JP2006503905A - Methods and reagents for the treatment of diseases and disorders associated with increased levels of inflammatory cytokines - Google Patents

Abstract

The present invention administers SSRI or an analog or metabolite thereof and optionally a corticosteroid or other compound to a patient diagnosed with or at risk of developing an immunoinflammatory disorder And a method of treating said patient. The invention also features a pharmaceutical composition containing SSRI or an analog or metabolite thereof and a corticosteroid or other compound for the treatment or prevention of an immunoinflammatory disorder.

Description

The present invention relates to the treatment of immunoinflammatory disorders.

  Immunoinflammatory disorders are characterized by inappropriate activation of the body's immune defenses. Rather than targeting infectious invaders, the immune response targets and damages the body's own tissue or transplanted tissue. Tissues targeted by the immune system vary with the disorder. For example, in multiple sclerosis, the immune response is directed to neuronal tissue, while in Crohn's disease the gastrointestinal tract is targeted. Immuno-inflammatory disorders affect millions of individuals, including asthma, allergic intraocular inflammatory disease, arthritis, atopic dermatitis, atopic eczema, diabetes, hemolytic anemia, inflammatory skin disease, inflammation Intestinal or gastrointestinal disorders (eg, Crohn's disease and ulcerative colitis), multiple sclerosis, myasthenia gravis, pruritus / inflammation, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus.

  Current treatment methods for immunoinflammatory disorders typically rely on immunosuppressive agents. The effectiveness of these agents can vary and their use is often accompanied by harmful side effects. Accordingly, there is a need for improved therapeutic agents and methods for the treatment of immunoinflammatory disorders.

SUMMARY OF THE INVENTION In one aspect, the present invention provides a selective serotonin reuptake inhibitor (SSRI) (or an amount sufficient to treat an immunoinflammatory disorder in a patient in need thereof together. Its composition comprising an analog or metabolite thereof) and a corticosteroid. If desired, the composition may comprise one or more additional compounds (eg, glucocorticoid receptor modulators, NSAIDs, COX-2 inhibitors, DMARDs, biologics, xanthines, anticholinergic compounds, beta receptor agonists , Bronchodilators, non-steroidal calcineurin inhibitors, vitamin D analogs, psoralens, retinoids, or 5-aminosalicylic acid). The composition can be formulated for local or systemic administration, for example.

  In another aspect, the invention provides SSRIs, or analogs or metabolites thereof, and corticosteroids at the same time or 14 days from each other in an amount sufficient to reduce secretion or production of inflammatory cytokines in a patient. Characterized in that the method reduces the secretion or production of inflammatory cytokines in said patient by administering to the patient within.

  In a related aspect, the present invention provides SSRI, or an analog thereof, in an amount sufficient to treat a patient diagnosed as having or at risk of developing an immunoinflammatory disorder. Or a method for treating said patient by administering to said patient a metabolite and a corticosteroid simultaneously or within 14 days of each other.

  In any of the above methods, the patient has one or more additional compounds (eg, glucocorticoid receptor modulators, NSAIDs, COX-2 inhibitors, DMARDs, biologics, xanthines, anticholinergic compounds, beta receptor agonists , Bronchodilators, non-steroidal calcineurin inhibitors, vitamin D analogs, prolarenes, retinoids, or 5-aminosalicylic acid).

  If desired, SSRIs and / or corticosteroids can be administered at low or high doses. The agents can desirably be administered within 10 days of each other, more preferably within 5 days of each other, even more preferably within 24 hours of each other, or even simultaneously (ie, together).

  In a related aspect, the present invention provides SSRIs (or their analogs or metabolism) in an amount that is more effective to treat an immunoinflammatory disorder than administration of corticosteroids in the absence of SSRIs. Product) and corticosteroids by simultaneous administration to the patient, characterized by a method of treating an immunoinflammatory disorder in a patient in need thereof.

  In yet another related aspect, the present invention provides SSRI (or in an amount more effective together to treat an immunoinflammatory disorder than administration of SSRI in the absence of corticosteroids. It features a method of treating an immunoinflammatory disorder in a patient in need thereof by simultaneously administering to the patient an analog or metabolite thereof) and a corticosteroid.

  In yet another related aspect, the invention administers corticosteroids to a patient; then immunoinflammatory in a patient in need thereof by administering SSRI (or an analog or metabolite thereof) to the patient. Characterized by a method of treating a disorder; (i) said corticosteroid and SSRI are administered together; and (ii) each amount of corticosteroid and SSRI administered to a patient is cortisate in the absence of SSRI. It is more effective in treating immunoinflammatory disorders compared to administration of costeroids or administration of SSRIs in the absence of corticosteroids.

  The invention also features a pharmaceutical composition in unit dosage form, the composition comprising a corticosteroid; and SSRI or an analog or metabolite thereof, wherein the amount of the corticosteroid and the SSRI is determined by the patient. When administered, it is more effective in treating immunoinflammatory disorders compared to administration of corticosteroids in the absence of SSRI or administration of SSRIs in the absence of corticosteroids.

  The invention also includes (i) a composition comprising SSRI, or an analog or metabolite thereof, and a corticosteroid; and (ii) instructions for administering the composition to a patient diagnosed with an immunoinflammatory disorder. Features a kit that includes a certificate.

  In a related aspect, the present invention administers SSRIs and corticosteroids to patients diagnosed with (i) SSRI (or analogs or metabolites thereof); (ii) corticosteroids; and (iii) immunoinflammatory disorders Features a kit containing instructions for.

  If desired, the corticosteroid can be replaced with a glucocorticoid receptor modulator or other steroid receptor modulator in the methods, compositions and kits of the invention.

  Accordingly, in another aspect, the present invention provides SSRI (or an analog or metabolite thereof) and glucocorticoid in an amount sufficient to treat an immunoinflammatory disorder together in a patient in need thereof. Features a composition comprising a receptor modulator. If desired, the composition can include one or more additional compounds. The composition can be formulated, for example, for local or systemic administration.

  In another aspect, the invention provides that SSRI (or an analog or metabolite thereof) and a glucocorticoid receptor modulator are simultaneously or mutually 14 in an amount sufficient to reduce secretion or production of inflammatory cytokines in a patient. Characterized by a method of reducing the secretion or production of inflammatory cytokines in a patient by administering to the patient within a day.

  In another aspect, the invention provides that SSRI (or an analog or metabolite thereof) and a glucocorticoid receptor modulator are simultaneously or mutually 14 in an amount sufficient to reduce secretion or production of inflammatory cytokines in a patient. Characterized by a method of reducing the secretion or production of inflammatory cytokines in a patient by administering to the patient within a day.

  In a related aspect, the present invention provides SSRI (or an analog thereof) in an amount sufficient to treat a patient diagnosed with or at risk of developing an immunoinflammatory disorder. Or a metabolite) and a glucocorticoid receptor modulator simultaneously or within 14 days of each other, characterized by a method of treating said patient. The drugs are desirably administered within 10 days from each other, more desirably within 5 days from each other, even more desirably within 24 hours from each other, or even simultaneously (or together).

  In a related aspect, the present invention, together, provides SSRI or an analog or metabolism thereof in an amount that is more effective in treating an immunoinflammatory disorder than administration of a glucocorticoid receptor modulator in the absence of SSRI. Features a method of treating an immunoinflammatory disorder in a patient by simultaneously administering the product and the glucocorticoid receptor modulator to the patient in need thereof.

  In yet another related aspect, the present invention, taken together, in an amount that is more effective in treating an immunoinflammatory disorder than administration of SSRI in the absence of a glucocorticoid receptor modulator, A method of treating an immunoinflammatory disorder in a patient by simultaneously administering the analog or metabolite and the glucocorticoid receptor modulator to the patient in need thereof.

  In yet another related aspect, the invention provides for administering the glucocorticoid receptor modulator to a patient in need thereof; then administering SSRI (or an analog or metabolite thereof) to the patient, Characterized in a method of treating an immunoinflammatory disorder in a patient; (i) a glucocorticoid receptor modulator and SSRI are administered simultaneously; (ii) each amount of glucocorticoid receptor modulator and SSRI administered to a patient is SSRI It is more effective in treating immunoinflammatory disorders compared to administration of a glucocorticoid receptor modulator in the absence of, or administration of SSRI in the absence of a glucocorticoid receptor modulator.

  The invention also features a pharmaceutical composition in unit dosage form, said composition comprising a glucocorticoid receptor modulator; and SSRI (or an analog or metabolite thereof), wherein the amount of glucocorticoid receptor modulator and SSRI is In treating an immunoinflammatory disorder when administered to a patient, compared to administration of a glucocorticoid receptor modulator in the absence of SSRI, or administration of SSRI in the absence of a glucocorticoid receptor modulator It is more effective.

  The invention also provides (i) a composition comprising SSRI (or an analog or metabolite thereof) and a glucocorticoid receptor modulator; and (ii) for administering the composition to a patient diagnosed with an immunoinflammatory disorder Features a kit containing instructions.

  In a related aspect, the present invention provides (i) SSRI, or an analog or metabolite thereof; (ii) a glucocorticoid receptor modulator; and (iii) SSRI and glucocorticoid receptor in a patient diagnosed with an immunoinflammatory disorder. Features a kit containing instructions for administering the modulator.

  As described herein, SSRIs in the absence of corticosteroids, or analogs or metabolites thereof, also have anti-inflammatory activity. Accordingly, the present invention provides for the secretion of one or more inflammatory cytokines in said patient by administering SSRI to said patient in an amount sufficient to inhibit the secretion of inflammatory cytokines in a patient in need thereof. The gist is also a method of suppressing the above.

  In a related aspect, the present invention provides the patient by administering SSRI (or an analog or metabolite thereof) to the patient in an amount and duration sufficient to treat the patient determined to be an immunoinflammatory disorder. Characterized by a method of treating.

  The invention also features a kit comprising (i) SSRI (or an analog or metabolite thereof) and (ii) instructions for administering SSRI to a patient diagnosed with an immunoinflammatory disorder.

  In another aspect, the present invention relates to SSRIs (or analogs or metabolites thereof) and xanthines, anticholinergic compounds, beta receptor agonists, bronchodilators, nonsteroidal calcineurin inhibitors, vitamin D analogs, psoalene A pharmaceutical composition comprising a second compound selected from the group consisting of: a retinoid, and 5-aminosalicylic acid.

  The invention also includes (a) contacting a cell with SSRI (or an analog or metabolite thereof) and a candidate compound in vitro; then (b) a combination of RRSI and the candidate compound is contacted with SSRI, To determine whether cytokine levels are reduced in blood cells that are stimulated to secrete cytokines against cells that are not in contact with cells or cells that are in contact with candidate compounds but are not in contact with SSRIs Characterized by a method of identifying a combination of compounds useful for inhibiting the secretion of inflammatory cytokines in patients in need thereof, wherein a reduction in cytokine levels treats patients in need of such treatment The combination is identified as a useful combination to do so.

  Compounds useful in the present invention include isomers such as diastereomers and enantiomers, salts, esters, solvates, and polymorphs of the compounds described herein and racemic mixtures and pure isomers. , Including any of its pharmaceutically acceptable forms as described herein.

  "SSRI" means (i) inhibits serotonin uptake by neurons of the central nervous system, (ii) has an inhibition constant (Ki) of 10 nM or less, and (iii) is superior to norepinephrine greater than 100 By any member of the class of compounds having selectivity for serotonin (ie the ratio of Ki (norepinephrine) to Ki (serotonin)). Typically, SSRI is administered at a dose greater than 10 mg per day when used as an antidepressant. Exemplary SSRIs for use with the present invention are described herein.

  “Corticosteroid” means any naturally occurring or synthetic compound characterized by a hydrogenated clopentanoperhydrophenanthrene ring system and having immunosuppressive and / or anti-inflammatory activity. Naturally occurring corticosteroids are generally produced by the adrenal cortex. Synthetic corticosteroids can be halogenated. Exemplary corticosteroids are provided herein.

  “Nonsteroidal immunophilin-dependent immunosuppressant” or “NsIDI” means any nonsteroidal agent that reduces the production or secretion of inflammatory cytokines, binds to immunophilin, and causes down-regulation of inflammatory responses To do. NsIDI is a calcineurin inhibitor such as cyclosporine, tacrolimus, ascomycin, pimecrolimus, and other agents that inhibit calcineurin phosphatase activity (peptides, peptide fragments, chemically modified peptides, or peptide mimetics) including. NsIDI also includes rapamycin (sirolimus) and everolimus that bind to the FK506-binding protein, FKBP-12, and block antigen-induced proliferation of white blood cells and cytokine secretion.

  A “low dose” is at least 5% lower than the lowest standard recommended dose of a particular compound formulated for a given route of administration for the treatment of any human disease or disorder (eg, at least 10% 20%, 50%, 80%, 90%, or even 95%). For example, a low dose of corticosteroid formulated for administration by inhalation will differ from a low dose of corticosteroid formulated for oral administration.

  “High dose” means at least 5% (eg, at least 10%, 20%, 50%, 100%, 200% or higher than the highest standard recommended dose of a particular compound for the treatment of any human disease or disorder (Even 300%) means more.

  “Medium dose” means a dose between a low dose and a high dose.

  A “dose equivalent to prednisolone dose” refers to a corticosteroid that, in combination with a given dose of SSRI, or an analog or metabolite thereof, produces the same anti-inflammatory effect in the patient as the dose of prednisolone combined with that dose. Means dose.

  “Treating” means administering or prescribing a pharmaceutical composition for the treatment or prevention of an immunoinflammatory disease.

  “Patient” means any animal (eg, human). Other animals that can be treated using the methods, compositions, and kits of the present invention include horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, Includes pigs, fish and birds. In one embodiment of the invention, the patient subjected to the treatment described herein is clinically depressed, anxious or panic disorder, obstructive / forced disorder, alcoholism, dietary disorder, attention-deficit disorder, borderline Has no personal disability, sleep disorders, headache, premenstrual syndrome, irregular heartbeat, schizophrenia, Turret syndrome or phobia.

  By “sufficient amount” is meant the amount of compound in the combination of the present invention necessary to treat or prevent immunoinflammatory diseases in a clinically relevant manner. Sufficient amounts of the active compounds used to practice the present invention for the therapeutic treatment of diseases caused by or contributing to immune inflammatory diseases will depend on the method of administration, the age, weight of the patient, and general Changes depending on health. Ultimately, the prescriber will decide the appropriate amount and dosage method. In addition, the effective amount is determined by a regulatory authority (such as US Food and Drug Administration) and the present invention is safe and effective in treating patients with immune inflammatory disease superior to each approved agent alone. The amount of the compound in the combination.

  “More effective” means that the treatment is more efficient than another treatment compared to it, or less toxic, safer, more convenient, or less expensive . Efficiency can be measured by a skilled practitioner using any standard method appropriate for a given symptom.

  The term “immunoinflammatory disorder” includes a variety of diseases including autoimmune diseases, proliferative skin diseases and inflammatory skin diseases. Immunoinflammatory disorders result in the destruction of healthy tissue by the inflammatory process, dysregulation of the immune system, and unwanted proliferation of cells. Examples of immune inflammatory disorders are acne vulgaris; acute respiratory distress syndrome; Addison's disease; allergic rhinitis; allergic intraocular inflammatory disease, ANCA-associated small vessel vasculitis; ankylosing myelitis; arthritis, asthma; Sclerosis; atopic dermatitis; autoimmune hemolytic anemia; autoimmune hepatitis; Behcet's disease; bell palsy; bullous pemphigoid; cerebral ischemia; chronic obstructive pulmonary disease; Disease; Cushing's syndrome; dermatomyositis; diabetes mellitus; discoid lupus erythematosus; eosinophilic fasciitis; erythema nodosum; deprived dermatitis; fibromyalgia; focal glomerulosclerosis; giant cell arthritis; Arthritis; Graft-versus-host disease; Hand eczema; Hönoho-Schönlein purpura; Genital herpes; hirsutism; Idiopathic serato scleritis; Idiopathic pulmonary fibrosis; Or Intestinal disorders, inflammatory dermatoses; lichen planus; erythematous nephritis; lymphoma bronchitis; varicella blisters; multiple sclerosis; myasthenia gravis; myositis; osteoarthritis; pancreatitis; Polyarteritis, rheumatic polymyalgia; scrotal pruritus; psoriatic pruritus / inflammation; psoriatic arthritis; rheumatoid arthritis; relapsing polychondritis; rosacea caused by sarcoidosis; caused by scleroderma Rosacea caused by sweet syndrome; rosacea caused by systemic lupus erythematosus; rosacea caused by urticaria; rosacea caused by shingles-related pain; sarcoidosis; scleroderma; Glomerulosclerosis; septic shock syndrome; shoulder tendonitis or bursitis; Sjogren's syndrome; Still's disease; Sweet's disease; systemic lupus erythematosus; systemic sclerosis; Takayasu's arteritis; a and Wegener's granulomatosis; temporary arteritis; toxic epidermal necrolysis; tuberculosis; type 1 diabetes; ulcerative colitis; uveitis; vasculitis.

  “Non-dermal inflammatory disorders” include, for example, rheumatoid arthritis, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease.

  “Skin inflammatory disorders” or “inflammatory skin diseases” include, for example, psoriasis, acute febrile dermatoses, eczema (eg, sebum-deficient eczema, allergic eczema, vesicular palmoplantar eczema), zone balanitis, Glans foreskinitis, Behcet's disease, efferent ring erythema, dyschromatogenic fixed erythema, erythema multiforme, ring granulomas, luster lichen, lichen planus, sclerosing atrophic lichen, chronic simple lichen, spiny Includes lichen, monetary dermatitis, pyoderma gangrenosum, sarcoidosis, subhorny pustular disease, urticaria, and transient thyrolysis dermatosis.

  By “proliferative skin disease” is meant a benign or malignant disease characterized by accelerated cell division in the epidermis or dermis. Examples of proliferative dermatoses are psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell carcinomas of the skin, foliate ichthyosis, epidermal exfoliating keratinous growth Premalignant keratosis, acne, and seborrheic dermatitis.

  As recognized by those skilled in the art, a particular disease, disorder, or condition can be characterized as both proliferative skin disease and inflammatory skin disease. An example of such a disease is psoriasis.

  “Sustained release” or “controlled release” means that a therapeutically beneficial blood level of an ingredient (but less than a toxic level) is maintained over an extended period of time, for example in the range of about 12 to about 24 hours, and thus Means, for example, that the therapeutically active ingredient is released from the formulation at a controlled rate to provide a 12 or 24 hour dosage form.

  In the general description of the compounds of the invention, the number of a particular type of atom in a substituent is generally given as a range. For example, an alkyl group containing 1 to 7 carbon atoms, or C1-7 alkyl. References to such ranges are intended to include special references to groups having each of the integers of atoms within a particular range. For example, an alkyl group of 1 to 7 carbon atoms includes each of C1, C2, C3, C4, C5, C6 and C7. C 1-7 heteroalkyl includes, for example, 1 to 7 carbon atoms in addition to one or more heteroatoms. Other numbers of atoms and other types of atoms can be indicated as well.

  “Acyl” means that R is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl. Means a chemical moiety having the formula RC (O)-, selected from

  “Alkoxy” means R is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-7 heteroalkyl Means a chemical substituent of the formula -OR selected from

  “Aryloxy” means a chemical substituent of the formula —OR where R is a C 6-12 aryl group.

  “C6-12 aryl” means an aromatic group having a ring system consisting of carbon atoms with conjugated π electrons (eg, phenyl). Aryl has 6 to 12 carbon atoms. Aryl groups may include monocyclic, bicyclic, and tricyclic rings, each ring desirably having 5 or 6 members. The aryl group may be substituted or unsubstituted. Exemplary substituents are alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, fluoroalkyl, carboxyl, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino, substituted amino, and Contains quaternary amino groups.

  “Amido” means a chemical substituent of the formula —NRR ′ where the nitrogen atom is part of the amide bond (eg, —C (O) —NRR ′) and R and R ′ are each independently Selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, and C1-7 heteroalkyl, as defined above. Or -NRR forms a C2-6 heterocyclyl ring as defined above, but contains, among other things, at least one nitrogen such as piperidino, morpholino, and azabicyclo.

  “Halide” or “halo” means bromine, chlorine, iodine or fluorine.

  The term “pharmaceutically acceptable salt” is suitable for use in contact with human and lower animal tissues without unnecessary toxicity, irritation, allergic response, etc., within sound medical judgment, Represents a suitable salt for a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Said salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base function with a suitable organic acid. Typical salts are acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulphate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate , Fumarate, glucoheptonate, glycerophosphate, hemisulphate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, isethionate, lactobionate, lactate, laurate, lauryl sulfate, malate, Maleate, Malonate, Mesylate, Methanesulfonate, 2-Naphthalenesulfonate, Nico Nate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate Contains salt. Exemplary alkali or alkaline earth metal salts include, but are not limited to, sodium, lithium, potassium, calcium, magnesium, etc., and non-toxic ammonia, quaternary ammonium, and amine cations. Including methylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.

  Compounds useful in the present invention include diastereomers and enantiomers, salts, esters, amides, thioesters, solvates, and polymorphs thereof, and racemic mixtures and pure isomers of the compounds described herein. Any pharmaceutically acceptable form thereof, including those described herein, including any such isomers. By way of example, “paroxetine” means the free base, as well as any pharmaceutically acceptable salt thereof (eg, paroxetine maleic acid, paroxetine hydrochloride hemihydrate, and paroxetine mesylate).

  Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.

DETAILED DESCRIPTION The present invention is a method, composition for the administration of an effective amount of SSRI or an analog or metabolite thereof, alone or in combination with a corticosteroid or other compound, for treating an immunoinflammatory disorder. Features objects and kits.

  In one embodiment of the invention, treatment of an immunoinflammatory disorder is performed by administering SSRI (or an analog thereof) and a corticosteroid to a patient in need of such treatment.

  The invention is described in more detail below.

Selective Serotonin Reuptake Inhibitors The methods, compositions and kits of the present invention use SSRIs, structural or functional analogs thereof. Suitable SSRIs include cerixamine (eg, celiclamine hydrochloride); citalopram (eg, citalopram hydrobromic acid); cloboxamine; cyanodothiepin; dapoxetine; escitalopram (escitalopram oxalate); ); Fluvoxamine (eg, fluvoxamine maleic acid); ifoxetine; indalpine (eg, indalpine hydrochloride); indeloxazine (eg, indeloxazine hydrochloride); ritoxetine; milnacipran (eg, minnacipran hydrochloride); paroxetine (eg, Paroxetine hydrochloride hemihydrate; paroxetine maleic acid; paroxetine methylate); sertraline (eg, sertraline hydrochloride); tametraline hydrochloride; Qualine; and zimeldine (eg, zimeldine hydrochloride).

Cericlamin Celiclamin has the following structure:

（式中、R1はC1-C4アルキルであって、R2はHまたはC1-4アルキルであり、R3はH、C1-4アルキル、C2-4アルケニル、フェニルアルキル、または3〜6の環炭素原子を持つシクロアルキルアルキル、アルカノイル、フェニルアルカノイル、または3〜6の環炭素原子を有するシクロアルキルカルボニルであり、あるいはR2およびR3は、それらに結合している窒素原子と一緒になって、窒素原子に直接的に結合していない第2のヘテロ原子として、酸素、硫黄または窒素を有することができる5〜7の鎖リンクで飽和したヘテロサイクルを形成し、後者の窒素へテロ原子は、恐らくは、C2-4アルキルを担う）
を有するもの、ならびにその薬学的に許容される塩である。 The structural analog of cericlamin is the formula:

Wherein R1 is C1-C4 alkyl, R2 is H or C1-4 alkyl, R3 is H, C1-4 alkyl, C2-4 alkenyl, phenylalkyl, or 3-6 ring carbon atoms Are cycloalkylalkyl, alkanoyl, phenylalkanoyl, or cycloalkylcarbonyl having 3 to 6 ring carbon atoms, or R2 and R3 together with the nitrogen atom bonded to them, Forming a saturated heterocycle with 5-7 chain links that can have oxygen, sulfur or nitrogen as the second heteroatom that is not directly bonded, the latter nitrogen heteroatom is probably C2 -4 bears alkyl)
As well as pharmaceutically acceptable salts thereof.

  Exemplary cericlamamine structural analogs are 2-methyl-2-amino-3- (3,4-dichlorophenyl) -propanol, 2-pentyl-2-amino-3- (3,4-dichlorophenyl) -propanol, 2-methyl- 2-methylamino-3- (3,4-dichlorophenyl) -propanol, 2-methyl-2-dimethylamino-3- (3,4-dichlorophenyl) -propanol, and any pharmaceutically acceptable salt thereof It is.

Citalopram Citalopram has the following structure.

（式中、R1およびR2の各々は、独立してブロモ、クロロ、フルオロ、トリフルオロメチル、シアノおよびR-CO-からなる群より選択され、RはC1-4アルキルである）
を有するもの、ならびにその薬学的に許容される塩である。 The structural analog of citalopram is the formula:

Wherein each of R 1 and R 2 is independently selected from the group consisting of bromo, chloro, fluoro, trifluoromethyl, cyano and R—CO—, wherein R is C 1-4 alkyl.
As well as pharmaceutically acceptable salts thereof.

  An exemplary citalopram structural analog (which is therefore an SSRI structural analog according to the present invention) is 1- (4′-fluorophenyl) -1- (3-dimethylaminopropyl) -5-bromophthalane; 1- (4′-cyclophenyl) ) -1- (3-Dimethylaminopropyl) -5-chlorophthalane; 1- (4′-bromophenyl) -1- (3-dimethylaminopropyl) -5-chlorophthalane; 1- (4′-fluorophenyl)- 1- (3-dimethylaminopropyl) -5-chlorophthalane; 1- (4′-chlorophenyl) -1- (3-dimethylaminopropyl) -5-trifluoromethyl-phthalane; 1- (4′-bromophenyl) -1- (3-dimethylaminopropyl) -5-trifluoromethyl-phthalane; 1- (4′-fluorophenyl) -1- (3-dimethylaminopropyl) -5-trifluoromethyl-phthalane; 4'-Fluorophenyl) -1- (3-dimethylaminopropyl) -5-fluoroph 1- (4'-chlorophenyl) -1- (3-dimethylaminopropyl) -5-fluorophthalane; 1- (4'-chlorophenyl) -1- (3-dimethylaminopropyl) -5-phthalane 1- (4′-fluorophenyl) -1- (3-dimethylaminopropyl) -5-phthalancarbonitrile; 1- (4′-cyanophenyl) -1- (3-dimethylaminopropyl)- 5-phthalanecarbonitrile; 1- (4′-cyanophenyl) -1- (3-dimethylaminopropyl) -5-chlorophthalane; 1- (4′-cyanophenyl) -1- (3-dimethylaminopropyl) -5-trifluoromethylphthalane; 1- (4'-fluorophenyl) -1- (3-dimethylaminopropyl) -5-phthalanecarbonitrile; 1- (4'-chlorophenyl) -1- (3- Dimethylaminopropyl) -5-ionylphthalane; 1- (4- (chlorophenyl) -1- (3-dimethylaminopropyl) -5-pro Pionylphthalan; and any pharmaceutically acceptable salt thereof.

Cloboxamine: Cloboxamine has the following structure:

（式中、Halはクロロ、ブロモ、またはフルオロ基であり、Rはシアノ、メトキシ、エトキシ、メトキシメチル、エトキシエチル、メトキシエトキシまたはシアノメチル基である）
を有するもの、およびその薬学的に許容される塩である。 The structural analog of cloboxamine is of the formula:

Wherein Hal is a chloro, bromo or fluoro group and R is a cyano, methoxy, ethoxy, methoxymethyl, ethoxyethyl, methoxyethoxy or cyanomethyl group.
And pharmaceutically acceptable salts thereof.

  Exemplary cloboxamine structural analogs are 4'-chloro-5-ethoxyvalerophenone O- (2-aminoethyl) oxime; 4'-chloro-5- (2-methoxyethoxy) valerophenone O- (2-aminoethyl) oxime; 4'-chloro-6-methoxycaprofenone O- (2-aminoethyl) oxime; 4'-chloro-6-ethoxycaprofenone O- (2-aminoethyl) oxime; 4'-bromo-5- ( 2-methoxyethoxy) valerophenone O- (2-aminoethyl) oxime; 4'-bromo-5-methoxyvalerophenone O- (2-aminoethyl) oxime; 4'-chloro-6-cyanocaprofenone O- ( 2-aminoethyl) oxime; 4′-chloro-5-cyanovalerophenone O- (2-aminoethyl) oxime; 4′-bromo-5-cyanovalerophenone O- (2-aminoethyl) oxime; A pharmaceutically acceptable salt thereof.

Femoxetine Femoxetine has the following structural formula:

（式中、R1はC1-4アルキルまたはC2-4アルキニル基、またはC1-4アルキル、C1-4アルキルチオ、C1-4アルコキシ、ブロモ、クロロ、フルオロ、ニトロ、アシルアミノ、メチルスルホニル、メチレンジオキシ、またはテトラヒドロナフチルによって置換されていてもよいフェニル基を表し、R2はC1-4アルキルまたはC2-4アルキニル基を表し、およびR3は水素、C1-4アルキル、C1-4アルコキシ、トリフルオロアルキル、ヒドロキシ、ブロモ、クロロ、フルオロ、メチルチオまたはアラルキルオキシを表す）
を有するものである。 The structural analog of femoxetine has the formula:

(Wherein R1 is a C1-4 alkyl or C2-4 alkynyl group, or C1-4 alkyl, C1-4 alkylthio, C1-4 alkoxy, bromo, chloro, fluoro, nitro, acylamino, methylsulfonyl, methylenedioxy, Or a phenyl group optionally substituted by tetrahydronaphthyl, R2 represents a C1-4 alkyl or C2-4 alkynyl group, and R3 represents hydrogen, C1-4 alkyl, C1-4 alkoxy, trifluoroalkyl, hydroxy Represents bromo, chloro, fluoro, methylthio or aralkyloxy)
It is what has.

  Exemplary femoxetine structural analogs are disclosed in Examples 7-67 of U.S. Patent No. 3,912,743, incorporated herein by reference.

Fluoxetine Fluoxetine has the following structure.

（式中、各R1は独立して水素またはメチルであり；Rはナフチルまたは

（R2およびR3の各々は独立してブロモ、クロロ、フルオロ、トリフルオロメチル、C1-4アルキル、C1-3アルコキシまたはC3-4アルケニルであり；nおよびmの各々は独立して0、1または2である）である）
を有する化合物ならびにその薬学的に許容される塩である。Rがナフチルである場合、それはα-ナフチルまたはβ-ナフチルいずれかであり得る。 The structural analog of fluoxetine is the formula:

Wherein each R1 is independently hydrogen or methyl; R is naphthyl or

(R2 and R3 are each independently bromo, chloro, fluoro, trifluoromethyl, C1-4 alkyl, C1-3 alkoxy or C3-4 alkenyl; each of n and m is independently 0, 1 or 2))
As well as pharmaceutically acceptable salts thereof. When R is naphthyl, it can be either α-naphthyl or β-naphthyl.

  Exemplary fluoxetine structural analogs are 3- (p-isopropoxyphenoxy) -3-phenylpropylamine methanesulfonate, N, N-dimethyl 3- (3 ′, 4′-dimethoxyphenoxy) -3-phenylpropylamine p-hydroxybenzoate N, N-dimethyl 3- (α-naphthoxy) -3-phenylpropylamine bromide, N, N-dimethyl 3- (β-naphthoxy) -3-phenyl-1-methylpropylamine iodide, 3- (2 ′ -Methyl-4 ', 5'-dichlorophenoxy) -3-phenylpropylamine nitrate, 3- (pt-butylphenoxy) -3-phenylpropylamine glutarate, N-methyl 3- (2'-chloro-p-tolyloxy) ) -3-Phenyl-1-methylpropylamine lactate, 3- (2 ', 4'-dichlorophenoxy) -3-phenyl-2-methylpropylamine citrate, N, N-dimethyl 3- (m- Anisyloxy) -3-phenyl-1-methylpropyla Numarate, N-methyl 3- (p-tolyloxy) -3-phenylpropylamine sulfate, N, N-dimethyl 3- (2 ', 4'-difluorophenoxy) -3-phenylpropylamine 2,4-dinitrobenzoic acid Acid salt, 3- (o-ethylphenoxy) -3-phenylpropylamine dihydrogen phosphate, N-methyl 3- (2'-chloro-4'-isopropylphenoxy) -3-phenyl-2-methylpropylamine malein Acid salt, N, N-dimethyl 3- (2′-alkyl-4′-fluorophenoxy) -3-phenyl-propylamine succinate, N, N-dimethyl 3- (o-isopropoxyphenoxy) -3- Phenyl-propylamine phenylacetate, N, N-dimethyl 3- (o-bromophenoxy) -3-phenyl-propylamine β-phenylpropionate, N-methyl 3- (p-iodophenoxy) -3-phenyl -Propylamine propiolate and N-methyl 3- (3-n-propylphenol Noxy) -3-phenyl-propylamine decanoate.

Fluvoxamine Fluvoxamine has the following structure:

（式中、Rはシアノ、シアノメチル、メトキシメチルまたはエトキシメチルである）
を有するもの、ならびにその薬学的に許容される塩である。 The structural analog of fluvoxamine is the formula:

(Wherein R is cyano, cyanomethyl, methoxymethyl or ethoxymethyl)
As well as pharmaceutically acceptable salts thereof.

Indal pins Indal pins have the following structure.

（式中、R1は水素原子、C1-C4アルキル基、またはそのアルキルが1または2個の炭素原子を有するアラルキル基であり、R2は水素、C1-4アルキル、C1-4アルコキシもしくはC1-4アルキルチオ、クロロ、ブロモ、フルオロ、トリフルオロメチル、ニトロ、ヒドロキシまたはアミノであり、後者は1または2個のC1-4アルキル基、アシル基またはC1-4アルキルスルホニル基で置換されていてもよく；Aは-COまたは-CH2-基を表し；nは0、1または2である）
を有するもの、またはその薬学的に許容される塩である。 The structural analog of indal pins is the formula:

Wherein R1 is a hydrogen atom, a C1-C4 alkyl group, or an aralkyl group in which the alkyl has 1 or 2 carbon atoms, and R2 is hydrogen, C1-4 alkyl, C1-4 alkoxy or C1-4 Alkylthio, chloro, bromo, fluoro, trifluoromethyl, nitro, hydroxy or amino, the latter optionally substituted by 1 or 2 C1-4 alkyl groups, acyl groups or C1-4 alkylsulfonyl groups; A represents -CO or -CH2- group; n is 0, 1 or 2)
Or a pharmaceutically acceptable salt thereof.

  Exemplary indulpine structural analogs are indolyl-3 (piperidyl-4 methyl) ketone; (methoxy-5-indolyl-3) (piperidyl-4 methyl) ketone; (chloro-5-indolyl-3) (piperidyl-4 methyl) (Indolyl-3) -1 (piperidyl-4) -3 propanone, indolyl-3 piperidyl-4 ketone; (methyl-1 indolyl-3) (piperidyl-4 methyl) ketone, (benzyl-1 indolyl-3) (Piperidyl-4methyl) ketone; [(methoxy-5indolyl-3) -2ethyl] -piperidine, [(methyl-1indolyl-3) -2ethyl] -4-piperidine; [(indolyl-3) -2 (Indolyl-3methyl) -4piperidine, [(Chloro-5indolyl-3) -2ethyl] -4piperidine; [(Indolyl-b3) -3propyl] -4piperidine; [( Benzyl-1 indolyl-3) -2 ethyl] -4 Perijin; and its one of pharmaceutically acceptable salts.

Indeloxazine Indeloxazine has the following structural formula.

（式中、R1およびR3は、各々、水素、C1-4アルキル、またはフェニルを表し；R2は水素、C1-4アルキル、C4-7シクロアルキル、フェニルまたはベンジルを表し；点線の一つは単結合を意味し、他は二重結合、またはその互変異性体混合物を意味する）
を有するもの、およびその薬学的に許容される塩である。 The structural analog of indeloxazine has the formula:

Wherein R 1 and R 3 each represent hydrogen, C 1-4 alkyl, or phenyl; R 2 represents hydrogen, C 1-4 alkyl, C 4-7 cycloalkyl, phenyl or benzyl; one of the dotted lines is a single Means a bond, the other means a double bond, or a mixture of tautomers thereof)
And pharmaceutically acceptable salts thereof.

  Exemplary indeloxazine structural analogs are 2- (7-indenyloxymethyl) -4-isopropylmorpholine; 4-butyl-2- (7-indenyloxymethyl) morpholine; 2- (7-indenyloxymethyl) ) -4-methylmorpholine; 4-ethyl-2- (7-indenyloxymethyl) morpholine, 2- (7-indenyloxymethyl) -morpholine; 2- (7-indenyloxymethyl) -4-propyl Morpholine; 4-cyclohexyl-2- (7-indenyloxymethyl) morpholine; 4-benzyl-2- (7-indenyloxymethyl) -morpholine; 2- (7-indenyloxymethyl) -4-phenylmorpholine 2- (4-indenyloxymethyl) morpholine; 2- (3-methyl-7-indenyloxymethyl) -morpholine; 4-isopropyl-2- (3-methyl-7-indenyloxymethyl) morpholine; 4-Isopropyl-2- (3-methyl -4-indenyloxymethyl) morpholine; 4-isopropyl-2- (3-methyl-5-indenyloxymethyl) morpholine; 4-isopropyl-2- (1-methyl-3-phenyl-6-indenyloxy) Methyl) morpholine; 2- (5-indenyloxymethyl) -4-isopropyl-morpholine, 2- (6-indenyloxymethyl) -4-isopropylmorpholine; and 4-isopropyl-2- (3-phenyl-6) -Indenyloxymethyl) morpholine; as well as any pharmaceutically acceptable salt thereof.

Milnacipram Milnasipram has the following structure.

（式中、各Rは、独立して、水素、ブロモ、クロロ、フルオロ、C1-4アルキル、C1-4アルコキシ、ヒドロキシ、ニトロまたはアミノを表し；R1およびR2の各々は、独立して、水素、C1-4アルキル、好ましくはパラ位において、ブロモ、クロロまたはフルオロによって置換されていてもよいC6-12アリールもしくはC7-14アルキルアリールを表すか、あるいはR1およびR2は隣接する窒素原子と一緒になって5または6員を有する複素環を形成し；R3およびR4は水素またはC1-4アルキル基を表すか、あるいはR3およびR4は隣接する窒素原子と一緒になって、窒素、硫黄および酸素から選択されるさらなるヘテロ原子を含んでもよい、5または6員を有する複素環を形成する）
を有するもの、ならびにその薬学的に許容される塩である。 The structural analog of milnacipram is the formula:

Wherein each R independently represents hydrogen, bromo, chloro, fluoro, C1-4 alkyl, C1-4 alkoxy, hydroxy, nitro or amino; each of R1 and R2 is independently hydrogen , C1-4 alkyl, preferably C6-12 aryl or C7-14 alkylaryl optionally substituted by bromo, chloro or fluoro in the para position, or R1 and R2 together with the adjacent nitrogen atom To form a 5- or 6-membered heterocycle; R3 and R4 represent hydrogen or a C1-4 alkyl group, or R3 and R4 together with the adjacent nitrogen atom form nitrogen, sulfur and oxygen Forming a 5- or 6-membered heterocycle, which may contain additional heteroatoms selected)
As well as pharmaceutically acceptable salts thereof.

  Exemplary milnacipram structural analogs are 1-phenyl 1-aminocarbonyl 2-dimethylaminomethyl cyclopropane; 1-phenyl 1-dimethylaminocarbonyl 2-dimethylaminomethyl cyclopropane; 1-phenyl 1-ethylaminocarbonyl 2-dimethylamino 1-phenyl 1-diethylaminocarbonyl 2-aminomethyl cyclopropane; 1-phenyl 2-dimethylaminomethyl N- (4′-chlorophenyl) cyclopropanecarboxamide; 1-phenyl 2-dimethylaminomethyl N- ( 4′-chlorobenzyl) cyclopropanecarboxamide; 1-phenyl-2-dimethylaminomethyl N- (2-phenylethyl) cyclopropanecarboxyamide; (3,4-dichloro-1-phenyl) 2-dimethylaminomethyl N, N-dimethylcyclopropanecarboxamide; 1-phenyl 1-pyrrolidino Carbonyl 2-morpholinomethylcyclopropane; 1-p-chlorophenyl 1-aminocarbonyl 2-aminomethylcyclopropane; 1-orthochlorophenyl 1-aminocarbonyl 2-dimethylaminomethylcyclopropane; 1-p-hydroxyphenyl 1-aminocarbonyl 1-p-nitrophenyl 1-dimethylaminocarbonyl 2-dimethylaminomethylcyclopropane; 1-p-aminophenyl 1-dimethylaminocarbonyl 2-dimethylaminomethylcyclopropane; 1-p- Tolyl 1-methylaminocarbonyl 2-dimethylaminomethylcyclopropane; 1-p-methoxyphenyl 1-aminomethylcarbonyl 2-aminomethylcyclopropane; and any pharmaceutically acceptable salt thereof.

Paroxetine Paroxetine has the following structure:

（式中、R1は水素またはC1-4アルキル基を表し、フッ素原子は利用可能な位置のいずれにあってもよい）
を有するもの、およびその薬学的に許容される塩である。 The structural analog of paroxetine is the formula:

(Wherein R1 represents hydrogen or a C1-4 alkyl group, and the fluorine atom may be in any available position)
And pharmaceutically acceptable salts thereof.

Sertraline Sertraline has the following structure.

（式中、R1は水素およびC1-4アルキルからなる群より選択され；R2はC1-4アルキルであり；XおよびYは、各々、水素、フルオロ、クロロ、ブロモ、トリフルオロメチル、C1-3アルコキシ、およびシアノからなる群より選択され；およびWは水素、フルオロ、クロロ、ブロモ、トリフルオロメチルおよびC1-3アルコキシからなる群より選択される）
を有するものである。好ましいセルトラリンアナログはシス-異性体立体配座である。用語「シス-異性体」はシクロヘキセン環上のNR1R2およびフェニル部分の相対的向きをいう（すなわち、それらは環の同一側に共に向いている）。双方の1-および4-炭素は非対称的にに置換されているので、各シス-化合物はシス-（1R）およびシス-（1S）エナンチオマーと呼ばれる（1-炭素に関して）2つの光学的に活性なエナンチオマーを有する。 The structural analog of sertraline is the formula:

Wherein R 1 is selected from the group consisting of hydrogen and C 1-4 alkyl; R 2 is C 1-4 alkyl; X and Y are each hydrogen, fluoro, chloro, bromo, trifluoromethyl, C 1-3 Selected from the group consisting of alkoxy and cyano; and W is selected from the group consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl and C1-3 alkoxy)
It is what has. A preferred sertraline analog is in the cis-isomer conformation. The term “cis-isomer” refers to the relative orientation of the NR1R2 and phenyl moieties on the cyclohexene ring (ie, they are facing together on the same side of the ring). Since both 1- and 4-carbons are asymmetrically substituted, each cis-compound is called two cis- (1R) and cis- (1S) enantiomers (relative to 1-carbon) The enantiomers.

  Particularly useful are the following compounds, either in the (1S) -enantiomer or in the (1S) (1R) racemic form, and pharmaceutically acceptable salts thereof. Cis-N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine; cis-N-methyl-4- (4-bromophenyl) -1,2, 3,4-tetrahydro-1-naphthaleneamine; cis-N-methyl-4- (4-chlorophenyl) -1,2,3,4-tetrahydro-1-naphthaleneamine; cis-N-methyl-4- (3 -Trifluoromethyl-phenyl) -1,2,3,4-tetrahydro-1-naphthalenamine; cis-N-methyl-4- (3-trifluoromethyl-4-chlorophenyl) -1,2,3,4 -Tetrahydro-1-naphthaleneamine; cis-N, N-dimethyl-4- (4-chlorophenyl) -1,2,3,4-tetrahydro-1-naphthaleneamine; cis-N, N-dimethyl-4- ( 3-trifluoromethyl-phenyl) -1,2,3,4-tetrahydro-1-naphthalenamine; and cis-N-methyl-4- (4-chlorophenyl) -7-chloro-1,2,3,4 -Tetrahydro-1-naphthalenamine. Also of interest is the (1R) -enantiomer of cis-N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine.

Dimerzine Dimerzine has the following structure.

（式中、ピリジン核は隣接する炭素原子に対してオルト位、メタ位またはパラ位に結合しており、R1はH、クロロ、フルオロおよびブロモからなる群より選択される）
を有する化合物およびその薬学的に許容される塩である。 Zimerzine's structural analog is the formula:

(Wherein the pyridine nucleus is bonded to the ortho, meta or para position relative to the adjacent carbon atom, and R1 is selected from the group consisting of H, chloro, fluoro and bromo)
And pharmaceutically acceptable salts thereof.

  Exemplary dimerzin analogs are (e)-and (z) -3- (4′-bromophenyl-3- (2 ″ -pyridyl) -dimethylallylamine; 3- (4′-bromophenyl) -3- ( 3 "-pyridyl) -dimethylallylamine; 3- (4'-bromophenyl) -3- (4" -pyridyl) -dimethylallylamine; and any pharmaceutically acceptable salt thereof.

  Any structural analog of SSRI is considered herein to be an SSRI analog and can therefore be used in any of the methods, compositions and kits of the invention.

Metabolites Any of the SSRI pharmacologically active metabolites can also be used in the methods, compositions and kits of the present invention. Exemplary metabolites are didesmethyl citalopram, desmethyl citalopram, desmethyl sertraline and norfluoxetine.

analog
Functional analogues of SSRI can also be used in the methods, compositions and kits of the present invention. An exemplary SSRI functional analog is provided below. One class of SSRI analogs are SNRIs (selective serotonin norepinephrine reuptake inhibitors), which include venlafaxine and duloxetine.

Venlafaxine Venlafaxine has the following structure.

（式中、Aは式：

（式中、点線は任意の不飽和を表し；R1は水素またはアルキルであり；R2はC1-4アルキルであり；R4は水素、C1-4アルキル、ホルミルまたはアルカノイルであり；R3は水素またはC1-4アルキルであり；R5およびR6は、独立して、水素、ヒドロキシル、C1-4アルキル、C1-4アルコキシ、C1-4アルカノイルオキシ、シアノ、ニトロ、アルキルメルカプト、アミノ、C1-4アルキルアミノ、ジアルキルアミノ、C1-4アルカンアミド、ハロ、トリフルオロメチル、あるいは一緒になってメチレンジオキシであり；およびnは0、1、2、3または4である）
の部分である）
を有する化合物、ならびにその薬学的に許容される塩である。 The structural analog of venlafaxine has the formula:

(Where A is the formula:

(Wherein the dotted line represents any unsaturation; R1 is hydrogen or alkyl; R2 is C1-4 alkyl; R4 is hydrogen, C1-4 alkyl, formyl or alkanoyl; R3 is hydrogen or C1 R5 and R6 are independently hydrogen, hydroxyl, C1-4 alkyl, C1-4 alkoxy, C1-4 alkanoyloxy, cyano, nitro, alkyl mercapto, amino, C1-4 alkylamino, Dialkylamino, C1-4 alkanamide, halo, trifluoromethyl, or together methylenedioxy; and n is 0, 1, 2, 3 or 4)
Part of
As well as pharmaceutically acceptable salts thereof.

Duloxetine Duloxetine has the following structure.

  The structural analog of duloxetine is the compound described by the formula disclosed in U.S. Patent No. 4,956,388, incorporated herein by reference.

  Other SSRI analogs are 1,2,3,4-tetrahydro-N-methyl-4-phenyl-1-naphthylamine hydrochloride; 1,2,3,4-tetrahydro-N-methyl-4-phenyl- (E) -1-naphthylamine hydrochloride; N, N-dimethyl-1-phenyl-1-phthalanpropylamine hydrochloride; γ- (4- (trifluoromethyl) phenoxy) -benzenepropanamine hydrochloride; BP554; CP 53261; O-desmethylvenlafaxine; WY 45,818; WY 45,881; N- (3-fluoropropyl) paroxetine; and Lu 19005.

Standard recommended doses Standard recommended doses for exemplary SSRIs are provided in Table 1 below. Other standard doses are, for example, Merck Manual of Diagnosis & Therapy (17th Ed. MH Beers et al., Merck & Co.) and Physicians' Desk Reference 2003 (57th Ed. Medical Economics Staff et al., Medical Economics Co. , 2002).

(Table 1)

Corticosteroids If desired, one or more corticosteroids can be administered in the methods of the invention or can be formulated in the compositions of the invention with SSRIs, or analogs or metabolites thereof. . Suitable corticosteroids are 11-α, 17-α, 21-trihydroxypregna-4-ene-3,20-dione; 11-β, 16-α, 17,21-tetrahydroxypregna-4- 11-β, 16-α, 17,21-tetrahydroxypregna-1,4-diene-3,20-dione; 11-β, 17-α, 21-trihydroxy- 6-α-methylpregna-4-ene-3,20-dione; 11-dehydrocorticosterone; 11-deoxycortisol; 11-hydroxy-1,4-androstadiene-3,17-dione; 11-ketotestosterone 14-hydroxyandrost-4-en-3,6,17-trione; 15,17-dihydroxyprogesterone; 16-methylhydrocortisone; 17,21-dihydroxy-16-α-methylpregna-1,4,9 (11 ) -Triene-3,20-dione; 17-α-hydroxypregna-4-ene-3,20-dione; 17-α-hydroxypregnenolone; 17-hydroxy-16-β-methyl-5-β-pregna -9 (11) -ene-3,20-dione; 17-hydr Roxy-4,6,8 (14) -pregnatriene-3,20-dione; 17-hydroxypregna-4,9 (11) -diene-3,20-dione; 18-hydroxycorticosterone; 18-hydroxy 18-oxocortisol; 21-deoxyaldosterone; 21-deoxycortisone; 2-deoxyecdysone; 2-methylcortisone; 3-dehydroecdysone; 4-pregnene-17-α, 20-β, 21-triol-3, 11-dione; 6,17,20-trihydroxypregn-4-en-3-one; 6-α-hydroxycortisol; 6-α-fluoroprednisolone, 6-α-methylprednisolone, 6-α-methylprednisolone 21-acetate, 6-α-methylprednisolone 21-hemisuccinate sodium salt, 6-β-hydroxycortisol, 6-α, 9-α-difluoroprednisolone 21-acetate 17-butyrate, 6-hydroxycorticosterone; 6 -Hydroxydexamethasone 6-hydroxyprednisolone; 9-fluorocortisone; alcromethasone dipropionate; aldosterone; algestone; alfaderm; amazinone; amsinonide; anastrone; androstenedione; Pionate monohydrate; betamethasone 17-valerate; betamethasone sodium acetate; betamethasone sodium phosphate; betamethasone valerate; borasterone; budesonide; carsterone; Crocortron; Crocortron pivalate; Crogeston Cortisol; cortisol acetate; cortisol butionate; cortisol cypionate; cortisol octanoate; cortisol sodium phosphate; cortisol sodium succinate; cortisol valerate; cortisone; cortisone acetate; cortodoxone; Deflazacort, 21-deoxycortisol, dehydroepiandrosterone; dermadinone; deoxycorticosterone; deprodon; descinolone; desonide; desoxymethazone; Acetate; Difluco Lutron; dihydroeratericin a; domopredonate; doxybetasol; ecdysone; ecdysterone; endolyson; enoxolone; furocinolone; fludrocortisone; fludrocortisone acetate; Nido; fluocinonide; 9-fluorocortisone; fluocortron; fluorohydroxyandrostenedione; fluorometholone; fluorometholone acetate; fluoxymesterone; fluprednidene; Formestane; formocortal; guest nolon; gridinine; Nido; flucanoside; halometasone; halopredone; haloprogesterone; hydrocortisone cypionate; hydrocortisone; hydrocortisone 21-butyrate; hydrocortisone aceponate; hydrocortisone acetate; hydrocortisone butteplate; hydrocortisone butyrate; Hydrocortisone Probutate; Hydrocortisone Sodium Phosphate; Hydrocortisone Sodium Succinate; Hydrocortisone Valerate; Hydroxyprogesterone; Inostosterone; Isoflupredon; Isoflupredon Acetate; Isoprednidone; Mechlorisone; Mecortron; Medrgestone; Medroxyprogesterone; Methylprednisolone acetate; methylprednisolone acetate; methylprednisolone hemisuccinate; methylprednisolone sodium succinate; methyltestosterone; metribolone; mometasone; Mometasone furoate; mometasone furoate monohydrate; nison; nonegestrol; norgestamate; norvinisterone; oxymesterone; parameterzone; parameterzone acetate; conasterone; prednisolamate; prednisolone; Prednisolone acetate; prednisolone farnesylate; prednisolone hemisuccinate; prednisolone Prednisolone metasulfobenzoate; prednisolone sodium phosphate; prednisolone stearate; prednisolone tebutate; prednisolone tetrahydrophthalate; prednisone; prednibal; Steron; Limexolone; Roxybolone; Lubrosterone; Stisophyllin; Tixocortle; Topterone; Triamcinolone; Triamcinolone acetonide; Triamcinolone acetonide 21-palmitate; Triamcinolone diacetate; Triamcinolone hexaacetonide;

  Standard recommended doses for various steroid / disease combinations are provided in Table 2 below.

(Table 2) Standard recommended corticosteroid dose

  Other standard recommended doses for corticosteroids are, for example, Merck Manual of Diagnosis & Therapy (17th Ed. MH Beers et al., Merck & Co.) and Physicians'Desk Reference 2003 (57th Ed. Medical Economics Staff et al , Medical Economics Co., 2002). In one embodiment, the dose of corticosteroid administered is a dose equivalent to prednisolone as defined herein. For example, a low dose of corticosteroid can be considered a dose equivalent to a low dose of prednisolone.

Steroid Receptor Modulators Steroid receptor modulators (eg, antagonists and agonists) can be used as an alternative to or in addition to corticosteroids in the methods, compositions and kits of the present invention. Accordingly, in one embodiment, the invention features a combination of SSRIs (or analogs or metabolites thereof) and glucocorticoid receptor modulators or other steroid receptor modulators, and methods for treating immunoinflammatory disorders therewith. .

  Glucocorticoid receptor modulators that can be used in the methods, compositions, and kits of the invention are US Pat. Nos. 6,380,207, 6,380,223, 6,448,405, 6,506,766, and 6,570,020, each of which is incorporated herein by reference. Application Publication Nos. 20030176478, 200301171585, 20030120081, 20030073703, 2002015631, 20020147336, 20020107235, 20020103217, and 20010041802, and the compounds described in PCT Publication No. WO00 / 66522. Other steroid receptor modulators can also be used in the methods, compositions and kits of the present invention, US Pat. Nos. 6,093,821, 6,121,450, 5,994,544, 5,696,133, 5,696,127, 5,693,647, 5,693,646, each incorporated herein by reference. 5,688,810, 5,688,808, and 5,696,130.

Other compounds Other compounds A-348441 (Karo Bio), adrenal cortex extract (GlaxoSmithKline), arsactide (as can be used as an alternative to or in addition to corticosteroids in the methods, compositions and kits of the present invention Aventis), Amebcolt (Schering AG), Amelomethasone (Taisho), ATSA (Pfizer), Vitorterol (Elan), CBP-2011 (InKine Pharmaceutical), Sevaracetam (Novartis), CGP-13774 (Kissei), Ciclesonide (Altana), Cyclomethasone (Aventis), clobetasone butyrate (GlaxoSmithKline), clopredonol (Hoffmann-La Roche), chorismycin A (Kirin), cucurbitacin E (NIH), deflazacort (Aventis), deprodon propionate (SSP), Dexamethasone acephrate (Schering-Plough), Dexamethasone linoleate (GlaxoSmithKline), Dexamethasone Nvalerate (Abbott), diflupredonate (Pfizer), domopredonate (Hoffmann-La Roche), shrimp tide (Aventis), etipredonol dicloacetate (IVAX), fluazacort (Vicuron), flumoxonide (Hoffmann-La Roche), fluocortin Butyl (Schering AG), fluocortodon monohydrate (Schering AG), GR-250495X (GlaxoSmithKline), halomethasone (Novartis), halopredone (Dainippon), HYC-141 (Fidia), icomethasone embutate (Hovione) , Itrosinonide (AstraZeneca), L-6485 (Vicuron), Lipocort (Draxis Health), Rosicolton (Aventis), Mechlorisone (Schering-Plough), Nafrocort (Bristol-Myers Squibb), NCX-1015 (NicOx), NCX-1020 ( NicOx), NCX-1022 (NicOx), Nicocortonide (Yamanouchi), NIK-236 (Nikken Chemicals), NS-126 (SSP), Org-2766 (Akzo Nobel) , Org-6632 (Akzo Nobel), P16CM, Propyl Mesterolone (Schering AG), RGH-1113 (Gedeon Richter), Rofleponide (AstraZeneca), Rofleponide Palmitate (AstraZeneca), RPR-106541 (Aventis), RU -26559 (Aventis), Sch-19457 (Schering-Plough), T25 (Matrix Theraputics), TBI-PAB (Sigma-Tau), Tikabeson propionate (Hoffmann-La Roche), Tifluadm (Solvay), Timobeson (Hoffmann) -La Roche), TSC-5 (Takeda), and ZK-73634 (Schering AG).

Therapies The invention is characterized by inhibiting the secretion of inflammatory cytokines as a means for treating immunoinflammatory disorders, proliferative skin diseases, organ transplant rejection, or graft-vs-host disease. Inhibition of cytokine secretion is achieved by administering one or more SSRIs, optionally in combination with one or more steroids. While the examples describe a single SSRI and a single steroid, it will be appreciated that combinations of multiple agents are often desirable. For example, methotrexate, hydroxychloroquinone and sulfasalazine are usually administered in the treatment of rheumatoid arthritis. Additional therapies are described below.

Chronic obstructive pulmonary disease In one embodiment, the methods, compositions and kits of the invention are used in the treatment of chronic obstructive pulmonary disease (COPD). If desired, typically one or more agents used to treat COPD are used as an alternative to or in addition to corticosteroids in the methods, compositions and kits of the present invention. Can do. Such agents include xanthines (eg, theophylline), anticholinergic compounds (eg, ipratropium, tiotropium), and beta receptor agonist / bronchodilators (eg, ibuterol sulfate, vitorterol mesylate, epinephrine, formoterol Fumaric acid, isoproteronol, levalbuterol hydrochloride, metaproterenol sulfate, pyrbuterol succinate, salmeterol xinafoate, and terbutaline). Thus, in one embodiment, the invention features a combination of SSRI (or an analog or metabolite thereof) and a bronchodilator and a method of treating COPD using it.

Psoriasis The methods, compositions and kits of the present invention can be used in the treatment of psoriasis. If desired, one or more anti-psoriatic agents typically used to treat psoriasis are typically used as an alternative to corticosteroids in the methods, compositions and kits of the present invention, or In addition, it can be used. Such agents include biologics (eg, alefacept, inflixamab, adelimumab, efalizumab, etanercept, and CDP-870), non-steroidal calcineurin inhibitors (eg, cyclosporine, tacrolimus, pimecrolimus, and ISAtx247), vitamin D Includes analogs (eg, calcipotriene, calcipotriol), psoralen (eg, methoxalene), retinoids (eg, acitretin, tazoletene), DMARD (eg, methotrexate), and anthralin. Accordingly, in one embodiment, the invention features a combination of SSRI (or an analog or metabolite thereof) and an anti-psoriatic agent, and a method of treating psoriasis using it.

Inflammatory Bowel Disease The methods, compositions and kits of the present invention can be used in the treatment of inflammatory bowel disease. If desired, typically one or more agents used to treat inflammatory bowel disease are used as an alternative to or in addition to corticosteroids in the methods, compositions and kits of the present invention. be able to. Such agents include biologics (eg, inflixamab, adelimumab, and CDP-870), non-steroidal calcineurin inhibitors (eg, cyclosporine, tacrolimus, pimecrolimus, and ISAtx247), 5-aminosalicylic acid (eg, mesalamine) Sulfasalazine, balsalazide disodium, and olsalazine sodium), DMARD (eg, methotrexate and azathioprine) and allosetron. Accordingly, in one embodiment, the invention features a combination of SSRIs (or analogs or metabolites thereof) and any of the foregoing agents, and methods of using them to treat inflammatory bowel disease.

Rheumatoid arthritis The methods, compositions and kits of the invention can be used in the treatment of rheumatoid arthritis. If desired, typically one or more agents used to treat rheumatoid arthritis are used as an alternative to or in addition to corticosteroids in the methods, compositions and kits of the present invention. be able to. Such agents include NSAIDs (eg, naproxen sodium, diclofenac sodium, diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam, indomethacin, ibuprofen, nabumetone, choline magnesium trisalicylate, sodium salicylate, salicylsalicylic acid (salsalate), phenoprofen , Flurbiprofen, ketoprofen, meclofenamate sodium, meloxicam, oxaprozin, sulindac and tolmetine), COX-2 inhibitors (eg, rofecoxib, celecoxib, valdecoxib, and lumiracoxib), biologics (eg, inflixamab, adelimumab, Etanercept and CDP-870), non-steroidal calcineurin inhibitors (eg, cycle Sporins, tacrolimus, pimecrolimus, and ISAtx247), 5-aminosalicylic acid (eg, mesalamine, sulfasalazine, balsalazide disodium, and olsalazine sodium), DMARD (eg, methotrexate, leflunomide, minocycline, auranofin, gold sodium thiomalate) , Aurothioglucose, and azathioprine), hydroxychloroquinone sulfate and penicillamine. Accordingly, in one embodiment, the invention features a combination of SSRI (or an analog or metabolite thereof) and any of the above agents, and methods of using it to treat rheumatoid arthritis.

Asthma The methods, compositions and kits of the invention can be used in the treatment of asthma. If desired, typically one or more agents used to treat asthma are used as an alternative to or in addition to corticosteroids in the methods, compositions and kits of the invention. it can. Such agents include beta-2 agonist / bronchodilator / leukotriene modifiers (eg, zafirlukast, montelukast, and zileuton), biologics (eg, omalizumab), anticholinergic compounds, xanthine, ephedrine, guaifenesin, cromolyn sodium , Nedocromil sodium, and potassium iodide. Thus, in one embodiment, the invention features a combination of SSRIs (or analogs or metabolites thereof) and any of the foregoing agents, and methods of using them to treat rheumatoid arthritis.

Non-steroidal immunophilin-dependent immunosuppressive agents In one embodiment, the present invention may be combined with corticosteroids or other agents described herein, SSRIs and non-steroidal immunophilin-dependent immunosuppressive agents. Features methods, compositions and kits using agents (NsIDI).

  In healthy individuals, the immune system uses cell effectors such as B cells and T cells to target infectious microorganisms and abnormal cell types while leaving normal cells intact. In individuals with autoimmune disease or transplanted organs, activated T cells damage healthy tissue. Calcineurin inhibitors (eg, cyclosporine, tacrolimus, pimecrolimus), and rapamycin target many types of immunoregulatory cells, including T cells, and suppress immune responses in organ transplantation and autoimmune disorders.

Cyclosporine Cyclosporine is a fungal metabolite comprising a class of cyclic oligopeptides that act as immunosuppressants. Cyclosporin A, and its deuterated analog ISAtx247, is a hydrophobic cyclic polypeptide consisting of 11 amino acids. Cyclosporine A binds to and forms a complex with the intracellular receptor cyclophilin. The cyclosporine / cyclophilin complex binds to and inhibits calcineurin, a Ca2 + -calmodulin-dependent serine-threonine-specific protein phosphatase. Calcineurin mediates signal transduction events necessary for T cell activation (reviewed in Schreiber et al., Cell 70: 365-368, 1991). Cyclosporine and its functional and structural analogs suppress T cell-dependent immune responses by inhibiting antigen-triggered signal conversion. This suppression reduces the expression of inflammatory cytokines such as IL-2.

  Many cyclosporines (eg, cyclosporine A, B, C, D, E, F, G, H and I) are produced by fungi. Cyclosporine A is commercially available from Novartis under the trade name NEORAL. Cyclosporine A structural and functional analogs include cyclosporine having one or more fluorinated amino acids (eg, as described in US Pat. No. 5,227,467); Patent Nos. 5,122,511 and 4,798,823); and deuterated cyclosporine such as ISAtx247 (described in US Patent Publication No. 20020132763). Further cyclosporine analogs are described in U.S. Patent No. 6,136,357, 4,384,996, 5,284,826, and 5,709,797. Cyclosporine analogs include, but are not limited to, D-Sar (α-SMe) 3Val2-DH described in Cruz et al., (Antimicrob. Agents Chemother. 44: 143-149, 2000). -Cs (209-825), allo-Thr-2-Cs, norvaline-2-Cs, D-Ala (3-acetylamino) -8-Cs, Thr-2-Cs, and D-MeSer-3-Cs , D-Ser (O-CH2CH2-OH) -8-Cs, and D-Ser-8-Cs.

  Cyclosporine is highly hydrophobic and precipitates easily in the presence of water (eg in contact with body fluids). Methods for providing cyclosporine formulations with improved bioavailability are described in U.S. Patent Nos. 4,388,307, 6,468,968, 5,051,402, 5,342,625, 5,977,066, and 6,022,852. Cyclosporine microemulsion compositions are described in U.S. Patent Nos. 5,866,159, 5,916,589, 5,962,014, 5,962,017, 6,007,840, and 6,024,978.

  Although cyclosporine can be administered either intravenously or orally, oral administration is preferred. To counteract the hydrophobicity of cyclosporin A, intravenous cyclosporin A is usually provided in an ethanol-polyoxyethylated castor oil solvent that must be diluted prior to administration. Cyclosporine A can be provided, for example, as a microemulsion in a 25 mg or 100 mg tablet, or 100 mg / ml oral solution (NEORAL ™).

  Typically, patient doses of oral cyclosporine vary according to the patient's condition, but here are some standard recommended doses in prior art treatment methods. Patients receiving organ transplants typically receive an initial dose of oral cyclosporin A in an amount between 12 and 15 mg / kg / day. The dose is then gradually reduced by 5% per week until a 7-12 mg / kg / day maintenance dose is reached. For intravenous administration, 2-6 mg / kg / day is preferred for most patients. In patients diagnosed with Crohn's disease or ulcerative colitis, a dose of 6-8 mg / kg / day is generally given. In patients diagnosed with systemic lupus erythematosus, a dose of 2.2-6.0 mg / kg / day is generally given. For psoriasis or rheumatoid arthritis, a dose of 0.5-4 mg / kg / day is typical. Other useful doses include 0.5-5 mg / kg / day, 5-10 mg / kg / day, 10-15 mg / kg / day, 15-20 mg / kg / day or 20-25 mg / kg / day. Often cyclosporine is administered in combination with other immunosuppressive agents such as glucocorticoids. Further information is provided in Table 3.

脚注
CsA＝サイクロスポリンA
RA＝慢性関節リウマチ
UC＝潰瘍性結腸炎
SLE＝全身性エリテマトーデス (Table 3) NsIDI

footnote
CsA = Cyclosporine A
RA = rheumatoid arthritis
UC = ulcerative colitis
SLE = systemic lupus erythematosus

Tacrolimus
Tacrolimus (PROGRAF, Fujisawa), also known as FK506, is an immunosuppressant that targets the intracellular signal transduction pathway of T cells. Tacrolimus binds to the intracellular protein FK506 binding protein (FKBP-12) that is not structurally related to cyclophilin (Harding et al., Nature 341: 758-7601, 1989; Siekienka et al., Nature 341: 755-757 1989, and Soltoff et al., J. Biol. Chem. 267: 17472-17477, 1992). The FKBP / FK506 complex binds to calcineurin and inhibits the phosphatase activity of calcineurin. This inhibition prevents dephosphorylation and nuclear translocation of nuclear components that initiate gene transcription required for NFAT, lymphokine (eg, IL-2, gamma interferon) production and T cell activation. Thus, tacrolimus inhibits T cell activation.

  Tacrolimus is a macrolide antibiotic produced by Streptomyces tsukubaensis. It suppresses the immune system and prolongs the survival of transplanted organs. It is currently available in oral and injection formulations. Tacrolimus capsules contain 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus in a gelatin capsule shell. The injection formulation contains 5 mg anhydrous tacrolimus in castor oil and alcohol diluted with 9% sodium chloride or 5% dextrose prior to injection. Although oral administration is preferred, patients who cannot be inoculated with oral capsules can receive injected tacrolimus. The initial dose should be administered no later than 6 hours after transplantation by continuous intravenous infusion.

  Tacrolimus and tacrolimus analogs are described in Tanaka et al., (J. Am. Chem. Soc., 109: 5031, 1987) and U.S. Patent No. 4,894,366, 4,929,611, and 4,956,352. FK506 related compounds including FR-900520, FR-900523 and FR-900525 are described in US Patent No. 5,254,562; O-aryl, O-alkyl, O-alkenyl and O-alkynyl macrolides are listed in US Pat. .5,250,678, 532,248, 5,693,648; amino O-aryl macrolides are described in US Patent No. 5,262,533; alkylidene macrolides are described in US Patent No. 5,284,840; N-heteroaryls; N-alkylheteroaryl, N-alkenylheteroaryl, and N-alkynylheteroaryl macrolides are described in US Patent No. 5,208,241; amino macrolides and derivatives thereof are described in USPatent No. 5,208,228; Fluoro macrolides are described in US Patent No. 5,189,042; amino O-alkyl, O-alkenyl, and O-alkynyl macrolides are described in US Patent No. 5,162, 334; and halomacrolide is described in U.S. Patent No. 5,143,918.

  Proposed doses will vary with the patient's condition, but standard recommended doses used in prior art treatment methods are provided below. Patients diagnosed with Crohn's disease or ulcerative colitis receive 0.1 to 0.2 mg / kg / day oral tacrolimus. Patients with transplanted organs typically receive a dose of 0.1-0.2 mg / kg / day of oral tacrolimus. Patients being treated for rheumatoid arthritis typically receive 1-3 mg / day oral tacrolimus. For the treatment of psoriasis, 0.01-0.15 mg / kg / day of oral tacrolimus is administered to the patient. Atopic dermatitis can be treated twice a day by applying a cream with 0.03-0.1% tacrolimus to the affected area. Patients receiving oral tacrolimus capsules typically receive the first dose more than 6 hours after implantation or do not continue for 8-12 hours after intravenous tacrolimus infusion. Other proposed tacrolimus doses are 0.005-0.01 mg / kg / day, 0.01-0.03 mg / kg / day, 0.03-0.05 mg / kg / day, 0.05-0.07 mg / kg / day, 0.07-0.10 mg / kg / Day, 0.10 to 0.25 mg / kg / day or 0.25 to 0.5 mg / kg / day.

  Tacrolimus is extensively metabolized by mixed-function oxidase systems, particularly the cytochrome P-450 system. An important metabolic mechanism is demethylation and hydroxylation. Although various tacrolimus metabolites appear to exhibit immunosuppressive biological activity, the 13-demethyl metabolite has been reported to have the same activity as tacrolimus.

Pimecrolimus and Ascomycin Derivatives Ascomycin is a close structural analog of FK506 and an excellent immunosuppressant. It binds to FKBP-12 and suppresses its proline rotamase activity. Ascomycin-FKBP complex inhibits calcineurin, type 2B phosphatase.

  Pimecrolimus (also known as SDZ ASM-981) is a 33-epi-chloro derivative of ascomycin. It is produced by the strain Streptomyces hygroscopicus var.ascomyceitus. Like tacrolimus, pimecrolimus (ELIDEL ™, Novartis) binds to FKBP-12, inhibits calcineurin phosphatase activity, and inhibits T cell activation by blocking transcription of early cytokines. In particular, pimecrolimus inhibits IL-2 production and the release of other inflammatory cytokines.

  The structural and functional analogs of pimecrolimus are described in U.S. Patent No. 6,384,073. Pimecrolimus is particularly useful in the treatment of atopic dermatitis. Pimecrolimus is currently available as a 1% cream. Individual doses will vary with the patient's condition, but some standard recommended doses are provided below. Oral pimecrolimus can be administered in the treatment of psoriasis or rheumatoid arthritis in an amount of 40-60 mg / day. For the treatment of Crohn's disease or ulcerative colitis, an amount of 80-160 mg / day of pimecrolimus can be administered. Patients with organ transplants can be administered 160-240 mg / day of pimecrolimus. Patients diagnosed with systemic lupus erythematosus can be administered 40-120 mg / day of pimecrolimus. Other useful doses of pimecrolimus include 0.5-5 mg / day, 5-10 mg / day, 10-30 mg / day, 40-80 mg / day, 80-120 mg / day, or even 120-200 mg / day.

Rapamycin Rapamycin (Rapamune® sirolimus, Wyeth) is a cyclic lactone produced by Steptomyces hygroscopicus. Rapamycin is an immunosuppressive agent that inhibits T-lymphocyte activation and proliferation. Like cyclosporine, tacrolimus, and pimecrolimus, rapamycin forms a complex with immunophilin FKBP-12, but the rapamycin-FKBP-12 complex does not inhibit calcineurin phosphatase activity. The rapamycin-immunophilin complex binds to and inhibits the mammalian target of rapamycin (mTOR), a kinase required for cell cycle progression. Inhibition of mTOR kinase activity blocks T-lymphocyte proliferation and lymphokine secretion.

  Structural and functional analogs of rapamycin are mono- and diacylated rapamycin derivatives (US Pat. No. 4,316,885); rapamycin water-soluble prodrugs (US Pat. No. 4,650,803); carboxylates (PCT Publication No. WO 92/05179) Carbamate (USPatent No.5,118,678); amide ester (USPatent No.5,118,678); biotin ester (USPatent No.5,504,091); fluorinated ester (USPatent No.5,100,883); acetal (USPatent No.5,151,413); Silyl ether (US Patent No. 5,120,842); Bicyclic derivative (US Patent No. 5,120,725); Rapamycin dimer (US Patent No. 5,120,727); O-aryl, O-alkyl, O-alkenyl and O-alkynyl derivatives (US Patent No. 5,258,389); and deuterated rapamycin (US Patent No. 6,503,921). Further rapamycin analogs are described in U.S. Patent Nos. 5,202,332 and 5,169,851.

  Everolimus (40-O- (2-hydroxyethyl) rapamycin; CERTICAN ™; Novartis) is an immunosuppressive macrolide that is structurally related to rapamycin when administered in combination with cyclosporin A It has been found to be particularly effective in preventing acute rejection of organ transplants.

  Rapamycin is currently available for oral administration in liquid and tablet formulations. RAPAMUNE ™ liquid contains 1 mg / mL rapamycin diluted in water or orange juice prior to administration. Tablets containing 1 or 2 mg rapamycin are also available. Rapamycin is preferably given once daily as soon as possible after transplantation. It is rapidly and completely absorbed after oral administration. Typically, patient doses of rapamycin vary according to the patient's condition, but some standard recommended doses are provided below. The initial loading dose for rapamycin is 6 mg. A subsequent maintenance dose of 2 mg / day is typical. Alternatively, a loading dose of 3 mg, 5 mg, 10 mg, 15 mg, 20 mg or 25 mg can be used with 1 mg, 3 mg, 5 mg, 7 mg or 10 mg per daily maintenance dose. In patients weighing less than 40 kg, the dose of rapamycin is typically adjusted according to body surface area; generally 3 mg / m2 / day loading dose and 1 mg / m2 / day maintenance dose are used.

Peptide sites Peptides, peptidomimetics, peptide fragments (either natural, synthetic or chemically modified) that impair calcineurin-mediated dephosphorylation and nuclear translocation of NFAT are suitable for use in the practice of the invention. Examples of peptides that act as calcineurin inhibitors by inhibiting NFAT activation and NFAT transcription factors are described, for example, in Aramburu et al. , Science 285: 2129-2133, 1999 and Aramburu et al. , Mol. Cell 1: 627-637,1998. As a class of calcineurin inhibitors, these agents are useful in the methods of the invention.

Administration In any particular embodiment of the methods of the invention, the compounds are administered within 10 days of each other, within 5 days of each other, within 24 hours of each other, or simultaneously. The compounds can be formulated together as a single composition or can be formulated and administered separately. One or both compounds can be administered at low or high doses, each as defined herein. Corticosteroids, NSAIDs (e.g. naproxen sodium, diclofenac sodium, diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam, indomethacin, ibuprofen, nabumetone, choline magnesium trisalicylate, sodium salicylate, salicylsalicylic acid, fenoprofen, flurbipro Other compounds such as phen, ketoprofen, sodium meclofenamate, meloxicam, oxaprozin, sulindac, and tolmethine), COX-2 inhibitors (eg, rofecoxib, celecoxib, valdecoxib and rubilacoxib), glucocorticoid receptor modulators or DMARD It may be desirable to administer to the patient. The combination therapies of the present invention are agents that affect cell adhesion, or biologics (ie, IL-6, IL-1, IL-2, IL-12, IL-15 or TNFα (eg, etamercept, adelimumab, infliximab or It is particularly useful in the treatment of immunoinflammatory disorders in combination with other anti-cytokine agents or agents that modulate the immune response that positively affects the disease, such as CDP-870)). In this example (that of an agent that blocks the effect of TNFα), combination therapy reduces cytokine production, and etanercept or infliximab acts on the remaining fraction of inflammatory cytokines, providing enhanced therapy.

  The therapy according to the present invention can be performed alone or in combination with another therapy and can be provided at home, doctor's office, clinic, hospital outpatient department, or hospital. Treatment can optionally be initiated at the hospital so that the physician can observe the effects of the therapy nearby and make any necessary adjustments, or it can be initiated on an outpatient basis. The duration of therapy depends on the type of illness or disorder to be treated, the age and condition of the patient, the stage and type of the patient's illness, and how the patient responds to the treatment. In addition, a person at greater risk of developing an inflammatory disease (eg, a person undergoing age-related hormonal changes) can receive treatment to inhibit or delay the onset of symptoms.

  The route of administration for the various embodiments is, but is not limited to, local (such as intravenous, intramuscular, subcutaneous, inhalation, rectal, buccal, vaginal, intraperitoneal, intraarticular, ocular or oral administration). Including transdermal and systemic administration. As used herein, “systemic administration” refers to all non-dermal routes of administration and specifically excludes topical and transdermal routes of administration.

  In combination therapy, the amount and frequency of administration of each component of the combination can be controlled independently. For example, one compound can be administered three times per day, while the second compound can be administered once per day. Combination therapy can be given in an on-and-off cycle involving the remaining organs so that the patient's body still has a chance to recover from any of the unpredictable side effects. The compounds can also be formulated together so that one administration delivers both compounds.

Formulation of Pharmaceutical Compositions Administration of the combinations of the present invention may be any suitable means that results in suppression of inflammatory cytokine levels in the target area. The compound can be included in any suitable amount in any suitable carrier material and is generally present at 1-95% by weight of the total weight of the composition. The composition can be provided in dosage forms suitable for oral, parenteral (eg, intravenous, intramuscular), rectal, subcutaneous, nasal, vaginal, inhalation, dermal (patch) or ocular routes of administration. Thus, the composition can be, for example, a tablet, capsule, pill, powder, granule, suspension, emulsion, solution, gel, including hydrogel, paste, ointment, cream, plaster, drench, osmotic delivery device, It can be in the form of a suppository, enema, injection, implant, spray or aerosol. The pharmaceutical composition can be formulated according to conventional pharmaceutical practice (eg, Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed. ARGennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds J. Swarbrick and JCBoylan, 1988-1999, Marcel Dekker, New York).

  Each compound of the combination can be formulated in various ways known in the art. For example, the first and second agents can be formulated together or separately. Desirably, the first and second agents are formulated together for simultaneous or near simultaneous administration of the agents. Such co-formulation compositions can include SSRIs and steroids formulated together in the same pills, capsules, solutions, and the like. When referring to a “SSIR / steroid combination” formulation, the formulation technique used is useful in formulating individual combinations of the combination as well as other combinations of the present invention (eg, SSRI / glucocorticoid receptor modulator combinations). is there. By using different formulation strategies for different agents, the pharmacokinetic profiles for each agent can be appropriately matched.

  Individually or separately formulated agents can be packaged together as a kit. Non-limiting examples include, for example, kits containing two pills, pills and powders, suppositories and liquids in vials, two topical creams and the like. The kit can include any component that assists in administering a unit dose to the patient, such as a vial to reconstitute the powder form, a syringe for injection, a conventional IV delivery system, an inhaler, and the like. In addition, the unit dose kit can include instructions for preparation and administration of the composition. The kit is a single use unit dose for a single patient, multiple use for a specific patient (at a fixed dose or individual compounds can change their ability as the therapy progresses) Or the kit can contain multiple doses (“bulk packaging”) suitable for administration to multiple patients. The components of the kit can be assembled in cartons, blister packs, bottles, tubes and the like.

Controlled Release Formulation Administration of an SSRI / steroid combination of the present invention in which one or both of the active agents is formulated for controlled release may result in the SSRI or the steroid having (i) a narrow therapeutic index (eg, adverse side effects or toxic reactions). The difference between the plasma concentration leading to the treatment and the plasma concentration leading to the therapeutic effect; in general, the therapeutic index TI is defined as the ratio of the median lethal dose (LD50) to the median effective dose (ED50)); (ii) gastrointestinal Have a narrow absorption window in the tube; (iii) a short biological half-life; or (iv) if the pharmacokinetic profiles of each component are used together, the contribution of each agent to cytokine suppression Useful if it must be modified to maximize to a therapeutically effective amount. Thus, sustained release formulations can be used to avoid frequent administration that may be necessary to maintain plasma levels of both agents at therapeutic levels. For example, in preferred oral pharmaceutical compositions of the present invention, a 10-20 hour half-life and average residence time for one or both agents of the combination of the present invention is observed.

  Many strategies can be pursued to obtain a controlled release whose release rate is greater than the rate of metabolism of the therapeutic compound. For example, controlled release can be obtained by appropriate selection of formulation parameters and ingredients (eg, appropriate controlled release compositions and coatings). Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches and liposomes. The release mechanism is such that when the initial release of one particular agent is preferred over the other, SSRIs and / or steroids are released at intervals and the release is simultaneous or delayed for one of the combination agents It can be controlled so that release can take place.

  Controlled release formulations can include degradable or non-degradable polymers, hydrogels, organogels, or other physical constructions that modify the bioabsorption, half-life or biodegradation of the agent. Controlled release formulations can be substances that are stained or applied internally or externally to the affected area. In one example, the present invention provides a biodegradable bolus or implant that is surgically inserted at or near a site of interest (eg, proximal to the arthritic joint). In another example, a controlled release prescription implant can be inserted into an organ, such as in the lower intestine for therapeutic inflammatory bowel disease.

  Hydrogels can be used in controlled release formulations for SSRI / steroid combinations of the present invention. Such polymers are formed from macromers having polymerizable non-degradable regions separated by at least one degradable region. For example, water-soluble non-degradable regions can form the central core of the macromer, and upon degradation, non-degradable regions (especially polymerized gels) are separated as described in US Patent No. 5,626,863. As such, it has at least two degradable regions attached to the core. Hydrogels can include acrylates that can be easily polymerized by several initiating systems such as eosin dyes, ultraviolet light or visible light. The hydrogel can also include polyethylene glycol (PEG), which is highly hydrophilic and biocompatible. Hydrogels can also include oligoglycolic acid, a poly (α-hydroxy acid) that can be easily degraded by hydrolysis of ester-linked glycolic acid, a non-toxic metabolite. Other chain extensions can include polylactic acid, polycaprolactone, polyorthoesters, polyanhydrides, or polypeptides. The entire network can be gelled into a biodegradable network, which can be used to capture and evenly distribute the SSRI / steroid combinations of the present invention for controlled rate delivery.

  Chitosan, and a mixture of chitosan and sodium carboxymethylcellulose (CMC-Na), as described by Inouye et al., Drug Design and Delivery 1: 297-305,1987, as a solvent for sustained release of drugs Has been used. These compound and SSRI / steroid combination drug mixtures of the present invention, when compressed under 200 kg / cm 2, form tablets from which the active agent is slowly released upon administration to the subject. The release profile can be altered by changing the ratio of chitosan, CMC-Na, and active agent. Tablets can also contain other additives including lactose, CaHPO4 dihydrate, sucrose, crystalline cellulose, or croscarmellose sodium. Some examples are provided in Table 4.

(Table 4)

  Baichwal, in US Patent No. 6,245,356, aggregates of amorphous forms of therapeutically active pharmaceuticals (eg, SSRI / steroid combinations of the present invention or components thereof), gelling agents, ionizable gel strength enhancers and inert diluents. Sustained release oral solid dosage forms containing the prepared particles are described. The gelling agent can be a mixture of xanthan gum and locust bean gum that can crosslink with xanthan gum when the gum is exposed to an environmental fluid. Preferably, the ionizable gel enhancing agent acts to increase the strength of the cross-linking between the xanthan gum and the locust bean gum, thereby delaying the release of the pharmaceutical component of the formulation. In addition to xanthan gum and locust bean gum, acceptable gelling agents that can also be used include gelling agents well known in the art. Examples include naturally occurring or polymers such as alginate, carrageenan, pectin, guar gum, modified starch, hydroxypropyl methylcellulose, methylcellulose, and other cellulosic materials or polymers such as sodium carboxymethylcellulose and hydroxypropylcellulose. Modified spontaneous flakes, and mixtures of the foregoing.

  In another formulation useful in the combination of the present invention, Baichwal and Staniforth in US Patent No. 5,135,757 in the presence of an aqueous solution (such as xanthan gum or a derivative thereof) and a heteropolysaccharide (such as galactomannan). About 20 to about 70 weight percent or more of a hydrophilic material, including a polysaccharide material capable of crosslinking a heteropolysaccharide, most preferably such as locust bean gum, and (eg, lactose, dextrose, sucrose, sorbitol, xylitol, Describes free-flowing delayed release granulation for use as a pharmaceutical excipient comprising from about 30 to about 80 weight percent of an inert pharmaceutical filler (such as fructose or mixtures thereof). After the excipient is mixed with the SSRI / steroid combination or combination of the present invention, the mixture is compressed directly into a solid dosage form such as a tablet. Tablets formed in this way are ingested and slowly release the drug when exposed to gastric juice. By varying the amount of excipients relative to the medicament, a delayed release profile can be achieved.

  In another formulation useful in the combination of the present invention, Shell describes in US Patent No. 5,007,790 a sustained release oral drug dosage form that releases drug in solution at a rate controlled by drug solubility. . The dosage form maintains its physical integrity for the life of the administration, but rapidly thereafter, into a hydrophilic, water-swellable crosslinked polymer (eg prednisolone, paroxetine, or the present invention). Including tablets or capsules containing a plurality of particles of drug dispersion of limited solubility (such as any other agent of the SSRI / steroid combination). Once ingested, the particles swell and promote gastric retention, allowing gastric juice to penetrate the particles, causing the drug to dissolve and take it out of the particles so that the drug is more effective against the stomach than the solid state drug. Ensure that the stomach is reached in a non-damaging solution. The programmed resulting dissolution of the polymer depends on the nature of the polymer and the degree of crosslinking. The polymer is non-fibrillar and is substantially water soluble in its uncrosslinked state, and the degree of crosslinking remains insoluble until the polymer is in the desired period, usually at least about 4 to 8 hours, up to 12 hours. The choice will depend on the drug being formulated and the associated pharmaceutical treatment. Examples of suitable cross-linked polymers that can be used in the present invention are gelatin, albumin, sodium alginate, carboxymethylcellulose, polyvinyl alcohol, and chitin. Depending on the polymer, crosslinking can be achieved by thermal or radiation treatment or through the use of crosslinking agents such as aldehydes, polyamino acids, metal ions and the like.

  Silicone microspheres for pH-controlled gastrointestinal drug delivery useful in the formulation of the SSRI / steroid combination of the present invention are described by Carelli et al., Int. J. Pharmaceuticals 179: 73-83,1999. The microspheres so described have various proportions of poly (methacrylic acid-co-methyl methacrylate) (Eudragit L100 or Eudragit S100) and cross-linked polyethylene glycol 8000 formulated into silicone microspheres in the size range of 500-1000 μm. A pH-sensitive semi-interpenetrating polymer hydrogel consisting of

  Delayed release formulations can include coatings that are not readily water soluble but can be slowly attacked and removed by water or allow water to slowly penetrate it. Thus, for example, the SSRI / steroid combinations of the present invention can be spray-coated with a solution of the binder under continuous liquefaction conditions as described by Kitamori et al., U.S. Patent No. 4,036,948. Examples of water-soluble binders include pre-gelatinized starch (eg pre-gelatinized corn starch, pre-gelatinized white potato starch), pre-gelatinized modified starch, water-soluble cellulose (eg hydroxypropyl-cellulose , Hydroxymethyl-cellulose, hydroxypropylmethyl-cellulose, carboxymethyl-cellulose), polyvinylpyrrolidone, polyvinyl alcohol, dextrin, gum arabic and gelatin, cellulose derivatives (eg cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose) Such organic solvent-soluble binders.

  Combinations of the present invention with sustained release characteristics, or components thereof, can also be formulated by spray drying techniques. In one example, a Mini Spray Dryer, model 190 (Buchi, Laboratorium Technik AG, Flawil, Germany) was used as described by Espositio et al., Pharm. Dev. Technol. 5: 267-78, 2000. Then, prednisolone was encapsulated in methyl acrylate microparticles (EudragitRS). Optimal conditions for microparticle formation include 0.5 mL / min feed (pump) rate of a solution containing 50 mg prednisolone in 10 mL acetonitrile, 600 L / hr atomizing air flow rate, drying heated at 80 ° C It was found that the air temperature and the suction dry air flow rate of 28 m3 / hr.

  Yet another form of sustained release SSRI / steroid combination can be prepared by microencapsulating particles of the combination in a membrane that acts as a microdialysis cell. In such a formulation, gastric fluid penetrates the walls of the microcapsules, swells the microcapsules and dialyzes the active agent (see, for example, Tsuei et al., U.S. Patent No. 5,589,194). One commercially available sustained release system of this kind consists of microcapsules with an acacia gum / gelatin / ethyl alcohol film. This product is available from Eurond Limited (France) under the trade name Diffucaps ™. Microcapsules so formulated could be carried in conventional gelatin capsules or tableted.

  Extended-and / or controlled-release formulations of both SSRIs and corticosteroids are known. For example, PaxilCR®, commercially available from GlaxoSmithKline, is an extension of paroxetine hydrochloride in a degradable polymer matrix that also has an intestinal coating to delay the onset of drug release until after the tablet has passed through the stomach The release form (see also GEOMATRIX ™, US Pat. Nos. 4,839,177, 5,102,666, and 5,422,123). For example, US Patent No. 5,102,666 is (1) a calcium polycarbophil component that is a water swellable but water insoluble fibrous cross-linked carboxy-functional polymer, said polymer (a) at least about 80% of which is at least about 80% A plurality of repeating units comprising one carboxyl function, and (b) from about 0.05 to about 1.5% crosslinker substantially free of polyalkenyl polyethers, said percentages comprising unpolymerized repeating units and crosslinking, respectively Based on the weight of the agent; and (2) a polymer controlled release composition comprising a reaction complex formed by interaction with water in the presence of an active agent selected from the group consisting of SSRIs such as paroxetine Is described. The amount of calcium polycarbophil present is from about 0.1 to about 99% by weight, for example about 10%. The amount of active agent present is from about 0.0001 to about 65% by weight, for example, between about 5 and 20%. The amount of water present is about 5 to about 200% by weight, for example, between about 5 and about 10%. The interaction occurs at a pH between about 3 and about 10, for example between about 6-7. Calcium polycarbophil originally exists in the form of calcium salts containing about 5 to about 25% calcium.

  Examples of other extended-release formulations are described in U.S. Patent No. 5,422,123. Thus, (a) a deposit-core comprising an effective amount of active substance and having a defined geometric form, and (b) a support-platform applied to said deposit-core, wherein said deposit-core At least one active ingredient, and (1) a polymeric material that swells upon contact with water or an aqueous liquid, and a gelable polymeric material, wherein the ratio of the swellable polymeric material to the gelable polymeric material is 1 Including at least one member selected from the group consisting of a single polymeric material having a range of 9 to 9: 1 and (2) having both swellability and gelation properties, wherein Said support-platform is an elastic support, a system for controlled release of active substances that are SSRIs such as paraxetine, it is partly deposited- Applied to the deposit-core to cover the surface of the core, follow the changes in the hydration of the deposit-core, and be slowly soluble and / or slowly gelable in aqueous fluids. The The support-platform may be a polymer such as hydroxypropyl methylcellulose, a plasticizer such as glyceride, a binder such as polyvinylpyrrolidone, a hydrophilic agent such as lactose or silica, and / or a hydrophobic such as magnesium stearate and glyceride. Sex agents can be included. The polymer typically comprises 30-90% by weight of the support-platform, for example about 35-40%. The plasticizer can comprise at least 2% by weight of the support-platform, eg, about 15-20%. The binder, hydrophilic agent and hydrophobic agent typically add up to about 50% by weight of the support-platform, for example about 40-50%.

  In another example, an extended-release formulation for venlafaxine (Effexor XR®) is commercially available from Wyeth Pharmaceuticals. This formulation contains verafaxin hydrochloride, microcrystalline cellulose and hydroxypropyl methylcellulose coated with a mixture of ethylcellulose and hydroxypropylmethylcellulose (see U.S. Patent Nos. 6,403,120 and 6,419,958). A controlled release formulation of budesonide (3 mg capsule) for the treatment of inflammatory bowel disease is available from AstraZeneca (sold as “Entocort ™”). Useful sustained-release formulations with corticosteroids are also described in US Patent No. 5,792,476, where the formulation releases at least 90% by weight of the glucocorticoid during about 40-80 minutes, Contains 2.5-7 mg of glucocorticoid as an active substance with controlled sustained-release, starting about 1-3 hours after entry of the corticoid into the patient's small intestine. In order to allow low dose levels of these active substances, the active substances, i.e. glucocorticoids such as prednisolone or prednisone, are micronized and mixed appropriately with known diluents such as starch and lactose, and PVP Granulate with (polyvinylpyrrolidone). In addition, the granules are laminated with a sustained release inner layer resistant to pH 6.8 and a sustained release outer layer resistant to pH 1.0. The inner layer is made of Eudragit® RL (a copolymer of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups) and the outer layer is Eudragit® L (methacrylic acid and methyl methacrylate) Anionic polymer synthesized from an ester).

  Bilayer tablets can be formed for the SSRI / steroid combination of the present invention, where different conventional granulations are made for each agent of the combination and the two agents are compressed into a bilayer press. Thus, a single tablet is formed. For example, 12.5 mg, 25 mg, 37.5 mg or 50 mg of paraxetine formulated for controlled release resulting in 15-20 hours of paroxetine t1 / 2 can be combined with 3 mg prednisolone in the same tablet, / 2 is prescribed to approximate that of paraxetine. Examples of paraxetine extended-release formulations, including those used in bilayer tablets, can be found in U.S. Patent No. 6,548,084. In addition to controlling the rate of prednisolone release in vivo, include an enteric or delayed release coating that delays the onset of drug release so that the Tmax of prednisolone approximates that of paraxetine (ie, 5-10 hours) Can do.

  Cyclodextrins are cyclic polysaccharides containing naturally occurring D (+)-glucopyranose units with α- (1,4) linkages. Α-, β- and γ-cyclodextrins, each containing 6, 7 or 8 glucopyranose units, are most commonly used and suitable examples are described in WO 91/11172, WO 94/02518 and WO 98/55148 Has been. Structurally, the cyclic nature of cyclodextrins is a torus or donut with an internal apolar or hydrophobic cavity, a secondary hydroxyl group located on one side of the cyclodextrin torus and a primary hydroxyl group located on the other. Form a shape. The side on which the secondary hydroxyl group is located has a wider diameter than the side on which the primary hydroxyl group is located. The hydrophobicity of the cyclodextrin internal cavity allows inclusion of various compounds (Comprehensive Supramolecular Chemistry, Volume 3, JLAtwood et al., Eds., Pergamon Press (1996); Cserhati, Analytical Biochemistry 225: 328-32 1995; Husain et al., Applied Spectroscopy 46: 652-8, 1992). Cyclodextrins can form non-covalent complexes by forming inclusion complexes with various drugs that can fit into the hydrophobic cavity of cyclodextrins, or with other biologically active molecules Have been used as delivery vehicles for various therapeutic compounds. US Patent No. 4,727,064 consists of a drug with substantially low water solubility and an amorphous water-soluble cyclodextrin-based mixture, where the drug forms an inclusion complex with the cyclodextrin of the mixture The formulation is described.

  The formulation of the drug-cyclodextrin complex can modify the solubility, dissolution rate, bioavailability, and / or stability characteristics of the drug. For example, cyclodextrins have been described to improve the bioavailability of prednisolone, as described by Uekama et al., J. Pharm Dyn. 6: 124-7, 1983. The β-cyclodextrin / prednisolone complex can be prepared by adding both components to water and stirring at 25 ° C. for 7 days. The resulting precipitate recovered is a 1: 2 prednisolone / cyclodextrin complex.

  Sulfobutyl ether-β-cyclodextrin (SBE-β-CD, commercially available from CyDex, Inc, Overland Park, KA, USA and sold as CAPTISOL®) is also a combination of the present invention. Can be used as an aid in the preparation of sustained-release formulations. For example, sustained-release tablets containing prednisolone and SBE-β-CD compressed in a hydroxypropylmethylcellulose matrix have been prepared (see Rao et al., J. Pharm. Sci. 90: 807-16,2001). . In another example of the use of various cyclodextrins, EP 1109806 B1 describes a cyclodextrin complex of parxetine, where an anhydrous or hydrated form of the agent for 1: 0.25 to 1:20 cyclodextrin The complex formation ratio [Eptakis (2-6-di-O-methyl) -β-cyclodextrin, (2,3,6-tri-O-methyl) -β-cyclodextrin, monosuccinyl eptakis (2, 6-Di-O-methyl) -β-cyclodextrin, or 2-hydroxypropyl-β-cyclodextrin is included] α-, γ- or β-cyclodextrin can be obtained.

  Polymeric cyclodextrins have also been prepared as described in U.S. Patent Application Serial Nos. 10 / 021,294 and 10 / 021,312. Cyclodextrin polymers so formed may be useful in the combination formulations of the present invention. These multifunctional polymer cyclodextrins are commercially available from Insert Therapeutics, Inc., Pasadena, CA, USA.

  As an alternative to directing complexation with the agent, cyclodextrin can be used as an auxiliary additive, for example as a carrier, diluent or solubilizer. Formulations containing cyclodextrin and other agents of the combination of the present invention (ie, SSRIs and / or steroids) can be prepared by methods similar to the preparation of cyclodextrin formulations described herein.

Liposome Formulation One or both components of the SSRI / steroid combination of the present invention, or a mixture of the two components together, can be integrated into a liposome carrier for administration. Liposome carriers are composed of three general types of vesicle-forming lipid components. The first includes vesicle-forming lipids that form a bulk of vesicle structure in the liposomes. In general, these vesicle-forming lipids include any amphipathic lipid with a hydrophobic and polar head group site, which (a) in bilayer vesicles in water, as exemplified by phospholipids (B) stably integrated into the lipid bilayer, its hydrophobic site is in contact with the internal hydrophobic region of the bilayer membrane, and its polar head group is the polar surface outside the membrane Head for.

  This type of vesicle-forming lipid is preferably one having two hydrocarbon chains, typically an acyl chain and a polar head group. This class includes phospholipids such as phosphatidylcholine (PC), PE, phosphatidic acid (PA), phosphatidylinositol (PI) and sphingomyelin (SM), where the two hydrocarbon chains are typically Has a length between about 14-22 carbon atoms and has varying degrees of unsaturation. Said lipids and phospholipids whose acyl chains have varying degrees of saturation are commercially available or can be prepared according to published methods. Other lipids that can be included in the present invention are glycolipids and sterols such as cholesterol.

  The second common component comprises vesicle-forming lipids derivatized with polymer chains that form a polymer layer in the composition. Vesicle-forming lipids that can be used as the second general vesicle-forming lipid component are any of those described for the first general vesicle-forming lipid component. Vesicle-forming lipids having a diacyl chain such as phospholipids are preferred. One exemplary phospholipid is phosphatidylethanolamine (PE), which provides a convenient reactive amino group for coupling to the activated polymer. An exemplary PE is distearyl PE (DSPE).

  The preferred polymer in the derivatized lipid is polyethylene glycol (PEG), preferably a PEG chain having a molecular weight between 1,000 and 15,000 daltons, more preferably between 2,000 and 10,000 daltons, most preferably between 2,000 and 5,000 daltons. . Other hydrophilic polymers that may be suitable are polyvinylpyrrolidone, polymethyloxazoline, polyethyloxazoline, polyhydroxypropylmethacrylamide, polymethylacrylamide and polydimethylacrylamide, polylactic acid, polyglycolic acid, and hydroxymethylcellulose or hydroxyethylcellulose. Derivatized cellulose.

  In addition, block copolymers or random copolymers of these polymers, particularly including PEG segments, are suitable. Methods for preparing lipids derivatized with hydrophilic polymers such as PEG are well known as described, for example, in U.S. Patent No. 5,013,556.

  A third common vesicle-forming lipid component that is optional is a lipid anchor, whereby the targeting site is anchored to the liposome via the polymer chain in the anchor. In addition, the targeting group is located at the end of the polymer chain so that the biological activity of the targeting site is not lost. Lipid anchors are activated or can be activated for covalent coupling to lipids in the outer layer of the liposome bilayer surface, polar head groups with the polymer internal ends covalently bound to it, and targeting sites It has a hydrophobic site that serves to anchor the (external) polymer ends. Methods for preparing this type of lipid anchor molecule are described below.

  The lipid component used to form the liposomes is preferably present in a molar ratio of about 70-90 percent vesicle-forming lipid, 1-25 percent polymer derivatized lipid, and 0.1-5 percent lipid anchor. . One exemplary formulation is 50-70 mole percent underivatized PE, 20-40 mole% cholesterol, 0.1-1 mole%, chemically reactive at its free end for coupling to the targeting site. PE-PEG (3500) polymer containing the following groups: 5-10 mol% PE derivatized with PEG3500 polymer chains, and 1 mol% alpha-tocopherol.

  Liposomes are preferably prepared to have a substantially uniform size, typically in a selected size range between about 0.03 and 0.5 microns. One effective sizing method for REV and MLV is to create an aqueous suspension of liposomes with a selected uniform pore size ranging from 0.03 to 0.2 microns, typically 0.05, 0.08, 0.1 or 0.2 microns. Extrusion through a series of polycarbonate membranes. The pore size of the membrane roughly corresponds to the largest size liposome produced by extrusion through the membrane, especially if the preparation is extruded more than once through the same membrane. Also, the homogenization method is useful for reducing the size of liposomes to a size of 100 nm or less.

  The liposome formulation of the present invention comprises at least one surfactant. Suitable surfactants useful in the SSRI / steroid combination formulations described herein include compounds belonging to the following classes: polyethoxylated fatty acids, PEG-fatty acid diesters, PEG-fatty acid monoesters and diesters Mixtures, polyethylene glycol glycerol fatty acid esters, alcohol-oil transesterification products, polyglycerized fatty acids, propylene glycol fatty acid esters, mixtures of polyethylene glycol esters and glycerol esters, mono- and diglycerides, sterol and sterol derivatives, polyethylene glycol sorbitan fatty acid esters, polyethylene Glycol alkyl ether, sugar ester, polyethylene glycol alkylphenol, polyoxyethylene-polyoxypropylene block copolymer, sol Vitan fatty acid esters, lower alcohol fatty acid esters, and ionic surfactants. Commercially available examples for each class of excipient are provided below.

  Polyethoxylated fatty acids can be used as excipients for the formulation of the SSRI / steroid combinations described herein. Examples of commercially available polyethoxylated fatty acid monoester surfactants are: PEG 4-100 monolaurate (Crodet L series, Croda), PEG 4-100 monooleate (Crodet O series, Croda), PEG 4- 100 monostearate (Crodet S series, Croda and Myrj series, Atlas / ICI), PEG400 distearate (Cithrol 4DS series, Croda), PEG100, 200, or 300 monolaurate (Cithrol ML series, Croda), PEG 100, 200 Or 300 monooleate (Cithrol MO series, Croda), PEG 400 dioleate (Cithrol 4DO series, Croda), PEG400-1000 monostearate (Cithrol MS series, Croda), PEG-1 stearate (Nikkol MYS-1EX, Nikko and Coster) K1, Condea), PEG-2 stearate (Nikkol MYS-2, Nikko), PEG-2 oleate (Nikkol MYO-2, Nikko), PEG-4 laurate (Mapeg (registered trademark) 200ML, PPG), PEG-4 Oleate (Mapeg (registered trademark) 200MO, PPG) PEG-4 stearate (Kessco® PEG 200MS, Stepan), PEG-5 stearate (Nikkol TMGS-5, Nikko), PEG-5 oleate (Nikkol TMGO-5, Nikko), PEG-6 oleate (Algon) OL 60, Auschem SpA), PEG-7 oleate (Algon OL 70, Auschem SpA), PEG-6 laurate (Kessco® PEG300 ML, Stepan), PEG-7 laurate (Lauridac 7, Condea), PEG-6 Stearate (Kessco® PEG300 MS, Stepan), PEG-8 laurate (Mapeg® 400 ML, PPG), PEG-8 oleate (Mapeg® 400MO, PPG), PEG-8 stearate (Mapeg (registered trademark) 400MS, PPG), PEG-9 oleate (Emulgante A9, Condea), PEG-9 stearate (Cremophor S9, BASF), PEG-10 laurate (Nikkol MYL-10, Nikko), PEG-10 Oleate (Nikkol MYO-10, Nikko), PEG-12 stearate (Nikkol MYS-10, Nikko), PEG-12 laurate (Kessco® PEG 600 ML, Stepan), PEG-12 oleate (Kessco (Registered trademark) PEG 600 MO, Stepan), PEG-12 resinoleate (CAS # 9004-97-1), PEG-12 stearate (Mapeg (registered trademark) 600 MS, PPG), PEG-15 stearate (Nikkol TMGS) -15, Nikko), PEG-15 oleate (Nikkol TMGO-15, Nikko), PEG-20 laurate (Kessco® PEG 1000 ML, Stepan), PEG-20 oleate (Kessco® PEG 1000 MO, Stepan), PEG-20 stearate (Mapeg (registered trademark) 1000 MS, PPG), PEG-25 stearate (Nikkol MYS-25, Nikko), PEG-32 laurate (Kessco (registered trademark) PEG 1540 ML, Stepan) PEG-32 oleate (Kessco® PEG 1540 MO, Stepan), PEG-32 stearate (Kessco® PEG 1540 MS, Stepan), PEG-30 stearate (Myrj 51), PEG-40 laurate (Crodet L40, Croda), PEG-40 oleate (Crodet O40, Croda), PEG-40 stearate (Emerest (registered trademark) 2715, Henkel), PEG-45 stearate (Nikkol MYS-45, Nikko), PEG- Five 0 Stearate (Myrj 53), PEG-55 stearate (Nikkol MYS-55, Nikko), PEG-100 oleate (Crodet O-100, Croda), PEG-100 stearate (Ariacel 165, ICI), PEG-200 Includes oleate (Albunol 200 MO, Taiwan Surf.), PEG-400 oleate (LACTOMUL, Henkel), and PEG-600 oleate (Albunol 600 MO, Taiwan Surf.). Formulations of one or both components of the SSRI / steroid combination according to the present invention may include one or more of the polyethoxylated fatty acids.

  Polyethylene glycol fatty acid diesters can also be used as excipients for the SSRI / steroid combinations described herein. Examples of commercially available polyethylene glycol fatty acid diesters are: PEG-4 dilaurate (Mapeg® 200 DL, PPG), PEG-4 dioleate (Mapeg® 200 DO, PPG), PEG-4 distearate (Kessco (registered trademark) 200DS, Stepan), PEG-6 dilaurate (Kessco (registered trademark) PEG 300 DL, Stepan), PEG-6 dioleate (Kessco (registered trademark) PEG 300 DO, Stepan), PEG-6 distearate ( Kessco® PEG 300 DS, Stepan), PEG-8 dilaurate (Mapeg® 400 DL, PPG), PEG-8 dioleate (Mapeg® 400 DO, PPG), PEG-8 distearate (Mapeg (Registered trademark) 400 DS, PPG), PEG-10 dipalmitate (Polyaldo 2PKFG), PEG-12 dilaurate (Kessco® PEG 600 DL, Stepan), PEG-12 distearate (Kessco® PEG 600 DS, Stepan), PEG-12 dioleate (Mapeg (registered trademark) 600 DO, PPG), PEG-20 dilaur (Kessco (R) PEG 1000 DL, Stepan), PEG-20 Dioleate (Kessco (R) PEG 1000 DO, Stepan), PEG-20 Distearate (Kessco (R) PEG 1000 DS, Stepan), PEG -32 dilaurate (Kessco® PEG 1540 DL, Stepan), PEG-32 dioleate (Kessco® PEG 1540 DO, Stepan), PEG-32 distearate (Kessco® PEG 1540 DS, Stepan), Includes PEG-400 dioleate (Cithrol4DO series, Croda) and PEG-400 distearate (Cithrol4DS series, Croda). Formulations of SSRI / steroid combinations according to the present invention can include one or more of the polyethylene glycol fatty acids described above.

  PEG-fatty acid mono- and di-ester mixtures can be used as excipients for the formulation of SSRI / steroid combinations described herein. Examples of commercially available PEG-fatty acid mono- and di-ester mixtures are: PEG 4-150 mono, dilaurate (Kessco® PEG 200-6000 mono, Dilaurate, Stepan), PEG 4-150 mono, dioleate (Kessco® PEG 200-6000 mono, Dioleate, Stepan), and PEG 4-150 mono, distearate (Kessco® 200-6000 mono, Distearate, Stepan). The formulation of the SSRI / steroid combination according to the present invention may comprise one or more of the PEG-fatty acid mono- and di-ester mixtures described above.

  In addition, polyethylene glycol glycerol fatty acid esters can be used as excipients for the formulation of the SSRI / steroid combinations described herein. Examples of commercially available polyethylene glycol glycerol fatty acid esters are: PEG-20 glyceryl laurate (Tagat® L, Goldschmidt), PEG-30 glyceryl laurate (Tagat® L2, Goldschmidt), PEG -15 glyceryl laurate (Glycerox L series, Croda), PEG-40 glyceryl laurate (Glycerox L series, Croda), PEG-20 glyceryl stearate (Capmul® EMG, ABITEC), and Aldo® MS-20 KFG, Lonza), PEG-20 glyceryl oleate (Tagat® O, Goldschmidt), and PEG-30 glyceryl oleate (Tagat® O2, Goldschmidt). Formulations of SSRI / steroid combinations according to the present invention can include one or more of the polyethylene glycol glycerol fatty acid esters described above.

  The alcohol-oil transesterification product can also be used as an excipient for the formulation of the SSRI / steroid combination described herein. Examples of commercially available alcohol-oil transesterification products are: PEG-3 castor oil (Nikkol CO-3, Nikko), PEG-5, 9 and 16 castor oil (ACCONON CA series, ABITEC), PEG-20 Castor oil (Emalex C-20, Nihon Emulsion), PEG-23 castor oil (Emulgante EL23), PEG-30 castor oil (Incrocas 30, Croda), PEG-35 castor oil (Incrocas-35, Croda), PEG-38 Castor oil (Emulgante EL 65, Condea), PEG-40 castor oil (Emalex C-40, Nihon Emulsion), PEG-50 castor oil (Emalex C-50, Nihon Emulsion), PEG-56 castor oil (Eumulgin®) ) PRT56, Pulcra SA), PEG-60 castor oil (Nikkol CO-60TX, Nikko), PEG-100 castor oil, PEG-200 castor oil (Eumulgin (registered trademark) PRT200, Pulcra SA), PEG-5 hydrogenated castor oil (Nikkol HCO-5, Nikko), PEG-7 hydrogenated castor oil (Cremophor WO7, BASF), PEG-10 hydrogenated castor oil (Nikkol HCO-10, Nikko), PEG-20 hydrogenated castor oil (Nikkol HCO-20, Nikko) ), PEG-25 hydrogenated castor oil (Simulsol (registered trademark) 1292, S eppic), PEG-30 hydrogenated castor oil (Nikkol HCO-30, Nikko), PEG-40 hydrogenated castor oil (Cremophor RH 40, BASF), PEG-45 hydrogenated castor oil (Cerex ELS 450, Auschem Spa), PEG-50 Hardened castor oil (Emalex HC-50, Nihon Emulsion), PEG-60 hardened castor oil (Nikkol HCO-60, Nikko), PEG-80 hardened castor oil (Nikkol HCO-80, Nikko), PEG-100 hardened castor oil ( Nikkol HCO-100, Nikko), PEG-6 corn oil (Labrafil® M 2125 CS, Gattefosse), PEG-6 almond oil (Labrafil® M 1966 CS, Gattefosse), PEG-6 apricot kernel oil (Labrafil (registered trademark) M 1944 CS, Gattefosse), PEG-6 olive oil (Labrafil (registered trademark) M 1980 CS, Gattefosse), PEG-6 peanut oil (Labrafil (registered trademark) M 1969 CS, Gattefosse), PEG- 6 hydrogenated palm kernel oil (Labrafil® M 2130 BS, Gattefosse), PEG-6 palm kernel oil (Labrafil® M 2130 CS, Gattefosse), PEG-6 triolein (Labrafil® M 2735) CS, Gattefosse), PEG-8 corn oil (Labrafil® WL 2609 BS, Gattefosse), PEG-20 corn glyceride (Crovol M40, Croda), PEG-20 almond glyceride (Crovol A40, Croda), PEG-25 trioleate ( TAGAT (registered trademark) TO, Gondschmidt), PEG-40 palm kernel oil (Crovol PK-70), PEG-60 corn glyceride (Crovol M70, Croda), PEG-60 almond glyceride (Crovol A70, Croda), PEG-4 Capryl / Capriglyceride (Labrafac (registered trademark) Hydro, Gattefosse), PEG-8 Capryl / Capringlyceride (Labrasol, Gattefosse), PEG-6 Capryl / Capringlyceride (SOFTIGEN (registered trademark) 767, Huls), Lauroyl Macrogol- 32 glycerides (GELUCIRE 44/14, Gattefosse), stearoyl macrogol glycerides (GELUCIRE 50/13, Gattefosse), mono, di, tri and tetra esters of vegetable oils and sorbitol (SorbitoGlyceride, Gattef osse), pentaerythrityl tetraisostearate (Crodamol PTIS, Croda), pentaerythrityl distearate (Albunol DS, Taiwan Surf.), pentaerythrityl tetraoleate (Liponate PO-4, Lipo Chem.), penta Erythrityl tetrastearate (Liponate PS-4, Lipo Chem.), Pentaerythrityl tetracaprylate tetracaprate (Liponate PE-810, Lipo Chem.), And pentaerythrityl tetraoctanoate (Nikkol Pentarate 408, Nikko )including. Also, as an oil, this category of surfactant includes oil-soluble vitamins such as vitamins A, D, E, K, and the like. Accordingly, derivatives of these vitamins such as tocopheryl PEG-1000 succinate (TPGS, available from Eastman) are also suitable surfactants. The formulation of the SSRI / steroid combination according to the present invention may include one or more of the alcohol-oil transesterification products described above.

  Polyglycerylated fatty acids can also be used as excipients for the formulation of the SSRI / steroid combinations described herein. Examples of commercially available polyglycerylated fatty acids are: polyglyceryl-2 stearate (Nikkol DGMS, Nikko), polyglyceryl-2 oleate (Nikkol DGMO, Nikko), polyglyceryl-2 isostearate (Nikkol DGMIS, Nikko), Polyglyceryl-3 oleate (Caprol® 3GO, ABITEC), polyglyceryl-4 oleate (Nikkol Tetraglyn 1-O, Nikko), polyglyceryl-4 stearate (Nikkol Tetraglyn 1-S, Nikko), polyglyceryl-6 oleate (Drewpol) 6-1-O, Stepan), polyglyceryl-10 laurate (Nikkol Decaglyn 1-L, Nikko), polyglyceryl-10 oleate (Nikkol Decaglyn 1-O, Nikko), polyglyceryl-10 stearate (Nikkol Decaglyn 1-S, Nikko) ), Polyglyceryl-6 ricinoleate (Nikkol Hexaglyn PR-15, Nikko), polyglyceryl-10 linoleate (Nikkol Decaglyn 1-LN, Nikko), polyglyceryl-6 pentaoleate Nikkol Hexaglyn 5-O, Nikko), polyglyceryl-3 dioleate (Cremophor GO32, BASF), polyglyceryl-3 distearate (Cremophor GS32, BASF), polyglyceryl-4 pentaoleate (Nikkol Tetraglyn 5-O, Nikko), polyglyceryl-6 Dioleate (Caprol® 6G20, ABITEC), polyglyceryl-2 dioleate (Nikkol DGDO, Nikko), polyglyceryl-10 trioleate (Nikkol Decaglyn 3-O, Nikko), polyglyceryl-10 pentaoleate (Nikkol Decaglyn 5-O, Nikko), polyglyceryl-10 septaoleate (Nikkol Decaglyn 7-O, Nikko), polyglyceryl-10 tetraoleate (Caprol® 10G4O, ABITEC), polyglyceryl-10 decaisostearate (Nikkol Decaglyn 10-IS, Nikko), polyglyceryl-101 decaoleate (Drewpol 10-10-O, Stepan), polyglyceryl-10 mono, dioleate (Caprol (registered trademark) PGE860, ABITE) C), and polyglyceryl polyricinoleate (Polymuls, Henkel). The formulation of the SSRI / steroid combination according to the present invention may comprise one or more of the polyglycerylated fatty acids.

  In addition, propylene glycol fatty acid esters can be used as excipients for the formulation of the SSRI / steroid combinations described herein. Examples of commercially available propylene glycol fatty acid esters are: propylene glycol monocaprylate (Capryol 90, Gattefosse), propylene glycol monolaurate (Lauroglycol 90, Gattefosse), propylene glycol oleate (Lutrol OP2000, BASF), propylene Glycol myristate (Mirpyl), propylene glycol monostearate (LIPO PGMS, Lipo Chem.), Propylene glycol hydroxystearate, propylene glycol ricinoleate (PROPYMULS, Henkel), propylene glycol isostearate, propylene glycol monooleate ( Myverol P-O6, Eastman), propylene glycol dicaprylate dicaprate (Captex® 200, ABITEC), propylene glycol dioctanoate (Captex® 800, ABITEC), propylene glycol cap Relate caprate (LABRAFAC PG, Gattefosse), propylene glycol dilaurate, propylene glycol distearate (Kessco® PGDS, Stepan), propylene glycol dicaprylate (Nikkol Sefsol 228, Nikko), and propylene glycol dicaprate (Nikkol) PDD, Nikko). The formulation of the SSRI / steroid combination according to the present invention may include one or more of the propylene glycol fatty acid esters described above.

  Mixtures of propylene glycol esters and glycerol esters can also be used as excipients for the formulation of the SSRI / steroid combinations described herein. One preferred mixture is composed of propylene glycol and glycerol oleate (Arlacel 186). Examples of these surfactants include: oleic acid (ATMOS 300, ARLACEL 186, ICI), and stearic acid (ATMOS 150). Formulations of SSRI / steroid combinations according to the present invention can include one or more of the propylene glycol ester and glycerol ester mixtures described above.

  In addition, mono- and diglycerides can be used as excipients for the formulation of the SSRI / steroid combinations described herein. Examples of commercially available mono- and diglycerides are: monopalmitolein (C16: 1) (Larodan), monoelaidin (C18: 1) (Larodan), monocaproin (C6) (Larodan), monocaprylin (Larodan), mono Caprin (Larodan), monolaurin (Larodan), glyceryl monomyristate (C14) (Nikkol MGM, Nikko), glyceryl monooleate (C18: 1), (PECEOL, Gattefosse), glyceryl monooleate (Myverol, Eastman), Glycerol monooleate / linoleate (OLICINE, Gattefosse), glycerol monolinoleate (Maisine, Gattefosse), glyceryl ricinoleate (Softigen® 701, Huls), glyceryl monolaurate (ALDO® MLD, Lonza ), Glycerol monopalmitate (Emalex GMS-P, Nihon), glycerol monostearate (Capmul (registered trademark) GMS, ABITEC) Glyceryl mono- and dioleate (Capmul® GMO-K, ABITEC), glyceryl palmitic / stearic (CUTINA MD-A, ESTAGEL-G18), glyceryl acetate (Lamegin® EE, Grunau GmbH), Glyceryl laurate (Imwitor® 312, Huls), glyceryl citrate / lactate / oleate / linoleate (Imwitor® 375, Huls), glyceryl caprylate (Imwitor® 308, Huls), glyceryl capri Rate / Caprate (Capmul® MCM, ABITEC), caprylic acid mono- and diglycerides (Imwitor® 988, Huls), capric / capric glycerides (Imwitor® 742, Huls), mono- And diacetylated monoglyceride (Myvacet® 9-45, Eastman), glyceryl monostearate (Aldo® MS, Arlacel 129, ICI), mono And diglyceride lactate (LAMEGIN GLP, Henkel), dicaproin (C6) (Larodan), dicaprin (C10) (Larodan), dioctanoin (C8) (Larodan), dimyristin (C14) (Larodan), dipalmitin (C16) (Larodan), distearin, glyceryl dilaurate (C12) (Capmul® GDL, ABITEC), glyceryl dioleate (Capmul® GDO, ABITEC), glycerol esters of fatty acids (GELUCIRE 39/01, Gattefosse), dipalmitrain (C16: 1) (Larodan), 1,2 and 1,3-diolein (C18: 1) (Larodan), dielidine (C18: 1) (Larodan), and dilinolein (C18: 2) ( Larodan). Formulations of SSRI / steroid combinations according to the present invention can include one or more of the mono- and diglycerides described above.

  Sterols and sterol derivatives can also be used as excipients for the formulation of the SSRI / steroid combinations described herein. Examples of commercially available sterols and sterol derivatives are: cholesterol, sitosterol, lanosterol, PEG-24 cholesterol ether (Solulan C-24, Amerchol), PEG-30 cholestanol (Phytosterol GENEROL series, Henkel), PEG-25 Phytosterol (Nikkol BPSH-25, Nikko), PEG-5 soyasterol (Nikkol BPS-5, Nikko), PEG-10 soyasterol (Nikkol BPS-10, Nikko), PEG-20 soyasterol (Nikkol BPS-20, Nikko) ), And PEG-30 soyasterol (Nikkol BPS-30, Nikko). The formulation of the SSRI / steroyl combination according to the present invention may include one or more of the sterols and sterol derivatives.

  Polyethylene glycol sorbitan fatty acid esters can also be used as excipients for the formulation of SSRI / steroid combinations described herein. Examples of commercially available polyethylene glycol fatty acid esters are: PEG-10 sorbitan laurate (Liposorb L-10, Lipo Chem.), PEG-20 sorbitan monolaurate (Tween® 20, Atlas / ICI) PEG-4 sorbitan monolaurate (Tween (registered trademark) 21, Atlas / ICI), PEG-80 sorbitan monolaurate (Hodag PSML-80, Calgene), PEG-6 sorbitan monolaurate (Nikkol GL-1, Nikko), PEG-20 sorbitan monopalmitate (Tween® 40, Atlas / ICI), PEG-20 sorbitan monostearate (Tween® 60, Atlas / ICI), PEG-4 sorbitan monostearate (Tween (registered trademark) 61, Atlas / ICI), PEG-8 sorbitan monostearate (DACOL MSS, Condea), PEG-6 sorbitan monostearate (Nikkol TS106, Nikko), PEG-20 sorbitan tristearate (Tween (Registered trademark) 65, Atlas / ICI), PEG-6 sorbitan tetras Allate (Nikkol GS-6, Nikko), PEG-60 sorbitan tetrastearate (Nikkol GS-460, Nikko), PEG-5 sorbitan monooleate (Tween (registered trademark) 81, Atlas / ICI), PEG-6 sorbitan Monooleate (Nikkol TO-106, Nikko), PEG-20 sorbitan monooleate (Tween® 80, Atlas / ICI), PEG-40 sorbitan oleate (Emalex ET 8040, Nihon Emulsion), PEG-20 Sorbitan trioleate (Tween® 85, Atlas / ICI), PEG-6 sorbitan tetraoleate (Nikkol GO-4, Nikko), PEG-30 sorbitan tetraoleate (Nikkol GO-430, Nikko), PEG- 40 sorbitan tetraoleate (Nikkol GO-440, Nikko), PEG-20 sorbitan monoisostearate (Tween® 120, Atlas / ICI), PEG sorbitol hexaoleate (Atlas G-1086, ICI), polysorbate 80 (Tween® 80, Pharma), polysorbate 85 (Tween Trademark) 85, Pharma), Polysorbate 20 (Tween® 20, Pharma), Polysorbate 40 (Tween® 40, Pharma), Polysorbate 60 (Tween® 60, Pharma), and PEG-6 Contains sorbitol hexastearate (Nikkol GS-6, Nikko). The SSRI / steroid combination formulation according to the present invention may comprise one or more of the polyethylene glycol sorbitan fatty acid esters.

  In addition, polyethylene glycol alkyl ethers can be used as excipients for the formulation of SSRI / steroid combinations described herein. Examples of commercially available polyethylene glycol alkyl ethers are: PEG-2 oleyl ether, oleth-2 (Brij 92/93, Atlas / ICI), PEG-3 oleyl ether, oleth-3 (Volpo 3, Croda), PEG-5 oleyl ether, oleth-5 (Volpo 5, Croda), PEG-10 oleyl ether, oleth-10 (Volpo 10, Croda), PEG-20 oleyl ether, oleth-20 (Volpo 20, Croda), PEG- 4 lauryl ether, laureth-4 (Brij 30, Atlas / ICI), PEG-9 lauryl ether, PEG-23 lauryl ether, laureth-23 (Brij 35, Atlas / ICI), PEG-2 cetyl ether (Brij 52, ICI) ), PEG-10 cetyl ether (Brij 56, ICI), PEG-20 cetyl ether (BriJ 58, ICI), PEG-2 stearyl ether (Brij 72, ICI), PEG-10 stearyl ether (Brij 76, ICI), PEG-20 stearyl ether (Brij 78, ICI) and PEG-100 stearyl ether (Brij 700, ICI). Formulations of SSRI / steroid combinations according to the present invention can include one or more of the polyethylene glycol alkyl ethers described above.

  Sugar esters can also be used as excipients for the formulation of the SSRI / steroid combinations described herein. Examples of commercially available sugar esters are: sucrose distearate (SUCRO ESTER 7, Gattefosse), sucrose distearate / monostearate (SUCRO ESTER 11, Gattefosse), sucrose dipalmitate, sucrose monostearate ( Crodesta F-160, Croda), sucrose monopalmitate (SUCRO ESTER 15, Gattefosse), and sucrose monolaurate (Saccharose monolaurate 1695, Mitsubisbi-Kasei). Formulations of SSRI / steroid combinations according to the present invention can include one or more of the sugar esters.

  Polyethylene glycol alkylphenols are also useful as excipients for the formulation of the SSRI / steroid combinations described herein. Examples of commercially available polyethylene glycol alkylphenols include: PEG-10-100 nonylphenol series (Triton X series, Rohm & Haas) and PEG-15-100 octylphenol ether series (Triton N-series, Rohm & Haas) . Formulations of SSIR / steroid combinations according to the present invention may include one or more of the polyethylene glycol alkylphenols.

Polyoxyethylene-polyoxypropylene block copolymers can also be used as excipients for the formulation of SSRI / steroid combinations described herein. These surfactants are available under various trade names, including one or more of the Synperonic PE series (ICI), Pluronic® series (BASF), Lutrol (BASF), Supronic, Monolan, Pluracare and Plurodac Is possible. The general term for these copolymers is “poloxamer” (CAS 9003-11-6). These polymers have the formula (X):
HO (C2H4O) a (C3H6O) b (C2H4O) aH (X)
(Wherein “a” and “b” indicate the number of polyoxyethylene and polyoxypropylene units, respectively)
Have These copolymers are available in molecular weights ranging from 1000 to 15000 daltons and the ethylene oxide / propylene oxide ratio is between 0.1 and 0.8 by weight. The SSRI / steroid combination formulation according to the present invention may include one or more of the polyoxyethylene-polyoxypropylene block copolymers.

  Polyoxyethylenes such as PEG300, PEG400, and PEG600 can be used as excipients for the formulation of the SSRI / steroid combinations described herein.

  Sorbitan fatty acid esters can also be used as excipients for the formulation of the SSRI / steroid combinations described herein. Examples of commercially available sorbitan fatty acid esters are: sorbitan monolaurate (Span-20, Atlas / ICI), sorbitan monopalmitate (Span-40, Atlas / ICI), sorbitan monolaurate (Span-80, Atlas / ICI), sorbitan monostearate (Span-60, Atlas / ICI), sorbitan trioleate (Span-85, Atlas / ICI), sorbitan sesquioleate (Arlacel-C, ICI), sorbitan tristearate (Span -65, Atlas / ICI), sorbitan monoisostearate (Crill 6, Croda), and sorbitan sesquiisostearate (Nikkol SS-15, Nikko). The formulation of the SSRI / steroid combination according to the present invention may include one or more of the sorbitan fatty acid esters.

  Esters of lower alcohols (C2-C4) and fatty acids (C8-C18) are suitable surfactants for use in the present invention. Examples of these surfactants are: ethyl oleate (Crodamol EO, Croda), isopropyl myristate (Crodamol IPM, Croda), isopropyl palmitate (Crodamol IPP, Croda), ethyl linoleate (Nikkol VF-E, Nikko) And isopropyl linoleate (Nikkol VF-IP, Nikko). The formulation of the SSRI / steroid combination according to the present invention may include one or more of the lower alcohol fatty acid esters.

  In addition, ionic surfactants can be used as excipients for the formulation of the SSRI / steroid combinations described herein. Examples of useful ionic surfactants are: sodium caproate, sodium caprylate, sodium caprate, sodium laurate, sodium myristate, sodium myristate, sodium palmitate, sodium palmitate, sodium oleate, sodium lysate Noreate, sodium linoleate, sodium linolenate, sodium stearate, sodium lauryl sulfate (dodecyl), sodium tetradecyl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, sodium taurocholate Sodium glycocholate, sodium deoxycholate, sodium taurodeoxycholate, sodium glycodeoxycholate, sodium Lium ursodeoxycholate, sodium chenodeoxycholate, sodium taurochenodeoxycholate, sodium glycochenodeoxycholate, sodium cholyl sarcosinate, sodium N-methyl taurocholate, egg yolk phosphatide, hardened soybean lecithin, dimyristoyl lecithin, lecithin, hydroxyl Lecithin, lysophosphatidylcholine, cardiolipin, sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidic acid, phosphatidylglycerol, phosphatidylserine, diethanolamine, phospholipids, polyoxyethylene-10 oleyl ether phosphate, fatty alcohol or fatty alcohol ethoxylate and phosphoric acid Or esterification product with anhydride, (fatty alcohol Ether carboxylates (by oxidation of terminal OH groups of ruethoxylates), succinylated monoglycerides, sodium stearyl fumarate, stearoyl propylene glycol hydrogen succinate, mono- and diglyceride mono / diacetylated tartaric acid esters, mono-, diglyceride citrate esters , Fatty acid glyceryl-lacto ester, acyl lactylate, fatty acid lactyl ester, sodium stearoyl-2-lactyrate, sodium stearoyl lactylate, alginate salt, propylene glycol alginate, ethoxylated alkyl sulfate, alkylbenzene sulfone, α-olefin sulfonate , Acyl isethionate, acyl taurate, alkyl glyceryl ether sulfonate, sodium octoate Sulfosuccinate, sodium undecylenamide-MEA-sulfosuccinate, hexadecyltriammonium bromide, decyltrimethylammonium bromide, decyltrimethylammonium bromide, cetyltrimethylammonium bromide, dodecylammonium chloride, alkylbenzyldimethylammonium salt , Diisobutylphenoxyethoxydimethylbenzylammonium salt, alkylpyridinium salt, betaine (trialkylglycine), laurylbetaine (N-lauryl, N, N-dimethylglycine), and ethoxylated amine (polyoxyethylene-15 coconut amine) . For simplicity, typical counter ions are provided above. However, it will be understood by those skilled in the art that any biologically acceptable counterion can be used. For example, the fatty acids are shown as sodium salts, but other cation counterions such as alkali metal cations or ammonium can also be used. The formulation of the SSRI / steroid combination according to the present invention may include one or more of the ionic surfactants.

  Excipients present in the formulations of the present invention are present in an amount such that the carrier forms a clear or opaque aqueous dispersion of SSRI, steroid, or SSRI / steroid combination sequestered within the liposomes. The relative amount of surface-active excipients required for the preparation of liposomes or solid liquid nanoparticle formulations is determined using known methods. For example, liposomes can be prepared by various techniques such as those described in detail in Szoka et al., 1980. Multilayer vesicles (MLV) can be formed by simple lipid-film hydration techniques. In this procedure, a liposome-forming lipid mixture of the type described in detail above dissolved in a suitable organic solvent is evaporated in a container to form a thin film which is then coated with an aqueous medium. The lipid film hydrates to form MLVs typically having a size between about 0.1-10 microns.

  Other established liposome formulation techniques can be applied as needed. For example, the use of liposomes to facilitate cell uptake is described in U.S. Patent Nos. 4,897,355, and 4,394,448.

Dosage Generally, when administered orally to humans, the SSRI dosage is usually about 0.001 mg to 200 mg per day, desirably about 1 mg to 100 mg per day, more desirably about 5 mg to 50 mg per day. A dose of up to 200 mg per day will be required. For administration of SSRI by injection, the dosage is usually about 1 mg to 250 mg per day, desirably about 5 mg to 200 mg per day, more desirably about 10 mg to 150 mg per day. Injections are desirably given 1 to 4 times daily.

  When administered systemically to humans, the corticosteroid dose used in combination with SSRIs is usually about 0.1 mg to 1500 mg per day, preferably about 0.5 mg to 10 mg per day, more preferably about 0.5 mg to 5 mg per day is there.

  The administration of each drug in the combination is independently from 1 to 4 times daily for a day to a year and may be for the patient's life. Chronic long-term administration will often be indicated.

Further Applications Using the compounds of the present invention in immunomodulation or mechanistic assays, other combinations, or single agents, can be performed using assays generally known in the art, examples of which are described herein. It can be used to determine whether it is as effective as a combination in inhibiting the secretion or production of inflammatory cytokines or modulating the immune response. For example, candidate compounds can be combined with SSRIs (or metabolites or analogs thereof) or corticosteroids to adapt to stimulated PBMC. After an appropriate time, the cells are examined for cytokine secretion or production or other appropriate immune response. Compare the relative effects of combinations vs. each other and vs a single agent to identify effective compounds and combinations.

  The combination of the present invention is also a useful tool in elucidating mechanistic information about biological pathways involved in inflammation. Such information can lead to the development of new combinations or single agents to inhibit inflammation caused by inflammatory cytokines. A pathway, or pathway, affected by contacting cells stimulated to produce inflammatory cytokines with a compound of the invention using methods known in the art for determining biological pathways Network can be determined. Such a method may comprise a cellular component that is expressed or suppressed after contact with a compound of the invention compared to an untreated positive or negative control compound and / or a new single agent and combination. Analyzing or analyzing several other metabolic activities of the cell, such as enzyme activity, nutrient uptake and proliferation. Analyzed cellular components can include gene transcripts and protein expression. Appropriate methods include observing compounds that bind to proteins using standard biochemical techniques, radioactive labeling of compounds of the invention (eg 14C or 3H labeling), and eg 2D gels, gene expression profiling. Can be included. Once identified, such compounds can be used in in vivo models to further validate tools or develop new anti-inflammatory agents.

  The following examples illustrate the invention. They are not intended to limit the invention in any way.

Example 1 Assay for Inflammatory Cytokine-Inhibitory Activity Compound dilution matrices were assayed for inhibition of IFNγ, IL-1β, IL-2, IL-4, IL-5 and TNFα as described below.

IFNγ
In each well of a polystyrene 384-well plate (NalgeNunc) by treatment with a final concentration of 10 ng / mL phorbol 12-myristate 13-acetate (Sigma, P-1585) and 750 ng / mL ionomycin (Sigma, I-0634) The 100 μL suspension of diluted human white blood cells contained was stimulated to secrete IFNγ. Various concentrations of each test compound were added at the time of stimulation. After 16-18 hours of incubation at 37 ° C. in a humidified incubator, the plates were centrifuged and the supernatant was coated with anti-IFNγ antibody (Endogen, # M-700A-E) in a white opaque polystyrene 384 well plate ( NalgeNunc, Maxisorb). After a 2 hour incubation, the plates were washed with phosphate buffered saline (PBS) containing 0.1% Tween20 (polyoxyethylene sorbitan monolaurate) (Tecan Power Washer 384) and another biotinylated label. Two additional incubations with one anti-IFNγ antibody (Endogen, M701B) and horseradish peroxidase (HRP) coupled to streptavidin (PharMingen, # 13047E). After the plate was washed with 0.1% Tween20 / PBS, HRP-luminescent substrate was added to each well and the light intensity was measured using an LJL Analyst plate luminometer.

IL-1β
A 100 μL suspension of diluted human white blood cells contained in each well of a polystyrene 384 well plate (NalgeNunc) was stimulated by treatment with lipopolysaccharide (Sigma L-4130) at a final concentration of 2 μg / mL to produce IL- 1β was secreted. Various concentrations of each test compound were added at the time of stimulation. After 18-18 hours of incubation at 37 ° C. in a humidified incubator, the plates were centrifuged and white opaque polystyrene 384 well plates (NalgeNunc, Maxisorb) coated with anti-IL-1β antibody (R & D, # MAB-601) The supernatant was transferred to. After 2 hours of incubation, the plates were washed with PBS containing 0.1% Tween 20 (Tecan Power Washer 384), another biotinylated anti-IL-1β antibody (R & D, BAF-201) and streptavidin Incubated for an additional hour with HRP coupled to (PharMingen, # 13047E). After washing the plate with 0.1% Tween 20 / PBS, HRP-luminescent substrate was added to each well and the light intensity was measured using an LJL Analyst plate luminometer.

IL-2
A 100 μL suspension of diluted human white blood cells contained in each well of a polystyrene 384 well plate (NalgeNunc) was added to a final concentration of 10 ng / mL phorbol 12-myristate 13-acetate (Sigma, P-1585) and 750 ng / IL-2 was secreted by treatment with mL ionomycin (Sigma, I-0634). Various concentrations of each test compound were added at the time of incubation. After 16-18 hours of incubation at 37 ° C. in a humidified incubator, the plate is centrifuged and topped onto a white opaque polystyrene 384 well plate (NalgeNunc, Maxisorb) coated with anti-IL-2 antibody (PharMingen, # 555051). The clear was transferred. After 2 hours of incubation, the plates were washed with PBS containing 0.1% Tween 20 (Tecen Power Washer 384) and cupped with another biotinylated anti-IL-2 antibody (Endogen, M600B) and streptavidin. Incubated for an additional hour with ringed HRP (PharMingen, # 13047E). After the plate was washed with 0.1% Tween 20 / PBS, HRP-luminescent substrate was added to each well and the light intensity was measured using an LJL Analyst plate luminometer.

IL4 and IL-5
The expression of IL-4 and IL-5 cytokines was analyzed using a BD PharMingen Cytometric 6 Bead Array system according to the manufacturer's instructions. Briefly, the supernatant from the buffy coat assay plate was incubated with a labeled cytokine detection bead cocktail. Samples were then washed, resuspended and read on a BD Pharmingen FACsCalibur flow cytometer. The data was then analyzed using BD Pharmingen CBA 6 Bead Analysis software.

TNFα
A 100 μL suspension of diluted human white blood cells contained in each well of a polystyrene 384 well plate (NalgeNunc) was stimulated to treat TNFα by treatment with lipopolysaccharide (Sigma L-4130) at a final concentration of 2 μg / mL. Secreted. Various concentrations of each test compound were added at the time of stimulation. After 16-18 hours of incubation at 37 ° C in a humidified incubator, the plate is centrifuged and the supernatant is placed in a white opaque polystyrene 384 well plate (NalgeNunc, Maxisorb) coated with anti-TNFα antibody (PharMingen, # 551220). Moved. After 2 hours of incubation, the plate was washed with PBS containing 0.1% Tween 20 (Tecan Power Washer 384) and coupled to another biotinylated anti-TNFα antibody (PharMingen, # 554511) and streptavidin. Incubated with HRP (PharMingen, # 13047E) for an additional hour. After the plate was washed with 0.1% Tween20 / PBS, HRP-luminescent substrate was added to each well and the light intensity was measured using an LJL Analyst plate luminometer.

Example 2: Compound Preparation Stock solutions containing corticosteroids or SSRIs were made in dimethyl sulfoxide (DMSO) at final concentrations between 0 and 40 μM. Master plates were prepared to contain dilutions of the stock solutions of the compounds described above. The master plate was sealed and stored at −20 ° C. until ready to use.

  Using a Packard Mini-Trak liquid handler, 1 μL stock solution from a specific master plate was added to 100 μL medium (RPMI; Gibco BRL, # 11875-085), 10% fetal calf serum (Gibco BRL, # 25140-097), The final single agent plate was made by transferring to a dilution plate containing 2% penicillin / streptomycin (Gibco BRL, # 15140-122). This dilution plate is then mixed and a 5 μL aliquot is transferred to a final assay plate pre-filled with 50 μL / well RPMI medium containing the appropriate stimulator to activate IFNγ, IL-1β, IL-2 or TNFα secretion (See Example 1, supra)

Example 3: Testing SSRIs, analogs and metabolites for inflammatory cytokine inhibitory activity A single agent is capable of inhibiting the secretion of IFNγ, IL-1β, IL-2 and TNFα from stimulated white blood cells. Tested to determine the percent inhibition of cytokine secretion relative to untreated stimulated white blood cells. The data is shown in Tables 5-14 below.

(Table 5) Fluoxetine

(Table 6) Fluvoxamine

(Table 7) Paroxetine

(Table 8) Sertraline

(Table 9) Venlafaxine

(Table 10) Norfluoxetine

Table 11: R (+) fluoxetine

Table 12: S (+) fluoxetine

(Table 13) Dimerzine

(Table 14) Citalopram

Example 4: SSRI test for TNFα inhibitory activity
A combination of SSRI and corticosteroid was tested for the ability to suppress TNFα secretion from stimulated white blood cells and the percent inhibition of cytokine secretion relative to untreated stimulated white blood cells was measured. Data are shown in Tables 15-22.

(Table 15)

(Table 16)

(Table 17)

(Table 18)

(Table 19)

(Table 20)

(Table 21)

(Table 22)

  The ability of the combination of prednisolone and paroxetine to inhibit IL-4 and IL-5 secretion in vitro was also tested. The results are shown in Tables 23 and 24.

(Table 23) IL-4

(Table 24) IL-5

Example 5: The combination of cyclosporin A and sertraline reduces IL-2 secretion in vitro.
Following stimulation with phorbol 12-myristate 13-acetate and ionomycin, IL-2 secretion was measured by ELISA as described above. The effects of various concentrations of cyclosporin A, sertraline, and the combination of sertraline and cyclosporin A were compared to control wells. These wells were stimulated with phorbol 12-myristate 13-acetate and ionomycin but did not receive cyclosporin A or sertraline.

  The results of this experiment are shown in Table 25. The effect of agents alone or in combination is shown as percent inhibition of IL-2 secretion.

(Table 25)

Example 6: The combination of cyclosporin A and sertraline reduces IFNγ secretion in vitro.
Following stimulation with phorbol 12-myristate 13-acetate and ionomycin, secretion of IFNγ was measured by ELISA as described above. The effect of cyclosporin A in combination with various concentrations of cyclosporin A, sertraline, and sertraline was compared to control wells stimulated without cyclosporin A or sertraline. The results of this experiment are shown in Table 26 below. The effect of the agent alone and in combination is shown as percent inhibition of IFNγ secretion.

(Table 26)

Example 7: The combination of cyclosporin A and sertraline reduces TNFα secretion in vitro.
Following stimulation with phorbol 12-myristate 13-acetate and ionomycin, TNFα secretion was measured by ELISA as described above. The effects of various concentrations of cyclosporin A, sertraline, and cyclosporin A in combination with sertraline were compared to control wells stimulated without either cyclosporin A or sertraline. The results are shown in Table 27 below. The effect of the agent alone and in combination is shown as percent inhibition of TNFα secretion.

(Table 27)

Example 8: The combination of cyclosporin A and fluoxetine reduces IL-2 secretion in vitro.
Following stimulation with phorbol 12-myristate 13-acetate and ionomycin, secretion of IL-2 was measured by ELISA as described above. The effect of cyclosporin A in combination with various concentrations of cyclosporin A, fluoxetine, and fluoxetine was compared to control wells stimulated without either cyclosporine A or fluoxetine. The results of this experiment are shown in Table 28 below. The effects of single and combined agents are shown as percent inhibition of IL-2 secretion.

(Table 28)

Example 9: Tacrolimus and fluvoxamine combination reduces IL-2 secretion in vitro.
Following stimulation with phorbol 12-myristate 13-acetate and ionomycin, secretion of IL-2 was measured by ELISA as described above. The effects of tacrolimus in combination with various concentrations of tacrolimus, fluvoxamine, and fluvoxamine were compared to control wells stimulated without either tacrolimus or fluvoxamine. The results of this experiment are shown in Table 29 below. The effects of single and combined agents are shown as percent inhibition of IL-2 secretion.

(Table 29)

Example 10: The combination of cyclosporin A and paroxetine reduces IL-2 secretion in vitro.
Following stimulation with phorbol 12-myristate 13-acetate and ionomycin, secretion of IL-2 was measured by ELISA as described above. The effects of cyclosporin A in combination with various concentrations of cyclosporin A, paroxetine, and paroxetine were compared to control wells stimulated without cyclosporin A or paroxetine. The results of this experiment are shown in Table 30 below. The effects of single and combined agents are shown as percent inhibition of IL-2 secretion.

(Table 30)

Other Embodiments Various modifications and variations of the described methods and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. While the invention has been described in connection with specific desired embodiments, it will be understood that the claimed invention should not be limited to such specific embodiments. In fact, various modifications of the described forms for carrying out the invention that are obvious to those skilled in the art of medicine, immunology, pharmacology, endocrinology, or related fields are intended to be within the scope of the present invention.

Claims (77)

  A composition comprising a selective serotonin reuptake inhibitor (SSRI) and a corticosteroid, in combination, in an amount sufficient to reduce secretion or production of inflammatory cytokines in vivo.   SSRI is celiclamine, citalopram, cloboxamine, cyanodothiepine, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, indeloxazine, ritoxetine, milnacipran, paroxetine, sertraline, melodiline, claim tradextrin, tametraline, claim The composition according to 1.   2. The composition of claim 1, wherein the corticosteroid is prednisolone, cortisone, budesonide, dexamethasone, hydrocortisone, methylprednisolone, fluticasone, prednisone, triamcinolone, or diflorazone.   2. The composition of claim 1, wherein the SSRI is fluoxetine or paroxetine and the corticosteroid is prednisolone.   2. The composition of claim 1, wherein the SSRI or corticosteroid is present in the composition at a low dose.   2. The composition of claim 1, wherein the SSRI or corticosteroid is present in the composition at a high dose.   NSAID, COX-2 inhibitor, biologic, DMARD, xanthine, anticholinergic compound, beta receptor agonist, bronchodilator, nonsteroidal calcineurin inhibitor, vitamin D analog, psoralen, retinoid, and 5-amino 2. The composition of claim 1, further comprising salicylic acid.   8. The composition of claim 7, wherein the NSAID is ibuprofen, diclofenac, or naproxen.   8. The composition of claim 7, wherein the COX-2 inhibitor is rofecoxib, celecoxib, valdecoxib, or lumiracoxib.   8. The composition of claim 7, wherein the biologic is adelimumab, etanercept, or infliximab.   8. The composition of claim 7, wherein DMARD is methotrexate or leflunomide.   8. The composition of claim 7, wherein the xanthine is theophylline.   8. The composition of claim 7, wherein the anticholinergic compound is ipratropium or tiotropium.   β receptor agonist is ibuterol sulfate, vitorterol mesylate, epinephrine, formoterol fumarate, isoproterenol, levalbuterol hydrochloride, metaproterenol sulfate, pyrbuterol scetate, salmeterol xinafoate, or terbutaline 8. The composition of claim 7, wherein   8. The composition of claim 7, wherein the non-steroidal calcineurin inhibitor is cyclosporine, tacrolimus, pimecrolimus, or ISAtx247.   8. The composition of claim 7, wherein the vitamin D analog is calcipotriene or calcipotriol.   8. The composition of claim 7, wherein the psoralen is methoxalene.   8. The composition of claim 7, wherein the retinoid is acitretin or tazoletene.   8. The composition of claim 7, wherein the 5-aminosalicylic acid is mesalamine, sulfasalazine, balsalazide disodium, or olsalazine sodium.   2. The composition of claim 1 formulated for topical administration.   2. The composition of claim 1, wherein the composition is formulated for systemic administration.   Administration of SSRIs and corticosteroids to a patient within 14 days simultaneously or from each other in an amount sufficient in vivo to reduce the secretion or production of the inflammatory cytokine in the patient. A method of reducing secretion or production.   Diagnosed or at risk of developing an immune inflammatory disorder that includes administering SSRIs and corticosteroids simultaneously or within 14 days of each other in a sufficient amount to treat the patient A method of treating a patient diagnosed as having.   Immune inflammation disorders include rheumatoid arthritis, Crohn's disease, ulcerative colitis, asthma, chronic obstructive pulmonary disease, rheumatic polymyalgia, giant cell arthritis, systemic lupus erythematosus, atopic dermatitis, multiple sclerosis, severe 24. The method of claim 23, which is myasthenia, psoriasis, ankylosing spondylitis, or psoriatic arthritis.   SSRI is celiclamine, citalopram, cloboxamine, cyanodothiepine, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, indeloxazine, ritoxetine, milnacipran, paroxetine, sertraline, melodiline, claim tradextrin, tametraline, claim The method according to 23.   24. The method of claim 23, wherein the corticosteroid is prednisolone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, fluticasone, prednisone, triamcinolone, or diflorazone.   NSAID, COX-2 inhibitor, biologic, DMARD, xanthine, anticholinergic compound, beta receptor agonist, bronchodilator, nonsteroidal calcineurin inhibitor, vitamin D analog, psoralen, retinoid, and 5-amino 24. The method of claim 23, further comprising administering salicylic acid to the patient.   28. The method of claim 27, wherein the NSAID is ibuprofen, diclofenac, or naproxen.   28. The method of claim 27, wherein the COX-2 inhibitor is rofecoxib, celecoxib, valdecoxib, or lumiracoxib.   28. The method of claim 27, wherein the biologic is adelimumab, etanercept, or infliximab.   28. The method of claim 27, wherein the DMARD is methotrexate or leflunomide.   28. The method of claim 27, wherein the xanthine is theophylline.   28. The method of claim 27, wherein the anticholinergic compound is ipratropium or tiotropium.   β receptor agonist is ibuterol sulfate, vitorterol mesylate, epinephrine, formoterol fumarate, isoproterenol, levalbuterol hydrochloride, metaproterenol sulfate, pyrbuterol scetate, salmeterol xinafoate, or terbutaline 28. The method of claim 27, wherein   28. The method of claim 27, wherein the non-steroidal calcineurin inhibitor is cyclosporine, tacrolimus, pimecrolimus, or ISAtx247.   28. The method of claim 27, wherein the vitamin D analog is calcipotriene or calcipotriol.   28. The method of claim 27, wherein the psoralen is methoxalene.   28. The method of claim 27, wherein the retinoid is acitretin or tazoletene.   28. The method of claim 27, wherein the 5-aminosalicylic acid is mesalamine, sulfasalazine, balsalazide disodium, or olsalazine sodium.   24. The method of claim 23, wherein the SSRI or corticosteroid is administered at a low dose.   24. The method of claim 23, wherein SSRI or corticosteroid is administered at a high dose.   24. The method of claim 23, wherein the SSRI and corticosteroid are administered within 10 days of each other.   43. The method of claim 42, wherein the SSRI and corticosteroid are administered within 5 days of each other.   44. The method of claim 43, wherein the SSRI and corticosteroid are administered within 24 hours of each other.   45. The method of claim 44, wherein SSRI and corticosteroid are administered simultaneously.   A composition comprising SSRI and a glucocorticoid receptor modulator in an amount sufficient to reduce combined secretion or production of inflammatory cytokines.   SSRI is celiclamine, citalopram, cloboxamine, cyanodothiepin, dopaxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, indeloxazine, ritoxetine, milnacipram, paroxetine, sertraline, dimerin, sertraline, dimethaline Composition.   NSAID, COX-2 inhibitor, biologic, DMARD, xanthine, anticholinergic compound, beta receptor agonist, bronchodilator, nonsteroidal calcineurin inhibitor, vitamin D analog, psoralen, retinoid, and 5-amino 48. The composition of claim 46, further comprising a compound selected from the group consisting of salicylic acid.   Inflammation in a patient comprising administering SSRI and a glucocorticoid receptor modulator to the patient simultaneously or within 14 days of each other in an amount sufficient to reduce the secretion or production of inflammatory cytokines in the patient in vivo A method of reducing the secretion or production of sex cytokines.   SSRIs and glucocorticoid receptor modulators are administered to patients at the same time or within 14 days of each other in an amount sufficient to treat a patient with or diagnosed to be at risk for developing an immunoinflammatory disorder. A method of treating the patient, comprising administering.   Immunoinflammatory disorders include rheumatoid arthritis, Crohn's disease, ulcerative colitis, asthma, chronic obstructive pulmonary disease, rheumatic polymyalgia, giant cell arthritis, systemic lupus erythematosus, atopic dermatitis, multiple sclerosis, 51. The method of claim 50, wherein the method is myasthenia gravis, psoriasis, ankylosing spondylitis, or psoriatic arthritis.   SSRI is celiclamine, citalopram, cloboxamine, cyanodothiepine, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, indeloxazine, ritoxetine, milnacipran, paroxetine, sertraline, melodiline, claim tradextrin, tametraline, claim 50. The method according to 50.   COX-2 inhibitor, NSAID, corticosteroid, DMARD, biologic, xanthine, anticholinergic compound, beta receptor agonist, bronchodilator, nonsteroidal calcineurin inhibitor, vitamin D analog, psoralen, retinoid, 51. The method of claim 50, further comprising administering 5-aminosalicylic acid to the patient.   51. The method of claim 50, wherein the SSRI and glucocorticoid receptor modulator are administered within 10 days of each other.   55. The method of claim 54, wherein the SSRI and glucocorticoid receptor modulator are administered within 5 days of each other.   56. The method of claim 55, wherein the SSRI and glucocorticoid receptor modulator are administered within 24 hours of each other.   57. The method of claim 56, wherein the SSRI and glucocorticoid receptor modulator are administered simultaneously.   (I) SSRI and (ii) xanthine, anticholinergic compounds, beta receptor agonists, bronchodilators, biologics, NSAIDs, DMARDs, COX-2 inhibitors, nonsteroidal calcineurin inhibitors, vitamin D analogs, A pharmaceutical composition comprising a second compound selected from the group consisting of psoralen, retinoid, and 5-aminosalicylic acid.   59. The composition of claim 58, wherein the NSAID is ibuprofen, diclofenac, or naproxen.   59. The composition of claim 58, wherein the COX-2 inhibitor is rofecoxib, celecoxib, valdecoxib, or lumiracoxib.   59. The composition of claim 58, wherein the biologic is adelimumab, etanercept, or infliximab.   59. The composition of claim 58, wherein the DMARD is methotrexate or leflunomide.   59. The composition of claim 58, wherein the xanthine is theophylline.   59. The composition of claim 58, wherein the anticholinergic compound is ipratropium or tiotropium.   β receptor agonist is ibuterol sulfate, vitorterol mesylate, epinephrine, formoterol fumarate, isoproterenol, levalbuterol hydrochloride, metaproterenol sulfate, pyrbuterol scetate, salmeterol xinafoate, or terbutaline 59. The composition of claim 58, wherein:   59. The composition of claim 58, wherein the non-steroidal calcineurin inhibitor is cyclosporine, tacrolimus, pimecrolimus, or ISAtx247.   59. The composition of claim 58, wherein the vitamin D analog is calcipotriene or calcipotriol.   59. The composition of claim 58, wherein the psoralen is methoxalene.   59. The composition of claim 58, wherein the retinoid is acitretin or tazoletene.   In an amount sufficient to reduce the secretion or production of inflammatory cytokines in patients in need thereof in vivo, (i) SSRI and (ii) xanthines, anticholinergic compounds, biologics, NSAIDs, DMARDs, A second compound selected from the group consisting of a COX-2 inhibitor, a β receptor agonist, a bronchodilator, a non-steroidal calcineurin inhibitor, a vitamin D analog, psoralen, a retinoid and 5-aminosalicylic acid, A method of inhibiting the secretion of one or more inflammatory cytokines in the patient comprising administering.   Inhibiting the secretion of one or more inflammatory cytokines in the patient, comprising administering SSRI to the patient in an amount sufficient to inhibit the secretion of the inflammatory cytokine in a patient in need thereof Method.   A method of treating a patient comprising administering SSRI to the patient in an amount sufficient to treat a patient diagnosed with an immunoinflammatory disorder and for a sufficient period of time. (I) a composition comprising SSRI and a corticosteroid; and (ii) to administer the composition to a patient diagnosed as having or at risk of developing an immunoinflammatory disorder. Instructions for
Including kit. (I) SSRI;
(Ii) a corticosteroid; and (iii) systemic administration of the SSRI and the corticosteroid to a patient diagnosed as having or at risk of developing an immunoinflammatory disorder. Directions;
Including kit.   A kit comprising (i) SSRI and (ii) instructions for administering the SSRI to a patient diagnosed with an immunoinflammatory disorder. (I) SSRI;
(Ii) Glucocorticoid receptor modulator, xanthine, anticholinergic compound, biologic, NSAID, DMARD, COX-2 inhibitor, β receptor agonist, bronchodilator, non-steroidal calcineurin inhibitor, vitamin D analog A second compound selected from the group consisting of psoralen, psoralen, retinoid and 5-aminosalicylic acid; and (iii) a patient diagnosed as having or at risk of developing an immunoinflammatory disorder Instructions for administering the SSRI and the second compound to
Including kit. (A) contacting a cell with SSRI and the candidate compound in vitro; then (b) a combination of the SSRI and candidate compound contacted with the SSRI but not contacted with the candidate compound, or a candidate Determining whether to reduce cytokine levels in blood cells stimulated to secrete cytokines to cells that have been contacted with the compound but not to the SSRI; Identifying the combination as a useful combination for treating a patient in need of treatment;
A method of identifying a combination of compounds useful for inhibiting the secretion of inflammatory cytokines in a patient in need of such treatment comprising a step.