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CN116981450A - Combination of antidepressants and dextromethorphan for the treatment of neuropsychiatric disorders - Google Patents

Combination of antidepressants and dextromethorphan for the treatment of neuropsychiatric disorders Download PDF

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CN116981450A
CN116981450A CN202280021306.8A CN202280021306A CN116981450A CN 116981450 A CN116981450 A CN 116981450A CN 202280021306 A CN202280021306 A CN 202280021306A CN 116981450 A CN116981450 A CN 116981450A
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赫里奥特·塔布提奥
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Abstract

Disclosed herein are dosage forms, drug delivery systems, and methods relating to sustained release of dextromethorphan or improved therapeutic effects. Typically, the antidepressant is administered orally to a person to be treated with dextromethorphan or being treated with dextromethorphan.

Description

Combination of antidepressants and dextromethorphan for the treatment of neuropsychiatric disorders
The inventors: huriott-Tab-Otto
Cross Reference to Related Applications
The present application claims the benefit of U.S. provisional patent application No. 63/138,757 filed on 1 month 18 of 2021, which is incorporated herein by reference in its entirety.
Disclosure of Invention
Antidepressant compounds are useful for improving the therapeutic properties of dextromethorphan, for example in the treatment of neurological and/or psychiatric disorders.
Some embodiments include a method of treating a neurological or psychiatric disorder comprising administering to a human in need thereof: a combination of an antidepressant compound and dextromethorphan, wherein the person is a fast metaboliser of dextromethorphan.
Drawings
Figure 1 is a graph of mean plasma concentrations of dextromethorphan over time after administration to a subject administered dextromethorphan alone or dextromethorphan and bupropion at day 8.
Figure 2 depicts the average dextromethorphan AUC for subjects administered dextromethorphan alone or dextromethorphan and bupropion on day 8 0-12 。
Figure 3 depicts the average dextromethorphan AUC for subjects administered dextromethorphan alone or dextromethorphan and bupropion on day 8 0-24 。
Figure 4 depicts the average dextromethorphan AUC for subjects administered dextromethorphan alone or dextromethorphan and bupropion on day 8 0-inf 。
Figure 5 depicts fold change in dextromethorphan AUC for subjects administered dextromethorphan alone on day 8 as compared to dextromethorphan and bupropion administration.
Figure 6 depicts the average dextromethorphan AUC for subjects administered dextromethorphan alone or dextromethorphan and bupropion on days 1 and 8 0-12 。
Figure 7 depicts the average dextromethorphan Sha Fengu plasma concentrations in subjects administered dextromethorphan alone or dextromethorphan and bupropion.
Figure 8 depicts the mean maximum plasma concentrations of dextromethorphan in subjects administered dextromethorphan alone or dextromethorphan and bupropion on days 1 and 8.
Figure 9 is a graph of mean plasma concentrations of dextrorphan over time following administration of dextromethorphan alone or dextromethorphan and bupropion to a subject administered on day 8.
Figure 10 depicts the mean maximum plasma concentrations of dextrorphan in subjects administered dextromethorphan alone or dextromethorphan and bupropion on days 1 and 8.
Figure 11 depicts the mean dextrorphan AUC of subjects on days 1 and 8 administered dextromethorphan alone or dextromethorphan and bupropion 0-12 。
Figure 12 depicts the efficacy of various antidepressant compounds for inhibiting the metabolism of dextromethorphan in human liver microsomes.
Fig. 13 is a graph of the change in average MADRS total score over time from baseline during a 6 week dosing period for subjects administered bupropion alone or dextromethorphan in combination with bupropion.
FIG. 14 depicts the percentage of subjects who achieved relief (MADRS.ltoreq.10) over time during the 6 week dosing period for subjects who were administered bupropion alone or who were administered dextromethorphan in combination with bupropion.
Fig. 15 is a graph of the decrease in total MADRS score over time for the subjects described in example 6.
Fig. 16 is a graph of the percentage of responders over time in the subject described in example 6.
Fig. 17 is a graph of the percentage of subjects who were relieved over time among the subjects described in example 6.
Detailed Description
Some embodiments include methods of treating neurological and/or psychiatric disorders comprising administering a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant.
Some embodiments include methods of enhancing the therapeutic properties of dextromethorphan in the treatment of a neurological disorder comprising co-administering dextromethorphan and an antidepressant.
Some embodiments include a method of increasing plasma levels of dextromethorphan in a human who is a fast metabolite of dextromethorphan comprising co-administering an antidepressant compound and dextromethorphan to the human.
Some embodiments include methods of inhibiting dextromethorphan metabolism comprising administering an antidepressant compound to a human, wherein the human is a fast metaboliser of dextromethorphan, and wherein dextromethorphan is present in the human concurrently with the antidepressant.
Some embodiments include methods of increasing the metabolic life of dextromethorphan, comprising increasing the elimination half-life of dextromethorphan (T 1/2 ). Comprising administering an antidepressant compound to a human, wherein the human is a fast metaboliser of dextromethorphan, and wherein dextromethorphan is normalized to the antidepressantThe compound is present in the human body at the same time.
Some embodiments include methods of correcting rapid metabolism of dextromethorphan comprising administering an antidepressant compound to a person in need thereof, e.g., a person in need of pain treatment.
Some embodiments include methods of improving the therapeutic properties of dextromethorphan in the treatment of neurological and/or psychiatric disorders comprising administering an antidepressant compound to a person in need of treatment of neurological and/or psychiatric disorders in combination with dextromethorphan administration.
Some embodiments include methods of treating neurological and/or psychiatric disorders comprising administering to a human in need thereof a combination of an antidepressant compound and dextromethorphan.
The co-administration of the antidepressant compound with dextromethorphan may occur one or more times within a single day, or one or more times within 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100 or more days of consecutive days. In some embodiments, co-administration is performed at least daily for at least two consecutive days.
In some embodiments, co-administration of the antidepressant compound with dextromethorphan may occur once a day for 1, 2, 3, 4, 5, 6, or 7 days, followed by co-administration twice a day.
Dextromethorphan has the structure shown below.
Dextromethorphan is used as an antitussive. Dextromethorphan should be administered 6 times per day (once every 4 hours), 4 times per day (once every 6 hours), or 3 times per day (once every 8 hours) as required by the FDA dextromethorphan product label under OTC monograph [21CFR341.74 ]. OTC monograph [21CFR341.74] also states that "the dose corresponds to an [ oral ] dose of dextromethorphan hydrobromide … … of 10 milligrams to 20 milligrams per 4 hours or 30 milligrams per 6 hours to 8 hours, no more than 120 milligrams within 24 hours, or as directed by a physician. "
Dextromethorphan is rapidly metabolized in the human liver. Such rapid liver metabolism may be limited to systemic drug exposure in individuals who are fast metabolizers. The people can be: 1) Fast metabolizers of dextromethorphan-they metabolize dextromethorphan rapidly; 2) Weak metaboliser of dextromethorphan-they only weakly metabolize dextromethorphan; or 3) intermediate metabolizers of dextromethorphan-they metabolize dextromethorphan somewhere between fast metabolizers and weak metabolizers. The fast metaboliser may also be an ultrafast metaboliser. The fast metabolizers of dextromethorphan are a substantial part of the human population. Dextromethorphan can be metabolized, for example, to dextrorphan.
When the same oral dose of dextromethorphan is administered, the plasma level of dextromethorphan is significantly higher in poor or medium metabolizers as compared to those of the broad metabolite of dextromethorphan. The low plasma concentration of dextromethorphan can limit its clinical utility as a single drug for dextromethorphan fast metabolizers and possibly intermediate metabolizers. Some therapeutically active compounds (including antidepressants) inhibit the metabolism of dextromethorphan and increase dextromethorphan plasma concentrations, thereby improving the therapeutic efficacy of dextromethorphan. Similarly, antidepressants may enable the less frequent administration of dextromethorphan without loss of therapeutic efficacy, such as once a day rather than twice a day, once a day rather than three times a day, once a day rather than four times a day, twice a day rather than three times a day, or twice a day rather than four times a day, or at lower dosages.
Co-administration of an antidepressant with dextromethorphan or dextrorphan may enhance the mechanism of action or pharmacological properties of dextromethorphan and dextrorphan. The mechanism of action of dextromethorphan and dextrorphan can include sigma-1 agonist and NMDA antagonist properties, calcium channel blockade, muscarinic binding, 5-hydroxytryptamine transporter (5 HTT) inhibition, and mu receptor potentiation.
Some embodiments include co-administering an antidepressant with dextromethorphan or dextrorphan to agonize, antagonize, or modulate the sigma-1 receptor or NMDA receptor; blocking calcium channels; binding to muscarinic receptors; inhibit 5-hydroxytryptamine transporter (5 HTT); or to enhance mu receptors.
Pharmacological properties of dextromethorphan and dextrorphan may include NMDA high affinity site activity, NMDR-2A activity and functional NMDR-2B receptor antagonism; sigma-1 stimulation; putative mTOR activation (by sigma-1 stimulation, mu enhancement, beta adrenergic receptor stimulation, and 5HTT inhibition); putative AMPA receptor trafficking (by mTOR activation, PCP antagonism, sigma-1 stimulation, beta stimulation, mu enhancement and 5HTT inhibition); and dendritic generation (dendritic), dendritic spinogenesis (spinogenisis), synaptogenesis (synaptogenesis), and neuronal survival by NMDA antagonism and sigma-1 and mTOR signaling. Some embodiments include co-administering an antidepressant with dextromethorphan or dextrorphan to bind, agonize, antagonize, stimulate, activate, inhibit, affect the transport of, or modulate: NMDA high affinity sites, NMDR-2A, functional NMDR-2B receptor, sigma-1 receptor, putative mTOR receptor (e.g., by stimulating sigma-1, enhancing mu receptor, stimulating beta adrenergic receptor or inhibiting 5 HTT), or putative AMPA receptor (e.g., by activating mTOR, antagonizing PCP activity, stimulating sigma-1 receptor, stimulating beta adrenergic receptor, enhancing mu receptor or inhibiting 5 HTT). Some embodiments include co-administering an antidepressant with dextromethorphan or dextrorphan to cause, increase, decrease, or otherwise modulate dendritic generation, dendritic spinogenesis, or synaptogenesis. Some embodiments include co-administering an antidepressant with dextromethorphan or dextrorphan to cause, increase, decrease, or otherwise modulate neuronal survival achieved through NMDA antagonism and/or sigma-1 and/or mTOR signaling.
Pharmacological properties of dextromethorphan and dextrorphan may include 5HTT and norepinephrine transporter inhibition, sigma-1 stimulation, NMDA and PCP antagonism, and possibly 5-hydroxytryptamine 5HT1b/d receptor stimulation. Some embodiments include co-administering an antidepressant with dextromethorphan or dextrorphan to bind, agonize, antagonize, stimulate, activate, inhibit, affect the transport of, or modulate: 5HTT and/or norepinephrine transporter, sigma-1 receptor, NMDA and/or PCP receptor, and/or stimulate 5-hydroxytryptamine 5HT1b/d receptor.
Other properties of dextromethorphan and dextrorphan may include possible presynaptic alpha-2 adrenergic receptor antagonism or postsynaptic alpha-2 stimulation, beta stimulation, and possible muscarinic and mu antagonism. Some embodiments include co-administering an antidepressant with dextromethorphan or dextrorphan to bind, agonize, antagonize, stimulate, activate, inhibit, affect the transport of, or modulate: presynaptic alpha-2 adrenergic receptors, postsynaptic alpha-2 receptors, beta adrenergic receptors, muscarinic receptors, or mu receptors. Dextromethorphan and dextrorphan can be glial cell modulators. Some embodiments include co-administering an antidepressant with dextromethorphan or dextrorphan to modulate glial cells.
Pain or other neurological and/or psychiatric disorders may be treated by increasing dextromethorphan plasma levels or increasing dextromethorphan bioavailability, for example, by a method comprising administering a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant compound to a human in need thereof.
Examples of neurological disorders that may be treated by increasing the level of dextromethorphan or that may be treated with increased efficacy (such as those achievable by a combination of dextromethorphan and an antidepressant) include, but are not limited to: affective disorders, mental disorders, brain dysfunction, movement disorders, dementia, motor neuron diseases, neurodegenerative diseases, seizure disorders (seizure disorders) and headaches.
Affective disorders treatable by increasing the level of dextromethorphan or by a combination of dextromethorphan and an antidepressant include, but are not limited to, depression, major depression, treatment resistant depression and treatment resistant bipolar depression, bipolar disorders including circulatory affective disorder (cyclohymia), seasonal affective disorder, mood disorder, chronic depression (dysthymia), psychotic depression, post-natal depression, premenstrual dysphoric disorder (premenstrual dysphoric disorder, PMDD), contextual depression (situational depression), atypical depression, mania, anxiety disorders, attention deficit disorder (attention deficit disorder, ADD), attention deficit disorder with hyperactivity disorder (ADD h) and attention deficit/hyperactivity disorder (AD/HD), bipolar and manic disorders, obsessive compulsive disorder, binge eating disorders, obesity or body weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, addiction, psycho-sexual dysfunction, pseudomarrow depression and unstable mood effects.
Depression may be manifested as symptoms of depression. These symptoms may include psychological changes such as mood changes, intense sadness, despair, mental retardation, inattention, pessimistic concerns (pessimistic worry), agitation, anxiety, agitation, guilt, anger, worthlessness, reckless behavior, suicidal thoughts or attempts, and/or self-detraction. Physical symptoms of depression may include insomnia, anorexia, loss of appetite, weight loss, weight gain, loss of energy and libido, fatigue, dysphoria, pain (aches), pains (pain), headache, cramps, digestive problems, and/or abnormal circadian rhythms of hormones.
Some patients, even after treatment with drugs such as antidepressants, may have an inadequate or no response to the treatment. Anti-therapeutic depression (TRD) or refractory depression is a condition that is generally associated with patients who have failed treatment with at least two antidepressants. Partial diagnosis of TRD is for patients who have an inadequate response to treatment with an antidepressant after an appropriate dose and an appropriate course of treatment, such as in current depressive episodes. TRD may be more difficult to treat due to complications of other medical or psychological diseases, such as drug/alcohol abuse or eating disorders or misdiagnosis of TRD. Some TRD patients either do not respond well to 1, 2, 3, or more adequate antidepressant therapy trials, or have failed to respond or do not respond well to 1, 2, 3, or more previous antidepressant therapies. In some embodiments, the patient undergoing treatment for the anti-therapeutic depression has failed at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more antidepressant therapies.
Metrics of therapeutic effects that can be improved by treatment with a combination of dextromethorphan and an antidepressant include, but are not limited to: montgomery-Abbe depression rating scale (Montgomery-Asberg Depression Rating Scale, MADRS), happiness and quality of life satisfaction questionnaire-profile, functional impairment measurement tool, hien disability scale, patient side effect assessment scale (Patient Rated Inventory of Side Effects, PRISE), columbia-suicide severity scale (Columbia-Suicide Severity Rating Scale, C-SSRS), depression symptom fast rating scale Self-rating scale (Quick Inventory of Depressive Symptomatology, self-Report, QIDS-SR), clinical efficacy total rating scale (Clinical Global Impression, CGI), mass-province total hospital cognitive and body function questionnaire (Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire, CPFQ), 17-part Hamiltonian depression rating scale (17-item Hamilton Rating Scale for Depression, HAM-D17), mass-province total hospital anti-depression treatment response questionnaire (Massachusetts General Hospital Antidepressant Treatment Response Questionnaire, MGH Q), 16-part depression symptom fast rating Self-rating scale (16-item Quick Inventory of Depressive Symptomatology-Self-Report, QIDS-SR 16), england scale (Sheehan Disability Scale, disease severity clinical impression (CG24, CGI), qoL-45, qoL-5, qoL-55, qoL-25, qoC-55, qoL-5 7generalanxietyscales(7-itemGeneralizedAnxietyDisorder,GAD-7),clinicalImprovementglobalimpression(ClinicalGlobalImpressions-Improvement,CGI-1),Hiendisabilityscale(SDS),16rapidassessmentofdepressivesymptomsscaleSelf-assessmentedition(16-itemQuickInventoryofDepressiveSymptomatology-SelfReport,QIDS-SR16),Hamiltoniananxietyscale(HamiltonAnxietyScale,HAM-A),generalhospitalcognitiveandsomaticfunctionquestionnairesinMassa(MassachusettsGeneralHospitalCognitiveandPhysicalFunctioningQuestionnaire,CPFQ),CPFQ-cognitivesub-scale(items4to7),briefpsychosisassessmentscale(BriefPsychiatricRatingScale,BPRS),andthelike; digital symbol substitution test (Digit Symbol Substitution Test, DSST), rayleigh hearing language learning task (Rey Auditory Verbal Learning Task, RAVLT), wire test (Trail Making Test, TMT), stropp color naming test (Stroop Colour Naming Test, STROOP), simple reaction time (Simple Reaction Time, SRT), selective reaction time (Choice Reaction Time, CRT), and the like. In some embodiments, treating a person with a combination of dextromethorphan and an antidepressant may improve (e.g., decrease) the score of the person in one of the above assessments by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 5-15%, about 15-25%, about 25-35%, about 35-45%, about 45-55%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100% as compared to baseline or placebo. In some embodiments, the improvement is compared to baseline. In some embodiments, the improvement is compared to placebo.
Administration of an antidepressant in combination with dextromethorphan can result in a rapid therapeutic effect, for example, within about 1 week, within about 2 weeks, within about 3 weeks, or within about 4 weeks of starting treatment.
In some embodiments, the enhanced bioavailability of dextromethorphan or a combination of dextromethorphan and an antidepressant may be effective within 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6-8 hours, 8-12 hours, one day, 1-7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, six weeks, or eight weeks.
Patients that may benefit from the treatment described herein include pediatric patients, such as patients under about 18 years old, about 0-5 years old, about 5-10 years old, about 10-12 years old, or about 12-18 years old; adult patients, for example, patients aged about 18-70 years, about 18-65 years, about 18-30 years, about 10-20 years, about 20-30 years, about 30-40 years, about 40-50 years, about 50-60 years, about 60-70 years, about 70-80 years, about 80-90 years, about 30-50 years, about 50-65 years; elderly patients, for example, older than 65 years old, about 65-75 years old, about 75-90 years old; or over 90 years and about 41 years or older.
In some embodiments, a person treated with a combination of dextromethorphan and an antidepressant (e.g., for one type of depression) has or is selected to have a diagnosis of major depressive disorder prior to treatment (e.g., on the same day as treatment initiation but prior to initiation of treatment, or within 0-1 week, 0-2 weeks, 0-3 weeks, 0-4 weeks, 0-2 months, 0-3 months, 0-4 months, 0-5 months, 0-6 months, or longer) according to manual for diagnosis and statistics of mental disorders (Diagnostic and Statistical Manual of Mental Disorders), fourth edition, text revision (DSM-IV-TR), structured clinical interview of manual for diagnosis and statistics of mental disorders (the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders), fifth edition, clinical trial version of SCID-5-CT. In some embodiments, the person currently meets the DSM-5 standard for MDD without psychotic features based on SCID-5-CT.
In some embodiments, a person (e.g., for one type of depression) treated with a combination of dextromethorphan and an antidepressant has or is selected to have major depressive episodes lasting between about 8 weeks and about 24 months, about 1-6 months, about 6-12 months, about 1-2 years, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 6 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 18 months, at least about 2 years, about 1-12 weeks, about 3-6 months, about 6-9 months, about 9-12 months, about 12-18 months, about 18-24 months, about 2-4 years, about 4-6 years, about 6-10 years, about 10-20 years or longer.
In some embodiments, a person treated with a combination of dextromethorphan and an antidepressant (e.g., for one type of depression) has or is selected to have about 1-100 or more life-long depressive episodes prior to treatment, e.g., life-long depressive episodes including at least 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 10, at least about 15, at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, about 1-5, about 5-10, about 10-20, about 20-30, about 30-40, about 40-50, about 50-60, about 60-70, about 70-80, about 80-90, about 90-100, or about 4-7.
In some embodiments, a person treated with a combination of dextromethorphan and an antidepressant (e.g., for one type of depression) has or is selected to have an inadequate response to one or more previous antidepressant therapies (e.g., 1, 2, 3, 4, 5, or more previous antidepressant therapies) that include a previous antidepressant therapy in a current depressive episode (e.g., a current major depressive episode).
In some embodiments, a person treated with a combination of dextromethorphan and an antidepressant (e.g., for one type of depression) has been used or selected to have used a background antidepressant therapy that is administered at a sufficient dose for at least 8 weeks and at a stable dose for at least 4 weeks prior to entering the double blind treatment period. In some embodiments, the antidepressant therapy is continued in combination with treatment with a combination of an antidepressant and dextromethorphan.
In some embodiments, the person treated with a combination of dextromethorphan and an antidepressant (e.g., for one type of depression) is a male, or is selected as a male. In some embodiments, the person treated with a combination of dextromethorphan and an antidepressant (e.g., for one type of depression) is a female, or is selected as a female.
In some embodiments, a person treated with a combination of dextromethorphan and an antidepressant (e.g., for one type of depression) has or is selected to have about 18-40kg/m prior to treatment (e.g., on the same day as treatment begins but prior to treatment beginning, or within 0-1 week, 0-2 weeks, 0-3 weeks, 0-4 weeks, 0-2 months, 0-3 months, 0-4 months, 0-5 months, 0-6 months, or longer) of the subject 2 About 18.5kg/m 2 Less than 18.5kg/m 2 About 19kg/m 2 About 19-25kg/m 2 About 25kg/m 2 About 25-29kg/m 2 About 29kg/m 2 More than 29kg/m 2 About 18-22kg/m 2 About 22-24kg/m 2 About 24-26kg/m 2 About 26-28kg/m 2 About 28-30kg/m 2 About 30-32kg/m 2 About 32-34kg/m 2 About 34-36kg/m 2 About 36-38kg/m 2 About 38-40kg/m 2 About 18-26kg/m 2 About 26-34kg/m 2 Or about 34-40kg/m 2 Is a body mass index of (a).
The therapeutic effect may be assessed at any suitable time, such as at week 1, week 1-2, week 1-3, week 1-4, week 1-6, week 4-6, week 6-8, week 8-12, week 12-16, week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, or any other time.
In some embodiments, the combination of dextromethorphan with an antidepressant is a novel and oral NMDA receptor antagonist having multimodal activity for the treatment of Central Nervous System (CNS) disorders. Dextromethorphan is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, also known as glutamate receptor modulator, which is a novel mechanism of action that acts differently than currently available therapies for depression.
Dextromethorphan is also a sigma-1 receptor agonist, a nicotinic acetylcholine receptor antagonist, and an inhibitor of 5-hydroxytryptamine and norepinephrine transporter. Antidepressants may increase the bioavailability of dextromethorphan.
In some embodiments, a combination of dextromethorphan and an antidepressant may be used to treat nicotine addiction. In some embodiments, the combination of dextromethorphan and an antidepressant may be administered to a human once or twice daily. In some embodiments, the combination of dextromethorphan and an antidepressant may be administered to a human twice daily. In some embodiments, dextromethorphan in combination with an antidepressant may be administered to a human once a day or twice a day for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, about 6-12 months, about 1 year, about 2 years, or longer. In some embodiments, the combination of dextromethorphan and an antidepressant may be administered to a human twice daily for at least 1 week, at least 2 weeks, at least 3 weeks, or more.
In some embodiments, the smoker can be or can be selected as an unrestricted smoker. In some embodiments, the smoker may be or may be selected to smoke on average 10 or more cigarettes per day, for example about 10, about 10-15, about 10-17, about 10-20, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20-25, about 25-30, about 30-40, about 40-50 or more cigarettes, prior to administration of the combination of dextromethorphan and the antidepressant.
In some embodiments, a combination of dextromethorphan and an antidepressant may be used to treat nicotine addiction, and the combination contains from about 30-100mg, from about 30-40mg, from about 40-50mg, from about 50-60mg, from about 60-70mg, from about 70-80mg, from about 80-90mg, from about 90-100mg, from about 35mg, about 45mg, about 55mg, about 65mg, about 75mg, about 85mg, about 90mg, or about 95mg of dextromethorphan in free base or salt form. In some embodiments, dextromethorphan is in the HBr salt form.
In some embodiments, administration of dextromethorphan in combination with an antidepressant to a human results in a decrease in the intensity of smoking, as measured using the amount of smoke smoked per day as assessed via a daily smoking diary.
In certain instances, administration of dextromethorphan in combination with an antidepressant to a human results in a reduction of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, about 5-10%, about 10-15%, about 15-20%, about 20-25%, about 25-30%, 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-80%, about 80-100%, about 20%, about 25% greater, about 30%, or about 50% in the average number of smoke inhaled per day over a period of time (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 3 months, 4 months, 6 months, or longer) compared to the antidepressant alone.
Administration of dextromethorphan in combination with an antidepressant to a smoker can result in an average reduction in the smoke drawn per day of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, at least 20, about 8-9, about 8-10, about 10-15, about 15-20, about 25 or more for some smokers.
Administration of dextromethorphan in combination with an antidepressant to a smoker can result in a greater proportion of smokers, such as at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, about 35%, about 50%, about 60-80%, about 80-90%, about 90-100%, experiencing a greater than 50% reduction in the level of exhaled carbon monoxide, which is a biochemical indicator of smoking strength, than those who are treated with the antidepressant alone. In some embodiments, the carbon monoxide exhalation level (a biochemical marker of smoking strength) of a given smoker may be reduced by more than 50% compared to administration of the antidepressant alone, or compared to baseline, or compared to prior to receiving the first dose of the combination.
Missed doses of dextromethorphan in combination with antidepressants may lead to increased smoking activity. For example, a smoker who is missing one or more doses of a combination of dextromethorphan and an antidepressant may have at least 1 or about 1-2 cigarettes more on the day of missing the dose, and at least 1, at least 2, about 1-2 or about 2-3 cigarettes more on the next day after missing the dose, as compared to a smoker who is not missing any dose of the combination.
In some embodiments, the enhanced bioavailability of dextromethorphan, or a combination of dextromethorphan and an antidepressant, can be used as an adjunct therapy in the treatment of any of the disorders described herein, including TRD. For example, the adjunct therapy may be used in combination with other antidepressants such as clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chlorimipramine, amitriptyline, amoxapine, desipramine, protirizine, trimipramine, phenelzine, isoxazolzine, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxyaminoindan, benatizine, escitalopram, fluvoxamine, venlafaxine, desmethylvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, doxofrofen, ibuprofen new, moldbenamine, rasagiline, nipagin, iprozide, iprocloxazine, toloxazone, butirizine, dulcitalol, fluxapine, flupirtine, oxonol, oxyphenbanone, fluvoxaglide, flupirone, flupirtine, or a pharmaceutically acceptable salt of any of these or the like.
A person with TRD may be treated with a combination of dextromethorphan and an antidepressant, and for some individuals may result in a reduction in symptoms of depression of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, up to about 100%, or any other reduction within a range defined by any of these values.
A combination of dextromethorphan and an antidepressant may be used to treat a person suffering from a psychotic disorder, including but not limited to anxiety disorders, including but not limited to phobia, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive compulsive disorder, and post-traumatic stress disorder (PTSD); mania, unipolar depression, stress disorders, somatoform disorders, personality disorders, psychosis, schizophrenia, delusional disorders, schizoaffective disorders, schizophreniform, aggression by Alzheimer's disease, agitation, and agitation by Alzheimer's disease.
Alzheimer's Disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline and behavioral and psychological symptoms including agitation. AD is the most common dementia, with about 600 tens of thousands in the united states, and by 2050, this figure is expected to increase to about 1400 tens of thousands. It is reported that up to 70% of AD patients experience agitation, manifesting as emotional distress, aggressive behavior, destructive irritability, and disinhibition. The stimulus may manifest as inappropriate speech, emotion, and/or physical behavior. Inappropriate behavior may include, but is not limited to: an uninteresting language disorder, improper emotional response, requiring attention (demands for attention), threat, dysphoria, depression, screaming, repeated questions, mood swings, curse, cachexia, 35881, curse (abused language), body burst (physical outbursts), mood trouble, dysphoria, tearing (shaping), sleep disorder, fantasy (delusion), hallucination, walking (sizing), wandering, searching (sizing), seeking (rumming), repetitive limb movements, hoarding (hoarding), following caregivers (shapeing), hits (hitting), scratches (biting), stings, multiple movements and/or kicks (kiking). Managing the challenge is a primary task for AD patients. The agitation of AD patients is associated with increased burden on caregivers, reduced function, accelerated cognitive decline, advanced nursing home placement time, and increased mortality. There is currently no FDA approved therapy for the treatment of the agitation of AD patients. A combination of dextromethorphan and an antidepressant may be used to treat a person suffering from a shock in alzheimer's disease, wherein in some embodiments, a decrease in the shock-related symptoms of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, up to about 100%, or any other decrease within a range defined by any of these values may be caused.
A combination of dextromethorphan and an antidepressant may be used to treat a person suffering from substance addiction and/or abuse including, but not limited to, drug dependence, addiction to cocaine, psychostimulants (e.g., cocaine, bolus, ice-toxin), nicotine, alcohol, opioids, sedatives and hypnotics, cannabis (cannabis or 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 addiction to chewing tobacco.
A combination of dextromethorphan and an antidepressant may be used to treat a person suffering from brain dysfunction including, but not limited to, conditions involving intellectual deficit such as senile dementia, dementia of the alzheimer's type, memory loss, amnesia/amnesia syndrome, epilepsy, disturbance of consciousness, coma, attention loss, language impairment, voice cramps, parkinson's disease, lennox-Gastaut syndrome, autism, hyperactivity syndrome and schizophrenia. Cerebral dysfunction also includes conditions caused by cerebrovascular disease including, but not limited to, stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, head injury, etc., where symptoms include disturbance of consciousness, senile dementia, coma, impaired attention, and language disorder.
Dyskinesias that may be treated by combination of dextromethorphan with an antidepressant include, but are not limited to, akathisia, akinesia, joint movement, athetosis, ataxia, tics, unilateral twitching, bradykinesia, cerebral palsy, chorea, huntington's disease, rheumatic chorea, cetoham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasticity torticollis, dopamine responsive dystonia, parkinson's disease, restless Leg Syndrome (RLS), tremor, essential tremor, and Tourette's syndrome, as well as wilson's disease.
Dementia that may be treated by combination of dextromethorphan with an antidepressant includes, but is not limited to, alzheimer's disease, parkinson's disease, vascular dementia, dementia with lewy bodies, dementia with mixed-mode, frontotemporal dementia, creutzfeldt-Jakob disease, atmospheric hydrocephalus, huntington's disease, wernike-Kelsh-Sac syndrome, and pick's disease.
Motor neuron diseases that may be treated by a combination of dextromethorphan and an antidepressant include, but are not limited to, amyotrophic Lateral Sclerosis (ALS), progressive bulbar paralysis, primary Lateral Sclerosis (PLS), progressive muscular atrophy, post Polio Syndrome (PPS), spinal Muscular Atrophy (SMA), spinal movement atrophy (spinal motor atrophies), saxophone disease, sandhoff disease, and hereditary spastic paraplegia.
Neurodegenerative diseases that may be treated by dextromethorphan in combination with an antidepressant include, but are not limited to, alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal Muscular Atrophy (SMA), bulbar muscular atrophy, friedel-crafts ataxia, huntington's disease, louis's disease, parkinson's disease, amyotrophic lateral sclerosis (ALS or Gray's disease), multiple Sclerosis (MS), multiple system atrophy, shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, wilson's disease, meniere's disease, adrenoleukodystrophy, autosomal dominant hereditary Cerebral Arterial Disease (CADASIL) with subcortical infarction and leukoencephalopathy, muscular dystrophy, creutzfeld-Jakob-Du Sishi disease (CMT), familial spasticity paraplegia, neurofibroma, olivopontoencephalopathy or degeneration, striatal degeneration, QI-Mary-Du Sishi, and spastic paraplegia.
Seizure disorders that can be treated by a combination of dextromethorphan and an antidepressant include, but are not limited to, epileptic seizures, non-epileptic seizures, epilepsy, febrile cramps; partial seizures, including but not limited to simple partial seizures, jack-son seizures, complex partial seizures, and persistent partial seizures; systemic attacks include, but are not limited to, systemic tonic clonic attacks, absence attacks, strabismus attacks, myoclonus attacks, juvenile myoclonus attacks, and infantile spasms; status epilepticus.
Types of headaches that may be treated by combination of dextromethorphan with an antidepressant include, but are not limited to, migraine, tension headache, and cluster headache.
Other neurological disorders that may be treated by a combination of dextromethorphan and an antidepressant include, rayleigh syndrome, autism, tinnitus, a conscious disturbance disorder, sexual dysfunction, intractable cough, narcolepsy, cataplexy; vocalization disorders due to uncontrolled laryngeal muscle spasms, including but not limited to abductor spasmodic vocalization disorders, adductor spasmodic vocalization disorders, muscle tone dystonia, and tremors; diabetic neuropathy, chemotherapy-induced neurotoxicity, such as methotrexate neurotoxicity; urinary incontinence, including but not limited to stress urinary incontinence, urge urinary incontinence, and fecal incontinence; erectile dysfunction.
In some embodiments, dextromethorphan in combination with an antidepressant can be used to treat pain, joint pain, pain associated with sickle cell disease, pseudobulbar effect, depression (including anti-therapeutic depression), memory and cognition related disorders, schizophrenia, parkinson's disease, amyotrophic Lateral Sclerosis (ALS), rette's syndrome, seizure disorders, cough (including chronic cough), and the like.
In some embodiments, a combination of dextromethorphan and an antidepressant is useful in treating refractory depression.
In some embodiments, a combination of dextromethorphan and an antidepressant may be used to treat allodynia.
In some embodiments, a combination of dextromethorphan and an antidepressant may be used to treat refractory hyperalgesia.
In some embodiments, a combination of dextromethorphan and an antidepressant may be used to treat dermatitis.
The analgesic properties of dextromethorphan can be enhanced by a method comprising co-administering dextromethorphan with an antidepressant to a human.
Analgesic properties of antidepressants may be enhanced by a method comprising co-administering dextromethorphan with an antidepressant.
In some embodiments, ketamine or another NMDA receptor antagonist may be administered with an antidepressant.
These methods may be used to treat or alleviate any type of pain, including but not limited to musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, nociceptive pain, inflammatory pain, arthritic pain, complex regional pain syndromes, and the like.
In some embodiments, co-administration of dextromethorphan with an antidepressant can be used to treat or reduce inflammation or inflammatory conditions, such as crohn's disease, including pain associated with inflammation.
In some embodiments, co-administration of dextromethorphan with an antidepressant can be used to treat psoriasis, cancer, viral infection, or as an adjunct treatment for multiple myeloma.
Examples of musculoskeletal pain include lumbago (i.e., lumbosacral pain), primary dysmenorrhea and arthritic pain (e.g., pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, axial spondyloarthritis (including ankylosing spondylitis), pain associated with vertebral body compression fractures, fibrous dysplasia, osteogenesis imperfecta, paget's disease, temporary osteoporosis, and hip temporary osteoporosis, among others.
In some embodiments, dextromethorphan in combination with an antidepressant may be orally administered to reduce musculoskeletal pain, including low back pain, as well as pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatism, periarticular disorders, axial-type spondyloarthritis including ankylosing spondylitis, paget's disease, fibrous dysplasia, SAPHO syndrome, hip joint temporary osteoporosis, vertebral compression fractures, osteoporosis, and the like.
In some embodiments, a combination of dextromethorphan and an antidepressant may be administered to relieve inflammatory pain, including musculoskeletal pain, arthritic pain, and complex regional pain syndromes.
Arthritis refers to an inflammatory joint disease that may be associated with pain. Examples of arthritic pain include pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatoid) arthritis, non-articular rheumatism, periarticular disorders, neuropathic arthropathy including Charcot's foot, central axis type spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome.
In some embodiments, the combination of dextromethorphan with an antidepressant is used to treat chronic musculoskeletal pain.
In some embodiments, a combination of dextromethorphan and an antidepressant may be administered to alleviate a complex regional pain syndrome, such as complex regional pain syndrome type I (CRPS-1), complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or another type of CRPS. CRPS is an inflammatory pain. CRPS may also have a neurological component. The complex localized pain syndrome is a debilitating pain syndrome. It is characterized by severe limb pain, which may be accompanied by oedema and autonomic nerves, motor and sensory changes.
In some embodiments, a combination of dextromethorphan and an antidepressant may be orally administered to relieve neuropathic pain.
Examples of neuropathic pain include diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathy, phantom limb pain, central pain, and the like. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-related neuropathy, radiation therapy and chemotherapy-related neuropathy, and the like.
In some embodiments, a combination of dextromethorphan and an antidepressant may be administered to alleviate fibromyalgia.
The term "treatment" includes any activity that diagnoses, cures, relieves, treats, or prevents a disease in a human or other animal, or otherwise affects the structure or any function of the human or other animal body.
Any antidepressant may be used in combination with dextromethorphan to improve the therapeutic properties of dextromethorphan. Dextromethorphan and an antidepressant compound can be administered in separate compositions or dosage forms. In some embodiments, dextromethorphan and an antidepressant compound may be administered in a single dosage form.
Antidepressant compounds that may be co-administered with dextromethorphan include, but are not limited to, clomipramine, doxepin, fluoxetine, mianserin, imipramine 2-chlorimipramine, amitriptyline, amoxapine, desipramine, protirizine, triclopyr, nortriptyline, maprotiline, phenelzine, isoxazolhydrazine, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxyaminoindan, benatizine, escitalopram, fluvoxamine, venlafaxine, desmethylvenlafaxine, duloxetine, mirtazodone, selegiline, sibutramine, milnacipran, tamoxifen, ibuprofen new, meclobemide, rasidone, ipratropine, ipratropium, oxypropion, fluvoxazine, oxyphenbutamine, fluvoxazine, prazidine, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
In some embodiments, the antidepressant may be a selective serotonin reuptake inhibitor, such as Citalopram (Citalopram) (celxa, cipramil), escitalopram (Escitalopram) (Lexapro, cipralex), fluoxetine (fluxetine) (Prozac, safe), fluvoxamine (Fluvoxamine) (Luvoxamine, faverin), paroxetine (Paroxydine) (Paxil, seroxat), sertraline (selpraline) (zol, lustral), or the like; serotonin-norepinephrine reuptake inhibitors (SNRI) such as desmethylvenlafaxine (pritiq), duloxetine (Duloxetine) (Cymbalta), levomilnacipran (levomipran) (Fetzima), milnacipran (Milnacipran) (Ixel, savella), venlafaxine (Venlafaxine) (Effexor), and the like; serotonin Modulators and Stimulators (SMS), such as Vilazodone (Viibryd), vortioxetine (tritellix), and the like; serotonin Antagonists and Reuptake Inhibitors (SARI), such as Nefazodone (Dutonin, nefadar, serzone), trazodone (Desyrel), dezazol (Desyrel) A Norepinephrine Reuptake Inhibitor (NRI) such as tomoxetine (stratera), reboxetine (Reboxetine) (Edronax), tenixazine (Teniloxazine) (lucean, metatone), viloxazine (Vivalan), and the like; tricyclic antidepressants (TCAs), such as Amitriptyline (Amitriptyline), amitriptyline oxide (Amitriptyline) (amixid, ambivalon, equilibrary), clomipramine (Clomipramine) (anaplail), desipramine (Desipramine) (norpramine, pertofranine), dibenzepine (Dibenzepin) (novril, victoriil), dimethrine (trimetaline) (Istonil), doxepin (dosupein) (Prothiaden), doxepin (Doxepin) (siequan), imipramine (Imipramine) (Tofranil), roflumin (Lofepramine) (rofeprazole, gamanil), melitrazine (Melitracen) (diutan, melphalan) (mexilan, tran, sha Xiping) (oxazin), oxazin (norvallin) (noxapine) (noxagline), oxazin (prothiolin) (protirine), oxazin (amolin) (protirimol), oxazin (amolin) (protirine) (protiripin) (protirine, oxazin) (norepine, oxazin) (amide) (Amitriptyline, oxazin) (amide) (Amitriptyline, oxazin) (Amitriptyline, oxazin); tetracyclic antidepressants (TeCA), such as Amoxapine (Asendin), maprotiline (Maprotiline) (ludinoml), mianserin (Tolvon), mirtazapine (Mirtazapine) (remmeron), sepptiline (Tecipul), etc.; monoamine oxidase inhibitors (MAOI) such as isoxazolyl hydrazine (Marplan), phenethyl hydrazine (Nardil), tranylcypromine (tranylcromine) (Parnate), selegiline (Selegiline) (Eldepryl, zelapar, emram), carboline Luo Shatong (Caroxazone) (Surodil, timostenil), metaline Qu Yinduo (Inkazan), mollobemide (molobemide) (Aurorix, manerix), pirlindol (pirlindle) (pirlindol), toloxadone (humoxicone) (humotone), epbefol, milnacipline (miniprine) (Brantur, cantor), diphenmelane (bimelane) (Alnert, celeqrap); agomelatine (Valdoxan), esketamine (Spravanto), ketamine (Ketamine) (Ketalar), tandospirone (Sediel), thianaprotene (Tianetin) (Stablon, coaxil), alpha-methyl primary amine [ alpha MT ] ](Indopan), ethylchromatin [ alpha-ethylchromatin (. Alpha.ET)](Monase), indenofloxazine (indeloxaz)ine) (Elen, noin), methoxamine (Cldifox, gerdaxyl), ox Sha Fusheng (Oxaflozane) (Conflictan), pitavagabine (Pivagabine) (Tonerg), ademetionine (Ademetionine) [ S-adenosyl-L-methionine (SAMe)](Heptral, transmetil, samyl), hypericum perforatum (Hypericum perforatum) [ St. John's grass (SJW)](Jarsin, kira, movina), oxitriptan [ 5-hydroxytryptophan (5-HTP)](cincoform, levozym, triptum), rubidium chloride [ RbCl](Rubinorm), tryptophan (Optimax, aminomine), magnesium, acetyl carnitine, saffron (Saffron), amisulpride (Amisulpride) (Solian), aripiprazole (Aripiprazole) (Abilify), epipiprazole (Brexpiprazole) (Rexulti), lurasidone (Lurasidone) (Latuda), olanzapine (Olazapine) (Zyprexa), quetiapine (Quetiapine) (Seroquel), risperidone (Risperdal), buspirone (Buspring), lithium (Eskalith, liobid), modafinil, thyroxine (T4), triiodothyronine (T3), minocycline (Minnomycin), amitriptyline/chlorazepine(Amitriptyline/chlordiazepine), amitriptyline/oxyphenazine (etatron), flupenthixol/melitracin (deaxit), olanzapine/fluoxetine (symbayax), tranylcypromine/trifluoperazine (Parstelin, parmodalin, jatrosom N, sterlapar); glutamatergic drugs including NMDA receptor modulators such as 4-Chlorokynurenine (4-Chlorokynurenine), AGN-241751, apitinib (apistinel) (NRX-1074), levoketamine (archetamine) (PCN-101, HR-071603); dextromethorphan (REL-1017), EVT-101 (ENS-101), ketamine (Ketalar), li Laina da (Rislendemdaz) (CERC-301, MK-0657), and the like, another type of glutamatergic drug, such as pasimrlukast (RG-7090); monoaminergic drugs such as monoamine reuptake inhibitors including AN-788 (NSD-788), tol Lu Dewen Lafaxine (ansofaxine; LY03005, LPM 570065), PDC-1421 (BLI-1005) and the like, monoamine reuptake inhibitors and receptor modulators such as MIN-117 (WF-516), TGBA01AD (FKB 01 MD) and the like; monoamine receptor modulators including Gepirone (Gepirone) (TGFK 07AD; travivo), pi Mo Fanse forest (Pima) vansterin) (Nuplazid; ACP-103; BVF-048) and Sirocarb (Psilocabin), etc.; atypical antipsychotics, including Brilaroxazine (RP-5063, RP-5000), lu Meipai (Lumateperione) (ITI-007), and the like; adenosylmethionine (SAMe; MSI-190, MSI-195, strada); a neurosteroid such as a GABAA receptor positive modulator including Ganaxolone (CCD-1042), zu Lanuo ketone (Zuranolone) (SAGE-217) and the like, and another neurosteroid such as 3β -Methoxypregnenolone (3β -Methoxypregnenolone) (MAP-4343), PH-10-vomeropherine and the like; opioid drugs such as kappa-opioid receptor antagonists including atticaprin (Aticaprin) (JNJ-67953994, CERC-501, LY-2456302), BTRX-335140 (BTRX-140), buprenorphine/sa Mi Duofen (Buprenorphine/samidorphan) (ALKS-5461), another opioid drug such as BTRX-246040 (LY-2940094); hydroxynorketamine (2R, 6R) -HNK, JNJ-39393406, JNJ-54175446, JNJ-61393215 (JNJ-3215, JNJ-61393215; orexin-1), NNI-351, NSI-189, NV-5138, onabotidinum toxinA (botulinum toxin A, baozuox), pramipexole (Pramipexole) (CTC-501, CTC-413), saeto Lei Sheng (Seltoxant) (MIN-202, JNJ-42847922 JN-922), west Lu Kushan anti (Sirukuumab) (CNTO-136), SUVN-911, TS-121, etc.; tramadol (Tramadol) (ETS 6103; viotra), cycloserine/lurasidone (cycloerine/lurasidone), 7, 8-dihydroxyflavone (7, 8-DHF), minocycline (Minycine), nitrous oxide, pramipexole (Pramipexole), R13, and the like. / >
In some embodiments, about 40-120mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg, or about 450-500mg of levomilnacipran (Fetzima) and about 30-60mg, about 40-50mg, or about 60-120mg of dextromethorphan (or another amount described herein) are administered (e.g., orally) to a human once or twice a day for the treatment of a neuropsychiatric disorder, such as the hyperor depression of Alzheimer's disease.
In some embodiments, about 0.5-1.4mg/kg (for children), about 40-100mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of tomoxetine (stratera) and about 30-60mg, about 40-50mg or about 60-120mg of dextromethorphan (or another amount as described herein) are administered to a person once or twice daily (e.g., orally) for the treatment of neuropsychiatric conditions, such as the hyperfiltration or depression of Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of tibetazine (lucell, meta) and about 30-60mg, about 40-50mg or about 60-50 mg of the amount of thiirane are administered to a human once or twice daily (e.g., orally), for the treatment of a disorder such as depression or another disorder.
In some embodiments, about 5-20mg, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of verazine (Vivalan), and about 30-60mg, about 40-50mg or about 60mg of the other such as described herein are administered to a human once or twice daily (e.g., orally), for the treatment of a depression or for the other such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of the alltein oxide (Amioxid, ambivalon, equilibrin), and about 30-60mg, about 40-50mg or about 120mg of the same amount of the present invention's or more of the same are administered (e.g., orally) to a human once or twice daily for the treatment of depression or another such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of dimetaline (Istonil), and about 30-60mg, about 40-50mg or about 60mg of the same amount of the same are administered (e.g., orally) to a human once or twice daily for the treatment of the depression or the other such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of meritroxine (Dixeran, melixalan, traban) and about 60-60 mg, about 40-50mg of the other such as those described herein are administered to a human once or twice daily (e.g., orally), for the treatment of depression or another disorder, such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of nitro Sha Xiping (Sinamil), and about 30-60mg, about 40-50mg or about 60-60 mg of the amount of dextromethorphan (e.g., L) are administered to a person once or twice daily (e.g., orally), for the treatment of one or more of the other of the mentioned neurological disorder, such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of norxillin (Agedil, elron, gedal), and about 30-60mg, about 40-60 mg or about 60mg of the other such as described herein are administered to a human once or twice daily (e.g., orally), for the treatment of depression of one or another of the disorder, such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of poffoxazine (Azaphen), and about 30-60mg, about 40-50mg or about 60mg of the other such as described herein are administered to a human once or twice daily (e.g., orally), for the treatment of a certain amount of Alzheimer's disease or depression.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of saprolipram (tepul), and about 30-60mg, about 40-50mg or about 60mg of the amount of the same are administered (e.g., orally) to a human once or twice daily for the treatment of the depression or another such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of card Luo Shatong (Suronil, timostel), and about 30-60mg, about 40-50mg or about 60mg of the other such as described herein are administered to a human once or twice daily (e.g., orally), for the treatment of a neurological disorder or depression of the other such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of mebendazole (Inzan), and about 30-60mg, about 40-50mg or about 60mg of mebendazole (or about 120 mg) are administered to a human once or twice daily (e.g., orally), for the treatment of one or more of the other such neurological disorder, such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of indole (Pirazil), and about 30-60mg, about 40-50mg or about 60mg of the same amount of the drug or the therapeutic agent for treating Alzheimer's disease, such as depression or depression, or another such as Alzheimer's disease, are administered to a human once or twice daily.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of eplerian (Befol), and about 30-60mg, about 40-50mg or about 60-50 mg of epstein are administered to a human once or twice daily (e.g., orally), for the treatment of the other neurological disorder such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of naproxen (Brantur, cantor) and about 30-60mg, about 40-50mg or about 60mg of the other such as described herein are administered (e.g., orally) to a human once or twice daily for the treatment of a depression or for the other such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of diphenmeyer (Alnert, celem) and about 30-60mg, about 40-50mg or about 60-50 mg of the amount of the same are administered (e.g., orally) to a human once or twice daily for the treatment of a human, such as depression or another disorder.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of algomelatine (valxan), and about 30-60mg, about 40-50mg or about 60-120mg of the same are administered to a human once or twice daily (e.g., orally), for the treatment of one or more of the other such neurological disorder.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of ai ketamine (Spravat), and about 30-60mg, about 40-50mg or about 60-120mg of the other such as described herein are administered (e.g., orally) to a human once or twice daily for the treatment of depression or another such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of concisel (sedel), and about 30-60mg, about 40-50mg or about 60-120mg of the other such as described herein or the amount of the present invention's nerve disorder is used for the treatment of depression or the Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of thianaproxen (Stablon, coaxil), and about 30-60mg, about 40-50mg or about 60mg of the other such as described herein are administered to a human once or twice daily (e.g., orally), for the treatment of a depression or a certain amount of Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of alpha-methyltryptamine [ alpha ] MT ] (Indan), and about 30-60mg, about 40-50mg or about 60-50 mg of the same, or about 60-120mg of the same, are administered to a human once or twice daily (e.g., orally), for the treatment of a certain neurological disorder, such as Alzheimer's disease or another such as depression.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of ethylchromamine [ alpha ] -ethylchromine (alpha) (Monase), and about 30-60mg, about 40-50mg or about 60mg of the present invention's or another therapeutic amount of the same for treating depression or the Alzheimer's disease, such as described herein, depression, or the like, are administered to a human once or twice daily.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of indenofloxazine (Elen, noin), and about 30-60mg, about 40-50mg or about 60-120mg of the present invention's or another amount of the therapeutic agent for treating depression or the Alzheimer's disease, such as Alzheimer's disease, are administered to a human once or twice daily (e.g., orally).
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg, or about 450-500mg of ox Sha Fusheng (Conflitan), and about 30-60mg, about 40-50mg, or about 60-120mg of the same amount of the present invention's or of the therapeutic agent for depression or the other such as Alzheimer's disease are administered to a human once or twice daily (e.g., orally).
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of pidium (Tonerg), and about 30-60mg, about 40-50mg or about 60mg of the amount of the same fluid for use in treating the same or other such as Alzheimer's disease or depression.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of adenomethionine [ S-adenosyl-L-methionine (SAMe) ] (Heptal, saptal, about 40-60 mg), or about 60-60 mg of the other such as for the treatment of depression or the depression of the human once or twice daily (e.g., oral), about 80-90mg, about 60-60 mg, about 60mg or about 60mg of the present invention' S of depression.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of Hypericum perforatum [ St. johnsons (SJKirsin, mora, about 60-60 mg) and about 60-60 mg of the present invention or another amount of depression (e.g., alzheimer's disease) are administered to a human once or twice daily (e.g., orally).
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of Oxiletan [ 5-hydroxy (5-HTum) ] (Cincarm, leum, rthum, or about 60-60 mg of the other such as those described herein) are administered to humans once or twice daily (e.g., orally), for the treatment of depression, or other such as those of human.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg tryptophan (Trypt, optimax, aminomine), and about 30-60mg, about 40-50mg or about 60mg are administered to a human once or twice daily (e.g., orally), for the treatment of a certain neurological disorder such as depression or the like.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of magnesium, acetylcarnitine, tibetan, amisulpride (Solian), and about 30-60mg, about 40-50mg or about 120mg of the other neurological disorder, or the present invention is useful for the treatment of depression or the depression of the other neurological disorder, such as Alzheimer's disease, once or twice daily.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of aripiprazole (ilify), and about 30-60mg, about 40-50mg or about 120mg of the same amount of Alzheimer's disease are administered to a human once or twice daily (e.g., orally), for the treatment of depression or another such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of eplerian (Rexulti), and about 30-60mg, about 40-50mg or about 60mg of eplerian (or about 60 mg) are administered to a human once or twice daily (e.g., orally), for the treatment of one or more of the other of depression, such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of lurasidone (Latuca), and about 30-60mg, about 40-50mg or about 60-120mg of the same amount of the present invention's or more are administered (e.g., orally) to a human once or twice daily for the treatment of a disorder such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg olanzapine (Zyprexa) and about 30-60mg, about 40-50mg or about 60mg of the other such as described herein or 120mg of the amount of the therapeutic agent for the treatment of Alzheimer's disease or depression is administered to a human once or twice daily (e.g., orally).
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg quel of quel (Seroque), and about 30-60mg, about 40-50mg or about 60-60 mg of the other such as described herein are administered (e.g., orally) to a human once or twice daily for the treatment of a depression or a disorder such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of Risperdal) and about 30-60mg, about 40-50mg or about 60mg of Risperdal (or about 60 mg) are administered to a human once or twice daily (e.g., orally), for the treatment of the other neurological disorder such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg buspirone (Buspar), and about 30-60mg, about 40-50mg or about 60mg of buspirone (Buspar) are administered to a human once or twice daily (e.g., orally), for the treatment of the other such as Alzheimer's disease or for depression of one or another of the present disorder.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of lithium (Eslit, lithid), and about 30-60mg, about 40-50mg or about 60-50 mg of lithium (kalithid) are administered to a human once or twice daily (e.g., orally), for the treatment of a certain neurological disorder, such as depression or depression, or the like.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of modafinil, and about 30-60mg, about 40-50mg or about 60-120mg of dextromethorphan (e.g., the amount of 62 to 120 mg) are administered to a human once or twice daily (e.g., orally), for the treatment of one or another of the neurological disorder such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg thyroxine (T4), and about 30-60mg, about 40-50mg or about 60-120mg of dextromethorphan (e.g., the amount of the same) are administered to a human once or twice daily (e.g., orally), for the treatment of a further disorder such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of triiodothyronine (T3), and about 30-60mg, about 40-50mg or about 60mg of the same amount of tri-iodothyronine (T3) are administered to a human once or twice daily (e.g., orally), for the treatment of one or more of the other of the depression, such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of minocycline, and about 30-60mg, about 40-50mg or about 60-120mg of dextromethorphan (e.g., the amount of the same) are administered to a human once or twice daily (e.g., orally), for the treatment of a disorder such as Alzheimer's disease or another depression.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-100 mg are administered (e.g., orally) to a human once or twice daily 300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg amitriptyline/clozapineAnd about 30-60mg, about 40-50mg, or about 60-120mg of dextromethorphan (or another amount described herein) for use in treating a neuropsychiatric disorder, such as the agitation of Alzheimer's disease or depression.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of alcrine/oxychloropromazine (etaf) and about 30-60mg, about 40-50mg or about 60mg of the other such as described herein are administered (e.g., orally) to a human once or twice daily for the treatment of depression, or for the other such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of flupentixin/melitracin (Deanxit), and about 30-60mg, about 40-50mg or about 60-120mg of the other such as described herein are administered to a human once or twice daily (e.g., orally), for the treatment of a depression or a disorder such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of olanzapine/fluoxetine (mbyax), and about 30-60mg, about 40-50mg or about 60mg of the other such as described herein are administered to a human once or twice daily (e.g., orally), for the treatment of depression or the other such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of tranexamine/trifluoracene (Parste, parstethoprofile, japamide, stepamide) and about 60-60 mg or about 60mg of the other such as those indicated for the treatment of depression or depression of the other neurological disorder, or the present disorder, or the like, are administered to a human once or twice daily.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of 4-chlorokynurenine, and about 30-60mg, about 40-50mg or about 60mg of dextromethorphan (e.g., the amount of the present invention) are administered to a person once or twice daily (e.g., orally), for the treatment of a certain depression or a certain amount of the other such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of AGN-241751, and about 30-60mg, about 40-50mg or about 60-120mg of dextromethorphan (e.g., the amount of dextromethorphan) are administered to a person once or twice daily (e.g., orally), for the treatment of a disorder such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of alzhi (NRX-4), and about 30-60mg, about 40-50mg or about 60mg of alzhi (or about 60mg of the right-120 mg) are administered to a human once or twice daily (e.g., orally), for the treatment of a depression or another such as alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of levoketamine (PCN-101, HR-071603), and about 30-60mg, about 40-50mg or about 60mg of the other neurological disorder (e.g., alzheimer's disease) are administered to a human once or twice daily (e.g., orally), for the treatment of depression or the other such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of dextromethorphan (Deromethadone) (REL-1017), about 30-60mg, about 40-50mg or about 60mg of dextromethorphan (e.g., L-60 mg) are administered to a person once or twice daily (e.g., orally), for the treatment of a disorder such as depression, or for the other neurological disorder.
In some embodiments, the method comprises administering (e.g., orally) about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of EVT-101 (ENS-101), and about 30-60mg, about 40-50mg or about 60mg of the amount of about 60-50 mg of the present invention's-120 mg to a person once or twice daily for the treatment of a disorder, such as depression, e.g., depression, alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of Li Laina da (CERC-301, MK-0657) and about 30-60mg, about 40-50mg or about 60-50 mg of the amount of dextromethorphan or the other such as described herein are administered to a human once or twice daily (e.g., orally), for the treatment of depression or the other such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of Pasteup (RG-7090), and about 30-60mg, about 40-50mg or about 60-50 mg of the amount of the drug is administered to a human once or twice daily (e.g., orally), for the treatment of the other neurological disorder, such as depression or the Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg AN-788 (NSD-788), and about 30-60mg, about 40-50mg or about 60mg of the other such as described herein are administered to a human once or twice daily (e.g., orally), for the treatment of depression or the other such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of tropane Lu Dewen (ansoxine; 03005, LPM 570065) and about 40-50mg of about 60-60 mg are administered to a human once or twice daily (e.g., orally), for the treatment of a certain neurological disorder, such as Alzheimer's disease, depression, or another amount of the present invention.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg PDC-1421 (BLI-1005), and about 30-60mg, about 40-50mg or about 60-120mg of the other such as described herein-120 mg of the amount of the drug is administered (e.g., orally) to a human once or twice daily for the treatment of the depression or the other such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg MIN-117 (WF-516), and about 30-60mg, about 40-50mg or about 60mg of the amount of dextromethorphan (e.g., about 40-50 mg) are administered to a person once or twice daily (e.g., orally), for the treatment of one or more of the other of the mentioned neurological disorder, such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of TGBA01AD (FKB 01 MD), and about 30-60mg, about 40-50mg or about 60mg of the other such as described herein or about 120mg of the amount of the neurological disorder is administered (e.g., orally) to a human once or twice daily.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of gepirone (FK 07AD; travo), and about 30-60mg, about 40-50mg or about 60mg of the other such as described herein are administered (e.g., orally) to a human once or twice daily for the treatment of depression, e.g., depression, or the other such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of pimavan (nuzid; ACP-103F-048), and about 60-60 mg, about 40-50mg or about 60mg of the other such as those described herein are administered to a human once or twice daily (e.g., orally), for the treatment of depression or another disorder such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of cetirizine, and about 30-60mg, about 40-50mg or about 60-120mg of dextromethorphan (e.g., the amount of the present invention) are administered to a person once or twice daily (e.g., orally), for the treatment of a disorder such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg Brilazine (RP-5063, RP-5000), and about 30-60mg, about 40-60 mg or about 60mg of the present invention is useful for the treatment of depression or the other neurological disorder, such as Alzheimer's disease, depression, or the like, once or twice daily to a human.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of Lu Meipai (ITI-007) and about 30-60mg, about 40-50mg or about 60-120mg of the same amount of the present invention's or of the same for the treatment of Alzheimer's disease or another neurological disorder, such as Alzheimer's disease, are administered to a human once or twice daily (e.g., orally).
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of adenosylmethionine (SAMe; MSI-190, MSI-195, stra) and about 40-60 mg, about 60-120mg or about 60mg of the present invention's or another neurological disorder, e.g., for the treatment of depression, or the like, of Alzheimer's disease, is administered to a human once or twice daily (e.g., orally).
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg ganaxolone (CCD-1042), and about 30-60mg, about 40-50mg or about 60-120mg of the present invention's or another amount of the same are administered (e.g., orally) to a human once or twice daily for the treatment of the depression or the other such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of Zu Lanuo ketone (E-217), about 30-60mg, about 40-50mg or about 60mg of the same or about 120mg of the present invention's or more of the amount of the same for the treatment of the depression or the depression of the Alzheimer's disease, or the other neurological disorder, are administered to a human once or twice daily (e.g., orally).
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of 3 beta-Methoxypgestrel (MAP) and about 30-60mg, about 40-50mg or about 60-50 mg of the amount of the present invention provides for the treatment of one or another such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of PH-10-vomeropherine, and about 30-60mg, about 40-50mg or about 60mg of the other such as described herein or about 120mg of the amount of the neurological disorder is administered (e.g., orally) to a human once or twice daily for the treatment of depression or another such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of Alzheimer's (J-679564, CERC-501, 3962) and about 40-60 mg or about 40-60 mg of the other such as described herein are administered to a human once or twice daily (e.g., orally), for the treatment of depression, e.g., depression, or other such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of BTRX-335140 (BTRX-140), and about 30-60mg, about 40-50mg or about 60mg of the other such as described herein or about 60-120mg of the amount of the same are administered (e.g., orally) to a human once or twice daily for the treatment of depression or the other such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about RX 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of buprenorphine/Mi Duofen (S-5461) about 40-246040 (BT84-60) and about 40-60 mg of about 60-60 mg of one or more of the other such as described herein are administered (e.g., orally) to a human once or twice daily for the treatment of depression, or for the other disorder, such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of Hydroxynorketamine (hydromorphone) ((2R, 6K) -and about 40-60 mg or another amount of dextromethorphan (about 60-60 mg) are administered to a person once or twice daily (e) for oral administration, for the treatment of neuropsychiatric disorders such as, for example, the agitation or depression of Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of JNJ-39393406, and about 30-60mg, about 40-50mg or about 60-120mg of dextral-120 mg of the other such as described herein are administered (e.g., orally) to a human once or twice daily, for the treatment of a depression or a further disorder such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of JNJ-54175446, and about 30-60mg, about 40-50mg or about 60-120mg of dextral-120 mg of the other such as described herein are administered (e.g., orally) to a human once or twice daily, for the treatment of a depression or a further disorder such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of JNJ-61393215, and about 30-60mg, about 40-50mg or about 60-120mg of dextral-120 mg of the other such as described herein are administered (e.g., orally) to a human once or twice daily, for the treatment of a depression or a further disorder such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg (JN J-3215, J-393215; orin-1) and about 30-60mg, about 40-60 mg or about 60mg (for use in the treatment of the other conditions such as depression or the depression of the human once or twice daily (e.g., oral), are administered to a human.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg NNI-351 and about 30-60mg, about 40-50mg or about 60-120mg of dextromethorphan (e.g., the amount of the same) are administered to a human once or twice daily (e.g., orally), for the treatment of a further disorder such as Alzheimer's disease or depression.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg NSI-189 and about 30-60mg, about 40-50mg or about 60-120mg of dextromethorphan (e.g., the amount of the same) are administered to a human once or twice daily (e.g., orally), for the treatment of a neurological disorder such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of NV-5138, and about 30-60mg, about 40-50mg or about 60-120mg of dextromethorphan (e.g., the amount of the same) are administered to a human once or twice daily (e.g., orally), for the treatment of a further disorder such as Alzheimer's disease or depression.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of Onootulindoxena (botulinum toxin A ), and about 40-60 mg, about 40-50mg or about 60mg of the other neurological disorder, such as described herein, are administered to a human once or twice daily (e.g., orally), for the treatment of depression or another disorder such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg Pramipexole (Prpexe) (CTC-501, CTC-413) and about 40-60 mg, about 40-50mg or about 60mg of the other neurological disorder, e.g., for use in the treatment of depression or depression of the other such as Alzheimer's disorder, or the present disorder, is administered to a human once or twice daily (e.g., orally).
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg Pramipexole (Prpexe) (CTC-501, CTC-413) and about 40-60 mg, about 40-50mg or about 60mg of the other neurological disorder, e.g., for use in the treatment of depression or depression of the other such as Alzheimer's disorder, or the present disorder, is administered to a human once or twice daily (e.g., orally).
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of tolper Lei Sheng (seltex) (MIN-202, J-42847922) and about 40-60 mg of JN-60 mg or about 60-60 mg of the other such as described herein are administered (e.g., orally) to a human once or twice daily, for the treatment of one or more of the symptoms of depression, such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of Si Lu Kushan anti (Sidrum) (CNAb-136) and about 30-60mg, about 40-50mg or about 60-60 mg of the other neurological disorder or the present invention is useful for the treatment of depression or the depression of the other such as Alzheimer's disease, or the like, one of the mental disorder, once or twice daily administration to a human.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of Si Lu Kushan anti (Sidrum) (CNAb-136) and about 30-60mg, about 40-50mg or about 60-60 mg of the other neurological disorder or the present invention is useful for the treatment of depression or the depression of the other such as Alzheimer's disease, or the like, one of the mental disorder, once or twice daily administration to a human.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg, and about 30-60mg, about 40-50mg or about 60-120mg of dextromethorphan (e.g., SUM) are administered to a human once or twice daily (e.g., orally), for the treatment of a further disorder such as Alzheimer's disease or depression.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg TS-121, and about 30-60mg, about 40-50mg or about 60-120mg of dextromethorphan (e.g., the amount of the same) are administered to a human once or twice daily (e.g., orally), for the treatment of a disorder such as Alzheimer's disease or another depression.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of Tramadol (Tramadol) (ETS 6103; viotra) and about 30-60mg, about 40-50mg or about 60mg of the present invention's or another amount of the same are administered (e.g., orally) to a human once or twice daily for the treatment of depression, such as described herein.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of Cycloserine/lurasidone (Cycloserine/lurasone), about 30-60mg, about 40-60 mg or about 60mg of the other such as described herein are administered to a human once or twice daily (e.g., orally), for the treatment of depression or the other such as Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of 7, 8-dihydroxyflavone (7, 8-DHF), and about 30-60mg, about 40-50mg or about 60mg of the other such as described herein are administered to a human once or twice daily (e.g., orally), for the treatment of the depression of one or another of the Alzheimer's disease.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of Minocycline (Minycine), and about 30-60mg, about 40-50mg or about 60-120mg of Minocycline (for use in the treatment of depression or the other such as Alzheimer's disease, depression or the like) are administered to a human once or twice daily.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of nitric oxide, and about 30-60mg, about 40-50mg or about 60-120mg of dextromethorphan (e.g., the amount of me) are administered to a human once or twice daily (e.g., orally), for the treatment of a disorder such as Alzheimer's disease or another depression.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg Pramipexole (Prpexe), and about 30-60mg, about 40-50mg or about 60-50 mg of the amount of the same Pramipexole (Prpexole) are administered to a human once or twice daily (e.g., orally), for the treatment of a disorder such as depression or a human.
In some embodiments, about 0.01-1mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 0.01-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 70-80mg, about 80-90mg, about 90-100mg, about 100-120mg, about 120-140mg, about 140-160mg, about 160-180mg, about 180-200mg, about 200-250mg, about 250-300mg, about 300-350mg, about 350-400mg, about 400-450mg or about 450-500mg of R13, and about 30-60mg, about 40-50mg or about 60-120mg of dextromethorphan (e.g., the amount of dextromethorphan) are administered to a person once or twice daily (e.g., orally), for the treatment of a disorder such as Alzheimer's disease or another disorder.
In some embodiments, a combination of about 10-60mg or about 20-30mg of agomelatine and about 30-60mg or about 40-50mg of dextromethorphan (or another amount as described herein) is administered (e.g., orally) to a human once or twice a day for use in treating a neuropsychiatric disorder, such as the agitation or depression of alzheimer's disease. The two compounds may be administered separately or in a single dosage form.
In some embodiments, a combination of about 2-10mg or about 3-5mg reboxetine and about 30-60mg or about 40-50mg dextromethorphan (or another amount as described herein) is administered (e.g., orally) to a human once or twice a day for the treatment of a neuropsychiatric disorder, such as the agitation or depression of Alzheimer's disease.
In some embodiments, a combination of about 2-10mg or about 3-5mg of oxaprozin (esreboxetine) and about 30-60mg or about 40-50mg of dextromethorphan (or another amount as described herein) is administered (e.g., orally) to a human once or twice a day for the treatment of a neuropsychiatric disorder, such as the agitation or depression of Alzheimer's disease.
In some embodiments, a combination of about 2-40mg, about 4-6mg, about 8-12mg, or about 16-24mg vortioxetine and about 30-60mg, or about 40-50mg dextromethorphan (or another amount described herein) is administered (e.g., orally) to a human once or twice a day for the treatment of a neuropsychiatric disorder, such as the agitation or depression of Alzheimer's disease.
In some embodiments, a combination of about 10-240mg or about 20-120mg of levomilnacipran and about 30-60mg or about 40-50mg of dextromethorphan (or another amount as described herein) is administered (e.g., orally) to a human once or twice a day for use in treating a neuropsychiatric disorder, such as the agitation or depression of alzheimer's disease.
In some embodiments, a combination of about 5-80mg, about 10-30mg, or about 20-40mg of vilazodone and about 30-60mg, or about 40-50mg of dextromethorphan (or another amount as described herein) is administered (e.g., orally) to a human once or twice a day for use in treating a neuropsychiatric disorder, such as the agitation of alzheimer's disease or depression.
In some embodiments, about 15-120 μg/kg/hour of brexanolone is administered (e.g., by intravenous injection) over 60 hours, about 60-120mg or about 80-100mg of dextromethorphan (or another amount described herein) is administered (e.g., orally) once or twice a day, to treat a neuropsychiatric disorder, such as the agitation or depression of alzheimer's disease.
The antidepressant in combination with dextromethorphan can provide higher efficacy, e.g., better pain relief, than either component alone. In fast metabolizers, dextromethorphan can be metabolized rapidly and sufficiently, even at high doses resulting in low systemic exposure. Antidepressants are inhibitors of dextromethorphan metabolism.
As described above, such inhibition may increase dextromethorphan plasma levels, producing additive or synergistic effects, such as relief from neurological conditions including pain, depression, smoking cessation, and the like. Thus, while inhibiting dextromethorphan metabolism is only one of many potential benefits of this combination, co-administration of dextromethorphan with an antidepressant may also enhance the efficacy of the antidepressant for many individuals. For many individuals, co-administration of dextromethorphan with an antidepressant can enhance the analgesic properties of the antidepressant. For many individuals, co-administration of dextromethorphan with an antidepressant can also enhance the antidepressant's antidepressant performance, including a faster onset time.
Another potential benefit of co-administration of dextromethorphan with an antidepressant is that it can be used to reduce the likelihood of adverse events associated with dextromethorphan treatment, such as drowsiness. This may be useful, for example, in human patients at risk of adverse events arising from dextromethorphan treatment.
Another potential benefit of co-administration of dextromethorphan with an antidepressant is that it can be used to reduce the likelihood of adverse events associated with antidepressant treatment, such as narcotic disorders. For example, this may be used in human patients at risk of experiencing adverse events resulting from treatment with antidepressants.
Co-administration of an antidepressant with dextromethorphan may reduce central nervous system adverse events, gastrointestinal events, or another type of adverse event associated with an antidepressant. Central Nervous System (CNS) adverse events include, but are not limited to, neurologic, dizziness, insomnia, dizziness-head, tremors, hallucinations, tics, CNS depression, fear, anxiety, headache, dysphoria or excitatory exacerbations, tinnitus, somnolence, dizziness, sedation, somnolence, confusion, disorientation, fatigue, movement disorders, fatigue, euphoria, neurologic, insomnia, sleep disorders, seizure, excitement, tension-like states (catatonic-like states), hysteria, hallucinations, delusions, headache, and/or migraine, and extrapyramidal symptoms such as eye movement crises (oculogyric crisis), torticollis, hyperexcitations, increased muscle tone, ataxia, and/or premenstrual processes (tongue protrusion).
Gastrointestinal adverse events include, but are not limited to, nausea, vomiting, abdominal pain, dysphagia, dyspepsia, diarrhea, abdominal distension, bloating, gastric ulcers with bleeding, loose stool, constipation, stomachache, heartburn, eructation, loss of appetite, satiety, dyspepsia, bloating, gastric hyperacidity, dry mouth, gastrointestinal disorders, and gastralgia.
Co-administration of dextromethorphan with an antidepressant does not necessarily require that the two compounds be administered in the same dosage form. For example, the two compounds may be administered in a single dosage form, or they may be administered in two separate dosage forms. In addition, both compounds may be administered simultaneously, but this is not required. These compounds may be administered at different times, so long as both are present in the human body for at least a portion of the time that treatment is by co-administration.
The side effects of antidepressants can be reduced by administering the antidepressant with dextromethorphan. Examples of side effects that may be reduced include abnormal sensations of rotation and movement, irritation, arm weakness, bloating, blurred vision, burning sensation of the eyes, changes in ear buzzing, vital signs (including but not limited to heart rate, respiratory rate, body temperature and blood pressure), cold sensation, constipation, difficulty concentrating, difficult sleeping, difficulty falling asleep, difficulty urination, difficulty defecation, discomfort of the ears, discomfort of the eyes, discomfort of the stomach, dizziness, dry lips, dry mouth, dry throat, dysmenorrhea, fatigue, feverish sensation, dizziness, feeling more than usual, feeling more tired than usual, feeling tired, hand tremors, hand weakness, headache, heartburn, hot flashes, increased blood pressure, increased skin sensitivity of the head and face, involuntary muscle contractions, involuntary whole body muscle contractions, knee pain, weakness, dizziness, loose stools, inappetence, low back pain, irregular menstruation, metallic taste, more than usual, dry mucous membranes, plugs, nausea, runny nose, eye, light pressure or sore eyes, shagginess, sore throat, sore eyes, sore throat, and/or shagginess, feeling of the hands, and throat, and/or shakiness, and the feeling of the hands, soft and/or sore throat. Any of these side effects may also be mentioned or grouped according to corresponding, equivalent or other related terms in the standard medical terminology set for drug administration (Medical Dictionary for Regulatory Activities, medRA).
In some embodiments, co-administration of the antidepressant with dextromethorphan results in both the antidepressant and dextromethorphan contributing to the pain relief properties of the combination. For example, the combination may have improved pain relief performance, including potentially faster onset times, compared to antidepressants alone, or compared to dextromethorphan alone.
In some embodiments, the combination has an improved pain relief performance compared to the antidepressant alone 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 100%, up to about 500% or up to about 1000%, about 0.5% to about 1000%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to 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% to about 200%, or any amount of pain relief defined by any of these values or in the range therebetween.
In some embodiments, the combination has an improved pain relief performance compared to dextromethorphan alone 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 100%, up to about 500% or up to about 1000%, about 0.5% to about 1000%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to 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 defined by or in the range between any of these values.
Unless otherwise indicated, any reference to a compound herein, such as dextromethorphan, an antidepressant, by structure, name, or any other means, includes pharmaceutically acceptable salts; alternative solid forms, such as polymorphs, solvates, hydrates, etc.; a tautomer; deuterium-modified compounds, such as deuterium-modified dextromethorphan; or any chemical species that can be rapidly converted to a compound described herein under the conditions of use as described herein.
In some embodiments, an excess of one stereoisomer of the antidepressant may be administered. In other embodiments, an antidepressant may be administered in excess of the S enantiomer (e.g., at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or enantiomerically pure S enantiomer) or in excess of the R enantiomer (e.g., at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or enantiomerically pure R enantiomer).
In some embodiments, both dextromethorphan and the antidepressant are formulated in immediate release. In some embodiments, both dextromethorphan and the antidepressant are formulated in a slow release. In some embodiments, dextromethorphan is formulated as an immediate release and the antidepressant is formulated as a sustained release. In some embodiments, dextromethorphan is formulated to be slow-release and the antidepressant is formulated to be quick-release.
Examples of deuterium modified dextromethorphan include, but are not limited to, those shown below.
d6-dextromethorphan
The dosage form or composition may be a blend or mixture of dextromethorphan and an antidepressant, either alone or in a carrier. For example, dextromethorphan and an antidepressant can be dispersed in one another or together in a carrier. The dispersion may comprise a mixture of solid materials in which the individual small particles are essentially one compound, but the small particles are dispersed within each other, as may occur, for example, if two powders of two different drugs are blended with a solid carrier material and the blending is performed in solid form. In some embodiments, dextromethorphan and an antidepressant may be substantially uniformly dispersed in a composition or dosage form. Alternatively, the dextromethorphan and the antidepressant may be in separate domains or phases within a composition or dosage form. For example, one drug may be in a coating and the other drug may be in a core within the coating. For example, one drug may be configured for sustained release while another drug may be configured for immediate release.
Some embodiments include administration of a tablet containing an antidepressant that provides a sustained release form and dextromethorphan that provides an immediate release form. Although there are many ways in which sustained release of an antidepressant can be achieved, in some embodiments, the antidepressant is in combination with hydroxypropyl methylcellulose. For example, antidepressant particles can be combined with microcrystalline cellulose and hydroxypropyl methylcellulose (e.g.) Blending to form a blend of blended powders. This can then be combined with immediate release dextromethorphan in a single tablet.
Dextromethorphan and/or an antidepressant (which, for convenience, are collectively referred to herein as a "therapeutic compound") may be combined with a drug carrier selected based on the chosen route of administration and standard pharmaceutical procedures such as described in Remington' sPharmaceutical Sciences, 2005. The relative proportions of active ingredient and carrier may be determined, for example, by the solubility and chemical nature of the compound, the route of administration selected, and standard pharmaceutical procedures.
The therapeutic compound may be administered by any means that results in contact of one or more active agents with one or more desired sites of action in the patient. The compounds may be administered as the sole therapeutic agent or combination of therapeutic agents by any conventional means that may be used in combination with a drug. For example, they may be administered as the sole active ingredient in a pharmaceutical composition, or they may be used in combination with other therapeutically active ingredients.
The therapeutic compounds may be administered to a human patient in a variety of forms suitable for the chosen route of administration (e.g., oral or parenteral). In this regard, parenteral administration includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transdermal (including transdermal), ocular, sublingual and buccal; topical applications include ophthalmic, dermal, ocular, rectal and by insufflation, nasal inhalation of aerosols, and rectal systems.
The amount of dextromethorphan in the therapeutic composition can vary. For example, some liquid compositions may comprise 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% 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), from about 3% (w/v) to about 5% (w/v), from about 5% (w/v) to about 7% (w/v), from about 7% (w/v) to about 10% (w/v), from about 10% (w/v) to about 15% (w/v), from about 15% (w/v) to about 20% (w/v), from about 20% (w/v) to about 30% (w/v), from about 30% (w/v) to about 40% (w/v), or from about 40% (w/v) to about 50% (w/v) dextromethorphan.
Some liquid dosage forms may contain an amount of dextromethorphan of about 10mg to about 500mg, about 30mg to about 350mg, about 50mg to about 200mg, about 50mg to about 70mg, about 20mg to about 50mg, about 30mg to about 60mg, about 40mg to about 50mg, about 40mg to about 55mg, about 40mg to about 42mg, about 42mg to about 44mg, about 44mg to about 46mg, about 46mg to about 48mg, about 48mg to about 50mg, about 80mg to about 100mg, about 110mg to about 130mg, about 170mg to about 190mg, about 45mg, about 60mg, about 90mg, about 120mg, or about 180mg, or any dextromethorphan defined by or within a range between any of these values.
Some solid compositions may comprise 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.
Some solid dosage forms may contain from about 10mg to about 500mg, from about 30mg to about 350mg, from about 20mg to about 50mg, from about 30mg to about 60mg, from about 40mg to about 50mg, from about 40mg to about 42mg, from about 42mg to about 44mg, from about 44mg to about 46mg, from about 46mg to about 48mg, from about 48mg to about 50mg, from about 50mg to about 200mg, from about 50mg to about 70mg, from about 80mg to about 100mg, from about 110mg to about 130mg, from about 170mg to about 190mg, from about 60mg, from about 90mg, about 120mg, or about 180mg of dextromethorphan, or any amount of dextromethorphan defined by or within the range between any of these values.
In some embodiments, the amount of dextromethorphan can be in a range of about 0.1mg/kg to about 20mg/kg, about 0.75mg/kg to about 7.5mg/kg, about 0.1mg/kg to about 5mg/kg, about 0.1mg/kg to about 3mg/kg, about 0.3mg/kg to about 0.9mg/kg, about 0.3mg/kg to about 1mg/kg, about 0.6mg/kg to about 0.8mg/kg, about 0.7mg/kg to about 0.8mg/kg, about 0.75mg/kg, about 0.4mg/kg to about 1.5mg/kg, about 1mg/kg to about 2mg/kg, about 10mg/kg to about 20mg/kg, about 12mg/kg to about 17mg/kg, about 15mg/kg to about 20mg/kg, about 1mg/kg to about 10mg/kg, or any value within these ranges or between these ranges, based on the weight of the patient.
The amount of antidepressant in the therapeutic composition may vary. If increasing the plasma level of dextromethorphan is desired, the antidepressant should be administered in an amount that increases the plasma level of dextromethorphan. For example, the antidepressant may be administered in an amount that results in a plasma concentration of dextromethorphan in the human being 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, at least about 80-fold greater than the same amount of dextromethorphan administered on day 8, day 9, or day 10.
In some embodiments, the antidepressant may result in an area under the 12 hour curve (AUC) at day 8, day 9, or day 10 from when dextromethorphan is administered 0-12 ) Or mean plasma concentration of a person 12 hours after administration of dextromethorphan (C avg ) 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, at least about 80-fold of the same amount of dextromethorphan without antidepressant is administered to a human.
In some embodiments, the antidepressant may result in a maximum plasma concentration of dextromethorphan in a human at day 8, day 9, or day 10 (C max Or C Maximum value ) 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 of the plasma concentration of dextromethorphan without an antidepressant is administered to a human in an amount that is the same as the administration of dextromethorphan.
For co-administration of an antidepressant with dextromethorphan, an increase in dextromethorphan plasma concentration can occur on the first day of antidepressant administration as compared to administration of the same amount of dextromethorphan without the antidepressant. For example, on the first day of administration of an antidepressant, dextromethorphan plasma levels may be at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 4 times, at least about 5 times, at least about 6 times, at least about 7 times, at least about 8 times, at least about 9 times, or at least about 10 times the level that would be obtained if the same amount of dextromethorphan was administered without the antidepressant.
In some embodiments, the AUC of dextromethorphan on the first day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with an antidepressant) can be at least 2 times the AUC obtained if the same amount of dextromethorphan is administered without an antidepressant.
In some embodiments, the AUC of dextromethorphan is the first day to increase the plasma level of dextromethorphan (e.g., by co-administering dextromethorphan with an antidepressant) 0-12 Can be at least about 15 ng.hr/mL, at least about 17 ng.hr/mL, at least about 19 ng.hr/mL, at least about 20 ng.hr/mL, at least about 22 ng.hr/mL, at least about 23 ng.hr/mL, at least about 24 ng.hr/mL, at least about 25 ng.hr/mL, at least about 26 ng.hr/mL, at least about 27 ng.hr/mL, at least about 28 ng.hr/mL, at least about 29 ng.hr/mL, at least about 30 ng.hr/mL, at least about 31 ng.hr/mL, at least about 32 ng.hr/mL, at least about 33 ng.hr/mL, at least about 34 ng.hr/mL, at least about 35 ng.hr/mL, at least about 36 ng.hr/mL, at least about 37 ng.hr/mL, at least about 38 ng.hr/mL, at least about 39 ng.hr/mL, at least about 40 ng.hr/mL, at least about 41 ng.hr/mL, at least about 42 ng.hr/mL, at least about 43 ng.hr, at least about 44 ng.hr/mL, at least about 46 ng.about 46 ng.hr/mL, at least about 46 ng.about 46.about 51 ng.hr/mL, at least about 46.about 35 ng.ml, at least about 46.about 35 ng.t.and at about 51 ng.t..
In some embodiments, the dextromethorphan AUC is increased (e.g., by co-administering dextromethorphan with an antidepressant) on the eighth day of increasing dextromethorphan plasma levels 0-12 Can be at least about 40 ng-hr/mL, at least about 50 ng-hr/mL, at least about 60 ng-hr/mL, at least about70 ng-hr/mL, at least about 80 ng-hr/mL, at least about 90 ng-hr/mL, at least about 100 ng-hr/mL, at least about 150 ng-hr/mL, at least about 200 ng-hr/mL, at least about 250 ng-hr/mL, at least about 300 ng-hr/mL, at least about 350 ng-hr/mL, at least about 400 ng-hr/mL, at least about 450 ng-hr/mL, at least about 500 ng-hr/mL, at least about 550 ng-hr/mL, from about 500 ng-hr/mL to about 600 ng-hr/mL, from about 500 ng-hr/mL to about 550 ng-hr/mL, from about 500 ng-hr/mL to about 525 ng-hr/mL, from about 525 ng-hr/mL, at least about 600 ng-hr/mL, at least about 650 ng-hr/mL, at least about 700 ng-hr/mL, at least about 750 ng-hr/mL, at least about 800 ng-hr/mL about 800 ng/hr/mL to about 900 ng/hr/mL, about 850 ng/hr/mL to about 875 ng/hr/mL, about 875 ng/hr/mL to about 900 ng/hr/mL, about 900 ng/hr/mL to about 1000 ng/hr/mL, about 1000 ng/hr/mL to about 1100 ng/hr/mL, about 1100 ng/hr/mL to about 1200 ng/hr/mL, about 1200 ng/hr/mL to about 1300 ng/mL, about 1300 ng/hr/mL to about 1400 ng/hr/mL, about 1400 ng/hr/mL to about 1500 ng/hr/mL, about 1500 ng/hr/mL to about 1600 ng/hr/mL, about 1700 ng/hr/mL to about 1700 ng/hr/mL, about 1800 ng/hr/mL, about 1200 ng/hr/mL to about 2000 ng/hr/mL, at least about 850 ng-hr/mL, at least about 900 ng-hr/mL, at least about 950 ng-hr/mL, at least about 1000 ng-hr/mL, at least about 1050 ng-hr/mL, at least about 1100 ng-hr/mL, at least about 1150 ng-hr/mL, at least about 1200 ng-hr/mL, at least about 1250 ng-hr/mL, at least about 1300 ng-hr/mL, at least about 1350 ng-hr/mL, at least about 1400 ng-hr/mL, at least about 1450 ng-hr/mL, at least about 1500 ng-hr/mL, at least about 1550 ng-hr/mL, at least about 1600 ng-hr/mL, at least about 1625 ng-hr/mL, at least about 1650 ng-hr/mL, at least about 1675 ng-hr/mL, or at least about 1686.3-hr/mL, and in some embodiments may be at most about 50000 ng-hr/mL.
In some embodiments, the dextromethorphan AUC is increased (e.g., by co-administering dextromethorphan with an antidepressant) on the eighth day of increasing dextromethorphan plasma levels 0-24 Can be at least about 50 ng-hr/mL, at least about 75 ng-hr/mL, at least about 100 ng-hr/mL, at least about 200 ng-hr/mL, at least about 300 ng-hr/mL, at least about 400 ng-hr/mL, at least about 500 ng-hr/mL, at least about 600 ng-hr/mL, at least about700 ng-hr/mL, at least about 800 ng-hr/mL, at least about 900 ng-hr/mL, at least about 1000 ng-hr/mL, at least about 1100 ng-hr/mL, at least about 1200 ng-hr/mL, at least about 1300 ng-hr/mL, at least about 1400 ng-hr/mL, at least about 1500 ng-hr/mL, at least about 1600 ng-hr/mL, at least about 1700 ng-hr/mL, at least about 1800 ng-hr/mL, at least about 1900 ng-hr/mL, at least about 2000 ng-hr/mL, at least about 2100 ng-hr/mL, at least about 2200 ng-hr/mL, at least about 2300 ng-hr/mL, at least about 2400 ng-hr/mL, at least about 2500 ng-hr/mL, at least about 2600 ng-hr/mL, at least about 2700 ng-hr/mL, at least about 2800 ng-hr/mL, at least about 1850-hr/mL, at least about 2900 ng-hr/mL, at least about 2950 ng-hr/mL, or at least about 2975.3 ng-hr/mL, and may be implemented in any manner up to 1000 ng-hr/mL.
In some embodiments, the dextromethorphan AUC is increased (e.g., by co-administering dextromethorphan with an antidepressant) on the eighth day of increasing dextromethorphan plasma levels 0-inf Can be at least about 75 ng.hr/mL, at least about 100 ng.hr/mL, at least about 200 ng.hr/mL, at least about 300 ng.hr/mL, at least about 400 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 1000 ng.hr/mL, at least about 1100 ng.hr/mL, at least about 1200 ng.hr/mL, at least about 1300 ng.hr/mL, at least about 1400 ng.hr/mL, at least about 1500 ng.hr/mL, at least about 1600 ng.hr/mL, at least about 1700 ng.hr/mL, at least about 1800 ng.hr/mL, at least about 1900 ng.hr/mL, at least about 2000 ng.hr/mL, at least about 2100 ng.hr/mL, at least about 2200 ng.hr/mL, at least about at least about 2300ng hr/mL, at least about 2400ng hr/mL, at least about 2500ng hr/mL, at least about 2600ng hr/mL, at least about 2700ng hr/mL, at least about 2800ng hr/mL, at least about 2900ng hr/mL, at least about 3000ng hr/mL, at least about 3100ng hr/mL, at least about 3200ng hr/mL, at least about 3300ng hr/mL, at least about 3400ng hr/mL, at least about 3500ng hr/mL, at least about 3600ng hr/mL, at least about 3700ng hr/mL, at least about 3800ng hr/mL, at least about 3900ng hr/mL, at least about 4000ng hr/mL, at least about 0ng hr/mL, at least about 4200ng hr/mL, at least about 4100ng hr/mL, at least about 4400ng hr/mL, at least about 4500 ng/mL, at least about to about 410 ng/hr/mL At least about 4600 ng-hr/mL, at least about 4700 ng-hr/mL, at least about 4800 ng-hr/mL, at least about 4900 ng-hr/mL, at least about 5000 ng-hr/mL, at least about 5100 ng-hr/mL, at least about 5200 ng-hr/mL, at least about 5300 ng-hr/mL, at least about 5400 ng-hr/mL, at least about 5500 ng-hr/mL, at least about 5600 ng-hr/mL, at least about 5700 ng-hr/mL, at least about 5800 ng-hr/mL, at least about 5900 ng-hr/mL, at least about 6000 ng-hr/mL, at least about 6100 ng-hr/mL, at least about 6200 ng-hr/mL, at least about 7100 ng-hr/mL, at least about 6400 ng-hr/mL, at least about 6500 ng-hr/mL, at least about 6700 ng-hr/mL, at least about 6800 ng-hr/mL, at least about 6900 ng-hr/mL, at least about 7000-about 72 ng-hr/mL, or at least about 72 ng-00 ng-hr/mL.
In some embodiments, the dextromethorphan AUC is increased (e.g., by co-administering dextromethorphan with an antidepressant) on the ninth day of increasing dextromethorphan plasma levels 0-12 Can be at least about 40 ng/hr/mL, at least about 50 ng/hr/mL, at least about 60 ng/hr/mL, at least about 70 ng/hr/mL, at least about 80 ng/hr/mL, at least about 90 ng/hr/mL, at least about 100 ng/hr/mL, at least about 150 ng/hr/mL, at least about 200 ng/hr/mL, at least about 250 ng/hr/mL, at least about 300 ng/hr/mL, at least about 350 ng/hr/mL, at least about 400 ng/hr/mL, at least about 450 ng/hr/mL, at least about 500 ng/hr/mL, at least about 550 ng/hr/mL, about 500 ng/hr/mL to about 600 ng/hr/mL, about 500 ng/hr/mL to about 525 ng/hr/mL, about 600 ng/hr/mL at least about 600 ng/hr/mL, at least about 650 ng/hr/mL, at least about 700 ng/hr/mL, at least about 750 ng/hr/mL, at least about 800 ng/hr/mL, about 800 ng/hr/mL to about 900 ng/hr/mL, about 850 ng/hr/mL to about 875 ng/hr/mL, about 875 ng/hr to about 900 ng/hr/mL, about 900 ng/hr/mL to about 1000 ng/hr, about 1000 ng/hr/mL to about 1100 ng/hr/mL, about 1100 ng/hr/mL to about 1200 ng/hr/mL, about 1200 ng/hr/mL to about 1300 ng/hr/mL, about 1400 ng/hr/mL to about 1500 ng/hr/mL, about 1600 ng/hr/mL ng.hr/mL to about 1700 ng.hr/mL, about 1700 ng.hr/mL to about 1800 ng.hr/mL, about 1800 ng.hr/mL to about 2000 ng.hr/mL, at least about 850 ng.hr/mL, at least about 900 ng.hr/mL, at least about 950 ng.hr/mL, at least about 1000 ng.hr/mL, at least about 1050 ng.hr/mL, at least about 1100 ng.hr/mL, at least about 1150 ng.hr/mL, at least about 1200 ng.hr/mL, at least about 1250 ng.hr/mL, at least about 1300 ng.hr/mL, at least about 1350 ng.hr/mL, at least about 1400 ng.hr/mL, at least about 1450 ng.hr/mL, at least about 1500 ng.hr/mL, at least about 1550 ng.hr/mL, at least about 1600 ng.hr/mL, at least about 1625 ng.hr/mL, at least about 1650.hr/mL, at least about 1675 ng.hr/mL, or at least about 1686.3.hr/mL, and may be implemented in a manner of at most about 500 ng.hr/mL.
In some embodiments, the dextromethorphan AUC is increased (e.g., by co-administering dextromethorphan with an antidepressant) on the ninth day of increasing dextromethorphan plasma levels 0-24 Can be at least about 50 ng.hr/mL, at least about 75 ng.hr/mL, at least about 100 ng.hr/mL, at least about 200 ng.hr/mL, at least about 300 ng.hr/mL, at least about 400 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 1000 ng.hr/mL, at least about 1100 ng.hr/mL, at least about 1200 ng.hr/mL, at least about 1300 ng.hr/mL, at least about 1400 ng.hr/mL, at least about 1500 ng.hr/mL at least about 1600 ng-hr/mL, at least about 1700 ng-hr/mL, at least about 1800 ng-hr/mL, at least about 1900 ng-hr/mL, at least about 2000 ng-hr/mL, at least about 2100 ng-hr/mL, at least about 2200 ng-hr/mL, at least about 2300 ng-hr/mL, at least about 2400 ng-hr/mL, at least about 2500 ng-hr/mL, at least about 2600 ng-hr/mL, at least about 2700 ng-hr/mL, at least about 2800 ng-hr/mL, at least about 1850 ng-hr/mL, at least about 2900 ng-hr/mL, at least about 2950 ng-hr/mL, or at least about 2975.3 ng-hr/mL, and in some embodiments may be at most about 100000 ng-hr/mL.
In some embodiments, the dextromethorphan AUC is increased (e.g., by co-administering dextromethorphan with an antidepressant) on the ninth day of increasing dextromethorphan plasma levels 0-inf Can be at least about 75 ng-hr/mL, at least about 100 ng-hr/mL, at least about 200 ng-hr/mL,At least about 300 ng-hr/mL, at least about 400 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 1000 ng-hr/mL, at least about 1100 ng-hr/mL, at least about 1200 ng-hr/mL, at least about 1300 ng-hr/mL, at least about 1400 ng-hr/mL, at least about 1500 ng-hr/mL, at least about 1600 ng-hr/mL, at least about 1700 ng-hr/mL, at least about 1800 ng-hr/mL, at least about 1900 ng-hr/mL, at least about 2000 ng-hr/mL, at least about 2100 ng-hr/mL, at least about 2300 ng-hr/mL, at least about 2400 ng-hr/mL, at least about 2500 ng-hr/mL, at least about 2600 ng-hr/mL at least about 2700 ng/hr/mL, at least about 2800 ng/hr/mL, at least about 2900 ng/hr/mL, at least about 3000 ng/hr/mL, at least about 3100 ng/hr/mL, at least about 3200 ng/hr/mL, at least about 3300 ng/hr/mL, at least about 3400 ng/hr/mL, at least about 3500 ng/hr/mL, at least about 3600 ng/hr/mL, at least about 3700 ng/hr/mL, at least about 3800 ng/hr/mL, at least about 3900 ng/hr/mL, at least about 4000 ng/hr/mL, at least about 4100 ng/hr/mL, at least about 4200 ng/hr/mL, at least about 4300 ng/hr/mL, at least about 4400 ng/hr/mL, at least about 4500 ng/hr/mL, at least about 4600 ng/hr/mL, at least about 4700 ng/hr/mL, at least about 4800 ng/hr/mL, at least about 4900 ng/hr/mL, at least about 5000 ng.hr/mL, at least about 5100 ng.hr/mL, at least about 5200 ng.hr/mL, at least about 5300 ng.hr/mL, at least about 5400 ng.hr/mL, at least about 5500 ng.hr/mL, at least about 5600 ng.hr/mL, at least about 5700 ng.hr/mL, at least about 5800 ng.hr/mL, at least about 5900 ng.hr/mL, at least about 6000 ng.hr/mL, at least about 6100 ng.hr/mL, at least about 6200 ng.hr/mL, at least about 6300 ng.hr/mL, at least about 6400 ng.hr/mL, at least about 6500 ng.hr/mL, at least about 6600 ng.hr/mL, at least about 6700 ng.hr/mL, at least about 6800 ng.hr/mL, at least about 6900.hr/mL, at least about 7000.hr/mL, at least about 7100 ng.hr/mL, at least about 50 ng.hr/mL, at least about 7100 ng.hr/mL, at least about 7200 ng.hr/mL, or at least about 62 ng.6.g.hr/mL, and up to a certain mode of 100000 ng.hr/mL.
In some embodiments, the dextromethorphan AUC is increased (e.g., by co-administering dextromethorphan with an antidepressant) on the tenth day of increasing dextromethorphan plasma levels 0-12 Can be at least about 40 ng/hr/mL, at least about 50 ng/hr/mL, at least about 60 ng/hr/mL, at least about 70 ng/hr/mL, at least about 80 ng/hr/mL, at least about 90 ng/hr/mL, at least about 100 ng/hr/mL, at least about 150 ng/hr/mL, at least about 200 ng/hr/mL, at least about 250 ng/hr/mL, at least about 300 ng/hr/mL, at least about 350 ng/hr/mL, at least about 400 ng/hr/mL, at least about 450 ng/hr/mL, at least about 500 ng/hr/mL, at least about 550 ng/hr/mL, about 500 ng/hr/mL to about 600 ng/hr/mL, about 500 ng/hr/mL to about 525 ng/hr/mL, about 600 ng/hr/mL, at least about 600 ng/hr/mL at least about 650 ng.hr/mL, at least about 700 ng.hr/mL, at least about 750 ng.hr/mL, at least about 800 ng.hr/mL, about 800 ng.hr/mL to about 900 ng.hr/mL, about 850 ng.hr/mL to about 875 ng.hr/mL, about 875 ng.hr/mL to about 900 ng.hr/mL, about 900 ng.hr/mL to about 1,000 ng.hr/mL, about 1,000 ng.hr/mL to about 1,100 ng.hr/mL, about 1,100 ng.hr/mL to about 1,200 ng.hr/mL, about 1,300 ng.hr/mL to about 1,400 ng.hr/mL, about 1,400.hr/mL, about 1,500 ng.hr/mL to about 600 ng.hr/mL, about 600 ng.hr/mL to about 1,600 ng.hr/mL, about 600 ng.hr/mL, about 1,700ng hr/mL to about 1,800ng hr/mL, about 1,800ng hr/mL to about 2,000ng hr/mL, at least about 850ng hr/mL, at least about 900ng hr/mL, at least about 950ng hr/mL, at least about 1000ng hr/mL, at least about 1050ng hr/mL, at least about 1100ng hr/mL, at least about 1150ng hr/mL, at least about 1200ng hr/mL, at least about 1250ng hr/mL, at least about 1300ng hr/mL, at least about 1350ng hr/mL, at least about 1400ng hr/mL, at least about 1450ng hr/mL, at least about 1500ng hr/mL, at least about 1550ng hr/mL, at least about 1600ng hr/mL, at least about 1625ng hr/mL, at least about 1655 ng hr/mL, or at least about 1686.3ng hr/mL, and in some embodiments may be at most about 50ng hr/mL.
In some embodiments, the dextromethorphan AUC is increased (e.g., by co-administering dextromethorphan with an antidepressant) on the tenth day of increasing dextromethorphan plasma levels 0-24 Can be at least about 50ng hr/mL, at least about 75ng hr/mL, at least about 100ng hr/mL, at least about 200ngAt least about 300 ng-hr/mL, at least about 400 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 1000 ng-hr/mL, at least about 1100 ng-hr/mL, at least about 1200 ng-hr/mL, at least about 1300 ng-hr/mL, at least about 1400 ng-hr/mL, at least about 1500 ng-hr/mL, at least about 1600 ng-hr/mL, at least about 1700 ng-hr/mL, at least about 1800 ng-hr/mL, at least about 1900 ng-hr/mL, at least about 2000 ng-hr/mL, at least about 2100 ng-hr/mL, at least about 900 ng-hr/mL, at least about 400 ng-hr/mL, at least about 2400 ng-hr/mL, at least about 2500 ng-hr/mL, at least about 2600 ng-hr/mL, at least about 2700 ng-hr/mL, at least about 280 ng-hr/mL, at least about 300 ng-0, at least about 300 ng-hr/mL, at least about 200 ng-0, at least about 300 ng-0, at least about 200 ng-52 ng-mL, at least about 200 ng-0, at least about 200 ng-mL, at least about 200 ng-0, or at least.
In some embodiments, the dextromethorphan AUC is increased (e.g., by co-administering dextromethorphan with an antidepressant) on the tenth day of increasing dextromethorphan plasma levels 0-inf Can be at least about 75 ng-hr/mL, at least about 100 ng-hr/mL, at least about 200 ng-hr/mL, at least about 300 ng-hr/mL, at least about 400 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 1000 ng-hr/mL, at least about 1100 ng-hr/mL, at least about 1200 ng-hr/mL, at least about 1300 ng-hr/mL, at least about 1400 ng-hr/mL, at least about 1500 ng-hr/mL, at least about 1600 ng-hr/mL, at least about 1700 ng-hr/mL, at least about 1800 ng-hr/mL, at least about 1900 ng-hr/mL, at least about 2000 ng-hr/mL at least about 2100ng hr/mL, at least about 2200ng hr/mL, at least about 2300ng hr/mL, at least about 2400ng hr/mL, at least about 2500ng hr/mL, at least about 2600ng hr/mL, at least about 2700ng hr/mL, at least about 2800ng hr/mL, at least about 2900ng hr/mL, at least about 3000ng hr/mL, at least about 3100ng hr/mL, at least about 3200ng hr/mL, at least about 3300ng hr/mL, at least about 3400ng hr/mL, at least about 3500ng hr/mL, at least about 3600ng hr/mL, at least about 3700ng hr/mL, at least about 3800ng hr/mL, at least about 3900ng hr/mL, at least about 4000ng hr/mL, at least about 4100n g.hr/mL, at least about 4200 ng.hr/mL, at least about 4300 ng.hr/mL, at least about 4400 ng.hr/mL, at least about 4500 ng.hr/mL, at least about 4600 ng.hr/mL, at least about 4700 ng.hr/mL, at least about 4800 ng.hr/mL, at least about 4900 ng.hr/mL, at least about 5000 ng.hr/mL, at least about 5100 ng.hr/mL, at least about 5200 ng.hr/mL, at least about 5300 ng.hr/mL, at least about 5400 ng.hr/mL, at least about 5500 ng.hr/mL, at least about 5600 ng.hr/mL, at least about 5700 ng.hr/mL at least about 5800 ng.hr/mL, at least about 5900 ng.hr/mL, at least about 6000 ng.hr/mL, at least about 6100 ng.hr/mL, at least about 6200 ng.hr/mL, at least about 6300 ng.hr/mL, at least about 6400 ng.hr/mL, at least about 6500 ng.hr/mL, at least about 6600 ng.hr/mL, at least about 6700 ng.hr/mL, at least about 6800 ng.hr/mL, at least about 6900 ng.hr/mL, at least about 7000 ng.hr/mL, at least about 7100 ng.hr/mL, at least about 7150 ng.hr/mL, at least about 7200 ng.hr/mL, or at least about 7237.3 ng-hr/mL, and in some embodiments may be at most about 100000 ng-hr/mL.
In some embodiments, dextromethorphan C is on the first day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with an antidepressant) max May be C obtained if dextromethorphan is administered in the same amount without an antidepressant max At least 2 times greater than the above.
In some embodiments, dextromethorphan C is on the first day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with an antidepressant) max Can be at least about 1.0ng/mL, at least about 1.5ng/mL, at least about 2.0ng/mL, at least about 2.5ng/mL, at least about 3.0ng/mL, at least about 3.1ng/mL, at least about 3.2ng/mL, at least about 3.3ng/mL, at least about 3.4ng/mL, at least about 3.5ng/mL, at least about 3.6ng/mL, at least about 3.7ng/mL, at least about 3.8ng/mL, at least about 3.9ng/mL, at least about 4.0ng/mL, at least about 4.1ng/mL, at least about 4.2ng/mL, at least about 4.3ng/mL, at least about 4.4ng/mL, at least about 4.5ng/mL, at least about 4.6ng/mL, at least about 4.7ng/mL, at least about 4.8ng/mL, at least about 4.9ng/mL, at least about 5.0ng/mL, at least about 5.1.7 ng/mL, at least about 5.5ng/mL, at least about 5.5.5 ng/mL, at least about 5.5.1 ng/mL, at least about 5.5.2 ng/mL, at least about 5.5.5 ng/mL, at least about 5.3.5 ng/mL, at least about 5.1ng/mL, at leastg/mL, at least about 5.9ng/mL, at least about 6.0ng/mL, at least about 6.1ng/mL, at least about 6.2ng/mL, at least about 6.3ng/mL, at least about 6.4ng/mL, at least about 6.5ng/mL, at least about 6.6ng/mL, at least about 6.7ng/mL, at least about 6.8ng/mL, at least about 6.9ng/mL, at least about 7.0ng/mL, at least about 7.1ng/mL, at least about 7.2ng/mL, at least about 7.3ng/mL, at least about 7.4ng/mL, at least about 7.5ng/mL, at least about 7.6ng/mL, at least about 7.7ng/mL, at least about 7.8ng/mL, at least about 7.9ng/mL, at least about 8.0ng/mL, at least about 8.1ng/mL, at least about 8.2ng/mL, at least about 8.3ng/mL, at least about 8.4ng/mL, at least about 8.5ng/mL, and may be implemented in any of the manner of at least about 1000 ng/mL.
In some embodiments, dextromethorphan C is increased on the eighth day of increasing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with an antidepressant) max Can be about 50 to about 60ng/mL, about 50 to about 55ng/mL, about 55 to about 60ng/mL, about 80 to about 90ng/mL, about 80 to about 85ng/mL, about 85 to about 90ng/mL, about 90 to about 95ng/mL, about 95 to about 100ng/mL, about 100 to about 105ng/mL, about 105 to about 110ng/mL, about 110 to about 115ng/mL, about 115 to about 120ng/mL, about 120 to about 130ng/mL, about 130 to about 135ng/mL, about 140 to about 140ng/mL, about 140 to about 145ng/mL, about 145 to about 150, about 150 to about 155ng/mL, about 155 to about 160ng/mL about 160 to about 170ng/mL, about 170 to about 200ng/mL, at least about 6.0ng/mL, at least about 7.0ng/mL, at least about 8.0ng/mL, at least about 9.0ng/mL, at least about 10ng/mL, at least about 15ng/mL, at least about 20ng/mL, at least about 25ng/mL, at least about 30ng/mL, at least about 35ng/mL, at least about 40ng/mL, at least about 45ng/mL, at least about 50ng/mL, at least about 55ng/mL, at least about 60ng/mL, at least about 65ng/mL, at least about 70ng/mL, at least about 75ng/mL, at least about 80ng/mL, at least about 85ng/mL, at least about 90ng/mL, at least about 95ng/mL, at least about 100ng/mL, at least about 105ng/mL, at least about 110ng/mL, at least about 115ng/mL, at least about 120ng/mL, at least about 125ng/mL, at least about 130ng/mL, at least about 135ng/mL, at least about 140ng/mL, at least about 145ng/mL, at least about About 150ng/mL, at least about 155ng/mL, or at least about 158.1ng/mL, and in some embodiments may be at most about 10000ng/mL.
In some embodiments, dextromethorphan C is increased (e.g., by co-administering dextromethorphan with an antidepressant) on the ninth day of increasing dextromethorphan plasma levels max Can be about 50 to about 60ng/mL, about 50 to about 55ng/mL, about 55 to about 60ng/mL, about 80 to about 90ng/mL, about 80 to about 85ng/mL, about 85 to about 90ng/mL, about 90 to about 95ng/mL, about 95 to about 100ng/mL, about 100 to about 105ng/mL, about 105 to about 110ng/mL, about 110 to about 115ng/mL, about 115 to about 120ng/mL, about 120 to about 130ng/mL, about 130 to about 135ng/mL, about 140 to about 140ng/mL, about 140 to about 145ng/mL, about 145 to about 150, about 150 to about 155ng/mL, about 155 to about 160ng/mL about 160 to about 170ng/mL, about 170 to about 200ng/mL, at least about 6.0ng/mL, at least about 7.0ng/mL, at least about 8.0ng/mL, at least about 9.0ng/mL, at least about 10ng/mL, at least about 15ng/mL, at least about 20ng/mL, at least about 25ng/mL, at least about 30ng/mL, at least about 35ng/mL, at least about 40ng/mL, at least about 45ng/mL, at least about 50ng/mL, at least about 55ng/mL, at least about 60ng/mL, at least about 65ng/mL, at least about 70ng/mL, at least about 75ng/mL, at least about 80ng/mL, at least about 85ng/mL, at least about 90ng/mL, at least about 95ng/mL, at least about 100ng/mL, at least about 105ng/mL, at least about 110ng/mL, at least about 115ng/mL, at least about 120ng/mL, at least about 125ng/mL, at least about 130ng/mL, at least about 135ng/mL, at least about 140ng/mL, at least about 145ng/mL, at least about 150ng/mL, at least about 155ng/mL, or at least about 158.1ng/mL, and in some embodiments may be at most about 10000ng/mL.
In some embodiments, dextromethorphan C is increased (e.g., by co-administering dextromethorphan with an antidepressant) on the tenth day of increasing dextromethorphan plasma levels max Can be about 50ng/mL to about 60ng/mL, about 50ng/mL to about 55ng/mL, about 55ng/mL to about 60ng/mL, about 80ng/mL to about 90ng/mL, about 80ng/mL to about 85ng/mL, about 85ng/mL to about 90ng/mL, about 90ng/mL to about 95ng/mL, about 95ng/mL to about 100ng/mL, about 100ng/mL to about 105ng/mL, about 105ng/mL to about 110ng/mL, about 110ng/mL to about 115ng/mL, about 115ng/mL to about 120ng/mL, about 120ng/mL to about 130ng/mL, about 130ng/mL to about 135ng/mL, about 135ng/mL to about 140ng/mL, about 140ng/mL to about 145ng/mL, about 145ng/mL to about 150ng/mL, about 150ng/mL to about 155ng/mL, about 155ng/mL to about 160ng/mL, about 160ng/mL to about 170ng/mL, about 170ng/mL to about 200ng/mL, at least about 6.0ng/mL, at least about 7.0ng/mL, at least about 8.0ng/mL, at least about 9.0ng/mL, at least about 10ng/mL, at least about 15ng/mL, at least about 20ng/mL, at least about 25ng/mL, at least about at least about 30ng/mL, at least about 35ng/mL, at least about 40ng/mL, at least about 45ng/mL, at least about 50ng/mL, at least about 55ng/mL, at least about 60ng/mL, at least about 65ng/mL, at least about 70ng/mL, at least about 75ng/mL, at least about 80ng/mL, at least about 85ng/mL, at least about 90ng/mL, at least about 95ng/mL, at least about 100ng/mL, at least about 105ng/mL, at least about 110ng/mL, at least about 115ng/mL, at least about 120ng/mL, at least about 125ng/mL, at least about 130ng/mL, at least about 135ng/mL, at least about 140ng/mL, at least about 145ng/mL, at least about 150ng/mL, at least about 155ng/mL, or at least about 158.1ng/mL, and in some embodiments may be up to about 10000ng/mL.
In some embodiments, to result in dextromethorphan C in the period between two separate and consecutive dextromethorphan administrations avg Antidepressants in combination with dextromethorphan are administered in the following amounts: at least about 4.0ng/mL, at least about 5.0ng/mL, at least about 6.0ng/mL, at least about 7.0ng/mL, at least about 8.0ng/mL, at least about 9.0ng/mL, at least about 10ng/mL, at least about 15ng/mL, at least about 20ng/mL, at least about 25ng/mL, at least about 30ng/mL, at least about 35ng/mL, at least about 40ng/mL, at least about 45ng/mL, at least about 50ng/mL, at least about 55ng/mL, at least about 60ng/mL, at least about 65ng/mL, at least about 70ng/mL, at least about 75ng/mL, at least about 80ng/mL, at least about 85ng/mL, at least about 90ng/mL, at least about 95ng/mL, at least about 100ng/mL, at least about 105ng/mL, at least about 110ng/mL, at least about 115ng/mL, at least about 120ng/mL, at least about 130ng/mL, at least about 135ng/mL, at least about 140ng to about 30ng/mL, at least about 40ng/mL40 to about 50, about 50 to about 55, about 55 to about 60, about 80 to about 90, about 80 to about 140, about 140 to about 145, about 145 to about 150, about 150 to about 155, about 155 to about 160, about 160 to about 170, about 200, and the like may be implemented in some ways. For example, if dextromethorphan is administered at 8 am and 8 pm on day 1 and is not administered after 8 am and before 8 pm on day 1, the period between two separate and consecutive administrations of dextromethorphan is immediately after 8 am to immediately before 8 pm on day 1.
In some embodiments, dextromethorphan C is increased on the eighth day of increasing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with an antidepressant) avg Can be at least about 4.0ng/mL, at least about 5.0ng/mL, at least about 6.0ng/mL, at least about 7.0ng/mL, at least about 8.0ng/mL, at least about 9.0ng/mL, at least about 10ng/mL, at least about 15ng/mL, at least about 20ng/mL, at least about 25ng/mL, at least about 30ng/mL, at least about 35ng/mL, at least about 40ng/mL, at least about 45ng/mL, at least about 50ng/mL, at least about 55ng/mL, at least about 60ng/mL, at least about 65ng/mL, at least about 70ng/mL, at least about 75ng/mL, at least about 80ng/mL, at least about 85ng/mL, at least about 90ng/mL, at least about 95ng/mL, at least about 100ng/mL at least about 105ng/mL, at least about 110ng/mL, at least about 115ng/mL, at least about 120ng/mL, at least about 125ng/mL, at least about 130ng/mL, at least about 135ng/mL, at least about 140ng/mL, or at least about 140.5ng/mL, about 20ng/mL to about 30ng/mL, about 30ng/mL to about 40ng/mL, about 40ng/mL to about 50ng/mL, about 50ng/mL to about 55ng/mL, about 55ng/mL to about 60ng/mL, about 80ng/mL to about 90ng/mL, about 80ng/mL to about 85ng/mL, about 85ng/mL to about 90ng/mL, about 90ng/mL to about 95ng/mL, about 95ng/mL to about 100ng/mL, about 100n g/mL to about 105ng/mL, about 105ng/mL to about 110ng/mL, about 110ng/mL to about 115ng/mL, about 115ng/mL to about 120ng/mL, about 120ng/mL to about 130ng/mL, about 130ng/mL to about 135ng/mL, about 135ng/mL to about 140ng/mL, about 140ng/mL to about 145ng/mL, about 145ng/mL to about 150ng/mL, about 150ng/mL to about 155ng/mL, about 155ng/mL to about 160ng/mL, about 160ng/mL to about 170ng/mL, about 170ng/mL to about 200ng/mL, and in some embodiments may be up to about 10000ng/mL. C given above avg The value may be for the period between two separate and consecutive administrations of dextromethorphan, or C if dextromethorphan is administered only once on day 8 avg Can be targeted 12 hours after the first dose of dextromethorphan.
In some embodiments, dextromethorphan C is increased (e.g., by co-administering dextromethorphan with an antidepressant) on the ninth day of increasing dextromethorphan plasma levels avg Can be at least about 4.0ng/mL, at least about 5.0ng/mL, at least about 6.0ng/mL, at least about 7.0ng/mL, at least about 8.0ng/mL, at least about 9.0ng/mL, at least about 10ng/mL, at least about 15ng/mL, at least about 20ng/mL, at least about 25ng/mL, at least about 30ng/mL, at least about 35ng/mL, at least about 40ng/mL, at least about 45ng/mL, at least about 50ng/mL, at least about 55ng/mL, at least about 60ng/mL, at least about 65ng/mL, at least about 70ng/mL, at least about 75ng/mL, at least about 80ng/mL, at least about 85ng/mL, at least about 90ng/mL, at least about 95ng/mL, at least about 100ng/mL, at least about 105ng/mL, at least about 110ng/mL, at least about 115ng/mL, at least about at least about 120ng/mL, at least about 125ng/mL, at least about 130ng/mL, at least about 135ng/mL, at least about 140ng/mL, or at least about 140.5ng/mL, about 20ng/mL to about 30ng/mL, about 30ng/mL to about 40ng/mL, about 40ng/mL to about 50ng/mL, about 50ng/mL to about 55ng/mL, about 55ng/mL to about 60ng/mL, about 80ng/mL to about 90ng/mL, about 80ng/mL to about 85ng/mL, about 85ng/mL to about 90ng/mL, about 90ng/mL to about 95ng/mL, about 95ng/mL to about 100ng/mL, about 100ng/mL to about 105ng/mL, about 105ng/mL to about 110ng/mL, about 110ng/mL to about 115ng/mL, about 115ng/mL to about 120ng/mL, about 120ng/mL to about 130ng/mL, about 130ng/mL to about 135ng/mL, about 135ng/mL to about 140ng/mL, about 140ng/mL to about 145ng/mL, about 145ng/mL to about 150ng/mL, about 150ng/mL to about 15 5ng/mL, about 155ng/mL to about 160ng/mL, about 160ng/mL to about 170ng/mL, about 170ng/mL to about 200ng/mL, and in some embodiments may be up to about 10000ng/mL. C given above avg The value may be for the period between two separate and consecutive administrations of dextromethorphan, or C if dextromethorphan is administered only once on day 9 avg Can be targeted 12 hours after the first dose of dextromethorphan.
In some embodiments, dextromethorphan C is increased (e.g., by co-administering dextromethorphan with an antidepressant) on the tenth day of increasing dextromethorphan plasma levels avg Can be at least about 4.0ng/mL, at least about 5.0ng/mL, at least about 6.0ng/mL, at least about 7.0ng/mL, at least about 8.0ng/mL, at least about 9.0ng/mL, at least about 10ng/mL, at least about 15ng/mL, at least about 20ng/mL, at least about 25ng/mL, at least about 30ng/mL, at least about 35ng/mL, at least about 40ng/mL, at least about 45ng/mL, at least about 50ng/mL, at least about 55ng/mL, at least about 60ng/mL, at least about 65ng/mL, at least about 70ng/mL, at least about 75ng/mL, at least about 80ng/mL, at least about 85ng/mL, at least about 90ng/mL, at least about 95ng/mL, at least about 100ng/mL, at least about 105ng/mL, at least about 110ng/mL, at least about 115ng/mL, at least about at least about 120ng/mL, at least about 125ng/mL, at least about 130ng/mL, at least about 135ng/mL, at least about 140ng/mL, or at least about 140.5ng/mL, about 20ng/mL to about 30ng/mL, about 30ng/mL to about 40ng/mL, about 40ng/mL to about 50ng/mL, about 50ng/mL to about 55ng/mL, about 55ng/mL to about 60ng/mL, about 80ng/mL to about 90ng/mL, about 80ng/mL to about 85ng/mL, about 85ng/mL to about 90ng/mL, about 90ng/mL to about 95ng/mL, about 95ng/mL to about 100ng/mL, about 100ng/mL to about 105ng/mL, about 105ng/mL to about 110ng/mL, about 110ng/mL to about 115ng/mL, about 115ng/mL to about 120ng/mL, about 120ng/mL to about 130ng/mL, about 130ng/mL to about 135ng/mL, about 135ng/mL to about 140ng/mL, about 140ng/mL to about 145ng/mL, about 145ng/mL to about 150ng/mL, about 150ng/mL to about 155ng/mL, about 155ng/mL to about 160ng/mL, about 160ng/mL to about 170ng/mL, about 170ng/mL to about 200ng/mL, and in some embodiments may be up to about 10000ng/mL. C given above avg The value may be for the period between two separate and consecutive administrations of dextromethorphan, orC if dextromethorphan is administered only once on day 10 avg Can be targeted 12 hours after the first dose of dextromethorphan.
The dextromethorphan fluctuation index value FI (%) can be determined by the following equation:
in some embodiments, on the eighth day of increasing the plasma level of dextromethorphan (e.g., by co-administering dextromethorphan with an antidepressant), dextromethorphan FI (%) can be at least 1.5-fold or at least 2-fold reduced as compared to the plasma level increase obtained by eight days of administration of dextromethorphan without, e.g., co-administering dextromethorphan with an antidepressant.
In some embodiments, on the ninth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with an antidepressant), dextromethorphan FI (%) can be at least 1.5-fold or at least 2-fold reduced as compared to the plasma level enhancement obtained by nine days of dextromethorphan administration without, e.g., co-administering dextromethorphan with an antidepressant.
In some embodiments, on the tenth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with an antidepressant), dextromethorphan FI (%) can be at least 1.5-fold or at least 2-fold reduced as compared to the ten days of dextromethorphan administration without, for example, the plasma level enhancement obtained by co-administering dextromethorphan with an antidepressant.
In some embodiments, on the eighth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with an antidepressant), dextromethorphan FI (%) can be less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any FI (%) value within a range defined by any of these values.
In some embodiments, on the ninth day of enhancing the plasma level of dextromethorphan (e.g., by co-administering dextromethorphan with an antidepressant), dextromethorphan FI (%) can be less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any FI (%) value within a range defined by any of these values.
In some embodiments, on the ninth day of enhancing the plasma level of dextromethorphan (e.g., by co-administering dextromethorphan with an antidepressant), dextromethorphan FI (%) can be less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any FI (%) value within a range defined by any of these values.
In some embodiments, on the eighth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with an antidepressant), dextrorphan FI (%) may be reduced by at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or at least 6-fold as compared to the plasma level enhancement obtained by eight days of dextromethorphan administration without, e.g., co-administering dextromethorphan with an antidepressant.
In some embodiments, on the ninth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with an antidepressant), dextrorphan FI (%) may be reduced by at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or at least 6-fold as compared to the plasma level enhancement obtained by nine days of administration of dextromethorphan without, e.g., co-administering dextromethorphan with an antidepressant.
In some embodiments, on the tenth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with an antidepressant), dextrorphan FI (%) may be reduced by at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or at least 6-fold as compared to the plasma level enhancement obtained by ten days of administration of dextromethorphan without, e.g., co-administering dextromethorphan with an antidepressant.
In some embodiments, on the eighth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with an antidepressant), dextrorphan FI (%) can be less than 100%, less than 70%, less than 60%, less than 50%, less than 40%, about 30-70%, about 30-60%, about 30-50%, or any FI (%) value within a range defined by any of these values.
In some embodiments, on the ninth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with an antidepressant), dextrorphan FI (%) can be less than 100%, less than 70%, less than 60%, less than 50%, less than 40%, about 30-70%, about 30-60%, about 30-50%, or any FI (%) value within a range defined by any of these values.
In some embodiments, on the ninth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with an antidepressant), dextrorphan FI (%) can be less than 100%, less than 70%, less than 60%, less than 50%, about 30-70%, about 30-60%, about 30-50%, or any FI (%) value within a range defined by any of these values.
In some embodiments, on the first day of administration of dextromethorphan with an antidepressant, dextromethorphan Sha Fengu levels (e.g., plasma levels 12 hours after administration, also referred to herein as "C min ") may be at least 2 times the trough level if administered in the same amount of dextromethorphan without antidepressant.
In some embodiments, dextromethorphan C is on the first day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with an antidepressant) min May be at least about 0.8ng/mL, at least about 0.9ng/mL, at least about 1.0ng/mL, at least about 1.1ng/mL, at least about 1.2ng/mL, at least about 1.3ng/mL, at least about 1.4ng/mL, at least about 1.5ng/mL, at least about 1.6ng/mL, at least about 1.7ng/mL, at least about 1.8ng/mL, at least about 1.9ng/mL, at least about 2.0ng/mL, at least about 2.1ng/mL, at least about 2.2ng/mL, at least about 2.3ng/mL, at least about 2.4ng/mL, at least about 2.5ng/mL, or at least about 2.5ng/mL, and may be at most about 100ng/mL.
In some embodiments, dextromethorphan C is increased on the fifth day of enhancing dextromethorphan plasma levels (e.g., by co-administering dextromethorphan with an antidepressant) min May be at least about 1.5ng/mL, at least about 2.0ng/mL, at least about 3.0ng/mL, at least about 4.0ng/mL, at least about 5.0ng/mL, at least about 6.0ng/mL, at least about 7.0ng/mL, at least about 8.0ng/mL, at least about 9.0ng/mL, at least about10ng/mL, at least about 15ng/mL, at least about 20ng/mL, at least about 25ng/mL, at least about 30ng/mL, at least about 35ng/mL, at least about 40ng/mL, at least about 45ng/mL, at least about 50ng/mL, at least about 55ng/mL, at least about 60ng/mL, at least about 65ng/mL, at least about 70ng/mL, at least about 75ng/mL, at least about 80ng/mL, or at least about 80.9ng/mL, and may be at most about 10000ng/mL.
In some embodiments, dextromethorphan C is increased (e.g., by co-administering dextromethorphan with an antidepressant) on the sixth day of increasing dextromethorphan plasma levels min May be at least about 1.5ng/mL, at least about 2.0ng/mL, at least about 3.0ng/mL, at least about 4.0ng/mL, at least about 5.0ng/mL, at least about 6.0ng/mL, at least about 7.0ng/mL, at least about 8.0ng/mL, at least about 9.0ng/mL, at least about 10ng/mL, at least about 15ng/mL, at least about 20ng/mL, at least about 25ng/mL, at least about 30ng/mL, at least about 35ng/mL, at least about 40ng/mL, at least about 45ng/mL, at least about 50ng/mL, at least about 55ng/mL, at least about 60ng/mL, at least about 65ng/mL, at least about 70ng/mL, at least about 75ng/mL, at least about 80ng/mL, at least about 85/mL, at least about 90ng/mL, at least about 95ng/mL, at least about 100ng/mL, or at least about 102.2ng/mL, and may be at most about 10000.
In some embodiments, dextromethorphan C is increased (e.g., by co-administering dextromethorphan with an antidepressant) on the seventh day of increasing dextromethorphan plasma levels min May be at least about 1.5ng/mL, at least about 2.0ng/mL, at least about 3.0ng/mL, at least about 4.0ng/mL, at least about 5.0ng/mL, at least about 6.0ng/mL, at least about 7.0ng/mL, at least about 8.0ng/mL, at least about 9.0ng/mL, at least about 10ng/mL, at least about 15ng/mL, at least about 20ng/mL, at least about 25ng/mL, at least about 30ng/mL, at least about 35ng/mL, at least about 40ng/mL, at least about 45ng/mL, at least about 50ng/mL, at least about 55ng/mL, at least about 60ng/mL, at least about 65ng/mL, at least about 70ng/mL, at least about 75ng/mL, at least about 80ng/mL, at least about 85/mL, at least about 90ng/mL, at least about 95ng/mL, at least about 100ng/mL, at least about 105ng/mL, at least about 110ng/mL, or at least about 110.6ng/mL, and may be at most about 110 ng/mL.
In some embodiments, the method is performed in (e.g., byCo-administration of dextromethorphan with an antidepressant) to enhance dextromethorphan plasma levels, dextromethorphan C min Can be at least about 1.5ng/mL, at least about 2.0ng/mL, at least about 3.0ng/mL, at least about 4.0ng/mL, at least about 5.0ng/mL, at least about 6.0ng/mL, at least about 7.0ng/mL, at least about 8.0ng/mL, at least about 9.0ng/mL, at least about 10ng/mL, at least about 15ng/mL, at least about 20ng/mL, at least about 25ng/mL, at least about 30ng/mL, at least about 35ng/mL, at least about 40ng/mL, at least about 45ng/mL, at least about 50ng/mL, at least about 55ng/mL, at least about 60ng/mL, at least about 65ng/mL, at least about 70ng/mL, at least about 75ng/mL, at least about 80ng/mL, at least about 85ng/mL, at least about 90ng/mL, at least about 95ng/mL, at least about 100ng/mL at least about 105ng/mL, at least about 110ng/mL, at least about 115ng/mL, at least about 119.3ng/mL, about 20ng/mL to about 30ng/mL, about 30ng/mL to about 40ng/mL, about 40ng/mL to about 50ng/mL, about 50ng/mL to about 55ng/mL, about 55ng/mL to about 60ng/mL, about 80ng/mL to about 90ng/mL, about 80ng/mL to about 85ng/mL, about 85ng/mL to about 90ng/mL, about 90ng/mL to about 95ng/mL, about 95ng/mL to about 100ng/mL, about 100ng/mL to about 105ng/mL, about 105ng/mL to about 110ng/mL, about 110ng/mL to about 115ng/mL, about 115ng/mL to about 120ng/mL, about 120ng/mL to about 130ng/mL, about 130ng/mL to about 135ng/mL, about 135ng/mL to about 140ng/mL, about 140ng/mL to about 145ng/mL, about 145ng/mL to about 150ng/mL, about 150ng/mL to about 155ng/mL, about 155ng/mL to about 160ng/mL, about 160ng/mL to about 170ng/mL, or about 170ng/mL to about 200ng/mL, and in some embodiments may be up to about 10000ng/mL.
In some embodiments, dextromethorphan C is increased (e.g., by co-administering dextromethorphan with an antidepressant) on the ninth day of increasing dextromethorphan plasma levels min Can be at least about 1.5ng/mL, at least about 2.0ng/mL, at least about 3.0ng/mL, at least about 4.0ng/mL, at least about 5.0ng/mL, at least about 6.0ng/mL, at least about 7.0ng/mL, at least about 8.0ng/mL, at least about 9.0ng/mL, at least about 10ng/mL, at least about 15ng/mL, at least about 20ng/mL, at least about 25ng/mL, at least about 30ng/mL, at least about 35ng/mL, at least about 40ng/mL, at least about 45ng/mL, at least about 50ng/mL, at least about 55ng/mL, at least about 60ng/mL, at least about 65ng/mL, at least about 70ng/mL, at least about 75ng/mL, at least about 80ng/mL, at least about 85ng/mL, at least about 90ng/mL, at least about 95ng/mL, at least about 100ng/mL, at least about 105ng/mL, at least about 110ng/mL, at least about 115ng/mL, at least about 119.3ng/mL, about 20ng/mL to about 30ng/mL, about 30ng/mL to about 40ng/mL, about 40ng/mL to about 50ng/mL, about 50ng/mL to about 55ng/mL, about 55ng/mL to about 60ng/mL, about 80ng/mL to about 90ng/mL, about 80ng/mL to about 85ng/mL, about 85ng/mL to about 90ng/mL, about 90ng/mL to about 95ng/mL, about 95ng/mL to about 100ng/mL, about 105ng/mL to about 110ng/mL, about 110ng to about 115ng/mL, about 135ng to about 115ng, about 135ng to about 120ng/mL, about 120ng to about 150ng/mL, about 130ng to about 150ng/mL, about 150ng to about 130ng/mL, about 150ng to about 150 ng/mL.
In some embodiments, dextromethorphan C is increased (e.g., by co-administering dextromethorphan with an antidepressant) on the tenth day of increasing dextromethorphan plasma levels min Can be at least about 1.5ng/mL, at least about 2.0ng/mL, at least about 3.0ng/mL, at least about 4.0ng/mL, at least about 5.0ng/mL, at least about 6.0ng/mL, at least about 7.0ng/mL, at least about 8.0ng/mL, at least about 9.0ng/mL, at least about 10ng/mL, at least about 15ng/mL, at least about 20ng/mL, at least about 25ng/mL, at least about 30ng/mL, at least about 35ng/mL, at least about 40ng/mL, at least about 45ng/mL, at least about 50ng/mL, at least about 55ng/mL, at least about 60ng/mL, at least about 65ng/mL, at least about 70ng/mL, at least about 75ng/mL, at least about 80ng/mL, at least about 85ng/mL at least about 90ng/mL, at least about 95ng/mL, at least about 100ng/mL, at least about 105ng/mL, at least about 110ng/mL, at least about 115ng/mL, at least about 119.3ng/mL, about 20ng/mL to about 30ng/mL, about 30ng/mL to about 40ng/mL, about 40ng/mL to about 50ng/mL, about 50ng/mL to about 55ng/mL, about 55ng/mL to about 60ng/mL, about 80ng/mL to about 90ng/mL, about 80ng/mL to about 85ng/mL, about 85ng/mL to about 90ng/mL, about 90ng/mL to about 95ng/mL, about 95ng/mL to about 100ng/mL, about 100ng/mL to about 105ng/mL, about 105ng/mL to about 110ng/mL, about 110ng/mL to about 115ng/mL mL, about 115ng/mL to about 120ng/mL, about 120ng/mL to about 130ng/mL, about 130ng/mL to about 135ng/mL, about 135ng/mL to about 140ng/mL, about 140ng/mL to about 145ng/mL, about 145ng/mL to about 150ng/mL, about 150ng/mL to about 155ng/mL, about 155ng/mL to about 160ng/mL, about 160ng/mL to about 170ng/mL, or about 170ng/mL to about 200ng/mL, and in some embodiments may be up to about 10000ng/mL.
In some embodiments, the antidepressant is administered on the first of at least two days of treatment with dextromethorphan, wherein a decrease in dextrorphan plasma levels occurs on the first day of co-administration of the antidepressant with dextromethorphan as compared to the same amount of dextromethorphan administered without the antidepressant. For example, the plasma level of dextrorphan on the first day may be reduced by at least 5% compared to the plasma level of dextrorphan that would be achieved by administering the same amount of dextromethorphan without the antidepressant.
In some embodiments, the antidepressant is co-administered with dextromethorphan for at least 5 consecutive days to a human in need of dextromethorphan treatment, wherein, on day 5, the dextromethorphan plasma level is higher than would be achieved if dextromethorphan were administered in the same amount for 5 consecutive days without the antidepressant. For example, dextromethorphan plasma levels at day 5 (e.g., 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) can be at least 5-fold, at least 10-fold, at least 20-fold, at least 40-fold, at least 50-fold, at least 60-fold, at least 65-fold, or up to about 500-fold that obtained if dextromethorphan is administered in the same amount for 5 days without an antidepressant.
In some embodiments, the antidepressant and dextromethorphan are co-administered to a human in need of treatment with dextromethorphan for at least 6 consecutive days, wherein, on day 6, the dextromethorphan plasma level is higher than that obtained if dextromethorphan were administered in the same amount for 6 consecutive days without the antidepressant. For example, dextromethorphan plasma levels at day 6 (e.g., 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) can be at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 75-fold, or up to about 500-fold that obtained if dextromethorphan is administered in the same amount for 6 consecutive days without an antidepressant.
In some embodiments, the antidepressant and dextromethorphan are co-administered to a human in need of treatment with dextromethorphan for at least 7 consecutive days, wherein, on day 7, the dextromethorphan plasma level is higher than that obtained if the same amount of dextromethorphan is administered for 7 consecutive days without the antidepressant. For example, dextromethorphan plasma levels at day 7 (e.g., 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) can be at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 70-fold, at least 80-fold, at least 90-fold, or up to about 500-fold that obtained if dextromethorphan is administered in the same amount for 7 consecutive days without an antidepressant.
In some embodiments, the antidepressant and dextromethorphan are co-administered for at least 8 consecutive days, wherein, on day 8, for example, 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after the administration of the antidepressant with dextromethorphan, the plasma level of dextromethorphan is at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, or up to about 1000-fold of the plasma level obtained if dextromethorphan is administered in the same amount for 8 consecutive days without the antidepressant.
In some embodiments, the antidepressant and dextromethorphan are co-administered to a human in need of treatment with dextromethorphan for at least 8 consecutive days, wherein, on day 8, the dextrorphan plasma level is lower than that obtained if dextromethorphan were administered in the same amount for 8 consecutive days without the antidepressant. For example, the dextrorphan plasma level at day 8 (e.g., 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% as compared to the dextrorphan plasma level obtained if dextromethorphan is administered in the same amount for 8 consecutive days without the antidepressant.
In some embodiments, the antidepressant and dextromethorphan are co-administered for at least nine consecutive days, wherein, on day nine, for example, 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after the administration of the antidepressant with dextromethorphan, the plasma level of dextromethorphan is at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, or up to about 1000-fold of the plasma level obtained if dextromethorphan is administered in the same amount for nine consecutive days without the antidepressant.
In some embodiments, the antidepressant and dextromethorphan are co-administered to a human in need of treatment with dextromethorphan for at least nine consecutive days, wherein, on day nine, the dextrorphan plasma level is lower than that obtained if dextromethorphan were administered in the same amount for nine consecutive days without the antidepressant. For example, the dextrorphan plasma level at day nine (e.g., 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% as compared to the dextrorphan plasma level obtained if dextromethorphan is administered in the same amount for nine consecutive days without the antidepressant.
In some embodiments, the antidepressant and dextromethorphan are co-administered for at least ten consecutive days, wherein, on day ten, for example, 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after the administration of the antidepressant with dextromethorphan, the plasma level of dextromethorphan is at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, or up to about 1000-fold of the plasma level obtained if dextromethorphan is administered in the same amount for ten consecutive days without the antidepressant.
In some embodiments, the antidepressant and dextromethorphan are co-administered to a human in need of treatment with dextromethorphan for at least ten consecutive days, wherein, on the tenth day, the dextrorphan plasma level is lower than that obtained if dextromethorphan were administered in the same amount for ten consecutive days without the antidepressant. For example, the blood plasma level of dextrorphan at day ten (e.g., 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% as compared to the blood plasma level of dextrorphan obtained if dextromethorphan is administered in the same amount for ten consecutive days without the antidepressant.
For compositions comprising dextromethorphan and an antidepressant, some liquids may comprise 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% 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 10% (w/v), from about 10% (w/v) to about 15% (w/v), from about 15% (w/v) to about 20% (w/v), from about 20% (w/v) to about 30% (w/v), from about 30% (w/v) to about 40% (w/v), or from about 40% (w/v) to about 50% (w/v) dextromethorphan in combination with an antidepressant, or an amount of any of these values between any of these values in the range or values.
Some solid compositions may comprise 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), about 80% (w/w) to about 90% (w/w) of dextromethorphan, and antidepressant combinations, or any amount in a range defined by any of these values or between any of these values.
The therapeutically effective amount of the therapeutic compound can vary depending on the circumstances. For example, in some cases the daily dose of dextromethorphan may be in the range of about 0.1mg to about 1000mg, about 40mg to about 1000mg, about 20mg to about 600mg, about 60mg to about 700mg, about 100mg to about 400mg, about 15mg to about 20mg, about 20mg to about 25mg, about 25mg to about 30mg, about 30mg to about 35mg, about 35mg to about 40mg, about 40mg to about 45mg, about 45mg to about 50mg, about 50mg to about 55mg, about 55mg to about 60mg, about 20mg to about 60mg, about 60mg to about 100mg, about 100mg to about 200mg, about 100mg to about 140mg, about 160mg to about 200mg, about 200mg to about 300mg, about 220mg to about 260mg, about 300mg to about 400mg, about 340mg to about 380mg, about 400mg to about 500mg, about 500mg to about 600mg, about 15mg, about 30mg, about 60mg, about 180mg, about 240mg, about 360mg, or any range therebetween. Dextromethorphan can be administered once a day; or twice daily or every 12 hours, 3 times daily, 4 times daily or 6 times daily, the amount administered being about half, one third, one fourth or one sixth of the daily dose, respectively.
In some embodiments: dextromethorphan in an amount of about 15 mg/day to about 60 mg/day, about 15 mg/day to about 30 mg/day, about 30 mg/day to about 45 mg/day, about 45 mg/day to about 60 mg/day, about 60 mg/day to about 100 mg/day, about 80 mg/day to about 110 mg/day, about 100 mg/day to about 150 mg/day, or about 100 mg/day to about 300 mg/day is administered to a human in need thereof.
The administration time of the antidepressant compound may be as long as is required to treat a neurological condition such as pain, depression, or cough. In some embodiments, the antidepressant compound and dextromethorphan are administered at least once a day, e.g., once or twice a day, for at least 1 day, at least 3 days, at least 5 days, at least 7 days, at least 8 days, at least 9 days, or at least 10 days, at least 14 days, at least 21 days, at least 28 days, at least 30 days, at least 35 days, at least 42 days, at least 60 days, at least 90 days, at least 6 months, at least 9 months, at least 180 days, at least 365 days, at least 18 months, at least 2 years, or more, up to 1 year, up to 18 months, up to 2 years, up to 3 years, up to 5 years, or more.
In some embodiments, co-administration of dextromethorphan with an antidepressant may occur once a day for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more days before co-administering dextromethorphan with an antidepressant twice a day.
The therapeutic compound may be formulated for oral administration, for example, with an inert diluent or an edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the diet of a diet. For oral therapeutic administration, the active compounds may be combined with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
Tablets, troches, pills, capsules and the like may also contain one or more of the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid and the like; lubricants such as magnesium stearate; sweeteners such as sucrose, lactose or saccharin; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain a liquid carrier in addition to materials of the type described above. A variety of 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 sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. It may be desirable that the materials in the dosage form or pharmaceutical composition be pharmaceutically pure and substantially non-toxic in the amounts employed.
Some compositions or dosage forms may be liquids, or may comprise a solid phase dispersed in a liquid.
The therapeutic compounds may be formulated for parenteral or intraperitoneal administration. Solutions of the active compounds as the free base or pharmacologically acceptable salts can be prepared by appropriate mixing with surfactants (e.g. hydroxypropylcellulose) in water. The dispersion may also have an oil dispersed in or in glycerin, liquid polyethylene glycol, and mixtures thereof. Under normal conditions of storage and use, these preparations may contain preservatives to prevent microbial growth.
In some embodiments, the human or patient is, or is selected to be, black or african americans.
In some embodiments, the human or patient is a white person, or is selected to be a white person.
In some embodiments, the human or patient is an asian or is selected as an asian.
In some embodiments, the human or patient is, or is selected as, a hawaiian resident or other pacific island citizen.
In some embodiments, the human or patient is, or is selected as, spanish or latin.
In some embodiments, the human or patient is or is selected as a american or alaska original resident.
In some embodiments, the human or patient is not spanish or latin, or is selected to be not spanish or latin.
Detailed description of the preferred embodiments
The following are examples of embodiments specifically contemplated by the inventors:
embodiment 1. A method of treating pain or a neurological and/or psychiatric disorder comprising administering to a human in need thereof a therapeutically effective amount of dextromethorphan in combination with an antidepressant compound.
Embodiment 2. A method of treating pain comprising administering to a person in need thereof a combination of an antidepressant compound and dextromethorphan.
Embodiment 3. A method of enhancing the pain relief performance of dextromethorphan comprising co-administering dextromethorphan and an antidepressant compound.
Embodiment 4. A method of increasing plasma levels of dextromethorphan in a human as a fast-metaboliser of dextromethorphan comprising co-administering an antidepressant compound to a human receiving a treatment comprising dextromethorphan administration.
Embodiment 5. A method of inhibiting dextromethorphan metabolism comprising administering an antidepressant compound to a human, wherein the human is a fast metaboliser of dextromethorphan, and wherein dextromethorphan is present in the human concurrently with the antidepressant compound.
Embodiment 6. A method of increasing the metabolic life of dextromethorphan comprising administering an antidepressant compound to a human, wherein the human is a fast metaboliser of dextromethorphan, and wherein dextromethorphan is present in the human concurrently with the antidepressant compound.
Embodiment 7. A method of correcting rapid metabolism of dextromethorphan comprising administering an antidepressant compound to a person in need thereof.
Embodiment 8. A method of improving the pain relief performance of dextromethorphan comprising administering an antidepressant compound to a person in need of treatment for pain in combination with the administration of dextromethorphan.
Embodiment 9. A method of improving the antitussive properties of dextromethorphan comprising administering an antidepressant compound to a person in need of treatment for cough in combination with the administration of dextromethorphan.
Embodiment 10. A method of treating cough comprising administering to a person in need thereof a combination of an antidepressant compound and dextromethorphan.
Embodiment 11. A method of improving the therapeutic properties of dextromethorphan comprising administering an antidepressant compound to a person in need of treatment for a neurological and/or psychiatric disorder in combination with the administration of dextromethorphan.
Embodiment 12. A method of treating a neurological and/or psychiatric disorder comprising administering to a human in need thereof a combination of an antidepressant compound and dextromethorphan.
Embodiment 13. The method of embodiment 12, wherein the human is a fast metaboliser of dextromethorphan.
Embodiment 14. The method of any of the preceding embodiments, e.g., embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the dextromethorphan is administered in a separate dosage form from the antidepressant compound.
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 20mg dextromethorphan and an effective amount of an antidepressant compound that inhibits the metabolism of dextromethorphan in a human that is a fast metabolite of dextromethorphan.
Embodiment 17 the oral dosage form of embodiment 16, wherein from about 30mg to about 350mg of dextromethorphan is present in the dosage form.
Embodiment 18. The method of any of the preceding embodiments, wherein dextromethorphan is administered to the human to treat the cough.
Embodiment 19 the method of any preceding embodiment, wherein the dextromethorphan is administered to the human at least once daily for at least 8 days, at least 9 days, or at least 10 days.
Embodiment 20. The method of any preceding embodiment, wherein the antidepressant is administered in an amount that results in a plasma concentration of dextromethorphan in the human at day 8 that is at least 10 times the plasma concentration when the same amount of dextromethorphan is administered and the antidepressant.
Embodiment 21. The method of any of the preceding embodiments, wherein the person is a fast metaboliser of dextromethorphan.
Embodiment 22. The method of any of the preceding embodiments, wherein dextromethorphan is administered to the human to treat pain.
Embodiment 23. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain comprises post-operative pain, cancer pain, arthritic pain, lumbosacral pain, musculoskeletal pain, central multiple sclerosis pain, nociceptive pain, or neuropathic pain.
Embodiment 24. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain comprises musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, or nociceptive pain.
Embodiment 25. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain comprises post-operative pain.
Embodiment 26. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain comprises cancer pain.
Embodiment 27. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain comprises arthritic pain.
Embodiment 28. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain comprises lumbosacral pain.
Embodiment 29. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain comprises musculoskeletal pain.
Embodiment 30. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain comprises neuropathic pain.
Embodiment 31. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain comprises nociceptive pain.
Embodiment 32. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain comprises chronic musculoskeletal pain.
Embodiment 33. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain is associated with rheumatoid arthritis.
Embodiment 34. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain is associated with juvenile rheumatoid arthritis.
Embodiment 35. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain is associated with osteoarthritis.
Embodiment 36. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain is associated with axial spondyloarthritis.
Embodiment 37. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain is associated with ankylosing spondylitis.
Embodiment 38. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain is associated with diabetic peripheral neuropathy.
Embodiment 39. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain is associated with post-herpetic neuralgia.
Embodiment 40. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain is associated with trigeminal neuralgia.
Embodiment 41. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain is associated with a monoradiculopathy.
Embodiment 42. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain is associated with phantom limb pain.
Embodiment 43. The method of any of the preceding embodiments, e.g., embodiment 43, wherein the pain is associated with central pain.
Embodiment 44. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain comprises cancer-related pain.
Embodiment 45. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain is associated with lumbar nerve root compression.
Embodiment 46. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain is associated with spinal cord injury.
Embodiment 47. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain is associated with post-stroke pain.
Embodiment 48. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain is associated with central multiple sclerosis pain.
Embodiment 49. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain is associated with HIV-associated neuropathy.
Embodiment 50. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain is associated with a neuropathy associated with radiation therapy.
Embodiment 51. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain is associated with chemotherapy-related neuropathy.
Embodiment 52. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain comprises dental pain.
Embodiment 53. The method of any of the preceding embodiments, e.g., embodiment 22, wherein the pain is associated with primary dysmenorrhea.
Embodiment 54. The method of any of the preceding embodiments, wherein 90 mg/day of dextromethorphan is administered to the human.
Embodiment 55. The method of any of the preceding embodiments, e.g., embodiment 54, wherein 45mg of dextromethorphan is administered to the human twice daily.
Embodiment 56. The method of any of the preceding embodiments, wherein the AUC that results in dextromethorphan is 0-12 Antidepressants are administered in an amount of at least about 40ng hr/mL.
Embodiment 57. The method of any preceding embodiment, wherein the AUC of dextromethorphan 0-12 Is at least about 50ng hr/mL.
Embodiment 58. The method of any of the preceding embodiments, wherein the human is in need of treatment with dextromethorphan.
Embodiment 59 the method of any preceding embodiment, wherein the dextromethorphan AUC on day 8, day 9, or day 10 0-12 Is at least about 100ng hr/mL.
Embodiment 60 the method of any preceding embodiment, wherein the dextromethorphan AUC on day 8, day 9, or day 10 0-12 Is at least about 400ng hr/mL.
Embodiment 61. The method of any preceding embodiment, wherein the dextromethorphan AUC on day 8, day 9, or day 10 0-12 Is at least about 800ng hr/mL.
Embodiment 62. The method of any of the preceding embodiments, wherein, inDextromethorphan AUC on day 8, day 9, or day 10 0-12 At least about 1500ng hr/mL.
Embodiment 63. The method of any preceding embodiment, wherein the dextromethorphan AUC on day 8, day 9, or day 10 0-24 Is at least about 100ng hr/mL.
Embodiment 64 the method of any preceding embodiment, wherein the dextromethorphan AUC on day 8, day 9, or day 10 0-24 At least about 1500ng hr/mL.
Embodiment 65 the method of any preceding embodiment, wherein the dextromethorphan AUC on day 8, day 9, or day 10 0-24 At least about 2900ng hr/mL.
Embodiment 66. The method of any preceding embodiment, wherein the dextromethorphan AUC on day 8, day 9, or day 10 0-inf Is at least about 100ng hr/mL.
Embodiment 67 the method of any preceding embodiment, wherein the dextromethorphan AUC on day 8, day 9, or day 10 0-inf At least about 1500ng hr/mL.
Embodiment 68. The method of any preceding embodiment, wherein the dextromethorphan AUC on day 8, day 9, or day 10 0-inf Is at least about 3500ng hr/mL.
Embodiment 69 the method of any preceding embodiment, wherein the dextromethorphan AUC on day 8, day 9, or day 10 0-inf At least about 5000ng hr/mL.
Embodiment 70. The method of any of the preceding embodiments, wherein the compound is selected to result in C of dextromethorphan max Antidepressants are administered in an amount of at least about 6 ng/mL.
Embodiment 71 the method of any preceding embodiment, e.g., embodiment 70, wherein dextromethorphan C on day 8, day 9, or day 10 max At least about 10ng/mL.
Embodiment 72 the method of any preceding embodiment, wherein dextromethorphan C on day 8, day 9, or day 10 max Is at least about20ng/mL。
Embodiment 73 the method of any preceding embodiment, wherein dextromethorphan C on day 8, day 9, or day 10 max At least about 60ng/mL.
Embodiment 74 the method of any preceding embodiment, wherein dextromethorphan C on day 8, day 9, or day 10 max Is at least about 120ng/mL.
Embodiment 75 the method of any preceding embodiment, wherein the administration of dextromethorphan is performed in a manner that results in dextromethorphan C over a 12 hour period after one administration avg Antidepressants are administered in an amount of at least about 5 ng/mL.
Embodiment 76 the method of any preceding embodiment, wherein dextromethorphan C on day 8, day 9, or day 10 avg At least about 20ng/mL.
Embodiment 77 the method of any preceding embodiment, wherein dextromethorphan C on day 8, day 9, or day 10 avg At least about 70ng/mL.
Embodiment 78 the method of any preceding embodiment, wherein dextromethorphan C on day 8, day 9, or day 10 avg Is at least about 120ng/mL.
Embodiment 79. The method of any of the preceding embodiments, wherein the AUC that results in dextromethorphan 0-12 Antidepressants are administered in an amount of at least about 40ng hr/mL.
Embodiment 80. The method of any preceding embodiment, wherein the AUC of dextromethorphan 0-12 Is at least about 50ng hr/mL.
Embodiment 81 the method of any preceding embodiment, wherein the antidepressant is co-administered with dextromethorphan for at least two consecutive days at least daily.
Embodiment 82. The method of any preceding embodiment, wherein the dextromethorphan AUC on day 8, day 9, or day 10 0-12 Is at least about 100ng hr/mL.
Embodiment 83. The method of any of the preceding embodiments, wherein on day 8, day 9, or day 10Dextromethorphan AUC of (C) 0-12 Is at least about 800ng hr/mL.
Embodiment 84. The method of any preceding embodiment, wherein the dextromethorphan AUC on day 8, day 9, or day 10 0-12 At least about 1500ng hr/mL.
Embodiment 85 the method of any preceding embodiment, wherein the dextromethorphan AUC on day 8, day 9, or day 10 0-24 Is at least about 100ng hr/mL.
Embodiment 86 the method of any preceding embodiment, wherein the dextromethorphan AUC on day 8, day 9, or day 10 0-24 At least about 1500ng hr/mL.
Embodiment 87 the method of any preceding embodiment, wherein the dextromethorphan AUC on day 8, day 9, or day 10 0-inf Is at least about 100ng hr/mL.
Embodiment 88 the method of any preceding embodiment, wherein the dextromethorphan AUC on day 8, day 9, or day 10 0-inf Is at least about 3500ng hr/mL.
Embodiment 89 the method of any preceding embodiment, wherein the dextromethorphan AUC on day 8, day 9, or day 10 0-inf At least about 5000ng hr/mL.
Embodiment 90. The method of any of the preceding embodiments, wherein about 0.6mg/kg to about 0.8mg/kg of dextromethorphan is orally administered to the human once or twice a day.
Embodiment 91. The method of any preceding embodiment, wherein the human suffers from an anti-therapeutic depression.
Embodiment 92. The method of any of the preceding embodiments, wherein the dextromethorphan is administered orally in a dosage form that provides immediate release of dextromethorphan.
Embodiment 93 the method of any preceding embodiment, wherein the antidepressant is administered orally in a dosage form that provides a sustained release of the antidepressant.
Embodiment 94. The method of any of the preceding embodiments, wherein the antidepressant and dextromethorphan are administered orally together in a single dosage form once or twice daily.
Embodiment 95. The method of any preceding embodiment, wherein the dextromethorphan and the antidepressant are administered orally for at least 5 weeks.
Embodiment 96. The method of any preceding embodiment, wherein the human suffers from major depressive disorder.
Embodiment 97 the method of any of the preceding embodiments, wherein the antidepressant comprises an enantiomeric excess of the R enantiomer.
Embodiment 98 the method of any preceding embodiment, wherein the antidepressant comprises an enantiomeric excess of the S enantiomer.
Embodiment 99. The method of any of the preceding embodiments, wherein the dextromethorphan comprises deuterium modified dextromethorphan.
Embodiment 100. The method of any of the preceding embodiments, wherein the human is currently suffering from depression and has been previously unsuccessful in treatment with at least two antidepressants.
Embodiment 101. A method of rapidly alleviating a symptom of depression, the method comprising administering to a person in need thereof a combination of an antidepressant and dextromethorphan once or twice daily, wherein the person experiences a therapeutic effect within 2 weeks of the first day of administration of the combination of an antidepressant and dextromethorphan.
Embodiment 102 use of a combination of an antidepressant and dextromethorphan in the manufacture of a medicament for the rapid relief of symptoms of depression, wherein said medicament is administered once or twice a day to achieve a therapeutic effect within 2 weeks of the first day of administration of said medicament.
Embodiment 103. The method or use of any preceding embodiment, wherein the human has previously had an inadequate response to at least one antidepressant therapy.
Embodiment 104. The method or use of any preceding embodiment, wherein the depression is major depression.
Embodiment 105 the method or use of any preceding embodiment, wherein the depression is an anti-therapeutic depression.
Embodiment 106. The method or use of any preceding embodiment, wherein the combination of an antidepressant and dextromethorphan is administered once a day or twice a day for at least 30 days.
Embodiment 107. The method or use of any preceding embodiment, wherein said combination of an antidepressant and dextromethorphan is administered once a day or twice a day for at least 42 days.
Embodiment 108. A method of treating a nicotine addiction associated with smoking, the method comprising administering to a person suffering from a nicotine addiction a combination of an antidepressant and dextromethorphan for at least 21 consecutive days, wherein the person is an unlimited smoker, wherein the person is administered a total amount of 80mg to 140mg of dextromethorphan per day, and wherein the method is more effective than administering the same amount of the antidepressant alone.
Embodiment 109 the method of embodiment 108, wherein the person takes the combination of antidepressant and dextromethorphan twice a day in 2 equal divided doses results in a greater decrease in the intensity of nicotine self-administration on the day or the next day than if the person took only one of the 2 divided doses or did not take the combination.
Embodiment 110 the method of embodiment 108 or 109, wherein the combination of antidepressant and dextromethorphan is administered to the human daily for at least 42 consecutive days.
Embodiment 111 the method of embodiment 108, 109 or 110, wherein about 90mg of dextromethorphan is administered to the human daily.
Embodiment 112 the method of any one of embodiments 109-111, wherein the human is administered a dose of about 40mg to 50mg of dextromethorphan twice daily.
Embodiment 113 the method of any of embodiments 109-112, wherein the method is more effective than administering dextromethorphan alone to a person addicted to nicotine.
Embodiment 114 the method of any one of embodiments 109-113, wherein said antidepressant is deuterium-enriched.
Embodiment 115. The method of embodiment 108, wherein dextromethorphan is deuterium-enriched.
Examples
The following examples illustrate the effect of a combination of bupropion (an antidepressant) and dextromethorphan on humans. Example 2 shows that bupropion results may also be observed with other antidepressants.
Example 1
15 human subjects were randomized into one of two treatment groups, receiving Dextromethorphan (DM) alone, or DM in combination with bupropion, as shown in Table 1 below.
TABLE 1 study design
All subjects were fast metabolizers of dextromethorphan, including ultrafast metabolizers, as determined by the CYP2D6 gene test. Dextromethorphan is administered at 12 hour intervals from day 1 to day 8, the last dose in the morning on day 8. Bupropion was administered once daily on days 1 to 3, followed by the last dose in the morning on day 8 at 12 hours intervals.
Plasma samples were collected on day 1 and day 8 for concentration analysis of dextromethorphan, total dextrorphan, bupropion, hydroxyanthrone, erythrohydroxyanthrone and threo hydroxyanthrone. Plasma samples were obtained approximately 12 hours after dosing on days 1, 5, 6 and 8 for determining the trough concentration of dextromethorphan.
The concentrations of dextromethorphan, total dextrorphan (unconjugated and glucuronide forms), bupropion, hydroxyanthrone, erythro-hydroxyanthrone and threo-hydroxyanthrone were determined using LC-MS/MS. Pharmacokinetic parameters were calculated.
Phenotyping of dextromethorphan metaboliser status was performed by calculating dextromethorphan/dextrorphan metabolic ratios as described in Jurica et al, journal of Clinical Pharmacy and Therapeutics,2012,37,486-490. With plasma concentrations of dextromethorphan and dextrorphan at 3 hours post-dose, a dextromethorphan/dextrorphan ratio of 0.3 or more indicates a weak metaboliser phenotype.
Results
With bupropion administration, the plasma concentration of dextromethorphan was significantly increased, as shown in fig. 1 and table 2.
TABLE 2 average dextromethorphan plasma concentration on day 8 (ng/mL)
Time (hours) Dextromethorphan (group A) Dextromethorphan + bupropion (group B)
0 1.2 110.6
1 2.4 129.3
2 3.6 153.9
3 3.6 151.6
4 3.3 149.1
6 2.5 150.0
8 1.9 144.4
12 1.1 119.3
24 0.4 95.3
36 0.1 69.0
As shown in fig. 2-4, the AUC of dextromethorphan was significantly increased with bupropion administration. As shown in fig. 5 and table 2A, the administration of bupropion together with dextromethorphan resulted in average dextromethorphan AUC, respectively, at day 8, as compared to the administration of dextromethorphan alone 0-12 、AUC 0-24 And AUC 0-inf About 60-fold, 80-fold, and 175-fold increase. As shown in fig. 6 and table 2B, an increase in dextromethorphan AUC occurred as early as day 1 (AUC 0-12 About a 3-fold increase).
Table 2A. Day 8 values
Table 2B. Values on day 1
As shown in fig. 7 and tables 2A and 3, with bupropion administration, the trough plasma concentration of dextromethorphan (also referred to as the "minimum mean plasma concentration" or "C min ") increases significantly. The administration of bupropion together with dextromethorphan resulted in an approximately 105-fold increase in dextromethorphan mean trough plasma concentration at day 8, as compared to dextromethorphan alone.
As shown in table 2A, at day 8, concomitant with bupropion administration, mean average plasma concentration of dextromethorphan (C avg ) The increase was about 60 times. Maximum mean plasma concentration (C max ) And also increases significantly, as shown in fig. 8 and table 2A.
TABLE 3 average Gu Youmei serum concentration of sand-fin (ng/mL)
Dextromethorphan (group A) Dextromethorphan + bupropion (group B) Fold change
Day 1 0.7 2.5 3.5
Day 5 1.2 80.9 70
Day 6 1.3 102.2 78
Day 7 1.2 110.6 94
Day 8 1.1 119.3 105
Concomitant with bupropion administration, dextromethorphan T on day 8 max And elimination half-life (T) 1/2el ) And increases significantly. T (T) 1/2el An increase in (c) indicates an increase in metabolic life of dextromethorphan. The administration of bupropion together with dextromethorphan resulted in an average T compared to dextromethorphan alone for 2.3 hours max For 3.6 hours. The administration of bupropion together with dextromethorphan resulted in an average T compared to dextromethorphan alone for 6.6 hours 1/2el 27.7 hours.
With bupropion administration, the plasma concentration of dextrorphan was significantly reduced, as shown in fig. 9 and table 4.
TABLE 4 mean dextrorphan plasma concentration on day 8 (ng/mL)
Time (hours) Dextromethorphan (group A) Dextromethorphan + bupropion (group B)
0 132.4 165.3
1 688.9 190.7
2 959.1 214.9
3 778.1 214.4
4 594.9 205.1
6 324.7 172.5
8 189.6 159.6
12 74.8 152.8
24 12.2 133.0
36 0.1 107.6
As shown in fig. 10-11, with bupropion administration, mean dextrorphan C on day 8 max About 78% reduction and average dextrorphan AUC 0-12 There is about 55% reduction.
Phenotypic determination of dextromethorphan metaboliser status showed that no subjects were poorly metabolised in either treatment group at day 1. However, 100% of subjects treated with bupropion converted to a state of weak metaboliser on day 8, compared to 0% of subjects treated with dextromethorphan alone. With bupropion administration, the average plasma dextromethorphan/dextrorphan metabolic ratio increased from 0.01 on day one to 0.71 on day 8. The average ratio in the DM alone administration group was 0.00 on the first day and remained unchanged on day 8.
On day 8, the average plasma concentrations of bupropion, hydroxyanthrone, erythro hydroxyanthrone, and threo hydroxyanthrone were at least 10ng/mL, 200ng/mL, 20ng/mL, and 100ng/mL, respectively, following bupropion administration.
As used in this section, the term "fold change" or "fold increase" refers to the ratio of the value for bupropion plus dextromethorphan to the same value for dextromethorphan alone (i.e., the value for bupropion plus dextromethorphan divided by the same value for dextromethorphan alone).
Example 2
Human liver microsomes were used to examine the ability of various antidepressant compounds to inhibit dextromethorphan metabolism. Each antidepressant compound was incubated with human liver microsomes (0.5 mg/mL) in duplicate at 37 ℃ in the presence of dextromethorphan (5 μm) at seven increasing concentrations (0.1-100 μm). In a 200mL assay final volume, the assay is performed in the presence of 2mM NADPH in 100mM potassium phosphate (pH 7.4) containing 5mM magnesium chloride.
After optimal incubation at 37 ℃, the reaction was stopped by adding methanol containing an internal standard for analytical quantification. The quenched samples were incubated at 4℃for 10 min and centrifuged at 4℃for 10 min. The supernatant was removed and the metabolite of dextromethorphan (dextrorphan) was analyzed by LC-MS/MS. Calculation of IC for each antidepressant compound using reduction in metabolite formation compared to vehicle control 50 Values (test concentration yielding 50% inhibition of dextromethorphan metabolism), with lower IC 50 Indicating a higher efficacy.
The results are summarized in table 5 below, and the corresponding efficacy is depicted in fig. 12.
TABLE 5 efficacy of various antidepressant compounds in inhibiting dextromethorphan metabolism in human liver microsomes
Test compounds Average IC 50 (μM)
Desmethylvenlafaxine 97.3
Venlafaxine 27.7
Escitalopram (escitalopram) 17.1
Citalopram 14.1
(2S, 3S) -hydroxy bupropion 12.5
Bupropion (bupropion) 9.1
(R, R) -hydroxy bupropion 8.2
Fluvoxamine 6.5
Sertraline 5.1
(S) -duloxetine 4.1
Su-type hydroxy bupropion 3.9
Erythro hydroxy bupropion 1.4
Example 3
Phase 2 clinical trial design:
phase 2 clinical trials with the combination of dextromethorphan and bupropion (DM/BU) were randomized, double-blind, actively controlled, multi-centered, us clinical trials using 80 adult patients diagnosed with moderate to severe Major Depressive Disorder (MDD) receiving twice daily doses for a 6 week treatment period. The dose group (1:1 randomization) included 43 patients with DM/BU (45 mg dextromethorphan/105 mg bupropion) or 37 patients with the active contrast bupropion (105 mg). 23% of these patients have received prior first-line treatment for depression. Clinical trials have a wide range of quality control measures.
Primary endpoint (or Primary endpoint) ：
The total score of the montgomery-asberg depression scale (MADRS) was calculated and averaged over the 6 week treatment period from baseline at each time point.
Fig. 13 and table a show the change in total MADRS score over time during the 6 week dosing period for subjects administered Bupropion (BU) or dextromethorphan in combination with bupropion (DM/BU).
Table a.
Primary endpoint DM+BU BU P value
Variation of MADRS total score (averaged) over a 6 week period -13.7 -8.8 <0.001
Variation of MADRS Total score at week 6 -17.2 -12.1 0.013
Secondary endpoint (or secondary endpoint)：
Table B lists secondary endpoints with P values.
Table B
* The P-value was used for DM/BU versus the active control Bupropion (BU). Multiple secondary endpoints favor DM/BU.
Fig. 14 shows the percentage of subjects who achieved remission over time during the 6 week dosing period (as determined by MADRS +.10) for subjects who were administered Bupropion (BU) or dextromethorphan in combination with bupropion (DM/BU).
Safety of：
Clinical studies showed that administration of DM/BU was safe and well tolerated, with similar adverse event rates in the DM/BU and bupropion groups. No serious adverse events were observed. There was no meaningful difference between the two treatment groups in terms of interruption due to adverse events. The most commonly reported adverse events in the DM/BU group were nausea, dizziness, dry mouth, loss of appetite, and anxiety. DM/BU is not associated with psychotropic effects, weight gain or increased sexual dysfunction.
Summary：
Statistically significant improvement in MADRS and DM/BU secondary efficacy endpoints was achieved in MDD patients. Early and sustained isolation of bupropion relative to the active control was observed. DM/BU administration was safe and well tolerated without psychotropic effects, weight gain or increased sexual dysfunction.
Thus, DM/BU showed significant and rapid antidepressant activity as well as favorable safety profile in MDD clinical trials.
Results：
Fig. 13 and 14 were prepared based on the results of a clinical trial in the united states with 80 patients with adult depression, 43 of which were treated with a combination of 45mg DM and 105mg BU, and 37 of which were treated with 105mg BU alone, the patients receiving twice daily doses for a 6 week treatment period. 23% of these patients have received prior first-line treatment for depression.
As shown in fig. 13 and table a, using the DM in combination with BU significantly reduced the MADRS total score (depression rating scale) even during the first week of treatment compared to BU alone. At week 6, administration of the DM/BU combination reduced the total MADRS score by about 42% compared to bupropion alone.
As shown in fig. 14, the rate of remission of the DM/BU combination was significantly higher (about 8-fold) than that of control BU alone, even as early as the second week of treatment, with the rate of remission being about 20% higher. At week 6 of treatment, administration of the combination DM/BU resulted in an approximately 30% higher rate of remission than control BU alone.
The clinical studies described above demonstrate that the administration of bupropion in combination with dextromethorphan (DM/BU) provides greater efficacy than that achieved by administration of bupropion alone. This clinical study showed that the combination of dextromethorphan and bupropion had additive or synergistic efficacy in treating depression.
Example 4: product suite：
In some embodiments, the product kit comprises a combination of dextromethorphan and bupropion for use in treating depression, wherein the product kit comprises a dosage form comprising from about 30mg to about 60mg dextromethorphan and from about 100mg to about 200mg bupropion, and wherein once daily or twice daily administration of the dosage form results in greater efficacy in humans as compared to administration of bupropion alone. In some embodiments, the product kit comprises 45mg dextromethorphan and 105mg bupropion.
In some embodiments, the product kit comprises an oral sustained release delivery system for dextromethorphan comprising bupropion in one dosage form; dextromethorphan; and a water soluble carrier, wherein the dosage form comprises from about 30mg to about 60mg of dextromethorphan and from about 100mg to about 200mg of bupropion, and wherein use of the dosage form once or twice daily for at least eight days results in a dosage form The elimination half-life of dextromethorphan on day eight compared to dextromethorphan alone (T 1/2 ) And (3) increasing.
Example 5:
nearly 4000 million american adults smoke and about 70% of them report a desire to quit smoking. According to the centers for disease control and prevention, tobacco use results in about 500000 premature deaths per year in the united states alone. Smoking is the single greatest cause of premature death worldwide, accounting for about 20% of all deaths in developed countries [ Dani JA and Heinemann S (1996) Neuron 16:5, pages 905-8 ]. In the united states alone, the cost of direct healthcare and lost productivity due to smoking annually is nearly $3000 billion. It is estimated that only 3% to 5% of smokers attempting to quit smoking succeed for 6-12 months without assistance, and that the relapse rate remains higher than 80% even with current treatments [ Hughes JR et al, (2004) additives 99:1, pages 29-38 ]. The need for new methods is highlighted because most smokers attempting to quit smoking fail. The combination of dextromethorphan and bupropion (DM/BU) has the potential to address this situation due to the novel mechanism of action of DM/BU.
The dextromethorphan component of DM/BU is a sigma-1 receptor agonist, a nicotinic acetylcholine receptor antagonist, and an inhibitor of 5-hydroxytryptamine and norepinephrine transporter. The bupropion component of DM/BU is used to increase the bioavailability of dextromethorphan and is a norepinephrine and dopamine reuptake inhibitor, as well as a nicotinic acetylcholine receptor antagonist. Both components of DM/BU are nicotinic acetylcholine receptor antagonists, a mechanism associated with nicotine dependency. Thus, DM/BU provides a potentially new mechanism of action for smoking cessation therapy.
Phase 2 clinical trial design:
the clinical trial was a phase 2, randomized, double-blind, actively controlled study that was used to evaluate the efficacy and safety of DM/BU for smoking cessation therapy. A total of 58 smokers were randomized at a 1:1 ratio to receive DM/BU twice daily (45 mg dextromethorphan/105 mg bupropion) (n=31) or the active control bupropion (105 mg) (n=27) and assessed over a period of 3 weeks. The enrolled subjects were daily smokers who used 10 cigarettes or more per day. The average number of cigarettes smoked per day for the DM/BU treatment group at baseline was 20, and the average number of cigarettes smoked per day for the bupropion treatment group at baseline was 17.
Primary endpoint：
The primary outcome measure is the change in smoking intensity measured using the number of cigarettes smoked per day assessed via a daily smoking diary.
Unlimited smoking reduction was chosen as the primary endpoint in this trial as it has been shown to be associated with smoking cessation.
Safety of：
Drug compliance was similar for both the morning dose (97.1% for DM/BU and 96.6% for bupropion) and the evening dose (76.3% for DM/BU and 79.4% for bupropion) between study groups. In this study, DM/BU was safe and well tolerated without serious adverse events. The most commonly reported side effects are headache, dry mouth and insomnia/realistic dreams, with similar incidence in both treatment groups.
Results:
treatment with DM/BU resulted in a 25% more reduction in the average number of cigarettes smoked per day over a 3 week period (pre-set primary endpoint) compared to bupropion (average 8.49 and 6.79 cigarettes per day for DM/BU and bupropion, p=0.0016).
Consistent with this finding, a greater proportion of smokers receiving DM/BU experienced a greater than 50% reduction in exhaled carbon monoxide levels (a biochemical indicator of smoking intensity) than those treated with bupropion (DM/BU 52.0%, whereas bupropion was 30.4% >, p=0.15).
In addition, compared to those who missed one or two doses of DM/BU, the human subjects who took DM/BU on the specified day, as specified, smoked 1.0 cigarettes (p=0.026) less on the day of DM/BU drug use and 1.2 cigarettes (p=0.008) less on the next day.
Summary：
Treatment with DM/BU achieved a pre-specified primary endpoint in the phase 2 smoking cessation trial. Treatment with DM/BU showed a statistically significant reduction in daily smoking (p=0.0016) compared to bupropion alone, an active control. Since DM/BU is compared to the approved smoking cessation therapy bupropion, the findings in this phase 2 clinical trial are important.
Furthermore, it is notable that the improvement in DM/BU over bupropion observed in humans in this clinical trial was similar in magnitude to the improvement reported over placebo in valover approved smoking cessation therapy in studies using similar designs. Valicarb is a prescribed drug for the treatment of smoking addiction. The drug is the first approved nicotinic receptor partial agonist. In particular, valdecolonium is a partial agonist of the alpha 4/beta 2 subtype of nicotinic acetylcholine receptors.
Example 6
A phase 3 randomized, double-blind, multi-centered placebo controlled clinical trial of a combination of Dextromethorphan (DM) and bupropion (BU or BUP) in Major Depressive Disorder (MDD) patients was performed in the united states. A total of 327 patients diagnosed with moderate to severe MDD were randomized at a 1:1 ratio to receive 45mg of dextromethorphan/105 mg of bupropion (DM/BU) (n=163) or placebo (n=164) once daily on the first 3 days (day 1, day 2, and day 3) and twice daily thereafter (starting on day 4) for a total of 6 weeks.
The baseline inclusion criteria included: men or women aged 18-65 years, met the DSM-5 standard for current MDD without psychotic features, the montgomery-asberg depression rating scale (MADRS) total score was at least 25 and the CGI-S score was at least 4. The exclusion criteria included: there is a history of electrical spasticity, vagal nerve stimulation, transcranial magnetic stimulation, or any experimental central nervous system treatment, schizophrenia, bipolar disorders, obsessive-compulsive disorders, and psychotic symptoms secondary to any other general medical condition during the current episode or in the past 6 months.
Demographic and baseline characteristics of the patients are shown in table 6 below:
TABLE 6
45mg DM/105mg BU Placebo
Age (age) 42.1(12.71) 41.1(13.78)
Female sex, n (%) 98(60.1％) 117(71.3％)
Race, n (%)
White seed person 88(54.0％) 92(56.1％)
Black or african americans 61(37.4％) 55(33.5％)
Asian people 9(5.5％) 8(4.9％)
Other or unreported 5(3.1％) 9(5.5％)
Body mass index (mg/kg) 2 ) 29.2(5.59) 29.4(5.66)
MADRS Total score 33.6(4.43) 33.2(4.36)
CGI-S score 4.6(0.59) 4.6(0.57)
Unless otherwise indicated, the data are all mean values (SD).
Abbreviations: BMI = body mass index; bu=bupropion; CGI-S = clinical global impression-severity; DM = dextromethorphan; MADRS = montgomery-asberg depression rating scale.
Demographic and baseline characteristics were similar for both treatment groups. The study completion rate was greater than 75% for both treatment groups.
The primary endpoint of the study was the change in total MADRS score from baseline at week 6. Secondary endpoints included MADRS changes, remissions, responses, clinical global impression-improvement (CGI-I), bed global impression-severity (CGI-S), patient global impression-improvement (PGI-1), MADRS-6, the haen disability scale (SDS), other quality of life metrics, safety, and tolerability at weeks 1 and 2. The P value is calculated based on a least squares mean estimate.
DM/BU met the primary endpoint and rapidly and significantly improved depressive symptoms. Specifically, DM/BU showed a rapid, sustained and statistically significant improvement in depression symptoms (p=0.002 for the primary endpoint) compared to placebo as measured by the MADRS total score. DM/BU exhibited a highly statistically significant decrease in the montgomery-asberg depression scale (MADRS) total score compared to placebo at week 6, with a 16.6 score decrease from baseline average for DM/BU and 11.9 score decrease from baseline average for placebo (p=0.002).
In addition, statistically significant improvement was observed at week 1 or only day 4 after the start of twice daily dosing. As shown in fig. 15, a statistically significant improvement in MADRS total score was observed at week 1, wherein the MADRS total score of DM/BU was reduced by 7.3 points, compared to the MADRS total score of placebo by 4.9 points (key secondary endpoint, p=0.007), wherein the statistical significance of the metric was maintained at all time points thereafter (e.g., week 2, week 3, week 4, week 5, or week 6). There are statistically significant improvements in: patient overall impression-improvement (PGI-1) (p=0.008); clinical global impression-severity (CGI-S) (p=0.013); clinical global impression-improvement (CGI-I) (p=0.035); rapid self-assessment of depressive symptoms (QIDS-SR-16) (p=0.016); happiness and quality of life satisfaction questionnaire-profile (Q-LES-Q-SF) (p=0.031); and other endpoints were also observed at week 1 and at each time point thereafter (e.g., week 2, week 3, week 4, week 5, or week 6).
As shown in FIG. 16, 54.0% response (defined as a total MADRS score improvement of > 50%) was observed in patients receiving DM/BU at week 6, compared to 34.0% response (p < 0.001) in patients receiving placebo.
As shown in fig. 17, the rate of depression relief (defined as madrs+.10) at week 2 (p=0.013) and at each time point thereafter (e.g., week 3, week 4, or week 6) was statistically significantly greater than placebo, with 39.5% of DM/BU patients achieving depression relief at week 6 compared to 17.3% of placebo patients achieving depression relief (p < 0.001).
DM/BU was also associated with a statistically significant reduction in functional impairment compared to placebo at week 2 (p=0.003) and at each time point thereafter (p=0.002 at week 6) as measured by the haen disability scale (SDS).
DM/BU showed statistically significant improvement at 6 th peripheral compared to placebo at all secondary endpoints including the following, reflecting increasing therapeutic effects over time: clinical response to total MADRS score (defined as ≡50%) (p < 0.001); PGI-1 (p=0.007); CGI-S (p=0.002); CGI-1 (p=0.016); QIDS-SR-16 (p=0.001); the green disability scale (SDS) (p=0.002); and Q-LES-Q-SF (p=0.011).
DM/BU was well tolerated in phase 3 clinical trials. The most commonly reported adverse events in the DM/BU group were dizziness, nausea, headache, diarrhea, somnolence and dry mouth. There was a serious adverse event in the DM/BU group that the investigator thought to be unrelated to the study drug. The interruption rate due to adverse events was lower in both treatment groups (DM/BU 6.2% and placebo 0.6%). Treatment with DM/BU was not associated with psychotropic effects or weight gain.
Unless otherwise indicated, all numbers expressing quantities of ingredients, properties (such as amounts, percentages) and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about" and precisely the values shown. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
Where an embodiment is described, especially in the context of the appended claims, where no quantitative word modification is used, it is to be understood that both the singular and the plural are covered unless this document otherwise stated or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of any claim. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the claims.
The grouping of alternative elements or embodiments disclosed herein should not be construed as limiting. Each group member may be referred to and claimed either alone or in any combination with other members of the group or other elements found herein. It is envisioned that one or more members of a group may be included in or deleted from the group for reasons of convenience and/or acceleration of the censoring procedure. When any such inclusion or deletion occurs, the specification is to be considered as containing the modified group and thus completing the written description of the entire markush group if used in the appended claims.
Certain embodiments are described herein, including the best mode known to the inventors for carrying out the claimed embodiments. Of course, variations of those described embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the claimed embodiments to be practiced otherwise than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is also contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.
Finally, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, and not limitation, alternative embodiments may be employed in accordance with the teachings herein. Accordingly, the claims are not limited to the embodiments just shown and described.

Claims (104)

1. A method of treating depression comprising administering to a human in need thereof a combination of an antidepressant and dextromethorphan, wherein the antidepressant comprises: levomilnacipran, vilazodone, vortioxetine, tomoxetine, reboxetine, tenisazine, viloxazine, amitriptyline oxide, dimetalin, melitracin, nifedipine Sha Xiping, nomotillin, pipofazine, sapercillin, carbo Luo Shatong, meldonol, porindoles, ependym, milnacipran, dibenzolam, agomelatine, esketamine, tandospirone, thianaproxen, alpha-mecrimine, ethanamine, alpha-ethanamine, indenclozine, mecisamine, ol Sha Fu-gen, pitavabine, adenomethionine, S-adenosyl-L-methionine, hypericum perforatum, exemestane, 5-hydroxytryptophan, rubidium chloride, tryptophan, magnesium, acetylcarnitine, safflower, sulfamide, aripiprazole, epiprazole, ruzol, olanzapine, quetiapine, lippine, risperidone, lithium, temustine, cyclosulfamide, thyroxine, and other than one Is selected from the group consisting of amitriptyline and oxyphenzoprazine, flupentixol and melitracin, olanzapine and fluoxetine, tranylcypromine and trifluoracezine, 4-chlorokynurenine, AGN-241751, apitene, levoketamine, dextromethorphan, EVT-101, li Laina da, pasimdagliclate, AN-788, tos Lu Dewen-Lafaxine, PDC-1421, MIN-117, TGBA01AD, gepirone, P Mo Fanse, siroccipine, brilaroxazine, lu Meipai, adenosylmethionine, flunine, and combinations thereof ganaxolone, zu Lanuo ketone, 3β -methoxypregnanolone, PH-10-vomeropherine, atecapelin, BTRX-335140, buprenorphine and saminoprofen combinations, BTRX-246040, hydroxynorketamine, JNJ-39393406, JNJ-54175446, JNJ-61393215, NNI-351, NSI-189, NV-5138, botulinum toxin a, pramipexole, racet Lei Sheng, cet Lu Kushan antibodies, SUVN-911, TS-121, tramadol, cycloserine and lurasidone combinations, 7, 8-dihydroxyflavone (7, 8-dhf), minocycline,Nitrous oxide, pramipexole, R13 or a combination thereof.
2. The method of claim 1, wherein the antidepressant comprises l-milnacipran.
3. The method of claim 1, wherein the antidepressant comprises vilazodone.
4. The method of claim 1, wherein the antidepressant comprises vortioxetine.
5. The method of claim 1, wherein the antidepressant comprises tomoxetine.
6. The method of claim 1, wherein the antidepressant comprises reboxetine.
7. The method of claim 1, wherein the antidepressant comprises tenisazine.
8. The method of claim 1, wherein the antidepressant comprises viloxazine.
9. The method of claim 1, wherein the antidepressant comprises amitriptyline oxide.
10. The method of claim 1, wherein the antidepressant comprises dimethyltaline.
11. The method of claim 1, wherein the antidepressant comprises melitracin.
12. The method of claim 1, wherein the antidepressant comprises nitro Sha Xiping.
13. The method of claim 1, wherein the antidepressant comprises norxillin.
14. The method of claim 1, wherein the antidepressant comprises piprazole.
15. The method of claim 1, wherein the antidepressant comprises saprotiline.
16. The method of claim 1, wherein the antidepressant comprises a card Luo Shatong.
17. The method of claim 1, wherein the antidepressant comprises a merozolol.
18. The method of claim 1, wherein the antidepressant comprises a pordole.
19. The method of claim 1, wherein the antidepressant comprises ependamine.
20. The method of claim 1, wherein the antidepressant comprises milnacipline.
21. The method of claim 1, wherein the antidepressant comprises benzphetamine.
22. The method of claim 1, wherein the antidepressant comprises agomelatine.
23. The method of claim 1, wherein the antidepressant comprises esketamine.
24. The method of claim 1, wherein the antidepressant comprises tandospirone.
25. The method of claim 1, wherein the antidepressant comprises a thianaproxen.
26. The method of claim 1, wherein the antidepressant comprises alpha-methyltryptamine.
27. The method of claim 1, wherein the antidepressant comprises tryptamine.
28. The method of claim 1, wherein the antidepressant comprises indenofloxazine.
29. The method of claim 1, wherein the antidepressant comprises methoxamine.
30. The method of claim 1, wherein the antidepressant comprises olo Sha Fu.
31. The method of claim 1, wherein the antidepressant comprises pitavagabine.
32. The method of claim 1, wherein the antidepressant comprises adenosylmethionine.
33. The method of claim 1, wherein the antidepressant comprises hypericum perforatum.
34. The method of claim 1, wherein the antidepressant comprises exenatide.
35. The method of claim 1, wherein the antidepressant comprises 5-hydroxytryptophan.
36. The method of claim 1, wherein the antidepressant comprises rubidium chloride.
37. The method of claim 1, wherein the antidepressant comprises tryptophan.
38. The method of claim 1, wherein the antidepressant comprises magnesium.
39. The method of claim 1, wherein the antidepressant comprises acetylcarnitine.
40. The method of claim 1, wherein the antidepressant comprises saffron.
41. The method of claim 1, wherein the antidepressant comprises amisulpride.
42. The method of claim 1, wherein the antidepressant comprises aripiprazole.
43. The method of claim 1, wherein the antidepressant comprises epipiprazole.
44. The method of claim 1, wherein the antidepressant comprises lurasidone.
45. The method of claim 1, wherein the antidepressant comprises olanzapine.
46. The method of claim 1, wherein the antidepressant comprises quetiapine.
47. The method of claim 1, wherein the antidepressant comprises risperidone.
48. The method of claim 1, wherein the antidepressant comprises buspirone.
49. The method of claim 1, wherein the antidepressant comprises lithium.
50. The method of claim 1, wherein the antidepressant comprises modafinil.
51. The method of claim 1, wherein the antidepressant comprises thyroxine.
52. The method of claim 1, wherein the antidepressant comprises triiodothyronine.
53. The method of claim 1, wherein the antidepressant comprises minocycline.
54. The method of claim 1, wherein the antidepressant comprises amitriptyline and clozapineIs a combination of (a) and (b).
55. The method of claim 1, wherein the antidepressant comprises a combination of amitriptyline and oxyphenchlorpromazine.
56. The method of claim 1, wherein the antidepressant comprises a combination of flupentixol and melitracen.
57. The method of claim 1, wherein the antidepressant comprises a combination of olanzapine and fluoxetine.
58. The method of claim 1, wherein the antidepressant comprises a combination of tranylcypromine and trifluoperazine.
59. The method of claim 1, wherein the antidepressant comprises 4-chlorokynurenine.
60. The method of claim 1, wherein the antidepressant comprises AGN-241751.
61. The method of claim 1, wherein the antidepressant comprises apiece.
62. The method of claim 1, wherein the antidepressant comprises levoketamine.
63. The method of claim 1, wherein the antidepressant comprises dextromethorphan.
64. The method of claim 1, wherein the antidepressant comprises EVT-101.
65. The method of claim 1, wherein the antidepressant comprises Li Laina.
66. The method of claim 1, wherein the antidepressant comprises pasmodus.
67. The method of claim 1, wherein the antidepressant comprises AN-788.
68. The method of claim 1, wherein the antidepressant comprises tol Lu Dewen Lafaxine.
69. The method of claim 1, wherein the antidepressant comprises PDC-1421.
70. The method of claim 1, wherein the antidepressant comprises MIN-117.
71. The method of claim 1, wherein the antidepressant comprises TGBA01AD.
72. The method of claim 1, wherein the antidepressant comprises gepirone.
73. The method of claim 1, wherein the antidepressant comprises pimavanserin.
74. The method of claim 1, wherein the antidepressant comprises a siroccin.
75. The method of claim 1, wherein the antidepressant comprises brilaroxazine.
76. The method of claim 1, wherein the antidepressant comprises Lu Meipai.
77. The method of claim 1, wherein the antidepressant comprises adenosylmethionine.
78. The method of claim 1, wherein the antidepressant comprises ganaxolone.
79. The method of claim 1, wherein the antidepressant comprises Zu Lanuo ketone.
80. The method of claim 1, wherein the antidepressant comprises 3β -methoxypregnanolone.
81. The method of claim 1, wherein the antidepressant comprises PH-10-vomeropherine.
82. The method of claim 1, wherein the antidepressant comprises atetopiramate.
83. The method of claim 1, wherein the antidepressant comprises BTRX-335140.
84. The method of claim 1, wherein the antidepressant comprises a combination of buprenorphine and saminoprofen.
85. The method of claim 1, wherein the antidepressant comprises hydroxynorketamine.
86. The method of claim 1, wherein the antidepressant comprises JNJ-39393406.
87. The method of claim 1, wherein the antidepressant comprises JNJ-54175446.
88. The method of claim 1, wherein the antidepressant comprises JNJ-61393215.
89. The method of claim 1, wherein the antidepressant comprises NNI-351.
90. The method of claim 1, wherein the antidepressant comprises NSI-189.
91. The method of claim 1, wherein the antidepressant comprises NV-5138.
92. The method of claim 1, wherein the antidepressant comprises botulinum toxin a.
93. The method of claim 1, wherein the antidepressant comprises pramipexole.
94. The method of claim 1, wherein the antidepressant comprises pito Lei Sheng.
95. The method of claim 1, wherein the antidepressant comprises a western Lu Kushan antibody.
96. The method of claim 1, wherein the antidepressant comprises SUVN-911.
97. The method of claim 1, wherein the antidepressant comprises TS-121.
98. The method of claim 1, wherein the antidepressant comprises tramadol.
99. The method of claim 1, wherein the antidepressant comprises a combination of cycloserine and lurasidone.
100. The method of claim 1, wherein the antidepressant comprises 7, 8-dihydroxyflavone.
101. The method of claim 1, wherein the antidepressant comprises minocycline.
102. The method of claim 1, wherein the antidepressant comprises nitrous oxide.
103. The method of claim 1, wherein the antidepressant comprises pramipexole.
104. The method of claim 1, wherein the antidepressant comprises R13.
CN202280021306.8A 2021-01-18 2022-01-18 Combination of antidepressants and dextromethorphan for the treatment of neuropsychiatric disorders Pending CN116981450A (en)

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