MX2007016114A - Combination therapy for the treatment of immunoinflammatory disorders - Google Patents

Abstract

The invention features a method for treating a patient diagnosed with, or at risk of developing, an iminunoinflainÏÇiatory disorder by administering a non-steroidal immunophilin-dependent immunosuppressant (NsIDI) and a Group A enhancer (e.g., antifungal agent, antigout agent, anti-infective agent, antiprotozoal agent, antiviral agent, humectant, sunscreen, vitamin D compound, microtubuline inhibitor, or zinc salt) or analog or metabolite thereof to the patient. The invention also features a pharmaceutical composition containing an NsIDI and Group A enhancer or analog or metabolite thereof for the treatment or prevention of an immunoinflammatory disorder.

Description

COMBINATION THERAPY FOR THE TREATMENT OF IMMUNOINFLAMMATORY DISORDERS Background of the Invention The invention relates to the treatment of immunoinflammatory disorders. Immunoinflammatory disorders are characterized by inappropriate activation of the body's immune defenses. Instead of targeting infectious invaders, the immune response targets and damages the body's own tissues or transplanted tissues. The tissue to which the immune system is directed varies with the disorder. For example, in multiple sclerosis, the immune response is directed against the neuronal tissue, whereas in Crohn's disease, it is directed towards the digestive tract. Immunoinflammatory disorders affect millions of individuals, and include conditions such as asthma, allergic inflammatory intraocular diseases, arthritis, atopic dermatitis, atopic eczema, diabetes, hemolytic anemia, inflammatory dermatosis, inflammatory bowel disorders or gastrointestinal disorders (eg, Crohn's disease). and ulcerative colitis), multiple sclerosis, myasthenia gravis, pruritis / inflammation, psoriasis, rheumatoid arthritis, cirrhosis, and systemic lupus erythematosus. Current treatment regimens for immunoinflammatory disorders usually rely on immunosuppressive agents. The effectiveness of these agents may vary, and their use is often accompanied by adverse side effects. Accordingly, better therapeutic agents and methods are needed for the treatment of immunoinflammatory disorders. SUMMARY OF THE INVENTION We have found that a combination of a non-spheroidal immunophilin-dependent immunosuppressant (NsIDI) (e.g., cyclosporin A) and an immunophilin-dependent immunosuppressant enhancer (NsIDIE) (e.g., a selective inhibitor of serotonin recovery) (SSRI), a tricyclic antidepressant, a phenoxy-phenol, an antihistamine, a phenothiazine, or an opioid receptor agonist mu), is more effective in suppressing the secretion of proinflammatory cytokines than any agent of them alone. Accordingly, combinations of an NsIDI and an NsIDIE, as well as their structural or functional analogs, can be used in an anti-immunoinflammatory combination of the invention. Compounds useful in the invention include those described herein, in any of their pharmaceutically acceptable forms, including isomers, such as diastere-reomers and enantiomers, salts, esters, solvates, and polymorphs thereof, as well as racemic mixtures. and the pure isomers of the compounds described herein.

In one aspect, the invention generally provides a composition containing an immunosuppressant dependent on non-spheroidal immunophilin (NsIDI) and an NsIDI enhancer.

(NsIDIE) in amounts that together are sufficient in vivo to reduce the secretion or production of proinflammatory cytokine, or to treat an immunoinflammatory disorder. Optionally, the composition also contains a non-spheroidal anti-inflammatory drug (NSAID), a COX-2 inhibitor, a biological product, an anti-rheumatic disease-modifying drug (DMARD), a xanthine, an anticholinergic compound , a beta receptor agonist, a bronchodilator, a non-spheroidal calcineurin inhibitor, a vitamin D analogue, a psoralen, a retinoid, or a 5-amino-salicylic acid. In some embodiments, the composition is formulated for topical or systemic administration. The invention also provides a method for reducing secretion or production of proinflammatory cytokine in a patient, the method including administering to the patient a composition containing an immunosuppressant dependent on non-spheroidal immunophilin (NsIDI) and an enhancer of NsIDI (NsIDIE) in a manner Simultaneously or within 14 days of each other, in sufficient quantities to reduce in vivo the secretion or production of proinflammatory cytokine in the patient. The invention also provides a method for reducing the secretion or production of proinflammatory cytokine in a patient. The method includes administering to the patient an NsIDI and an NsIDIE in a simultaneous manner or within 14 days of each other, in sufficient quantities to reduce in vivo the secretion or production of proinflammatory cytokine in the patient. In addition, the invention provides a method for the treatment of a patient diagnosed with, or at risk of developing, an immunoinflammatory disorder. The method includes administering to the patient an NsIDI and an NsIDIE in a simultaneous manner or within 14 days of each other, in sufficient quantities to treat the patient. The invention also provides a method for reducing the secretion or production of proinflammatory cytokine in a cell (e.g., a mammalian cell in vi). The method includes contacting the cell with an NsIDI and an NsIDIE in a simultaneous manner or within 14 days of each other, in sufficient quantities to reduce in vivo the secretion or production of proinflammatory cytokine in the cell. The invention further provides a therapeutic kit containing a composition containing an NsIDI and an NsIDIE; and instructions for administering the composition to a patient diagnosed with, or at risk of developing, an immunoinflammatory disorder. The invention also provides a therapeutic kit containing an NsIDI, an NsIDIE; and instructions for administering the NsIDI and NsIDIE to a patient diagnosed with, or at risk of developing, an immunoinflammatory disorder. The invention also provides a therapeutic kit containing an NsIDI; and instructions for administering the NsIDI and an NsIDIE to a patient diagnosed with, or at risk of developing, an immunoinflammatory disorder. In addition, the invention provides a therapeutic kit containing an NsIDIE, and instructions for administering the NsIDIE and an NsIDI to a patient diagnosed with, or at risk of developing, an immunoinflammatory disorder. The invention also provides a method for identifying combinations of compounds useful for suppressing the secretion of proinflammatory cytokines in a patient in need of such treatment. The method includes (a) contacting the cells in vi tro with an NsIDI and a candidate compound; and (b) determining whether the combination of the NsIDI and the candidate compound reduces the levels of cytokine in the blood cells stimulated to secrete the cytokines in relation to the cells that were contacted with the NsIDI, but did not come into contact with the candidate compound, or the cells that were contacted with the candidate compound but not with the NsIDI, wherein a reduction of the cytokine levels identifies the combination as a combination that is useful for the treatment of a patient in need of such treatment . In the preferred embodiments of any of the above aspects, an NsIDI is, for example, a calcineurin inhibitor, such as cyclosporin, tacrolimus, ascomycin, pimecrolimus, or ISAtx247, or an FK506 binding protein, such as rapamycin or everolimus. In the preferred embodiments of any of the above aspects, an NsIDI enhancer (NsIDIE) is, for example, a selective serotonin recovery inhibitor (SSRI), a tricyclic antidepressant (TCA), a phenoxy-phenol, an antihistamine, a phenothiazine, or a mu opioid receptor agonist. "Non-spheroidal immunophilin-dependent immunosuppressant" or "NsIDI" means any non-spheroidal agent that reduces the production or secretion of proinflammatory cytokine, which binds to an immunophilin, or that causes a decrease in 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. The NsIDIs also include rapamycin (sirolimus) and everolimus, which bind to a binding protein of FK506, FKBP-12, and block the antigen-induced proliferation of white blood cells and cytokine secretion. "Non-spheroidal immunophilin-dependent immunosuppressant enhancer" or "NsIDIE" means any compound that increases the efficacy of an immunosuppressant dependent on non-spheroidal immunophilin. NsIDIEs include selective inhibitors of serotonin recovery, tricyclic antidepressants, phenoxy phenols (eg, triclosan), antihistamines, phenothiazines, and mu opioid receptor agonists. "Anti-histamine" means a compound that blocks the action of histamine. The classes of anti-histamines include, but are not limited to, ethanolamines, ethylenediamine, phenothiazine, alkylamines, piperazines, and piperidines. "Selective Serotonin Reuptake Inhibitor" or "SSRI" means any member of the class of compounds that (i) inhibit the recovery of serotonin by central nervous system neurons, (ii) have a constant of inhibition (Ki). ) of 10 nm or less, and (iii) a selectivity for serotonin over norepinephrine (ie, the ratio of Ki (norepinephrine) to Ki (serotonin)) greater than 100. Normally, SSRIs are administered in dosages greater than 10 mg per day when used as antidepressants. Exemplary SSRIs for use in the invention are described herein. "Tricyclic anti-depressant" or "TCA" means a compound having one of the formulas (I), (II), (III), or (IV): 25 where 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, (CH2), CH20, CH2NH, CHN, or CH2S; Z is C or S; A is a branched or unbranched, saturated or monounsaturated hydrocarbon chain having between 3 and 6 carbon atoms, inclusive; each B is, independently, H, Cl, F, Br, I, CX3, CH2CH3, OCX3, or OCX2CX3; and D is CH2, O, NH, S (O) 0_2. In the 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. The exemplary tricyclic anti-depressants are maprotiline, amoxapine, 8-hydroxy-amoxapine, 7-hydroxy-amoxapine, loxapine, loxapine succinate, loxapine hydrochloride, 8- hydroxy-loxapine, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, desipramine, nortriptyline, and protripyline. "Corticosteroid" means any naturally occurring or synthetic compound characterized by a hydrogenated cyclopentane-perhydrophenanthrene ring system, and having an immunosuppressive and / or anti-inflammatory activity. Corticosteroids that occur naturally are produced in general by the adrenal cortex. Synthetic corticosteroids may be halogenated. Examples of corticosteroids are provided herein. "Small molecule immunomodulator" means a non-spheroidal compound that is not NsIDI, which reduces the production or secretion of proinflammatory cytokine, which causes a decrease in the proinflammatory reaction, or which otherwise modulates the immune system in a manner independent of the immunophilin. Exemplary small molecule immunomodulators are p38 MAP kinase inhibitors such as VX 702 (Vertex 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 (Vertex Pharmaceuticals).

"Low dosage" means at least 5 percent less (for example, at least 10 percent, 20 percent, 50 percent, 80 percent, 90 percent, or even 95 percent) than the lowest recommended standard dosage of a particular compound formulated for a given route of administration for the treatment of any human disease or condition. For example, a low dosage of the corticosteroid formulated to be administered by inhalation will be different from a low dosage of the corticosteroid formulated for oral administration. A "high dosage" means at least 5 percent (for example, at least 10 percent, 20 percent, 50 percent, 100 percent, 200 percent, or even 300 percent) more than the highest standard recommended dosage of a particular compound for the treatment of any human disease or condition. A "moderate dosage" means the dosage between low dosage and high dosage. "Treat" means administering or prescribing a pharmaceutical composition for the treatment or prevention of an immunoinflammatory disease. "Patient" means any animal (for example, a human being). Other animals that can be treated using the methods, compositions, and therapeutic kits of the invention, include horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, cattle, fish, and birds. In one embodiment of the invention, the patient subject to a treatment employing an SSRI or an ACT described herein, has no clinical depression, an anxiety or panic disorder, an obsessive / compulsive disorder, alcoholism, a disorder in eating , an attention deficit disorder, a borderline personality disorder, a sleep disorder, a headache, premenstrual syndrome, an irregular heart rhythm, schizophrenia, Tourette syndrome, or phobias. "Sufficient amount" means the amount of a compound in the methods, compositions, and therapeutic kits of the invention, required to treat or prevent an immunoinflammatory 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 immunoinflammatory disease, varies depending on the mode of administration, age, body weight, and general health of the patient. patient. Finally, those who prescribe will decide the appropriate amount and dosage regimen. "More effective" means that a method, composition, or therapeutic package 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 therapeutic with which you are comparing. The efficiency can be measured by an expert practitioner using any conventional method that is appropriate for a given indication. The term "immunoinflammatory disorder" encompasses a variety of conditions, including autoimmune diseases, skin proliferative diseases, and inflammatory dermatoses. Immunoinflammatory disorders result in the destruction of healthy tissue by an inflammatory process, poor regulation of the immune system, and unwanted proliferation of cells. Examples of immunoinflammatory disorders are acne vulgaris; acute respiratory failure syndrome; Addison's disease; allergic rhinitis; Inflammatory infra-ocular inflammatory diseases, small vessel vasculitis associated with ANCA, ankylosing spondylitis; arthritis, asthma; atherosclerosis, atopic dermatitis, autoimmune hepatitis; autoimmune hemolytic anemia; autoimmune hepatitis; Behcet's disease; Bell's palsy; bullous pemphigoid; cerebral ischemia; chronic obstructive pulmonary disease; cirrhosis; Cogan syndrome; contact dermatitis; COPD; Crohn's disease; Cushing's syndrome; dermatomyositis, diabetes mellitus, discoid lupus erythematosus; eosinophilic fasciitis; erythema nodosum; exfoliative dermatitis; fibromyalgia; focal glomerulosclerosis; focal segmental glomerulosclerosis; giant cell arteritis; drop; gouty arthritis; graft disease against the host; eczema of the hand; Henoch-Schonlein purple; gestational herpes, hirsutism; idiopathic kerato-scleritis; idiopathic pulmonary fibrosis; idiopathic thrombocytopenic purpura; immune thrombocytopenic purpura; inflammatory bowel or gastrointestinal disorders, inflammatory dermatoses; lichen planus; lupus nephritis; lymphatic tracheobronchitis; macular edema; multiple sclerosis; myasthenia gravis; myositis; non-specific fibrosis lung disease; osteoarthritis, pancreatitis; gestational pemphigoid, pemphigo vulgaris; periodontitis; polyarteritis nodosa; Polymyalgia rheumatica; pruritus scroti; Pruritis / inflammation; psoriasis; psoriatic arthritis; histoplas-mosis pulmonar; rheumatoid arthritis; recurrent polychondritis; 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 by pain associated with Zoster; sarcoidosis; scleroderma; Segmental glomerulosclerosis; septic shock syndrome; shoulder tendinitis or bursitis; Sjogren's syndrome; Still's disease; cerebral cell death induced by embolism; Sweet's disease; systemic lupus erythematosus; systemic sclerosis; Takayasu arteritis; Temporal arteritis; toxic epidermal necrolysis; transplant rejection and syndromes related to transplant rejection; tuberculosis; Diabetes type 1; Ulcerative colitis; uveitis, vasculitis; and egener 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., astheatotic eczema, dyshidrotic eczema, vesicular palmoplantar eczema), circumscripta balanitis plasmacelularis, balanoposthitis, Behcet's disease, Centrifugal annular erythema, erythema discrómico perstants, erythema multiforme, granuloma annulare, lichen nítido, lichen planus, lichen sclerosus and artrófico, lichen simplex chronic, lichen espinulose, nummular dermatitis, pyoderma gangrenosum, sarcoidosis, subcorneal postnatal dermatosis, urticaria, and transient acantholytic dermatosis . "Proliferative skin disease" means a benign or malignant disease characterized by accelerated cell division in the epidermis or dermis. Examples of skin proliferative diseases are psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, squamous and basal cell carcinomas of the skin, lamellar ichthyosis, epidermolytic hyperkeratosis, premalignant keratosis, acne. , and seborrheic dermatitis. As will be appreciated by one skilled in the art, a particular disease, disorder, or condition may be characterized as both a proliferative skin disease and an inflammatory dermatosis. An example of this disease is psoriasis. "Sustained release" or "controlled release" means that the therapeutically active component is released from the formulation at a controlled rate, such that the therapeutically beneficial blood levels (but below the toxic levels) of the component are maintained. a prolonged period of time which may be, for example, from about 12 to about 24 hours, thereby providing, for example, a 12-hour or 24-hour dosage form. In the generic descriptions of the compounds of this invention, the number of atoms of a particular type in a substituent group is generally given as a range, for example, an alkyl group containing from 1 to 7 carbon atoms, or alkyl C ^ ,. The reference to this range is intended to include specific references to groups having each of the entire number of atoms within the specified range. For example, an alkyl group of 1 to 7 carbon atoms includes each of C C2, C3, C4, Cs, C6, and C7. A heteroalkyl of 1 to 7 carbon atoms, for example, includes from 1 to 7 carbon atoms in addition to one or more heteroatoms. Other numbers of atoms and other types of atoms can be indicated in a similar way.

"Acyl" means a chemical fraction with the formula RC (O) -, wherein it is selected from alkyl of 1 to 7 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, heterocyclyl of 2 to 6 carbon atoms, aryl of 6 to 12 carbon atoms, alkaryl of 7 to 14 carbon atoms, alkyl heterocyclyl of 3 to 10 carbon atoms, or heteroalkyl of 1 to 7 carbon atoms. "Alkoxy" means a chemical substituent of the formula -OR, wherein R is selected from alkyl of 1 to 7 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, heterocyclyl of 2 to 6 carbon atoms, aryl of 6 to 12 carbon atoms, alkaryl of 7 to 14 carbon atoms, alkyl heterocyclyl of 3 to 10 carbon atoms, or heteroalkyl of 1 to 7 carbon atoms. "Aryloxy" means a chemical substituent of the formula -OR, wherein R is an aryl group of 6 to 12 carbon atoms. "Aryl of 6 to 12 carbon atoms" means an aromatic group having a ring system comprised of carbon atoms with conjugated p-electrons (e.g., phenyl). The aryl group has from 6 to 12 carbon atoms. The aryl groups may optionally include the monocyclic, bicyclic, or tricyclic rings, wherein each ring desirably has 5 or 6 members. The aryl group may be substituted or unsubstituted. Exemplary substituents include alkyl, hydroxyl, alkoxy, aryloxy, sulfhydryl, thioalkyl, thioaryl, halide, fluoroalkyl, carboxyl, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino, disubstituted amino, and quaternary amino groups. "Amido" means a chemical substituent of the formula -NRR ', wherein the nitrogen atom is part of an amide bond (e.g., -C (O) -NRR'), and wherein R and R 'are each independently selected from alkyl of 1 to 7 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, heterocyclyl of 2 to 7 carbon atoms, aryl of 6 to 12 carbon atoms, alkaryl of 7 to 14 carbon atoms, alkyl-heterocyclyl of 3 to 10 carbon atoms, and heteroalkyl of 1 to 7 carbon atoms, or -NRR 'forms a heterocyclyl ring of 2 to 7 carbon atoms, as defined above, but containing at least one carbon atom. nitrogen, such as piperidino, morpholino, and azabicyclo, among others. "Halide" or "halo" means bromine, chlorine, iodine, or fluorine. The term "pharmaceutically acceptable salt" means salts which, within the scope of good medical judgment, are suitable for use in contact with the tissues of human and lower animals without undue toxicity, irritation, allergic response, and the like, and they are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable saltsa are well known in the art. The salts can be prepared in itself during the isolation and final purification of the compounds of the invention, or separately by reaction of the free base function with a suitable organic acid. Representative acid addition salts include the salts of acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorrate, canfersulfonate, citrate, cyclopentan-propionate, digluconate, dodecyl sulfate, ethanesulfone-to , fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, iodhydrate, 2-hydroxy-ethanesulfonate, isethionate, lactobionate, lactate, laurate, lauryl-sulfate, malate, maleate, malonate, mesylate, methanesulfonate, 2-naphthalene sulfonate, mycelinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, and Similar. Representative alkali metal 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, tetramethyl- ammonium, tetraethyl ammonium, methyl amine, dimethylamine, trimethyl amine, triethylamine, ethyl amine, and the like. Compounds useful in the invention include those described herein, in any of their pharmaceutically acceptable forms, including isomers, such as diastere-reomers and enantiomers, salts, esters, amides, thioesters, solvates, and polymorphs thereof, as well as the racemic mixtures and the pure isomers of the compounds described herein. As an example, "paroxetine" means the free base, as well as any pharmaceutically acceptable salt thereof (eg, paroxetine maleate, paroxetine hydrochloride hemihydrate, and paroxetine mesylate). Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. Detailed Description The invention provides methods, compositions, and therapeutic kits for the administration of an effective amount of a non-spheroidal immunophilin-dependent immunosuppressant (NsIDI), such as cyclosporin, and a non-spheroidal immunophilin-dependent immunosuppressant enhancer.

(NsIDIE), for example a selective inhibitor of serotonin recovery, a tricyclic anti-depressant, a phenoxy-phenol, an anti-histamine, a phenothiazine, or a mu opioid receptor agonist. The invention is described in more detail below. Nonsteroidal Immunophilin Dependent Immunosuppressants In one embodiment, the invention provides methods, compositions, and therapeutic kits employing an NsIDI and an NsIDIE, optionally with a corticosteroid or other agent described herein. In healthy individuals, the immune system uses cellular effectors, such as B-cells and T-cells, to target infectious microbes and abnormal cell types, while leaving normal cells intact. In individuals with an autoimmune disorder or a transplants organ, activated T-cells damage healthy tissues. Calcineurin inhibitors (eg, cyclosporins, tacrolimus, pimecrolimus), and rapamycin, target many types of immune-regulatory cells, including T-cells, and suppress the immune response in organ transplantation and disorders. autoimmune Cyclosporins Cyclosporins are fungal metabolites that comprise a class of cyclic oligopeptides that act as immunosuppressants. Cyclosporin A, and its deuterated analog ISAtx247, is a hydrophobic cyclic polypeptide consisting of 11 amino acids. Cyclosporin A binds and forms a complex with the intracellular cyclophilin receptor. The cyclosporin / cyclophilin complex binds to, and inhibits, calcineurin, a calmodulin-dependent Ca2 + serine-threonine-specific protein phosphatase. Calcineurin mediates the signal transduction events required for the activation of T-cells (reviewed in Schreiber et al., Cell 70: 365-368, 1991). Cyclosporins and their functional and structural analogs suppress the immune response dependent on T-cells, by inhibiting the transduction of the signal triggered by the antigen. This inhibition reduces the expression of proinflammatory cytokines, such as IL-2. Many cyclosporins (eg, cyclosporin A, B, C, D, E, F, G, H, and I) are produced by fungi. Cyclosporin A is commercially available under the trade name NEORAL from Novartis. The structural and functional analogues of cyclosporin A include cyclosporins having one or more fluorinated amino acids (described, for example, in US Pat. No. 5,227,467); cyclosporins having modified amino acids (described, for example, in US Patents 5,122,511 as well as 4,798,823); and deuterated cyclosporins, such as ISAtx427 (described in US 20020132763). Additional cyclosporin analogs are described in US Pat. No. 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, Norvaline-2-Cs, D-Ala ( 3-acetylamino) -8-Cs, Thr-2-Cs, and D-MeSer-3 -Cs, D-Ser- (0-CH2CH2-OH) -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 to provide cyclosporin formulations with improved bioavailability are described in US Patents 4,388,307; 6,468,968; 5,051,402; 5,342,625; 5,977,066, and 6,022,852. Cyclosporin microemulsion compositions 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. In order to counteract the hydrophobicity of cyclosporin A, an intravenous cyclosporin A is usually provided in an ethanol vehicle-polyoxyethylated castor oil, which must be diluted prior to administration. Cyclosporin A can be provided, for example, as a microemulsion in 25 mg or 100 mg tablets, or in a 100 mg / ml oral solution (NEORAL®). Normally, the dosage of an oral cyclosporin per patient varies according to the condition of the patient, but some recommended standard dosages are given in the prior art treatment regimens herein. Patients who undergo organ transplantation usually receive an initial dose of oral cyclosporin A in amounts between 12 and 15 mg / kg / day. Then the dosage is gradually reduced by 5 percent per week, until a maintenance dose of 7 to 12 mg / kg / day is reached. For intravenous administration, 2 to 6 mg / kg / day are preferred for most patients. For patients diagnosed with Crohn's disease or ulcerative colitis, dosage amounts of 6 to 8 mg / kg / day are generally given. For patients diagnosed as having systemic lupus erythematosus, dosage amounts of 2.2 to 6.0 mg / kg / day are generally given. For psoriasis or rheumatoid arthritis, dosage amounts of 0.5 to 4 mg / kg / day are typical. Other useful dosages include 0.5 to 5 mg / kg / day, 5 to 10 mg / kg / day, 10 to 15 mg / kg / day, 15 to 20 mg / kg / day, or 20 to 25 mg / kg / day. Frequently, cyclosporins are administered in combination with other immunosuppressive agents, such as glucocorticoids. Additional information is provided in Table 1.

Table 1 NsIDIs Caption: CsA = ciclosporin A. RA = rheumatoid arthritis. UC = ulcerative colitis. SLE = systemic lupus erythematosus. Tacrolimus Tacrolimus (PROGRAF, Fujisawa), also known as FK506, is an immunosuppressive agent that targets the intracellular signal transduction pathways of T-cells. Tacrolimus binds to an intracellular protein FK506 binding protein (FKBP-12), which 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 complex of FKBP / FK506 binds to calcineurin, and inhibits the activity of calcineurin phosphatase. This inhibition prevents the dephosphorylation and nuclear translocation of NFAT, a nuclear component that initiates the genetic transcription required for the production of lymphokine (for example, IL-2, inferred gamma) and the activation of T-cells. Therefore, tacrolimus inhibits the activation of T-cells. Tacrolimus is a macrolide antibiotic that is produced by Streptomyces tsukubaensi s. It suppresses the immune system and prolongs the survival of the transplanted organs. It is currently available in oral and injectable formulations. Tacrolimus capsules contain 0.5 mg, 1 mg, or 5 mg of anhydrous tacrolimus inside a gelatin capsule shell. The injectable formulation contains 5 mg of anhydrous tacrolimus in castor oil and alcohol that is diluted with 9 percent sodium chloride or 5 percent dextrose before injection. Although oral administration is preferred, patients unable to take oral capsules may receive tacrolimus injection. The initial dose should be administered not earlier than 6 hours after the transplant, by continuous intravenous infusion. Tacrolimus and tacrolimus analogues 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. The compounds related to FK506, including FR-900520, FR-900523, and FR-900525, are described in US patent 5,254,562; the O-aryl, O-alkyl, O-alkenyl, and O-alkynyl macrolides are described in US Pat. No. 5,250,678; 532,248; 5,693,648; the amino-O-aryl macrolides are described in US patent 5,262,533; the alkylidene macrolides are described in US Pat. No. 5,284,840; the macrolides of N-heteroaryl, N-alkyl-heteroaryl, N-alkenyl-heteroaryl, and N-alkynyl-heteroaryl are described in US Pat. No. 5,208,241; aminomacrolides and their derivatives are described in US Pat. No. 5,208,241; fluoromacrolides are described in US Pat. No. 5,189,042; the amino-O-alkyl, O-alkenyl, and O-alkynyl macrolides are described in US Pat. No. 5,162,334; and halomacrolides are described in US Pat. No. 5,143,918. Although the suggested dosages will vary with the condition of the patient, standard recommended dosages used in the prior art treatment regimens are provided below. Patients diagnosed with Crohn's disease or ulcerative colitis are given 0.1 to 0.2 mg / kg / day of oral tacrolimus. Patients who have a transplanted organ usually receive doses of 0.1 to 0.2 mg / kg / day of oral tacrolimus. Patients who are being treated for rheumatoid arthritis usually receive 1 to 3 mg / day of oral tacrolimus. For the treatment of psoriasis, 0.01 to 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 that has 0.03 to 0.1 percent tacrolimus in the affected area. Patients receiving oral tacrolimus capsules usually receive the first dose no earlier than 6 hours after the transplant, or 8 to 12 hours after the intravenous infusion of tacrolimus has been discontinued. Other dosages of tacrolimus suggested include 0.005 to 0.01 mg / kg / day, from 0.01 to 0.03 mg / kg / day, from 0.03 to 0.05 mg / kg / day, from 0.05 to 0.07 mg / kg / day, from 0.07 to 0.10 mg / kg / day, from 0.10 to 0.25 mg / kg / day , or from 0.25 to 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 it is likely that different metabolites of tacrolimus exhibit an immunosuppressive biological activity, it is reported that the metabolite of 13-demethyl has the same activity as tacrolimus. Derivatives of Pimecrolimus and Ascomycin Ascomycin is a close structural analog of FK506, and is a potent immunosuppressant. It binds to FKBP-12, and suppresses its rotamase activity. The complex of ascomycin-FKBp inhibits calcineurin, a type 2B phosphatase.

Pimecrolimus (also known as SDZ ASM-981) is a 33-epi-chloro derivative of ascomycin. It is produced by the strain Streptomyces hygroscopicus var. ascomycei tus. Like tacrolimus, pimecrolimus (ELIDEL®, Novartis) binds to FKBP-12, inhibits the activity of calcineurin phosphatase, and inhibits the activation of T-cells by blocking the transcription of early cytokines. In particular, pimecrolimus inhibits the production of IL-2 and the release of other proinflammatory cytokines. The structural and functional analogs of pimecrolimus are described in patent US 6,384,073. Pimecrolimus is particularly useful for the treatment of atopic dermatitis. Pimecrolimus is currently available as a 1 percent cream. Although the individual dosage will vary with the patient's condition, standard recommended dosages are provided below. Oral pimecrolimus can be given for the treatment of psoriasis or rheumatoid arthritis in amounts of 40 to 60 mg / day. For the treatment of Crohn's disease or ulcerative colitis, amounts of 80 to 160 mg / day of pimecrolimus can be given. Patients who have organ transplants can be given 160 to 240 mg / day of pimecrolimus. Patients diagnosed with systemic lupus erythematosus can be given 40-120 mg / day of pimecrolimus. Other useful dosages of pimecrolimus include from 0.5 to 5 mg / day, from 5 to 10 mg / day, from 10 to 30 mg / day, from 40 to 80 mg / day, from 80 to 120 mg / day, or even 120 to 200 mg / day. Rapamycin Rapamycin (Sirolimus RAPAMUNE®, yeth) is a cyclic lactone produced by Streptomyces hygroscopicus. Rapamycin is an immunosuppressive agent that inhibits the activation and proliferation of T-lymphocytes. Like the cyclosporins, tacrolimus, and pimecrolimus, rapamycin forms a complex with the immunophilin FKBP-12, but the rapamycin-FKBP-12 complex does not inhibit the activity of calcineurin phosphatase. The rapamycin-immunophilin complex binds to, and inhibits, the mammalian target of rapamycin (mTOR), a kinase that is required for cell cycle progress. The inhibition of mTOR kinase activity blocks the proliferation of T-lymphocytes and the secretion of lymphokine. The structural and functional analogues of rapamycin include the mono- and di-acylated rapamycin derivatives (US Pat. No. 4,316,885); water-soluble rapamycin prodrugs (US Patent 4,650,803); esters of carboxylic acids (publication WO 92/05179); carbamates (US patent ,118,678); amide esters (US patent 5,118,678); biotin esters (US patent 5,504,091); fluorinated esters (US patent) ,100,883); acetals (US patent 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). In US Patents 5,202,332 and 5,169,851, additional rapamycin analogs are described. Everolimus (40-O- (2-hydroxyethyl) rapamycin; CERTICAN®; Novartis) is an immunosuppressive macrolide that is structurally related to rapamycin, and has been found to be particularly effective in preventing acute rejection of organ transplantation when given in combination with cyclosporin A. Rapamycin is currently available for oral administration in liquid formulations and tablets. RAPAMUNE® liquid contains 1 mg / ml rapamycin, which is diluted in water or orange juice before administration. Also available are tablets containing 1 or 2 mg of rapamycin. Rapamycin is given preference once a day, as soon as possible after transplantation. It is absorbed quickly and completely after oral administration. Typically, the dosage of rapamycin for the empty patient according to the patient's condition, but some recommended standard dosages are provided below. The initial loading dose for rapamycin is 6 mg. Typical maintenance doses of 2 mg / day are typical. Alternatively, a loading dose of 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg may be used, with a maintenance dose of 1 mg, 3 mg, 5 mg, 7 mg, or 10 mg a day. In patients weighing less than 40 kg, rapamycin dosages are usually adjusted based on the body surface area; In general, a loading dose of 3 mg / square meter / day is used, and a maintenance dose of 1 mg / square meter / day. Peptide Fractions Peptides, peptide mimetics, peptide fragments, whether natural, synthetic, or chemically modified, which impair calcineurin-mediated dephosphorylation and the nuclear translocation of NFAT, are suitable for use in the practice of the invention. Examples of peptides that act as inhibitors of calcineurin by inhibiting the activation of NFAT and the transcription factor NFAT are described, for example, 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. Selective Serotonin Recovery Inhibitors In one embodiment, the methods, compositions, and therapeutic kits of the invention employ a selective serotonin reuptake inhibitor (SSRI), or a structural or functional analogue thereof, in combination with an immunosuppressant. dependent on non-spheroidal immunophilin (NsIDI).

Suitable SSRIs include cericlamine (e.g., cericlamin hydrochloride); citalopram (for example, citalopram hydrobromide); clovoxamine; cyanodotiepine; dapoxetine; escitalopram (escitalopram oxalate); femoxetine (for example, femoxetine hydrochloride); fluoxetine (e.g., fluoxetine hydrochloride); fluvoxamine (eg, fluvoxamine maleate); ifoxetine; indalpine (for example, indalpine hydrochloride); indeloxazine (e.g., indeloxazine hydrochloride), -litoxetine; milnacipram (for example, milnacipram hydrochloride); paroxetine (eg, paroxetine hydrochloride hemihydrate paroxetine maleate, paroxetine mesylate); sertraline (eg, sertraline hydrochloride); sibutramine, tametralin hydrochloride; vicualina; and zimeldine (for example, zimeldin hydrochloride). SSRIs are drugs that inhibit the recovery of -hydroxy-triptamine (5-HT) by neurons of the central nervous system. The SSRIs show selectivity with respect to 5-HT on the recovery of norepinephrine. They are less likely than tricyclic antidepressants to cause anticholinergic side effects, and are less dangerous in an over-dose. SSRIs, such as paroxetine, sertraline, fluoxetine, citalopram, fluvoxamine, nor ^ citalopram, venlafaxine, milnacipram, nor2-citalopram, nor-fluoxetine, or nor-sertraline, are used to treat a variety of psychiatric disorders, including depression, disorders of anxiety, panic attacks, and obsessive-compulsive disorder. The dosages given here are the recommended standard doses for psychiatric disorders. In the practice of the methods of the invention, the effective amounts may be different. The administration of each drug in the combination can be independently from one to four times a day for a day up to a year, and can even be for the entire life of the patient. In many cases chronic long-term administration will be indicated. Typically, the dosage of an SSRI to the patient varies according to the condition of the patient. The SSRIs can be administered orally, by suppository, or by injection. Doses are often given orally once a day as a tablet or as a liquid concentrate. Cericlamine Cericlamine has the following structure: The structural analogs of cericlamine are those that have the formula: as well as the pharmaceutically acceptable salts thereof, wherein Rx is an alkyl of 1 to 4 carbon atoms, and R2 is H or alkyl of 1 to 4 carbon atoms, R3 is H, alkyl of 1 to 4 carbon atoms , alkenyl of 2 to 4 carbon atoms, phenylalkyl, or cycloalkyl-alkyl with 3 to 6 cyclic carbon atoms, alkanoyl, phenylalkanoyl, or cycloalkyl-carbonyl having from 3 to 6 cyclic carbon atoms, or R2 and R3 form, together with the nitrogen atom with which they are bound, a heterocycle saturated with 5 to 7 chain bonds that may have, as the second heteroatom not directly connected to the nitrogen atom, an oxygen, a sulfur, or a nitrogen, carrying possibly the last nitrogen heteroatom an alkyl of 2 to 4 carbon atoms. The structural analogues of example cericlamine are 2-methyl-2-amino-3- (3,4-dichloro-phenyl) -propanol, 2-pentyl-2-amino-3- (3,4-dichloro-phenyl) - propanol, 2-methyl-2-methyl-amino-3- (3,4-dichloro-phenyl) -propanol, 2-methyl-2-dimethyl-amino-3- (3,4-dichloro-phenyl) -propanol, and the pharmaceutically acceptable salts of any of them.

Citalopram Citalopram HBr (CELEXA®) is a racemic bicyclic phthalane derivative designated as (±) -1- (3-dimethyl-amino-propyl) -1- (4-fluoro-phenyl) -1,3-dihydro-isobenzofuran -5-carbonitrile, Hbr. Citalopram undergoes extensive metabolism; norj-citalopram and nor2-citalopram are the main metabolites. Citalopram is available in 10 mg, 20 mg, and 40 mg tablets for oral administration. The CELEXA® oral solution contains one equivalent of citalopram HBr of 2 mg / ml citalopram base. CELEXA® is normally administered in an initial dose of 20 mg once a day, usually with an increase up to a dose of 40 mg / day. Typically, dose increases occur in increments of 20 mg at intervals of not less than one week. Citalopram has the following structure: The structural analogs of citalopram are those that have the formula: as well as pharmaceutically acceptable salts thereof, wherein each of Rx and R2 is independently selected from the group consisting of bromine, chlorine, fluorine, trifluoromethyl, cyano, and R-CO-, wherein R is alkyl 1 to 4 carbon atoms. The structural analogues of exemplary citalopram (which, therefore, are the structural analogues of the SSRI according to the invention) are 1- (4'-fluoro-phenyl) -1- (3-dimethyl-amino-propyl) -5 -bromo-phthalan; 1- (4'-chloro-phenyl) -1- (3-dimethyl-amino-propyl) -5-chloro-phthalane; 1- (4'-bromo-phenyl) -1- (3-dimethyl-amino-propyl) -5-chloro-phthalane; 1- (4 '-fluoro-phenyl) -1- (3-dimethyl-amino-propyl) -5-chloro-phthalane; 1- (4'-chloro-phenyl) -1- (3-dimethyl-amino-propyl) -5-trifluoromethyl-phthalane; 1- (4'-bromo-phenyl) -1- (3-dimethyl-amino-propyl) -5-trifluoromethyl-phthalane; 1- (4 '-fluorophenyl) -1- (3-dimethyl-amino-propyl) -5-trifluoromethyl-phthalane; 1- (4 '-fluoro-phenyl) -1- (3-dimethyl-amino-propyl) -5-fluoro-phthalane; 1- (4'-chloro-phenyl) -1- (3-dimethyl-amino-propyl) -5-fluoro-phthalane; 1- (4'-chloro-phenyl) -1- (3-dimethyl-amino-propyl) -5-phthalan-carbonitrile; 1- (4 '-fluoro-phenyl) -1- (3-dimethyl-amino-propyl) -5-phthalan-carbonitrile; 1- (4'-cyano-phenyl) -1- (3-dimethyl-amino-propyl) -5-phthalan-carbonitrile; 1- (4'-cyano-phenyl) -1- (3-dimethyl-amino-propyl) -5-chloro-phthalane; 1- (4'-cyano-phenyl) -1- (3-dimethyl-amino-propyl) -5-trifluoromethyl-phthalane; 1- (4 '-fluoro-phenyl) -1- (3-dimethyl-amino-propyl) -5-phthalan-carbonitrile; 1- (4'-chloro-phenyl) -1- (3-dimethyl-amino-propyl) -5-ionyl-phthalane; 1- (4-chloro-phenyl) -1- (3-dimethyl-amino-propyl) -5-propionyl-phthalane; and the pharmaceutically acceptable salts of any of them. Clovoxamine Clovoxamine has the following structure: The structural analogs of clovoxamine are those that have the formula: as well as the pharmaceutically acceptable salts thereof, wherein Hal is a chloro, bromo, or fluoro group, and R is a cyano, methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxyethoxy, or cyanomethyl group. Exemplary structural analogs of clovoxamine are 4'-chloro-5-ethoxy-valero-phenone O- (2-amino-ethyl) oxime; 4'-chloro-5- (2-methoxy-ethoxy) -valero-phenone 0- (2-amino-ethyl) -oxime; 4'-chloro-6-methoxy-caprofenone 0- (2-amino-ethyl) oxime; 4'-chloro-6-ethoxy-caprofenone 0- (2-amino-ethyl) oxime; 4'-bromo-5- (2-methoxy-ethoxy) -valerophenone O- (2-amino-ethyl) -oxime; 4'-bromo-5-methoxy -valerophenone O- (2-amino-ethyl) -oxime; 4'-chloro-6-cyano-caprofenone O- (2-amino-ethyl) oxime; 4'-chloro-5-cyano-valerophenone O- (2-amino-ethyl) oxime; 4'-bromo-5-cyano-valerophenone O- (2-amino-ethyl) oxime; and the pharmaceutically acceptable salts of any of them. Femoxetine Femoxetine has the following structure: The structural analogues of femoxetine are those that have the formula: where R represents an alkyl group of 1 to 4 carbon atoms or alkynyl of 2 to 4 carbon atoms, or a phenyl group optionally substituted by alkyl of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, alkoxy 1 to 4 carbon atoms, bromine, chlorine, fluorine, nitro, acylamino, methyl-sulfonyl, methylene-dioxyl, or tetrahydro-naphthyl; R2 represents an alkyl group of 1 to 4 carbon atoms or alkynyl of 2 to 4 carbon atoms, and R3 represents hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, trifluoroalkyl, hydroxyl, bromine , chlorine, fluorine, thiomethyl, or aralkyloxy. Exemplary structural femoxetine analogs are disclosed in Examples 7 to 67 of US Patent 3,912,743, incorporated herein by reference. Fluoxetine Fluoxetine hydrochloride ((+) - N -methyl-3-phenyl-3- [((alpha), (alpha), (alpha) -trifluoro-p-tolyl) -oxy] -propyl-amine hydrochloride) It is sold as PROZAC® in 10 mg, 20 mg, and 40 mg tablets for oral administration. The main metabolite of fluoxetine is nor-fluoxetine. Fluoxetine hydrochloride can also be administered as an oral solution equivalent to 20 mg / 5 ml of fluoxetine. A delayed-release formulation contains enteric-coated granules of fluoxetine hydrochloride equivalent to 90 mg fluoxetine. As the initial dose, a dose of 20 mg / day, administered in the morning, is usually recommended. An increase in dose may be considered after several weeks if no clinical improvement is observed. Doses greater than 20 mg / day may be given in a program once a day (in the morning) or twice a day (for example, in the morning and in the afternoon), and must not exceed a maximum dose of 80 mg / day. Fluoxetine has the following structure: The structural analogues of fluoxetine are the compounds having the formula: as well as the pharmaceutically acceptable salts thereof, wherein each Rx is independently hydrogen or methyl; R is naphthyl or wherein each of R2 and R3 is independently bromo, chloro, fluoro, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 3 carbon atoms, or alkenyl of 3 to 4 carbon atoms; and each of n and m is independently 0, 1, or 2. When R is naphthyl, it can be -naphthyl or β-naphthyl. Exemplary structural fluoxetine analogs are 3- (p-isopropoxy-phenoxy) -3-phenyl-propyl-amine methanesulfonate, N, N-dimethyl-3- (3 ', 4'-dimethoxy-phenoxy) p-hydroxybenzoate ) -3-phenyl-propyl-amine, N, N-dimethyl-3- (a-naphthoxy) -3-phenyl-propyl-amine bromide, N, N-dimethyl-3 - (b-naphthoxy) - iodide 3-phenyl-1-methyl-propyl-amine, 3- (2 '-methyl-4', 5'-dichloro-phenoxy) -3-phenyl-propyl-amine nitrate, 3 - (pt-butyl-) glutarate phenoxy) -3-phenyl-propyl-amine, N-methyl-3- (2'-chloro-p-tolyloxy) -3-phenyl-1-methyl-propyl-amine lactate, 3- (2 ') citrate, 4'-dichloro-phenoxy) -3-phenyl-2-methyl-propyl-amine, N, N-dimethyl-3 - (m-anisoyloxy) -3-phenyl-1-methyl-propyl-amine maleate, N-methyl-3- (p-tolyloxy) -3-phenyl-propyl-amine, 2,4-dinitro-benzoate of N, N-dimethyl-3- (2 ', 4'-difluoro-phenoxy) -3- phenyl-propyl-amine, 3- (o-ethyl-phenoxy) -3-phenyl-propyl-amine diacid phosphate, N-methyl-3- (2'-chloro-4 '-isopropyl-phenoxy) -3-maleate -phenyl-2-methyl-propyl -amine, N, N-dimethyl-3- (2'-alkyl-4'-fluoro-phenoxy) -3-phenyl-propylamine succinate, N, N-dimethyl-3- (o-) phenyl acetate isopropoxy-phenoxy) -3-phenyl-propyl-amine, N, N-dimethyl-3- (o-bromo-phenoxy) -3-phenyl-propyl-amine β-phenylpropionate, N-methyl-3 propiolate - (p-iodo-phenoxy) -3-phenyl-propyl-amine, and N-methyl-3- (3-n-propy1-phenoxy) -3-pheny1-propyl-amine decanoate. Fluvoxamine Fluvoxamine maleate (LUVOX®) is chemically designed as 5-methoxy-4 '- (trifluoromethyl) -valerophenone (E) -0- (2-amino-ethyl) -oxime maleate. Fluvoxamine maleate is supplied as 50 mg and 100 mg tablets. Treatment is usually started with 50 mg given once a day at bedtime, and then increased to 100 mg a day at bedtime after a few days, as tolerated. The effective daily dose is usually between 100 and 200 mg, but can be administered up to a maximum of 300 mg. Fluvoxamine has the following structure: The structural analogs of fluvoxamine are those that have the formula: as well as the pharmaceutically acceptable salts thereof, wherein R is cyano, cyano-methyl, methoxy-methyl, or ethoxy-methyl. Indalpina Indalpina has the following structure: The structural analogues of indalpine are those that have the formula: or the pharmaceutically acceptable salts thereof, wherein R? is a hydrogen atom, an alkyl group of 1 to 4 carbon atoms, or an aralkyl group of which the alkyl has 1 or 2 carbon atoms, R2 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or thioalkyl of 1 to 4 carbon atoms, chlorine, bromine, fluorine, trifluoromethyl, nitro, hydroxyl, or amino, the latter optionally being substituted by one or two alkyl groups of 1 to 4 carbon atoms , an acyl group, or an alkyl sulfonyl group of 1 to 4 carbon atoms; A represents a group -CO or -CH2-; and n is 0, 1, or 2. The example structural analogues of indalpine are indolyl-3 (piperidyl-4-methyl) -ketone; (methoxy-5-indolyl-3) - (piperidyl-4-methyl) -ketone; (chloro-5-indolyl-3) - (piperidyl-4-methyl) -ketone; (indolyl-3) -1- (piperidyl-4) -3-propanone, indolyl-3-piperidyl-4-ketone; (methyl-l-indolyl-3) - (piperidyl-4-methyl) -ketone; (benzyl-1-indolyl-3) - (piperidyl-4-methyl) -ketone; [(methoxy-5-indolyl-3) -2-ethyl] -piperidine; [(methyl-l-indolyl-3) -2-ethyl] -4-piperidine; [(indolyl-3) -2-ethyl] -4 -piperidine; (indolyl-3-methyl) -4-piperidine, [(chloro-5-indolyl) -2-ethyl] -4-piperidine; [(indolyl-b-3) -3-propyl] -4-piperidine, [(benzyl-l-indolyl-3) -2-ethyl] -4-piperidine; and the pharmaceutically acceptable salts of any of them. Indeloxazine Indeloxazine has the following structure: The structural analogs of indeloxazine are those that have the formula: and the pharmaceutically acceptable salts thereof, wherein R? and R3 each represents hydrogen, alkyl of 1 to 4 carbon atoms, or phenyl; R 2 represents hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 4 to 7 carbon atoms, phenyl, or benzyl; one of the dotted lines means an individual link, and the other means a double bond, or the tautomeric mixtures thereof. Exemplary structural analogues of indeloxazine are 2- (7-indeloxy-methyl) -4-isopropylmorpholine; 4-butyl-2- (7-indenyloxymethyl) -morpholine; 2- (7-indenyloxy-methyl) -4-methyl-morpholine; 4-ethyl-2- (7-indenyloxymethyl) -morpholine; 2- (7-indenyloxymethyl) -morpholine; 2- (7-indenyloxy-methyl) -4-propylmorpholine; 4-cyclohexyl-2- (7-indenyloxymethyl) -morpholine; 4-benzyl-2- (7-indenyloxymethyl) -morpholine; 2- (7-indenyloxy-methyl) -4-phenyl-morpholine; 2- (4-indenyloxymethyl) -morpholine; 2- (3-methyl-7-indenyloxy-methyl-yl) -morpholine; 4-isopropyl -2 - (3-met-il-7-indenyloxy-methyl) -morpholine; 4-isopropyl-2- (3-methyl-4-indenyloxy-methyl) -morpholine; 4-isopropyl-2- (3-methyl-5-indenyloxy-methyl) -morpholine; 4-isopropyl-2- (l-methyl-3-phenyl-6-indenyloxy-methyl) -morpholine; 2- (5-indenyloxy-methyl) -4-isopropyl-morpholine; 2- (6-indenyloxy-methyl) -4-isopropyl-morpholine; and 4-isopropyl-2- (3-phenyl-6-indenyloxy-methyl) -morpholine; as well as the pharmaceutically acceptable salts of any of them. Milnacipram Milnacipram (IXEL®, Cypress Biosciences Inc.) has the chemical formula of (Z) -l-diethyl-amino-carbonyl-2-amino-ethyl-1-phenyl-cyclopropan) -hydrochlorate, and is available in tablets of 25 mg and 50 mg for oral administration. It is usually given in dosages of 25 mg once a day, 25 mg once a day, or 50 mg twice a day, for the treatment of severe depression. The milnacipram has the following structure: The structural analogues of milnacipram are those that have the formula: as well as the pharmaceutically acceptable salts thereof, wherein each R independently represents hydrogen, bromine, chlorine, fluorine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxyl, nitro, or amino; each of Rx and R2 independently represent hydrogen, alkyl of 1 to 4 carbon atoms, aryl of 6 to 12 carbon atoms, or alkylaryl of 7 to 14 carbon atoms, optionally substituted, preferably in the para position, by bromine , chlorine, or fluorine, or Rx and R2 together form a heterocycle having 5 or 6 members with the adjacent nitrogen atoms; R3 and R4 represent hydrogen or an alkyl group of 1 to 4 carbon atoms, or R3 and R4 form, with the adjacent nitrogen atom, a heterocycle having 5 or 6 members, optionally containing an additional heteroatom selected from nitrogen , sulfur, and oxygen. Exemplary minalciprano structural analogs are 1-phenyl-1-amino-carbonyl-2-dimethyl-amino-methyl-cyclopropane; 1-phenyl-1-dimethyl-amino-carbonyl-2-dimethyl-amino-methyl-cyclopropane; 1-phenyl-1-ethyl-amino-carbonyl-2-dimethyl-amino-methyl-cyclopropane; 1-phenyl-1-diethyl-amino-carbonyl-2-amino-methyl-cyclopropane; 1-phenyl-2-dimethyl-amino-methyl N- (4'-chloro-phenyl) -cyclopropane carboxamide; 1-phenyl-2-dimethyl-amino-methyl N- (4'-chloro-benzyl) -cyclopropane carboxamide; 1-phenyl-2-dimethyl-amino-methyl N- (2-phenyl-ethyl) -cyclopropane carboxamide; (3,4-dichloro-1-phenyl) -2-dimethyl-amino-methyl N, N-dimethyl-cyclopropane carboxamide; 1-phenyl-1-pyrrolidino-carbonyl 2-morpholino-methyl-cyclopropane; 1-p-chloro-phenyl-1-amino-carbonyl 2-amino-methyl-cyclopropane; 1-ortho-chloro-phenyl-1-amino-carbonyl-2-dimethyl-amino-methyl-cyclopropane; 1-p-hydroxy-phenyl-1-amino-carbonyl-2-dimethyl-amino-methyl-cyclopropane; 1-p-Nitro-phenyl-1-dimethyl-amino-carbonyl-2-dimethyl-amino-methyl-cyclopropane; 1-p-amino-phenyl-1-dimethyl-il-amino-carbonyl-2-dimethyl-yl-methyl-cyclopropane; 1-p-tolyl 1-methyl-amino-carbonyl 2-dimethyl-amino-methyl-cyclopropane; 1-p-methoxy-phenyl-1-amino-methyl-carbonyl-2-amino-methyl-cyclopropane; and the pharmaceutically acceptable salts of any of them. Paroxetine Paroxetine hydrochloride ((-) - trans-4R- (4 '-fluoro-phenyl) -3S- [(3', 4'-methylenedioxy-phenoxy) -methyl] -piperidine hydrochloride hemihydrate) is provided as PAXIL®. The controlled-release tablets contain paroxetine hydrochloride equivalent to paroxetine in dosages of 12.5 mg, 25 mg, or 37.5 mg. One layer of the tablet consists of a degradable barrier layer, and the other contains the active material in a hydrophilic matrix. The recommended initial dose of PAXIL® is 25 mg / day. Some patients who do not respond to a dose of 25 mg, can benefit from increases in the dose, in increments of 12.5 mg / day, up to a maximum of 62.5 mg / day. Dosage changes usually occur at intervals of at least one week.

Paroxetine has the following structure The structural analogs of paroxetine are those that have the formula: and pharmaceutically acceptable salts thereof, wherein R 1 represents hydrogen or an alkyl group of 1 to 4 carbon atoms, and the fluorine atom may be in any of the available positions. Sertraline Sertraline ((lS-cis) -4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-N-methyl-1-naphthalene-amine hydrochloride) is provided as ZOLOFT® in 25 mg, 50 mg, and 100 mg tablets, for oral administration. Because sertraline undergoes intense metabolic transformation in a number of metabolites that can be therapeutically active, these metabolites can be used to replace sertraline in an anti-inflammatory combination of the invention. The metabolism of sertraline includes, for example, oxidative N-demethylation to N-demethyl-sertraline (nor-sertraline). ZOLOFT is normally administered in a dose of 50 mg once a day. Sertraline has the following structure: The structural analogs of sertraline are those that have the formula: where R? is selected from the group consisting of hydrogen and alkyl of 1 to 4 carbon atoms; R2 is alkyl of 1 to 4 carbon atoms; X and Y are each selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, alkoxy of 1 to 3 carbon atoms, and cyano; and W is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, and alkoxy of 1 to 3 carbon atoms. The preferred sertraline analogues are in the cis-isomeric configuration. The term "isomeric-cis" refers to the relative orientation of the NRXR2 and phenyl moieties on the cyclohexene ring (ie, both are oriented on the same side of the ring). Because both carbon atoms 1 and 4 are asymmetrically substituted, each cis-compound has two optically active enantiomeric forms denoted (with reference to carbon atom-1) as the cis- (IR) and cis- (lS) enantiomers. Particularly useful are the following compounds, either in the enantiomeric form (1S) or in the racemic (1S) forms (IR), and their pharmaceutically acceptable salts: cis-N-methyl-4- (3,4-dichloromethane). phenyl) -1,2, 3, 4-tetrahydro-1-naphthalene-amine; cis-N-methyl-4- (4-bromo-phenyl) -1,2,3,4-tetrahydro-1-naphthalene-amine; cis-N-methyl-4- (4-chloro-phenyl) -1,2,3,4-tetrahydro-1-naphthalene-amine; cis-N-methyl-4- (3-trifluoromethyl-phenyl) -1,2,3,4-tetrahydro-1-naphthalene-amine; cis-N-methyl-4- (3-trifluoromethyl-4-chloro-phenyl) -1,2,3,4-tetrahydro-1-naphthalene-amine; cis-N, N-dimethyl-4- (4-chloro-phenyl) -1,2,3,4-tetrahydro-1-naphthalene-amine; cis-N, N-dimethyl-4- (3-trifluoromethyl-phenyl) -1,2,3,4-tetrahydro-1-naphthalene-amine; Y , cis-N-methyl-4- (4-chloro-phenyl) -7-chloro-1,2,3,4-tetrahydro-1-naphthalene-amine. Also of interest is the enantiomer- (IR) of cis-N-methyl-4- (3,4-dichloro-phenyl) -1,2,3-tetrahydro-1-naphthalene-amine. Sibutramine hydrochloride monohydrate Sibutramine hydrochloride monohydrate (MERIDIAMR) is an orally administered agent for the treatment of obesity. Sibutramine hydrochloride is a racemic mixture of the (+) and (-) enantiomers of cyclobutan-methanamine, 1- (4-chloro-phenyl) -N, N-dimethyl- (alpha) - (2) hydrochloride monohydrate -methyl-propyl). Each MERIDIA® capsule contains 5 mg, 10 mg, or 15 mg of sibutramine hydrochloride monohydrate. The recommended initial dose of MERIDIA® is 10 mg administered once a day with or without food. If there is inadequate weight loss, the dose can be titrated after four weeks to a total of 15 mg once a day. The 5 mg dose is normally reserved for patients who do not tolerate the 10 mg dose. Zimeldina Zimeldine has the following structure: The structural analogues of zimeldine are the compounds that have the formula: and pharmaceutically acceptable salts thereof, wherein the pyridine nucleus is bonded in the ortho, meta or para position, to the adjacent carbon atom, and wherein R x is selected from the group consisting of H, chloro, fluorine, and bromine. Exemplary zimeldin analogs are (e) and (z) -3-3- (4'-bromo-phenyl -3- (2"-pyridyl) -dimethyl-allyl-amino; 3- (4'-bromo- phenyl) -3- (3"-pyridyl) -dimethyl-allyl-amino; 3- (4'-bromo-phenyl) -3- (4" -pyridyl) -dimethyl-allylamine; and the pharmaceutically acceptable salts of Any of the same structural analogs of any of the above SSRIs, are considered herein as the SSRI analogs, and therefore, can be employed in any of the methods, compositions, and therapeutic kits of the invention. The pharmacologically active metabolites of any of the above SSRIs can also be used in the methods, compositions, and therapeutic kits of the invention The exemplary metabolites are didesmethyl-sitalopram, desmethyl-sitralopram, desmethyl-sertraline, and nor-fluoxetine. Functional analogs of SSRIs can also be used in methods, compositions, and kits methods of the invention. Exemplary functional SSRI analogues are provided below. One class of SSRI analogues are the SNRIs (selective serotonin-norepinephrine recovery inhibitors), which include venlafaxine and duloxetine. Venlafaxine Venlafaxine hydrochloride (EFFEXOR®) is an anti-depressant for oral administration. It is designated as (R / S) -1- [2-dimethyl-amino) -1- (4-methoxy-phenyl) -ethyl] -cyclohexanol hydrochloride or (+) -1 - [(alpha) - [ (dimethylamino) -methyl] -p-methoxy-benzyl] -cyclohexanol. Compressed tablets contain venlafaxine hydrochloride equivalent to 25 mg, 37.5 mg, 50 mg, 75 mg, or 100 mg of venlafaxine. The recommended initial dose for venlafaxine is 75 mg / day, administered in two or three divided doses, taken with food. Depending on the tolerability and the need for an additional clinical effect, the dose can be increased up to 150 mg / day. If desired, the dose can be further increased up to 225 mg / day. When the dose is increased, increases of up to 75 mg / day are usually made at intervals of not less than 4 days. Venlafaxine has the following structure: The structural analogs of venlafaxine are the compounds that have the formula: as well as the pharmaceutically acceptable salts thereof, wherein A is a fraction of the formula: Or where the dotted line represents optional unsaturation; Rj is hydrogen or alkyl; R2 is alkyl of 1 to 4 carbon atoms; R 4 is hydrogen, alkyl of 1 to 4 carbon atoms, formyl, or alkanoyl; R3 is hydrogen or alkyl of 1 to 4 carbon atoms; R5 and R6 are independently hydrogen, hydroxyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkanoyloxy of 1 to 4 carbon atoms, cyano, nitro, alkyl mercapto, amino, alkyl-amino 1 to 4 carbon atoms, dialkyl amino, alkanoid of 1 to 4 carbon atoms, halogen, trifluoromethyl, or taken together, methylenedioxyl; and n is 0, 1, 2, 3, or 4. Duloxetine Duloxetine has the following structure: The structural analogs of duloxetine are the compounds described by the formula disclosed in US Pat. No. 4,956,388, incorporated herein by reference.

Other SSRI analogues are 4- (2-fluoro-phenyl) -6-methyl-2-piperazine-thieno [2,3-d] -pyrimidine, 1,2,3,4-tetrahydro-N-methyl- hydrochloride 4-phenyl-1-naphthyl-amine; l, 2,3,4-tetrahydro-N-methyl-4-phenyl- (E) -1-naphthyl-amine hydrochloride; N, N-dimethyl-1-phenyl-1-phthalan-propylamine hydrochloride; gamma- (4-trifluoromethyl) -phenoxy) -benzene-propanamine hydrochloride; BP 554; CP 53261; O-demethyl-venlafaxine; WY 45,818; WY 45,881; N- (3-fluoro-propyl) -paroxetine; Lu 19005; and the SNRIs described in WO 04/004734. Recommended SSRI Dosages The recommended standard dosages for example SSRIs are provided in the following Table 2. Other standard dosages are provided, for example, in the Merck Manual of Diagnostics & 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 2 Tricyclic Anti-Depressants In another embodiment, the methods, compositions, and therapeutic kits of the invention employ a tricyclic anti-depressant (TCA), or a structural or functional analogue thereof, in combination with an immunosuppressant dependent on non-spheroidal immunophilin ( NsIDI). Maprotiline (brand name LUDIOMIL) is a tricyclic secondary amine depressant that inhibits the recovery of norepinephrine, and is structurally related to imipramine, a dibenzazepine. Although these agents have been used for the treatment of anxiety and depression, we report here that maprotiline increases the potency of an immunosuppressive agent, and is useful in an anti-inflammatory combination of the invention. Maprotiline (brand name LUDIOMIL) and the structural analogs of maprotiline have three-ring molecular nuclei (see Formula (IV), supra). These analogs include other tricyclic anti-depressants (TCAs), which have secondary amine side chains (eg, nortriptyline, protriptyline, desipramine), as well as N-demethylated metabolites of TCAs having tertiary amine side chains. Preferred structural and functional analogues of maprotiline include tricyclic anti-depressants which are selective inhibitors of norepinephrine recovery. Tricyclic compounds that can be used in the methods, compositions, and therapeutic kits of the invention, include amitriptyline, amoxapine, clomipramine, decipramine, dotiepin, doxepin, imipramine, lofepramine, maprotiline, mianserin, mirtazapine, nortriptyline, octriptilin, oxaprotiline, protriptyline , trimipramine, 10- (4-methyl-piperazin-1-yl) -pyrido (4, 3-b) (1,4) benzothiazepine; 11- (4-methyl-1-piperazinyl) -5H-dibenzo (b, e) (1,4) -diazepine; 5,10-dihydro-7-chloro-10- (2- (morpholino) -ethyl) -HH-dibenzo (b, e) (1,4-diazepin-11-one; 2- (2- (7-hydroxy -4-dibenzo (b, f) (1,4-thiazepin-ll-yl-1-piperazinyl) ethoxy) ethanol; 2-chloro-11 - (4-methyl-1-piperazinyl) -5H-dibenzo (b) , e) (1, 4) -diazepine; 4- (HH-dibenz (b, e) -azepin-6-yl) -piperazine; 8-chloro-l- (4-methyl-l-piperazinyl) -5H- dibenzo (b, e) (1,4) -diazepin-2-ol; 8-chloro-l- (4-methyl-1-piperazinyl) -5H-dibenzo (b, e) (1,4) - monohydrochloride diazepine; (Z) -2-butenedioate 5H-dibenzo (b, e) (1,4) -diazepine; adinazolam; amineptine; amitriptyloxide; butriptiline; ciotiapine; clozapine; demexiptiline; 11- (4-methyl-1-piperazinyl); -dibenz (b, f) (1,4) -oxazepine; 11- (4-methyl-1-piperazinyl) -2-nitro-dibenz (b, f) (1,4) -oxazepine, 2- monohydrochloride chloro-ll- (4-methyl-l-piperazinyl) -dibenz (b, f) (1,4) -oxazepine; dibenzepine; 11- (4-methyl-l-piperazinyl) -dibenzo (b, f) (1 , 4) - tiazepine, dimetacrine fluacizine, fluperlapine, imipramine N-oxide, ip rindol lofepramine; melitraceno; metapramine; metiapine; metralindol mianserin; Mirtazapine; 8-chloro-6- (4-methyl-1-piperazinyl) -morphantridine; N-acetylamoxapine; Nomifensine; 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 the phenothiazine compounds that are adjusted in Formula (I) of patent applications US 10 / 617,424 or 60 / 504,310. TCAs are generally used in individual oral doses up to the equivalent of 150 mg of imipramine. TCAs are metabolized by oxidation by hepatic microsomal enzymes, followed by conjugation with glucuronic acid. The TCA metabolites can be used to replace tricyclic secondary amine antidepressants, such as maprotiline, in the anti-inflammatory combination of the invention. The 10-hydroxyl metabolites of TCAs are particularly useful in the methods of the invention, since they have the biological activities of the original anti-depressant tricyclic, but are less toxic. Recommended Standard Dosages of TCA Typically, the patient's maprotiline dosages vary according to the patient's condition, but some recommended standard dosages are provided here. Maprotiline, which is currently available in tablets of 25, 50, and 100 mg, is most often administered in doses of 100 to 150 mg / day, although the recommended standard dosages of 1 to 25 mg / day can be administered. at 100 mg / day, 100 to 150 mg / day, 150 to 225 mg / day, or 225 to 350 mg / day. Most anti-depressants are well absorbed when administered orally, although intramuscular administration of some TCAs is also possible (eg, amitriptyline, clomipramine). Triclosan In one embodiment, the methods, compositions, and therapeutic kits of the invention employ triclosan or another phenoxy phenol, or a structural or functional analogue thereof, in combination with an immunosuppressant dependent on non-spheroidal immunophilin (NsIDI). Triclosan is a chloro-substituted phenoxy-phenol that acts as a broad-spectrum antibiotic. We report here that triclosan also increases the potency of immunosuppressive agents, such as cyclosporin, and is useful in the anti-inflammatory combination of the invention for the treatment of an immunoinflammatory disorder, a proliferative skin disease, rejection of transplantation of organs, or in graft disease against the host. Structural analogues of triclosan include chloro-substituted phenoxy-phenols, such as 5-chloro-2- (2,4-dichloro-phenoxy) -phenol, hexachlorophene, dichlorophen, as well as other halogenated hydroxydiphenyl ether compounds. Functional analogues of triclosan include clotrimazole, as well as different antimicrobials, such as selenium sulfide, ketoconazole, triclocarbon, zinc pyrithione, itraconazole, asian acid, hinokitiol, mipirocin, clinacicin hydrochloride, benzoyl peroxide, benzyl peroxide, minocycline, octopirox, ciclopirox, erythromycin, zinc, tetracycline, azelaic acid and its derivatives, phenoxy-ethanol, ethyl acetate, clindamycin, meclocycline. Functional and / or structural analogues of triclosan are also described, for example, in US Pat. Nos. 5,043,154; 5,800,803; 6,307, 049, and 6,503, 903. Triclosan can achieve its antibacterial activity by binding to, and inhibition of, the bacterial Fabl enzyme, which is required for the synthesis of bacterial fatty acids. Structural or functional analogs of triclosan, including antibiotics that bind to Fabl, may also be useful in the combinations of the invention.

Recommended Standard Dosages of Triclosan Although the suggested dosages vary with the patient's condition, the recommended standard dosages are provided below. Normally, a patient will receive 3.24 mg per kg, although amounts between 0.5 and 3.24, or between 3.24 and 5.0 can also be used. Other dosages of useful triclosan include 0.5 mg / kg, 1.0 mg / kg, 1. 5 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, and 4.5 mg / kg for humans. Preferably, triclosan is applied topically in a formulation containing 0.5 to 3 percent of triclosan. Other useful formulations contain 0.1 percent, 0.5 percent, 1 percent, 2 percent, 3 percent, 4 percent, 5 percent, 7.5 percent, or 10 percent of triclosan. Anti-Histamines In yet another embodiment of the invention, the methods, compositions, and therapeutic kits of the invention, employ a histamine receptor antagonist (or an analog thereof), and a non-spheroidal immunophilin-dependent inhibitor, to a patient I need such treatment. Anti-histamines are compounds that block the action of histamine. The classes of anti-histamines include: (1) Ethanolamines (for example, bromodiphenhydramine, carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, diphenylpyraline, and doxylamine); (2) ethylenediamines (e.g., pheniramine, pyrilamine, tripelenamine, and triprolidine); (3) phenothiazines (e.g., dietzine, ethopropazine, methdialzine, promethazine, triethylperazine, and trimeprazine); (4) alkylamines (for example, acrivastine, brompheniramine, chlorferinamine, desbromf eniramine, dexchlorpheniramine, pyrrobutamine, and triprolidine); (5) piperazines (e.g., buclizine, cetirizine, chlorcyclizine, cyclizine, meclizine, hydroxyzine); (6) piperidines (e.g., astemizole, azatadine, cyproheptadine, desloratadine, fexofenadine, loratadine, ketotifen, olopatadine, phenindamine, and terfenadine); (7) atypical antihistamines (for example, azelastine, levocabastine, metapirilene, and phenyltoxamine). In the methods, compositions, and therapeutic kits of the invention, both non-sedating and sedative anti-histamines may be employed. Particularly desirable anti-histamines for use in the methods, compositions, and therapeutic kits of the invention are non-sedating anti-histamines, such as loratadine and desloratadine. Sedative antihistamines can also be used in the methods, compositions, and therapeutic kits of the invention. Preferred anti-histamine sedatives for use in the methods, compositions, and therapeutic kits of the invention are azatadine, bromodiphenhydramine; chlorpheniramine; clemizol; cyproheptadine; dimenhydrinate; diphenhydramine; doxylamine; meclizine; promethazine; pyrilamine; triethylperazine; and tripelenamine. Other anti-histamines suitable for use in the methods and compositions of the invention are acrivastine; ahistan; antazoline; astemizole; azelastine (for example, azelastine hydrochloride); bamipina; Bepotastine; bietanautin; brompheniramine (for example, brompheniramine maleate); carbinoxamine (for example, carbinoxamine maleate); cetirizine (for example, cetirizine hydrochloride); ketoxime; chlorocyclizine; chloropyramine; chloroten; Chlorfenoxamine; cinnarizine; clemastine (for example, clemastine fumarate); clobenzepam; clobenztropine; Chlocinizine; cyclizine (e.g., cyclizine hydrochloride; cyclizine lactate); deptropine; dexchlorferinamine; dexchlorpheniramine maleate; diphenylpyraline; doxepin; ebastine; embramina; emedastine (e.g., emedastine difumarate); epinastine; ethimemazine hydrochloride; fexofenadine (for example, fexofenadine hydrochloride); histapyriramine; hydroxyzine (for example, hydroxyzine hydrochloride, hydroxyzine pamoate); isoprometazine; isothiopendyl; levocabastine (for example, levocabastine hydrochloride); mebhydroline; mequitazine; metafurylene; metapyrilidene; metron; mizolastin; olapatadine (e.g., olapatadine hydrochloride); Orfenandrin; phenindamine (for example, phenindamine tartrate); phenylamine; phenyltoloxamine; p-methyl-diphenhydramine; pyrrobutamine; setastine; talastine; terfenadine; tenyldiamine; thiazinium (for example, thiazinium methylsulfate); tonzilamine hydrochloride; Tolpropamine; triprolidine; and tritocualin. The structural analogues of the anti-histamines can also be used according to the invention. Anti-histamine analogues include, without limitation, 10-piperazinyl-propyl-phenothiazine; 4- (3- (2-chlorophenothiazin-10-yl) -propyl) -1-piperazine-ethanol dihydrochloride; 1- (10- (3- (4-methyl-1-piperazinyl) -propyl) -lOH-phenothiazin-2-yl) - (9C1) 1-propanone; 3-methoxy-pyrroheptadine; 4- (3- (2-chloro-10H-phenothiazin-10-yl) -propyl) -piperazin-1-ethanol hydrochloride; 10, 11-dihydro-5- (3- (4-ethoxy-carbonyl-4-phenyl-piperidino) -propylidene) -5H-dibenzo (a, d) -cycloheptene; aceprometazine; acetophenazine; alimemazine (for example, alimemazine hydrochloride); aminopromazine; benzimidazole; Butaperazine; carfenazine; chlorphenetazine; clormidazole; cimprazol; desmethylastemizole; desmetilciproheptadine; dietzine (for example, dietzine hydrochloride); ethopropazine (e.g., ethopropazine hydrochloride); 2- (p-bromophenyl- (p1-tolyl) -methoxy) -N, N-dimethyl-ethylamine hydrochloride; N, N-dimethyl-2- (diphenyl-methoxy) -ethylamine methyl bromide; EX-10-542A; phenetazine; fuprazol; methyl 10- (3- (4-methyl-1-piperazinyl) -propyl) -phenot-iazin-2-yl-ketone; lerisetron; Medrylamine; mesoridazine; methylpromazine; N-demethyl-promethazine; nilprazole; nortioridazine; perphenazine (e.g., perphenazine enanthate); 10- (3-dimethyl-amino-propyl) -2-thiomethyl-phenothiazine; 4- (dibenzo- (b, e) tiepin-6 (11H) -ylidene) -1-methyl-piperidine hydrochloride; prochlorperazine; promazine; propiomazine (e.g., propiomazine hydrochloride); rotoxamine; rupatadine; Sch 37370; Sch 434; tecastemizole; thiazinium; thiopropazate; thioridazine (for example, thioridazine hydrochloride); and 3- (10,11-dihydro-5H-dibenz (a, d) -cyclohepten-5-ylidene) -tropane. Other compounds that are suitable for use in the invention are AD-0261; AHR-5333; alinastine; arpromidine; ATI-19000; bermastine; bilastine; Bron-12; carebastine; Chlorphenamine; corsima DF-1105501; DF-11062; DF-1111301; EL-301; elbanizina; F-7946T; F-9505; HE-90481; HE-90512; hivenil; HSR-609; icotidine KAA-276; KY-234; lamiakast; LAS-36509; LAS-36674; levocetirizine levoprothiline; metoclopramide; PIN-531; noberastine; oxatomide PR-881-884A; quisultazine; rocastin; selenotifen; SK & F-94461 SODAS-HC; tagorizina; TAK-427; temelastin; UCB-34742; UCB-35440 VUF-K-8707; Wy-49051; and ZCR-2060. Still other compounds that are suitable for use in the invention are described in US Pat. No. 3,956,296; 4,254,129; 4,254,130; 4,282,833; 4,283,408; 4,362,736 4,394,508; 4,285,957; 4,285,958; 4,440,933; 4,510,309; 4,550,116 4,692,456; 4,742,175; 4,833,138; 4,908,372; 5,204,249; 5,375,693 5,578,610; 5,581,011; 5,589,487; 5,663,412; 5,994,549; 6,201,124 and 6,458,958. Recommended Standard Dosages of Anti-Histamine The recommended standard dosages for various exemplary antihistamines are shown in Table 3. Other standard dosages are provided, for example, in the Merck Manual of Diagnostics & 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 3 An Example Histamine Receptor Antagonist: Loratadine Loratadine (CLARITIN) is a tricyclic piperidine which acts as a selective peripheral histamine Hl receptor antagonist. We report here that loratadine and structural and functional analogues thereof, such as piperidines, tricyclic piperidines, histamine Hl receptor antagonists, are useful in the anti-immunoinflammatory combination of the invention, for the treatment of immunoinflammatory disorders, rejection of transplanted organ, and graft disease against the host. Functional and / or structural analogues of loratadine include other Hl receptor antagonists, such as AHR-11325, acrivastine, antazoline, astemizole, azatadine, azelastine, bromopheniramine, carebastine, cetirizine, chlorpheniramine, chlorcyclizine, clemastine, cyproheptadine, descarboethoxyloratadine, dexchlorpheniramine , dimenhydrinate, diphenylarthine, diphenhydramine, ebastine, fexofenadine, hydroxyzine, ketotifen, lodoxamide, levocabastine, metdilazine, mequitazine, oxatomide, phenylamine, pyrilamine, promethazine, pyrilamine, setastine, taziphiline, temelastin, terfenadine, trimeprazine, tripelenamine, triprolidine, utrizine, and similar compounds (described, for example, in US Patents 3,956,296; 4,254,129; 4,254,130; 4,283,408; 4,362,736; 4,394,508; 4,285,957; 4,285,958; 4,440,933; 4,510,309; 4,550,116; 4,692,456; 4,742,175; 4,908,372; 5,204,249; 5,375,693; 5,578,610; 5,581,011; 5,589,487; 5,663,412; 5,994,549; 6,201,124; and 6,458,958. Loratadine, cetirizine, and fexofenadine, are the second-generation Hl receptor antagonists, which lack the sedative effects of many Hl receptor antagonists of the first generation. Antagonists of the piperidine Hl receptor include loratadine, ciproheptadine hydrochloride (PERIACTIN), and phenindiamine tartrate (NOLAHIST). Antagonists of the piperazine Hl receptor include hydroxyzine hydrochloride (ATARAX), hydroxyzine pamoate (VISTARIL), cyclizine hydrochloride (MAREZINE), cyclizine lactate, and meclizine hydrochloride. Recommended Standard Dosages of Loratadine Oral formulations of loratadine include tablets, redi-tabs, and syrup. Loratadine tablets contain 10 mg of micronized loratadine. Loratadine syrup contains 1 mg / ml of micronized loratadine, and redi-tabs (tablets that disintegrate rapidly) contain 10 mg of micronized loratadine in tablets that disintegrate rapidly in the mouth. Although the suggested dosages will vary with the patient's condition, standard recommended dosages are provided below. Loratadine is normally administered once a day in a dose of 10 mg, although other daily dosages useful in the anti-immunoinflammatory combination of the invention include 0.01 to 0.05 mg, 0.05 to 1 mg, 1 to 3 mg, 3 to 5 mg, 5 to 10 mg, 10 to 15 mg, 15 to 20 mg, 20 to 30 mg, and 30 to 40 mg. Loratadine is rapidly absorbed following oral administration. It is metabolized in the liver to descarboethoxyloratadine by cytochrome P450 3A4 and cytochrome P450 2D6. The loratadine metabolites are also useful in the anti-immunoinflammatory combination of the invention. Phenothiazines In another embodiment, the methods, compositions, and therapeutic kits of the invention employ a phenothiazine, or a structural or functional analogue thereof, in combination with an immunosuppressant dependent on non-spheroidal immunophilin (NsIDI). The phenothiazines which are useful in the methods, compositions, and therapeutic kits of the invention include compounds having the general formula (V): or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of: CF3, Cl, F, OCH3, COCH3, CN, OCF3, COCH2CH3, CO (CH2) 2CH3, and SCH2CH3; R9 is selected from the group consisting of: each of R1, R3, R4, R5, R6, R7, and R8 is independently H, OH, F, OCF3, or OCH3; and W is selected to and from the group consisting of: In some embodiments, phenothiazine is a phenothiazine conjugate that includes a phenothiazine covalently linked via a linker to a bulky group greater than 200 daltons, or a charged group less than 200 daltons. These conjugates retain their anti-inflammatory activity in vivo, and have a reduced activity in the central nervous system compared to the parent phenothiazine. The phenothiazine conjugates which are useful in the methods, therapeutic kits, and compositions of the invention, are the compounds having the general formula (VI): In Formula (VI), R2 is selected from the group consisting of CF3, halogen, OCH3, COCH3, CN, OCF3, COCH2CH3, CO (CH2) 2CH3, S (0) 2CH3, S (0) 2N (CH3 ) 2, and SCH2CH3; A1 is selected from the group consisting of G1, each of R1, R3, R4, R5, R6, R7, and R8 is independently H, OH, F, OCF3, or 0CH3; R32, R33, R34, and R35 are each independently selected from H or alkyl of 1 to 6 carbon atoms; W is selected from the group consisting of: NO, and G1 is a bond between the phenothiazine and a linker, L. The linker L is described by Formula (VII): G1- (Z1) ..- (Y1) ^ 2), - (R9) - (Z3) t- (Y2) v- (Z4) p-G2 (VII) In Formula (VII), G1 is a link between the phenothiazine and the linker, G2 is a bond between the linker and the bulky group, or between the linker and the charged group, each of Z1, Z2, Z3, and Z4 is independently selected from O, S, and NR39; R39 is hydrogen or an alkyl group of 1 to 6 carbon atoms; each of Y1 and Y2 is independently selected from carbonyl, thiocarbonyl, sulfonyl, phosphoryl, or similar acid forming groups; n, p, s, t, u, and v are each independently 0 or 1; and R9 is an alkyl of 1 to 10 carbon atoms, a straight or branched heteroalkyl of 1 to 10 carbon atoms, an alkene of 2 to 10 carbon atoms, an alkyne of 2 to 10 carbon atoms, an aryl of 5 carbon atoms, to 10 carbon atoms, a cyclic system of 3 to 10 carbon atoms, - (CH2CH20) qCH2CH2-, where q is an integer from 1 to 4, or a chemical bond linking G1- (Z1) 0- (Y1 ) u (Z2) s- with (Z3) t- (Y2) v- (Z4) p-G2. The bulky group can be a naturally occurring polymer, or a synthetic polymer. Natural polymers that can be used include, without limitation, glycoproteins, polypeptides, or polysaccharides. Desirably, when the bulky group includes a natural polymer, the natural polymer is selected from alpha-1-acid glycoprotein and hyaluronic acid. Synthetic polymers that can be used as the bulky groups include, without limitation, polyethylene glycol, and the synthetic polypeptide N-hxg. The most commonly prescribed member of the phenothiazine family is chlorpromazine, which has the structure: Chlorpromazine is a phenothiazine that has been used for a long time to treat psychotic disorders. Phenothiazines include the functional and structural analogues of chlorpromazine, such as azepromazine, chlorphenetazine, chlorpromazine, ciamemazine, enanthate, fluphenazine, mepazine, mesoridazine besylate, methotrimeprazine, methoxypromazine, norchlorpromazine, perazine, perphenazine, prochlorperazine, promethazine, propiomazine, putaperazine, thienylperazine , thiopropazate, thioridazine, trifluoperazine, or triflupromazine (or a salt of any of the foregoing); and functional analogs that act as dopamine D2 antagonists (e.g., sulpride, pimozide, spiperone, clebopride, bupropion, and haloperidol). Chlorpromazine is currently available in the following forms: tablets, capsules, suppositories, concentrates and oral syrups, and formulations for injection. Because chlorpromazine undergoes intense metabolic transformation in a number of metabolites that can be therapeutically active, these metabolites can be used to replace chlorpromazine in the anti-inflammatory combination of the invention. The metabolism of chlorpromazine produces, for example, the oxidative N-demethylation of the corresponding primary and secondary amine, the aromatic oxidation gives a phenol, the N-oxidation gives the N-oxide, the S-oxidation gives the sulphoxide or sulfone, the oxidative deamination of the aminopropyl side chain gives the phenothiazine nuclei, and the glucuronidation of the phenolic hydroxyl groups and the tertiary amino group gives a quaternary ammonium glucuronide. In other examples of chlorpromazine metabolites useful in the anti-inflammatory combination of the invention, each of the 3, 7, and 8 positions of the phenothiazine can be independently substituted with a hydroxyl or methoxyl moiety. Another phenothiazine is etopropazine (brand name) PARSITAN), an anticholinergic phenothiazine which is used as an antidiskinetic for the treatment of movement disorders, such as Parkinson's disease. Ethopropazine also has antihistaminic properties. We report here that ethopropazine also increases the potency of immunosuppressive agents, such as cyclosporins. Unlike antipsychotic phenothiazines, which have 3 carbon atoms between the 10-position of the central ring and the first amino-nitrogen atom of the side chain in this position, the strongly anticholinergic phenothiazines (eg, ethopropazine, dietzine) have only two carbon atoms that separate the amino group from the 10-position of the central ring. Structural analogs of ethopropazine include trifluoroperazine dihydrochloride, thioridazine hydrochloride, and promethazine hydrochloride. Additional structural ethopropazine analogues include 10- [2,3-bis (dimethylamino) -propyl] -phenothiazine, 10- [2,3-bis (dimethylamino) -propyl] -phenothiazine hydrochloride, 10- [ 2- (dimethylamino) -propyl] -phenothiazine; 10- [2- (dimethylamino) -propyl] -phenothiazine hydrochloride, and 10- [2- (diethylamino) -ethyl] -phenothiazine hydrochloride, and mixtures thereof (see, for example, US Pat. No. 4,833,138). Ethopropazine acts by inhibiting butyryl cholinesterase. Functional analogues of ethopropazine include other anticholinergic compounds, such as Artano (trihexyphenidyl), Cogentin (benztropine), biperiden (US patent 5,221,536), caramiphen, ethopropazine, procyclidine (Kemadrina), and trihexyphenidyl. Anticholinergic phenothiazines are extensively metabolized, primarily to N-dealkylated and hydroxylated metabolites. The etopropazine metabolites can be used to replace ethopropazine in the anti-immunoinflammatory combination of the invention. Recommended Standard Dosages of Phenothiazine Typically, the chlorpromazine dosage of the patient varies according to the patient's condition, but some recommended standard dosages are provided below. Chlorpromazine can be administered orally, by suppository, or by injection. Dose is often given at 4 to 6 hour intervals over the course of a day. Each dose is generally between 0.25 and 0.5 mg, 0.5 and 1.0 mg, and 5 mg, 0.5 and 2 mg, 5 and 10 mg, 10 and 25 mg, 25 and 50 mg, 50 and 75 mg, or 75 and 100 mg. In general, a total dose of 0.25 grams, 0.50 grams, 0.75 grams, 1.0 grams, 1.5 grams, or 2.0 grams per day is provided. Ethopropazine, which is currently available in 10 and 50 mg tablets, is usually administered orally. Initially, patients are typically administered a 50 mg dose of ethopropazine once or twice a day. Other recommended standard dosages for ethopropazine are 1 to 10 mg / day, 10 to 25 mg / day, 50 to 100 mg / day, 100 to 400 mg / day, 500 to 600 mg / day, or 600 to 700 mg / day.

Mu Opioid Receptor Agonists In yet another embodiment, the methods, compositions, and therapeutic kits of the invention, employ a mu opioid receptor agonist (or analog thereof), and a non-spheroidal immunophilin-dependent inhibitor, to a patient in need said treatment. Loperamide hydrochloride (IMMODIUM) is a mu opioid receptor agonist useful in the treatment of diarrhea (US patent 3,714,159). We report here that loperamide and loperamide analogues increase the potency of an immunosuppressive agent, and are useful in the treatment of an immunoinflammatory disorder, organ transplant rejection, or graft-versus-host disease. Loperamide is a piperidin-butyramide derivative that is related to meperidine and diphenoxylate. It works by relaxing the smooth muscles, and slowing intestinal mobility. Other functionally and / or structurally related compounds include meperidine, diphenoxylate, and the related propanamines. Additional functional and structural analogues of loperamide are described, for example, in US Pat. Nos. 4,066,654; 4,069,223; 4,072,686; 4,116,963; 4,125,531; 4,194,045; 4,824,853; 4,898,873; 5,143,938; 5,236,947; 5,242,944; 5,849,761; and 6,353,004. Functional analogues of loperamide include mu-peptide and small molecule opioid receptor agonists (described in US Pat. No. 5,837,809). These agents are also useful in the anti-inflammatory combination of the invention. Loperamide acts through its binding to opioid receptors within the intestine, and altering gastrointestinal motility. Recommended Standard Dosages of Loperamide Loperamide is currently available in oral formulations as a 2 mg tablet. Although the suggested dosages will vary with the patient's condition, the recommended standard dosages are given below. Typically, one dose for adults is initially 4 mg, followed by subsequent doses of 2 mg, or 16 mg per day. Other useful dosages include 0.5 to 1 mg, 1 to 2 mg, 2 to 4 mg, 4 to 8 mg, 8 to 12 mg, or 12 to 16 mg. Corticosteroids If desired, the compositions and methods of the invention can be used with conventional therapeutics, including corticosteroids. One or more corticosteroids may be administered in a method of the invention, or they may be formulated with the non-spheroidal immunophilin-dependent enhancer, or the analog or metabolite thereof, in a composition of the invention. Suitable corticosteroids include 11-alpha, 17-alpha, 21-trihydroxypregn-4-ene-3, 20-dione; libeta, 16 -alpha, 17, 21- tetrahydroxyprg-4-ene-3, 20 -dione; 11-beta, 16-alpha, 17, 21-tetrahydroxyprg-1, 4-diene-3, 20 -dione; beta, 17-alpha, 21-trihydroxy-6-alpha-methylpregn-4-ene-3, -dione; 11-dehydrocorticosterone; 11-deoxycortisol; 11-hydroxy-l, 4-androstadiene-3, 17-dione; 11-quetotestosterone; 14-hydroxy-androst-4-ene-3, 6, 17-trione; 15, 17-dihydroxy-progesterone; 16-methy1hydro-cortisone; 17, 21-dihydroxy-16-alpha-methylpregna-1,4,9 (11) -triene-3,20-dione; 17-alpha-hydroxyprg-4-ene-3, 20-dione; 17-alpha-hydroxy-pregnenolone; 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-hydroxy-corticosterone; 18-hydroxycortisone; 18-oxocortisol, 21-deoxyaldosterone; 21-deoxycortisone; 2-deoxyecdysone; 2-methylcortisone; 3-dehydroecdysone; 4-pregneno-17 -alpha, 20 -beta, 21-triol-3, 11 -dione; 6.17, 20-trihydroxypregn-4-ene-3-one; 6-alpha-hydroxycortisol; 6-alpha-fluoroprednisolone; 6-alpha-methylprednisolone; 21-acetate 6-alpha-methylprednisolone; Sodium salt of 21-hemisuccinate of 6-alpha-methylprednisolone; 6-beta-hydroxycortisol; 17-butyrate of 6-alpha 21-acetate, 9-alpha-difluoro-prednisolone; 6-hydroxy-corticosterone; 6-hydroxy -dexametasone; 6-hydroxy-prednisolone; 9-fluorocortisone, alclometasone dipropionate; aldosterone; algestone; alfaderm; amadinone; ameinonide; anagestone; androstenedione; anecortave acetate; beclomethasone; Beclomethasone dipropionate; beclomethasone dipropionate monohydrate; 17-betamethasone valerate; betamethasone sodium acetate; sodium phosphate of betamethasone; betamethasone valerate; bolasterone; budesonide; calusterona; Chlormadinone; chloroprednisone; chloroprednisone acetate; cholesterol; 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; shortdoxona; daturaolone; deflazacort; 21-deoxycortisol; dehydro-epiandrosterone; delmadinone; Deoxycorticosterone; deprodone; descinolone; desonida; deoxymethasone; dexfeno; dexamethasone; 21-dexamethasone acetate; dexamethasone acetate; dexamethasone sodium phosphate; dichlorisone; diflorasona; diflorasone diacetate; diflucortolone; dihydroelatericin a; domoprednate; doxibetasol; ecdysone; ecdysterone; endrisone; enoxolone; flucinolone; fludrocortisone; fludrocortisone acetate; Flugestone; flumethasone; flumethasone pivalate; flumoxonide; flunisolide; fluocinolone; fluocinolone acetonide; fluocinonide; 9-fluorocortisone; fluocortolone; fluoro-hydroxy-androstenedione; fluorometholone; fluorometholone acetate; Fluoxymesterone; fluprednidene; fluprednisolone; flurandrenolide; fluticasone; fluticasone propionate; formebolone; formestane; formocortal, gestonorone; gliderinin; Halcinonide; hircanoside; Halometasone; halopredone; haloprogesterone; hydrocortisone cypionate; hydrocortisone; twenty-one - . 21-hydrocortisone butyrate; hydrocortisone aceponate; hydrocortisone acetate; hydrocortisone buteprate; hydrocortisone butyrate; hydrocortisone cypionate; hydrocortisone hemisucinate; hydrocortisone probutate; sodium hydrocortisone phosphate; sodium hydrocortisone succinate; hydrocortisone valerate; hydroxyprogesterone; inocosterone; isoflupredone; isoflupredone acetate; isoprednidene; mechloridane; mecortolon; 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; norgestometre; norvinisterone; oxymesterone; parametasone; parametasone acetate; ponasterone; Prednisolylate; prednisolone; 21-prednisolone hemisuccinate; 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; roxibolone; rubrosterone; Stizophylline; tixocortol; topterone; triamcinolone; triamcinolone acetonide; 21-triamcinolone acetonide palmitate; triamcinolone diacetate; triamcinolone hexacetonide; trimegestone; turquesterone; and wortmanina.

The recommended standard dosages for different spheroid / disease combinations are given in the following Table 4.

Table 4. Recommended Corticosteroid Standard Dosages Other recommended standard dosages for corticosteroids are provided, for example, in the 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). In one embodiment, the dosage of the corticosteroid administered is a dosage equivalent to a prednisolone dosage, as defined herein. For example, a low dosage of a corticosteroid can be considered as the dosage equivalent to a low dosage of prednisolone. Steroid Receptor Modulators Optionally, the compositions and methods of the invention can be used in combination with steroid receptor modulators (eg, antagonists and agonists), as a substitute for, or in addition to, a corticosteroid. Accordingly, in one embodiment, the invention provides the combination of an NsIDI (or an analog or metabolite thereof), and an NsIDIE, and optionally, a glucocorticoid receptor modulator or other steroid receptor modulator, and methods for treatment of immunoinflammatory disorders with them. Glucocorticoid receptor modulators that can be used in the methods, compositions, and therapeutic kits of the invention, include the compounds described in US Pat. No. 6,380,207; 6,380,223; 6,448,405; 6,506,766; and 6,570,020; in the publications US 20030176478, 20030171585, 20030120081, 20030073703, 2002015631, 20020147336, 20020107235, 20020103217, and 20010041802, and in the publication WO 00/66522, each of which is incorporated herein by reference. Other steroid receptor modulators can also be used in the methods, compositions, and therapeutic kits of the invention, and are described in US Pat. No. 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 in addition to a combination of NsIDI / NsIDIE in the methods, compositions, and therapeutic kits of the invention, are A-348441 (Karo Bio), adrenal cortex extract (GlaxoSmithKline), alsactide (Aventis), amebucort (Schering AG), amelomethasone (Tarisho), ATSA (Pfizer), bitolterol ( Elan), CBP-2011 (InKine Pharmaceutical), cebaracetam (Novartis), CGP-13774 (Kissei), ciclesonide (Altana), cyclometasone (Aventis), clobetasone butyrate (GlaxoSmithKline), cloprednol (Hoffmann-La Roche), colismicin A (Kirin), cucurbitacin E (NIH), deflazacort (Aventis), deprodone propionate (SSP), dexamethasone acefurate (Schering-Plow), dexamethasone linoleate (GlaxoSmithKline), dexamethasone valerate (Abbott), difluprednate (Pfizer), domoprednate (Hoffmann-La Roche), ebiratide (Aventis), ethylednol dicloacetate (IVAX), fluazacort (Vicuron), flumoxonide (Hoffmann-La Roche), fluocortin -butyl (Schering AG), fluocortolone monohydrate (Schering AG), GR-250495X (GlaxoSmithKline), halometasone (Novartis), halopredone (Dainippon), HYC-141 (Fidia), icometasone enbutate (Hovione), itrocinonide (AstraZeneca) , L-6485 (Vicuron), Lipocort (Draxis Health), locicortone (Aventis), mechlorisone (Schering-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 (Gedeon Richter), rofleponide (AstraZeneca), palmitated rofleponide (AstraZeneca), RPR-106541 (Aventis), RU-26559 (Aventis), Sch-19457 (Schering-Plow), T25 (Matrix Therapeutics), TBI-PAB (Sigma-Tau), ticabesone propionate (Hoffmann-La Roche ), tifluadom (Solvay), timobesone (Hoffmann-La Roche), TSC-5 (Takeda), and ZK-73634 (Schering AG). Therapy The invention provides methods for suppressing the secretion of proinflammatory cytokines as a means for the treatment of an immunoinflammatory disorder, of a proliferative skin disease, of organ transplant rejection, or of graft-versus-host disease. The suppression of cytokine secretion is achieved by the administration of one or more NsIDIEs in combination with one or more NsIDIs. Although the examples describe NsIDIEs, NsIDIs, it is understood that a 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. Chronic Obstructive Pulmonary Disease In one embodiment, the methods, compositions, and therapeutic 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, an NSIDI, in the methods, compositions, and therapeutic kits of the invention. These agents include xanthines (e.g., theophylline), anticholinergic compounds (e.g., ipratropium, tiotropium), biologics, small molecule immunomodulators, and beta-bronchodilator receptor agonists (e.g., ibuterol sulfate, bitolterol mesylate, epinephrine , formoterol fumarate, isoprotorenol, levalbuterol hydrochloride, sulfate and metaproterenol, pyrbuterol escetate, salmeterol xinafoate, and terbutaline). Accordingly, in one embodiment, the invention provides the combination of a tricyclic compound and a bronchodilator, and methods for the treatment of COPD therewith. Psoriasis The methods, compositions, and therapeutic kits of the invention can be used for the treatment of psoriasis. If desired, one or more antipsoriatic agents typically used for the treatment of psoriasis can be used as a substitute for, or in addition to, an NSIDI, in the methods, compositions, and therapeutic kits of the invention. These agents include biological products (eg, alefacept, inflixamab, adelimumab, efalizumab, etanercept, and CDP-870), small molecule immunomodulators (eg, VX 702, SCIO 469, doramapimod, RO 30201195, SCIO 323, DPC 333, pranalcasan, mycophenolate, and merimepodib), non-spheroidal immunophilin-dependent immunosuppressants (eg, cyclosporine, tacrolimus, pimecrolimus, and ISAtx247), vitamin D analogues (eg, calcipotriene, calcipotriol), psoralens (e.g., methoxsalen), retinoids (e.g., acitretin, tazoretene), DMARDs (e.g., methotrexate), and anthralin. Accordingly, in one embodiment, the invention provides the combination of a tricyclic compound and an antipsoriatic agent, and method for the treatment of psoriasis therewith. Inflammatory Bowel Disease The methods, compositions, and therapeutic 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, an NsIDI in the methods, compositions, and therapeutic kits of the invention. These agents include biological products (eg, inflixamab, adelimumab, and CDP-870), small molecule immunomodulators (eg, VX 702, SCIO 469, doramapimod, RO 30201195, SCIO 323, DPC 333, pranalcasan, mycophenolate, and merimepodib ), non-spheroidal immunophilin-dependent immunosuppressants (e.g., cyclosporine, tacrolimus, pimecrolimus, and ISAtx247), 5-amino-salicylic acid (e.g., mesalamine, sulfasalazine, disodium balsalazide, and sodium olsalazine), DMARDs (e.g., methotrexate) and azathioprine), and alosetron. Accordingly, in one embodiment, the invention provides the combination of a tricyclic compound and any of the foregoing agents, and methods for the treatment of inflammatory bowel disease therewith. Rheumatoid Arthritis The methods, compositions, and therapeutic 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, an NsIDI in the methods, compositions, and therapeutic kits of the invention. These agents include NSAIDs (e.g., 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), COX-2 inhibitors (eg, rofecoxib, celecoxib, valdecoxib, and lumiracoxib), biological products (eg, inflixamab, adelimumab, etanercept, CDP-870 , tiruximab, and atlizumab), small molecule immunomodulators (eg, VX 702, SCIO-469, dorapamimod, RO 30201195, SCIO 323, DPC 333, pranalcasan, mycophenolate, and merimepodib), immunosuppressants dependent on non-spheroidal immunophilin (e.g. , cyclosporine, tacrolimus, pimecrolimus, and ISAtx247), 5-amino-salicylic acid (eg, mesalamine, sulfasalazine, balsalazide disodium, and olsalazine sodium), DMARDs (for example, methotrexate, leflunomide, minocycline, auranofin, gold sodium thiomalate, aurothioglucose, and azathioprine), hydroxychloroquine sulfate, and penicillamine. Accordingly, in one embodiment, the invention provides the combination of a tricyclic compound with any of the above agents, and methods for the treatment of rheumatoid arthritis therewith. Asthma The methods, compositions, and therapeutic 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, an NsIDI in the methods, compositions, and therapeutic kits of the invention. These agents include beta 2 agonists / bronchodilators / modifications of leukotriene (e.g., zafirlukast, montelukast, and zileuton), biological products (e.g., omalizumab), small molecule immunomodulators, anticholinergic compounds, xanthines, ephedrine, guaifenesin, cromolyn sodium, nedocromil sodium, and potassium iodide. Therefore, in one embodiment, the invention provides the combination of a tricyclic compound and any of the above agents, and methods for treating asthma therewith. Administration In the particular embodiments of any of the methods of the invention, an NsIDI and an NsIDIE are administered within 10 days of each other, within 5 days of each other, within 24 hours of each other, or in a simultaneous manner. 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 dosage or in a high dosage, each of which is defined herein. It may be desirable to administer to the patient other compounds, such as a corticosteroid, NSAID (eg, naproxen sodium, diclofenac sodium, diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam, indomethacin, ibuprofen, nabumetone, magnesium trisalicylate choline, salicylate sodium, salicylsalicylic acid, fenoprofen, flubiprofen, ketoprofen, meclofenamate sodium, meloxicam, oxaprozin, sulindac, and tolmetin), a COX-2 inhibitor (eg, rofecoxib, celecoxib, valdecoxib, and lumiracoxib), a glucocorticoid receptor modulator , or a DMARD. The combination therapies of the invention are especially useful for the treatment of immunoinflammatory disorders in combination with other anti-cytokine agents or agents that modulate the immune response to positively affect the disease, such as agents that influence cell adhesion, or biological products (ie agents that block the action of IL-6, IL-1, IL-2, IL-12, IL-15, or TNF) (eg, etanercept, adelimumab, infliximab, or CDP-870) . In this example (that of the agents that block the effect of TNFa), the combination therapy reduces the production of cytokines, etanercept or infliximab act on the remaining fraction of the inflammatory cytokines, providing an improved treatment. The therapy according to the invention can be carried out alone or in conjunction with another therapy, and can be provided at home, in the doctor's office, in a clinic, in an outpatient department of a hospital, or in a hospital. 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 be initiated on an outpatient 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 illness of the patient, and the way in which the patient responds to treatment. Additionally, a person who is at increased risk of developing an inflammatory disease (for example, a person who is undergoing age-related hormonal changes) may be treated to inhibit or delay the establishment of symptoms. Routes of administration for the different modalities include, but are not limited to, topical, transdermal, and systemic administration (such as intravenous, intramuscular, subcutaneous, inhalation, rectal, buccal, vaginal, intraperitoneal, intra-articular, ophthalmic, or oral). As used herein, "systemic administration" refers to all non-dermal administration routes, and specifically excludes routes of topical and transdermal administration. In combination therapy, the dosage and frequency of administration of each component of the combination can be controlled independently. For example, a compound can be administered three times a day, while the second compound can be administered once a day. The combination therapy can be given in cycles of activation and deactivation that include periods of rest, in such a way that the body of the patient has an opportunity to recover from any side effects still unforeseen. The compounds can also be formulated together, in such a way that one administration supplies both compounds.

Formulation of Pharmaceutical Compositions Administration of a combination of the invention (eg, a combination of NsIDI / NsIDIE) can be by any suitable means that results in the suppression of proinflammatory cytokine levels in the target region. A compound may be contained in any suitable amount in any suitable carrier substance, and is generally present in an amount of 1 to 95 weight percent of the total weight of the composition. The composition may be provided in a dosage form that is suitable for the oral, parenteral (eg, intravenous, intramuscular, rectal, cutaneous, nasal, vaginal, inhalant, skin (patch), or ocular route of administration . Accordingly, the composition may be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, soaks, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols. The pharmaceutical compositions can be formulated in accordance with conventional pharmaceutical practice (see, for example, Remington: The Science and Practice of Pharmacy, 20th edition, 2000, Editor AR Gennaro, Lippincott Williams &Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology , editors, J. Swarbrick and JC 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. These co-formulated compositions may include NsIDI and an NsIDIE formulated together in the same pill, capsule, liquid, and the like. It should be understood that, when referring to the formulation of "combinations of NsIDI / NsIDIE", 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. By using different formulation strategies for different agents, the pharmacokinetic profiles for each agent can be matched. Agents formulated individually or separately can be packaged together as a therapeutic package. Non-limiting examples include kits containing, for example, two pills, a pill and a powder, a suppository and a liquid in a bottle, two topical creams, and the like. The therapeutic kit may include optional components that aid in the administration of the unit dose to patients, such as bottles for reconstituting powder forms, syringes for injection, custom-made intravenous delivery systems, inhalers, and the like. Additionally, the unit dose kit may contain instructions for the preparation and administration of the compositions. The therapeutic kit can be manufactured as a single dose for single use for a patient, multiple uses for a particular patient (in a constant dose, or where the individual compounds can vary in potency as the therapy progresses); or the therapeutic kit may contain multiple doses suitable for administration to multiple patients ("bulk packaging"). The components of the therapeutic kit can be assembled into cartons, blister packs, bottles, tubes, and the like. Controlled Release Formulations The administration of a combination of NsIDl / NsIDIE of the invention, wherein one or both active agents are formulated for controlled release, is useful where the NsIDI or the NsIDIE has (i) a narrow therapeutic index (eg. For example, the difference between the plasma concentration leading to dangerous side effects or toxic reactions, and the plasma concentration leading to a therapeutic effect, is small, in general, the therapeutic index, TI, is defined as the proportion of the mean lethal dose (LD50) at the mean effective dose (ED50)); (ii) a narrow absorption window in the gastrointestinal tract; (iii) a short biological half-life; or (iv) the pharmacokinetic 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. In accordance with the above, a sustained release formulation can be used to avoid frequent dosing that may be required in order to maintain the plasma levels of both agents at a therapeutic level. For example, in the preferred oral pharmaceutical compositions of the invention, the half-life and average residence times of 10 to 20 hours are observed for one or both agents of the combination of the invention. Many strategies can be followed to obtain controlled release, wherein the release rate exceeds the rate of metabolism of the therapeutic compound. For example, controlled release can be obtained by appropriate selection of the parameters of the formulation and the ingredients (e.g., controlled release compositions and appropriate coatings). Examples include single or multiple tablet or capsule unit compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes. The release mechanism can be controlled in such a way that the NsIDI and / or the NsIDIE are released at periodic intervals, that the release can be simultaneous, or that a delayed release of one of the agents of the combination can be effected, when prefer the earlier release of one particular agent over the other. Controlled release formulations may include a degradable or non-degradable polymer, hydrogel, organogel, or other physical construction that modifies bioabsorption, half-life, or biodegradation of people. 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 an implant that is surgically inserted into or near a site of interest (eg, proximal to an arthritic joint). In another example, the implant of the controlled release formulation 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 the NsIDI / NsIDIE combinations of the present invention. These polymers are formed from macromers with a non-degradable, polymerizable region, which is separated by at least one degradable region. For example, the non-degradable region, soluble in water, can form the central core of the macromer, and can have at least two degradable regions that are attached to the core, such that when degraded, the non-degradable regions are separated (in particular a polymerized gel), as described in US Pat. No. 5,626,863. Hydrogels can include acrylates, which can be easily polymerized by various initiator systems, such as eosin dye, ultraviolet or visible light. Hydrogels can also include polyethylene glycols (PEGs), which are highly hydrophilic and biocompatible. Hydrogels can also include oligoglycolic acid, which is a poly (α-hydroxy acid), which can be easily degraded by hydrolysis of the ester linkage into glycolic acid, a non-toxic metabolite. Other chain extensions may include poly-lactic acid, poly-caprolactone, poly-orthoesters, poly-anhydrides, or poly-peptides. The entire network can be gelled in a biodegradable network that can be used to trap and disperse in a homogeneous manner the combinations of NsIDI / NsIDIE of the invention, to be delivered at a controlled rate. The chitosan, and mixtures of chitosan with sodium carboxymethylcellulose (CMC-Na), have been used as vehicles for the sustained release of drugs, as described by Inouye et al., Drug Design and Delivery 1: 297-305, 1987. Mixtures of these compounds and the agents of the NsIDI / NsIDIE combinations of the invention, when compressed under 200 kg / cm 2, form a tablet from which the active agent is slowly released when administered to a subject. The release profile can be changed by varying the proportions of chitosan, CMC-Na, and active agents. The tablets may also contain other additives, including lactose, CaHP04 dihydrate, sucrose, crystalline cellulose, or croscarmellose sodium. Several examples are given in Table 5.

Table 5 Baichwal, in US Pat. No. 6,245,356, discloses a sustained release oral solid dosage form that includes agglomerated particles of a therapeutically active medicament (eg, a combination of NsIDI / NsIDIE or a component thereof of the present invention) in a amorphous form, a gelling agent, an ionizable gel strength enhancing agent, and an inert diluent. The gelling agent can be a mixture of xanthan gum and a locust bean gum capable of crosslinking with the xanthan gum when exposing the gums to an environmental fluid. Preferably, the ionizable gel enhancing agent acts to improve the crosslinking force between the xanthan gum and the locust bean gum, and thereby prolong the release of the medicament component from the formulation. In addition to the xanthan gum and the locust bean gum, the acceptable gelling agents which may also be used include the gelling agents well known in the art. Examples include gums that occur naturally, or gums that occur naturally modified, such as alginates, carrageenan, pectin, guar gum, modified starch, hydroxypropyl methyl cellulose, methyl cellulose, and other cellulosic or polymeric materials, such as, for example, sodium carboxymethyl cellulose and hydroxypropylcellulose, and mixtures of the foregoing. In another formulation useful for the combinations of the invention, Baichwal and Staniforth in US Pat. No. 5,135,757, describe a slow-release, free-flowing 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 more preferably locust bean gum), in the presence of aqueous solutions, and from about 30 to about 80 weight percent of an inert pharmaceutical filler (such as, for example, lactose, dextrose, sucrose, sorbitol, xylitol, fructose, or mixtures thereof). After mixing the excipient with a combination of NsIDI / NsIDIE, or with the combination agent, of the invention, the mixture is directly compressed 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 obtained. In another formulation useful for the 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 the drug's solubility. The dosage form comprises a tablet or capsule that includes a plurality of particles of a dispersion of a drug of limited solubility in a water-swellable, hydrophilic, crosslinked polymer, which maintains its physical integrity during the lifetime of the dosage, but which then it dissolves quickly. Once ingested, the particles swell to promote gastric retention and allow the gastric fluid to penetrate the particles, dissolve the drug, and leach it from the particles, ensuring that the drug reaches the stomach in the state in solution, which It is less harmful to the stomach than 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 non-fibrillating and substantially soluble in water in its non-crosslinked state, and the degree of crosslinking is sufficient to enable the polymer to remain insoluble for the desired period of time, normally at least from approximately 4 hours to 8 hours and up to 12 hours, depending on the choice of the incorporated drug and the medical treatment involved. Examples of suitable cross-linked polymers that can be used in the invention are gelatin, albumin, sodium alginate, carboxymethyl cellulose, polyvinyl alcohol, and chitin. Depending on the polymer, the crosslinking can be achieved by heat or radiation treatment, or through the use of crosslinking agents, such as aldehydes, poly-amino acids, metal ions, and the like. The silicone microspheres for the delivery of pH-controlled gastrointestinal drugs that are useful in the formulation of the NsIDl / NsIDIE combinations of the invention, have been described by Carelli et al., Int. J. Pharmaceutics 179: 73-83, 1999. The microspheres thus described are semi-interpenetrating pH sensitive polymer hydrogels made of different proportions of poly (methacrylic acid-co-methyl methacrylate) (Eudragit L100 or Eudragit S100), and cross-linked polyethylene glycol 8000, which are encapsulated in microspheres of silicone in a range of sizes from 500 to 1,000 microns. Slow release formulations include a coating that is not readily soluble in water, but that is slowly attacked and removed by water, or through which water can slowly permeate. Accordingly, for example, the combinations of NsIDl / NsIDIE of the invention can be spray coated with a solution of a binder under continuously fluidizing conditions, such as are described by Kitamori et al., US Patent 4,036,948. Examples of water-soluble binders include pregelatinized starch (eg, pregelatinized maize starch, pregelatinized white potato starch), pregelatinized modified starch, water soluble celluloses (eg, hydroxypropyl cellulose, hydroxymethyl cellulose). , hydroxypropylmethylcellulose, carboxymethylcellulose), polyvinylpyrrolidone, polyvinyl alcohol, dextrin, gum arabic and gelatin, binders soluble in organic solvents, such as cellulose derivatives (for example, phthalate cellulose acetate, hydroxy-propyl-methyl-cellulose phthalate, ethyl-cellulose).

Combinations of the invention, or a component thereof, with sustained release properties can also be formulated by spray drying techniques. Still another form of sustained release NsIDI / NsIDIE combinations can be prepared by microencapsulating particles of the membrane combination agents, which act as microdialysis cells. In this formulation, the gastric fluid permeates the walls of the microcapsule, and the microcapsule swells, allowing the active agents to dialyze outwards (see, for example, Tsuei et al., US Pat. No. 5,589,194). A commercially available sustained release system of this class consists of microcapsules having acacia gum / gelatin / ethyl alcohol membranes. This product is available on Eurand Limited (France) under the trade name DiffucapsX. The microcapsules thus formulated could be carried in a conventional gelatin capsule, or they could be formed into tablets. Sustained and / or controlled release formulations of NsIDIEs, such as SSRIs, are known. For example, Paxil CR®, commercially available from GlaxoSmithKline, is a prolonged release form of paroxetine hydrochloride in a degradable polymer matrix (GEOMATRIX ™, see also US Patents 4, 839, 177; 5,102.66, 5,422,123), which also it has an enteric coating to delay the onset of drug release until after the tablets have passed through the stomach. For example, US Pat. No. 5,102,666 discloses a polymer controlled release composition comprising a reaction complex formed by the interaction of (1) a calcium polycarbophil component, which is a water-insoluble, fibrous cross-linked carboxy-functional polymer, containing the polymer (a) a plurality of repeating units, of which at least about 80 percent contain at least one carboxyl functionality, and (b) from about 0.05 to about 1.5 percent crosslinking agent substantially free of charge. polyalkenyl polyether, the percentages being based on the weights of the unpolymerized repeat unit and the crosslinking agent, respectively, with (2) water, in the presence of an active agent selected from the group consisting of the SSRIs, such as paroxetine. The amount of calcium polycarbophil present is from about 0.1 to about 99 weight percent, for example about 10 percent. The amount of active agent present is from about 0.0001 to about 65 weight percent, for example between about 5 and 20 percent. The amount of water present is from about 5 to about 200 weight percent, for example between about 5 and 10 percent. The interaction is carried out at a pH of between about 3 and about 10, for example from about 6 to 7. The calcium polycarbophil is opginantly present in the form of a calcium salt containing from about 5 to about 25%. percent of calcium. Other examples of sustained release formulation are described in US Patent 5,422,123. Accordingly, a system for the controlled release of an active substance that is an SSRI, such as paroxetine, comprising (a) a deposit core comprising an effective amount of the active substance, and having a defined geometric shape, and (b) a support platform applied to the reservoir core, wherein the reservoir core contains at least the active substance, and at least one member selected from the group consisting of (1) a polymeric material that swells at contact with water or aqueous liquids, and a gellable polymeric material, wherein the proportion of the swellable polymeric material to the gellable polymeric material is in the range of 1: 9 to 9: 1, and (2) a single polymeric material having both wetting and gelling properties, and wherein the supporting platform is an elastic support, applied to the deposit core, in such a way that it partially covers the surface of the deposit core and it follows the changes due to the hydration of the deposit core, it is slowly soluble and / or slowly gellable in the aqueous fluids. The support platform may comprise polymers such as hydroxypropyl methyl cellulose, plasticizers such as a glyceride, binders such as polyvinyl pyrrolidone, hydrophilic agents such as lactose and silica, and / or hydrophobic agents such as magnesium stearate and glycerides. . The polymers typically form from 30 to 90 weight percent of the support platform, for example from about 35 to 40 percent. The plasticizer can form at least 2 weight percent of the support platform, for example from about 15 to 20 percent. The binders, hydrophilic agents, and hydrophobic agents, typically total up to about 50 weight percent of the support platform, for example from about 40 to 50 percent.

In another example, a sustained release formulation for venlafaxine (Effexor XR®), is commercially available from Wyeth Pharmaceuticals. This formulation includes venlafaxine hydrochloride, microcrystalline cellulose, and hydroxypropyl methyl cellulose, coated with a mixture of ethyl cellulose and hydroxypropyl methyl cellulose (see US 6,403,120 and 6,419,958). A controlled release formulation of budesonide (3 mg capsules) for the treatment of inflammatory bowel disease is available from AstraZeneca (sold as "Entocort ™"). To enable low dose levels of the active substance, the active substance 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 internal layer of sustained release resistant to a pH of 6.8, and with an external layer of sustained release resistant to a pH of 1.0. The inner layer is made of Eudragit® RL (copolymer of acrylic and methacrylic esters with a low content of quaternary ammonium groups), and the outer layer is made of Eudragit® L (anionic polymer synthesized from methacrylic acid and methyl ester of methacrylic acid). A bilayer tablet can be formulated for a combination of NsIDI / NsIDIE of the invention, wherein different granulations are made to measure for each agent of the combination, and the two agents are compressed in a bilayer press to form a single tablet. . For example, 12.5 mg, 25 mg, 37.5 mg, or 50 mg of paroxetine, an NsIDIE, is formulated for a controlled release that results in a paroxetine t12 of 15 to 20 hours, which can be combined in the same tablet with cyclosporine, which is formulated in such a way that t1 / 2 approaches that of paroxetine. Examples of paroxetine extended-release formulations, including those used in bilayer tablets, can be found in US Pat. No. 6,548,084. In addition to controlling the release rate of cyclosporin in vivo, an enteric or delayed-release coating may be included that delays the onset of drug release, such that Tmax of cyclosporin approaches that of paroxetine (i.e. from 5 to 10 hours). Cyclodextrins are cyclic polysaccharides containing naturally occurring D (+) - glucopyranose units 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 International Publications Nos. W091 / 11172, WO94 / 02518 , and W098 / 55148. Structurally, the cyclic nature of a cyclodextrin forms a bull or a donut-like shape having an apolar or hydrophobic cavity, the secondary hydroxyl groups being located on one side of the cyclodextrin bull, and the primary hydroxyl groups being on the other side. 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 internal cavity of the cyclodextrin allows a variety of compounds to be included. (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 for different therapeutic compounds, by the formation of inclusion complexes with different drugs that fit in the hydrophobic cavity of the cyclodextrin, or by the formation of non-covalent association complexes with other molecules biologically active US Patent 4,727,064 discloses pharmaceutical preparations consisting of a drug with a substantially low water solubility, and an amorphous mixture based on cyclodextrin, soluble in water, wherein the drug forms an inclusion complex with the cyclodextrins of the mixture. The formation of a drug-cyclodextrin complex can modify the properties of solubility, dissolution rate, bioavailability, and / or stability of the drug. Sulfo-butyl ether-β-cyclodextrin (SBE-β-CD, commercially available from CyDex, Inc., Overland Park, KA, USA, and sold as CAPTISOL®) can also be used as an aid in the preparation of formulations of sustained release of the agents of the combinations of the present invention. For example, a sustained-release tablet including prednisolone and SBE-β-CD, compressed in a hydroxy-propyl-methyl-cellulose matrix has been prepared (see Rao et al, J. Pharm.Sci.90: 807-16 , 2001). In another example of the use of different cyclodextrins, patent EP 1109806 Bl discloses paroxetine cyclodextrin complexes, wherein a-, β-, or β-cyclodextrins, including eptacytoses (2,6-di-a-methyl), can be obtained. ) -β-cyclodextrin, (2,3,6-tri-O-methyl) -β-cyclodextrin, mono-succinyl-eptakis- (2,6-di-O-methyl-β-cyclodextrin, or 2-hydroxy) propyl-β-cyclodextrin, in an anhydrous or hydrated form, in proportions of the agent to cyclodextrin complex from 1: 0.25 to 1:20.

Polymeric cyclodextrins have also been prepared, as described in patent applications US 10 / 021,294 and 10 / 021,312. The cyclodextrin polymers thus formed may be useful for the formulation of the agents of the combinations of the present invention. These multifunctional polymeric cyclodextrins are commercially available from Insert Therapeutics Inc., Pasadena, CA, USA. As an alternative to direct complex formation with the agents, the cyclodextrins can be used as an auxiliary additive, for example as a carrier, diluent, or solubilizer. Formulations including cyclodextrins and other agents of the combinations of the present invention (ie, an NsIDI or NsIDIE) can be prepared by methods similar to the preparations of the cyclodextrin formulations described herein. Liposomal Formulations One or both components of a combination of NsIDI / NsIDIE 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 the vesicle-forming lipids, which will form the volume of the vesicle structure in the liposome. In general, these vesicle-forming lipids include any amphipathic lipids having hydrophobic and polar head group moieties, and which (a) can spontaneously form in bilayer vesicles in water, as exemplified by phospholipids, or (b) are incorporated stably in lipid bilayers, with its hydrophobic fraction in contact with the inner hydrophobic region of the bilayer membrane, and its polar head group fraction oriented towards the outer polar surface of the membrane. Vesicle-forming lipids of this type are preferably those having two hydrocarbon chains, usually acyl chains, and a polar head group. This class includes phospholipids, such as phosphatidylcholine (PC), PE, phosphatidic acid (PA), phosphatidyl-inositol (Pl), and espingomyelin (SM), wherein the two hydrocarbon chains are typically between 14 and 22 carbon atoms in length, and have different degrees of unsaturation. The lipids and phospholipids described above, whose acyl chains have a variety of degrees of saturation, can be obtained commercially, or can be prepared according to published methods. Other lipids that can be included in the invention are glycolipids and sterols, such as cholesterol. The second general component includes a vesicle-forming lipid, which is derived with a polymer chain that will form the polymer layer in the composition. The vesicle-forming lipids that can be used as the second component of general vesicle-forming lipid are any of those described for the first general vesicle-forming lipid component. Preferred are vesicle-forming lipids with diacyl chains, such as phospholipids. An example phospholipid is phosphatidylethanolamine (PE), which provides a reactive amino group, which is convenient for coupling with the activated polymers. An example PE is distearyl-PE (DSPE). The preferred polymer in a derivatized lipid is polyethylene glycol (PEG), preferably a PEG chain having a molecular weight of between 1,000 and 15,000 Daltons, more preferably between 2,000 and 10,000 Daltons, and most preferably between 2,000 and 10,000 Daltons. 5,000 Daltons Other hydrophilic polymers that may be suitable include polyvinylpyrrolidone, polymethyl-oxazoline, polyeth-il-oxazoline, polyhydroxy-propyl-methacryl-amide, polymethacryl-amide and polydimethyl-acrylamide, poly-lactic acid, poly-glycolic acid, and celluloses derived , such as hydroxy-methylcellulose or hydroxy-ethyl-cellulose. Additionally, block copolymers or random copolymers of these polymers may be suitable, in particular including PEG segments. Methods for preparing derivatized lipids with hydrophilic polymers, such as PEG, are well known, for example as described in US Pat. No. 5,013,556. A third component of general vesicle-forming lipid, which is optional, is a lipid anchor, by which an address fraction is anchored to the liposome, through a polymer chain at the anchor. Additionally, the steering group is positioned at the distal end of the polymer chain, such that the biological activity of the steering fraction is not lost. The lipid anchor has a hydrophobic fraction, which serves to anchor the lipid in the outer layer of the bilayer surface of the liposome, a polar head group with which the inner end of the polymer is covalently bound, and a free end (external) ) of the polymer, which is activated or can be activated for its covalent coupling with the address fraction. The methods for preparing lipid anchor molecules of these types are described below. The lipid components used in the formation of the liposomes are preferably present in a molar ratio of about 70 to 90 percent of vesicle-forming lipids, 1 to 25 percent of polymer-derived lipid, and 0.1 to 5 percent. percent lipid anchor. An exemplary formulation includes from 50 to 70 mole percent non-derivatized PE, from 20 to 40 mole percent cholesterol, from 0.1 to 1 mole percent of a PE-PEG polymer (3500) with a chemically reactive group in its free end for coupling to a directional fraction, 5 to 10 mole percent PE derived with PEG 3500 polymer chains, and 1 mole percent alpha-tocopherol.

Liposomes are preferably prepared to have substantially homogeneous sizes in a selected size range, typically between about 0.03 and 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 approximately to the larger sizes of the liposomes produced by extrusion through that membrane, in particular when the preparation is extruded two or more times through the same membrane. Homogenization methods are also useful for reducing the size of liposomes to sizes of 100 nanometers 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 NsIDl / NsIDIE combinations described herein include the compounds belonging to the following classes: polyethoxylated fatty acids, fatty acid diesters of PEG, mixtures of mono-esters and di- PEG fatty acid esters, polyethylene glycol glycerol fatty acid esters, alcohol-oil transesterification products, polyglycerized fatty acids, propylene glycol fatty esters, mixtures of propylene glycol esters and glycerol esters, mono- and di-esters. -glycerides, sterol and sterol derivatives, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol alkyl ethers, sugar esters, polyethylene glycol alkyl phenols, polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acid esters, esters of lower alcohol fatty acids, and ionic surfactants. Commercially available examples for each kind of excipient are provided below. Polyethoxylated fatty acids can be used as excipients for the formulation of combinations of NsIDl / NsIDIE described in this. Examples of the commercially available polyethoxylated fatty acid monoester surfactant surfactants include: PEG monolaurate 4-100 (Crodet L series, Croda), PEG 4-100 mono-oleate (Crodet O series, Croda), PEG-4-100 monostearate (Crodet S series, Croda, and Myrj series, Atlas / ICI), PEG distearate 400 (Cithrol 4DS series, Croda), PEG 100, 200, or 300 monolaurate (Cithrol ML series, Croda), PEG-100, 200, or 300 mono-oleate (Cithrol MO series, Croda), PEG 400 dioleate (Cithrol 4DO series, Croda), PEG 400 monostearate (Cithrol MS series, Croda), stearate PEG 1 (Nikkol MYS-1EX, Nikko, and Coster Kl, Condea), stearate PEG-2 (Nikkol MYS-2, Nikko), PEGA oleate (Nikkol MYO-2, Nikko), PEG-4 laurate (Mapeg® 200 ML, PPG), PEG-4 oleate (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 ), PEG-6 oleate (Algon OL 60, Auschem SpA), PEG-7 oleate (Algon OL 70, Auschem SpA), PEG-6 laurate (Kesscol® PEG300 ML, Stepan), PEGA laurate (Lauridac 7) , Condea), PEG-6 stearate (Kesscol® PEG300 MS, Stepan), PEG-8 laurate (Mapeg® 400 ML, PPG), PEG-8 oleate (Mapeg® 400 MO, PPG), PEG-stearate 8 (Mapeg® 400 MS, PPG), oleate of PEG-9 (Emulsifier A9, Condea), stearate of PEG-9 (Cremophor S9, BASF), laurate of PEG-10 (Nikkol MYL-10, Nikko), oleate of PEG-10 (Nikkol MYO-10, Nikko), PEG-12 stearate (Nikkol MYS-10, Nikko), laurate of PEG-12 (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), PEG-15 stearate (Nikkol TMGS-15, Nikko), oleate of PEG-15 (Nikkol TMGO-15, Nikko), lau time of PEG-20 (Kessco® PEG 1000 ML, Stepan), PEG-20 oleate (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), PEG-50 stearate (Myrj 53), PEG-55 stearate (Nikkol MYS-55, Nikko), PEG-100 oleate (Crodet O-100, Croda), stearate of PEG-100 (Ariacel 165, ICI), oleate of PEG-200 (Albunol 200 MO, Taiwan Surf.), Oleate of PEG-400 (LACTOMUL, Henkel), and oleate of PEG-600 (Albunol 600 MO, Taiwan Surf.). The formulations of one or both components of the NsIDl / NsIDIE combinations according to the invention may include one or more of the above polyethoxylated fatty acids. Diesters of polyethylene glycol fatty acids can also be used as excipients for the NsIDl / NsIDIE combinations described herein. Examples of the commercially available polyethylene glycol fatty acid diesters include: PEG-4 dilaurate (Mapeg® 200 DL, PPG), PEG-4 dioleate (Mapeg® 200 OD, PPG), PEG-4 distearate (Mapeg® 200 DS, Stepan), PEGA 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 dioleate -8 (Mapeg® 400 DO, PPG), distearate of PEG-8 (Mapeg® 400 DS, PPG), dipalmitate of PEG-10 (Polyaldo 2PKFG), dilaurate of PEG-12 (Kessco® PEG 600 DL, Stepan), distearate of PEG-12 (Kessco® PEG 600 DS, Stepan), PEG-12 dioleate (Mapeg® 600 OD, PPG), PEG-20 dilaurate (Kessco® PEG 1000 DL, Stepan), PEG-20 dioleate ( Kessco® PEG 1000 DO, Stepan), PEG-20 distearate (Kessco® PEG 1000 DS, Stepan), PEG-32 dilaurate (Kessco® PEG 1540 DL, Stepan), PEG-32 dioleate (Kessco® PEG 1540 OD , Stepan), distearate of PEG-32 (Kessco® PEG 1540 DS, Stepan), PEG-400 dioleate (Cithrol series 4D0, Croda), and distearate of PEG-400 (Cithrol series 4DS, Croda). The formulations of a combination of NsIDl / NsIDIE according to the invention can include one or more of the polyethylene glycol fatty acid diesters above. Mixtures of mono- and di-esters of PEG fatty acids can be used as excipients for the formulation of a combination of NsIDI / NsIDIE described herein. Examples of commercially available PEG fatty acid mono- and di-ester mixtures include: mono-, di-laurate of PEG 4-150 (Kessco® PEG 200-600, mono, dilaurate, Stepan), mono-, PEG-150 dioleate (Kessco® PEG 200-6000 mono, dioleate, Stepan), and mono-, di-stearate of PEG 4-150 (Kessco® 200-6000 mono, distearate, Stepan). The formulations of the NsIDl / NsIDIE combinations according to the invention may include one or more of the mixtures of mono- and di-esters of PEG fatty acids above. In addition, polyethylene glycol glycerol fatty acid esters can be used as excipients for the formulation of the NsIDI / NsIDIE combinations described herein. Examples of the commercially available polyethylene glycol glycerol fatty acid esters include: glyceryl laurate-PEG-20 (Tagat® L, Goldschmidt), glyceryl laurate-PEG-30 (Tagat® L2, Goldschmidt), glyceryl laurate- PEG-15 (Glycerox L series, Croda), glyceryl laurate-PEG-40 (Glycerox L series, Croda), glyceryl stearate-PEG-20 (Capmul® EMG, ABITEC, and Aldo® MS-20 KFG, Lonza) , glyceryl oleate-PEG-20 (Tagat® 0, Goldschmidt), and glyceryl oleate-PEG-30 (Tagat® 02, Goldschmidt). The formulations of the NsIDl / NsIDIE combinations according to the invention can include one or more of the polyethylene glycol glycerol fatty acid esters mentioned above. The alcohol-oil transespherification products can also be used as excipients for the formulation of the NsIDI / NsIDIE combinations described herein. Examples of the commercially available alcohol-oil transesterification products include: PEG-3 castor oil (Nikkol COA, 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 CAO, 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), PEG-5 hydrogenated castor oil (Nikkol HCO-5) , Nikko), hydrogenated castor oil from PEG-7 (Cremophor W07, BASF), hydrogenated castor oil from PEG-10 (Nikkol HCO-10, Nikko), hydrogenated castor oil from PEG-20 (Nikkol HCO-20, Nikko), PEG-25 hydrogenated castor oil (Simulsol® 1292, Seppic), hydrogenated P castor oil EG-30 (Nikkol HCO-30, Nikko), hydrogenated castor oil from PEG-40 (Cremophor RH 40, BASF), hydrogenated castor oil from PEG-45 (Cerex ELS 450, Auschem Spa), hydrogenated castor oil from PEG-50 (Emalex HC-50, Nihon Emulsion), hydrogenated castor oil from PEG-60 (Nikkol HCO-60, Nikko), hydrogenated castor oil from PEG-80 (Nikkol HCO-80, Nikko), castor oil hydrogenated PEG-100 (Nikkol HCO-100, Nikko), corn oil PEG-6 (Labrafil® M 2125 CS, Gattefosse), almond oil PEG-6 (Labrafil® M 1966 CS, Gattefosse), oil apricot seed of PEG-6 (Labrafil® M 1944 CS, Gattefosse), olive oil of PEG-6 (Labrafil® M 1980 CS, Gattefosse), peanut oil of PEGA (Labrafil® M 1969 CS, Gattefosse), oil of hydrogenated palm seed of PEG-6 (Labrafil® M2130 BS, Gattefosse), palm seed oil of PEG-6 (Labrafil® M 2130 CS, Gattefosse), PEG-6 triolein (Labrafil® M 2735 CS, Gattefosse), PEG-8 corn oil (Labrafil® WL 2609 BS, Gattefosse), corn glycerides from PEG-20 (Crovol M40, Croda), almond glycerides from PEG-20 (Crovol A40, Croda), PEG-25 trioleate (TAGAT® TO, Goldschmidt), seed oil of PEG-40 palm (Crovol PK-70), corn glycerides of PEG-60 (Crovol M70, Croda), almond glycerides from PEG-60 (Crovol) A70, Croda), caprylic / capric triglycerides of PEG-4 (Labrafac® Hydro, Gattefosse), caprylic / capric glycerides of PEG-8 (Labrasol, Gattefosse), caprylic / capric glycerides of PEG-6 (SOFTIGEN®767, Huís) , glyceride of lauroyl-macrogol-32 (GELUCIRE 44/14, Gattefosse), stearoyl glyceride -macrogol (GELUCIRE 50/13, Gattefosse), mono-, di-, tri-, 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.) Tetracaprylate / pentaerythrityl tetracaprate (Liponate PE-810 Lipo Chem.), and pentaerythritol tetraoctanoate (Nikkol Pentarate 408, Nikko). Oil-soluble vitamins, such as vitamins A, D, E, K, etc., are also included as oils in this category of surfactants. Accordingly, derivatives of these vitamins, such as tocopherol-PEG-1000 succinate (TPGS, available from Eastman), are also suitable surfactants. The formulations of the NsIDl / NsIDIE combinations according to the invention may include one or more of the above alcohol-oil transesterification products. Polyglycerized fatty acids can also be used as excipients for the formulation of the NsIDI / NsIDIE combinations described herein. Examples of commercially available polyglycerized fatty acids include: polyglyceryl-2 stearate (Nikkol DGMS, Nikko), polyglyceryl-2 oleate (Nikkol DGMO, Nikko), polyglyceryl-2 isostearate (Nikkol DGMIS, Nikko), polyglyceryl oleate -3 (Caprol® 3G0, 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) , polyglyceryl-6-ricinoleate (Nikkol Hexaglyn PR-15, Nikko), polyglyceryl-10 linoleate (Nikkol Decaglyn 1-LN, Nikko), polyglyceryl-6-pentaoleate (Nikkol Hexaglyn 5-0, Nikko), polyglyceryl dioleate 3 (Cremophor G032, BASF), polyglyceryl-3 distearate (Cremophor GS32, BASF), polyglyceryl-4 pentaoleate (Nikkol Tetraglyn 5-0, Nikko) , polyglyceryl-6 dioleate (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 Decaglyn 7-0, Nikko), polyglyceryl-10 tetraoleate (Caprol® 10G40, ABITEC), polyglyceryl-10 decastisostearate (Nikkol Decaglyn 10-1S, Nikko), decaoleate of polyglyceryl-101 (Drewpol 10-10-0, Stepan), polyglyceryl mono-, di-oleate-10 (Caprol® PGE 860, ABITEC), and polyglyceryl polyricinoleate (Polymuls, Henkel). The formations of the combinations of NsIDI / NsIDIE according to the invention may include one or more of the above polyglycerized fatty acids.

In addition, propylene glycol fatty acid esters can be used as excipients for the formulation of the NsIDI / NsIDIE combinations described herein. Examples of the commercially available propylene glycol fatty acid esters 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 mono-oleate (Myverol P-06, Eastman), propylene glycol dicaprylate / dicaprate (Captex® 200, ABITEC), propylene glycol dioctanoate (Captex® 800, ABITEC), caprylate / propylene glycol caprate (LABRAFAC PG, Gattefosse), propylene glycol dilaurate, propylene glycol distearate (Kessco® PGDS, Stepan), propylene glycol dicaprylate (Nikkol Sefsol 228, Nikko), and propylene glycol dicaprate (Nikkol PDD, Nikko). The formulations of the NsIDl / NsIDIE 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 the NsIDl / NsIDIE 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). The formulations of the NsIDI / NsIDIE combinations according to the invention may include one or more of the mixtures of propylene glycol esters and glycerol esters above. In addition, mono- and di-glycerides can be used as excipients for the formulation of the NsIDI / NsIDIE combinations described herein. Examples of commercially available mono- and di-glycerides include: monopalmitolein (C16: 1) (Larodan), monoelaidine (C18: 1) (Larodan), monocaproin (C6) (Larodan), monocaprylin (Larodan), monocaprin (Larodan), monolaurin (Larodan), glyceryl monomiristate (C14) (Nikkol MGM, Nikko), glyceryl mono-oleate (C18: l) (PECEOL, Gattefosse), glyceryl mono-oleate (Myverol, Eastman), mono-oleate / glycerol linoleate (OLICINE, Gattefosse), glycerol monolinoleate (Maisine, Gattefosse), glyceryl ricinoleate (Softigen® 701, Huís), glyceryl monolaurate (ALDO® MLD, Lonza), glycerol monopalmitate (Emalex GMS-P, Nihon), glycerol monostearate (Capmul® GMS, ABITEC), glyceryl mono- and di-oleate (Capmul® GMO-K, ABITEC ), palmitic / glyceryl stearic (CUTINA MD-A, ESTAGEL-G18), glyceryl acetate (Lamegin® EE, Grunau GmbH), glyceryl laurate (Imwitor® 312, Huís), citrate / lactate / oleate / glyceryl linoleate (Imwitor® 375, Huís), glyceryl caprylate (Imwitor® 308, Huís), caprylate / glyceryl caprate (Capmul® MCM, ABITEC), mono- and di-glycerides of caprylic acid (Imwitor® 988, Huís), caprylic / capric glycerides (Imwitor® 742, Huís), mono- and di-acetylated monoglycerides (Myvacet® 9-45, Eastman), glyceryl monostearate (Aldo® MS, Arlacel 129, ICI), lactic acid esters of the mono- and di-glycerides (LAMEGIN GLP, Henkel), dicaproin (C6) (Larodan), dicaprin (CIO) (Larodan), dioctanoin (C8) (Larodan), dimiristin (C14) (Larodan), dipalmitin (C16) (Larodan), distetearin (Larodan), glyceryl dilaurate (C12) (Capmul® GDL, ABITEC), glyceryl dioleate (Capmul® GDO, ABITEC), glycerol-fatty acid esters (GELUCIRE) 39/01, Gattefosse), dipalmitolein (C16: 1) (Larodan), 1,2- and 1,3-diolein (C18: 1) (Larodan), dielaidine (C18: 1) (Larodan), and dilinolein (C18 : 2) (Larodan). The formulations of the NsIDI / NsIDIE 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 the combinations of NsIDl / NsIDIE described in this. Examples of sterol and commercially available sterol derivatives include: cholesterol, cytosterol, lanosterol, PEG-24 cholesterol ether (Solulan C-24, Amerchol), PEG-30 colestanol (Phytosterol series GENEROL, Henkel), phytosterol from PEG-25 (Nikkol BPSH-25, Nikko), PEG-5 soyaterol (Nikkol BPS-5, Nikko), PEG-10 soya-sterol (Nikkol BPS-10, Nikko), PEG soyaterol -20 (Nikkol BPS-20, Nikko), and Syaesterol from PEG-30 (Nikkol BPS-30, Nikko). The formulations of the NsIDI / NsIDIE 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 the NsIDI / NsIDIE combinations described herein. Examples of commercially available polyethylene glycol sorbitan fatty acid esters include: sorbitan laurate of PEG-10 (Liposorb L-10, Lipo Chem.), Sorbitan monolaurate from PEG-20 (Tween® 20, Atlas / lCI), sorbitan monolaurate from PEG-4 (Tween® 21, Atlas / lCI), sorbitan monolaurate from PEG-80 (Hodag PSML -80, Colgene), sorbitan monolaurate from PEGA (Nikkol GL-1, Nikko), sorbitan monopalmitate from PEG-20 (Tween® 40, Atlas / ICI), sorbitan monostearate from PEG-20 (Tween® 60, Atlas / ICI), sorbitan monostearate of PEG-4 (Tween® 61, Atlas / ICI), sorbitan monostearate of PEG-8 (DACOL MSS, Condea), sorbitan monostearate of PEG-6 (Nikkol TS106, Nikko), sorbitan tristearate of PEG-20 (Tween® 65, Atlas / ICI), sorbitan tetrastearate of PEG-6 (Nikkol GS-6, Nikko), sorbitan tetra-stearate of PEG-60 (Nikkol GS-460, Nikko ), sorbitan mono-oleate of PEG-5 (Tween® 81, Atlas / ICI), sorbitan mono-oleate of PEG-6 (Nikkol TO-106, Nikko), sorbitan monooleate of PEG-20 (Tween® 80 , Atlas / ICI), sorbitan oleate of PEG-40 (Emalex ET 8040, Nihon Emulsion), sorbitan trioleate of PEG-20 (Tween® 85, Atlas / ICI), sorbitan tetraoleate of PEG-6 (Nikkol GO- 4, Nikko), sorbitan tetraoleate of PEG-30 (Nikkol GO-430, Nikko), sorbitan tetraoleate of PEG-40 (Nikkol GO-440, Nikko), sorbitan monoisostearate of PEG-20 (Tween® 120, Atlas / ICI), sorbitol hexaoleate of PEG (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 sorbitan hexa-stearate bitol of PEG-6 (Nikkol GS-6, Nikko). The formulations of the NsIDI / NsIDIE 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 the NsIDI / NsIDIE combinations described herein. Examples of commercially available polyethylene glycol alkyl ethers include: PEGA oleyl ether, oleth-2 (Brij 92/93, Atlas / lCl), PEGA oleyl ether, oleth-3 (Volpo 3, Croda), oleyl - PEG-5, oleth-5 (Volpo 5, Croda), PEG-10 oleyl ether, oleth-10 (Volpo 10, Raw), PEG-20 oleyl ether, oleth-20 (Volpo 20, Croda), laureth-ether of PEG-4, laureth-4 (Brij 30, Atlas / lCI), lauryl-ether of PEG-9, lauryl-ether of PEG-23, laureth-23 (Brij 35, Atlas / ICI) , cetyl ether of PEGA (Brij 52, ICI), cetyl ether of PEG-10 (Brij 56, ICI), cetyl ether of PEG-20 (Brij 58, ICI), stearyl ether of PEG-2 (Brij 72, ICI), stearyl ether of PEG-10 (Brij 76, ICI), stearyl ether of PEG-20 (Brij 78, ICI), and stearyl ether of PEG-100 (Brij 700, ICI). The formulations of the NsIDI / NsIDIE combinations according to the invention may include one or more of the above polyethylene glycol alkyl ethers. Sugar esters can also be used as excipients for the formulation of the NsIDI / NsIDIE 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), sucrose monopalmitate (SUCRO ESTER 15, Gattefosse), and sucrose monolaurate (sucrose monolaurate 1695, Mitsubisbi-Kasei). The formulations of the NsIDl / NsIDIE combinations according to the invention may include one or more of the above sugar esters. The polyethylene glycol alkyl phenols are also useful as excipients for the formulation of the NsIDI / NsIDIE combinations described herein. Examples of the commercially available polyethylene glycol alkyl phenols include: the nonyl phenol series of PEG-10-100 (X-series Triton, Rohm S Haas), and the octyl-phenol-ether series of PEG-15-100 (Triton N series, Rohm &Haas). The formulations of the NsIDI / NsIDIE 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 the NsIDI / NsIDIE combinations described herein. These surfactants are available under different trade names, including one or more of the Synperonic PE (ICI) series, Pluronic® series (BASF), Lutrol (BASF), Supronic, Mon an, Pluracare, and Plurodac. The generic term for these copolymers is "poloxamer" (CAS 9003-11-6). These polymers have the Formula (X): HO (C2H40) n (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 in the range of 1,000 to 15,000 Daltons, and with proportions of ethylene oxide / propylene oxide of between 0.1 and 0.8 by weight. The formulations of the NsIDl / NsIDIE combinations according to the invention may include one or more of the above polyoxyethylene-polyoxypropylene block copolymers. Polyoxyethylenes, such as PEG 300, PEG 400, and PEG 600, can be used as excipients for the formulation of the NsIDl / NsIDIE combinations described herein. Sorbitan fatty acid esters can also be used as excipients for the formulation of the NsIDl / NsIDIE combinations described herein. Examples of commercial sorbitan fatty acid esters include: sorbitan monolaurate (Span-20, Atlas / lCI), sorbitan monopalmitate (Span-40, Atlas / ICI), sorbitan mono-oleate (Span-80, Atlas / ICI), sorbitan monostearate (Span-80, Atlas / ICI), sorbitan trioleate (Span-85, Atlas / ICI), sorbitan sesquioleate (Arlacel-C, ICI), sorbitan tristearate (Span-65, Atlas / lCI), sorbitan monoisostearate (Crill 6, Croda), and sorbitan sesquistearate (Nikkol SS-15, Nikko). The formulations of the NsIDl / NsIDIE combinations according to the invention may include one or more of the above sorbitan fatty acid esters. The esters of the lower alcohols (of 2 to 4 carbon atoms) and of the fatty acids (of 8 to 18 carbon atoms) 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). The formulations of the NsIDI / NsIDIE combinations according to the invention may include one or more of the above fatty alcohol fatty acid esters. In addition, ionic surfactants can be used as excipients for the formulation of the NsIDI / NsIDIE combinations described herein. Examples of useful ionic surfactants include: sodium caproate, sodium caprylate, sodium caprate, sodium laurate, sodium myristate, sodium myristolate, 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 phosphatides, hydrogenated soy lecithin , dimyristoyl-lecithin, lecithin, hydroxylated lecithin, 1 isophosphatidylcholine, cardiol ipina, sphingol ina, phosphatidylcholine, phosphatidyl-ethanolamine, phosphatidic acid , phosphatidyl-glycerol, phosphat idyl-serine, diethanolamine, phospholipids, polyoxyethylene-10 oleyl ether phosphate, the esterification products of fatty alcohols or fatty alcohol ethoxylates, with acid or phosphoric anhydride, ether carboxylates (by oxidation of the terminal OH group, of fatty alcohol ethoxylates), succinylated monoglycerides, sodium stearyl fumarate, stearoyl-propylene glycol succinate, mono / diacetylated tartaric acid esters of mono- and di-glycerides, esters of citric acid of mono-, 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 sulfonates, acyl isethionates, acryl taurates, glyceryl ether alkyl sulfonates, sodium octyl sulfosuccinate, undecylenamido-MEA-sodium sulfosuccinate, hexadecyl triamonium bromide, decyltrimethyl ammonium bromide, cetyl trimethyl ammonium bromide, dodecyl ammonium chloride, alkyl benzyl dimethyl ammonium salts, salts of di-isobutyl-phenoxy-ethoxy-dimethyl-benzyl-ammonium, alkyl-pyridinium salts, betaines (trialkyl-glycine), lauryl-betaine (N-lauryl, N, N-dimethyl-glycine), and ethoxylated amines ( polyoxyethylene coconut amine-15). For simplicity, typical counter-ions are provided above. One of skill in the art will appreciate, however, that any bio-acceptable counter ion can be used. For example, although the fatty acids are shown as sodium salts, other cationic counterions may also be used, such as, for example, alkali metal or ammonium cations. The formulations of the NsIDI / NsIDIE 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 combination of NsIDI, NsIDIE, or the combination of NsIDI / NsIDIE sequestered within the liposome. The relative amount of the excipient of surface activity necessary for the preparation of the formulations in liposomal nanoparticles or solid lipids is determined using the known methodology. For example, liposomes can be prepared by a variety of techniques, such as those detailed in Szoka et al., 1980. Multilamellar vesicles (MLVs) can be formed by simple lipid film hydration techniques. In this process, a mixture of liposome-forming lipids of the type detailed above, dissolved in a suitable organic solvent, is evaporated in a vessel to form a thin film, which is then covered by an aqueous medium. The lipid film is hydrated to form multilamellar vesicles, typically with sizes between about 0.1 and 10 microns. Other established liposomal formulation techniques may be applied, as necessary. For example, the use of liposomes to facilitate cellular recovery is described in US Patents 4,897,355 and 4,394,448.

Additional Applications The compounds of the invention can be used in immunomodulatory or mechanical assays to determine whether other combinations, or individual agents, are as effective as the combination to inhibit the secretion or production of proinflammatory cytokines, or to modulate the immune response using the assays generally known in the art, examples of which are described herein. For example, candidate compounds can be combined with an NsIDI (or a metabolite or analogue therein) or with an NsIDI, and can be applied to stimulated PBMCs. After a suitable time, the cells are examined for cytokine secretion or production, or other suitable immune response. The relative effects of the combinations against each other, and against the individual agents, are compared and the compounds and the effective combinations are identified. The combinations of the invention are also useful tools for elucidating mechanical information about the biological pathways involved in the information. This information can lead to the development of new combinations or individual agents to inhibit the inflammation caused by proinflammatory cytokines. The methods known in the art can be used to determine the biological pathways, in order to determine the pathway, or pathway network, affected by the contact of the cells stimulated to produce proinflammatory cytokines with the compounds of the invention. These methods may include analyzing cellular constituents that are expressed or repressed after their contact with the compounds of the invention, compared to untreated positive or negative control compounds, and / or new individual agents and combinations, or to analyze some other activity Metabolic cell, such as enzymatic activity, nutrient recovery, and proliferation. The cellular components analyzed may include genetic transcripts, and protein expression. Suitable methods can include conventional biochemistry techniques, radiolabelling of the compounds of the invention (eg, labeled with 14C or 3H), and observation of compounds that bind to proteins, for example using two-dimensional gels, or profiling of gene expression. Once identified, these compounds can be used in in vivo models to further validate the tool or develop new anti-inflammatory agents.

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

Example 1: Assay to determine the suppressive activity of proinflammatory cytokine. Dilution matrices of compounds were tested for the suppression of IFN ?, IL-lβ, IL-2, IL-4, IL-5, and TNFα, as described below. IFNy A suspension of 100 microliters of diluted human white blood cells contained within each well of a 384-well polystyrene plate (NalgeNunc), was stimulated to secrete IFN? by treatment with a final concentration of 10 nanograms / ml of Forbol 12-myristate 13 -acetate (Sigma, P-1585), and 750 nanograms / ml of ionomycin (Sigma, I-0634). Different concentrations of each test compound were added at the time of the stimulus. After 16 to 18 hours of incubation at 370C in a humidified incubator, the plate was centrifuged, and the supernatant was transferred to a white opaque 384 well polystyrene plate (Nalge Nunc, Maxisorb) coated with an anti-IFNy antibody (Endogen , # M-700A-E). After a 2 hour incubation, the plate was washed (Tecan PowerWasher 384) with phosphate buffered saline (PBS) containing 0.1 percent Tween 20 (polyoxyethylene sorbitan monolaurate), and incubated for an additional 1 hour with another antibody anti-IFNy that was labeled with biotin (Endogen, M701B) and horseradish peroxidase (HRP) coupled with streptavidin (PharMingen, # 13047E). After the plate was washed with Tween to 0.1 percent / phosphate regulated serum, a luminescent substrate with horseradish peroxidase was added to each well, and the light intensity was measured using a LJL Analyst plate luminometer.

IL-2 A suspension of 100 microliters of diluted human white blood cells contained within each well of a 384-well polystyrene plate (NalgeNunc), was stimulated to secrete IL-2 by treatment with a final concentration of 10 nanograms / ml of Forbol 12-myristate 13-myristate (Sigma, P-1585), and 750 nanograms / ml of ionomycin (Sigma, I-0634). Different concentrations of each test compound were added at the time of the stimulus. After 16 to 18 hours of incubation at 31 ° C in a humidified incubator, the plate was centrifuged, and the supernatant was transferred to a white and opaque 384-well polystyrene plate (NalgeNunc, Maxisorb) coated with an anti-IL antibody. -2 (PharMingen, # 555051). After 2 hours of incubation, the plate was washed (Tecan PowerWasher 384) with Tween-containing phosphate-buffered serum to 0.1 percent, and incubated for an additional 1 hour with another anti-IL-2 antibody that was labeled with biotin (Endogen, M600B) and horseradish peroxidase coupled with streptavidin (PharMingen, # 13047E). After the plate was washed with 0.1 percent Tween 20 / phosphate buffered serum, a luminescent substrate with horseradish peroxidase was added to each well, and the intensity of the light was measured using a LJL Analyst plate luminometer. Stimulation of TNFy with 13-Forbol 12-myristate acetate. The effects of the combinations of the test compounds on the TNFy secretion in white blood cells were tested from the human spongy coating stimulated with phorbol 12-myristate 13-acetate as follows. The human blood white blood cells from the sponge coating were diluted 1:50 in the medium (RPMl, Gibco BRL, # 11875-085); in each well of the assay plate, 10 percent fetal bovine serum (Gibco BRL, # 25140-097), 2 percent penicillin / streptomycin (Gibco BRL, # 15140-122), and 50 microliters of the white blood cells diluted. The drugs were added to the indicated concentration. After 16 to 18 hours of incubation at 37 ° C with 5 percent C0a in a humidified incubator, the plate was centrifuged, and the supernatant was transferred to a white opaque 384 well polystyrene plate (NalgeNunc, Maxisorb) coated with an anti-TNFa antibody (PharMingen, # 551220). After 2 hours of incubation, the plate was washed (Tecan PowerWasher 384) with phosphate-regulated serum containing 0.1 percent Tween 20, and incubated for an additional 1 hour with biotin-labeled anti-TNFa antibody (PharMingen, # 554511) and horseradish peroxidase coupled with streptavidin (PharMingen, # 13047E). Then the plate was washed again with 0.1 percent Tween 20 / serum phosphate regulated. A luminescent substrate with horseradish peroxidase was added to each well, and the light intensity of each well was measured using a plate luminometer.

Stimulation of TNFa with Lipopolysaccharide A suspension of 100 microliters 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 micrograms / ml of lipopolysaccharide (Sigma L-4130). Different concentrations of each test compound were added at the time of the stimulus. After 16 to 18 hours of incubation at 37 ° C in a humidified incubator, the plate was centrifuged, and the supernatant was transferred to a white opaque 384-well polystyrene plate (Nalge Nunc, Maxisorb) coated with an anti-TNFa antibody. (PharMingen, # 551220). After 2 hours of incubation, the plate was washed (Tecan PowerWasher 384) with phosphate-regulated serum containing 0.1 percent Tween 20, and incubated for an additional 1 hour with another anti-TNFα antibody that was labeled with biotin (PharMingen, # 554511), and horseradish peroxidase coupled with streptavidin (PharMingen, # 13047E). After the plate was washed with 0.1 percent Tween 20 / phosphate buffered serum, a luminescent substrate with horseradish peroxidase was added to each well, and the intensity of the light was measured using a LJL Analyst plate luminometer. Inhibition Percentage The percent inhibition (% I) for each well was calculated using the following formula:% I = [(untreated wells average - well treated) / (average untreated wells)] x 100 The value of the untreated well Average (average untreated wells) is the arithmetic mean of 40 wells from the same test plate, treated with vehicle only. Negative inhibition values result from local variations in treated wells, compared to untreated wells. Example 2: Preparation of the compounds. Supply solutions containing NsIDI and an NsIDIE in dimethyl sulfoxide (DMSO) were made in a final concentration between 0 and 40 μM. Master plates were prepared containing dilutions of the delivery solutions of the compounds described above. The master plates were sealed and stored at -20 ° C until ready for use. Supplies of NsIDI The supply solution containing cyclosporin A was made at a concentration of 1.2 mg / ml in dimethyl sulfoxide. The tacrolimus supply solution was made at a concentration of 0.04 mg / ml in dimethyl sulfoxide. Supply of NsIDIE Supply solutions were made containing sertraline, fluoxetine, or fluvoxamine at a concentration of 10 mg / ml, in dimethyl sulfoxide. The supply solution containing maprotiline was made at a concentration of 10 mg / ml, in dimethyl sulfoxide. The supply solution containing triclosan was made at a concentration of 10 mg / ml, in dimethyl sulfoxide. The delivery solution containing loratadine was made at a concentration of 10 mg / ml in dimethyl sulfoxide. The delivery solution containing chlorpromazine or ethopropazine was made at a concentration of 10 mg / ml in dimethyl sulfoxide. The delivery solution containing loperamide was made at a concentration of 10 mg / ml in dimethyl sulfoxide. Master plates were prepared containing dilutions of the delivery solutions of the compounds described above. The master plates were sealed and stored at -20 ° C, until they were ready to be used. The plates of the final individual agents were generated by transferring one microliter of the delivery solution from the specific master plate to a dilution plate containing 100 microliters of the medium (RPM).; Gibco BRL, # 11875-085), 10 percent fetal bovine serum (Gibco BRL, # 25140-097), 2 percent penicillin / streptomycin (Gibco BRL, # 15140-122), using a Packard liquid handler Mini-Trak This dilution plate was then mixed, and a 5 microliter aliquot was transferred to the final assay plate, which had been previously filled with 50 microliters / well of the RPMl medium containing the appropriate stimulant to activate the secretion of IFN ?, IL -lß, IL-2, or TNFa (see Example 1, supra). Example 3: The Combination of Cyclosporin A and Sertraline Reduces Secretion of IL-2 in Vi tro The secretion of IL-2 was measured by ELISA as described above, after being stimulated with 12-phorbol 12-myristate acetate and ionomycin. . The effects of varying the concentrations of cyclosporin A, sertraline, and a combination of sertraline and cyclosporin A, were compared with the control wells. These wells were stimulated with phorbol 12-myristate 13-acetate and ionomycin, but did not receive cyclosporin A or sertraline. The results of this experiment are shown in Table 26. The effects of the agents alone and in combination are shown as the percentage of inhibition of IL-2 secretion. The data demonstrate that, in the present assay, cyclosporin A maximally inhibits IL-2 production by 83.5 percent at concentrations of 1 μM. The addition of 8 μM sertraline reduces the concentration of cyclosporin A required for the same inhibition up to 0.031 μM, a 32-fold reduction in the concentration of cyclosporin A.

Table 6.% Inhibition of IL-2 PBMC Pl Cyclosporin A (μM) Example 4: The combination of Cyclosporin A and Sertraline Reduces the Secretion of IFN? in vi tro The secretion of IFN? by ELISA as described above, after being stimulated with 12-phorbol 12-myristate acetate and ionomycin. The effect of different concentrations of cyclosporin A, sertraline, and cyclosporin A in combination with sertraline was compared to stimulated control wells without cyclosporin A or sertraline. The results of this experiment are shown in Table 7 below. The effects of the agents alone and in combination are shown as the percentage of inhibition of IFN? Secretion. The data show that, in the present assay, cyclosporin A maximally inhibits IFNα production. by 95.5 percent in concentrations of 1 μM. The addition of 8 μM sertraline demonstrates a dose dispersion effect with cyclosporin A, which almost doubles the inhibition of IFNα. by cyclosporin A 0.062 μM, reaching an inhibition of 83.4 percent.

Example 5: The combination of Cyclosporin A and Sertraline Reduces Secretion of TNFa in vi tro The secretion of TNFα was measured by ELISA as described above, after being stimulated with phorbol 12-myristate 13-acetate and ionomycin. The effect of different concentrations of cyclosporin A, sertraline, and cyclosporin A in combination with sertraline was compared with stimulated control wells without cyclosporin A or sertraline. The results are shown in Table 8 below. The effects of the agents alone and in combination are shown as the percentage inhibition of TNFa secretion. The data show that, in the present assay, cyclosporin A maximally inhibits TNFa production by 94.2 percent at concentrations of 1 μM. The addition of 8 μM sertraline demonstrates a dose dispersion effect with cyclosporin A, which doubles TNFa inhibition by the 0.031 μM porin A cycles, reaching an inhibition of 85.4 percent.

Example 6: The combination of Cyclosporin A and Fluoxetine Reduces the Secretion of IL-2 in vi tro The secretion of IL-2 was measured by ELISA as described above, after being stimulated with phorbol 12-myristate 13-myristate and ionomycin . The effect of different concentrations of cyclosporin A, fluoxetine, and cyclosporin A in combination with fluoxetine was compared with stimulated control wells without cyclosporin A or fluoxetine. The results of this experiment are shown in Table 9 below. The effects of the agents alone and in combination are shown as the percentage of inhibition of IL-2 secretion. The data demonstrate that, in the present assay, the addition of 21 μM fluoxetine in combination with cyclosporin A 0.062 μM inhibits the secretion of IL-2 by 98.8 percent, an improvement of the inhibition with cyclosporin A 0.062 μM provided alone.

Example 7: The combination of Tacrolimus and Fluvoxamine Reduces the Secretion of IL-2 in vi tro The secretion of IL-2 was measured by ELISA as described above, after being stimulated with phorbol 12-myristate 13-acetate and ionomycin. The effect of different concentrations of tacrolimus, fluvoxamine, and tacrolimus A in combination with fluvoxamine was compared with stimulated control wells without tacrolimus or fluvoxamine. The results of this experiment are shown in Table 10 below. The effects of the agents alone and in combination are shown as the percentage of inhibition of IL-2 secretion. The data show that, in the present assay, tacrolimus maximally inhibits IL-2 production by 87 percent at concentrations of 0.05 μM. The addition of 10 μM fluvoxamine demonstrates a dose dispersion effect with cyclosporin A, reaching an 85 percent inhibition of IL-2 with 0.013 μM tacrolimus.

Table 10.% Inhibition of IL-2 PBMC Pl Tacrolimus A (μM) Example 8: The combination of Cyclosporin A and Paroxetine Reduces Secretion of IL-2 in vitro The secretion of IL-2 was measured by ELISA as described above, after being stimulated with phorbol 12-myristate 13 -acetate and ionomycin. The effect of different concentrations of cyclosporin A, paroxetine, and cyclosporin A in combination with paroxetine was compared with stimulated control wells without cyclosporin A or paroxetine. The results of this experiment are shown in Table 11 below. The effects of the agents alone and in combination are shown as the percentage of inhibition of IL-2 secretion. The data show that, in the present assay, cyclosporin A inhibits the production of IL-2 by 97.7 percent at concentrations of 1 μM. The addition of paroxetine 8.9 μM demonstrates a dose dispersion effect with cyclosporin A, reaching a 90.7 percent inhibition of IL-2 with cyclosporin A 0.062 μM.

Example 9: The combination of Cyclosporin A and Paroxetine Reduces the Secretion of IL-2 in vi tro The IL-2 secretion was measured by ELISA as described above, after being stimulated with phorbol 12-m-ristate 13-acetate. and ionomycin. The effect of different concentrations of cyclosporin A, paroxetine, and cyclosporin A in combination with paroxetine was compared with stimulated control wells without cyclosporin A or paroxetine. The results of this experiment are shown in Table 12 below. The effects of the agents alone and in combination are shown as the percentage of inhibition of IL-2 secretion.

Example 10: The combination of Cyclosporin A and Maprotiline Reduces the Secretion of IL-2 in vi tro The secretion of IL-2 was measured by ELISA as described above, after being stimulated with 12-phorbol 12-myristate acetate and ionomycin . The effects of different concentrations of cyclosporin A, maprotiline, and a combination of maprotiline and cyclosporin A, were compared with the control wells. These wells were stimulated with phorbol 12-myristate 13-acetate and ionomicma, but did not receive cyclosporin A or maprotiline.

The results of this experiment are shown in Table 13. The effects of the agents alone and in combination are shown as a percentage of inhibition of IL-2 secretion. These results were averaged from the experiments carried out with white blood cells taken from two different donors.

Example 11: The combination of Cyclosporin A and Maprotiline Reduces Secretion of TNFa in vi tro The secretion of TNFα was measured by ELISA as described above, followed by stimulation with lipopolysaccharide. The effect of different concentrations of cyclosporin A, maprotiline, and cyclosporin A in combination with maprotiline, was compared with stimulated control wells without cyclosporin A or maprotiline. The results are shown in Table 14. The effects of the agents alone and in combination are shown as a percentage of inhibition of TNFa secretion. These results are the average of the experiments carried out with white blood cells obtained from two donors.

Example 12: The combination of Cyclosporin A and Triclosan Reduces the Secretion of IL-2 in vi tro The secretion of IL-2 was measured by ELISA as described above, after being stimulated with 12-phorbol 12-myristate acetate and ionomycin . The effects of different concentrations of ciclopopna A, triclosan, and a combination of triclosan and cyclosporin A, were compared with the control wells. These wells were stimulated with phorbol 12-myristate 13-mymethate and ionomycin, but did not receive cyclosporin A or triclosan. The results of this experiment are shown in Table 15. The effects of the agents alone and in combination are shown as a percentage of inhibition of IL-2 secretion. These results were averaged from the experiments carried out with white blood cells taken from two different donors.

Example 13: The combination of Cyclosporin A and Triclosan Reduces Secretion of TNFa in vi tro The secretion of TNFα was measured by ELISA as described above, after being stimulated with lipopolysaccharide. The effect of different concentrations of cyclosporin A, triclosan, and cyclosporin A in combination with triclosan was compared to stimulated control wells without cyclosporin A or triclosan. The results of this experiment are shown in Table 16. The effects of the agents alone and in combination are shown as a percentage inhibition of TNFa secretion. The results of this experiment are the average of the experiments carried out with white blood cells obtained from two donors.

Example 14: The combination of Cyclosporin A and Loratadine Reduces the Secretion of IL-2 in vi tro The secretion of IL-2 was measured by ELISA as described above, after being stimulated with 12-phorbol 12-myristate acetate and ionomycin . The effects of different concentrations of cyclosporin A, loratadine, and a combination of loratadine and cyclosporin A, were compared with the control wells. These wells were stimulated with phorbol 12-myristate 13-mymethate and ionomycin, but did not receive cyclosporin A or loratadine. The results of this experiment are shown in Table 17. The effects of the agents alone and in combination are shown as a percentage of inhibition of IL-2 secretion. The results shown below are from a single representative experiment.

Example 15: The combination of Cyclosporin A and Loratadine Reduces the Secretion of TNFa in vi tro The secretion of TNFα was measured by ELISA as described above, after being stimulated with lipopolysaccharide. The effect of varying the concentrations of cyclosporin A, loratadine, and cyclosporin A, in combination with loratadine, was compared with stimulated control wells without cyclosporin A or loratadine. The results of this experiment are shown in Table 18 below. The effects of the agents alone and in combination are shown as a percentage of inhibition of TNFa secretion. These results are the average of the experiments carried out with white blood cells obtained from two donors. The results shown below are from a single representative experiment.

Example 16: The combination of Cyclosporin A and Desloratadine Reduces the Secretion of TNFa in vi tro The secretion of TNFa was assayed as described above, after its stimulation with phorbol 12-myristate 13-acetate. The effect of varying the concentrations of cyclosporine and desloratadine was compared with stimulated control wells without cyclosporin A or loratadine. The results of this experiment are shown in Table 19 below.

Example 17: The combination of Cyclosporin A and Loratadine Reduces the Secretion of TNFa in vi tro The secretion of TNFa was assayed as described above, after its stimulation with phorbol 12-myristate 13-acetate. The effect of varying the concentrations of ciclospopna and loratadine was compared with stimulated control wells without cyclosporin A or loratadine. The results of this experiment are shown in Table 20 below.

Example 18: The combination of Cyclosporin A and Chlorpromazine Reduces the Secretion of IL-2 in vi tro The secretion of IL-2 was measured by ELISA as described above, after being stimulated with 12-phorbol 12-myristate acetate and ionomycin. . The effects of varying the concentrations of ciclopopna A, chlorpromazine, and a combination of chlorpromazine and cyclosporin A, were compared with the control wells. These wells were stimulated with phorbol 12-myristate 13-mymethate and ionomycin, but did not receive cyclosporin A or chlorpromazine. The results of this experiment are shown in Table 21. The effects of the agents alone and in combination are shown as a percentage of inhibition of IL-2 secretion. The results shown below are from a single representative experiment. (μM) Example 19: The combination of Cyclosporin A and Chlorpromazine Reduces the Secretion of TNFa in vi tro The secretion of TNFα was measured by ELISA as described above, after being stimulated with lipopolysaccharide. The effect of varying the concentrations of cyclosporin A, chlorpromazine, and cyclosporin A in combination with chlorpromazine was compared with stimulated control wells without cyclosporin A or chlorpromazine. The results of this experiment are shown in Table 22 below. The effects of the agents alone and in combination are shown as a percentage of inhibition of TNFa secretion. These results are the average of the experiments carried out with white blood cells obtained from two donors.

Table 22.% Cyclosporin A Inhibition (μM) Example 20: The combination of Cyclosporin A and Etopropazine Reduces the Secretion of IL-2 in vi tro The secretion of IL-2 was measured by ELISA as described above, after being stimulated with 13-phorbol 12-m-ristate acetate and ionomycin. The effects of varying the concentrations of cyclosporin A, ethopropazine, and a combination of ethopropazine and cyclosporin A, were compared with the control wells. These wells were stimulated with phorbol 12-myristate 13-ionic acetate and ionomicma, but did not receive cyclosporin A or ethopropazm. The results of this experiment are shown in Table 23. The effects of the agents alone and in combination are shown as a percentage of inhibition of IL-2 secretion. These results are the average of the experiments carried out with white blood cells obtained from two donors.

Example 21: The combination of Cyclosporin A and Etopropazine Reduces the Secretion of TNFa in vi tro The secretion of TNFα was measured by ELISA as described above, after being stimulated with lipopolysaccharide. The effect of varying the concentrations of cyclosporin A, ethopropazine, and cyclosporin A in combination with ethopropazine, was compared with stimulated control wells without cyclosporin A, or ethopropazine. The results of this experiment are shown in Table 24 below. The effects of the agents alone and in combination are shown as a percentage and inhibition of TNFa secretion. These results are the average of the experiments carried out with white blood cells obtained from two donors.

Example 22: The combination of Cyclosporin A and Loperamide Reduces Secretion of IL-2 in vi tro The secretion of IL-2 was measured by ELISA as described above, after being stimulated with 12-acetate 12-phorbol myristate and ionomycin . The effects of varying the concentrations of ciclosporma A, loperamide, and a combination of loperamide and cyclosporin A, were compared with the control wells. These wells were stimulated with phorbol 12-myristate 13-mymethate and ionomycin, but did not receive cyclosporin A or loperamide. The results of this experiment are shown in Table 25. The effects of the agents alone and in combination are shown as a percentage of inhibition of IL-2 secretion. The results of this experiment are the average of the experiments carried out with white blood cells obtained from two donors.

Example 23: The combination of Cyclosporin A and Loperamide Reduces Secretion of TNFa in vi tro The secretion of TNFα was measured by ELISA as described above, after its stimulation with lipopolysaccharide. The effect of varying the concentrations of cyclosporin A, loperamide, and cyclosporin A in combination with loperamide was compared with stimulated control wells without cyclosporin A or loperamide. The results of this experiment are shown in Table 26. The effects of the agents alone and in combination are shown as a percentage of inhibition of TNFa secretion. The results of this experiment are the average of the experiments carried out with blood cells obtained from two donors.

Other Modalities Different modifications and variations of the described method and system of the invention will be apparent to those skilled in the art, without departing from the scope and spirit of the invention.

Claims (87)

1. CLAIMS 1. A composition comprising a tricyclic compound and a corticosteroid in amounts that together are sufficient to treat an immuno-inflammatory disorder when administered to a patient.
2. 2. The composition of claim 1, wherein said tricyclic compound is amitriptyline, amoxapine, clomipramine, dothiepin, doxepin, desipramine, imipramine, lofepramine, loxapine, maprotiline, mianserin, mirtazapine, oxaprotiline, nortriptyline, octriptilina, protriptyline, trimipramine or.
3. 3. The composition of claim 1 wherein said steroid is prednisolone cortical, cortisone, budesonide, dexamethasone, hydrocortisone, methylprednisolone, fluticasone, prednisone, triamcinolone, or diflorasone.
4. 4. The composition of claim 1, wherein said tricyclic compound is nortriptyline and said cortico-steroid is budesonide.
5. The composition of claim 1, wherein said tricyclic compound or said cortico-steroid are present in said composition in a low dose.
6. The composition of claim 1, wherein said tricyclic compound or said cortico-steroid are present in said composition in a high dose.
7. 7. The composition of claim 1, further co-do prendien an NSAID, COX-2 inhibitor, biologic, DMARD, immunomodulatory small molecule, xanthine, anti-cholinergic compound, beta receptor agonist, bronchodilator, immuno- non-spheroidal immunophilin-dependent suppressor, vitamin D analogue, psoralen, retinoid, or 5-amino-salicylic acid.
8. The composition of claim 7, wherein said NSAID is ibuprofen, diclofenac, or naproxen.
9. The composition of claim 7, wherein said COX-2 inhibitor is rofecoxib, celecoxib, valdecoxib, or lumiracoxib.
10. The composition of claim 7, wherein said biological is adelimumab, etanercept, infliximab, CDP-870, rituximab, or atlizumab.
11. The composition of claim 7, wherein said DMARD is methotrexate or leflunomide.
12. 12. The composition of claim 7, wherein said xanthine is theophylline.
13. The composition of claim 7, wherein said anti-cholinergic compound is ipratropium or tiotropium.
14. 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 non-spheroidal immunophilin-dependent immuno-suppressor is cyclosporin, tacrolimus, pimecrolimus, or ISAtx247.
16. 16. The composition of claim 7, wherein said vitamin D analog is calcipotriene or calcipotriol.
17. 17. The composition of claim 7, wherein said psoralen is methoxsalen.
18. 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, balsalazide disodium, or olsalazine sodium.
20. 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.
21. The composition of claim 1, wherein said composition is formulated for topical administration.
22. 22. The composition of claim 1, wherein said composition is formulated for systemic administration.
23. 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. 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. 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.
26. 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.
27. The method of claim 1, wherein said cortico-steroid is prednisolone, cortisone, budesonide, dexamethasone, hydrocortisone, methylprednisolone, fluticasone, prednisone, triamcinolone, or diflorasone.
28. 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-spheroidal immunophilin, vitamin D analog, psoralen, retinoid, or 5-amino salicylic acid.
29. 29. The method of claim 28, wherein said NSAID is ibuprofen, diclofenac, or naproxen.
30. 30. The method of claim 28, wherein said COX-2 inhibitor is rofecoxib, celecoxib, valdecoxib, or lumiracoxib.
31. 31. The method of claim 28, wherein said biological is adelimumab, etanercept, infliximab, CDP-870, rituximab, or atlizumab.
32. 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. 33. The method of claim 28, wherein said DMARD is methotrexate or leflunomide.
34. 34. The method of claim 28, wherein said xanthine is theophylline.
35. 35. The method of claim 28, wherein said anti-cholinergic compound is ipratropium or tiotropium.
36. 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. 37. The method of claim 28, wherein said non-spheroidal immunophilin-dependent immuno-suppressor is cyclosporin, tacrolimus, pimecrolimus, or ISAtx247.
38. 38. The method of claim 28, wherein said vitamin D analog is calcipotriene or calcipotriol.
39. 39. The method of claim 28, wherein said psoralen is methoxsalen.
40. 40. The method of claim 28, wherein said retinoid is acitetrin or tazoretene.
41. 41. The method of claim 28, wherein said 5-amino salicylic acid is mesalamine, sulfasalazine, balsalazide disodium, or olsalazine sodium.
42. 42. The method of claim 24, wherein said tricyclic compound or said cortico-steroid is administered in a low dose.
43. 43. The method of claim 24, wherein said tricyclic compound or said cortico-steroid is administered in a high dose.
44. 44. The method of claim 24, wherein said tricyclic compound and said cortico-steroid are administered within 10 days of each other.
45. 45. The method of claim 44, wherein said tricyclic compound and said cortico-steroid are administered within five days together.
46. 46. The method of claim 45, wherein said tricyclic compound and said cortico-steroid are administered within twenty-four hours together.
47. 47. The method of claim 46, wherein said tricyclic compound and said cortico-steroid are administered simultaneously.
48. 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. 49. The composition of claim 48, wherein said tricyclic compound is amitriptyline, amoxapine, clomiphoramine, dotiepin, doxepin, desipramine, imipramine, lofepramine, loxapine, maprotiline, mianserin, mirtazapine, oxaprotiline, nortriptyline, octriptilin, protriptyline, or trimipramine .
50. 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, immunosuppressant-dependent non-spheroidal immunophilin, vitamin D analog, psoralen, retinoid, or 5-amino salicylic acid.
51. 51. A method for decreasing the secretion or production of a 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 to each other in sufficient amounts in I live to decrease the secretion or production of pro-inflammatory cytokine in said patient.
52. 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. 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. 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. 55. The method of claim 52, further comprising an NSAID, biological COX-2 inhibitor, DMARD, small molecule immuno-modulator, xanthine, anti-cholinergic compound, beta receptor agonist, bronchodilator, immunosuppressant dependent on non-spheroidal immunophilin, vitamin D analogue, psoralen, retinoid, or 5-amino salicylic acid.
56. 56. The method of claim 52, wherein said tricyclic compound and said cortico-steroid are administered within 10 days of each other.
57. 57. The method of claim 56, wherein said tricyclic compound and said cortico-steroid are administered within five days to each other.
58. 58. The method of claim 57, wherein said tricyclic compound and said cortico-steroid are administered within twenty-four hours together.
59. 59. The method of claim 58, wherein said tricyclic compound and said cortico-steroid are administered simultaneously.
60. 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, immunosuppressant dependent on non-spheroidal immunophilin, vitamin D analog, psoralen, retinoid, or 5-amino salicylic acid.
61. 61. The composition of claim 60, wherein said NSAID is ibuprofen, diclofenac, or naproxen.
62. 62. The composition of claim 60, wherein said COX-2 inhibitor is rofecoxib, celecoxib, valdecoxib, or lumiracoxib.
63. 63. The composition of claim 60, wherein said biological is adelimumab, etanercept, infliximab, CDP-870, rituximab, or atlizumab.
64. 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. 65. The composition of claim 60, wherein said DMARD is methotrexate or leflunomide.
66. 66. The composition of claim 60, wherein said xanthine is theophylline.
67. 67. The composition of claim 60, wherein said anti-cholinergic compound is ipratropium or tiotropium.
68. 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. 69. The composition of claim 60, wherein said non-spheroidal immunophilin-dependent immuno-suppressor is cyclosporin, tacrolimus, pimecrolimus, or ISAtx247.
70. 70. The composition of claim 60, wherein said vitamin D analog is calcipotriene or calcipotriol.
71. 71. The composition of claim 60, wherein said psoralen is methoxsalen.
72. 72. The composition of claim 60, wherein said retinoid is acitetrin or tazoretene.
73. 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, non-spheroidal 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. 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. 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. 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. 77. A kit, comprising: (i) a tricyclic compound; (ii) a cortico-steroid; and (iii) instructions for systematically administering said tricyclic compound and said corticosteroid to a patient diagnosed with or at risk of developing an immuno-inflammatory disorder.
78. 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. 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, immunosuppressant dependent on non-spheroidal immunophilin, 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. 80. A kit comprising (i) a tricyclic compound and (ii) instructions for administering said tricyclic compound and a corticosteroid to a patient diagnosed with or at risk of developing an immuno-inflammatory disorder.
81. 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 receptor agonist, bronchodilator, biologic, NSAID, DMARD, COX-2 inhibitor, immunosuppressant dependent on non-spheroidal immunophilin, vitamin D analogue, psoralen, retinoid, or 5-amino salicylic acid to a patient diagnosed with or at risk of developing an immuno-inflammatory disorder.
82. 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. 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. 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. 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-spheroid 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. 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 contacted with said identified compound in step (a) or in contact 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 can be useful for the treatment of an immuno-inflammatory disorder.
87. 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.