Compositions and methods for enhancing deramciclane therapeutic concentration

Abstract

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

Description

COMPOSITIONS AND METHODS FOR ENHANCING DERAMCICLANE THERAPEUTIC CONCENTRATION RELATED APPLICATION INFORMATION

[0001] This application claims priority to U.S. Application No. 63 / 745,222 filed on January 14, 2025, the contents 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 related to deramciclane.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 for development 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 deramciclane 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 deramciclane in a subject in need of treatment thereof. The method comprises:

[0008] administering to a subject in need of treatment with deramciclane, 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) deramciclane administered to the subject produces an AUC0-12 of deramciclane of at least about 50 ng*hr / ml in the subject; and

[0012] c) the administration of the combination of dextromethorphan and deramciclane produces an AUC0-12 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 deramciclane alone, without the dextromethorphan.

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

[0014] In other 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 still further aspects of the above method, the dextromethorphan and deramciclane are 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 further aspects of the above method, the increase in deramciclane plasma level is observed on the first day of administration to the subject of the combination of dextromethorphan and deramciclane whereas no increase in deramciclane plasma level is observed on the first day of administration to the subject of deramciclane alone without dextromethorphan.

[0020] 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 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 deramciclane alone, without the dextromethorphan.

[0021] In still further aspects of the above method, about 10 mg to about 120 mg of dextromethorphan is administered to the subject per day and about 10 mg to about 120 mg of deramciclane is administered to the subject per day.

[0022] In another embodiment, the present disclosure relatees to a method of treating a subject in need of treatment thereof. The method comprises:

[0023] administering to a subject in need of treatment thereof, 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

[0024] further wherein:

[0025] 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;

[0026] b) deramciclane administered to the subject produces an AUC0-12 of deramciclane of at least about 50 ng*hr / ml in the subject;

[0027] c) the administration of the combination of dextromethorphan and deramciclane produces an AUC0-12 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 deramciclane alone, without the dextromethorphan; and

[0028] d) the subject is suffering from an anxiety disorder, a cognitive disorder, a mood and depressive disorder, psychosis, a substance-related and addictive behavior disorders, or a combination thereof.

[0029] In some aspects of the above method, the subject is suffering from dementia, Alzheimer’s disease, Parkinson’s disease, depression, a major depressive disorder, schizophrenia, psychosis, generalized anxiety disorder, social anxiety disorder, post-traumatic stress disorder, or a combination thereof.

[0030] In still further aspects of the above method, the subject is suffering from dementia or Alzheimer’s disease.

[0031] In still further aspects of the above method, the subject is suffering from behavioral and psychological symptoms of dementia.

[0032] In still yet further aspects of the above method, the subject is suffering from neuropsychiatric symptoms resulting from dementia, insomnia resulting from dementia, psychosis resulting from dementia, and / or anxiety resulting from dementia.

[0033] In still further aspects of the above method, the dextromethorphan and deramciclane are administered sequentially.

[0034] In yet further aspects of the above method, the dextromethorphan and deramciclane are administered simultaneously.

[0035] In yet further aspects of the above method, the dextromethorphan and deramciclane are administered as separate compositions.

[0036] In still further aspects of the above method, the dextromethorphan and deramciclane are administered once per day.

[0037] In yet still further aspects of the above method, the dextromethorphan and deramciclane are administered twice per day.

[0038] In still yet further aspects of the above method, the dextromethorphan is deuterated, the deramciclane is deuterated, or the dextromethorphan is deuterated and the deramciclane is deuterated.

[0039] In still yet further aspects of the above method, the increase in deramciclane plasma level is observed on the first day of administration to the subject of the combination of dextromethorphan and deramciclane whereas no increase in deramciclane plasma Isevel isobserved on the first day of administration to the subject of deramciclane alone without dextromethorphan.[00401 Inyet 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 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 deramciclane alone, without the dextromethorphan.

[0041] In still yet further aspects of the above method, about 10 mg to about 120 mg of dextromethorphan is administered to the subject per day and about 10 mg to about 120 mg of deramciclane is administered to the subject per day.BRIEF DESCRIPTION OF FIGURES

[0042] FIGURE 1 shows the plasma concentration of deramciclane with or without coadministration of dextromethorphan. Data are presented as mean (±95% confidence intervals) Cmax achieved after deramciclane (30 mg bid) was administered alone or in combination with dextromethorphan (45 mg or 60 mg bid). * p < 0.05.

[0043] FIGURE 2 shows the plasma concentration of deramciclane with or without coadministration of dextromethorphan. Data are presented as mean (±95% confidence intervals) Cmin achieved after deramciclane (30 mg bid) was administered alone or in combination with dextromethorphan (45 mg or 60 mg bid). * p < 0.05.

[0044] FIGURE 3 shows the plasma concentration of deramciclane with or without coadministration of dextromethorphan. Data are presented as mean (±95% confidence intervals) AUCo-12 achieved after deramciclane (30 mg bid) was administered alone or in combination with dextromethorphan (45 mg or 60 mg bid). * p < 0.05.

[0045] FIGURE 4 shows the plasma concentration of deramciclane with or without coadministration of dextromethorphan. Data are presented as mean plasma concentration (ng / ml) achieved after deramciclane (30 mg bid) was administered alone (left panel) or in combination with dextromethorphan (60 mg bid; right panel). The dotted line indicates plasma concentration of 78 ng / ml corresponding to the maximum possible occupancy of frontal cortical 5 -HT2 A receptors.

[0046] FIGURE 5 shows the occupancy of frontal cortical 5 -HT2 A receptors as a function of plasma concentration of deramciclane in a human PET study.

[0047] FIGURE 6 shows the hours per day with maximal possible occupancy of 5-HT2A receptors achieved by deram ci clane (30 mg bid) at steady-state when given alone or in combination with dextromethorphan (45 mg or 60 mg bid). Data is presented as medians with 95% confidence intervals.DETAILED DESCRIPTION OF THE INVENTION

[0048] In some embodiments, the present disclosure relates to methods of increasing the plasma levels of deramciclane 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.

[0049] 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.

[0050] In some embodiments, the present disclosure relates to methods of treating a subject suffering from neuropsychiatric symptoms resulting from dementia, insomnia resulting from dementia, psychosis resulting from dementia, and / or anxietyresulting from dementia by administering to the subject in need of treatment thereof a therapeutically effective amount of a combination of dextromethorphan and deramciclane.

[0051] In some embodiments, the present disclosure relates to methods of treating a subject 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.

[0052] In some embodiments, the present disclosure relates to methods of treating a subj ect 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.

[0053] In some embodiments, the present disclosure relates to methods of treating a subj ect 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.

[0054] In some embodiments, the present disclosure relates to methods of treating a subj ect suffering from psychosis by administering to the subject in need of treatment thereof, a therapeutically effective amount of a combination of dextromethorphan and deramciclane.

[0055] In some embodiments, the present disclosure relates to methods of treating a subjectsuffering from a substance-related 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

[0056] 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.

[0057] 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.

[0058] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range 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.

[0059] 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.

[0060] The term “administering” refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasalor 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] The term “agitation” includes aggressive and non-aggressive forms of verbal and motor agitated behaviors.

[0065] 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)

[0066] 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.

[0067] 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.

[0068] 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 lacob 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.

[0069] 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.

[0070] “Day 1” or “day one” as used interchangeably herein refers to the first day of administration of a pharmaceutically active compound to a subject.

[0071] “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.

[0072] “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.

[0073] “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.

[0074] “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.

[0075] “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.

[0076] “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.

[0077] “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.

[0078] “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.

[0079] “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.

[0080] “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.

[0081] 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:

[0082] and enantiomers, metabolites, derivatives, prodrugs, diastereomers, pharmaceutically acceptable salts thereof, or any combinations thereof.

[0083] 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).

[0084] Metabolites of deramciclane include, for example,N-methyl-2-[(l,7,7-trimethyl-2-phenyl-2-bicyclo[2.2.1]heptanyl)oxy]ethanamine.

[0085] 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.

[0086] As used herein, the abbreviation “DSM-V” refers to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, text revision published by the American Psychiatric Association (APA).

[0087] 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.

[0088] As used herein, “dextromethorphan” or “3 -m ethoxy -N-methylmorphinan” as used interchangeably herein, refers to a compound of Formula (II):

[0089] 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.

[0090] Examples of metabolites include dextrorphan, 3-Methoxymorphinan, 3-Hydroxymorphinan, or combinations thereof. Derivatives of dextromethorphan include, for example, deuterated dextromethorphan, dimemorfan, or combinations thereof.

[0091] 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.

[0092] Examples include addition salts of dextromethorphan, 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 hydrogenformate, 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.

[0093] The metabolic phenotype of dextromethorphan is determined primarily based on the activity of the cytochrome P4502D6 enzyme (CYP2D6). Genotypic "Activity Scores" are also increasingly used to predict these phenotypes.

[0094] 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.

[0095] 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.

[0096] In 2022, FDA approved dextromethorphan / bupropion (Auvelity) for major depressive disorder.

[0097] 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.

[0098] Dextromethorphan's neuroprotective profile extends beyond simple NMDA blockadeAs used herein, the term “ICD-H” refers to the International Classification of Diseases 11thRevision published by the World Health Organization.

[0099] 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.

[0100] 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.

[0101] 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, anti-oxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents.

[0102] As used herein, the term “pharmaceutically active compound” refers to deramciclane or dextromethorphan.

[0103] 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.

[0104] 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)

[0105] As used herein, the term “psychosis” includes the diagnosis and classification of these mental disorders as 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, 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, shared psychotic 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 and / or psychosis.

[0106] As used herein, the term substance-related and addictive behavior 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, 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.

[0107] 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.

[0108] 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.

[0109] 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 patient afflicted with such disorders with an effective amount of a pharmaceutically active compound (e.g., deramciclane or dextromethorphan).IL Methods of Increasing Plasma Levels of Deramciclane in a Subject in Need of Treatment thereof

[0110] In one embodiment, the present disclosure relates to a method for increasing plasma levels of deramciclane in a subject in need of treatment. Specifically, it was found that the plasma levels of deramciclane can be increased in a subject in need of treatment by coadministering dextromethorphan to the subject in combination with deramciclane. Moreover, it was found that the co-admini strati on of the combination of dextromethorphan and deramciclaneto 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 deramciclane: (a) of at least about 50 ng*hr; and (b) at least 20% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days.

[0111] 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-related and addictive behavior disorder, 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-related and addictive behavior disorder.

[0112] 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, or a combination thereof.

[0113] 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, insomnia resulting from dementia, psychosis resulting from dementia, and / or anxietyresulting from dementia.

[0114] In some aspects, the subject is need of treatment thereof is a human. In some aspects, the human in need of treatment thereof is a poor metabolizer of dextromethorphan. In other aspects, the human in need of treatment thereof is a normal metabolizer of dextromethorphan. In still further aspects, the human in need of treatment thereof is an intermediate metabolizer of dextromethorphan.

[0115] 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-related and addictive behavior disorder, 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-related and addictive behavior disorder.

[0116] 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.

[0117] 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 deramciclane. In still other aspects, C is administered first followed by the administration of dextromethorphan.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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.

[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) 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.

[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) 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.

[0132] 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.

[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) 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.

[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) 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.

[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) 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.

[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) 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.

[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) 7months. 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.

[0138] 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.

[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) 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.

[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) 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.

[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) 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.

[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) 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.

[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) 13 months. 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) 13 months.[001441 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) 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.

[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) 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.

[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) 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.

[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) 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.

[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) 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.

[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) 19 months. 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) 19 months.[001501 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) 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.

[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) 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.

[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) 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.

[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) 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.

[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) 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.

[0155] The amount of dextromethorphan that can be administered to the subject (e.g., human) can be between about 10 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 10 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 15 mg ofdextromethorphan per day. In other aspects, the subject (e.g., human) is administered 20 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 25 mg of dextromethorphan per day. In other 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.

[0156] The amount of deramciclane that can be administered to the subject (e.g., human) can be between about 10 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 10 mg of deramciclane per day. In other aspects, the subject (e.g., human) is administered 15 mg of deramciclane per day. In other 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 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 otheraspects, 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.

[0157] The amount of dextromethorphan administered to the subject (e.g., human) may vary. If increasing the plasma level of deramciclane in the subject (e.g., human) is desired, dextromethorphan should be administered to the subject (e.g., human) in a dose that increases deramciclane plasma levels of the subject (e.g., human), which can be determined using routine techniques known in the art.

[0158] 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 deramciclane (e.g., day 2) in an amount that results in an increase in the deramciclane plasma level on the first day of co-administration, as compared to the same amount of deramciclane administered to the subject (e.g., human) without dextromethorphan on day 1. For example, on the first day (e.g., day 1) co-administration of the combination to the subject (e.g., human), the deramciclane plasma level may be increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 80%, at least about 90%, at least about 100%, at least about 110%, at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least about 200% as compared to the deramciclane plasma level resulting from the administration of the same amount of deramciclane to the subject (e.g., human) without dextromethorphan on day 1.

[0159] In some further aspects, the co-administration of dextromethorphan with deramciclane may be administered to the subject (e.g., human) once or twice a day for 8 consecutive days, until day 8, in an amount that results in a plasma concentration of deramciclane in the subject (e.g., human) that is at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70%, at least about 2 times, at least about 3 times, or at least about 4 times higher than the plasma concentration of the sameamount of deramciclane administered to the subject (e.g., human) without dextromethorphan for the same 8 consecutive days.[001601 Insome aspects, the co-administration of dextromethorphan with deramciclane may be administered to a subject in an amount that results in an AUC0-12, or average plasma concentration in the subject (e.g., human) for the 12 hours following dosing (Cavg) of deramciclane, on day 8, that is at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%o, or at least about 70%, at least about 2 times, at least about 3 times, or at least about 4 times higher than the plasma concentration of the same amount of deramciclane administered to the subject without dextromethorphan for the same 8 consecutive days.

[0161] In some embodiments, the co-administration of dextromethorphan with deramciclane in an amount that results in a maximum plasma concentration (Cmax) of deramciclane in the subject (e.g., human), on day 8, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70%, at least about 2 times, at least about 3 times, or at least about 4 times higher than the plasma concentration of the same amount of deramciclane administered to the subject (e.g., human) without dextromethorphan for the same 8 consecutive days (e.g., day 8).

[0162] 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.

[0163] 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 170ng / 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, or at least about 500 ng / mL.[001641 Insome 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, the administration of the combination of dextromethorphan and deramciclane to the subject (e.g., human) results in the subject having an AUC0-12 of deramciclane of at least about 50 ng*hr. In some aspects, the subject has an AUC0-12 of deramciclane of at least about 55 ng*hr. In other aspects, the subject has an AUC0-12 of deramciclane of at least about 60 ng*hr. In other aspects, the subject has an AUC0-12 of deramciclane of at least about 65 ng*hr. In some aspects, the subject has an AUC0-12 of deramciclane of at least about 70 ng*hr. In still further aspects, the subject has an AUC0-12 of deramciclane of at least about 75 ng*hr. In other aspects, the subject has an AUC0-12 of deramciclane ranging from about 50 ng*hr to about 75 ng*hr.

[0165] In other aspects, in addition, or alternatively, the administration of the combination of dextromethorphan and deramciclane to the subject (e.g., human) results in the subject having an AUC0-12 of deramciclane that is at least 20% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days (i.e., day 10). In other aspects, the subject (e.g., human) has an AUCo-12 of deramciclane that is at least 21% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 22% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 23% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 24% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 25% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 ofderamciclane that is at least 26% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 27% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 28% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 29% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 30% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUCo-i2of deramciclane that is at least 31% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 32% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 33% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 34% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 35% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days.III. Methods of Treating a Subject

[0166] In another embodiment, the present disclosure relates to a method of treating a subject that 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-related and addictivebehavior 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-related and addictive behavior disorder.

[0167] The method involves administering to a subject suffering from at least one anxiety disorder, at least one cognitive disorder, at least one mood and depressive disorder, psychosis, at least one substance-related and addictive behavior disorder, 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 deramciclane can be increased in a subject in need of treatment thereof by co-administering dextromethorphan to the subject in combination with deramciclane. Moreover, 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-12 of deramciclane: (a) of at least about 50 ng*hr; and (b) at least 20% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days.

[0168] In some aspects, the subject in need of treatment thereof is a poor metabolizer of dextromethorphan. In other aspects, the subject in need of treatment thereof is a normal metabolizer of dextromethorphan. In still further aspects, the subject in need of treatment thereof is an intermediate metabolizer of dextromethorphan.

[0169] 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, or a combination thereof.

[0170] 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, insomnia resulting from dementia, psychosis resulting from dementia, and / or anxiety resulting from dementia.

[0171] In some aspects, the subject is need of treatment thereof is a human. In some aspects, the human in need of treatment thereof is a poor metabolizer of dextromethorphan. In other aspects, the human in need of treatment thereof is a normal metabolizer of dextromethorphan. In still further aspects, the human in need of treatment thereof is an intermediate metabolizer of dextromethorphan.

[0172] 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-related and addictive behavior disorder, 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-related and addictive behavior disorder.

[0173] 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.

[0174] 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, dextromethorphan is administered first followed by the administration of deramciclane. In still other aspects, deramciclane is administered first followed by the administration of dextromethorphan .

[0175] 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)! 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.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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.

[0186] 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.

[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) 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.

[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) 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.

[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) 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.

[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) 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.

[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) 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.

[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) 5months. 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.

[0193] 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.

[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) 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.

[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) 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.

[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) 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.

[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) 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.

[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) 11 months. 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) 11 months.[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) 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.

[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) 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.

[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) 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.

[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) 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.

[0203] 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.

[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) 17 months. 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) 17 months.[002051 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) 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.

[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) 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.

[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) 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.

[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) 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.

[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) 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.

[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) 23 months. 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) 23 months.[002111 Insome aspects, the combination of dextromethorphan and deramci clane 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.

[0212] The amount of dextromethorphan that can be administered to the subject (e.g., human) can be between about 10 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 10 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 15 mg of dextromethorphan per day. In other aspects, the subject (e.g., human) is administered 20 mg of dextromethorphan per day. In other aspects, the subject (e g., human) is administered 25 mg of dextromethorphan per day. In other 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.

[0213] The amount of deramciclane that can be administered to the subject (e.g., human) can be between about 10 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 10 mg of deramciclane perday. In other aspects, the subject (e.g., human) is administered 15 mg of deramciclane per day. In other 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 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.

[0214] The amount of dextromethorphan administered to the subject (e.g., human) may vary. If increasing the plasma level of deramciclane in the subject (e.g., human) is desired, dextromethorphan should be administered to the subject (e.g., human) in a dose that increases deramciclane plasma levels of the subject (e.g., human), which can be determined using routine techniques known in the art.

[0215] 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 deramciclane (e.g., day 2) in an amount that results in an increase in the deramciclane plasma level on the first day of co-administration, as compared to the same amount of deramciclane administered to the subject (e.g., human) without dextromethorphan on day 1. For example, on the first day (e.g., day 1) co-administration of the combination to the subject (e.g., human), the deramciclane plasma level may be increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 80%, at least about 90%, at least about 100%, at least about 110%, at least 120%, atleast 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least about 200% as compared to the deram ci clane plasma level resulting from the administration of the same amount of deramciclane to the subject (e.g., human) without dextromethorphan on day 1.

[0216] In some further aspects, the co-administration of dextromethorphan with deramciclane may be administered to the subject (e.g., human) once or twice a day for 8 consecutive days, until day 8, in an amount that results in a plasma concentration of deramciclane in the subject (e.g., human) that is at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70%, at least about 2 times, at least about 3 times, or at least about 4 times higher than the plasma concentration of the same amount of deramciclane administered to the subject (e.g., human) without dextromethorphan for the same 8 consecutive days.

[0217] In some aspects, the co-administration of dextromethorphan with deramciclane may be administered to a subject in an amount that results in an AUC0-12, or average plasma concentration in the subject (e.g., human) for the 12 hours following dosing (Cavg) of deramciclane, on day 8, that is at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70%, at least about 2 times, at least about 3 times, or at least about 4 times higher than the plasma concentration of the same amount of deramciclane administered to the subject without dextromethorphan for the same 8 consecutive days.

[0218] In some embodiments, the co-administration of dextromethorphan with deramciclane in an amount that results in a maximum plasma concentration (Cmax) of deramciclane in the subject (e.g., human), on day 8, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70%, at least about 2 times, at least about 3 times, or at least about 4 times higher than the plasma concentration of the same amount of deramciclane administered to the subject (e.g., human) without dextromethorphan for the same 8 consecutive days (e.g., day 8).

[0219] 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 500ng*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.

[0220] 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, or at least about 500 ng / mL.

[0221] 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, the administration of the combination of dextromethorphan and deramciclane to the subject (e.g., human) results in the subject having an AUC0-12 of deramciclane of at least about 50 ng* hr. In some aspects, the subject has an AUC0-12 of deramciclane of at least about 55 ng* hr. In other aspects, the subject has an AUC0-12 of deramciclane of at least about 60 ng*hr. In other aspects, the subject has an AUC0-12 of deramciclane of at least about 65 ng* hr. In some aspects, the subject has an AUC0-12 of deramciclane of at least about 70 ng*hr. In still further aspects, the subject has an AUC0-12 of deramciclane of at least about 75 ng*hr. In other aspects, the subject has an AUC0-12 of deramciclane ranging from about 50 ng*hr to about 75 ng*hr.

[0222] In other aspects, in addition, or alternatively, the administration of the combination of dextromethorphan and deramciclane to the subject (e.g., human) results in the subject having an AUC0-12 of deramciclane that is at least 20% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days (i.e., day 10). In other aspects, the subject (e.g., human) has an AUCo-12 of deramciclane that is at least 21% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 22% higher thanin a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 23% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 24% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 25% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUCo-nof deramciclane that is at least 26% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 27% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 28% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 29% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 30% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 31% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 32% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 33% higher than in a subject administered deramciclane alone without any co-administration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane thatis at least 34% higher than in a subject administered deramciclane alone without any coadministration of dextromethorphan over the same 10 consecutive days. In other aspects, the subject (e.g., human) has an AUC0-12 of deramciclane that is at least 35% higher than in a subject administered deramciclane alone without any co-admini strati on of dextromethorphan over the same 10 consecutive days.IV. Dosage Forms and Modes of Administration

[0223] 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, 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 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 deramciclane. In still other aspects, deramciclane is administered first followed by the administration of the dextromethorphan.

[0224] 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 beformulated for sustained release and another pharmaceutically active compound may be formulated for immediate release.[002251 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.

[0226] 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.

[0227] 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 fdlers 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.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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 inparenterally 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.

[0233] 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.

[0234] 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.

[0235] The present disclosure has multiple aspects, illustrated by the following non-limiting examples.EXAMPLE 1: PLASMA CONCENTRATION OF DERAMCICLANE

[0236] A drug-drug interaction study was conducted at clinical research sites in the European Union to evaluate the safety, tolerability and pharmacokinetics of deramciclane and dextromethorphan in healthy elderly volunteers. Over 10 days, separate groups of healthy elderly males and females received 30 mg of deramciclane orally twice daily, either alone or in combination with dextromethorphan (45 mg or 60 mg). Blood samples for pharmacokinetic analyses of deramciclane were taken before and at nine time points up to 12 hours after the morning dose on Days 1 and 11. PET measurements of frontal cortical 5-HT2A receptor occupancy were performed only after a single deramciclane administration.

[0237] Co-administration of dextromethorphan, 45 mg or 60 mg, enhanced Cmax, Cmin and AUCo-12 of plasma concentration of deramciclane when measured on Day 11 (Figures 1-3). In the presence of dextromethorphan, average plasma concentration of deramciclane exceeded 78 ng / ml at all times (i.e., time points) when measured on Day 11 (Figure 4). Deramciclane plasma concentration of 78 ng / ml corresponded to maximum possible frontal cortical receptor occupancy according to PET measurements (Figure 5). When deramciclane was given togetherwith dextromethorphan 45 mg or 60 mg but not alone for 10 days after the first dose, plasma deramciclane levels exceeded the 78 ng / ml level at all time points in most subjects (Figure 6).[002381 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.

[0239] 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.

[0240] For reasons of completeness, various aspects of the disclosure are set out in the following numbered clauses:

[0241] Clause 1. A method of increasing plasma levels of deramciclane in a subj ect in need of treatment thereof, the method comprising:

[0242] administering to a subject in need of treatment with deramciclane, 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

[0243] further wherein:

[0244] 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;

[0245] b) deramciclane administered to the subject produces an AUC0-12 of deramciclane of at least about 50 ng*hr / ml in the subject; and

[0246] c) the administration of the combination of dextromethorphan and deramciclane produces an AUC0-12 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 deramciclane alone, without the dextromethorphan.

[0247] Clause 2. The method of clause 1, wherein the dextromethorphan and deramciclane are administered sequentially.

[0248] Clause 3. The method of clause 1, wherein the dextromethorphan and deramciclane are administered simultaneously.

[0249] Clause 4. The method of any of clauses 1 -3, wherein the dextromethorphan and deramciclane are administered as separate compositions.

[0250] Clause 5. The method of any of clauses 1-4, wherein the dextromethorphan and deramciclane are administered once per day.

[0251] Clause 6. The method of any of clauses 1-4, wherein the dextromethorphan and deramciclane are administered twice per day.

[0252] 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.

[0253] Clause 8. The method of any of clauses 1-7, wherein the increase in deramciclane plasma level is observed on the first day of administration to the subject of the combination of dextromethorphan and deramciclane whereas no increase in deramciclane plasma level is observed on the first day of administration to the subject of deramciclane alone without dextromethorphan.

[0254] Clause 9. The method of any of clauses 1-8, wherein the administration to the subject of the combination of dextromethorphan and deramciclane produces an AUC0-12 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 deramciclane alone, without the dextromethorphan.

[0255] Clause 10. The method of any of clauses 1-9, wherein about 10 mg to about 120 mg of dextromethorphan is administered to the subject per day and about 10 mg to about 120 mg of deramciclane is administered to the subject per day.

[0256] Clause 11. A method of treating a subject in need of treatment thereof, the method comprising:

[0257] administering to a subject in need of treatment thereof, 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

[0258] further wherein:

[0259] 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;

[0260] b) deramciclane administered to the subject produces an AUC0-12 of deramciclane of at least about 50 ng*hr / ml in the subject;

[0261] c) the administration of the combination of dextromethorphan and deramciclane produces an AUC0-12 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 deramciclane alone, without the dextromethorphan; and

[0262] d) the subject is suffering from an anxiety disorder, a cognitive disorder, a mood and depressive disorder, psychosis, a substance-related and addictive behavior disorders, or a combination thereof.

[0263] Clause 12. The method of clause 11, wherein the subject is suffering from dementia, Alzheimer’s disease, Parkinson’s disease, depression, a major depressive disorder, schizophrenia, psychosis, generalized anxiety disorder, social anxiety disorder, post -traumatic stress disorder, or a combination thereof.

[0264] Clause 13. The method of clause 12, wherein the subject is suffering from dementia or Alzheimer’s disease.

[0265] Clause 14. The method of clause 13, wherein the subject is suffering from behavioral and psychological symptoms of dementia.

[0266] Clause 15. The method of clause 13, wherein the subject is suffering from neuropsychiatric symptoms resulting from dementia, insomnia resulting from dementia, psychosis resulting from dementia, and / or anxietyresulting from dementia.

[0267] Clause 16. The method of any of clauses 11-15, wherein the dextromethorphan and deramciclane are administered sequentially.

[0268] Clause 17. The method of any of clauses 11-15 wherein the dextromethorphan and deramciclane are administered simultaneously.

[0269] Clause 18. The method of any of clauses 11-16, wherein the dextromethorphan and deramciclane are administered as separate compositions.

[0270] Clause 19. The method of any of clauses 11-18, wherein the dextromethorphan and deramciclane are administered once per day.

[0271] Clause 20. The method of any of clauses 11-18, wherein the dextromethorphan and deramciclane are administered twice per day.

[0272] Clause 21. The method of any of clauses 11 -20 wherein the dextromethorphan is deuterated, the deramciclane is deuterated, or the dextromethorphan is deuterated and the deramciclane is deuterated.

[0273] Clause 22. The method of any of clauses 11-21, wherein the increase in deramciclane plasma level is observed on the first day of administration to the subject of the combination of dextromethorphan and deramciclane whereas no increase in deramciclane plasma Isevel is observed on the first day of administration to the subject of deramciclane alone without dextromethorphan.

[0274] Clause 23. The method of any of clauses 11-22, wherein the administration to the subject of the combination of dextromethorphan and deramciclane produces an AUC0-12 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 deramciclane alone, without the dextromethorphan.

[0275] Clause 24. The method of any of clauses 11-23 wherein about 10 mg to about 120 mg of dextromethorphan is administered to the subject per day and about 10 mg to about 120 mg of deramciclane is administered to the subject per day.

Claims

Claims:

1. A method of increasing plasma levels of deramciclane in a subject in need of treatment thereof, the method comprising:administering to a subject in need of treatment with deramciclane, 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) deramciclane administered to the subject produces an AUC0-12 of deramciclane of at least about 50 ng*hr / ml in the subject; andc) the administration of the combination of dextromethorphan and deramciclane produces an AUC0-12 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 deramciclane alone, without the dextromethorphan.

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 increase in deramciclane plasma level is observed on the first day of administration to the subject of the combination of dextromethorphan and deramciclane whereas no increase in deramciclane plasma level is observed on the first day of administration to the subject of deramciclane alone without dextromethorphan.

9. The method of any of claims 1-8, wherein the administration to the subject of the combination of dextromethorphan and deramciclane produces an AUC0-12 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 deramciclane alone, without the dextromethorphan.

10. The method of any of claims 1-9, wherein about 10 mg to about 120 mg of dextromethorphan is administered to the subject per day and about 10 mg to about 120 mg of deramciclane is administered to the subject per day.

11. A method of treating a subject in need of treatment thereof, the method comprising:administering to a subject in need of treatment thereof, 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:d) 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;e) deramciclane administered to the subject produces an AUC0-12 of deramciclane of at least about 50 ng*hr / ml in the subject;f) the administration of the combination of dextromethorphan and deramciclane produces an AUC0-12 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 deramciclane alone, without the dextromethorphan; andg) the subject is suffering from an anxiety disorder, a cognitive disorder, a mood and depressive disorder, psychosis, a substance-related and addictive behavior disorders, or a combination thereof.

12. The method of claim 11, wherein the subject is suffering from dementia, Alzheimer’s disease, Parkinson’s disease, depression, a major depressive disorder, schizophrenia, psychosis, generalized anxiety disorder, social anxiety disorder, post-traumatic stress disorder, or a combination thereof.

13. The method of claim 12, wherein the subject is suffering from dementia or Alzheimer’s disease.

14. The method of claim 13, wherein the subject is suffering from behavioral and psychological symptoms of dementia.

15. The method of claim 13, wherein 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 resulting from dementia.

16. The method of any of claims 11-15, wherein the dextromethorphan and deramciclane are administered sequentially.

17. The method of any of claims 11-15 wherein the dextromethorphan and deramciclane are administered simultaneously.

18. The method of any of claims 11-16, wherein the dextromethorphan and deramciclane are administered as separate compositions.

19. The method of any of claims 11-18, wherein the dextromethorphan and deramciclane are administered once per day.

20. The method of any of claims 11-18, wherein the dextromethorphan and deramciclane are administered twice per day.

21. The method of any of claims 11-20 wherein the dextromethorphan is deuterated, the deramciclane is deuterated, or the dextromethorphan is deuterated and the deramciclane is deuterated.

22. The method of any of claims 11-21, wherein the increase in deramciclane plasma level is observed on the first day of administration to the subject of the combination of dextromethorphan and deramciclane whereas no increase in deramciclane plasma Isevel is observed on the first day of administration to the subject of deramciclane alone without dextromethorphan.

23. The method of any of claims 11-22, wherein the administration to the subject of the combination of dextromethorphan and deramciclane produces an AUC0-12 in the subject thatis 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 deramciclane alone, without the dextromethorphan.

24. The method of any of claims 11-23 wherein about 10 mg to about 120 mg of dextromethorphan is administered to the subject per day and about 10 mg to about 120 mg of deramciclane is administered to the subject per day.

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