Methods and Devices for Reducing Tissue Damage After Ischemic Injury
Methods and devices are provided for the local delivery of anti-ischemic agents which reduce myocardial tissue damage due to ischemia or reperfusion, in combination with compounds that sensitize the response of the tissue to the anti-ischemic agent. The therapeutic agents are delivered to the myocardial tissue over an administration period sufficient to achieve reduction in ischemic or reperfusion injury of the tissue.
1 . A method for reducing tissue damage following ischemic injury in a patient, comprising:
administering to the patient an anti-ischemic agent which reduces tissue damage due to ischemia and one or more drug sensitizers that sensitize the tissue to the anti-ischemic agent, wherein at least one of the anti-ischemic agent and the one or more drug sensitizers are administered locally to or near the site of ischemic injury.
2 . The method of claim 1 , wherein at least one of the anti-ischemic agent and sensitizer is administered in a medical device implanted at or near the site of ischemic injury.
3 . The method of claim 2 , wherein the device is selected from the group consisting of stents, polymeric delivery devices, polymeric particles and polymeric coatings.
4 . The method of claim 3 , wherein the at least one of anti-ischemic agent and one or more drug sensitizers is administered into a blood vessel.
5 . The method of claim 4 , wherein the at least one of anti-ischemic agent and one or more drug sensitizers are administered for periods of time sufficient to reduce ischemic injury.
6 . The method of claim 4 , wherein the device further comprises an anti-restenotic drug to inhibit restenosis, wherein the anti-restenotic drug is delivered primarily from a mural side of the medical device, and wherein the anti-ischemic agent and the drug sensitizer are delivered primarily from a luminal side of the medical device.
7 . The method of claim 2 , wherein the anti-ischemic agent is administered systemically and the sensitizer is administered from the medical device implanted at or near the site of ischemic injury.
8 . The method of claim 2 , wherein the sensitizer is administered systemically and the anti-ischemic agent is administered from the medical device implanted at or near the site of ischemic injury.
9 . The method of claim 2 , wherein the sensitizer and the anti-ischemic agent are administered from the medical device implanted at or near the site of ischemic injury.
10 . The method of claim 9 , wherein the medical device is a stent.
11 . The method of claim 3 , wherein the device further comprises an anti-restenotic drug to inhibit restenosis, wherein the anti-restentotic drug is delivered primarily from a mural side of the medical device, and wherein the anti-ischemic agent is delivered primarily from a luminal side of the medical device.
12 . The method of claim 1 , wherein the anti-ischemic agent is insulin.
13 . The method of claim 12 , wherein the drug sensitizer is an insulin sensitizer.
14 . The method of claim 13 , wherein the insulin sensitizer is selected from the group consisting of biguanides, thiazolidinediones, and glitazars.
15 . The method of claim 11 , wherein the anti-restenotic drug is selected from the group of compounds consisting of antineoplastics, antiangiogenics, angiogenic factors, anti-thrombotics, antiproliferatives, and anti-inflammatories.
16 . The method of claim 13 , wherein the insulin and insulin sensitizer are delivered from a stent having a therapeutic dosage of insulin and the insulin sensitizer affixed thereto which is implanted at or near an occlusion site.
17 . The method of claim 13 , wherein the insulin and insulin sensitizer are delivered by a catheter to an occlusion site.
18 . The method of claim 13 , wherein the insulin and insulin sensitizer are delivered from a polymer.
19 . The method of claim 18 , wherein the polymer is in the form of polymeric coatings or particles located at or near an occlusion site.
20 . The method of claim 18 , wherein the insulin, insulin sensitizer, and a biocompatible polymer matrix are deposited within openings in an implantable medical device for local delivery to an occlusion site.
21 . The method of claim 20 , wherein the insulin, insulin sensitizer, and biocompatible polymer are deposited within openings in the implantable medical device and wherein a barrier layer is provided which substantially prevents delivery of the insulin to the artery wall.
22 . The method of claim 13 , wherein the insulin sensitizer is the PPAR farglitizar.
23 . A device for use in the method of any of claims 1 - 22 .
24 . The device of claim 23 , wherein the anti-ischemic agent and/or sensitizer is released for at least one hour.
25 . The device of claim 24 , wherein the anti-ischemic agent and/or sensitizer is released for about 10 to about 48 hours.
26 . The device of claim 24 , wherein the anti-ischemic agent is insulin and the therapeutic dosage is about 5 to about 800 micrograms.
27 . An implantable stent for reducing tissue damage following ischemic injury in a patient, comprising:
an expandable stent structure:
an anti-ischemic agent affixed to the stent structure, wherein the anti-ischemic agent reduces tissue damage due to ischemia; and
one or more drug sensitizers that sensitize the tissue to the anti-ischemic agent.
28 . The stent of claim 27 , wherein the anti-ischemic agent and/or sensitizer is released for at least one hour.
29 . The stent of claim 27 , wherein the anti-ischemic agent and/or sensitizer is released for about 10 to about 48 hours.
30 . The stent of claim 27 , wherein the anti-ischemic agent is insulin and the therapeutic dosage is about 5 to about 800 micrograms.
31 . The stent of claim 30 , wherein the insulin is affixed to the stent by depositing in holes in the stent.
32 . The stent of claim 27 , wherein the anti-ischemic agent and sensitizer are affixed to the stent by depositing in holes in the stent.
33 . The stent of claim 30 , wherein the sensitizer is an insulin sensitizer.