PEROXISOME-PROLIFERATOR ACTIVATED RECEPTOR-ALPHA AGONISTS FOR ORGAN PRESERVATION

Abstract

Methods and compositions for reducing, preventing or reversing organ damage and/or enhancing organ preservation by administration of a peroxisome-proliferator activated receptor-alpha (PPARα) agonist to the organ.

Description

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 is a graph of the histology score for control kidney and kidney exposed to mannitol, gemfibrozil, or mannitol+gemfibrozil.

FIG. 2 is a graph of the Na-K-ATPase/beta-actin level in normal, control, and mannitol, gemfibrozil and mannitol+gemfibrozil treated kidney tissue.

FIG. 3 is a graph of perfusion pressure over time in control and tissue exposed to gemfibrozil, mannitol and mannitol+gemfibrozil.

FIG. 4A is a graph of initial urine flow rate in control kidney and kidney exposed to mannitol, gemfibrozil, or mannitol+gemfibrozil.

FIG. 4B is a graph of the terminal flow rate in control kidney and kidney exposed to mannitol, gemfibrozil, or mannitol+gemfibrozil.

FIG. 4C is a graph of the total urine volume in control kidney and kidney exposed to mannitol, gemfibrozil, or mannitol+gemfibrozil.

Claims

1. A method for preventing, reducing or reversing organ damage or enhancing organ preservation comprising contacting the organ with a PPARα agonist in an amount effective to prevent, reduce or reverse organ damage or enhance organ preservation.

2. The method of claim 1, wherein the PPARα agonist comprises a fibric acid derivative.

3. The method of claim 2, wherein the fibric acid derivative is selected from the group consisting of gemfibrozil, clofibrate, fenofibrate, ciprofibrate and bezafibrate.

4. The method of claim 1, wherein the PPARα agonist is gemfibrozil.

5. The method of claim 1, wherein the PPARα agonist is 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid.

6. The method of claim 1, further comprising contacting the organ with a cell-impermeable solute.

7. The method of claim 6, wherein the cell-impermeable solute comprises mannitol.

8. The method of claim 7, wherein the PPARα agonist is gemfibrozil.

9. The method of claim 7, wherein the PPARα agonist is 4-chloro-6-(2,3-xylidino)-2-pyrimidinyl thioacetic acid.

10. The method of claim 1 or 6, wherein the organ is kidney, liver, heart, skin and lung.

11. The method of claim 1 or 6, wherein the organ is a kidney.

12. The method of claim 1, wherein the PPARα agonist is delivered into the organ's blood supply while the organ is being perfused by a cardiovascular system.

13. The method of claim 6, wherein the PPARα agonist and cell-impermeable solute are delivered into the organ's blood supply while the organ is being perfused by a cardiovascular system.

14. A method for preventing, reducing or reversing organ damage or enhancing organ preservation comprising contacting an organ with a preservation solution wherein the preservation solution comprises a PPARα agonist in an amount effective to prevent, reduce or reverse organ damage or enhance organ preservation.

15. The method of claim 14, wherein the PPARα agonist comprises a fibric acid derivative.

16. The method of claim 14, wherein the fibric acid derivative is selected from the group consisting of gemfibrozil, clofibrate, fenofibrate, ciprofibrate and bezafibrate.

17. The method of claim 14, wherein the PPARα agonist is gemfibrozil.

18. The method of claim 14, wherein the PPARα agonist is 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid.

19. The method of claim 14, wherein the preservation solution further comprises a cell-impermeable solute.

20. The method of claim 19, wherein the cell-impermeable solute comprises mannitol.

21. The method of claim 19, wherein the PPARα agonist is gemfibrozil.

22. The method of claim 19, wherein the PPARα agonist is 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid.

23. The method of claim 14 or 19, wherein the organ is selected from the group consisting of kidney, liver, heart, skin and lung.

24. The method of claim 14 or 19, wherein the organ is a kidney.

25. The method of claim 14 or 19, wherein the preservation solution is flushed or continuously perfused or intermittently perfused through blood vessels of the organ.

26. The method of claim 14 or 19, wherein the preservation solution is contacted with the organ while the organ is within a subject.

27. The method of claim 14 or 19, wherein the preservation solution is contacted with the organ during or after the removal of the organ from a subject.

28. A composition for preventing, reducing or reversing organ damage and enhancing organ preservation comprising a PPARα agonist and a carrier, wherein the PPARα agonist is present in an amount effective to prevent, reduce or reverse organ damage or enhance organ preservation.

29. The composition of claim 28, wherein the PPARα agonist comprises a fibric acid derivative.

30. The composition of claim 29, wherein the fibric acid derivative is selected from the group consisting of gemfibrozil, clofibrate, fenofibrate, ciprotribrate and bezafibrate.

31. The composition of claim 28, wherein the PPARα agonist is gemfibrozil.

32. The composition of claim 28, wherein the PPARα agonist is 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid.

33. The composition of claim 28, further comprising a cell-impermeable solute.

34. The composition of claim 33, wherein the cell-impermeable solute comprises mannitol.

35. The composition of claim 33, comprising gemfibrozil and mannitol.

36. The composition of claim 33, comprising 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid.