Dosage forms and therapeutic uses of L-4-chlorokynurenine
Inventors
Snodgrass, H. Ralph • CATO, Allen E. • HICKLIN, Jack S.
Assignees
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Publication Number
US-10632091-B2
Publication Date
2020-04-28
Expiration Date
Abstract
Compositions of L-4-chlorokynurenine are provided, as are methods for the treatment of neurologica dyslinction.
Core Innovation
The disclosed invention provides unit-dose oral pharmaceutical compositions comprising L-4-chlorokynurenine (AV-101). It is framed for therapeutic use in neurological disorders involving NMDA receptor overactive glutamatergic transmission and links the approach to glycine B co-agonist site antagonism through conversion to 7-chlorokynurenic acid in astrocytes.
The pharmaceutical compositions are presented with therapeutically effective amounts and unit doses of L-4-chlorokynurenine. The disclosure also characterizes pharmacokinetic behavior by reporting plasma levels of 7-chlorokynurenic acid and a Phase 1b clinical study in healthy subjects.
A central therapeutic application described in the document is ameliorating the side effect of dyskinesia induced by administration of L-DOPA. The disclosure therefore uses administration of L-4-chlorokynurenine to a subject receiving L-DOPA to address levodopa-induced dyskinesia, and it further frames the approach in connection with conditions involving allodynia and mechanical and heat hyperalgesia.
Claims Coverage
The independent claim set is directed to a method of ameliorating an L-DOPA-induced dyskinesia side effect by administering L-4-chlorokynurenine, with dependent claim refinements adding quantitative unit-dose constraints and specifying oral and unit-dose forms. The claims present 5 inventive features.
Ameliorating L-DOPA-induced dyskinesia using L-4-chlorokynurenine
Administering a therapeutically effective amount of L-4-chlorokynurenine to a subject to ameliorate the side effect of dyskinesia induced by administration of L-DOPA.
Unit-dose pharmaceutical composition with an L-4-chlorokynurenine amount range
Administering a pharmaceutical composition per unit dose containing about 50 to about 1,800 mg of L-4-chlorokynurenine plus a pharmaceutically acceptable ingredient.
Preferred unit-dose range of L-4-chlorokynurenine
Administering a pharmaceutical composition per unit dose containing essentially L-4-chlorokynurenine in an amount of about 360 to about 1,440 mg.
Tablet or capsule unit dose form
Carrying out the method in which the pharmaceutical unit dose form is a tablet or a capsule.
Oral administration
Including orally administering L-4-chlorokynurenine.
Overall, the claims cover amelioration of L-DOPA-induced dyskinesia by administering L-4-chlorokynurenine, with claim coverage refined by specific unit-dose composition amounts and by oral delivery in tablet or capsule unit-dose forms.
Stated Advantages
Amelioration of the side effect of dyskinesia induced by administration of L-DOPA (levodopa-induced dyskinesia).
Better safety rationale versus classic NMDA antagonists based on glycine B co-agonist site antagonism through conversion to 7-chlorokynurenic acid in astrocytes.
Antihyperalgesic effects trends in capsaicin-induced hyperalgesia, including decreased AUPC for allodynia and mechanical and heat hyperalgesia.
Mood/well-being reports suggestive of antidepressant activity.
Documented Applications
Therapeutic use for neurological disorders involving NMDA receptor overactive glutamatergic transmission, framed around glycine B co-agonist site antagonism and conversion to 7-chlorokynurenic acid in astrocytes.
Ameliorating the side effect of dyskinesia induced by administration of L-DOPA in a subject.
Antihyperalgesic assessment in capsaicin-induced hyperalgesia, including outcomes for allodynia and mechanical and heat hyperalgesia.
Mood/well-being assessment with reports suggestive of antidepressant activity.
Phase 1b randomized double-blind placebo-controlled study in healthy subjects evaluating pharmacokinetics of L-4-chlorokynurenine and 7-chlorokynurenic acid after multiple oral doses.
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