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Publication Number
US-11576945-B2
Publication Date
2023-02-14
Expiration Date
Abstract
Carbamathione agent protects brain tissue exposed to a cerebral ischemia/reperfusion injury, and minimizes the size of infarcts that develop as a result of the injury.
Core Innovation
The invention relates to minimizing the size of a brain infarct that develops in a mammalian subject in response to cerebral ischemia/reperfusion injury by administering a carbamathione agent. The amount of the carbamathione agent is effective for minimizing the size of the brain infarct that develops as a result of the cerebral ischemia/reperfusion injury. Carbamathione is described as a [S-(N,N-diethylcarbamoyl)glutathione] agent.
The document frames a problem of cerebral ischemia/reperfusion injury in which a brain infarct develops, and it aims to reduce the infarct size following that injury. The disclosure provides experimental support showing that carbamathione improves outcomes in cellular injury conditions and in a BCAO stroke model with corresponding brain tissue biomarker changes.
The disclosure further connects the carbamathione treatment context to ischemic stroke and evaluates cellular and brain tissue markers associated with ER-stress and apoptosis, including Hsp27/70, GRP78, CHOP, AKT/P-AKT, Bax, Bcl2, cleaved caspase-3, caspase-12, ATF4/6, XBP1, and ER stress pathway markers. The brain infarct effect is supported by reduced infarct volume with behavioral outcome assessments such as Corner test and locomotor activity.
Claims Coverage
The independent claim covers a method for minimizing the size of a brain infarct caused by cerebral ischemia/reperfusion injury through administering a carbamathione agent at an amount effective to minimize infarct size. The dependent claims add refinement features that constrain subject context, co-treatment context, formulation, timing, regimen, and a quantitative histological endpoint.
Minimizing brain infarct size via carbamathione administration
A method of minimizing the size of a brain infarct that develops in a mammalian subject in response to a cerebral ischemia/reperfusion injury, comprising administering to the subject a carbamathione agent, wherein the amount of the carbamathione agent is effective for minimizing the size of a brain infarct that develops in the mammalian subject as a result of the cerebral ischemia/reperfusion injury.
Administration within 24 hours after onset of ischemic stroke symptoms
The method includes administering a carbamathione agent to the subject within 24 hours after the onset of ischemic stroke symptoms.
Repeated daily administration for at least 3 days
The method includes repeatedly administering a carbamathione agent to the subject at least once per day for at least 3 days.
Continuation until at least 50% fibrotic infarct
The method further specifies repeatedly administering a carbamathione agent until the infarct becomes at least 50% fibrotic.
Carbamathione in a pharmaceutical composition formulated for injection
The method is carried out where the carbamathione agent is included in a pharmaceutical composition formulated for injection.
Subject has been administered tissue plasminogen activator
The method is carried out in a subject who has been administered tissue plasminogen activator.
Across the independent and dependent claims, the inventive coverage centers on administering a carbamathione agent in an amount effective to minimize brain infarct size from cerebral ischemia/reperfusion injury, with additional claim refinements that specify injection formulation, ischemic stroke context, optional prior administration of tissue plasminogen activator, administration timing within 24 hours, repeated daily dosing for at least 3 days, and a continuation endpoint defined by infarct fibrosis.
Stated Advantages
Minimizes the size of a brain infarct that develops in a mammalian subject in response to cerebral ischemia/reperfusion injury.
Reduces infarct volume in a BCAO stroke model with corresponding behavioral outcome changes.
Modulates ER-stress and apoptosis-associated biomarkers in brain tissue following injury conditions.
Documented Applications
Use of carbamathione to protect brain tissue and minimize infarct size in cerebral ischemia/reperfusion injury and ischemic stroke contexts in a mammalian subject.
Support for cellular injury contexts including glutamate-induced injury and hypoxia/reoxygenation in PC-12 cells, including increased cell viability after carbamathione treatment.
BCAO stroke model application to reduce infarct volume, with behavioral outcome assessments including Corner test and locomotor activity.
Use in a subject context that may include prior or co-treatment with tissue plasminogen activator, as described in the claim set.
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