Targeting NCCa-ATP channel for organ protection following ischemic episode
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Publication Number
US-10898496-B2
Publication Date
2021-01-26
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), regulated by sulfonylurea receptor type 1 (SUR1), expressed in various cells including neurons, glia, and endothelial cells. This channel is activated by intracellular calcium and inhibited by intracellular ATP, conducting monovalent cations such as Na+, K+, Cs+, and Li+. It functions in tissues outside the central nervous system (CNS) following ischemic episodes or trauma.
The core innovation involves the discovery that activation of this SUR1-regulated NCCa-ATP channel leads to cell depolarization by allowing Na+ influx, which in turn causes cytotoxic edema, oncotic cell swelling, and ultimately necrotic cell death. Blocking this channel, for example by sulfonylurea compounds such as glibenclamide, inhibits channel opening, prevents Na+ influx and cell depolarization, reduces edema formation, hemorrhagic conversion, and cell death. The invention further provides therapeutic methods for administering NCCa-ATP channel inhibitors or antagonists to protect organs, tissues, or cells outside of the CNS following ischemic or hypoxic injury to reduce secondary or delayed injury.
The problem being solved is the lack of molecular understanding and treatment for progressive secondary injury following ischemia/hypoxia outside the CNS, particularly the mechanisms of cytotoxic edema, ionic edema, and hemorrhagic conversion. Secondary injury, involving delayed tissue damage and expansion of lesions after the primary ischemic event, is associated with cellular swelling, endothelial dysfunction, and capillary failure causing edema and hemorrhage, which worsen outcomes and increase morbidity and mortality. Current treatments do not adequately address the molecular targets responsible for secondary injury and hemorrhagic conversion.
Claims Coverage
The patent includes multiple independent claims directed to methods of treating subjects suffering from cerebral edema, intracranial pressure following hemorrhagic infarction, or acute ischemic stroke by administering NCCa-ATP channel inhibitors. The inventive features relate to specific dosing regimens, types of inhibitors, administration routes, and treatment timing.
Method of treating cerebral edema or intracranial pressure using NCCa-ATP channel inhibition with specific dosing regimen
Administering an inhibitor of NCCa-ATP channel that is a SUR1 antagonist and/or a TRPM4 antagonist as a loading bolus dose followed by a constant maintenance infusion, wherein the bolus dose is 30-90 times the maintenance dose by weight per minute or the SUR1 antagonist dosage is less than 3.5 mg per day.
Use of specific SUR1 antagonists and TRPM4 antagonists
Employing SUR1 antagonists such as glibenclamide (glyburide), tolbutamide, and related sulfonylureas or meglitinides, and TRPM4 antagonists including flufenamic acid, mefanimic acid, niflumic acid, and antagonists of VEGF, MMP, NOS, TNFα, NFκB, or thrombin for treatment.
Various administration routes and timings for NCCa-ATP channel inhibitors
Administering the inhibitor intravenously, subcutaneously, intramuscularly, intracutaneously, intragastrically, or orally; administration may occur prior to, concurrent with, or following ischemic episodes.
Dosing considerations and treatment duration
SUR1 antagonist dosage can be less than 3.5 mg per day or less than 0.8 mg/kg body weight within 24 hours, with maintenance dose administered as constant infusion for six or more to twenty-four or more hours.
Combination with additional therapeutic agents
The method may include co-administration of additional agents such as antacids, immunosuppressants, antivirals, antibacterials, antifungals, or mixtures thereof including anti-thymocyte globulin, basiliximab, methylprednisolone, tacrolimus, mycophenolate mofetil, prednisone, sirolimus, rapamycin, and azathioprine.
The independent claims cover therapeutic methods for protecting against damage associated with cerebral edema, intracranial pressure, and ischemic stroke by administering SUR1 and/or TRPM4 antagonists with specific bolus and infusion dosing regimens, particular inhibitor types, administration routes, timing relative to ischemic episodes, optionally combined with other therapeutic agents.
Stated Advantages
Reduced mortality and cerebral edema in rodent models of stroke upon administration of SUR1 antagonists.
Prevention or reduction of cytotoxic edema and necrotic cell death of neurons, astrocytes, and endothelial cells.
Amelioration of secondary injury including hemorrhagic conversion and preservation of capillary integrity after ischemic insult or trauma.
Improved neurological functional recovery following spinal cord injury after treatment with low-dose glibenclamide.
Ability to extend therapeutic window for thrombolytic agents in stroke treatment by several hours via co-administration with NCCa-ATP channel antagonists.
Documented Applications
Protection and treatment of organs and tissues outside the CNS following ischemic episodes, including heart, kidney, lung, liver, eye, pancreas, spleen, cornea, skin, bone marrow, heart valve, or connective tissue.
Organ preservation for transplantation such as liver, kidney, bladder, intestines, pancreas, lung, heart, and vascular grafts used in coronary artery bypass grafting.
Treatment of cerebral edema and intracranial pressure after hemorrhagic infarction and acute ischemic stroke.
Treatment of secondary injury in spinal cord injury, including reduction of edema and hemorrhagic conversion and neurological recovery.
Therapeutic modulation for conditions involving ischemia/hypoxia such as heart attack, stroke, tachycardia, atherosclerosis, hypotension, thromboembolism, organ transplantation, trauma, and mass-occupying lesions.
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