Compositions and methods for modulating plasma levels of brain-derived neurotrophic factor

Abstract

Disclosed herein are methods of modulating the therapeutic plasma concentration of dextromethorphan and the plasma concentration of dextrorphan by administering dextromethorphan in combination with deramciclane to a subject, such as a human being. Compositions, dosage forms, combinations, therapeutic formulations, symptomatic and disease-modifying treatments, therapies, and methods related to dextromethorphan and deramciclane are also disclosed.

Description

COMPOSITIONS AND METHODS FOR MODULATING PLASMA LEVELS OF BRAIN-DERIVED NEUROTROPHIC FACTORRELATED APPLICATION INFORMATION

[0001] This application claims priority to U.S. Application No. 63 / 711,370 filed on November 8, 2025 and U.S. Application No. 63 / 745,222 filed on January 14, 2025, the contents of each of which are herein incorporated by reference.TECHNICAL FIELD

[0002] The present disclosure relates to compositions, dosage forms, combinations, therapeutic formulations, symptomatic and disease-modifying treatments, therapies, and methods of modulation plasma levels of dextromethorphan in a subject, plasma levels of dextrorphan in a subject and / or plasma levels of brain-derived neurotrophic factor in a subject.BACKGROUND

[0003] Diseases affecting the brain and central nervous system represent one of the largest global healthcare challenges and greatest medical needs due to the devastating personal and economic consequences for patients, caregivers and society. Mental, neurological and substance use disorders account for more than 10% of global disability-adjusted life years (DALYs) and more than 28% of global years lived with disability (YLDs), making them the leading cause of YLDs. Mental disorders account for the largest proportion of DALYs (56.7%), followed by neurological disorders (28.6%) and substance use disorders (14.7%). Depressive disorders account for 40.5% of DALY s caused by mental and substance use disorders.

[0004] Given the projected trends in population ageing and population growth, impact of diseases affecting the brain and central nervous system is expected to grow. For example, it is estimated that the number of people with dementia will increase from 57.4 million cases globally in 2019 to 152.8 million cases in 2050.

[0005] Growth in the number of individuals living with dementia underscores the need fordevelopment of new compositions, combinations, therapeutic formulations, symptomatic and disease-modifying treatments, and therapies addressing the needs of people suffering from diseases affecting the brain and central nervous system.SUMMARY OF THE INVENTION

[0006] Various embodiments of the disclosure relate to methods of increasing the therapeutic plasma concentration of dextromethorphan by administering dextromethorphan in combination with deramciclane to a human being.

[0007] In one embodiment, the present disclosure relates to a method of increasing plasma levels of dextromethorphan and maintaining or increasing plasma levels of dextrorphan in a subject in need of treatment thereof. The method comprises the steps of:

[0008] administering to a subject in need of treatment a therapeutically effective amount of a combination of dextromethorphan and deramciclane, wherein the dextromethorphan and deramciclane are administered to the subject either simultaneously or sequentially, and in any order, and

[0009] further wherein:

[0010] a) the administration of the combination of dextromethorphan and deramciclane to the subject is once or twice per day for a minimum of at least 10 consecutive days;

[0011] b) the deramciclane is administered to the subject in an amount of at least about 200 ng*hr to produce an AUCo- of deramciclane; and

[0012] c) the administration of the combination of dextromethorphan and deramciclane produces an AUC0-12 of dextromethorphan and dextrorphan in the subject that is higher on the tenth day after the start of administration of the combination than on the tenth day after the start of administration of dextromethorphan alone, without the deramciclane.

[0013] In some aspects of the above method, the dextromethorphan and deramciclane are administered sequentially.

[0014] In further aspects of the above method, the dextromethorphan and deramciclane are administered simultaneously.

[0015] In still further aspects of the above method, the dextromethorphan and deramciclane are administered as separate compositions.

[0016] In yet further aspects of the above method, the dextromethorphan and deramciclaneare administered once per day.

[0017] In yet further aspects of the above method, the dextromethorphan and deramciclane are administered twice per day.

[0018] In yet still further aspects of the above method, the dextromethorphan is deuterated, the deramciclane is deuterated, or the dextromethorphan is deuterated and the deramciclane is deuterated.

[0019] In still yet further aspects of the above method, the administration to the subject of the combination of dextromethorphan and deramciclane produces an AUC0-12 in the subject that is at least 4 times higher on the tenth day after the start of administration of the combination than on the tenth day after the start of administration of dextromethorphan alone, without the deramciclane.

[0020] In yet still further aspects of the above method, about 30 mg to about 120 mg of dextromethorphan is administered to the subject per day and about 20 mg to about 20 mg of deramciclane is administered to the subject per day.

[0021] In another embodiment, the present disclosure relates to a method of increasing plasma levels of brain-derived neurotrophic factor (BDNF) in a subject in need of treatment thereof. In some aspects, the method involves the steps of

[0022] administering to a subject in need of treatment a therapeutically effective amount of a combination of dextromethorphan and deramciclane, wherein the dextromethorphan and deramciclane are administered to the subject either simultaneously or sequentially, and in any order, and

[0023] further wherein:

[0024] a) the administration of the combination of dextromethorphan and deramciclane to the subject is once or twice per day for a minimum of at least 10 consecutive days;

[0025] b) the deramciclane is administered to the subject in an amount of at least about 200 ng*hr to produce an AUCo-i2of deramciclane; and

[0026] c) the administration of the combination of dextromethorphan and deramciclane produces an AUC0-12 of dextromethorphan and dextrorphan in the subject that is at least about 20 higher on the tenth day after the start of administration of the combination than on the tenth day after the start of administration of dextromethorphan alone, without the deramciclane.

[0027] In some aspects of the above method, the dextromethorphan and deramciclane are administered sequentially.

[0028] In further aspects of the above method, the dextromethorphan and deramci clane are administered simultaneously.

[0029] In yet further aspects of the above method, the dextromethorphan and deramciclane are administered as separate compositions.

[0030] In still further aspects of the above method, the dextromethorphan and deramciclane are administered once per day.

[0031] In still further aspects of the above method, the dextromethorphan and deramciclane are administered twice per day.

[0032] In still other aspects of the above method, the dextromethorphan is deuterated, the deramciclane is deuterated, or the dextromethorphan is deuterated and the deramciclane is deuterated.

[0033] In yet further aspects of the above method, about 30 mg to about 120 mg of dextromethorphan is administered to the subject per day and about 20 mg to about 20 mg of deramciclane is administered to the subject per day.

[0034] In still further embodiments, the present disclosure relates to a method of treating a subject in need of treatment thereof. The method comprises:

[0035] administering to a subject in need of treatment a therapeutically effective amount of a combination of dextromethorphan and deramciclane, wherein the dextromethorphan and deramciclane are administered to the subject either simultaneously or sequentially, and in any order, and

[0036] further wherein:

[0037] a) the administration of the combination of dextromethorphan and deramciclane to the subject is once or twice per day for a minimum of at least 10 consecutive days;

[0038] b) the deramciclane is administered to the subject in an amount of at least about 200 ng*hr to produce an AUCo-nof deramciclane;

[0039] c) the administration of the combination of dextromethorphan and deramciclane produces an AUC0-12 of dextromethorphan and dextrorphan in the subject that is higher on the tenth day after the start of administration of the combination than on the tenth day after the start of administration of dextromethorphan alone, without the deramciclane; and

[0040] d) the subject is suffering from an anxiety disorder, a cognitive disorder, a mood and depressive disorder, psychosis, a substance use disorders, coughing, or a combination thereof.

[0041] In some aspects of the above method, the subject is suffering from dementia, Alzheimer’s disease, Parkinson’s disease, depression, a major depressive disorder, a minor depressive disorder, schizophrenia, psychosis, coughing or a combination thereof.

[0042] In yet further aspects of the above method, the subject is suffering from dementia or Alzheimer’s disease.

[0043] In still yet further aspects of the above method, the subject is suffering from behavioral and psychological symptoms of dementia.

[0044] In yet still further aspects of the above method, the dextromethorphan and deramciclane are administered simultaneously.

[0045] In still yet further aspects of the above method, the dextromethorphan and deramciclane are administered as separate compositions.

[0046] In still yet further aspects of the above method, the dextromethorphan and deramciclane are administered once per day.

[0047] In still yet further aspects of the above method, wherein the dextromethorphan and deramciclane are administered twice per day.

[0048] In still yet further aspects of the above method, wherein the dextromethorphan is deuterated, the deramciclane is deuterated, or the dextromethorphan is deuterated and the deramciclane is deuterated.

[0049] In still yet further aspects of the above method, the administration to the subject of the combination of dextromethorphan and deramciclane produces an AUC0-12 in the subject that is at least 4 times higher on the tenth day after the start of administration of the combination than on the tenth day after the start of administration of dextromethorphan alone, without the deramciclane.

[0050] In still yet further aspects of the above method, about 30 mg to about 120 mg of dextromethorphan is administered to the subject per day and about 20 mg to about 20 mg of deramciclane is administered to the subject per day.BRIEF DESCRIPTION OF FIGURES

[0051] FIGURE 1 shows the plasma concentration of dextromethorphan and dextrorphan with or without co-administration of deramciclane as described in Example 1.

[0052] FIGURE 2 shows a digit symbol substitution test as described in Example 1. DC, deramciclane (30 mg b.i.d.); DM45, dextromethorphan (45 mg b.i.d.); DM60, dextromethorphan(60 mg b.i.d.).

[0053] FIGURE 3 shows the results of a body sway test as described in Example 1. BL, baseline; DC, deramciclane (30 mg b.i.d.); DM45, dextromethorphan (45 mg b.i.d.); DM60, dextromethorphan (60 mg b.i.d.).

[0054] FIGURE 4 shows plasma BDNF concentration as a function of dextrorphan plasma concentration as described in Example 1. BL, baseline; BDNF, brain-derived neurotrophic factor; DC, deramciclane (30 mg b.i.d.); DM45, dextromethorphan (45 mg b.i.d.); DM60, dextromethorphan (60 mg b.i.d ).DETAILED DESCRIPTION OF THE INVENTION

[0054] In some embodiments, the present disclosure relates to methods of increasing the plasma levels of dextromethorphan while maintaining or increasing the plasma levels of dextrorphan in a subject in need of treatment thereof by administering to the subject in need of treatment with deramciclane, a therapeutically effective amount of a combination of dextromethorphan and deramciclane.

[0055] In some embodiments, the present disclosure relates to methods of treating a subject suffering from an anxiety disorder by administering to the subject in need of treatment thereof a therapeutically effective amount of a combination of dextromethorphan and deramciclane.

[0056] In some embodiments, the present disclosure relates to methods of treating a subject suffering from neuropsychiatric symptoms of dementia by administering to the subject in need of treatment thereof a therapeutically effective amount of a combination of dextromethorphan and deramciclane.

[0057] In some embodiments, the present disclosure relates to methods of treating a subj ect suffering from insomnia or day -night cycle disturbances by administering to the subject in need of treatment thereof a therapeutically effective amount of a combination of dextromethorphan and deramciclane.

[0058] In some embodiments, the present disclosure relates to methods of treating a subject suffering from a cognitive disorder by administering to the subject in need of treatment thereof a therapeutically effective amount of a combination of dextromethorphan and deramciclane.

[0059] In some embodiments, the present disclosure relates to methods of treating a subject with a mood or depressive disorder by administering to the subject in need of treatment thereof, a therapeutically effective amount of a combination of dextromethorphan and deramciclane.

[0060] In some embodiments, the present disclosure relates to methods of treating a subject suffering from psychosis by administering to the subject in need of treatment thereof, a therapeutically effective amount of a combination of dextromethorphan and deramciclane.

[0061] In some embodiments, the present disclosure relates to methods of treating a subject suffering from a substance use disorders by administering to the subject in need of treatment thereof, a therapeutically effective amount of a combination of dextromethorphan and deramciclane.

[0062] In some embodiments, the present disclosure relates to methods of treating a subject suffering from a coughing and addictive behavior disorders by administering to the subject in need of treatment thereof, a therapeutically effective amount of a combination of dextromethorphan and deramciclane.I. Definitions

[0063] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present disclosure. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0064] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of’ and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

[0065] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for therange of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.[00661 As used herein, the terms “about” and “approximately” should be understood to mean within an acceptable range for the particular value as determined by one of ordinary skilled in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean a range of up to 30%, up to 20%, up to 10%, up to 9%, up to 8%>, up to 7%, up to 6%, up to 5%, up to 4%, up to 3%, up to 2% or up to 1% of a given value.

[0067] The term “administering” refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.

[0068] As used herein, the term “anxiety disorders” includes the diagnosis and classification of these mental disorders as described in DSM-V or ICD-11, and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, anxiety disorders such as, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and / or anxiety due to a general medical condition.

[0069] The term “AUC” refers to the area under the time / plasma concentration curve after a single-dose administration of pharmaceutically active compound (e.g., deramciclane or dextromethorphan). AUCo. / denotes the area under the plasma concentration versus time curve from time 0 to infinity and AUCo-t denotes the area under the plasma concentration versus time curve from time 0 to time t, as calculated by the linear trapezoidal method. As used herein, the term “AUC0-12," means the area under the plasma concentration versus time curve, from time 0 to the 12-hour time point, as calculated by the linear trapezoidal method.

[0070] The phrases, “behavioral and psychological symptoms of dementia (BPSD)” or “neuropsychiatric symptoms (NPS)”, as used interchangeable herein as used herein, refer to symptoms that accompany a syndrome of dementia, characterized by emotional, perceptual, cognitive, motor, verbal, and vegetative disturbances that are not solely attributable to another psychiatric, medical, or substance-related disorder, and that appear either at or after the time of dementia onset. BPSD or NPS encompasses disturbances such as but not limited to: i) decreased drive and motivation including apathy and appetite or eating disturbances; ii) affective and emotional; dysregulation including depression, mood lability and anxiety; iii) impulsivity including irritability and aggression; iv) social inappropriateness including disinhibition and agitation; and / or v) abnormal perceptions or thoughts including delusions and hallucinations.

[0071] BPSD or NPS is common in patients suffering from Alzheimer’s disease, Parkinson’s disease dementia, and dementia with Lewy bodies (DLB), vascular dementia (VaD), and frontotemporal lobar degeneration (FTLD).

[0072] “Brain-derived neurotrophic factor” or “BDNF” as used herein refers to a small molecule dimer protein, and the main member of the neurotrophic protein family in the brain. BDNF is widely expressed in the central nervous system (CNS), endocrine system, bone and cartilage tissue, and is particularly highly concentrated within the hippocampus and cortex in the brain. BDNF plays an important role in the survival, proliferation, and differentiation of neurons and glial cells, axon growth, synapse formation, and regulation of synaptic transmission and plasticity. Conversely, disorder of BDNF signaling induces dysfunctions in CNS. Recent studies have found abnormal levels of BDNF in a variety of CNS diseases (e.g., stroke, depression, anxiety, Alzheimer’s disease, and Parkinson’s disease. BDNF is involved in the pathogenesis and / or course of these diseases. Moreover, regulating BDNF signaling represents a potential treatment for such diseases.

[0073] The term “Cavg” refers to the average concentration of a pharmaceutically active compound in the blood following an administration of a pharmaceutically active compound as described in the present disclosure.

[0074] The term “Cmax” refers to the maximum concentration of a pharmaceutically active compound in the blood following an administration of a pharmaceutically acceptable compound as described in the present disclosure.

[0075] As used herein, the term “cognitive disorders” includes the diagnosis and classification of these disorders as described in DSM-V or ICD-11, and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, disorders that comprise as a symptom a deficiency in attention and / or cognition, such as dementia (including that associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, intracranial tumors, cerebral trauma, vascular problems or stroke, multi-infarct dementia, Fronto temporal dementia, alcoholic dementia or other drug-related dementia, AIDS, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse, dementia with Lewy bodies (DLB), vascular dementia (VaD), and / or frontotemporal lobar degeneration (FTLD)), Alzheimer's disease, Parkinson’s disease, delirium, stroke, traumatic brain injury, Huntington’s disease, multiple sclerosis, Down’s syndrome, amnestic disorders and / or age related cognitive decline. In some aspects, the cognitive disorder is dementia, Alzheimer’s disease, Parkinson’s disease, delirium, and / or stroke.

[0076] As used herein, the term “composition” refers to a formulation suitable for administration to an intended subject for therapeutic purposes that contains at least one pharmaceutically active compound and at least one pharmaceutically acceptable carrier or excipient.

[0077] “Day 1” or “day one” as used interchangeably herein refers to the first day of administration of a pharmaceutically active compound to a subject.

[0078] “Day 2” or “day two” as used interchangeably herein refers to the first day after administration of a pharmaceutically active compound to a subject (e.g., 24 hours post-dose) on day 1.

[0079] “Day 3” or “day three” as used interchangeably herein, refers to the 2ndday after administration of a pharmaceutically active compound to a subject on day 1.

[0080] “Day 4” or “day four” as used interchangeably herein, refers to the 3rd day after administration of a pharmaceutically active compound to a subject on day 1.

[0081] “Day 5” or “day five” as used interchangeably herein, refers to the 4th day after administration of a pharmaceutically active compound to a subject on day 1.

[0082] “Day 6” or “day six” as used interchangeably herein, refers to the 5th day after administration of a pharmaceutically active compound to a subject on day 1.

[0083] “Day 7” or “day seven” as used interchangeably herein, refers to the 6th day after administration of a pharmaceutically active compound to a subject on day 1.

[0084] “Day 8” or “day eight” as used interchangeably herein, refers to the 7th day after administration of a pharmaceutically active compound to a subject on day 1.

[0085] “Day 9” or “day nine” as used interchangeably herein, refers to the 8th day after administration of a pharmaceutically active compound to a subject on day 1.

[0086] “Day 10” or “day ten” as used interchangeably herein, refers to the 9th day after administration of a pharmaceutically active compound to a subject on day 1.

[0087] “Day 11” or “day eleven” as used interchangeably herein, refers to the 10thday after administration of a pharmaceutically active compound to a subject on day 1.

[0088] As used herein, “deramci clane”, “EGIS-3886”, or “dimethyl(2-{[(lR,2S,4R)-l,7,7-trimethyl-2-phenylbicyclo[2.2.1]heptan-2-yl]oxy}ethyl)amine” as used interchangeably herein, refers to a compound of Formula I:

[0089] and enantiomers, metabolites, derivatives, prodrugs, diastereomers, pharmaceutically acceptable salts thereof, or any combinations thereof.

[0090] Deramciclane is a specific (1R,2S,4R) enantiomer of (2)-N,N-dimethyl-2-((l,7,7-trimethyl-2-phenylbicyclo-[2,2, l]-hept-2-yl)oxy}-ethamine-2-(E)-butendioate with inverse agonist activity at 5-HT2A and 5-HT2C receptors at clinically relevant doses that is relatively selective against a range of other receptors (Gacsalyi I et al., Receptor binding profile and anxiolytic-type activity of deramciclane (EGIS-3886) in animal models. Drug Dev Res (1997) 40:333-348). While deramciclane is an inverse agonist at both 5-HT2A and 5-HT2C receptors, it does not induce down-regulation of these receptors (Palvimaki EP et al., Deramciclane, a putative anxiolytic drug, is a serotonin 5-HT2C receptor inverse agonist but fails to induce 5-HT2C receptor down-regulation. Psychopharmacology (1998) 136:99-104).

[0091] Metabolites of deramciclane include, for example,N-methyl-2-[(l,7,7-trimethyl-2-phenyl-2-bicyclo[2.2.1]heptanyl)oxy]ethanamine.

[0092] Salts of deramciclane include acid addition salts, such as, deramciclane acetate, deramciclane acetyl salicylate, deramciclane adipate, deramciclane butyrate, deramciclane caprate, deramciclane caproate, deramciclane caprylate, deramciclane enanthate, deramciclane formate, deramciclane fumarate, deramciclane glutarate, deramciclane isophthallate, deramciclane maleate, deramciclane malonate, deramciclane oxalate, deramciclane pelargonate, deramciclane pimelate, deramciclane propionate, deramciclane phthallate, deramciclane salicylate , deramciclane sebacate, deramciclane succinate, deramciclane terephthallate, deramciclane tyrosinate, deramciclane tryptophanate, or deramciclane valerate; or a combination thereof.

[0093] As used herein, the abbreviation “DSM-V-TR” refers to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, text revision published by the American Psychiatric Association (APA).

[0094] The term “deuterated” as used herein, means substituted deuterium atoms. The term “deuterated analog” as used herein alone or as part of a group, means substituted deuterium atoms in place of hydrogen. A deuterated analog may be a fully or partially deuterium substituted derivative.

[0095] As used herein, “dextromethorphan” or “3 -m ethoxy -N-methylmorphinan” as used interchangeably herein, refers to a compound of Formula (II):

[0096] and enantiomers, metabolites, derivatives, prodrugs, diastereomers, pharmaceutically acceptable salts thereof, or any combinations thereof. Specifically, dextromethorphan is the dextrorotatory enantiomer of the morphinan backbone. Levomethorphan is the levorotatory enantiomer of morphinan. Dextromethorphan possesses three chiral centers at positions 9, 13, and 14 of the morphinan backbone.

[0097] Examples of metabolites include dextrorphan, 3 -Methoxymorphinan, 3-Hydroxymorphinan, or combinations thereof. Derivatives of dextromethorphan include, for example, deuterated dextromethorphan, dimemorfan, or combinations thereof.

[0098] Salts of dextromethorphan include, acid addition salts such as dextromethorphan hydrogen acetate, dextromethorphan hydrogen acetyl salicylate, dextromethorphan hydrogen adipate, dextromethorphan hydrogen aspartate, dextromethorphan hydrogen butyrate, dextromethorphan hydrogen caprate, dextromethorphan hydrogen caproate, dextromethorphan hydrogen caprylate, dextromethorphan hydrogen enanthate, dextromethorphan hydrogen formate, dextromethorphan hydrogen fumarate, dextromethorphan hydrogen glutarate, dextromethorphan hydrogen isophthallate, dextromethorphan hydrogen maleate, dextromethorphan hydrogen malonate, dextromethorphan hydrogen oxalate, dextromethorphan hydrogen pelargonate, dextromethorphan hydrogen pimelate, dextromethorphan hydrogen propionate, dextromethorphan hydrogen phthallate, dextromethorphan hydrogen salicylate , dextromethorphan hydrogen sebacate, dextromethorphan hydrogen succinate, dextromethorphan hydrogen terephthallate, dextromethorphan hydrogen tyrosinate, dextromethorphan hydrogen tryptophanate, and dextromethorphan hydrogen valerate.

[0099] The metabolic phenotype of dextromethorphan is determined primarily based on the activity of the cytochrome P4502D6 enzyme (CYP2D6). An example of a way of defining such activity is the Metabolic Ratio (MR), calculated as the concentration of dextromethorphan divided by the concentration of its metabolite, dextrorphan. The MR is typically measured in urine collected over a set period (typically, 4-8 hours) after administration of a specific dose of dextromethorphan. Genotypic "Activity Scores" are also increasingly used to predict these phenotypes.

[0100] As used herein, a “poor metabolizer” or “PM” of dextromethorphan refers to an individual with little or no functional CYP2D6 enzyme activity. In these subjects, the hydroxylation of dextromethorphan to dextrorphan is severely impaired, leading to significantly elevated plasma concentrations of the parent drug and a prolonged elimination half-life. Such individuals often have: (1) A urinary metabolic ratio (DM / Dextrorphan) of greater than 0.3 (logwMR > -0.52); and / or (2) An Activity Score (AS) of 0. This typically corresponds to an individual carrying two non-functional alleles (e.g., *4 / *4, *3 / *4, *4 / *5).

[0101] As used herein, a “normal metabolizer” or “NM” of dextromethorphan (also referred to as "Extensive Metabolizer" or “EM”) refers to an individual with fully functional CYP2D6 activity. These individuals efficiently convert dextromethorphan to dextrorphan. Such individuals have: (1) A urinary metabolic ratio (DMZDextrorphan) of less than 0.03 (specifically between 0.0003 and 0.03); and (2) An Activity Score (AS) of 1.25 to 2.25. Individuals with two normal-function alleles (e.g., *1 / *1) or combinations of normal and decreased-function alleles that result in standard activity.

[0102] As used herein, an “intermediate metabolizer” or “IM” of dextromethorphan refers to an individual between a poor and a normal metabolizer. These individuals possess residual but reduced enzyme activity, resulting in slower clearance than NMs but faster clearance than PMs. Such individuals have: (1) A urinary metabolic ratio (DM / Dextrorphan) between 0.03 and 0.3; and (2) An Activity Score (AS) of 0.25 to 1.0.

[0103] Dextromethorphan is a widely available over-the-counter antitussive (i.e., anticough) sold under the brand name Robitussin®, among others, that has evolved into a platform technology for novel prescription formulations addressing psychiatric and neurological indications.

[0104] Dextromethorphan in combination with quinidine (Nuedexta) received FDA approval in 2010 for the treatment of pseudobulbar affect, a condition characterized by uncontrollable laughing or crying episodes.

[0105] In 2022, FDA approved dextromethorphan / bupropion (Auvelity) for major depressive disorder.

[0106] Dextromethorphan has been investigated for the treatment of Parkinson’ s patients. Multiple investigations support dextromethorphan's potential in Parkinson's disease (PD), targeting both motor and non -motor symptoms. A 1998 clinical trial demonstrated that dextromethorphan (60-120 mg / day) reduced levodopa-induced dyskinesias by 25% (physician ratings) and 40% (UPDRS ratings) without compromising antiparkinsonian efficacy. Verhagen Metman L, Blanchet PJ, van den Munckhof P, Del Dotto P, Natte R, Chase TN. A trial of dextromethorphan in parkinsonian patients with motor response complications. Mov Disord. 1998 May;13(3):414-7. doi: 10.1002 / mds.870130307. PMID: 9613730. examining dextromethorphan's effects on psychomotor function in Parkinson's patients.

[0107] As used herein, the term “TCD-11” refers to the International Classification of Diseases 11thRevision published by the World Health Organization.

[0108] As used herein, the terms “modulate” or “modulating” as used herein refers to changing or varying the amount or level of a target molecule or protein. In some contexts, “modulate” or “modulating” means increasing the level of a target molecule or protein relative to a control or baseline level. In other aspects, “modulate” or “modulating” refers to “increasing the amount or level of a target molecule or protein compared to a control or baseline level of the same target molecule or protein, one or more properties. For example, in some aspects, the term “modulating” means increasing the amount or level of dextrorphan in a subject in need of treatment thereof. Specifically, in some aspects, “modulating” means increasing the plasma level of dextrorphan in a subject in need of treatment thereof when the subject is administered a combination of dextromethorphan and deramciclane compared to when the subject is administered just dextromethorphan alone without being administered deramciclane.

[0109] As used herein, the term “mood and depressive disorders” includes the diagnosis and classification of these medical conditions and disorders described in the DSM-V or ICD-11 and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, bipolar disorders, mood disorders including depressive disorders, major depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a hypomanic mood episode, a depressive episode with atypical features, a depressive episode with melancholic features, a depressive episode with catatonic features, a mood episode with postpartum onset, post-stroke depression; major depressive disorder, dysthymic disorder, minor depressive disorder, premenstrual dysphoric disorder, post-psychotic depressive disorder of schizophrenia, a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia, a bipolar disorder, for example, bipolar I disorder, bipolar II disorder, cyclothymic disorder, depression including unipolar depression, seasonal depression and post-partum depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), mood disorders due to a general medical condition, and substance-induced mood disorders. In some aspects, the mood and depressive disorders are major depressive episode of the mild, moderate or severe type, major depressive disorder, and / or minor depressive disorder.

[0110] The term “pharmaceutically acceptable” indicates that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a subject, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectables.

[0111] As used herein, the phrase “pharmaceutically acceptable excipient” refers to a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate the administration of the pharmaceutically active compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically acceptable excipients include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents.

[0112] As used herein, the term “pharmaceutically active compound” refers to deramciclane or dextromethorphan.

[0113] The terms “prevent”, “preventing”, “prevention” and grammatical variations thereof as used herein, refers to a method of wholly or partially delaying or precluding the onset or recurrence of a disease, disorder or condition and / or one or more of its attendant symptoms or barring a subject from acquiring or reacquiring a disorder or condition or reducing a subject's risk of developing or requiring a disorder or condition or one or more of its attendant symptoms.

[0114] As used herein, the term “prodrugs” is intended to include any covalently bonded carriers that release a pharmaceutically active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs as per the present invention are prepared by modifying functional groups present in deramciclane or dextromethorphan in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound (e.g., deramciclane or dextromethorphan)

[0115] As used herein, the term “psychosis” includes the diagnosis and classification of these mental disorders as described in the DSM-Vor ICD-11, and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, conditions or diseases such as schizophrenia or psychosis, including schizophrenia (paranoid, disorganized, catatonic, undifferentiated, or residual type), schizophreniform disorder, schizoaffective disorder, for example of the delusional type or the depressive type, delusional disorder, psychotic disorder, brief psychotic disorder, sharedpsychotic disorder, psychotic disorder due to a general medical condition and substance-induced or drug-induced (for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, phencyclidine, ketamine and other dissociative anaesthetics, and other psychostimulants), psychosis, psychotic disorder, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, “schizophrenia-spectrum” disorders such as schizoid or schizotypal personality disorders, personality disorder of the paranoid type, personality disorder of the schizoid type, illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), including both the positive and the negative symptoms of schizophrenia and other psychoses. In some aspects, the psychosis is schizophrenia.

[0116] As used herein, the term “substance use disorders” includes the diagnosis and classification of these mental disorders as described in DSM-Vor ICD-1 land the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, substance-induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder, drug addiction, tolerance, and dependence or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics.

[0117] As used herein, the term “subject,” or “patient,” as used interchangeably herein refers to a living organism including, but not limited to, human and non-human vertebrates, e.g. any mammal, such as a human, other primates, sports animals and animals of commercial interest such as cattle, horses, ovines, or porcines, rodents, or pets such as dogs and cats.

[0118] In some aspects, the subject or patient is an adult human. An “adult human” as used herein refers to a human of 18 years of age or older. In other aspects, the subject or patient is a pediatric or minor (e.g., child) human. An “pediatric” or “minor” human, as used herein, refers to a human less than 18 years of age.

[0119] The term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician. It is recognized that one skilled in the art may affect the neurological and psychiatric disorders by treating a patient presently afflicted with the disorders or by prophylactically treating a patientafflicted with such disorders with an effective amount of a pharmaceutically active compound (e g., deramciclane or dextromethorphan).II. Methods of Increasing Plasma Levels of Dextromethorphan, Dextrorphan and / or Brain-Derived Neurotrophic Factor in a Subject in Need of Treatment thereof

[0120] In one embodiment, the present disclosure relates to a method for (a) increasing plasma levels of dextromethorphan in a subject in need of treatment; (b) maintaining or increasing the plasma levels of the metabolite dextrorphan in a subject in need of treatment thereof; (c) increasing plasma levels of dextromethorphan in a subject in need thereof and maintaining or increasing the plasma levels of detrophan in a subject in need of treatment thereof; and / or (d) increasing the plasma levels of brain-derived neurotrophic factor (BDNF) in a subject in need of treatment thereof. Specifically, it was found that the plasma levels of dextromethorphan can be increased in a subject in need of treatment by co-administering dextromethorphan to the subject in combination with deram ci clane, when compared to a subject in need of treatment thereof administered the same dose of dextromethorphan without deramciclane. Additionally, it was found that subjects co-administered dextromethorphan in combination with deramciclane maintain or have increased plasma levels of dextrorphan when compared to a subject administered the same dose of dextromethorphan without deramciclane. In some aspects, subjects co-administered dextromethorphan in combination with deramciclane maintain (e.g., do not decrease) their plasma levels of dextrorphan compared to a subject administered the same dose of dextromethorphan without deramciclane. In other aspects, subjects co-administered dextromethorphan in combination with deramciclane exhibit increased plasma levels of dextrorphan compared to a subject administered the same dose of dextromethorphan without deramciclane. Further, in additional aspects, it was found that subjects co-administered dextromethorphan in combination with deramciclane have increased plasma levels of BDNF compared to a subject administered the same dose of dextromethorphan without deramciclane.

[0121] Moreover, in some aspects, it was found that the co-administration of the combination of dextromethorphan and deramciclane to a subject once or twice a day for at least 10 consecutive days (i.e., day 10) resulted in the subject having an AUCo- of deramciclane thatwas at least 4 times higher than a subject administered the same dose of dextromethorphan alone without any co-administration of deramci clane over the same 10 consecutive days.[001221 Instill further aspects, co-administration of the combination of dextromethorphan and deramciclane, where deramciclane is administered in an amount of at least about 200 ng*hr to a subject once or twice a day for at least 10 consecutive days (i.e., day 10) resulted in the subject having an AUC0-12 of dextromethorphan and / or dextrorphan that was at least 4 times higher than a subject administered the same dose of dextromethorphan alone without any deramciclane over the same 10 consecutive days. In some aspects, the deramciclane is administered to a subject (e.g., a human) in an amount of at least about 210 ng*hr, about 220 ng*hr, about 230 ng*hr, about 240 ng*hr, about 250 ng*hr, about 260 ng*hr, about 270 ng*hr, about 280 ng*hr, about 290 ng*hr, and about 300 ng*hr. In some aspects, the deramciclane is administered to a subject (e.g., a human) in an amount between about 200 ng*hr to about 300 ng*hr. Additionally, in further aspects, the co-administration of the combination of dextromethorphan and deramciclane to a subject (e.g., a human) in need of treatment thereof results in the subject having an AUC0-12 of dextromethorphan and / or dextrorphan that is at least 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, about 9.5, or about 10 times higher than a subject administered the same dose of dextromethorphan without any co-administration of deramciclane over the same 10 consecutive days.

[0123] In still further aspects, co-administration of the combination of dextromethorphan and deramciclane, where the deramciclane is administered in an amount of at least about 200 ng*hr to a subject once or twice a day for at least 10 consecutive days (i.e., day 10) resulted in the subject having an AUC0-12 of BDNF that was at least 4 times higher than a subject administered the same dose of dextromethorphan alone without any deramciclane over the same 10 consecutive days. In some aspects, the deramciclane is administered to a subject (e.g., a human) in an amount of at least about 210 ng*hr, about 220 ng*hr, about 230 ng*hr, about 240 ng*hr, about 250 ng*hr, about 260 ng*hr, about 270 ng*hr, about 280 ng*hr, about 290 ng*hr, and about 300 ng*hr. In some aspects, the deramciclane is administered to a subject (e.g., a human) in an amount between about 200 ng*hr to about 300 ng*hr. Additionally, in further aspects, the co-administration of the combination of dextromethorphan and deramciclane to a subject (e.g., a human) in need of treatment thereof results in the subject having an AUC0-12 ofBDNF that is at least 4.1 , about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, about 9.5, or about 10 times higher than a subject administered the same dose of dextromethorphan without any co-administration of deramci clane over the same 10 consecutive days.

[0124] In addition, in some further aspects, the subject in need of treatment thereof is suffering from at least one anxiety disorder, at least one cognitive disorder, at least one mood and depressive disorder, psychosis, at least one substance use disorder, a cough, or any combination thereof. In further aspects, the subject is suffering from at least one anxiety disorder. In other aspects, the subject is suffering from at least one cognitive disorder. In still other aspects, the subject is suffering from at least one mood and depressive disorder. In yet still further aspects, the subject is suffering from psychosis. In still further aspects, the subject is suffering from at least one substance use disorder. In still further aspects, the subject is suffering from a cough.

[0125] In still yet further aspects, the subject is suffering dementia, Alzheimer’s disease, Parkinson’s disease, depression, a major depressive disorder, a minor depressive disorder, schizophrenia, psychosis, a cough, or a combination thereof.

[0126] In still yet further aspects, the subject is suffering from dementia. In further aspects, the subject is suffering from dementia associated with Alzheimer’s disease, dementia associated with Parkinson’s disease, dementia with Lewy bodies (DLB), vascular dementia (VaD), and / or frontotemporal lobar degeneration (FTLD). In still further aspects, the subject suffering from dementia further exhibits symptoms of behavioral and psychological symptoms of dementia. In yet further aspects, subjects with dementia associated with Alzheimer’s disease, dementia associated with Parkinson’s disease, dementia with Lewy bodies (DLB), vascular dementia (VaD), and / or frontotemporal lobar degeneration (FTLD) further exhibit symptoms of behavioral and psychological symptoms of dementia. In still further aspects, the subject is suffering from neuropsychiatric symptoms resulting from dementia, agitation resulting from dementia, insomnia resulting from dementia, psychosis resulting from dementia, and / or anxiety reesulting from dementia.

[0127] In addition, in further aspects, the human is suffering from at least one anxiety disorder, at least one cognitive disorder, at least one mood and depressive disorder, psychosis, at least one substance use disorder, a cough, or any combination thereof. In further aspects, thehuman is suffering from at least one anxiety disorder. In other aspects, the human is suffering from at least one cognitive disorder. In still other aspects, the human is suffering from at least one mood and depressive disorder. In yet still further aspects, the human is suffering from psychosis. In still further aspects, the human is suffering from at least one substance use disorder.

[0128] In addition, in yet further aspects, the human is suffering from dementia. In further aspects, the human is suffering from dementia associated with Alzheimer’s disease, dementia associated with Parkinson’s disease, dementia with Lewy bodies (DLB), vascular dementia (VaD), and / or frontotemporal lobar degeneration (FTLD). In still further aspects, the human is suffering from dementia further exhibits behavioral and psychological symptoms of dementia. In yet further aspects, the human with dementia associated with Alzheimer’s disease, dementia associated with Parkinson’s disease, dementia with Lewy bodies (DLB), vascular dementia (VaD), and / or frontotemporal lobar degeneration (FTLD) further exhibit symptoms of behavioral and psychological symptoms of dementia.

[0129] The method of the present disclosure involves administering to a subject, such as a human, in need of treatment with deramciclane, a therapeutically effective amount of a combination of dextromethorphan and deramciclane. The dextromethorphan and deramciclane can be administered to the subject (e.g., human) simultaneously or sequentially, in any order. Moreover, the dextromethorphan and deramciclane can be administered to the subject (e.g., human) as separate dosage forms or combined in a single dosage form. In some aspects, when the dextromethorphan and deramciclane are administered as separate dosage forms, the dextromethorphan is administered first followed by the administration of the deramciclane. In still other aspects, the deramciclane is administered first followed by the administration of the dextromethorphan.

[0130] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 1 day. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 1 day.

[0131] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 2 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane isadministered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 2 consecutive days.[001321 Insome aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 3 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 3 consecutive days.

[0133] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 4 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 4 consecutive days.

[0134] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 5 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least twice per day for at least (e.g., a minimum) 5 consecutive days.

[0135] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least once per day for at least (e.g., a minimum) 6 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 6 consecutive days.

[0136] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least once per day for at least (e.g., a minimum) 7 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 7 consecutive days.

[0137] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 8 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane isadministered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 8 consecutive days.[001381 Insome aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 9 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 9 consecutive days.

[0139] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 10 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 10 consecutive days.

[0140] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 14 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least twice per day for at least (e.g., a minimum) 14 consecutive days.

[0141] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least once per day for at least (e.g., a minimum) 21 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 21 consecutive days.

[0142] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least once per day for at least (e.g., a minimum) 28 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 28 consecutive days.

[0143] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 1 month. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 1 month.

[0144] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 2 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 2 months.

[0145] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 3 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 3 months.

[0146] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e g., a minimum) 4 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 4 months.

[0147] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 5 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least twice per day for at least (e.g., a minimum) 5 months.

[0148] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 6 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least twice per day for at least (e.g., a minimum)6 months.

[0149] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least once per day for at least (e.g., a minimum) 7 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 7 months.

[0150] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 8 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 8 months.

[0151] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 9 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 9 months.

[0152] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e g., a minimum) 10 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 10 months.

[0153] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 11 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least twice per day for at least (e.g., a minimum) 11 months.

[0154] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 12 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least twice per day for at least (e.g., a minimum) 12 months.

[0155] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least once per day for at least (e.g., a minimum) 13 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 13 months.

[0156] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 14 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 14 months.

[0157] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 15 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 15 months.

[0158] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e g., a minimum) 16 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 16 months.

[0159] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 17 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least twice per day for at least (e.g., a minimum) 17 months.

[0160] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 18 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least twice per day for at least (e.g., a minimum) 18 months.

[0161] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least once per day for at least (e.g., a minimum) 19 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 19 months.

[0162] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 20 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 20 months.

[0163] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 21 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 21 months.

[0164] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e g., a minimum) 22 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 22 months.

[0165] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 23 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least twice per day for at least (e.g., a minimum) 23 months.

[0166] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 24 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least twice per day for at least (e.g., a minimum) 24 months.

[0167] The amount of dextromethorphan that can be administered to the subject (e.g., human) can be between about 30 to about 120 mg per day (e.g., total amount administered to the subject each day). In some aspects, the subject (e.g., human) is administered 30 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 35 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 40 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 45 mg ofdextromethorphan per day. In other aspects, the subject (e.g., human) is administered 50 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 60 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 70 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 75 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 80 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 90 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 100 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 110 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 120 mg of dextromethorphan per day. In some aspects, the subject (e.g., human) is administered 45 mg or 60 mg of dextromethorphan per day.

[0168] The amount of deramciclane that can be administered to the subject (e.g., human) can be between about 20 to about 120 mg per day (e.g., total amount administered to the subject each day). In some aspects, the subject (e.g., human) is administered 20 mg of deram ci clane per day. In other aspects, the subject (e.g., human) is administered 25 mg of deramciclane per day. In other aspects, the subject (e g., human) is administered 30 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 35 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 40 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 45 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 50 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 60 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 70 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 75 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 80 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 90 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 100 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 110 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 120 mg of deramciclane per day. In some aspects, the subject (e.g., human) is administered 30 mg or 60 mg of deramciclane per day.

[0169] The amount of deramciclane administered to the subject (e.g., human) may vary. If increasing the plasma level of dextromethorphan and / or maintaining and / or maintaining orincreasing the plasma level of dextrorphan in the subject (e.g., human) is desired, deramciclane should be administered to the subject (e.g., human) in a dose that increases dextromethorphan plasma levels and / or maintains or increases dextrorphan plasma levels of the subject (e.g., human), which can be determined using routine techniques known in the art.

[0170] In some aspects, the co-administration of dextromethorphan with deramciclane to a subject (e.g., a human) results in a higher plasma level on the first day the deramciclane is administered to the subject (e.g., on day 1) than in a subject (e.g., a human) administered dextromethorphan without deramciclane on day 1. For example, the dextromethorphan plasma level on the first day after the co-administration of dextromethorphan and deramciclane can be at least 1.5 times, at least 2 times, at least 2.5 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, or at least 10 times the plasma level of a subject (e.g., a human) administered dextromethorphan without deramciclane on day 1.

[0171] In some aspects, the co-administration of dextromethorphan with deramciclane may administered to a subject (e.g., human) on the first day (day 1) of at least two days of treatment with dextromethorphan (e.g., day 2) in an amount that results in an increase in the dextromethorphan plasma level and / or maintenance or increase in the plasma level of dextrorphan on the first day of co-administration, as compared to the same amount of dextromethorphan administered to the subject (e.g., human) without deramciclane on day 1. For example, in some aspects, the plasma level of dextrorphan is increased by at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% the dextrorphan plasma level resulting from the administration of the same amount of dextromethorphan to the subject (e.g., human) without deramciclane on day 1.

[0172] In some embodiments, the co-administration of dextromethorphan with deramciclane to a subject (e.g., a human) in need of treatment thereof results a plasma level of dextromethorphan on day 8 that is at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 50 times, at least 60times, at least 70 times, or at least 90 times the plasma level of dextromethorphan in a subject (e.g., human) administered the same amount of dextromethorphan without deramciclane on day 8.

[0173] In some embodiments, the co-administration of dextromethorphan with deramciclane to a subject (e.g., a human) in need of treatment thereof results in an AUCo-i2or Cavg of dextromethorphan on day 8 that is at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 50 times, at least 60 times, at least 70 times, or at least 90 times the AUC0-12 or Cavg of a subject (e.g., human) administered the same amount of dextromethorphan without deramciclane on day 8.

[0174] In some embodiments, the deramciclane administered co-administered with dextromethorphan to a subject in need of treatment thereof is administered in an amount that results in a Cmaxof dextromethorphan in the subject on day 8 that is at least at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times the Cmaxof a subject (e.g., human) administered the same amount of dextromethorphan without deramciclane on day 8.

[0175] In some embodiments, the co-administration of dextromethorphan with deramciclane may be administered to a subject in an amount that results in an AUC0-12 of deramciclane in the subject, on day 8, that is 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 1,000 ng*hr / mL, at least about 1,200 ng*hr / mL, at least 1,600 ng*hr / mL, or up to about 5,000 ng*hr / mL.

[0176] In some embodiments, the co-administration of dextromethorphan with deramciclane may be administered to a subject in an amount that results in a Cavg of a compound of deramciclane in the subject, on day 8, that is at least about 10 ng / mL, at least about 20 ng / mL, at least abour 30 ng / mL, at least about 40 ng / mL, at least about 50 ng / mL, at least about 60 ng / mL, at least about 70 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, at least about100 ng / mL, at least about 110 ng / mL, at least about 120 ng / mL, at least about 130 ng / mL, at least about 140 ng / mL, at least about 150 ng / mL, at least about 160 ng / mL, at least about 170 ng / mL, at least about 180 ng / mL, at least about 190 ng / mL, at least about 200 ng / mL, at least about 300 ng / mL, at least about 400 ng / mL, at least about 500 ng / mL, at least 600 ng / mL, at least 700 ng / mL, at least 800 ng / mL, at least 900 ng / mL, at least 1000 ng / mL, at least 1100 ng / mL, at least 1200 ng / mL, at least 1300 ng / mL, at least 1400 ng / mL or at least 1500 ng / mL.

[0177] In some embodiments, the dextromethorphan with deramciclane may be coadministered to a subject (e g., a human) once or twice daily for at least 10 consecutive days (i.e., day 10). In some aspects, on day 10 of the co-admini strati on, at 0 hours, 1 hour, 3 hours, 6 hours, 12 hours, the subject (e.g., human) has a dextromethorphan plasma level that is at least about 5%, at least about 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% the dextromethorphan plasma level in a subject administered the same amount of dextromethorphan without deramciclane on day 10.III. Methods of Treating a Subject

[0178] In another embodiment, the present disclosure relates to a method of treating a subject that is suffering from agitation, at least one anxiety disorder, at least one cognitive disorder, at least one mood and depressive disorder, psychosis, at least one substance use disorder, or any combination thereof. In some aspects, the subject is suffering from at least one anxiety disorder. In other aspects, the subject is suffering from at least one cognitive disorder. In still other aspects, the subject is suffering from at least one mood and depressive disorder. In yet still further aspects, the subject is suffering from psychosis. In still further aspects, the subject is suffering from at least one substance use disorder.

[0179] The method involves administering to a subject suffering from agitation, at least one anxiety disorder, at least one cognitive disorder, at least one mood and depressive disorder, psychosis, at least one substance use disorder, a cough, or any combination thereof, and in need of treatment thereof, a therapeutically effective amount of a combination of dextromethorphan and deramciclane. Specifically, it was found that the plasma levels of dextromethorphan can be increased and / or the plasma levels of dextrorphan can be maintained or increased in a subject inneed of treatment thereof by co-administering dextromethorphan to the subject in combination with deramciclane.[001801 Moreover, in some aspects, it was found that the co-administration of the combination of dextromethorphan and deramciclane to a subject once or twice a day for at least 10 consecutive days (i.e., day 10) resulted in the subject having an AUCo- of deramciclane that was at least 4 times higher than a subject administered the same dose of dextromethorphan alone without any co-administration of deramciclane over the same 10 consecutive days.

[0181] In still further aspects, co-administration of the combination of dextromethorphan and deramciclane, where the deramciclane is administered in an amount of at least about 200 ng*hr to a subject once or twice a day for at least 10 consecutive days (i.e., day 10) resulted in the subject having an AUC0-12 of dextromethorphan and / or dextrorphan that was at least 4 times higher than a subject administered the same dose of dextromethorphan alone without any deramciclane over the same 10 consecutive days. In some aspects, the deramciclane is administered to a subject (e.g., a human) in an amount of at least about 210 ng*hr, about 220 ng*hr, about 230 ng*hr, about 240 ng*hr, about 250 ng*hr, about 260 ng*hr, about 270 ng*hr, about 280 ng*hr, about 290 ng*hr, and about 300 ng*hr. In some aspects, the deramciclane is administered to a subject (e.g., a human) in an amount between about 200 ng*hr to about 300 ng*hr. Additionally, in further aspects, the co-administration of the combination of dextromethorphan and deramciclane to a subject (e.g., a human) in need of treatment thereof results in the subject having an AUC0-12 of dextromethorphan and / or dextrorphan that is at least 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, about 9.5, or about 10 times higher than a subject administered the same dose of dextromethorphan without any co-administration of deramciclane over the same 10 consecutive days.

[0182] In still yet further aspects of the above method, the subject is suffering dementia, Alzheimer’s disease, Parkinson’s disease, depression, a major depressive disorder, a minor depressive disorder, schizophrenia, psychosis, a cough, or a combination thereof.

[0183] In still yet further aspects, the subject is suffering from dementia. In further aspects, the subject is suffering from dementia associated with Alzheimer’s disease, dementia associated with Parkinson’s disease, dementia with Lewy bodies (DLB), vascular dementia (VaD), and / or frontotemporal lobar degeneration (FTLD). In still further aspects, the subjectsuffering from dementia further exhibits symptoms of behavioral and psychological symptoms of dementia. In yet further aspects, subjects with dementia associated with Alzheimer’s disease, dementia associated with Parkinson’s disease, dementia with Lewy bodies (DLB), vascular dementia (VaD), and / or frontotemporal lobar degeneration (FTLD) further exhibit symptoms of behavioral and psychological symptoms of dementia.

[0184] In addition, in further aspects, the human is suffering from agitation, at least one anxiety disorder, at least one cognitive disorder, at least one mood and depressive disorder, psychosis, at least one substance use disorder, a cough, or any combination thereof. In further aspects, the human is suffering from at least one anxiety disorder. In other aspects, the human is suffering from at least one cognitive disorder. In still other aspects, the human is suffering from at least one mood and depressive disorder. In yet still further aspects, the human is suffering from psychosis. In still further aspects, the human is suffering from at least one substance use disorder. In still further aspects, the human is suffering from a cough.

[0185] In addition, in yet further aspects, the human is suffering from dementia. In further aspects, the human is suffering from dementia associated with Alzheimer’s disease, dementia associated with Parkinson’s disease, dementia with Lewy bodies (DLB), vascular dementia (VaD), and / or frontotemporal lobar degeneration (FTLD). In still further aspects, the human is suffering from dementia further exhibits behavioral and psychological symptoms of dementia. In yet further aspects, the human with dementia associated with Alzheimer’s disease, dementia associated with Parkinson’s disease, dementia with Lewy bodies (DLB), vascular dementia (VaD), and / or frontotemporal lobar degeneration (FTLD) further exhibit symptoms of behavioral and psychological symptoms of dementia. In still further aspects, the subject is suffering from neuropsychiatric symptoms resulting from dementia, agitation resulting from dementia, insomnia resulting from dementia, psychosis resulting from dementia, and / or anxiety reesulting from dementia.

[0186] The method of the present disclosure involves administering to a subject, such as a human, in need of treatment with deramciclane, a therapeutically effective amount of a combination of dextromethorphan and deramciclane. The dextromethorphan and deramciclane can be administered to the subject (e.g., human) simultaneously or sequentially, in any order. Moreover, the dextromethorphan and deramciclane can be administered to the subject (e.g., human) as separate dosage forms or combined in a single dosage form. In some aspects, whenthe dextromethorphan and deramciclane are administered as separate dosage forms, the dextromethorphan is administered first followed by the administration of the deramciclane. In still other aspects, the deramciclane is administered first followed by the administration of the dextromethorphan .

[0187] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 1 day. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 1 day.

[0188] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 2 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 2 consecutive days.

[0189] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 3 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 3 consecutive days.

[0190] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 4 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 4 consecutive days.

[0191] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 5 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least twice per day for at least (e.g., a minimum) 5 consecutive days.

[0192] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 6 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane isadministered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 6 consecutive days.[001931 Insome aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 7 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 7 consecutive days.

[0194] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 8 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 8 consecutive days.

[0195] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 9 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least twice per day for at least (e.g., a minimum) 9 consecutive days.

[0196] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least once per day for at least (e.g., a minimum) 10 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 10 consecutive days.

[0197] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least once per day for at least (e.g., a minimum) 14 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum)14 consecutive days.

[0198] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 21 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane isadministered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 21 consecutive days.[001991 Insome aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 28 consecutive days. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 28 consecutive days.

[0200] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 1 month. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 1 month.

[0201] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least once per day for at least (e.g., a minimum) 2 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 2 months.

[0202] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 3 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 3 months.[002031 Insome aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 4 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 4 months.

[0204] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 5 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 5 months.

[0205] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 6 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum)6 months.

[0206] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 7 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 7 months.

[0207] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e g., a minimum) 8 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 8 months.

[0208] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 9 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least twice per day for at least (e.g., a minimum) 9 months.

[0209] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 10 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least twice per day for at least (e.g., a minimum) 10 months.

[0210] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least once per day for at least (e.g., a minimum) 11 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 11 months.

[0211] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 12 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 12 months.

[0212] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 13 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 13 months.

[0213] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e g., a minimum) 14 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 14 months.

[0214] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 15 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least twice per day for at least (e.g., a minimum) 15 months.

[0215] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 16 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least twice per day for at least (e.g., a minimum) 16 months.

[0216] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least once per day for at least (e.g., a minimum) 17 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 17 months.

[0217] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 18 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 18 months.

[0218] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 19 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 19 months.

[0219] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e g., a minimum) 20 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 20 months.

[0220] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 21 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least twice per day for at least (e.g., a minimum) 21 months.

[0221] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least once per day for at least (e.g., a minimum) 22 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least twice per day for at least (e.g., a minimum) 22 months.

[0222] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least once per day for at least (e.g., a minimum) 23 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 23 months.

[0223] In some aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e g., human) at least once per day for at least (e.g., a minimum) 24 months. In other aspects, the combination of dextromethorphan and deramciclane is administered to the subject (e.g., human) at least twice per day for at least (e.g., a minimum) 24 months.

[0224] The amount of dextromethorphan that can be administered to the subject (e.g., human) can be between about 30 to about 120 mg per day (e.g., total amount administered to the subject each day). In some aspects, the subject (e.g., human) is administered 30 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 35 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 40 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 45 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 50 mg of dextromethorphan per day. In other aspects, the subject (e g., human) is administered 60 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 70 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 75 mg of dextromethorphan per day. In other aspects, the subject (e g., human) is administered 80 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 90 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 100 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 110 mg of dextromethorphan per day. In other aspects, the subject (e g., human) is administered 120 mg of dextromethorphan per day. In some aspects, the subject (e.g., human) is administered 45 mg or 60 mg of dextromethorphan per day.

[0225] The amount of deramciclane that can be administered to the subject (e.g., human) can be between about 20 to about 120 mg per day (e.g., total amount administered to the subject each day). In some aspects, the subject (e.g., human) is administered 20 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 25 mg of deramciclane per day. In other aspects, the subject (e g., human) is administered 30 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 35 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 40 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 45 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 50 mg of deramciclane per day. In otheraspects, the subject (e.g., human) is administered 60 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 70 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 75 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 80 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 90 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 100 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 110 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 120 mg of deramciclane per day. In some aspects, the subject (e.g., human) is administered 30 mg or 60 mg of deramciclane per day.

[0226] The amount of deramciclane administered to the subject (e.g., human) may vary. If increasing the plasma level of dextromethorphan and / or maintaining and / or maintaining or increasing the plasma level of dextrorphan in the subject (e.g., human) is desired, deramciclane should be administered to the subject (e.g., human) in a dose that increases dextromethorphan plasma levels and / or maintains or increases dextrorphan plasma levels of the subject (e.g., human), which can be determined using routine techniques known in the art.

[0227] In some aspects, the co-administration of dextromethorphan with deramciclane to a subject (e.g., a human) results in a higher plasma level on the first day the deramciclane is administered to the subject (e.g., on day 1) than in a subject (e.g., a human) administered dextromethorphan without deramciclane on day 1. For example, the dextromethorphan plasma level on the first day after the co-administration of dextromethorphan and deramciclane can be at least 1.5 times, at least 2 times, at least 2.5 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, or at least 10 times the plasma level of a subject (e.g., a human) administered dextromethorphan without deramciclane on day 1.

[0228] In some aspects, the co-administration of dextromethorphan with deramciclane may administered to a subject (e.g., human) on the first day (day 1) of at least two days of treatment with dextromethorphan (e.g., day 2) in an amount that results in an increase in the dextromethorphan plasma level and / or maintenance or increase in the plasma level of dextrorphan on the first day of co-administration, as compared to the same amount of dextromethorphan administered to the subject (e.g., human) without deramciclane on day 1. For example, in some aspects, the plasma level of dextrorphan is increased by at least 5%, at least6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% the dextrorphan plasma level resulting from the administration of the same amount of dextromethorphan to the subject (e.g., human) without deram ci clane on day 1.

[0229] In some embodiments, the co-administration of dextromethorphan with deramciclane to a subject (e.g., a human) in need of treatment thereof results a plasma level of dextromethorphan on day 8 that is at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 50 times, at least 60 times, at least 70 times, or at least 90 times the plasma level of dextromethorphan in a subject (e.g., human) administered the same amount of dextromethorphan without deramciclane on day 8.

[0230] In some embodiments, the co-administration of dextromethorphan with deramciclane to a subject (e.g., a human) in need of treatment thereof results in an AUCo-i2or Cavg of dextromethorphan on day 8 that is at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 50 times, at least 60 times, at least 70 times, or at least 90 times the AUC0-12 or CaVg of a subject (e.g., human) administered the same amount of dextromethorphan without deramciclane on day 8.

[0231] In some embodiments, the deramciclane administered co-administered with dextromethorphan to a subject in need of treatment thereof is administered in an amount that results in a Cmaxof dextromethorphan in the subject on day 8 that is at least at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times the Cmaxof a subject (e.g., human) administered the same amount of dextromethorphan without deramciclane on day 8.

[0232] In some embodiments, the co-administration of dextromethorphan with deramciclane may be administered to a subject in an amount that results in an AUC0-12 of deramciclane in the subject, on day 8, that is 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 1,000 ng*hr / mL, at least about 1,200 ng*hr / mL, at least 1,600 ng*hr / mL, or up to about 5,000 ng*hr / mL.

[0233] In some embodiments, the co-administration of dextromethorphan with deramciclane may be administered to a subject in an amount that results in a Cavg of a compound of deramciclane in the subject, on day 8, that is at least about 10 ng / mL, at least about 20 ng / mL, at least abour 30 ng / mL, at least about 40 ng / mL, at least about 50 ng / mL, at least about 60 ng / mL, at least about 70 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, at least about 100 ng / mL, at least about 110 ng / mL, at least about 120 ng / mL, at least about 130 ng / mL, at least about 140 ng / mL, at least about 150 ng / mL, at least about 160 ng / mL, at least about 170 ng / mL, at least about 180 ng / mL, at least about 190 ng / mL, at least about 200 ng / mL, at least about 300 ng / mL, at least about 400 ng / mL, at least about 500 ng / mL, at least 600 ng / mL, at least 700 ng / mL, at least 800 ng / mL, at least 900 ng / mL, at least 1000 ng / mL, at least 1100 ng / mL, at least 1200 ng / mL, at least 1300 ng / mL, at least 1400 ng / mL or at least 1500 ng / mL.

[0234] In some embodiments, the dextromethorphan with deramciclane may be coadministered to a subject (e g., a human) once or twice daily for at least 10 consecutive days (i.e., day 10). In some aspects, on day 10 of the co-administration, at 0 hours, 1 hour, 3 hours, 6 hours, 12 hours, the subject (e.g., human) has a dextromethorphan plasma level that is at least about 5%, at least about 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% the dextromethorphan plasma level in a subject administered the same amount of dextromethorphan without deramciclane on day 10.IV. Dosage Forms and Modes of Administration

[0235] As discussed in Sections II and III, the methods of the present disclosure involve administering to a subject, such as a human, in need of treatment with deramciclane, atherapeutically effective amount of a combination of dextromethorphan and deramciclane. The dextromethorphan and deramciclane can be administered to the subject (e.g., human) simultaneously or sequentially, in any order. Moreover, the dextromethorphan and deramciclane can be administered to the subject (e.g., human) as separate dosage forms or compositions or combined in a single dosage form or single composition. In some aspects, when the dextromethorphan and deramciclane are administered as separate dosage forms, the dextromethorphan is administered first followed by the administration of the deramciclane. In still other aspects, the deramciclane is administered first followed by the administration of the dextromethorphan .

[0236] The dosage forms (or compositions) used in the methods described herein may be a blend or mixture of dextromethorphan and deramciclane, either alone or within a pharmaceutically acceptable excipient. For example, dextromethorphan and deramciclane, may be dispersed within each other or dispersed together within a pharmaceutically acceptable excipient. A dispersion may include a mixture of solid materials wherein small individual particles are substantially one compound, but the small particles are dispersed within one another, such as might occur if two powders of two different pharmaceutically active compounds are blended with a solid vehicle material, and the blending is done in the solid form. In some aspects, dextromethorphan and deramciclane may be substantially uniformly dispersed within a dosage form or composition. Alternatively, dextromethorphan and deramciclane, may be in separate domains or phases in a dosage form or composition. For example, one pharmaceutically active compound may be in a coating, and the other pharmaceutically active compound may be in a core within the coating. For example, one pharmaceutically active compound may be formulated for sustained release and another pharmaceutically active compound may be formulated for immediate release.

[0237] The dextromethorphan and deramciclane may be administered by any means that may result in the contact of the pharmaceutically active compounds with the desired site or site(s) of action in the body of a subject. The pharmaceutically active compounds may be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. For example, they may be administered as the sole active agents in a dosage form or composition, or they can be used in combination with other therapeutically active ingredients.

[0238] The dosage forms and pharmaceutically active compound described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms. The dosage forms may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation. In some aspects, the dosage forms are formulated for intravenous or oral administration.

[0239] For oral administration, the pharmaceutically active compounds the disclosure may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension. . Oral tablets may include the pharmaceutically active compound(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0240] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the pharmaceutically active compound with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and diglycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0241] In other aspects, solid dosage forms (e.g., tablets and capsules) may contain about 10 mg to about 50 mg, about 30 mg to about 60 mg, about 40 mg to about 50 mg, about 40 mg to about 42 mg, about 42 mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about 48 mg to about 50 mg, about 50 mg to about 200 mg, about 50 mg to about 70 mg,about 80 mg to about 100 mg, about 110 mg to about 130 mg, about 170 mg to about 190 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg of deramciclane, or any amount of deramciclane in a range bounded by, or between, any of these values.

[0242] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

[0243] In some aspects, liquid dosage forms may contain about 10 mg to about 50 mg, about 30 mg to about 60 mg, about 40 mg to about 50 mg, about 40 mg to about 42 mg, about 42 mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about 48 mg to about 50 mg, about 80 mg to about 100 mg, about 110 mg to about 130 mg, about 170 mg to about 190 mg, about 45 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg of deramciclane, or any amount of deramciclane in a range bounded by, or between, any of these values.

[0244] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the pharmaceutically active compounds of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form, such as ampoules or disposable injection devices, in multi-dose forms, such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.

[0245] For nasal, inhaled, or oral administration, the dosage forms containing the pharmaceutically active compound(s) may be administered using, for example, a spray formulation also containing a suitable carrier. The dosage forms may be formulated for rectal administration as a suppository.

[0246] For topical applications, the pharmaceutically active compounds of the present disclosure can be formulated as creams, ointments, or a similar vehicle suitable for topical administration. Another mode of administering the pharmaceutically active agents of the disclosure may utilize a patch formulation to effect transdermal delivery.

[0247] The present disclosure has multiple aspects, illustrated by the following non-limiting examples.EXAMPLE 1: EXAMPLE 1: CLINICAL STUDIES

[0248] A Phase 1 two-part randomized adaptive drug-drug interaction study was conducted at two clinical research sites in the Netherlands and Hungary to evaluate the safety, tolerability and pharmacokinetics of deramciclane and dextromethorphan, alone and combined, in healthy elderly volunteers. In Part A of the study, one group of 8 elderly healthy males and females received deramciclane orally for 11 days in an open-label design. While at the research center, subjects received the morning dose of 30 mg deramciclane 30 minutes after a standard breakfast, and the evening dose 12 hours later. In Part B, two groups of 16 male and female subjects each with a CYP2D6 intermediate or normal metabolizer genotype received dextromethorphan orally for 14 days in combination with deramciclane or placebo orally in a double-blind design. While at the research center, subjects received the morning doses of dextromethorphan (45 mg or 60 mg) and deramciclane (30 mg) 30 minutes after a standard breakfast, and the evening doses 12 hours later.EXAMPLE 1A: PLASMA CONCENTRATION OF DEXTROMETHORPHAN AND DEXTRORPHAN

[0249] Blood samples for pharmacokinetic analyses of deramciclane and dextromethorphan (and their metabolites) were taken at pre(moming)dose and 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post(morning) dose on Day 1 and on the last day of treatment. The results are shown in Figure 1 : unlike conventional CYP2D6 inhibitors, deramciclane increases plasma concentration of dextromethorphan while maintaining or even increasing levels of dextrorphan. These results indicate that impact of deramciclane on metabolism of dextromethorphan goes beyond CYP2D6 inhibition.EXAMPLE IB: DIGIT SYMBOL SUBSTITUTION TEST AND BODY SWAY TEST

[0250] The Digit Symbol Substitution Test (DSST) is a subtest from the Wechsler Adult Intelligence Scale. The DSST is a paper-and-pencil cognitive test presented on a single sheet of paper that requires the participant to match symbols to numbers according to a key located on thetop of the page. The participant copies the symbol into spaces below a row of numbers. The number of correct symbols within the allowed time (120 seconds) constitutes the score. This task involves many cognitive factors (i.e., motor coordination, reaction time, eye-hand coordination, scanning ability, and short-term memory). DSST was done on Day -1 (baseline) and on the last treatment day approximately 2 to 6 hours post(morning)dose (but always completed before lunch). A body sway test is used to test physical balance / postural stability.

[0251] Study participants dosed as described herein were given DSST and body sway tests. A body sway test assesses neurological control of balance and stability, which depends on the integration of vestibular, proprioceptive, cerebellar, spinal, and peripheral nervous system inputs.

[0252] The results are shown in Figures 2 and 3 indicating that treatment with the combination of dextromethorphan and deramciclane does not result in impairment in cognitive or ability to maintain the body posture and balance.EXAMPLE 1C: PLASMA CONCENTRATION OF BDNF

[0253] Blood sampling for BDNF was performed at pre(moming) dose on Day 1, and at 4 and 12 hours post (morning) dose on Day 11 (as described previously herein). The results are shown in Figure 4: i) dextromethorphan alone and in combination with deramciclane increased plasma concentration of BDNF, and ii) this increase correlates with plasma concentration of dextrorphan but not dextromethorphan. These results indicate that plasma concentration of dextrorphan may be of therapeutic significance in diseases and disease states that benefit from greater levels of BDNF.

[0254] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the disclosure, which is defined solely by the appended claims and their equivalents.

[0255] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, compositions, formulations, or methods of use of the disclosure, may be made without departing from the spirit and scope thereof.

[0256] For reasons of completeness, various aspects of the disclosure are set out in the following numbered clauses:

[0257] Clause 1. A method of increasing plasma levels of dextromethorphan and maintaining or increasing plasma levels of dextrorphan in a subject in need of treatment thereof, the method comprising:

[0258] administering to a subject in need of treatment a therapeutically effective amount of a combination of dextromethorphan and deramciclane, wherein the dextromethorphan and deramciclane are administered to the subject either simultaneously or sequentially, and in any order, and

[0259] further wherein:

[0260] a) the administration of the combination of dextromethorphan and deramciclane to the subject is once or twice per day for a minimum of at least 10 consecutive days;

[0261] b) the deramciclane is administered to the subject in an amount of at least about 200 ng*hr to produce an AUC0-12 of deramciclane; and

[0262] c) the administration of the combination of dextromethorphan and deramciclane produces an AUC0-12 of dextromethorphan and dextrorphan in the subject that is higher on the tenth day after the start of administration of the combination than on the tenth day after the start of administration of dextromethorphan alone, without the deramciclane.

[0263] Clause 2. The method of clause 1, wherein the dextromethorphan and deramciclane are administered sequentially.

[0264] Clause 3. The method of clause 1, wherein the dextromethorphan and deramciclane are administered simultaneously.

[0265] Clause 4. The method of any of clauses 1-3, wherein the dextromethorphan and deramciclane are administered as separate compositions.

[0266] Clause 5. The method of any of clauses 1-4, wherein the dextromethorphan and deramciclane are administered once per day.

[0267] Clause 6. The method of any of clauses 1-4, wherein the dextromethorphan and deramciclane are administered twice per day.

[0268] Clause 7. The method of any of clauses 1-6, wherein the dextromethorphan is deuterated, the deramciclane is deuterated, or the dextromethorphan is deuterated and the deramciclane is deuterated.

[0269] Clause 8. The method of any of clauses 1-7, wherein the administration to the subject of the combination of dextromethorphan and deramciclane produces an AUC0-12 in the subjectthat is at least 4 times higher on the tenth day after the start of administration of the combination than on the tenth day after the start of administration of dextromethorphan alone, without the deramci cl ane.

[0270] Clause 9. The method of any of clauses 1-8, wherein about 30 mg to about 120 mg of dextromethorphan is administered to the subject per day and about 20 mg to about 20 mg of deramciclane is administered to the subject per day.

[0271] Clause 10. A method of increasing plasma levels of brain-derived neurotrophic factor (BDNF) in a subject in need of treatment thereof, the method comprising:

[0272] administering to a subject in need of treatment a therapeutically effective amount of a combination of dextromethorphan and deramciclane, wherein the dextromethorphan and deramciclane are administered to the subject either simultaneously or sequentially, and in any order, and

[0273] further wherein:

[0274] a) the administration of the combination of dextromethorphan and deramciclane to the subject is once or twice per day for a minimum of at least 10 consecutive days;

[0275] b) the deramciclane is administered to the subject in an amount of at least about 200 ng*hrto produce an AUCo-i2of deramciclane; and

[0276] c) the administration of the combination of dextromethorphan and deramciclane produces an AUC0-12 of dextromethorphan and dextrorphan in the subject that is at least about 20 higher on the tenth day after the start of administration of the combination than on the tenth day after the start of administration of dextromethorphan alone, without the deramciclane.

[0277] Clause 11. The method of clause 10, wherein the dextromethorphan and deramciclane are administered sequentially.

[0278] Clause 12. The method of clause 10, wherein the dextromethorphan and deramciclane are administered simultaneously.

[0279] Clause 13. The method of any of clauses 10-12, wherein the dextromethorphan and deramciclane are administered as separate compositions.

[0280] Clause 14. The method of any of clauses 10-13, wherein the dextromethorphan and deramciclane are administered once per day.

[0281] Clause 15. The method of any of clauses 10-13, wherein the dextromethorphan and deramciclane are administered twice per day.

[0282] Clause 16. The method of any of clauses 10-15, wherein the dextromethorphan is deuterated, the deramciclane is deuterated, or the dextromethorphan is deuterated and the deramciclane is deuterated.

[0283] Clause 17. The method of any of clauses 10-17, wherein about 30 mg to about 120 mg of dextromethorphan is administered to the subject per day and about 20 mg to about 20 mg of deramciclane is administered to the subject per day.

[0284] Clause 18. A method of treating a subject in need of treatment thereof, the method comprising:

[0285] administering to a subject in need of treatment a therapeutically effective amount of a combination of dextromethorphan and deramciclane, wherein the dextromethorphan and deramciclane are administered to the subject either simultaneously or sequentially, and in any order, and

[0286] further wherein:

[0287] a) the administration of the combination of dextromethorphan and deramciclane to the subject is once or twice per day for a minimum of at least 10 consecutive days;

[0288] b) the deramciclane is administered to the subject in an amount of at least about 200 ng*hr to produce an AUC0-12 of deramciclane;

[0289] c) the administration of the combination of dextromethorphan and deramciclane produces an AUC0-12 of dextromethorphan and dextrorphan in the subject that is higher on the tenth day after the start of administration of the combination than on the tenth day after the start of administration of dextromethorphan alone, without the deramciclane;

[0290] d) the subject is suffering from an anxiety disorder, a cognitive disorder, a mood and depressive disorder, psychosis, a substance use disorders, coughing, or a combination thereof.

[0291] Clause 19. The method of clause 18, wherein the subject is suffering from dementia, Alzheimer’s disease, Parkinson’s disease, depression, a major depressive disorder, a minor depressive disorder, schizophrenia, psychosis, coughing or a combination thereof.

[0292] Clause 20. The method of clause 18, wherein the subject is suffering from dementia or Alzheimer’s disease.

[0293] Clause 21. The method of clause 18, wherein the subject is suffering from behavioral and psychological symptoms of dementia.

[0294] Clause 22. The method of clause 18, wherein the dextromethorphan and deramciclane are administered simultaneously.

[0295] Clause 23. The method of any of clauses 18-22, wherein the dextromethorphan and deramciclane are administered as separate compositions.

[0296] Clause 24. The method of any of clauses 18-22, wherein the dextromethorphan and deramciclane are administered once per day.

[0297] Clause 25. The method of any of clauses 18-23, wherein the dextromethorphan and deramciclane are administered twice per day.

[0298] Clause 26. The method of any of clauses 18-25, wherein the dextromethorphan is deuterated, the deramciclane is deuterated, or the dextromethorphan is deuterated and the deramciclane is deuterated.

[0299] Clause 27. The method of any of clauses 18-26, wherein the administration to the subject of the combination of dextromethorphan and deramciclane produces an AUC0-12 in the subject that is at least 4 times higher on the tenth day after the start of administration of the combination than on the tenth day after the start of administration of dextromethorphan alone, without the deramciclane.

[0300] Clause 28. The method of any of clauses 18-27, wherein about 30 mg to about 120 mg of dextromethorphan is administered to the subject per day and about 20 mg to about 20 mg of deramciclane is administered to the subject per day.

Claims

Claims:

1. A method of increasing plasma levels of dextromethorphan and maintaining or increasing plasma levels of dextrorphan in a subject in need of treatment thereof, the method comprising:administering to a subject in need of treatment a therapeutically effective amount of a combination of dextromethorphan and deramciclane, wherein the dextromethorphan and deramciclane are administered to the subject either simultaneously or sequentially, and in any order, andfurther wherein:a) the administration of the combination of dextromethorphan and deramciclane to the subject is once or twice per day for a minimum of at least 10 consecutive days;b) the deramciclane is administered to the subject in an amount of at least about 200 ng*hr to produce an AUC0-12 of deramciclane; andc) the administration of the combination of dextromethorphan and deramciclane produces an AUC0-12 of dextromethorphan and dextrorphan in the subject that is higher on the tenth day after the start of administration of the combination than on the tenth day after the start of administration of dextromethorphan alone, without the deramciclane.

2. The method of claim 1, wherein the dextromethorphan and deramciclane are administered sequentially.

3. The method of claim 1, wherein the dextromethorphan and deramciclane are administered simultaneously.

4. The method of any of claims 1-3, wherein the dextromethorphan and deramciclane are administered as separate compositions.

5. The method of any of claims 1-4, wherein the dextromethorphan and deramciclane are administered once per day.

6. The method of any of claims 1-4, wherein the dextromethorphan and deramciclane are administered twice per day.

7. The method of any of claims 1-6, wherein the dextromethorphan is deuterated, the deramciclane is deuterated, or the dextromethorphan is deuterated and the deramciclane is deuterated.

8. The method of any of claims 1 -7, wherein the administration to the subject of the combination of dextromethorphan and deramci clane produces an AUC0-12 in the subject that is at least 4 times higher on the tenth day after the start of administration of the combination than on the tenth day after the start of administration of dextromethorphan alone, without the deramci clane.

9. The method of any of claims 1-8, wherein about 30 mg to about 120 mg of dextromethorphan is administered to the subject per day and about 20 mg to about 20 mg of deramciclane is administered to the subject per day.

10. A method of increasing plasma levels of brain-derived neurotrophic factor (BDNF) in a subject in need of treatment thereof, the method comprising:administering to a subject in need of treatment a therapeutically effective amount of a combination of dextromethorphan and deramciclane, wherein the dextromethorphan and deramciclane are administered to the subject either simultaneously or sequentially, and in any order, andfurther wherein:a) the administration of the combination of dextromethorphan and deramciclane to the subject is once or twice per day for a minimum of at least 10 consecutive days;b) the deramciclane is administered to the subject in an amount of at least about 200 ng*hr to produce an AUC0-12 of deramciclane; andc) the administration of the combination of dextromethorphan and deramciclane produces an AUC0-12 of dextromethorphan and dextrorphan in the subject that is at least about 20 higher on the tenth day after the start of administration of the combination than on the tenth day after the start of administration of dextromethorphan alone, without the deramciclane.

11. The method of claim 10, wherein the dextromethorphan and deramciclane are administered sequentially.

12. The method of claim 10, wherein the dextromethorphan and deramciclane are administered simultaneously.

13. The method of any of claims 10-12, wherein the dextromethorphan and deramciclane are administered as separate compositions.

14. The method of any of claims 10-13, wherein the dextromethorphan and deramciclane are administered once per day.

15. The method of any of claims 10-13, wherein the dextromethorphan and deramciclane are administered twice per day.

16. The method of any of claims 10-15, wherein the dextromethorphan is deuterated, the deramciclane is deuterated, or the dextromethorphan is deuterated and the deramciclane is deuterated.

17. The method of any of claims 10-17, wherein about 30 mg to about 120 mg of dextromethorphan is administered to the subject per day and about 20 mg to about 20 mg of deramciclane is administered to the subject per day.

18. A method of treating a subject in need of treatment thereof, the method comprising:administering to a subject in need of treatment a therapeutically effective amount of a combination of dextromethorphan and deramciclane, wherein the dextromethorphan and deramciclane are administered to the subject either simultaneously or sequentially, and in any order, andfurther wherein:a) the administration of the combination of dextromethorphan and deramciclane to the subject is once or twice per day for a minimum of at least 10 consecutive days;b) the deramciclane is administered to the subject in an amount of at least about 200 ng*hr to produce an AUC0-12 of deramciclane;c) the administration of the combination of dextromethorphan and deramciclane produces an AUC0-12 of dextromethorphan and dextrorphan in the subject that is higher on the tenth day after the start of administration of the combination than on the tenth day after the start of administration of dextromethorphan alone, without the deramciclane; andd) the subject is suffering from agitation, an anxiety disorder, a cognitive disorder, a mood and depressive disorder, psychosis, a substance use disorders, or a combination thereof.

19. The method of claim 18, wherein the subject is suffering from dementia, Alzheimer’s disease, Parkinson’s disease, depression, a major depressive disorder, a minor depressive disorder, schizophrenia, psychosis, or a combination thereof.

20. The method of claim 18, wherein the subject is suffering from dementia or Alzheimer’s disease.

21. The method of claim 18, wherein the subject is suffering from behavioral and psychological symptoms of dementia.

22. The method of claim 18, wherein the dextromethorphan and deramci clane are administered simultaneously.

23. The method of any of claims 18-22, wherein the dextromethorphan and deramciclane are administered as separate compositions.

24. The method of any of claims 18-22, wherein the dextromethorphan and deramciclane are administered once per day.

25. The method of any of claims 18-23, wherein the dextromethorphan and deramciclane are administered twice per day.

26. The method of any of claims 18-25, wherein the dextromethorphan is deuterated, the deramciclane is deuterated, or the dextromethorphan is deuterated and the deramciclane is deuterated.

27. The method of any of claims 18-26, wherein the administration to the subject of the combination of dextromethorphan and deramciclane produces an AUC0-12 in the subject that is at least 4 times higher on the tenth day after the start of administration of the combination than on the tenth day after the start of administration of dextromethorphan alone, without the deramciclane.

28. The method of any of claims 18-27, wherein about 30 mg to about 120 mg of dextromethorphan is administered to the subject per day and about 20 mg to about 20 mg of deramciclane is administered to the subject per day.

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