Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-10-06
2001-11-20
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
active
06319955
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to treatments for tissue damage associated with ischemia, particularly brain damage associated with ischemia resulting from stroke.
BACKGROUND OF THE INVENTION
Ischemic diseases are significant causes of mortality in industrialized nations. It is well established that tissue damage results from ischemia (stoppage of blood flow to the tissue) followed by reperfusion of the tissue. The ischemic injury with the consecutive reperfusion is responsible for the disturbance of microcirculation with ensuing tissue damage and organ dysfunction.
One well-known example of ischemia and its effects is stroke, which is a condition resulting from a reduction or blockage of blood flow to the brain (cerebral ischemia). About 500,000 Americans suffer strokes each year, 80% of which are caused by a blood clot blocking one of the cerebral blood vessels. Symptoms of stroke include weakness, numbness or paralysis of the face, arm or leg; sudden loss or dimness of vision; loss of speech or difficulty using or understanding language; sudden, severe unexplained headache; or unexplained dizziness, unsteadiness or sudden falls (particularly if associated with one of the above symptoms).
Other organs are also affected by ischemia. For example, tissues such as kidney, heart, liver, pancreas, lung, intestine, are also known to sustain damage following ischemia and reperfusion.
The phosphorylation of ERK/MAP kinase in response to brain ischemia has been demonstrated previously. However, it is not known what, if any, role the ERK/MAP kinase pathway plays in the causation of tissue damage following ischemia and/or reperfusion.
SUMMARY OF THE INVENTION
It has now been discovered that MEK1 kinase activity is involved in ischemia-induced tissue damage. Using a mouse model of stroke in which permanent or transient focal cerebral ischemia is induced by middle cerebral artery occlusion, it has been demonstrated that MEK1 inhibitors can decrease the tissue damage which results from ischemia and reperfusion, in some cases even if the MEK1 inhibitor is administered after the onset of ischemia. It also has been demonstrated that MEK1 inhibitors can protect cells from glutamate toxicity and hypoxia.
According to one aspect of the invention, a method for treating a subject having a condition characterized by ischemia is provided. The method includes administering to a subject in need of such treatment a MEK1 inhibitor in an amount effective to reduce MEK1 activity, wherein the subject is free of symptoms otherwise calling for treatment with the MEK1 inhibitor. In certain embodiments, the symptoms otherwise calling for treatment with the MEK1 inhibitor are the symptoms of a proliferative disease. In other embodiments, the MEK1 inhibitor is selected from the group consisting of small molecule organic compounds, inhibitory antibodies, synthetic kinase substrate peptides, dominant negative MEK1 proteins, .antisense nucleic acids, and ribozymes which reduce the expression of translatable MEK1 transcripts. Preferably the MEK1 inhibitor is a small molecule organic compound, particularly a tricyclic flavone or a (phenylthio)butadiene compounds. In certain preferred embodiments, the MEK1 inhibitor is 2-(2-amino-3-methoxyphenyl)-4-oxo-4H-[1]benzopyran (PD98059), 1,4-diamino-2,3-dicyano-1,4-bis-(phenylthio)butadiene (U0125) or 1,4-diamino-2,3-dicyano- 1,4-bis-(2-aminophenylthio)butadiene (U0126). In particularly preferred embodiments the MEK1 inhibitor is (1,4-diamino-2,3-dicyano-1,4-bis-(2-aminophenylthio)butadiene (U0126). In other preferred embodiments, the MEK1 inhibitor is administered to a subject who has had an ischemic stroke, or is administered prophylactically to a subject at risk of having an ischemic stroke. It is preferred that the MEK1 inhibitor is administered parenterally, particularly intravenously.
According to another aspect of the invention, a pharmaceutical composition is provided. The pharmaceutical composition includes a MEK1 inhibitor and a non-MEK1 inhibitor anti-stroke agent, together in an amount effective for treating an ischemic condition. Preferred inhibitors and agents are as described elsewhere.
According to still another aspect of the invention, a kit is provided. The kit includes a package housing a first container containing a MEK1 inhibitor, and instructions for using the MEK1 inhibitor in the treatment of an ischemic condition. In certain embodiments, the kit also includes a second container containing a non-MEK1 inhibitor anti-strokf agent.
According to another aspect of the invention, a medical product is provided which includes an isolated organ in a perfusion fluid containing a MEK1 inhibitor.
According to another aspect of the invention, a medical product is provided which includes an organ perfusion fluid containing a MEK1 inhibitor.
In another aspect of the invention, the use of the foregoing MEK1 inhibitors in the preparation of a medicament for the foregoing treatments of conditions characterized by ischemia, particularly stroke, is provided.
These and other objects of the invention will be described in further detail in connection with the detailed description of the invention.
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Alessandrini Alessandro
Bonventre Joseph
Moskowitz Michael A.
Namura Shobu
Henley III Raymond
The General Hospital Corporation
Wolf Greenfield & Sacks P.C.
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