THERAPEUTIC AGENTS TARGETING THE NCCa-ATP CHANNEL AND METHODS OF USE THEREOF
The present invention is directed to therapeutic compositions targeting the NC Ca-ATP channel of an astrocyte, neuron or capillary endothelial cell and methods of using same. More specifically, agonists and antagonists of the NC Ca-ATP channel are contemplated. The therapeutic compositions are used to treat cancer, more specifically, a metastatic brain tumor, wherein a tumor-brain barrier is present. Such treatments are contemplated in combination with conventional anti-cancer therapies. Alternatively, the compositions are used to prevent cell death and to treat cerebral edema that result from ischemia, due to interruption of blood flow, to tissue trauma or to increased tissue pressure.
1 . A method of reducing disruption of blood brain barrier in a subject in need thereof comprising administering glibenclamide or a pharmaceutically acceptable salt thereof and a thrombolytic agent to said subject.
2 . The method of claim 1 , wherein the thrombolytic agent is a tissue plasminogen activator (tPA).
3 . The method of claim 1 , wherein the thrombolytic agent is urokinase, prourokinase, streptokinase, anistreplase, reteplase, or tenecteplase.
4 . The method of claim 1 , further comprising administering to the subject an anticoagulant or antiplatelet.
5 . The method of claim 4 , wherein the anticoagulant or antiplatelet is aspirin, warfarin or coumadin.
6 . The method of claim 1 , further comprising administering to the subject one or more statins, diuretics, or vasodilators.
7 . The method of claim 1 , further comprising administering mannitol to the subject.
8 . The method of claim 1 , wherein the glibenclamide or pharmaceutically acceptable salt thereof is administered alimentarily.
9 . The method of claim 8 , wherein alimentarily comprises orally, buccally, rectally, or sublingually.
10 . The method of claim 1 , wherein the glibenclamide or pharmaceutically acceptable salt thereof is administered parenterally.
11 . The method of claim 10 , wherein parenterally comprises intravenously, intradermally, intramuscularly, intraarterially, intrathecally, subcutaneously, intraperitoneally, or intraventricularly.
12 . The method of claim 10 , wherein parenterally comprises injection into the brain parenchyma.
13 . The method of claim 1 , wherein the glibenclamide or pharmaceutically acceptable salt thereof is administered at a dosage of 0.001 μg/kg/day to 100 μg/kg/day.
14 . The method of claim 1 , wherein the glibenclamide or pharmaceutically acceptable salt thereof is administered at a loading dosage of 0.1 μg/kg to 100 μg/kg.
15 . The method of claim 1 , wherein release of matrix metalloproteinase-2 and/or matrix metalloproteinase-9 from brain tissue of said subject is reduced.