Combination therapies using cyclosporine and aromatic cationic peptides
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. 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.
2. The method of claim 1 , wherein the pharmaceutically acceptable salt comprises acetate salt or trifluoroacetate salt.
3. The method of claim 1 , 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 trifluoroacetate salt.
4. A pharmaceutical composition comprising (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.
5. The pharmaceutical composition of claim 4 , wherein the pharmaceutically acceptable salt comprises acetate salt or trifluoroacetate salt.
6. The pharmaceutical composition of claim 5 , 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 and trifluoroacetate salt.
7. A composition comprising: an (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-Nth; 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.
8. The composition of claim 7 , wherein the pharmaceutically acceptable salt comprises acetate salt or trifluoroacetate salt.
9. The composition of claim 8 , 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 trifluoroacetate salt, and wherein the linker comprises an enzyme-cleavable linker.
10. The method of claim 1 , wherein the aromatic-cationic peptide is administered intravenously, intradermally, intraperitoneally, subcutaneously, orally, transdermally, topically, intraocularly, iontophoretically, transmucosally, or by inhalation.
11. The method of claim 1 , wherein the ischemia and/or reperfusion injury comprises vessel occlusion injury or cardiac ischemia-reperfusion injury.
12. The pharmaceutical composition of claim 5 , wherein the aromatic-cationic peptide is formulated to be administered intravenously, intradermally, intraperitoneally, subcutaneously, orally, transdermally, topically, intraocularly, iontophoretically, transmucosally, or by inhalation.
13. The composition of claim 8 , wherein the aromatic-cationic peptide is formulated to be administered intravenously, intradermally, intraperitoneally, subcutaneously, orally, transdermally, topically, intraocularly, iontophoretically, transmucosally, or by inhalation.
14. The composition of claim 8 , 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 and trifluoroacetate salt, and wherein the linker comprises a pH-sensitive linker.