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Publication Number
US-10945986-B2
Publication Date
2021-03-16
Expiration Date
Abstract
Granulocyte colony-stimulating factor (G-CSF; a stem cell enhancer and facilitator), DETC-MeSO (a glutamate receptor partial antagonist and anti-excitotoxicity agent), and sulindac (a potent anti-oxidant and anti-inflammatory agent) each can protect brain tissue exposed to a cerebral ischemia/reperfusion injury, and minimize the size of infarcts that develop as a result of the injury. When administered in combination, these agents are effective at protecting brain tissue and minimizing the size of an infarct resulting from the injury at much lower concentrations compared to using a single agent.
Core Innovation
The disclosed invention is directed to a method of treating reperfusion injury in the brain of a mammalian subject in which the reperfusion injury is caused by a stroke. The method includes administering a N-diethylthiocarbamate sulfoxide (DETC-MeSO) agent to the subject. In this context, the document characterizes DETC-MeSO as a glutamate receptor partial antagonist and an anti-excitotoxic agent relevant to stroke and ischemia/reperfusion injury.
The document further describes combined treatment approaches that administer DETC-MeSO together with other agents, including G-CSF and sulindac. G-CSF is described as a stem cell enhancer or stem cell facilitator, and sulindac is described as an anti-oxidant and anti-inflammatory agent. The combination regimens are reported to act together to reduce brain infarct size and to modulate molecular markers associated with cell stress and apoptosis in the reperfusion injury setting.
As reported in the provided description, the combination regimens reduce infarct size at much lower doses than single agents and modulate markers including CHOP and P-IRE-1 reduction, ER stress/pro-apoptotic Bax/Bak/GRP78 reduction, and increased anti-apoptotic and protective proteins such as Bcl-2 and increased pAKT, HSP27, and HSP70. The document ties these effects to ischemic stroke and ischemia-reperfusion injury in a mammalian model using MCAO with reperfusion.
Claims Coverage
The provided independent claim focuses on administering DETC-MeSO to treat reperfusion injury in the brain caused by stroke, with additional inventive features directed to timing, repeated dosing, and combination regimens with tissue plasminogen activator, sulindac, and optionally G-CSF plus sulindac.
DETC-MeSO treatment of stroke-caused brain reperfusion injury
Administering to a mammalian subject a N-diethylthiocarbamate sulfoxide (DETC-MeSO) agent for treating reperfusion injury in the brain, wherein the reperfusion injury is caused by a stroke.
Timed DETC-MeSO administration within 24 hours
Administering the DETC-MeSO agent to the subject within 24 hours after stroke symptom onset.
Repeated once-per-day DETC-MeSO dosing
Repeatedly administering the DETC-MeSO agent to the subject at least once per day for at least 3 days.
DETC-MeSO following treatment with tissue plasminogen activator
Applying the method to a subject who has been administered tissue plasminogen activator to treat the stroke.
DETC-MeSO combined with sulindac
Further carrying out the method by administering a sulindac agent to the subject.
DETC-MeSO combined with sulindac and G-CSF
Further carrying out the method by administering a granulocyte colony-stimulating factor (G-CSF) agent together with a sulindac agent to the subject.
The claim set is centered on administering a DETC-MeSO agent to a mammalian subject to treat stroke-caused reperfusion injury in the brain, with further coverage for within-24-hour initiation, repeated once-per-day dosing for at least 3 days, and combination regimens including sulindac and optionally G-CSF, including a context where tissue plasminogen activator has been administered.
Stated Advantages
Reduces brain infarct size in the reperfusion injury/ischemia-reperfusion injury setting.
Reduces infarct size at much lower doses than single agents.
Modulates molecular markers associated with ER stress and apoptosis, including CHOP and P-IRE-1 reduction, ER stress/pro-apoptotic Bax/Bak/GRP78 reduction, and increased anti-apoptotic and protective proteins such as Bcl-2, pAKT, HSP27, and HSP70.
Documented Applications
Treating ischemic stroke or ischemia/reperfusion injury (stroke-caused reperfusion injury) in a mammalian subject by administering DETC-MeSO, including combination regimens with G-CSF and sulindac.
Use in a stroke context where tissue plasminogen activator has been administered to treat the stroke.
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