Targeting NCCA-ATP channel for organ protection following ischemic episode
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Publication Number
US-12121526-B2
Publication Date
2024-10-22
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 problem being solved is that injury to vital organs and tissues following ischemic events triggers cellular damage leading to cytotoxic edema, cell swelling, progressive hemorrhagic necrosis (PHN), and ultimately cell death. Current understanding lacked molecular mechanisms underlying progressive endothelial dysfunction after ischemic/hypoxic injury, as well as treatments targeting such secondary or delayed injury, including hemorrhagic conversion which worsens outcomes. Existing therapies do not address the role of NCCa-ATP channel regulated by SUR1 in this pathology.
Claims Coverage
The patent contains one independent claim outlining a method of treating cerebral edema and intracranial pressure following hemorrhagic infarction by administering glibenclamide in specific dosing regimens.
Method of treating cerebral edema with specific dosing of glibenclamide
Administering glibenclamide or its pharmaceutically acceptable salt as a loading bolus dose followed by a constant infusion maintenance dose where the bolus dose is 40-80 times the weight of the maintenance dose per minute, or administering glibenclamide intravenously at less than 3.5 mg per day. The maintenance dose is administered for six or more hours, up to twenty-four or more hours.
Timing and adjunct therapeutic administration
Glibenclamide can be administered prior to, concurrent with, or following an ischemic episode. The method may further include delivery of additional therapeutic agents such as antacids, immunosuppressants, antivirals, antibacterials, antifungals, and specific immunosuppressants such as anti-thymocyte globulin or tacrolimus.
Method of treating acute ischemic stroke with defined glibenclamide regimen
Administration of glibenclamide as a loading bolus dose followed by a constant infusion maintenance dose with similar dosing constraints as for cerebral edema, particularly applied to acute ischemic stroke in a cerebral artery (e.g., middle cerebral artery).
Method of reducing matrix metalloproteinases following stroke
Administering glibenclamide as a loading bolus dose followed by a constant infusion maintenance dose under the defined dosing regimens to reduce matrix metalloproteinases after stroke.
The independent claim of the patent is focused on therapeutic methods involving glibenclamide dosing regimens for treatment of cerebral edema, intracranial pressure, acute ischemic stroke, and reduction of matrix metalloproteinases following stroke, emphasizing specific loading and maintenance doses and timing, including combination with other therapeutic agents.
Stated Advantages
Blockade of the SUR1-regulated NCCa-ATP channel by glibenclamide reduces cerebral edema, hemorrhagic conversion, infarct volume, and mortality after ischemic stroke and spinal cord injury.
Glibenclamide treatment significantly improves neurological function following spinal cord injury.
The channel targeted is newly expressed following injury, making the treatment selective for injured tissue and increasing therapeutic efficacy.
Administration of glibenclamide increases the therapeutic window for thrombolytic agents by several hours, allowing safer and more effective treatment of ischemic events.
Documented Applications
Treatment and protection of organs and tissues outside the central nervous system following ischemic episodes, including organ preservation for transplantation, angina pectoris, and kidney reperfusion injury.
Treatment of ischemic/hypoxic injuries such as heart attack, stroke, spinal cord injury, and trauma through modulation of the NCCa-ATP channel.
Use of inhibitors of SUR1-regulated NCCa-ATP channels to reduce secondary injury including edema, hemorrhagic conversion, and progressive hemorrhagic necrosis in ischemia and trauma.
Combination therapy with SUR1 antagonists and thrombolytic agents, anticoagulants, or immunosuppressants to improve outcomes in ischemic stroke and organ transplantation.
Diagnosis and assessment of ischemic damage by assaying expression or activity of the NCCa-ATP channel in organs or tissues.
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