Angiogenesis inhibitors

Abstract

Described herein are methods of inhibiting angiogenesis, and treating or preventing a disease or disorder (or symptoms thereof) associated with angiogenesis, wherein an anti-angiogenesis compound is administered to a subject.

1 . A method of inhibiting angiogenesis in a subject, the method comprising administering to the subject an effective amount of an anti-angiogenic compound, wherein the compound is danazol. 
     
     
         2 . A sustained release device for implantation in a patient and sustained release of an anti-angiogenic compound for at least a period of 30 days, wherein the anti-angiogenic compound is danazol. 
     
     
         3 . A sustained release drug device adapted for implantation in or adjacent to the eye of a patient, the drug delivery device comprising: (i) a drug core comprising anti-angiogenic compound, wherein the anti-angiogenic compound is danazol; (ii) an impermeable coating disposed about the core that is substantially impermeable to the passage of the anti-angiogenic compound, having one or more openings therein which permit diffusion of the anti-angiogenic compound, and which is substantially insoluble and inert in body fluids and compatible with body tissues; and, optionally, (iii) one or more permeable polymer members or coatings disposed in the flow path of the anti-angiogenic compound through said openings in said impermeable coating, said permeable polymer being permeable to the passage of the anti-angiogenic compound, and which is substantially insoluble and inert in body fluids and compatible with body tissues; wherein the impermeable coating and permeable polymer members or coatings are disposed about the drug core so as to produce, when implanted, a substantially constant rate of release of the anti-angiogenic compound from the device. 
     
     
         4 . A sustained release formulation for depot injection in a patient and sustained release of an anti-angiogenic compound for at least a period of 30 days, wherein the formulation includes:
 an viscous gel formulation comprising a bioerodible, biocompatible, polymer; and   an anti-angiogenic agent dissolved or dispersed therein, wherein the anti-angiogenic agent is danazol.   
     
     
         5 . The method of  claim 1 , wherein the anti-angiogenic compound is provided in an amount effective for treatment of retinoblastoma, cystoid macular edema (CME), exudative age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema, or ocular inflammatory disorders. 
     
     
         6 . The method of  claim 1 , wherein the subject is suffering from a tumor and the administering treats the tumor. 
     
     
         7 . The method of  claim 1 , wherein the subject is suffering from a disease or disorder selected from dermis, epidermis, endometrium, retina, gastrointestinal tract, umbilical cord, liver, kidney, reproductive system, lymphoid system, central nervous system, breast tissue, urinary tract, circulatory system, bone, muscle, respiratory tract and a surgical wound. 
     
     
         8 . The method of  claim 1 , wherein the administering eliminates or reduces undesired tissue in a patient. 
     
     
         9 . The method of  claim 8 , wherein the undesired tissue is fat. 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 1 , further comprising an additional therapeutic agent. 
     
     
         12 . The method of  claim 11 , wherein the additional therapeutic agent is an angiogenesis-inhibiting compound. 
     
     
         13 . The method of  claim 11 , wherein the additional therapeutic agent is an anticancer compound. 
     
     
         14 . The method of  claim 1 , wherein the administering comprises administering the compound orally, topically, parentally, intravenously or intramuscularly. 
     
     
         15 . The method of  claim 14 , wherein the administering is carried out in a controlled and sustained release. 
     
     
         16 . The method of  claim 1 , wherein the administering comprises administering the compound in a dosage of between about 0.1 and 100 mg/kg/day. 
     
     
         17 . The method of  claim 1 , wherein the administering comprises administering the compound in a dosage of less than about 500 mg/day. 
     
     
         18 . A kit comprising an effective amount of an anti-angiogenic compound in unit dosage form, together with instructions for administering the anti-angiogenic compound to a subject suffering from or susceptible to a disease or disorder or symptoms thereof associated with angiogenesis, wherein the anti-angiogenic compound is danazol. 
     
     
         19 . The method of  claim 1 , wherein the subject is suffering from a disease or disorder selected from tumor, cancer growth, neoplasia, skin disorders, neovascularization, and inflammatory and arthritic diseases. 
     
     
         20 . The method of  claim 19 , wherein the disease or disorder associated with angiogenesis is tumor, cancer growth or neoplasia. 
     
     
         21 . The method of  claim 20 , wherein the disease or disorder is: eye or ocular cancer, rectal cancer, colon cancer, cervical cancer, prostate cancer, breast cancer and bladder cancer, oral cancer, benign and malignant tumors, stomach cancer, liver cancer, pancreatic cancer, lung cancer, corpus uteri, ovary cancer, prostate cancer, testicular cancer, renal cancer, brain cancer, CNS cancer, throat cancer, skin melanoma, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing's Sarcoma, Kaposi's Sarcoma, basal cell carinoma and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, Wilms Tumor, neuroblastoma, mouth/pharynx cancer, esophageal cancer, larynx cancer, lymphoma, neurofibromatosis, tuberous sclerosis, hemangiomas, and lymphangiogenesis. 
     
     
         22 . The method of  claim 19 , wherein the disease or disorder is a skin disorder. 
     
     
         23 . The method of  claim 22 , wherein the disease or disorder is psoriasis, acne, rosacea, warts, eczema, hemangiomas, lymphangiogenesis, Sturge-Weber syndrome, venous ulcers of the skin, neurofibromatosis, and tuberous sclerosis. 
     
     
         24 . The method of  claim 19 , wherein the disease or disorder is neovascularization. 
     
     
         25 . The method of  claim 24 , wherein the disease or disorder is: diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrolental fibroplasias, epidemic keratoconjunctivitis, vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, Sjogren's, acne rosacea, phylectenulosis, syphilis, Mycobacteria infections, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, herpes simplex infections, herpes zoster infections, protozoan infections, Kaposi's sarcoma, Mooren's ulcer, Terrien's marginal degeneration, marginal keratolysis, trauma, rheumatoid arthritis, systemic lupus, polyarteritis, Wegener's sarcoidosis, scleritis, Stevens-Johnson disease, pemphigoid, radial keratotomy, corneal graft rejection, macular edema, macular degeneration, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget's disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, mycobacterial infections, Lyme disease, systemic lupus erythematosus, retinopathy of prematurity, Eales' disease, Behcet's disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, trauma and post-laser complications, and diseases associated with rubeosis. 
     
     
         26 . The method of  claim 25 , wherein the disease or disorder is rheumatoid arthritis, diabetic retinopathy, macular edema, or macular degeneration. 
     
     
         27 . The method of  claim 19 , wherein the disease or disorder is inflammatory and arthritic disease. 
     
     
         28 . The method of  claim 27 , wherein the disease or disorder is: rheumatoid arthritis, osteoarthritis, lupus, scleroderma, Crohn's disease, ulcerative colitis, psoriasis, sarcoidosis, Sarcoidosis, skin lesions, hemangiomas, Osler-Weber-Rendu disease, hereditary hemorrhagic telangiectasia, and osteoarthritis. 
     
     
         29 . The method of  claim 1 , wherein the subject is a human.