Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-11-24
2001-08-07
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S252100, C514S421000
Reexamination Certificate
active
06271199
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to treatment of ischemia and reperfusion injury, including preventing or reducing the size of infarct after vascular occlusion.
BACKGROUND OF THE INVENTION
All tissues are sensitive to hypoperfusion and the resulting lack of oxygen, ischemia. Prolonged ischemia will result in cellular damage. The magnitude of the injury and the potential for tissue rescue depends upon the degree and duration of the ischemia. With long ischemic periods, cellular death occurs (infarction) and under these conditions the injury is irreversible. On the other hand, dying cells or cells targeted for cell death may be rescued by drug treatment, if applied in a timely fashion.
Major ischemic events of therapeutic concern include, but are not limited to, heart attacks and stroke. In man, stroke accounts for 10% of all premature deaths, and of those that survive the insult, 50% are left severely disabled. Only a small fraction, 10%, of patients actually recover full function.
Over 1,500,000 Americans suffer from myocardial infarctions each year. About half of these do not survive to reach the hospital. However, with the acceptance of thrombolytic therapy such as streptokinase or tissue plasminogen activator (TPA), the one month survival rate for patients who do reach the hospital is as high as 93.6% (Werns, S. W.
Textbook of Interventional Cardiology
, ed. Topol, E. J. WB Saunders: 1994, pp142-153). By lysing the clot early in the course of infarct, ischemic muscle and tissue can be salvaged. However, reperfusion in and of itself leads to tissue damage.
Reperfusion injury may occur as a result of one or more of the following events: cellular acidosis leading to calcium overload; increased intracellular osmotic loads of catabolites leading to cell swelling; free radicals from neutrophils and other inflammatory cells.
Neutrophils are seen in reperfused myocardium shortly after reperfusion. Monocytes/macrophages appear within 24 to 48 hours. Neutrophil infiltration is three to five fold greater in reperfused myocardium than in ischemic myocardium, is initiated by adhesion to endothelial cells, and occurs within 10 minutes of reperfusion. Neutrophils in and of themselves may become trapped in capillaries and impede reperfusion. Intravascular neutrophils may block up to 27% of the capillaries, and have been shown to be related to decreased regional blood flow (Forman et al.,
Acute Myocardial Infarction
, eds. Gersh et al. Elsevier: 1991, pp 347-370). This can result in the “no-reflow” phenomenon, where blood flow continues to decrease after reperfusion.
It is known that neutrophils must first adhere themselves to the endothelial cell wall through the interactions with adhesion molecules. Once attached to the vessel cell wall, the neutrophils then force themselves between adjacent endothelial cells and move into the brain tissue, where they release cytotoxic cytokines. The expression of such adhesion molecules is increased following cell damage including ischemia. In addition, endothelial cell walls become more permeable to infiltrating cells due to the release of nitric oxide (NO). Agents that inhibit the movement (diapedesis) of neutrophils from surrounding blood vessels into the damaged tissue may thus be of value in allowing dying cells time to recover from the ischemic insult.
There is a need in the art for effective therapies to prevent or reduce the consequences of ischemia.
SUMMARY OF THE INVENTION
In a first aspect, the present invention is directed to a method of treating ischemia in a mammal comprising administering to said mammal an effective amount of an NF-&kgr;B activation inhibitor. Preferred NF-&kgr;B activation inhibitors are selected from the group consisting of proteasome inhibitors, ubiquitin pathway inhibitors, inhibitors of serine phosphorylation of I&kgr;B-&agr;. and mixtures thereof. Preferably, the agent is administered to the mammal after the onset of transient vascular occlusion and prior to induction of permanent ischemic damage.
In a second aspect, the present invention is directed to a method of preventing or lessening the severity reperfusion injury in a mammal comprising administering to said mammal an effective amount of an NF-&kgr;B activation inhibitor. Preferred NF-&kgr;B activation inhibitors are selected from the group consisting of proteasome inhibitors, ubiquitin pathway inhibitors, inhibitors of serine phosphorylation of I&kgr;B-&agr;. and mixtures thereof.
In a third aspect, the present invention is directed to a method of preventing, reducing the size of, or lessening the severity of infarction in a mammal comprising administering to said mammal an effective amount of an NF-&kgr;B activation inhibitor. Preferred NF-&kgr;B activation inhibitors are selected from the group consisting of proteasome inhibitors, ubiquitin pathway inhibitors, inhibitors of serine phosphorylation of I&kgr;B-&agr;. and mixtures thereof. In preferred embodiments, the method according to this aspect of the invention prevents or lessens severity of infarction after occlusion of a cerebral vessel or a cardiac vessel. In certain preferred embodiments, the method prevents the occlusion from resulting in stroke, or lessens the severity of a stroke resulting from cerebral vessel occlusion.
In a fourth aspect, the present invention is directed to a method of treating ischemia or reperfusion injury, including preventing or lessening the severity of infarction in a mammal comprising administering to the mammal an adjunct therapeutic, in addition to administering an NF-&kgr;B activation inhibitor. Preferred NF-&kgr;B activation inhibitors are selected from the group consisting of proteasome inhibitors, ubiquitin pathway inhibitors, inhibitors of serine phosphorylation of I&kgr;B-&agr;. and mixtures thereof. Certain preferred adjunct therapeutics include without limitation, agents such as steroids which further inhibit NF-&kgr;B activation or inhibit the expression or action of proinflammatory cytokines or cellular adhesion molecules; agents which act to either reperfuse or oxygenate tissues, such antiedema drugs, thrombolytics such as TPA, streptokinase and urokinase, polyanions such as heparin, anticoagulants; and agents that assist in temperature normalization.
Preferred NF-&kgr;B activation inhibitors inhibit NF-&kgr;B activation by the ubiquitin-proteasome pathway. In certain preferred embodiments, the NF-&kgr;B activation inhibitor inhibits phosphorylation of I&kgr;B-&agr;. In certain preferred embodiments, the NF-&kgr;B activation inhibitor is a proteasome inhibitor. Preferably, the proteasome inhibitor is selected from the group consisting of peptidyl aldehydes, boronic acids, boronic esters, lactacystin, and lactacystin analogs. In certain preferred embodiments, NF-&kgr;B activation inhibitor is a ubiquitin pathway inhibitor.
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Brand Stephen J
Elliott Peter J.
Goldberg Alfred L.
Plamondon Louis
Soucy Francois
Hale and Dorr LLP
Henley III Raymond
Millennium Pharmaceuticals Inc.
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