Methods and device for synergistic mitigation of reperfusion injury after an ischemic event

1. A method for mitigating reperfusion injury to a tissue in a subject suffering from an ischemic event in a blood vessel, the method comprising:

locally administering a calpain inhibitor to an ischemic blood vessel during a cycle of inflation and deflation of a balloon within the ischemic blood vessel during a postconditioning procedure,

wherein the calpain inhibitor is locally administered to an area of the blood vessel distal to a lesion.

2. The method of claim 1 , wherein the beneficial agent is sequentially locally administered to the blood vessel during the postconditioning procedure, the postconditioning procedure including sequentially reducing perfusion to the tissue by inflating a balloon within the blood vessel for a first period of time, and allowing perfusion of the tissue by deflating the balloon within the blood vessel for a second period of time.

3. The method of claim 1 , wherein the calpain inhibitor exhibits increased uptake into the tissue of the blood vessel as compared to uptake at healthy tissue.

4. The method of claim 3 , wherein the increased uptake is at least four-fold as compared to uptake at healthy tissue.

5. The method of claim 1 , wherein blood plasma of the subject has a concentration of calpain inhibitor at least 60 minutes after the postconditioning has ceased.

6. The method of claim 5 , wherein the blood plasma has a concentration of calpain inhibitor at least 120 minutes after postconditioning has ceased.

7. The method of claim 1 , wherein the tissue is myocardial, cerebral, peripheral, skeletal, or spinal.

8. A method for mitigating reperfusion injury to a tissue of a mammal, the method comprising:

sequentially reducing perfusion to the tissue by inflating a balloon within an ischemic blood vessel for a first period of time, and allowing perfusion of the tissue by deflating the balloon within the ischemic blood vessel for a second period of time, and

locally administering a beneficial agent selected from the group consisting of endothelin receptor blockers, pH stabilizing agents, and calpain inhibitors during postconditioning to a subject, wherein the beneficial agent enhances mitigation of reperfusion injury to an organ or tissue distal to an ischemia,

wherein the beneficial agent is in a vehicle having a biomaterial.

9. The method of claim 8 , wherein the tissue is cerebral, myocardial, skeletal, or peripheral tissue.

10. The method of claim 9 , wherein the method mitigates cerebral injury after a stroke.

11. The method of claim 9 , wherein the method mitigates myocardial injury after a heart attack.

12. The method of claim 8 , wherein the biomaterial increases residence time of the beneficial agent in the blood vessel.

13. The method of claim 8 , wherein the endothelin receptor blocker is atrasentan.

14. The method of claim 8 , wherein the pH stabilizing agent is selected from oxygen, nitric oxide, a mixture of sodium carbonate and citric acid, mixture of carbon dioxide and nitrogen dioxide.

15. A method for mitigating tissue infarction after an ischemic event, the method comprising:

introducing a balloon catheter into an ischemic blood vessel, the balloon catheter having a compliant balloon;

engaging an actuator in one motion to inflate the balloon within the ischemic blood vessel to occlude the blood flow therethrough for a first period of time;

disengaging the actuator in one motion to deflate the balloon within the blood vessel to permit at least partial reperfusion of blood flow through the blood vessel for a second period of time;

alternating the engaging and disengaging steps to alternate the inflation and deflation rounds for at least two cycles to achieve postconditioning of the ischemic blood vessel; and

sequentially administering a beneficial agent locally to the blood vessel during either inflation or deflation of the balloon, wherein the infarcted tissue exhibits a four-fold increase in uptake of the beneficial agent as compared to uptake at healthy tissue.

16. The method of claim 15 , wherein the uptake of beneficial agent is increased at least forty-fold as compared to uptake at healthy tissue.

17. The method of claim 15 , wherein the uptake of beneficial agent is increased at least one-hundred-fold as compared to uptake at healthy tissue.