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United States Patent (19) 11 Patent Number: 5,627,195 Hu 45 Date of Patent: May 6, 1997

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United States Patent (19) 11 Patent Number: 5,627,195 Hu 45 Date of Patent: May 6, 1997 USOO5627195A United States Patent (19) 11 Patent Number: 5,627,195 Hu 45 Date of Patent: May 6, 1997 54 TREATMENT FOR OCULAR Ferrante, et al., Tetrandrine, a Plant Alkaloid, Inhibits the NFLAMMATON Production of Tumour Necrosis Factor-Alpha (Cachectin) by Human Monocytes, Clin, exp. Immunol. 80:232–235 75 Inventor: Shixing Hu, Cambridge, Mass. (1990). Kondo, et al., Inhibitory Effect of Bisbenzylisoquinoline 73) Assignee: Massachusetts Eye and Ear Alkaloids on the Quick Death of Mice Treated with BCG/ Infirmary, Boston, Mass. LPS, Chem. Pharm. bull. 38(10):287-2889 (1990). Ph.D. dissertation of Shixing Hu, Sun Yat-Sen University of 21 Appl. No.: 420,244 Medical Sciences, Guang Zhou, Guang Dong China, 1989. 22 Filed: Apr. 11, 1995 Seow, et al. In Vitro Immunosuppressive Properties of Teh Plant Alkaloid Tetrandrine. Int. Archs Allergy appl. Immun. [51] Int. Cl. ... A61K 31/445 85:410-415 (1988). 52 514/321: 514/912 Rao. et al., Modulation of Lens-Induced Uvetis by Super 58 Field of Search ...................................... 54/321, 912 oxide Dismutase, Opthlalmic Res. 18:41-46 (1986). Abal et al., Clinical Evaluation of Berberine in Mycotic 56 References Cited Infections, Ind. J. Ophthalm. 34:91-2 (1986). FOREIGN PATENT DOCUMENTS Mohan, et al. Berberine: An Indigenous Drug in Experi mental Herpetic Uveitis. Ind.J. Ophthalm. 31:65-68 (1983). 46-21396 6/1971 Japan. Yao Hsueh Tung Pao 1983; 18:31-36 The Natural Sources 3-44323 2/1991 Japan. and Biological Activities of Bisbenzylisoquinoline (BBI) 4–99723 3/1992 Japan. Alkaloids. OTHER PUBLICATIONS Babbar, et al., Effect of Berberine Chloride Eye Drops on Marshall, et al. In Vitro Antiplasmodial, Antiamoebic, and Clinically Positive Trachoma Patients, Ind. J. Med Res. 76 Cytotoxic Activities of a Series of Bisbenzylisoquinoline (Supp):83-88 (1982). Alkaloids. Antimicrobial Agents and Chemotherapy, Sabir, et al., Experimental Study of Antitrachoma Action of 38(1):96-103 (1994). Berberine, Ind. J Med Res 64(8): 1160–1167 (1976). Jigao, et al. Inhibitory Effects of Tetrandrine on Bovine Primary Examiner Zohreh Fay Serum Albumin-Induced Uvetis in Rabbits, Journal of Ocular Pharmacology, 9(2):151-156 (1993). Attorney, Agent, or Firm-Fish & Richardson PC. Kondo, et al. Inhibitory Effect of Bisbenzylisoquinoline 57 ABSTRACT Alkaloids on Nitric Oxide Production in Activated Mac rophages, Biochemical Pharmacology, 46(11):1887-1892 A method of treating a subject with ocular inflammation (1993). associated with keratitis or conjunctivitis, which method Xiao, et al., Inhibitory Effect on Tetrandrine on Lens Pro includes administering to the subject an amount of a phar teins-Induced Ocular Inflammation in Rabbits Journal of maceutical composition containing tetrandrine or a tetran Ocular Pharmacology, 8(4):309-315 (1992). drine agonist, the amount being effective to reduce the Castranova, et al., Inhibition of Stimulant-Induced Activa ocular inflammation. tion of Phagocytic Cells with Tetrandrine Journal of Leu kocyte Biology 50:412-422 (1991). 20 Claims, No Drawings 5,627,195 1 2 TREATMENT FOR OCULAR 1-induced keratitis in BALB/c mice. Treatment with tetran NFLAMMATION drine or its agonists improves the clinical signs of keratitis and down-regulates mRNA gene expression of proinflam BACKGROUND OF THE INVENTION matory cytokine IL-1B in the corneas of treated mice (see This invention is related to the treatment of ocular inflam Example 2 below). mation of pathogenic or allergenic origin. For example, In addition, treatment with tetrandrine or its agonists allergic conjunctivitis is an atopic phenomenon caused by reduces the allergic inflammation of conjunctiva involving many common airborne allergens. In contrast to the general subcutaneous tissues of the lids. This reduction, measured population. Subjects with allergic conjunctivitis experience clinically and histopathologically, is statistically significant itching and burning of the ocular surface when exposed to 10 when compared with untreated groups. Tetrandrine Sup such allergens. Clinical signs include chemosis, tearing, presses not only the infiltration of eosinophils and mast cells conjunctival hyperemia, and lid edema. In a second example but also degranulation of mast cells which mediate allergic of inflammation, keratitis can be caused by pathogens such responses. Thus, tetrandrine and its agonists are not only as viruses. bacteria, and fungi. Symptoms of keratitis inhibitors of eosinophil and mast cell migration, but also include pain, vision impairment, tearing, and photophobia. 15 mast cell stabilizers. Corneal inflammation is particularly difficult to treat, due to It is well known that activated eosinophils and mast cells the avascularity of the cornea. can produce granule proteins (14 kD. 15 kD. 17 kD. 18 kD. 19 kD, 21 kD and 55 kD), lipid mediators including leu SUMMARY OF THE INVENTION kotrines C4, D4 and E4, and histamine. Interleukin 1 (IL-1) is involved in specific and non-specific inflammatory reac In general, the invention relates to a method of treating a tions. Both mast cells and eosinophis produce this cytokine subject with ocular inflammation associated with keratitis or (as well as IL-3, IL-5, IL-6, tumor necrosis factor and conjunctivitis. The method includes administering (e.g., transforming growth factor). Tetrandrine and its agonists topically, orally. Subconjunctivally, or intramuscularly) to inhibit the synthesis or release of these inflammatory media the subject a composition which contains an amount of 25 tOS. tetrandrine or a tetrandrine agonist and a pharmaceutically The method disclosed herein is effective to treat ocular acceptable carrier, the amount being effective to reduce the inflammation caused by many pathogens, Substances (e.g. inflammation. The pharmaceutical composition may be for allergens), and environmental conditions (e.g., trauma. mulated as a tablet, a capsule, a liquid, ointment, or cream. degeneration, or vitamin A deficiency). Examples of ocular The method of this invention can be used to treat keratitis 30 inflammatory pathogens include (i) viruses such as HSV-1 caused by, among others, a virus (e.g., herpes simplex virus, virus, HSV-2 virus, varicella-zoster virus, variola virus. varicella-zoster virus, variola virus, vacceiniai virus, vacceinial virus, adenovirus, measles virus, rubella Virus, adenovirus, measles virus, rubella virus, and mumps virus). and mumps virus; (ii) bacteria such as Pneumococcus, Similarly, it can be used to treat conjunctivitis caused by Pseudomonas. Moraxella (diplobacillus), Streptococcus allergens and any other chemical or biological agents. 35 pyogenes, Klebsiella pneumonieae, Staphylococcus aureus, Other features or advantages of the present invention will Staphylococcus epidermidis, Streptococcus viridans, Myco be apparent from the following detailed description, and also bacterium fortuitum, and Nocardia; (iii) fungi Such as from the appending claims. Candida, Fusarium, Aspergillus, Penicillium, and Cepha losporium; (iv) Chlamydia; and (v) parasites. Examples of DETALED DESCRIPTION OF THE 40 inflammatory substances include acidic or alkali INVENTION compounds, toxic compounds, or immunogenic agents. Inflammation is a protective response of an injured tissue, According to the invention, treatment of ocular inflam which is designed to destroy, dilute, or isolate an injurious mation caused by any of the above includes administering a agent. Such agents include pathogens, allergens, toxic composition which includes tetrandrine or a tetrandrine compounds, acidic or alkali agents, and trauma. 45 agonist. Tetrandrine, a benzylisoquinoline, was first isolated More specifically, inflammatory responses caused by in 1935 from a Chinese herbal remedy "hanfangchi,” the keratitis include irregularity of the corneal epithelium, ulcer plant Stephania tetrandra S. Moore of the Menispermaceae ative formation, stroma oedema, neovascularization of the family. J. Biol Chem. 109:681–685 (1935). Tetrandrine (6,6,7,12-tetramethoxy-2,2'-dimethylberbaman) was first cornea, presence of abnormally large numbers of mono 50 nuclear leukocytes, neutrophils, or a combination thereof, synthesized in 1968. Inubushi, Y. et al. Tetra. Lett. 3399 and an increased serum specific antibody response to a (1968). Numerous structural analogs of tetrandrine and keratitis pathogen. Corneal inflammation, such as that tetrandrine-like isoquinolines, bisis oduinolines, caused by keratitis, also impairs the subject's vision. Inflam benzylisoquinolines, and bisbenzylisoquinolines have been matory responses caused by conjunctivitis include edema of isolated or synthesized. Such analogs are examples of tet the eyelid, conjunctival congestion, redness, itching, and 55 randrine agonists. Tetrandrine agonists which can be used to infiltration of abnormal eosinophils and mast cells. practice the therapeutic method of the present invention Effective treatment of inflammation includes the reduc include, but are not limited to, those covered by formulasin, tion of one or more of the inflammatory responses described or those specifically recited in, the publications set forth above. Such reduction can be measured by clinical obser below. Likewise, numerous syntheses and methods of iso vation (e.g., edema, see Table 1. Example 1 below), and by lation of tetrandrine or its agonists are provided in the several immunohistological or biochemical analyses known publications set forth below. by those in the art to be related to inflammation (e.g., U.S. Pat. No. 2.206.407 (1940) migration of mast cells,
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