Treatment of inflammatory diseases

Abstract

The present invention provides mebendazole for use in the treatment or prevention of a chronic inflammatory disease, and in particular wherein the chronic inflammatory disease is an autoimmune disease, such as sarcoidosis, systemic lupus erythematosus (SLE), Huntington's disease, end-stage kidney disease, systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, multiple sclerosis, sicca syndrome, rheumatoid arthritis, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Graff's disease, Edison's disease, tuberculosis, Crohn's disease, and the like. , ulcerative colitis, inflammatory bowel disease, Alzheimer's disease, and celiac disease. Also provided is a method for treating or preventing a chronic inflammatory disease comprising administering an effective amount of mebendazole or a pharmaceutical composition of mebendazole. Also provided is the use of mebendazole for the preparation of a medicament for the treatment of chronic inflammatory diseases.

Description

[0001] This application is a divisional application of the invention patent application with the invention name “Treatment of Inflammatory Diseases” and application number “201880086722.X” filed on December 19, 2018. Technical Field

[0002] The present invention relates to the treatment or prevention of chronic inflammatory diseases (eg autoimmune diseases), in particular sarcoidosis and systemic lupus erythematosus (SLE).The treatment of the present invention comprises administering mebendazole to a patient suffering from a chronic inflammatory disease. Background Art

[0003] Inflammation is part of the normal biological response to harmful stimuli, such as tissue damage, pathogens, and irritants. Chronic inflammation may develop due to persistent stimuli, such as irritants or pathogens, or due to abnormal immune system function, such as in autoimmune diseases.

[0004] Chronic inflammatory diseases (CIDs) are various conditions and disorders characterized by the presence of chronic inflammation. CIDs can cause significant and prolonged suffering. Many CIDs are autoimmune diseases. Examples of CIDs include dermatomyositis, Grave's disease, multiple sclerosis, myasthenia gravis, systemic lupus erythematosus (SLE), sarcoidosis, Sjögren's syndrome ( syndrome, amyloidosis, Hashimoto thyroiditis, vasculitis, rheumatoid arthritis, reactive arthritis, polymyositis, scleroderma, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, severe celiac disease, type 1 diabetes, psoriasis, and pulmonary fibrosis (MedlinePlus medical encyclopedia-autoimmune disorders, National Institutes of Health); https: / / medlineplus.gov / ency / article / 000816.htm ; reviewed on May 21, 2017; accessed on November 24, 2017).

[0005] Treatment for CID varies depending on the basis of the condition. Sarcoidosis is a type of CID that causes small patches of red and swollen tissue (granulomas) to form within the body's organs. It commonly affects the lungs and skin. Symptoms of sarcoidosis depend on the organs affected but often include coughing, difficulty breathing, red or painful eyes, swollen glands, rash, pain in the joints, muscles or bones, and numbness or weakness in the face, arms and legs. (Information from the Sarcoidosis UK website http: / / sarcoidosisuk.org / , accessed November 24, 2017). Treatment of sarcoidosis includes prednisone, hydroxychloroquine or chloroquine, and immunosuppressants such as methotrexate, azathioprine, or leflunomide (from the National Heart, Lung, and Blood Institute website https: / / www.nhlbi.nih.gov / health / health-topics / topics / sarc / treatment , accessed November 24, 2017).

[0006] Systemic lupus erythematosus (also known as "SLE" or simply "Lupus") is an autoimmune disease characterized by acute and chronic inflammation of various tissues of the body. Common lupus signs and symptoms include fatigue, low-grade fever, loss of appetite, muscle aches, hair loss, arthritis, ulcers in the mouth and nose, facial rash ("butterfly rash"), abnormal sensitivity to sunlight (photosensitivity), chest pain caused by inflammation of the lining surrounding the lungs (pleurisy) and heart (pericarditis), and poor blood circulation in the fingers and toes with cold exposure (Raynaud's phenomenon). Treatments for SLE include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, immunosuppressants, hydroxychloroquine, and methotrexate. There is currently no cure for SLE, and none of the current treatments are completely effective in controlling the disease.

[0007] For most CIDs, currently available treatments are not completely effective. There remains a strong need for additional, more effective treatments. In particular, there remains a need for safe and well-tolerated treatments with manageable side effects.

[0008] Mebendazole is an antiparasitic agent used clinically to treat various forms of helminthiasis. The structure of mebendazole is as follows:

[0009]

[0010] Mebendazole at low doses ( It has been widely used for local intestinal helminth infections at doses of 100 mg per day, up to 100 mg x 2 for up to 5 days, depending on the strain), but also at relatively high doses (e.g., 40 mg / kg / day for months to years) against invasive Echinococcus infections (Luder PJ et al., Eur J Clin Pharmacol 31:443-448, 1986; Witassek et al., Eur J Clin Pharmacol 20:427-433, 1981; Woodtli, W. et al., Am J Trop Med Hyg 34:754-760, 1985; WHO: Guidelines for treatment of cystic and alveolar echinococcosis in humans. Bulletin of the World Health Organization Org)74:231-242,1996).

[0011] The present inventors have discovered that mebendazole can be used to treat CID, such as autoimmune diseases, in particular CID mediated by impaired ERK activity and / or decreased ERK signaling and / or ERK inactivation (eg, sarcoidosis and SLE). Summary of the invention

[0012] The present invention provides mebendazole for use in treating chronic inflammatory diseases (CID).

[0013] For example, CID is an autoimmune disease. For example, CID is selected from sarcoidosis, Huntington's disease, psoriasis, multiple sclerosis, primary biliary cirrhosis, autoimmune hepatitis, Graves' disease, Crohn's disease, ulcerative colitis, celiac disease, Addison's disease, Sjögren's syndrome, systemic lupus erythematosus (SLE) and rheumatoid arthritis. For example, CID is sarcoidosis, psoriasis, multiple sclerosis, primary biliary cirrhosis, autoimmune hepatitis, Graves' disease, Crohn's disease, ulcerative colitis, celiac disease, Addison's disease, Sjögren's syndrome, systemic lupus erythematosus (SLE) and rheumatoid arthritis. For example, CID is sarcoidosis and systemic lupus erythematosus (SLE). For example, CID is characterized by granulomatous inflammation. For example, CID is sarcoidosis.

[0014] In addition, for example, the CID is selected from systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, multiple sclerosis, Sjögren's syndrome, rheumatoid arthritis, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and Alzheimer's disease. For example, the CID is selected from systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, multiple sclerosis, Sjögren's syndrome, rheumatoid arthritis, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Addison's disease and tuberculosis. For example, the CID is selected from systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, and sarcoidosis.

[0015] The present invention further provides mebendazole for use in treating CID, wherein the therapeutic dose of mebendazole administered to the patient is 1 mg to 4000 mg, 10 mg to 3000 mg, 10 mg to 2000 mg, 10 mg to 1000 mg, 10 mg to 750 mg, 10 mg to 500 mg, 20 to 400 mg, 25 mg to 300 mg or 30 mg to 200 mg. Preferably, the therapeutic dose administered achieves a plasma concentration of mebendazole in the patient of 1 ng / ml to 1000 ng / ml (e.g., 1 ng / ml to 900 ng / ml, 1 ng / ml to 800 ng / ml, 1 ng / ml to 750 ng / ml, 1 ng / ml to 600 ng / ml, 1 ng / ml to 500 ng / ml, 1 ng / ml to 400 ng / ml, 1 ng / ml to 300 ng / ml, 1 ng / ml to 200 ng / ml, or 1 ng / ml to 100 ng / ml; or, for example, 100 ng / ml to 900 ng / ml, 100 ng / ml to 800 ng / ml, 100 ng / ml to 750 ng / ml 100ng / ml to 600ng / ml, 100ng / ml to 500ng / ml, 100ng / ml to 400ng / ml, 100ng / ml to 300ng / ml or 100ng / ml to 200ng / ml; or for example 250ng / ml to 900ng / ml, 250ng / ml to 800ng / ml, 250ng / ml to 750ng / ml, 250ng / ml to 600ng / ml or 250ng / ml to 500ng / ml; or for example 100ng / ml to 900ng / ml, 250ng / ml to 900ng / ml, 400ng / ml to 900ng / ml, 400ng / ml to 800ng / ml, or 400ng / ml to 700ng / ml or 400ng / ml to 600ng / ml)

[0016] In one embodiment, the administered therapeutic dose reaches a plasma concentration of mebendazole in the patient's body of 20ng / ml to 100ng / ml (e.g., 20ng / ml to 40ng / ml, 40ng / ml to 60ng / ml, 60ng / ml to 80ng / ml, or 80ng / ml to 100ng / ml). In another embodiment, the administered therapeutic dose reaches a plasma concentration of mebendazole in the patient's body of 50 to 250ng / ml (e.g., 50ng / ml to 100ng / ml, 50ng / ml to 150ng / ml, 100ng / ml to 200ng / ml, 150ng / ml to 200ng / ml, or 200ng / ml to 250ng / ml). In another embodiment, the administered therapeutic dose reaches a plasma concentration of mebendazole in the patient's body of 100ng / ml to 500ng / ml (e.g., 100ng / ml to 200ng / ml, 200ng / ml to 300ng / ml, 300ng / ml to 400ng / ml, or 400ng / ml to 500ng / ml). In another embodiment, the administered therapeutic dose reaches a plasma concentration of mebendazole in the patient's body of 250 to 750ng / ml (e.g., 250ng / ml to 400ng / ml, 300ng / ml to 450ng / ml, 350ng / ml to 500ng / ml, 400ng / ml to 550ng / ml, or 450ng / ml to 600ng / ml). In another embodiment, the administered therapeutic dose achieves a plasma concentration of mebendazole in the patient of 500 to 1000 ng / ml (e.g., 500 ng / ml to 600 ng / ml, 600 ng / ml to 700 ng / ml, 700 ng / ml to 800 ng / ml, 800 ng / ml to 900 ng / ml, or 900 ng / ml to 1000 ng / ml).

[0017] In another embodiment, the administered therapeutic dose achieves a plasma concentration of mebendazole in the patient of 1 ng / ml to 400 ng / ml, 1 ng / ml to 300 ng / ml, 1 ng / ml to 200 ng / ml, 1 ng / ml to 100 ng / ml, preferably 20 ng / ml to 40 ng / ml, 40 ng / ml to 60 ng / ml, 60 ng / ml to 80 ng / ml or 80 ng / ml to 100 ng / ml.

[0018] The present invention further provides a pharmaceutical composition comprising mebendazole for use in treating CID, such as autoimmune diseases.

[0019] The present invention further provides a method for treating or preventing CID, such as an autoimmune disease, comprising administering an effective amount of or a pharmaceutical composition comprising mebendazole to a patient suffering from CID. Preferably, the patient is a human.

[0020] The present invention further provides a pharmaceutical composition comprising mebendazole in combination with at least one additional active ingredient selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, immunosuppressants and disease-modifying antirheumatic drugs (DMARDs).

[0021] The present invention further provides the use of mebendazole for preparing a medicament for treating CID such as autoimmune diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Correlation of gene expression changes induced by mebendazole and other tubulin-active agents (termed "signatures") with MEK / ERK inhibitors is shown.

[0023] Figure 2 Shown are the effects of mebendazole and other tubulin active agents on phospho-ERK (p-ERK) in monocytic THP-1 cells.

[0024] Figure 3 Shown is the effect of mebendazole on monocytic THP-1 cells ( Figure 3 a) and peripheral blood mononuclear cells (PBMC) ( Figure 3 b) The effect of p-ERK.

[0025] Figure 4 Shown is the effect of mebendazole on p-ERK levels in CD4+ T cells isolated from PBMCs of SLE patients compared to CD4+ cells isolated from normal PBMCs.

[0026] Figure 5a and 5b Shown are the effects of mebendazole, fenbendazole and control (DMSO) on THP-1 monocytes ( Figure 5a ) and PMA-differentiated THP-1 macrophages ( Figure 5b ) in vitro and in vivo.

[0027] Figure 6 A positron emission tomography (PET) scan of a patient with sarcoidosis prior to administration of mebendazole is shown. Administration of mebendazole resulted in remission of sarcoidosis.

[0028] Figure 7 Shown are anti-(double-stranded)-DNA antibody levels in the serum of NZBNZWF1 mice before (week 14), during (weeks 16 to 24), and after treatment until termination (week 30) with vehicle, positive control (methotrexate (MTX)), or 25 mg / kg or 50 mg / kg mebendazole (MBZ). DETAILED DESCRIPTION

[0029] The inventors of the present invention surprisingly found that mebendazole has particularly beneficial properties for treating or preventing chronic inflammatory diseases (CID). Specifically, the inventors of the present invention surprisingly found that mebendazole has particularly beneficial properties for treating or preventing CID (specifically autoimmune disease CID), wherein CID is associated with impaired ERK activity and / or reduced ERK signaling and / or ERK inactivation, and preferably wherein CID is mediated by (e.g., caused by or resulting from) impaired ERK activity and / or reduced ERK signaling and / or ERK inactivation (e.g., CID can be treated or prevented by increasing ERK activity and / or increasing ERK signaling and / or activating ERK). In particular, the inventors of the present invention have surprisingly discovered that mebendazole has particularly beneficial properties for treating or preventing CID that is associated with defective ERK signaling (e.g., CID is a disease caused by defects in ERK signaling), and / or associated with an increased type 1 interferon (interferon α and / or β) response of plasmacytoid dendritic cells or other immune cells, and / or associated with increased p38 MAP kinase signaling.

[0030] CID is a variety of diseases and conditions characterized by chronic inflammation. Many CIDs are autoimmune diseases. Inflammation is part of the normal biological response to harmful stimuli (such as tissue damage, pathogens or irritants). Inflammation can be classified as acute or chronic. Acute inflammation is the initial protective response to harmful stimuli. Chronic inflammation may be caused by persistent stimuli (such as irritants or pathogens) or by abnormal immune system function (such as in autoimmune diseases).

[0031] In many cases, chronic inflammation may lead to human tissue destruction, abnormal organ growth and / or organ function changes. Chronic inflammation includes granulomatous, suppurative, serous and / or ulcerative inflammation. Granulomatous inflammation is characterized by the formation of granulomas. Granulomas are tumor-like masses containing immune cells such as macrophages and lymphocytes (such as natural killer cells, T cells and B cells). Suppurative inflammation is characterized by the accumulation of pus containing dead cells, body fluids and immune cells. Serous inflammation is characterized by the accumulation of serous body fluids. Ulcerative inflammation is characterized by the formation of ulcers by epithelial necrosis.

[0032] The inflammatory response is closely regulated by intracellular signaling pathways such as the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway contains proteins called mitogen-activated protein kinases (MAPKs). MAPKs can be divided into three major protein families, namely, extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases / stress-activated protein kinases (JNK / SAPKs), and p-38 proteins. Other proteins involved in the MAPK pathway include Ras, Raf, and MEK.

[0033] Defects in ERK signaling are associated with chronic inflammatory diseases, such as sarcoidosis, SLE, Huntington's disease, and end-stage renal disease (Gorelik G., Richardson B., Autoimmunity 2010;43:17-22; Sawalha AH et al., Genes Immun 2008;9:368-378; Maher P. et al., Hum Mol Genet 2010;20:261-270; Huang L. et al., Immun Ageing 2017;14:14; and Rastogi R. et al., Am J Respir Crit Care Med 2011;183:500-510).

[0034] For example, it has been shown that inhibition of ERK signaling by agents such as hydralazine can induce lupus and lupus-like autoimmune diseases (Gorelik G., Richardson B., Autoimmunity 2010; 43: 17-22; Sawalha AH et al., Genes and Immunity 2008; 9: 368-378). In addition, it has been reported that ERK expression is reduced in CD4+T cells from patients with sarcoidosis (Celada LJ et al., American Journal of Respiratory and Critical Care Medicine 191; 2015: A3747). MAPK (such as ERK) dysfunction may be the result of loss-of-function mutations, gain-of-function mutations, reduced MAPK expression and / or increased MAPK expression. In the present invention, mebendazole is particularly preferably used to treat or prevent CID, wherein CID is a disease caused by defects in ERK signaling.

[0035] As discussed in more detail below, the inventors were surprised to find that mebendazole significantly increased the level of p-ERK in monocyte-like cells and macrophages. This is particularly surprising because other tubulin activators, including other benzimidazoles, such as fenbendazole, do not significantly increase the p-ERK level in those cells. The inventors were also surprised to find that mebendazole increased the activity of ERK in peripheral blood mononuclear cells (PBMC) and CD4+T cells from patients with SLE. The inventors have also demonstrated that mebendazole is effective in treating patients with sarcoidosis and is effective in treating SLE in a mouse model. Without wishing to be bound by any theory, the inventors believe that mebendazole increases the activity of ERK, thereby reducing inflammation in patients with CID (such as SLE, sarcoidosis, Huntington's disease and end-stage renal failure). As described in detail above, defects in known ERK signaling are relevant to those diseases. Therefore, preferably, the CID used for treatment in the present invention is a CID associated with defective ERK signaling, and in particular a CID caused by a defect in ERK signaling.

[0036] In addition, many autoimmune diseases are driven (and possibly caused) by increased responses to type 1 interferons (interferon α and / or β) from plasmacytoid dendritic cells or other immune cells. This response can be inhibited by ERK activation (Janovec V. et al., Front Immunol 2018; 9: 364; Yang HT. et al., J Immunol 2011; 186: 1989-1996). Therefore, mebendazole can be used to treat autoimmune diseases, and specifically CID associated with increased responses to type 1 interferons (interferon α and / or β) from plasmacytoid dendritic cells or other immune cells. Examples of such diseases include systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, multiple sclerosis, Sjögren's syndrome, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Addison's disease, and tuberculosis (e.g., see, =L., Eloranta ML., Curr Opin Rheumatol 2013;25:248-253; Brkic Z. et al., Ann Rheum Dis 2016;75:1567-1573; Crow MK, Arthritis Res Ther 2010;12 Suppl 1:S5; Namiki K. et al., J Biol Chem 2012;287:24228-24238; Toro-Domínguez D. et al., Arthritis Res Ther 2014;16:325-8; Schett G. et al., Ann Rheum Dis 2008;67:909-916; Nestle FO et al., J Exp Med Med 2005;202:135-143; Yao Y. et al., PLoS ONE 2008;3:e2737; Takii Y. et al., Lab Invest 2005;85:908-920; Israel J. et al., Saudi J Gastroenterol 2011;17:348-9; Ruiz-Riol M. et al., Journal of Autoimmunity 2011;36:189-200; Krysiak R. et al., The American Journal of the Medical Sciences 2011;341:504-507; and Maertzdorf J. et al., Proc Natl Acad Sci USA) 2012; 109:7853-7858)

[0037] It is also known that increased p38 MAP kinase signaling is a key driver of inflammation in several autoimmune diseases (Kumar S. et al., Nat Rev Drug Discov 2003; 2: 717-726). ERK activation can downregulate p38 MAP kinase signaling by inducing dual specificity phosphatase (MKP-1) (Kondoh K. et al., Biochim Biophys Acta 2007; 1773: 1227-1237; and Toulouse A., Neural Regen Res 2015; 10: 1748-1749). Therefore, mebendazole can be used to treat autoimmune diseases, and specifically CIDs associated with increased p38 MAP kinase signaling. Examples of such diseases include Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD) and Alzheimer's disease. (Feng YJ, Li Y.Y., J Dig Dis 2011; 12:327-332; and Waetzig GH et al., The Journal of Immunology 2002; 168:5342-5351; Munoz L, Ammit AJ., Neuropharmacology 2010; 58:561-568).

[0038] Mebendazole

[0039] Mebendazole has been used as an anthelmintic since 1971. It is known to be safe and well tolerated at low doses. The safety of low-dose mebendazole (Vermox) was evaluated in 6276 subjects who participated in 39 clinical trials for the treatment of single or mixed parasitic infections of the gastrointestinal tract. In these 39 clinical trials, relevant adverse events occurred in less than 1% of mebendazole-treated subjects. It is also known that long-term high-dose (≥40 mg / kg / day) treatment of invasive parasitic infestations with mebendazole is generally well tolerated, with transient alopecia, gastrointestinal problems, reversible transaminase elevations, and mild leukopenia and thrombocytopenia being prominent adverse events (Woodtli, W. et al., American Journal of Tropical Medicine and Hygiene 34:754-760, 1985; WHO: Guidelines for the treatment of cystic and alveolar echinococcosis in humans. Bulletin of the World Health Organization 74:231-242, 1996; Davis, A. et al., Bulletin of the World Health Organization 67:503-508, 1989).

[0040] The well-established tolerability and safety profile of mebendazole is another advantage of using mebendazole to treat CID.

[0041] Although mebendazole is an established treatment for various forms of helminthiasis, it has not been reported to be effective against any CID associated with impaired ERK activity and / or decreased ERK signaling and / or ERK inactivation.

[0042] Mebendazole has the following structure:

[0043]

[0044] The CAS ID of mebendazole is 31431-39-7. Mebendazole is sold as a pharmaceutical composition for oral administration under the trade name Vermox. In Vermox, mebendazole is in the form of a free base. The mebendazole used in the methods and treatments of the present invention may also be in the form of a salt, a solvate or a prodrug. Mebendazole has various polymorphs. The mebendazole used in the methods and treatments of the present invention may be in any polymorph form. Preferably, mebendazole is in polymorph form A and / or B and / or C, and more preferably mebendazole is in polymorph form C or polymorph form A and / or C.

[0045] Suitable salts for use with mebendazole of the present invention are those in which the counterion is pharmaceutically acceptable. Suitable salts include salts formed with organic or inorganic acids or bases. Specifically, suitable salts formed with acids according to the present invention include those formed with mineral acids, strong organic carboxylic acids (such as alkanecarboxylic acids of 1 to 4 carbon atoms that are not substituted or substituted with, for example, halogens, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, such as amino acids) or with organic sulfonic acids (such as (C1-C4) alkylsulfonic acids or arylsulfonic acids that are not substituted or substituted with, for example, halogens). Pharmaceutically acceptable acid addition salts include those formed from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, citric acid, tartaric acid, acetic acid, phosphoric acid, lactic acid, pyruvic acid, trifluoroacetic acid, succinic acid, perchloric acid, fumaric acid, maleic acid, glycolic acid, lactic acid, salicylic acid, oxalic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, isethionic acid, ascorbic acid, malic acid, phthalic acid, aspartic acid and glutamic acid, lysine and arginine. Other acids, although not pharmaceutically acceptable per se, may be used as intermediates for obtaining the compounds of the invention and pharmaceutically acceptable acid addition salts thereof.

[0046] Particular salts of mebendazole include acid addition salts such as those formed from hydrochloric, hydrobromic, acetic, p-toluenesulfonic, tartaric, sulfuric, succinic, phosphoric, oxalic, nitric, methanesulfonic, malic, maleic and citric acids and, in particular, hydrochloric acid.

[0047] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they react or precipitate or crystallize. These complexes are referred to as "solvates". For example, complexes with water are referred to as "hydrates". Mebendazole used in the present invention can be in the form of a solvate.

[0048] Compounds that can be converted into mebendazole or its active metabolites or residues after being applied to a recipient are referred to as "prodrugs". Prodrugs can be converted into active forms with medical effects in vivo, for example, by hydrolysis in the blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series (1976); "Design of Prodrugs" editor H. Bundgaard, Elsevier, 1985; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference. As described above, the mebendazole used in embodiments of the present invention can be in the form of a prodrug.

[0049] Mebendazole for embodiments of the present invention is preferably in the form of a pharmaceutical composition. Pharmaceutical compositions available according to the present invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous (bolus or infusion) and intraarticular), suction (including fine particle dust or mist that can be generated by various types of metered dose pressurized sprays, sprayers or insufflators), rectal, intraperitoneal and body surface (including skin, oral, sublingual and intraocular) administration, but the most appropriate approach may depend on, for example, the patient's condition and illness of the recipient. Preferably, the pharmaceutical composition is suitable for oral administration.

[0050] Pharmaceutical compositions of the invention suitable for oral administration may be presented as discrete units, such as capsules, cachets or tablets each containing a predetermined amount of mebendazole; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. Mebendazole may also be presented as boluses, electuaries or pastes. Various pharmaceutically acceptable carriers and formulations thereof are described in standard formulation discussions, e.g., Remington's Pharmaceutical Sciences by EW Martin. See also Wang, YJ and Hanson, MA, Journal of Parenteral Science and Technology, Technical Report No. 10, Supplement. 42: 2S, 1988.

[0051] For oral administration, mebendazole is preferably provided in the form of a pharmaceutical composition of tablets or other presentation forms provided in discrete units, and the discrete units contain 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250, 500 or 1000mg of mebendazole for symptom adjustment of the dosage of the patient to be treated. The medicine comprising mebendazole usually contains the mebendazole of about 10mg to about 1000mg, preferably the mebendazole of about 10mg to about 500mg, for example the mebendazole of 50, 100, 200, 400 or 500mg. During constant rate infusion, intravenous injection, the most preferred dosage range is about 0.1 to about 50mg / kg / minute. Mebendazole can be used with a single therapeutic dose every day, or can be used as a divided dose twice, three times or four times or more every day, to provide a daily therapeutic dose. Preferably, mebendazole is used in divided doses twice every day, to provide a daily therapeutic dose.

[0052] Compositions for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that make the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. Compositions may be present in unit dose or multi-dose containers, such as sealed ampoules and vials, and may be stored under freeze drying (lyophilization) conditions that require only the addition of a sterile liquid carrier (e.g., saline or water for injection) immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the aforementioned types. Exemplary compositions for parenteral administration include injectable solutions or suspensions, which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents (such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution); or other suitable dispersing or wetting agents and suspending agents (including synthetic mono- or diglycerides) and fatty acids (including oleic acid or Cremaphor).

[0053] Exemplary compositions for nasal aerosol or inhalation administration include solutions in saline, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and / or other solubilizing or dispersing agents as are known in the art.

[0054] Pharmaceutical compositions for rectal administration may be presented as suppositories with conventional carriers such as cocoa butter, synthetic glycerides or polyethylene glycols. Such carriers are generally solid at ordinary temperatures but liquefy and / or dissolve in the rectal cavity to release the drug.

[0055] Compositions for topical administration in the mouth (e.g., buccal or sublingual) include lozenges containing mebendazole in a flavored base such as sucrose and acacia or tragacanth, and lozenges containing mebendazole in a base such as gelatin and glycerin or sucrose and acacia. Exemplary compositions for topical administration include topical carriers such as a composite ointment base (Plastibase) of liquid paraffin and polyethylene (mineral oil gelled with polyethylene).

[0056] Preferred unit dosage compositions are those containing an exploratory or therapeutic dose of mebendazole, as herein above recited, or an appropriate fraction thereof.

[0057] It should be understood that the compositions of this invention may include, in addition to the ingredients particularly mentioned above, other agents conventional in the art having regard to the type of composition in question, for example those suitable for oral administration may include flavoring agents.

[0058] Although mebendazole or its salt for various embodiments of the present invention can be used as the only active ingredient, mebendazole can also be used in combination with one or more other activating agents. Therefore, the present invention also provides mebendazole for the treatment of CID or for the treatment method of CID according to the present invention together with other activating agents, for simultaneous, sequential or separate use. This type of other activating agent can be a reagent or other pharmaceutically active material that can be used for the treatment of CID, but is preferably a reagent known for the treatment of CID such as autoimmune diseases. This type of reagent is known in the art. The specific examples for other therapeutic agents of the present invention include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, immunosuppressants and disease-modifying antirheumatic drugs (DMARDs), such as hydroxychloroquine, methotrexate, prednisone, azathioprine and leflunomide.

[0059] When used in combination, the precise dosage of the additional active agent(s) will vary depending on the dosing schedule, the oral efficacy of the particular agent selected, the age, size, sex and condition of the subject / patient (typically a mammal or human; preferably a human), the nature and severity of the condition, and other relevant medical and physical factors. Thus, a caregiver or clinician can readily determine the precise pharmaceutically effective amount. An appropriate amount can be determined by routine experimentation in animal models and human clinical studies. For humans, one of ordinary skill in the art will know or otherwise be able to determine an effective dose.

[0060] The individual components of such combinations may be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment.

[0061] When used in combination with the compounds useful in the present invention, the aforementioned additional active agent(s) may be used, for example, in those amounts specified in the Physicians' Desk Reference (PDR) or otherwise determined by one of ordinary skill in the art.

[0062] Chronic inflammatory diseases

[0063] The present invention provides mebendazole or a salt thereof for treating CID. In one embodiment of the present invention, CID is selected from acne, acid reflux / heartburn, age-related macular degeneration (AMD), allergies, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, appendicitis, arteritis, asthma, atherosclerosis, balanitis, blepharitis, bronchopulmonary bullous pemphigoid, burns, bursitis, carditis, celiac disease, cellulitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, chronic obstructive pulmonary disease (COPD), and pulmonary edema. PD), cirrhosis (such as primary biliary cirrhosis), colitis (such as ulcerative colitis), congestive heart failure, conjunctivitis, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, common cold, Crohn's disease, lacrimal gland inflammation, dementia, dermatitis, dermatomyositis, digestive system diseases, eczema, emphysema, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, fibrosis, fibrositis, Foreign body granuloma, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, heart valve dysfunction, hepatitis (e.g., autoimmune hepatitis), hidradenitis suppurativa, Huntington's disease, hyperlipidemic pancreatitis, hypertension, ileitis, infection (e.g., viral, bacterial, fungal), inflammatory bowel disease, inflammatory cardiomegaly, inflammatory neuropathy, inflammatory lung disease, neuropathic insulin resistance, interstitial cystitis, interstitial nephritis, iritis, ischemia, ischemic heart disease Heart disease, keratitis, keratoconjunctivitis, laryngitis, systemic lupus erythematosus, lupus nephritis, mastitis, mastoiditis, meningitis, metabolic syndrome (X syndrome), migraine, multiple sclerosis, myelitis, myocarditis, myositis, neurological disorders, nephritis, nonalcoholic fatty hepatitis, obesity, omphalitis, oophoritis, orchitis, osteochondritis, osteopenia, osteomyelitis, osteoporosis, osteitis, otitis, pancreatitis, Parkinson's disease (Parkinson's disease), mumps, pelvic inflammatory disease, pemphigus, pericarditis, peritonitis, phlebitis, pleurisy, pneumonia, polycystic nephritis, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, portal vein inflammation, renal failure, reperfusion injury, retinitis, rheumatic fever, salpingitis, sarcoidosis, sialadenitis, spastic colon, stricture, stomatitis, stroke, surgical complications, synovitis, tendinitis, tendinosis, tenosynovitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, transplant rejection, trigoneitis, tuberculosis, tumors, urethritis, Achilles tendon bursitis, uveitis, vaginitis, vasculitis and vulvitis. CID can also be selected from type 1 diabetes, systemic sclerosis (also known as scleroderma), Sjögren's syndrome, rheumatoid arthritis, Grave's disease, Addison's disease and end-stage renal disease. In certain preferred embodiments, CID is a CID characterized by granulomatous inflammation.

[0064] In one embodiment of the present invention, CID is selected from Alzheimer's disease, cirrhosis (such as primary biliary cirrhosis), colitis (such as ulcerative colitis), Crohn's disease, hepatitis (such as autoimmune hepatitis), Huntington's disease, inflammatory bowel disease, systemic lupus erythematosus, multiple sclerosis, myositis, psoriasis, renal failure (such as end-stage renal disease), sarcoidosis and tuberculosis. CID can also be selected from type 1 diabetes, systemic sclerosis (also known as scleroderma), Sjögren's syndrome, rheumatoid arthritis, Grave's disease and Addison's disease.

[0065] In one embodiment of the present invention, CID is selected from Alzheimer's disease, cirrhosis (such as primary biliary cirrhosis), colitis (such as ulcerative colitis), Crohn's disease, hepatitis (such as autoimmune hepatitis), Huntington's disease, inflammatory bowel disease, systemic lupus erythematosus, multiple sclerosis, myositis, psoriasis, renal failure (such as end-stage renal disease), sarcoidosis and tuberculosis. CID can also be selected from type 1 diabetes, systemic sclerosis (also known as scleroderma), Sjögren's syndrome, Grave's disease and Addison's disease.

[0066] In one embodiment of the present invention, CID is selected from Alzheimer's disease, cirrhosis (such as primary biliary cirrhosis), colitis (such as ulcerative colitis), Crohn's disease, hepatitis (such as autoimmune hepatitis), Huntington's disease, inflammatory bowel disease, systemic lupus erythematosus, myositis, renal failure (such as end-stage renal disease), sarcoidosis and tuberculosis. CID can also be selected from type 1 diabetes, systemic sclerosis (also known as scleroderma) and Addison's disease.

[0067] In one embodiment of the present invention, CID is selected from Alzheimer's disease, cirrhosis (such as primary biliary cirrhosis), colitis (such as ulcerative colitis), Crohn's disease, hepatitis (such as autoimmune hepatitis), Huntington's disease, inflammatory bowel disease, myositis, renal failure (such as end-stage renal disease), sarcoidosis and tuberculosis. CID can also be selected from type 1 diabetes, systemic sclerosis (also known as scleroderma) and Addison's disease.

[0068] In one embodiment of the present invention, CID is a disease associated with impaired ERK activity and / or reduced ERK signaling and / or ERK inactivation (and more preferably, CID is a disease mediated by impaired ERK activity and / or reduced ERK signaling and / or ERK inactivation (e.g., CID is a disease that can be treated or prevented by increasing ERK activity and / or increasing ERK signaling and / or activating ERK)); and / or CID is associated with defective ERK signaling (e.g., CID is caused by a defect in ERK signaling), and / or is associated with an increased type 1 interferon (interferon α and / or β) response of plasmacytoid dendritic cells or other immune cells, and / or is associated with increased p38 MAP kinase signaling. Examples of such CIDs include systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, multiple sclerosis, Sjögren's syndrome, rheumatoid arthritis, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and Alzheimer's disease.

[0069] In one embodiment of the invention, CID is a disease caused by impaired ERK activity and / or reduced ERK signaling and / or inactivated ERK (e.g., CID is a disease that can be treated or prevented by increasing ERK activity and / or increasing ERK signaling and / or activating ERK); and / or CID is associated with defective ERK signaling (e.g., CID is caused by a defect in ERK signaling), and / or is associated with an increased type 1 interferon (interferon α and / or β) response of plasmacytoid dendritic cells or other immune cells, and / or is associated with increased p38 MAP kinase signaling. Examples of such CIDs include systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, multiple sclerosis, Sjögren's syndrome, rheumatoid arthritis, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and Alzheimer's disease.

[0070] In certain preferred embodiments, CID is a disease associated with impaired ERK activity and / or reduced ERK signaling and / or ERK inactivation (and more preferably, CID is a disease mediated by impaired ERK activity and / or reduced ERK signaling and / or ERK inactivation (e.g., CID is a disease that can be treated or prevented by increasing ERK activity and / or increasing ERK signaling and / or activating ERK)); and / or CID is associated with defective ERK signaling (e.g., CID is caused by a defect in ERK signaling), and / or is associated with an increased type 1 interferon (interferon alpha and / or beta) response of plasmacytoid dendritic cells or other immune cells, and / or is associated with increased p38 MAP kinase signaling, and the CID is selected from the group consisting of:

[0071] systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also called scleroderma), myositis, type 1 diabetes, multiple sclerosis, Sjögren's syndrome, rheumatoid arthritis, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and Alzheimer's disease; or

[0072] systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also called scleroderma), myositis, type 1 diabetes, multiple sclerosis, Sjögren's syndrome, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and Alzheimer's disease; or

[0073] systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also called scleroderma), myositis, type 1 diabetes, primary biliary cirrhosis, autoimmune hepatitis, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and Alzheimer's disease; or

[0074] Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, primary biliary cirrhosis, autoimmune hepatitis, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and Alzheimer's disease.

[0075] In certain preferred embodiments, CID is a disease associated with impaired ERK activity and / or reduced ERK signaling and / or ERK inactivation (and more preferably, CID is a disease mediated by impaired ERK activity and / or reduced ERK signaling and / or ERK inactivation (e.g., CID is a disease that can be treated or prevented by increasing ERK activity and / or increasing ERK signaling and / or activating ERK)); and / or CID is associated with defective ERK signaling (e.g., CID is caused by a defect in ERK signaling), and / or is associated with an increased type 1 interferon (interferon α and / or β) response of plasmacytoid dendritic cells or other immune cells, and CID is selected from the group consisting of:

[0076] systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also called scleroderma), myositis, type 1 diabetes, multiple sclerosis, Sjögren's syndrome, rheumatoid arthritis, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Addison's disease, and tuberculosis; or

[0077] systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also called scleroderma), myositis, type 1 diabetes, multiple sclerosis, Sjögren's syndrome, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Addison's disease, and tuberculosis; or

[0078] systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also called scleroderma), myositis, type 1 diabetes, primary biliary cirrhosis, autoimmune hepatitis, Addison's disease, and tuberculosis; or

[0079] Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, primary biliary cirrhosis, autoimmune hepatitis, Addison's disease, and tuberculosis.

[0080] In certain preferred embodiments, CID is a disease associated with impaired ERK activity and / or reduced ERK signaling and / or ERK inactivation (and more preferably, CID is a disease mediated by impaired ERK activity and / or reduced ERK signaling and / or ERK inactivation (e.g., CID is a disease that can be treated or prevented by increasing ERK activity and / or increasing ERK signaling and / or activating ERK)); and / or CID is associated with defective ERK signaling (e.g., CID is caused by a defect in ERK signaling), and CID is selected from the group consisting of:

[0081] Systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, and sarcoidosis; or

[0082] Huntington's disease, end-stage renal disease, and sarcoidosis; or

[0083] Autoimmune diseases

[0084] In an embodiment of the present invention, CID is an autoimmune disease. For example, CID is an autoimmune disease selected from the group consisting of dermatomyositis, Grave's disease, multiple sclerosis, myasthenia gravis, systemic lupus erythematosus (SLE), sarcoidosis, Sjögren's syndrome, amyloidosis, Hashimoto's thyroiditis, vasculitis, rheumatoid arthritis, reactive arthritis, scleroderma (also known as systemic sclerosis), Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, severe celiac disease, pulmonary fibrosis, Huntington's disease, Crohn's disease, and primary biliary cirrhosis. For example, CID is an autoimmune disease selected from the group consisting of Grave's disease, multiple sclerosis, systemic lupus erythematosus (SLE), sarcoidosis, Sjögren's syndrome, rheumatoid arthritis, scleroderma (also known as systemic sclerosis), Addison's disease, Huntington's disease, Crohn's disease, and primary biliary cirrhosis. Preferably, the autoimmune disease is selected from the group consisting of systemic lupus erythematosus and sarcoidosis.

[0085] In one embodiment of the invention, CID is an autoimmune disease, and is, for example, selected from sarcoidosis, Huntington's disease, psoriasis, multiple sclerosis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Crohn's disease, ulcerative colitis, celiac disease, Addison's disease, Sjögren's syndrome, systemic lupus erythematosus (SLE) and rheumatoid arthritis. For example, CID is an autoimmune disease, and is sarcoidosis, psoriasis, multiple sclerosis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Crohn's disease, ulcerative colitis, celiac disease, Addison's disease, Sjögren's syndrome, systemic lupus erythematosus (SLE) and rheumatoid arthritis. For example, CID is an autoimmune disease, and is sarcoidosis and systemic lupus erythematosus (SLE). For example, CID is an autoimmune disease characterized by granulomatous inflammation. For example, CID is the autoimmune disease sarcoidosis.

[0086] In another embodiment, CID is an autoimmune disease, and is, for example, selected from sarcoidosis, Huntington's disease, psoriasis, multiple sclerosis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Crohn's disease, ulcerative colitis, Addison's disease, Sjogren's syndrome, and systemic lupus erythematosus (SLE). For example, CID is an autoimmune disease, and is sarcoidosis, psoriasis, multiple sclerosis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Crohn's disease, ulcerative colitis, Addison's disease, Sjogren's syndrome, and systemic lupus erythematosus (SLE). For example, CID is an autoimmune disease, and is sarcoidosis and systemic lupus erythematosus (SLE). For example, CID is an autoimmune disease characterized by granulomatous inflammation. For example, CID is the autoimmune disease sarcoidosis.

[0087] In another embodiment, CID is an autoimmune disease, and is, for example, selected from sarcoidosis, Huntington's disease, primary biliary cirrhosis, autoimmune hepatitis, Crohn's disease, ulcerative colitis, Addison's disease, and systemic lupus erythematosus (SLE). For example, CID is an autoimmune disease, and is sarcoidosis, primary biliary cirrhosis, autoimmune hepatitis, Crohn's disease, ulcerative colitis, Addison's disease, and systemic lupus erythematosus (SLE). For example, CID is sarcoidosis and systemic lupus erythematosus (SLE). For example, CID is an autoimmune disease characterized by granulomatous inflammation. For example, CID is the autoimmune disease sarcoidosis.

[0088] In another embodiment, CID is an autoimmune disease and is, for example, selected from sarcoidosis, Huntington's disease, primary biliary cirrhosis, autoimmune hepatitis, Crohn's disease, ulcerative colitis, and Addison's disease. For example, CID is an autoimmune disease and is sarcoidosis, primary biliary cirrhosis, autoimmune hepatitis, Crohn's disease, ulcerative colitis, and Addison's disease. For example, CID is an autoimmune disease characterized by granulomatous inflammation. For example, CID is the autoimmune disease sarcoidosis.

[0089] In a particularly preferred embodiment, the CID is an autoimmune disease and is selected from systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, multiple sclerosis, Sjögren's syndrome, rheumatoid arthritis, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and Alzheimer's disease. More preferably, the CID is an autoimmune disease and is selected from systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, multiple sclerosis, Sjögren's syndrome, rheumatoid arthritis, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Addison's disease and tuberculosis. Even more preferably, CID is an autoimmune disease and is selected from systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease and sarcoidosis. For example, CID is an autoimmune disease and is selected from systemic lupus erythematosus (SLE) and sarcoidosis.

[0090] In another particularly preferred embodiment, the CID is an autoimmune disease and is selected from systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, multiple sclerosis, Sjögren's syndrome, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and Alzheimer's disease. More preferably, the CID is an autoimmune disease and is selected from systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, multiple sclerosis, Sjögren's syndrome, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Addison's disease and tuberculosis. Even more preferably, CID is an autoimmune disease and is selected from systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease and sarcoidosis. For example, CID is an autoimmune disease and is selected from systemic lupus erythematosus (SLE) and sarcoidosis.

[0091] In another particularly preferred embodiment, CID is an autoimmune disease and is selected from systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, primary biliary cirrhosis, autoimmune hepatitis, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and Alzheimer's disease. More preferably, CID is an autoimmune disease and is selected from systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, primary biliary cirrhosis, autoimmune hepatitis, Addison's disease and tuberculosis. Even more preferably, CID is an autoimmune disease and is selected from systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease and sarcoidosis. For example, CID is an autoimmune disease and is selected from systemic lupus erythematosus (SLE) and sarcoidosis.

[0092] In another particularly preferred embodiment, CID is an autoimmune disease and is selected from Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, primary biliary cirrhosis, autoimmune hepatitis, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and Alzheimer's disease. More preferably, CID is an autoimmune disease and is selected from Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Addison's disease and tuberculosis. Even more preferably, CID is an autoimmune disease and is selected from Huntington's disease, end-stage renal disease and sarcoidosis. For example, CID is the autoimmune disease sarcoidosis.

[0093] Types of inflammation

[0094] In an embodiment of the invention, CID is characterized by the presence of granulomatous, suppurative, serous and / or ulcerative inflammation. Preferably, CID is characterized by the presence of granulomatous inflammation. CIDs that may be characterized by the presence of granulomatous inflammation include sarcoidosis, tuberculosis, Crohn's disease, hepatic granulomatous diseases, histiocytosis, orofacial granulomatosis, Blau's syndrome, and foreign body granulomas such as beryllium granuloma, zirconium granuloma, silica granuloma, and talc granuloma. For example, CID is sarcoidosis or tuberculosis, and in particular sarcoidosis.

[0095] In certain preferred embodiments, CID is a disease associated with impaired ERK activity and / or reduced ERK signaling and / or ERK inactivation (and more preferably, CID is a disease mediated by impaired ERK activity and / or reduced ERK signaling and / or ERK inactivation (e.g., CID is a disease that can be treated or prevented by increasing ERK activity and / or increasing ERK signaling and / or activating ERK)); and / or CID is associated with an increased type 1 interferon (interferon alpha and / or beta) response of plasmacytoid dendritic cells or other immune cells, and / or is associated with increased p38 MAP kinase signaling, and CID is characterized by the presence of granulomatous, purulent, serous and / or ulcerative inflammation. Preferably, it is characterized by the presence of granulomatous inflammation. For example, CID is sarcoidosis, tuberculosis or Crohn's disease, and in particular sarcoidosis.

[0096] Mebendazole therapeutic dose

[0097] In certain embodiments of the present invention, the purposes of mebendazole comprises the mebendazole of therapeutic dose to the patient.Preferably, the patient is the human being.Depending on the type of the patient and the CID to be treated, the mebendazole of therapeutic dose can be repeatedly applied, for example, every day, every two days or every three days, every week, every two weeks, every three weeks or every four weeks or even as a high single therapeutic dose.The mebendazole of therapeutic dose can be repeatedly applied in a short term or long term.For example, the therapeutic dose can be repeatedly applied in the time of a few days, a few weeks, a few months or several years.

[0098] The amount of mebendazole required to achieve a therapeutic effect will vary with the specific route of administration and the characteristics of the patient being treated, such as species, age, weight, sex, medical condition, specific disease and its severity, and other relevant medical and physical factors. One of ordinary skill can readily determine and administer the effective amount of mebendazole required to treat or prevent CID.

[0099] Preferably, the therapeutic dose of mebendazole is 1mg to 4000mg, preferably 10mg to 3000mg, more preferably 10mg to 2000mg. Preferably, the therapeutic dose of mebendazole can be 10mg to 1000mg, 10mg to 750mg, 10mg to 500mg, 20 to 400mg, 25mg to 300mg or 30mg to 200mg. Alternatively, the therapeutic dose of mebendazole can be 50mg to 150mg, 250mg to 350mg, 350mg to 450mg, 450mg to 550mg, 500mg to 1000mg, 1000mg to 1500mg, 1500mg to 2000mg, 2000 to 3000mg or 3000 to 4000mg. For example, a therapeutic dose of mebendazole can be, for example, 10, 20, 25, 30, 24, 50, 60, 70, 75, 80, 90, 95, 100, 105, 110, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 210, 220, 225, 250, 275, 300, 325 , 350, 375, 400, 425, 450, 475, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1250, 1300, 1400, 1500, 1750, 2000, 2250, 2500, 2750, 3000, 3250, 3500, 3750 or 4000 mg. Preferably 50, 100, 200, 300, 400 or 500 mg. Most preferably 200 mg or 400 mg.

[0100] In certain embodiments, the mebendazole of therapeutic dose is applied in a single dose in one day. For example, for the therapeutic dose of 100 mg, a single 100 mg dose is applied. In certain embodiments, the mebendazole of therapeutic dose is applied in two or more divided doses in one day. For example, for the therapeutic dose of 200 mg, two 100 mg doses or four 50 mg doses can be applied in one day. As another example, for the therapeutic dose of 400 mg, two 200 mg doses or four 100 mg doses can be applied in one day. The therapeutic dose can be applied in two or more divided doses in one day, for example, 2, 3, 4, 5 or 6 divided doses in one day, three or more divided doses in one day, four or more divided doses in one day, five or more divided doses in one day, or 6 or more divided doses in one day. The therapeutic dose can be administered in up to 8 divided doses in a day, or up to 7 divided doses in a day, up to 6 divided doses in a day, up to 4 divided doses in a day, 3 divided doses in a day, or twice divided doses in a day. In a preferred embodiment, the therapeutic dose of mebendazole can be administered in two divided doses in a day.

[0101] In embodiments where a therapeutic dose of mebendazole is administered in two or more divided doses in one day, the dose administered in each divided therapeutic dose may be the same, e.g., two 50 mg doses for a 100 mg therapeutic dose. Alternatively, each divided therapeutic dose may be different, e.g., one 50 mg dose and one 100 mg dose for a 150 mg therapeutic dose. Preferably, the dose administered in each divided therapeutic dose is the same.

[0102] Certain embodiments of the invention comprise administering to a patient a therapeutic dose of mebendazole, wherein the dose is sufficient to achieve a certain plasma concentration of mebendazole.

[0103] The dose may be sufficient to achieve a plasma concentration of mebendazole of 1 ng / ml to 1000 ng / ml (e.g., 1 ng / ml to 900 ng / ml, 1 ng / ml to 800 ng / ml, 1 ng / ml to 750 ng / ml, 1 ng / ml to 600 ng / ml, 1 ng / ml to 500 ng / ml, 1 ng / ml to 400 ng / ml, 1 ng / ml to 300 ng / ml, 1 ng / ml to 200 ng / ml, or 1 ng / ml to 100 ng / ml; or, for example, 100 ng / ml to 900 ng / ml, 100 ng / ml to 800 ng / ml, 100 ng / ml to 750 ng / ml, 100 ng / ml to 600 ng / ml, 100 ng / ml to or, for example, from 100 ng / ml to 900 ng / ml, 250 ng / ml to 900 ng / ml, 400 ng / ml to 900 ng / ml, 400 ng / ml to 800 ng / ml, 400 ng / ml to 700 ng / ml or 400 ng / ml to 600 ng / ml).

[0104] In one embodiment, the dosage may be enough to reach a plasma concentration of mebendazole of 20ng / ml to 100ng / ml (e.g., 20ng / ml to 40ng / ml, 40ng / ml to 60ng / ml, 60ng / ml to 80ng / ml, or 80ng / ml to 100ng / ml). In another embodiment, the dosage may be enough to reach a plasma concentration of mebendazole of 50 to 250ng / ml (e.g., 50ng / ml to 100ng / ml, 50ng / ml to 150ng / ml, 100ng / ml to 200ng / ml, 150ng / ml to 200ng / ml, or 200ng / ml to 250ng / ml). In another embodiment, the dosage may be enough to reach a plasma concentration of mebendazole of 100 ng / ml to 500 ng / ml (e.g., 100 ng / ml to 200 ng / ml, 200 ng / ml to 300 ng / ml, 300 ng / ml to 400 ng / ml, or 400 ng / ml to 500 ng / ml). In another embodiment, the dosage may be enough to reach a plasma concentration of mebendazole of 250 to 750 ng / ml (e.g., 250 ng / ml to 400 ng / ml, 300 ng / ml to 450 ng / ml, 350 ng / ml to 500 ng / ml, 400 ng / ml to 550 ng / ml, or 450 ng / ml to 600 ng / ml). In another embodiment, the dose may be sufficient to achieve a plasma concentration of mebendazole of 500 to 1000 ng / ml (e.g., 500 ng / ml to 600 ng / ml, 600 ng / ml to 700 ng / ml, 700 ng / ml to 800 ng / ml, 800 ng / ml to 900 ng / ml, or 900 ng / ml to 1000 ng / ml).

[0105] In one embodiment, the dosage may be sufficient to achieve the following plasma concentration of mebendazole: 1 ng / ml to 400 ng / ml, preferably 1 ng / ml to 300 ng / ml, preferably 1 ng / ml to 200 ng / ml, more preferably 1 ng / ml to 100 ng / ml. For example, the plasma concentration of mebendazole is 1 ng / ml to 20 ng / ml, preferably 20 ng / ml to 40 ng / ml, preferably 40 ng / ml to 60 ng / ml, preferably 60 ng / ml to 80 ng / ml, preferably 80 ng / ml to 100 ng / ml. Most preferably 60 ng / ml to 80 ng / ml.

[0106] Certain embodiments of the invention comprise administering to a patient a therapeutic dose of mebendazole, wherein the dose is sufficient to achieve a certain steady-state maximum plasma concentration of mebendazole.

[0107] The dose may be sufficient to achieve a steady-state maximum plasma concentration of mebendazole of 1 ng / ml to 1000 ng / ml (e.g., 1 ng / ml to 900 ng / ml, 1 ng / ml to 800 ng / ml, 1 ng / ml to 750 ng / ml, 1 ng / ml to 600 ng / ml, 1 ng / ml to 500 ng / ml, 1 ng / ml to 400 ng / ml, 1 ng / ml to 300 ng / ml, 1 ng / ml to 200 ng / ml, or 1 ng / ml to 100 ng / ml; or, for example, 100 ng / ml to 900 ng / ml, 100 ng / ml to 800 ng / ml, 100 ng / ml to 750 ng / ml, 100 ng / ml to 600 ng / ml, 100 ng / ml to to 500ng / ml, 100ng / ml to 400ng / ml, 100ng / ml to 300ng / ml or 100ng / ml to 200ng / ml; or for example 250ng / ml to 900ng / ml, 250ng / ml to 800ng / ml, 250ng / ml to 750ng / ml, 250ng / ml to 600ng / ml or 250ng / ml to 500ng / ml; or for example 100ng / ml to 900ng / ml, 250ng / ml to 900ng / ml, 400ng / ml to 900ng / ml, 400ng / ml to 800ng / ml or 400ng / ml to 700ng / ml or 400ng / ml to 600ng / ml).

[0108] In one embodiment, the dosage may be enough to reach a stable maximum plasma concentration of mebendazole of 20ng / ml to 100ng / ml (e.g., 20ng / ml to 40ng / ml, 40ng / ml to 60ng / ml, 60ng / ml to 80ng / ml, or 80ng / ml to 100ng / ml). In another embodiment, the dosage may be enough to reach a stable maximum plasma concentration of mebendazole of 50 to 250ng / ml (e.g., 50ng / ml to 100ng / ml, 50ng / ml to 150ng / ml, 100ng / ml to 200ng / ml, 150ng / ml to 200ng / ml, or 200ng / ml to 250ng / ml). In another embodiment, the dosage may be enough to reach a steady-state maximum plasma concentration of mebendazole of 100 ng / ml to 500 ng / ml (e.g., 100 ng / ml to 200 ng / ml, 200 ng / ml to 300 ng / ml, 300 ng / ml to 400 ng / ml, or 400 ng / ml to 500 ng / ml). In another embodiment, the dosage may be enough to reach a steady-state maximum plasma concentration of mebendazole of 250 to 750 ng / ml (e.g., 250 ng / ml to 400 ng / ml, 300 ng / ml to 450 ng / ml, 350 ng / ml to 500 ng / ml, 400 ng / ml to 550 ng / ml, or 450 ng / ml to 600 ng / ml). In another embodiment, the dose may be sufficient to achieve a steady-state maximum plasma concentration of mebendazole of 500 to 1000 ng / ml (e.g., 500 ng / ml to 600 ng / ml, 600 ng / ml to 700 ng / ml, 700 ng / ml to 800 ng / ml, 800 ng / ml to 900 ng / ml, or 900 ng / ml to 1000 ng / ml).

[0109] In one embodiment, the dosage may be sufficient to achieve the following steady-state maximum plasma concentration of mebendazole: 1 ng / ml to 400 ng / ml, preferably 1 ng / ml to 300 ng / ml, preferably 1 ng / ml to 200 ng / ml, more preferably 1 ng / ml to 100 ng / ml. For example, the plasma concentration of mebendazole is 1 ng / ml to 20 ng / ml, preferably 20 ng / ml to 40 ng / ml, preferably 40 ng / ml to 60 ng / ml, preferably 60 ng / ml to 80 ng / ml, preferably 80 ng / ml to 100 ng / ml. Most preferably 60 ng / ml to 80 ng / ml.

[0110] The effectiveness of mebendazole in treating or preventing chronic inflammatory diseases is demonstrated in Examples 2 to 7 below, which describe the activity of mebendazole in increasing ERK signaling, effectively treating patients with sarcoidosis, and effectively treating SLE mouse models. Many CIDs contain defective ERK signaling. In addition, ERK activation can inhibit other driving factors of autoimmune diseases, such as increased response to type 1 interferons (interferon α and / or β) of plasmacytoid dendritic cells (or other immune cells) and increased P38 MAP kinase signaling. Thus, the data show that it is expected that the present invention will effectively treat various CIDs, and specifically those CIDs associated with the above-mentioned pathways, and more generally those CIDs associated with (and preferably mediated by) impaired ERK activity and / or reduced ERK signaling and / or ERK inactivation. (e.g., CIDs that can be treated or prevented by increasing ERK activity and / or increasing ERK signaling and / or activating ERK). Specifically, such CIDs include sarcoidosis, SLE, Huntington's disease, end-stage renal disease, and rheumatoid arthritis; for example, sarcoidosis, SLE, Huntington's disease, and end-stage renal disease.

[0111] Examples

[0112] Examples 1 to 5

[0113] Material

[0114] Mebendazole, albendazole, fenbendazole, oxibendazole, thiabendazole, vinblastine, and PMA were purchased from Sigma, St. Louis, MO. Vincristine and docetaxel were purchased from Selleckchem (Houston, TX). Compounds were stored in dimethyl sulfoxide (DMSO, Sigma, St. Louis, MO) or sterile water as 10 mM stock solutions and further diluted with culture medium as needed.

[0115] Cell culture methods

[0116] Peripheral blood mononuclear cells (PBMCs) from healthy donors were isolated by centrifugation over 1.077 g / ml Ficoll-Paque and cryopreserved as described by Larsson et al. (Int J Cancer 1992; 50: 177-185). Cell viability was determined by trypan blue exclusion test. SLE PBMCs were obtained from Astarte Biologics, WA, USA (Cat. No. 1035, Batch 3429DE16) in cryopreserved vials (10 million cells). They were then cultured with 1% paraformaldehyde (PVA) according to the manufacturer's description and the method described by Gorelik et al. (J. Immunol. 2007; 179(8): 5553-5563). CD4+ cells were isolated using the CD4+ Isolation Kit from Miltenyi Biotec.

[0117] Monocytic THP-1 cells were obtained from ATCC (Manassas, VA) and cultured in RPMI-1640 medium supplemented with 10% heat-inactivated fetal bovine serum (HIFBS), 2 mM L-glutamine, 100 U / 100 mg / mL penicillin / streptomycin, and 0.05 mM 2-mercaptoethanol (all from Sigma, St. Louis, MO). All cell lines were cultured at 37° C. in a humidified atmosphere containing 5% CO2.

[0118] Measurement of Phospho-ERK 1 / 2 (p-ERK)

[0119] The ERK 1 / 2 Bioplex Pro Cell Signaling Assay Kit (Biorad) and Luminex were used according to the manufacturer's instructions. The system measured the activity of phospho-ERK 1 / 2 (p-ERK). The measurement of p-ERK in CD4+ cells followed the protocol described by Gorelik et al. (J Immunology 2007; 179(8): 5553-5563).

[0120] Example 1. Gene expression signature of mebendazole compared with that of MEK / ERK inhibitors using the LINCS Connectivity Map (CMap) database.

[0121] The drug-induced gene expression perturbations of mebendazole were investigated using the public LINCS Connectivity Map (CMap) database (www.clue.io), which contains a collection of thousands of L1000 gene expression profiles from cells grown in monolayers exposed to a large number of small molecules and genetic perturbations (www.clue.io). The presence of mebendazole in the database allowed gene expression to be compared with other drugs and perturbations (pertubargens).

[0122] The LINCS CMap database was used to enter the mebendazole signature as a query to identify compounds that induce similar or opposite gene expression signatures. For each compound query, the database provided an enrichment (relevance) score based on Kormogorov Smirnov statistics (Lamb J et al., Science 2006; 313: 1929-35) for sets of compounds representing different pharmacological classes. For mebendazole, a negative enrichment score of -99.05 was observed for a group of 9 MEK inhibitors: PD-198306 (ID 7950), MEK 1 / 2 inhibitor (ID 4279), U-0126 (ID 7490), U0126 (ID 9449), Selumetinib (ID 0016), PD-98059 (ID 0658), PD-0325901 (ID 5102), AS-703026 (ID 4967), and PD-184352 (ID 4563). This enrichment was specific to mebendazole and was not observed for other benzimidazoles or tubulin inhibitors. These results suggest that mebendazole strongly induces MEK / ERK activation.

[0123] Example 2. Effects of mebendazole and other tubulin-active agents on p-ERK in monocytic THP-1 cells.

[0124] Upstream MAPK proteins (such as MEK) phosphorylate ERK, leading to ERK activation. The measurement of p-ERK levels in cells is used as an indicator of ERK signaling. The Bioplex Pro Cell Signaling Assay Kit for ERK 1 / 2 was used for (Bio-Rad) and Luminex The system measures the level of p-ERK in monocytic THP-1 cells. The assay is based on the binding of the target of interest via antibodies to magnetic beads. The target is detected using a biotinylated antibody and a fluorescent reporter. The assay is performed according to the manufacturer's instructions.

[0125] Figure 2The effect of mebendazole and other tubulin active agents on p-ERK levels in THP-1 cells is shown. Mebendazole significantly increased the level of p-ERK in THP-1 cells. Other tubulin active agents tested did not increase the level of p-ERK in THP-1 cells.

[0126] Example 3. Effect of mebendazole on p-ERK in monocytic THP-1 cells and peripheral blood mononuclear cells (PBMCs) in the presence of the MEK / ERK inhibitor U0126.

[0127] The ERK 1 / 2-targeted Bioplex Pro Cell Signaling Assay Kit (Bio-Rad) and Luminex The system measured the level of p-ERK in monocytic THP-1 cells and PBMC cells. The assay was based on the binding of the target of interest via antibodies to magnetic beads. The target was detected using biotinylated antibodies and fluorescent reporters. The assay was performed according to the manufacturer's instructions.

[0128] Figure 3 The effect of mebendazole on THP-1 cells treated with and without the MEK / ERK inhibitor U0126 is shown. Figure 3 a) and PBMC cells treated with and without the MEK / ERK inhibitor U0126 ( Figure 3 b) Effect of p-ERK levels in THP-1 cells not treated with U0126, p-ERK levels increased with increasing doses of mebendazole. At 1 μm mebendazole, the fluorescence reading was approximately 500 arb units, and at 30 μM mebendazole, the fluorescence reading increased to approximately 1200 arb units. In THP-1 cells treated with U0126, only low levels of p-ERK were detected, with approximate fluorescence readings of approximately 5 to 15 arb units recorded. These data indicate that mebendazole increases p-ERK levels and thus ERK activity in THP-1 cells, and that this activation is eliminated in the presence of U0126. Similar results were observed in PMBCs, where p-ERK levels increased with increasing doses of mebendazole.

[0129] Example 4. Effect of mebendazole on p-ERK in CD4+ T cells isolated from PBMCs of SLE patients compared to CD4+ cells isolated from normal PBMCs.

[0130] CD4+ T cells were isolated from PBMCs obtained from venous blood of healthy donors and patients with SLE using the method described by Gorelik et al. (J. Immunol. 2007; 179(8):5553-5563). The BioplexPro Cell Signaling Assay Kit for ERK 1 / 2 (BioRad) and Luminex The system measured the level of p-ERK in isolated CD4+ T cells.

[0131] like Figure 4 As shown, administration of 10 μM and 30 μM mebendazole to CD4+ T cells restored p-ERK activity to at least the same level as that observed in CD4+ T cells obtained from healthy donors. This data indicates that mebendazole is able to restore p-ERK activity in CD4+ T cells obtained from patients with CID caused by defective p-ERK activity.

[0132] Example 5. Effects of Mebendazole and Fenbendazole on Phospho-ERK (p-ERK) Activity in Monocyte-like THP-1 Cells and PMA-differentiated THP-1 Macrophages

[0133] Upstream MAPK proteins (such as MEK) phosphorylate ERK, leading to ERK activation. The measured value of p-ERK level in cells is used as an indicator of ERK signaling. Therefore, in this example, the effects of mebendazole and fenbendazole on p-ERK levels in monocytic THP-1 cells and PMA-differentiated THP-1 macrophages after exposure to either compound were studied.

[0134] Use the above Luminex The system and commercially available kit (Bio-Rad, Hercules, CA) measure the level of phosphoprotein phospho-ERK (p-ERK) in monocyte-like THP-1 cells and PMA-differentiated THP-1 macrophages after exposure to mebendazole (10 μM), fenbendazole (10 μM) or control (DMSO) for 1 hour. The assay is based on the binding of the target of interest via antibodies to magnetic beads. The target is detected using biotinylated antibodies and fluorescent reporters. The assay is performed according to the manufacturer's instructions. In brief, the protein concentration in the cell lysate is first determined using the Micro-BCA method (ThermoFischer Scientific, Waltham, MA, USA) to ensure that the amount of the sample in the assay is equal, and then the cell lysate sample is incubated with beads, then with detection antibodies, and finally with streptavidin-PE for measurement. Fluorescence was measured using a MAGPIX instrument (Bio-Rad), and concentration levels were determined by fitting a standard curve.

[0135] Figure 5a and 5b Shown are the effects of mebendazole (10 μM), fenbendazole (10 μM) and control (DMSO) on monocytic THP-1 cells ( Figure 5a ) and PMA-differentiated THP-1 macrophages ( Figure 5b Mebendazole significantly increased the level of p-ERK in both THP-1 cell types. Fenbendazole did not increase the level of p-ERK in both types of THP-1 cells.

[0136] Example 6. Treatment of Sarcoidosis Patients with Mebendazole

[0137] The patient was a male who underwent surgery for colon cancer at the age of 56. One year later, the patient suffered a recurrence of liver metastases. He refused standard treatment with chemotherapy and instead began experimental treatment with mebendazole. Mebendazole was administered 200 mg per day for six consecutive days (dosed as 2×100 mg). At that time, a PET / CT examination was performed, which, in addition to the known liver metastases, showed enlarged hilar and mediastinal lymph nodes with elevated FDG signals compatible with the radiological diagnosis of sarcoidosis (the tissue involved is indicated by an arrow; Figure 6 Center left). A previous CT scan during cancer surgery also suggested this diagnosis.

[0138] The mebendazole dose was increased to 400 mg per day (2 x 200 mg) and a new PET scan was performed six weeks later, which showed disappearance / reduction in the FDG signal and size of the hilar and mediastinal nodes ( Figure 6 (center right, compared to the same area in the left), where the radiological diagnosis of sarcoidosis was in remission. The serum mebendazole concentration at this time was 71 ng / ml. In summary, mebendazole has been shown to be effective in reducing the size of sarcoid tissue in patients with sarcoidosis.

[0139] Example 7. In vivo efficacy study in mice with systemic lupus erythematosus (SLE)

[0140] Materials and Equipment

[0141] Dulbecco's phosphate buffered saline and goat anti-mouse IgG-HRP were obtained from Life Technologies. Methotrexate, calf thymus DNA, poly-L-lysin, and TMB solution were obtained from Sigma. 4% paraformaldehyde and Tween 20 were obtained from Merck. Calf thymus Sm / RNP was obtained from GenWay Biotech. Fetal bovine serum was obtained from Biochrom.

[0142] Combur test strips for urine testing were obtained from Swevet. Costar 3590 ELISA plates and V-bottom well dilution plates were obtained from VWR. Microtubes were obtained from VWR and Eppendorf. Microvette 500 Z-Gel and 10 ml tubes were obtained from Sarstedt. 0.6×2.5 mm needles were obtained from Terumo Neolus. 1 ml syringes were obtained from Codan.

[0143] Methotrexate was obtained from Sigma-Aldrich (St. Louis, MO).

[0144] Mebendazole was obtained from Recipharm (Sweden). For oral administration, it was dissolved in a sesame oil / PBS 1:1 mixture (volume). Sesame oil was obtained from Sigma-Aldrich. Thus, the vehicle for the control was a sesame oil / PBS 1:1 mixture (volume)

[0145] Methods and Results

[0146] NZBNZWF1 mice spontaneously develop an autoimmune syndrome with significant similarities to human systemic lupus erythematosus (SLE), and therefore this type of mouse can be used as a model for SLE.

[0147] Before the start of the experiment, 40 female NZBNZWF1 mice (Envigo Europe) were fed and watered ad libitum and acclimatized for about 1 week. At the start of the experiment, the mice were 14 weeks old and the start of treatment was 16 weeks. At the start of the experiment, the mice were divided into 4 groups of 10 mice each.

[0148] 1. Vehicle control: treatment with vehicle only

[0149] 2. Positive control: treatment with methotrexate (15 mg / kg)

[0150] 3. Treat with low dose of mebendazole (25 mg / kg)

[0151] 4. Treatment with high doses of mebendazole (50 mg / kg)

[0152] Treatment groups were mixed between cages to avoid cage effects. Cages were housed with 2 to 10 mice.

[0153] Vehicle control treatment and low-dose and high-dose mebendazole treatment were administered orally (po) daily for 5 consecutive days per week for 8 weeks (mice age 16-24 weeks). Positive control treatment of 15 mg / kg methotrexate was administered intraperitoneally 3 times per week for 8 weeks (mice age 16-24 weeks). Table 1 contains full details of the treatment groups.

[0154] Table 1 Summary of treatment groups

[0155]

[0156] Mice with wounds that did not heal (defined as "wet wounds" for more than 3 consecutive days) were removed from the experiment. Mice that were in poor health (dehydration and kyphotic posture) or exhibited other severe adverse effects from drug administration were removed from the experiment.

[0157] The body weight of mice was measured weekly during the treatment period. When the research terminated, the spleen weight of all animals was determined. Urine sampling was carried out monthly in the first 8 weeks, and then urine sampling was carried out every other week until termination. At the beginning of the experiment (14 weeks of mouse age), when the treatment began (16 weeks of mouse age) and every two weeks (18, 20, 22 and 24 weeks of mouse age), after the treatment (26 and 28 weeks of mouse age) and when the termination (30 weeks of mouse age), serum was collected from all mice. The level of the antibody (anti-ds-DNA antibody) for double-stranded DNA (dsDNA) in the analysis serum sample was analyzed. Anti-(double-stranded)-DNA antibody is a highly specific marker of the autoimmune syndrome of human SLE and NZBNZWF1 mice. Anti-(double-stranded)-DNA antibody is often found with very high level in the patient suffering from various systemic rheumatic diseases (comprising SLE) and in the autoimmune syndrome in NZBNZWF1 mice.

[0158] The results of analysis of anti-ds-DNA antibodies in serum samples collected during and after treatment are shown in Figure 7 In. From Figure 7 It can be seen that the group treated with mebendazole (MBZ) showed a lower concentration of anti-dsDNA antibodies in serum samples than the vehicle control group or the methotrexate (MTX) positive control group, indicating that the disease activity of SLE is lower in the group treated with mebendazole. In addition, the group treated with a higher dose (50 mg / kg) of mebendazole showed a lower concentration of anti-dsDNA antibodies than the group treated with a lower dose (25 mg / kg), indicating that a higher dose of mebendazole is more effective in treating SLE.

Claims

Mebendazole for use in treating or preventing chronic inflammatory diseases.

2. Mebendazole for use according to claim 1, wherein the chronic inflammatory disease is an autoimmune disease.

3. Mebendazole for use according to any one of claims 1 to 2, wherein the chronic inflammatory disease is a disease associated with (e.g., mediated by) impaired ERK activity and / or reduced ERK signaling and / or ERK inactivation; and / or wherein the chronic inflammatory disease is associated with defective ERK signaling (eg, the chronic inflammatory disease is a disease caused by a defect in ERK signaling); and / or wherein the chronic inflammatory disease is associated with an increased type 1 interferon (interferon α and / or β) response of plasmacytoid dendritic cells or other immune cells; and / or The chronic inflammatory disease is associated with increased p38 MAP kinase signaling.

4. Mebendazole for use according to any one of claims 1 to 3, wherein the chronic inflammatory disease is a disease that can be treated or prevented by increasing ERK activity and / or increasing ERK signaling and / or activating ERK.

5. Mebendazole for use according to any one of claims 1 to 4, wherein the chronic inflammatory disease is selected from sarcoidosis, systemic lupus erythematosus, Huntington's disease, psoriasis, multiple sclerosis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Crohn's disease, ulcerative colitis, celiac disease, Addison's disease, Sjögren's syndrome and rheumatoid arthritis (e.g. sarcoidosis, systemic lupus erythematosus, Huntington's disease, psoriasis, multiple sclerosis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Crohn's disease, ulcerative colitis, celiac disease, Addison's disease and Sjögren's syndrome; and preferably sarcoidosis, systemic lupus erythematosus, Huntington's disease, primary biliary cirrhosis, autoimmune hepatitis, Crohn's disease, ulcerative colitis, celiac disease and Addison's disease).

6. Mebendazole for use according to any one of claims 1 to 4, wherein the chronic inflammatory disease is selected from sarcoidosis, systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, multiple sclerosis, Sjögren's syndrome, rheumatoid arthritis, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and Alzheimer's disease (e.g. ... The preferred embodiments include but are not limited to: systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, multiple sclerosis, Sjögren's syndrome, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and Alzheimer's disease; and preferably sarcoidosis, systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, primary biliary cirrhosis, autoimmune hepatitis, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and Alzheimer's disease).

7. Mebendazole for use according to any one of claims 1 to 6, wherein the chronic inflammatory disease is selected from sarcoidosis and systemic lupus erythematosus.

8. Mebendazole for use according to claims 1 to 7, wherein the chronic inflammatory disease is characterized by granulomatous inflammation.

9. Mebendazole for use according to claims 1 to 8, wherein the chronic inflammatory disease is sarcoidosis.

10. Mebendazole for use according to any one of claims 1 to 9, wherein the therapeutic dose of mebendazole administered to a patient is 1 mg to 4000 mg, 10 mg to 3000 mg, 10 mg to 2000 mg, 10 mg to 1000 mg, 10 mg to 750 mg, 10 mg to 500 mg, 20 to 400 mg, 25 mg to 300 mg or 30 mg to 200 mg.

11. Mebendazole for use according to any one of claims 1 to 10, wherein the therapeutic dose administered achieves a plasma concentration of mebendazole in the patient of 1 ng / ml to 1000 ng / ml (e.g. 1 ng / ml to 900 ng / ml, 1 ng / ml to 800 ng / ml, 1 ng / ml to 750 ng / ml, 1 ng / ml to 600 ng / ml, 1 ng / ml to 500 ng / ml, 1 ng / ml to 400 ng / ml, preferably 1 ng / ml to 300 ng / ml, preferably 1 ng / ml to 200 ng / ml, more preferably 1 ng / ml to 100 ng / ml; or for example 100 ng / ml to 900 ng / ml, 100 ng / ml to 800 ng / ml, 100 ng / ml to 750 ng / ml, 100 ng / ml or for example 100ng / ml to 900ng / ml, 250ng / ml to 900ng / ml, 400ng / ml to 900ng / ml, 400ng / ml to 800ng / ml or 400ng / ml to 700ng / ml or 400ng / ml to 600ng / ml).1 ng / ml to 900 ng / ml, 1 ng / ml to 800 ng / ml, 1 ng / ml to 750 ng / ml, 1 ng / ml to 600 ng / ml, 1 ng / ml to 500 ng / ml, 1 ng / ml to 400 ng / ml, 1 ng / ml to 300 ng / ml, 1 ng / ml to 200 ng / ml or 1 ng / ml to 100 ng / ml; or for example 100 ng / ml to 900 ng / ml, 100 ng / ml to 800 ng / ml, 100 ng / ml to 750 ng / ml, 100 ng / ml to 600 ng / ml, 100 ng / ml to 500 ng / ml, 100 ng / ml to 40 0 ng / ml, 100 ng / ml to 300 ng / ml or 100 ng / ml to 200 ng / ml; or for example 250 ng / ml to 900 ng / ml, 250 ng / ml to 800 ng / ml, 250 ng / ml to 750 ng / ml, 250 ng / ml to 600 ng / ml or 250 ng / ml to 500 ng / ml; or for example 100 ng / ml to 900 ng / ml, 250 ng / ml to 900 ng / ml, 400 ng / ml to 900 ng / ml, 400 ng / ml to 800 ng / ml or 400 ng / ml to 700 ng / ml or 400 ng / ml to 600 ng / ml).

12. A pharmaceutical composition comprising mebendazole for use as defined in any one of claims 1 to 11.

13. A pharmaceutical composition for the treatment or prevention of chronic inflammatory diseases, comprising mebendazole in combination with at least one additional active ingredient selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, immunosuppressants and disease-modifying antirheumatic drugs (DMARDs).

14. A pharmaceutical composition comprising a combination of mebendazole and at least one additional active ingredient selected from the group consisting of corticosteroids, immunosuppressants and disease-modifying antirheumatic drugs (DMARDs).

15. A method for treating or preventing a chronic inflammatory disease, comprising administering an effective amount of mebendazole or a pharmaceutical composition comprising mebendazole or a pharmaceutical composition according to claim 13 or 14.

16. Use of mebendazole for preparing a medicament for treating chronic inflammatory diseases.

17. The method according to claim 15 or the use according to claim 16, wherein the chronic inflammatory disease is an autoimmune disease.

18. The method of claim 15 or 17 or the use of claim 16 or 17, wherein the chronic inflammatory disease is a disease associated with (e.g., mediated by) impaired ERK activity and / or reduced ERK signaling and / or ERK inactivation; and / or wherein the chronic inflammatory disease is associated with defective ERK signaling (eg, the chronic inflammatory disease is a disease caused by a defect in ERK signaling); and / or wherein the chronic inflammatory disease is associated with an increased type 1 interferon (interferon α and / or β) response of plasmacytoid dendritic cells or other immune cells; and / or The chronic inflammatory disease is associated with increased p38 MAP kinase signaling.

19. The method according to claim 15, 17 or 18 or the use according to any one of claims 16 to 18, wherein the chronic inflammatory disease is a disease that can be treated or prevented by increasing ERK activity and / or increasing ERK signaling and / or activating ERK.

20. The method of claim 15 or 17 to 19 or the use of any one of claims 16 to 19, wherein the chronic inflammatory disease is any one of the following: sarcoidosis, Huntington's disease, multiple sclerosis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Crohn's disease, ulcerative colitis, celiac disease, Addison's disease, Sjögren's syndrome, systemic lupus erythematosus and rheumatoid arthritis (e.g. sarcoidosis, systemic lupus erythematosus Huntington's disease, psoriasis, multiple sclerosis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Crohn's disease, ulcerative colitis, celiac disease, Addison's disease and Sjögren's syndrome; and preferably sarcoidosis, systemic lupus erythematosus, Huntington's disease, primary biliary cirrhosis, autoimmune hepatitis, Crohn's disease, ulcerative colitis, celiac disease and Addison's disease).

21. The method of claim 15 or 17 to 19 or the use of any one of claims 16 to 19, wherein the chronic inflammatory disease is any one of systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, sarcoidosis, systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, multiple sclerosis, Sjögren's syndrome, rheumatoid arthritis, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and Alzheimer's disease (e.g. ... Preferably, the present invention comprises at least one of the following: end-stage renal disease, sarcoidosis, systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, multiple sclerosis, Sjögren's syndrome, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Grave's disease, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and Alzheimer's disease; and preferably sarcoidosis, systemic lupus erythematosus (SLE), Huntington's disease, end-stage renal disease, systemic sclerosis (also known as scleroderma), myositis, type 1 diabetes, primary biliary cirrhosis, autoimmune hepatitis, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and Alzheimer's disease).

22. The method of claim 16 or 18 to 21 or the use of claim 17 or 18 to 21, wherein the chronic inflammatory disease is characterized by granulomatous inflammation.

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