Methods of treating ischemic stroke at risk for cerebral or cerebellar edema

Inventors

Jacobson, Sven Martin • MacAllister, Thomas W.

Assignees

Remedy Pharmaceuticals Inc

Abstract

The invention relates to the treatment of ischemic stroke at risk of brain swelling using SUR1-TRPM4 channel inhibitors in combination with mechanical thrombectomy. In some embodiments, the methods include treating patients suffering from a large hemispheric infarction. In certain embodiments, patients have a 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 decompressive therapy.

Core Innovation

The disclosure describes treating an ischemic stroke patient at risk of cerebral edema and/or cerebellar edema by administering a SUR1-TRPM4 channel inhibitor. The treatment is directed to patients with lesion volume criteria, including lesion volume of 180 cm3 or less, and may include patients who have experienced a wake-up stroke. Patient selection is framed using imaging lesion-volume, including MRI diffusion-weighted imaging (DWI) and/or CT perfusion (CTP), and related scoring such as ASPECTS.

The disclosure connects administration of a SUR1-TRPM4 channel inhibitor with mechanical thrombectomy. In specific embodiments, the inhibitor administration is performed in relation to the mechanical thrombectomy before or during, or after, and eligibility is constrained by lesion-volume thresholds and/or clinical scores. The description emphasizes outcome analyses using ordinal mRS, including mRS 5/6 severe disability, and ordinal mRS shift analysis.

For implementation of the SUR1-TRPM4 channel inhibitor approach, the disclosure provides formulation concepts for glyburide, including pharmaceutically acceptable salts, intended to address container/filter sorption and degradation during storage. The formulation concepts include using a buffering agent, a base, and a sugar alcohol, with the formulation pH being outside the buffering capacity of the buffering agent, and the buffering agent having a pKa in the range of 7.7 to 9.2. The disclosure includes example saline infusion compositions and storage-stability considerations directed to degradation products measured by HPLC.

Claims Coverage

The partial content provides four independent claims, covering administration of a SUR1-TRPM4 channel inhibitor to ischemic stroke patients meeting imaging/clinical lesion-volume or scoring thresholds, with particular emphasis on wake-up stroke and/or combination with mechanical thrombectomy. Across the independent claims, the inventive features include lesion-volume constraints, timing relative to mechanical thrombectomy, mechanistic inhibition of the SUR1 regulatory subunit, enumerated inhibitor selections, and a glyburide formulation defined by buffering-agent and pH/buffering-capacity relationships, including buffering-agent pKa.

Across the independent claims, coverage centers on treating ischemic stroke patients using SUR1-TRPM4 channel inhibitors, with eligibility constrained by lesion volume, wake-up stroke criteria, and/or clinical or imaging thresholds such as ASPECTS and NIHSS. Additional inventive coverage includes administering the inhibitor in combination with mechanical thrombectomy, with timing relative to thrombectomy as further refined in dependents, and defining the inhibitor and glyburide formulation, including SUR1 regulatory subunit inhibition and buffering-agent/pH constraints.

Stated Advantages

Documented Applications

No documented applications found