SUR1-TRPM4 Inhibition With Thrombectomy for Stroke Edema

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Ischemic stroke patients, particularly those with large vessel occlusions, face significant challenges from brain swelling due to cellular swelling and transcapillary influx, which complicates treatment and increases the risk of adverse effects such as hemorrhage during mechanical thrombectomy, limiting effective interventions like tPA and thrombolytics.

Innovation Solution

Administering a SUR1-TRPM4 channel inhibitor, such as glibenclamide, in combination with mechanical thrombectomy, through continuous infusion over several days, to reduce brain edema and improve outcomes in patients with large ischemic lesions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Speed

If mechanical thrombectomy is performed to remove large vessel occlusion, then blood flow is restored to the brain, but brain swelling and intracranial pressure increase leading to harmful effects

Engineering Contradiction:

Improveblood flow restoration speedVSAvoidbrain swelling and intracranial pressure

Core Design Contradiction:

SpeedVSObject-affected harmful factors

Solution Approach 1:

The patent applies preliminary anti-action by administering a SUR1-TRPM4 channel inhibitor before mechanical thrombectomy to pre-establish protection against brain swelling. The inhibitor is given in a dosage range of 0.01-10 mg/kg body weight, preferably 0.1-1 mg/kg, to block the SUR1-TRPM4 channel and prevent excessive fluid influx into brain cells during the thrombectomy procedure, thereby counteracting the harmful effect of rapid reperfusion before it occurs.

Inventive Principle:

Principle #9Preliminary anti-action

2Reliability

If thrombolytics like tPA are administered to treat ischemic stroke, then clot dissolution is achieved, but treatment window is narrow and harm increases with delayed administration

Engineering Contradiction:

Improveclot dissolution effectivenessVSAvoidtreatment window duration

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

The patent applies preliminary action by administering the SUR1-TRPM4 channel inhibitor within the first 10 hours of stroke onset, preferably within the first 6 hours, to establish protective effect before the harmful effects of delayed treatment manifest. This preliminary action extends the effective treatment window by preventing brain swelling that would otherwise occur 24-72 hours after stroke onset, making patients eligible for thrombolytic therapy even when the traditional window is exceeded.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The SUR1-TRPM4 channel inhibitor acts as an intermediary substance that mediates between the stroke injury and the harmful effect of brain swelling. By blocking the SUR1-TRPM4 channel, this intermediary drug prevents direct harmful interactions between reperfusion and brain tissue, allowing safer use of thrombolytics and mechanical thrombectomy while protecting against edema.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Productivity

If rapid reperfusion is achieved through mechanical thrombectomy, then ischemic tissue is saved, but hemorrhage and adverse effects increase

Engineering Contradiction:

Improvetissue salvage rateVSAvoidhemorrhage and adverse effects

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The patent applies preliminary anti-action by pre-administering the SUR1-TRPM4 channel inhibitor before mechanical thrombectomy to establish protection against hemorrhage and adverse effects. The inhibitor blocks the SUR1-TRPM4 channel that mediates fluid influx and swelling during rapid reperfusion, thereby counteracting the harmful effects of tissue salvage before they occur.

Inventive Principle:

Principle #9Preliminary anti-action

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The combination therapy effectively reduces the risk of late neurological deterioration and mortality, improving functional outcomes in patients with large ischemic strokes, as measured by the Modified Rankin Scale, while minimizing severe disability.

Implementation Method 1

This channel is a non-selective Ca2+ activated ATP sensitive cation channel that is activated when neuronal cells are depleted of intracellular ATP. The NCCA.ATP channel is believed to be composed of regulatory subunits, including a sulfonylurea type receptor 1 (SUR1) and a pore subunit related to transient receptor potential cation channel subfamily M member 4 (TRPM4).

Methodology Applied

Scientific EffectChannel inhibition:

Implementation Method 2

Cellular swelling of the neurons and astrocytes occurs as a result of ion gradient changes between the cells and the extracellular space.

Methodology Applied

Scientific EffectIon gradient changes:

Data Source

PatentUS20250345347A1Methods of treating ischemic stroke at risk for cerebral or cerebellar edema

Publication Date: 2025.11.13 REMEDY PHARMACEUTICALS INC

AI summary

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.