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  Carbazole formulations for the treatment of psoriasis and angiogenesisRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Silicon Containing DoaiThe Patent Description & Claims data below is from USPTO Patent Application 20060003966. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of priority of U.S. Ser. No. 60/580,050, filed Jun. 16, 2004, entitled "Carbazole Formulations for the Treatment of Angiogenesis," the teachings of which are expressly incorporated herein by reference. FIELD OF THE INVENTION [0003] The invention is generally in the field of methods and compositions for inhibiting angiogenesis and signal transduction. BACKGROUND OF THE INVENTION [0004] Psoriasis is a common inflammatory condition found in 1-2% of the population. Mild psoriasis is treated with primarily topical glucocorticoids, and other topical agents such as vitamin D and topical retinoids having a smaller role due to decreased efficacy. Severe psoriasis is often treated with systemic medications, including methotrexate, cyclosporine, and retinoids, and more recently with biological agents, such as soluble receptors to tumor necrosis factor .alpha. (TNF.alpha.), or antibodies to TNF.alpha. receptors. While these therapies are effective under some settings, all of them are associated with side effects. Hepatotoxicity is a major issue for long-term use of methotrexate and retinoids, while hypertension, nephropathy and systemic immunosuppression complicate the use of cyclosporine. Thus, there is a pressing need for effective topical therapies for psoriasis, especially those working through mechanisms that differ from those currently available. [0005] The epidermal growth factor receptor (EGFR) is a cell membrane growth factor receptor. Aberrant signaling through the EGFR appears to be associated with angiogenesis. Normal angiogenesis plays an important role in a variety of processes including embryonic development, wound healing and several components of female reproductive function. However, undesirable or pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et al (1995) Trends Pharmacol, 16: 57-66; Folkman (1995) Nat. Med. 1: 27-31). Development of effective preventive and treatment means has been hampered by inadequate understanding of the factors controlling this process. [0006] Accordingly, a need exists for methods of treating a mammal having a disease or condition characterized by increased angiogenesis or aberrant EGFR signaling. SUMMARY OF THE INVENTION [0007] The present invention is based, in part, on the discovery that carbazole isolated from coal tar, exhibits signal transduction regulating activity, (e.g., epidermal growth factor receptor (EGFR) regulating activity), as well as angiogenesis modulating activity. [0008] In one aspect, the invention pertains to a method for treating disorders characterized by elevated, or aberrant signaling (e.g., elevated levels of epidermal growth factor, or aberrant epidermal growth factor receptor signaling), comprising administering an effective amount of a carbazole, or a derivative thereof, having the general formula: wherein, R1-R9 can be a hydrogen atom, halogen atom, alkyl group, trihaloalkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, amino group, aryl group, substituted aryl, heteroaryl group, heterocycloalkyl group, heterocycloalkenyl group, heteroalicyclic group, hydroxyl group, alkoxy group, cycloalkoxy group, aryloxy group, heteroaryloxy group, heteroalicycloxy group, thiohydroxy group, thioalkyoxy group, thiocycloalkoxy group, thioheteroaryloxy group, thioheteroalicycloxy group, cyano group, carbamyl group, C--O-carbamyl group, N-carbamyl group, O-thiocarbamyl group, N-thiocarbamyl group, silyl group, phosphonyl group, C-carboxy group, O-carboxy group, N-amido group, C-amido group, sulfinyl group, sulfonyl group, S-sulfonamido group, N-sulfonamido group, trihalomethanesulfonyl group, guanyl group, guanidine group, and trihalomethanesulfonamido group. [0009] The disorder may further be characterized by angiogenesis. In one embodiment, R1-R9 groups of the carbazole are all hydrogen atoms. In another embodiment, the carbazole can be hydroxylated, oxidized, or halogenated. Exemplary hydroxylated carbazoles can be selected from the group consisting of 2-hydroxy-carbazole, 3-hydroxy-carbazole, 4-hydroxy-carbazole, 2,2-hydroxy-carbazole, and 2,4-hydroxycarbazole. In yet another embodiment, the carbazole is carbamazepine. [0010] The carbazole can also be formulated in a pharmaceutically acceptable carrier for topical administration. The carrier can be selected from the group consisting of ointments, gels, lotions, sprays, shampoos, powders, foams, and solutions, and the carbazole can be present in the carrier at a concentration of about 1-20% by weight. [0011] The carbazole can be used to treat any disorder characterized by elevated levels of angiogenesis or aberrant signaling (e.g., aberrant epidermal growth factor receptor signaling). Examples of such disorders include skin disorders such as psoriasis, acne, rosacea, and eczema. In one embodiment, the skin disorder is psoriasis. [0012] The methods and compositions of the invention can also be used to modulate a pathway (e.g., a rac pathway), or a step in a pathway, associated with skin disorders. The modulation can result in an amelioration and/or treatment of the disorders associated with the pathway. [0013] Accordingly, in another aspect, the invention pertains to a method for treating disorders associated with a rac signaling pathway, comprising administering an effective amount of carbazole or a derivative thereof having the general formula described above. [0014] In yet another aspect, the invention pertains to a pharmaceutically acceptable carbazole formulation, comprising an effective amount of purified carbazole, or a derivative thereof, having the general formula: [0015] wherein, R1-R9 can be a hydrogen atom, halogen atom, alkyl group, trihaloalkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, amino group, aryl group, heteroaryl group, heteroalicyclic group, hydroxyl group, alkoxy group, cycloalkoxy group, aryloxy group, heteroaryloxy group, heteroalicycloxy group, thiohydroxy group, thioalkyoxy group, thiocycloalkoxy group, thioheteraryloxy group, thioheteralicycloxy group, cyano group, carbamyl group, C--O-carbamyl group, N-carbamyl group, O-thiocarbamyl group, N-thiocarbamyl group, silyl group, phosphonyl group, C-carboxy group, O-carboxy group, N-amido group, C-amido group, sulfinyl group sulfonyl group S-sulfonamido group, N-sulfonamido group, trihalomethanesulfonyl group, guanyl group, guanidine group, trihalomethanesulfonamido group; and a pharmaceutically acceptable carrier. BRIEF DESCRIPTION OF DRAWINGS [0016] FIG. 1 is a bar graph which demonstrates the effect of carbazole and carbazole derivatives on the proliferation of transformed murine endothelial cells. The graph shows concentration of drug (.mu.l/ml) versus cell growth (total cell number); [0017] FIG. 2A is a graph showing that is carbazole inhibits T and NK cell activation in peripheral blood mononuclear cells. Production of IL-15 is stimulated by treatment with polysaccharide K (PSK), and is downregulated by carbazole treatment; [0018] FIG. 2B is a graph showing that PSK induces signaling lymphocyte activator molecule associated protein (SAP) expression in lymphocytes, and SAP expression is inhibited by carbazole; [0019] FIG. 2C is a graph showing that cell viability of monocytes is not affected by carbazole; [0020] FIG. 3A is a photograph of a membrane showing the effect of carbazole on iNOS translation in vitro; [0021] FIG. 3B is a photograph of a membrane showing the effect of carbazole on iNOS expression in cultured cells HEK293; Continue reading... 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