Combination serotonin specific reuptake inhibitor and serotonin 1A receptor partial agonist for reducing L-DOPA-induced dyskinesia
Inventors
Bishop, Christopher Roy • West, Anthony • Manfredsson, Fredric
Assignees
Rosalind Franklin University of Medicine and Science • Michigan State University MSU • Research Foundation of the State University of New York
Publication Number
US-12285426-B2
Publication Date
2025-04-29
Expiration Date
2039-10-25
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Abstract
A method of treating and attenuating L-DOPA-induced dyskinesia, comprising administering an effective dose of at least one pharmacological agent, e.g., vilazodone, having serotonin-specific reuptake inhibition (SSRI) and serotonin receptor 1A (5-HT1AR) partial agonism activity, in conjunction with L-DOPA. Other agents, such as an L-DOPA decarboxylase inhibitor, e.g., carbidopa, or other adjunct treatments may also be provided.
Core Innovation
The invention provides a combination therapy and pharmaceutical oral dosage form for treating or reducing the risk of L-DOPA-induced dyskinesia (LID) in patients with Parkinson's Disease. Specifically, it involves administering at least one agent having selective serotonin reuptake inhibitor (SSRI) activity and serotonin 1A (5-HT1A) receptor partial agonist activity, such as vilazodone or vortioxetine, in combination with L-DOPA. The agent may be co-administered in a single dosage form with additional drugs including DOPA decarboxylase inhibitors, catechol-O-methyl transferase inhibitors, monoamine oxidase type B inhibitors, dopamine receptor agonists, anticholinergic agents, antimuscarinic agents, or cannabinoids.
The problem addressed by the invention, as outlined in the background, is the high incidence of debilitating dyskinesias resulting from chronic L-DOPA treatment in Parkinson’s disease patients—a complication that occurs in up to 90% of those receiving L-DOPA therapy over time. Existing drugs, such as amantadine, offer limited and transient effectiveness and may cause problematic side effects. Prior attempts to manage LID using SSRI or 5-HT1A partial agonists individually have not successfully translated into effective clinical therapies due to either limited efficacy or negative impacts on L-DOPA’s positive motor effects.
The core innovation leverages the dual mechanism of agents like vilazodone (SSRI and 5-HT1A partial agonist) to suppress development and expression of LID while preserving L-DOPA’s anti-parkinsonian benefits. Preclinical studies with animal models have shown that this approach significantly reduces LID and normalizes associated striatal gene expression, without compromising motor improvement. The invention encompasses oral dosage forms that may additionally contain L-DOPA, DOPA decarboxylase inhibitors, and other adjunctive drugs, with specified dosing regimens suited for chronic administration in humans.
Claims Coverage
There are two main inventive features claimed as independent claims in the patent.
Oral unit dose containing vilazodone or vortioxetine plus at least one adjunct agent for treating L-DOPA-induced dyskinesia
A pharmaceutically-acceptable oral unit dose for treating or reducing risk of L-DOPA induced dyskinesia in a human patient having Parkinson's Disease, comprising: - At least one agent selected from vilazodone and vortioxetine, in a sufficient amount to treat the L-DOPA induced dyskinesia. - At least one 'second agent' selected from: - DOPA decarboxylase inhibitor in an effective amount to reduce peripheral decarboxylation of L-DOPA - Catechol-O-methyl transferase inhibitor - Monoamine oxidase type B inhibitor - Dopamine receptor agonist - Anticholinergic agent - Antimuscarinic agent - Cannabinoid Optional features include specifying that the adjunct agent is cannabidiol, amantadine, or a cannabinoid, and further optionally including L-DOPA in an amount of 100–250 mg per dose.
Oral unit dose with vilazodone or vortioxetine and DOPA decarboxylase inhibitor
A pharmaceutically-acceptable oral unit dose for treating or reducing risk of L-DOPA-induced dyskinesia in a human patient having Parkinson’s Disease, comprising: - Vilazodone or vortioxetine in an amount between 0.5 mg and 10 mg per unit dose - A peripheral-acting DOPA decarboxylase inhibitor in an effective amount to reduce peripheral decarboxylation of the L-DOPA Optional features include further comprising L-DOPA (100–250 mg per dose), a catechol-O-methyl transferase inhibitor, monoamine oxidase type B inhibitor, dopamine receptor agonist, anticholinergic agent, antimuscarinic agent, cannabinoid, or amantadine, as well as particular dosage ranges for vilazodone or vortioxetine.
The claims define inventive pharmaceutical oral dosage forms and combination therapies integrating a dual-action agent (SSRI and 5-HT1A partial agonist, such as vilazodone or vortioxetine) with specified adjunct agents, designed to treat or reduce L-DOPA-induced dyskinesia in Parkinson’s Disease.
Stated Advantages
The combination of a serotonin-specific reuptake inhibitor and 5-HT1A receptor partial agonist (e.g. vilazodone) suppresses L-DOPA-induced dyskinesia without reducing the anti-parkinsonian motor efficacy of L-DOPA.
Vilazodone and similar agents maintain or improve motor function while reducing abnormal involuntary movements and normalizing dyskinesia-related gene expression in the striatum.
The approach allows for chronic administration with maintained efficacy and a favorable side effect profile compared to existing treatments such as amantadine.
Combination therapy may provide increased flexibility in L-DOPA dosing and enable more protracted chronic treatment.
Documented Applications
Treatment and attenuation of L-DOPA-induced dyskinesia in patients with Parkinson's Disease receiving L-DOPA therapy.
Prophylactic use in patients at risk of developing L-DOPA-induced dyskinesia.
Treatment of movement disorders such as multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, encephalitis lethargica, or dopamine-responsive dystonia (DRD).
Potential application in treating non-motor neural deficits associated with L-DOPA treatment.
Application to tardive dyskinesia in schizophrenic patients taking typical antipsychotics.
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