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Assignees
Member
Oklahoma Medical Research FoundationFounded in 1946, this independent nonprofit biomedical research institute conducts basic, translational, and clinical research in critical areas such as heart disease, cancer, autoimmune, and neurodegenerative diseases. Its mission focuses on understanding biological mechanisms and advancing diagnostics and therapeutics. Activities include conducting clinical trials, managing a patent portfolio, commercializing biotechnologies, and supporting the biotech community. Research efforts are funded by grants and philanthropy, and the institute hosts advanced facilities, interdisciplinary research teams, and collaborations with academia and industry.
Founded in 1946, this independent nonprofit biomedical research institute conducts basic, translational, and clinical research in critical areas such as heart disease, cancer, autoimmune, and neurodegenerative diseases. Its mission focuses on understanding biological mechanisms and advancing diagnostics and therapeutics. Activities include conducting clinical trials, managing a patent portfolio, commercializing biotechnologies, and supporting the biotech community. Research efforts are funded by grants and philanthropy, and the institute hosts advanced facilities, interdisciplinary research teams, and collaborations with academia and industry.
Publication Number
US-10022346-B2
Publication Date
2018-07-17
Expiration Date
Abstract
The treatment options for treating blast-induced and noise-induced traumatic brain injury and tinnitus are limited. Thus, the current invention provides methods for treating traumatic brain injury and tinnitus. The methods involve administering a pharmaceutically effective amount of a composition comprising 2,4-disulfonyl α-phenyl tertiary butyl nitrone and N-acetylcysteine (NAC).
Core Innovation
The invention provides methods for treating noise-induced and blast-induced traumatic brain injury and noise-induced tinnitus by administering 2,4-disulfonyl a-phenyl tertiary butyl nitrone (HPN-07 / 2,4-disulfonyl PBN) alone or in combination with N-acetylcysteine (NAC). Alternative formulations include 4-hydroxy-α-phenyl butyl nitrone (4-OHPBN) with NAC and Acetyl-L-Carnitine (ALCAR), and the composition may optionally include antioxidant peptides such as Szeto-Schiller peptides or other antioxidants. The disclosure reports biomarker and histological effects in animal models and describes routes of administration including oral, intravenous, intraperitoneal and nanoparticle formulations.
The background identifies noise and blast exposure as causing injury to the cochlear nucleus and associated pathological changes including up-regulation of c-fos in cochlear nuclei, synaptic degeneration, increases in amyloid precursor protein (APP) and GFAP, and long-term elevation of repair markers such as doublecortin, and the invention addresses these pathological outcomes by pharmacological intervention. Experimental evidence in the disclosure shows down-regulation of c-fos, preservation of synaptic markers, reduced APP and GFAP increases, and reduced long-term doublecortin elevation following administration of the disclosed compositions. Examples describe administration within a defined post-exposure window [procedural detail omitted for safety] and report an unexpected increase in blood-brain barrier permeability with HPN-07 that enables increased CNS bioavailability of co-administered agents.
Claims Coverage
Overview: Two main inventive features are extracted from two independent claims concerning methods of treating cochlear nucleus injury and compositions comprising 2,4-disulfonyl a-phenyl tertiary butyl nitrone with or without N-acetylcysteine.
Method of treating noise-induced or blast-induced injury to cochlear nucleus with 2,4-disulfonyl a-phenyl tertiary butyl nitrone
A method comprising administering to a patient in need thereof a pharmaceutically effective amount of a composition comprising 2,4-disulfonyl a-phenyl tertiary butyl nitrone to treat noise- or blast-induced injury to the cochlear nucleus.
Composition comprising 2,4-disulfonyl a-phenyl tertiary butyl nitrone alone or in combination with N-acetylcysteine
A pharmaceutical composition comprising 2,4-disulfonyl a-phenyl tertiary butyl nitrone, either alone or in combination with N-acetylcysteine, for use in treating noise- or blast-induced injury to the cochlear nucleus.
The independent claims claim (a) methods of treating noise- or blast-induced injury to the cochlear nucleus by administering the disclosed pharmaceutical compositions and (b) pharmaceutical compositions comprising 2,4-disulfonyl a-phenyl tertiary butyl nitrone, either alone or in combination with N-acetylcysteine, as the principal inventive elements.
Stated Advantages
Down-regulation of c-fos expression in cochlear nuclei following noise exposure.
Preservation of synaptic markers and reduction of synaptic degeneration.
Reduction of amyloid precursor protein (APP) and GFAP increases after blast exposure.
Reduction of long-term elevation of the repair marker doublecortin.
Unexpected increase in blood–brain barrier permeability by HPN-07 that enables increased central nervous system bioavailability of co-administered agents.
Documented Applications
Treatment of noise-induced traumatic brain injury, including injury to the cochlear nucleus.
Treatment of blast-induced traumatic brain injury, including injury to the cochlear nucleus.
Treatment of noise-induced tinnitus.
Use of HPN-07 to increase blood–brain barrier permeability and thereby increase CNS bioavailability of co-administered therapeutic agents.
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