MXPA06005457A - Methods and reagents for the treatment of inflammatory disorders - Google Patents

Abstract

The invention features a method for treating a patient diagnosed with, or at risk of developing, an immunoinflammatory disorder by administering a tricyclic compound and, optionally, a corticosteroid or other compound to the patient. The invention also features a pharmaceutical composition containing a tricyclic compound and a corticosteroid or other compound for the treatment or prevention of an immunoinflammatory disorder.

Description

METHODS AND REAGENTS FOR THE TREATMENT OF IMMUNO-FLAMMATORY DISORDERS Background of the Invention The invention relates to the treatment of immune-inflammatory disorders. Immune-inflammatory disorders are characterized by inappropriate activation of the body's immune defenses. Instead of attacking infectious invaders, the immune response targets and damages the tissues of the transplanted body or tissues. The tissue targeted by the immune system varies with the disorder. For example, in multiple sclerosis, the immune response is directed against neuronal tissue, while in Crohn's disease it is targeted to the digestive tract. Immune-inflammatory disorders affect millions of individuals and include conditions such as asthma, allergic intraocular inflammatory diseases, arthritis, atopic dermatitis, atopic eczema, diabetes, hemolytic anemia, inflammatory dermatoses, inflammatory bowel or gastro-intestinal disorders (v .gr., Crohn's disease and ulcerative colitis), multiple sclerosis, myasthenia gravis, pruritis / inflammation, psoriasis, rheumatoid arthritis, cirrhosis, and systemic lupus erythematosus. Current treatment regimens for immune-inflammatory disorders typically depend on immunosuppressive agents. The effectiveness of these agents can vary and their use is often accompanied by adverse side effects. Thus, improved therapeutic agents and methods for the treatment of immune-inflammatory disorders are needed. SUMMARY OF THE INVENTION In one aspect, the invention features a composition that includes a tricyclic compound and a cortico-steroid in amounts that together are sufficient to treat an immuno-inflammatory disorder in a patient in need thereof. If desired, the composition may include one or more additional compounds (e.g., a glucocorticoid receptor modulator, NSAID, COX-2 inhibitor, DMARD, biological, xanthine, small molecule immuno-modulator). , anti-cholinergic compound, beta receptor agonist, bronchodilator, immuno-suppressor dependent on nonsteroidal immunophilin, vitamin D analogue, psoralen, retinoid, or 5-amino salicylic acid). The composition can be formulated, for example, for topical administration or systemic administration. In another aspect, the invention features a method of treating a patient diagnosed with or at risk of developing an immuno-inflammatory disorder by administering a tricyclic compound and a cortico-steroid to the patient simultaneously or within 14 days of each other in sufficient amounts to treat the patient. In a related aspect, the invention features a method for modulating an immune response (e.g., by decreasing the secretion or production of pro-inflammatory cytokine, or by modulating adhesion, gene expression, chemokine secretion, MHC complex presentation. , presentation of co-stimulation signals, or cell surface expression of other mediators) in a patient by administering to the patient a tricyclic compound and a cortico-steroid simultaneously or within 14 days to each other in sufficient quantities to modulate the immune response in the patient. In any of the above methods, the patient may also be administered one or more additional compounds (e.g., a glucocorticoid receptor modulator, NSAID, COX-2 inhibitor, DMARD, biological, xanthine, immuno- small molecule modulator, anti-cholinergic compound, beta receptor agonist, bronchodilator, immuno-suppressor dependent nonsteroidal immunophilin, vitamin D analogue, psoralen, retinoid, or 5-amino salicylic acid). If desired, the tricyclic and / or cortico-steroid compound can be administered in a low dose or in a high dose. The drugs are desirably administered within 10 days to each other, more desirably within five days to each other, and even more desirably within twenty-four hours to each other or even simultaneously (i.e., concomitantly). In a related aspect, the invention features a method for treating an immuno-inflammatory disorder in a patient in need thereof by concomitantly administering to the patient a tricyclic compound and a cortico-steroid in amounts that together are more effective in treating the disorder immuno-inflammatory than cortico-steroid administration in the absence of the tricyclic compound. In yet another related aspect, the invention features a method for treating an immuno-inflammatory disorder in a patient in need thereof by concomitantly administering to the patient a tricyclic compound and a corticosteroid in amounts which together are more effective in treating the immune-inflammatory disorder than the administration of the tricyclic compound in the absence of the cortico-steroid. In still another related aspect, the invention presents a method for treating an immuno-inflammatory disorder in a patient in need thereof by administering a cortico-steroid to the patient; and administering a tricyclic compound to the patient; where: (i) the cortico-steroid and the tricyclic compound are administered concomitantly and (ii) the respective amounts of the cortico-steroid and the tricyclic compound administered to the patient are more effective in treating the immune-inflammatory disorder compared to the administration of the cortico-steroid in the absence of the tricyclic compound or the administration of the tricyclic compound in the absence of the cortico-steroid. The invention also features a pharmaceutical composition in unit dose form, the composition including a cortico-steroid; and a tricyclic compound, where the amounts of the cortico-steroid and the tricyclic compound, when administered to the patient, are more effective in treating the immune-inflammatory disorder compared with cortico-steroid administration in the absence of the tricyclic compound or the administration of the tricyclic compound. tricyclic compound in the absence of the cortico-steroid. The invention also features a kit that includes (i) a composition that includes a tricyclic compound and a cortico-steroid; and (ii) instructions for administering the composition to a patient diagnosed with an immuno-inflammatory disorder. In a related aspect, the invention features a kit that includes: (i) a tricyclic compound; (ii) a cortico-steroid; and (iii) instructions for administering the tricyclic compound and the cortico-steroid to a patient diagnosed with an immuno-inflammatory disorder. The invention also features a kit that includes (i) a tricyclic compound; and (ii) instructions for administering the tricyclic compound and a corticosteroid to a patient diagnosed with or at risk of developing an immuno-inflammatory disorder. If desired, the corticosteroid can be replaced in the methods, compositions, and kits of the invention with a glucocorticoid receptor modulator or other steroid receptor modulator.

Thus, in another aspect, the invention features a composition that includes a tricyclic compound and a glucocorticoid receptor modulator in amounts that together are sufficient to treat an immuno-inflammatory disorder in a patient in need thereof. If desired, the composition may include one or more additional compounds. The composition can be formulated, for example, for topical administration or systemic administration. In a related aspect, the invention features a method for treating a patient diagnosed with or at risk of developing an immuno-inflammatory disorder by administering to the patient a tricyclic compound and a glucocorticoid receptor modulator simultaneously or within 14 days between Yes in sufficient quantities to treat the patient. The drugs are desirably administered within 10 days to each other, more desirably within five days to each other, and even more desirably within twenty-four hours to each other or even simultaneously (ie, concomitantly). In another aspect, the invention features a method for modulating an immune response (e.g., by decreasing secretion or production of pro-inflammatory cytokine, or by modulating adhesion, gene expression, chemokine secretion, MHC complex presentation, presentation of costimulation signals, or cell surface expression of other mediators) in a patient by administering to the patient a tricyclic compound and a glucocorticoid receptor modulator simultaneously or within 14 days to each other in sufficient quantities to modulate the immune response in the patient . In a related aspect, the invention features a method for treating an immuno-inflammatory disorder in a patient in need thereof by concomitantly administering to the patient a tricyclic compound and a glucocorticoid receptor modulator in amounts that together are more effective when treating the immune-inflammatory disorder that the administration of the glucocorticoid receptor modulator in the absence of the tricyclic compound. In yet another related aspect, the invention features a method for treating an immuno-inflammatory disorder in a patient in need thereof by concomitantly administering to the patient a tricyclic compound and a glucocorticoid receptor modulator in amounts which together are effective in treating the immune-inflammatory disorder than the administration of the tricyclic compound in the absence of the glucocorticoid receptor modulator. In yet another related aspect, the invention features a method for treating an immuno-inflammatory disorder in a patient in need thereof by administering a glucocorticoid receptor modulator to the patient; and administering a tricyclic compound to the patient; wherein: (i) the glucocorticoid receptor modulator and the tricyclic compound are administered concomitantly and (ii) the respective amounts of the glucocorticoid receptor modulator and the tricyclic compound administered to the patient are most effective in treating the immune disorder -inflammatory compared to the administration of the glucocorticoid receptor modulator in the absence of the tricyclic compound or the administration of the tricyclic compound in the absence of the glucocorticoid receptor modulator. The invention also features a pharmaceutical composition in unit dose form, the composition comprising a glucocorticoid receptor modulator; and a tricyclic compound, where the amounts of the glucocorticoid receptor modulator and the tricyclic compound, when administered to the patient, are more effective in treating the immune-inflammatory disorder compared to the administration of the glucocorticoid receptor modulator. corticoid in the absence of the tricyclic compound or administration of the tricyclic compound in the absence of the glucocorticoid receptor modulator. The invention also features a kit that includes (i) a composition that includes a tricyclic compound and a glucocorticoid receptor modulator; and (ii) instructions for administering the composition to a patient diagnosed with an immuno-inflammatory disorder. In a related aspect, the invention features a kit that includes: (i) a tricyclic compound; (ii) a glucocorticoid receptor modulator; and (iii) instructions for administering the tricyclic compound and the glucocorticoid receptor modulator to a patient diagnosed with an immuno-inflammatory disorder. In a related aspect, the invention features a kit that includes (i) a tricyclic compound; and (ii) instructions for administering the tricyclic compound and a second compound selected from the group consisting of a glucocorticoid receptor modulator, small molecule immuno-modulator, xanthine, anti-cholinergic, biological compound, NSAID, DMARD , COX-2 inhibitor, beta receptor agonist, bronchodilator, nonsteroidal immunophilin-dependent immuno-suppressant, vitamin D analog, psoralen, retinoid, or 5-amino salicylic acid to a patient diagnosed with or at risk of developing a disorder immuno-inflammatory. As described herein, tricyclic compounds, in the absence of a cortico-steroid, have anti-inflammatory activity. Thus, the invention also features a method for suppressing the secretion of one or more pro-inflammatory cytokines or otherwise modulating the immune response (such as adhesion, gene expression, chemokine secretion, MHC complex presentation, co-stimulation, or cell surface expression of other mediators) in a patient in need thereof by administering to the patient a tricyclic compound in an amount sufficient to suppress the secretion of pro-inflammatory cytokines or otherwise modulate the immune response in the patient . In a related aspect, the invention features a method for treating a patient diagnosed with an immuno-inflammatory disorder by administering to the patient a tricyclic compound in an amount and for a duration sufficient to treat the patient. The invention also features a kit that includes (i) a tricyclic compound and (ii) instructions for administering the tricyclic compound to a patient diagnosed with an immuno-inflammatory disorder. In another aspect, the invention features a pharmaceutical composition that includes a tricyclic compound and a second compound selected from the group consisting of a glucocorticoid receptor modulator, NSAID, COX-2 inhibitor, DMARD, biological, xanthine, small molecule immuno-modulator, anti-cholinergic compound, beta-receptor agonist, bronchodilator, immuno-suppressor dependent on non-steroidal immunophilin, vitamin D analogue, psoralen, retinoid, or 5-amino salicylic acid. The invention presents another kit that includes (i) a cortico-steroid; and (ii) instructions for administering said cortico-steroid and a tricyclic compound to a patient diagnosed with or at risk of developing an immuno-inflammatory disorder. The invention also features methods for identifying compounds or combinations of compounds that may be useful for modulating an immune response (e.g., by decreasing the secretion or production of pro-inflammatory cytokine, or by modulating adhesion, gene expression, secretion of chemokines, presentation of the MHC complex, presentation of costimulation signals, or cell surface expression of other mediators). Such a method includes the steps of: (a) contacting in vi tro cells with a tricyclic compound and a candidate compound; and (b) determining whether the combination of the tricyclic compound and the candidate compound reduces the secretion of pro-inflammatory cytokine to cells contacted with the tricyclic compound but not contacted with the candidate compound or cells contacted with the candidate compound. but not with the tricyclic compound. A modulation of secretion or production of pro-inflammatory cytokine, adhesion, gene expression, chemokine secretion, MHC complex presentation, presentation of co-stimulation signals, or cell surface expression of other mediators, identifies the combination as a combination that is useful for treating a patient in need for such treatment. Another method of the invention includes the steps of: (a) contacting cells in vi tro with a cortico-steroid and a candidate compound; and (b) determining whether the combination of the cortico-steroid and the candidate compound modulates an immune response, in relation to the immune response of cells contacted with the corticosteroid but not in contact with the candidate compound. As above, a modulation of the immune response identifies the combination as a combination that may be useful for the treatment of an immuno-inflammatory disorder. In another aspect, the invention features a method for identifying a combination that may be useful for the treatment of an immuno-inflammatory disorder by: (a) identifying a compound that modulates the immune response; (b) contacting proliferative cells in vi tro with a tricyclic compound and the compound identified in step (a); and (c) determining whether the combination of the tricyclic compound and the compound identified in step (a) modulates the immune response, with respect to the immune response of cells contacted with the tricyclic compound but not contacted with the identified compound in step (a) or placed in contact with the compound identified in step (a) but not in contact with the tricyclic compound. A modulation in the immune response (e.g., a reduction in the production or secretion of pro-inflammatory cytokines) identifies the combination as a combination that may be useful for the treatment of an immuno-inflammatory disorder.

The invention also provides a method for identifying combinations of compounds useful for suppressing the secretion of pro-inflammatory cytokines in a patient in need of such treatment by: (a) contacting cells in vi tro with a tricyclic compound and a candidate compound; and (b) determining whether the combination of the tricyclic compound and the candidate compound reduces cytokine levels in blood cells stimulated to secrete the cytokines relative to cells contacted with the tricyclic compound but not contacted with the candidate compound or cells placed in contact with the candidate compound but not placed in contact with the tricyclic compound, where a reduction of cytokine levels identifies the combination as a combination that is useful for treating a patient in need of such treatment. Compounds useful in the invention include those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, esters, solvates, and polymorphs thereof, as well as racemic mixtures and pure isomers of the compounds described at the moment. By "tricyclic compound" is meant a compound having one of the formulas (I), (II), (III), or (IV): wherein each X is, independently, H, Cl, F, Br, I, CH3, CF3, OH, OCH3, CH2CH3, or OCH2CH3; Y is CH2, O, NH, S (O) 0_2, (CH2) 3, (CH) 2, CH20, CH2NH, CHN, or CH2S; Z is C or S; A is a saturated or monounsaturated, branched or unbranched hydrocarbon chain, having between 3 and 6 carbons, inclusive; each B is, independently, H, Cl, F, Br, I, CX3, CH2CH3, OCX3, or OCX2CX3; and D is CH2, O, NH, or S (O) 0_2. In preferred embodiments, each X is, independently, H, Cl, or F; Y is (CH2) 2, Z is C; A is (CH2) 3; and each B is, independently, H, Cl, or F. Other tricyclic compounds are described below. Tricyclic compounds include tricyclic anti-depressants such as amoxapine, 8-hydroxymoxapine, 7-hydroxy-moxapine, loxapine (e.g., loxapine succinate, loxapine hydrochloride), 8-hydroxyloxapine, amitriptyline, clomipamin, doxepin, imipramine, trimipramine, desipramine, nortriptyline, and protriptyline, although the compounds do not need to have anti-depressant activities to be considered tricyclic compounds of the invention. By "cortico-steroid" is meant any compound of natural or synthetic occurrence characterized by a ring system of hydrogenated cyclopentanehydrophenanthrene and having immunosuppressive or anti-inflammatory activity. Cortico-steroids of natural occurrence are usually produced by the adrenal cortex. Cortico-synthetic steroids can be halogenated.

Examples of cortico-steroids are provided herein. By "non-steroidal immunophilin-dependent immuno-suppressor" or "NsIDI" is meant any non-steroidal agent that decreases the production or secretion of pro-inflammatory cytokine, binds an immunophilin, or causes a down regulation of the pro-inflammatory reaction. NsIDIs include calcineurin inhibitors, such as cyclosporin, tacrolimus, ascomycin, pimecrolimus, as well as other agents (peptides, peptide fragments, chemically modified peptides, or peptide mimics) that inhibit calcineurin phosphatase activity. NsIDIs also include rapamycin (sirolimus) and everolimus, which bind to a protein that binds to FK506, FKBP-12, and proliferation induced by white blood cell block antigen and cytokine secretion. By "small molecule immuno-modulator" is meant a non-steroidal compound, not NsIDI, which decreases the production or secretion of pro-inflammatory cytokine, causes a down-regulation of the pro-inflammatory reaction, or otherwise modulates the system immune in an independent manner of immunophilin. Immuno-modulators of exemplary small molecules are p38 MAP kinase inhibitors such as? 7X 702 (Vértex Pharmaceuticals), SCIO 469 (Scios), doramapimod (Boehrin-ger Ingelheim), RO 30201195 (Roche), and SCIO 323 (Scios), TACE inhibitors such as DPC 333 (Bristol Myers Squibb), ICE inhibitors such as pranalcasan (Vertex Pharmaceuticals), and inhibitors of IMPDH such as mycophenolate (Roche) and merimepodib (Vértex Pharmaceuticals). A "low dose" means at least 5% less (e.g., at least 10%, 20%, 50%, 80%, 90%, or even 95%) than the lowest standard recommended dose of a particular compound formulated for a given administration route for treatment of any disease or human condition. For example, a low dose of a steroid-corticosteroid formulated for administration by inhalation will differ from a low dose of steroid-corticosteroid formulated for oral administration. A "high dose" means at least 5% (eg, at least 10%, 20%, 50%, 100%, 200%, or even 300%) more than the highest recommended standard dose of a particular compound for treatment of any disease or human condition. A "moderate dose" means a dose between the low dose and the high dose. By a "dose equivalent to a dose of prednisolone" is meant a dose of a cortico-steroid which, in combination with a given dose of a tricyclic compound, produces the same anti-inflammatory effect in a patient as a dose of prednisolone in combination with that dose. By "treating" is meant administering or prescribing a composition for the treatment or prevention of an immuno-inflammatory disease. By "patient" is meant any animal (eg, a human). Other animals that can be treated using the methods, compositions, and kits of the invention include horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, piglets, rats, mice, lizards, snakes, sheep, cattle. , fish, and birds. In one embodiment of the invention, the patient subjected to a treatment described herein has no clinical depression, an anxiety or panic disorder, an obsessive / compulsive disorder, alcoholism, an eating disorder, an attention deficit disorder, a borderline personality disorder, a sleep disorder, a headache, pre-menstrual syndrome, an irregular heartbeat, schizophrenia, Tourette's syndrome, or phobias. By "a sufficient amount" is meant the amount of a compound, in a combination of the invention, required to treat or prevent an immuno-inflammatory disease in a clinically relevant manner. A sufficient amount of an active compound used to practice the present invention for therapeutic treatment of conditions caused by or contributing to an immuno-inflammatory disease varies depending on the manner of administration, age, body weight, and general health of the patient. Finally, the doctors will decide the appropriate amount and dosage regimen. By "more effective" it is understood that a method, composition, or kit exhibits greater efficacy, is less toxic, safer, more convenient, better tolerated, or less expensive, or provides more treatment satisfaction than another method, composition, or kit with which you are comparing. The efficiency can be measured by a person skilled in the art using any method that is appropriate for a given indication. The term "immuno-inflammatory disorder" encompasses a variety of conditions, including autoimmune diseases, proliferative skin diseases, and inflammatory dermatoses. Immune-inflammatory disorders result in the destruction of healthy tissue by an inflammatory process, deregulation of the immune system, and unwanted proliferation of cells. Examples of immune-inflammatory disorders are acne vulgaris; acute respiratory distress syndrome; Addison's disease; adrenocortical insufficiency; adrenogenital syndrome; allergic conjunctivitis; allergic rhinitis; Allergic inflammatory intraocular diseases, small vessel vasculitis associated with ANCA; angioedema; ankylosing spondylitis; aphthous stomatitis; arthritis; asthma; atherosclerosis; atopic dermatitis; autoimmune disease; autoimmune hemolytic anemia; autoimmune hepatitis; Behcet's disease; Bell palsia; berylliosis; bronchial asthma; bullous dermatitis herpetiformis; bullous pemphigoid; carditis; Celiac Disease; cerebral ischemia; chronic obstructive pulmonary disease; cirrhosis; Cogan syndrome; contact dermatitis; COPD; Crohn's disease; Cushing's syndrome; dermatomyositis; Mellitus diabetes; discoid lupus erythematosus; eosinophilic fasciitis; epicondolitis; erythema nodosum; exfoliative dermatitis; fibromyalgia; focal glomeru -clerosis; giant cell arteritis; drop; gouty arthritis; graft versus host disease; hand eczema; Henoch-Schonlein purple; herpes gestationis; hirustism; reactions to drugs due to hypersensitivity; idiopathic cerato-scleritis; idiopathic pulmonary fibrosis; idiopathic thrombocytopenic purpura; disorders of intestines or inflammatory gastrointestinal, inflammatory dermatoses; Juvenile rheumatoid arthritis; laryngeal edema; lichen planus; Loeffler's syndrome; lupus nephritis; lupus vulgaris; lymphatic tracheobronchitis; macular edema; multiple sclerosis; muscle-skeletal and connective tissue disorder; myasthenia gravis; myositis; obstructive pulmonary disease; ocular inflammation; rejection of organ transplantation; osteoarthritis; pancreatitis; pemphigoid gestationis pénfigus vulgaris; polyarteritis nodosa; polymyalgia rheumatica primary adrenocortical insufficiency; primary biliary cirrhosis pruritus scroti; Pruritis / inflammation, psoriasis; psoriatic arthritis; Reiter's disease; Recurrent polychondritis; rheumatic carditis; rheumatic fever; rheumatoid arthritis; Rosacea caused by sarcoidosis; Rosacea caused by scleroderma; Rosacea caused by Sweet's syndrome; Rosacea caused by systemic lupus erythematosus; rosacea caused by urticaria; Rosacea caused with pain associated with zoster; sarcoidosis; scleroderma; Segmental glomerulosclerosis; septic shock syndrome; whey disease; tendinitis or shoulder bursitis; Sjorgen syndrome; Still's disease; brain cell death induced by infarction; Sweet disease systemic dermatomyositis; systemic lupus erythematosus systemic sclerosis; Takayasu arteritis; temporal arteritis toxic epidermal necrolysis; tuberculosis; type 1 diabetes ulcerative colitis; uveitis; vasculitis; and Wegener's granulomatosis. "Non-dermal inflammatory disorders" include, for example, rheumatoid arthritis, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease. "Dermal inflammatory disorders" or "inflammatory dermatoses" include, for example, psoriasis, acute febrile neutrophilic dermatosis, eczema (e.g., asteatotic eczema, dyshidrotic eczema, vesicular palmoplantar eczema), circumscribed plasmacellularis balanitis, balanoposthitis, Behcet's disease, Centrifugal annular erythema, erythema dyschromic perstans, erythema multiforme, granuloma annulare, lichen nítido, lichen plano, lichen sclerosus and atrophic, lichen simplex chronic, lichen espinoloso, dermatitis nummular, pyoderma gangrenosum, sarcoidosis, pustular subcorneal dermatosis, urticaria, and acanthoma dermatosis transient ethics. By "proliferative skin disease" is meant a benign or malignant disease characterized by division of accelerated cells in the epidermis or dermis. Examples of proliferative skin diseases are psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell carcinomas of the skin, lamellar ichthyosis, epidermolytic hyperkeratosis, pre-malignant keratosis, acne, and seborrheic dermatitis. As will be appreciated by one skilled in the art, a particular disease, disorder, or particular condition can be characterized as both a proliferative skin disease and an inflammatory dermatosis. An example of such a disease is psoriasis. By "sustained release" or "controlled release" is meant that the therapeutically active component is released from the formulation at a controlled rate such that therapeutically beneficial blood levels (but below toxic levels) of the component are maintained over a period of time extended varying from v.gr., about 12 to about 24 hours, thus, providing, for example, a 12-hour or 24-hour dose form. The term "pharmaceutically acceptable salt" means those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human and lower animals without undue toxicity, irritation, allergic and the like, and are provided with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. The salts can be prepared in itself during the isolation and purification of the compounds of the invention, or separately by reacting the function of free base with a suitable organic acid. Representative acid addition salts include salts of acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camforate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate , heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, isethionate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, and the like. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Compounds useful in the invention include those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, esters, amides, thioesters, solvates, and polymorphs thereof, as well as racemic mixtures and pure isomers. of the compounds described herein. As an example, "loxapine" is understood to mean the free base, as well as any of its pharmaceutically acceptable salts (e.g., loxapine hydrochloride, loxapine succinate). Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.

DETAILED DESCRIPTION The invention features methods, compositions, and kits for the administration of an effective amount of a tricyclic compound, either alone or in combination with a corticosteroid or other compound to treat immuno-inflammatory disorders. In one embodiment of the invention, treatment of an immuno-inflammatory disorder is carried out by administering a tricyclic compound and a corticosteroid to a patient in need of such treatment. The invention is described in greater detail below. Tricyclic Compounds Tricyclic compounds that can be used in the methods, compositions, and kits of the invention include amitriptyline, amoxapine, clomipramine, desipramine, dotiepin, doxepin, imipramine, lofepramine, maprotiline, mianserin, mirtazapine, nortriptyline, octriptilin, oxaprotiline. , protripylline, trimipramine, 10- (4-methylpiperazin-1-yl) pyrido (4, 3-b) (1,4) benzothiazepine; 11- (4-methyl-l-piperazinyl) -5H-dibenzo (b, e) (1,4) diazepine; 5, 10-dihydro-7-chloro-10- (2- (morpholino) ethyl) -1H-dibenzo (b, e) (1,4) diazepin-11-one; 2 - (2 - (7-Hydroxy-4-dibenzo (b, f) (1,4) thiazepin-11-yl-l-piperazinyl) ethoxy) ethanol; 2-chloro-11- (4-methyl-l-piperazinyl) -5H-dibenzo (b, e) (1,4) diazepine; 4- (HH-dibenz (b, e) azepin-6-yl) piperazine; 8-chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo (b, e) (1, 4) diazepin-2-ol; 8-chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo (b, e) (1,4) diazepine monochloride; (Z) -2-butenedioate 5H-dibenzo (b, e) (1,4) diazepine; adinazolam; amineptine; amitriptyloxide; butriptilin; clotiapina; clozapine; demexiptilin; 11- (4-methyl-l-piperazinyl) -dibenz (b, f) (1,4) oxazepine; 11- (4-methyl-l-piperazinyl) -2-nitro-dibenz (b, f) (1, 4) oxazepine; 2-Chloro-11- (4-methyl-1-piperazinyl) -2-nitro-dibenz (b, f) (1,4) -oxazepine monochloride; dibenzepine; 11- (4-methyl-l-piperazinyl) -dibenzo (b, f) (1,4) thiazepine; Dimethacrine; fluacizine; fluperlapin; Imipramine N-oxide; iprindola; lofepramine; melitraceno; metapramine; metiapine; metralindola; mianserin; Mirtazapine; 8-chloro-6- (4-methyl-1-piperazinyl) -morphantridine; N-acetylamoxapine; nomifenesin; norclomipramine; -norclozapine; noxiptilin; opipramol; oxaprotiline; perlapin; pizotiline; propizepina; quetiapine; quinupramine; thianeptin; tomoxetine; flupenthixol; clopenthixol; piflutixol; chlorprothixene; and thiothixene. Other tricyclic compounds are described, for example, in US Patents 2,554,736; 3,046,283; 3,310,553 3,177,209; 3,205,264; 3,244,748; 3,271,451; 3,272,826; 3,282,942 3,299,139; 3,312,689; 3,389,139; 3,399,201; 3,409,640; 3,419,547 3,438,981; 3,454,554; 3,467,650; 3,505,321; 3,527,766; 3,534,041 3,539,573; 3,574,852; 3,622,565; 3,637,660; 3,663,696; 3,758,528 3,922,305; 3,963,778; 3,978,121; 3,981,917; 4,017,542; 4,017,621 4,020,096; 4,045,560; 4,045,580; 4,048,223; 4,062,848; 4,088,647 4,128,641; 4,148,919; 4,153,629; 4,224,321; 4,224,344; 4,250,094 4,284,559; 4,333,935; 4,358,620; 4,548,933; 4,691,040; 4,879,288 5,238,959; 5,266,570; 5,399,568; 5,464,840; 5,455,246; 5,512,575; 5,550,136; 5,574,173; 5,681,840; 5,688,805; 5,916,889; 6,545,057; and 6,600,065, and phenothiazine compounds that fit within Formula (I) of patent applications US 10 / 617,424 or 60 / 504,310. Standard recommended doses for various tricyclic anti-depressants are provided in Table 1, below. Other standard doses are provided, e.g., in Merck Manual of Diagnosis & Therapy (17th edition, MH Beers et al., Merck &Co.) And Physicians' Desk Reference 2003 (57th edition, Medical Economics Staff et al., Medical Economics Co., 2002). Table 1 Cortico-steroids If desired, one or more corticosteroids can be administered in a method of the invention or can be formulated with a tricyclic compound in a composition of the invention. Suitable cortico-steroids include 11-alpha, 17-alpha, 21-trihydroxypregn-4-ene-3, -dione; 11-beta, 16-alpha, 17, 21-tetrahydroxypregn-4-ene-3, 20 -dione; 11-beta, 16-alpha, 17, 21-tetrahydroxypregn-1,4-diene-3, 20-dione; 11-beta, 17-alpha, 21-trihydroxy-6-alpha-methylpregn-4-ene-3, 20-dione; 11-dehydrocorti-coesterone; 11-deoxycortisol; 11-hydroxy-1,4-androstadiene-3, 17-dione; 11-ketotetosterone; 14-hydroxyandrost-4-ene-3, 6, 17-trione; 15, 17-dihydroxyprogesterone; 16-methylhydrocortisone; 17, 21-dihydroxy-16-alpha-methylpregna-1,4, 9 (11) -triene-3,20-dione; 17-alpha-hydroxyprg-4-ene-3, 20-dione; 17-alpha-hydroxipregnenolo-na; 17-hydroxy-16-beta-methyl-5-beta-pregn-9 (11) -eno-3, 20-dione; 17-hydroxy-4,6,8 (14) -pregnatriene-3,20-dione; 17-hydroxypregna-4,9 (11) -diene-3,20-dione; 18-hydroxycorticosterone; 18-hydroxy-cortisone; 18-oxocortisol; 21-acetoxipregnenolone; 21-deoxyal-dosterone; 21-deoxycortisone; 2-deoxyecdysone; 2-methylcortiso-na; 3-dehydroecdisone; 4-pregneno-17-alpha, 20-beta, 21-triol-3, 11-dione; 6.17, 20-trihydroxypregn-4-ene-3-one; 6-alpha-hydroxycorti-sol; 6-alpha-fluoroprednisolone; 6-alpha-methylprednisolone; 21-acetate 6-alpha-methylprednisolone; sodium salt of 21-hemisuccinate 6-alpha-methylprednisolone; 6-beta-hydroxycortisol; 21-acetate 17-butyrate 6-alpha, 9-alpha-difluoroprednisolone; 6-hydroxycorticosterone; 6-hydroxydexamethasone; 6-hydroxyprednis-canvas; 9-fluorocortisone; alclometasone dipropionate; aldosterone; algestone; alfaderm; amadinone; amcinonide; anagestone; androstenedione; anechortavo acetate; beclomethasone; beclomethasone dipropionate; 17-betamethasone valerate; betamethasone sodium acetate; sodium phosphate of betamethasone; betamethasone valerate; bolasterone; budesonide; calusterona; Chlormadinone; chloroprednisone; chloroprednisone acetate; cholesterol; ciclesonide; clobetasol; clobetasol propionate; clobetasone; clocortolone; clocortolone pivalate; clogestone; cloprednol; corticosterone; cortisol; cortisol acetate; cortisol butyrate; cortisol cypionate; cortisol octanoate; sodium cortisol phosphate; sodium cortisol succinate; cortisol valerate; cortisone; cortisone acetate; Cortivazole; short-na daturaolone; deflazacort; 21-deoxycortisol; dehydroepian-drosterone; delmadinone; Deoxycorticosterone; deprodone; descinolone; desonida; deoxymethasone; dexfeno; dexamethasone; 21-dexamethasone acetate; dexamethasone acetate; dexamethasone sodium phosphate; dichlorisone; diflorasone; diflorasone diacetate; diflucortolone; difluprednate; Dihydroelatericin A; domoprednate; doxibetasola; ecdysone; ecdysterone; emoxolone; endrisone; enoxolone; fluzacort; flucinolone; flucloronide; fludrocortisone; fludrocortisone acetate; Flugestone; flumethasone; flumethasone pivalate; flumoxonide; flunisolide; fluocinolone; fluocinolone acetonide; fluocinonide; fluocortin butyl; 9-fluorocortisone; fluocortolone; fluorohydroxyandroste-nedione; fluorometholone; fluorometholone acetate; Fluoxymesterone; fluperolone acetate; fluprednidene; fluprednisolone flurandrenolide; fluticasone; fluticasone propionate formebolone; formestaño; formocortal; gestonorone; glidinin halcinonide; halobetasol propionate; Halometasone; halopredno-na; haloprogesterone; hydrocortamate; hydrocortose-na cypionate; hydrocortisone; 21-hydrocortisone butyrate; hydrocortisone aceponate; hydrocortisone acetate; hydrocor-tisone buteprate; hydrocortisone butyrate; hydrocortisone cypionate; hydrocortisone hemisuccinate; hydrocortisone probutate; sodium hydrocortisone phosphate; sodium hydrocortisone succinate; hydrocortisone valerate; hydroxyprogesterone; inokoste-roña; isoflupredone; isoflupredone acetate; isoprednidene; loteprednol etabonate; mechloridane; mecortolone; medrogestone; medroxyprogesterone; medrisona; megestrol; Megestrol acetate; melengestrol; meprednisone; Methandrostenolone; methylprednisolone; methylprednisolone aceponate; methylprednisolone acetate; methylprednisolone hemisuccinate; Methylprednisolone Sodium Succinate; methyltestosterone; metribolone; mometasone; Mometasone furoate; mometasone furoate monohydrate; nisone; nomegestrol; norgestomet; norvinisterone; oximesterone; parameta-sona; parametasone acetate; ponasterone; Prednisolylate; prednisolone; Prednisolone diethylaminoacetate; 21-hemisuccinate prednisolone; prednisolone acetate; prednisolone farnesylate; prednisolone hemisuccinate; prednisolone-21 (beta-D-glucuronide); prednisolone metasulphobenzoate; prednisolone sodium phosphate; prednisolone estealate; prednisolone tebutate; prednisolone tetrahydrophthalate; prednisone; prednival; prednilidene; pregnenolone; procinonide; tralonida; progesterone; promegestone; rapontisterone; rimexolone; roxibolo-na; rubrosterone; Stizophylline; tixocortol; topterone; triamcinolone; triamcinolone acetonide; 21-triamcinolone palmitate acetonide; triamcinolone benetonide; triamcinolone diacetate; triamcinolone hexacetonide; trimegestone; turkesterone; and wortmanina. Standard recommended doses for various steroid / disease combinations are provided in Table 2, below. Table 2 - Recommended Corticosteroid Steroids Dosage Other recommended standard doses for corticosteroids are provided, e.g., in Merck Manual of Diagnosis S Therapy (17th edition, MH Beers et al., Merck &Co.) and Physicians' Desk Reference 2003 (57th edition, Medical Economics Staff and collaborators, Medical Economics Co., 2002). In one embodiment, the dose of cortico-steroid administered is a dose equivalent to a dose of prednisolone, as defined herein. For example, a low dose of a corticosteroid can be considered as the dose equivalent to a low dose of prednisolone. Modulators of the Steroid Receptor Modulators of the steroid receptor (v.gr., antagonists and agonists) can be used as a substitute for or in addition to a corticosteroid in the methods, compositions, and kits of the invention. Thus, in one embodiment, the invention features the combination of a tricyclic compound and a glucocorticoid receptor modulator or other steroid receptor modulator, and methods of treating immuno-inflammatory disorders therewith. Glucocorticoid receptor modulators that can be used in the methods, compositions, and kits of the invention include compounds described in US Patents 6,380,207, 6,380,223, 6,448,405, 6,506,766, and 6,570,020, US Patent Applications 2003/0176478, 2003 / 0171585, 2003/0120081, 2003/0073703, 2002/015631, 2002/0147336, 2002/0107235, 2002/0103217, and 2001/0041802, and PCT publication WO 00/66522, each of which is incorporated in the present by reference. Other steroid receptor modulators that can also be used in the methods, compositions, and kits of the invention are described in US Pat. Nos. 6,093,821, 6,121,450, 5,994,544, 5,696,133, 5,696,127, 5,693,647, 5,693,646, 5,688,810, 5,688,808, and 5,696,130, each of which is incorporated herein by reference. Other Compounds Other compounds that can be used as a substitute for or in addition to a cortico-steroid in the methods, compositions, and kits of the invention are A-348441 (Karo Bio), adrenal cortex extract (GlaxoSmithKine), alsactide (Aventis) , amebucort (Schering AG), amelomethasone (Taisho), ATSA (Pfizer), bitolterol (Elan), CBP-2011 (InKine Pharmaceutical), cebaracetam (Novartis), CGP-13774 (Kissei), ciclesonide (Altana), cyclomethasone (Aventis) ), clobetasone butyrate (GlaxoSmithKine), cloprednol (Hoffmann-La Roche), colismicin A (Kirin), cucurbitacin E (NIH), deflazacort (Aventis), deprodone propionate (SSP), dexamethasone acefurate (Schering-Plow), dexamethasone linoleate (GlaxoSmithKine), dexamethasone valerate (Abbott), difluprednate (Pfizer), domoprednate (Hoffmann-La Roche), ebiratide (Aventis), etiprednol dicloacetate (IVAX), fluazacort (Vicuron), flumoxonide (Hoffmann-La Roche), fluocortin butyl (Schering AG), fluocortolone monohydrate (Schering AG), GR-250495X (GlaxoSmithKIine), halometasone (Novartis), halopredo-na (Dainippon), HYC-141 (Fidia), enometate of icometasone (Hovione), itrocinonide (AstraZeneca), L-6485 (Vicuron), Lipocort (Draxis Health), locicortone (Aventis), meclorisone ( Sche-ring-Plow), naflocort (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, propylmesterolone (Schering AG), RGH-1113 (Gideon Richter), refleponed (AstraZeneca), rylleponide palmitate (AstraZeneca), RPR-106541 (Aventis), RU-26559 (Aventis), Sch-19457 (Schering-Plow), T25 (Matrix Therapeutics), TBI-PAB (Sigma-Tau), ticabesone propionate (Hoffmann-La Roche), tiflua Sun (Solvay), Timobesone (Hoffmann-La Roche), TSC-5 (Takeda), and ZK-73634 (Schering AG). Non-steroidal anti-inflammatory drugs (NSAIDs) If desired, the tricyclic compound of the invention can be administered in conjunction with one or more non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen sodium, diclofenac sodium, diclofenac potassium, aspirin , sulindaco, diflunisal, piroxicam, indomethacin, ibuprofen, nabumetone, choline magnesium trisalicylate, sodium salicylate, salicylsalicylic acid (salsalate), fenoprofen, flurbiprofen, ketoprofen, meclofenamate sodium, meloxicam, oxaprozin, sulindac, and tolmetin. When a tricyclic compound is administered in combination with acetylsalicylic acid, it is desirable that the combination be effective in modulating an immune response (suppress TNFa, IL-1, IL-2, or IFN-α in vi tro). Accordingly, the combination of a tricyclic compound in combination with acetylsalicylic acid and its analogues may be more effective in treating immuno-inflammatory diseases, particularly those mediated by TNFa, IL-1, IL-2, or IFN-α. than any agent alone. Acetylsalicylic acid, also known under the brand name aspirin, is an acetyl derivative of salicylic acid and has the following structural formula: Aspirin is useful in the relief of headache and joint and muscle pain. Aspirin is also effective in reducing fever, inflammation, and swelling and has thus been used for the treatment of rheumatoid arthritis, rheumatic fever, and mild infections. Thus, in one aspect, the combination of a tricyclic compound and acetylsalicylic acid (aspirin) or an analogue thereof can also be administered to improve the treatment or prevention of diseases mentioned above. An NSAID can be administered in conjunction with any of the combinations described in this application. For example, a patient suffering from an immuno-inflammatory disorder can initially be treated with a combination of a tricyclic compound and a corticosteroid and then treated with an NSAID, such as acetylsalicylic acid, in conjunction with the combination described above. Amounts of acetylsalicylic acid doses are known to those skilled in the art, and generally range from about 70 to about 350 mg per day. When a lower or higher dose of aspirin is needed, a formulation containing dipyridamole and aspirin may contain 0-25, 25-50, 50-70, 70-75, 75-80, 80-85, 85-90, 90-95 , 95-100, 100-150, 150-160, 160-250, 250-300, 300-350, or 350-1,000 mg of aspirin. When the combinations of the invention are used for treatment in conjunction with an NSAID it is possible to reduce the dose of the individual components substantially to a point below the doses that would be required to achieve the same effects by administering NSAIDs (e.g., acetylsalicylic acid) or a tricyclic compound alone or by administering a combination of an NSAID (e.g., acetylsalicylic acid) and a tricyclic compound. In one aspect, the composition that includes a tricyclic compound and an NSAID has improved effectiveness, safety, tolerance, or treatment satisfaction of a patient suffering from or at risk of suffering from an immuno-inflammatory disorder compared to a composition having a tricyclic compound or an NSAID alone. Immuno-Suppressors Non-steroidal Immunophilin-Dependent In one embodiment, the invention features methods, compositions, and kits employing a tricyclic compound and a non-steroidal immunophilin dependent immuno-suppressor (NsIDI), optionally with a cortico-steroid or other agent described herein. In healthy individuals the immune system uses cellular effectors, such as B cells and T cells, to attack infectious microbes and abnormal cell types while leaving normal cells intact. In individuals with an autoimmune disorder or a transplanted organ, activated T cells damage healthy tissues. Inhibitors of calcineurin (eg, cyclosporins, tacrolimus, pimecrolimus), and rapamycin attack many types of immune-regulatory cells, including T cells, and suppress the immune response in organ transplantation and auto-immune disorders. In one embodiment, the NsIDI is cyclosporine, and is administered in an amount between 0.05 and 50 milligrams per kilogram per day (e.g., orally in an amount between 0.1 and 12 milligrams per kilogram per day). In another embodiment, the NsIDI is tacrolimus and is administered in an amount between 0.0001-20 milligrams per kilogram per day (e.g., orally in an amount between 0.01-0.2 milligrams per kilogram per day). In another embodiment, the NsIDI is rapamycin and is administered in an amount between 0.1-502 milligrams per day (e.g., at a single loading dose of 6 mg / day, followed by a maintenance dose of 2 mg. / day) . In another embodiment, the NsIDI is everolimus, administered at a dose of 0.75-8 mg / day. In still other embodiments, the NsIDI is pimecrolimus, administered in an amount between 0.1 and 200 milligrams per day (e.g., as a 1% cream / twice a day to treat atopic dermatitis or 60 mg per day for the treatment of psoriasis), or the NsIDI is a peptide that binds to calcineurin administered in an amount and frequency sufficient to treat the patient. Two or more NsIDIs can be administered contemporaneously. Cyclosporins Cyclosporins are fungal metabolites that comprise a class of cyclic oligopeptides that act as immunosuppressants. Cyclosporin A is a hydrophobic cyclic polypeptide consisting of eleven amino acids. It binds and forms a complex with intracellular receptor cyclophilin. The cyclosporin / cyclophilin complex binds to and inhibits calcineurin, a serine-threonine-specific protein phosphatase dependent on Ca2 + ~ calmodulin. Calcineurin regulates signal transduction events required for T cell activation (reviewed in Schreiber et al., Cell 70: 365-368, 1991). Cyclosporins and their functional and structural analogs suppress the T cell-dependent immune response by inhibiting signal transduction triggered by antigen. This inhibition decreases the expression of pro-inflammatory cytokines, such as IL-2. Many different cyclosporins (eg, cyclosporin A, B, C, D, E, F, G, H, and I) are produced by fungi. Cyclosporin A is commercially available under the brand name NEORAL from Novartis. Structural and functional analogues of ciclosporin A include cyclosporins having one or more fluorinated amino acids (described, e.g., in US Patent 5,227,467); cyclosporins having modified amino acids (described, e.g., in US Patents 5,122,511 and 4,798,823); and deuterated cyclosporins, such as ISAtx247 (described in patent application US 2002/0132763 Al). Additional cyclosporin analogues are described in US Patents 6,136,357, 4,384,996, 5,284,826, and 5,709,797. Cyclosporin analogues include, but are not limited to, D-Sar (a-SMe) 3 Val2-DH-Cs (209-825), Allo-Thr-2-Cs, Norvalin-2-Cs, D-Ala (3 -acetylamino) -8-Cs, Thr-2-Cs, and D-MeSer-3-Cs, D-Ser (0CH2CH2-0H) -8-Cs, and D-Ser-8-Cs, which are described in Cruz et al (Antimicrob Agents Chemother, 44: 143-149, 2000). Cyclosporins are highly hydrophobic and readily precipitate in the presence of water (eg, in contact with body fluids). Methods for providing cyclosporin formulations with improved bioavailability are described in US Pat., 388,307, 6,468,968, 5,051,402, 5,342,625, 5,977,066, and 6,022,852. Mixture-emulsion compositions of cyclosporin are described in US Patents 5,866,159, 5,916,589, 5,962,014, 5,962,017, 6,007,840, and 6,024,978. Cyclosporins can be administered either intravenously or orally, but oral administration is preferred. To overcome the hydrophobicity of cyclosporin A, an intravenous cyclosporin A is usually provided in polyoxyethylated castor oil with ethanol which must be diluted prior to administration. Cyclosporin A can be provided, e.g. , as a miero-emulsion in tablets of 25 or 100 mg, or in an oral solution of 100 mg / ml (NEORAL). Typically, a patient dose of an oral cyclosporin varies according to the patient's condition, but some standard recommended doses are provided herein. Patients suffering from organ transplantation typically receive an initial dose of oral cyclosporin A in amounts ben 12 and 15 mg / kg / day. The dose then gradually decreases by 5% per week until a maintenance dose of 7-12 mg / kg / day is reached. For intravenous administration 2-6 mg / kg / day is preferred for most patients. For patients diagnosed as having Crohn's disease or ulcerative colitis, dose amounts of 6-8 mg / kg / day are usually given. For patients diagnosed as having systemic lupus erythematosus, dosage amounts of 2.2-6.0 mg / kg / day are usually given. For psoriasis or rheumatoid arthritis, dose amounts of 0.5-4 mg / kg / day are typical. A suggested dosing schedule is shown in Table 3. Other useful doses include 0.5-5, 5-10, 10-15, 15-20, or 20-25 mg / kg / day. Frequently cyclosporins are administered in combination with other immunosuppressive agents, such as glucocorticoids. Table 3 Table Legend CsA = cyclosporin A RA = rheumatoid arthritis UC = ulcerative colitis SLE = systemic lupus erythematosus Tacrolimus Tacrolimus (FK506) is an immunosuppressive agent that attacks the transduction trajectories of intracellular T cell signals. Tacrolimus is linked to a protein that binds to intracellular protein FK506 (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 activity of calcineurin phosphatase. This inhibition prevents the dephosphorylation and nuclear translocation of the nuclear factor of activated T cells (NFAT), a nuclear component that initiates the transcription of genes required for production of pro-inflammatory cytokine (e.g., IL-2, gamma interferon) and T cell activation. Thus, tacrolimus inhibits the activation of T cells. Tacrolimus is a macrolide antibiotic that is produced by Streptomyces tsukubaensis. It suppresses the immune system and prolongs the survival of transplanted organs. It is currently available in oral and injectable formulations. Tacrolimus capsules contain 0.5, 1, or 5 mg of anhydrous tacrolimus with a capsule shell of gelatin. The injectable formulation contains 5 mg of anhydrous tacrolimus in castor oil and alcohol that is diluted with 0.9% sodium chloride or 5% dextrose prior to injection. Although oral administration is preferred, patients unable to take oral capsules may receive tacrolimus injection. The dose should be administered no earlier than six hours after the transplant by continuous intravenous infusion. Tacrolimus and tacrolimus analogs are described by Tanaka et al., (J. Am. Chem. Soc., 109: 5031, 1987) and in US Patents 4,894,366, 4,929,611, and 4,956,352. Compounds related to FK506, including FR-900520, FR-900523, and FR-900525, are described in US patent 5,254,562; O-aryl, O-alkyl, O-alkenyl, and O-alkynyl macrolides are described in US patents 5,250,678, 5,532,248, 5,693,648; amino O-aryl macrolides are described in US patent 5,262,533; alkylidene macrolides are described in US Pat. No. 5,284,840; N-heteroaryl, N-alkylheteroaryl, N-alkenylheteroaryl, and N-alkynylhete-roaryl macrolides are described in US Pat. No. 5,208,241; aminomacrolides and their derivatives are described in US Pat. No. 5,208,228; fluoromacrolides are described in US Pat. No. 5,189,042; amino O-alkyl, O-alkenyl, and O-alkenyl macrolides are described in US patent 5,162,334; and halomacrolides are described in US Pat. No. 5,143,918. Although suggested doses will vary with a patient's condition, standard recommended doses are provided below. Typically patients diagnosed as having Crohn's disease or ulcerative colitis are administered with 0.1-0.2 mg / kg / day of oral tacrolimus. Patients having a transplanted organ typically receive doses of 0.1-0.2 mg / kg / day of oral tacrolimus. Patients being treated for rheumatoid arthritis typically receive 1-3 mg / day of oral tacrolimus. For the psoriasis treatment, 0.01-0.15 mg / kg / day of oral tacrolimus is administered to a 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 no earlier than six hours after the transplant, or eight to twelve hours after the infusion of intravenous tacrolimus was discontinued. Other suggested doses of tacrolimus include 0.005-0.01, 0.01-0.03, 0.03-0.05, 0.05-0.07, 0.07-0.10, 0.10-0.25, or 0.25-0.5 mg / kg / day. Tacrolimus is extensively metabolized by the mixed-function oxidase system, in particular, by the cytochrome P-450 system. The primary mechanism of metabolism is demethylation and hydroxylation. Although several metabolites of tacrolimus are likely to exhibit immunosuppressive biological activity, the 13-desmethyl metabolite is reported to have the same activity as tacrolimus. Pimecrolimus Pimecrolimus is the 33-epi-chloro derivative of the ascomycin macrolactam. Structural and functional analogs of pimecrolimus are described in US Pat. No. 6,348,073. Pimecrolimus is particularly useful for the treatment of atopic dermatitis. Pimecrolimus is currently available as a 1% cream. The suggested dosage schedule for pimecrolimus is shown in Table 3. Although individual dosage will vary with the patient's condition, some recommended standard doses are provided below. Oral Pimecrolimus can be given for the treatment of psoriasis or rheumatoid arthritis in amounts of 40-60 mg / day. Amounts of 80-160 mg / day of pimecrolimus can be given for the treatment of Crohn's disease or ulcerative colitis. Patients having an organ transplant can be administered with 160-240 mg / day of pimecrolimus. Patients diagnosed as having systemic lupus erythematosus can be administered with 40-120 mg / day of pimecrolimus. Other useful dosages of pimecrolimus include 0.5-5, 5-10, 10-30, 40-80, 80-120, or even 120-200 mg / day. Rapamycin Rapamycin is a cyclic lactone produced by Streptomyces hygroscopicus. Rapamycin is an immunosuppressive agent that inhibits the activation and proliferation of T cells. Like the cyclosporins and tacrolimus, rapamycin forms a complement with the immunophilin FKBP-12, but the complex of rapamycin-FKBP-12 does not inhibit the activity of calcineurin phosphatase . The immunophilin complex of rapamycin binds to and inhibits the mammalian kinase target of rapamycin (mTOR). MTOR is a kinase that is required for cell cycle progression. The inhibition of mTOR kinase activity blocks the activation of T cells and the secretion of pro-inflammatory cytokine. Structural and functional analogues of rapamycin include mono- and di-acetylated rapamycin derivatives (patent US 4,316,885); water-soluble rapamycin pro-drugs (US Patent 4,650,803); esters of carboxylic acids (PCT publication WO 92/05179); carbamates (US patent 5,118,678); amide esters (US patent 5,118,678); biotin esters (US patent 5,504,091); fluorinated esters (US patent 5,100,883); Acétalos (patent US 5,151,413); Silyl ethers (US patent 5,120,842); bicyclic derivatives (US patent 5,120,725); rapamycin dimers (US patent 5,120,727); O-aryl, O-alkyl, O-alkenyl and O-alkynyl derivatives (US patent 5,258,389); and deuterated rapamycin (US patent 6,503,921). Additional rapamycin analogs are described in US Pat. No. 5,202,332 and 5,169,851. Rapamycin is currently available for oral administration in liquid and tablet formulations. RAPAMUNE liquid contains 1 mg / mL of rapamycin that is diluted in water or orange juice prior to administration. Tablets containing 1 or 2 mg of rapamycin are also available. Rapamycin is preferably given once a day as soon as possible after transplantation. It is absorbed quickly and completely after oral administration. Typically, rapamycin patient dose varies according to the patient's condition, but some standard recommended doses are provided below. The initial loading dose for rapamycin is 6 mg. Subsequent maintenance doses of 0.5-2 mg / day are typical. Alternatively, a loading dose of 3, 5, 10, 15, 20, or 25 mg can be used with a maintenance dose of 1, 3, 5, 7, or 10 mg per day. In patients weighing less than 40 kg, the doses of rapamycin are typically adjusted based on the surface area of the body; generally a loading dose of 3 mg / m2 / day and a maintenance dose of 1 mg / m2 / day are used. Peptide Fractions Peptides, peptide mimetics, peptide fragments, whether natural, synthetic or chemically modified, which impart 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 the activation of NFAT and the transcription factor of NFAT are described, e.g., by 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. Therapy The invention features methods for suppressing secretion of pro-inflammatory cytokines as a means of treating an immune-inflammatory disorder, proliferative skin disease, rejection of transplanted organs, or graft-versus-host disease. The suppression of cytokine secretion is achieved by administering one or more tricyclic compounds in combination, optionally, with one or more steroids. Although the examples describe a single tricyclic compound and a single steroid, it is understood that the combination of multiple agents is often desirable. For example, methotrexate, hydroxychloroquine, and sulfasalazine are commonly administered for the treatment of rheumatoid arthritis. Additional therapies are described below. Desirably, the methods, compositions, and kits of the invention are more effective than other methods, compositions and kits. By "more effective" it is understood that a method, composition, or kit exhibits greater efficacy, is less toxic, safer, more convenient, better tolerated, or less expensive, or provides more treatment satisfaction than another method, composition, or kit with which you are comparing. Chronic Obstructive Pulmonary Disease In one embodiment, the methods, compositions, and kits of the invention are used for the treatment of chronic obstructive pulmonary disease (COPD). If desired, one or more agents typically used to treat COPD can be used as a substitute for or in addition to a corticosteroid in the methods, compositions, and kits of the invention. Such agents include xanthines (e.g., theophylline), anticholinergic compounds (e.g., ipratropium, tiotropium), biologics, small molecule immuno-modulators, and beta-receptor agonists / bronchi-dilators (e.g., ibuterol sulfate, bitolterol mesylate, epinephrine, formoterol fumarate, isoproteronol , levalbuterol hydrochloride, metaproterenol sulfate, pirbute-rol sectate, salmeterol xinafoate, and terbutaline). Thus, in one embodiment, the invention features the combination of a tricyclic compound and a bronchodilator, and methods of treating COPD therewith. Psoriasis The methods, compositions, and kits of the invention can be used for the treatment of psoriasis. If desired, one or more anti-psoriatic agents typically used to treat psoriasis may be used as a substitute for or in addition to a corticosteroid in the methods, compositions, and kits of the invention. Such agents include biologics (e.g., alefacept, inflixamab, adelumumab, efalizumab, etanercept, and CDP-870), small molecule immuno-modulators (e.g., VX 702, SCIO 469, doramapimod, RO 30201195, SCIO 323, DPC 333, pranalcasan, mycophenolate, and merimepodib), non-steroidal immunophilin-dependent immuno-suppressants (e.g., cyclosporine, tacrolimus, pimecrolimus, and ISAtx247), vitamin D analogues (e.g., calcipotriene, calcipotriol ), psoralens (e.g., methoxsalen), retinoids (e.g., acitretin, tazoretene), DMARDs (e.g., methotrexate), and anthralin. Thus, in one embodiment, the invention features the combination of a tricyclic compound and an anti-psoriatic agent, and methods of treating psoriasis therewith. Inflammatory Bowel Disease The methods, compositions, and kits of the invention can be used for the treatment of inflammatory bowel disease. If desired, one or more agents typically used to treat inflammatory bowel disease may be used as a substitute for or in addition to a corticosteroid in the methods, compositions, and kits of the invention. Such agents include biological (e.g., inflixamab, adelimumab, and CDP-870), small molecule immuno-modulators (e.g., VX 702, SCIO 469, doramapimod, RO 30201195, SCIO 323, DPC 333, pranalcasan , mycophenolate, and merimepodib), non-steroidal immunophilin-dependent immuno-suppressants (e.g., cyclosporin, tacrolimus, pimecrolimus, and ISAtx247), 5-amino salicylic acid (e.g., mesalamine, sulfasalazine, disodium balsalazide, and olsalazine sodium), DMARDs (e.g., methotrexate and azathioprine) and alosetrone. Thus, in one embodiment, the invention features the combination of a tricyclic compound and any of the foregoing agents, and methods of treating inflammatory bowel disease therewith. Rheumatoid Arthritis The methods, compositions, and kits of the invention can be used for the treatment of rheumatoid arthritis. If desired, one or more agents typically used to treat rheumatoid arthritis may be used as a substitute for or in addition to a corticosteroid in the methods, compositions, and kits of the invention. Such agents include NSAlDs (e.g., naproxen sodium, diclofenac sodium, diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam, indomethacin, ibuprofen, nabumetone, choline magnesium trisalicylate, sodium salicylate, salicylsalicylic acid (salsalate), fenoprofen, flurbiprofen, ketoprofen, meclofenamate sodium, meloxicam, oxaprozin, sulindac, and tolmetin), inhibitors of COX-2 (e.g., rofecoxib, celecoxib, valdecoxib, and lumiracoxib), biological (e.g., inflixamab, adelimumab, etanercept , CDP-870, rituximab, and atlizumab), small molecule immuno-modulators (eg, VX 702, SCIO 469, doramapimod, RO 30201195, SCIO 323, DPC 333, pranalcasan, mycophenolate, and merimepodib), immuno- non-steroidal immunophilin-dependent suppressors (e.g., cyclosporine, tacrolimus, pimecrolimus, and ISAtx247), 5-amino salicylic acid (e.g., mesalamine, sulfasalazine, balsalazide disodium, and olsalazine sodium), DMARDs (e.g., methotrexate, leflunomide, minocycline, auranofin, gold sodium thiomalate, aurothioglucose, and azathioprine), hydroxychloroquine sulfate, and penicillamine. Thus, in one embodiment, the invention features the combination of a tricyclic compound with any of the above agents, and methods of treating rheumatoid arthritis therewith. Asthma The methods, compositions, and kits of the invention can be used for the treatment of asthma. If desired, one or more agents typically used to treat asthma may be used as a substitute for or in addition to a corticosteroid in the methods, compositions, and kits of the invention. Such agents include beta 2 agonists / bronchodilators / leukotriene modifiers (e.g., zafirlukast, montelukast, and zileutone), biologics (e.g., omalizumab), small molecule immuno-modulators, anti-cholinergic compounds, xanthines , ephedrine, guaifenesin, cromolyn sodium, nedocromil sodium, and potassium iodide. Thus, in one embodiment, the invention features the combination of a tricyclic compound and any of the foregoing agents, and methods of treating asthma therewith. Administration In particular embodiments of any of the methods of the invention, the compounds are administered within 10 days to each other, within five days to each other, within twenty-four hours to 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 in a low dose or in a high dose, each of which is defined herein. It may be desirable to administer to the patient other compounds, such as a corticosteroid, NSAID (e.g., naproxen sodium, diclofenac sodium, diclofenac potassium, aspirin, sulindaco, diflunisal, piroxicam, indomethacin, ibuprofen, nabumetone, trisalicylate choline magnesium , sodium salicylate, salicylsalicylic acid, fenoprophenone, flurbiprofen, ketoprofen, meclofenamate sodium, meloxi-cam, oxaproxzine, sulindac, and tolmetin), COX-2 inhibitor (e.g., rofecoxib, celecoxib, valdecoxib, and lumiracoxib), glucocorticoid receptor modulator, or DMARD. Combination therapies of the invention are especially useful for the treatment of immuno-inflammatory disorders in combination with other agents - either biological or small molecules - that modulate the immune response to affect the disease in a positive manner. Such agents include those that deplete key inflammatory cells, influence cell adhesion, or influence cytokines involved in the immune response. This latter category includes both agents that resemble or increase the action of anti-inflammatory cytokines such as IL-10, as well as agents that inhibit the activity of pro-inflammatory cytokines such as IL-6, IL-1, IL-2, IL. -12, IL-15 or TNFa. Agents that inhibit TNFa include etanercept, adelimumab, infliximab, and CDP-870. In this example (that of agents blocking the effect of TNFa), the combination therapy reduces the production of cytokines, etanercept or infliximab act on the remaining fraction of inflammatory cytokines, providing increased treatment. Immuno-modulators of small molecules include, e.g., p38 MAP kinase inhibitors such as VX 702, SCIO 469, doramapimod, RO 30201195, SCIO 323, TACE inhibitors such as DPC 333, ICE inhibitors such as pranalca-healthy , and inhibitors of IMPDH such as mycophenolate and merimepo-dib. The therapy according to the invention can be carried out alone or in conjunction with another therapy and can be provided at home, the doctor's office, a clinic, an outpatient department of a hospital patient, or a hospital. The treatment optionally begins in a hospital so that the doctor can observe the effects of the therapy closely and make any adjustments that are needed, or can start on a patient's departure basis. The duration of the therapy depends on the type of disease or disorder being treated, the age and condition of the patient, the stage and type of the patient's illness, and how the patient responds to treatment. Additionally, a person having a higher risk of developing an immuno-inflammatory disease (e.g., a person suffering from age-related hormonal changes) may be treated to inhibit or delay the establishment of symptoms. Routes of administration for the various embodiments include, but are not limited to, topical, transdermal, nasal, and systemic administration (such as intravenous, intramuscular, subcutaneous, inhalation, rectal, buccal, vaginal, intra-peritoneal administration , intra-articular, ophthalmic, otic, or oral). As used herein, "systemic administration" refers to non-dermal administration routes, and specifically excludes routes of topical and transdermal administration. In combination therapy, the dose and frequency of administration of each component of the combination can be controlled independently. For example, a compound can be administered three times per day, while the second compound can be administered once per day. The combination therapy can occur in active and inactive cycles that include rest periods such that the patient's body has an opportunity to recover from any unforeseen side effects. The compounds can also be formulated together such that an administration delivers both compounds. Formulation of Pharmaceutical Compositions Administration of a combination of the invention can be by any suitable means resulting in suppression of pro-inflammatory cytokine levels in the target region. The compound may be contained in any suitable amount in any suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition. The composition can be provided in a dosage form that is suitable for the oral administration route, parenteral (e.g., intravenously, intramuscularly), rectal, cutaneous, nasal, vaginal, inhaled, skin (patch), otic or ocular. Thus, the composition may be in the form of, e.g., tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, soaks, osmotic delivery, suppositories, enemas, injectables, implants, sprays, or aerosols. The pharmaceutical compositions can be formulated in accordance with conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed. A. R. Gennaro, Lippincott Williams &; Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Techono-logy, editors, J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York). Each compound of the combination can be formulated in a variety of ways that are 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 the simultaneous or almost simultaneous administration of the agents. Such co-formulated compositions may include the tricyclic compound and the steroid formulated together in the same pill, capsule, liquid, etc. It should be understood that, when referring to the formulation of "tricyclic / cortico-steroid compound combinations", the formulation technology employed is also useful for the formulation of the individual agents of the combination, as well as other combinations of the invention ( e.g., a combination of tricyclic compound / glucocorticoid receptor modulator). By using different formulation strategies for different agents, the pharmacokinetic profiles for each agent can be matched appropriately. Agents formulated individually or separately can be packaged together as a kit. Non-limiting examples include kits containing, e.g., two pills, a pill and a powder, a suppository and a liquid in a bottle, two topical creams, etc. The kit may include optional components that aid in the administration of the unit dose to patients, such as bottles to reconstitute powdered forms, syringes for injection, custom IV delivery systems, inhalers, etc. Additionally, the unit dose kit may contain instructions for the preparation and administration of the compositions. The kit can be manufactured as a single-use unit dose for a patient, of multiple uses for a particular patient (at a constant dose or in which individual compounds can vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple patients ("bulk packaging"). The kit components can be assembled into cartons, blister packs, bottles, tubes, and the like. Controlled Release Formulations The administration of a combination of the invention in which one or both of the active agents is formulated for controlled release is useful where the tricyclic compound or the steroid has (i) a narrow therapeutic index (e.g. the difference between the concentration of plasma leading to harmful side effects or toxic reactions and the concentration of plasma leading to a therapeutic effect is small, usually the therapeutic index, TI, is defined as the ratio of the median lethal dose (LD50) at the median effective dose (ED50)); (ii) a narrow absorption window in the gastro-intestinal tract; (iii) a short biological half-life; or (iv) the drug-kinetic profile of each component must be modified to maximize the contribution of each agent, when used together, to an amount that is therapeutically effective for cytokine suppression. Accordingly, a sustained release formulation can be used to avoid frequent dosing that may be required to sustain the plasma levels of both agents at a therapeutic level. For example, in preferred oral pharmaceutical compositions of the invention, half-life and median residence times of 10 to 20 hours for one or both of the agents of the combination of the invention are observed. Many strategies can be followed to obtain controlled release in which the rate of release exceeds the rate of metabolism of the therapeutic compound. For example, controlled release can be obtained by the appropriate selection of parameters and formulation ingredients (e.g., appropriate controlled release compositions and coatings). Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, micro-capsules, microspheres, nano-particles, patches, and liposomes. The release mechanism can be controlled such that the tricyclic compound and / or steroid are released at intervals of periods, the release can be simultaneous, or a delayed release of one of the agents of the combination can be affected, when the early release of a particular agent is preferred over the other.

Controlled release formulations may include a degradable or non-degradable polymer, hydrogel, organ-gel, or other physical construction that modifies the bio-absorption, half-life or bio-degradation of the agent. The controlled release formulation can be a material that is painted or otherwise applied to the afflicted site, either internally or externally. In one example, the invention provides a biodegradable bolus or implant that is surgically inserted into or near a site of interest (eg, next to an arthritic joint). In another example, the controlled release formulation implant can be inserted into an organ, such as in the lower intestine for the treatment of inflammatory bowel disease. Hydrogels can be used in controlled release formulations for any of the combinations of this invention. Such polymers are formed of macromers with a polymerizable, non-degradable region, which is separated by at least one degradable region. For example, the water-soluble, non-degradable region can form the central core of the macromer and have at least two degradable regions that bind to the core, such that upon degradation, the non-degradable regions (in particular a polymerized gel) will separate, as described in US Pat. No. 5,626,863. Hydrogels can include acrylates, which can be easily polymerized by various starting systems such as eosin stain, ultraviolet or visible light. Hydrogels can also include polyethylene glycols (PEGs), which are highly hydrophilic and biocompatible. Hydrogels can also include an oligoglycolic acid, which is a poly (a-hydroxy acid) which can be easily degraded by hydrolysis of the ester linkage to glycolic acid, a non-toxic metabolite. Other chain extensions may include poly (lactic acid), polycaprolactone, polyorthoesters, polyanhydrides or polypeptides. The entire network can be gelled into a biodegradable network that can be used to trap and homogeneously disperse various combinations of the invention for delivery at a controlled rate. Chitosan and mixtures of chitosan with sodium carboxymethylcellulose (CMC-Na) have been used as vehicles for sustained release of drugs, as described by Inouye et al., Drug Design and Delivery 1: 297-305, 1987. Mixtures of these compounds and agents of any of the combinations described above, when compressed under 200 kg / cm 2, form a tablet from which the active agent is slowly released upon administration to a subject. The release profile can be changed by varying the rates of chitosan, CMC-Na, and active agent (s). The tablets may also contain other additives, including lactose, CaHP04 dihydrate, sucrose, crystalline cellulose, or croscarmellose sodium. Several examples are given in Table 4.

Table 4 Baichwal, in US Pat. No. 6,245,356, describes solid sustained release oral dosage forms which include agglomerated particles of a medically therapeutically active in amorphous form, a gelation agent, an ionizable gel resistance enhancing agent and an inert diluent. The gelation agent can be a mixture of a xanthan gum and a locust bean gum capable of crosslinking with the xanthan gum when the gums are exposed to an environmental fluid. Preferably, the ionizable gel improving agent acts to improve the crosslinking resistance between the xanthan gum and the locust bean gum and thereby prolongs the release of the medicament component from the formulation. In addition to xanthan gum and locust bean gum, acceptable gelation agents that may also be used include those gelation agents known in the art. Examples include natural or naturally occuring modified gums such as alginates, carrageenan, pectin, guar gum, modified starch, hydroxypropylmethylcellulose, methyl cellulose, and other cellulosic materials or polymers, such as, for example, sodium carboxymethyl cellulose and hydroxypropyl cellulose, and mixtures of the foregoing. In another formulation useful for the combinations of the invention, Baichwall and Staniforth in US Pat. No. 5,135,757 describe a free flowing slow release granulation for use as a pharmaceutical excipient which includes from about 20 to about 70 percent or more by weight of a hydrophilic material that includes a heteropolysaccharide (such as, for example, xanthan gum or a derivative thereof) and a polysaccharide material capable of crosslinking the heteropolysaccharide (such as, for example, galactomannans, and most preferably locust bean gum) in the presence of aqueous solutions, and from about 30 to about 80 percent by weight of an inert pharmaceutical filler (such as, for example, lactose, dextrose, sucrose, sorbitol, xylitol, fructose or their mixtures). After mixing the excipient with a combination tricyclic / cortico-steroid compound, or combination agent, of the invention, the mixture is compressed directly into solid dosage forms such as tablets. The tablets thus formed slowly release the drug when ingested and exposed to gastric fluids. By varying the amount of excipient relative to the medicament, a slow release profile can be achieved. In another formulation useful for combinations of the invention, Shell, in US Pat. No. 5,007,790, discloses sustained-release oral drug dosage forms that release a drug in solution at a rate controlled by drug solubility. The dosage form comprises a tablet or capsule which includes a plurality of particles of a dispersion of a drug of limited solubility (such as, for example, prednisolone, paroxetine, or any other agent of any or all of the combination of the present invention ) in a hydrophilic crosslinked polymer, which swells in water, which maintains its physical integrity over the dosing lifetime but which subsequently dissolves rapidly. Once ingested, the particles swell to promote gastric retention and allow the gastric fluid to penetrate the particles, dissolve the drug and separate it from the particles, ensuring that the drug reaches the stomach in the state of solution which is less harmful to the stomach that the drug in solid state. The eventual programmed dissolution of the polymer depends on the nature of the polymer and the degree of crosslinking. The polymer is not fibrillary and is substantially soluble in water in its non-crosslinked state, and the degree of crosslinking is sufficient to allow the polymer to remain insoluble for the desired period of time, typically at least about 4 to 8 hours up to 12 hours , with the choice depending on the drug incorporated and the medical treatment involved. Examples of suitable crosslinked polymers that can be used in the invention are gelatin, albumin, sodium alginate, carboxymethylcellulose, polyvinyl alcohol and chitin. Depending on the polymer, the 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. Silicon microspheres for delivery of pH-controlled gastro-intestinal drugs that are useful in the formulation of any or all of the combinations of the invention have been described by Carelli et al., Int. J. Pharmaceuticals 179: 73-83, 1999 The microspheres thus described are pH sensitive semi-interpenetrating polymer hydrogels made of varying proportions of poly (methacrylic acid-co-methylmetacrilat) (Eudragil L100 or Eudragit S100) and crosslinked polyethylene glycol 8000 which are encapsulated in silicone micro-spheres in the size range of 500 to 1,000 μm. Slow release formulations may include a coating that is not readily soluble in water but is slowly attacked and removed by water, or through which water can slowly permeate. Thus, for example, the combinations of the invention can be spray coated with a solution of a binder under continuous fluidization conditions, as described by Kitamori et al., US Patent 4,036,948. Water-soluble binders include pregelatinized starch (e.g., pre-gelatinized maize starch, pre-gelatinized white potato starch), pre-gelatinized modified starch, water soluble celluloses (e.g., hydroxypropyl cellulose) , hydroxymethyl cellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose), polyvinylpyrrolidone, polyvinyl alcohol, dextrin, gum arabic and gelatin, and binders soluble in organic solvent, such as cellulose derivatives (e.g., cellulose acetate phthalate, phthalate of hydroxypropylmethylcellulose, ethylcellulose). Combinations of the invention, or a component thereof, with sustained release properties can be formulated by spray drying techniques. In an example, as described by Espositio et al., Pharm. Dev. Technol. 5: 267-78, 2000, prednisolone was encapsulated in methacrylate micro-particles (Eudragit RS) using a Mini Spray Dryer, model 190 (Buchi, Laboratorium Technik AG, Flawil, Germany). Optimal conditions for formation of micro-particles were found at a feed rate (pump) of 0.5 mL / min of a solution containing 50 mg of prednisolone in 10 mL of acetonitrile, a nebulized air flow rate of 600 L / hr, temperature heating with dry air at 80 ° C, and a suction drying air flow rate of 28 m3 / hr. Still another form of sustained-release combinations can be prepared by micro-encapsulation of combination agent particles in membranes that act as micro-dialysis cells. In such a formulation, gastric fluid permeates the microcapsule walls and swells the microcapsule, allowing the active agents to be dialyzed (see, for example, Tsuei et al., US Patent 5,589,194). A commercially available sustained release system of this type consists of microcapsules having acacia gum / gelatin / ethyl alcohol membranes. This product is available from Eurand Limited (France) under the trade name Diffucaps. Microcapsules thus formulated can be carried in a conventional gelatin capsule or formed into tablets. A sustained release formulation useful for corticosteroids is also described in US Patent 5,792,476, where the formulation includes 2.5-7 mg of a glucocorticoid as an active substance with a regulated sustained release such that at least 90% by weight of the glucocorticoid is released for a period of about 40-80 minutes, starting about 1-3 hr after the entry of said glucocorticoid into the patient's small intestine. To make these possible low levels of active substance, the active substance, ie, the glucocorticoid, such as prednisolone or prednisone, is micronized, suitably mixed with known diluents, such as starch and lactose, and granulated with PVP (polyvinyl pyrrolidone). In addition, the granulate is laminated with an inner layer of sustained release resistant to a pH of 6.8 and an outer layer of sustained release resistant to a pH of 1.0. The inner layer is made of Eudragit RL (acrylic and methacrylic ester copolymer with a low content of quaternary ammonium groups) and the outer layer is made of Eudragil L (anionic polymer of methacrylic acid and methyl ester of methacrylic acid). A two-layer tablet can be formulated for a combination of the invention in which different customized granulations are made for each combination agent and the two agents are compressed in a two-layer press to form a single tablet. For example, 100 mg of amoxapine, formulated for controlled release resulting in a half-life (t12) of amoxapine from 8 to 12 hours and a mean residence time (MRT) from 10 to 16 hours after administration, it can be combined in the same tablet with 3 mg of prednisolone, which is formulated such that t12 and MRT approach that of amoxapine (ie, 8 to 12 hours and 10 to 16 hours, respectively). In addition to controlling the release rate of prednisolone in vivo, an enteric or delayed release coating can be included that delays the onset of drug release such that the Tmax of prednisolone approaches that of amoxapine. Cyclodextrins are cyclic polysaccharides containing D (+) - glucopyranose units of natural occurrence in an α- (1,4) bond. Alpha-, beta- and gamma-cyclodextrins, which contain, respectively, six, seven or eight glucopyranose units, are most commonly used and suitable examples are described in PCT publications WO 91/11172, WO 94/02518 and WO 98 / 55148.

Structurally, the cyclic nature of a cyclodextrin forms a bull or donut-like shape having an apolar or hydrophobic inner cavity, the secondary hydroxyl groups located on one side of the cyclodextrin bull and the primary hydroxyl groups located on the other. The side on which the secondary hydroxyl groups are located has a wider diameter than the side on which the primary hydroxyl groups are located. The hydrophobic nature of the inner cavity of cyclodextrin allows for the inclusion of a variety of compounds. (Comprehensive Supramolecular Chemistry, volume 3, J. L. Atwood et al., Editors, Pergamon Press (1996), Cserhati, Analytical Biochemistry 225: 328-32, 1995, Husain et al., Applied Spectroscopy 46: 652-8, 1992). Cyclodextrins have been used as a delivery vehicle with various therapeutic compounds by forming inclusion complexes with various drugs that can fit into the hydrophobic cavity of the cyclodextrin or by forming non-covalent association complexes with other biologically active molecules. US Patent 4,727,064 discloses pharmaceutical preparations consisting of a drug with substantially low water solubility and an amorphous water-soluble cyclodextrin-based mixture in which the drug forms an inclusion complex with the cyclodextrins of the mixture. The formation of a drug-cyclodextrin complex can modify the solubility of the drug, the rate of dissolution, bio-availability, and / or stability properties. For example, cyclodextrins have been described to improve the bioavailability of prednisolone, as described by Uekama et al., J. Pharm. Dyn. 6: 124: 127, 1983. A complex of β-cyclodextrin / prednisolone 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, Kan., And marketed as CAPTISOL) can also be used as an adjunct in the preparation of sustained release formulations of agents of the combinations of the present invention. For example, a sustained release tablet has been prepared that includes prednisolone and SBE-β-CD tablets in a hydroxypropyl methylcellulose matrix (see Rao et al, J. Pharm, Sci 90: 807-16, 2001). Polymeric cyclodextrins have also been prepared, as described in the patent application publications US 2003/0017972 and 2003/008818. The cyclodextrin polymers thus formed may be useful for formulating agents of the combinations of the present invention. These multi-functional polymeric cyclodextrins are commercially available from Insert Therapeutics, Inc., Pasadena, California, United States. As an alternative to direct complex formation with agents, cyclodextrins can be used as an auxiliary additive, e.g., as a carrier, diluent, or solubilizer. Formulations including cyclodextrins and other agents of the combinations of the present invention (ie, tricyclic and / or steroidal compounds) can be prepared by methods similar to the preparations of the cyclodextrin formulations described herein. Liposomal Formulations One or both components of any of the combinations of the invention, or mixtures of the two components together, can be incorporated into liposomal vehicles for administration. Liposomal vehicles are composed of three general types of vesicle-forming lipid components. The first includes vesicle-forming lipids that form the bulk of the vesicle structure in the liposome. Generally, these vesicle-forming lipids include any amphipathic lipid having hydrophobic and polar head group fractions, and which (a) can spontaneously form in two-layered vesicles in water, as exemplified by phospholipids, or (b) is stably incorporated into two lipid layers, with its hydrophobic fraction in contact with the interior, the hydrophobic region of the two-layer membrane, and its polar head group fraction oriented towards the outer, polar surface of the membrane. Vesicle-forming lipids of this type are preferably having two hydrocarbon chains, typically acyl chains, and a polar head group. Included in this class are phospholipids, such as phosphatidylcholine (PC), PE, phosphatidic acid (PA), phosphatidinilinositol (Pl), and sphingomyelin (SM), where the two hydrocarbon chains are typically between about 14-22 atoms carbon in length, and have varying degrees of unsaturation. The above described lipids and phospholipids whose acyl chains have a variety of degrees of saturation can be obtained commercially, or prepared according to published methods. Other lipids that may be included in the invention are glycolides and sterols, such as cholesterol. The second general component includes a vesicle-forming lipid that is derived with a polymer chain which will form the polymer layer in the composition. The vesicle-forming lipids that can be used with the second general vesicle-forming lipid component are those described for the first general vesicle-forming lipid component. Vesicle-forming lipids with diacyl chains, such as phospholipids, are preferred. An exemplary phospholipid is fophatidylethanolamine (PE), which provides a reactive amino group which is convenient for coupling to activated polymers. 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 1,000-15,000 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 include polyvinylpyrrolidone, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyl methacrylamide, polymethacrylamide and polydimethylacrylamide, poly (lactic acid), poly (glycolic acid), and derived celluloses, such as hydroxymethylcellulose or hydroxyethylcellulose. Additionally, block copolymers or random copolymers of these polymers, particularly including PEG segments, may be suitable. Methods for preparing derivatized lipids with hydrophilic polymers, such as PEG, are well known, e.g., as described in US Pat. No. 5,133,556. A third component of general vesicle-forming lipid, which is optional, is a lipid anchor by which a target fraction is anchored to the liposome, through a polymer chain at the anchor. Additionally, the target group is positioned at the far end of the polymer chain in such a way that the biological activity of the target fraction is not lost. The lipid anchor has a hydrophobic fraction which serves to anchor the lipid in the outer layer of the surface of two liposome layers, a polar head group to which the inner end of the polymer is covalently attached, and one end of free polymer (exterior) which is or can be activated for covalent coupling with the target fraction. Methods for preparing lipid anchor molecules of these types are described below. The lipid components used in forming the liposomes are preferably present in a molar ratio of about 70-90 percent of vesicle-forming lipids, 1-25 percent of lipids derived from polymers, and 0.1-5 percent of lipid anchor. An exemplary formulation includes 50-70 molar percent non-derivatized PE, 20-40 molar percent cholesterol, 0.1-1 molar percent PE-PEG polymer (3500) with a chemically reactive group at its free end for coupling to a fraction objective, 5-10 molar percent of PE derived with PEG 3500 polymer chains, and 1 molar percent of alpha-tocopherol. Liposomes are preferably prepared to have substantially homogeneous sizes in a selected range of sizes, typically between about 0.03 to 0.5 microns. An effective sizing method for REVs and MLVs involves extruding an aqueous suspension of the liposomes through a series of polycarbonate membranes having a uniform pore size selected in the range of 0.03 to 0.2 microns, typically 0.05, 0.08, 0.1, or 0.2 microns. The pore size of the membrane corresponds more or less to the larger sizes of liposomes produced by extrusion through that membrane, particularly where the preparation is extruded two or more times through the same membrane. Homogenization methods are also useful for reducing liposomes to sizes of 100 nm or less. The liposomal formulations of the present invention include at least one surface active agent. Suitable surface active agents useful for the formulation of the various combinations described herein include compounds belonging to the following classes: polyethoxylated fatty acids, fatty acid diesters-PEG, mixtures of mono-ester and fatty acid diester-PEG, esters of fatty acids polyethylene glycol glycerol, alcohol-oil transesterification products, polyglycerized fatty acids esters of propylene glycol fatty acid, mixtures of propylene glycol esters and glycerol esters, mono- and di-glycerides, sterol and sterol derivatives, esters of polyethylene glycol sorbitan fatty acid, polyethylene glycol alkyl ethers, sugar esters, polyethylene glycol alkyl phenols, polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acid esters, lower alcohol fatty acid esters, and ionic surfactants. Commercial examples available for each kind of excipient are provided below. Polyethoxylated fatty acids can be used as excipients for the formulation of any of the combinations described herein. Examples of available monoether surfactants of polyethoxylated fatty acids include: PEG monolaurate 4-100 (Crodet L series, Croda), PEG monooleate 4-1000 (Crodet 0 series, Croda), PEG monostearate 4-100 (Crodet S series) , Croda, and series Myrj, Atlas / lCI), distearate of PEG 400 (series Citrhol 4DS, Croda), monolaurate of PEG 100, 200, or 300 (series Cithrol ML, Croda), monooleate of PEG 100, 200, or 300 (Cithrol MO series, Croda), PEG 400 dioate (Cithrol 4DO, Croda), PEG 400-1000 monostearate (Cithrol MS series, Croda), PEG-1 stearate (Nikkol MYS-13X, Nikko, and Coster Kl, Condea), stearate of PEG-2 (Nikkol MYS-2, Nikko), oleate of PEG-2 (Nikkol MYO-2, Nikko), laurate of PEG-4 (Mapeg 200 ML, PPG), oleate of PEG-4 ( Mapeg 200 MO, PPG), PEG-4 stearate (Kessco PEG 200 MS, Stepan), PEG-5 stearate (Nikkol TMGS-5, Nikko), PEG-5 oleate (Nikkol TMGO-5, Nikko), oleate of PEG-6 (Algon OL60, Auschem SpA), PEG-7 oleate (Algon OL 70, Auschem SpA), laur PEG-6 (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 400 MO, PPG), PEG-8 stearate (Mapeg 400 MS, PPG), PEG-9 oleate (Emulative 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 PEG 600 MO, Stepan), PEG-12 ricinoleate (CAS # 9004-97-1), PEG-12 stearate (Mapeg 600 MS, PPG), stearate of PEG-15 (Nikkol TMGS-15, Nikko), oleate of PEG-15 (Nikkol TMGO-15, Nikko), laurate of PEG-20 (Kessco PEG 1000 ML, Stepan), oleate of PEG-20 (Kessco PEG 1000 MO, Stepan), PEG-20 stearate (Mapeg 1000 MS, PPG), PEG-25 stearate (Nikkol MYS-25, Nikko), PEG-32 laurate (Kessco 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 2715, Henkel), PEG-45 stearate (Nikkol MYS-45, Nikko), stearate of PEG-50 (Myrj 53), stearate of PEG-55 (Nikkol MYS-55, Nikko), PEG-100 oleate (Crodet O-100, Croda), PEG-100 stearate (Ariacel 165, ICI), PEG-200 oleate (Albunol 200 MO, Taiwan Surf.), PEG-400 oleate (LACTOMUL, Henkel), and oleate from PEG-600 (Albunol 600 MO, Taiwan Surf.).

Formulations of one or both components of any or all of the combinations according to the invention may include one or more of the above polyethoxylated fatty acids. Polyethylene glycol fatty acid diesters can also be used as excipients for any or all of the combinations described herein. Examples of polyethylene glycol fatty acid diesters commercially available include: PEG-4 dilaurate (Mapeg 200 DL, PPG), PEG-4 dioleate (Mapeg 200 OD, PPG), PEG-4 distearate (Kessco 200 DS, Stepan) , PEG-6 dilaurate (Kessco PEG 300 DL, Stepan), PEG-6 dioleate (Kessco PEG 300 DO, Stepan), PEG-6 distearate (Kessco PEG 300 DS, Stepan), PEG-8 dilaurate (Mapeg) 400 DL, PPG), PEG-8 dioleate (Mapeg 400 OD, PPG), PEG-8 distearate (Mapeg 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 600 OD, PPG), PEG-20 dilaurate (Kessco PEG 1000 DL, Stepan), PEG dioleate -20 (Kessco PEG 1000 OD, Stepan), distearate of PEG-20 (Kessco PEG 1000 DS, Stepan), dilaurate of PEG-32 (Kessco PEG 1540 DL, Stepan), PEG-32 dioleate (Kessco PEG 1540 OD, Stepan), PEG-32 distearate (Kessco PEG 1540 DS, Stepan), P dioleate EG-400 (Cithrol 4DO series, Croda), and distearate of PEG-400 (Cithrol 4DS series, Croda). Formulations of any of the combinations according to the invention may include one or more of the above polyethylene glycol fatty acid diesters. Fatty acid mono- and di-ester mixtures PEG can be used as excipients for the formulation of any and all combinations described herein. Examples of mixtures of fatty acid mono- and di-ester PEG include: mono, PEG 4-150 dilaurate (Kessco PEG 200-6000 mono, Dilaurate, Stepan), mono, PEG 4-150 dioleate (Kessco PEG- 200-6000 mono, Dioleate, Stepan), and mono, distearate of PEG 4-150 (Kessco 200-6000 mono, Distearate, Stepan). Formulations of any and all of the combinations according to the invention may include one or more of the above mono- and di-fatty acid-PEG mixtures. In addition, polyethylene glycol glycerol fatty acid esters can be used as excipients for the formulation of any and all of the combinations described herein. Examples of polyethylene glycol glycerol fatty acid esters include: PEG-20 glyceryl laurate (Tagat L, Goldschmidt), PEG-30 glyceryl laurate (Tagat L2, Goldschmidt), PEG-15 glyceryl laurate (Glycerox L series, Croda ), glyceryl laurate from PEG-40 (Glycerox L series, Croda), glyceryl stearate from PEG-20 (Capmul EMG, ABITEC and Aldo MS-20 KFG, Lonza), glyceryl oleate from PEG-20 (Tagat O, Goldschmidt), and PEG-30 glyceryl oleate (Tagat 02, Goldschmidt). Formulations of any or all of the combinations according to the invention may include one or more polyethylene glycol glycerol fatty acid esters above. Alcohol-oil transesterification products can be used as excipients for the formulation of any or all of the combinations described herein. Examples of alcohol-oil transesterification products commercially available include: 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 (Emulsifier EL23), castor oil from PEG-30 (Incrocas 30, Croda), castor oil from PEG-35 (Incrocas-35, Croda), castor oil from PEG-38 (Emulsifier EL 65, Condea), castor oil of PEG-40 (Emalex C-40, Nihon Emulsion), castor oil of PEG-50 (Emalex C-50, Nihon Emulsion), castor oil of PEG-56 (Eumulgin PRT 56, Pulcra SA), castor oil of PEG-60 (Nikkol CO-60TX, Nikko), PEG-100 castor oil, PEG-200 castor oil (Eumulgin PRT 200, Pulcra SA), hydrogenated PEG-5 castor oil (Nikkol HCO-5) , Nikko), hydrogenated PEG-7 castor oil (Cremophor W07, BASF), hydrogenated PEG-10 castor oil (Nikkol HCO-10, Nikko), hydrogenated PEG-20 castor oil (Nikkol HCO-20, Nikko), hydrogenated PEG-25 castor oil (Simulsol 1292, Seppic), PEG-30 h castor oil oxygenated (Nikkol HCO-30, Nikko), hydrogenated PEG-40 castor oil (Cremophor RH 40, BASF), hydrogenated PEG-45 castor oil (Cerex ELS 450, Auschem SpA), hydrogenated PEG-50 castor oil (Emalex HC-50, Nihon Emulsion), hydrogenated PEG-60 castor oil (Nikkol HCO-60, Nikko), hydrogenated PEG-80 castor oil (Nikkol HCO-80, Nikko), hydrogenated PEG-100 castor oil (Nikkol HCO-100, Nikko), PEG-6 corn oil (Labrafil M 2125 CS, Gattefosse), almond oil from PEG-6 (Labrafil M 1966 CS, Gattefosse), chabacano bone oil from PEG-6 (Labrafil M 1944 CS, Gatefosse), olive oil from PEG-6 (Labrafil M 1980 CS, Gattefosse), PEG-6 peanut oil (Labrafil M 1969 CS, Gattefosse), hydrogenated PEG-6 palm seed oil (Labrafil M 2130 CS, Gattefosse), PEG-6 triolein ( Labrafil M 2735 CS, Gattefosse), corn oil of PEG-8 (Labrafil WL 2609 BS, Gattefosse), corn glycerides of PEG-20 (Crovol M40, Croda), almond glycerides of PEG-20 (Crovol A40, Croda ), PEG-25 trioleate (TAGAT TO, Goldschmidt), PEG-40 palm seed oil (Crovol PK-70), PEG-60 corn glycerides (Crovol M70, Croda), PEG-almond glycerides 60 (Crovol A70, Croda), capr triglycerides ileal / capric of PEG-4 (Labrafac Hydro, Gattefosse), caprylic / capric glycerides of PEG-8 (Labrasol, Gattefosse), caprylic / capric glycerides of PEG-6 (SOFTIGEN 767, Huís), lauroyl glyceride macrogol-32 ( GELUCIRE 44/14, Gattefosse), stearoyl macrogol glyceride (GELUCIRE 50/13, Gattefosse), mono-, di-, tri-, and tetra-esters of vegetable oils and sorbitol (SorbitoGlyceride, Gattefosse) pentaerythrityl tetraisostearate (Crodamol PTIS , Croda) pentaerythrityl distearate (Albunol DS, Taiwan Surf.) Pentaerythrityl tetraoleate (Liponate PO-4, Lipo Chem.) Pentaerythritil tetrastearate (Liponate PS-4, Lipo Chem.) Pentaerythrityl tetracaprylate tetracaprylate (Liponate PE-810 Lipo Chem.), And pentaerythrityl tetraoctanoate (Nikkol Pentarate 408, Nikko). Also included as oils in this category of surfactants are oil-soluble vitamins, such as vitamins A, D, E, K, etc. Thus, derivatives of these vitamins, such as tocopheryl PEG-1000 succinate (TPGS, available from Eastman), are also suitable surfactants. Formulations of any and all combinations according to the invention may include one or more prior alcohol-oil transesterification products. Polyglycerized fatty acids can also be used as excipients for the formulation of any or all of the combinations described herein. Examples of commercially available polyglycerized fatty acids available include: 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 1-0, Nikko), polyglyceryl-4 stearate (Nikkol Tetraglyn 1-S, Nikko), polyglyceryl-6 oleate (Drewpol 6-1-0, Stepan), polyglyceryl-10 laurate (Nikkol Decaglyn 1-L, Nikko), polyglyceryl-10 oleate (Nikkol Decaglyn 1-0, Nikko), polyglyceryl-10 stearate (Nikkol Decaglyn 1-S, Nikko), ricinoleate polyglyceryl-6 (Nikkol Hexaglyn PR-15, Nikko), polyglyceryl-10 linoleate (Nikkol Decaglyn 1-LN, Nikko), polyglyceryl-6 pentaoleate (Nikkol Hexaglyn 5-0, Nikko), polyglyceryl-3 dioleate (Cremophor G032, BASF), polyglyceryl-3 distearate (Cremophor GS32, BASF), polyglyceryl-4 pentaoleate (Nikkol Tetraglyn 5-0, Nikko), diolea polyglyceryl-6 (Caprol 6G20, ABITEC), polyglyceryl-2 dioleate (Nikkol DGD0, Nikko), polyglyceryl-10 trioleate (Nikkol Decaglyn 3-0, Nikko), polyglyceryl-10 pentaoleate (Nikkol Decaglyn 5-0) , Nikko), polyglyceryl-10-setaoleate (Nikkol Decaglyin 7-0, Nikko), polyglyceryl-10 tetraoleate (Caprol 10G40, ABITEC), polyglyceryl-decaisostearate-10 (Nikkol Decaglyn 10-IS, Nikko), polyglyceryl-101 decaoleate (Drewpol 10-10-O, Stepan), polyglyceryl-10 mono-, di-oleate (Caprol PGE 860, ABITEC), and polyglyceryl polyricinoleate (Polymuls, Henkel). Formulations of any or all of the combinations according to the invention may include one or more above polyglycerized fatty acids. In addition, the propylene glycol fatty acid esters can be used as excipients for the formulation of the tetra-substituted pyrimidopyrimidine of any or all of the combinations described herein. Examples of commercially available propylene glycol fatty acid esters available include: 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-06, Eastman), propylene glycol dicaprylate (Captex 200, ABITEC), propylene glycol dioctanoate (Captex 800, ABITEC), propylene glycol caprylate (LABRAFAC PG, Gattefosse), propylene glycol dilaurate, propylene glycol distearate (Kessco PGDS, Stepan) , propylene glycol dicaprylate (Nikkol Sefsol 228, Nikko), and propylene glycol dicaprate (Nikko PDD, Nikko). Formulations of any or all of the combinations of the invention may include one or more of the above propylene glycol fatty acid esters. Mixtures of propylene glycol esters and glycerol esters can also be used as excipients for the formulation of any or all of the combinations described herein. A preferred mixture is composed of the oleic acid esters of propylene glycol and glycerol (Arlacel 186). Examples of these surfactants include: oleic (ATMOS 300, ARLACEL 186, ICI), and stearic (ATMOS 150). Formulations of any or all of the combinations according to the invention may include one or more of the blends of propylene glycol esters and glycerol esters above. Additionally, mono- and di-glycerides can be used as excipients for the formulation of any or all of the combinations described herein. Examples of commercially available mono- and diglycerides include: monopalmitolein (C16: 1) (Larodan), monoelaidin (C18: 1) (Larodan), monocaproin (C6) (Larodan), monocaprylin (Larodan), monocaprin (Larodan), monolaurin ( Larodan), glyceryl monomiristate (C14) (Nikkol MGM, Nikko), glyceryl monooleate (C18: 1) (PECEOL, Gattefosse), glyceryl monooleate (Myverol, Eastman), monooleate-to / glycerol linoleate (OLICINE, Gattefosse ), glycerol monolinoleate (Maisine, Gattefosse), glyceryl ricinoleate (Softigen 701, Huís), glyceryl monolaurate (ALDOL MLD, Lonza), glycerol monopalmitate (Emalex GMS-P, Nihon), glycerol monostearate (Capmul GMS, ABITEC), glyceryl mono- and di-oleate (Capmul GMO-K, ABITEC), palmitic / stearic glyceryl (CUTINA MD-A, ESTAGEL-G18), glyceryl acetate (Lamegin EE, Grunau GmbH), glyceryl laurate ( Imwitor 312, Huís), citrate / lactate / oleate / glyceryl linoleate (Imwitort 375, Huís), glyceryl caprylate or (Imwitor 308, Huís), glyceryl caprylate / caprate (Capmul MCM, ABITEC), mono- and di-glycerides of caprylic acid (Imwitor 988, Huís), caprylic / capric glycerides (Imwitor 742, Huís), monoglycerides mono- and di-acetylated (Myvacet 9-45, Eastman), glyceryl monostearate (Aldo MS, Arlacel 129, ICI), lactic acid esters of mono- and di-glycerides (LAMEGIN GLP, Henkel), dicaproic acid ( C6) (Larodan), dicaprine (CIO) (Larodan), dioctanoin (C8) (Larodan), dimiristine (C14) (Larodan), dipalmitin (C16) (Larodan), distearyin (Larodan), glyceryl dilaurate (C12) (Capmul GDL, ABITEC), glyceryl dioleate (Capmul GDO, ABITEC), glycerol esters of fatty acids (GELUCIRE 39/01, Gattefosse), dipalmitolein (C16: 1) (Larodan), 1,2 and 1,3-diolein (C18: l) (Larodan), dielaidine (C18: 1) (Larodan), and dilinolein (C18: 2) (Larodan). Formulations of any or all of the combinations according to the invention may include one or more of the above mono- and di-glycerides. Sterol and sterol derivatives can also be used as excipients for the formulation of any or all of the combinations described herein. Examples of available sterol and commercially available sterol derivatives include: cholesterol, sitosterol, lanosterol, PEG-24 cholesterol ether (Solulan C-24, Amerchol), PEG-30 cholestanol (series Phytosterol GENEROL, Henkel), PEG-25 phytosterol (Nikkol BPSH) -25, Nikko), PEG-5 soyaterol (Nikkol BPS-5, Nikko), PEG-10 soyaterol (Níkkol BPS-10, Nikko), PEG-20 soyaterol (Nikkol BPS-20, Nikko), and PEG-30 soyaterol (Nikkol BPS-30, Nikko). Formulations of any or all of the combinations according to the invention may include one or more of the above sterols and sterol derivatives. Polyethylene glycol sorbitan fatty acid esters can also be used as excipients for the formulation of any or all of the combinations described herein. Examples of commercially available polyethylene glycol sorbitan fatty acid esters available include: PEG-10 sorbitan laurate (Liposorb L-10, Lipo Chem.), PEG-20 sorbitan monolaurate (Tween 20, Atlas / lCl), monolaurate of PEG-4 sorbitan (Tween 21, Atlas / ICI), monolaurate of PEG-80 sorbitan (Hodag PSML-80, Calgene), monolaurate of PEG-6 sorbitan (Nikkol GL-1, Nikko), monopalmitate of PEG-20 sorbitan (Tween 60, Atlas / lCl), PEG-4 sorbitan monostearate (Tween 61, Atlas / lCl), PEG-8 sorbitan monostearate (DACOL MSS, Condea), PEG-6 sorbitan monostearate (Nikkol TS106, Nikko), PEG-20 sorbitan tristearate (Tween 65, Atlas / lCI), PEG-6 sorbitan tetraestearate (Nikkol GS-6, Nikko), PEG-60 sorbitan tetrastearate (Nikkol GS-460, Nikko), PEG monooleate -5 sorbitan (Tween 81, Atlas / lCI), monooleate of PEG-6 sorbitan (Nikkol TO-106, Nikko), monooleate of PEG-20 sorbitan (Tween 80, Atlas / lCI), oleate of PEG-40 sorbitan (Emalex ET 8040, N ihon 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), tetraoleate of PEG-40 sorbitan (Nikkol GO-440, Nikko), mono-stearate of PEG-20 sorbitan (Tween 120, Atlas / lCl), PEG-sorbitol hexaoleate (Atlas G-1086, ICI), polysorbate 80 (Tween 80, Pharma) , polysorbate 85 (Tween 85, Pharma), polysorbate 20 (Tween 20, Pharma), polysorbate 40 (Tween 40, Pharma), polysorbate 60 (Tween 60, Pharma), and PEG-6 sorbitol hexastate (Nikkol GS-6, Nikko). Formulations of any or all of the combinations according to the invention may include one or more of the above polyethylene glycol sorbitan fatty acid esters. In addition, polyethylene glycol alkyl ethers can be used as excipients for the formulation of any or all of the combinations described herein. Examples of commercially available polyethylene glycol alkyl ethers include: PEG-2 oleyl ether, olet-2 (Brij 92/93, Atlas / lCl), PEG-3 oleyl ether, olet-3 (Volpo 3, Croda), PEG-5 oleyl ether, olet-5 (Volpo 5, Croda), PEG-10 oleyl ether, olet-10 (Volpo 10, Croda), PEG-20 oleyl ether, olet-20 (Volpo 20, Croda), PEG-4 lauryl ether , lauret-4 (Brij 30, Atlas / lCI), PEG-9 lauryl ether, PEG-23 lauryl ether, lauret-23 (Brij 35, Atlas / lCI), 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 any or all of the combinations according to the invention may include one or more of the above polyethylene glycol alkyl ethers. Sugar esters may also be used as excipients for the formulation of any or all of the combinations described herein. Examples of commercially available sugar esters include: sucrose distearate (SUCRO ESTER 7, Gattefosse), distearate / sucrose monostearate (SUCRO ESTER 11, Gattefosse), sucrose dipalmitate, sucrose monostearate (Crodesta F-160, Croda), monopalmitate of sucrose (SUCRO ESTER 15, Gattefosse), and sucrose monolaurate (Saccharose monolaurate 1695, Mitsubishi-Kasei). Formulations of any or all of the combinations according to the invention may include one or more of the above sugar esters. Polyethylene glycol alkyl phenols are also useful as excipients for the formulation of any or all of the combinations described herein. Examples of commercially available polyethylene glycol alkyl phenols include: nonylphenol series of PEG-10-100 (Triton X series, Rohm &; Haas) and octylphenol ether series of PEG-15-100 (Triton N, Rohm &Haas series). Formulations of any or all of the combinations of the invention may include one or more of the above polyethylene glycol alkyl phenols. Polyoxyethylene-polyoxypropylene block copolymers can also be used as excipients for the formulation of any or all of the combinations described herein. These surfactants are available under various trade names, including one or more of the Synperonic PE (ICI) series, Pluronic series (BASF), Lutrol (BASF), Surponic, Monolan, Pluracare, and Plurodac. The generic term for these polymers is "poloxamer" (CAS 9003-11-6). These polymers have the formula shown below: HO (C2H40) a (C3H60) b (C2H40) aH (X) where "a" and "b" denote the number of polyoxyethylene and polyoxypropylene units, respectively. These copolymers are available in molecular weights ranging from 1,000 to 15,000 Daltons, with the ratios of ethylene oxide / propylene oxide by weight between 0.1 and 0.8. Formulations of any or all of the combinations according to the invention may include one or more above polyoxyethylene-polyoxypropylene block copolymers. Polyoxyethylene, such as PEG 300, PEG 400, and PEG 600, can be used as excipients for the formulation of any or all of the combinations described herein. Sorbitan fatty acid esters can also be used as excipients for the formulation of any or all of the combinations described herein. Examples of commercially available sorbitan fatty acid esters available include: sorbitan monolaurate (Span-20, Atlas / lCl), sorbitan monopalmitate (Span-40, Atlas / ICI), sorbitan monooleate (Span-80, Atlas / lCl), sorbitan monostearate (Span-60, Atlas / lCI), sorbitan trioleate (Span-85, Atlas / ICI), sorbitan sesquioleate (Arlacel-C, ICI), sorbitan tristearate (Span-65, Atlas / ICI), sorbitan monoisostearate (Crill 6, Croda), and sorbitan sesquistearate (Nikkol SS-15, Nikko). Formulations of any and all of the combinations according to the invention may include one or more sorbitan fatty acid esters above. Esters of lower alcohols (C2 to C4) and fatty acids (Ca to C18) are suitable surfactants for use in the invention. Examples of these surfactants include: 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). Formulations of any and all of the combinations according to the invention may include one or more lower alcohol esters-previous fatty acids. In addition, ionic surfactants can be used as excipients for the formulation of any or all of the combinations described herein. Examples of useful ionic surfactants include: sodium caproate, sodium caprylate, sodium caprate, sodium laurate, sodium myristate, sodium myristocyte, sodium palmitate, sodium palmitoleate, sodium oleate, sodium ricinoleate, linoleate sodium, 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 ursodeoxycholate, sodium chenodeoxycholate, sodium taurokenedeoxycholate, sodium glycoquenodeoxycholate, sodium colilsarcosinate, sodium N-methyl taurocholate, egg yolk phosphatide, hydrogenated soybean lecithin, dimiristoil lecithin, lecithin , hydroxylated lecithin, lysophosphatidylcholine, cardiolipin, sphingomyelin, phosphatidylcholine, phosphatidyl ethanolamine, phosphatidic acid, phosphatidyl gly cerol, phosphatidyl serine, diethanolamine, phospholipids, polyoxyethylene-10-oleyl ether phosphate, esterifi cation products of fatty alcohols or ethoxylates of fatty alcohols, with acid or phosphoric anhydride, ether carboxylates (by oxidation of terminal OH group of fatty alcohol ethoxylates) ), succinylated monoglycerides, sodium stearyl fumarate, stearoyl propylene glycol hydrogen succinate, mono / di-acetylated tartaric acid esters of mono- and di-glycerides, citric acid esters of mono- and di-glycerides, glyceryl lacto esters of fatty acids, acyl lactylates, lactyl esters of fatty acids, sodium stearoyl-2-lactylate, sodium stearoyl lactylate, alginate salts, propylene glycol alginate, ethoxylated alkyl sulphates, alkyl benzene sulfones, α-olefin sulphonates, acyl isethionates, acyl taurates, alkyl glyceryl ether sulphonates, sodium octyl sulfosuccinate, undecylenamido-MEA-sodium sulfusuccinate, hexadecyl tri-bromide ammonium, decyl trimethyl ammonium bromide, cetyl trimethyl ammonium bromide, dodecyl ammonium chloride, alkyl benzyldimethylammonium salts, diisobutyl phenoxyethoxydimethyl benzylammonium salts, alkylpyridinium salts, betaines (trialkylglycine), lauryl betaine (N-lauryl, N) -dimethylglycine), and ethoxylated amines (polyoxyethylene-15 coco amine). For simplicity, typical counterions are provided above. It will be appreciated by one skilled in the art, however, that any bio-acceptable counterion can be used. For example, although the fatty acids are shown as sodium salts, counterions of another cation may also be used, such as, for example, alkali metal or ammonium cations. Formulations of any or all of the combinations according to the invention may include one or more of the above ionic surfactants. The excipients present in the formulations of the invention are present in amounts such that the carrier forms a clear, or opalescent, aqueous dispersion of the tricyclic compound, the cortico-steroid, or the combination sequestered within the liposome. The relative amount of an excipient of active surface necessary for the preparation of liposomal formulations or of nano-particles of solid lipids is determined using known methodology. For example, liposomes can be prepared by a variety of techniques. Multi-lamellar vesicles (MLVs) can be formed by hydration techniques of simple lipid films. In this process, a mixture of liposome-forming lipids of the type detailed above dissolved in a suitable organic solvent are evaporated in a vessel to form a thin film, which is then covered by an aqueous medium. The lipid film is hydrated to form MLVs, typically with sizes between about 0.1 and 10 microns. Other established liposomal forming techniques can be applied as necessary. For example, the use of liposomes to facilitate cellular uptake is described in US Patents 4,897,355 and 4,394,448. Dosage The dose of each compound of the claimed combinations depends on several factors, including: the method of administration, the disease to be treated, the severity of the disease, whether the disease is to be treated or prevented, and age, weight, and health of the person to be treated. Additionally, drug-genomic information (the effect of the genotype on the drug-kinetics, drug-dynamics or efficacy profile of a therapeutic) about a particular patient may affect the dose used. Continuous daily dosing with the combinations of the invention may not be required. A therapeutic regimen may require cycles, during which time a drug is not administered, or therapy may be provided on a need basis during periods of acute inflammation. As described above, the compound in question can be administered orally in the form of tablets, capsules, elixirs or syrups, or rectally in the form of suppositories. Parenteral administration of a compound is carried out suitably, for example, in the form of saline solutions or with the compound incorporated in liposomes. In cases where the compound itself is not soluble enough to dissolve, a solubilizer such as ethanol can be applied. Below, for illustrative purposes, dosages for amoxapine and prednisolone are described. A person skilled in the art will readily be able to evaluate adequate doses for other tricyclic and cortico-steroidal compounds. For example, a tricyclic compound may be given in a dose equivalent to a dose of amoxapine provided below, and a corticosteroid may be given in a dose equivalent to a dose of prednisolone provided below. In one embodiment, the cortico-steroid is a cortico-steroid of low dose. Oral Administration For amoxapine adapted for oral administration for systemic use, the total daily dose is usually around 1-600 mg (0.01-8.5 mg / kg), preferably around 25-400 mg (0.35-5.7 mg / kg), and more preferably around 200-300 mg (1.4-4.2 mg / kg) of the total daily dose. The administration can be from one to three times daily for a day to a year, and may even be for the life of the patient. Chronic, long-term administration will be indicated in many cases. Daily doses of up to 600 mg may be necessary. For prednisolone adapted for oral administration for systemic use, the daily dose is usually around 0.05-200 mg (0.7-2.800 mcg / kg), preferably around 0.1-60 mg (1-850 mcg / kg), and more preferably about 0.1-5 mg (4-70 mcg / kg). Due to the improving effect exhibited by amoxapine on the anti-inflammatory activity of prednisolone, low doses of prednisolone (eg, 0.2, 0.4, 0.6, 0.8, 1, 2, 3, 4, or 5 mg / day), when combined with a tricyclic compound, they can be effective in treating inflammation. Administration one to four times daily is desirable. Like amoxapine, prednisolone can be administered for a day to a year, and may even be for the life of the patient. Dosage of up to 200 mg per day may be necessary. Rectal Administration For compositions adapted for rectal use to prevent disease, a somewhat high amount of a compound is usually preferred. Thus, a total daily dose of amoxapine is usually around 1-600 mg (0.01-8.5 mg / kg). Rectal administration of amoxapine is usually one to three times daily. A total daily dose of prednisolone is usually around 0.1-100 mg (1-1.420 mcg / kg). Rectal administration of prednisolone is usually one to four times daily. Intravenous Administration For intravenous administration of amoxapine, a total daily dose is about 1-400 mg (0.014-5.7 mg / kg), preferably around 10-200 mg (0.14-2.8 mg / kg) and more preferably about 25-100 mg (0.35-1.4) mg / kg). The intravenous administration of amoxapine is usually one to four times daily, but it can be infused continuously. For intravenous administration of prednisolone, a total daily dose is about 0.05-200 mg (0.0007-2.8 g / kg), preferably about 0.1-60 mg (0.001-0.85 mg / kg), and more preferably about 0.1-5 mg (4-70 mcg / kg). Low doses of prednsolone, described above, are most preferred. The intravenous administration of prednisolone is usually one to four times daily, but, like amoxapine, it can be infused continuously. Additional Administration Routes For intramuscular, subcutaneous, inhalation, topical, vaginal, or ophthalmic administration of amoxapine, a total daily dose is around 1-400 mg (0.014-5.7 mg / kg), preferably around 10 -200 mg (0.14-2.8 mg / kg), and more preferably around 25-100 mg (0.35-1.4 mg / kg), and a total daily dose of prednisolone is around 0.1-100 mg (0.0014-1.42 mg / kg). For these routes, the administration of each amoxapine and prednisolone is, independently, one to four times daily. Additional Applications The compounds of the invention can be used in immunomodulatory or mechanistic assays to determine whether other combinations, or agents alone, are as effective as the combination in inhibiting secretion or production of pro-inflammatory cytokines or modulating the immune response using generally known assays. in the matter, examples of which are described herein. For example, candidate compounds can be combined with a tricyclic compound or a corticosteroid and applied to stimulated PBMCs. After a suitable time, the cells are examined for secretion or cytokine production or other suitable immune response. The relative effects of combinations with each other, and against single agents are compared, and effective compounds and combinations are identified. The combinations of the invention are also useful tools for elucidating mechanistic information about the biological trajectories involved in inflammation. Such information may lead to the development of new combinations or agents alone to inhibit inflammation caused by pro-inflammatory cytokines. Methods known in the art for determining biological trajectories can be used to determine the trajectory, or network of affected trajectories by contacting stimulated cells to produce cytokines with the compounds of the invention. Such methods may include, analyzing cellular constituents that are expressed or repressed after contact with the compounds of the invention as compared to positive or negative, untreated control compounds, and / or single agents and novel combinations, or analyzing some other activity metabolic of the cell such as enzyme activity, nutrient uptake, and proliferation. Analyzed cellular components can include gene transcr, and protein expression. Suitable methods may include standard biochemistry techniques, radiolabel the compounds of the invention (e.g., labeled by 14C or 3H), and observe the ligand-to-protein compounds, e.g. , using 2d gels, trace gene expression profile. Once identified, such compounds can be used in vivo to additionally validate the tool or develop new anti-inflammatory agents. The following examples are to illustrate the invention. They are not intended to limit the invention in any way.

EXAMPLES Methods TNFa Secretion Assay The effects of combinations of test compounds on TNFa secretion were tested on human white blood cell cells stimulated with LPS or phorbol 12-myristate 13-acetate and ionomycin as follows. LPS A suspension of 100 μl of diluted human white blood cells contained within each well of a 384 well polystyrene plate (NalgeNunc) was stimulated to secrete TNFa by treatment with a final concentration of 2 μg / mL liposaccharide (Sigma L- 4130). Various concentrations of each test compound were added to the stimulation time. After 16-18 hours of incubation at 37 ° C with 5% C02 in a humidified incubator, the plate was centrifuged and the supernatant was transferred to a 384 well plate of white opaque polystyrene (NalgeNunc, Maxisorb) coated with an antibody anti-TNFa (PharMingen, # 551220). After a two-hour incubation, the plate was washed (Tecan Powerwasher 384) with PBS containing 0.1% Tween 20 and incubated for an additional hour with biotin labeled anti-TNFa antibody (PharMingen, # 554511). And HRP coupled to Streptavidin (PharMingen, # 13047E). The plate was then washed again with 0.1% Tween 20 / PBS. A luminescent HRP substrate was added to each well, and the light intensity of each well was measured using a LJL Analyst plate luminometer. PMA / Ionomycin A suspension of 100 μl of diluted human white blood cells contained within each well of a 384 well polystyrene plate (NalgeNunc) was stimulated to secrete TNFa by treatment with a final concentration of 10 μg / mL of 12-myristate Phorbol 13-acetate (Sigma, P-1585) and 750 ng / mL of ionomycin (Sigma, 1-0634). Various concentrations of each test compound were added to the stimulation time. After 16-18 hours of incubation at 37 ° C with 5% C02 in a humidified incubator, the plate was centrifuged and the supernatant was transferred to a 384 well plate of white opaque polystyrene (NalgeNunc, Maxisorb) coated with an antibody anti-TNFa (PharMingen, # 551220). After a two hour incubation, the plate was washed (Tecan Powerwasher 384) with PBS containing 0.1% Tween 20 and incubated for an additional hour with biotin labeled anti-TNFa antibody (PharMingen, # 554511) and HRP coupled to streptavidin. (PharMingen, # 13047E). The plate was then washed again with 0.1% Tween 20 / PBS. A luminescent HRP substrate was added to each well, and the light intensity of each well was measured using a LJL Analyst plate luminometer. Results The ability of combinations of tricyclic / cortico-steroid compound to inhibit TNFa secretion from blood stimulated with LPS is shown in Tables 5-13. The effects of the agents alone and in combination are shown as percent inhibition of TNFa secretion relative to untreated controls.

The ability of combinations of tricyclic / cortico-steroid compound to inhibit TNFa secretion from blood stimulated with PMA / ionomycin is shown in Tables 14-22. The effects of the agents alone and in combination are shown as percent inhibition of TNF secretion relative to untreated controls.

The ability of combinations of tricyclic / cortico-steroid compound to inhibit TNFa secretion from blood stimulated with PMA / ionomycin is shown in Tables 23-68. The effects of the agents alone and in combination are shown as percent inhibition of TNFa secretion relative to untreated controls.

Individual tricyclic compounds were tested for their ability to suppress cytokine secretion in vitro. The data are presented in Tables 69-87 as percentage of inhibition in relation to untreated controls.

Table 69 - Amoxapina Table 70 - Maprotiline Table 74 - Desipramine Table 77 - Imipramine Table 78 - Doxepin Table 80 - Olanzapine Table 83 - Hydroxyloxapine Table 84 Tomoxetine Other Ways of Making Various modifications and variations of the described methods and compositions of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific desired embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes of carrying out the invention that are obvious to those skilled in the art in the fields of medicine, immunology, pharmacology, endocrinology, or related fields are intended to be within the scope of the invention. All publications mentioned in this specification are incorporated herein by reference to the same extent that each independent publication was specifically and individually incorporated by reference.

Claims (87)

1. CLAIMS 1. A composition comprising a tricyclic compound and a corticosteroid in amounts which together are sufficient to treat an immuno-inflammatory disorder when administered to a patient. The composition of claim 1, wherein said tricyclic compound is amitriptyline, amoxapine, clomipramine, dotiepin, doxepin, desipramine, imipramine, lofepramine, loxapine, maprotiline, mianserin, mirtazapine, oxaprotiline, nortriptyline, octriptilin, protriptyline, or trimipramine. 3. The composition of claim 1 wherein said steroid is prednisolone cortical, cortisone, budesonide, dexamethasone, hydrocortisone, methylprednisolone, fluticasone, prednisone, triamcinolone, or diflorasone. 4. The composition of claim 1, wherein said tricyclic compound is nortriptyline and said cortico-steroid is budesonide. The composition of claim 1, wherein said tricyclic compound or said cortico-steroid are present in said composition in a low dose. The composition of claim 1, wherein said tricyclic compound or said cortico-steroid are present in said composition in a high dose. The composition of claim 1, further comprising a NSAID, biological COX-2 inhibitor, DMARD, small molecule immuno-modulator, xanthine, anti-cholinergic compound, beta receptor agonist, bronchodilator, immuno-suppressant dependent on non-steroidal immunophilin, vitamin D analogue, psoralen, retinoid, or 5-amino salicylic acid. The composition of claim 7, wherein said NSAID is ibuprofen, diclofenac, or naproxen. The composition of claim 7, wherein said COX-2 inhibitor is rofecoxib, celecoxib, valdecoxib, or lumiracoxib. The composition of claim 7, wherein said biological is adelimumab, etanercept, infliximab, CDP-870, rituximab, or atlizumab. The composition of claim 7, wherein said DMARD is methotrexate or leflunomide. 12. The composition of claim 7, wherein said xanthine is theophylline. The composition of claim 7, wherein said anti-cholinergic compound is ipratropium or tiotropium. 14. The composition of claim 7, wherein said beta receptor agonist is ibuterol sulfate of, bitolterol mesylate, epinephrine, formoterol fumarate, isoproteronol, levalbuterol hydrochloride, metaproterenol sulfate, pirbuterol escetato, salmeterol xinafoate, or terbutaline . 15. The composition of claim 7, wherein said nonsteroidal immunophilin-dependent immuno-suppressor is cyclosporin, tacrolimus, pimecrolimus, or ISAtx247. 16. The composition of claim 7, wherein said vitamin D analog is calcipotriene or calcipotriol. 17. The composition of claim 7, wherein said psoralen is methoxsalen. 18. The composition of claim 7, wherein said retinoid is acitetrin or tazoretene. 19. The composition of claim 7, wherein said 5-amino salicylic acid is mesalamine, sulfasalazine, disodium balsalazi-da, or olsalazine sodium. 20. The composition of claim 7, wherein said immunomodulator is VX small molecule 702, SCIO 469, doramapimod, RO 30201195, SCIO 323, DPC 333, pranalcasano, mycophenolate, or merimepodib. The composition of claim 1, wherein said composition is formulated for topical administration. 22. The composition of claim 1, wherein said composition is formulated for systemic administration. 23. A method of decreasing secretion or production of proinflammatory cytokine in a patient, said method comprising administering to the patient a tricyclic compound and a cortico-steroid simultaneously or within 14 days each other in amounts sufficient to reduce cytokine secretion or production pro-inflammatory in said patient. 24. A method to treat a patient diagnosed with or at risk of developing an immune-inflammatory disorder, said method comprising administering to the patient a tricyclic compound and a cortico-steroid simultaneously or within 14 days of each other in sufficient quantities to treat said patient. 25. The method of claim 24, wherein said immuno-inflammatory disorder is rheumatoid arthritis, Crohn's disease, ulcerative colitis, asthma, chronic obstructive pulmonary disease, polymyalgia rheumatica, giant cell arteritis, systemic lupus erythematosus, atopic dermatitis, multiple sclerosis, myasthenia gravis, psoriasis, ankylosing spondolitis, or psoriasis arthritis. The method of claim 24, wherein said tricyclic compound is amitriptyline, amoxapine, clomipramine, dotiepin, doxepin, desipramine, imipramine, lofepramine, loxapine, maprotiline, mianserin, mirtazapine, oxaprotiline, nortriptyline, octriptilin, protriptyline, or trimipramine. The method of claim 1, wherein said cortico-steroid is prednisolone, cortisone, budesonide, dexamethasone, hydrocortisone, methylprednisolone, fluticasone, prednisone, triamcinolone, or diflorasone. The method of claim 24, further comprising a NSAID, biological COX-2 inhibitor, DMARD, small molecule immuno-modulator, xanthine, anti-cholinergic compound, beta receptor agonist, bronchodilator, immuno-suppressor dependent on non-steroidal immunophilin, vitamin D analog, psoralen, retinoid, or 5-amino salicylic acid. 29. The method of claim 28, wherein said NSAID is ibuprofen, diclofenac, or naproxen. 30. The method of claim 28, wherein said COX-2 inhibitor is rofecoxib, celecoxib, valdecoxib, or lumiracoxib. 31. The method of claim 28, wherein said biological is adelimumab, etanercept, infliximab, CDP-870, rituximab, or atlizumab. 32. The method of claim 28, wherein said small molecule immunomodulator is VX 702, SCIO 469, doramapimod, RO 30201195, SCIO 323, DPC 333, pranalcasan, mycophenolate, or merimepodib. 33. The method of claim 28, wherein said DMARD is methotrexate or leflunomide. 34. The method of claim 28, wherein said xanthine is theophylline. 35. The method of claim 28, wherein said anti-cholinergic compound is ipratropium or tiotropium. 36. The method of claim 28, wherein said beta receptor agonist is ibuterol sulfate, bitolterol mesylate, epinephrine, formoterol fumarate, isoproteronol, levalbuterol hydrochloride, metaproterenol sulfate, pirbuterol esceptate, salmeterol xinafoate, or terbutaline. . 37. The method of claim 28, wherein said non-steroidal immunophilin-dependent immuno-suppressor is cyclosporin, tacrolimus, pimecrolimus, or ISAtx247. 38. The method of claim 28, wherein said vitamin D analog is calcipotriene or calcipotriol. 39. The method of claim 28, wherein said psoralen is methoxsalen. 40. The method of claim 28, wherein said retinoid is acitetrin or tazoretene. 41. The method of claim 28, wherein said 5-amino salicylic acid is mesalamine, sulfasalazine, balsalazi-disodium, or olsalazine sodium. 42. The method of claim 24, wherein said tricyclic compound or said cortico-steroid is administered in a low dose. 43. The method of claim 24, wherein said tricyclic compound or said cortico-steroid is administered in a high dose. 44. The method of claim 24, wherein said tricyclic compound and said cortico-steroid are administered within 10 days of each other. 45. The method of claim 44, wherein said tricyclic compound and said cortico-steroid are administered within five days together. 46. The method of claim 45, wherein said tricyclic compound and said cortico-steroid are administered within twenty-four hours together. 47. The method of claim 46, wherein said tricyclic compound and said cortico-steroid are administered simultaneously. 48. A composition comprising a tricyclic compound and a glucocorticoid receptor modulator in amounts that together are sufficient to decrease the secretion or production of pro-inflammatory cytokine. 49. The composition of claim 48, wherein said tricyclic compound is amitriptyline, amoxapine, clomipramine, dotiepin, doxepin, desipramine, imipramine, lofepramine, loxapine, maprotiline, mianserin, mirtazapine, oxaprotiline, nortriptyline, octriptilin, protriptyline, or trimipramine. 50. The composition of claim 48, further comprising an NSAID, biological COX-2 inhibitor, DMARD, small molecule immuno-modulator, xanthine, anti-cholinergic compound, beta receptor agonist, bronchodilator, immuno-suppressor dependent on non-steroidal immunophilin, vitamin D analogue, psoralen, retinoid, or 5-amino salicylic acid. 51. A method for decreasing the secretion or production of pro-inflammatory cytokine in a patient, said method comprising administering to a patient a tricyclic compound and a glucocorticoid receptor modulator simultaneously or within 14 days of each other in sufficient amounts in vivo to decrease the secretion or production of pro-inflammatory cytokine in said patient. 52. A method for treating a patient diagnosed with or at risk of developing an immuno-inflammatory disorder, said method comprising administering to the patient a tricyclic compound and a glucocorticoid receptor modulator simultaneously or within 14 days to each other in amounts enough to treat that patient. 53. The method of claim 52, wherein said immuno-inflammatory disorder is rheumatoid arthritis, Crohn's disease, ulcerative colitis, asthma, chronic obstructive pulmonary disease, polymyalgia rheumatica, giant cell arteritis, systemic lupus erythematosus, atopic dermatitis, multiple sclerosis, myasthenia gravis, psoriasis, ankylosing spondolitis, or psoriasis arthritis. 54. The method of claim 52, wherein said tricyclic compound is amitriptyline, amoxapine, clomipramine, dotiepin, doxepin, desipramine, imipramine, lofepramine, loxapine, maprotiline, mianserin, mirtazapine, oxaprotiline, nortriptyline, octriptilin, protriptyline, or trimipramine. 55. The method of claim 52, further comprising an NSAID, COX-2 inhibitor, biological, DMARD, small molecule immuno-modulator, xanthine, anti-cholinergic compound, beta receptor agonist, bronchodilator, immuno-suppressor dependent on non-steroidal immunophilin, vitamin D analogue, psoralen, retinoid, or 5-amino salicylic acid. 56. The method of claim 52, wherein said tricyclic compound and said cortico-steroid are administered within 10 days of each other. 57. The method of claim 56, wherein said tricyclic compound and said cortico-steroid are administered within five days to each other. 58. The method of claim 57, wherein said tricyclic compound and said cortico-steroid are administered within twenty-four hours together. 59. The method of claim 58, wherein said tricyclic compound and said cortico-steroid are administered simultaneously. 60. A composition comprising (i) a tricyclic compound and (ii) a second compound selected from the group consisting of small molecule immuno-modulator, xanthine, anti-cholinergic compound, beta receptor agonist, bronchodilator, biological, NSAID, DMARD, COX-2 inhibitor, non-steroidal immunophilin-dependent immuno-suppressor, vitamin D analogue, psoralen, retinoid, or 5-amino salicylic acid. 61. The composition of claim 60, wherein said NSAID is ibuprofen, diclofenac, or naproxen. 62. The composition of claim 60, wherein said COX-2 inhibitor is rofecoxib, celecoxib, valdecoxib, or lumiracoxib. 63. The composition of claim 60, wherein said biological is adelimumab, etanercept, infliximab, CDP-870, rituximab, or atlizumab. 64. The composition of claim 60, wherein said small molecule immunomodulator is VX 702, SCIO 469, doramapimod, RO 30201195, SCIO 323, DPC 333, pranalcasan, mycophenolate, or merimepodib. 65. The composition of claim 60, wherein said DMARD is methotrexate or leflunomide. 66. The composition of claim 60, wherein said xanthine is theophylline. 67. The composition of claim 60, wherein said anti-cholinergic compound is ipratropium or tiotropium. 68. The composition of claim 60, wherein said beta receptor agonist is ibuterol sulfate, bitolterol mesylate, epinephrine, formoterol fumarate, isoproteronol, levalbuterol hydrochloride, metaproterenol sulfate, pirbuterol esceptate, salmeterol xinafoate, or terbutaline. . 69. The composition of claim 60, wherein said non-steroidal immunophilin-dependent immuno-suppressor is cyclosporin, tacrolimus, pimecrolimus, or ISAtx247. 70. The composition of claim 60, wherein said vitamin D analog is calcipotriene or calcipotriol. 71. The composition of claim 60, wherein said psoralen is methoxsalen. 72. The composition of claim 60, wherein said retinoid is acitetrin or tazoretene. 73. A method for suppressing the secretion of one or more pro-inflammatory cytokines in a patient in need thereof, said method comprising administering to the patient (i) a tricyclic compound and (ii) a second compound selected from the group consisting of in small molecule immuno-modulator, xanthine, anti-cholinergic compound, beta receptor agonist, bronchodilator, biological, NSAID, DMARD, COX-2 inhibitor, nonsteroidal immunophilin-dependent immuno-suppressor, vitamin D analogue, psoralen, retinoid, or 5-amino salicylic acid in sufficient quantities to decrease the secretion or production of pro-inflammatory cytokine in said patient. 74. A method for suppressing the secretion of one or more pro-inflammatory cytokines in a patient in need thereof, said method comprising administering to the patient a tricyclic compound in amounts sufficient to suppress the secretion of pro-inflammatory cytokines in said patient. 75. A method for treating a patient diagnosed with an immuno-inflammatory disorder, said method comprising administering to the patient a tricyclic compound in an amount and for a duration sufficient to treat said patient. 76. A kit, comprising: (i) a composition comprising a tricyclic compound and a cortico-steroid; and (ii) instructions for administering said composition to a patient diagnosed with or at risk of developing an immuno-inflammatory disorder. 77. A kit, comprising: (i) a tricyclic compound; (ii) a cortico-steroid; and (iii) instructions for systematically administering said tricyclic compound and said cortico-steroid to a patient diagnosed with or at risk of developing an immuno-inflammatory disorder. 78. A kit comprising (i) a tricyclic compound and (ii) instructions for administering said tricyclic compound to a patient diagnosed with an immuno-inflammatory disorder. 79. A kit, comprising: (i) a tricyclic compound; (ii) a second compound selected from the group consisting of a glucocorticoid receptor modulator, small molecule immuno-modulator, xanthine, anti-cholinergic compound, beta receptor agonist, bronchio-dilator, biological, NSAID, DMARD, COX-2 inhibitor, non-steroidal immunophilin-dependent immunosuppressant, vitamin D analogue, psoralen, retinoid, or 5-amino-salicylic acid; and (iii) instructions for administering said tricyclic compound and said second compound to a patient diagnosed with or at risk of developing an immuno-inflammatory disorder. 80. A kit comprising (i) a tricyclic compound and (ii) instructions for administering said tricyclic compound and a cortico-steroid to a patient diagnosed with or at risk of developing an immuno-inflammatory disorder. 81. A kit comprising (i) a tricyclic compound and (ii) instructions for administering said tricyclic compound and a second compound consisting of a glucocorticoid receptor modulator, small molecule immuno-modulator, xanthine, anti-cholinergic compound beta-agonist, bronchodilator, biologic, NSAID, DMARD, COX-2 inhibitor, nonsteroidal immunophilin-dependent immuno-suppressor, vitamin D analog, psoralen, retinoid, or 5-amino salicylic acid to a patient diagnosed with or at risk of developing an immune-inflammatory disorder. 82. A kit comprising (i) a cortico-steroid and (ii) instructions for administering said cortico-steroid to a patient diagnosed with or at risk of developing an immuno-inflammatory disorder. 83. A method for identifying combinations of compounds useful for suppressing the secretion of pro-inflammatory cytokines in a patient in need of such treatment, said method comprising the steps of: (a) contacting cells in vi tro with a tricyclic compound and a candidate compound; and (b) determining whether the combination of said tricyclic compound and said candidate compound reduces cytokine levels in blood cells stimulated to secrete cytokines relative to cells contacted with said tricyclic compound but not contacted with said candidate compound or cells. placed in contact with said candidate compound but not with said tricyclic compound, wherein a reduction of said cytokine levels identifies said combination as a combination that is useful for treating a patient in need of such treatment. 84. A method for identifying a combination of compounds that may be useful for the treatment of an immuno-inflammatory disorder, said method comprising the steps of: (a) contacting cells in vi tro with a tricyclic compound and a candidate compound; and (b) determining whether the combination of said tricyclic compound and said candidate compound reduces the secretion of pro-inflammatory cytokines, relative to cells contacted with said tricyclic compound but not put in contact with said candidate compound, where a reduction in the Pro-inflammatory cytokine secretion identifies the combination as a combination that may be useful for the treatment of an immuno-inflammatory disorder. 85. A method for identifying a combination of compounds that may be useful for the treatment of an immuno-inflammatory disorder, said method comprising the steps of: (a) contacting cells in vi tro with a cortico-steroid and a candidate compound; and (b) determining whether the combination of said cortico-steroid and said candidate compound reduces the secretion of pro-inflammatory cytokines, relative to cells contacted with said cortico-steroid but not put in contact with said candidate compound, where a reduction in the secretion of pro-inflammatory cytokine identifies the combination as a combination that may be useful for the treatment of an immuno-inflammatory disorder. 86. A method for identifying a combination of compounds that may be useful for the treatment of an immuno-inflammatory disorder, said method comprising the steps of: (a) identifying a compound that reduces the secretion of pro-inflammatory cytokines; (b) contacting proliferating cells in vi tro with a tricyclic compound and a compound identified in step (a), - and (c) determining whether the combination of said tricyclic compound and said compound identified in step (a) reduces the secretion of pro-inflammatory cytokines, relative to cells contacted with said tricyclic compound but not put in contact with said compound identified in step (a) or contacted with the compound identified in step (a) but not in contact with the tricyclic compound, where a reduction in pro-inflammatory cytokine secretion identifies the combination as a combination that may be useful for the treatment of an immuno-inflammatory disorder. 87. A method for identifying a combination of compounds that may be useful for the treatment of an immuno-inflammatory disorder, said method comprising the steps of: (a) identifying a compound that reduces the secretion of pro-inflammatory cytokines; (b) contacting proliferating cells in vi tro with a cortico-steroid and a compound identified in step (to); and (c) determining whether the combination of said cortico-steroid and said compound identified in step (a) reduces the secretion of pro-inflammatory cytokines, relative to cells contacted with said cortico-steroid but not put in contact with said compound identified in step (a) or contacted with the compound identified in step (a) but not in contact with the cortico-steroid, where a reduction in pro-inflammatory cytokine secretion identifies the combination as a combination that can be useful for the treatment of an immuno-inflammatory disorder.