Treatment of macrophage-related disorders

Abstract

The present invention provides a method of treating a macrophage related disease comprising administering to a subject in need thereof an effective amount of an oxidative agent or an immunosuppressive agent. The present invention also provides a method of modulating macrophage accumulation or activation comprising administering to a subject in need thereof an effective amount of an oxidative agent or an immunosuppressive agent. The oxidative agent can be chlorite or a chlorite containing compound.

1 . A method of reducing the side effects of an immunomodulator administered to a subject in need thereof, said method comprising administering an oxidative agent to said subject in combination with said immunomodulator. 
     
     
         2 . The method of  claim 1 , wherein said immunomodulator is administered for the treatment of a macrophage-related disorder selected from the group consisting of cancer, multiple sclerosis, rheumatoid arthritis, macrophage activation syndrome, atherosclerosis, Type I diabetes, Type II diabetes, Kawasaki disease, asthma, hemophagocytic lymphohistiocytosis, sarcoidosis, periodontitis, Whipple's disease, pulmonary alveolar proteinosis, macrophage-related pulmonary disease, Leishmaniasis, hemodialysis-related inflammation, microbial infection, transplant-related complications, metabolic syndrome, hypertension, and inflammatory neurological diseases. 
     
     
         3 . The method of  claim 1 , wherein said immunomodulator is selected from the group consisting of immunosuppressants, macrophage migration inhibitors, anti-inflammatory agents, and immunomodulatory antibodies. 
     
     
         4 . The method of  claim 1 , wherein said oxidative agent is selected from
 i) non-halogen activated-oxygen compounds selected from potassium nitrate (KNO 3 ), permanganate salts, ammonium cerium(IV) nitrate, hexavalent chromium compounds, chromate/dichromate compounds, ammonium silver nitrate, sulfoxides, persulfuric acid, osmium tetroxide (OsO 4 ), nitric acid, nitrous oxide (N 2 O), hydrogen peroxide, organic peroxides, superoxides, and ozone;   ii) non-oxygen activated-halogen compounds selected from fluorine, chlorine, bromine, and iodine;   iii) activated-halogen activated-oxygen compounds selected from sodium chlorite and tetrachlorodecaoxygen; and   iv) N-halo compounds selected from the group consisting of N-halophthalimide, N-halosuccinimide, N-halosaccharin, N,N-dihalourethane, N-haloacetanilide, 1,3-dihalo-5,5-dimethylhydantoin, trihaloisocyanuric acid, and sodium dihaloisocyanurate.   
     
     
         5 . The method of  claim 1 , wherein said oxidative agent is sodium chlorite. 
     
     
         6 . A method of potentiating the effect of an immunomodulator administered to a subject in need thereof, said method comprising administering an oxidative agent to said subject in combination with said immunomodulator. 
     
     
         7 . The method of  claim 6 , wherein said immunomodulator is administered for the treatment of a macrophage-related disorder selected from the group consisting of cancer, multiple sclerosis, rheumatoid arthritis, macrophage activation syndrome, atherosclerosis, Type I diabetes, Type II diabetes, Kawasaki disease, asthma, hemophagocytic lymphohistiocytosis, sarcoidosis, periodontitis, Whipple's disease, pulmonary alveolar proteinosis, macrophage-related pulmonary disease, Leishmaniasis, hemodialysis-related inflammation, microbial infection, transplant-related complications, metabolic syndrome, hypertension, and inflammatory neurological diseases. 
     
     
         8 . The method of  claim 6 , wherein said immunomodulator is selected from the group consisting of immunosuppressants, macrophage migration inhibitors, anti-inflammatory agents, and immunomodulatory antibodies. 
     
     
         9 . The method of  claim 6 , wherein said oxidative agent is selected from
 i) non-halogen activated-oxygen compounds selected from potassium nitrate (KNO 3 ), permanganate salts, ammonium cerium(IV) nitrate, hexavalent chromium compounds, chromate/dichromate compounds, ammonium silver nitrate, sulfoxides, persulfuric acid, osmium tetroxide (OsO 4 ), nitric acid, nitrous oxide (N 2 O), hydrogen peroxide, organic peroxides, superoxides, and ozone;   ii) non-oxygen activated-halogen compounds selected from fluorine, chlorine, bromine, and iodine;   iii) activated-halogen activated-oxygen compounds selected from sodium chlorite and tetrachlorodecaoxygen; and   iv) N-halo compounds selected from the group consisting of N-halophthalimide, N-halosuccinimide, N-halosaccharin, N,N-dihalourethane, N-haloacetanilide, 1,3-dihalo-5,5-dimethylhydantoin, trihaloisocyanuric acid, and sodium dihaloisocyanurate.   
     
     
         10 . The method of  claim 6 , wherein said oxidative agent is sodium chlorite. 
     
     
         11 . A method of treating a disease associated with migration of activated macrophages, said method comprising administering a therapeutically-effective amount of an oxidative agent to a subject in need thereof, wherein said oxidative agent is selected from the group consisting of non-halogen activated-oxygen compounds, non-oxygen activated-halogen compounds, activated-halogen activated-oxygen compounds, and N-halo compounds. 
     
     
         12 . The method of  claim 11 , wherein
 i) the non-halogen activated-oxygen compounds are selected from potassium nitrate (KNO 3 ), permanganate salts, ammonium cerium(IV) nitrate, hexavalent chromium compounds, chromate/dichromate compounds, ammonium silver nitrate, sulfoxides, persulfuric acid, osmium tetroxide (OsO 4 ), nitric acid, nitrous oxide (N 2 O), hydrogen peroxide, organic peroxides, superoxides, and ozone;   ii) the non-oxygen activated-halogen compounds are selected from fluorine, chlorine, bromine, and iodine;   iii) the activated-halogen activated-oxygen compounds are selected from sodium chlorite and tetrachlorodecaoxygen; and   iv) the N-halo compounds are selected from the group consisting of N-halophthalimide, N-halosuccinimide, N-halosaccharin, N,N-dihalourethane, N-haloacetanilide, 1,3-dihalo-5,5-dimethylhydantoin, trihaloisocyanuric acid, and sodium dihaloisocyanurate.   
     
     
         13 . The method of  claim 11 , wherein said oxidative agent is sodium chlorite. 
     
     
         14 . A method of treating a disease associated with excess activation of monocytes to activated macrophages, said method comprising administering a therapeutically-effective amount of an oxidative agent to a subject in need thereof, wherein said oxidative agent is selected from the group consisting of non-halogen activated-oxygen compounds, non-oxygen activated-halogen compounds, and N-halo compounds. 
     
     
         15 . The method of  claim 14 , wherein
 i) the non-halogen activated-oxygen compounds are selected from potassium nitrate (KNO 3 ), permanganate salts, ammonium cerium(IV) nitrate, hexavalent chromium compounds, chromate/dichromate compounds, ammonium silver nitrate, sulfoxides, persulfuric acid, osmium tetroxide (OsO 4 ), nitric acid, nitrous oxide (N 2 O), hydrogen peroxide, organic peroxides, superoxides, and ozone;   ii) the non-oxygen activated-halogen compounds are selected from fluorine, chlorine, bromine, and iodine; and   iii) the N-halo compounds are selected from the group consisting of N-halophthalimide, N-halosuccinimide, N-halosaccharin, N,N-dihalourethane, N-haloacetanilide, 1,3-dihalo-5,5-dimethylhydantoin, trihaloisocyanuric acid, and sodium dihaloisocyanurate.   
     
     
         16 . The method of  claim 14 , wherein said oxidative agent is selected from 1,3-dichloro-5,5-dimethylhydantoin and chloramine-T. 
     
     
         17 . The method of  claim 14 , wherein said disease is associated with excess CD14CD16 expression. 
     
     
         18 . The method of  claim 14 , wherein said disease is a neurodegenerative disease selected from the group consisting of amyotrophic lateral sclerosis (ALS), Parkinson's Disease (PD), Alzheimer's Disease (AD), and complications thereof. 
     
     
         19 . A sodium chlorite compound, wherein said compound is a crystalline solid of greater than 95% purity. 
     
     
         20 . The compound of  claim 19 , wherein said compound is a crystalline solid of greater than 99% purity. 
     
     
         21 . The compound of  claim 19 , wherein said compound has an x-ray powder diffraction pattern with peaks expressed in degrees 20 at about 21, 30, 31, 32, 34, and 39. 
     
     
         22 . A pharmaceutical composition comprising one or more pharmaceutical excipients and the compound of  claim 19 , wherein said composition is a solid. 
     
     
         23 . A pharmaceutical composition comprising:
 (a) the compound of  claim 19 ;   (b) a pH adjusting agent; and   (c) a pharmaceutically acceptable excipient or carrier,   
       wherein said composition is a liquid that exhibits 25% less pH drift compared to an identical composition without said pH adjusting agent. 
     
     
         24 . The composition of  claim 23 , wherein said pH adjusting agent is sodium phosphate dibasic. 
     
     
         25 . A method of treating Type II diabetes or related complications comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising chlorite or a chlorite-containing agent. 
     
     
         26 . A method of treating a disease associated with migration of monocytes or activated macrophages, said method comprising administering a therapeutically-effective amount of an oxidative agent to a subject in need thereof, wherein said oxidative agent is selected from the group consisting of non-halogen activated-oxygen compounds, non-oxygen activated-halogen compounds, activated-halogen activated-oxygen compounds, and N-halo compounds. 
     
     
         27 . The method of  claim 26 , wherein said disease is characterized by elevated CD16 expression levels in CD14+ cells. 
     
     
         28 . The method of  claim 27 , wherein said oxidative agent is selected from sodium chlorite, 1,3-dichloro-5,5-dimethylhydantoin and chloramine-T. 
     
     
         29 . The method of  claim 26 , wherein said disease is characterized by migration of PBMCs in response to chemoattractant. 
     
     
         30 . The method of  claim 29 , wherein said oxidative agent is sodium chlorite. 
     
     
         31 . A method of treating a disease associated with excess production of sCD14 and/or sCD163 by activated macrophages, said method comprising administering a therapeutically-effective amount of an oxidative agent to a subject in need thereof, wherein said oxidative agent is selected from the group consisting of non-halogen activated-oxygen compounds, non-oxygen activated-halogen compounds, activated-halogen activated-oxygen compounds, and N-halo compounds. 
     
     
         32 . The method of  claim 31 , wherein said oxidative agent is sodium chlorite. 
     
     
         33 . A method of diagnosing a macrophage related disease in a subject comprising measuring the level of a biomarker in the subject and correlating the measured level of biomarker to normal and diseased levels of said biomarker, wherein said biomarker is selected from CD16 expression in CD14+ cells, sCD14, sCD163, expression of chemoattractants by macrophages, and combinations thereof. 
     
     
         34 . A method of determining efficacy of treatment with an oxidative agent for a macrophage related disease in a subject comprising:
 i) initiating treatment with an oxidative agent;   ii) measuring the level of a biomarker in the subject; and   iii) correlating the measured level of biomarker to normal and diseased levels of said biomarker and/or levels of biomarker in said subject prior to treatment;   wherein said biomarker is selected from CD16 expression in CD14+ cells, sCD14, sCD163, expression of chemoattractants by macrophages, and combinations thereof.   
     
     
         35 . The method of  claim 34 , wherein said oxidative treatment is sodium chlorite.