Combination therapies using cyclosporine and aromatic cationic peptides

Abstract

The invention provides compositions and methods for preventing or treating an ischemia-reperfusion injury, such as occurs during acute myocardial infarction and organ transplant in a mammalian subject. The methods comprise administering to the subject an effective amount of an aromatic-cationic peptide or a pharmaceutically acceptable salt thereof, and one or more additional active agents such as cyclosporine.

1 .- 20 . (canceled) 
     
     
         21 . A method for treating ischemia and/or reperfusion injury in a subject in need thereof, the method comprising administering simultaneously, separately or sequentially an effective amount of (i) an aromatic-cationic peptide or a pharmaceutically acceptable salt thereof, wherein the aromatic-cationic peptide is selected from the group consisting of: Tyr- D -Arg-Phe-Lys-NH 2 ; 2′,6′-Dmt- D -Arg-Phe-Lys-NH 2 ; Phe- D -Arg-Phe-Lys-NH 2 ; 2′,6′-Dmp- D -Arg-Phe-Lys-NH 2 ; and  D -Arg-2′,6′-Dmt-Lys-Phe-NH 2  and (ii) an additional active agent comprising a functional analogue of cyclosporine, wherein the aromatic-cationic peptide is linked to the additional active agent by a linker. 
     
     
         22 . The method of  claim 21 , wherein the pharmaceutically acceptable salt comprises acetate salt or trifluororacetate salt. 
     
     
         23 . The method of  claim 21 , wherein the aromatic-cationic peptide comprises D-Arg-2′6′-Dmt-Lys-Phe-NH 2  or a pharmaceutically acceptable salt thereof selected from acetate salt or trifluororacetate salt. 
     
     
         24 . The method of  claim 21 , wherein the linker comprises an enzyme-cleavable linker or a pH-sensitive linker. 
     
     
         25 . The method of  claim 21 , wherein the aromatic-cationic peptide is administered intravenously, intradermally, intraperitoneally, subcutaneously, orally, transdermally, topically, intraocularly, iontophoretically, transmucosally, or by inhalation. 
     
     
         26 . The method of  claim 21 , wherein the ischemia and/or reperfusion injury comprises vessel occlusion injury or cardiac ischemia-reperfusion injury.