WO2025054599A1

WO2025054599A1 - Treatment and prevention of cerebral atrophy

Info

Publication number: WO2025054599A1
Application number: PCT/US2024/045834
Authority: WO
Inventors: Christopher U. Missling
Original assignee: Anavex Life Sciences Corp
Current assignee: Anavex Life Sciences Corp
Priority date: 2023-09-08
Filing date: 2024-09-09
Publication date: 2025-03-13
Anticipated expiration: 2026-03-08

Abstract

The present disclosure provides methods and kits for treating or preventing brain atrophy in a subject. The methods involve administration of a Sigma-1 receptor agonist and/or a dual modulator of Sigma-1 receptor and muscarinic receptor. The brain atrophy may be related to or associated with neurological disorders.

Description

TREATMENT AND PREVENTION OF CEREBRAL ATROPHY

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 63/581 ,517 filed September s, 2023, entitled “TREATMENT AND PREVENTION OF BRAIN ATROPHY”, the disclosure of which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present disclosure relates to methods of treating or preventing brain atrophy related to or associated with neurological disorders.

BACKGROUND OF THE INVENTION

[0003] Brain atrophy, or cerebral atrophy refers to loss of brain cells (neurons), connections between brain cells, and/or loss of brain volume, and when accelerated over the normal brain atrophy of aging is associated with many different diseases that can affect the brain. Brain atrophy can manifest in a generalized form across the entire brain or can be more localized to a portion of the brain. Depending on the area and extent of tissue loss and atrophy, various brain functions including executive functions can be impacted. Symptoms of brain atrophy may include seizures, dementia, memory loss and aphasias.

[0004] Diseases and conditions of the brain that may involve brain atrophy include among others, Alzheimer’s disease, stroke, traumatic brain injury, Pick’s disease, fronto-temporal dementia, cerebral palsy, Huntington’s disease, leukodystrophies, mitochondrial encephalomyopathies, multiple sclerosis, and infectious diseases such as encephalitis, neurosyphilis, and AIDS.

[0005] Brain atrophy may be detected and monitored by various non- or minimally invasive brain imaging techniques, such as magnetic resonance imaging (MRI). However, treatments for brain atrophy are limited. Blood thinners, cholesterol- lowering agents such as statins, and certain antihypertensive medications have been used to address brain atrophy. Medications used to treat Alzheimer's disease such as Aricept (donepezil) and Namenda (memantine), have also been used to slow down atrophy. These medications are however not for suitable for everyone and can have limited to no significant effect in reducing or preventing abnormal brain atrophy. Thus, in an aging population an urgent need exists for novel approaches to prevent, slow, reduce or stop brain atrophy.

SUMMARY OF THE INVENTION

[0006] One aspect of the present disclosure encompasses a method of treating or preventing brain atrophy in a human subject comprising administering to the subject a therapeutically effective amount of a therapeutic agent modulating both the sigma- 1 receptor and the muscarinic acetylcholine receptor. In one aspect, the therapeutic agent is selected from: tetrahydro-N, N-dimethyl-2,2-diphenyl-3- furanmethanamine (A2-73 Freebase); 1-(2,2-diphenyltetrahydrofuran-3-yl)-N- methylmethanamine (A19-144 Freebase); tetrahydro-N, N-dimethyl-5,5-diphenyl-3- furanmethanamine (A1-41 Freebase); an enantiomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable crystal thereof, a pharmaceutically acceptable co-crystal thereof, and any combination thereof. In another aspect, the pharmaceutically acceptable salt is selected from a hydrochloride salt, a hydrobromide salt, a fumarate salt, a sulfate salt, a dihydrogen phosphate salt, a benzoate salt, a maleate salt, a mesylate salt, an edysilate salt, or an oxalate salt. In yet another aspect, the pharmaceutically acceptable salt is the hydrochloride salt, and the agent is selected from the group consisting of tetrahydro- N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (A2-73); 1 -(2,2- diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride (A19-144); tetrahydro-N, N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride (A1-41 ); an enantiomer thereof, a pharmaceutically acceptable crystal thereof, a pharmaceutically acceptable co-crystal thereof, and any combination thereof. In one aspect, the pharmaceutically acceptable co-crystal is formed between (i) A2-73 Freebase, A2-73, A19-144 Freebase, A19-144, A1 -41 Freebase, A1-41 , an enantiomer therefore, a crystal thereof; and (ii) an acid or an ionic salt. In one aspect, the acid is selected from fumaric acid, sulfuric acid, phosphoric acid, hydrogen phosphoric acid, dihydrogen phosphoric acid, benzoic acid, salicylic acid, oxalic acid, ethanedisulfonic acid, tartaric acid, citric acid, maleic acid, and any combination thereof. The ionic salt may be selected from a quaternary ammonium cationicsalt, a salt of a transitional metal, a salt of an alkaline earth metal, or a salt of alkali metal. In one aspect, the ionic salt is selected from lithium chloride, sodium chloride, magnesium chloride, potassium chloride, calcium chloride, zinc chloride, iron (II) chloride, iron (III) chloride, titanium chloride, chromium (III) chloride, scandium (III) chloride, manganese (II) chloride, copper (I) chloride, copper (II) chloride, nickel chloride, or aluminum chloride. In another aspect, the therapeutic agent is selected from A2-73 Freebase, a crystal thereof, an enantiomer thereof, a crystal of the enantiomer thereof, a pharmaceutically acceptable salt thereof, an enantiomer of the pharmaceutically acceptable salt thereof, a crystal of the pharmaceutically acceptable salt thereof, or a co-crystal thereof. In another aspect, the therapeutic agent is selected from A2-73, a crystal thereof, an enantiomer thereof, a crystal of the enantiomer thereof, and a co-crystal thereof. In various aspects, the therapeutic agent is selected from A2-73 Freebase in amorphous form, A2-73 Freebase in crystal Form I, A2-73 in amorphous form, A2-73 crystal Form I, A2-73 crystal Form II, A2-73 crystal Form III, (+)A2-73 enantiomer, (-)A2-73 enantiomer, A2-73 Freebase fumarate salt in amorphous form, A2-73 Freebase hydrogen fumarate salt in crystal Form I, A2-73 Freebase hydrogen fumarate salt in crystal Form II, A2-73 Freebase hydrogen fumarate salt in crystal Form III, A2-73 Freebase hydrogen fumarate salt in crystal Form IV, A2-73 Freebase hydrogen fumarate salt in crystal Form V, A2-73 Freebase Mesylate Form I, A2-73 Freebase Sulfate Form I, A2-73 Freebase Sulfate Form II, A2-73 Freebase Oxalate Form I, A2- 73 Freebase Oxalate Form II, A2-73 Freebase Oxalate Form III, A2-73 Freebase Dihydrogen phosphate Form I, A2-73 Freebase Edisylate Form I, A2-73 Freebase Benzoate Form I, A2-73 Freebase hydrobromide crystal Form A, A2-73 Freebase hydrobromide crystal Form B, A2-73 Freebase maleate crystal Form S5, A2-73 Freebase maleate crystal Form S6, co-crystal Form CSII of A2-73 co-crystal with tartaric acid, co-crystal Form CSIII of A2-73 co-crystal with citric acid, or co-crystal Form CSIV of A2-73 co-crystal with malic acid, a co-crystal of A2-73 with zinc chloride, or a combination thereof. In yet another aspect, the therapeutic agent is selected from A2-73 Crystal Form I, A2-73 Form II, A2-73 Form III, and any combination thereof. Or alternatively, the therapeutic agent is selected from (-) A2-73 enantiomer, (+) A2-73 enantiomer, a crystal of the (-) A2-73 enantiomer, a crystal of the (+) A2-73 enantiomer, a co-crystal of the (-) A2-73 enantiomer, a co-crystal of the (+) A2-73 enantiomer, and any combination thereof. In one aspect, the therapeutic agent is selected from A2-73 Crystal Form I, A2-73 Crystal Form III, (-) A2-73 enantiomer, a crystal of the (-) A2-73 enantiomer, a co-crystal of the (-) A2-73 enantiomer, and any combination thereof. In another aspect, the therapeutic agent is a co-crystal of (-) A2-73 enantiomer with zinc chloride in a molar ratio from about 1 :1 to about 2:1.

[0007] In various aspects of the methods, a therapeutically effective amount comprises from about 0.5 mg to about 100 mg per day, such as from about 1 mg to about 60 mg per day, or is selected from about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg per day. In one aspect, a therapeutically effective amount is from about 10 mg to about 50 mg per day. The therapeutically effective amount can be administered through a dosage form selected from an oral dosage form, an intravenous dosage form, and a transdermal dosage form. In one aspect, the dosage form is a capsule formulated for oral administration. In another aspect, the administration is daily administration for at least about 30 days or up to about 96 weeks. In one aspect, the administration comprises an intermittent dosing regimen of at least two cycles, each cycle comprising (a) a dosing period during which the therapeutically effective amount of the agent is administered to the subject; and thereafter (b) a resting period. The dosing period and the resting period can be of the same duration, or of different durations. In one aspect, the dosing period is at least about 10 days, 11 days, 12 days, 13 days, and 14 days. In another aspect, the resting period is about 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, or 14 days.

[0008] In various aspects of the present disclosure, the subject exhibits amyloid plaques or deposits in the brain. In one aspect, the subject suffers from or is suspected of suffering from a neurological disease. The neurological disease may be selected from cognitive impairment, Lewy body dementia, stroke, traumatic brain injury, infections, spinal cord injury, Alzheimer’s disease, Parkinson’s disease, dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, Rett Syndrome, Fragile X Syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Smith -Magenis syndrome, multiple sclerosis, Fronto-temporal dementia, motor neuron disease (MND), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), autism spectrum disorder, schizophrenia, post-traumatic stress disorder (PTSD), and any combination thereof. [0009] Another aspect of the present disclosure encompasses a method of preventing brain atrophy in a subject at risk of developing brain atrophy, by administering to the subject a prophylactically effective amount of an agent modulating both sigma-1 receptor and muscarinic acetylcholine receptor. In one aspect, the brain atrophy is manifested by shrinkage or loss of volume in brain tissue in at least one brain region as compared to brain tissue volume in a control sample wherein the brain region is selected from frontal lobe, insular cortex, limbic lobe, parietal lobe, temporal lobe, hippocampus, whole brain white matter and whole brain grey matter, and wherein the control sample is obtained from a healthy individual or is a prior sample from the subject. In another aspect, the brain atrophy is associated with or is suspected of being associated with a brain infection, brain inflammation, a neurological disease, or any combination thereof. A neurological disease may be selected from cognitive impairment, Lewy body dementia, stroke, traumatic brain injury, spinal cord injury, infections, Alzheimer’s disease, Parkinson’s disease, dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, Rett Syndrome, Fragile X Syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Smith -Magen is syndrome, multiple sclerosis, Fronto-temporal dementia, motor neuron disease (MND), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), autism spectrum disorder, schizophrenia, post-traumatic stress disorder (PTSD), and any combination thereof. In one aspect, the risk of developing brain atrophy is associated with one or more symptoms in the subject selected from forgetfulness, difficulty speaking, difficulty writing, loss of language, inability to understand words, memory impairment, cognitive dysfunction, hallucination, mood and personality change, irrational judgment, convulsion, loss of consciousness, spasms, teeth clenching, or any combination thereof. In yet another aspect, the risk of developing brain atrophy is associated with one or more disorders selected from cerebral palsy, Lewy body dementia, encephalitis, HIV, AIDS, cognitive impairment, stroke, traumatic brain injury, spinal cord injury, infections, Alzheimer’s disease, Parkinson’s disease, dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, Rett Syndrome, Fragile X Syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Smith-Magen is syndrome, multiple sclerosis, Fronto-temporal dementia, motor neuron disease (MND), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), autism spectrum disorder, schizophrenia, post-traumatic stress disorder (PTSD), and any combination thereof.

[0010] In various aspects, methods of preventing brain atrophy in a subject in need thereof comprise administering to the subject a prophylactically effective amount of a prophylactic agent modulating both sigma-1 receptor and muscarinic acetylcholine receptor, in which the prophylactic agent is selected from: tetrahydro-N, N-dimethyl- 2,2-diphenyl-3-furanmethanamine (A2-73 Freebase); 1-(2,2-diphenyltetrahydrofuran- 3-yl)-N-methylmethanamine (A19-144 Freebase); tetrahydro-N, N-dimethyl-5,5- diphenyl-3-furanmethanamine (A1-41 Freebase); an enantiomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable crystal thereof, a pharmaceutically acceptable co-crystal thereof, and any combination thereof. In another aspect, the pharmaceutically acceptable salt is selected from a hydrochloride salt, a hydrobromide salt, a fumarate salt, a sulfate salt, a dihydrogen phosphate salt, a benzoate salt, a maleate salt, a mesylate salt, an edysilate salt, or an oxalate salt. In yet another aspect, the pharmaceutically acceptable salt is the hydrochloride salt, and the prophylactic agent is selected from the group consisting of tetrahydro-N, N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (A2-73); 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride (A19-144); tetrahydro-N, N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride (A1-41 ); an enantiomer thereof, a pharmaceutically acceptable crystal thereof, a pharmaceutically acceptable co-crystal thereof, and any combination thereof. In one aspect, the pharmaceutically acceptable co-crystal is formed between (i) a compound selected from A2-73 Freebase, A2-73, A19-144 Freebase, A19-144, A1- 41 Freebase, A1-41 , an enantiomer therefore, a crystal thereof; and (ii) an acid or an ionic salt. In one aspect, the acid is selected from fumaric acid, sulfuric acid, phosphoric acid, hydrogen phosphoric acid, dihydrogen phosphoric acid, benzoic acid, salicylic acid, oxalic acid, ethanedisulfonic acid, tartaric acid, citric acid, maleic acid, and any combination thereof. And the ionic salt is selected from a quaternary ammonium cationic salt, a salt of a transitional metal, a salt of an alkaline earth metal, or a salt of alkali metal. In one aspect, the ionic salt is selected from lithium chloride, sodium chloride, magnesium chloride, potassium chloride, calcium chloride, zinc chloride, iron (II) chloride, iron (III) chloride, titanium chloride, chromium (III) chloride, scandium (III) chloride, manganese (II) chloride, copper (I) chloride, copper (II) chloride, nickel chloride, or aluminum chloride. In another aspect, the prophylactic agent is selected from A2-73 Freebase, a crystal thereof, an enantiomer thereof, a crystal of the enantiomer thereof, a pharmaceutically acceptable salt thereof, an enantiomer of the pharmaceutically acceptable salt thereof, a crystal of the pharmaceutically acceptable salt thereof, or a co-crystal thereof. In one aspect, the prophylactic agent is selected from A2-73, a crystal thereof, an enantiomer thereof, a crystal of the enantiomer thereof, and a co-crystal thereof. In various aspects, the prophylactic agent is selected from A2-73 Freebase in amorphous form, A2-73 Freebase in crystal Form I, A2-73 in amorphous form, A2-73 crystal Form I, A2-73 crystal Form II, A2-73 crystal Form III, (+)A2-73 enantiomer, (-)A2-73 enantiomer, A2-73 Freebase fumarate salt in amorphous form, A2-73 Freebase hydrogen fumarate salt in crystal Form I, A2-73 Freebase hydrogen fumarate salt in crystal Form II, A2-73 Freebase hydrogen fumarate salt in crystal Form III, A2-73 Freebase hydrogen fumarate salt in crystal Form IV, A2-73 Freebase hydrogen fumarate salt in crystal Form V, A2-73 Freebase Mesylate Form I, A2-73 Freebase Sulfate Form I, A2-73 Freebase Sulfate Form II, A2-73 Freebase Oxalate Form I, A2- 73 Freebase Oxalate Form II, A2-73 Freebase Oxalate Form III, A2-73 Freebase Dihydrogen phosphate Form I, A2-73 Freebase Edisylate Form I, A2-73 Freebase Benzoate Form I, A2-73 Freebase hydrobromide crystal Form A, A2-73 Freebase hydrobromide crystal Form B, A2-73 Freebase maleate crystal Form S5, A2-73 Freebase maleate crystal Form S6, co-crystal Form CSII of A2-73 co-crystal with tartaric acid, co-crystal Form CSIII of A2-73 co-crystal with citric acid, or co-crystal Form CSIV of A2-73 co-crystal with malic acid, a co-crystal of A2-73 with zinc chloride, or a combination thereof. In yet another aspect, the prophylactic agent is selected from A2-73 Crystal Form I, A2-73 Form II, A2-73 Form III, and any combination thereof. Or alternatively, the prophylactic agent is selected from (-) A2- 73 enantiomer, (+) A2-73 enantiomer, a crystal of the (-) A2-73 enantiomer, a crystal of the (+) A2-73 enantiomer, a co-crystal of the (-) A2-73 enantiomer, a co-crystal of the (+) A2-73 enantiomer, and any combination thereof. In one aspect, the prophylactic agent is selected from A2-73 Crystal Form I, A2-73 Crystal Form III, (-) A2-73 enantiomer, a crystal of the (-) A2-73 enantiomer, a co-crystal of the (-) A2-73 enantiomer, and any combination thereof. In another aspect, the prophylactic agent is a co-crystal of (-) A2 -73 enantiomer with zinc chloride in a molar ratio from about 1 :1 to about 2:1. [0011] In various aspects of the present disclosure, the methods comprise administering a prophylactically effective amount to the subject, in which the prophylactically effective amount is from about 0.5 mg to about 100 mg per day, such as from about 1 mg to about 60 mg per day, or is selected from about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg per day. In one aspect, prophylactically effective amount is from about 10 mg to about 50 mg per day. The prophylactically effective amount may be administered to the subject through a dosage form selected from an oral dosage form, an intravenous dosage form, and a transdermal dosage form. In one aspect, the dosage form is a capsule formulated for oral administration. Administration may be daily administration for at least about 30 days or up to about 96 weeks. In one aspect, the administration comprises an intermittent dosing regimen of at least two cycles, each cycle comprising (a) a dosing period during which the prophylactically effective amount of the prophylactic agent is administered to the subject; and thereafter (b) a resting period. The dosing period and the resting period may be of the same durations, or of different durations. In one aspect, the dosing period is at least about 10 days, 11 days, 12 days, 13 days, and 14 days. In another aspect, the resting period is about 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, or 14 days.

REFERENCE TO COLOR DRAWINGS

[0012] The application file contains at least one drawing executed in color. Copies of this patent application publication with color drawings will be provided by the Office upon request and payment of the necessary fee.

BRIEF DESCRIPTION OF THE FIGURES

[0013] FIG. 1 depicts changes in percentage volume of distinct parts of the brain before and after treating with ANAVEX®2-73 at week 48. Statistical significance is indicated by asterisks [*, **, ***, ****] in cases where p value < 0.05, 0.01 , 0.001 , or 0.0001 , respectively. (*-****) as determined by two-tailed unpaired t-test.

[0014] FIG. 2 depicts mean change in brain volume before and after treating with ANAVEX®2-73 at week 48. DETAILED DESCRIPTION

[0015] The present disclosure is based in part on the discovery that a dual modulator of Sigma-1 receptor and muscarinic receptor, such as ANAVEX®2-73, is useful to treat and/or prevent brain atrophy. As used herein, treating brain atrophy means reducing or reversing an existing brain atrophy. Preventing brain atrophy means blocking the formation or onset of brain atrophy and/or slowing down progression of brain atrophy.

[0016] The present disclosure encompasses methods of treating or preventing brain atrophy by administering a therapeutically effective amount of the dual modulator to a subject in need thereof. The therapeutically effective amount is the amount effective in treating and/or preventing brain atrophy in a human subject. In one aspect, the brain atrophy is manifested by shrinkage or loss of brain volume in at least one brain region selected from the group consisting of whole brain grey matter, frontal lobe, insular cortex, limbic lobe, parietal lobe, temporal lobe, hippocampus, and whole brain white matter.

[0017] In various aspects, brain atrophy is related to or associated with cognitive impairment, stroke, Alzheimer's disease, Parkinson’s disease, traumatic brain injury, multiple sclerosis, or infections. The methods may comprise steps of detecting brain atrophy in a subject and administering to the subject the dual modulator as described herein. Methods described herein may further include monitoring the change in brain atrophy before and after administration. The method may also comprise other steps or methods to facilitate and/or enhance the treatment and/or prevention of brain atrophy.

[0018] In an other aspect, brain atrophy is used to determine or diagnose if a subject suffers from or is suspected of suffering from a brain infection, a brain inflammation, a neurodegenerative disorder, a neurodevelopmental disorder, or any combination thereof. In yet another aspect, changes in brain atrophy are used to determine deterioration or amelioration of a disease underlying or associated with the brain atrophy, and such disease comprises brain infection, brain inflammation, a neurodegenerative disorder, a neurodevelopmental disorder, or any combination thereof. I. Brain Atrophy

[0019] One aspect of the present disclosure encompasses treating and/or preventing brain atrophy. Brain atrophy can be observed and monitored using magnetic resonance imaging (MRI) or other imaging tools such as computerized tomography (CT), positron emission tomography (PET) or single-photon emission computerized tomography (SPECT) scans, each of which can produce objective measures of atrophy by brain mass, size, volume, density, connectivity, hydration level, and/or neuron counts.

[0020] In one aspect, brain atrophy in a test subject can be determined by determining the whole brain volume of the subject using any imaging method and comparing a change in volume relative to a control or reference volume for the subject, or to control values for brain volume obtained from a population of healthy age-matched subjects. Alternatively, the brain atrophy in a test subject can be determined by determining the brain volume in a selected brain region of the subject and comparing to a control or reference volume of the brain region of the subject, or to control values for the brain region obtained from a population of healthy age- matched subjects. Brain volume can be determined by measuring volume of whole brain grey matter, frontal lobe, insular cortex, limbic lobe, parietal lobe, temporal lobe, hippocampus, and whole brain white matter.

[0021] Brain atrophy is observed in whole brain structures including whole brain grey matter, whole brain white matter, and in parts of the brain, most frequently in the frontal lobe, insular cortex, limbic lobe, parietal lobe, hippocampus and temporal lobe regions. Symptoms of brain atrophy vary depending on which area of the brain is affected, and/or the underlying disease or disorder causing the brain atrophy. Typical symptoms of brain atrophy include dementia, memory loss and performance of everyday tasks. Brain atrophy may result in loss of executive function such as the ability to thin and reason.

[0022] Naturally, the volume of human brain changes with age and stage of physical development. By 6 years of age, the human brain has attained about 90% of its volume in adulthood. Beginning sometime in the fourth decade of life, the human brain starts to shrink, with the rate of shrinkage increasing to about 5% annually by about age 40. Thus, some degree of atrophy is a normal and expected part of human aging. On the other hand, abnormally fast or substantial brain shrinkage of the brain or a brain region may be associated with a disease or disorder of the brain, or a brain injury.

[0023] Certain progressive neurological diseases, such as those of the central nervous system, are associated with brain atrophy caused by degeneration of certain cells in the brain. These diseases include, but are not necessarily limited to, Lewy body dementia, stroke, neuroinfections, Alzheimer’s disease, Parkinson’s disease, dementia, Huntington’s disease, Prion disease, Rett Syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Smith-Magenis syndrome, multiple sclerosis, motor neuron diseases (MND) such as amyotrophic lateral sclerosis, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), autism spectrum disorder, cerebral palsy, Rett syndrome, Angelman syndrome, Williams syndrome, multiple sclerosis, Fragile X, infantile spasms and Smith- Magenis syndrome, schizophrenia, post-traumatic stress disorder (PTSD), and any neuronal injury such as injury resulting from a stroke, traumatic brain injury, spinal cord injury, and Fronto-temporal dementia. Acquired diseases such as AIDS or Wernicke-Korsakoff syndrome can also cause progressive brain atrophy. Congenital conditions such a cerebral palsy may cause brain atrophy. Brain atrophy may occur due to an acute brain injury from stroke, head trauma, an infection of the CNS (e.g., encephalitis), or a brain tumor.

[0024] The methods disclosed herein expressly contemplate treatment of other neurological diseases or disorders that can involve abnormal or accelerated brain atrophy which include, but are not necessarily limited to Prion diseases, motor neuron diseases (MND) such as amyotrophic lateral sclerosis, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), dementia, autism spectrum disorder, Rett syndrome, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), multiple sclerosis, childhood disintegrative disorder, Fragile X, infantile spasms and Smith-Magenis syndrome, schizophrenia, post-traumatic stress disorder (PTSD), and any neuronal injury such as injury resulting from a traumatic brain injury or spinal cord injury.

[0025] The present disclosure also encompasses methods of preventing brain atrophy, such as blocking, deterring, delaying, slowing, or avoiding the onset of brain atrophy in a subject. In another aspect, the subject is at risk of developing brain atrophy. In another aspect, such risk is manifested by one or more symptoms comprising forgetfulness, difficulty speaking, difficulty writing, loss of language, inability to understand words, memory impairment, cognitive dysfunction, hallucination, mood and personality change, irrational judgment, convulsion, loss of consciousness, spasms, teeth clenching, or any combination thereof. In another aspect, such risk is associated with one or more disorders suffered by the subject, comprising cerebral palsy, encephalitis, HIV, AIDS, Huntington’s disease, leukodystrophies, multiple sclerosis, stroke, syphilis, traumatic brain injury, Alzheimer’s disease, an infectious disorder, alcohol use disorder, a physical brain injury, or any combination thereof.

II. Treating Neurological Diseases and Disorders

[0026] Another aspect of the present invention provides methods of treating and/preventing brain atrophy related to or caused by neurological diseases or disorders as described herein.

[0027] In one aspect, the present disclosure encompasses methods of treating and/or preventing brain atrophy associated with or related to Alzheimer’s disease (AD). The most defining hallmark of AD pathology is the gradual loss of brain matter or brain volume, i.e. brain atrophy. Without wishing to be bound by theory, the brain atrophy commonly observed in Alzheimer’s patients may relate to the formation of A|3 plaques. Specifically, Amyloid Theory hypothesizes that amyloid beta may appear at an advanced stage of AD, which may be beyond the reach of existing antiAlzheimer drugs, such as inhibitors of [3-Site amyloid precursor protein cleaving enzyme (anti-BACE) or blockers of tau expressions. Capturing the disease at earlier stages has also been challenging, due to lack of reliable genomic markers that may be prognostic of the AD onset. Some biomarkers have become an essential component of AD research. Because of the pervasiveness of AD pathology in the elderly, the same biomarkers are used in cognitive aging research. An unbiased descriptive classification scheme for these biomarkers would be the “A/T/N” system in which major AD biomarkers are divided into 3 binary categories based on the nature of the pathophysiology. “A” refers to the value of a [3-amyloid biomarker (e.g., Ab42/40 ratio); “T,” the value of a tau biomarker (e.g., p-tau); and “N,” biomarkers of neurodegeneration or neuronal injury (e.g., structural MRI). As of today, the only therapeutic interventions with demonstrated efficacy are anti-beta amyloid monoclonal Antibodies (mAbs) targeting the “A” category. There is a need to stop or slow down the progression of brain atrophy in Alzheimer’s patients. Non-invasive brain imaging techniques such as (MRI) can be used to measure the atrophy levels in the brain.

[0028] Additionally, monitoring changes in brain atrophy may be used to evaluate therapeutic effect of a potential AD drug intervention. Stages of AD include early signs of AD, early-on set AD, or late-onset Alzheimer. Early-onset Alzheimer’s disease (EOAD) refers to AD onset at an age of 65 years old or younger. EOAD is often delayed in diagnosis and overshadowed by the more common late-onset AD (LOAD). EOAD comprises about 5% of AD and differs significantly from LOAD, such as aggressive in its course and demanding age-related psychosocial support. A substantial percentage of EOAD is phenotypic variants that differ from the usual memory-disordered presentation of typical AD. Patients with EOAD often have greater parietal atrophy, more white matter abnormalities, and less hippocampal volume loss, compared to those with LOAD. The phenotypic variants also have atrophy and white matter changes corresponding anatomically to the cognitive changes and appear to involve alternate neural networks relative to typical AD. Management of EOAD is similar to th at for LOAD, but special emphasis should be placed on targeting the specific cognitive areas involved and more age-appropriate psychosocial support and education. In one aspect, the present disclosure provides therapy for both EOAD and LOAD. In another aspect, the present disclosure provides therapy specifically for EOAD or early signs of AD.

[0029] In another aspect, the present disclosure provides methods of treating and/or preventing brain atrophy related to and/or associated with Rett syndrome (RSS), also referred to as cerebroatrophic hyperammonemia. RSS is a progressive disorder predominant in females and associated with cortical atrophy, stereotyped hand movements mimicking handwashing, severe mental deficiency, and cortical and extrapyramidal dysfunction. The clinical progression of RSS is consistent with an arrested neuronal development that may be due to either impaired cellular differentiation or the lack of proper trophic factors. Neuropathological studies on RS patients have confirmed (1 ) a generalized brain atrophy involving the cerebrum and cerebellum; (2) a decrease in neuronal cell size and increased cell packing density throughout the brain; (3) a reduction in the number of basal forebrain cholinergic neurons; and (4) a reduction in the concentration of melanin-containing neurons in the substantia nigra. Additionally, biochemical studies have identified (1 ) a decrease in cholinergic markers in the neocortex, hippocampus, thalamus and basal ganglia; (2) inconsistent and variable changes in biogenic amine biomarkers in post-mortem tissues and cerebrospinal fluid (CSF); (3) an elevation of beta-endorphin levels in the thalamus and glutamate levels in the CSF; and (4) no evidence for mitochondrial dysfunction. Taken together, these data suggest that RSS patients experience a primary deficit in brain neuro-activity, and the formation and progression of brain atrophy mightunderlie some of the higher cognitive impairments and extrapyramidal dysfunction. Overall, the clinical, biochemical and neuropathological data suggest that RSS is a neurodevelopmental disorder related to or associated with brain atrophy. Genetically, Rett syndrome is most typically caused by a mutation in the gene MECP2 located on the X chromosome. The mutation can arise sporadically or from germline mutations but is not typically inherited. In less than 10% of RSS cases, mutations in the genes CDKL5 or FOXG1 have also been found. RSS is initially diagnosed by clinical observation, but the diagnosis is definitive when there is a genetic defect in the MECP2 gene. The onset and seventy of RSS vary from subject to subject. Before the onset of symptoms, the subject generally appears to grow and develop normally. Early subtle abnormalities even in early infancy, can include loss of muscle tone (hypotonia), difficulty feeding, and jerkiness in limb movements. Next, gradually, mental and physical symptoms begin to manifest. The subject loses purposeful use of hands and the ability to speak and can experience other early symptoms including problems in crawling or walking and/or diminished eye contact. The loss of functional use of the hands is followed by compulsive hand movements such as wringing and washing. Apraxia, the inability to perform motor functions, can interfere with all body movements, including eye gaze and speech. Children with RSS can also show autistic-like behaviors, such as incontinence, screaming fits, inconsolable crying, breath holding, hyperventilation or air swallowing, avoidance of eye contact, lack of social/emotional reciprocity, markedly impaired use of nonverbal behaviors to regulate social interaction, loss of speech, and sensory problems. Other symptoms include walking on the toes, sleep problems, a wide-based gait, teeth grinding, difficulty in chewing, slowed growth, seizures, cognitive disabilities, and apnea (breath holding), possible short stature, hypotonia, delayed or absent ability to walk, ataxia, microcephaly, gastrointestinal problems, spasticity, chorea, and dystonia. Currently, there is no cure for RSS, but restoration of MECP2, for example using Insulin-like Growth Factor-1 (IGF-1 ), has shown promise in a mouse model (Tropea, et al., Proc Natl Acad Sci USA., 106(6): 2029-2034 (2009)). NMDA receptor antagonists have also shown promise. Symptoms can also be treated using, for example, sleep aids, selective serotonin reuptake inhibitors (SSRIs), anti-psychotics (for self-harming behaviors), beta-blockers (for long QT syndrome), and agents to manage gastrointestinal dysfunction and malnutrition.

[0030] In another aspect, the present disclosure provides methods of treating and/or preventing brain atrophy related to or associated with dementia. Dementia is a general term for severe thinking problems that interfere with daily tasks. There’s a connection between brain atrophy and dementia. Studies show that dementia typically starts with shrinkage of brain tissue that may be restricted to certain parts of the brain. For example, in frontotemporal dementia, the frontal and temporal lobes of the brain shrink. Genetic mutations have been linked to frontotemporal dementia. There are also Creutzfeldt-Jakob disease related dementia, which deteriorates unusually fast. Other types of dementia, such as Alzheimer’s dementia or dementia with Lewy bodies may progress more slowly. Alzheimer related dementia accounts for 60-80% of all dementia patients. Vascular dementia caused by microscopic bleeding and blood vessel blockage in the brain, is the second most common cause of dementia. Those who experience brain changes caused by multiple types of dementia have mixed dementia. In sum, dementia may relate to, associate with, and result from brain atrophy. Progression of brain atrophy further deteriorates dementia. The present disclosure provides methods of treating and/or preventing dementia- related brain atrophy, by reversing, reducing, slowing, halting, and/or blocking brain cell loss, neuron cell toxication, and/or brain shrinkage.

[0031] The present disclosure also provides methods to modulate brain atrophy that is related to, associated with, and/or resulted from Parkinson’s Disease (PD). PD is caused by a loss of nerve cells in part of the brain called the substantia nigra. It is often age-related and characterized by brain cell degeneration. Such degeneration leads to a dopamine reduction in the brain. Since dopamine plays a vital role in regulating the movement of the body, PD is best known for causing slowed movements, tremors, and balance problems. Researchers noted that many changes occur in the brains of people with Parkinson’s disease, such as appearance and/or presence of Lewy bodies. Clumps of specific substances within brain cells are microscopic markers of Parkinson’s disease. Cortical and subcortical atrophy is often seen in early stages after the onset of PD and becomes prominent in later stages of PD due to the development of cognitive, non-motor and mood dysfunctions. Structural MRI may be used to monitor and/or predict disease progression in PD. The present disclosure provides methods to modulate PD-related brain atrophy, by reversing, reducing, slowing, halting, and/or blocking brain cell loss, neuron cell toxication, and/or brain shrinkage.

III. Methods of Use

[0032] In one aspect, brain atrophy in a test subject can be determined by determining the whole brain volume of the subject and comparing change in volume relative to a control or reference volume for the subject, or to control values for brain volume obtained from a population of healthy age-matched subjects. Alternatively, the brain atrophy in a test subject can be determined by determining the brain volume in a selected brain region of the subject and comparing to a control or reference volume of the brain region of the subject, or to control values for the brain region obtained from a population of healthy age-matched subjects. Brain volume can be determined by measuring volume of whole brain grey matter, frontal lobe, insular cortex, limbic lobe, parietal lobe, temporal lobe, hippocampus, and whole brain white matter.

[0033] In one aspect, the present disclosure relates to methods of treating brain atrophy after it has been detected in a subject. Such treatment includes, but is not limited to, reducing or reversing brain shrinkage; halting, slowing, ameliorating or reversing brain volume loss or brain cell loss; halting, slowing, or reversing brain cell death. Such treatment may be achieved by administering to the subject one or more therapeutically active agents, such as a Sigma-1 receptor agonist, and/or a dual modulator of Sigma-1 receptor and muscarinic receptor.

[0034] The present disclosure also encompasses methods of preventing brain atrophy. In one aspect, such prevention comprises blocking, deterring, delaying, slowing, or avoiding the onset of brain atrophy in a subject. In another aspect, the subject is at risk of developing brain atrophy. Such prophylactic method may be achieved by administering to the subject one or more prophylactically active agents, such as a Sigma-1 receptor agonist, and/or a dual modulator of Sigma-1 receptor and muscarinic receptor. [0035] The modulation methods of the present disclosure also comprise any suitable and available tools, instrumentation, apparatus, and/or techniques of monitoring or detecting brain features in various parts of the brain. Such brain feature may include measurements of brain mass, size, volume, density, hydration level, neuron counts, and/or neuron connections. Such tools may include structural MRI.

IV. Therapeutic and/or Prophylactic Agents

[0036] Sigma-1 receptor expression or activity is linked to neuroactivity in neurodevelopment/neurodegeneration, and the activation of the Sigma-1 receptor is associated with neuroprotection in human subjects and in different in vitro and in vivo models. Such neuroprotection may be needed in a subject that have been diagnosed with, or is suspected to have, a neurological disorder, such as a neurodegenerative or a neurodevelopmental disorder. Thus, one aspect of the disclosure encompasses restoring brain volume, halting and/or ameliorating neuron loss, and/or reducing or reversing brain atrophy in such subject with a therapeutic agent or a prophylactic agent which is a Sigma-1 receptor agonist, or is a dual modulator of Sigma-1 receptor and muscarinic receptor.

[0037] Non-limiting examples of the therapeutic agent or the prophylactic agent include but not limited to entacapone, nebicapone, nitecapone, opicapone, tolcapone, tetrahydro-N, N-dimethyl-2,2-diphenyl-3-furanmethanamine (Anavex 2-73 Freebase), tetrahydro-N, N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEXO2-73, AV2-73, A2-73, or blarcamesine), 1 -(2,2- diphenyltetrahydrofuran-3-yl)-N-methylmethanamine (ANAVEX19-144 Freebase), 1- (2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride (ANAVEXO19-144 or A19-144), tetrahydro-N, N-dimethyl-5,5-diphenyl-3- furanmethanamine (ANAVEX1-41 Freebase), tetrahydro-N, N-dimethyl-5,5- diphenyl-3-furanmethanamine hydrochloride (ANAVEX®1-41 orA1-41 ), 1-(3- 4(((1 R,3S,5S)-adamantan-1-yl)(phenyl)methyl)propyl)-4-methylpiperazine (ANAVEX™ 1066 or “AV1066”), (1-(2,8-di methyl- l-thia-3,8-diazaspiro(4.5)dec-3-yl)- 3-(IH-indol-3-yl)propan-l-one) (ANAVEX3-71 , also known as AF710B), PRE-084, donepezil, fluvoxamine, amitriptyline, L-687,384, and combinations thereof. Such listed therapeutic agent also encompasses their enantiomers, stereoisomers, crystal forms, salt forms, co-crystal forms, and may be administered in a therapeutically effective amount to a subject in need, therefore. In one aspect, the Sigma-1 receptor agonist is A2-73, A2-73 Freebase, or an enantiomer, a crystal form, a pharmaceutically acceptable salt, an analog or a metabolite thereof. The A2-73, A2- 73 Freebase or its salt may be in the form of a racemic, a stereoisomer, an enantiomer, a polymorph, or a co-crystal. In one aspect, the enantiomer may be (+) or (-) rotation or expressed as (R) or (S) forms. In one aspect, a pharmaceutically acceptable co-crystal is formed between: (i) A2-73 Freebase, A2-73, A19-144 Freebase, A19-144, A1-41 Freebase, A1-41 , an enantiomer therefore, a polymorph thereof; and (ii) an acid or an ionic salt. In another aspect, the acid comprises fumaric acid, sulfuric acid, phosphoric acid, hydrogen phosphoric acid, dihydrogen phosphoric acid, benzoic acid, salicylic acid, oxalic acid, ethanedisulfonic acid, tartaric acid, citric acid, maleic acid, or a combination thereof. The ionic salt comprises a quaternary ammonium cationic salt, a salt of a transitional metal, a salt of an alkaline earth metal, or a salt of alkali metal. In one aspect, the ionic salt comprises lithium chloride, sodium chloride, magnesium chloride, potassium chloride, calcium chloride, zinc chloride, iron (II) chloride, iron (III) chloride, titanium chloride, chromium (III) chloride, scandium (III) chloride, manganese (II) chloride, copper (I) chloride, copper (II) chloride, nickel chloride, or aluminum chloride.

[0038] In one aspect, the therapeutic agent or the prophylactic agent comprises tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine (A2-73 Freebase), a polymorph thereof, an enantiomer thereof, a polymorph of the enantiomer thereof, a pharmaceutically acceptable salt thereof, an enantiomer of the pharmaceutically acceptable salt thereof, a polymorph of the pharmaceutically acceptable salt thereof, or a co-crystal thereof. In another aspect, the agent comprises tetrahydro-N,N- dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (A2-73), a polymorph thereof, an enantiomer thereof, a polymorph of the enantiomer thereof, or a cocrystal thereof. In yet another aspect, the agent comprises of A2-73 Freebase in amorphous form, A2-73 Freebase in crystal Form I, A2-73 in amorphous form, A2-73 crystal Form I, A2-73 crystal Form II, A2-73 crystal Form III, (+)A2-73 enantiomer, (- )A2-73 enantiomer. The A2-73 Freebase in crystal Form I is disclosed and characterized in W02019200345A1 , which is incorporated by reference in its entirety. Specifically, the A2-73 Freebase in crystal Form I is characterized substantially by XRPD pattern shown in FIG. 16 and particle shapes depicted in FIG. 15. In one aspect, A2-73 crystal is the Form I, Form II, and/or Form III crystals as disclosed and characterized in WO2017013498A2, the disclosure of which is herein incorporated by reference in its entirety. Specifically, the A2-73 crystal Form I is characterized substantially by XRPD pattern shown in FIG. 1 and particle shapes depicted in FIGs. 2 and 3. The A2-73 crystal Form II is characterized substantially by XRPD pattern shown in FIG. 4, particle shapes depicted in FIG. 7, and the FTIR spectrum shown in FIG. 5. The A2-73 crystal Form III is characterized substantially by XRPD pattern shown in FIG. 8, particle shapes depicted in FIG. 11 , and the FTIR spectrum shown in FIG. 9. The analog of A2-73 may include A1 -41 . The metabolite of A2-73 may include A19-144. In one aspect, the pharmaceutically acceptable salt comprises a hydrochloride salt, a hydrobromide salt, a fumarate salt, a sulfate salt, a dihydrogen phosphate salt, a benzoate salt, a mesylate salt, an edysilate salt, or an oxalate salt. In another aspect, the co-crystal comprises a A2-73 pharmaceutically acceptable salt with an organic acid comprising tartaric acid, citric acid, maleic acid, or a combination thereof. In another aspect, the A2-73 is A2-73 amorphous form, A2- 73 Freebase crystal Form I, A2-73 crystal Form I, A2-73 crystal Form II, A2-73 crystal Form III, (+)A2-73 enantiomer, (-)A2-73 enantiomer. In one aspect, the active is A2-73 freebase fumarate salt and/or its crystals, such as A2-73 Freebase fumarate salt in amorphous form, A2-73 Freebase hydrogen fumarate salt crystal Form I, A2-73 Freebase hydrogen fumarate salt crystal Form II, A2-73 Freebase hydrogen fumarate salt crystal Form III, A2-73 Freebase hydrogen fumarate salt crystal Form IV, A2-73 Freebase hydrogen fumarate salt crystal Form V, all of which are disclosed and characterized in W02019200345A1 , such as XRPD patterns shown in FIG. 29, FIG. 30, FIG. 32 FIG. 33, and FIG. 34, respectively. In another aspect, the A2-73 is other salt crystals, such as A2-73 Freebase Mesylate Form I, A2-73 Freebase Sulfate Form I, A2-73 Freebase Sulfate Form II, A2-73 Freebase Oxalate Form I, A2-73 Freebase Oxalate Form II, A2-73 Freebase Oxalate Form III, A2-73 Freebase Dihydrogen phosphate Form I, A2-73 Freebase Edisylate Form I, A2-73 Freebase Benzoate Form I, all of which are disclosed and characterized in W02019200345A1 , such as XRPD patterns shown in FIGs. 18-23 and 25-27, respectively. In yet another aspect, the active is A2-73 Freebase hydrobromide crystal Form A, A2-73 Freebase hydrobromide crystal Form B, A2-73 maleate crystal Form S5, or A2-73 maleate crystal Form S6. They are disclosed and characterized in WO2021 158586A1 , the disclosure of which is herein incorporated by reference in its entirety. In yet another aspect, the active is co-crystal Form CSII of A2-73 co-crystal with tartaric acid, co-crystal Form CSIII of A2-73 co-crystal with citric acid, or cocrystal Form CSIV of A2-73 co-crystal with malic acid. They are disclosed and characterized in WO2023208133A1 , which is incorporated by reference in its entirety. In yet another aspect, the active is co-crystal of A2-73 with zinc chloride disclosed in U.S. Patent No. 12,018,005B1 , which is incorporated by reference in its entirety.

[0039] When the therapeutic agent or the prophylactic agent is A2-73 or A2-73 Freebase, or their salts, enantiomers, polymorphs, co-crystals, the therapeutically effective amount or the prophylactically effective amount of A2-73 may range from about 0.5 mg to about 100 mg, about 1 mg to about 80 mg, about 10 mg to about 70 mg, about 15 mg to about 55 mg, about 30 mg to about 50 mg, or about 3 mg to about 5 mg. When the therapeutic agent is A2-73, the therapeutically effective amount may range from 0.5 mg to 100 mg, 1 mg to 80 mg, 10 mg to 70 mg, 15 mg to 55 mg, 30 mg to 50 mg, or 3 mg to 5 mg. When the agent is A2-73, the therapeutically effective amount may be about 0.5 mg, about 1 .0 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 22 mg, about 25 mg, about 30 mg, about 32 mg, about 35 mg, about 38 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 58 mg, about 60 mg, about 65 mg, about 68 mg, about 70 mg, about 72 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg. In one aspect, when the agent is A2-73, the therapeutically effective amount or the prophylactically effective amount may be 0.5 mg, 1 .0 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 22 mg, 25 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 45 mg, 50 mg, 55 mg, 58 mg, 60 mg, 65 mg, 68 mg, 70 mg, 72 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg. In yet another aspect, the therapeutic agent is A2-73 crystal Form I, A2-73 crystal Form II or A2-73 crystal Form III, and their therapeutically effective amounts or the prophylactically effective amounts may range from about 0.5 mg to about 100 mg, about 1 mg to about 60 mg, about 30 mg to about 50 mg, or about 3 mg to about 5 mg.

[0040] When the therapeutic agent or the prophylactic agent is 1 -(2,2- diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride (A19-144), or 1- (2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine (A19-144 Freebase), or their salts, enantiomers, polymorphs, co-crystals, the therapeutically effective amount or the prophylactically effective amount may range from about 0.5 mg to about 200 mg, about 1 mg to about 180 mg, about 10 mg to about 170 mg, about 15 mg to about 155 mg, about 30 mg to about 150 mg, about 40 mg to about 130 mg, about 50 mg to about 110 mg, about 60 mg to about 100 mg, about 70 mg to about 90 mg, about 80 mg to about 85 mg, or about 3 mg to about 5 mg. When the agent is A 19-144, the therapeutically effective amount may range from 0.5 mg to 200 mg, 1 mg to 180 mg, 10 mg to 170 mg, 15 mg to 155 mg, 30 mg to 150 mg, 40 mg to 130 mg, 50 mg to 110 mg, 60 mg to 100 mg, 70 mg to 90 mg, 80 mg to 85 mg, or 3 mg to 5 mg. In one aspect, when the agent is A19-144, the therapeutically effective amount may be about 0.5 mg, about 1 .0 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 22 mg, about 25 mg, about 30 mg, about 32 mg, about 35 mg, about 38 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 58 mg, about 60 mg, about 65 mg, about 68 mg, about 70 mg, about 72 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 115 mg, about 120 mg, about 122 mg, about 125 mg, about 130 mg, about 132 mg, about 135 mg, about 138 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 158 mg, about 160 mg, about 165 mg, about 168 mg, about 170 mg, about 172 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, or about 200 mg. In one aspect, when the therapeutic agent is A19-144, the therapeutically effective amount or the prophylactically effective amount may be 0.5 mg, 1 .0 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 22 mg, 25 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 45 mg, 50 mg, 55 mg, 58 mg, 60 mg, 65 mg, 68 mg, 70 mg, 72 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 115 mg, 120 mg, 122 mg, 125 mg, 130 mg, 132 mg, 135 mg, 138 mg, 140 mg, 145 mg, 150 mg, 155 mg, 158 mg, 160 mg, 165 mg, 168 mg, 170 mg, 172 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg.

[0041] When the therapeutic agent or the prophylactic agent is tetrah yd ro-N, N- dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride (A1-41 ), tetrahydro-N, N- dimethyl-5,5-diphenyl-3-furanmethanamine (A1-41 Freebase), or its salts, enantiomers, polymorphs, co-crystals, the therapeutically effective amount or the prophylactically effective amount may range from about 0.5 mg to about 200 mg, about 1 mg to about 180 mg, about 10 mg to about 170 mg, about 15 mg to about 155 mg, about 30 mg to about 150 mg, about 40 mg to about 130 mg, about 50 mg to about 110 mg, about 60 mg to about 100 mg, about 70 mg to about 90 mg, about 80 mg to about 85 mg, or about 3 mg to about 5 mg. When the therapeutic agent is A 1-41 , the therapeutically effective amount or the prophylactically effective amount may range from 0.5 mg to 200 mg, 1 mg to 180 mg, 10 mg to 170 mg, 15 mg to 155 mg, 30 mg to 150 mg, 40 mg to 130 mg, 50 mg to 110 mg, 60 mg to 100 mg, 70 mg to 90 mg, 80 mg to 85 mg, or 3 mg to 5 mg. In one aspect, when the therapeutic agent is A1-41 , the therapeutically effective amount or the prophylactically effective amount may be about 0.5 mg, about 1 .0 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 22 mg, about 25 mg, about 30 mg, about 32 mg, about 35 mg, about 38 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 58 mg, about 60 mg, about 65 mg, about 68 mg, about 70 mg, about 72 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 115 mg, about 120 mg, about 122 mg, about 125 mg, about 130 mg, about 132 mg, about 135 mg, about 138 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 158 mg, about 160 mg, about 165 mg, about 168 mg, about 170 mg, about 172 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, or about 200 mg. In one aspect, when the therapeutic agent or the prophylactic agent is A1-41 , the therapeutically effective amount or the prophylactically effective amount may be 0.5 mg, 1 .0 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 22 mg, 25 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 45 mg, 50 mg, 55 mg, 58 mg, 60 mg, 65 mg, 68 mg, 70 mg, 72 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 115 mg, 120 mg, 122 mg, 125 mg, 130 mg, 132 mg, 135 mg, 138 mg, 140 mg, 145 mg, 150 mg, 155 mg, 158 mg, 160 mg, 165 mg, 168 mg, 170 mg, 172 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg.

[0042] In one aspect, the therapeutic agent or the prophylactic agent is A2-73 and A2-73 Freebase, and the effective therapeutic amount comprises the combined amount of about 0.5 mg to about 100 mg, about 1 mg to about 80 mg, about 10 mg to about 70 mg, about 15 mg to about 55 mg, about 30 mg to about 50 mg, or about 3 mg to about 5 mg. In another aspect, the therapeutic agent is A2-73 and A19-144, and the therapeutically effective amount comprises the combined amount of about 0.5 mg, about 1 .0 mg, about 3 mg, about 5 mg, about 10 mg, 15 mg, about 20 mg, about 22 mg, about 25 mg, about 30 mg, about 32 mg, about 35 mg, about 38 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 58 mg, about 60 mg, about 65 mg, about 68 mg, about 70 mg, about 72 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg. In another aspect, the therapeutic agent is A2-73 and A1 -41 , and the therapeutic effective amount comprises the combined amount of 0.5 mg, 1 .0 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 22 mg, 25 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 45 mg, 50 mg, 55 mg, 58 mg, 60 mg, 65 mg, 68 mg, 70 mg, 72 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg.

[0043] In one aspect, the therapeutic agent or the prophylactic agent is administered daily, every other day, or three times per week, or once per week. In other aspect, the agent is administered once day, twice daily or three times daily. In yet another aspect, the therapeutically effective amount may range from about 0.5 mg/day to about 100 mg/day, from about 1 to about 60 mg/day, from about 20 to about 50 mg/day, from about 20 to about 30 mg/day, or from about 15 to about 25 mg/day. In another aspect, the therapeutically effective amount of A2-73 may range from 0.5 mg/day to 100 mg/day, from 1 to 60 mg/day, from 20 to 50 mg/day, from 20 to 30 mg/day, or from 15 to 25 mg/day. In one aspect, administering the therapeutic effective amount or the prophylactically effective amount may provide blood levels of about 10 ng/ml to about 12 ng/ml of A2-73. In one aspect, administering the therapeutic effective amount of A2-73 can provide blood levels of 10 ng/ml to 12 ng/ml of A2-73. In another aspect, administering the therapeutic effective amount or the prophylactically effective amount of A2-73 can provide blood levels of about 10 ng/ml, about 10.2 ng/ml, about 10.5 ng/ml, about 10.8 ng/ml, about 11 ng/ml, about 11.2 ng/ml, about 11.5 ng/ml, or about 12 ng/ml of A2-73. In another aspect, administering the therapeutic effective amount of A2-73 can provide blood levels of 10 ng/ml, 10.2 ng/ml, 10.5 ng/ml, 10.8 ng/ml, 11 ng/ml, 11.2 ng/ml, 11.5 ng/ml, or 12 ng/ml of A2-73.

[0044] The therapeutic agent or the prophylactic agent, such as A2-73, A19-144, A1-41 , or their freebases, salts, or enantiomers, may be administered to the subject daily or every other day for a treatment period, or following an intermittent dosing regimen. For example, A2-73 may be administered every 2, 3, 4, 5, 6, 7, 14, or every 30 days. Frequency of administration can be one time, two times, or three times on the dosing days. The therapeutic agent, such as A2-73, may be administered over a period ranging from about 1 day to about 1 year, from about 1 day to about 1 week, from about 3 days to about 1 month, from about 2 weeks to about 6 months, or from about 2 months to about 4 months. The therapeutic agent may be administered over a period of about 1 day, about 7 days, about 30 days, about 60 days, about 120 days, or about 180 days or more. In some aspect, the therapeutic agent A2 -73 is administered over a period of about 12 weeks, over a period of about 24 weeks, over a period of about 36 weeks, over a period of about 48 weeks, over a period of about 57 weeks, over a period of about 96 weeks, or about 148 weeks, or about 208 weeks, indefinitely, or until resolution of the condition being treated. Further, the dosage regimens may comprise administering to the subject as a pharmaceutical composition or dosage form comprising the therapeutically effective amount of the agent. In one aspect, such administration follows an intermittent dosing regimen of at least two cycles, each cycle comprising (a) a dosing period during which a therapeutically effective amount of said pharmaceutical composition is administered to said patient and, thereafter, (b) a resting period. In some embodiments the dosing period and the resting period are of the same duration or are of different durations. Attention is brought to the dosing period and the resting period in the range of a lower limit (more than) of about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, and 14 days to an upper limit (shorter than) of about 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19, days, 18 days, 17 days, 16 days, 15 days, and 14 days. Also noted is the dosing period of between about 1 day and 12 days and a resting period between about 1 day and 12 days. In one aspect, a dosing period is 12 days and the resting period is 12 days. Such regimen is usefully employed wherein the therapeutically effective amount of said therapeutic agent or its pharmaceutical composition is about 1 mg to about 100 mg and particularly about 30 mg to about 50 mg, and particu larly for oral dosage forms. Also contemplated are A2-73 dosages of about 3 mg to about 5 mg with intravenous administration. [0045] Other methods of administering the therapeutic agent or the prophylactic agent, such as A2-73 Freebase, A19-144, A19-144 Freebased, A1-41 or A1-41 Freebase, can be found in, e.g., U.S. Patent No. 9750746, U.S. Patent Publication No. 20170360798, U.S. Patent Publication No. 20190022052, U.S. Patent Publication No. 20180360796, U.S. Patent Publication No. 20180169059, U.S.

Patent Publication No. 20180177756, U.S. Patent Publication No. 20180169060, and U.S. Patent Publication No. 20190117615. The disclosures of each of the above patents and applications are expressly incorporated herein in their entirety.

V. Pharmaceutical Compositions [0046] One aspect of the present disclosure encompasses a pharmaceutical composition, also called a pharmaceutical formulation, for delivery of the therapeutic agents, such as a Sigma-1 receptor agonist, or a dual modulator of Sigma-1 receptor and muscarinic receptor. A pharmaceutical formulation comprises a therapeutic agent and a pharmaceutically acceptable excipient or carrier. Another aspect of the present disclosure encompasses a dosage form (also called “unit dose”). It refers to the end-product encompassing the pharmaceutical composition and being packaged in a form suitable to be marketed and used. Depending on the method/route of administration, dosage form may be in the form of a liquid, a solid, or a semisolid. The present disclosure provides dosage forms suitable for the delivery of the therapeutic agent, such as in the forms of pills, tablets, capsules, drinks, injections, among many others.

[0047] One aspect of the present disclosure encompasses a pharmaceutical composition or a dosage form comprising a therapeutic amount of the therapeutic agent. The therapeutic agent can be a freebase form, or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts of the compound comprising organic and inorganic salt, such as acetate, aspartate, benzoate, bitartrate, citrate, formate, gluconate, glucuronate, glutamate, fumarate, hydrochloride, hydrobromide, hydroiodide, hypophosphite, isobutyrate, isocitrate, lactate, malate, maleate, meconate, methylbromide, methanesulfonate, monohydrate, mucate, nitrate, oxalate, phenylpropionate, phosphate, phthalate, propionate, pyruvate, salicylate, stearate, succinate, sulfate, tannate, tartrate, terephthalate, valerate, and the like.

[0048] When the therapeutic agent or the prophylactic agent is A2-73, A2-73 Freebase or its salts, the pharmaceutical composition may comprise from about 1 mg to about 50 g, from about 0.1 to about 5 g, from about 0.5 g to about 3 g, from about 1 mg to about 55 mg, from about 40 mg to about 60 mg, from about 80 mg to about 120 mg, from about 180 mg to about 220 mg, from about 0.1 g to about 5 g, or from about 0.5 g to about 3 g of A2-73. Compositions or formulations comprising A2- 73 can be found in, e.g., U.S. Patent No. 9750746, U.S. Patent Publication No.

20170360798, U.S. Patent Publication No. 20190022052, U.S. Patent Publication No. 20180360796, U.S. Patent Publication No. 20180169059, U.S. Patent Publication No. 20180177756, U.S. Patent Publication No. 20180169060, and U.S. Patent Publication No. 20190117615, the disclosures of each of which are incorporated herein in their entirety.

[0049] When the therapeutic agent or the prophylactic agent is A2-73, A2-73 Freebase or its salts, a composition or formulation may comprise A2-73 in an amount of about 0.5 mg to about 100 mg, about 1 mg to about 80 mg, about 10 mg to about 70 mg, about 15 mg to about 55 mg, about 30 mg to about 50 mg, or about 3 mg to about 5 mg. When the therapeutic agent is A2-73, a formulation may comprise A2 -73 in an amount from 0.5 mg to 100 mg, 1 mg to 80 mg, 10 mg to 70 mg, 15 mg to 55 mg, 30 mg to 50 mg, or 3 mg to 5 mg. When the therapeutic agent is A2-73, a formulation may comprise A2-73 in the amount of about 0.5 mg, about 1 .0 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 22 mg, about 25 mg, about 30 mg, about 32 mg, about 35 mg, about 38 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 58 mg, about 60 mg, about 65 mg, about 68 mg, about 70 mg, about 72 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg. In one aspect, when the therapeutic agent is A2-73, a formulation may comprise A2-73 in the amount of 0.5 mg, 1 .0 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 22 mg, 25 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 45 mg, 50 mg, 55 mg, 58 mg, 60 mg, 65 mg, 68 mg, 70 mg, 72 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg.

[0050] When the therapeutic agent or the prophylactic agent is A19-144, A19-144 Freebase or its salts, a composition may comprise A19-144 in the amount ranging from about 0.5 mg to about 200 mg, about 1 mg to about 180 mg, about 10 mg to about 170 mg, about 15 mg to about 155 mg, about 30 mg to about 150 mg, about 40 mg to about 130 mg, about 50 mg to about 110 mg, about 60 mg to about 100 mg, about 70 mg to about 90 mg, about 80 mg to about 85 mg, or about 3 mg to about 5 mg. When the therapeutic agent is A19-144, a composition may comprise A19-144 in an amount ranging from 0.5 mg to 200 mg, 1 mg to 180 mg, 10 mg to 170 mg, 15 mg to 155 mg, 30 mg to 150 mg, 40 mg to 130 mg, 50 mg to 110 mg, 60 mg to 100 mg, 70 mg to 90 mg, 80 mg to 85 mg, or 3 mg to 5 mg. In one aspect, When the therapeutic agent is A19-144, a formulation may comprise A19-144 in an amount of about 0.5 mg, about 1 .0 mg, about 3 mg, about 5 mg, about 10 mg, about

15 mg, about 20 mg, about 22 mg, about 25 mg, about 30 mg, about 32 mg, about

35 mg, about 38 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about

58 mg, about 60 mg, about 65 mg, about 68 mg, about 70 mg, about 72 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 115 mg, about 120 mg, about 122 mg, about 125 mg, about 130 mg, about 132 mg, about 135 mg, about 138 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 158 mg, about 160 mg, about 165 mg, about 168 mg, about 170 mg, about 172 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, or about 200 mg. In one aspect, when the therapeutic agent is A19-144, a formulation may comprise A19-144 in an amount of 0.5 mg, 1 .0 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 22 mg, 25 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 45 mg, 50 mg, 55 mg, 58 mg, 60 mg, 65 mg, 68 mg, 70 mg, 72 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 115 mg, 120 mg, 122 mg, 125 mg, 130 mg, 132 mg, 135 mg, 138 mg, 140 mg, 145 mg, 150 mg, 155 mg, 158 mg, 160 mg, 165 mg, 168 mg, 170 mg, 172 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg.

[0051] When the therapeutic agent or the prophylactic agent is A1-41 , A1-41 Freebase, or its salts, a formulation may comprise A1 -41 in an amount ranging from about 0.5 mg to about 200 mg, about 1 mg to about 180 mg, about 10 mg to about 170 mg, about 15 mg to about 155 mg, about 30 mg to about 150 mg, about 40 mg to about 130 mg, about 50 mg to about 110 mg, about 60 mg to about 100 mg, about 70 mg to about 90 mg, about 80 mg to about 85 mg, or about 3 mg to about 5 mg. When the therapeutic agent or the prophylactic agent is A 1 -41 , a formulation may comprise A1 -41 in an amount ranging from 0.5 mg to 200 mg, 1 mg to 180 mg, 10 mg to 170 mg, 15 mg to 155 mg, 30 mg to 150 mg, 40 mg to 130 mg, 50 mg to 110 mg, 60 mg to 100 mg, 70 mg to 90 mg, 80 mg to 85 mg, or 3 mg to 5 mg. In one aspect, When the therapeutic agent is A1-41 , a formulation may comprise A1-41 in an amount of about 0.5 mg, about 1 .0 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 22 mg, about 25 mg, about 30 mg, about 32 mg, about 35 mg, about 38 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 58 mg, about 60 mg, about 65 mg, about 68 mg, about 70 mg, about 72 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 115 mg, about 120 mg, about 122 mg, about 125 mg, about 130 mg, about 132 mg, about 135 mg, about 138 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 158 mg, about 160 mg, about 165 mg, about 168 mg, about 170 mg, about 172 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, or about 200 mg. In one aspect, when the therapeutic agent or the prophylactic agent is A1-41 , a formulation may comprise A1-41 in an amount of 0.5 mg, 1 .0 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 22 mg, 25 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 45 mg, 50 mg, 55 mg, 58 mg, 60 mg, 65 mg, 68 mg, 70 mg, 72 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 115 mg, 120 mg, 122 mg, 125 mg, 130 mg, 132 mg, 135 mg, 138 mg, 140 mg, 145 mg, 150 mg, 155 mg, 158 mg, 160 mg, 165 mg, 168 mg, 170 mg, 172 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg.

[0052] In yet another aspect, the therapeutic agent or the prophylactic agent is A2- 73 crystal Form I, A2-73 crystal Form II or A2-73 crystal Form III, and their therapeutically effective amounts may range from 0.5 mg to 100 mg, 1 mg to 60 mg, 30 mg to 50 mg, or 3 mg to 5 mg. When the agonist is A2-73, the therapeutically effective amount or the prophylactically effective amount of A2-73 can range from about 0.5 mg to about 100 mg, about 1 mg to about 60 mg, about 30 mg to about 50 mg, or about 3 mg to about 5 mg. In another aspect, the therapeutically effective amount or the prophylactically effective amount of A2-73 can range from about 0.5 mg/day to about 100 mg/day, from about 1 to about 60 mg/day, from about 20 to about 50 mg/day, from about 20 to about 30 mg/day, or from about 15 to about 25 mg/day. In another aspect, the therapeutically effective amount of A2-73 can range from 0.5 mg/day to 100 mg/day, from 1 to 60 mg/day, from 20 to 50 mg/day, from 20 to 30 mg/day, or from 15 to 25 mg/day. Administering the therapeutic effective amount or the prophylactically effective amount of A2-73 can provide blood levels of about 10 ng/ml to about 12 ng/ml of A2-73. In one aspect, administering the therapeutic effective amount of A2-73 can provide blood levels of 10 ng/ml to 12 ng/ml of A2-73. In another aspect, administering the therapeutic effective amount of A2-73 can provide blood levels of about 10 ng/ml, about 10.2 ng/ml, about 10.5 ng/ml, about 10.8 ng/ml, about 11 ng/ml, about 11 .2 ng/ml, about 11 .5 ng/ml, or about 12 ng/ml of A2-73. In another aspect, administering the therapeutic effective amount or the prophylactically effective amount of A2-73 can provide blood levels of 10 ng/ml, 10.2 ng/ml, 10.5 ng/ml, 10.8 ng/ml, 11 ng/ml, 11.2 ng/ml, 11.5 ng/ml, or 12 ng/ml of A2-73.

[0053] The therapeutic agent or the prophylactic agent can be formulated and administered to a subject by several different means. For instance, a composition can generally be administered parenterally, intraperitoneally, intravascularly, transdermally, subcutaneously, or intrapulmonarily in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable adjuvants, carriers, excipients, and vehicles as desired.

[0054] The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intrathecal, or intrasternal injection, or infusion techniques.

Formulation of pharmaceutical compositions is discussed in, for example, Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (1975), and Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y. (1980).

[0055] In another aspect, the therapeutic agent can be formulated to be suitable for administration to a particular type of subjects, such as an elderly or a pediatric subject, a subject with difficulty in swallowing, a subject prone to seizure, or a subject prone to vomiting or nauseating. As used herein, an elderly is a human being of 65 years of age or older. For a person older than 79 years, aged may also be used. A pediatric comprises an infant (ages 0-2 yr), a child (ages 2-12), or an adolescent (ages 13-18). For example, to facilitate administration of the therapeutic agent to a pediatric subject, the formulation may comprise an excipient desirable by a pediatric subject, such as flavored oral suspensions, flavored caplets, or flavored capsules. Such flavor may be strawberry flavor, apple flavor, bubblegum flavor, grape flavor, or orange flavor. And such formu lation meets all the necessary criteria for pediatric use. [0056] A pharmaceutical formulation comprises one or more pharmaceutically acceptable excipients or carriers. Non-limiting examples of excipients or carriers include chemical enhancers, humectants, pressure sensitive adhesives, antioxidants, solubilizers, thickening agents, plasticizers, adjuvants, carriers, excipients, vehicles, coatings, and any combinations thereof. One or more excipients can be selected for oral, transdermal, parenteral, intraperitoneal, intravascular, subcutaneous, by inhalation spray, rectal, or intrapulmonary administration.

[0057] In another aspect, the therapeutic agent may in general be formulated for improving patient compliance, preventing a subject from removing the drug-delivery device. For instance, the therapeutic agent could be formulated for improved patient compliance and preventing removal of a drug-delivery device by providing formulations for extended delivery. Extended delivery can range for periods ranging from more than one day, to months. This may be especially relevant for patients with compromised cognitive and/or motor-control abilities. Extended delivery for periods can range from about 1 day to about 1 year, from about 1 day to about 1 week, from about 3 days to about 1 month, from about 2 weeks to about 6 months, orfrom about 2 months to about 4 months.

[0058] Extended-release formulations could be used for substantially continuous delivery of drug at a preselected rate. For example, for a crystalline of A2-73, the drug can be delivered at a rate of from about 0.5 mg to about 100 mg/day, from about 40 to about 60 gm/day, or from about 10 to about 30 gm/day. Appropriate amounts of crystalline A2-73 can be readily determined by the ordinarily skilled artisan based upon, for example, the intended duration of administration of the drug by the extended-release formulation, the delivery mechanism, the formulation, and the relative potency of the drug among other factors.

/. Binders

[0059] Non-limiting examples of binders suitable for the formulations of various aspects include starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethyl cellulose, polyacrylamides, polyvinyloxoazolidone, polyvinyl alcohols, C12-C18 fatty acid alcohols, polyethylene glycol, polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, and combinations thereof. The polypeptide may be any arrangement of amino acids ranging from about 100 to about 300,000 Daltons.

[0060] The binder can be introduced into the mixture to be granulated in a solid form, including but not limited to a crystal, a particle, a powder, or any other finely divided solid form known in the art. Alternatively, the binder can be dissolved or suspended in a solvent and sprayed onto the mixture in a granulation device as a binder fluid during granulation.

//. Diluents

[0061] Non-limiting examples of diluents (also referred to as “fillers” or “thinners”) include carbohydrates, inorganic compounds, and biocompatible polymers, such as polyvinylpyrrolidone (PVP). Other non-limiting examples of diluents include dibasic calcium sulfate, tribasic calcium sulfate, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starches, saccharides such as sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol, and sorbitol, polyhydric alcohols; starches; pre-manufactured direct compression diluents; and mixtures of any of the foregoing.

Hi. Disinfectants

[0062] Disintegrants can be effervescent or non -effervescent. Non-limiting examples of non -effervescent disintegrants include starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, and tragacanth. Suitable effervescent disintegrants include but are not limited to sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid. iv. Preservatives

[0063] Non-limiting examples of preservatives include, but are not limited to, ascorbic acid and its salts, ascorbic palmitate, ascorbic stearate, anoxomer, N- acetylcysteine, benzyl isothiocyanate, m-aminobenzoicacid, o-aminobenzoicacid, p- aminobenzoic acid (PABA), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), caffeic acid, canthaxantin, alpha-carotene, beta-carotene, beta-caraotene, beta-apo-carotenoic acid, carnosol, carvacrol, catechins, cetyl gallate, chlorogenic acid, citric acid and its salts, clove extract, coffee bean extract, p-coumaric acid, 3,4-dihydroxybenzoic acid, N,N’-diphenyl-p-phenylenediamine (DPPD), dilauryl thiodipropionate, distearyl thiodipropionate, 2,6-di-tert-butylphenol, dodecyl gallate, edetic acid, ellagic acid, erythorbic acid, sodium erythorbate, esculetin, esculin, 6-ethoxy-1 ,2-dihydro-2, 2, 4-trimethylqu incline, ethyl gallate, ethyl maltol, ethylenediaminetetraacetic acid (EDTA), eucalyptus extract, eugenol, ferulic acid, flavonoids (e.g., catechin, epicatechin, epicatechin gallate, epigallocatechin (EGC), epigallocatechin gallate (EGCG), polyphenol epigallocatechin-3-gallate), flavones (e.g., apigenin, chrysin, luteolin), flavonols (e.g., datiscetin, myricetin, daemfero), flavanones, fraxetin, fumaric acid, gallic acid, gentian extract, gluconic acid, glycine, gum guaiacum, hesperetin, alpha-hydroxybenzyl phosphinic acid, hydroxycinammic acid, hydroxyglutaric acid, hydroquinone, N-hydroxysuccinic acid, hydroxytryrosol, hydroxyurea, rice bran extract, lactic acid and its salts, lecithin, lecithin citrate; R-alpha-lipoic acid, lutein, lycopene, malic acid, maltol, 5-methoxy tryptamine, methyl gallate, monoglyceride citrate; monoisopropyl citrate; morin, betanaphthoflavone, nordihydroguaiaretic acid (NDGA), octyl gallate, oxalic acid, palmityl citrate, phenothiazine, phosphatidylcholine, phosphoric acid, phosphates, phytic acid, phytylubichromel, pimento extract, propyl gallate, polyphosphates, quercetin, trans-resveratrol, rosemary extract, rosmarinic acid, sage extract, sesamol, silymarin, sinapic acid, succinic acid, stearyl citrate, syringic acid, tartaric acid, thymol, tocopherols (i.e., alpha-, beta-, gamma- and delta-tocopherol), tocotrienols (i.e., alpha-, beta-, gamma- and delta-tocotrienols), tyrosol, vanilic acid, 2,6-di-tert- butyl-4-hydroxymethylphenol (i.e., lonox 100), 2,4-(tris-3’ ,5’-bi-tert-bu tyl-4’- hydroxybenzyl)-mesitylene (i.e., lonox 330), 2,4,5-trihydroxybutyrophenone, ubiquinone, tertiary butyl hydroquinone (TBHQ), thiodipropionic acid, trihydroxy butyrophenone, tryptamine, tyramine, uric acid, vitamin K and derivates, vitamin Q10, wheat germ oil, zeaxanthin, or combinations thereof. v. Flavor-modifying agents

[0064] Suitable flavor-modifying agents include flavorants, taste-masking agents, sweeteners, and the like. Flavorants include, but are not limited to, synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits, and combinations thereof. Other non-limiting examples of flavors include cinnamon oils, oil of Wintergreen, peppermint oils, clover oil, hay oil, anise oil, eucalyptus, vanilla, citrus oils such as lemon oil, orange oil, grape and grapefruit oil, fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.

[0065] Taste-masking agents include but are not limited to cellulose hydroxypropyl ethers (HPC) such as Klucel®, Nisswo HPC and PrimaFlo HP22; low-substituted hydroxypropyl ethers (L-HPC); cellulose hydroxypropyl methyl ethers (HPMC) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Opadry YS, PrimaFlo, MP3295A, Benecel MP824, and Benecel MP843; methylcellulose polymers such as Methocel® and Metolose®; Ethylcelluloses (EC) and mixtures thereof such as E461 , Ethocel®, Aqualon®-EC, Surelease; Polyvinyl alcohol (PVA) such as Opadry AMB; hydroxyethylcelluloses such as Natrosol®; carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aualon®-CMC; polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR®; monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit® EPO, Eudragit® RD100, and Eudragit® E100; cellulose acetate phthalate; sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures of these materials. In other aspects, additional taste-masking agents contemplated are those described in U.S. Pat. Nos. 4,851 ,226; 5,075,114; and 5,876,759, each of which is hereby incorporated by reference in its entirety.

[0066] Non-limiting examples of sweeteners include glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia rebaudiana (Stevioside); ch loro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, sylitol, hydrogenated starch hydrolysates and the synthetic sweetener 3, 6-dihydro-6-methyl-1 ,2,3-oxathiazin-4-one-2,2-dioxide, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof. vi. Lubricants and glidants

[0067] The lubricant compositions may be utilized to lubricate ingredients that form a pharmaceutical composition. As a glidant, the lubricant facilitates removal of solid dosage forms during the manufacturing process. Non-limiting examples of lubricants and glidants include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil. The pharmaceutical composition will generally comprise from about 0.01 % to about 10% by weight of a lubricant. In some aspect, the pharmaceutical composition will comprise from about 0.1 % to about 5% by weight of a lubricant. In a further aspect, the pharmaceutical composition will comprise from about 0.5% to about 2% by weight of a lubricant. vii. Dispersants

[0068] Dispersants may include but are not limited to starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high hydrophilic-lipophilic balance (HLB) emulsifier surfactants. v/77. Colorants

[0069] Depending upon the aspect of the disclosure, it may be desirable to include a coloring agent. Suitable color additives include butare not limited to food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C). These colors or dyes, along with their corresponding lakes, and certain natural and derived colorants, may be suitable for use in various aspects of the disclosure. ix. pH modifiers

[0070] Non-limiting examples of pH modifiers include citric acid, acetic acid, tartaric acid, malic acid, fumaric acid, lactic acid, phosphoric acid, sorbic acid, benzoic acid, sodium carbonate and sodium bicarbonate. x. Chelating agents

[0071] A chelating agent may be included as an excipient to immobilize oxidative groups, including but not limited to metal ions, to inhibit the oxidative degradation of the morphinan by these oxidative groups. Non-limiting examples of chelating agents include lysine, methionine, glycine, gluconate, polysaccharides, glutamate, aspartate, and disodium ethylenediaminetetraacetate (Na2EDTA). xi. Antimicrobial agents

[0072] An antimicrobial agent may be included as an excipient to minimize the degradation of the compound according to this disclosure by microbial agents, including but not limited to bacteria and fungi. Non-limiting examples of antimicrobials include parabens, chlorobutanol, phenol, calcium propionate, sodium nitrate, sodium nitrite, Na2EDTA, and sulfites including but not limited to sulfur dioxide, sodium bisulfite, and potassium hydrogen sulfite. xii. Release-controlling polymers

[0073] Release-controlling polymers may be included in the various aspects of the solid dosage pharmaceutical compositions incorporating compounds according to this disclosure. In one aspect, the release-controlling polymers may be used as a tablet coating. In other aspects, including but not limited to bi layer tablets, a releasecontrolling polymer may be mixed with the granules and other excipients prior to the formation of a tablet by a known process including but not limited to compression in a tablet mold. Suitable release-controlling polymers include but are not limited to hydrophilic polymers and hydrophobic polymers.

[0074] Suitable hydrophilic release-controlling polymers include, but are not limited to, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose ethers, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, nitrocellulose, crosslinked starch, agar, casein, chitin, collagen, gelatin, maltose, mannitol, maltodextrin, pectin, pu Hu Ian , sorbitol, xylitol, polysaccharides, ammonia alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, alginate sodium carmellose, calcium carmellose, carrageenan, fucoidan, furcellaran, arabic gum, carrageens gum, ghafti gum, guar gum, karaya gum, locust bean gum, okra gum, tragacanth gum, scleroglucan gum, xanthan gum, hypnea, laminaran, acrylic polymers, acrylate polymers, carboxyvinyl polymers, copolymers of maleic anhydride and styrene, copolymers of maleic anhydride and ethylene, copolymers of maleic anhydride propylene or copolymers of maleic anhydride isobutylene), crosslinked polyvinyl alcohol and poly N-vinyl-2- pyrrolidone, diesters of polyglucan, polyacrylamides, polyacrylic acid, polyamides, polyethylene glycols, polyethylene oxides, poly(hydroxyalkyl methacrylate), polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, polystyrenes, polyvinylpyrrolidone, anionic and cationic hydrogels, and combinations thereof. x/77. Coatings

[0075] A solid dosage comprising a compound according to this disclosure may comprise a coating, wherein such a coating may control release of the compound, function as a moisture barrier, or buffer or modify pH. A “control releasing coat” or “controlled release coat” as used herein is defined to mean a functional coat which can for example comprise at least one pH independent polymer, pH dependent polymer (for example enteric or reverse enteric type polymers), soluble polymer, insoluble polymer, lipids, lipidic materials, or combinations thereof. The coating, when applied onto a dosage form, may slow (for example when applied to a normal release matrix dosage form), further slow (for example when applied to a controlled release matrix dosage form) or modify the rate of release of a compound according to this disclosure when applied to an uncoated dosage form. For example, the control releasing coat can be designed such that when the control releasing coat is applied to a dosage form, the dosage form in conjunction with the control releasing coat can exhibit the release of the compound according to this disclosure, such as a “modified-release”, “control led-release”, “sustained-release”, “extended-release”, “delayed-release”, “prolonged-release,” or combinations thereof. The “control releasing coat” may optionally comprise additional materials that may alter the functionality of the control releasing coat.

[0076] The term “moisture barrier” as used herein is one which impedes or retards the absorption of moisture. Compounds according to this disclosure may be hygroscopic and, as such, may be susceptible to decomposition overtime under highly humid conditions. The proportion of the components of the moisture barrier and the amount of the moisture barrier optionally applied onto the control-releasing coating or onto the core are typically such that the moisture barrier does not fall within the USP definition and requirement for an enteric coat. Suitably, the moisture barrier may comprise an enteric and/or acrylic polymer, suitably an acrylic polymer, optionally a plasticizer, and a permeation enhancer. The permeation enhancer is a hydrophilicsubstance, which allows water to enter without physical disruption of the coating. The moisture barrier may additionally comprise other conventional inert excipients, which may improve processing of an extended-release formulation. [0077] Coating and matrix materials which may be used in accordance with the invention are those known in the art for use in control led-release formulations, such as synthetic polymers of the polyvinyl type, e.g., polyvinylchloride, polyvinylacetate and copolymers thereof, polyvinylalcohol, and polyvinylpyrrolidone; synthetic polymers of the polyethylene type, e.g., polyethylene and polystyrene; acrylic acid polymers; biopolymers or modified biopolymers, such as cellulosic polymers, shellac and gelatin; fats, oils, higher fatty acids and higher alcohols (i.e., acids and alcohols containing alkyl chains of at least 10 carbon atoms), for example aluminum monostearate, cetylalcohol, hydrogenated beef tallow, hydrogenated castor oil, 12- hydroxystearl alcohol, glyceryl mono- or dipalmitate; glyceryl mono-, di- or tristearate; myristyl alcohol, stearic acid, stearyl alcohol, and polyethyleneglycols; waxes; sugars and sugar alcohols.

[0078] The pH-buffering properties of a coating may be strengthened by introducing into the coating substances chosen from a group of compounds usually used in antacid formulations, for example magnesium oxide, hydroxide or carbonate, aluminum or calcium hydroxide, carbonate or silicate; composite aluminum/magnesium compounds, for example Al2O3-6MgO CO2-12H2O, (Mg6Al2(OH)i6CO3'4H2O), MgO Al2O3-2SiO2.nH2O, aluminum bicarbonate coprecipitate or similar compounds; or other pharmaceutically acceptable pH- buffering compounds, for example the sodium, potassium, calcium, magnesium and aluminum salts of phosphoric, carbonic, citric or other suitable, weak, inorganic or organic acids; or suitable organic bases, including basic amino acids; and salts or combinations thereof. [0079] A pH-dependent coating serves to release the drug in desired areas of the gastrointestinal (Gl) tract, e.g., the stomach or small intestine. When a pH- independent coating is desired, the coating is designed to achieve optimal release regardless of pH-changes in the environmental fluid, e.g., the Gl tract. When the coating is formulated to release a compound according to this disclosure in the intestines (especially the upper small intestines), the coating is often called an “enteric coating”. A pH-dependent coating may include, but is not limited to, acrylic acid polymers and copolymers, for example polymers formed from acrylic acid, methacrylic acid, methyl acrylate, amino methylacrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate (e.g., Eudragit™); cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate (CAP), cellulose acetate trimel litate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate and carboxymethylcellulose sodium; shellac (purified lac); vinyl polymers and copolymers such as polyvinyl pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate (PVAP), vinylacetate croton ic acid copolymer, and ethylene-vinyl acetate copolymers; zein; and salts and combinations thereof.

VI. Dosage Forms

[0080] One aspect of the present disclosure encompasses a dosage form (also called “unit dose”) of a Sigma-1 receptor agonist, or a dual modulator of Sigma-1 receptor and muscarinic receptor. It refers to the end-product encompassing the pharmaceutical composition and being packaged in a form suitable to be marketed and used. Depending on the method/route of administration, dosage form may be in the form of a liquid, a solid, or a semisolid. The present disclosure provides dosage forms suitable for delivery of the therapeutic agent, such as in the forms of pills, tablets, capsules, drinks, injections, among many others. The present disclosure provides dosage forms suitable for delivery of the therapeutic agent to the designated patient groups, such as elder patients, pediatric patients, or in the forms suitable to be administered by the health care providers, and/or caregivers.

[0081] Another aspect of the disclosure encompasses dosage forms of the Sigma-1 receptor agonist, or a dual modulator of Sigma-1 receptor and muscarinic receptor, in either therapeutically effective or prophylactical ly effective amount. Specifically, when such agonist is A2-73 or A2-73 Freebase, the dosage form may comprise from about 1 mg to about 50 g, from about 1 mg to about 500 mg, from about 1 mg to about 100 mg, from about 1 mg to about 500 mg, from about 50 to about 400 mg, from about 75 to about 150 mg, from about 150 to about 200 mg, from about 40 mg to about 60 mg, from about 80 mg to about 120 mg, or from about 180 mg to about 220 mg of A2-73. For instance, the dosage form can comprise 1 , 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, or 300 or more mg of A2-73. In some aspect, dosage forms can comprise from about 1 mg to about 500 mg, or about 1 mg to about 100 mg of A2-73.

[0082] Dosage forms include those formulated for extended or slow release, and those formulated for immediate release. For example, an immediate release dosage form may include a crystalline form of A2-73 Freebase, A2-73, a A2-73 Freebase salt as disclosed herein. For example, a fast-dissolve oral dosage form may include for example A2-73 crystal Form I. Alternatively, a dosage form may comprise a crystalline Form I of A2-73 Freebase, or crystalline Form I of A2-73 Freebase fumarate salt formulated for inhalation drug delivery, either as a dry powder or aerosol spray.

[0083] Dosage forms also include those formulated for topical administration. For instance, a dosage form can be formulated as one or more of a gel, ointment, emulsion, microemulsion, solution, suspension, paste, gel, foam, spray, lotion, or cream. In one aspect, a topical administration dosage form is a transdermal patch. When the dosage form is formulated as a transdermal patch, the transdermal patch can contain from about 40 mg to about 60 mg, from about 80 mg to about 120 mg, or from about 180 mg to about 220 mg of A2-73 Freebase in crystalline form.

[0084] Dosage forms can alternatively be formulated for oral administration.

Dosage forms formulated for oral administration can be tablets to swallow, chew, or dissolve in water or under the tongue, capsules and chewable capsules, powders, granules, teas, drops, or liquid medications or syrups. In some aspect, the dosage form is an enteric coated oral formulation.

[0085] When the dosage form is an enteric coated oral formulation, the formulation can comprise from about 0.1 mg to about 60 mg A2-73 Freebase, preferably from about 1 mg to about 50 mg A2-73 Freebase.

[0086] An enteric coated oral formulation can also contain A2-73 Freebase salt in crystalline forms. The A2-73 Freebase salt can be a fumarate salt, a sulfate salt, a mesylate salt, a dihydrogen phosphate salt, an edisylate salt, a benzoate salt, a hydrochloride salt, and an oxalate salt. In one aspect, the A2-73 salt is a fumarate salt. When the A2-73 salt is a fumarate salt, the enteric coated oral formulation can comprise from about 0.1 to about 100 mg of A2 -73 fumarate salt, preferably from about 1 mg to about 55 mg of A2-73 fumarate salt.

[0087] Dosage forms also encompass those formulated for subcutaneous and/or intramuscular injection. For example, an intramuscular dosage form may comprise A2-73 in the free base form, dissolved in an oil matrix for intramuscular injection, or alternatively prepared as a suspension of the free base for intramuscular injection. A dosage form formulated for subcutaneous or intramuscular injection may comprise A2-73 in a salt or free base form as disclosed herein, prepared as microspheres using methods known in the art. Alternatively, A2-73 in free base or salt form may be coated, for example using Atomic Layer Deposition (ALD) techniques, with a thin layer coating such as a coating of zinc oxide and used in a formulation for subcutaneous or intramuscular injection. Alternatively, A2-73 free base may be dissolved in a biodegradable polymer matrix, and then implanted subcutaneously (or used in a transdermal patch as detailed further below).

VII. Kits

[0088] In one aspect, the present disclosure provides kits to practice the methods disclosed herein . The kits may comprise one or more therapeutic agents, pharmaceutically acceptable carriers, solvents, buffers, and the like. The kits may also include instructions for practicing the methods. Instructions included in the kits may be affixed to packaging material or may be included as a package insert. While the instructions are typically written or printed materials, they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this disclosure. Such media include, but are not limited to, electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. As used herein, the term “instructions” may include the address of an internet site that provides the instructions.

DEFINITIONS [0089] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. The following references provide one of skill with a general definition of many of the terms used in this invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991 ); and Hale & Marham, The Harper Collins Dictionary of Biology (1991 ). As used herein, the following terms have the meanings ascribed to them unless specified otherwise.

[0090] When introducing elements of the present disclosure or the preferred aspects(s) thereof, the articles “a”, “an”, “the” and “said” are intended to mean that there are one or more of the elements. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0091] As used herein, the term “or” can be conjunctive or disjunctive.

[0092] The term “comprising” means “including, but not necessarily limited to”; it specifically indicates open-ended inclusion or membership in a so-described combination, group, series and the like. The terms “comprising” and “including” as used herein are inclusive and/or open-ended and do not exclude additional, unrecited elements or method processes. The term “consisting essentially of” is more limiting than “comprising” but not as restrictive as “consisting of.” Specifically, the term “consisting essentially of” limits membership to the specified materials or steps and those that do not materially affect the essential characteristics of the claimed invention.

[0093] As used herein, terms such as “include,” “including,” “contain,” “containing,” “having,” and the like mean “comprising.” 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.

[0094] As used herein, the term “substantially” means to a great or significant extent, but not completely.

[0095] As used herein, the term “about” or “approximately” as applied to one or more values of interest, refers to a value that is similar to a stated reference value, or within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, such as the limitations of the measurement system. In one aspect, the term “about” refers to any values, including both integers and fractional components that are within a variation of up to ±10% of the value modified by the term “about.” Alternatively, “about” can mean within 3 or more standard deviations, per the practice in the art. Alternatively, such as with respect to biological systems or processes, the term “about” can mean within an order of magnitude, in some embodiments within 5-fold, and in some embodiments within 2-fold, of a value. As used herein, the symbol means “about” or “approximately.”

[0096] All ranges disclosed herein include both end points as discrete values as well as all integers and fractions specified within the range. For example, a range of 0.1 -2.0 includes 0.1 , 0.2, 0.3, 0.4 . . . 2.0. If the end points are modified by the term “about,” the range specified is expanded by a variation of up to ±10% of any value within the range or within 3 or more standard deviations, including the end points. [0097] As used herein, the terms “active ingredient” or “active pharmaceutical ingredient” refer to a pharmaceutical agent, active ingredient, compound, or substance, compositions, or mixtures thereof, that provide a pharmacological, often beneficial, effect.

[0098] As used herein, the terms “control,” or “reference” are used herein interchangeably. A “reference” or “control” level may be a predetermined value or range, which is employed as a baseline or benchmark against which to assess a measured result. “Control” also refers to control experiments or control cells.

[0099] As used herein, the term “dose” denotes any form of an active ingredient formulation or composition, including cells, that contains an amount sufficient to initiate or produce a therapeutic effect with at least one or more administrations. “Formulation” and “composition” are used interchangeably herein.

[0100] As used herein, the term “prophylaxis” refers to preventing or reducing the progression of a disorder, either to a statistically significant degree or to a degree detectable by a person of ordinary skill in the art.

[0101] As used herein, the term “gene” means a segment of DNA that contains all the information for the regulated biosynthesis of an RNA product, including promoters, exons, introns, and other untranslated regions that control expression. [0102] As used herein, the terms “disorder”, “disease”, “condition”, and “dysfunction” are used interchangeably and encompass but are not limited to abnormal state that adversely affects the structure or function of all or part of an organism. A disease may be caused by external factors such as pathogens or by internal dysfunctions. For example, internal dysfunctions of the immune system may produce a variety of different diseases, including various forms of immunodeficiency, hypersensitivity, allergies, and autoimmune disorders. In humans, disease is often referred to any injuries, disabilities, disorders, syndromes, infections, deviant behaviors, or atypical variations of structure and function condition that causes pain, dysfunction, distress, social problems, or death to the person affected. Diseases can affect people not only physically but also mentally, as contracting and living with a disease can alter the affected person's perspective on life. A disease often manifests or is associated with specific signs and symptoms. Intervention or treatment is often desired to eliminate, reduce, and/or reverse the course of a disease, and/or to relieve or ameliorate physical and/or psychological symptoms therein.

[0103] As used herein, the terms “polymorph”, “polymorphic form”, “crystal”, and “crystalline” are used interchangeably and refer to an ordered solid form, wherein atoms, ions, and/or molecules are arranged and patterned in specific ways, which give rise to a specific and unique three-dimensional format. One molecule may exist in multiple crystalline forms, which may possess different physiochemical or biological properties. Different polymorphic forms of the same active pharmaceutical ingredient (API) can lead to changes in API’s solubility, dissolution rate, pharmacokinetics and ultimately its bioavailability and efficacy in therapeutic uses. Developing polymorphic forms and identifying which polymorphic form is the most stable and/or most favorable is crucial in drug design and manufacturing.

[0104] As used herein, the terms “co-crystal” and “cocrystal” are used interchangeably and refer to solids that are crystalline, single-phase materials composed of two or more different molecular or ionic compounds generally in a specific stoichiometric ratio. In essence, a co-crystal consists of two or more components that form a unique crystalline structure and has unique properties. A cocrystal may comprise an organic compound with an acid orwith an ionic salt. Widely encountered cocrystals include hydrates, solvates and clathrates. Co-crystals are often stable and possess their own physiochemical and/or biological properties different from the individual components made up the co-crystals.

[0105] As used herein, the terms “enantiomer”, “optical isomer”, or “optical antipode” are used interchangeably and refer to one of the two stereoisomers that are non-superposable onto their own mirror image, due to the chirality of the carbon atom. No amount of re-orientation of a molecule as a whole or conformational change converts one chemical into its enantiomer. Chemical structures with chirality rotate plane-polarized light. Therefore, an enantiomer can be expressed as (-) or (+) form, indicating the direction of the optical rotation. There are three common naming conventions for specifying one of the two enantiomers (the absolute configuration) of a given chiral molecule: the R/S system is based on the geometry of the molecule; the (+)- and (-)- system is based on its optical rotation properties; and the D/L system is based on the molecule's relationship to enantiomers of glyceraldehyde. When a molecule is denoted dextrorotatory, it rotates the plane of polarized light clockwise and can also be denoted as (+). When it is denoted as levorotatory, it rotates the plane of polarized light counterclockwise and can also be denoted as (-). A mixture of equal amounts of each enantiomer, called “a racemic mixture” or a “racemate”, does not rotate light. The two enantiomers of the same molecule may have different physiochemical or biological properties, imparting difference in solubility, dissolution rate, pharmacokinetics and ultimately bioavailability. Additionally, one enantiomer may have different crystal structures, i.e. polymorphs. And one enantiomer may form co-crystal with other compounds or molecules. Stereoisomers include both enantiomers and diastereomers. Diastereomers, like enantiomers, share the same molecularformula and are also non -superposable onto each other; however, they are not mirror images of each other.

[0106] As used herein, the term “polypeptide” means any polypeptide comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres. Polypeptide refers to both short chains, commonly referred to as peptides, glycopeptides or oligomers, and to longer chains, generally referred to as proteins. Polypeptides may contain amino acids other than the 20 gene-encoded amino acids. Polypeptides include amino acid sequences modified either by natural processes, such as post-translational processing, or by chemical modification techniques that are well-known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature.

[0107] As used herein, the terms “inhibit,” “inhibition,” and “inhibiting” refer to reducing or suppressing a given biological process, condition, symptom, disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process. [0108] As used herein, the terms “treatment” and “treating” refer to prophylaxis of, preventing, suppressing, repressing, reversing, alleviating, ameliorating, or inhibiting the progress of biological process including a disorder or disease, or eliminating a disease. A treatment may be either performed in an acute or chronic way. The term “treatment” also refers to reducing the seventy of a disease or symptoms associated with such disease prior to affliction with the disease. “Repressing” or “ameliorating” a disease, disorder, or the symptoms thereof involves administering a cell, composition, or compound described herein to a subject after clinical appearance of such disease, disorder, or its symptoms. “Prophylaxis of” or “preventing” a disease, disorder, or the symptoms thereof involves administering a cell, composition, or compound described herein to a subject prior to onset of the disease, disorder, or the symptoms thereof. “Suppressing” a disease or disorder involves administering a cell, composition, or compound described herein to a subject after induction of the disease or disorder thereof but before its clinical appearance or symptoms thereof have manifest.

[0109] As used herein, the terms “treatment,” “therapy,” and “therapy regimen” also refer to a clinical intervention made in response to a disease, disorder, or physiological condition manifested by a patient or to which a patient may be susceptible. The aim of treatment includes the alleviation or prevention of symptoms, slowing or stopping the progression or worsening of a disease, disorder, or condition and/or the remission of the disease, disorder, or condition (e.g., a depressive disorder).

[0110] The terms “effective amount” and “therapeutically effective amount” refer to an amountsufficient to effect beneficial or desirable biological and/or clinical results. [0111] As used herein, the term “administering” an agent, such as a therapeutic entity to treat a depressive disorder to an animal or cell, is intended to refer to dispensing, delivering, or applying the substance to the intended target. In terms of the therapeutic agent, the term “administering” is intended to refer to contacting or dispensing, delivering or applying the therapeutic agent to a subject by any suitable route for delivery of the therapeutic agent to the desired location in the animal, including delivery by either the parenteral or oral route, intramuscular injection, subcutaneous/intradermal injection, intravenous injection, intrathecal administration, buccal administration, transdermal delivery, topical administration, and administration by the intranasal or respiratory tract route. The term “administration” includes self-administration and administration to a subject by another.

[0112] As used herein, the terms “prevent” and “prevention” refer to prophylaxis or reducing the probability of developing a disease, disorder or condition in a subject, who does not have, but is at risk of or is deemed susceptible to developing the disease, disorder or condition.

[0113] As used herein, the term “subject” refers to an animal. Typically, the subject is a mammal, and may be a primate (e.g., humans, male orfemale; infant, adolescent, or adult), non-human primates, rats, mice, rabbits, pigs, cows, sheep, goats, horses, dogs, cats, fish, birds, and the like. In one aspect, the subject is a human. A subject may be a laboratory animal (e.g., cynomolgus monkey, rats, mice, guinea pigs and the like). A human subject expressly encompasses any age, size, gender, and race, including an infant, children, teen, adult, or senior (over 65 years of age).

[0114] It should be appreciated that the various modes of treatment or prevention of medical conditions as described herein are intended to mean “substantial”, which includes total but also less than total treatment or prevention, and wherein a detectable, biologically or medically relevant result is achieved.

[0115] As various changes could be made in the above-described cells and methods without departing from the scope of the invention, it is intended that all matter contained in the above description and in the examples given below, shall be interpreted as illustrative and not in a limiting sense.

Examples

[0116] The above disclosure is provided solely for their disclosure before the filing date of the present application. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0117] The following examples are included to demonstrate the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the following examples represent techniques discovered by the inventors to function well in the practice of the disclosure. Those of skill in the art should, however, in light of the present disclosure, appreciate that many changes could be made in the disclosure and still obtain a like or similar result without departing from the spirit and scope of the disclosure, therefore all matter set forth is to be interpreted as illustrative and not in a limiting sense.

Example 1 : Study Design for Brain Atrophy Related to Alzheimer Patients [0118] ANAVEX®2-73 (used interchangeably with “A2-73” or“blarcamesine” herein) was evaluated in a multicenter (52 medical research centers/hospitals in 5 countries), randomized, double-blind, placebo-controlled, 48-week phase 2b/3 trial (ANAVEX2-73-AD-004). The trial enrolled 508 participants with early symptomatic Alzheimerdisease (mild cognitive impairment/mild dementia) from July 2018 to June 2021 (last patient visit for primary outcome in June 2022). The trial results demonstrated positive outcomes on the endpoints of cognition and function with blarcamesine at doses between 10 mg daily up to 50 mg daily (patients were given A2-73 in the daily doses of about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg.)

Example 2: Changes in Brain Atrophy in Alzheimer’s Patients

[0119] Changes in level of brain atrophy were monitored using structural MRI, by comparing the MRIs at beginning of the trial to those obtained at the end of trial at Week 48. The comparison showed a slowing and sometimes a reversing of brain atrophy in the key areas of the entire brain with blarcamesine. Such effect was absent from the placebo group. Significant reduction in atrophy was observed in patients in the blarcamesine treatment group compared to placebo (See Table 1 and FIG. 1 ). Percent change in volume in whole brain, whole brain grey matter, frontal lobe, insular cortex, limbic lobe, parietal lobe and temporal lobe regions was reduced significantly in treatment group compared with placebo group (p < 0.005), with hippocampus and whole brain white matter volume demonstrating a trend of reduction of atrophy without reaching statistical significance.

Table 1: Summary of Changes in Brain Atrophy

Example 3. Discussion on Treatment of Brain Atrophy Related to Alzheimer Disease

[0120] The above clinical results showed that ANAVEX®2-73 treatment met the primary endpoints and reduced clinical decline on the global cognitive and functional scales over 48 weeks in the analysis of the Intent-to-treat (ITT) population.

ANAVEX®2-73 demonstrated visible improvement in patients with Alzheimer’s disease. Patients treated with ANAVEX®2-73 were 84% more likely, to have improved cognition by ADAS-Cog score change of -0.50 points or better from baseline to end of treatment than patients on placebo, with Odds Ratio being 1 .84 (p = 0.015). On average, patients, who improved cognitively with ANAVEX®2-73 treatment, improved by ADAS-Cog cognition score of -4.03 points. ANAVEX®2-73 treatment was 167% more likely to improve function compared with placebo, at a clinically meaningful improvement of ADCS-ADL score change of +3.5 points or better, with Odds Ratio being 2.67 (p=0.0255). These data reflected a robust improvement compared to the placebo group. The data also demonstrated clinically meaningful outcome in cognition and function from baseline. Additionally, treatment with ANAVEX®2-73 statistically and significantly reduced cognitive decline, measured with ADAS-Cog, when comparing to the placebo at the end of treatment by 45%. These data represented a treatment difference in mean score change of - 1 .85 points (p=0.033).

[0121] ANAVEX®2-73 treatment also met the secondary endpoint of reduction in clinical decline of cognition and function assessed by the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) compared to placebo, by a treatment difference in mean score change of -0.42 points (p=0.040), representing 27% reduction in the ITT population.

[0122] ANAVEX®2-73 was generally safe and well tolerated. The incidence of treatment emergent adverse events (TEAEs) was similar in the active and placebo arms with dizziness being the most common TEAE. TEAEs over 7.5% threshold were predominantly mild or moderate. No clinically significant changes in vital signs, laboratory values and ECG parameters in active and placebo arms were observed. Safety findings in the study were consistent with the known safety profile of ANAVEX®2-73. In addition to safety and efficacy demonstrated on the primary and key secondary endpoints, a pre-specified analysis of patients without the SIGMAR1 gene mutation provides further confidence of the robustness of the SIGMAR1 activation in the treatment of neurodegenerative diseases. Approximately 80% of the total worldwide population lack a SIGMAR1 gene mutation. ANAVEX®2-73 was more efficacious in this pre-specified population. This effect was consistent with the observations from prior clinical trials of ANAVEX®2 -73.

[0123] In addition to the above results and observations, the changes in brain atrophy coordinated with the therapeutic effects in the treatment group. It showed that statistically significant reduction in brain atrophy was observed in the treatment group compared to the placebo group. The reduction included reduced atrophy volume in whole brain, whole brain grey matter, frontal lobe, insular cortex, limbic lobe, parietal lobe and temporal lobe regions. This was the first reported brain atrophy reduction or reversion by a drug therapy. Therefore, ANAVEX®2-73 was effective in reducing and reversing brain atrophy.

Example 4: Treatment of Brain Atrophy Related with Rett Syndrome

[0124] An 8-year-old girl is diagnosed with Rett syndrome. Her neuropathological exam reveals a generalized brain atrophy involving the cerebrum and cerebellum. The exam also shows a decrease in neuronal cell size and increased cell packing density throughout the brain. The girl is given oral capsules of ANAVEX®2-73 at a dose of 20 mg once daily for 16 weeks, a reduction and reversion of brain atrophy is detected.

Example 5: Treatment of Brain Atrophy Related with Parkinson

[0125] A 68-year-old man is diagnosed with Parkinson disease with dementia. MRI exam reveals cortical and subcortical atrophy. He is treated with oral ANAVEX®2-73 at a dose of 30 mg once daily for 48 weeks, atrophy progression is slowed down in cortical and subcortical areas.

Example 6: Treatment of Brain Atrophy Related with Dementia

[0126] A 72-year-old man is diagnosed with dementia of idiopathic origin. MRI exam reveals brain shrinkage in the frontal and temporal lobes. He is treated with oral ANAVEX®2-73 at a dose of 35 mg once daily for 48 weeks, brain shrinkage is controlled and confined, no further shrinkage is observed.

Example 7: Prevention of Brain Atrophy

[0127] Two 67-year-old men experience similar forgetfulness over2 months: starting with forgetting the whereabout of their car keys, then progressing to forgetting how to drive back to their homes. MRI exam reveals no observable brain shrinkage in eitherman. One man is administered with oral ANAVEX®2-73 at a daily dose of 20 mg for 8 weeks. His memory is improved, he never forgets his home location or car keys, and his MRI does not show any brain shrinkage. The other man does not take ANAVEX®2-73 or any medication. His forgetfulness deteriorates to the pointthat he could not drive anymore. His MRI reveals significant brain shrinkage. In conclusion, ANAVEX®2-73 is effective in preventing the onset of brain atrophy.

Claims

We claim:

1 . A method of treating brain atrophy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a therapeutic agent modulating both the sigma-1 receptor and muscarinic acetylcholine receptor.

2. The method of claim 1 , wherein the therapeutic agent is selected from: tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine; 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine; tetrahydro-N, N-dimethyl-5,5-diphenyl-3-furanmethanamine; an enantiomer thereof; a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable crystal thereof; a pharmaceutically acceptable co-crystal thereof; and any combination thereof.

3. The method of claim 2, wherein the pharmaceutically acceptable salt is selected from a hydrochloride salt, a hydrobromide salt, a fumarate salt, a sulfate salt, a dihydrogen phosphate salt, a benzoate salt, a maleate salt, a mesylate salt, an edysilate salt, or an oxalate salt.

4. The method of claim 2 or claim 3, wherein the therapeutic agent is selected from: tetrahydro-N, N-dimethyl-2,2-diphenyl-3-fu ran methanamine hydrochloride; 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride; tetrahydro-N, N-dimethyl-5,5-diphenyl-3-fu ran methanamine hydrochloride; an enantiomer thereof, a pharmaceutically acceptable crystal thereof, a pharmaceutically acceptable co-crystal thereof, and any combination thereof.

5. The method of any one of claims 2-4, wherein the pharmaceutically acceptable co-crystal is formed between:

(i) a compound selected from tetrahydro-N, N-dimethyl-2,2-diphenyl-3-furanmethanamine; 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine; tetrahydro-N, N-dimethyl-5,5-diphenyl-3-furanmethanamine; tetrahydro-N, N-dimethyl-2,2-diphenyl-3-fu ran methanamine hydrochloride; 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride; tetrahydro-N, N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride; an enantiomer thereof, or a crystal thereof; and

(ii) an acid or an ion ic salt.

6. The method of claim 5, wherein the acid is selected from fumaric acid, sulfuric acid, phosphoric acid, hydrogen phosphoric acid, dihydrogen phosphoric acid, benzoicacid, salicylic acid, oxalicacid, ethanedisulfonic acid, tartaric acid, citric acid, maleic acid, and any combination thereof.

7. The method of claims 5 or claim 6, wherein the ionic salt is selected from a quaternary ammonium cationic salt, a salt of a transitional metal, a salt of an alkaline earth metal, or a salt of alkali metal.

8. The method of any one of claims 5-7, wherein the ionic salt is selected from lithium chloride, sodium chloride, magnesium chloride, potassium chloride, calcium chloride, zinc chloride, iron (II) chloride, iron (III) chloride, titanium chloride, chromium (III) chloride, scandium (III) chloride, manganese (II) chloride, copper (I) chloride, copper (II) chloride, nickel chloride, or aluminum chloride.

9. The method of any one of claims 1-8, wherein the therapeutic agent is selected from tetrahydro-N, N-dimethyl-2,2-diphenyl-3-furanmethanamine, a crystal thereof, an enantiomer thereof, a crystal of the enantiomer thereof, a pharmaceutically acceptable salt thereof, an enantiomer of the pharmaceutically acceptable salt thereof, a crystal of the pharmaceutically acceptable salt thereof, and a co-crystal thereof.

10. The method of any one of claims 1-9, wherein the therapeutic agent is selected from tetrahydro-N, N-dimethyl-2,2-diphenyl-3-fu ran methanamine hydrochloride, a crystal thereof, an enantiomer thereof, a crystal of the enantiomer thereof, and a cocrystal thereof.

11 . The method of any one of claims 1-10, wherein the therapeutic agent is selected from: tetrahydro-N, N-dimethyl-2,2-diphenyl-3-furanmethanamine in amorphous form; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form I (A2-73 crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form II (A2-73 crystal Form II); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form III (A2-73 crystal Form III);

(+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in amorphous form;

(-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in amorphous form;

(+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in a crystal form;

(-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in a crystal form; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in amorphous form; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form III; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form IV; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form V; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine mesylate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine sulfate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine sulfate in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine oxalate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine oxalate in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine dihydrogen phosphate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine edisylate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine benzoate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrobromide in crystal Form A; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrobromide in crystal Form B; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine maleate in crystal Form S5; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine maleate in crystal Form S6; co-crystal Form CSII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with tartaric acid; co-crystal Form CSIII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with citric acid; co-crystal Form CSIV of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with malic acid; a co-crystal of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride; a co-crystal of (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride; a co-crystal of (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride; and any combination thereof.

12. The method of any one of claims 1-11 , wherein the therapeutic agent is selected from: tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form III; a co-crystal of any thereof; and any combination thereof.

13. The method of any one of claims 1-11 , wherein the therapeutic agent is selected from:

(-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in a crystal form; a co-crystal thereof; and any combination thereof.

14. The method of any one of claims 1-11 , wherein the therapeutic agent is selected from tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form I (A2-73 crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form III (A2-73 crystal Form III);

15. The method of any one of claims 1-11 , wherein the therapeutic agent is a cocrystal of (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride in a molar ratio from about 1 :1 to about 2:1.

16. The method of any one of claims 1-15, wherein the therapeutically effective amount comprises from about 0.5 mg to about 100 mg per day.

17. The method of any one of claims 1-16, wherein the therapeutically effective amount is from about 1 mg to about 60 mg per day, or is selected from about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg per day.

18. The method of any one of claims 1-17, wherein the therapeutically effective amount is from about 10 mg to about 50 mg per day.

19. The method of any one of claims 1-18, wherein the therapeutically effective amount is administered through a dosage form selected from an oral dosage form, an intravenous dosage form, and a transdermal dosage form.

20. The method of claim 19, wherein the dosage form is a capsule formulated for oral administration.

21 . The method of any one of claims 1-20, wherein the administration is daily administration for at least about 30 days.

22. The method of any one of claims 1-21 , wherein the administration is daily administration for up to about 96 weeks.

23. The method of any one of claims 1-22, wherein the administration comprises an intermittent dosing regimen of at least two cycles, each cycle comprising (a) a dosing period during which the therapeutically effective amount of the agent is administered to the subject; and thereafter (b) a resting period.

24. The method of claim 23, wherein the dosing period and the resting period are of the same duration.

25. The method of claim 23, wherein the dosing period and the resting period are of different durations.

26. The method according to any one of claims 23-25, wherein the dosing period is at least about 10 days, 11 days, 12 days, 13 days, and 14 days,

27. The method according to any one of claims 23-25, wherein the resting period is shorter than about 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, or 14 days.

28. The method of any one of claims 1-27, wherein the subject exhibits amyloid plaques or deposits in the brain.

29. The method of any one of claims 1-28, wherein the subject suffers from or is suspected of suffering from a neurological disease.

30. The method of claim 29, wherein the neurological disease is selected from cognitive impairment, Lewy body dementia, stroke, traumatic brain injury, infections, spinal cord injury, Alzheimer’s disease, Parkinson’s disease, dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, Rett Syndrome, Fragile X Syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Smith-Magen is syndrome, multiple sclerosis, Fronto-temporal dementia, motor neuron disease (MND), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), autism spectrum disorder, schizophrenia, post-traumatic stress disorder (PTSD), and any combination thereof.

31 . A method of preventing brain atrophy in a subject at risk of developing brain atrophy, by administering to the subject a prophylactical ly effective amount of an agent modulating both sigma-1 receptor and muscarinic acetylcholine receptor.

32. The method of claim 31 , wherein the brain atrophy is manifested by shrinkage or loss of volume in brain tissue in at least one brain region as compared to brain tissue volume in a control sample of wherein the brain region is selected from frontal lobe, insular cortex, limbic lobe, parietal lobe, temporal lobe, hippocampus, whole brain white matter and whole brain grey matter, and wherein the control sample is obtained from a healthy individual or is a prior sample from the subject.

33. The method of claims 31-32, wherein the brain atrophy is associated with or is suspected of being associated with a brain infection, brain inflammation, a neurological disease, or any combination thereof.

34. The method of claim 33, wherein the neurological disease is selected from cognitive impairment, Lewy body dementia, stroke, traumatic brain injury, spinal cord injury, infections, Alzheimer’s disease, Parkinson’s disease, dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, Rett Syndrome, Fragile X Syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Smith-Magenis syndrome, multiple sclerosis, Fronto-temporal dementia, motor neuron disease (MND), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), autism spectrum disorder, schizophrenia, post-traumatic stress disorder (PTSD), and any combination thereof.

35. The method of any one of claims 31-34, wherein the risk of developing brain atrophy is associated with one or more symptoms in the subject selected from forgetfulness, difficulty speaking, difficulty writing, loss of language, inability to understand words, memory impairment, cognitive dysfunction, hallucination, mood and personality change, irrational judgment, convulsion, loss of consciousness, spasms, teeth clenching, or any combination thereof.

36. The method of any one of claims 31-35, wherein the risk of developing brain atrophy is associated with one or more disorders selected from cerebral palsy, Lewy body dementia, encephalitis, HIV, AIDS, cognitive impairment, stroke, traumatic brain injury, spinal cord injury, infections, Alzheimer’s disease, Parkinson’s disease, dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, Rett Syndrome, Fragile X Syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Smith -Magen is syndrome, multiple sclerosis, Fronto-temporal dementia, motor neuron disease (MND), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), autism spectrum disorder, schizophrenia, post-traumatic stress disorder (PTSD), and any combination thereof.

37. The method of any one of claims 31-36, wherein the agent is selected from: tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine; 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine; tetrahydro-N, N-dimethyl-5,5-diphenyl-3-furanmethanamine; an enantiomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable crystal thereof, a pharmaceutically acceptable co-crystal thereof, and any combination thereof.

38. The method of claim 37, wherein the pharmaceutically acceptable salt is selected from a hydrochloride salt, a hydrobromide salt, a fumarate salt, a sulfate salt, a dihydrogen phosphate salt, a benzoate salt, a maleate salt, a mesylate salt, an edysilate salt, and an oxalate salt.

39. The method of claims 37-38, wherein pharmaceutically acceptable salt is hydrochloride salt, and the therapeutic agent is selected from the group consisting of tetrahydro-N, N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride;

1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride; tetrahydro-N, N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride; an enantiomer thereof, a pharmaceutically acceptable crystal thereof, a pharmaceutically acceptable co-crystal thereof, and any combination thereof.

40. The method of any one of claims 37-39, wherein the pharmaceutically acceptable co-crystal is formed between:

(i) a compound selected from tetrahydro-N, N-dimethyl-2,2-diphenyl-3-furanmethanamine; 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine; tetrahydro-N, N-dimethyl-5,5-diphenyl-3-furanmethanamine; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride; 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride; tetrahydro-N, N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride; an enantiomer thereof, or a crystal thereof; and

(ii) an acid or an ionic salt.

41 . The method of claim 40, wherein the acid is selected from fumaric acid, sulfuric acid, phosphoric acid, hydrogen phosphoric acid, dihydrogen phosphoric acid, benzoic acid, salicylicacid, oxalicacid, ethanedisulfonic acid, tartaric acid, citric acid, maleic acid, and any combination thereof.

42. The method of claims 40-41 , wherein the ionic salt is selected from a quaternary ammonium cationic salt, a salt of a transitional metal, a salt of an alkaline earth metal, and a salt of alkali metal.

43. The method of any one of claims 40-42, wherein the ionic salt is selected from lithium chloride, sodium chloride, magnesium chloride, potassium chloride, calcium chloride, zinc chloride, iron (II) chloride, iron (III) chloride, titanium chloride, chromium (III) chloride, scandium (III) chloride, manganese (II) chloride, copper (I) chloride, copper (II) chloride, nickel chloride, and aluminum chloride.

44. The method of any one of claims 31 -43, wherein the agent is selected from tetrahydro-N, N-dimethyl-2,2-diphenyl-3-furanmethanamine, a crystal thereof, an enantiomer thereof, a crystal of the enantiomer thereof, a pharmaceutically acceptable salt thereof, an enantiomer of the pharmaceutically acceptable salt thereof, a crystal of the pharmaceutically acceptable salt thereof, and a co-crystal thereof.

45. The method of any one of claims 31-44, wherein the agent is selected from tetrahydro-N, N-dimethyl-2,2-diphenyl-3-fu ran methanamine hydrochloride, a crystal thereof, an enantiomer thereof, a crystal of the enantiomer thereof, and a co-crystal thereof.

46. The method of any one of claims 31 -45, wherein the agent is selected from: tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in amorphous form; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form I (A2-73 crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form II (A2-73 crystal Form II); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form III (A2-73 crystal Form III);

(-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in a crystal form; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in amorphous form; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form III; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form IV; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form V; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine mesylate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine sulfate in crystal

Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine sulfate in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine oxalate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine oxalate in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine dihydrogen phosphate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine edisylate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine benzoate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrobromide in crystal Form A; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrobromide in crystal Form B; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine maleate in crystal Form S5; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine maleate in crystal Form S6; co-crystal Form CSII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with tartaric acid; co-crystal Form CSIII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with citric acid; co-crystal Form CSIV of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with malic acid; a co-crystal of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride; a co-crystal of (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride; a co-crystal of (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride; and any combination thereof.

47. The method of any one of claims 31-46, wherein the agent is selected from tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form III; a co-crystal thereof; and any combination thereof.

48. The method of any one of claims 31-46, wherein the agent is selected from:

49. The method of any one of claims 31-46, wherein the agent is selected from: tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form III;

(-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in a crystal form; co-crystal thereof; and any combination thereof.

50. The method of any one of claims 31-49, wherein the agent is a co-crystal of (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride in a molar ratio from about 1 :1 to about 2:1 .

51 . The method of any one of claims 31-50, wherein the prophylactical ly effective amount comprises from about 0.5 mg to about 100 mg per day.

52. The method of any one of claims 31-51 , wherein the prophylactical ly effective amount is from about 1 mg to about 60 mg per day, or is selected from about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg per day.

53. The method of any one of claims 31-52, wherein the prophylactically effective amount is from about 10 mg to about 50 mg per day.

54. The method of any one of claims 31-53, wherein the prophylactically effective amount is administered through a dosage form selected from an oral dosage form, an intravenous dosage form, and a transdermal dosage form.

55. The method of claim 54, wherein the dosage form is an oral capsule.

56. The method of any one of claims 31-55, wherein the administration is daily administration for at least about 30 days.

57. The method of any one of claims 31-56, wherein the administration is daily administration for up to about 96 weeks.

58. The method of any one of claims 31 -57, wherein the administration comprises an intermittent dosing regimen of at least two cycles, each cycle comprising (a) a dosing period during which the prophylactically effective amount of the agent is administered to the subject; and thereafter (b) a resting period.

59. The method of claim 58, wherein the dosing period and the resting period are of the same duration.

60. The method of claims 58, wherein the dosing period and the resting period are of different durations.

61 . The method of claims 58-60, wherein the dosing period is at least about 10 days, 11 days, 12 days, 13 days, or 14 days.

62. The method of claims 58-60, wherein the resting period is shorter than about 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, or 14 days.