independently hydrogen or methyl, and where each R 1  and R 2  are independently:  
       
         
           
           
               
               
           
         
       
       where R 4  is hydrogen or methyl; where each R 5  is independently hydrogen, —OH, or —OR 6  wherein at least one R 5  group is —OR 6 ; wherein each R 6  is independently: alkyl; aryl; -alkyl-N(R 7 ) 2 ; -aryl-N(R 7 ) 2 ; -alkyl-N +  (R 7 ) 3 ; -aryl-N + (R 7 ) 3 ; -alkyl-CO 2 R 7 ; -aryl-CO 2 R 7 ; -alkyl-CO 2 —; -aryl-CO 2   − ; —O—C(O)—R 8 ; —P(O)(OR 8 ) 2 ; —S(O)(OR 8 ) 2 ; an amino acid; a peptide, a carbohydrate; —C(O)—(CH 2 ).—CO 2 R 9 ; a nucleoside reside, or a co-antioxidant; where R 7  is hydrogen, alkyl, or aryl; wherein R 8  is hydrogen, alkyl, aryl, benzyl or a co-antioxidant; where R 9  is hydrogen; alkyl; aryl; —P(O)(OR 8 ) 2 ; —S(O)(OR 8 ) 2 ; an amino acid; a peptide, a carbohydrate; a nucleoside, or a co-antioxidant; and where n is 1 to 9.  
     
   
   
       2 . The method of  claim 1 , further comprising administering to the subject at least one anti-inflammatory drug.  
   
   
       3 . The method of  claim 2 , wherein at least one of the anti-inflammatory drugs are selected from the list consisting of cortisol; hydrocortisone; Prednisone; Prednisolone; Methylprednisolone; Meprednisone; Triamcicolone; Paramethasone; Fluprednisolone; Betamethasone; Dexamethasone; Fludrocortisone; Aspirin; Diclofenac; Diflunisal; Etodolac; Fenoprofen; Floctafenine; Flurbiprofen; Ibuprofen; Indomethacin; Ketorolac; Ketoprofen; Meclofenamate; Mefenamic Acid; Meloxicam; Nabumetone; Naproxen; Nimesulide; Oxaprozin; Phenylbutazone; Piroxicam; Salsalate; Sulindac; Tenoxicam; Tiaprofenic Acid; Tolmetin; Celecoxib; rofecoxib; etoricoxib; and valdecoxib.  
   
   
       4 . The method of  claim 1 , wherein the formulation is administered prior to the onset of an inflammatory response.  
   
   
       5 . (canceled)  
   
   
       6 . (canceled)  
   
   
       7 . (canceled)  
   
   
       8 . The method of  claim 1 , wherein the composition comprises one or more carotenoid derivatives or analogs having the structure:  
     
       
         
         
             
             
         
       
       where each R 1  and R 2  are independently:  
       
         
           
           
               
               
           
         
       
       where each R 5  is independently hydrogen, —OH, or —OR 6  wherein at least one R 5  group is —OR 6 ; wherein each R 6  is independently: alkyl; aryl; -alkyl-N 7 ) 2 ; -aryl-N(R 7 ) 2 ; -alkyl-N + (P 7 ) 3 ; -aryl-N + (R 7 ) 3 ; -alkyl-CO 2 R 7 ; -aryl-CO 2 R 7 ; -alkyl-CO 2 —; -aryl-CO 2   − ; —O—C(O)—R 8 ; —P(O)(OR 8 ) 2 ; —S(O)(OR 8 ) 2 ; an amino acid; a peptide, a carbohydrate; —C(O)—(CH 2 ), —CO 2 R 9 ; a nucleoside reside, or a co-antioxidant; where R 7  is hydrogen, alkyl, or aryl; wherein R 8  is hydrogen, alkyl, aryl, benzyl, or a co-antioxidant; and where R 9  is hydrogen; alkyl; aryl; —P(O)(OR 8 ) 2 ; —S(O)(OR 8 ) 2 ; an amino acid; a peptide, a carbohydrate; a nucleoside, or a co-antioxidant; and where n is 1 to 9.  
     
   
   
       9 . The method of  claim 1 , wherein the composition comprises one or more carotenoid derivatives or analogs having the structure:  
     
       
         
         
             
             
         
       
       where each R 1  and R 2  are independently:  
       
         
           
           
               
               
           
         
       
       where each R 5  is independently hydrogen, —OH, or —OR 6  wherein at least one R 5  group is —OR 6 ; wherein each R 6  is independently:  
       
         
           
           
               
               
           
         
       
       or a co-antioxidant; wherein R 8  is hydrogen, alkyl, aryl, benzyl, Group IA metal, or a co-antioxidant; wherein R′ is CH 2 ; and where n is 1 to 9.  
     
   
   
       10 . The method of  claim 1 , wherein the composition comprises one or more carotenoid derivatives or analogs having the structure:  
     
       
         
         
             
             
         
       
       wherein each —OR 6  is independently:  
       
         
           
           
               
               
           
         
       
       or a co-antioxidant; wherein R 8  is hydrogen, alkyl, aryl, benzyl, Group IA metal, or a co-antioxidant; wherein R′ is CH 2 ; and where n is 1 to 9.  
     
   
   
       11 . The method of  claim 1 , wherein the composition comprises one or more carotenoid derivatives or analogs having the structure:  
     
       
         
         
             
             
         
       
     
     wherein each —OR 6  is independently:  
     
       
         
         
             
             
         
       
     
     or a co-antioxidant; wherein R 8  is hydrogen, alkyl, aryl, benzyl, Group IA metal, or a co-antioxidant; wherein R′ is CH 2 ; and where n is 1 to 9.  
   
   
       12 . The method of  claim 1 , wherein the composition comprises two or more carotenoid derivatives or analogs having the structures:  
     
       
         
         
             
             
         
       
     
     wherein each —OR 6  is independently:  
     
       
         
         
             
             
         
       
     
     or a co-antioxidant; wherein R 8  is hydrogen, alkyl, aryl, benzyl, Group IA metal, or a co-antioxidant; wherein R′ is CH 2 ; and where n is 1 to 9.  
   
   
       13 . The method of  claim 12 , wherein each —OR 6  independently comprises:  
     
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
     
     and, wherein R is independently H, alkyl, aryl, benzyl, Group IA metal, or co-antioxidant.  
   
   
       14 . The method of  claim 12 , wherein each —OR 6  independently comprises:  
     
       
         
         
             
             
         
       
     
     or a co-antioxidant; wherein R 8  is hydrogen, alkyl, aryl, benzyl, Group IA metal, or a co-antioxidant; wherein R′ is CH 2 ; and where n is 1 to 9.  
   
   
       15 . (canceled)  
   
   
       16 . (canceled)  
   
   
       17 . (canceled)  
   
   
       18 . (canceled)  
   
   
       19 . The method of  claim 1 , wherein the composition comprises one or more carotenoid derivatives or analogs having the structures:  
     
       
         
         
             
             
         
       
       where each R is independently H, alkyl, aryl, benzyl, Group LX metal, or a co-antioxidant.  
     
   
   
       20 . The method of  claim 1 , wherein the composition comprises one or more carotenoid derivatives or analogs having the structures:  
     
       
         
         
             
             
         
       
     
     where each R is independently H, alkyl, aryl, benzyl, Group IA metal, or a co-antioxidant.  
   
   
       21 . The method of  claim 1 , wherein the co-antioxidant comprises Vitamin C, Vitamin C analogs, Vitamin C derivatives, Vitamin E, Vitamin E analogs, Vitamin E derivatives, flavonoids, flavonoid derivatives, or flavonoid analogs.  
   
   
       22 . The method of  claim 1 , wherein the flavonoids comprise quercetin, xanthohumol, isoxanthohumol, or genistein.  
   
   
       23 . The method of  claim 1 , wherein the composition comprises one or more carotenoid derivatives or analogs having the structures:  
     
       
         
         
             
             
         
       
       where each R is independently H, alkyl, aryl, benzyl, or a Group IA metal.  
     
   
   
       24 . (canceled)  
   
   
       25 . (canceled)  
   
   
       26 . (canceled)  
   
   
       27 . (canceled)  
   
   
       28 . The method of  claim 1 , wherein the composition is administered orally.  
   
   
       29 . The method of  claim 1 , wherein the composition is administered parenterally.  
   
   
       30 . The method of  claim 1 , wherein the composition is administered as an aqueous solution.  
   
   
       31 . The method of  claim 1 , wherein the composition is administered as an aqueous dispersion.  
   
   
       32 . The method of  claim 1 , wherein the composition is administered intravenously.  
   
   
       33 . The method of  claim 1 , wherein the composition is administered intravascularly.  
   
   
       34 . The method of  claim 1 , wherein the composition is administered by intramuscular injection.  
   
   
       35 . The method of  claim 1 , wherein the composition is administered subcutaneously.  
   
   
       36 . The method of  claim 1 , wherein the composition is administered transdermally.  
   
   
       37 - 47 . (canceled)  
   
   
       48 . A pharmaceutical composition comprising: 
 a synthetic carotenoid analog or a carotenoid derivative having the structure                          where each R 3  is independently hydrogen or methyl, and where each R 1  and R 2  are independently:                          where R 4  is hydrogen or methyl; where each R 5  is independently hydrogen, —OH, or —OR 6  wherein at least one R 5  group is —OR 6 ; wherein each R 6  is independently: alkyl; aryl; -alkyl-N(R 7 ) 2 ; -aryl-N(R 7 ) 2 ; -alkyl-N + (R 7 ) 3 ; -aryl-N + (R 7 ) 3 ; -alkyl-CO 2 R 7 ; -aryl-CO 2 R 7 ; -alkyl-CO 2 —; -aryl-CO 2   − ; —O—C(O)—R 8 ; —P(O)(OR 8 ) 2 ; —S(O)(OR 8 ) 2 ; an amino acid; a peptide, a carbohydrate; —C(O)—(CH 2 ) n —CO 2 R 9 ; a nucleoside reside, or a co-antioxidant; where R 7  is hydrogen, alkyl, or aryl; wherein R 8  is hydrogen, alkyl, aryl, benzyl or a co-antioxidant; where R 9  is hydrogen; alkyl; aryl; —P(O)(OR 8 ) 2 ; —S(O)(OR 8 ) 2 ; an amino acid; a peptide, a carbohydrate; a nucleoside, or a co-antioxidant; and where n is 1 to 9; and    at least one pharmaceutically inactive carrier; and    at least one additional anti-inflammatory agent.    
   
   
       49 - 59 . (canceled)