Methods of treating ischemic stroke at risk for cerebral or cerebellar edema
Inventors
Jacobson, Sven Martin • MacAllister, Thomas W.
Assignees
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Publication Number
US-12251388-B1
Publication Date
2025-03-18
Expiration Date
Abstract
This disclosure relates to the treatment of ischemic stroke at risk of brain swelling using SUR1-TRPM4 channel inhibitors. In some embodiments, the methods include treating patients suffering from a large hemispheric infarction. In certain embodiments, patients have a baseline NIHSS of ≤20. In other embodiments, patients have lesion volume of less than 140 cm3 or less than 125 cm3 as measured by MRI DWI or CTP. The patient may have suffered a wake-up stroke. Some embodiments involve treating patients who also undergo treatment with a thrombolytic agent and/or decompressive therapy.
Core Innovation
The disclosure describes methods of improving outcomes in a patient diagnosed with an ischemic stroke by assessing outcomes using Modified Rankin Scale (mRS) scores. The methods are directed to patients who have experienced a wake-up stroke and meet specified imaging and clinical criteria, including a lesion volume of at least 50 cm3 on MRI diffusion-weighted imaging (DWI) or computed tomography perfusion (CTP), or an Alberta Stroke Program Early CT Score (ASPECTS) of 1 to 5, together with a National Institutes of Health Stroke Scale (NIHSS) score of 10 to 20.
The improvement is achieved by administering glyburide or a pharmaceutically acceptable salt thereof in a formulation comprising a buffering agent, a base, and a sugar alcohol. The formulation is characterized by a pH outside of the buffering capacity of the buffering agent and by the buffering agent having a pKa of 7.7 to 9.2, with glyburide loading about 2.7 to 3.1% (w/w) and/or sugar alcohol loading about 84 to 90% (w/w).
The formulation is further constrained by a sugar alcohol to glyburide or pharmaceutically acceptable salt weight ratio of 27 to 40:1. The disclosure also describes wake-up stroke timing using defined time windows associated with a midpoint between sleep onset or last known to be normal and the time of waking, and administration using one or more continuous infusions with a total duration of at least 72 hours.
Claims Coverage
The provided material contains two independent method claims. Both share the same core inventive requirements: treating a wake-up ischemic stroke patient meeting specific lesion or ASPECTS criteria and an NIHSS score of 10 to 20, and administering glyburide or a pharmaceutically acceptable salt in a defined buffered formulation with a pH outside the buffering capacity, a buffering-agent pKa of 7.7 to 9.2, constrained glyburide and sugar-alcohol loadings, and a sugar-alcohol-to-glyburide or salt weight ratio of 27 to 40:1.
Improving wake-up ischemic stroke outcomes using mRS-based assessment with glyburide formulation
A method of improving outcomes compared to placebo in a patient diagnosed with an ischemic stroke by assessing outcomes using Modified Rankin Scale (mRS) scores, wherein the patient has experienced a wake-up stroke and, at the time of treatment, has a lesion volume threshold or ASPECTS threshold and an NIHSS score of 10 to 20, comprising administering glyburide or a pharmaceutically acceptable salt thereof in a formulation comprising a buffering agent, a base, and a sugar alcohol, where the formulation has a pH outside of the buffering capacity of the buffering agent and the buffering agent has a pKa of 7.7 to 9.2, with glyburide loading about 2.7 to 3.1% (w/w) and/or sugar alcohol loading about 84 to 90% (w/w), and wherein the formulation comprises the sugar alcohol and the glyburide or pharmaceutically acceptable salt thereof in a weight ratio of 27 to 40:1.
Treating wake-up ischemic stroke patients with specified lesion or ASPECTS and NIHSS criteria using glyburide formulation
A method of treating a patient having a brain lesion volume of at least 50 cm3 on MRI diffusion-weighted imaging (DWI) or computed tomography perfusion (CTP), or an ASPECTS of 1 to 5, and having an NIHSS score of 10 to 20, wherein the patient has experienced a wake-up stroke, comprising administering glyburide or a pharmaceutically acceptable salt thereof in a formulation comprising a buffering agent, a base, and a sugar alcohol, where the formulation has a pH outside of the buffering capacity of the buffering agent and the buffering agent has a pKa of 7.7 to 9.2, with glyburide loading about 2.7 to 3.1% (w/w) and/or sugar alcohol loading about 84 to 90% (w/w), and wherein the formulation comprises the sugar alcohol and the glyburide or pharmaceutically acceptable salt thereof in a weight ratio of 27 to 40:1.
Across the two independent claims, the coverage centers on wake-up ischemic stroke patient selection using defined lesion or ASPECTS criteria and NIHSS criteria, together with administration of glyburide in a specific buffering-agent/base/sugar-alcohol formulation characterized by defined pH, buffering-agent pKa, loadings, and weight ratio.
Stated Advantages
Improving outcomes compared to placebo as assessed by Modified Rankin Scale (mRS) scores.
Documented Applications
Treating acute ischemic stroke patients with wake-up stroke who meet lesion-volume or ASPECTS and NIHSS criteria, using a glyburide formulation characterized by defined buffering and pH conditions.
In some embodiments, administering the method in combination with tissue plasminogen activator.
In some embodiments, compatibility with decompressive craniectomy is described.
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