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Publication Number
US-9987244-B2
Publication Date
2018-06-05
Expiration Date
Abstract
The present invention relates to use of DHA analogs and their pharmaceutical compositions for treating ototoxicity, by administering these compounds or pharmaceutical compositions to subjects in need thereof. Ototoxicity is defined as damage to the structures of the ear, such as the cochlea and vestibular system, by drugs or toxins. Ototoxicity can result in irreversible hearing loss, tinnitus, dysequilibrium, Meniere's disease, or vertigo.
Core Innovation
The invention relates to a method for treating ototoxicity by administering a therapeutically effective amount of (4Z,7Z,10R,11E,13E,15Z,17S,19Z)-10,17-dihydroxydocosa-4,7,11,13,15,19-hexaenoic acid or a pharmaceutically acceptable salt thereof. The document associates ototoxicity with ear damage involving the cochlea and the vestibular system, leading to hearing loss and related disorders.
The described therapeutic approach includes alleviating at least one symptom or sign of ototoxicity and/or delaying onset or progression of ototoxicity. The document further states that the treatment reduces cell death and/or increases survival of cochlear hair cells, cells of the vestibular system, stria vascularis cells, or auditory neurons.
The disclosed compounds are provided as Formula I–IV with variable substituents, and are defined to include salts, esters, solvates, hydrates, prodrugs, metabolites, analogs, and derivatives. The document also provides stereoisomeric dihydroxydocosa acids and related pharmaceutically acceptable forms, including a sodium salt exemplar, within pharmaceutical compositions suitable for administration to a subject.
Claims Coverage
The coverage centers on one independent claim for treating ototoxicity by administering a therapeutically effective amount of a specific dihydroxydocosa hexaenoic acid or a pharmaceutically acceptable salt. The identified dependent claims add sodium-salt form, functional treatment endpoints, symptom or sign selections, and administration constraints.
Treating ototoxicity with specific dihydroxydocosa hexaenoic acid or salt
A method for treating ototoxicity comprising administering to a subject in need thereof a therapeutically effective amount of (4Z,7Z,10R,11E,13E,15Z,17S,19Z)-10,17-dihydroxydocosa-4,7,11,13,15,19-hexaenoic acid or a pharmaceutically acceptable salt thereof.
Specific salt identity as sodium salt of the corresponding hexaenoate
The method further specifies that the pharmaceutically acceptable salt is a sodium salt and that the compound includes (4Z,7Z,10R,11E,13E,15Z,17S,19Z)-10,17-dihydroxydocosa-4,7,11,13,15,19-hexaenoate.
Functional treatment endpoints for ototoxicity
Treating ototoxicity is done by delaying its onset or progression or by alleviating at least one symptom or sign of ototoxicity.
Selected symptom or sign list for ototoxicity
The method further specifies that the symptom or sign of ototoxicity is selected from a specified list of auditory, vestibular, and related functional symptoms.
Daily dosage constraint in mg/kg/day
The method further specifies administering the compound at a daily dosage of about 0.1 to 1.0 mg per kg body weight.
Intraaural/intratympanic administration with intratympanic dosage constraint
The method further provides for intratympanic administration of the compound at a dosage ranging from about 0.01 to 1 mg.
The claims focus on administering a therapeutically effective amount of (4Z,7Z,10R,11E,13E,15Z,17S,19Z)-10,17-dihydroxydocosa-4,7,11,13,15,19-hexaenoic acid or a pharmaceutically acceptable salt for ototoxicity, with refinement to sodium-salt form, functional endpoints, symptom or sign selection, and dosage and route constraints.
Stated Advantages
Delaying onset or progression of ototoxicity.
Alleviating at least one symptom or sign of ototoxicity.
Reducing cell death.
Increasing survival of cochlear hair cells, cells of the vestibular system, stria vascularis cells, or auditory neurons.
Improves cell viability and survival in cisplatin-damaged UB/OC-1 cells.
Prevents apoptosis and reduces ROS generation.
Decreases stress/inflammatory marker expression including TRPV-1, TNFα, NOX3, and iNOS.
Documented Applications
Treating ototoxicity in a subject, including associated conditions such as hearing loss, tinnitus, disequilibrium, Ménière’s disease, and vertigo.
In vitro treatment-use context supported by NPD1 (Compound 1) examples showing increased cell viability and survival in cisplatin-damaged UB/OC-1 cells and reduction of apoptosis, ROS generation, and stress/inflammatory marker expression.
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