Compounds and combinations thereof for treating neurological and psychiatric conditions
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Solution Overview
Problem
Current treatments for major depressive disorder, particularly in patients with renal impairment, concomitant use of CYP2D6 inhibitors, or CYP2D6 poor metabolizers, are limited by potential adverse effects such as QT prolongation and dissociation, and there are no approved therapies for agitation in Alzheimer's disease.
Innovation Solution
A combination therapy of bupropion hydrochloride and dextromethorphan hydrobromide, administered in specific doses and formulations, to treat major depressive disorder and other neurological and psychiatric conditions without causing QT prolongation or dissociation, and to manage agitation in Alzheimer's disease.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antidepressant treatments are used in patients with renal impairment or CYP2D6 poor metabolizer status, then treatment coverage is provided, but QT prolongation and dissociation adverse effects occur
Solution Approach 1:
The patent applies parameter changes by adjusting the dosage regimen based on patient metabolism status. For CYP2D6 poor metabolizers and patients with renal impairment, the patent prescribes lower doses or alternative dosing schedules to reduce plasma concentrations of dextromethorphan and its metabolites, thereby minimizing QT prolongation and dissociation while maintaining antidepressant efficacy.
Solution Approach 2:
The patent uses bupropion as an intermediary agent in combination with dextromethorphan. Bupropion acts as a CYP2D6 inhibitor that modulates the metabolism of dextromethorphan, creating a synergistic effect that allows for reduced dosing of dextromethorphan while maintaining or enhancing antidepressant efficacy, thus reducing adverse effects in vulnerable populations.
2Reliability
If dextromethorphan is administered at standard doses, then antidepressant effect is achieved, but dissociation and QT prolongation occur in susceptible patients
Solution Approach 1:
The patent merges dextromethorphan with bupropion in a fixed-dose combination formulation. This combination allows the two agents to work synergistically, where bupropion's mechanism of action (dopamine and norepinephrine reuptake inhibition) complements dextromethorphan's NMDA receptor antagonism and sigma-1 agonism, providing enhanced antidepressant efficacy at lower doses of dextromethorphan, thereby reducing dissociation and QT prolongation risks.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The combination effectively treats major depressive disorder and neurological conditions like Alzheimer's disease-related agitation without significant adverse effects, providing a safer and more effective alternative to existing treatments.
Implementation Method 1
the dextromethorphan acts as an uncompetitive antagonist of the NMDA receptor
Implementation Method 2
the dextromethorphan acts as an uncompetitive antagonist of the NMDA receptor and a sigma-1 receptor agonist
Data Source
AI summary
This disclosure relates to administration of a combination of: 1) about 100-110 mg, about 104-106 mg, or about 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of bupropion; and 2) about 40-50 mg, about 44-46 mg, or about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base form or another salt form of dextromethorphan in certain patient populations, such as patients having moderate renal impairment, patients receiving a concomitant strong CYP2D6 inhibitor, patients who are known CYP2D6 poor metabolizers, those in need of an NMDA antagonist that does not cause dissociation, and those at risk of QT prolongation.