Triple reuptake inhibitors used in the treatment of behavioral immune-metabolic cluster disorders or diseases

Abstract

This article discloses a method for treating or preventing behavioral immune-metabolic cluster (BIMC) syndromes or diseases in subjects by administering a composition containing a triple uptake inhibitor to subjects in need.

Description

Background Technology

[0001] Behavioral immuno-metabolic cluster (BIMC) refers to one or more conditions or disorders typically associated with immune-metabolic dysregulation and related behavioral or emotional adaptation and disorders. Conditions or disorders falling under the BIMC category are usually characterized by alterations in biological pathways related to the homeostatic control of energy regulation, leading to dysregulation of immune signaling and increased inflammation. Neurobiological and behavioral adaptations to underlying inflammation can result in a range of symptoms that, when combined, present as a unique pathology in each individual patient. These differences in presentation among patients and the often unidentified underlying sources of pathology make proper diagnosis and effective treatment of BIMC diseases or conditions extremely challenging. This disclosure provides methods and compositions for treating BIMC diseases or conditions. Summary of the Invention

[0002] This disclosure is based in part on the finding that a range of pathological symptoms in behavioral immune-metabolic cluster (BIMC) syndrome or disease can be treated by administration of a therapeutic agent that is a triple reuptake inhibitor (TRI).

[0003] In some embodiments, methods and compositions for treating or preventing BIMC symptoms or disease in a subject of need are disclosed herein, the method comprising administering to the subject a therapeutically effective amount of a triple reuptake inhibitor (TRI). In some embodiments, treatment or prevention comprises (a) alleviating one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) symptoms of BIMC symptoms or disease in the subject; and / or (b) modulating the immune response in the subject.

[0004] In some implementations, the subject exhibits one or more symptoms associated with the neurological disorder. In some implementations, the subject exhibits one or more psychological symptoms associated with the neurological disorder. In some implementations, the one or more psychological symptoms are selected from: (a) emotional responsiveness; (b) depressed mood; (c) low self-esteem; (d) leadenness; (f) fatigue; (g) malaise; (h) somnolence; (i) anhedonia; (j) rumination; (k) irritability; (l) decreased libido; and (m) suicidal ideation. In some implementations, the one or more psychological symptoms are selected from: (a) depressed mood; (b) fatigue; and (c) fatigue.

[0005] In some implementations, subjects exhibit one or more behavioral symptoms associated with neurosis. In some implementations, subjects exhibit one or more behavioral symptoms selected from the following: (a) increased sleep; (b) excessive sleep; (c) binge eating unrelated to the routine use of inappropriate compensatory behaviors; (d) binge eating not only during the course of anorexia nervosa or bulimia nervosa; (e) recurrent inappropriate compensatory behaviors; (f) recurrent episodes of binge eating; (g) overeating; (h) feelings of guilt after eating; (i) distress during eating; (j) impaired impulse control; (k) anorexia; (l) insufficient food intake; (m) extreme fear of weight gain; and (n) body image anxiety. In some implementations, subjects exhibit one or more behavioral symptoms selected from the following: (a) increased sleep; (b) excessive sleep; (c) recurrent episodes of binge eating; (d) overeating; and (e) impaired impulse control.

[0006] In some implementations, the subject exhibits one or more cognitive symptoms associated with neurological disorders. In some implementations, the one or more cognitive symptoms are selected from: (a) impaired memory; (b) impaired attention; (c) impaired concentration; (d) impaired language ability; (e) impaired learning ability; (f) impaired perception; (g) impaired reasoning ability; (h) executive dysfunction; (i) impaired psychomotor ability; (j) impaired processing speed; and (k) thought disorder.

[0007] In some implementations, the subject exhibits one or more symptoms associated with a metabolic disorder. In some implementations, the one or more symptoms associated with a metabolic disorder are selected from: (a) hypertension; (b) hyperglycemia; (c) insulin resistance; (d) leptin resistance; (e) prediabetes; (f) hypercholesterolemia; (g) hypertriglyceridemia; (h) low serum levels of high-density lipoprotein (HDL); (i) abdominal obesity; (j) hyperuricemia; (k) gastrointestinal dysfunction; and (l) liver dysfunction.

[0008] In some implementations, the subject exhibits one or more symptoms associated with an immune disorder. In some implementations, the one or more symptoms associated with an immune disorder are selected from: (a) joint pain, stiffness, or swelling caused by inflammation; (b) recurrent infections; (c) gastrointestinal disturbances; (d) anemia; (e) rash; (f) cold extremities; (g) dry eye; (h) fatigue; (i) fever; and (j) headache.

[0009] In some implementations, TRI is compound 1: , Or its pharmaceutically acceptable salt.

[0010] In some embodiments, this document discloses a method for modulating an immune response in a subject who has BIMC symptoms or disease or is at risk of developing BIMC symptoms or disease, the method comprising administering a therapeutically effective amount of TRI to the subject. In some embodiments, TRI is compound 1: , Or a pharmaceutically acceptable salt thereof. In some embodiments, modulating the immune response in a subject includes modulating the activity of immune cells in the subject. In some embodiments, the activity of immune cells includes cytokine production, migration, proliferation, recruitment, differentiation, activation, polarization, reactive oxygen species (ROS) production, degranulation, maturation, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent phagocytosis (ADCP), antigen presentation, lymph node homing, and lymph node egress. In some embodiments, modulating the immune response in a subject includes reducing the blood levels of one or more pro-inflammatory mediators associated with BIMC symptoms or disease in the subject compared to the blood levels of one or more pro-inflammatory mediators in the subject prior to administration of TRI. In some embodiments, the one or more pro-inflammatory mediators associated with BIMC symptoms or disease include one or more of the following: TNFα, IFNα, sTNFR2, IL-1β, IL-1RA, IL-6, IL-2R, IL-18, IL-12, CCL2, CRP, and MIF, or any combination thereof. In some embodiments, the one or more pro-inflammatory mediators associated with BIMC symptoms or disease are TNFα. In some embodiments, after treatment with TRI, the blood levels of the one or more pro-inflammatory mediators associated with BIMC symptoms or disease in the subject are reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more. In some embodiments, the patient has been identified as exhibiting elevated levels of one or more pro-inflammatory mediators associated with BIMC prior to treatment. In some embodiments, the patient has been identified as exhibiting elevated levels of one or more pro-inflammatory mediators associated with BIMC prior to treatment. In some embodiments, the method further includes measuring the levels of one or more pro-inflammatory mediators associated with BIMC symptoms or disease before, during, and / or after TRI administration. In some embodiments, modulating the immune response in a subject involves increasing the blood levels of one or more anti-inflammatory mediators associated with BIMC symptoms or disease in the subject, compared to the blood levels of one or more anti-inflammatory mediators in the subject prior to TRI administration. In some embodiments, the one or more anti-inflammatory mediators associated with BIMC symptoms or disease include one or more of the following: IL-10, IL-4, IL-13, TGFβ, adiponectin, or any combination thereof.In some embodiments, after treatment with TRI, the blood levels of the one or more anti-inflammatory mediators associated with BIMC symptoms or disease increase by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100%, 120%, 140%, 160%, 180%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, or more. In some embodiments, prior to treatment, the patient has been identified as exhibiting a reduction in the levels of one or more anti-inflammatory mediators associated with BIMC. In some embodiments, the method further includes measuring the levels of one or more anti-inflammatory mediators associated with BIMC symptoms or disease before, during, and / or after TRI administration. In some implementations, the blood levels of one or more pro-inflammatory and / or anti-inflammatory mediators are measured at least 1 hour (hr), 2 hours, 3 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months or longer before and / or after treatment with TRI. In some embodiments, the blood levels of one or more pro-inflammatory and / or anti-inflammatory mediators are measured at least 1 hour (hr), 2 hours, 3 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or longer after treatment with TRI. In some embodiments, the blood levels are whole blood levels, plasma levels, or serum levels. In some embodiments, the immune cells are selected from: regulatory T cells (Tregs), T effector cells, T helper cells, Th1 cells, Th2 cells, Th17 cells, B cells, natural killer (NK) cells, innate lymphoid cell 1 (ILC1), ILC2 cells, ILC3 cells, monocytes, macrophages, dendritic cells, M1 macrophages, M2 macrophages, and antigen-presenting cells. In some embodiments, the immune mediator is a cytokine.In some implementation schemes, the immune mediator is a chemokine.

[0011] In some embodiments, this document discloses a method for treating metabolic disorders in subjects who have BIMC symptoms or disease or are at risk of developing BIMC symptoms or disease, the method comprising administering a therapeutically effective amount of TRI to the subject. In some embodiments, the metabolic disorder includes one or more of the following symptoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more): (a) hypertension; (b) hyperglycemia; (c) insulin resistance; (d) leptin resistance; (e) prediabetes; (f) hypercholesterolemia; (g) hypertriglyceridemia; (h) low serum levels of high-density lipoprotein; (i) abdominal obesity; (j) hyperuricemia; (k) gastrointestinal disorders; and (l) hepatic dysfunction.

[0012] In some implementations, TRI is compound 1: , Or its pharmaceutically acceptable salt.

[0013] In some embodiments, this document discloses a method for treating or preventing neuroinflammation in the central nervous system of a subject in need, the method comprising administering a therapeutically effective amount of TRI to the subject. In some embodiments, the treatment or prevention comprises one or more of the following: (a) modulating immune cell activity in the subject; and / or (b) reducing one or more (e.g., 1, 2, 3, 4, 5, or more) symptoms of neuroinflammation associated with BIMC symptoms or disease in the subject. In some embodiments, immune cell activity comprises cytokine production, migration, proliferation, recruitment, differentiation, activation, polarization, ROS production, degranulation, maturation, ADCC, ADCP, antigen presentation, lymph node homing, and lymph node efflux. In some embodiments, the immune cells are selected from: Tregs, T effector cells, T helper cells, Th1 cells, Th2 cells, Th17 cells, B cells, NK cells, ILC1 cells, ILC2 cells, ILC3 cells, monocytes, macrophages, dendritic cells, M1 macrophages, M2 macrophages, and antigen-presenting cells. In some embodiments, one or more symptoms of neuroinflammation associated with BIMC symptoms or disease are present, and the treated symptoms may include one or more symptoms selected from: mood reactivity, interpersonal rejection sensitivity (e.g., having a long-term pattern and causing severe social or occupational impairment), depressed mood, low self-esteem, lead paralysis, fatigue, malaise, somnolence, aphrodisiac, rumination, irritability, low libido, suicidal ideation, impaired memory, impaired attention, impaired concentration, executive dysfunction, impaired psychomotor ability, impaired processing speed, thought disorder; insomnia; and fatigue. In some embodiments, the neuroinflammation is located in the subject's brain. In some embodiments, the neuroinflammation is the result of aseptic injury, infection, aging, toxic metabolites, or an autoimmune reaction. In some embodiments, the neuroinflammation is located in the subject's spinal cord. In some embodiments, TRI is compound 1: , Or its pharmaceutically acceptable salt.

[0014] In some embodiments, the subject has been identified as exhibiting one or more symptoms of BIMC or a disease. In some embodiments, the subject has one or more symptoms of BIMC or a disease secondary to a primary immune disease. In some embodiments, the method includes identifying the presence of one or more symptoms of BIMC or a disease in the subject. In some embodiments, the subject has difficulty receiving prior treatment for BIMC or a disease with one or more therapeutic agents other than TRI. In some embodiments, the subject has not received any prior treatment for BIMC or a disease.

[0015] In some implementations, the therapeutically effective dose is between 1 mg and 30 mg per day (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 mg per day).

[0016] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter pertains. It should be understood that the foregoing general description and the following detailed description are illustrative and explanatory only and do not limit any of the topics described. Section headings used herein are for organizational purposes only and should not be construed as limiting the topics described.

[0017] Throughout this specification, when a composition is described as having, including, or comprising specific components, or when a process or method is described as having, including, or comprising specific steps, it is also considered that there are compositions of the invention that are substantially composed of or constituted by the listed components, and there are processes and methods of the invention that are substantially composed of or constituted by the listed processing steps.

[0018] In this application, when an element or component is referred to as being included in and / or selected from the list of listed elements or components, it should be understood that the element or component may be any of the listed elements or components, or the element or component may be selected from two or more of the listed elements or components.

[0019] Furthermore, it should be understood that the elements and / or features of the compositions or methods described herein can be combined in various ways without departing from the spirit and scope of the invention, whether explicit or implicit herein. For example, unless the context otherwise requires, when a particular compound is referred to, that compound can be used in various embodiments of the methods of the invention. In other words, within this application, the description and depiction of embodiments are intended to make the writing and drawing of this application clear and concise, but it is intended and should be understood that embodiments can be combined or separated in various ways without departing from the teachings and the invention. For example, it should be understood that all features described and depicted herein are applicable to all aspects of the invention described and depicted herein.

[0020] Unless the context clearly indicates otherwise, as used herein, the singular forms “a,” “an,” and “the” include a plural referent. Thus, for example, reference to “a compound” includes a single compound or multiple (e.g., two or more) compounds.

[0021] Unless otherwise specifically stated or understood from the context, the use of the terms “comprise”, “comprises”, “comprising”, “include”, “includes”, “including”, “have”, “has”, “having”, “contains”, or “containing” (including its syntactic equivalents) should generally be understood as open-ended and non-restrictive, for example, not excluding other unlisted elements or steps.

[0022] Unless the context explicitly indicates otherwise, as used herein, all numerical values ​​or ranges include all integers within or covering such ranges, as well as fractions of values ​​or integers within or covering such ranges. Thus, for example, references to a range of 90% to 100% include 91%, 92%, 93%, 94%, 95%, 95%, 97%, etc., and 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so on. In another example, the range of 1 to 5,000 times includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times, as well as 1.1, 1.2, 1.3, 1.4, 1.5 times, 2.1, 2.2, 2.3, 2.4, 2.5 times, and so on.

[0023] As used herein, “about” refers to a range including the value and from 10% lower to 10% higher. “About” refers to a range from 10% lower to 10% higher than the upper limit of the range.

[0024] Unless asserted, any and all instance or illustrative language used herein, such as "suchas" or "including," is intended only to better illustrate the invention and not to limit its scope. The language in this specification should not be construed as indicating that any unclaimed element is essential to the practice of the invention.

[0025] Generally, unless otherwise specified, percentages of compositions are expressed by weight. Furthermore, if a variable is not defined, its previously defined form shall prevail.

[0026] As used herein, the term "administration" means delivering the pharmaceutical agent or composition disclosed herein to a subject via any acceptable route. Non-limiting examples of acceptable routes of administration include oral administration, administration as a suppository, local contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, transmucosal administration (e.g., oral, sublingual, nasal, or percutaneous), or subcutaneous administration, or implantation of a slow-release device (e.g., a microosmotic pump) into the subject. Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other modes of delivery include, but are not limited to, the use of liposome formulations, intravenous infusion, percutaneous patches, etc.

[0027] As used herein, the term “behavioral immune-metabolic cluster (BIMC) syndrome or disease” is a collective term referring to any syndrome or disease associated with a range of dysregulations in inflammation, metabolism, and bioenergy signaling pathways, as well as related neurological and physiological disorders. In some implementations, BIMC syndrome or disease is associated with a diverse and complex set of neurophenotypes presenting one or more psychological, behavioral, and / or cognitive symptoms. For example, a subject with BIMC may exhibit one or more psychological disorders selected from: emotional responsiveness, interpersonal rejection sensitivity (e.g., with a long-term pattern causing severe social or occupational impairment), depressed mood, low self-esteem, leadenness, fatigue, malaise, somnolence, euphoria, rumination, irritability, hypoactive libido, and suicidal ideation. Alternatively, subjects with BIMC may exhibit one or more behavioral symptoms selected from the following: increased sleep, hypersomnia, binge eating (e.g., binge eating unrelated to the regular use of inappropriate compensatory behaviors, binge eating not only during the course of anorexia nervosa or bulimia nervosa, and / or recurrent binge eating), recurrent inappropriate compensatory behaviors, overeating, feelings of guilt after eating, distress during eating, impaired impulse control, anorexia, undereating, extreme fear of weight gain, and body image anxiety. Alternatively, subjects with BIMC may exhibit one or more cognitive symptoms, including but not limited to impaired memory, impaired attention, impaired concentration, impaired language ability, impaired learning ability, impaired perception, impaired reasoning ability, executive dysfunction, impaired psychomotor ability, impaired processing speed, and thought disorders (e.g., delusions). Alternatively, subjects with BIMC may present with one or more symptoms associated with metabolic disorders, including but not limited to hypertension, hyperglycemia, insulin resistance, leptin resistance, prediabetes, hypercholesterolemia, hypertriglyceridemia, low serum levels of high-density lipoprotein (HDL), abdominal obesity, hyperuricemia, liver dysfunction, and gastrointestinal disorders. Alternatively, subjects with BIMC may present with one or more symptoms associated with immune disorders, such as joint pain, stiffness or swelling due to inflammation, recurrent infections, gastrointestinal disorders, anemia, rash, cold extremities, dry eye, fatigue, fever, and / or headache. In some implementations, any of the above symptoms of BIMC may be associated with an abnormal immune response (e.g., chronic low-grade inflammation associated with changes in blood levels of immune mediators such as cytokines and chemokines). BIMC symptoms or disease can be characterized by a complex clinical phenotype presenting with various combinations of psychological, behavioral, cognitive, immune, and metabolic disorders, as well as associated symptoms and / or compensatory behaviors (such as those described above). BIMC symptoms or disease can be caused by a genetic predisposition to immune metabolic disorders and / or by environmental or empirical factors, alone or in combination, that can produce the BIMC phenotype. In some implementations, BIMC symptoms or disease are idiopathic.

[0028] As used herein, the term "immune mediator" refers to any endogenous biomolecule (e.g., carbohydrates, nucleic acids, lipids, or proteins) capable of modulating (e.g., increasing or decreasing) the immune response in an organism or cell. Non-limiting examples of immune mediators include cytokines, chemokines, antibodies, immune receptors, antigens, hormones, vasoactive amines, peptides, eicosanoic acid-like substances, bile acids, etc.

[0029] As used herein, the phrase “regulation of the immune response” refers to any alteration of the cells of the immune system or any change in the activity of cells involved in the immune response. Such regulation includes an increase or decrease in the number of various cell types, an increase or decrease in the activity of these cells, or any other changes that may occur within the immune system. Cells involved in the immune response include, but are not limited to, T lymphocytes (T cells), B lymphocytes (B cells), natural killer (NK) cells, innate lymphoid cells (ILCs), macrophages, eosinophils, mast cells, dendritic cells, and neutrophils.

[0030] As used herein, the term "metabolic disorder" refers to a condition in which a subject's metabolism (including processes such as breaking down carbohydrates, proteins, and fats in food to release energy, and converting chemicals into other substances and transporting them into cells for energy use and / or storage) operates outside the normal physiological range. Some symptoms of metabolic disorders include high serum triglycerides, high low-density lipoprotein (LDL) cholesterol, low high-density lipoprotein (HDL) cholesterol, and / or high fasting insulin levels, elevated fasting blood glucose, abdominal (central) obesity, and high blood pressure. Metabolic disorders increase the risk of other diseases, such as cardiovascular disease. Exemplary conditions or diseases characterized by metabolic disorders include any condition or disease falling within the scope of BIMC, as well as obesity, type 1 diabetes, and type 2 diabetes.

[0031] As used herein, the term “regulation” and its variations refer to decreasing or increasing the value of a parameter describing a particular system. For example, in the context of regulating immune cell activity, “regulation” can mean increasing or decreasing one or more (e.g., 1, 2, 3, 4, 5 or more) parameters of immune cell activity, including but not limited to cytokine production, migration, proliferation, recruitment, differentiation, activation, polarization, reactive oxygen species (ROS) production, degranulation, maturation, ADCC, ADCP, antigen presentation, lymph node homing, and lymph node efflux. “Regulation” can be achieved in any amount. For example, in the context of increasing immune cell activity, the increase in immune cell activity may be at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 220%, 240%, 260%, 280%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, 1,000%, or more. In the context of reducing immune cell activity, the reduction in immune cell activity may be at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more.

[0032] As used herein, the term “neuritis” refers to the immune and inflammatory response of the central nervous system (CNS) during normal function or development, or in response to immune events. Diagnosis of neuroinflammation can be indicated by the presentation of one or more symptoms selected from the following: emotional responsiveness, social rejection sensitivity (e.g., with a long-term pattern and causing depressed mood), leadenness, fatigue, somnolence, aphrodisiacs, rumination, irritability, decreased libido, impaired memory, impaired attention, impaired concentration, executive dysfunction, impaired psychomotor abilities, and impaired processing speed. Symptoms of neuroinflammation can be identified using known methods, including psychomotor and behavioral assessments. Neuroinflammation itself can be detected in living patients, for example, using conventional medical neuroimaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). For example, neuroimaging can be used in vivo to detect blood-brain barrier (BBB) ​​permeability, a known biomarker of neuroinflammation. Dynamic contrast-enhanced or perfusion imaging protocols can be performed using intravenously injected iodine- or gadolinium-based contrast agents on MRI or CT scanners. BBB permeability measurements can then be obtained using known pharmacokinetic modeling methods. Furthermore, the presence of specific immune cells in the CNS can be detected using conventional methods. For example, patients can be infused with labeled agents bound to immune cell-specific markers. Subsequently, PET-based detection methods can be used to identify the presence of specific immune cells within the CNS. Additional methods for assessing neuroinflammation in subjects include the use of micron-sized iron oxide particles (MPIO) functionalized with antibodies against protein markers of neuroinflammation, such as TNFα, IFNα, sTNFR2, IL-1β, IL-1RA, IL-6, IL-2R, IL-18, IL-12, CCL2, CRP, MIF, P-selectin, E-selectin, VCAM-1, and ICAM-1. Common triggers for neuroinflammation may include aseptic injury (e.g., tissue damage caused by mechanical injury), bacterial or viral infection, aging, toxic metabolites, autoimmune processes, or spontaneous or idiopathic immune events (e.g., idiopathic systemic inflammatory response syndrome; SIRS). Any of these events present in the medical history of patients with BIMC may support a positive diagnosis of neuroinflammation.

[0033] As used herein, a “pharmaceutical composition” or “pharmaceutical formulation” is a composition or formulation having pharmacological activity or other direct action in the relief, treatment or prevention of disease, and / or its finished dosage form or formulation, and is indicated for human use.

[0034] As used herein, the term “pharmaceutically acceptable” means a compound, molecular entity, composition, substance, and / or dosage form that, when administered to animals or humans as appropriate, does not produce harmful, allergic, or other adverse reactions, and / or is approved or may be approved by a federal or state regulatory agency or its counterpart in a country other than the United States, or is listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals and more specifically for use in humans.

[0035] As used herein, “pharmaceutically acceptable salt” means any salt containing an acidic or basic group that may be present in the compounds of the present invention (e.g., compound 1) and is compatible with pharmaceutical administration. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Other acids (such as oxalic acid), although not pharmaceutically acceptable on their own, may be used to prepare salts suitable as intermediates to obtain the compounds described herein and their pharmaceutically acceptable acid addition salts. Examples of bases include, but are not limited to, alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and NW4. + Compound, where W is C 1-4 Alkyl groups, etc. Examples of salts include, but are not limited to, acetates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, butates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, disaccharides, dodecyl sulfates, ethanesulfonates, transbutenediacetes, fluoroheptates, glycerophosphates, hemisulfates, heptates, hexanoates, hydrochlorides, hydrobromide, hydroiodates, 2-hydroxyethanesulfonates, lactates, maleic anhydride, methanesulfonates, monosulfates, 2-naphthalenesulfonates, nicotinates, oxalates, palmite, pectates, persulfates, phenylpropionates, picrates, pentanoates, propionates, succinates, tartrates, thiocyanates, toluenesulfonates, undecanoates, etc. Other examples of salts include those that combine the anions of the compounds of the present invention with suitable cations (such as Na+). + K + Ca 2+ NH4 + and NW4 + (where W can be C) 1-4 Salts obtained by alkyl groups, and their analogues.

[0036] For therapeutic use according to the methods disclosed herein, salts of the compounds of the present invention are contemplated to be pharmaceutically acceptable. However, salts of pharmaceutically unacceptable acids and bases may also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0037] As used herein, “pharmaceuticalally acceptable excipient” means a substance that facilitates administration of the active agent to a subject and / or absorption by the subject, and may be included in the compositions of the present invention without causing significant adverse toxicological effects on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, standard saline solutions (such as phosphate-buffered saline (PBS) solutions), emulsions (e.g., oil / water or water / oil emulsions), lactated Ringer's solutions, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose, or starch), fatty acid esters, hydroxymethyl cellulose, polyvinylpyrrolidone, and colorants, etc. These formulations may be sterilized and, as needed, mixed with excipients (such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants, and / or aromatic substances, etc.) that will not adversely react with the compounds of the present invention. For examples of excipients, see Martin, Remington's Pharmaceutical Sciences, 15th edition, Mack Publ. Co., Easton, PA (1975).

[0038] As used herein, the term "solid dosage form" means a drug in solid form, such as tablets, capsules, granules, powders, capsules, resolvable powders, dry powder inhalers, and chewable tablets.

[0039] As used herein, the terms “subject” and “patient” refer to an animal (e.g., a mammal, such as a human). A subject treated according to the methods described herein may be a subject diagnosed with a specific condition or a subject at risk of developing such conditions. Diagnosis can be made by any method or technique known in the art. Those skilled in the art will understand that a subject treated according to this disclosure may be subject to standard testing or may be identified without examination as a subject at risk due to the presence of one or more risk factors associated with a disease or condition. In some embodiments, the subject is a human (i.e., male or female of any age group, such as a child subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, middle-aged adult, or older adult)) and / or a non-human animal, such as a mammal, such as a primate (e.g., a rhesus monkey, etc.), a cow, a pig, a horse, a sheep, a goat, a rodent, a cat, and / or a dog. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal.

[0040] As used herein, the term "therapeuticly effective amount" for the pharmaceutical agents or compositions described herein (e.g., compositions comprising compound 1 or a pharmaceutically acceptable salt thereof) means an amount sufficient to produce a beneficial or desired outcome (including effects at the cellular, tissue, or clinical level) when administered to a subject (including mammals, such as humans). Therefore, "therapeuticly effective amount" or its synonyms depend on the context in which they are applied. For example, in the context of treating BIMC symptoms or diseases, it refers to an amount of pharmaceutical agent or composition sufficient to produce a therapeutic response compared to a response obtained without the administration of the pharmaceutical agent or composition. The amount of a given pharmaceutical agent or composition described herein that corresponds to this amount will vary depending on various factors, such as the given pharmaceutical agent, the pharmaceutical formulation, the route of administration, the type of symptoms or diseases, the identity of the subject (e.g., age, sex, and weight), or the host being treated, but can still be conventionally determined by those skilled in the art. Furthermore, as used herein, the "therapeuticly effective amount" of the pharmaceutical agents or compositions of this disclosure is an amount that produces a beneficial or desired outcome in a subject compared to a control. As defined herein, the therapeutically effective amount of the pharmaceutical agent or composition disclosed herein can be readily determined by those skilled in the art using conventional methods known in the art. Dosing regimens can be adjusted to provide an optimal therapeutic response.

[0041] As used herein, “treatment” and “treating” refer to the medical management of a subject with the intention of improving, alleviating, stabilizing (i.e., preventing deterioration), preventing, or curing a disease, pathological condition, or symptom. This term includes proactive treatment (treatment aimed at improving a disease, pathological condition, or symptom), causal treatment (treatment addressing the underlying cause of a disease, pathological condition, or symptom), palliative treatment (treatment designed to alleviate symptoms), preventative treatment (treatment aimed at minimizing or partially or completely suppressing the development of a disease, pathological condition, or symptom); and supportive treatment (treatment used to complement another therapy). Treatment also includes reducing the severity of a disease or condition; preventing the spread of a disease or condition; delaying or slowing the progression of a disease or condition; improving or alleviating a disease or condition; and remission (whether partial or overall), whether detectable or undetectable. "Improvement" or "mitigation" of a disease or condition means a reduction in the severity and / or undesirable clinical manifestations and / or a slowing or prolonging of the progression of the disease, symptom, or condition compared to its severity or duration without treatment. "Treatment" can also mean an extension of survival compared to the expected survival without treatment. Those requiring treatment include those who already have a condition or disease, those who are susceptible to a condition or disease, or those who need prevention of a condition or disease.

[0042] As used herein, the term "triple reuptake inhibitor (TRI)" refers to an agent (e.g., a small molecule) capable of inhibiting the reuptake of serotonin by blocking the serotonin transporter (SERT) protein at the synaptic tip of serotonin-releasing neurons; (2) inhibiting the reuptake of norepinephrine by blocking the norepinephrine transporter (NAT) protein at the synaptic tip of norepinephrine-releasing neurons; and (3) inhibiting the reuptake of dopamine by blocking the dopamine transporter (DAT) protein at the synaptic tip of dopamine-releasing neurons. The inhibition of reuptake of each of serotonin, norepinephrine, and / or dopamine can be achieved independently by any amount, such as at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. Exemplary TRIs of this disclosure include, but are not limited to, compound 1: Or its pharmaceutically acceptable salt. Attached Figure Description

[0043] Figure 1 A graph illustrating the dose-dependent reduction in LPS-induced serum TNFα levels (pg / mL) in Wistar Han rats treated with mediator (0); compound 1 at 3, 10, and 30 mg / kg; or positive control compound 2 (a JNK inhibitor) at 30 mg / kg.

[0044] Figure 2 Bar graphs showing immobility time in rats during the forced swimming test. Rats were treated with a medium (0.3% Tween 80 in distilled water), or compound 1 at 1 mg / kg, 3 mg / kg, or 10 mg / kg. Data are mean ± standard error of mean (SEM) for 10 animals per group. * = p < 0.05 relative to the medium control; ** = p < 0.01 relative to the medium control; and *** = p < 0.001 relative to the medium control, based on Dunnett's post-hoc test.

[0045] Figure 3 Bar graph showing immobility time in mice during the tail suspension test. Mice were treated with a mediator (HPMC), compound 1 at 0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg, or duloxetine (DLX30) at 30 mg / kg. * = p < 0.05 relative to the mediator control.

[0046] Figures 4A to 4DBar graphs illustrating the effects of compound 1 (1 mg / kg, 3 mg / kg, or 10 mg / kg), 10 mg / kg chlordiazepoxide (CDZ10), and the mediator control (0.3% Tween / NaCl 0.9%) on mice in the elevated plus-maze. Figure 4A This refers to the effect of time spent in the open arms of the elevated cross-shaped maze. Figure 4B () represents the effect on the distance traveled in the open arms of the elevated cross-shaped maze. Figure 4C (This represents the percentage effect of the open arms leading into the elevated cross-shaped maze.) Figure 4D () represents the effect of speed on movement within the open arms of the elevated cross-shaped maze.

[0047] Figure 5A and Figure 5B The image shows a bar graph depicting the pressing of a control lever by an adult male Sprague-Dawley rat during a progressive ratio / feeding selection task. Figure 5A Bar graph showing the mean (±SEM) total control lever presses in adult male Sprague Dolly rats (n=31) during a 30-minute phase, where **p<0.001: significant difference in control lever presses between compound 1 treatment and the vehicle (VEH). Figure 5B The bar graph shows the average (±SEM) number of total lever presses during the 30-minute phase, where **p<0.001: the difference in lever presses between compound 1 dose treatment and VEH is significant.

[0048] Figure 6A and Figure 6B A bar graph depicting feed intake in adult male Sprague-Dawley rats during a progressive ratio / feed selection task. Figure 6A (A bar graph showing the mean (±SEM) of feed intake (in grams) in adult male Spraguedoli rats (n=31) during a 30-minute phase, where **p<0.001: there were significant differences in the therapeutic effects of compound 1 and the mediator (VEH) on feed consumption between groups.) Figure 6B The bar graph shows the mean (±SEM) of feed intake (in grams) during the 30-minute phase, where **p<0.001, *p<0.01: there were significant differences in the therapeutic effects of dose-dependent compound 1 and VEH on feed consumption between the groups.

[0049] Figure 7To illustrate the mean (±SEM) total control lever presses in adult male Sprague Dolly rats (n=31) during the 30-minute operation phase, where **p<0.001: there was a significant difference in control lever presses between compound 1 treatment (n=16) and the mediator (VEH) (n=15).

[0050] Figure 8A and Figure 8B A graph illustrating the appetite-suppressing effect of compound 1 on rats in a binge-eating chocolate test. Figure 8A This is a graph showing the mean (±SEM) of chocolate intake during the 12 one-hour training phases in the chocolate intake experiment. Figure 8B (A bar graph showing chocolate consumption in rats treated with VEH, or compound 1 at 5, 10 or 20 mg / kg)

[0051] Figure 9A and Figure 9B A bar graph illustrating the effect of compound 1 on sleep in rats. Figure 9A This is a bar chart showing the average (±SEM) delay of the first 6 consecutive periods of non-rapid eye movement (NR) sleep. Figure 9B This is a bar chart showing the average (±SEM) delay of the first three consecutive periods of rapid eye movement (REM) sleep.

[0052] Figures 10A to 10C A bar graph illustrating the effect of compound 1 on rats in a five-choice serial-reaction task (5CSRTT) test. Figure 10A A bar graph showing the relationship between the percentage of correct nose probes in rats trained in the 5CSRTT task and the dosage of compound 1. Figure 10B (A bar graph showing the relationship between premature (PREM) response in rats during the 5CSRTT task and the dosage of compound 1 administered.) Figure 10C The bar graph shows the relationship between sustained (PSV) response in rats and the dosage of compound 1 in the 5CSRTT task. Detailed Implementation

[0053] This article discloses methods and compositions for treating behavioral immune-metabolic cluster (BIMC) conditions or diseases in human subjects with triple reuptake inhibitors (TRI; i.e., serotonin-norepinephrine-dopamine reuptake inhibitors). The methods include, but are not limited to, administering to the subject a composition containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof.

[0054] Behavioral Immuno-Metabolic Cluster BIMC refers to one or more disorders or conditions typically characterized by immune-metabolic dysregulation and related behavioral or emotional disturbances. Disorders or conditions falling under the category of BIMC are usually characterized by alterations in biological pathways related to the homeostatic control of energy regulation, dysregulation of immune signaling that predisposes to inflammation, and corresponding neurobiological changes (e.g., alterations in neurogenesis, neuroplasticity, and hypothalamic-pituitary-adrenal (HPA) axis activity) and neurological symptoms and indications. The neurophenotype of BIMC patients may be characterized by psychological and behavioral disturbances and / or cognitive impairment.

[0055] Immune signaling dysregulation in BIMC can be associated with a chronic increase in serum levels of one or more pro-inflammatory biomarkers (such as IL-6, TNFα, IL-1β, IFNγ, IL-18, IL-1RA, sTNFR2, CCL2, CXCL4, and CXCL7) and / or a decrease in levels of one or more anti-inflammatory biomarkers (such as IL-10, IL-4, IL-13, TGFβ, and adiponectin). Other immune changes associated with BIMC may include, but are not limited to, increased activation of inflammatory monocytes and T cells, decreased regulatory T (Treg) cell activity, and increased infiltration of peripheral immune cells into the CNS parenchyma (e.g., due to increased blood-brain barrier permeability) and the resulting neuroinflammation.

[0056] Disruption of the homeostatic mechanisms of energy balance and metabolic dysregulation in BIMC can lead to changes in body shape (e.g., abdominal obesity), appetite, and eating disorders. Therefore, patients with BIMC may experience chronic physiological symptoms, including hypertension, hyperglycemia, insulin resistance, leptin resistance, prediabetes, hypercholesterolemia, hypertriglyceridemia, low serum high-density lipoprotein (HDL) levels, hyperuricemia, liver dysfunction, and / or gastrointestinal disorders. Although the causal relationships between the various pathophysiological, immune, metabolic, behavioral, and psychological changes in BIMC remain unclear, these changes can exist in various combinations and are accompanied by a range of symptom combinations arising from underlying biological pathways. Therefore, BIMC is a highly heterogeneous indication associated with different endogenous phenotypes, which can be related to a variety of genetic and / or environmental factors.

[0057] This disclosure is based, at least in part, on the discovery that a novel TRI, compound 1, reduces lipopolysaccharide (LPS)-induced TNFα release in rodents and exhibits antidepressant-like properties in mouse and rat behavioral despair models. Furthermore, this disclosure demonstrates that compound 1 reduces impulsivity and compulsive behaviors and promotes wakefulness. These results indicate that compound 1 can effectively treat various pathophysiological processes and symptoms underlying and / or associated with BIMC. Therefore, this disclosure provides methods and compositions for treating BIMC in patients of need.

[0058] Treatment application An effective amount of the compound or composition described herein may be administered to a subject using standard methods to treat BIMC symptoms or diseases. For example, the agent may be administered via any of a variety of different routes, including, for example, oral (enteral), parenteral (by injection), rectal, percutaneous, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal administration. The most suitable route of administration in any given situation will depend on the following: the specific agent being administered, the patient, the specific disease or condition being treated, the method of drug preparation, the method of administration (e.g., the time and route of administration), the patient's age, weight, sex, the severity of the disease being treated, the patient's diet, and the patient's excretion rate.

[0059] The pharmaceutical compositions provided herein may also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof for an extended period of time (e.g., over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc.), or may be administered indefinitely, for example, for the remainder of the subject’s life. In some embodiments, long-term administration is intended to provide a constant level of the compound in the blood, for example, within a therapeutic window during the extended period.

[0060] dose The compounds and compositions disclosed herein are administered in a manner compatible with pharmaceutical formulations and at a therapeutically effective amount. In some embodiments, the amount administered depends on the subject being treated. The precise amount of active ingredient to be administered depends on the practitioner's judgment and is specific to each subject. A suitable regimen for initial administration is, but typically, subsequent administrations of repeated doses at one-hour intervals or longer after the initial administration. Alternatively, continuous administration sufficient to maintain blood concentrations may be included.

[0061] The amount of active ingredient in the composition (e.g., a compound of this disclosure or a pharmaceutically acceptable salt thereof), the formulation of the composition, and the mode of administration are factors that vary in order to provide an amount of active ingredient that effectively achieves the desired therapeutic response in each subject without causing excessive toxicity to the subject. The selected dose level will depend on a variety of factors, including the activity of the particular compound used, the route of administration, the time of administration, the rate of elimination or metabolism of the particular compound used, the duration of treatment, other drugs, compounds, and / or substances used in combination with the particular composition used, the age, sex, weight, condition, general health status, diet, and prior medical history of the subject being treated, and similar factors well known in medical technology.

[0062] In some embodiments, the compound described herein or a pharmaceutically acceptable salt thereof is administered to the subject at various dosages and over various time ranges. Additionally, in some embodiments, the compound is administered at doses that are twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, once every twelve weeks, or any combination of such weeks. Dosing cycles are also covered, such as administering the compound once or twice a week for four weeks, followed by two weeks of no treatment. Additional dosing cycles are also covered in this disclosure, including, for example, different combinations of dosages and weekly cycles described herein.

[0063] In some embodiments, the therapeutically effective dose of the composition varies depending on the severity of the disease, the subject's weight, and the general condition of the treated subject. In some embodiments, depending on the response to the disease or symptom and the subject's tolerance to the therapy, it may be administered once daily, every other day, weekly, twice monthly, once monthly, or at a higher or lower frequency as needed. In some embodiments, a maintenance dose is required for a longer period, such as 4, 5, 6, 7, 8, 10, or 12 weeks or longer, until the symptoms of the disease are suppressed as required, and the dose may be adjusted as needed. The progress of this therapy can be easily monitored using routine techniques and analysis.

[0064] In some cases, a physician with ordinary skills in the art can easily determine and specify the required effective amount (ED) of the composition. 50 For example, a physician may start the composition at a level below that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. Alternatively, in some embodiments, the dose is kept constant.

[0065] The compounds and pharmaceutical compositions provided herein are available in unit dosage forms to facilitate precise dosing. The terms "unit dose" or "unit dosage form" refer to a physical discrete unit suitable as a unit dose for use in human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, and suitable pharmaceutical excipients. In some embodiments, the pharmaceutical dosage forms described herein can be administered in unit dose form. Typical unit dosage forms include pre-filled liquid compositions, ampoules or syringes of predetermined quantities, or, in the case of solid compositions, pills, tablets, capsules, etc.

[0066] The dosage of the compounds disclosed herein or compositions comprising such compounds may vary depending on a variety of factors, such as the pharmacodynamic properties of the compound, the administration method, the recipient's age, health status or weight, the nature and severity of symptoms, the frequency of treatment, the type of concurrent therapy (if present), and the clearance rate of the compound in the treated animals. Those skilled in the art can determine an appropriate dosage based on these factors. The compounds disclosed herein or pharmaceutically acceptable salts thereof may initially be administered at a suitable dosage, adjusted as needed, based on clinical response. Generally, satisfactory results are obtained when the compounds disclosed herein are administered to humans at daily doses, for example, between 0.05 mg and 3000 mg (measured in solid form). Dosage ranges include, for example, between 0.1 and 1000 mg (e.g., 0.2 to 950, 0.4 to 900, 0.6 to 850, 0.8 to 800, 1 to 750, 1 to 20, 2 to 16, 2 to 700, 4 to 650, 6 to 600, 8 to 550, 10 to 500, 15 to 450, 20 to 400, 30 to 350, 40 to 300, 50 to 250, 75 to 200, or 100 to 150 mg). In some embodiments, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg of the compound of this disclosure or a pharmaceutically acceptable salt thereof may be administered daily. A single dose or multiple doses may be administered over a 24-hour period. For example, in some implementations, the compound is administered to the subject once or more, such as twice, at a dose of 0.5 to 8 mg (e.g., 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, or 15 mg).

[0067] Alternatively, the dosage can be calculated using the patient's weight. For example, the dosage of the compound or pharmaceutical composition thereof administered to the patient may be 0.005 to 5 (0.01 to 4.8, 0.02 to 4.6, 0.04 to 4.4, 0.06 to 4.2, 0.08 to 4.0, 0.1 to 3.8, 0.2 to 3.6, 0.3 to 3.4, 0.4 to 3.2, 0.5 to 3.0, 0.6, 2.8, 0.7 to 2.6, 0.8 to 2.4, 0.9 to 2.2, 1 to 2, 1.1 to 1.9, 1.2 to 1.8, 1.3 to 1.7, or 1.4 to 1.6) mg / kg. In illustrative, non-limiting embodiments, the dosage may be in the range of 0.005 to 1 mg / kg (e.g., 0.01 to 0.5, 0.01 to 0.2, or 0.01 to 0.1 mg / kg).

[0068] Therapeutic effects A response is achieved when a subject experiences partial or complete relief or reduction of signs or symptoms of the disease after treatment with the compounds or compositions disclosed herein. In some embodiments, the compounds or compositions of this disclosure described herein are administered in an amount and for a duration that can effectively induce relief of one or more (e.g., one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more) symptoms associated with BIMC syndrome or disease. As discussed herein, subjects with BIMC syndrome or disease may have one or more psychological, behavioral, cognitive, metabolic, and / or immune symptoms.

[0069] i. Assessment of treatment for psychological symptoms Therefore, the therapeutic efficacy of the compounds or compositions disclosed herein in treating BIMC symptoms or disease can be demonstrated, for example, by alleviating one or more psychological symptoms of BIMC symptoms or disease. In some embodiments, one or more psychological symptoms of BIMC symptoms or disease include, but are not limited to: emotional reactivity, interpersonal rejection sensitivity (e.g., having a long-term pattern and causing severe social or occupational impairment), depressed mood, low self-esteem, leadenness, fatigue, malaise, somnolence, aphrodisiac, rumination, irritability, low libido, and suicidal ideation. Diagnosis of one or more psychological symptoms associated with BIMC symptoms or disease can be made using known and conventional methods, including subjective self-report and / or observation by a skilled clinician.Non-restrictive examples of tests that can be used for the psychological assessment of test subjects include the Back Depression Inventory (BDI), the Center for Epidemiologic Studies of Depression Scale (CES-D), the EQ-5D (testing activity, self-care, daily activities, pain / discomfort, and anxiety / depression), the Hamilton Depression Rating Scale, the Montgomery-Asberg Depression Rating Scale (MADRS), the Social Problem-Solving Inventory-Revised (SPSI-RTM), the Beck Hopelessness Scale, the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR), the Patient Health Questionnaire (PHQ-9), and the Reminiscence Scale. The following questionnaires are available: Functions Scale (RFS), Short Form Health Survey (SF-36), Social Adjustment Scale-Self Report (SAS-SR), Social Functioning Questionnaire (SFQ), Geriatric Depression Scale (GDS), and Life Satisfaction Index (LSI). If assessed by the above methods, a reduction in the intensity or frequency of one or more of the listed symptoms, or their complete disappearance, may indicate the therapeutic efficacy of the compounds or compositions disclosed herein.

[0070] ii. Assessment of treatment for behavioral symptoms In some embodiments, the therapeutic efficacy of the compounds or compositions disclosed herein in treating BIMC symptoms or disease may be demonstrated, for example, by alleviating one or more behavioral symptoms of BIMC symptoms or disease. In some embodiments, one or more behavioral symptoms of BIMC symptoms or disease include, but are not limited to, increased sleep, hypersomnia, binge eating (e.g., binge eating unrelated to the usual use of inappropriate compensatory behaviors, binge eating not only during the course of anorexia nervosa or bulimia nervosa, and / or recurrent binge eating), recurrent inappropriate compensatory behaviors, overeating, feelings of guilt after eating, distress during eating, impaired impulse control, anorexia, inadequate food intake, extreme fear of weight gain, and body image anxiety. Diagnosis of one or more behavioral symptoms associated with BIMC symptoms or disease may be performed using known and conventional methods, including subjective self-reporting and / or observation by a skilled clinician. In embodiments where the behavioral symptoms relate to sleep disorders (e.g., increased sleep, hypersomnia, and insomnia), tests that can be used to diagnose the subject include tests known in the art, such as multichannel sleep recording, multiple sleep latency tests, and wakefulness maintenance tests. In the implementation plan for behavioral disorders relating to eating disorders (e.g., binge eating, overeating, recurrent inappropriate compensatory behaviors, feelings of guilt after eating, distress during eating, impaired impulse control, anorexia, inadequate food intake, extreme fear of weight gain, and body image anxiety), tests that can be used to diagnose the subject include, but are not limited to, physical examination, psychological assessment (e.g., using the diagnostic methods disclosed herein), assessment of blood glucose levels, electrolyte levels, liver and kidney function, urinalysis, electrocardiogram, complete blood cell count, comprehensive metabolic profile, serum magnesium and phosphate tests, thyroid screening, and self-diagnosis. A decrease in the intensity or frequency, or complete disappearance, of one or more of the symptoms listed above, as assessed by the above methods, may indicate the therapeutic efficacy of the compounds or compositions disclosed herein.

[0071] iii. Assessment of treatment for cognitive symptoms In some embodiments, the therapeutic efficacy of the compounds or compositions disclosed herein in treating BIMC symptoms or disease can be demonstrated, for example, by reducing one or more cognitive symptoms of BIMC symptoms or disease. In some embodiments, one or more cognitive symptoms of BIMC symptoms or disease include, but are not limited to, impaired memory, impaired attention, impaired concentration, impaired language ability, impaired learning ability, impaired perception ability, impaired reasoning ability, executive dysfunction, impaired psychomotor ability, impaired processing speed, and thought disorders (e.g., delusions). Diagnosis of one or more of the cognitive symptoms associated with BIMC symptoms or disease can be made using known and routine methods, including the Eight-item Informant Interview to Differentiate Aging and Dementia (AD8), Annual Wellness Visit (AWV), General Practitioner Assessment of Cognition (GPCOG), Health Risk Assessment (HRA), Memory Impairment Screen (MIS), Mini Mental Status Exam (MMSE), Montreal Cognitive Assessment (MoCA), St. Louis University Mental Status Exam (SLUMS), and Short Informant Questionnaire on Cognitive Decline in the Elderly (ShortIQCODE). If assessed by the methods described above, a reduction in the intensity or frequency of one or more of the symptoms listed above, or their complete disappearance, may indicate the therapeutic efficacy of the compounds or compositions disclosed herein.

[0072] iv. Evaluation of treatment for metabolic symptoms In some embodiments, the therapeutic efficacy of the compounds or compositions disclosed herein in treating BIMC symptoms or disease can be demonstrated, for example, by reducing one or more metabolic symptoms of BIMC symptoms or disease. In some embodiments, one or more metabolic symptoms of BIMC symptoms or disease include, but are not limited to, hypertension, hyperglycemia, insulin resistance, leptin resistance, prediabetes, hypercholesterolemia, hypertriglyceridemia, low serum levels of high-density lipoprotein (HDL), abdominal obesity, hyperuricemia, liver dysfunction, and gastrointestinal disorders. Diagnosis of the aforementioned one or more metabolic symptoms associated with BIMC symptoms or disease can be performed using known and conventional methods, including physical examination, assessment of blood glucose and / or A1C levels, electrolyte levels, liver and kidney function, urinalysis, electrocardiogram, complete blood cell count, comprehensive metabolic profile, serum magnesium and phosphate tests, thyroid screening, blood pressure measurement, and lipid profile testing. A reduction in the intensity or frequency, or complete disappearance, of one or more of the symptoms listed above, as assessed by the above methods, may indicate the therapeutic efficacy of the compounds or compositions disclosed herein.

[0073] v. Evaluation of treatment for immune symptoms In some embodiments, the therapeutic efficacy of the compounds or compositions disclosed herein in treating BIMC symptoms or disease can be demonstrated, for example, by reducing one or more immune symptoms of BIMC symptoms or disease. In some embodiments, one or more immune symptoms of BIMC symptoms or disease include, but are not limited to, inflammation, recurrent infections, gastrointestinal disturbances, anemia, rash, cold extremities, dry eye, fatigue, fever, and / or headache. Diagnosis of the one or more immune symptoms associated with BIMC symptoms or disease can be performed using known and conventional methods, including physical examination, temperature measurement, complete blood count, and urinalysis. A reduction in the intensity or frequency, or complete disappearance, of one or more of the symptoms listed above, as assessed by the above methods, may indicate the therapeutic efficacy of the compounds or compositions disclosed herein.

[0074] As discussed herein, a therapeutic response can be achieved by modulating the immune response in a subject with BIMC symptoms or disease, for example by administering to the subject a dose (e.g., an effective amount) and time sufficient to modulate the immune response in the subject. One way to modulate the immune response is by modulating the activity of immune cells. This modulation can occur in vivo (e.g., in human subjects or animal models). The types of cells that can be modulated include T cells (e.g., peripheral T cells, cytotoxic T cells / CD8+ T cells, T helper cells / CD4+ T cells, memory T cells, regulatory T cells / Treg, natural killer T cells / NKT, mucosa-associated inertial T cells, and γδ T cells), B cells (e.g., memory B cells, plasmablasts, plasma cells, follicular B cells / B-2 cells, marginal zone B cells, B-1 cells, regulatory B cells / Breg), dendritic cells (e.g., bone marrow DCs / regular DCs, plasmacytoid DCs, or follicular DCs), granulocytes (e.g., eosinophils, mast cells, neutrophils, and basophils), monocytes, macrophages (e.g., peripheral macrophages or tissue-resident macrophages), bone marrow-derived suppressor cells, natural killer (NK) cells, innate lymphoid cells (e.g., ILC1, ILC2, and ILC3), thymocytes, and megakaryocytes.

[0075] Immune cell activities that can be modulated by administering to a subject an effective amount of the compounds or compositions of this disclosure described herein include activation, phagocytosis, antibody-dependent phagocytosis, antibody-dependent cytotoxicity, polarization, proliferation, lymph node homing, lymph node efflux, recruitment, migration, differentiation, cytokine production and / or secretion by immune cells, antigen presentation, maturation, and degranulation. Modulation can increase or decrease these activities.

[0076] In some embodiments, an effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof is sufficient to modulate (e.g., increase or decrease) one or more (e.g., two or more, three or more, four or more) of the following immune cell activities in a subject or cells: T cell polarization; T cell activation; dendritic cell activation; neutrophil activation; eosinophil activation; basophil activation; T cell proliferation; B cell proliferation; T cell proliferation; monocyte proliferation; macrophage proliferation; dendritic cell proliferation; NK cell proliferation; ILC proliferation; mast cell proliferation; neutrophil proliferation; eosinophil proliferation; basophil proliferation; cytotoxic T cell activation; circulating monocytes; and external... Peripheral blood hematopoietic stem cells; macrophage polarization; macrophage phagocytosis; macrophage ADCP, neutrophil phagocytosis; monocyte phagocytosis; mast cell phagocytosis; B cell phagocytosis; eosinophil phagocytosis; dendritic cell phagocytosis; macrophage activation; antigen presentation (e.g., dendritic cell, macrophage, and B cell antigen presentation); antigen-presenting cell migration (e.g., dendritic cell, macrophage, and B cell migration); lymph node immune cell homing and efflux (e.g., T cell, B cell, dendritic cell, or macrophage lymph node homing and efflux); NK cell activation; NK cell ADCC, mast cell degranulation; NK cell degranulation; ILC activation, ILC ADCC, ILC degranulation, cytotoxic T cell degranulation; neutrophil degranulation; eosinophil degranulation; basophil degranulation; neutrophil recruitment; eosinophil recruitment; NKT cell activation; B cell activation; regulatory T cell differentiation; and dendritic cell maturation. In some embodiments, the immune response (e.g., the immune cell activity listed herein) in the subject or cells increases or decreases by at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 100%, 150%, 200%, 300%, 400%, 500%, or more compared to pre-administration levels. In some embodiments, the immune response in the subject or cells increases or decreases by 5% to 20%, 5% to 50%, 10% to 50%, 20% to 80%, 20% to 70%, 50% to 200%, or 100% to 500% compared to pre-administration levels.

[0077] Before and / or after administration of the compounds of this disclosure or their pharmaceutically acceptable salts to treat a patient or to contact cells, readings can be used to assess the effect on immune cell activity. Immune cells can be isolated from the subject using, for example, blood samples, lymph node biopsies, or tissue samples. Immune cell activity can also be assessed by measuring cytokines, chemokines, or markers associated with a specific immune cell type using routine analytical methods. In some embodiments, the cytokines or chemokines are selected from: TNFα, IFNα, sTNFR2, IL-1β, IL-1RA, IL-6, IL-2R, IL-18, IL-12, CCL2, CRP, and MIF, or any combination thereof. In some embodiments, an increase or decrease in the blood (e.g., whole blood, plasma, or serum) level of one or more of the aforementioned cytokines or chemokines can indicate a therapeutically effective response in a subject treated with the compounds or compositions of this disclosure. In some embodiments, compared with pre-application levels, the blood levels of said one or more cytokines or chemokines in the subject increase or decrease by at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 100%, 150%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, or more. In some embodiments, the blood levels of said one or more cytokines or chemokines in the subject increase or decrease by 5% to 20%, 5% to 50%, 10% to 50%, 20% to 80%, 20% to 70%, 50% to 200%, or 100% to 500%. In some embodiments, after treatment with a compound or composition of this disclosure, the blood levels of said one or more cytokines or chemokines in the subject decrease. In some embodiments, after treatment with the compounds or compositions of this disclosure, the blood levels of said one or more cytokines or chemokines in the subject increase. In some embodiments, after treatment with the compounds or compositions of this disclosure, the blood levels of said one or more cytokines or chemokines in the subject decrease. Methods for analyzing immune cell activity are known and include, but are not limited to, using, for example, flow cytometry, immunohistochemistry, in situ hybridization, ELISA, western blot analysis, and other analyses that allow the measurement of cell markers to assess cell surface markers on the surface of T cells.

[0078] In some implementations, therapeutic efficacy is measured over different timeframes, including, for example, from months to years, depending on prognostic factors, including the number of relapses, disease stage, and other factors.

[0079] In some embodiments, the methods described herein include identifying a patient as having or at risk of developing BIMC symptoms or disease as described herein. For example, representative methods include: (a) identifying (e.g., diagnosing) a patient as having or at risk of developing BIMC symptoms or disease; and (b) in some embodiments, treating the patient by administering a therapeutically effective dose of the disclosed compound or composition. The method may further optionally include (c) assessing a reduction in the severity or frequency of the aforementioned symptoms in the patient to determine whether the composition causes a therapeutically effective reduction in the degree or frequency of one or more of the aforementioned symptoms of BIMC symptoms or disease.

[0080] Subject selection Subjects who can be treated as described herein are those who have a disease or condition, such as the BIMC condition or disease described herein. For example, subjects who have or are at risk of developing a BIMC condition or disease are those who may have one or more symptoms associated with BIMC, including but not limited to behavioral disorders, immune disorders, metabolic disorders, and / or mood disorders. Non-limiting examples of behavioral disorders may include increased sleep, hypersomnia, interpersonal rejection sensitivity, binge eating, overeating, undereating, compensatory behaviors, impaired impulse control, etc. Examples of immune disorders may include, but are not limited to, chronic low-grade inflammation (e.g., a persistent increase in blood levels of one or more pro-inflammatory cytokines), autoimmune diseases, immune disorders resulting from the use of immunotherapy, and immune disorders resulting from infection (e.g., bacterial or viral infection). In some implementations, metabolic disorders associated with BIMC may include one or more of the following symptoms: hypertension, hyperglycemia, insulin resistance, leptin resistance, mitochondrial dysfunction, prediabetes, hypercholesterolemia, hypertriglyceridemia, low serum levels of high-density lipoprotein (HDL), abdominal obesity, gastrointestinal disorders, hyperuricemia, and liver dysfunction. Non-limiting examples of affective disorders include mood reactivity, depressed mood, low self-esteem, euphoria, rumination, irritability, low libido, suicidal ideation, leadenness, a long-term pattern of interpersonal rejection and sensitivity, feelings of guilt (e.g., after eating), extreme fear of weight gain, body image anxiety, etc.

[0081] Triple reuptake inhibitors Triple reuptake inhibitors (TRIs) are serotonin-norepinephrine-dopamine reuptake inhibitors, acting as combined reuptake inhibitors of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. TRIs simultaneously block the reuptake of these neurotransmitters at serotonin transporter (SERT), norepinephrine transporter (NAT), and dopamine transporter (DAT), respectively. Inhibition of these neurotransmitters increases their extracellular concentrations, leading to increased serotonergic, norepinephrine, and dopaminergic neurotransmission in the central nervous system (CNS). The affinity of the TRI compounds disclosed herein for any of SERT, NAT, and / or DAT can be determined by measuring the percentage inhibition of these transporters using cells expressing human transporters via radioligand binding assays. Relevant radioligand binding assays for determining affinity are well known in the art.

[0082] Compound 1 As described below, compound 1 is a triple reuptake inhibitor, also known as (3,4-dichlorophenyl)-((S)-3-propyl-pyrrolidine-3-yl)-methyl ketone: (Compound 1).

[0083] The methods for chemically synthesizing compound 1 are described in U.S. Patent Nos. 8,084,623 and 9,527,810, which are incorporated herein by reference in their entirety.

[0084] In some embodiments, a pharmaceutically acceptable salt of compound 1 may be a salt of compound 1 with a physiologically compatible inorganic acid (such as hydrochloric acid, sulfuric acid, sulfurous acid, or phosphoric acid); or with an organic acid (such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid, or salicylic acid).

[0085] In some embodiments, a pharmaceutically acceptable salt of compound 1 is a hydrochloride salt, which is in hydrated or anhydrous form (e.g., anhydrous, hemihydrate, monohydrate, or quarter-hydrate). In some embodiments, a pharmaceutically acceptable salt of compound 1 is a hydrochloride salt, which is in quarter-hydrate form.

[0086] In some implementations, a pharmaceutically acceptable salt of compound 1 is , Or its hydrates.

[0087] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is in an amorphous form. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is in a crystalline form. In some embodiments, the crystalline form is a crystalline polymorph or its hydrate. In some embodiments, the crystalline polymorph is (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidine-3-yl)-methyl ketone hydrochloride quarter hydrate (form 1). In some embodiments, the crystalline polymorph is (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidine-3-yl)-methyl ketone hydrochloride (form 2).

[0088] Form 1 In some embodiments, the compound is in the form of a crystalline quarter-hydrate of the hydrochloride salt of compound 1 (form 1). In some embodiments, form 1 is characterized by at least three peaks selected from those obtained by Cu at 2θ (2 Theta). Kα The X-ray powder diffraction peaks obtained by radiation are: 5.5±0.20°, 9.4±0.20°, 10.6±0.20°, 12.5±0.20°, 14.6±0.20°, 16.2±0.20°, 16.6±0.20°, 17.3±0.20°, 18.6±0.20°, 19.6±0.20°, 22.2±0.20°, 22.7±0.20°, 23.1±0.20°, 23.7±0.20°, and 25.3±0.20°.

[0089] Form 2 In some embodiments, the compound is in the crystalline form of the hydrochloride salt of compound 1 (form 2). In some embodiments, form 2 is characterized by at least three peaks selected from those obtained by Cu at 2θ (2 Theta). Kα The X-ray powder diffraction peaks obtained by radiation are: 5.2±0.20°, 10.5±0.20°, 12.3±0.20°, 15.3±0.20°, 15.6±0.20°, 16.0±0.20°, 17.1±0.20°, 18.8±0.20°, 23.0±0.20°, 23.9±0.20°, 27.2±0.20°, 28.2±0.20°, and 30.5±0.20°.

[0090] In some embodiments, the pharmaceutical composition described herein comprises a therapeutically effective amount of the free base form of compound 1.

[0091] In some embodiments, the pharmaceutical composition described herein comprises a therapeutically effective amount of a pharmaceutically acceptable salt of compound 1. In some embodiments, the pharmaceutically acceptable salt of compound 1 may be a salt of compound 1 with a physiologically compatible inorganic acid (such as hydrochloric acid, sulfuric acid, sulfurous acid, or phosphoric acid), or with an organic acid (such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid, or salicylic acid).

[0092] Pharmaceutical Composition The compounds or compositions disclosed herein may be incorporated into pharmaceutical compositions suitable for administration to a subject (e.g., a human). These compositions typically comprise a pharmaceutical agent and a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is known. Such media may be used in the compositions of the present invention unless any conventional media or agent is incompatible with the active compound. Additional active compounds may also be incorporated into the compositions.

[0093] Pharmaceutical compositions may be formulated to be compatible with their intended route of administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous administration may include the following components: sterile diluents, such as water for injection, saline solution, non-volatile oils, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates, or phosphates; and tonic modifiers, such as sodium chloride or dextrose. The pH may be adjusted with an acid or base (such as hydrochloric acid or sodium hydroxide). Parenteral preparations may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0094] The pharmaceutical compositions described herein may be presented in a sustained-release form. A sustained-release form is a formulation designed to slowly release a therapeutic agent in the body over an extended period of time. A sustained-release form may be formulated to maintain, for example, the effect of a compound over an extended period of time. A sustained-release form may be formulated to provide an effective dose of any of the compounds described herein (e.g., to provide a physiologically effective blood profile) over about 4, about 8, about 12, about 16, or about 24 hours.

[0095] In some embodiments, the pharmaceutical composition provided herein is administered to a patient in a solid dosage form. In some embodiments, the solid dosage form is a capsule. In some embodiments, the solid dosage form is a tablet.

[0096] In some embodiments, the pharmaceutical compositions provided herein comprise compound 1 or a pharmaceutically acceptable salt thereof as the sole active agent, or in combination with other active agents.

[0097] Although the descriptions of the pharmaceutical compositions provided herein are generally relating to those suitable for human administration, those skilled in the art will understand that these compositions are generally suitable for administration to all types of animals. It should be fully understood that modifications can be made to pharmaceutical compositions suitable for human administration to make them suitable for administration to a variety of animals, and that such modifications can be designed and / or performed by a generally skilled veterinary pharmacologist using standard experiments. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example... Remington: The Science and Practice of Pharmacy 21st edition, Lippincott Williams & Wilkins, 2005.

[0098] medicine In some embodiments, this disclosure provides the use of the compounds and compositions described herein in the preparation of pharmaceutical agents for treating the conditions, diseases, or ailments described herein. In some embodiments, the pharmaceutical agent is formulated based on the physical characteristics of a subject requiring treatment and is formulated as a single or more formulations based on the stage of the condition, disease, or ailment. In some embodiments, the pharmaceutical agent is packaged in a suitable package with appropriate labeling for distribution to hospitals and clinics, wherein the labeling indicates treatment for a subject suffering from the disease described herein. In some embodiments, the pharmaceutical agent is packaged as a single or multiple units. In some embodiments, instructions regarding dosage and administration of the composition are included in the package described below. This disclosure further relates to pharmaceutical agents comprising the compounds described herein and pharmaceutically acceptable carriers. Example

[0099] The following examples are provided to provide those skilled in the art with a description of how the compositions and methods described herein can be used, prepared, and evaluated, and are intended to be purely illustrative of this disclosure and are not intended to limit the scope of the inventors’ view of their invention.

[0100] In the embodiments provided below, the following abbreviations are used: "PROG" refers to progressive ratio; "FR1" refers to fixed ratio one or fixed ratio 1; "SEM" refers to the standard error of the mean; "VEH" refers to the medium; "ANOVA" refers to the analysis of variance test; "NR" refers to non-rapid eye movement sleep; "REM" refers to rapid eye movement sleep; "po" or "per os" refers to oral reuptake; "CAF" refers to caffeine; and "TRI" refers to triple reuptake inhibitor.

[0101] Example 1: In vivo effects of triple reuptake inhibitors on LPS-induced TNFα release in rat serum The current study was conducted to evaluate the effect of the triple uptake inhibitor (compound 1) of this disclosure on LPS-induced secretion of TNFα into rat serum. LPS is a bacterial endotoxin containing proteins and polysaccharides and is a stable activator of the immune system. When administered in vivo, LPS induces an acute inflammatory response characterized by elevated levels of the pro-inflammatory cytokine TNFα in the peripheral circulation. LPS-induced TNFα release has been used as a first-line acute model to test the anti-inflammatory therapeutic effect of the candidate drug and to determine the range of effective therapeutic doses before testing in a chronic inflammatory model.

[0102] Animals and drug administration To evaluate the in vivo effects of compound 1 on LPS-induced TNFα release, female WistarHan rats (n = 8) were administered either 1 mL / 100 g of the carrier (HPMC; TG10, pH 3.5) or compound 1 (3 mg / kg) intraperitoneally prior to LPS administration. At 0 h, LPS was injected intraperitoneally at 50 µg / kg. 1.5 h post-LPS injection, animals were euthanized by CO2 inhalation and blood was aspirated via cardiac puncture. Serum was separated and maintained at -20°C until ready for TNFα measurement by ELISA. Plasma was also collected in a plasma separator catheter for pharmacokinetic (PK) analysis.

[0103] result Dose-response assessment was performed 1.5 hours after LPS exposure. In this case, the LPS-induced serum TNFα level was 10,621 pg / mL. Pretreatment with compound 1 resulted in a dose-dependent reduction of TNFα levels of 80.2% at 3 mg / kg, 90.7% at 10 mg / kg, and 93.5% at 30 mg / kg, all of which were statistically significant. Figure 1 Unexpectedly, administration of 30 mg / kg caused seizures in animals 20 minutes after administration. Therefore, these animals were immediately sacrificed (70 minutes earlier than expected). Compound 2 (refer to JNK inhibitors and positive controls) reduced TNFα levels by 82.8% at a dose of 30 mg / kg. Figure 1 An overview of this data is presented in Table 1 below. Drug exposure in plasma is presented in Table 2.

[0104] Table 1: Effects of compound 1 on LPS-induced TNFα release in rat plasma Table 2: Concentration of compound 1 in plasma samples from Wistar Han rats after LPS stimulation In summary, compound 1 inhibited LPS-induced TNFα release in rat serum in a dose-dependent manner. A high dose of 30 mg / kg may not be well tolerated due to its potential to induce seizures.

[0105] Example 2: Effects of triple reuptake inhibitors on rats in forced swimming test This study was conducted to test the antidepressant-like effects of compound 1 in rats during a forced swimming test. The forced swimming test relies on the principle that when rodents are placed in water, they initially engage in vigorous activity for a period of time before assuming a characteristic immobile posture, making only the minimal movements necessary to remain afloat. A reduction in immobility time is considered an indication of the potential antidepressant-like properties of a particular drug.

[0106] animal Adult female Wistar rats weighing approximately 100 to 130 g were used. The animals were housed in groups of four in cages (8-10 cm) with wood shavings bedding. 2 In addition to a continuous supply of tap water and standard laboratory feed during the testing period, the animal enclosures were maintained in a 12:12 hour light-dark cycle, with light exposure beginning at 6:00 AM. Room temperature (21–23°C) and humidity (55–65%) were kept constant. At the end of the test, the rats were euthanized by CO2 inhalation.

[0107] Swimming test In the forced swimming test, untreated rats were placed individually in vertical glass resin cylinders (height: 40 cm; diameter: 17.5 cm) containing water at a depth of 16 cm and maintained at 23–24°C. After 15 minutes in the water, they were carefully removed, dried with a towel, and further dried under a heat lamp for 15 minutes before being returned to their cages. Twenty-four hours later, they were retested under the same conditions for 5 minutes, and the total duration of immobility was measured. Rats were considered immobile if they remained passively floating in the water in a slightly bent but upright position with their heads just above the water surface. Four rats were monitored simultaneously using automated video tracking, according to a balance protocol for both the treatment and the cylinder.

[0108] Drug administration Compound 1 was suspended in 0.3% Tween 80 in distilled water. Compound 1 was administered orally (via tube feeding) 24 hours, 16 hours, and 2 hours before testing. The injection volume was 5 mL / kg body weight. Dosage refers to the free base of the drug.

[0109] Statistical analysis The data were analyzed using a one-way ANOVA followed by a one-tailed Dunnett post-hoc test. A p-value < 0.05 was considered significant.

[0110] result Compound 1 significantly reduced the duration of immobility at 10 mg / kg, but did not at lower doses. Figure 2 (and Table 3). These data provide in vivo evidence of the antidepressant-like properties of compound 1 after oral administration.

[0111] Table 3: Effects of Compound 1 on rats in the forced swimming test Example 3: The role of triple reuptake inhibitors in mouse tail suspension test The mouse tail suspension test is a well-documented animal behavioral test for sensitivity to standard classes of antidepressants. The antidepressant effect of compound 1 at oral doses ranging from 0.3 to 10 mg / kg was examined in a mouse tail suspension model. Compound 1 was administered to male A / J mice (n = 15 to 17) 120 minutes prior to the test. Oral administration of compound 1 at 1, 3, and 10 mg / kg significantly reduced activity time (p < 0.05). Duloxetine (30 mg / kg, intraperitoneally, 120 minutes prior to treatment), used as a positive control, showed a significant reduction in immobility time.

[0112] animal Male A / J mice (9 to 10 weeks old) were housed in corn cob bedding with free access to food and water. They were kept in a 12-hour light-dark cycle for at least seven days prior to testing.

[0113] Drug administration Compound 1 (0.3, 1, 3, and 10 mg / kg) was freshly prepared in Generic HPMC (5 mg / mL hydroxypropyl methylcellulose, 4 mg / mL polysorbate-80, and 9 mg / mL benzyl alcohol in sterile water) and administered orally in an acute dose 120 minutes prior to the test. Duloxetine (30 mg / kg) was dissolved in sterile water and administered intraperitoneally in an acute dose 120 minutes prior to the test. After the appropriate injection test interval, mice were suspended in the air by attaching their tails to hooks connected to a load-bearing amplifier circuit (test cabinet) using tape. This circuit calculated the total immobility time during the six-minute test period.

[0114] Statistical analysis Statistical analysis was performed on all dose groups using overall variance analysis. Then, the Dunnett test was used to compare the immobility time of each dose with that of the carrier in pairs. The analysis was validated by comparing single doses of duloxetine (positive control) with the carrier using an unpaired t-test.

[0115] result Compared with animals treated with the vector, compound 1 (1, 2, and 10 mg / kg) significantly (p<0.05) reduced immobility time. Figure 3 The positive control, duloxetine (30 mg / kg), also showed a significant reduction in immobility time. These findings further demonstrate the antidepressant properties of compound 1.

[0116] Example 4: Effects of triple reuptake inhibitors on rats in the elevated plus-maze test. This study investigated the behavioral effects of compound 1 on rats in an elevated cross maze. This test relied on the principle that rodents avoid open and exposed environments (the open arms of the cross maze) and prefer to spend time in protected areas (the closed arms of the apparatus). Increased time spent, distance traveled, and percentage of entry into the open arms were considered indicators of anxiolytic-like properties of the specific drug, while the opposite effect was considered anxiolytic-like properties.

[0117] animal Adult male Sprague-Dawley rats, weighing approximately 200 g at the start of the experiment, were used. The rats were housed in groups of four in Macrolon 3 cages (810 cm²) with wood-based bedding. 2The animals are kept in a 12:12 hour light-dark cycle, with lighting beginning at 6:00 AM, and they have free access to tap water and food. Room temperature (21 to 23°C) and humidity (55 to 65%) are kept constant.

[0118] elevated cross maze The elevated cruciform maze consists of two open arms and two closed arms (each 10 cm wide × 50 cm long), extending from the central open area. The two open arms are perpendicular to the two closed arms. The apparatus is made of gray PVC plastic and placed 50 cm above the floor. The closed arms face each other and are surrounded by walls 48 cm high. The apparatus is located in a soundproof observation room with controlled lighting (200 lux on the central platform of the cruciform maze). The cruciform maze is placed in a closed, dark environment, and animals are observed via a closed-circuit video camera mounted vertically above the maze. Behavioral analysis is performed using a computerized system. Rats are tested in a randomized order. Testing begins by placing the animals on the central platform facing the closed arms. The test lasts for 5 minutes. The apparatus is cleaned with 70% ethanol before introducing each animal.

[0119] Each treatment group consisted of 12 rats. Each animal was used for a single experiment only. Rats were treated with compound 1 at doses of 1, 3, or 10 mg / kg, the mediator (0.3% Tween-NaCl 0.9%), or 10 mg / kg chlordiazepoxide (as a positive control). Rats were isolated in cages free of sawdust and water for 60 minutes, and then placed in a cruciform maze.

[0120] The parameters selected to represent anxiety-related behaviors were the time spent in the open arm (seconds), the distance traveled in the open arm (cm), and the percentage of transition between the central platform and the open arm. The measure used to quantify motor activity was the distance traveled per second in the closed arm (speed).

[0121] Drug administration Compound 1 and chlordiazepoxide were suspended in 0.3% Tween / 0.9% NaCl. These compounds were administered orally (via tube feeding) at a dose of 5 mL / kg body weight. Control animals received an equal volume of the mediator. The pretreatment time for the mediator and compound 1 was 120 minutes, and the pretreatment time for chlordiazepoxide was 60 minutes.

[0122] Statistical analysis For compound 1, data were analyzed by one-way ANOVA followed by Dunnett's post-hoc test. Statistical significance was determined at p-value < 0.05. The effect of the positive control chlordiazepoxide was analyzed using an unpaired t-test.

[0123] result Compound 1's time spent in the open arm ( Figure 4A (and Table 4), the distance traveled in the open arm ( Figure 4B (and Table 5) or the percentage entering the open arm ( Figure 4C (and Table 6) had no effect. Chlorazine significantly increased the time spent and distance traveled in the open arm, but did not significantly increase the percentage of animals entering the open arm (p>0.01). The speed in the closed arm was neither affected by compound 1 nor by chlorazine (p>0.01). Figure 4D (and Table 7). These findings indicate that, at the administered doses, compound 1 did not exhibit anxiolytic or anxiolytic-like effects in rodents.

[0124] Table 4: Time (seconds) in the open arm Table 5: Distance traveled in the open arm Table 6: Percentage Entering the Open Arm Table 7: Velocity (cm / s) in the closed arm Example 5: Evaluation of the appetite-suppressing effect of compound 1 in rats using a progressive ratio / feed selection task. A study was conducted to evaluate the appetite-suppressing effect of compound 1. The PROG / feed selection program was used as a test, which was designed to assess the effort rats were willing to make to eat palatable food by pressing a lever rather than eating freely available standard food.

[0125] method Thirty-one (n = 31) adult male Sprague-Dolly rats were used in this study. Animals were restricted to 85% of their free-feeding weight and allowed appropriate growth throughout the study period. Animals were assessed using an operant conditioning chamber. Animals were first introduced to high-carbohydrate pellets (“appetizing food”) and trained for one week using a continuous reinforcement schedule with a fixed ratio of 1 (FR1 = one active lever press triggering appetizing food delivery). Subsequently, rats were trained for nine weeks with a progressive ratio schedule (requiring gradually increasing lever pressure to trigger appetizing food delivery), at which point a diet (“standard diet”) (=PROG / feeding selection program) was introduced, and animals were trained for an additional 5 weeks to establish a stable baseline. Each phase lasted 30 minutes and the rats were run in the chamber once daily, five days a week (Monday through Friday). After the training period, the mediator (VEH) or compound 1 at doses of 5, 10, and 20 mg / kg was administered orally once weekly (Thursday or Friday). Treatment conditions were randomly selected. After each operation stage, record the control lever presses and feed consumption (including spills).

[0126] Statistical analysis Data were assessed using repeated measures analysis of variance (ANOVA) and prior comparisons. Factorial ANOVA was used to assess group × treatment interactions. If a significant interaction was found, prior comparisons (using the total error term) were used to assess each group individually. The Dunnett test was also used to analyze differences between drug treatments and VEH. For all analyses, a p-value <0.05 was considered statistically significant.

[0127] result like Figure 6A As shown, compared with VEH (5.0 mg / kg: [F(1,90)=15.589, p<0.001], 10.0 mg / kg [F(1,90)=159.881, p<0.001], and 20.0 mg / kg: [F(1,90)=236.567, p<0.001]), all treatments showed a significant reduction in standard feed intake. No significant difference in control lever pressure was observed between VEH and the 5.0 mg / kg dose [F(1,90)=0.391, p = not significant]. Figure 5A As shown, the control lever presses were significantly reduced at both the 10.0 mg / kg dose [F(1,90)=13.534, p<0.001] and the 20.0 mg / kg dose [F(1,90)=38.407, p<0.001].

[0128] Studies have shown that compound 1 exhibits an appetite-suppressing effect, as demonstrated in the PROG / feed selection task study, which showed a pattern of control lever pressing and reduced feed intake.

[0129] High responders vs. low responders Factorial ANOVA tests on control lever presses showed a significant group × treatment interaction [F(3,90)=13.824, p<0.001; ηp] 2 = 0.323] and a significant interaction of linear trends (p<0.001). Due to this significant interaction, lever presses were analyzed separately in high-responder and low-responder groups. Significant therapeutic effects were found in both groups (high: p<0.001; low: p=0.01). Lever presses in high-responder groups showed a significant linear trend (p<0.001). Pre-hospital comparisons with VEH showed a significant reduction in lever presses at both 10.0 mg / kg [F(1,42)=26.735, p<0.001] and 20.0 mg / kg [F(1,42)=55.797, p<0.001]. No significant difference was found when comparing the 5.0 mg / kg dose with VEH conditions [F(1,42)=3.372, p=not significant](F(1,42)=3.372, p=not significant). Figure 5B When comparing any of the drug conditions with VEH, no significant differences were found in the prior comparisons (5.0 mg / kg: [F(1,45)=0.319, p=not significant], 10.0 mg / kg: [F(1,45)=0.079, p=not significant], 20.0 mg / kg: [F(1,45)=3.157, p=not significant]). However, a significant secondary trend was found in the low-responder group (p=0.01). Figure 5B Factorial ANOVA was also used to assess concurrent feed intake. A significant group × treatment interaction was found [F(3,90)=3.191, p<0.05; ηp] 2 =0.099] ( Figure 6A The interaction between high and low responders was significant (p<0.05). This significant interaction allowed for independent analysis of high and low responders. Significant therapeutic effects (p<0.001) and a significant linear trend (p<0.001) were observed in both high and low responders. Figure 6BIn the high-responder group, compared with VEH, significantly reduced feed intake was observed in the 5.0 mg / kg [F(1,42)=13.450, p<0.010], 10.0 mg / kg [F(1,42)=70.714, p<0.001], and 20.0 mg / kg [F(1,42)=100.204, p<0.001] groups. Low-responders also showed significantly reduced control lever presses at all dose treatments (5.0 mg / kg [F(1,45)=16.976, p<0.001], 10.0 mg / kg [F(1,45)=156.918, p<0.001], 20.0 mg / kg [F(1,45)=226.122, p<0.001]), as determined by the Dunnett test.

[0130] Example 6: Evaluation of the appetite-suppressing effect of compound 1 in rats using a fixed-ratio time course. A second study was conducted to evaluate the appetite-suppressing effect of compound 1. A fixed ratio 1 (FR1) timescale was used. This task represents the most food-intensive and appetite-dependent operational timescale, and is highly sensitive to appetite-related manipulations such as prefeeding and appetite-suppressing drugs.

[0131] method The same adult male Sprague-Dolly rats (n = 31) used in this study as in Example 5. Animals were trained once daily from Monday to Thursday using the PROG / feed selection program. On Friday, the test day, animals were switched from the PROG / feed selection program to the previously untrained FR1. Each phase lasted 30 minutes, and lever presses were recorded at the end of the run. Drug treatment and FR1 probe administration occurred on Friday following the two-week clearance period of Example 5. Compound 1 or the carrier was administered orally via tube feeding at a dose of 20 mg / kg on the test day. Only the highest dose was tested in this study because, in Example 5, this dose produced the most stable reduction in lever presses and feed intake compared to VEH. Treatment conditions were randomly assigned. Differences between treatment groups were assessed using unpaired t-tests. A p-value < 0.05 was considered statistically significant.

[0132] result In the FR1 probe study, compound 1 produced a significant reduction in control lever pressure, as measured by an unpaired t-test (t = 9.74; p < 0.001). Figure 7As shown, a significant reduction was observed at a dose of 20 mg / kg compared to the mediator (VEH). Importantly, 6 out of 16 rats receiving the high dose pressed the control lever but did not consume some of the pellets. After the 30-minute administration phase, approximately 5 to 10 uneaten pellets remained in the food bowls of these animals, another marker of appetite suppression. Therefore, combined with the results from the study in Example 5, this study demonstrates that compound 1 exhibits appetite-suppressing properties.

[0133] Example 7: Evaluation of the appetite-suppressing effect of compound 1 on rats using a chocolate binge-eating diet This is the third study to evaluate the appetite-suppressing effect of compound 1 using a chocolate-based binge-eating diet model.

[0134] method A new group of male Sprague-Dawley rats (n = 8; initial weight 300 to 325 g) were used in a binge-eating diet experiment. They were housed in pairs under the same conditions described in Examples 5 and 6 above, but with unrestricted food access and free access to food (laboratory feed) and water in their cages. Binge-eating diet intake occurred during 12 exposure phases. Prior to chocolate exposure, rats were habituated to empty cages with ceramic dishes for 3 days, 1 hour each. Under chocolate exposure, rats received chocolate (0.3 g fat, 0.57 g carbohydrates, and 0.073 g protein, totaling 5.34 kcal / g) on ​​days 1, 2, 4, 6, 7, 9, 12, 14, 15, 18, 23, and 28. On the exposure day, rats were placed in empty cages with ceramic dishes containing chopped chocolate for 1 hour. Chocolate weight was measured before and after each phase to determine intake. These acquisition procedures resulted in a gradual increase in chocolate intake levels across the stages (from 0.9 ± 0.3 g chocolate in stage 1 to 5.5 ± 0.5 g in stage 12) (see [link to relevant documentation]). Figure 8A ).

[0135] Drug administration After completing 12 acquisition phases of the binge-like diet, rats were exposed to a chocolate phase for 1 hour twice weekly in empty cages with ceramic dishes containing chocolate. One phase was used to maintain the binge-like behavior, and a second phase was used for drug treatment. These phases were randomized throughout the week, with the maintenance phase always preceding the drug treatment phase. Compound 1 was dissolved in 0.3% Tween 80 in dH2O. The mediator (VEH) or doses of Compound 1 at 5, 10, and 20 mg / kg were administered weekly via oral feeding for testing purposes. A four-hour pretreatment time was used. An within-subjects design was used in this study, with each rat receiving treatment weekly for a total of four weeks. Treatment conditions were randomized.

[0136] Data Analysis The effect of compound 1 on a chocolate binge-like diet was assessed using repeated measures ANOVA and prior comparative studies.

[0137] result The results of the binge-eating-like diet experiment are shown in Table 8. Figure 8A and Figure 8B middle.

[0138] Table 8: Statistical Analysis of the Binge Eating Experiment Paired comparison: VEH comparison at 10 mg / kg: p < 0.05** VEH comparison at 20 mg / kg: p < 0.05** Figure 8A The acquisition of binge-like chocolate intake was depicted during 12 training phases. Figure 8B The study demonstrated the inhibitory effect of compound 1 on binge eating. Treatment with compound 1 had an overall significant effect [F(3,21) = 17.3, p<0.001]. Prior comparisons showed that a dose of 5 mg / kg did not significantly inhibit chocolate intake [F(1,21) = 1.5, not significant], but at doses of 10 [F(1,21) = 20.4, p<0.001] and 20 [F(1,21) = 4.09, p<0.001] mg / kg, chocolate intake was significantly reduced.

[0139] Example 8: Evaluation of the effect of compound 1 on sleep in rats Using a count-balanced repeated measures design, the effects of three doses of compound 1 (1, 3, and 10 mg / kg; orally) on sleep / wake parameters in adult male Sprague-Dowley rats (n = 8) were tested. The results were compared with the effects on caffeine (10 mg / kg).

[0140] method Eight adult male Sprague-Dolly rats (n = 8) were used in this study. Each rat received three doses (1, 3, and 10 mg / kg) of compound 1, a mediator (purified H2O – negative control), and caffeine (10 mg / kg – positive control). Treatment was administered orally at intervals of at least 3 days during the middle of the rats' normal inactive period. Sleep parameters (non-rapid eye movement sleep, NR; rapid eye movement sleep, REM) were recorded, and the records for the first 6 hours after administration were analyzed. Figure 9A and Figure 9B As shown, the results are compared with the medium.

[0141] result Compound 1, at 10 mg / kg (oral), had a wakefulness-promoting effect in rats, as demonstrated by complete inhibition of REM sleep. 3 mg / kg also significantly increased wakefulness and reduced REM sleep, but to a lesser extent.

[0142] Example 9: Evaluation of the effects of compound 1 on attention and impulsivity in rats The 5-Choose Continuous Reaction Time Task (5-CSRTT) is widely used to measure attentional performance and response control (motor impulses) in rodents. Its advantage lies in its adaptability to task modifications. Variations in stimulus duration and frequency of stimulus presentation, among others, have been commonly used to elicit performance under attentional and response control conditions. The primary objective of these studies was to examine the effect of compound 1 on attentional performance and response control, defined as measurements of premature response (PREM) and sustained response (PSV), impulsive behavior, and compulsive behavior. Two experimental procedures were performed to elicit performance in different ways. Specifically, (1) compound 1 (1, 3, 10 mg / kg) was tested under standard test conditions of 0.75 seconds stimulus duration (SD), 5 seconds inter-trial interval (ITI), and 100 trials, and (2) compound 1 (1, 3 mg / kg) was tested for a long ITI stimulus. The long ITI stimulus was designed to enhance PREM and PSV responses and thus provides a way to examine the effects of the two test items on measures of impulsive and compulsive behavior.

[0143] Material Media Comparison Dosage form: 0.3% Tween 80 in 0.9% saline solution. Pre-processing time: 180 minutes Compound 1 Dosage form: Compound 1 was suspended in 0.3% Tween 80 in 0.9% saline and sonicated. The drug was administered orally (PO) at a volume of 5 mL / kg.

[0144] Pre-processing time: 180 minutes The tested doses were: Phase 1: 1, 3, and 10 mg / kg; Phase 2: 1 and 3 mg / kg. Subjects: 24 male Long Evans rats Settlement and Management of the Testing System: After a one-week familiarization period with the testing facility, animals were placed in a restricted diet program, where, after completion of the study procedures, they were fed approximately 20 g of standard laboratory feed (corresponding to about 80% of normal food consumption) once daily (between 4:00 PM and 6:00 PM). Therefore, total food intake was based on the food received during the five optional training / testing phases and the feed received at the end of each study day. On days without training / testing, the daily allocated laboratory feed was increased to approximately 24 g per animal. Water was available freely except during the five optional training / testing phases. Animals were maintained in a 12-hour / 12-hour light / dark cycle, with all tests conducted during the animals' light cycle.

[0145] 5-Select Continuous Reaction Time Task: A 5-selection operating chamber is housed in a soundproof and ventilated enclosure. The chamber consists of an aluminum enclosure (25 × 30 cm) containing a reward cassette connected to a food pellet dispenser and an interior light on one wall. On the opposite wall are five square niches (2.5 × 2.5 × 2.5 cm) mounted on a curved panel, raised 2.5 cm from the grid floor. LEDs are located on the back of each niche. Each niche and reward cassette also contains photocells to detect head entry. The test chamber is software-controlled.

[0146] The 5-CSRTT schedule begins with room lighting and the delivery of food pellets. The first trial is initiated by a nose poke into a dark cassette tray, consisting of the following: an inter-trial interval (ITI, 5 seconds), followed by a fixed interval (stimulus duration, SD) of one of five lights being randomly illuminated. If a nose poke is recorded in an illuminated niche before the end of the SD or before the fixed interval (limited hold, LH) following this period, an additional pellet is allocated and recorded as a correct trial. An incorrect nose poke (incorrect trial) or failure to respond within the allocated time (trial missed) results in a 5-second timeout (TO) period with the room lights off. A response to one of the five niches during the ITI (PREM response) generates an additional TO. PSV responses are not penalized by TO.

[0147] Each phase is run 100 times or for 60 minutes, depending on which phase endpoint is achieved first. Animals are trained through a series of steps until the final testing conditions are 0.75 seconds SD, 5 seconds ITI, and 5 seconds limited maintenance. The target performance is stable performance near a critical threshold of 80% accuracy ([correct / (correct + incorrect)] × 100) and <20% omission rate for at least two weeks. At this point, drug testing begins according to a repeated measures design, in which animals are treated during repeated testing phases. Testing phases are run twice weekly according to the standard (5-second ITI) and long ITI durations to achieve drug clearance and re-establish baselines for subjects between cycles.

[0148] Phase 1: The effect of compound 1 (1, 3, 10 mg / kg) or the mediator control on test performance was investigated under the following standard test conditions: 0.75 sec SD, 5 sec ITI, 5 sec LH, for a total of 100 trials. Treatments were administered in a randomized order.

[0149] Phase 2: The effects of compound 1 (1 and 3 mg / kg) or the mediator control were investigated in five selected time periods within a 10-second ITI (10-second ITI, 0.3-second SD, 5-second LH, 100 trials). Treatments were administered in a randomized order.

[0150] Statistical analysis The main metrics of performance from 5-CSRTT, namely accuracy (correctness delay), response speed (correctness delay), incomplete trials (missed trials), and total number of trials, are expressed as averages and SEMs, measured as correct% ([correctness percentage / correctness percentage + incorrectness percentage] × 100) or hit percentage ([correctness percentage / correctness percentage + incorrectness percentage + missed trials] × 100).

[0151] result Phase 1: Effects of Compound 1 on Performance in the 5-Selection Task: Standard Conditions: Compound 1 was tested in all rats at doses of 1, 3, and 10 mg / kg using a repeated measures design. The vehicle pretreatment group served as the control. Major therapeutic effects were found on the overall test (F3,69=4.4; P<0.01), PREM response (F3,69=5.1; P<0.01), and PSV response (F3,69=4.6; P<0.01). These major effects reflected dose-related reductions in PREM and PSV responses relative to the vehicle control after pretreatment with Compound 1. Additionally, the number of trials was reduced at the 10 mg / kg dose. No major therapeutic effects were found on any other task metrics, including accuracy. 5-CSRTT results obtained under standard test conditions (0.75-second stimulus duration, 5-second ITI, 100 trials) are presented in [Table data would be inserted here]. Figures 10A to 10C .

[0152] Phase 2: Effect of Compound 1 on Performance in a 5-Selection Task: 10-Second ITI: Compound 1 was tested in all rats at doses of 1 and 3 mg / kg at a repeated measures design with a 10-second ITI duration. The mediator pretreatment group served as a control. Increasing the ITI from 5 seconds to 10 seconds, and from 0.75 seconds to 0.3 seconds of visual stimulus duration, decreased accuracy (correct; 5-second ITI: 83.9 ± 1.5%; 10-second ITI: 68.5 ± 2.4%; P < 0.01) and increased PREM (5-second ITI: 6.0 ± 1.2; 10-second ITI: 46.7 ± 10.2; P < 0.01) and PSV (5-second ITI: 20.9 ± 3.4; 10-second ITI: 33.8 ± 7.4; P < 0.05) responses to both. The effect of Compound 1 on task performance at a 10-second ITI duration was assessed under the same conditions relative to mediator pretreatment. When all rats (N=21) were included in the analysis, there was no major therapeutic effect on any measure (F2,40≤2.5; not significant), i.e., no therapeutic effect on accuracy (correctness %, hit %) or PREM / PSV response. Subsequently, rats were subdivided into low impulsivity (LI) and high impulsivity (HI) based on PREM response levels after mediator pretreatment at 10-second ITI durations (i.e., PREM:LI: 16.7±2.4; PREM:HI: 93.9±21.6; P<0.01). This subdivision yielded major effects of subgroups on PREM (F1,12=8.0; P=0.02) and PSV response (F1,12=8.3; P=0.01), reflecting significantly higher PREM and PSV responses in HI rats compared to their LI counterparts. Regarding the effects of compound 1 on task performance in these subgroups, note the major therapeutic effects and subgroup-treatment interactions on PREM (treatment: F2,24=6.7; P<0.01; subgroup × treatment: F2,24=10.2; P<0.01) and PSV response (treatment: F2,24=4.2; P=0.02; subgroup × treatment: F2,24=7.7; P<0.01). This reflects the selective reduction of PREM and PSV response in the HI subgroup by both 1 and 3 mg / kg doses of NOE-115.

[0153] Other implementation plans Various modifications and variations of this disclosure will be apparent to those skilled in the art without departing from its scope and spirit. Although this disclosure has been described in conjunction with specific embodiments, it should be understood that the claimed disclosure should not be unduly limited to those specific embodiments. Indeed, various modifications to the described model that are obvious to those skilled in the art and intended for the implementation of this disclosure are intended to be within the scope of this disclosure. Other embodiments are set forth in the claims.

Claims

1. A method of treating or preventing a behavioral immunometabolic cluster (BIMC) disorder or disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a triple reuptake inhibitor (TRI).

2. The method of claim 1, wherein the treating or preventing comprises: a) reducing one or more symptoms of the BIMC disorder or disease in the subject; and / or b) modulating an immune response in the subject.

3. The method of claim 1 or 2, wherein the subject exhibits one or more symptoms associated with a neurological disorder.

4. The method of claim 3, wherein the subject exhibits one or more psychological symptoms associated with a neurological disorder.

5. The method of claim 4, wherein the one or more psychological symptoms are selected from: a) emotional reactivity; b) low mood; c) low self-esteem; d) leaden paralysis; e) a long-standing pattern of interpersonal rejection sensitivity that elicits significant social or occupational impairment; f) fatigue; g) malaise; h) hypersomnia; i) anhedonia; j) ruminative thinking; k) irritability; l) low libido; and m) suicidal ideation.

6. The method of any one of claims 3 to 5, wherein the subject exhibits one or more behavioral symptoms associated with a neurological disorder.

7. The method of claim 6, wherein the subject exhibits one or more behavioral symptoms selected from: a) increased sleep; b) hypersomnia; c) binge eating unrelated to inappropriate compensatory behaviors in the context of bulimia nervosa or of binge eating disorder; d) binge eating that occurs in the context of anorexia nervosa only during the course of anorexia nervosa; e) recurrent inappropriate compensatory behaviors; f) recurrent episodes of binge eating; g) excessive food intake; h) feelings of guilt after eating; i) feelings of distress during eating; j) impaired impulse control; k) loss of appetite; l) inadequate food intake; m) extreme fear of weight gain; and n) body image disturbance.

8. The method of any one of claims 3 to 7, wherein the subject exhibits one or more cognitive symptoms associated with a neurological disorder.

9. The method of claim 8, wherein the one or more cognitive symptoms are selected from: a) impaired memory; b) impaired attention; c) impaired concentration; d) impaired language; e) impaired learning; f) impaired perception; g) impaired reasoning; h) executive dysfunction; i) impaired psychomotor; j) impaired processing speed; and k) thought disorder.

10. The method of any one of claims 1 to 9, wherein the subject exhibits one or more symptoms associated with a metabolic disorder.

11. The method of claim 10, wherein the one or more symptoms associated with a metabolic disorder are selected from: a) hypertension; b) hyperglycemia; c) insulin resistance; d) leptin resistance; e) prediabetes; f) hypercholesterolemia; g) hypertriglyceridemia; h) low serum levels of high-density lipoprotein (HDL); i) abdominal obesity; j) hyperuricemia; k) gastrointestinal disturbances; and l) liver dysfunction.

12. The method of any one of claims 1-11, wherein the subject exhibits one or more symptoms associated with an immune disorder.

13. The method of claim 12, wherein the one or more symptoms associated with an immune disorder are selected from: a) joint pain, stiffness, or swelling caused by inflammation; b) recurrent infections; c) gastrointestinal disturbances; d) anemia; e) skin rash; f) cold extremities; g) dry eye; h) fatigue; i) fever; and j) headache.

14. A method of modulating an immune response in a subject having or at risk of having a BIMC disorder or disease, the method comprising administering to the subject a therapeutically effective amount of a TRI.

15. The method of claim 14, wherein modulating an immune response in the subject comprises decreasing a blood level of one or more pro-inflammatory mediators associated with the BIMC disorder or disease in the subject compared to a blood level of the one or more pro-inflammatory mediators in the subject prior to administration of the TRI.

16. The method of claim 15, wherein the one or more pro-inflammatory mediators associated with the BIMC disorder or disease comprise one or more of: TNFa, IFNa, sTNFR2, IL-1b, IL-1RA, IL-6, IL-2R, IL-18, IL-12, CCL2, CRP, and MIF, or any combination thereof.

17. The method of claim 15 or 16, wherein the one or more pro-inflammatory mediators associated with the BIMC disorder or disease is TNFa.

18. The method of any one of claims 15-17, wherein the blood level of the one or more pro-inflammatory mediators associated with the BIMC disorder or disease in the subject is decreased by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more after treatment with the TRI compared to the blood level of the one or more pro-inflammatory mediators in the subject prior to administration of the TRI.

19. The method of any one of claims 14-18, wherein prior to treatment, a patient has been identified as exhibiting an increase in the level of one or more pro-inflammatory mediators associated with the BIMC.

20. The method of any one of claims 14-19, further comprising measuring the level of one or more pro-inflammatory mediators associated with the BIMC disorder or disease prior to, concurrently with, and / or after administration of the TRI.

21. The method of any one of claims 14-20, wherein modulating an immune response in the subject comprises increasing a blood level of one or more anti-inflammatory mediators associated with the BIMC disorder or disease in the subject compared to a blood level of the one or more anti-inflammatory mediators in the subject prior to administration of the TRI.

22. The method of claim 21, wherein the one or more anti-inflammatory mediators associated with the BIMC condition or disease comprise one or more of: IL-10, IL-4, IL-13, TGFp, adiponectin, or any combination thereof.

23. The method of claim 21 or 22, wherein the blood levels of the one or more anti-inflammatory mediators associated with the BIMC condition or disease in the subject are increased by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100%, 120%, 140%, 160%, 180%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000% or more after treatment with the TRI compared to the blood levels of the one or more anti-inflammatory mediators in the subject prior to administration of the TRI.

24. The method of any one of claims 14-23, wherein prior to treatment, the patient has been identified as exhibiting reduced levels of one or more anti-inflammatory mediators associated with the BIMC.

25. The method of any one of claims 14-24, further comprising measuring the levels of one or more anti-inflammatory mediators associated with the BIMC condition or disease prior to, concurrently with, and / or after administration of the TRI.

26. The method of any one of claims 15-25, wherein the blood levels of one or more pro- inflammatory mediators or anti-inflammatory mediators are measured at least 1 hour (hr), 2 hrs, 3 hrs, 3 hrs, 4 hrs, 5 hrs, 6 hrs, 7 hrs, 8 hrs, 9 hrs, 10 hrs, 11 hrs, 12 hrs, 13 hrs, 14 hrs, 15 hrs, 16 hrs, 17 hrs, 18 hrs, 19 hrs, 20 hrs, 21 hrs, 22 hrs, 23 hrs, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or more before and / or after treatment of the subject with the TRI.

27. The method of any one of claims 15-26, wherein the blood levels are whole blood levels, plasma levels, or serum levels.

28. A method of modulating immune cell activity in a subject having or at risk of developing a BIMC condition or disease, the method comprising administering to the subject a therapeutically effective amount of a TRI.

29. A method of treating metabolic dysregulation in a subject having or at risk of developing a BIMC condition or disease, the method comprising administering to the subject a therapeutically effective amount of a TRI.

30. A method of treating or preventing neuroinflammation in the central nervous system of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a TRI.

31. The method of claim 30, wherein the treating or preventing comprises one or more of: a) modulating immune cell activity in the subject; and / or b) reducing one or more symptoms of the BIMC in the subject.

32. The method of claim 30 or 31, wherein the immune cell activity comprises cytokine production, migration, proliferation, recruitment, differentiation, activation, polarization, reactive oxygen species (ROS) production, degranulation, maturation, ADCC, ADCP, antigen presentation, lymph node homing, or efferent lymph.

33. The method of any one of claims 30-32, wherein the neuroinflammation is a result of sterile injury, infection, aging, toxic metabolites, or an autoimmune reaction.

34. The method of any one of claims 30-33, wherein the neuroinflammation is located in the brain of the subject.

35. The method of any one of claims 30-34, wherein the neuroinflammation is located in the spinal cord of the subject.

36. The method of any one of claims 1-35, wherein the TRI is Compound 1: or a pharmaceutically acceptable salt thereof.

37. The method of any one of claims 1-36, wherein the subject has been identified as exhibiting one or more symptoms of the BIMC disorder or disease.

38. The method of any one of claims 1-37, wherein the subject has one or more symptoms of the BIMC disease or disorder secondary to a primary immune disease.

39. The method of any one of claims 1-38, wherein the method comprises identifying the presence of one or more symptoms of the BIMC disorder or disease in the subject.

40. The method of any one of claims 1-39, wherein the subject is refractory to prior treatment of the BIMC disorder or disease with one or more therapeutic agents other than the TRI.

41. The method of any one of claims 1-39, wherein the subject has not received any prior treatment for the BIMC disorder or disease.

42. The method of any one of claims 1-41, wherein the therapeutically effective amount is between 1 mg per day and 30 mg per day.

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