Targeting NCCA-ATP channel for organ protection following ischemic episode
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Publication Number
US-9511075-B2
Publication Date
2016-12-06
Expiration Date
2028-01-11
Abstract
The present invention concerns protection of an organ or tissue following an ischemic episode In particular aspects, the invention concerns organ preservation for transplantation, angina pectoris, kidney reperfusion injury, and so forth In specific embodiments, the organ is subjected to an inhibitor of an NCCa-ATP channel that is regulated by SUR1 Exemplary inhibitors include sulfonylurea compounds, such as glibenclamide, for example.
Core Innovation
The present invention concerns protection of an organ or tissue following an ischemic episode, with specific focus on a novel non-selective monovalent cationic ATP-sensitive ion channel (NCCa-ATP channel) coupled to sulfonylurea receptor type 1 (SUR1). This channel is expressed in various cells such as neurons, glia, endothelial cells, and tissues including cornea, retina, bone, heart valves, and others after trauma or ischemia/hypoxia.
The NCCa-ATP channel has a single-channel conductance to potassium ion (K+) between 20 and 50 pS, is stimulated by intracellular calcium in the range from 10⁻⁸ to 10⁻⁵ M, inhibited by cytoplasmic ATP in the range from 10⁻¹ to 5 mM, and permeable to monovalent cations (K+, Cs+, Li+, Na+) with permeability ratios between 0.5 and 2. The channel is regulated by SUR1 and is blocked by compounds such as sulfonylureas (e.g., glibenclamide) and non-sulfonylurea compounds (e.g., repaglinide). Blocking the channel reduces cell swelling and necrotic cell death triggered by ATP depletion.
The problem solved by the invention arises from the serious cellular and tissue damage following injurious events including ischemia/hypoxia, such as heart attack, stroke, and organ transplantation. This damage includes cytotoxic edema characterized by neural cell swelling due to various mediators and leads to secondary injury such as progressive hemorrhagic necrosis (PHN). Prior to this invention, no molecular mechanism for progressive endothelial dysfunction involved in PHN had been identified nor had selective treatments been reported that reduce PHN and ischemia/hypoxia associated injury by targeting SUR1-regulated NCCa-ATP channels.
Claims Coverage
The patent contains one independent claim describing a method to treat or reduce ischemic damage in organs or tissues by delivering an inhibitor of the NCCa-ATP channel to an individual.
Method of treating ischemic damage with targeted NCCa-ATP channel inhibitors
Delivering to an individual an effective amount of an inhibitor of an NCCa-ATP channel in a pharmaceutically acceptable carrier to treat or reduce ischemic damage in organs or tissues including the heart, liver, pancreas, spleen, intestine, cornea, skin, bone marrow, heart valve, or connective tissue.
Use of specified inhibitors targeting SUR1 or TRPM4
The inhibitor used is a SUR1 antagonist, a Transient Receptor Potential cation channel subfamily M member 4 (TRPM4) antagonist, or selected from flufenamic acid, mefanimic acid, niflumic acid, antagonists of matrix metalloproteinase (MMP), or combinations thereof.
Specific SUR1 antagonists
SUR1 antagonists include glibenclamide (glyburide), tolbutamide, acetohexamide, chlorpropamide, tolazimide, glipizide, gliquidone, repaglinide, nateglinide, meglitinide, gliclazide, glimepiride, and their active metabolites.
Administration methods and timing
The inhibitor is delivered by intravenous, subcutaneous, intramuscular, intracutaneous, intragastric or oral routes and may be administered prior to, concurrent with, or following an ischemic episode, including those related to organ preservation for transplantation, angina pectoris, or kidney reperfusion injury.
Dosage and dosing regimen
Administration may be as a loading dose followed by constant infusion, with dosages less than 3.5 mg per day or less than 0.8 mg/kg body weight within a 24-hour period.
Application to organ transplantation processes
Delivering the inhibitor directly to the organ or tissue prior to, during, or after extraction from the donor, or to the recipient prior to, during, or after transplantation.
Combination with additional therapeutic agents
Further comprising delivery of additional therapeutic agents such as antacids, immunosuppressants, antivirals, antibacterials, antifungals or combinations thereof, specifically immunosuppressants like anti-thymocyte globulin, basiliximab, methylprednisolone, tacrolimus, mycophenolate mofetil, prednisone, sirolimus, rapamycin, azathioprine.
Diagnostic method incorporating presence of NCCa-ATP channel
Determining the presence of the NCCa-ATP channel in one or more cells of the organ or tissue and subjecting the tissue or organ to the inhibitor accordingly, by methods including patch clamp analysis.
The claims cover methods for treating ischemic damage in various organs or tissues by administering inhibitors of the SUR1-regulated NCCa-ATP channel or related agents via multiple routes and timings, with specific therapeutic agents identified, application in transplantation contexts, and diagnostic methods related to channel presence assessment.
Stated Advantages
Significant reduction in cerebral and spinal cord edema, stroke volume, and mortality following ischemic injury.
Reduction of necrotic cell death and cytotoxic edema by blocking NCCa-ATP channel with inhibitors like glibenclamide.
Potent and selective inhibition of NCCa-ATP channels resulting in preservation of capillary integrity and reduction of hemorrhagic conversion.
Improved neurological functional recovery in animal models of ischemic stroke and spinal cord injury.
Extension of therapeutic window for administration of thrombolytic agents when co-administered with NCCa-ATP channel inhibitors.
Documented Applications
Protection and preservation of organs or tissues following ischemic episodes including but not limited to organ transplantation (heart, liver, kidney, lung, pancreas, spleen, gastrointestinal tract organs), angina pectoris, and kidney reperfusion injury.
Treatment and prevention of ischemia/hypoxia associated injuries in the central nervous system such as stroke and spinal cord injury.
Reduction of cytotoxic, ionic and vasogenic edema, and prevention of hemorrhagic conversion in stroke, traumatic brain injury, and spinal cord injury.
Use in surgical procedures including coronary artery bypass grafting and other vascular transplants to reduce ischemic damage to graft tissue during removal, storage, or transplantation.
Screening and identification of compounds that modulate NCCa-ATP channel activity for therapeutic use.
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