Methods for pharmacologic treatment of stroke
Inventors
Liang, Bruce • Verma, Rajkumar • Jacobson, Kenneth A.
Assignees
University of Connecticut • US Department of Health and Human Services
Publication Number
US-10695355-B2
Publication Date
2020-06-30
Expiration Date
2038-03-23
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Abstract
Described herein are methods for the treatment of a human subject who has had a stroke by administering to the subject a pharmaceutical composition including an antagonist of the P2X4 receptor. The antagonist of the P2X4 receptor can be administered in the acute phase of stroke, optionally in combination with a thrombolytic therapeutic or a procedure on the subject involving a clot-removal device.
Core Innovation
The invention provides methods for treating a human subject who has had a stroke by administering a pharmaceutical composition comprising an antagonist of the P2X4 receptor. This antagonist can be administered during the acute phase of stroke (from stroke onset to up to 7 days post-stroke), and optionally in combination with thrombolytic therapeutics or clot-removal procedures.
The P2X4 receptor is an ATP-activated ion channel highly expressed in the central nervous system, especially on microglia. During stroke, excessive ATP release activates P2X4 receptors, leading to inflammasome activation, excitotoxic neuronal death, and microglial secretion of pro-inflammatory cytokines. While P2X4 receptor activation also mediates release of beneficial factors like BDNF important for cognition and recovery, its precise role in stroke pathophysiology was not fully understood before.
Current stroke treatments like thrombolytics have limitations including narrow treatment windows, risk of bleeding, and limited applicability to ischemic strokes. Mechanical clot removal applies to less than 10% of embolic stroke cases. Therefore, there is an unmet need for improved therapies for ischemic stroke, particularly targeting molecular players like P2X4 receptor. The invention addresses this need by identifying P2X4 receptor antagonism as a novel therapeutic approach to improve neuronal protection and functional outcomes in stroke.
Claims Coverage
The patent contains one independent method claim covering treatment of stroke by administering a pharmaceutical composition comprising an antagonist of the P2X4 receptor, specifically defined by chemical Formula (II). There is one independent claim with multiple dependent claims outlining specific embodiments and administration details.
Method of treating stroke by administering a P2X4 receptor antagonist of Formula (II)
Administering to a human subject who has had a stroke a pharmaceutical composition comprising an antagonist of the P2X4 receptor defined by the chemical structure Formula (II).
Use of specific chemical embodiments of the P2X4 receptor antagonist
Employing compounds of Formula (IIa), and specific substituents such as R7 being 1,2,4-oxadiazol-3-yl-5(4H)-thione or 1,2,4-oxadiazol-3-yl-5(4H)-one. One particular compound is 5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione or its pharmaceutically acceptable salts.
Treating ischemic stroke using P2X4 receptor antagonists
The method specifically includes treatment of ischemic stroke by administering the antagonist.
Administration timing and phases of treatment
The antagonist is administered during the acute phase and can be ceased after day 7 post-stroke or continued through subacute and/or chronic phases.
Routes and methods of administration
The antagonist can be administered orally or by intravenous injection, including targeted infusion near the blockage site.
Administration in conjunction with thrombolytic therapeutics or clot-removal devices
The antagonist can be given before, concurrently with, or after thrombolytic therapy or mechanical clot-removal procedures, including via an endovascular catheter that has been used to deliver thrombolytics or clot removal.
Dosage range
The antagonist is administered at dosages ranging from about 0.05 mg/kg to about 5 mg/kg of body weight.
The claims focus on methods of treating stroke by administering a defined chemical antagonist of the P2X4 receptor, with various specific structures, modes of administration, timing, and combination with existing stroke treatments, providing a novel therapeutic approach to stroke management.
Stated Advantages
Acute inhibition of P2X4 receptor after stroke provides neuroprotection and improved neurological outcomes.
The antagonist can be used in combination with existing thrombolytic therapies or mechanical clot removal, potentially enhancing treatment efficacy.
P2X4 receptor antagonists reduce infarct size and neurological deficit scores in stroke animal models.
Oral or intravenous administration options allow flexible delivery in clinical settings.
Treatment during the acute phase targets early pathophysiology, and continued use may benefit chronic recovery phases.
Documented Applications
Pharmacological treatment of ischemic stroke in human subjects during the acute phase by administering a P2X4 receptor antagonist.
Adjunct therapy combined with thrombolytic therapeutics such as tissue plasminogen activator or clot removal devices.
Use of specific chemical compounds (e.g. 5-BDBD or NP-1815-PX) as P2X4 receptor antagonists to reduce brain infarct volume and improve neurological scores in animal models of stroke.
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