US 2011 0195031A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0195031 A1 Du (43) Pub. Date: Aug. 11, 2011

(54) METHODS FOR THE USE OF A6IP3L/00 (2006.01) PROGESTOGENASA GLUCOCORTICOD A6IP 25/00 (2006.01) SENSTIZER A6IP27/02 (2006.01) A6IP 29/00 (2006.01) (75) Inventor: Tao Tom Du, North Potomac, MD A6IP II/00 (2006.01) (US) A6IP3/00 (2006.01) (73) Assignee: PRAIRIE (52) U.S. Cl...... 424/43: 514/1 6; 26, . PHARMACEUTICALS, LLC, s Bethesda, MD (US) (57) ABSTRACT (21) Appl. No.: 13/021,950 Provided are methods and kits for administering progestogen as a glucocorticoid sensitizer to restore corticosteroid sensi (22) Filed: Feb. 7, 2011 tivity or reverse the glucocorticoid insensitivity or enhance glucocorticoid sensitivity, in order to treat one or more glu Related U.S. Application Data cocorticoid insensitivity related diseases or conditions. For (60) Provisional8, 2010. application No. 61/302,325, filed on Feb. co1d 1nsensitivityPl thes e include in a su st ject havingfor no historys the of FISA menstrua cycle-related exacerbation or allergy to self-hormones, par O O ticularly progesterone. Such as premenstrual or perimenstrual Publication Classification E.in the SNE 9. NASA worsening (51) Int. Cl. of atopic dermatitis or premenstrual exacerbations of asthma, A 6LX 39/395 (2006.01) and exhibiting relatively or totally refractory responses to A6 IK3I/56 (2006.01) glucocorticoid therapy, e.g., glucocorticoid resistance. The A6 IK 9/12 (2006.01) methods and kits provide for the administration of a sex A 6LX 3/57 (2006.01) hormone to the subject who is corticosteroid dependent or A6 IK 38/13 (2006.01) corticoid resistant or unresponsive or intolerant to corticos A6IP 9/00 (2006.01) teroids. Patent Application Publication Aug. 11, 2011 Sheet 1 of 12 US 2011/O195031 A1

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METHODS FOR THE USE OF 0004 Diseases/conditions related to glucocorticoid insen PROGESTOGENASA GLUCOCORTICOD sitivity may include: refractory inflammatory bowel disease, SENSTIZER such as Refractory ulcerative colitis and children with severe Crohn disease, corticosteroid refractory asthma or glucocor CROSS-REFERENCE TO RELATED ticoid resistant asthma or symptomatic corticosteroid depen APPLICATIONS dent asthma, descquamative interstitial pneumonia refractory to corticosteroid, refractory inflammatory myopathies, 0001. This application claims priority to U.S. Provisional refractory myasthenia gravis, refractory pemphigus Vulgaris, Patent Application Ser. No. 61/302.325 that was filed on Feb. methotrexaterefractory RA patients, refractory nephrotic 8, 2010, the entire disclosure of which is hereby incorporated syndrome in adults, corticosteroid dependent systemic lupus by reference. erythematosus (SLE), primary Sjogren's syndrome, systemic vasculitis and polymyositis, chronic graft-Versus-host dis FIELD OF THE INVENTION ease, corticosteroid dependent or refractory multiple Sclero sis, refractory sprue-like disease, Steroid-resistant sarcoido 0002 Glucocorticoid insensitivity presents a profound sis, refractory mucosal lesions of pemphigus Vulgaris, management problem in diseases/conditions treated with glu refractory Schnitzler syndrome, resistant dermatitis of the cocorticoids because the therapy is not effective. The present head and neck, severe refractory atopic dermatitis, refractory invention relates to methods and kits for administering Idiopathic thrombocytopenia purpura, refractory orbital progestogen as a glucocorticoid sensitizer to restore corticos myositis, refractory or recurrent lymphomas, critically ill teroid sensitivity or reverse the glucocorticoid insensitivity or patients with sepsis or acute respiratory distress syndrome enhance glucocorticoid sensitivity, in order to treat one or (ARDS) or relative adrenal insufficiency, corticosteroid-de more glucocorticoid insensitivity related diseases or condi pendent conditions (e.g., rosacea, polymyalgia rheumatic, tions. For example, the present invention relates to methods giant cell arteritis, polymyositis, dermatomyositis, Kawasaki for reversing the glucocorticoid insensitivity in a Subject hav syndrome, Guillain-Barre Syndrome, chronic inflammatory ing no history of menstrual cycle-related exacerbation or demyelinating polyneuropathy, multifocal motor neuropathy, allergy to self-hormones, particularly progesterone, such as Stiff man syndrome etc.). Glucocorticoid insensitivity has premenstrual or perimenstrual deterioration in the symptoms, serious health, Societal, and economic costs. For example, a e.g., premenstrual worsening of atopic dermatitis or premen small percentage of patients with asthma (5-10%) have severe strual exacerbations of asthma, and exhibiting relatively or corticosteroid-refractory condition that often fails to respond totally refractory responses to glucocorticoid therapy, e.g., but these patients account for >50% of the total asthma health glucocorticoid resistance. The methods and kits of the present Care COStS. invention provide for the administration of a sex hormone to 0005 Glucocorticoids suppress inflammation mainly as a the subject who is corticosteroid dependent or corticoid resis result of both activation of anti-inflammatory genes and Sup tant or unresponsive or intolerant to corticosteroids. pression of pro-inflammatory genes. The activation of anti inflammatory gene expression starts as glucocorticoid binds BACKGROUND OF THE INVENTION cytosolic glucocorticoid receptor (GR), which is activated and translocates to the nucleus. Once in the nucleus, it binds 0003 Glucocorticoids are the first-line treatment for vari to glucocorticoid response elements (GREs) and transcrip ous immune-inflammatory and allergic diseases. For tional coactivator molecules, and causes acetylation of core example, the autoimmune diseases include more than 70 histones, which leads to the expression of anti-inflammatory chronic disorders that affect about 5% of the US population, genes. Inflammatory stimuli Switch on multiple inflammatory and include those that most occur in women (>80%) such as genes that encode cytokines, chemokines, adhesion mol Sjogren's syndrome, SLE, autoimmune thyroid disease ecules, inflammatory enzymes, and receptors via pro-inflam (Hashimoto's thyroiditis and well as Graves’ disease) and matory transcription factors, such as nuclear factor KB scleroderma, or relatively common among women (60-75%) (NFKB) and activator protein 1, and the recruitment of co such as rheumatoid arthritis (RA), multiple sclerosis (MS) repressor molecules. Activated glucocorticoid receptors bind and myasthenia gravis; or those that occurata similar female: to the coactivators in the nucleus to inhibit histone acetyl male ratio Such as Sarcoid and inflammatory bowel diseases. transferase (HAT) activity directly and recruit histone Glucocorticoid insensitivity presents a profound manage deacetylase 2 (HDAC2), leading to Suppression of the acti ment problem in those diseases/conditions treated with ste vated inflammatory genes. roids, and twenty to forty percent of patients may fail to 0006. Several possible molecular mechanisms of gluco achieve disease control. The glucocorticoid insensitivity may corticoid resistance have been recognized, and include present as relatively or totally refractory to glucocorticoid genetic susceptibility, lack of or defective binding to GR and therapy; unresponsive or intolerant to corticosteroids; unre translocation, reduced GR expression, lack of co-repressor sponsive to an adequate induction dose of corticosteroids; activity, or enhanced activation of inflammatory pathways. initially responsive to corticosteroids but relapses quickly For example, glucocorticoid receptors might be phosphory upon drug withdrawal or dose tapering (corticosteroid depen lated by several kinases (e.g., p38 mitogen-activated protein dent); corticoid resistant, e.g., requires a very high dose treat kinase, c-Jun N-terminal kinase, and extracellular signal ment; or “difficult to treat' or severe condition. For example, regulated kinase) that results in the defective binding, alter 20-30% of patients with severe and steroid-resistant Crohn's ations in their stability, translocation to the nucleus, binding Disease will not respond to steroid therapy (Michetti P. Mot to DNA, and interaction with other proteins. Excessive acti tet C, Juillerat P. Felley C, Vader J.-P. Burnand B, Gonvers J-J, Vation of the transcription factor activator protein 1 can pre Froehlich F: Severe and Steroid-Resistant Crohn's Disease. vent GRS binding to glucocorticoid response elements Digestion 2005: 71:19-25). (GREs) or inhibiting nuclear factor KB: Nitric oxide (NO) can US 2011/O 195031 A1 Aug. 11, 2011

nitrate tyrosine residues on GRs; GRs can also be ubiquiti 0011 Progestogen products have been extensively used in nated (Ub), which results in degradation of GR by the pro a wide range of reproductive diseases/conditions for more teasome; reduced histone deacetylase-2 (HDAC2) expres than 60 years, and known to have anti-inflammatory effects. Sion, raised macrophage migration inhibitory factor, and The majority of studies related to inflammatory responses increased P-glycoprotein-mediated drug efflux (Peter J Bar were conducted in pregnancy-associated models. Progester nes, Ian M Adcock. Glucocorticoid resistance in inflamma one/PR Maintains Uterine Quiescence via Antiinflammatory tory diseases. Lancet 2009; 373: 1905-17). Actions (Carole R. Mendelson. Minireview: Fetal-Maternal 0007. The clinical and biological mechanisms of steroid Hormonal Signaling in Pregnancy and Labor Molecular dependency are not well understood compared with those Endocrinology 23: 947-954, 2009). Gellersen (2009) pro determining steroid-resistance. Steroid-dependency and Ste vided a comprehensive review of non-genomic progesterone roid-resistance may share some common intrinsic mecha actions, and Summarized possible mechanisms of progester nisms while other mechanisms are simply clinical orpharma one anti-inflammatory effects, including that progesterone cological. opposes prostaglandin production in the uterus of pregnancy, 0008. Many attempts have been made to ameliorate the partially by inhibiting cyclooxygenase (COX-2) expression; effects of glucocorticoid insensitivity. A common approach is immunoregulatory function in human T-lymphocytes via to use broad-spectrum anti-inflammatory treatments such as G-protein activation and K+ channel Inhibition; progester immunosuppressive or immunomodulators agents (e.g., one-induced blocking factor (PIBF) acts on the phospholi cyclosporine, methotrexate, gold, 6-mercaptopurine, bio pase A2 enzyme, interferes with arachidonic acid metabo logic products such as intravenous immunoglobulin and lism, induces a Th2 biased immune response, and exerts an Mepolizumab), and calcineurin inhibitors (e.g., cyclosporin, anti-abortive effect by controlling NK activity (Gellersen Bet tacrolimus). Various approaches have been proposed or al. Non-genomic progesterone actions in female reproduction developed to reverse glucocorticoid resistance Such as p38 Human Reproduction Update, Vol. 15, No. 1 pp. 119-138, MAP kinase inhibitors, JNK inhibitors (decrease API), Vita 2009). Another review by Challies (2009) suggests other min D in Steroid-resistant asthma (increase regulatory T possible mechanisms: progesterone blocks mitogen-stimu cells), MIF inhibitors. Histone deacety late-2 activators, Theophylline, Phosphoinositide-3-kinase-8 inhibitors, anti lated lymphocyte proliferation, modulates antibody produc oxidants, iNOS inhibitors and P-glycoprotein inhibitors. The tion, decreases the oxidative burst of monocytes, reduces the use of progestogen for reversing the glucocorticoid-insensi production of proinflammatory cytokines by macrophages in tivity has not been discussed or presented anywhere, and the response to bacterial products, and alters cytokine secretion present invention represents a significant, Surprising and of T-cell clones to favor IL-10 production, upregulates Toll unexpected advance in the art. like receptor 4 (TLR-4) expression and suppresses TLR-2 0009. The different approaches for management of gluco response to infection in intrauterine tissues, resulting in a corticoid insensitivity have had limited Success. Some agents protective role with respect to preterm delivery, inhibits basal may work in a condition, but not others. Methotrexate is and cytokine-enhanced matrix metalloproteinases (MMP)-1 effective for rheumatoid arthritis, but it might be ineffective in and MMP-3 expression in cultured decidual cells demonstrat cases of glucocorticoid-resistant inflammatory bowel disease ing protection against preterm delivery (Challis J R et al. caused by increased P-glycoprotein expression. Similarly, Inflammation and Pregnancy Reproductive Sciences 2009: calcineurin inhibitors are useful in Some patients with gluco 16; 206). Since the concept of using progestogen for reversing corticoid-resistant inflammatory bowel disease, but they have the glucocorticoid-insensitivity has not been disclosed, not proven to be effective in glucocorticoid-resistant asthma. taught, Suggested, discussed, or presented anywhere, the Further, the uses of those agents are often associated with present discovery represents a significant and unexpected significant adverse events. A high percentage of patients (60 advance in the art. 70%) may fail treatment with methotrexate because of side 0012 Menstrual cycle-related exacerbation of common effects. Phosphodiesterase-4 inhibitors for COPD and medical conditions is a well-recognized phenomenon, and inflammatory conditions have dose-limiting side-effects of may include migraine, epilepsy, asthma, irritable bowel syn nausea, diarrhea, and headaches. Significant toxicity and side-effects have hampered the drug development programs drome, autoimmune progesterone dermatitis and stomatitis, for p38 MAP-kinase inhibitors and selective inhibitors to and diabetes. Exacerbation is influenced by hormonal block inhibition of NFkB kinase (IKKB)/NFkB (Peter J Bar changes of the menstrual cycle. The majority of these effects nes, Ian M Adcock. Glucocorticoid resistance in inflamma occur during the luteal and menstrual phases of the cycle. For tory diseases. Lancet 2009; 373: 1905-17). example, premenstrual asthma denotes worsening of asthma 0010 Given that a considerable proportion of patients symptoms shortly before and/or during menstruation. Accu with autoimmune, allergic, and lymphoproliferative diseases rate documentation of symptoms on a menstrual calendar are refractory to glucocorticoid therapy as well many differ allows identification of women with cyclic alterations in dis ent inflammatory diseases share similar molecular mecha ease activity. Female sex-steroid hormones play an important nisms in glucocorticoid insensitivity, there exists a heretofore role but the exact mechanism is still unknown. Several theo unmet need in the art for methods for developing a common ries exist to explain these menstrual cycle-related effects. therapeutic strategy to reverse the steroid-insensitivity. The These include fluctuations in levels of sex steroids, cyclic use of progestogen, in accordance with the present invention, alterations in the immune system, increased airway hyperre has been discovered to present a Surprising, unexpected, and sponsiveness, changing perceptions of disease severity also practicable method to help patients with diseases/condi brought about by premenstrual alterations in mood, as seen in tions that are unresponsive or intolerant to corticosteroids or premenstrual syndrome, and allergy to self-hormones par corticosteroid dependent and resistant. ticularly progesterone. Menstrual cycle-related exacerbation US 2011/O 195031 A1 Aug. 11, 2011 might be ameliorated by progesterone Supplementation Alli 0016 Activation of mitogen-activated protein kinases son M. Case and Robert L. Reid. Menstrual cycle effects on (MAPKs) is a critical event in mitogenic signal transduction. common medical conditions. Journal Comprehensive Ruzycky AL (1996) determined the effects of 17 beta-estra Therapy Issue Volume 27, Number 1/March, 2001: Beynon H diol and progesterone on mitogen-activated protein kinase L. Severe premenstrual exacerbations of asthma: effect of expression and activity. MAPK expression and activity was intramuscular progesterone. Lancet—13-Aug.-1988: examined in uterine Smooth muscle from rats pretreated with 2(8607): 370-2: Roby, Russell Ret al. Sublingual progester estradiol-17 beta alone or with estradiol-17 beta and proges one dilutions as bronchodilator in asthmatic females. World terone. MAPK expression was detected by immunoblotting using erk1/2 antibodies. MAPK activity was detected by Allergy Organization Journal: November 2007 Volume— measurement of the phosphorylation of a MAPK-specific Issue—p S148. peptide sequence of myelin basic protein. Steroid treatment 0013 Glucocorticoid insensitivity often correlates with caused a modest (20%) decline in erk 1 and 2 expression in other factors believed to contribute to relatively or totally membrane and cytosolic fractions. Both estrogen and proges refractory responses to glucocorticoid therapy. These include terone increased MAPK tyrosine phosphorylation and mem the various risk factors noted above Such as genetic suscep brane-associated MAPKactivity. Steroid treatment increased tibility, abnormalities in the glucocorticoid receptor gene, cytosolic MAPK tyrosine phosphorylation, but not enzymatic viral infection and oxidative stress. For example, oxidative activity. The above-described study and results are described DNA damage is known to be a primary cause of the process of in Ruzycky AL (Effects of 17 beta-estradiol and progesterone mutation and a leading cause of aging, cancer and other on mitogen-activated protein kinase expression and activity diseases because guanine, one of the four basic nucleotides that make up DNA and form the genetic code of life, is in ratuterine smooth muscle. EurJ Pharmacol. 1996 Apr. 11; particularly sensitive to oxidative damage, and a predominant 300(3):247-54). number of genetic mutations are linked to guanine. Thus, there exists a need in the art for methods for reducing the SUMMARY OF THE INVENTION occurrence of glucocorticoid insensitivity related conditions 0017 Certain embodiments of the present invention are (e.g., refractory asthma, refractory rheumatoid arthritis, directed to methods for restoring corticosteroid sensitivity or refractory inflammatory bowel disease, chronic obstructive reversing the glucocorticoid insensitivity or enhancing glu pulmonary disease and acute respiratory distress syndrome) cocorticoid sensitivity. associated with Such risk factors. 0018. Other embodiments of the present invention are 0014. A menstrual rhythm has been documented for exac directed to methods for administering a pharmaceutical com erbations of asthma, which may have important clinical rel position comprising a steroid hormone to a Subject having no evance to the patient with severe asthma. Beynon et al. (1988) history of menstrual cycle-related exacerbation, and Suffering reported 3 cases of severe premenstrual exacerbations of from one or more glucocorticoid insensitivity related condi asthma that were treated with intramuscular progesterone. tions. Glucocorticoid insensitivity related conditions include, The patients hadn't responded to conventional treatment, for instance, a range of corticoid resistant diseases and including high-dose corticosteroids. In all cases there was a immune-inflammatory disorders treated with steroids when fall premenstrually in peak flow rate. The addition of intra the therapy becomes ineffective or intolerant or dependent or muscular progesterone (100 mg daily in two cases and 600 unresponsive or refractory to corticosteroids, and combina mg twice a week in one) to the regimen eliminated the pre tions thereof. menstrual dips in peak flow, and daily doses of prednisolone 0019. In one embodiment, a method of the present inven were reduced in the three patients. The above-described study tion comprises administering a pharmaceutical composition and results are described in Beynon et al. (Severe premen comprising a steroid hormone to a Subject having no history strual exacerbations of asthma: effect of intramuscular of menstrual cycle-related exacerbation, wherein the subject progesterone. Lancet—13-Aug.-1988; 208607): 370-2.). is at risk for developing glucocorticoid insensitivity due to 0015. In another study, Russell R et al (2007) tested the exposure to oxidative stress. hypothesis that pre-menstrual asthma is associated with 0020. Yet other embodiments of the present invention are allergy to self-hormones particularly progesterone by using directed to methods for restoring corticosteroid sensitivity or Sublingual progesterone dilutions as bronchodilator. Sixteen reversing the glucocorticoid insensitivity or enhancing glu females who had a previous diagnosis of severe asthma and cocorticoid sensitivity, and treating one or more conditions who were nebulization dependent were selected for the study. selected from the group consisting of corticoid resistant dis Spirometric studies were performed on these subjects. Study eases, corticosteroid refractory, corticosteroid-dependent showed changes over time of the forced expiratory Volume in immune-inflammatory disorders, and combinations thereof. one second (FEV1), the forced vital capacity (FVC), and the Certain exemplary glucocorticoid resistant conditions peak expiratory flow (PEF) measured at three times: (1) include, but are not limited to, glucocorticoid resistant before treatment, (2) after Sublingual normal saline treatment asthma, refractory rheumatoid arthritis, refractory inflamma (3) after Sublingual progesterone treatment. After treatment tory bowel disease, chronic obstructive pulmonary disease with Sublingual progesterone, twelve of the sixteen patients and acute respiratory distress syndrome, interstitial pulmo (75%) experienced a bronchodilator effect (greater than 12% nary fibrosis, and cystic fibrosis. Certain exemplary gluco increase) in either FEV1 or FVC. Eight (50%) experienced an corticoid refractory conditions include, but are not limited to, increase in both FEV1 and FVC. Eight (50%) had an increase refractory ulcerative colitis, children with severe Crohn dis of 27% or greater in PEF. The above-described study and ease, corticosteroid refractory asthma, descquamative intersti results are described in Russell Ret al. (Sublingual progest tial pneumonia refractory to corticosteroid, refractory inflam erone dilutions as bronchodilatorinasthmatic females. World matory myopathies, refractory myasthenia gravis, refractory Allergy Organization Journal: November 2007 Volume— pemphigus Vulgaris, methotrexate-refractory RA patients, Issue—p S148.). refractory nephrotic syndrome, refractory multiple Sclerosis, US 2011/O 195031 A1 Aug. 11, 2011

refractory sprue-like disease, Steroid-resistant sarcoidosis, 0024. It is to be understood that the embodiments refractory mucosal lesions of pemphigus Vulgaris, refractory described above are provided as representative embodiments Schnitzler syndrome, resistant dermatitis of the head and of the present invention, and in no way are to be construed as neck, severe refractory atopic dermatitis, refractory Idio limiting the Scope of the present invention. pathic thrombocytopenia purpura, refractory orbital myosi tis, refractory or recurrent lymphomas, critically ill patients BRIEF DESCRIPTION OF THE DRAWINGS with sepsis or acute respiratory distress syndrome (ARDS) 0025 FIGS. 1-12 are graphical depictions of the results of and relative adrenal insufficiency. Certain exemplary gluco several examples which illustrate certain embodiments of the corticoid dependent conditions include, but are not limited to, invention, but in now way limit the scope of the invention. rosacea, polymyalgia rheumatic, giant cell arteritis, poly (0026 FIG. 1 depicts IL-2 levels at baseline, after PHA myositis, dermatomyositis, Kawasaki Syndrome, Guillain stimulation and dose-dependent inhibition of IL-2 by dexam Barre syndrome, chronic inflammatory demyelinating poly ethasone. neuropathy, multifocal motor neuropathy, Stiff man 0027 FIG.2 depicts that addition of IL-2 and IL-4 induces syndrome, corticosteroid dependent systemic lupus erythe steroid resistance. matosus, corticosteroid dependent multiple Sclerosis, Symp 0028 FIG. 3 depicts progestogen's effects (% Imax) in tomatic corticosteroid dependent asthma, primary Sjogren's reversing steroid resistance: comparing 17HPC, P4 and MPA syndrome, systemic vasculitis and polymyositis, organ trans under low dose Dexamethasone (hereinafter, “Dexametha plants, graft-versus-host disease, and glucocorticoid depen sone”) (10 M). dent cancer. 0029 FIG. 4 depicts progestogen's effects (% Imax) in reversing steroid resistance: comparing 17HPC, P4 and MPA 0021 Still other embodiments of the present invention are under high dose Dexamethasone (10 M). directed to kits comprising (i) a pharmaceutical composition 0030 FIG. 5 depicts that 17HPC restores corticosteroid comprising a steroid hormone and one or more pharmaceuti sensitivity. cally acceptable excipients; and (ii) instructions for adminis 0031 FIG. 6 depicts that 17HPC reverses steroid resis tering the pharmaceutical composition to a subject preferably tance and individual response patterns. having no history of menstrual cycle-related exacerbation, 0032. The results depicted in FIG. 7 show that 9 out 11 and Suffering from one or more glucocorticoid insensitivity subjects had a more than 10% improvement in maximal Dex related conditions. Glucocorticoid insensitivity related con amethasone inhibition after receiving a dose of 17HPC, ditions include, for instance, a range of corticoid resistant which is consistent with the results presented in FIG. 6. diseases and immune-inflammatory disorders treated with 0033. The results depicted in FIG. 8 show that 6 out of 8 steroids when the therapy becomes ineffective or intolerantor subjects had a more than 10% improvement in maximal Dex dependent or unresponsive or refractory to corticosteroids, amethasone inhibition after receiving a dose of natural and combinations thereof. progesterone, which is similar to 17HPC. 0022. In another embodiment, the kits of the present 0034. The results depicted in FIG. 9 shows that MPA invention comprise (i) a pharmaceutical composition com treatment leads a total different response pattern: a “split’ prising a steroid hormone and one or more pharmaceutically response. A Sub-group had a great improvement up to 58% acceptable excipients; and (ii) instructions for administering while another sub-group presented with a worsening in cor the pharmaceutical composition to a subject who is at high ticosteroid sensitivity, a reduction up to 88%. risk to develop glucocorticoid insensitivity, but preferably has 0035. The effects of 17HPC on dexamethasone sensitivity measured by IL-2 inhibition in smokers are shown in Table 1 no history of menstrual cycle-related exacerbation, and pref and FIG. 10. FIG. 10 shows add-on effect of 17HPC is erably is at risk for developing one or more glucocorticoid improvement of steroid sensitivity. insensitivity related conditions due to oxidative stress. 0036. The maximal anti-inflammatory effect of Dexam 0023 Yet other embodiments of the present invention are ethasone is 78% inhibition of PHA-induced IL-2 production directed to kits comprising (i) a pharmaceutical composition at 10 M. The add-on treatment of 17HPC produces a comprising a steroid hormone and one or more pharmaceuti significantly better responsiveness and results in near 100% cally acceptable excipients; and (ii) instructions for adminis suppression of PHA induced IL-2 (FIG. 11). FIG. 11 thus tering the pharmaceutical composition to a Subject that pref depicts a better treatment responsiveness with the 17HPC erably has no history of menstrual cycle-related exacerbation, add-on. and wherein the Subject is suffering from one or more gluco 0037. The combination of 17HPC with Dexamethasone corticoid insensitivity related conditions in order to achieve consistently increases dexamethasone's anti-inflammatory the glucocorticoid-sensitizer effects of steroid-sparing in cor effects, and is better than their uses individually. FIG. 12 ticosteroid-dependent patients, better responsiveness or tol shows that the combination leads to a synergetic effect, with erance to corticosteroids, achieving efficacy by using a lower 25-37% improvements in Dexamethasone efficacy. FIG. 12 dose of corticosteroid, preventing individuals at risk for thus depicts synergetic effects of combination of 17HPC with developing corticosteroid refractory responses or resistance Dexamethasone. or exacerbations in response to antigen exposures, infections, exercise, or irritants, achieving optimal immune-functions, DETAILED DESCRIPTION OF THE PREFERRED easier responses for the Subject or patient when steroid EMBODIMENTS administration is tapered or withdrawn, or in prolonged 0038. Described herein are preferred methods, composi administration of corticosteroids, decreased risks for devel tions, and kits according to the present invention which are oping corticosteroid-related adverse events such as opportu Suitable for restoring corticosteroid sensitivity, enhancing nistic infections and bone loss, and combinations thereof. glucocorticoid sensitivity and/or reversing the glucocorticoid US 2011/O 195031 A1 Aug. 11, 2011 insensitivity in a subject experiencing corticosteroid depen gen exposures, infections, exercise, or irritants, achieving dence or corticoid resistance or unresponsiveness or intoler optimal immune-functions, easier responses when steroid ance to corticosteroids. Glucocorticoid insensitivity related administration is tapered or withdrawn, or in prolonged conditions include, for instance, a range of immune-inflam administration of corticosteroids, and decreased risks for matory disorders/diseases treated with steroids when the developing corticosteroid-related adverse events such as therapy fails to achieve disease control or is not effective or opportunistic infections and bone loss. Preferably, the meth intolerant or dependent or resistant to corticosteroids, and ods of the present invention are suitable for substantially combinations thereof. More specifically, the methods, com negating the effect of at least one risk factor or underlying positions, and kits of the present invention are effective to mechanism associated with glucocorticoid insensitivity. achieve the glucocorticoid-sensitizer effects of Steroid-spar Thus, various embodiments of the present invention are ing in corticosteroid-dependent patients, better responsive directed to methods for reversing the glucocorticoid insensi ness or tolerance to corticosteroids, achieving efficacy by tivity in a Subject preferably having no history of menstrual using a lower dose of corticosteroid, preventing individuals at cycle-related exacerbation and Suffering from one or more risk for developing corticosteroid refractory responses or glucocorticoid insensitivity related conditions. In these and resistance or exacerbations in response to antigen exposures, infections, exercise, or irritants, achieving optimal immune various other embodiments, the subject to be treated is either functions, easier responses for the Subject or patient when male or female, and of any age. Various other embodiments steroid administration is tapered or withdrawn, or in pro are directed to treating subjects that either have their first or longed administration of corticosteroids, decreased risks for already experienced repeated disease attacks without men developing corticosteroid-related adverse events such as strual cycle-related exacerbation. opportunistic infections and bone loss, and combinations 0040 Although progesterone has anti-inflammatory prop thereof. More specifically, glucocorticoid insensitivity erties trials of progesterone for inflammatory disorders such related conditions include various conditions/disorders asso as rheumatoid arthritis have generally failed to demonstrate ciated with and/or attributed to glucocorticoid resistance, glu an effective and reproducible method for symptom control or cocorticoid refractory responses, corticosteroid dependence better clinical outcomes. Subjects exhibiting a glucocorti and corticosteroid intolerance. A primary risk factor in devel coid-resistant or refractory response are a Subset of the dis oping glucocorticoid insensitivity is oxidative stress. ease population, but a well-defined, “difficult to treat sub 0039. Despite the serious consequences of glucocorticoid population. For example, 20-30% of patients with severe and insensitivity, there has been limited Success in the treatment steroid-resistant Crohn's Disease will not respond to steroid of subjects who suffer from various conditions/disorders therapy. One of the preferred objectives of the present inven associated with and/or attributed to glucocorticoid resistance, tion is to use progesterone for treating a glucocorticoid-resis glucocorticoid refractory responses, corticosteroid depen tant or refractory condition demonstrated by steroid-sparing dence and corticosteroid intolerance. Calcineurin inhibitors in corticosteroid-dependent patients, better responsiveness or and methotrexate may be useful in a few selected conditions, tolerance to corticosteroids, achieving efficacy by using a but they have not proven to be effective in most glucocorticoid lower dose of corticosteroid, preventing individuals at risk for insensitivity related conditions. Moreover there are signifi developing refractory responses or resistance or exacerba cant adverse events associated with their uses. Significant tions in response to antigen exposures, infections, exercise, or toxicity and side-effects have also hampered the drug devel irritants, achieving optimal immune-functions, easier opment programs for p38 MAP-kinase inhibitors, selective responses for the Subject when steroid administration is inhibitors to block inhibition of NFkB kinase and Phosphodi tapered or withdrawn, or in or after prolonged administration esterase-4 inhibitors. The majority of glucocorticoid insensi of corticosteroids, decreased risks for developing corticoster tivity disorders don’t have any association with menstrual oid-related adverse events such as opportunistic infections cycle, and most Subjects Suffering from glucocorticoid insen and bone loss, and combinations thereof. Furthermore, sitivity disorders don't experience menstrual cycle-related MAPK activation is a critical event that leads to corticoster exacerbation, including allergy to progesterone. Advanta oid-insensitivity. It has been reported that progesterone geously in accordance with the present invention, the meth increases MAPK activity (Ruzycky A L. Effects of 17 beta ods detailed herein are believed to significantly restore corti estradiol and progesterone on mitogen-activated protein costeroid sensitivity in a Subject preferably having no history kinase expression and activity in rat uterine Smooth muscle. of menstrual cycle-related exacerbation. The treatments and Eur J Pharmacol. 1996 Apr. 11; 300(3):247-54). Without methods of the present invention have been Surprisingly being bound to a particular theory, it is currently believed that determined to reverse the glucocorticoid insensitivity and/or a skilled artisan would expect that MAPK activation induces enhance glucocorticoid sensitivity in Subjects suffering from a loss of GR nuclear translocation and function, leading to the at least one condition/disorder associated with and/or attrib development of corticosteroid-insensitivity related condi uted to glucocorticoid resistance, glucocorticoid refractory tions. Again, without being bound to a particular theory, it is responses, corticosteroid dependence and corticosteroid further currently believed that a skilled artisan would expect intolerance. Thus, the methods of the present invention are that the increased MAPK by progesterone would aggravate suitable for achieving the glucocorticoid-sensitizer effects of corticosteroid-insensitivity. However, in accordance with the steroid-sparing in corticosteroid-dependent patients, better present invention it has been Surprisingly and unexpectedly responsiveness or tolerance to corticosteroids, achieving effi discovered that the molecular effects of increased MAPK by cacy by using a lower dose of corticosteroid, preventing indi progesterone do not interfere with the effectiveness of viduals at risk for developing corticosteroid refractory progesterone in treating a glucocorticoid-resistant or refrac responses or resistance or exacerbations in response to anti tory condition. It has further been Surprisingly and unexpect US 2011/O 195031 A1 Aug. 11, 2011

edly discovered that administration of progesterone Such as against loss of glucocorticoid sensitivity, and used for treat 17alpha12 hydroxyprogesterone caproate (17-HPC) to a sub ing, preventing, or ameliorating one or more of the symptoms ject with a glucocorticoid-resistant or refractory or corticos of diseases or disorders associated with glucocorticoid insen teroid-dependent condition achieves the glucocorticoid-sen sitivity (e.g., corticosteroid dependent or corticoid resistant or sitizer effects such as steroid-sparing. Thus, in accordance unresponsive or intolerant to corticosteroids). Therapeutic with the present invention, it is currently believed that admin effects of the use of a glucocorticoid sensitizer include any, istration of progesterone (e.g., 17-HPC) can significantly but are not limited to, steroid-sparing in corticosteroid-depen restore corticosteroid sensitivity, enhance glucocorticoid sen dent patients, better responsiveness or tolerance to corticos sitivity and/or reverse glucocorticoid insensitivity. teroids, achieving efficacy by using a lower dose of corticos 0041. In comparison to the use of progesterone for its teroid, preventing individuals at risk for developing anti-inflammatory effects, the present discovery has surpris refractory responses or resistance or exacerbations in ingly identified a new function of progestogen and its uses, response to antigen exposures, infections, exercise, or irri i.e., reversing corticosteroid insensitivity, and clearly identi tants, achieving optimal immune functions, easier responses fies a well-defined patient population who would benefit from for the subject or patient when steroid administration is the treatment, i.e., patients exhibiting corticosteroid resis tapered or withdrawn, or after prolonged administration of tance, corticosteroid dependence, corticosteroid refractory corticosteroids, decreased risks for developing corticoster responses, and/or corticosteroid intolerance. Since most glu oid-related adverse events such as opportunistic infections, cocorticoid insensitivity related conditions occur in Subjects bone loss, pathologic fracture, diabetes, cataract, and combi that do not have a history of menstrual cycle-related exacer nations thereof. bation, the present discovery also represents a significant 0049. As used herein, the terms “treating or “treatment advance in the art. encompass either or both responsive and prophylactic mea Sures, e.g., designed to inhibit or delay the onset of the disease Definitions or disorder, achieve a full or partial reduction of the symptoms or disease state, and/or to alleviate, ameliorate, lessen, or cure 0042. As noted, glucocorticoids remain the first-line treat the disease or disorder and/or its symptoms. Treatment also ment for a range of immune/inflammatory and allergic dis encompasses any pharmaceutical use of the compositions of eases. However, 30% of patients fail to achieve disease con the present invention, Such as use for treating a glucocorticoid trol at tolerable systemic doses and continue to have an insensitivity related disease or disorder or condition. Amelio increased immune response with poor clinical outcomes. The ration of the symptoms of a particular disorder by adminis glucocorticoid insensitivity is an important factor in the tration of a particular compound or pharmaceutical compo pathogenesis and prognosis of many diseases. It presents sition of the present invention refers to any lessening, whether considerable management problems and cost burdens to permanent or temporary, lasting or transient that can be attrib health services. As used herein, the term “glucocorticoid uted to or associated with administration of the composition. insensitivity” is intended to include, but is not limited to, 0050. Subject is defined herein as an animal, typically a corticosteroid resistance, corticosteroid dependence, corti mammal, including human. As used herein, the term “patient’ costeroid refractory responses, corticosteroid intolerance, includes human and animal Subjects. and other types of corticosteroid ineffectiveness. It has been 0051. In practicing the methods of the present invention, recognized that several distinct molecular mechanisms con effective amounts of the progesterone compounds or compo tribute to decreased anti-inflammatory effects of glucocorti sitions containing therapeutically effective concentrations of coids. Different inflammatory diseases may share similar the compounds, which are formulated for systemic delivery, molecular mechanisms, and a single disease may have a het erogeneity of mechanisms. including parenteral, oral, or intravenous or pulmonary deliv 0043 Corticosteroid resistance to the anti-inflammatory ery, or for local or topical application, can be used for the effects of corticosteroids is defined as no clinical improve treatment of glucocorticoid-insensitivity related diseases or ment after treatment with high-dose glucocorticoid. disorders, or conditions, including, but not limited to, gluco 0044 Corticosteroid dependence is defined as a condition corticoid resistant conditions (e.g., glucocorticoid resistant that initially responds to corticosteroids but relapses quickly asthma, refractory rheumatoid arthritis, refractory inflamma upon drug withdrawal or dose tapering. tory bowel disease, chronic obstructive pulmonary disease 0045 Corticosteroid refractory response is defined as a and acute respiratory distress syndrome, interstitial pulmo condition that does not respond to an adequate induction dose nary fibrosis, and cystic fibrosis); glucocorticoid refractory of corticosteroids. It includes relatively or totally refractory conditions (e.g., refractory ulcerative colitis, children with responses to glucocorticoid therapy, and often needs to be severe Crohn disease, corticosteroid refractory asthma, controlled by add-on treatment. descuamative interstitial pneumonia refractory to corticoster 0046. Other types of corticosteroid ineffectiveness oid, refractory inflammatory myopathies, refractory myas includes need for a very high dose treatment, “difficult to thenia gravis, refractory pemphigus Vulgaris, methotrexate treat' and “do not respond well' or severe cases, and impaired refractory RA patients, refractory nephrotic syndrome, in vitro and in Vivo responsiveness. refractory multiple Sclerosis, refractory sprue-like disease, 0047 Corticosteroid intolerance is defined as toxicity of steroid-resistant sarcoidosis, refractory mucosal lesions of the therapy and/or risks for developing corticosteroid-related pemphigus Vulgaris, refractory Schnitzler syndrome, resis adverse events such as opportunistic infections and bone loss. tant dermatitis of the head and neck, severe refractory atopic 0048 Glucocorticoid sensitizer is defined as a pharmaceu dermatitis, refractory Idiopathic thrombocytopenia purpura, tical agent and product that has a function in restoring corti refractory orbital myositis, refractory or recurrent lympho costeroid sensitivity, enhancing glucocorticoid sensitivity, mas, critically ill patients with sepsis or acute respiratory reversing the glucocorticoid insensitivity, and protecting distress syndrome (ARDS) and relative adrenal insuffi US 2011/O 195031 A1 Aug. 11, 2011 ciency); glucocorticoid dependent conditions (e.g., rosacea, and gonanes), and spironolactone derivatives. Generally, the polymyalgiarheumatic, giant cell arteritis, polymyositis, der progestogen for use in accordance with the present invention matomyositis, Kawasaki syndrome, Guillain-Barre Syn is selected from the group consisting of progesterons and drome, chronic inflammatory demyelinating polyneuropathy, their derivatives or active metabolites. Specific examples of multifocal motor neuropathy, Stiff man syndrome, corticos progestogens that may be used in the methods and kits of the teroid dependent systemic lupus erythematosus, corticoster present invention include, but are not limited to, 17alpha oid dependent multiple Sclerosis, symptomatic corticosteroid HPC hydroxyprogesterone, natural progesterone, dydroges dependent asthma, primary Sjogren's syndrome, systemic terone, medrogestone, medroxyprogesterone, megestrol vasculitis, polymyositis, organ transplants, and graft-Versus acetate, chlormadinone acetate, cyproterone acetate, gesto host disease); and other inflammatory diseases, autoimmune norone caproate, nomegestrol acetate, demegestone, prome diseases, hyperproliferative diseases, and other such disease gestone, nestorone, trimegestone, norethisterone acetate, when glucocorticoid-insensitivity is implicated. Exemplary norethisterone, lynestrenol, ethynodiol diacetate, norgestrel, levonorgestrel, desogestrel, etonogestrel (3-ketodesogestrel), of these diseases are lupus, osteoarthritis, rhinosinusitis, pol gestodene, norgestimate, norelgestromin (17-deacetyl norg yarteritis nodosa, Wegener's granulomatosis, giant cell arteri estimate), dienogest, drospirenone, norethynodrel, norg tis, allergic rhinitis, urticaria, hereditary angioedema, ten estrel, desogestrel, etonogestrel, 19-nortestosterone, donitis, bursitis, autoimmune chronic active hepatitis, dienogest, norethynodrel, cyproterone acetate, tibolone, cirrhosis, transplant rejection, psoriasis, dermatitus, malig 19-norprogesterone, and drospirenone. nancies (e.g., leukemia, myelomas, lymphomas), acute adre 0053 Other agents that can be used in accordance with the nal insufficiency, rheumatic fever, granulomatous disease, methods and kits of the present invention include, for immune proliferation/apotosis, hypothalamic-pituitary-adre example, any pharmaceutically-acceptable progestogen nal (HPA) axis Suppression and regulation, hypercorti derivatives, i.e., derivatives of 17alpha-HPC hydroxyproges solemia, modulation of the Th1/Th2 cytokine balance, terone, natural progesterone, dydrogesterone, medrogestone, chronic kidney disease, spinal cord injury, cerebral edema, medroxyprogesterone, megestrol, chlormadinone, cyproter thrombocytopenia, Little's syndrome. Addison's disease, one, gestonorone caproate, nomegestrol acetate, demege autoimmune hemolytic anemia, uveitis, pemphigus Vulgaris, stone, promegestone, nestorone, trimegestone, norethister nasal polyps, sepsis, infections (e.g., bacterial, viral, rickett one, norethisterone, lynestrenol, ethynodiol diacetate, sial, parasitic), type II diabetes, obesity, metabolic syndrome, norgestrel, levonorgestrel, desogestrel, etonogestrel (3-ke depression, schizophrenia, mood disorders, Cushing's syn todesogestrel), gestodene, norgestimate, norelgestromin (17 drome, anxiety, sleep disorders, memory and learning deacetyl norgestimate), dienogest, drospirenone, norethyno enhancement, or glucocorticoid-induced glaucoma, atopic drel, norgestrel, desogestrel, etonogestrel, dermatitis, drug hypersensitivity reactions, serum sickness, 19-nortestosterone, dienogest, norethynodrel, cyproterone, bullous dermatitis herpetiformis, contact dermatitis, exfolia tibolone, 19-norprogesterone, and drospirenone. Each tive erythroderma, mycosis fungoides, pemphigus, nonsup progestogen can be derivatized as the corresponding salts, purative thyroiditis, sympathetic ophthalmia, uveitis and ocu esters, enol ethers oresters, acids, bases, Solvates, hydrates or lar inflammatory conditions unresponsive to topical steroids, prodrugs prior to formulation, as described herein. Represen allergic bronchopulmonary aspergillosis, fulminating or dis tative pharmaceutically-acceptable salts include, but are not seminated pulmonary tuberculosis when used concurrently limited to, amine salts, such as but not limited to, chlorop rocaine, choline, ammonia, diethanolamine and other with appropriate chemotherapy, hyperSensitivity pneumoni hydroxyalkylamines, ethylenediamine, Nimethylglucamine, tis, idiopathic bronchiolitis obliterans with organizing pneu procaine, diethylamine and other alkylamines, piperazine and monia, idiopathic eosinophilic pneumonias, idiopathic pull tris(hydroxymethyl)aminomethane; alkali metal salts, such monary fibrosis, pneumocystis carinii pneumonia (PCP) as but not limited to lithium, potassium and sodium; alkali associated with hypoxemia occurring in an HIV(+) individual earth metal salts, such as but not limited to barium, calcium who is also under treatment with appropriate anti-PCP anti and magnesium; transition metal salts, such as but not limited biotics, a diuresis or remission of proteinuria in nephritic to Zinc, aluminum, and other metal salts, such as but not syndrome, without uremia, of the idiopathic type or that due limited to Sodium hydrogen phosphate and disodium phos to lupus erythematosus, ankylosing spondylitis, polymyalgia phate; and also including, but not limited to, salts of mineral rheumatic, psoriatic arthritis, relapsing polychondritis, trichi acids, such as but not limited to hydrochlorides and sulfates: nosis with neurologic or myocardial involvement, and tuber and salts of organic acids, such as but not limited to acetates, culous meningitis. lactates, malates, tartrates, citrates, ascorbates, succinates, 0052 Generally, inaccordance with the present invention, butyrates, Valerates and fumarates. For example, the organic the methods described herein for the treatment of glucocor acid of acetates is often used Such as megestrol acetate, chlo ticoid-insensitivity related diseases or disorders, or condi rmadinone acetate, cyproterone acetate, gestonorone tions comprise administering a pharmaceutical composition caproate, nomegestrol acetate, and cyproterone acetate. comprising a steroid hormone. Typically, the lipophilic 0054 Additional representative agents that can be used in gonadal steroid hormone is a progestogen. The progestogen accordance with the methods and kits of the present invention may be a naturally occurring progestogen or a synthetic include, for example, any progestogen active metabolite progestogen (i.e., a progestin). Progestogens that can be used including, but not limited to, active metabolites of 17alpha in accordance with the present invention are grouped into the HPC hydroxyprogesterone, natural progesterone, dydroges following categories: progesterone, retroprogesterone, terone, medrogestone, medroxyprogesterone, megestrol progesterone derivative, 17C.-OH progesterone derivatives acetate, chlormadinone acetate, cyproterone acetate, gesto (both pregnanes and norpregnanes), 19-norprogesterone norone caproate, nomegestrol acetate, demegestone, prome derivatives, 19-nortestosterone derivatives (both estranges gestone, nestorone, trimegestone, norethisterone acetate, US 2011/O 195031 A1 Aug. 11, 2011

norethisterone, lynestrenol, ethynodiol diacetate, norgestrel, selected. In various embodiments, the pharmaceutical com levonorgestrel, desogestrel, etonogestrel (3-keto position is preferably administered at an interval exceeding desogestrel), gestodene, norgestimate, norelgestromin (17 daily or once per week. For example, the pharmaceutical deacetyl norgestimate), dienogest, drospirenone, norethyno composition may be administered once every other week, drel, norgestrel, desogestrel, etonogestrel, once monthly, once every two months, or once every three 19-nortestosterone, dienogest, norethynodrel, cyproterone months. In various other embodiments, the pharmaceutical acetate, tibolone, 19-norprogesterone, and drospirenone. For composition is administered once weekly, or at an interval of example, active metabolites of progesterone include allo less than one week (e.g., daily or every other day). For pregnanolone and 5alphapregnan-3.20-dione the active example, when the steroid hormone is 17alpha-hydrox metabolite. Active metabolites of 17-HPC include M13 yprogesterone caproate (17-HPC), administration may suit monohydroxy-; M12, monohydroxy-; M19, monohydroxy-: ably be via daily, once-weekly or once every two-week, or M7, dihydroxy-; and M16, monohydroxy-. once-monthly or once every 3-month injections. Those 0055. In various embodiments, another group of steroid skilled in the art will understand that the route of administra hormone, glucocorticoids, for use in accordance with the tion and frequency of administration for the pharmaceutical present invention is preferably selected from the group con compositions used in the methods and kits of the present sisting of naturally produced steroid hormones, or synthetic invention will depend on a variety of factors including, for compounds, that inhibit the process of inflammation. Specific example, the particular steroid hormone(s) used, the formu examples of glucocorticoids include, but are not limited to, lation in which it is delivered, the tissue being treated, the age hydrocortisone (cortisol), cortisone acetate, dexamethasone and gender of the individual treated, in vivo or in vitro test (hereinafter, “Dexamethasone’), prednisone, prednisolone, data, and the professional judgment of the particular patient's methylprednisolone, betamethasone, triamcinolone, beclom needs. The dosing frequency ranges set forth herein are exem etaSone, Paramethasone, fluticaSone, fludrocortisone acetate, plary only and are not intended to limit the scope or practice deoxycorticosterone acetate (DOCA), Fluprednisolone, flu of formulations provided herein. ticasone propionate, budesonide, beclomethasone dipropi 0058. The skilled artisan will also appreciate that appro onate, flunisolide and triamcinolone acetonide. priate dosing of the steroid hormone will depend on the ste 0056. In practicing the methods of the present invention, roid hormone(s) selected, the route of administration and effective amounts of the compounds or compositions contain dosage form, the frequency of administration, the disease(s) ing therapeutically effective concentrations of the com to be treated, the metabolic stability and length of action of pounds, are preferably formulated for systemic delivery, that compound, the species, age, body weight, general health, including parenteral, oral, or intravenous delivery, or for local and diet of the Subject, rate of excretion, drug combination, or topical application. For example, the pharmaceutical com and severity of the particular condition. The effective amount position may be administered by Subcutaneous, intravenous, of a steroid hormone provided herein can be determined by intraperitoneal, intraarterial or intramuscular injection; rec one of ordinary skill in the art, and includes exemplary dosage tally; by transdermally delivery; intravaginal delivery; or buc amounts for a mammal of from about 0.001 to 100 mg/kg of cally; or by oral delivery. When administered by subcutane body weight of active compound given orally per day. For ous or intramuscular injection, the steroid hormone is Suitably example, to achieve the endometrium and antigonadotropic formulated as a depot formulation to allow for sustained effects (i.e., dose for ovulation inhibition), 0.15 mg/day p.o. release of the steroid hormone over an extended period of for Levonorgestrel or Desogestrel is preferably desired while time. When administered by topical administration, including the required amount is much higher, 5-10 mg/day for intravaginal delivery, delivery may suitably be, for example, Medroxyprogesterone acetate or 200-300 mg/day for Proges via a solution, Suspension, emulsions or the like and are terOne. preferably formulated as creams, gels, ointments, emulsions, 0059. The skilled artisan will also appreciate that appro Solutions, elixirs, lotions, Suspensions, tinctures, pastes, priate dosing of the steroid hormone will depend on gender as foams, aerosols, irrigations, sprays, Suppositories, bandages, progestogen is the sex hormone. Progesterone is primarily dermal patches or any other formulations suitable for the secreted by the granulosa cells and the corpus luteum in the route. When an inhalation route of administration is used, ovary. During pregnancy, a major source of progesterone also delivery may preferably be, for example, via anaerosol spray comes from the placenta. Males produce progesterone in the or powder mixture in a pressurized pack or a nebulizer or in an adrenal gland and testes, as this is a precursor of testosterone. inhaler. In women, progesterone levels are relatively low during the 0057 With respect to the frequency of administration, any preovulatory phase of the menstrual cycle, rise after ovula frequency which achieves the desired result (i.e., steroid tion, and are elevated during the luteal phase. Progesterone sparing in corticosteroid-dependent patients, better respon levels tend to be <2 ng/ml prior to ovulation, and >5 ng/ml siveness or tolerance to corticosteroids, achieving efficacy by after ovulation. If pregnancy occurs, progesterone levels are using a lower dose of corticosteroid, preventing individuals at initially maintained at luteal levels. With the onset of the risk for developing refractory responses or resistance or exac luteal-placental shift in progesterone Support of the preg erbations in response to antigen exposures, infections, exer nancy, levels start to rise further and may reach 100-200 cise, or irritants, achieving optimal immune-functions, easier ng/ml at term. The reference range for progesterone levels in responses for the Subject when steroid administration is adult men is 0.13-0.97 ng/ml. Adult males have levels similar tapered or withdrawn, or after prolonged administration of to those in women during the follicular phase of the menstrual corticosteroids, decreased risks for developing corticoster cycle as well as the level in postmenopausal women. Clearly, oid-related adverse events such as opportunistic infections women regularly experience a 17-fold change in serum and bone loss, and combinations thereof, may be used. The progesterone concentration during the menstrual cycle, or frequency of administration will preferably be determined, at more than 100-fold increase in pregnancy. Thus, tolerance or least in part, by the steroid hormone(s) and/or dosage form maximum dose or minimal effective dose of progestogen US 2011/O 195031 A1 Aug. 11, 2011

treatment would be higher in women than in males. For 0061. In addition to administration of a progestogen hor example, when the steroid hormone is 17alpha-hydrox mone, the methods of the present invention may further com yprogesterone caproate (17-HPC) and a common dosage prise one or more additional therapies aimed at the treatment used is 150-500 mg weekly injection for its uses in women of glucocorticoid insensitivity related diseases or disorders, or conditions, as discussed herein. The one or more additional health related indications. Given some important effects of treatments may include, for example, glucocorticoid (e.g., progesteron on restoring corticosteroid sensitivity are hydrocortisone, cortisone acetate, dexamethasone, pred assumed to be mediated non-genomically through different nisone, prednisolone, methylprednisolone, betamethasone, molecular biological modes of action (i.e., functions not triamcinolone, beclometasone, Paramethasone, fluticaSone, related to progestational activity), this may result in some fludrocortisone acetate, deoxycorticosterone acetate, Flu pharmacodynamic variability. A much lower or higher dose prednisolone, fluticasone propionate, budesonide, beclom of progesterone (e.g. 17-HPC) may be selected as well as a ethasone dipropionate, flunisolide and triamcinolone different dosage level for male Subjects. The dosing ranges set acetonide, an androgen (e.g., dehydroepiandrosterone forth herein are exemplary only and are not intended to limit (DHEA)), an estrogen (e.g., estradiol), immunosuppressive the scope or practice of formulations provided herein. or immunomodulators agents (e.g., cyclosporine, methotrex 0060 Preferably, the pharmaceutical compositions of the ate, gold, 6-mercaptopurine, biologic products such as inflix present invention contain: i) a physiologically acceptable car imab, etanercept, and adalimumab, intravenous immunoglo rier, diluent, or excipient, or a combination thereof, and ii) bulin and Mepolizumab), and calcineurin inhibitors (e.g., one or more steroid hormone(s) as described herein. The ciclosporin, tacrolimus), p38 MAP kinase inhibitors, JNK compositions can be formulated for single dosage adminis inhibitors (decrease API), Vitamin D, MIF inhibitors. Histone tration or for multiple dosages. Dosage forms or composi deacetylate-2 activators, Theophylline, Phosphoinositide-3- tions containing steroid hormone(s) in the range of 0.005% to kinase-6 inhibitors, leukotriene modifiers, long-acting beta 100% with the balance made up from non-toxic carrier can be agonists, antioxidants, iNOS inhibitors and P-glycoprotein prepared. For example, the pharmaceutical composition may inhibitors, and combinations thereof. The above other phar contain one or more diluents, one or more carriers, one or maceutical agents, when employed in combination with the more binders, one or more coatings, one or more lubricants, agents described herein, can be used, for example, in those one or more solvents, one or more buffers, one or more amounts indicated in the Physicians’ Desk Reference (PDR) preservatives, one or more flavoring agents, one or more dyes, or as otherwise determined by one of ordinary skill in the art. and/or one or more absorption enhancers, and/or one or more The amount of an agent used with non-oral routes is prefer biodegradable polymers. The particular excipient(s) included ably determined based upon corresponding serum concentra in the pharmaceutical composition will depend on the par tion level of an oral dosage or containing a quantity of the ticular steroid hormone(s) and dosage form selected, and the active compound in an amount Sufficient to alleviate the skilled artisan will be able to readily select appropriate excipi symptoms of the treated subject. In the methods provided ents once the steroid hormone(s) and the dosage form there herein, Such other pharmaceutical agent(s) can be adminis fore have been chosen. For example, for oral administration, tered prior to, simultaneously with, or following the admin a pharmaceutically acceptable non-toxic composition can be istration of the compounds provided herein. Therapeutic formed by the incorporation of any of the normally employed effects of the use of a glucocorticoid sensitizer include any, excipients, such as, for example pharmaceutical grades of but not limited to, dosing-sparing of concurrent treatment mannitol, lactose, starch, magnesium Stearate, talcum, cellu drugs above, better responsive or tolerant to concurrent treat lose derivatives, sodium crosscarmellose, glucose, Sucrose, ment drugs, achieving efficacy by using lower dose of con magnesium carbonate or sodium saccharin. Such composi current treatment drugs, preventing individuals at risk for tions preferably include Solutions, Suspensions, tablets, cap developing refractory responses or resistance of concurrent Sules, powders and Sustained release formulations. Such as, treatment drugs, achieving optimal immune-functions, easier but not limited to, implants and microencapsulated delivery responses after tapering or withdrawal of concurrent treat systems, and biodegradable, biocompatible polymers, such ment drugs, or prolonged administration of concurrent treat as collagen, ethylene vinyl acetate, polyanhydrides, polygly ment drugs, decreased risks for developing drug-related colic acid, polyorthoesters, polylactic acid and others. For adverse events due to concurrent treatment drugs, and com another example, conventional injectables can be prepared in binations thereof. Examples 1-2 demonstrate the establish conventional forms, either as liquid solutions or Suspensions, ment of study models in evaluating steroid sensitivity and Solid forms suitable for Solution or Suspension in liquid prior steroid resistance, i.e., PHA-induced IL-2 production and to injection, or as emulsions. Suitable excipients include, for IL-2/4 induced steroid resistance in human peripheral blood example, water, saline, dextrose, glycerol, mannitol. 1,3-bu mononuclear cells (PBMCs) from healthy male Smokers. tanediol, Ringer's solution, an isotonic sodium chloride Solu 0062) Examples 1 and 2 demonstrate the establishment of tion or ethanol. For another example, injectable Suspensions study models in evaluating steroid sensitivity and steroid are prepared using appropriate liquid carriers, Suspending resistance, i.e., PHA-induced IL-2 production and IL-2/4 agents and the like. Certain pharmaceutical compositions for induced steroid resistance in human peripheral blood mono injection are presented in unit dosage form, e.g., in ampules or nuclear cells (PBMCs) from healthy male Smokers. in multi dose containers. Certain pharmaceutical composi 0063 Examples 3, 4 and 5 demonstrate that progestogen tions for injection are suspensions, Solutions or emulsions in reverses corticosteroid resistance and improves corticoster oily or aqueous vehicles, and may contain formulatory agents oid sensitivity under a steroid-resistant condition (i.e., IL-2/4 Such as Suspending, stabilizing and/or dispersing agents. Cer induced). tain solvents suitable for use in pharmaceutical compositions 0064. Examples 6, 7 and 8 demonstrate that progestogen for injection include, but are not limited to, lipophilic solvents improves corticosteroid sensitivity under a non-steroid-resis and fatty oils, such as sesame oil, synthetic fatty acid esters, tant condition (i.e., PHA-induced IL-2 production without Such as ethyl oleate or triglycerides, and liposomes. adding IL-2/4). US 2011/O 195031 A1 Aug. 11, 2011

0065. It has been surprisingly discovered, in accordance Dexamethasone (Dexamethasone) (CAS No: 50-02-2) and with the present invention, that the effects of the use of a PHA from Sigma Ltd (US); recombinant IL-2 and IL-4 from glucocorticoid sensitizer include, but are not limited to, Ste PeproTech, IL-2 immunosorbent assay kit (ELISA for IL-2) roid-sparing in corticosteroid-dependent patients, better from ExCell Biology, Shanghai China; anti-human anti-CD3 responsiveness or tolerance to corticosteroids, achieving effi and anti-CD28 from R&D Systems (US). cacy by using a lower dose of corticosteroid, preventing indi viduals at risk for developing refractory responses or resis Isolation of PBMCs tance or exacerbations in response to antigen exposures, infections, exercise, or irritants, achieving optimal immune (0071 PBMCs were isolated from human blood buffy functions, easier responses for a patient when Steroid admin coats provided by a regional blood center. Random buffy coat istration is tapered or withdrawn, or prolonged administration cells from male donors were a by-product of blood processed of corticosteroids, decreased risks for developing corticoster for clinical use and no details (i.e., personal identification and oid-related adverse events such as opportunistic infections, background) were provided except for tobacco use. Almost bone loss, pathologic fracture, diabetes, cataract, and combi all of the male blood donors were cigarette smokers. PBMCs nations thereof. were separated using a porous high density polyethylene barrier (HISTOPAQUE from GEHealthcare Bio-Sciences In Vitro Screening Materials and Methods AB (US). After centrifugation of blood samples in each tube Overview (35 minutes at 800xg at room temperature, or RT), PBMCs 0066 IL-2/4 induced steroid resistance in human periph were collected and washed twice with Hank's buffered saline eral blood mononuclear cells (PBMCs) is a well-recognized solution (HBSS). PBMCs were resuspended in RPMI-1640 study model to evaluate potential modifiers of steroid resis medium containing 10% fetal calf serum (FCS) and 15 mM tance and sensitivity (Kam, J. C. etc. Combination IL-2 and glutamine and cells were counted and plated. IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids. J. Immunol 1993. 151: 3460 Culture of Cells 3466. Irusen, E. etc. p38 mitogen-activated protein kinase induced glucocorticoid receptor phosphorylation reduces its 0072 PBMCs (2x10) were incubated with or without activity: role in Steroid-insensitive asthma. J Allergy Clin. IL-2 (13 ng/ml) and IL-4 (6.5 ng/ml) for 48 hours in RPMI Immunol 2002. 109: 649-657. Creed TJ etc. The Effects of 1640 medium containing 10% FCS and 2 mM glutamine. Cytokines on PBMCs were counted and plated again at 107 cells/mi before 0067 Suppression of Lymphocyte Proliferation by Dex stimulating with or without 17o-HYDROXYPROGESTER amethasone. J Immunol 2009; 183; 164-171). The dexam ONE CAPROATE (17HPC), Progesterone (P4) and ethasone inhibition of lymphocyte proliferation and cytokine MEDROXYPROGESTERONE. ACETATE (MPA) for 12 assay correlates well with the outcome of steroid therapy in hours prior treatment of Dexamethasone dexamethasone. patients with inflammatory diseases. The Suppression of IL-2 and IL-4 stimulated PBMCs were also plated at a con cytokine releases by dexamethasone (also referred to herein centration of 10° cells/ml in 96-well plates ready for PHA (15 in this application as “Dexamethasone') in healthy volunteers ug/mL, 24 hours) stimulation of cytokine release and detec is used to measure changes in steroid sensitivity and steroid tion by ELISA. resistance. Following PBMCs stimulation with mitogen phy tohemagglutinin (PHA), there is a strong correlation between Sandwich-ELISA (Enzyme LinkedImmunosorbent Assay) cytokine secretion levels and steroid resistance as well as steroid sensitivity in vitro. Addition of IL-2, IL-4 and TNF (0073 PBMC Cells (10 cells/ml) were plated in 96-well reducesteroid sensitivity. plates and stimulated with or without dexamethasone (10 0068. The objective of one study was to evaluate the com 12M to 10M) for 1 hour before transferring the cells in a pounds’ effect on reversing corticosteroid resistance, mea 96-well plate with or without PHA(15ug/mL)24 hours at 37° sured by an increase in the ability of dexamethasone to inhibit C., 5% CO. Serial dilutions of standards and PBMCs super PHA-induced IL-2 release in the IL-2 and IL-4 induced ste natants were measured by enzyme linked immunosorbent roid resistant model. assay to determine IL-2 at baseline and its levels after 17HPC, 0069. The compounds’ effects were assessed in improving corticosteroid sensitivity, measured by IC50 improvement, P4 and MAP treatments. Optical density was measured at 450 steroid-sparing, achieving a similar anti-inflammatory effi nm and corrected with 550 nm. The concentration of IL-2 was cacy by using a lower dose of corticosteroid, better respon calculated using the standard curve and taking into account siveness and combination of synergetic effects in the PHA the supernatant dilution used. Detection limit for IL-2 is 4.0 induced IL-2 release in PBMCs. pg/ml.

Materials Statistical Analysis 0070 PBMCs (peripheral blood mononuclear cells; 0074 Data are expressed as meant-SD. The efficacies of PBMCs) separation system: Accuspin system-Histopaque the drug treatments were analyzed by paired t-test. One-way from GEHealthcare Bio-Sciences AB (US); RPMI-1640 analysis of variance was used to compare three or more Medium from HyClone, Beijing China, dimethyl sulfoxide matched groups and 95% CI was performed to present groups (DMSO) from Sigma (US), 17o-HYDROXYPROGESTER differences. All graphs indicate mean values of results or % ONE CAPROATE (17HPC) (CAS No: 630-56-8), inhibition of PHA-stimulated IL-2. IC50 values were calcu MEDROXYPROGESTERONE. ACETATE (MPA) (CAS lated by using a sigmoidal model (BioDataFit). A p values.O. No. 71-58-9), natural Progesterone (P4) (CAS No. 57-83-0), 05 was considered Statistically significant. US 2011/O 195031 A1 Aug. 11, 2011

Results EXAMPLE 2 Simultaneous Measurement of Steroid Sensitivity in PBMCs Progestogen Improves Corticosteroid Sensitivity or Reverses Corticosteroid Resistance Among Male (10° Cells/ml) Smokers 0075) To measure glucocorticoid sensitivity simulta 0078 Corticosteroid insensitivity or resistance can be neously, PBMCs (10° cells/ml) were plated in 96-well plates reversed pharmacologically. We investigated the effects of and stimulated with or without serial dilutions of dexametha progestogen drug class which is currently unknown for its sone (10M to 10 M) for 1 hour, and then were subse function in reversing steroid resistance, and test Progestogen quently with PHA (15ug/mL) for 24 hours at 37°C., 5% CO. drugs of 17a-HYDROXYPROGESTERONE CAPROATE IL-2 levels were quantified using ELISA. Results in FIG. 1 (17HPC), MEDROXYPROGESTERONEACETATE (MPA) include IL-2 levels at baseline, after PHA stimulation and and natural Progesterone (P4) on their effects in improving dose-dependent inhibition of IL-2 by dexamethasone. The glucocorticoid sensitivity in peripheral blood mononuclear cells (PBMCs) from healthy male smokers. levels of IL-2 in PBMCs were 19+25 pg/ml at baseline in (0079 PBMCs (10 cells/ml) stimulated with IL-2 (13 healthy Male smokers (n=11), 677+447 pg/ml after PHA ng/ml) and IL-4 (6.5 ng/ml) were cultured in 96-well plates stimulation PHA (n=20), 371 +447 pg/ml at dexamethasone for 48 hours and subsequently stimulated with 17HPC (10' 10'’M (n=11), 287+313 pg/ml at dexamethasone 10' M M, 107M and 10.5 M) or P4 or MPA (100M, 10 Mand (n=14), 293+338 pg/ml at dex10M (n=17) and 144+157 10M) for 12 hours before being exposed with or without pg/ml at dexamethasone 10M (n=17). The Dexamethasone low and high doses of dexamethasone (10'M and 10M) and 17HPC treatments have no significant effect in basal IL-2 for 1 hour, and then were subsequently with PHA (15ug/mL) level (data not shown). FIG. 1 thus shows IL-2 levels (mean) for 24 hours at 37°C., 5% CO2 (n=11 for the combinations of at baseline, after PHA stimulation and effect of dexametha 17HPC+Dexamethasone groups). IL-2 levels were quantified sone on PHA-induced IL-2 production (n=20) (p<0.001). using ELISA. A 10% increase in maximal Dexamethasone inhibition (Imax) under a steroid-resistant condition repre Dexamethasone shows a significant, dose-response inhibi sents a clinical meaningful improvement (Creed TJ etc. The tion of IL-2 production (FIG. 1). Effects of Cytokines on Suppression of Lymphocyte Prolifera tion by Dexamethasone. J Immunol 2009; 183; 164-171). EXAMPLE 1. 0080. The results depicted in FIGS. 3-4 show that progestogen consistently improves corticosteroid insensitiv Addition of IL-2 and IL-4 Reduces Steroid Sensitiv ity by all three progestogen agents (17HPC, P4 and MPA) ity or Induces Steroid Resistance Among Male when the low dose of dexamethasone is used. The Imax Smokers improves from 9% to 33%. FIG. 3 depicts progestogen's effects (% Imax) in reversing steroid resistance: comparing 0076 IL-2/4 induced steroid resistance in PBMCs, a well 17HPC, P4 and MPA under low dose Dexamethasone (10' recognized study model, was used to evaluate potential modi M). FIG. 4 depicts progestogen's effects (% Imax) in revers fiers of steroid resistance and sensitivity. PBMCs from ing steroid resistance: comparing 17HPC, P4 and MPA under healthy smokers were collected. Corticosteroid insensitivity high dose dexamethasone (10 M). or resistance was induced by adding IL-2 and IL-4 in periph I0081. The effects in reversing corticosteroid resistance are eral blood mononuclear cells (PBMCs) from healthy male observed when the high dose of Dexamethasone is used (FIG. smokers (n=11). PBMCs (10° cells/ml) stimulated with or 4). Each progestogen agent has its own dose-response pattern. Among the three tested drugs, 17HPC has the best treatment without IL-2 (13 ng/ml) and IL-4 (6.5 ng/ml) were cultured in effects, i.e., highest improvement rate (of 18%) and consis 96-well plates for 48 hours and subsequently being exposed tency at all dose levels (16-18%). serial dilutions of dexamethasone (10'M, 10M to 10 I0082 Progestogen (e.g., 17HPC, P4 and MPA) thus has M) for 1 hour, and then were stimulated with PHA (15ug/mL) the Surprising and unexpected effect of reversing glucocorti for 24 hours at 37° C., 5% CO2. IL-2 levels were quantified coid resistance and improving glucocorticoid sensitivity in using ELISA. Percentage of inhibition on PHA-induced IL-2 cigarette Smokers. Progestogen, therefore, can be used to production was calculated as % Inhibition=1-(IL-2 with treated Smoking-induced glucocorticoid resistance diseases Dexamethasone/IL-2 without Dexamethasone). Such as, for instance, chronic obstructive pulmonary disease 0077. The results depicted in FIG. 2 show that inhibition (COPD). ability of dexamethasone on PHA-induced IL-2 production was significantly reduced with addition of IL-2 and IL-4 EXAMPLE 3 among male Smokers. For example, 9% inhibition with low dose Dexamethasone 10-' M was completely lost: 52% vs. 17HPC Reverses Corticosteroid Resistance Among no inhibition, and with higher dose Dexamethasone 10-M: Male Smokers 87% vs. 21%, a significant reduction. Addition of IL-2 and I0083 PBMCs (10 cells/ml) stimulated with IL-2 (13 IL-4 reduces steroid sensitivity or induces steroid resistance ng/ml) and IL-4 (6.5 ng/ml) were cultured in 96-well plates for 48 hours and subsequently stimulated with 17HPC (10' among male Smokers, a valid steroid-resistant model/condi M, 107M and 10M) for 12 hours before being exposed tion. with or without three doses of dexamethasone (10"M, US 2011/O 195031 A1 Aug. 11, 2011 12

10M and 10M) for 1 hour, and then were subsequently EXAMPLE 5 with PHA(15ug/mL) for 24 hours at 37°C., 5% CO2 (n=11). IL-2 levels were quantified using ELISA. Progestogen (e.g., 17HPC) Improves Corticosteroid 0084 FIG. 5 shows that the addition of IL-2 and IL-4 reduced steroid sensitivity significantly at all three Dexam Sensitivity Under a Non-Steroid Resistant Condition ethasone concentrations. The improvement of dexametha sone inhibition of PHA-induced IL-2 release is achieved by 0090. To determine the effect of add-on treatment of adding 17HPC. 17HPC reverses the glucocorticoid insensi 17HPC on glucocorticoid sensitivity simultaneously, PBMCs tivity in a dose-response pattern. 17HPC thus restores corti (10° cells/ml) were plated in 96-well plates and stimulated costeroid sensitivity. For example, PHA-induced IL-2 level with 17HPC (10 M to 10 M) for 12 hours before being with Dexamethasone'M, but without 17HPC was 2364 pg/mL vs. significantly improved cytokine Suppression of exposed with or without serial dilutions of dexamethasone 2119, 1805 and 1595 pg/mL after adding 17HPC at 10'M, (10'’M to 10 M) for 1 hour, and then were subsequently 107M and 10M respectively (p<0.05 in both 17HPC with PHA (15 ug/mL) for 24 hours at 37°C., 5% CO2. IL-2 107M and 10M groups). levels were quantified using ELISA. ICso values were calcu 0085 FIG. 6 shows individual responses before-and-after lated by using a sigmoidal model (BioDataFit). The value (of 17HPC treatment when the high dose of Dexamethasone 10 IL-2=734) from negative control (i.e., cell--PHA without M was given. Ten out of 11 subjects had a more than 10% Dexamethasone or 17HPC) was artificially set as Dexametha improvement (in % maximal Dexamethasone inhibition) sone-'M or 17HPCM (i.e., assuming drug concentration after 17HPC treatment, and only one subject (#6) had no s0M) to fit the sigmoidal model when calculating Dexam improvement (p<0.05 in Chi Square Test for all three 17HPC dose groups). 17HPC thus reverses steroid resistance and ethasone-ICs and 17HPC-ICs (N=14). individual response patterns. (0091. The effects of 17HPC on dexamethasone sensitivity EXAMPLE 4 measured by IL-2 inhibition in smokers are shown in Table 1 and FIG. 10. FIG. 10 shows add-on effect of 17HPC is Individual Response Patterns with Three Progesto gen Agents: 17HPC, P4 and MPA improvement of steroid sensitivity. 17HPC, especially at I0086 Example 3 above showed that Progestogen reverses lower concentrations, significantly enhances steroid sensitiv corticosteroid resistance among male smokers. FIG.7-9 com ity measured by Dexamethasone-ICso, which is improved pares individual response patterns with three progestogen from ICs 7.5 (Dexamethasone only) to 10.2-12.0 (Dexam agents: 17HPC, P4 and MPA with the same Dexamethasone ethasone+17HPC) (p=0.0052 in ANOVA). The higher dose dose 1 O'M: of 17HPC (at 17HPCM) had minimal or no effect.

TABLE 1.

17HPC effect in improving corticosteroid sensitivity (mean IL-2 pg/mL and IC.so)

Dexamethasone 17HPC 17HPC 17HPC 17HPC PR2005 Dexamethasone only 10 IIM 10-10M 107M 1O-3M IC50

O 734.6692754 448.22O8447 420.609SO24 466.31 O3053 225.5846837 6.4344O1 10-12M 371.741.0856 275.1887924 132.298398 111.SSO3S1S 176.2274.866 10.924.52 10-10M 312.6599339 164.3874O69 177.7437283 104.5164134 138.578.293 11.64492 1OM 398.132707 167.8640405 173.5466S53 229.301 1166 136.1965467 6.242864 1O-6M 160.629.3856 9. OSO29983S 27.18227874. 9.9141852.77 24.6061311 NA Dexamethasone 7.509749 12.O1514 10.20306 NA 7.595664 IC50

I0087. The results depicted in FIG. 7 show that 9 out 11 EXAMPLE 6 subjects had a more than 10% improvement in maximal Dex amethasone inhibition after receiving a dose of 17HPC, Progestogen (e.g., 17HPC) has Significant Steroid which is consistent with the results presented in FIG. 6. Sparing Effects 0092. To determine effect of add-on treatment of 17HPC I0088. The results depicted in FIG. 8 show that 6 out of 8 on glucocorticoid sparing simultaneously, PBMCs (10° cells/ subjects had a more than 10% improvement in maximal Dex nil) were plated in 96-well plates and stimulated with 17HPC amethasone inhibition after receiving a dose of natural (10' M to 10M) for 12 hours before being exposed with progesterone, which is similar to 17HPC. or without serial dilutions of dexamethasone (10'’M to 10 M) for 1 hour, and then were subsequently with PHA (15 0089 The results depicted in FIG. 9 shows that MPA ug/mL) for 24 hours at 37° C., 5% CO2. IL-2 levels were treatment leads a total different response pattern: a “split 99 quantified using ELISA. The % inhibition of PHA stimula response. A sub-group had a great improvement up to 58% tion of IL-2 (pg/mL) by 17HPC and/or Dexamethasone (Dex while another Sub-group presented with a worsening in cor amethasone) in PBMCs was calculated. The value (of ticosteroid sensitivity, a reduction up to 88%. IL-2–734.7) from the negative control (i.e., cell--PHA with US 2011/O 195031 A1 Aug. 11, 2011

out any drug treatment) was set as Zero 96 inhibition, and all suppression of PHA induced IL-2 (FIG. 11). FIG. 11 thus other '% inhibition values were derived from the formula: depicts a better treatment responsiveness with the 17HPC (1-(treatment IL-2 level/714.5)x100%, (N=14) (note: 714.5 add-on. ng/mL (PHA-induced IL-2) was the mean value from the 14 0097. Further, the combination of 17HPC with Dexam Subjects). ethasone consistently increases Dexamethasone's anti-in 0093. The add-on of 17HPC can achieve similar efficacy flammatory effects, and is better than their uses individually. by using a lower dose of corticosteroid FIG. 12 shows that the combination leads to a synergetic 0094 (Table 2). The percentage of suppression of IL-2 effect, with 25-37% improvements in Dexamethasone effi releases by higher dose of 10 M. dexamethasone (Imax) in cacy. FIG. 12 thus depicts synergetic effects of combination healthy smokers is 78%. The add-on treatment of 17HPC of 17HPC with Dexamethasone. will significantly reduce the dose requirement for Dexam ethasone. Table 2 shows that add-on of the low doses of 17HPC (10' M or 10' M) will achieve a similar anti EXAMPLE 8 inflammatory effect (27.8% IL-2 inhibition) when comparing to Dexamethasone 10 M), i.e., only using the /1,000" to Add-On of Other Progestogen Compounds (e.g., P4 /100,000th of the original Dexamethasone dose, a Substantial and MPA) Shows Similar Effects in Enhancing Glu steroid-sparing effect. Therefore, the add-on of 17HPC may cocorticoid Sensitivity prevent individuals at risk for developing refractory responses or resistance or exacerbations or tolerance to cor 0098. To determine effect of add-on treatment of ticosteroids as well as improving safety profiles. MEDROXYPROGESTERONE. ACETATE (MPA) and natu ral Progesterone (P4) on glucocorticoid sparing simulta TABLE 2 neously, PBMCs (10 cells/ml) were plated in 96-well plates and stimulated with P4 or MPA (10M, 10 Mand 10M) Add-on Effect of 17HPC: Steroid-sparing effects measured for 12 hours before being exposed with or without dexam by 90 inhibition of PHA stimulation of IL-2 ethasone (10''M to 10 M) for 1 hour, and then were sub Dexamethasone 17HPC 17HPC 17HPC 17HPC sequently with PHA (15ug/mL) for 24 hours at 37°C., 5% only 1OM 100M 107M 10 M CO2 (n-6 for the combinations of P4 or MAP+Dexametha Dexamethasone O% 39% 43% 37% 69% sone). IL-2 levels were quantified using ELISA. The % inhi OM Dexamethasone 49% 63% 82% 85% 76% bition of PHA stimulation of IL-2 (pg/mL) by P4, or MPA, 10-12M and/or Dexamethasone (Dexamethasone) in PBMCs was cal Dexamethasone 57% 78% 76% 86% 81% culated. The value (of IL-2=765) from the negative control 10-10M Dexamethasone 46% 770, 76% 69% 81% (i.e., cell--PHA without any drug treatment, n=25) was set as 108M Zero '% inhibition, and all other '% inhibition values were Dexamethasone 78% 99% 96% 99% 97% derived from the formula: (1-(treatment IL-2 level/765)x 1OM 100%. Values represent the % inhibition of PHA stimulation of IL-2 (pg/mL) by 17HPC only, 0099 Table 3 and Table 4 show that both P4 and MPA have Dexamethasone only and 17HPC plus Dexamethasone at different concentrations in the similar effects in enhancing glucocorticoid sensitivity Such as PBMC model. steroid-sparing and Synergetic effects of combination. For examples, the percentage of Suppression of IL-2 releases by EXAMPLE 7 10 M. dexamethasone is improved from 67% to 96% when MPA 10M is added (P=0.035 in pared T-Test). The add-on Add-On of Progestogen (e.g., 17HPC) Leads to a of the low dose of either P4 or MPA (10'M) will achieve a Better Treatment Responsiveness, and the Combina similar anti-inflammatory effect (28.6% IL-2 inhibition) tion of 17HPC with Dexamethasone Results in Syn when comparing to Dexamethasone 10M), i.e., only using ergetic Effects the /100" of the original Dexamethasone dose, a substantial 0095 To determine the effect of add-on treatment of steroid-sparing effect. 17HPC on glucocorticoid sparing simultaneously, PBMCs (10° cells/in) were plated in 96-well plates and stimulated TABLE 3 with 17HPC (10'' M to 10 M) for 12 hours before being Add-on effects of Medroxyprogesterone Acetate (MPA) on exposed with or without serial dilutions of dexamethasone enhancing glucocorticoid sensitivity (Mean IL-2 pg/mL and (10'’M to 10 M) for 1 hour, and then were subsequently 90 inhibition of PHA-induced IL-2 production with PHA (15 ug/mL) for 24 hours at 37°C., 5% CO2. IL-2 levels were quantified using ELISA. The % inhibition of PHA MPA MPA MPA stimulation of IL-2 (pg/mL) by 17HPC and/or Dexametha 10-10M 108M 1O-M sone (Dexamethasone) in PBMCs was calculated. The value PHA 765.0 2O6.1 166.9 39.8 (of IL-2–734.7) from the negative control (i.e., cell--PHA (0.0%) (73%) (78%) (95%) DEXAMETHASONE 216.1 1291 without any drug treatment) was set as Zero 96 inhibition, and 1OE-11M (72%) (83%) all other 96 inhibition values were derived from the formula: DEXAMETHASONE 251.6 44.7 29.2 12.3 (1-(treatment IL-2 level/714.5)x100%, (N=14). 1OE-8M (67%) (94%) (96%) (98%) 0096. The maximal anti-inflammatory effect of Dexam DEXAMETHASONE 109.6 ethasone is 78% inhibition of PHA-induced IL-2 production 1OE-6M (86%) at 10 M. The add-on treatment of 17HPC produces a significantly better responsiveness and results in near 100% US 2011/O 195031 A1 Aug. 11, 2011

unresponsive or refractory to corticosteroids, and combina TABLE 4 tions thereof, the method comprising administering a phar maceutical composition comprising a steroid hormone to a Add-on effects of natural progesterone (P4) on enhancing glucocorticoid sensitivity (Mean IL-2 pg/mL and % inhibition Subject having no history of menstrual cycle-related exacer of PHA-induced IL-2 production bation and wherein the Subject exhibits one or more gluco corticoid insensitivity related diseases, disorders, or condi P4 P4 P4 10-10M 10-8M 1OM tions selected from the group consisting of glucocorticoid resistant asthma, refractory rheumatoid arthritis, refractory PHA 765.0 SO6.9 486.2 113.8 inflammatory bowel disease, chronic obstructive pulmonary (0.0%) (34%) (36%) (85%) DEXAMETHASONE 216.1 100.8 disease, acute respiratory distress syndrome, interstitial pull 1OE-11M (72%) (87%) monary fibrosis, cystic fibrosis, refractory ulcerative colitis, DEXAMETHASONE 251.6 59.6 91.4 81.2 children with severe Crohn disease, corticosteroid refractory 1OE-8M (67%) (92%) (88%) (89%) DEXAMETHASONE 109.6 asthma, desquamative interstitial pneumonia refractory to 1OE-6M (86%) corticosteroid, refractory inflammatory myopathies, refrac tory myasthenia gravis, refractory pemphigus Vulgaris, meth otrexate-refractory RA patients, refractory nephrotic Syn What is claimed is: drome, refractory multiple Sclerosis, refractory sprue-like 1. A method for the treatment of glucocorticoid insensitiv disease, Steroid-resistant sarcoidosis, refractory mucosal ity, restoring corticosteroid sensitivity, enhancing glucocor lesions of pemphigus Vulgaris, refractory Schnitzler Syn ticoid sensitivity or reversing the glucocorticoid insensitivity drome, resistant dermatitis of the head and neck, severe in a Subject experiencing corticosteroid dependence or corti refractory atopic dermatitis, refractory Idiopathic thromb coid resistance or unresponsiveness or intolerance to corti ocytopenia purpura, refractory orbital myositis, refractory or costeroids, comprising administering a pharmaceutical com recurrent lymphomas, critically ill patients with sepsis or position comprising a steroid hormone (progestogen) as a acute respiratory distress syndrome (ARDS) and relative glucocorticoid sensitizer to the Subject exhibiting one or more adrenal insufficiency, rosacea, polymyalgia rheumatic, giant glucocorticoid insensitivity related conditions, wherein the cell arteritis, polymyositis, dermatomyositis, Kawasaki Syn drome, Guillain-Barre Syndrome, chronic inflammatory Subject has no history of menstrual cycle-related exacerba demyelinating polyneuropathy, multifocal motor neuropathy, tion, and further wherein the glucocorticoid insensitivity Stiffman syndrome, corticosteroid dependent systemic lupus related conditions comprise a range of immune-inflammatory erythematosus, corticosteroid dependent multiple Sclerosis, disorders/diseases treated with steroids when the therapy fails symptomatic corticosteroid dependent asthma, primary to achieve disease control or is not effective or intolerant or Sjogren's syndrome, systemic vasculitis, polymyositis, organ dependent to corticosteroids, and combinations thereof. transplants, graft-Versus-host disease, inflammatory diseases, 2. A method for the treatment of glucocorticoid insensitiv autoimmune diseases, hyperproliferative diseases, lupus, ity related diseases, or disorders, or conditions, the method osteoarthritis, rhinosinusitis, polyarteritis nodosa, Wegener's comprising: administering a pharmaceutical composition granulomatosis, giant cell arteritis, allergic rhinitis, urticaria, comprising a steroid hormone (progestogen) as a glucocorti hereditary angioedema, tendonitis, bursitis, autoimmune coid sensitizer to a Subject exhibiting the glucocorticoid chronic active hepatitis, cirrhosis, transplant rejection, pso insensitivity, wherein the glucocorticoid insensitivity com riasis, dermatitus, malignancies, leukemia, myelomas, lym prises corticosteroid dependence or corticoid resistance or phomas, acute adrenal insufficiency, rheumatic fever, granu unresponsiveness or intolerance to corticosteroids, and lomatous disease, immune proliferation/apotosis, wherein the subject has no history of menstrual cycle-related hypothalamic-pituitary-adrenal (HPA) axis Suppression and exacerbation. regulation, hypercortisolemia, modulation of the Th1/Th2 3. The method of claim 2, wherein the effects of the admin cytokine balance, chronic kidney disease, spinal cord injury, istration of the glucocorticoid sensitizer include, but are not cerebral edema, thrombocytopenia, Little's syndrome. Addi limited to, Steroid-sparing in corticosteroid-dependent son's disease, autoimmune hemolytic anemia, uveitis, pem phigus Vulgaris, nasal polyps, sepsis, bacterial infections, patients, better responsiveness or tolerance to corticosteroids, viral infections, rickettsial infections, parasitic infections, achieving efficacy by using a lower dose of corticosteroid, type II diabetes, obesity, metabolic syndrome, depression, preventing individuals at risk from developing refractory or Schizophrenia, mood disorders, Cushing's syndrome, anxi resistance or exacerbations in response to antigen exposures, ety, sleep disorders, memory and learning enhancement, glu infections, exercise, or irritants, achieving optimal immune cocorticoid-induced glaucoma, atopic dermatitis, drug hyper functions, easier administrations of steroids that can be sensitivity reactions, serum sickness, bullous dermatitis tapered or withdrawn, or reducing intolerance to prolonged herpetiformis, contact dermatitis, exfoliative erythroderma, administration of corticosteroids, decreased risks for devel mycosis fungoides, pemphigus, nonsuppurative thyroiditis, oping corticosteroid-related adverse events such as opportu sympathetic ophthalmia, uveitis, ocular inflammatory condi nistic infections and bone loss, and combinations thereof. tions unresponsive to topical Steroids, allergic bronchopul 4. A method for restoring corticosteroid sensitivity or monary aspergillosis, fulminating or disseminated pulmo reversing the glucocorticoid insensitivity or enhancing glu nary tuberculosis when used concurrently with appropriate cocorticoid sensitivity to treat one or more glucocorticoid chemotherapy, hypersensitivity pneumonitis, idiopathic insensitivity related conditions selected from the group con bronchiolitis obliterans with organizing pneumonia, idio sisting of a range of corticoid resistant diseases and immune pathic eosinophilic pneumonias, idiopathic pulmonary fibro inflammatory disorders treated with glucocorticoid when the sis, pneumocystis carinii pneumonia (PCP) associated with therapy becomes ineffective or intolerant or dependent or hypoxemia occurring in an HIV(+) individual who is also US 2011/O 195031 A1 Aug. 11, 2011

under treatment with appropriate anti-PCP antibiotics, a 20. The method of claim 1, wherein the progestogen is diuresis or remission of proteinuria in nephrotic syndrome, selected from the group consisting of 17alpha-hydrox without uremia, of the idiopathic type or that due to lupus yprogesterone or a derivative thereof, natural progesterone, erythematosus, ankylosing spondylitis, polymyalgia rheu dydrogesterone or a derivative or metabolite thereof, matic, psoriatic arthritis, relapsing polychondritis, trichinosis medrogestone or a derivative or metabolite thereof, medrox with neurologic or myocardial involvement, and tuberculous yprogesterone or a derivative or metabolite thereof, megestrol meningitis. or a derivative or metabolite thereof, chlormadinone or a 5. The method of claim 1, further comprising evaluating derivative or metabolite thereof, cyproterone or a derivative whether the subject exhibits the one or more glucocorticoid or metabolite thereof, gestonorone or a derivative or metabo insensitivity related diseases, disorders, or conditions. lite thereof, nomegestrol or a derivative or metabolite thereof, 6. The method of claim 1, wherein the steroid hormone is a demegestone or a derivative or metabolite thereof, promege progestogen. stone or a derivative or metabolite thereof, nestorone or a 7. The method of claim 1, wherein the pharmaceutical derivative or metabolite thereof, trimegestone or a derivative composition is designed to inhibit or delay the onset of the or metabolite thereof, norethisterone, norethisterone or a disease or disorder, reduce the risk of relapse, achieve a full or derivative or metabolite thereof, lynestrenol or a derivative or partial reduction of the symptoms or disease state, and alle metabolite thereof, ethynodiol or a derivative or metabolite viate, ameliorate, lessen, or cure the disease, disorder or thereof, diacetate, norgestrel or a derivative or metabolite symptoms. thereof, levonorgestrel or a derivative or metabolite thereof, desogestrel or a derivative or metabolite thereof, etonogestrel 8. The method of claim 1, wherein the subject is male or (3-keto-desogestrel) or a derivative or metabolite thereof, female at any age and exhibits the one or more glucocorticoid gestodene or a derivative or metabolite thereof, norgestimate insensitivity related diseases, disorders, or conditions. or a derivative or metabolite thereof, norelgestrornin (17 9. The method of claim 1, wherein the pharmaceutical deacetyl norgestimate) or a derivative or metabolite thereof, composition is administered daily. dienogest or a derivative or metabolite thereof, drospirenone 10. The method of claim 1, wherein the pharmaceutical or a derivative or metabolite thereof, norethindrone or a composition is administered according to a dosing regimen derivative or metabolite thereof, norethynodrel or a derivative selected from the group consisting of an administration inter or metabolite thereof, norgestrel or a derivative or metabolite Val less than one week, once weekly or exceeding once per thereof, drospirenone or a derivative thereof, or metabolite or week. a derivative thereof, etonogestrel or a derivative or metabolite 11. The method of claim 10, wherein the interval is selected thereof, 19-nortestosterone or a derivative or metabolites from the group consisting of once per day, twice per day, three thereof, dienogest or a derivative or metabolite thereof, nor times per day, up to 24 times per day, and continuous infusion. ethynodrel or a derivative or metabolite thereof, cyproterone 12. The method of claim 10, wherein the interval is selected or a derivative or metabolite thereof, tibolone or a derivative from the group consisting of once every other week, once or metabolite thereof, 19-norprogesterone or a derivative or monthly, once every two months, and once every three metabolite thereof, and combinations thereof. months. 21. The method of claim 20, wherein the derivative of 13. The method of claim 1, wherein the pharmaceutical progestogen is selected from the group consisting of an amine composition is administered once monthly. salt, alkali metal salt, transition metal salt, other metal salt, 14. The method of any claim 1, wherein the pharmaceutical salt of a mineral acid, salt of an organic acid, an ester, enol composition is administered systemically or locally delivered ether or ester, acid, base, Solvate, hydrate or prodrug prior to by a method selected from the group consisting of parenteral, formulation. intravenous, pulmonary, oral, rectal, buccal, transdermal, 22. The method of claim 21, wherein the derivative of intravaginal delivery, local application, topical application, 17alpha-hydroxyprogesterone is a carboxylic acid ester of depot injection, Subcutaneous, intraperitoneal, intraarterial 17alpha-hydroxyprogesterone. and intramuscular injection. 23. The method of claim 21, wherein the derivative of 15. The method of claim 14, wherein the transdermal deliv medroxyprogesterone is medroxyprogesterone acetate, the ery is administered by a formulation selected from the group derivative of megestrol is megestrol acetate, the derivative of consisting of a patch, cream, gel, and spray. chlormadinone is chlormadinone acetate, the derivative of 16. The method of claim 14, wherein the intravaginal deliv cyproterone is cyproterone acetate, the derivative of gestono ery is administered by a formulation selected from the group rone is gestonorone caproate, the derivative of nomegestrol is consisting of a Suppository, gel, and cream. nomegestrol acetate, the derivative of norethisterone is nore 17. The method of claim 14, wherein the pulmonary drug thisterone acetate, and the derivative of ethynodiol is ethyno delivery is administered by a formulation selected from the diol diacetate. group consisting of a medical aerosol and an inhalant delivery 24. The method of claim 1, wherein the progestogen is device. administered prior to, simultaneously with, or following the 18. The method of any claim 1, wherein the progestogen is administration of glucocorticoid. a progestin. 25. The method of claim 1, wherein the glucocorticoid is 19. The method of any claim 1, wherein the progestogen is selected from the group consisting of hydrocortisone (corti selected from the group consisting of progesterone, retro sol), cortisone acetate, dexamethasone, prednisone, predniso progesterone, progesterone derivative, 17C.-OH progesterone lone, methylprednisolone, betamethasone, triamcinolone, derivatives (both pregnanes and norpregnanes), 19-nor beclometaSone, Paramethasone, fluticasone, fludrocortisone progesterone derivatives, 19-nortestosterone derivatives acetate, deoxycorticosterone acetate (DOCA), Flupredniso (both estranges and gonanes), Spironolactone derivatives, and lone, fluticaSone propionate, budesonide, beclomethasone a combination thereof. dipropionate, flunisolide and triamcinolone acetonide. US 2011/O 195031 A1 Aug. 11, 2011

26. The method of claim 1, further comprising one or more consisting of corticoid resistant diseases and immune-inflam additional treatments for restoring corticosteroid sensitivity matory disorders treated with glucocorticoid when the or reversing the glucocorticoid insensitivity or enhancing therapy becomes ineffective or intolerant or dependent or glucocorticoid sensitivity to treat one or more glucocorticoid unresponsive or refractory to corticosteroids, and combina insensitivity related conditions. tions thereof, wherein the subject has no history of menstrual 27. The method of claim 26, wherein the one or more additional treatments are selected from the group consisting cycle-related exacerbation and exhibits one or more gluco of an androgen, an estrogen, immunosuppressive or immu corticoid insensitivity related diseases, disorders, or condi nomodulator agent, calcineurin inhibitor, p38 MAP kinase tions selected from the group consisting of glucocorticoid inhibitor, JNK inhibitor, Vitamin D, MIF inhibitor, Histone resistant asthma, refractory rheumatoid arthritis, refractory deacetylate-2 activator. Theophylline, Phosphoinositide-3- inflammatory bowel disease, chronic obstructive pulmonary kinase-8 inhibitor, antioxidant, iNOS inhibitor, P-glycopro disease, acute respiratory distress syndrome, interstitial pull tein inhibitor, and combinations thereof. monary fibrosis, cystic fibrosis, refractory ulcerative colitis, 28. The method of claim 26, wherein the progestogen is severe Crohn's disease, corticosteroid refractory asthma, administered prior to, simultaneously with, or following the descuamative interstitial pneumonia refractory to corticoster administration of an agent selected from the group consisting oid, refractory inflammatory myopathies, refractory myas of dehydroepiandrosterone (DHEA), estradiol, cyclosporine, thenia gravis, refractory pemphigus Vulgaris, methotrexate methotrexate, gold, 6-mercaptopurine, infliximab, etaner refractory RA patients, refractory nephrotic syndrome, cept, adalimumab, intravenous immunoglobulin, Mepoli refractory multiple Sclerosis, refractory sprue-like disease, Zumab, cyclosporin, tacrolimus, p38 MAP kinase inhibitor, JNK inhibitor, Vitamin D, MIF inhibitor. Histone deacety steroid-resistant sarcoidosis, refractory mucosal lesions of late-2 activator. Theophylline, Phosphoinositide-3-kinase-8 pemphigus Vulgaris, refractory Schnitzler syndrome, resis inhibitor, antioxidant, iNOS inhibitor, P-glycoprotein inhibi tant dermatitis of the head and neck, severe refractory atopic tor, and combinations thereof. dermatitis, refractory Idiopathic thrombocytopenia purpura, 29. The method of claim 1, wherein the pharmaceutical refractory orbital myositis, refractory or recurrent lympho composition is administered to the Subject via oral ingestion, mas, sepsis, acute respiratory distress syndrome (ARDS). further wherein the composition comprises from about 0.001 relative adrenal insufficiency, rosacea, polymyalgia rheu to 100 mg/kg of body weight of progestogen given orally per matic, giant cell arteritis, polymyositis, dermatomyositis, day. Kawasaki syndrome, Guillain-Barre Syndrome, chronic 30. A kit comprising a pharmaceutical composition, inflammatory demyelinating polyneuropathy, multifocal wherein the pharmaceutical composition comprises a steroid motor neuropathy, Stiffman syndrome, corticosteroid depen hormone, one or more pharmaceutically acceptable excipi dent systemic lupus erythematosus, corticosteroid dependent ents, and instructions for administering the pharmaceutical multiple Sclerosis, symptomatic corticosteroid dependent composition to a subject having no history of menstrual asthma, primary Sjogren's syndrome, systemic vasculitis, cycle-related exacerbation, wherein the subject exhibits one polymyositis, organ transplants, graft-Versus-host disease, or more glucocorticoid insensitivity related conditions. inflammatory diseases, autoimmune diseases, hyperprolif 31. A kit comprising a pharmaceutical composition, erative diseases, lupus, osteoarthritis, rhinosinusitis, pol wherein the pharmaceutical composition comprises a steroid yarteritis nodosa, Wegener's granulomatosis, giant cell arteri hormone, one or more pharmaceutically acceptable excipi tis, allergic rhinitis, urticaria, hereditary angioedema, ents, and instructions for administering the pharmaceutical tendonitis, bursitis, autoimmune chronic active hepatitis, cir composition as a glucocorticoid sensitizer to a Subject exhib rhosis, transplant rejection, psoriasis, dermatitus, malignan iting glucocorticoid insensitivity, wherein the Subject has no cies, leukemia, myelomas, lymphomas, acute adrenal insuf history of menstrual cycle-related exacerbation. ficiency, rheumatic fever, granulomatous disease, immune 32. A kit comprising a pharmaceutical composition, proliferation/apotosis, hypothalamic-pituitary-adrenal wherein the pharmaceutical composition comprises a steroid (HPA) axis Suppression and regulation, hypercortisolemia, hormone, one or more pharmaceutically acceptable excipi ents, and instructions for administering the pharmaceutical modulation of the Th1/Th2 cytokine balance, chronic kidney composition as a glucocorticoid sensitizer to achieve the disease, spinal cord injury, cerebral edema, thrombocytope effects of steroid-sparing in corticosteroid-dependent nia, Little's syndrome, Addison's disease, autoimmune patients, better responsiveness or tolerance to corticosteroids, hemolytic anemia, uveitis, pemphigus Vulgaris, nasal polyps, achieving efficacy by using a lower dose of corticosteroid, sepsis, bacterial infections, viral infections, rickettsial infec preventing individuals at risk for developing refractory or tions, parasitic infections, type II diabetes, obesity, metabolic resistance or exacerbations in response to antigen exposures, syndrome, depression, Schizophrenia, mood disorders, Cush infections, exercise, or irritants, achieving optimal immune ing's syndrome, anxiety, sleep disorders, memory and learn functions, easier steroid tapered or withdrawn, or prolonged ing enhancement, glucocorticoid-induced glaucoma, atopic administration of corticosteroids, decreased risks for devel dermatitis, drug hypersensitivity reactions, serum sickness, oping corticosteroid-related adverse events such as opportu bullous dermatitis herpetiformis, contact dermatitis, exfolia nistic infections and bone loss, and combinations thereof. tive erythroderma, mycosis fungoides, pemphigus, bullous 33. A kit comprising a pharmaceutical composition, pemphigoid, nonSuppurative thyroiditis, sympathetic oph wherein the pharmaceutical composition comprises a steroid thalmia, uveitis, ocular inflammatory conditions unrespon hormone and one or more pharmaceutically acceptable sive to topical steroids, allergic bronchopulmonary excipients; and instructions for administering the pharmaceu aspergillosis, fulminating or disseminated pulmonary tuber tical composition to a subject to treat one or more glucocor culosis when used concurrently with appropriate chemo ticoid insensitivity related conditions selected from the group therapy, hypersensitivity pneumonitis, idiopathic bronchioli US 2011/O 195031 A1 Aug. 11, 2011

tis obliterans with organizing pneumonia, idiopathic 46. The kit of claim 44, wherein the instructions comprise eosinophilic pneumonias, idiopathic pulmonary fibrosis, instructions for administering the pharmaceutical composi pneumocystis carinii pneumonia (PCP) associated with tion intravaginally via a formulation selected from the group hypoxemia occurring in an HIV(+) individual who is also consisting of a Suppository, gel, and cream. 47. The kit of claim 44, wherein the instructions comprise under treatment with appropriate anti-PCP antibiotics, a instructions for administering the pharmaceutical composi diuresis or remission of proteinuria in nephritic syndrome, tion pulmonarily via a formulation selected from the group without uremia, of the idiopathic type or that due to lupus consisting of an inhaled medical aerosol and an inhalant erythematosus, ankylosing spondylitis, polymyalgia rheu delivery device. matic, psoriatic arthritis, relapsing polychondritis, trichinosis 48. The kit of claim 30, wherein the progestogen is a with neurologic or myocardial involvement, and tuberculous progestin. meningitis. 49. The kit of claim30, wherein the progestogen is selected 34. The kit of claim 30, further comprising instructions for from the group consisting of progesterone, retroprogesterone, evaluating whether the subject exhibits the one or more glu progesterone derivative, 17a-OH progesterone derivatives cocorticoid insensitivity related diseases, disorders, or con (both pregnanes and norpregnanes), 19-norprogesterone ditions. derivatives, 19-nortestosterone derivatives (both estranges 35. A kit comprising a pharmaceutical composition com and gonanes), spironolactone derivatives, and a combination prising a steroid hormone and one or more pharmaceutically thereof. acceptable excipients; and instructions for administering the 50. The kit of claim30, wherein the progestogen is selected pharmaceutical composition. from the group consisting of 17alpha-hydroxyprogesterone or a derivative thereof, natural progesterone, dydrogesterone 36. The kit of claim 30, wherein the steroid hormone is a or a derivative or metabolite thereof, medrogestone or a progestogen. derivative or metabolite thereof, medroxyprogesterone or a 37. The kit of claim 30, wherein the pharmaceutical com derivative or metabolite thereof, megestrol or a derivative or position is designed to inhibit or delay the onset of the disease metabolite thereof, chlormadinone or a derivative or metabo or disorder, reduce the risk of relapse, achieve a full or partial lite thereof, cyproterone or a derivative or metabolite thereof, reduction of the symptoms or disease state, or alleviate, ame gestonorone or a derivative or metabolite thereof, nomege liorate, lessen, or cure the disease or disorder and/or its symp strol or a derivative or metabolite thereof, demegestone or a tOmS. derivative or metabolite thereof, promegestone or a derivative 38. The kit of claim 30, wherein the subject is male or or metabolite thereof, nestorone or a derivative or metabolite female of any age, and exhibits the one or more glucocorti thereof, trimegestone or a derivative or metabolite thereof, coid insensitivity related diseases, disorders, or conditions. norethisterone or a derivative or metabolite thereof, lynestre 39. The kit of claim 30, wherein the instructions comprise nol or a derivative or metabolite thereof, ethynodiol or a instructions for administering the pharmaceutical composi derivative or metabolite thereof, norgestrel or a derivative or tion daily. metabolite thereof, levonorgestrel or a derivative or metabo 40. The kit of any claim 30, wherein the instructions com lite thereof, desogestrel or a derivative or metabolite thereof, prise instructions for administering the pharmaceutical com etonogestrel (3-keto-desogestrel) or a derivative or metabo position at an interval less than one week, once weekly or lite thereof, gestodene or a derivative or metabolite thereof, exceeding once per week. norgestimate or a derivative or metabolite thereof, norel gestromin (17-deacetyl norgestimate) or a derivative or 41. The kit of claim 30, wherein the instructions comprise metabolite thereof, dienogest or a derivative or metabolite instructions for administering the pharmaceutical composi thereof, drospirenone or a derivative or metabolite thereof, tion at an interval selected from the group consisting of once norethindrone or a derivative or metabolite thereof, nor per day, twice per day, three times per day, up to 24 times per ethynodrel or a derivative or metabolite thereof, norgestrel or day, and by continuous infusion. a derivative or metabolite thereof, drospirenone or a deriva 42. The kit of claim 30, wherein the instructions comprise tive or metabolite thereof, etonogestrel or a derivative or instructions for administering the pharmaceutical composi metabolite thereof, 19-nortestosterone or a derivative or tion at an interval selected from the group consisting of once metabolite thereof, dienogest or a derivative or metabolite every other week, once monthly, once every two months, and thereof, norethynodrel or a derivative or metabolite thereof, once every three months. cyproterone or a derivative or metabolite thereof, tibolone or 43. The kit of claim 30, wherein the instructions comprise a derivative or metabolite thereof, 19-norprogesterone or a instructions for administering the pharmaceutical composi derivative or metabolite thereof, and combinations thereof. tion once monthly. 51. The kit of claim30, wherein the progestogen is selected 44. The kit of claim 30, wherein the instructions comprise from the group consisting of the corresponding progestogen instructions for administering the pharmaceutical composi amine salt, alkali metal salt, transition metal salt, other metal tion by a method selected from the group consisting of salt, salt of a mineral acid, Salt of an organic acid, ester, enol parenteral, intravenous, pulmonary, oral, rectal, buccal, trans ether orester, acid, base, Solvate, hydrate, and prodrug prior to dermal, intravaginal delivery, local application, topical appli formulation. cation, depot injection, Subcutaneous, intraperitoneal, 52. The kit of claim 51, wherein the derivative of 17alpha intraarterial, and intramuscular injection. hydroxyprogesterone is a carboxylic acid ester of 17alpha 45. The kit of claim 44, wherein the instructions comprise hydroxyprogesterone. instructions for administering the pharmaceutical composi 53. The kit of claim 51, wherein the derivative of medrox tion transdermally via a formulation selected from the group yprogesterone is medroxyprogesterone acetate, the derivative consisting of a patch, cream, gel, and spray. of megestrol is megestrol acetate, the derivative of chlorma US 2011/O 195031 A1 Aug. 11, 2011

dinone is chlormadinone acetate, the derivative of cyproter 58. The kit of claim 30, wherein the instructions comprise one is cyproterone acetate, the derivative of gestonorone is instructions for administering the progestogen prior to, gestonorone caproate, the derivative of nomegestrol is nome simultaneously with, or following the administration of an gestrol acetate, the derivative of norethisterone is norethister agent selected from the group consisting of dehydroepi one acetate, and the derivative of ethynodiol is ethynodiol androsterone (DHEA), estradiol, cyclosporine, methotrexate, diacetate. gold, 6-mercaptopurine, infliximab, etanercept, adalimumab, 54. The kit of claim 30, wherein the instructions comprise intravenous immunoglobulin, Mepolizumab, ciclosporin, instructions for administering the progestogen prior to, simultaneously with, or following the administration of glu tacrolimus, p38 MAP kinase inhibitor, JNK inhibitor, Vita cocorticoid. min D, MIF inhibitor. Histone deacetylate-2 activator. Theo 55. The kit of claim 54, wherein the derivative of gluco phylline, Phosphoinositide-3-kinase-8 inhibitor, antioxidant, corticoid is selected from the group consisting of hydrocor iNOS inhibitor, P-glycoprotein inhibitor, and combinations tisone (cortisol), cortisone acetate, dexamethasone, pred thereof. nisone, prednisolone, methylprednisolone, betamethasone, 59. The kit of claim 30, comprising a pharmaceutical com triamcinolone, beclometasone, paramethasone, fluticaSone, position comprising a steroid hormone and one or more phar fludrocortisone acetate, deoxycorticosterone acetate maceutically acceptable excipients; and instructions for (DOCA), Fluprednisolone, fluticasone propionate, budes administering the pharmaceutical composition to the Subject onide, beclomethasone dipropionate, flunisolide and triamci via oral ingestion, wherein the composition comprises from nolone acetonide. about 0.001 to 100 mg/kg of body weight of progestogen 56. The kit of claim 30, wherein the instructions comprise given orally per day, and further wherein the amount used instructions for providing one or more additional treatments with non-oral routes is determined based upon corresponding for restoring corticosteroid sensitivity or reversing the gluco serum concentration level of an oral dosage or containing a corticoid insensitivity or enhancing glucocorticoid sensitivity quantity of the active compound in an amount Sufficient to to treat one or more glucocorticoid insensitivity related con alleviate the symptoms of the treated subject. ditions. 60. A method of treating a Smoking-induced glucocorti 57. The kit of claim 56, wherein the one or more additional coid resistance disease, comprising administering at least one treatments are selected from the group consisting of an andro progestogen. gen, an estrogen, immunosuppressive or immunomodulator 61. The method of claim 60, wherein the progestogen is agent, calcineurin inhibitor, p38 MAP kinase inhibitor, JNK selected from the group consisting of 17HPC, P4 and MPA. inhibitor, Vitamin D, MIF inhibitor, histone deacetylate-2 62. The method of claim 60, wherein the disease is chronic activator, theophylline, phosphoinositide-3-kinase-8 inhibi obstructive pulmonary disease (COPD). tor, antioxidant, iNOS inhibitor, p-glycoprotein inhibitor, and combinations thereof. c c c c c