Combination use of bupropion and dextromethorphan

Abstract

To provide a method of treating a neurological disorder.SOLUTION: An antidepressant compound and dextromethorphan, which is represented by the following formula, are administered to a human being who is an extensive metabolizer of dextromethorphan in need of the treatment of a neurological disorder.SELECTED DRAWING: Figure 7

Description

[Background technology]

[0001] Dextromethorphan is a widely used cough suppressant. Bupropion is an antidepressant approved for the treatment of depression and smoking cessation. Summary of the Invention [Means for solving the problem]

[0002] Antidepressant compounds such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites, or prodrugs of any of these compounds, can be used to improve the therapeutic properties of dextromethorphan, such as for the treatment of neurological disorders. Bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites, or prodrugs of any of these compounds, regardless of stereochemistry, may be effective in inhibiting or reducing the metabolism of dextromethorphan in some humans. This can be achieved by co-administering bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or metabolites, or prodrugs of any of these compounds, with dextromethorphan.

[0003] Some embodiments include a method of treating a neurological disorder comprising administering an antidepressant and dextromethorphan to a human being in need thereof, wherein the human being is an extensive metabolizer of dextromethorphan.

[0004] Some embodiments include a method of increasing dextromethorphan plasma levels in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering dextromethorphan and bupropion to the human being.

[0005] Some embodiments include a method of inhibiting the metabolism of dextromethorphan, comprising administering bupropion to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human's body simultaneously with bupropion.

[0006] Some embodiments include a method of increasing the metabolite lifetime of dextromethorphan, comprising administering bupropion to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human being's body simultaneously with bupropion.

[0007] Some embodiments include a method of correcting an extensive metabolite of dextromethorphan, comprising administering bupropion to a human being in need thereof.

[0008] Some embodiments include a method of improving the antitussive properties of dextromethorphan, comprising administering bupropion in combination with administration of dextromethorphan to a human being in need of treatment for cough.

[0009] Some embodiments include a method of treating cough comprising administering a combination of bupropion and dextromethorphan to a human being in need thereof.

[0010] Some embodiments include a method of treating a neurological disorder comprising administering bupropion and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered at least once daily for eight days.

[0011] Some embodiments include a method of treating a neurological disorder comprising administering to a human being in need thereof about 150 mg / day to about 300 mg / day of bupropion and about 15 mg / day to about 60 mg / day of dextromethorphan.

[0012] Some embodiments include a method of increasing dextromethorphan plasma levels in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering hydroxybupropion, or a prodrug thereof, with dextromethorphan to the human being.

[0013] Some embodiments include a method of increasing dextromethorphan plasma levels in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan to the human being.

[0014] Some embodiments include a method of increasing dextromethorphan plasma levels in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering threohydroxybupropion, or a prodrug thereof, with dextromethorphan to the human being.

[0015] Some embodiments include a method of inhibiting the metabolism of dextromethorphan, comprising administering bupropion to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human's body simultaneously with bupropion.

[0016] Some embodiments include a method of inhibiting the metabolism of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human's body simultaneously with hydroxybupropion.

[0017] Some embodiments include a method of inhibiting the metabolism of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human's body simultaneously with erythrohydroxybupropion.

[0018] Some embodiments include a method of inhibiting the metabolism of dextromethorphan, comprising administering threohydroxybupropion, or a prodrug thereof, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human being's body simultaneously with threohydroxybupropion.

[0019] Some embodiments include a method of increasing the metabolic lifetime of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human being's body simultaneously with hydroxybupropion.

[0020] Some embodiments include a method of increasing the metabolic lifetime of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human being's body simultaneously with erythrohydroxybupropion.

[0021] Some embodiments include a method of increasing the metabolic lifetime of dextromethorphan, comprising administering threohydroxybupropion, or a prodrug thereof, to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human being's body simultaneously with threohydroxybupropion.

[0022] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering bupropion and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein bupropion is administered on the first day of at least two days of co-administration of dextromethorphan with bupropion (at least two days of co-administration), and wherein an increase in dextromethorphan plasma levels occurs on the first day that bupropion and dextromethorphan are co-administered compared to administration of the same amount of dextromethorphan without bupropion.

[0023] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the hydroxybupropion or a prodrug thereof is administered on the first day of at least two days of co-administration of dextromethorphan with hydroxybupropion or a prodrug thereof, and wherein an increase in dextromethorphan plasma levels occurs on the first day that hydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered compared to administration of the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof.

[0024] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the erythrohydroxybupropion or a prodrug thereof is administered on the first day of at least two days of co-administration of dextromethorphan with hydroxybupropion or a prodrug thereof, and wherein an increase in dextromethorphan plasma levels occurs on the first day that erythrohydroxybupropion or a prodrug thereof and dextromethorphan are co-administered compared to administration of the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.

[0025] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the threohydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of co-administration of dextromethorphan with hydroxybupropion, or a prodrug thereof, and wherein an increase in dextromethorphan plasma levels occurs on the first day that threohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered compared to administration of the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof.

[0026] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering bupropion and dextromethorphan, for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein on the fifth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without bupropion for five consecutive days.

[0027] Some embodiments include a method of increasing dextromethorphan plasma levels, comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, for at least five consecutive days, wherein on the fifth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without hydroxybupropion, or a prodrug thereof, for five consecutive days.

[0028] Some embodiments include a method of increasing dextromethorphan plasma levels, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, for at least five consecutive days, wherein on the fifth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion, or a prodrug thereof, for five consecutive days.

[0029] Some embodiments include a method of increasing dextromethorphan plasma levels, comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, for at least five consecutive days, wherein on the fifth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion, or a prodrug thereof, for five consecutive days.

[0030] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering bupropion and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein on the sixth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without bupropion for six consecutive days.

[0031] Some embodiments include a method of increasing dextromethorphan plasma levels, comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, for at least six consecutive days, wherein on the sixth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without hydroxybupropion or a prodrug thereof for six consecutive days.

[0032] Some embodiments include a method of increasing dextromethorphan plasma levels, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein on the sixth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion, or a prodrug thereof, for six consecutive days.

[0033] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, for at least six consecutive days, wherein on the sixth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion, or a prodrug thereof, for six consecutive days.

[0034] Some embodiments include a method of reducing dextromethorphan plasma levels comprising co-administering bupropion and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein bupropion is administered on the first day of at least two days of dextromethorphan treatment, and wherein a reduction in dextromethorphan plasma levels occurs on the first day that bupropion and dextromethorphan are co-administered compared to the same amount of dextromethorphan administered without bupropion.

[0035] Some embodiments include a method of reducing dextromethorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the hydroxybupropion or a prodrug thereof is administered on the first day of at least two days of dextromethorphan treatment, and wherein a reduction in the dextromethorphan plasma level occurs on the first day that hydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, compared to the same amount of dextromethorphan administered without hydroxybupropion or a prodrug thereof.

[0036] Some embodiments include a method of reducing dextromethorphan plasma levels comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the erythrohydroxybupropion or a prodrug thereof is administered on the first day of at least two days of dextromethorphan treatment, and wherein a reduction in the dextromethorphan plasma level occurs on the first day that erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, compared to the same amount of dextromethorphan administered without erythrohydroxybupropion or a prodrug thereof.

[0037] Some embodiments include a method of reducing dextromethorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the threohydroxybupropion or a prodrug thereof is administered on the first day of at least two days of dextromethorphan treatment, and wherein a reduction in the dextromethorphan plasma level occurs on the first day that threohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, compared to the same amount of dextromethorphan administered without threohydroxybupropion or a prodrug thereof.

[0038] Some embodiments include a method of reducing dextrorphan plasma levels comprising co-administering bupropion and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the dextrorphan plasma level is less than the dextrorphan plasma level achieved by administering the same amount of dextromethorphan administered without bupropion for eight consecutive days.

[0039] Some embodiments include a method of reducing dextrorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the dextrorphan plasma level is less than the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without hydroxybupropion or a prodrug thereof, for eight consecutive days.

[0040] Some embodiments include a method of reducing dextrorphan plasma levels comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the dextrorphan plasma level is less than the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion or a prodrug thereof, for eight consecutive days.

[0041] Some embodiments include a method of reducing dextrorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the dextrorphan plasma level is less than the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion or a prodrug thereof, for eight consecutive days.

[0042] Some embodiments include a method of reducing the trough effect of dextromethorphan comprising co-administering bupropion with dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the dextromethorphan has a plasma concentration 12 hours after co-administration of bupropion with dextromethorphan that is at least twice the plasma concentration achieved by administration of the same amount of dextromethorphan without bupropion.

[0043] Some embodiments include a method of reducing the trough effect of dextromethorphan comprising co-administering hydroxybupropion, or a prodrug thereof, with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein the dextromethorphan has a plasma concentration 12 hours after co-administration of hydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma concentration achieved by administration of the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof.

[0044] Some embodiments include a method of reducing the trough effect of dextromethorphan comprising co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein the dextromethorphan has a plasma concentration 12 hours after co-administration of erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma concentration achieved by administration of the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.

[0045] Some embodiments include a method of reducing the trough effect of dextromethorphan comprising co-administering threohydroxybupropion, or a prodrug thereof, with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein the dextromethorphan has a plasma concentration 12 hours after co-administration of threohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof.

[0046] Some embodiments include a method of reducing adverse events associated with treatment with dextromethorphan comprising co-administering bupropion and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing an adverse event as a result of treatment with dextromethorphan.

[0047] Some embodiments include a method of reducing adverse events associated with treatment with dextromethorphan comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing an adverse event as a result of treatment with dextromethorphan.

[0048] Some embodiments include a method of reducing adverse events associated with treatment with dextromethorphan comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing an adverse event as a result of treatment with dextromethorphan.

[0049] Some embodiments include a method of reducing adverse events associated with treatment with dextromethorphan comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing an adverse event as a result of treatment with dextromethorphan.

[0050] Some embodiments include a method of reducing adverse events associated with treatment with bupropion, comprising co-administering dextromethorphan and bupropion to a human patient in need of bupropion treatment, wherein the human patient is at risk of experiencing the same adverse events as a result of treatment with bupropion.

[0051] Some embodiments include a method of correcting an extensive metabolite of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, to a human being in need thereof.

[0052] Some embodiments include a method of correcting an extensive metabolite of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, to a human being in need thereof.

[0053] Some embodiments include a method of correcting an extensive metabolite of dextromethorphan, comprising administering threohydroxybupropion, or a prodrug thereof, to a human being in need thereof.

[0054] Some embodiments include a method of improving the antitussive properties of dextromethorphan, comprising administering bupropion in combination with administration of dextromethorphan to a human being in need of treatment for cough.

[0055] Some embodiments include a method of improving the antitussive properties of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, in combination with administration of dextromethorphan to a human being in need of treatment for cough.

[0056] Some embodiments include a method of improving the antitussive properties of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, in combination with administration of dextromethorphan to a human being in need of treatment for cough.

[0057] Some embodiments include a method of improving the antitussive properties of dextromethorphan, comprising administering threohydroxybupropion, or a prodrug thereof, in combination with administration of dextromethorphan to a human being in need of treatment for cough.

[0058] Some embodiments include a method of treating cough comprising administering to a human being in need thereof a combination of hydroxybupropion, or a prodrug thereof, and dextromethorphan.

[0059] Some embodiments include a method of treating cough comprising administering a combination of erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof.

[0060] Some embodiments include a method of treating cough comprising administering to a human being in need thereof a combination of threohydroxybupropion, or a prodrug thereof, and dextromethorphan.

[0061] Some embodiments include a method of treating a neurological disorder comprising administering bupropion and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered once daily for at least eight days.

[0062] Some embodiments include a method of treating a neurological disorder comprising administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered once daily for at least eight days.

[0063] Some embodiments include a method of treating a neurological disorder comprising administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered once daily for at least eight days.

[0064] Some embodiments include a method of treating a neurological disorder comprising administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered once daily for at least eight days.

[0065] Some embodiments include an oral sustained-release delivery system for dextromethorphan, comprising bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any of these compounds, dextromethorphan, and an aqueous vehicle.

[0066] Some embodiments include a method of reducing the number of doses of dextromethorphan that can be administered without loss of efficacy, comprising orally administering to a human being in need of dextromethorphan treatment an effective amount of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any of these compounds.

[0067] Some embodiments include a pharmaceutical composition, dosage form, or medicament comprising a therapeutically effective amount of dextromethorphan, an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any of these compounds, and a pharmaceutically acceptable excipient. [Brief explanation of the drawings]

[0068] [Figure 1] FIG. 1 is a plot of the mean plasma concentrations of dextromethorphan over time after administration on Day 8 for subjects receiving dextromethorphan alone or dextromethorphan and bupropion. [Figure 2] FIG. 2 shows the mean AUC of dextromethorphan on Day 8 for subjects receiving dextromethorphan alone or dextromethorphan and bupropion. [Figure 3] FIG. 3 shows the mean AUC of dextromethorphan on Day 8 for subjects receiving dextromethorphan alone or dextromethorphan and bupropion. [Figure 4] FIG. 4 shows the mean AUCO-inf of dextromethorphan on Day 8 for subjects receiving dextromethorphan alone or dextromethorphan and bupropion. [Figure 5] FIG. 5 shows the fold change in the AUC of dextromethorphan on Day 8 for subjects administered dextromethorphan alone compared to dextromethorphan and bupropion. [Figure 6] FIG. 6 shows the mean AUC of dextromethorphan on Days 1 and 8 for subjects receiving dextromethorphan alone or dextromethorphan and bupropion. [Figure 7] FIG. 7 shows the mean dextromethorphan in plasma concentrations for administration to subjects of dextromethorphan alone, or dextromethorphan and bupropion. [Figure 8] FIG. 8 shows the mean maximum dextromethorphan plasma concentrations on days 1 and 8 for subjects receiving dextromethorphan alone, or dextromethorphan and bupropion. [Figure 9] FIG. 9 shows a plot of the mean plasma concentration of dextrorphan over time after dosing on day 8 for subjects receiving dextromethorphan alone, or dextromethorphan and bupropion. [Figure 10] FIG. 10 shows the mean maximum dextrorphan plasma concentrations after dosing on days 1 and 8 for subjects receiving dextromethorphan alone, or dextromethorphan and bupropion. [Figure 11] FIG. 11 shows the mean AUC of dextromethorphan on Days 1 and 8 for administration to subjects of dextromethorphan alone, or dextromethorphan and bupropion. DETAILED DESCRIPTION OF THE INVENTION

[0069] Some embodiments include a method of treating a neurological disorder comprising administering to a person in need thereof a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of these compounds.

[0070] Some embodiments include a method of enhancing the therapeutic properties of dextromethorphan in treating a neurological disorder, comprising co-administering dextromethorphan with an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of these compounds.

[0071] Some embodiments include a method of increasing dextromethorphan plasma levels in a human being who is an extensive metabolizer of dextromethorphan, comprising co-administering to the human being an antidepressant compound, such as bupropion, and dextromethorphan.

[0072] Some embodiments include a method of inhibiting the metabolism of dextromethorphan, comprising administering an antidepressant compound, such as bupropion, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human's body simultaneously with the antidepressant.

[0073] Some embodiments include a method of increasing the metabolic lifetime of dextromethorphan, comprising administering an antidepressant compound, such as bupropion, to a human being, where the human being is an extensive metabolizer of dextromethorphan, and where dextromethorphan is present in the human's body simultaneously with the antidepressant compound.

[0074] Some embodiments include a method of correcting an advanced metabolite of dextromethorphan, comprising administering an antidepressant compound, such as bupropion, to a human in need thereof, such as a human in need of treatment for pain.

[0075] Some embodiments include a method of improving the therapeutic properties of dextromethorphan in the treatment of neurological disorders, comprising administering an antidepressant compound, such as bupropion, in combination with administration of dextromethorphan to a human being in need of such treatment.

[0076] Some embodiments include a method of treating a neurological disorder comprising administering to a human being in need of treatment an antidepressant compound, such as bupropion, and dextromethorphan in combination.

[0077] Dextromethorphan has the following structure: [ka]

[0078] Dextromethorphan is used as a cough suppressant. According to the FDA's labeling requirements for dextromethorphan products under the OTC monograph [21 CFR 341.74], dextromethorphan should be administered six times daily (every four hours), four times daily (every six hours), or three times daily (every eight hours).

[0079] Dextromethorphan is metabolized very rapidly in the human liver. This very rapid hepatic metabolism can limit systemic drug exposure in individuals who are extensive metabolizers. Humans can be 1) extensive dextromethorphan metabolizers—those who metabolize dextromethorphan very rapidly; 2) poor dextromethorphan metabolizers—those who metabolize dextromethorphan only slightly; or 3) intermediate dextromethorphan metabolizers—those whose metabolism of dextromethorphan falls somewhere between extensive and poor metabolizers. Extensive dextromethorphan metabolizers can also be very rapid metabolizers. Extensive dextromethorphan metabolizers represent a significant portion of the population. For example, dextromethorphan can be metabolized to dextrorphan.

[0080] When given the same oral dose of dextromethorphan, the plasma concentration of dextromethorphan is significantly higher in poor or intermediate metabolizers than in extensive metabolizers of dextromethorphan. Low plasma concentrations of dextromethorphan can limit its clinical usefulness as a single agent for extensive and, in some cases, intermediate metabolizers of dextromethorphan. Some antidepressants, such as bupropion, can inhibit the metabolism of dextromethorphan, thereby improving its therapeutic efficacy. Similarly, antidepressants can allow dextromethorphan to be given less frequently, such as once daily instead of twice daily, once daily instead of three times daily, once daily instead of four times daily, once daily instead of four times daily, twice daily instead of three times daily, or twice daily instead of four times daily, without losing therapeutic efficacy.

[0081] Pain or other neurological disorders may be treated by a method comprising administering to a person in need of treatment for pain or other neurological disorders a therapeutically effective amount of dextrorphan and a therapeutically effective amount of an antidepressant compound, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0082] Examples of neurological disorders that may be treated or treated with increased efficacy by a combination of dextrorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, affective disorders, psychiatric disorders, brain function disorders, movement disorders, dementia, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches.

[0083] Affective disorders that may be treated with a combination of dextromethorphan and an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, include, but are not limited to, depression, major depression, treatment-resistant depression and treatment-resistant bipolar depression, bipolar disorder including cyclothymia, seasonal affective disorder, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit disorder hyperactivity (ADDH) including hyperactivity, attention deficit / hyperactivity disorder (AD / HD), bipolar and manic states, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psychosexual dysfunction, pseudo-affect, and mood lability.

[0084] Depression can be manifested by mood changes, feelings of intense sadness, hopelessness, decreased mental function, difficulty concentrating, pessimistic worries, agitation, and self-deprecation. Physical symptoms of depression include insomnia, loss of appetite, weight loss, reduced energy and libido, and abnormal hormonal circadian rhythms.

[0085] Psychiatric disorders that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, anxiety disorders including, but not limited to, phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD), mania, manic-depressive illness, hypomania, unipolar depression, depression, stress disorders, somatoform disorders, personality disorders, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizophreniformity, aggression, aggression in Alzheimer's disease, agitation, and agitation in Alzheimer's disease.

[0086] Substance addictions and abuse that may be treated by a combination of dextromethorphan and an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, include, but are not limited to, drug dependence and addiction to cocaine, psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids, anxiolytics and hypnotics, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes all known forms of nicotine addiction, such as smoking cigarettes, cigars, and / or pipes, as well as chewing tobacco.

[0087] Brain dysfunctions that may be treated with the combination of dextromethorphan and an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, include, but are not limited to, senile dementia, Alzheimer's dementia, memory loss, amnesia / amnestic syndrome, epilepsy, impaired consciousness, coma, decreased attention, speech impediments, vocal spasms, and intellectual disabilities such as Parkinson's disease, Lennox-Gastaut syndrome, autism, attention deficit hyperactivity syndrome, and schizophrenia. Brain dysfunctions also include, but are not limited to, disorders caused by cerebrovascular disease, including, but not limited to, stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, and head trauma, whose symptoms include impaired consciousness, senile dementia, coma, decreased attention, and speech impediments.

[0088] Movement disorders that may be treated by a combination of dextromethorphan and an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, include, but are not limited to, akathisia, akinesia, associated movements, athetosis, ataxia, ballismus, hemiballismus, bradykinesia, cerebral palsy, chorea, Huntington's disease, rheumatic chorea, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless legs syndrome (RLS), tremor, essential tremor, and Tourette's syndrome, and Wilson's disease.

[0089] Dementias that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, dementia with Lewy bodies, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff syndrome, and Pick's disease.

[0090] Motor neuron diseases that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal muscular atrophy, Tay-Sachs disease, Sandhoff disease, and hereditary spastic paraplegia.

[0091] Neurodegenerative diseases that may be treated by a combination of dextromethorphan and an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar degeneration (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, myelopathy, and encephalopathy. These include amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophy, Charcot-Marie-Tooth (CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplegia.

[0092] Seizure disorders that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, epileptic seizures, nonepileptic seizures, epilepsy, febrile convulsions, partial seizures including, but not limited to, simple partial seizures, Jacksonian seizures, complex partial seizures, and epilepsy partialis continua, generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and generalized seizures including, but not limited to, infantile spasms, and status epilepticus.

[0093] Types of headaches that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, migraine, tension, and cluster headaches.

[0094] Other neurological disorders that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include Rett syndrome, autism, tinnitus, disturbances of consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy, voice disorders due to uncontrolled laryngeal muscle spasms including, but not limited to, abductor spasmodic dysphonia, adductor spasmodic dysphonia, muscle tension dysphonia, and vocal tremor, diabetic neuropathy, chemotherapy-induced neurotoxicity such as methotrexate neurotoxicity, incontinence including, but not limited to, stress urinary incontinence, urge urinary incontinence, and fecal incontinence, and erectile dysfunction.

[0095] In some embodiments, the combination of dextromethorphan and an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, may be used to treat pain, emotional dysregulation, depression (including treatment-resistant depression), memory and dementia-related disorders, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rett syndrome, seizures, cough (including chronic cough), and the like.

[0096] In some embodiments, a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds may be used to treat dermatitis.

[0097] The pain-relieving properties of dextromethorphan can be enhanced by methods including co-administering dextromethorphan with an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0098] The pain-relieving properties of bupropion may be enhanced by methods including co-administering dextromethorphan with bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0099] These methods may be used to treat or provide relief from any type of pain, including, but not limited to, musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, nociceptive pain, and the like.

[0100] Examples of musculoskeletal pain include lower back pain (i.e., lumbosacral pain), primary dysmenorrhea, and articular pain such as pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, and axial spondyloarthritis such as ankylosing spondylitis.

[0101] In some embodiments, a combination of dextrorphan and an antidepressant such as bupropion may be used to treat chronic musculoskeletal pain.

[0102] Examples of neuropathic pain include diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, central pain, etc. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-associated neuropathy, radiation or chemotherapy-associated neuropathy, etc.

[0103] The terms "treating" or "treatment" include the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or other animals, or any activity that otherwise affects the structure or any function of the human or other animal body.

[0104] Any antidepressant may be used in combination with dextromethorphan to improve the therapeutic properties of dextromethorphan. The dextromethorphan and antidepressant compound may be administered in separate compositions or dosage forms, or in a single composition or dosage form containing both.

[0105] Antidepressant compositions that may be co-administered with dextrorphan include, but are not limited to, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-clomipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxyindanamines, benactyzine, escitalopram, fulvic acid, and the like. and benzodiazepine, benzocaine, benzodiazepine, benzophenone, benzocaine, benzodiazepine ...

[0106] Bupropion has the structure shown below (bupropion hydrochloride form shown): [ka]

[0107] The combination of dextromethorphan and bupropion can provide greater benefits, such as greater pain relief, than can be achieved by administering either component alone. In extensive metabolizers, dextromethorphan can be rapidly and extensively metabolized, resulting in low systemic exposure even at high doses. In addition to having antidepressant and analgesic properties, bupropion is an inhibitor of dextromethorphan metabolism. Bupropion's metabolites, including hydroxybupropion, threohydroxybupropion (also known as threohydrobupropion or threodihydrobupropion), and erythrohydroxybupropion (also known as erythrohydrobupropion or erythrodihydrobupropion), are also inhibitors of dextromethorphan metabolism. Thus, bupropion, including forms of bupropion that are rapidly transformed in the body (e.g., salts, hydrates, solvates, polymorphs, etc.), is a prodrug of propion, hydroxybupropion, threohydrobupropion, and erythrohydrobupropion.

[0108] As discussed above, this inhibition may increase plasma concentrations of dextromethorphan, resulting in additive or synergistic effects such as relief of neurological disorders, including pain, depression, smoking cessation, etc. Thus, while inhibition of dextromethorphan metabolism is only one of many potential benefits of the combination, co-administration of bupropion with dextromethorphan may thereby enhance the efficacy of bupropion in many individuals. Co-administration of bupropion with dextromethorphan may enhance the analgesic properties of bupropion in many individuals. Co-administration of bupropion with dextromethorphan may also enhance the antidepressant properties of bupropion in many individuals, including a more rapid onset of action.

[0109] Another potential advantage of co-administration of dextromethorphan and bupropion is that it may be useful in reducing the likelihood of adverse events, such as somnolence, associated with dextromethorphan treatment, which may be useful, for example, in human patients at risk of experiencing adverse events as a result of being treated with dextromethorphan.

[0110] Another potential advantage of co-administering dextromethorphan and bupropion is that it may be useful for reducing the likelihood of adverse events, such as seizures, associated with treatment with bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds. This may be useful, for example, in human patients at risk of experiencing adverse events as a result of treatment with bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0111] With respect to dextromethorphan, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, co-administration may reduce central nervous system adverse events, gastrointestinal events, or other types of adverse events associated with any of these compounds. Central nervous system (CNS) adverse events include, but are not limited to, nervousness, dizziness, insomnia, lightheadedness, tremors, hallucinations, convulsions, CNS depression, fear, anxiety, headache, increased irritability or excitement, tinnitus, drowsiness, vertigo, sedation, somnolence, confusion, disorientation, fatigue, incoordination, fatigue, euphoria, irritability, insomnia, sleep disturbances, seizures, excitement, tension-like states, hysteria, hallucinations, delusions, paranoia, headache and / or migraine, and extrapyramidal symptoms such as oculomotor crisis, torticollis, hyperexcitability, increased muscle tone, ataxia, and tongue protrusion.

[0112] Gastrointestinal adverse events include, but are not limited to, nausea, vomiting, abdominal pain, dysphagia, dyspepsia, diarrhea, abdominal distension, flatulence, peptic ulcer with bleeding, loose stools, constipation, stomach pain, heartburn, gas, loss of appetite, stomach bloating, dyspepsia, bloating, hyperacidity, dry mouth, gastrointestinal upset, and stomach pain.

[0113] Co-administration of dextromethorphan with an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, does not necessarily require that the two compounds be administered in the same dosage form. For example, the two compounds can be administered in a single dosage form, or they can be administered in two separate dosage forms. Furthermore, the two compounds can be administered simultaneously, although this is not required. The compounds can be administered at different times, as long as both are present in the human body at the same time for at least part of the time that co-administration treatment is being performed.

[0114] In some embodiments, co-administration of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds in combination with dextromethorphan results in both bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds and dextromethorphan contributing to the pain-relieving properties of the combination. For example, compared to bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds alone or dextromethorphan alone, the combination may have improved pain-relieving properties, including a potentially faster onset of action.

[0115] In some embodiments, the combination has an improvement of at least about 0.5%, at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 100%, up to about 500%, or up to 1000%, between about 0.5% and about 1000%, between about 10% and about 20%, between about 20% and about 30%, between about 30% and about 40%, between about 40% and about 500%, or up to 1000%, compared to bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds alone. The pain relief properties may be improved by about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, about 100% to about 110%, about 110% to about 120%, about 120% to about 130%, about 130% to about 140%, about 140% to about 150%, about 150% to about 160%, about 160% to about 170%, about 170% to about 180%, about 180% to about 190%, about 190% to about 200%, or any amount of pain relief in a range bounded by any of these values, or any amount of pain relief between any of these values.

[0116] In some embodiments, the combination provides a reduction in serotonin levels compared to dextrorphan alone by at least about 0.5%, at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 100%, up to about 500%, or up to 1000%, between about 0.5% and about 1000%, between about 10% and about 20%, between about 20% and about 30%, between about 30% and about 40%, between about 40% and about 50%, between about 50% and about 60%, between about 60% and about 70%, between about 70% and about 80%, The pain relief properties may be improved by about 80% to about 90%, about 90% to about 100%, about 100% to about 110%, about 110% to about 120%, about 120% to about 130%, about 130% to about 140%, about 140% to about 150%, about 150% to about 160%, about 160% to about 170%, about 170% to about 180%, about 180% to about 190%, about 190% to about 200%, or any amount of pain relief in a range bounded by any of these values, or any amount of pain relief between any of these values.

[0117] Unless otherwise indicated, references to the compounds described herein, such as dextromethorphan, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, by structure, name, or any other means, include pharmaceutically acceptable salts, polymorphs, alternative solid forms such as solvates, hydrates, tautomers, deuterium modifications such as deuterium-modified dextromethorphan, and any chemical species that may be rapidly converted to the compounds described herein under the conditions in which the compounds are used as described herein.

[0118] Examples of deuterium-modified dextromethorphan include, but are not limited to, those shown below: [ka]

[0119] The dosage form or composition may be a blend or mixture of dextromethorphan alone or in a vehicle with a compound that inhibits the metabolism of dextromethorphan, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, dextromethorphan and bupropion may be dispersed together in a vehicle, or may be dispersed together in a vehicle. A dispersion comprises a mixture of solid materials, with small individual particles that are essentially one compound, but are dispersed together in a solid form, such as may occur when two powders of two different drugs are blended with a solid vehicle material. In some embodiments, dextromethorphan and bupropion may be substantially uniformly dispersed within the composition or dosage form. Alternatively, dextromethorphan and bupropion may be in separate domains or phases within the composition or dosage form. For example, one drug may be in the coating, and the other drug may be in the core within the coating. For example, one agent may be formulated for sustained release and the other for immediate release.

[0120] Some embodiments involve administering a tablet containing bupropion in a dosage form providing sustained release and dextromethorphan in a dosage form providing immediate release. While there are various ways in which sustained release of bupropion can be achieved, in some embodiments, bupropion is combined with hydroxypropyl methylcellulose. For example, particles of bupropion hydrochloride can be blended with microcrystalline cellulose and hydroxypropyl methylcellulose (e.g., METHOCEL®) to form a blended powder mixture. This can be combined with immediate-release dextromethorphan in a single tablet.

[0121] Dextromethorphan and / or antidepressants such as bupropion, hydroxybupropion, threohydrobupropion, and erythrohydrobupropion, or non-bupropionic antidepressants (all collectively referred to herein for convenience as "therapeutic compounds") may be combined with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice, e.g., as described in Remington's Pharmaceutical Sciences, 2005. The relative proportions of active ingredient and carrier may be determined, for example, by the solubility and chemical properties of the compounds, the chosen route of administration, and standard pharmaceutical practice.

[0122] Therapeutic compounds can be administered by any means that results in contact of the active agent with the desired site or sites of action in the patient's body. The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. For example, they can be administered as the sole active agent in a pharmaceutical composition, or they can be used in combination with other therapeutically active ingredients.

[0123] Therapeutic compounds can be administered to human patients in a variety of forms compatible with the chosen route of administration, for example, orally or parenterally. In this regard, parenteral administration includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transdermal, transepithelial, including ophthalmic, sublingual, and buccal; topical administration, including ophthalmic, cutaneous, ophthalmic, rectal, and nasal inhalation, insufflation, aerosol, and rectal systemic.

[0124] The ratio of dextromethorphan to bupropion can vary. In some embodiments, the weight ratio of dextromethorphan to bupropion is 0.1 to about 10, about 0.1 to about 2, about 0.2 to about 1, about 0.1 to about 0.5, about 0.1 to about 0.3, about 0.2 to about 0.4, about 0.3 to about 0.5, about 0.5 to about 0.7, about 0.8 to about 1, about 0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or any ratio in a range bounded by any of these values, or any ratio therebetween. A ratio of 0.1 indicates that the weight of dextromethorphan is 1 / 10 of that of bupropion. A ratio of 10 indicates that the weight of dextromethorphan is 10 times that of bupropion.

[0125] The amount of dextromethorphan in the therapeutic composition can vary. For example, some liquid compositions contain from about 0.0001% (w / v) to about 50% (w / v), from about 0.01% (w / v) to about 20% (w / v), from about 0.01% (w / v) to about 10% (w / v), from about 0.001% (w / v) to about 1% (w / v), from about 0.1% (w / v) to about 0.5% (w / v), from about 1% (w / v) to about 3% (w / v), or from about 3% (w / v) to about 5% (w / v). , about 5% (w / v) to about 7% (w / v), about 7% (w / v) to about 10% (w / v), about 10% (w / v) to about 15% (w / v), about 15% (w / v) to about 20% (w / v), about 20% (w / v) to about 30% (w / v), about 30% (w / v) to about 40% (w / v), or about 40% (w / v) to about 50% (w / v) of dextromethorphan.

[0126] Some liquid dosage forms can contain about 10 mg to about 500 mg, about 30 mg to about 350 mg, about 50 mg to about 200 mg, about 50 mg to about 70 mg, about 20 mg to about 50 mg, about 30 mg to about 60 mg, about 40 mg to about 50 mg, about 40 mg to about 42 mg, about 42 mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about 48 mg to about 50 mg, about 80 mg to about 100 mg, about 110 mg to about 130 mg, about 170 mg to about 190 mg, about 45 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg of dextromethorphan, or any amount of dextromethorphan in a range bounded by, or between, any of these values.

[0127] Some solid compositions have a solubility of at least about 5% (w / w), at least about 10% (w / w), at least about 20% (w / w), at least about 50% (w / w), at least about 70% (w / w), at least about 80%, about 10% (w / w) to about 30% (w / w), about 10% (w / w) to about 20% (w / w), about 20% (w / w) to about 30% (w / w), about 30% (w / w) to about 50% (w / w), about 30% (w / w) to about 40% (w / w), about 40% (w / w) to about 50% (w / w), about 50% (w / w) to about 80% (w / w), about 50% (w / w) to about 60% (w / w), about 70% (w / w) to about 80% (w / w), or about 80% (w / w) to about 90% (w / w) dextromethorphan.

[0128] Some solid dosage forms can contain about 10 mg to about 500 mg, about 30 mg to about 350 mg, about 20 mg to about 50 mg, about 30 mg to about 60 mg, about 40 mg to about 50 mg, about 40 mg to about 42 mg, about 42 mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about 48 mg to about 50 mg, about 50 mg to about 200 mg, about 50 mg to about 70 mg, about 80 mg to about 100 mg, about 110 mg to about 130 mg, about 170 mg to about 190 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg of dextromethorphan, or any amount of dextromethorphan in a range bounded by, or between, any of these values.

[0129] The amount of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds in the therapeutic composition can vary. If an increase in the plasma concentration of dextromethorphan is desired, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds should be administered in an amount that will increase the plasma concentration of dextromethorphan. For example, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, can be administered in an amount that, on day 8, results in a plasma concentration of dextromethorphan in a human that is at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, at least about 40 times, at least about 50 times, at least about 60 times, at least about 70 times, or at least about 80 times the plasma concentration of the same amount of dextromethorphan administered without bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0130] In some embodiments, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, has a 12-hour area under the curve (AUC) from the time of administration, on day 8, that is at least about 2-fold, at least about 5-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 60-fold, at least about 70-fold, or at least about 80-fold greater than the plasma concentration of the same amount of dextromethorphan administered without bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds. 0-12 ) or 12 hours after administration (C 平均 ) can be administered to a human in an amount of dextromethorphan that results in an average plasma concentration in humans of

[0131] In some embodiments, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, has a maximum plasma concentration in a human (C) on day 8 that is at least about 2-fold, at least about 5-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 30-fold, or at least about 40-fold the plasma concentration of the same amount of dextromethorphan administered without bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds. 最大 Dextromethorphan can be administered to humans in an amount that results in a

[0132] Due to co-administration of bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, an increase in dextromethorphan plasma concentrations may occur on the first day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered compared to the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, the dextromethorphan plasma concentration on the first day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered can be at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, or at least about 10-fold the level that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0133] In some embodiments, the dextromethorphan AUC on the first day when bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered will be at least twice the AUC that would be achieved with the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0134] In some embodiments, the dextromethorphan C on the first day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered 最大 can be achieved with the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. 最大 may be at least twice as large.

[0135] In some embodiments, the dextromethorphan trough concentration (e.g., plasma concentration 12 hours after administration) on the first day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered may be at least twice the trough level that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0136] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered on the first day of at least two days of treatment with dextromethorphan, and a reduction in dextromethorphan plasma concentration occurs on the first day when bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds and dextromethorphan are co-administered compared to the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, the dextromethorphan plasma concentration on the first day may be reduced by at least 5% compared to the dextromethorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan without bupropion.

[0137] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is co-administered to a human being in need of treatment with dextromethorphan for at least five consecutive days, wherein the dextromethorphan plasma concentration on the fifth day is greater than the dextromethorphan plasma concentration that would be achieved by administering the same amount without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds for five consecutive days. For example, the dextromethorphan plasma concentration on day 5 (e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) can be at least 5 times, at least 10 times, at least 20 times, at least 40 times, at least 50 times, at least 60 times, at least 65 times, or up to about 500 times the level that would be achieved by administering the same amount of dextromethorphan administered for 5 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0138] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds and dextromethorphan are co-administered to a human being in need of treatment with dextromethorphan for at least six consecutive days, wherein the dextromethorphan plasma concentration on the sixth day is greater than the dextromethorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds for six consecutive days. For example, the dextromethorphan plasma concentration on day 6 (e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) can be at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 75 times, or up to about 500 times the level that would be achieved by administering the same amount of dextromethorphan administered for 6 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0139] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds and dextromethorphan are co-administered to a human being in need of treatment with dextromethorphan for at least seven consecutive days, wherein the dextromethorphan plasma concentration on the seventh day is greater than the dextromethorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds for seven consecutive days. For example, the dextromethorphan plasma concentration on day 7 (e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) can be at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 70 times, at least 80 times, at least 90 times, or up to about 500 times the level that would be achieved by administering the same amount of dextromethorphan administered for 7 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0140] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds and dextromethorphan are co-administered for at least 8 consecutive days, and on the 8th day, dextromethorphan has a plasma concentration, e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after co-administration, that is at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or up to about 1000 times the plasma concentration that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds for 8 consecutive days.

[0141] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds and dextromethorphan are co-administered to a human being in need of dextromethorphan treatment for at least eight consecutive days, wherein the dextromethorphan plasma concentration on the eighth day is lower than the dextromethorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds for eight consecutive days. For example, the dextrorphan plasma concentration on day 8 (e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to the dextrorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan administered for 8 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0142] In some embodiments, bupropion has an AUC of bupropion in humans on day 8 that is at least about 100 ng·hr / mL, at least about 200 ng·hr / mL, at least about 500 ng·hr / mL, at least about 600 ng·hr / mL, at least about 700 ng·hr / mL, at least about 800 ng·hr / mL, at least about 900 ng·hr / mL, at least about 1,000 ng·hr / mL, at least about 1,200 ng·hr / mL, at least 1,600 ng·hr / mL, or up to about 15,000 ng·hr / mL. 0-12 can be administered to a human in an amount that results in

[0143] In some embodiments, bupropion has a C of bupropion in humans on day 8 that is at least about 10 ng / mL, at least about 20 ng / mL, at least about 40 ng / mL, at least about 50 ng / mL, at least about 60 ng / mL, at least about 70 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, at least about 100 ng / mL, at least 120 ng / mL, or up to about 1,500 ng / mL. 平均 can be administered to a human in an amount that results in

[0144] In some embodiments, bupropion has a C of bupropion in humans on day 8 that is at least about 10 ng / mL, at least about 20 ng / mL, at least about 50 ng / mL, at least about 90 ng / mL, at least about 100 ng / mL, at least about 110 ng / mL, at least about 120 ng / mL, at least about 130 ng / mL, at least about 140 ng / mL, at least 200 ng / mL, or up to about 1,500 ng / mL. 最大 can be administered to a human in an amount that results in

[0145] Some liquid compositions have a % w / v content of about 0.0001% (w / v) to about 50% (w / v), about 0.01% (w / v) to about 20% (w / v), about 0.01% to about 10% (w / v), about 1% (w / v) to about 3% (w / v), about 3% (w / v) to about 5% (w / v), about 5% (w / v) to about 7% (w / v), about 5% (w / v) to about 15% (w / v), about 7% (w / v) to about 10% (w / v), about 10% (w / v) to about 15% (w / v), about 15% (w / v) to about 20% (w / v), about 20% (w / v) to about 30% (w / v), about 30% (w / v) to about 40% (w / v), or about 40% (w / v) to about 50% (w / v) bupropion, or any amount of bupropion in a range bounded by, or between, any of these values.

[0146] Some liquid dosage forms may contain about 10 mg to about 1000 mg, about 50 mg to about 1000 mg, about 10 mg to about 50 mg, about 50 mg to about 100 mg, about 40 mg to about 90 mg, about 200 mg to about 300 mg, about 70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg to about 200 mg, about 110 mg to about 140 mg, about 180 mg to about 220 mg, about 280 mg to about 320 mg, about 200 mg, about 150 mg, or about 300 mg of bupropion, or any amount of bupropion in a range bounded by, or between, any of these values.

[0147] Some solid compositions have a mass fraction of at least about 5% (w / w), at least about 10% (w / w), at least about 20% (w / w), at least about 50% (w / w), at least about 70% (w / w), at least about 80%, about 10% (w / w) to about 30% (w / w), about 10% (w / w) to about 20% (w / w), about 20% (w / w) to about 30% (w / w), about 30% (w / w) to about 50% (w / w), about 30% (w / w) to about The composition may contain 40% (w / w), about 40% (w / w) to about 50% (w / w), about 50% (w / w) to about 80% (w / w), about 50% (w / w) to about 60% (w / w), about 70% (w / w) to about 80% (w / w), or about 80% (w / w) to about 90% (w / w) bupropion, or any amount of bupropion in a range bounded by, or between, any of these values.

[0148] Some solid dosage forms may contain about 10 mg to about 1000 mg, about 50 mg to about 1000 mg, about 10 mg to about 50 mg, about 50 mg to about 100 mg, about 40 mg to about 90 mg, about 200 mg to about 300 mg, about 70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg to about 200 mg, about 110 mg to about 140 mg, about 50 mg to about 150 mg, about 180 mg to about 220 mg, about 280 mg to about 320 mg, about 200 mg, about 150 mg, or about 300 mg of bupropion, or any amount of bupropion in a range bounded by, or between, any of these values.

[0149] In some embodiments, bupropion is administered at a dose that results in a bupropion plasma concentration of about 0.1 μM to about 10 μM, about 0.1 μM to about 5 μM, about 0.2 μM to about 3 μM, 0.1 μM to about 1 μM, about 0.2 μM to about 2 μM, 1 μM to about 10 μM, about 1 μM to about 5 μM, about 2 μM to about 3 μM, or about 2.8 μM to about 3 μM, about 1.5 μM to about 2 μM, about 4.5 μM to about 5 μM, about 2.5 μM to about 3 μM, about 1.8 μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, or any plasma concentration in a range bounded by, or between, any of these values.

[0150] In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion is administered at a dose that results in a hydroxybupropion plasma concentration of 0.1 μM to about 10 μM, about 0.1 μM to about 5 μM, about 0.2 μM to about 3 μM, 0.1 μM to about 1 μM, about 0.2 μM to about 2 μM, 1 μM to about 10 μM, about 1 μM to about 5 μM, about 2 μM to about 3 μM, or about 2.8 μM to about 3 μM, about 1.5 μM to about 2 μM, about 4.5 μM to about 5 μM, about 2.5 μM to about 3 μM, about 1.8 μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, or any plasma concentration in a range bounded by, or between, any of these values.

[0151] In some embodiments, the bupropion, hydroxybupropion, or prodrug of hydroxybupropion has an AUC of hydroxybupropion in humans on day 8 that is at least about 3,000 ng·hr / mL, at least about 7,000 ng·hr / mL, at least about 10,000 ng·hr / mL, at least about 15,000 ng·hr / mL, at least about 20,000 ng·hr / mL, at least about 30,000 ng·hr / mL, with an upper limit of about 50,000 ng·hr / mL, with an upper limit of about 150,000 ng·hr / mL, or any AUC in a range bounded by, or between, any of these values. 0-12 can be administered to a human in an amount that results in

[0152] In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion has a C of at least about 300 ng / mL, at least about 700 ng / mL, at least about 1,000 ng / mL, at least about 1,500 ng / mL, at least about 2,000 ng / mL, at least about 4,000 ng / mL, with an upper limit of about 10,000 ng / mL, with an upper limit of about 50,000 ng / mL, or any C in a range bounded by any of these values, on day 8. 最大 , or any C between these values 最大 The C of hydroxybupropion in humans is 最大 can be administered to a human in an amount that results in

[0153] In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion has a C of at least about 200 ng / mL, at least about 300 ng / mL, at least about 700 ng / mL, at least about 1,000 ng / mL, at least about 1,500 ng / mL, at least about 2,000 ng / mL, at least about 4,000 ng / mL, with an upper limit of about 10,000 ng / mL, with an upper limit of about 50,000 ng / mL, or any C in a range bounded by any of these values, on day 8. 平均 , or any C between these values 平均 The C of hydroxybupropion in humans is 平均 can be administered to a human in an amount that results in

[0154] In some embodiments, bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion is administered at a dose that results in a threohydroxybupropion plasma concentration of about 0.1 μM to about 10 μM, about 0.1 μM to about 5 μM, about 0.2 μM to about 3 μM, 0.1 μM to about 1 μM, about 0.2 μM to about 2 μM, 1 μM to about 10 μM, about 1 μM to about 5 μM, about 2 μM to about 3 μM, or about 2.8 μM to about 3 μM, about 1.5 μM to about 2 μM, about 4.5 μM to about 5 μM, about 2.5 μM to about 3 μM, about 1.8 μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, or any plasma concentration in a range bounded by, or between, any of these values.

[0155] In some embodiments, bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion has an AUC of threohydroxybupropion in humans on day 8 that is at least about 1,000 ng·hr / mL, at least about 2,000 ng·hr / mL, at least about 4,000 ng·hr / mL, at least about 5,000 ng·hr / mL, at least about 8,000 ng·hr / mL, with an upper limit of about 10,000 ng·hr / mL, with an upper limit of about 40,000 ng·hr / mL, or any AUC in a range bounded by, or between, any of these values. 0-12 can be administered to a human in an amount that results in

[0156] In some embodiments, bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion has a C of at least about 100 ng / mL, at least about 200 ng / mL, at least about 400 ng / mL, at least about 500 ng / mL, at least about 600 ng / mL, at least about 800 ng / mL, up to about 2,000 ng / mL, up to about 10,000 ng / mL, or any C in a range bounded by any of these values, on day 8. 最大 , or any C between these values 最大 The C of threohydroxybupropion in humans is 最大 can be administered to a human in an amount that results in

[0157] In some embodiments, bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion has a C of at least about 100 ng / mL, at least about 300 ng / mL, at least about 400 ng / mL, at least about 600 ng / mL, at least about 800 ng / mL, up to about 2,000 ng / mL, up to about 10,000 ng / mL, or any C in a range bounded by any of these values, on day 8. 平均 , or any C between these values 平均 The C of threohydroxybupropion in humans is 平均can be administered to a human in an amount that results in

[0158] In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion is administered at a dose that results in an erythrohydroxybupropion plasma concentration of about 0.1 μM to about 10 μM, about 0.1 μM to about 5 μM, about 0.2 μM to about 3 μM, 0.1 μM to about 1 μM, about 0.2 μM to about 2 μM, 1 μM to about 10 μM, about 1 μM to about 5 μM, about 2 μM to about 3 μM, or about 2.8 μM to about 3 μM, about 1.5 μM to about 2 μM, about 4.5 μM to about 5 μM, about 2.5 μM to about 3 μM, about 1.8 μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, or any plasma concentration in a range bounded by, or between, any of these values.

[0159] In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion, on day 8, has an AUC of erythrohydroxybupropion in humans that is at least about 200 ng·hr / mL, at least about 400 ng·hr / mL, at least about 700 ng·hr / mL, at least about 1,000 ng·hr / mL, at least about 1,500 ng·hr / mL, at least about 3,000 ng·hr / mL, with an upper limit of about 5,000 ng·hr / mL, with an upper limit of about 30,000 ng·hr / mL, or any AUC in a range bounded by, or between, any of these values. 0-12 can be administered to a human in an amount that results in

[0160] In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion has a C of at least about 30 ng / mL, at least about 60 ng / mL, at least about 90 ng / mL, at least about 100 ng / mL, at least about 150 ng / mL, at least about 200 ng / mL, at least about 300 ng / mL, an upper limit of about 1,000 ng / mL, or any C in a range bounded by any of these values, on day 8. 最大 , or any C between these values 最大 C of erythrohydroxybupropion in humans, 最大 can be administered to a human in an amount that results in

[0161] In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion has a C of at least about 20 ng / mL, at least about 30 ng / mL, at least about 50 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, at least about 100 ng / mL, at least about 150 ng / mL, at least about 200 ng / mL, at least about 300 ng / mL, with an upper limit of about 1,000 ng / mL, with an upper limit of about 5,000 ng / mL, or any C of a range bounded by any of these values, on day 8. 平均 , or any C between these values 平均 C of erythrohydroxybupropion in humans, 平均 can be administered to a human in an amount that results in

[0162] For compositions containing dextromethorphan and bupropion, some liquids are from about 0.0001% (w / v) to about 50% (w / v), from about 0.01% (w / v) to about 20% (w / v), from about 0.01% (w / v) to about 10% (w / v), from about 1% (w / v) to about 3% (w / v), from about 3% (w / v) to about 5% (w / v), from about 5% (w / v) to about 7% (w / v), from about 5% (w / v) to about 15% (w / v), from about 7% (w / v) to about 1 The formulation may contain 0% (w / v), about 10% (w / v) to about 15% (w / v), about 15% (w / v) to about 20% (w / v), about 20% (w / v) to about 30% (w / v), about 30% (w / v) to about 40% (w / v), about 40% (w / v) to about 50% (w / v) of combined dextromethorphan and bupropion, or any amount in a range bounded by, or between, any of these values. Some solid compositions have a mass fraction of at least about 5% (w / w), at least about 10% (w / w), at least about 20% (w / w), at least about 50% (w / w), at least about 70% (w / w), at least about 80%, about 10% (w / w) to about 30% (w / w), about 10% (w / w) to about 20% (w / w), about 20% (w / w) to about 30% (w / w), about 30% (w / w) to about 50% (w / w), about 30% (w / w) to about 40% (w / w), or % (w / w), about 40% (w / w) to about 50% (w / w), about 50% (w / w) to about 80% (w / w), about 50% (w / w) to about 60% (w / w), about 70% (w / w) to about 80% (w / w), about 80% (w / w) to about 90% (w / w) of combined dextromethorphan and bupropion, or any amount in a range bounded by, or between, any of these values. In some embodiments, the weight ratio of dextromethorphan to bupropion in a single composition or dosage form can be about 0.1 to about 2, about 0.2 to about 1, about 0.1 to about 0.3, about 0.2 to about 0.4, about 0.3 to about 0.5, about 0.5 to about 0.7, about 0.8 to about 1, about 0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or any value in a range bounded by, or between, any of these values.

[0163] The therapeutically effective amount of a therapeutic compound can vary depending on the situation. For example, the daily dose of dextromethorphan in some examples is from about 0.1 mg to about 1000 mg, from about 40 mg to about 1000 mg, from about 20 mg to about 600 mg, from about 60 mg to about 700 mg, from about 100 mg to about 400 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, from about 35 mg to about 40 mg, from about 40 mg to about 45 mg, from about 45 mg to about 50 mg, from about 50 mg to about 55 mg, from about 55 mg to about 60 mg, from about 20 mg to about 60 mg, from about 60 mg to about 100 mg. The daily dose may be in the range of about 100 mg, about 100 mg to about 200 mg, about 100 mg to about 140 mg, about 160 mg to about 200 mg, about 200 mg to about 300 mg, about 220 mg to about 260 mg, about 300 mg to about 400 mg, about 340 mg to about 380 mg, about 400 mg to about 500 mg, about 500 mg to about 600 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 180 mg, about 240 mg, about 360 mg, or a range bounded by any of these values, or any daily dose therebetween. Dextromethorphan may be administered once daily, twice daily or every 12 hours, three times daily, four times daily, or six times daily in an amount of about half, one-third, one-quarter, or one-sixth of the daily dose, respectively.

[0164] The daily dose of bupropion, in some examples, is from about 10 mg to about 1000 mg, from about 50 mg to about 600 mg, from about 100 mg to about 2000 mg, from about 50 mg to about 100 mg, from about 70 mg to about 95 mg, from about 100 mg to about 200 mg, from about 105 mg to about 200 mg, from about 100 mg to about 150 mg, from about 150 mg to about 300 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 200 mg to about 350 mg, from about 25 ... The daily dose may be in the range of about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 500 mg, about 400 mg to about 600 mg, about 360 mg to about 440 mg, about 560 mg to about 640 mg, or about 500 mg to about 600 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or a range bounded by any of these values, or any daily dose therebetween. Bupropion may be administered once daily; or twice daily or every 12 hours, or three times daily, in an amount of about half, or one-third, of the daily dose, respectively.

[0165] In some embodiments, 1) about 50 mg / day to about 100 mg / day, about 100 mg / day to about 150 mg / day, about 150 mg / day to about 300 mg / day, about 150 mg / day to about 200 mg / day, about 200 mg / day to about 250 mg / day, about 250 mg / day to about 300 mg / day, or about 300 mg / day to about 500 mg / day of bupropion; and / or 2) From about 15 mg / day to about 60 mg / day, from about 15 mg / day to about 30 mg / day, from about 30 mg / day to about 45 mg / day, from about 45 mg / day to about 60 mg / day, from about 60 mg / day to about 100 mg / day, from about 80 mg / day to about 110 mg / day, from about 100 mg / day to about 150 mg / day, or from about 100 mg / day to about 300 mg / day of dextromethorphan is administered to a human being in need thereof.

[0166] In some embodiments, about 150 mg / day of bupropion and about 30 mg / day of dextromethorphan, about 150 mg / day of bupropion and about 60 mg / day of dextromethorphan, about 150 mg / day of bupropion and about 90 mg / day of dextromethorphan, about 150 mg / day of bupropion and about 120 mg / day of dextromethorphan, about 200 mg / day of bupropion and about 30 mg / day of dextromethorphan, about 200 mg / day of bupropion and about 60 mg / day of dextromethorphan , about 200 mg / day of bupropion and about 90 mg / day of dextromethorphan, about 200 mg / day of bupropion and about 120 mg / day of dextromethorphan, about 300 mg / day of bupropion and about 30 mg / day of dextromethorphan, about 300 mg / day of bupropion and about 60 mg / day of dextromethorphan, about 300 mg / day of bupropion and about 90 mg / day of dextromethorphan, or about 300 mg / day of bupropion and about 120 mg / day of dextromethorphan is administered to a human.

[0167] In some embodiments, a human being is administered about 100 mg / day of bupropion and about 15 mg / day of dextromethorphan for 1, 2, or 3 days, followed by about 200 mg / day of bupropion and about 30 mg / day of dextromethorphan. In some embodiments, a human being is administered about 100 mg / day of bupropion and about 30 mg / day of dextromethorphan for 1, 2, or 3 days, followed by about 200 mg / day of bupropion and about 60 mg / day of dextromethorphan.

[0168] In some embodiments, a human being is administered about 75 mg / day of bupropion and about 15 mg / day of dextromethorphan for 1, 2, or 3 days, followed by about 150 mg / day of bupropion and about 30 mg / day of dextromethorphan. In some embodiments, a human being is administered about 75 mg / day of bupropion and about 30 mg / day of dextromethorphan for 1, 2, or 3 days, followed by about 150 mg / day of bupropion and about 60 mg / day of dextromethorphan.

[0169] An antidepressant compound such as bupropion can be administered as needed to treat a neurological condition such as pain, depression, or cough. In some embodiments, the antidepressant composition such as bupropion and dextromethorphan are administered at least once daily, such as once daily or twice daily, for at least 1 day, at least 3 days, at least 5 days, at least 7 days, at least 8 days, at least 14 days, at least 30 days, at least 60 days, at least 90 days, at least 180 days, at least 365 days, or longer.

[0170] Therapeutic compound can be formulated for oral administration, for example, with an inert diluent or edible carrier.Alternatively, it can be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or directly incorporated into dietary food.For oral therapeutic administration, active compound can be incorporated with excipients and used in the form of oral ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc.

[0171] Tablets, troches, pills, capsules, etc. may also contain one or more of the following: binders such as tragacanth gum, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrating agents such as corn starch, potato starch, or alginic acid; lubricants such as magnesium stearate; sweeteners such as sucrose, lactose, or saccharin; or flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring. When the unit dosage form is a capsule, it may contain a liquid carrier in addition to the above-mentioned types of materials. Various other materials may be present as coatings; for example, tablets, pills, or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compound, sucrose as a sweetener, methyl and propylparabens as preservatives, a dye, and a flavoring such as cherry or orange flavor. It may be desirable for the materials in the dosage form or pharmaceutical composition to be pharmaceutically pure and substantially non-toxic in the amounts used.

[0172] Some compositions or dosage forms may be liquid or may contain a solid phase dispersed in a liquid.

[0173] Therapeutic compounds can be formulated for parenteral or intraperitoneal administration.The solution of active compound, such as free base or pharmaceutically acceptable salt, can be prepared in water appropriately mixed with surfactant such as hydroxypropylcellulose.Dispersion can also have oil dispersed in glycerol, liquid polyethylene glycol and their mixtures or in them.Under normal conditions of storage and use, these preparations may contain preservatives to prevent the growth of microorganisms.

[0174] Particularly Contemplated Embodiments (Embodiment 1) 1. A method of treating pain or a neurological disorder, comprising administering to a person in need thereof a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant compound. (Embodiment 2) 1. A method of treating pain comprising administering to a human being in need thereof a combination of an antidepressant compound and dextromethorphan. (Embodiment 3) A method of enhancing the pain-relieving properties of dextromethorphan, comprising co-administering dextromethorphan and an antidepressant compound. (Embodiment 4) 1. A method of increasing dextromethorphan plasma concentrations in a human being who is an extensive metabolizer of dextromethorphan, comprising co-administering an antidepressant compound to the human being receiving treatment that includes dextromethorphan. (Embodiment 5) A method of inhibiting the metabolism of dextromethorphan comprising administering an antidepressant compound to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human's body simultaneously with the antidepressant compound. (Embodiment 6) A method of increasing the metabolic lifetime of dextromethorphan comprising administering an antidepressant compound to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human's body simultaneously with the antidepressant compound. (Embodiment 7) A method of correcting the extensive metabolism of dextromethorphan, comprising administering an antidepressant compound to a human being in need thereof. (Embodiment 8) A method for improving the pain-relieving properties of dextromethorphan, comprising administering an antidepressant compound in conjunction with administration of dextromethorphan to a human in need of treatment for pain. (Embodiment 9) A method for improving the antitussive properties of dextromethorphan, comprising administering an antidepressant compound in conjunction with administration of dextromethorphan to a human in need of treatment for cough. (Embodiment 10) A method of treating cough comprising administering to a human being in need thereof a combination of an antidepressant compound and dextromethorphan. (Embodiment 11) A method for improving the therapeutic properties of dextromethorphan, comprising administering an antidepressant compound in conjunction with administration of dextromethorphan to a human in need of treatment for a neurological disorder. (Embodiment 12) A method of treating a neurological disorder comprising administering to a human being in need thereof a combination of an antidepressant compound and dextromethorphan. (Embodiment 13) 1. A method of treating a neurological disorder comprising administering an antidepressant compound and dextromethorphan to a human being in need thereof, wherein the human being is an extensive metabolizer of dextromethorphan. (Embodiment 14) The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the dextromethorphan and the antidepressant compound are administered in separate dosage forms. (Embodiment 15) A pharmaceutical composition comprising a therapeutically effective amount of dextromethorphan, a therapeutically effective amount of an antidepressant compound, and a pharmaceutically acceptable excipient. (Embodiment 16) An oral dosage form comprising at least 20 mg of dextromethorphan and an effective amount of an antidepressant compound to inhibit the metabolism of dextromethorphan in humans who are extensive metabolizers of dextromethorphan. (Embodiment 17) The oral dosage form of embodiment 16, wherein about 30 mg to about 350 mg of dextromethorphan is present in the dosage form. (Embodiment 18) 18. The oral dosage form of embodiment 16 or 17, wherein about 100 mg to about 400 mg of bupropion is present in the dosage form. (Embodiment 19) The oral dosage form of embodiment 16, 17, or 18, comprising an amount of bupropion that results in a bupropion plasma concentration of about 0.1 μM to about 10 μM when the oral dosage form is administered to a human. (Embodiment 20) The oral dosage form of embodiment 19, comprising an amount of bupropion that results in a bupropion plasma concentration of about 0.1 μM to about 2 μM when the oral dosage form is administered to a human. (Embodiment 21) The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein bupropion is administered in an amount that results in a bupropion plasma concentration of about 0.1 μM to about 10 μM. (Embodiment 22) 22. The method of embodiment 21, wherein bupropion is administered in an amount that results in a bupropion plasma concentration of about 0.3 μM to about 1 μM. (Embodiment 23) 18. The method, composition, or dosage form of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17, wherein the antidepressant compound is bupropion or a metabolite thereof. (Embodiment 24) The method, composition, or dosage form of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17, wherein the antidepressant compound is bupropion. (Embodiment 25) 18. The method, composition, or dosage form of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17, wherein the antidepressant compound is clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-clomipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, oxindamine, benactyzine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, or a pharmaceutically acceptable salt thereof. (Embodiment 26) The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 14, 21, 22, 23, 24, or 25, wherein dextromethorphan is administered to the human being for the treatment of cough. (Embodiment 27) A method of treating a neurological disorder comprising administering to a human being in need thereof about 150 mg / day to about 300 mg / day of bupropion and about 30 mg / day to about 120 mg / day of dextromethorphan. (Embodiment 28) 1. A method of treating a neurological disorder, comprising administering bupropion and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered at least once daily for at least 8 days. (Embodiment 29) The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, or 27, wherein bupropion is administered to the human at least daily for at least 8 days. (Embodiment 30) The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, or 28, wherein dextromethorphan is administered to the human being at least daily for at least 8 days. (Embodiment 31) The method of embodiment 28, 29, or 30, wherein bupropion is administered in an amount that results in a plasma concentration of dextromethorphan in the human being, on day 8, that is at least 10 times the plasma concentration of the same amount of dextromethorphan administered without bupropion. (Embodiment 32) Bupropion has an AUC of hydroxybupropion of at least approximately 3000 ng·h / mL on day 8. 0-12 32. The method of embodiment 28, 29, 30, or 31, wherein the medicament is administered in an amount that results in (Embodiment 33) Bupropion has an AUC of erythrohydroxybupropion of at least approximately 400 ng·h / mL on day 8. 0-12 33. The method of embodiment 28, 29, 30, 31 or 32, wherein the medicament is administered in an amount that results in (Embodiment 34) Bupropion has an AUC of threohydroxybupropion of at least approximately 2000 ng·hr / mL on day 8. 0-12 34. The method of embodiment 28, 29, 30, 31, 32 or 33, wherein the medicament is administered in an amount that results in (Embodiment 35) 35. The method, composition, or dosage form of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27, 28, 29, 30, 31, 32, 33, or 34, wherein the weight ratio of dextromethorphan to bupropion is from about 0.1 to about 0.5. (Embodiment 36) The method of embodiment 27, 28, 29, 30, 31, 32, 33, 34, or 35, wherein the human being is an extensive metabolizer of dextromethorphan. (Embodiment 37) The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 150 mg / day of bupropion and about 30 mg / day of dextromethorphan are administered to the human being. (Embodiment 38) The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 150 mg / day of bupropion and about 60 mg / day of dextromethorphan are administered to the human being. (Embodiment 39) The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 200 mg / day of bupropion and about 30 mg / day of dextromethorphan are administered to the human being. (Embodiment 40) 37. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 100 mg / day of bupropion and about 15 mg / day of dextromethorphan are administered to the human being for about 1 to about 3 days, followed by about 200 mg / day of bupropion and about 30 mg / day of dextromethorphan. (Embodiment 41) The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 200 mg / day of bupropion and about 60 mg / day of dextromethorphan are administered to the human being. (Embodiment 42) 37. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 100 mg / day of bupropion and about 30 mg / day of dextromethorphan are administered to the human being for about 1 to about 3 days, followed by about 200 mg / day of bupropion and about 60 mg / day of dextromethorphan. (Embodiment 43) The method of embodiment 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42, wherein dextromethorphan is administered to the human being for the treatment of pain. (Embodiment 44) 44. The method of embodiment 43, wherein the pain comprises post-operative pain, cancer pain, arthritis pain, lumbosacral pain, musculoskeletal pain, central multiple sclerosis pain, nociceptive pain, or neuropathic pain. (Embodiment 45) 44. The method of embodiment 43, wherein the pain comprises musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, or nociceptive pain. (Embodiment 46) 44. The method of embodiment 43, wherein the pain comprises post-operative pain. (Embodiment 47) 44. The method of embodiment 43, wherein the pain comprises cancer pain. (Embodiment 48) 44. The method of embodiment 43, wherein the pain comprises joint pain. (Embodiment 49) 44. The method of embodiment 43, wherein the pain comprises lumbosacral pain. (Embodiment 50) 44. The method of embodiment 43, wherein the pain comprises musculoskeletal pain. (Embodiment 51) 44. The method of embodiment 43, wherein the pain comprises neuropathic pain. (Embodiment 52) 44. The method of embodiment 43, wherein the pain comprises nociceptive pain. (Embodiment 53) 44. The method of embodiment 43, wherein the pain comprises chronic musculoskeletal pain. (Embodiment 54) 44. The method of embodiment 43, wherein the pain is associated with rheumatoid arthritis. (Embodiment 55) The method of embodiment 43, wherein the pain is associated with juvenile rheumatoid arthritis. (Embodiment 56) 44. The method of embodiment 43, wherein the pain is associated with osteoarthritis. (Embodiment 57) The method of embodiment 43, wherein the pain is associated with axial spondyloarthritis. (Embodiment 58) The method of embodiment 43, wherein the pain is associated with ankylosing spondylitis. (Embodiment 59) 44. The method of embodiment 43, wherein the pain is associated with diabetic peripheral neuropathy. (Embodiment 60) 44. The method of embodiment 43, wherein the pain is associated with post-neuralgia. (Embodiment 61) The method of embodiment 43, wherein the pain is associated with trigeminal neuralgia. (Embodiment 62) 44. The method of embodiment 43, wherein the pain is associated with monoradiculopathies. (Embodiment 63) The method of embodiment 43, wherein the pain is associated with phantom limb pain. (Embodiment 64) 44. The method of embodiment 43, wherein the pain is associated with central pain. (Embodiment 65) 44. The method of embodiment 43, wherein the pain comprises cancer-related pain. (Embodiment 66) The method of embodiment 43, wherein the pain is associated with lumbar nerve root compression. (Embodiment 67) 44. The method of embodiment 43, wherein the pain is associated with spinal cord injury. (Embodiment 68) 44. The method of embodiment 43, wherein the pain is associated with post-stroke pain. (Embodiment 69) 44. The method of embodiment 43, wherein the pain is associated with central multiple sclerosis pain. (Embodiment 70) 44. The method of embodiment 43, wherein the pain is associated with HIV-associated neuropathy. (Embodiment 71) 44. The method of embodiment 43, wherein the pain is associated with radiation therapy-associated neuropathy. (Embodiment 72) 44. The method of embodiment 43, wherein the pain is associated with chemotherapy-associated neuropathy. (Embodiment 73) 44. The method of embodiment 43, wherein the pain comprises toothache. (Embodiment 74) 44. The method of embodiment 43, wherein the pain is associated with primary dysmenorrhea. (Embodiment 75) The method of embodiment 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, or 74, wherein 90 mg / day of dextromethorphan is administered to the human being. (Embodiment 76) The method of embodiment 75, wherein 45 mg of dextromethorphan is administered to the human being twice a day. (Embodiment 77) The method of embodiment 75 or 76, wherein 150 mg / day of bupropion is administered to the human being. (Embodiment 78) The method of embodiment 75 or 76, wherein 180 mg / day of bupropion is administered to the human being. (Embodiment 79) The method of embodiment 75 or 76, wherein 200 mg / day of bupropion is administered to the human being. (Embodiment 80) 125. The method of claim 123 or 124, wherein 300 mg / day of bupropion is administered to the human.

[0175] US Provisional Patent Application No. 61 / 900,354 is incorporated herein by reference in its entirety. [Example]

[0176] Example 1 As shown in Table 1 below, 15 human subjects were randomized to one of two treatment groups receiving dextromethorphan (DM) alone or DM in combination with bupropion. [Table 1]

[0177] All subjects were extensive (including ultrarapid) metabolizers of dextromethorphan as determined by CYP2D6 genetic testing. Dextromethorphan was administered at 12-hour intervals for days 1 through 8, with the final dose administered in the morning of day 8. Bupropion was administered once daily for days 1 through 3 and twice daily for days 4 through 8.

[0178] Plasma samples were collected for analysis of dextromethorphan, total dextrorphan, bupropion, hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion concentrations on days 1 and 8. Plasma samples for determination of dextromethorphan trough concentrations were obtained approximately 12 hours after dosing on days 1, 5, 6, and 8.

[0179] Concentrations of dextromethorphan, total dextrorphan (unconjugated and glucuronide forms), bupropion, hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion were measured using LC-MS / MS. Pharmacokinetic parameters were calculated.

[0180] Dextromethorphan metabolism phenotypes were determined by calculating the dextromethorphan / dextrorphan metabolic ratio as described by Jurica et al. Journal of Clinical Pharmacy and Therapeutics, 2012, 37, 486-490. Plasma concentrations of dextromethorphan and dextrorphan 3 hours after administration were used, with a dextromethorphan / dextrorphan ratio of 0.3 or greater indicating a poor metabolizer phenotype.

[0181] result As shown in Figure 1 and Table 2, plasma concentrations of dextromethorphan increased significantly with bupropion administration. [Table 2]

[0182] As shown in Figures 2-4, the AUC of dextromethorphan was significantly increased with bupropion administration. As shown in Figure 5, administration of bupropion with dextromethorphan significantly increased the mean dextromethorphan AUC of each on Day 8 compared to administration of dextromethorphan alone. 0-12 , AUC 0-24 , and AUC 0-inf As shown in Figure 6, the increases in dextromethorphan AUC occurred as early as day 1 (AUC 0-12 (approximately three times the increase in

[0183] As shown in Figure 7 and Table 3, trough plasma concentrations of dextromethorphan were significantly increased with administration of bupropion. Administration of bupropion with dextromethorphan resulted in an approximately 105-fold increase in mean trough plasma concentrations of dextromethorphan on Day 8 compared to administration of dextromethorphan alone.

[0184] Mean plasma concentrations of dextromethorphan on day 8 (C 平均 ) was increased approximately 60-fold with bupropion administration compared with administration of dextromethorphan alone. 最大 ) also increased significantly, as shown in Figure 8. [Table 3]

[0185] Dextromethorphan T 最大 and elimination half-life (T 1 / 2el) significantly increased with bupropion administration on day 8. Administration of bupropion with dextromethorphan resulted in a mean T of 3.6 hours compared with 2.3 hours with dextromethorphan alone. 最大 Administration of bupropion with dextromethorphan resulted in a mean T of 27.7 hours compared with 6.6 hours for dextromethorphan alone. 1 / 2el This resulted in...

[0186] As shown in Figure 9 and Table 4, plasma concentrations of dextrphan were significantly reduced with bupropion administration. [Table 4]

[0187] As shown in Figures 10-11, the average dextrorphan C 最大 and a reduction of approximately 78% in the mean dextrorphan AUC on day 8 of bupropion administration. 0-12 There was a decrease of about 55% in

[0188] Phenotyping of dextromethorphan metabolic status showed that no subjects in either treatment group were poor metabolizers on Day 1. However, by Day 8, 100% of subjects treated with bupropion converted to poor metabolizer status, compared with 0% of subjects treated with dextromethorphan alone. The mean plasma dextromethorphan / dextrorphan metabolic ratio increased with bupropion administration from 0.01 on Day 1 to 0.71 on Day 8. The mean ratio in the DM-alone group was 0.00 on Day 1 and remained unchanged on Day 8.

[0189] On day 8, mean plasma concentrations of bupropion, hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion were at least 10 ng / mL, 200 ng / mL, 20 ng / mL, and 100 ng / mL, respectively, after bupropion administration.

[0190] As used in this section, the term "fold change" or "fold increase" refers to the ratio of the value of bupropion with dextromethorphan to the same value of dextromethorphan alone (i.e., the value of bupropion with dextromethorphan divided by the same value of dextromethorphan alone).

[0191] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and the like used in the specification and claims should be understood in all instances as indicating both the exact value indicated and that value as modified by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the conditions under which desired properties may be obtained. At the very least, and without limiting the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed at least in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0192] As used in the context of describing the present invention (particularly in the context of the claims that follow), the terms "a," "an," and similar references should be construed to include both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to further clarify the invention and does not limit the scope of any claim. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0193] Groups of alternative elements or embodiments disclosed herein are not to be construed as limiting. Each group member may be presented and claimed individually or in any combination with other group members or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is deemed to include the group as modified to fulfill all Markush group descriptions used in the appended claims.

[0194] Certain embodiments are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventor anticipates that such variations will be employed by those skilled in the art as appropriate, and intends that the invention be practiced otherwise than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

[0195] Finally, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other variations that may be employed are within the scope of the claims. Thus, by way of example, but not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Accordingly, the claims are not limited to the exact embodiments as shown and described.

[0196] (Addendum) (Appendix 1) A method of treating a neurological disorder comprising administering an antidepressant compound and dextromethorphan to a human being who is an extensive metabolizer of dextromethorphan and who is in need of such treatment.

[0197] (Appendix 2) 2. The method of claim 1, wherein the neurological disorder is depression.

[0198] (Appendix 3) 2. The method of claim 1, wherein the neurological disorder is cough.

[0199] (Appendix 4) 4. The method of claim 1, 2, or 3, wherein the antidepressant comprises hydroxybupropion or a prodrug thereof.

[0200] (Appendix 5) 5. The method of claim 1, 2, 3, or 4, wherein the antidepressant comprises erythrohydroxybupropion or a prodrug thereof.

[0201] (Appendix 6) 6. The method of claim 1, wherein the antidepressant comprises threohydroxybupropion or a prodrug thereof.

[0202] (Appendix 7) 1. A method of increasing the plasma concentration of dextromethorphan in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering bupropion with dextromethorphan to the human being.

[0203] (Appendix 8) 1. A method of increasing dextromethorphan plasma concentrations in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering hydroxybupropion, or a prodrug thereof, with dextromethorphan to the human being.

[0204] (Appendix 9) 1. A method of increasing dextromethorphan plasma levels in a human being in need of dextromethorphan treatment, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan to the human being.

[0205] (Appendix 10) 1. A method of increasing dextromethorphan plasma concentrations in a human being in need of dextromethorphan treatment, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering threohydroxybupropion, or a prodrug thereof, with dextromethorphan to the human being.

[0206] (Appendix 11) 1. A method for inhibiting the metabolism of dextromethorphan, comprising administering bupropion to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human's body simultaneously with bupropion.

[0207] (Appendix 12) 1. A method for inhibiting the metabolism of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human's body simultaneously with hydroxybupropion.

[0208] (Appendix 13) 1. A method for inhibiting the metabolism of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human's body simultaneously with erythrohydroxybupropion.

[0209] (Appendix 14) 1. A method for inhibiting the metabolism of dextromethorphan, comprising administering threohydroxybupropion or a prodrug thereof to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human's body simultaneously with threohydroxybupropion.

[0210] (Appendix 15) 1. A method for increasing the metabolic lifetime of dextromethorphan, comprising administering bupropion to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being simultaneously with bupropion.

[0211] (Appendix 16) 1. A method for increasing the metabolic lifetime of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being simultaneously with hydroxybupropion.

[0212] (Appendix 17) 1. A method for increasing the metabolic lifetime of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human's body simultaneously with erythrohydroxybupropion.

[0213] (Appendix 18) 1. A method for increasing the metabolic lifetime of dextromethorphan, comprising administering threohydroxybupropion, or a prodrug thereof, to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human's body simultaneously with threohydroxybupropion.

[0214] (Appendix 19) 1. A method of increasing dextromethorphan plasma levels comprising co-administering bupropion and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the bupropion is administered on the first day of at least two days of co-administration of dextromethorphan with bupropion (at least two days of co-administration), and wherein an increase in dextromethorphan plasma levels occurs on the first day that bupropion and dextromethorphan are co-administered compared to administration of the same amount of dextromethorphan without bupropion.

[0215] (Appendix 20) 20. The method of claim 19, wherein on the first day that bupropion and dextromethorphan are co-administered, the dextromethorphan plasma concentration is at least twice the level that would be achieved by administering the same amount of dextromethorphan without bupropion.

[0216] (Appendix 21) 1. A method of increasing dextromethorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the hydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of co-administration of dextromethorphan with hydroxybupropion or a prodrug thereof, and wherein an increase in dextromethorphan plasma levels occurs on the first day that hydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered compared to administration of the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof.

[0217] (Appendix 22) 22. The method of claim 21, wherein on the first day when hydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, the dextromethorphan plasma concentration is at least twice the level that would be achieved by administering the same amount of dextromethorphan without hydroxybupropion, or a prodrug thereof.

[0218] (Appendix 23) 1. A method of increasing dextromethorphan plasma levels comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the erythrohydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of co-administration of dextromethorphan with erythrohydroxybupropion, or a prodrug thereof, and wherein an increase in dextromethorphan plasma levels occurs on the first day that erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered compared to administration of the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.

[0219] (Appendix 24) 24. The method of claim 23, wherein on the first day when erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, the dextromethorphan plasma concentration is at least twice the level that would be achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion, or a prodrug thereof.

[0220] (Appendix 25) 1. A method of increasing dextromethorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the threohydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of co-administration of dextromethorphan with threohydroxybupropion or a prodrug thereof, and wherein an increase in dextromethorphan plasma levels occurs on the first day that threohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered compared to administration of the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof.

[0221] (Appendix 26) 26. The method of claim 25, wherein on the first day when threohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, the dextromethorphan plasma concentration is at least twice the level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion, or a prodrug thereof.

[0222] (Appendix 27) 1. A method of increasing dextromethorphan plasma levels, comprising co-administering bupropion and dextromethorphan, for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein on the fifth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan without bupropion for five consecutive days.

[0223] (Appendix 28) 28. The method of claim 27, wherein on the fifth day when bupropion and dextromethorphan are co-administered, the dextromethorphan plasma concentration is at least 20-fold higher than the level that would be achieved by administering the same amount of dextromethorphan without bupropion for five consecutive days.

[0224] (Appendix 29) 1. A method of increasing dextromethorphan plasma levels, comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein on the fifth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without hydroxybupropion, or a prodrug thereof, for five consecutive days.

[0225] (Appendix 30) 30. The method of claim 29, wherein on the fifth day when hydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, the dextromethorphan plasma concentration is at least 20-fold higher than the level that would be achieved by administering the same amount of dextromethorphan without hydroxybupropion, or a prodrug thereof, for five consecutive days.

[0226] (Appendix 31) 1. A method of increasing dextromethorphan plasma levels, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein on the fifth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion, or a prodrug thereof, for five consecutive days.

[0227] (Appendix 32) 32. The method of claim 31, wherein on the fifth day when erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, the dextromethorphan plasma concentration is at least 20-fold higher than the level that would be achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion, or a prodrug thereof, for five consecutive days.

[0228] (Appendix 33) 1. A method of increasing dextromethorphan plasma levels, comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein on the fifth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion, or a prodrug thereof, for five consecutive days.

[0229] (Appendix 34) 34. The method of claim 33, wherein on the fifth day when threohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, the dextromethorphan plasma concentration is at least 20-fold higher than the level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion, or a prodrug thereof, for five consecutive days.

[0230] (Appendix 35) 1. A method of increasing dextromethorphan plasma levels, comprising co-administering bupropion and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein on the sixth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without bupropion for six consecutive days.

[0231] (Appendix 36) 36. The method of claim 35, wherein on the sixth day when bupropion and dextromethorphan are co-administered, the dextromethorphan plasma concentration is at least 30-fold higher than the level that would be achieved by administering the same amount of dextromethorphan without bupropion for six consecutive days.

[0232] (Appendix 37) 1. A method of increasing dextromethorphan plasma levels, comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein on the sixth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without hydroxybupropion, or a prodrug thereof, for six consecutive days.

[0233] (Appendix 38) 38. The method of claim 37, wherein on the sixth day when hydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, the dextromethorphan plasma concentration is at least 30-fold higher than the level that would be achieved by administering the same amount of dextromethorphan without hydroxybupropion, or a prodrug thereof, for six consecutive days.

[0234] (Appendix 39) 1. A method of increasing dextromethorphan plasma levels, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein on the sixth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion, or a prodrug thereof, for six consecutive days.

[0235] (Appendix 40) 40. The method of claim 39, wherein on the sixth day when erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, the dextromethorphan plasma concentration is at least 30-fold higher than the level that would be achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion, or a prodrug thereof, for six consecutive days.

[0236] (Appendix 41) 1. A method of increasing dextromethorphan plasma levels, comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein on the sixth day, the dextromethorphan plasma level is greater than the dextromethorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion, or a prodrug thereof, for six consecutive days.

[0237] (Appendix 42) 42. The method of claim 41, wherein the dextromethorphan plasma concentration on the sixth day when threohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered is at least 30-fold the level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion, or a prodrug thereof, for six consecutive days.

[0238] (Appendix 43) 1. A method of reducing dextromethorphan plasma levels comprising co-administering bupropion and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the bupropion is administered on the first of at least two days of dextromethorphan treatment, and wherein a reduction in dextromethorphan plasma levels occurs on the first day that bupropion and dextromethorphan are co-administered compared to the same amount of dextromethorphan administered without bupropion.

[0239] (Appendix 44) 44. The method of claim 43, wherein the plasma concentration of dextromethorphan on the first day that bupropion and dextromethorphan are co-administered is reduced by at least 5% compared to the dextromethorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan without bupropion.

[0240] (Appendix 45) 1. A method of reducing dextromethorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the hydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of dextromethorphan treatment, and wherein a reduction in dextromethorphan plasma levels occurs on the first day that hydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, compared to the same amount of dextromethorphan administered without hydroxybupropion or a prodrug thereof.

[0241] (Appendix 46) 46. ​​The method of claim 45, wherein the plasma concentration of dextrorphan on the first day when hydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered is reduced by at least 5% compared to the dextrorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan without hydroxybupropion, or a prodrug thereof.

[0242] (Appendix 47) 1. A method of reducing dextromethorphan plasma levels comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the erythrohydroxybupropion or a prodrug thereof is administered on the first day of at least two days of dextromethorphan treatment, and wherein a reduction in dextromethorphan plasma levels occurs on the first day that erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered compared to the same amount of dextromethorphan administered without erythrohydroxybupropion or a prodrug thereof.

[0243] (Appendix 48) 48. The method of claim 47, wherein the plasma concentration of dextrorphan on the first day when erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered is reduced by at least 5% compared to the dextrorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion, or a prodrug thereof.

[0244] (Appendix 49) 1. A method of reducing dextromethorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the threohydroxybupropion or a prodrug thereof is administered on the first day of at least two days of dextromethorphan treatment, and wherein a reduction in dextromethorphan plasma levels occurs on the first day that threohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered compared to the same amount of dextromethorphan administered without threohydroxybupropion or a prodrug thereof.

[0245] (Appendix 50) 50. The method of claim 49, wherein the plasma concentration of dextrorphan on the first day when threohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered is reduced by at least 5% compared to the dextrorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion, or a prodrug thereof.

[0246] (Appendix 51) 1. A method of reducing dextrorphan plasma levels, comprising co-administering bupropion and dextromethorphan, for at least eight consecutive days, to a human being in need of treatment with dextromethorphan, wherein on the eighth day, the dextrorphan plasma level is less than the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without bupropion for eight consecutive days.

[0247] (Appendix 52) 52. The method of claim 51, wherein the plasma concentration on the eighth day when bupropion and dextromethorphan are co-administered is reduced by at least 30% compared to the dextromethorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan without bupropion for eight consecutive days.

[0248] (Appendix 53) 1. A method of reducing dextrorphan plasma levels, comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least eight consecutive days, to a human being in need of treatment with dextromethorphan, wherein on the eighth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without hydroxybupropion, or a prodrug thereof, for eight consecutive days.

[0249] (Appendix 54) 54. The method of claim 53, wherein the plasma concentration on the eighth day when hydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered is reduced by at least 30% compared to the dextromethorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan without hydroxybupropion, or a prodrug thereof, for eight consecutive days.

[0250] (Appendix 55) 1. A method of reducing dextrorphan plasma levels, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least eight consecutive days, to a human being in need of treatment with dextromethorphan, wherein on the eighth day, the dextrorphan plasma level is less than the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion, or a prodrug thereof, for eight consecutive days.

[0251] (Appendix 56) 56. The method of claim 55, wherein the plasma concentration on the eighth day when erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered is reduced by at least 30% compared to the dextromethorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion, or a prodrug thereof, for eight consecutive days.

[0252] (Appendix 57) 1. A method of reducing dextrorphan plasma levels, comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least eight consecutive days, to a human being in need of treatment with dextromethorphan, wherein on the eighth day, the dextrorphan plasma level is less than the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion, or a prodrug thereof, for eight consecutive days.

[0253] (Appendix 58) 58. The method of claim 57, wherein the plasma concentration on the eighth day when threohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered is reduced by at least 30% compared to the dextromethorphan plasma concentration that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion, or a prodrug thereof, for eight consecutive days.

[0254] (Appendix 59) 1. A method for reducing the trough effect of dextromethorphan comprising co-administering bupropion with dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the dextromethorphan has a plasma concentration 12 hours after co-administration of bupropion with dextromethorphan that is at least twice the plasma concentration achieved by administration of the same amount of dextromethorphan without bupropion.

[0255] (Appendix 60) 60. The method of claim 59, wherein after the first co-administration of bupropion with dextromethorphan, the dextromethorphan has a plasma concentration 12 hours after co-administration of bupropion with dextromethorphan that is at least twice the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without bupropion.

[0256] (Appendix 61) 1. A method for reducing the trough effect of dextromethorphan comprising co-administering hydroxybupropion, or a prodrug thereof, with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein the dextromethorphan has a plasma concentration 12 hours after co-administration of hydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma concentration achieved by administration of the same amount of dextromethorphan without hydroxybupropion, or a prodrug thereof.

[0257] (Appendix 62) 62. The method of claim 61, wherein after the first co-administration of hydroxybupropion, or a prodrug thereof, with dextromethorphan, the dextromethorphan has a plasma concentration 12 hours after co-administration of hydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without hydroxybupropion, or a prodrug thereof.

[0258] (Appendix 63) 1. A method for reducing the trough effect of dextromethorphan comprising co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein the dextromethorphan has a plasma concentration 12 hours after co-administration of erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma concentration achieved by administration of the same amount of dextromethorphan without erythrohydroxybupropion, or a prodrug thereof.

[0259] (Appendix 64) 64. The method of claim 63, wherein after the first co-administration of erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan, the dextromethorphan has a plasma concentration 12 hours after co-administration of erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma concentration that would be achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion, or a prodrug thereof.

[0260] (Appendix 65) 1. A method for reducing the trough effect of dextromethorphan comprising co-administering threohydroxybupropion, or a prodrug thereof, with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein the dextromethorphan has a plasma concentration 12 hours after co-administration of threohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma concentration achieved by administration of the same amount of dextromethorphan without threohydroxybupropion, or a prodrug thereof.

[0261] (Appendix 66) 66. The method of claim 65, wherein after the first co-administration of threohydroxybupropion, or a prodrug thereof, with dextromethorphan, the dextromethorphan has a plasma concentration 12 hours after co-administration of threohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without threohydroxybupropion, or a prodrug thereof.

[0262] (Appendix 67) 61. The method of claim 1, 2, 3, 7, 11, 15, 19, 20, 27, 28, 35, 36, 43, 44, 51, 52, 59, or 60, wherein bupropion is co-administered with dextromethorphan for at least five consecutive days, and on the fifth day, dextromethorphan has a plasma concentration 12 hours after co-administration of bupropion with dextromethorphan that is at least 40 times the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without bupropion.

[0263] (Appendix 68) 63. The method of claim 1, 2, 3, 4, 8, 12, 16, 21, 22, 29, 30, 37, 38, 45, 46, 53, 54, 61, or 62, wherein hydroxybupropion, or a prodrug thereof, is co-administered with dextromethorphan for at least five consecutive days, and on the fifth day, dextromethorphan has a plasma concentration 12 hours after co-administration of hydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 40 times the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without hydroxybupropion, or a prodrug thereof.

[0264] (Appendix 69) 65. The method of claim 1, 2, 3, 5, 9, 13, 17, 23, 24, 31, 32, 39, 40, 47, 48, 55, 56, 63, or 64, wherein erythrohydroxybupropion, or a prodrug thereof, is co-administered with dextromethorphan for at least five consecutive days, and on the fifth day, dextromethorphan has a plasma concentration 12 hours after co-administration of erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 40 times the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without erythrohydroxybupropion, or a prodrug thereof.

[0265] (Appendix 70) 67. The method of claim 1, 2, 3, 6, 10, 14, 18, 25, 26, 33, 34, 41, 42, 49, 50, 57, 58, 65, or 66, wherein threohydroxybupropion, or a prodrug thereof, is co-administered with dextromethorphan for at least five consecutive days, and on the fifth day, dextromethorphan has a plasma concentration 12 hours after co-administration of threohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 40 times the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without threohydroxybupropion, or a prodrug thereof.

[0266] (Appendix 71) 68. The method of claim 1, 2, 3, 7, 11, 15, 19, 20, 27, 28, 35, 36, 43, 44, 51, 52, 59, 60, or 67, wherein bupropion is co-administered with dextromethorphan for at least six consecutive days, and on the sixth day, dextromethorphan has a plasma concentration 12 hours after co-administration of bupropion with dextromethorphan that is at least 50 times the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without bupropion.

[0267] (Appendix 72) 69. The method of claim 1, 2, 3, 4, 8, 12, 16, 21, 22, 29, 30, 37, 38, 45, 46, 53, 54, 61, 62, or 68, wherein hydroxybupropion, or a prodrug thereof, is co-administered with dextromethorphan for at least six consecutive days, and on the sixth day, dextromethorphan has a plasma concentration 12 hours after co-administration of hydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 50 times the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without the hydroxybupropion, or a prodrug thereof.

[0268] (Appendix 73) 70. The method of claim 1, 2, 3, 5, 9, 13, 17, 23, 24, 31, 32, 39, 40, 47, 48, 55, 56, 63, 64, or 69, wherein erythrohydroxybupropion, or a prodrug thereof, is co-administered with dextromethorphan for at least six consecutive days, and on the sixth day, dextromethorphan has a plasma concentration 12 hours after co-administration of erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 50 times the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without the erythrohydroxybupropion or prodrug thereof.

[0269] (Appendix 74) 71. The method of claim 1, 2, 3, 6, 10, 14, 18, 25, 26, 33, 34, 41, 42, 49, 50, 57, 58, 65, 66, or 70, wherein threohydroxybupropion, or a prodrug thereof, is co-administered with dextromethorphan for at least six consecutive days, wherein on the sixth day, dextromethorphan has a plasma concentration 12 hours after co-administration of threohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 50 times the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without the threohydroxybupropion, or a prodrug thereof.

[0270] (Appendix 75) 72. The method of claim 1, 2, 3, 7, 11, 15, 19, 20, 27, 28, 35, 36, 43, 44, 51, 52, 59, 60, 67, or 71, wherein bupropion is co-administered with dextromethorphan for at least seven consecutive days, and on the seventh day, dextromethorphan has a plasma concentration 12 hours after co-administration of bupropion with dextromethorphan that is at least 70 times the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without bupropion.

[0271] (Appendix 76) 73. The method of claim 1, 2, 3, 4, 8, 12, 16, 21, 22, 29, 30, 37, 38, 45, 46, 53, 54, 61, 62, 68, or 72, wherein hydroxybupropion, or a prodrug thereof, is co-administered with dextromethorphan for at least seven consecutive days, and on the seventh day, dextromethorphan has a plasma concentration 12 hours after co-administration of hydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 70 times the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without the hydroxybupropion, or a prodrug thereof.

[0272] (Appendix 77) 74. The method of claim 1, 2, 3, 5, 9, 13, 17, 23, 24, 31, 32, 39, 40, 47, 48, 55, 56, 63, 64, 69, or 73, wherein erythrohydroxybupropion, or a prodrug thereof, is co-administered with dextromethorphan for at least seven consecutive days, and on the seventh day, dextromethorphan has a plasma concentration 12 hours after co-administration of erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 70 times the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without the erythrohydroxybupropion or prodrug thereof.

[0273] (Appendix 78) 75. The method of claim 1, 2, 3, 6, 10, 14, 18, 25, 26, 33, 34, 41, 42, 49, 50, 57, 58, 65, 66, 70, or 74, wherein threohydroxybupropion, or a prodrug thereof, is co-administered with dextromethorphan for at least seven consecutive days, and on the seventh day, dextromethorphan has a plasma concentration 12 hours after co-administration of threohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 70 times the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without the threohydroxybupropion, or a prodrug thereof.

[0274] (Appendix 79) 76. The method of claim 1, 2, 3, 7, 11, 15, 19, 20, 27, 28, 35, 36, 43, 44, 51, 52, 59, 60, 67, 71, or 75, wherein bupropion is co-administered with dextromethorphan for at least eight consecutive days, and on the eighth day, dextromethorphan has a plasma concentration 12 hours after co-administration of bupropion with dextromethorphan that is at least 80 times the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without bupropion.

[0275] (Appendix 80) 77. The method of claim 1, 2, 3, 4, 8, 12, 16, 21, 22, 29, 30, 37, 38, 45, 46, 53, 54, 61, 62, 68, 72, or 76, wherein hydroxybupropion, or a prodrug thereof, is co-administered with dextromethorphan for at least eight consecutive days, and on the eighth day, dextromethorphan has a plasma concentration 12 hours after co-administration of hydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 80 times the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without the hydroxybupropion, or a prodrug thereof.

[0276] (Appendix 81) 78. The method of claim 1, 2, 3, 5, 9, 13, 17, 23, 24, 31, 32, 39, 40, 47, 48, 55, 56, 63, 64, 69, 73, or 77, wherein erythrohydroxybupropion, or a prodrug thereof, is co-administered with dextromethorphan for at least eight consecutive days, and on the eighth day, dextromethorphan has a plasma concentration 12 hours after co-administration of erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 80 times the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without the erythrohydroxybupropion or prodrug thereof.

[0277] (Appendix 82) 80. The method of claim 1, 2, 3, 6, 10, 14, 18, 25, 26, 33, 34, 41, 42, 49, 50, 57, 58, 65, 66, 70, 74, or 78, wherein threohydroxybupropion, or a prodrug thereof, is co-administered with dextromethorphan for at least eight consecutive days, and on the eighth day, dextromethorphan has a plasma concentration 12 hours after co-administration of threohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 80 times the plasma concentration that would be achieved by administration of the same amount of dextromethorphan without the threohydroxybupropion, or a prodrug thereof.

[0278] (Appendix 83) 1. A method for reducing an adverse event associated with treatment with dextromethorphan comprising co-administering bupropion and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing the adverse event as a result of being treated with dextromethorphan.

[0279] (Appendix 84) 1. A method for reducing an adverse event associated with treatment with dextromethorphan comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing the adverse event as a result of being treated with dextromethorphan.

[0280] (Appendix 85) 1. A method for reducing an adverse event associated with treatment with dextromethorphan comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing the adverse event as a result of being treated with dextromethorphan.

[0281] (Appendix 86) 1. A method for reducing an adverse event associated with treatment with dextromethorphan comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing the adverse event as a result of being treated with dextromethorphan.

[0282] (Appendix 87) 87. The method of claim 86, wherein the adverse event is drowsiness.

[0283] (Appendix 88) 1. A method for reducing an adverse event associated with treatment with bupropion, comprising co-administering dextromethorphan and bupropion to a human patient in need of bupropion treatment, wherein the human patient is at risk of experiencing the adverse event as a result of treatment with bupropion.

[0284] (Appendix 89) 89. The method of claim 88, wherein the adverse event is a seizure.

[0285] (Appendix 90) 1. A method for correcting an extensive metabolite of dextromethorphan, comprising administering bupropion to a human being in need thereof.

[0286] (Appendix 91) 1. A method for correcting an extensive metabolite of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, to a human in need thereof.

[0287] (Appendix 92) 1. A method for correcting an extensive metabolite of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, to a human in need thereof.

[0288] (Appendix 93) 1. A method for correcting an extensive metabolite of dextromethorphan, comprising administering threohydroxybupropion, or a prodrug thereof, to a human in need thereof.

[0289] (Appendix 94) 94. The method of any one of claims 1-93, wherein bupropion is administered to the human being at least daily for at least 8 days.

[0290] (Appendix 95) 95. The method of any one of claims 1-94, wherein dextromethorphan is administered to the human being at least daily for at least 8 days.

[0291] (Appendix 96) 96. The method of any one of claims 1-95, wherein dextromethorphan is administered to the human being for the treatment of cough.

[0292] (Appendix 97) 1. A method of improving the antitussive properties of dextromethorphan, comprising administering bupropion in combination with administration of dextromethorphan to a human in need of treatment for cough.

[0293] (Appendix 98) 1. A method of improving the antitussive properties of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, in combination with administration of dextromethorphan to a human in need of treatment for cough.

[0294] (Appendix 99) 1. A method of improving the antitussive properties of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, in combination with administration of dextromethorphan to a human in need of treatment for cough.

[0295] (Appendix 100) 1. A method of improving the antitussive properties of dextromethorphan, comprising administering threohydroxybupropion, or a prodrug thereof, in combination with administration of dextromethorphan to a human in need of treatment for cough.

[0296] (Appendix 101) A method of treating cough comprising administering a combination of bupropion and dextromethorphan to a human in need thereof.

[0297] (Appendix 102) 1. A method of treating cough comprising administering a combination of hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human in need thereof.

[0298] (Appendix 103) 1. A method of treating cough comprising administering a combination of erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human in need thereof.

[0299] (Appendix 104) 1. A method of treating cough, comprising administering to a human in need thereof a combination of threohydroxybupropion, or a prodrug thereof, and dextromethorphan.

[0300] (Appendix 105) 1. A method of treating a neurological disorder, comprising administering bupropion and dextromethorphan to a human being in need of such treatment, wherein the bupropion and dextromethorphan are administered at least once daily for at least 8 days.

[0301] (Appendix 106) 1. A method for treating a neurological disorder, comprising administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of such treatment, wherein the bupropion and dextromethorphan are administered at least once daily for at least 8 days.

[0302] (Appendix 107) 1. A method for treating a neurological disorder, comprising administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of such treatment, wherein the bupropion and dextromethorphan are administered at least once daily for at least 8 days.

[0303] (Appendix 108) 1. A method for treating a neurological disorder, comprising administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of such treatment, wherein the bupropion and dextromethorphan are administered at least once daily for at least 8 days.

[0304] (Appendix 109) 109. The method of any one of claims 1-108, wherein the human being is an extensive metabolizer of dextromethorphan.

[0305] (Appendix 110) 109. The method of any one of claims 1-109, wherein bupropion is administered in an amount that, on day 8, results in a plasma concentration of dextromethorphan in the human being that is at least 10 times the plasma concentration of the same amount of dextromethorphan administered without bupropion.

[0306] (Appendix 111) Bupropion, hydroxybupropion, or a prodrug of hydroxybupropion has an AUC of hydroxybupropion of at least about 3000 ng·hr / mL on day 8. 0-12 111. The method of any one of claims 1 to 110, wherein the patient is administered in an amount that results in

[0307] (Appendix 112) Bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion has an AUC of at least about 400 ng·hr / mL of erythrohydroxybupropion on day 8. 0-12 112. The method of any one of claims 1 to 111, wherein the patient is administered in an amount that results in

[0308] (Appendix 113) Bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion has an AUC of at least about 2000 ng·hr / mL of erythrohydroxybupropion on day 8. 0-12 111. The method of any one of claims 1 to 110, wherein the patient is administered in an amount that results in

[0309] (Appendix 114) 114. The method of any one of claims 1 to 113, wherein the weight ratio of dextromethorphan to bupropion is about 0.1 to about 0.5.

[0310] (Appendix 115) A method of treating a neurological disorder, comprising administering from about 150 mg / day to about 300 mg / day of bupropion and from about 15 mg / day to about 60 mg / day of dextromethorphan to a human being in need of such treatment.

[0311] (Appendix 116) 116. The method of claim 115, wherein the human is an extensive metabolizer of dextromethorphan.

[0312] (Appendix 117) 116. The method of claim 115, wherein about 150 mg / day of bupropion and about 30 mg / day of dextromethorphan are administered to the human being.

[0313] (Appendix 118) 116. The method of claim 115, wherein about 150 mg / day of bupropion and about 60 mg / day of dextromethorphan are administered to the human being.

[0314] (Appendix 119) 116. The method of claim 115, wherein about 200 mg / day of bupropion and about 30 mg / day of dextromethorphan are administered to the human being.

[0315] (Appendix 120) 120. The method of claim 119, wherein about 100 mg / day of bupropion and about 15 mg / day of dextromethorphan are administered to the human being for about 1 to about 3 days, followed by about 200 mg / day of bupropion and about 30 mg / day of dextromethorphan.

[0316] (Appendix 121) 116. The method of claim 115, wherein about 200 mg / day of bupropion and about 60 mg / day of dextromethorphan are administered to the human being.

[0317] (Appendix 122) 122. The method of claim 121, wherein about 100 mg / day of bupropion and about 30 mg / day of dextromethorphan are administered to the human being for about 1 to about 3 days, followed by about 200 mg / day of bupropion and about 60 mg / day of dextromethorphan.

[0318] (Appendix 123) bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any of these compounds; Dextromethorphan, and a water-soluble vehicle, 1. An oral sustained-release delivery system for dextromethorphan, comprising:

[0319] (Appendix 124) 124. The oral sustained release delivery system of claim 123, comprising about 45 mg of dextromethorphan.

[0320] (Appendix 125) 124. The oral sustained-release delivery system of claim 123, comprising about 60 mg of dextromethorphan.

[0321] (Appendix 126) 126. The oral sustained release delivery system of claim 123, 124, or 125, comprising about 70 mg to about 95 mg of bupropion.

[0322] (Appendix 127) 126. The oral sustained release delivery system of claim 123, 124, or 125, comprising about 105 mg to about 200 mg of bupropion.

[0323] (Appendix 128) 126. The oral sustained-release delivery system of claim 123, 124, or 125, comprising about 150 mg of bupropion.

[0324] (Appendix 129) 129. The oral sustained release delivery system of claim 123, 124, 125, 126, 127, or 128, wherein the bupropion is in a form that allows for sustained release when the sustained release delivery system is swallowed.

[0325] (Appendix 130) 1. A method for reducing the number of doses of dextromethorphan that can be administered without loss of efficacy, comprising orally administering to a human in need of treatment with dextromethorphan an effective amount of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any of these compounds.

[0326] (Appendix 131) 131. The method of claim 130, wherein bupropion is administered to the patient.

[0327] (Appendix 132) 131. The method of claim 130, wherein hydroxybupropion is administered to the patient.

[0328] (Appendix 133) 131. The method of claim 130, wherein erythrohydroxybupropion is administered to the patient.

[0329] (Appendix 134) 131. The method of claim 130, wherein threohydroxybupropion is administered to the patient.

[0330] (Appendix 135) 135. The method of claim 131, 132, 133, or 134, wherein the patient takes dextromethorphan twice daily and the treatment is as effective as administering the same amount of dextromethorphan four times daily without administration of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any of these compounds.

[0331] (Appendix 136) 135. The method of claim 131, 132, 133, or 134, wherein the patient takes dextromethorphan twice daily, and the treatment is as effective as administering the same amount of dextromethorphan three times daily without administration of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any of these compounds.

Claims

[Claim 1] A method of treating a neurological disorder comprising administering an antidepressant compound and dextromethorphan to a human being who is an extensive metabolizer of dextromethorphan and who is in need of such treatment.

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