Targeting NCCA-ATP channel for organ protection following ischemic episode
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Publication Number
US-10166244-B2
Publication Date
2019-01-01
Expiration Date
2028-01-11
Abstract
The present invention concerns protection of an organ or tissue outside of the central nervous system 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 invention concerns a novel non-selective monovalent cationic ATP-sensitive ion channel (NCCa-ATP channel) that is activated by intracellular calcium and blocked by intracellular ATP, regulated by sulfonylurea receptor type 1 (SUR1). It is expressed in cells including neurons, astrocytes, and capillary endothelial cells in tissues undergoing ischemia, trauma, or hypoxia. The NCCa-ATP channel facilitates influx of Na+, leading to cell depolarization, cytotoxic edema, and oncotic (necrotic) cell death.
The problem being solved is the lack of effective treatments to protect organs or tissues outside of the central nervous system following ischemic episodes, such as ischemia/hypoxia injury or organ transplantation-related damage. Secondary injury involving progressive hemorrhagic necrosis (PHN), cytotoxic edema, and hemorrhagic conversion following ischemia worsens tissue damage and morbidity, with no prior molecular mechanism identified for progressive endothelial dysfunction or effective targeted therapies. The invention addresses reducing secondary injury by targeting the SUR1-regulated NCCa-ATP channel with specific inhibitors like sulfonylurea compounds (e.g., glibenclamide).
The invention provides methods and compositions for modulating the NCCa-ATP channel to treat or prevent ischemia/hypoxia-associated conditions by administering antagonists or inhibitors of the channel, alone or in combination with additional therapeutic compounds. This modulatory treatment reduces cellular swelling, edema, and cell death by preventing depolarization and ionic influx in cells expressing the channel, thereby preserving organ and tissue integrity during or after ischemic insults.
Claims Coverage
The claims present a method with key inventive features related to treating ischemic damage via administration of NCCa-ATP channel inhibitors, focusing on SUR1 and TRPM4 antagonists administered as a bolus and maintenance infusion.
Method of treating ischemic damage with NCCa-ATP channel inhibitors administered as loading bolus and maintenance infusion
A method of treating or reducing ischemic damage in a subject by administering an inhibitor of an NCCa-ATP channel that is a SUR1 antagonist and/or a TRPM4 antagonist as a loading bolus dose followed by a constant infusion of a maintenance dose, wherein the bolus is 30-90 times the maintenance dose.
Use of specific SUR1 antagonists for ischemic damage treatment
The SUR1 antagonist is selected from glibenclamide, tolbutamide, acetohexamide, chlorpropamide, tolazimide, glipizide, gliquidone, repaglinide, nateglinide, meglitinide, gliclazide, glimepiride, or their pharmaceutically acceptable salts or active metabolites.
Use of specific TRPM4 antagonists and additional molecular antagonists
The TRPM4 antagonist is selected from flufenamic acid, mefanimic acid, niflumic acid, and antagonists of VEGF, MMP, NOS, TNFα, NFkB, and/or thrombin.
Various administration routes for inhibitor delivery
The inhibitor is delivered by intravenous, subcutaneous, intramuscular, intracutaneous, intragastric, or oral administration.
Timing of inhibitor administration relative to ischemic episode
The inhibitor is administered prior to, concurrent with, or both prior and concurrent with an ischemic episode.
Post-ischemic administration of inhibitor
The inhibitor is administered following an ischemic episode.
Direct delivery of inhibitor to organ or tissue
The method includes delivering the inhibitor directly to the organ or tissue.
Inhibitor delivery in relation to organ or tissue extraction
The method includes delivering the inhibitor to the subject prior to extraction of an organ or tissue, during extraction, or both.
Inhibitor delivery relative to extraction timing
The method includes delivering the inhibitor to the organ or tissue prior to extraction, during extraction, subsequent to extraction, or combined thereof.
Inhibitor delivery relative to transplantation timing
The method includes delivering the inhibitor to recipient prior to transplantation, during transplantation, and/or after transplantation of the organ or tissue.
Treatment of ischemic damage related to organ preservation and conditions
The ischemic damage is related to organ preservation for transplantation, angina pectoris, or kidney reperfusion injury.
Co-delivery of additional therapeutic agents
The method further comprises delivery of an additional therapeutic agent.
Additional agents include various therapeutic compound classes
The additional therapeutic agent comprises an antacid, immunosuppressant, antiviral, antibacterial, antifungal compound, or a combination thereof.
Types of immunosuppressants included as additional therapeutic agents
The immunosuppressant is anti-thymocyte globulin, basiliximab, methylprednisolone, tacrolimus, mycophenolate mofetil, prednisone, sirolimus, rapamycin, azathioprine, or mixtures thereof.
Dosage ranges for SUR1 antagonist administration
SUR1 antagonist is administered at less than 3.5 mg per day or at less than 0.8 mg/kg body weight within a 24-hour period.
Use of constant infusion and dosing duration
The maintenance dose is administered as a constant infusion for six or more hours or for twenty-four or more hours.
The claims cover inventive features directed to a specific method of administering SUR1 and TRPM4 antagonists via loading bolus and maintenance infusion with specified doses and timing, covering inhibitor selection, administration routes, timing relative to ischemic episodes and transplantation, additional therapeutic compounds, and dosage regimens to reduce ischemic damage effectively.
Stated Advantages
Reduction of mortality in ischemia/hypoxia through inhibition of NCCa-ATP channels.
Significant reduction in cerebral and spinal cord edema and lesion size.
Inhibition of cytotoxic and ionic edema and prevention of hemorrhagic conversion.
Improvement of neurological function and recovery following ischemic injury.
Protection and preservation of organs and tissues following ischemic episode or trauma.
Enhancement of therapeutic window for thrombolytic agents when co-administered with NCCa-ATP channel antagonists.
Documented Applications
Treatment of ischemic damage in organs or tissues outside of the central nervous system such as heart, kidney, liver, lung, pancreas, spleen, cornea, skin, bone marrow, or connective tissue.
Organ preservation and protection for transplantation including pre-extraction, during extraction, post-extraction, and post-transplantation treatment.
Reduction of edema and hemorrhagic conversion following ischemic stroke, spinal cord injury, heart attack, or reperfusion injury.
Treatment or prevention of secondary injury including secondary hemorrhagic necrosis in spinal cord injury.
Use in combinatorial therapies including thrombolytic agents, antiplatelets, anticoagulants, statins, diuretics, vasodilators, antacids, immunosuppressants, antivirals, antibacterials, antifungals, and others.
Screening assays for identifying modulators of the NCCa-ATP channel for therapeutic use.
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