| Method of identifying therapeutic compounds for a treatment of hepatic disorders -> Monitor Keywords |
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Method of identifying therapeutic compounds for a treatment of hepatic disordersRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, In Vivo Diagnosis Or In Vivo Testing, Testing Efficacy Or Toxicity Of A Compound Or Composition (e.g., Drug, Vaccine, Etc.)Method of identifying therapeutic compounds for a treatment of hepatic disorders description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060120963, Method of identifying therapeutic compounds for a treatment of hepatic disorders. Brief Patent Description - Full Patent Description - Patent Application Claims
TECHNICAL FIELD [0001] The present invention relates to a method of identifying therapeutic compounds and in particular to a method of identifying therapeutic compounds for use in treating hepatic disorders. BACKGROUND [0002] Hepatic disease is a major cause of morbidity in western countries. Hepatitis C, for example, is transmitted by contamination and many current cases represent infection from blood transfusion prior to universal blood testing. Most new cases are drug (of addiction) related. About 80% of those affected develop chronic hepatitis (20% with cirrhosis) while about 10% will eventually develop hepatoma. Until recently, the only effective therapy has been intetferon, which is expensive, is given parentally has many side effects, and is of limited value. [0003] Alcohol consumption can lead to hepatic disorders. It affects normal immune function, especially cell-mediated immunity.sup.1-3. T cells play an important role in the progression of alcohol-related diseases.sup.4-6. Studies of alcoholic liver disease in humans and animals have shown that T cell proliferation is significantly altered in response to mitogens such as concanavalin A (Con A) or phytohemagglutinin (PHA) in vitro.sup.7-9. In rats or mice fed alcohol, the blood T cell proliferative response to Con-A stimulation was depressed whereas the response to PHA was elevated, with CD4.sup.+ T helper cells being the responding cell type.sup.2,3,8,10. This suggests that the level of T-cell activations.sup.10 the responding cell phenotype.sup.3 and the pattern of cytokine secretion.sup.11 following exposure to ethanol probably all play a role in alcohol related liver disease. Ethanol-fed rats infected with Con A developed more severe hepatic necrosis with infiltration of CD4.sup.+ and CD8.sup.+ T cells in the portal vein and central vein areas compared with sucrose or isocaloric sucrose fed rats. In these rats increased numbers of activated liver-associated CD4.sup.+ T cells secreting high levels of TNF-.alpha. and IL-6 in culture were observed.sup.4-6. These alcohol-fed rats have been used as a basic research tool to study the role of T lymphocytes in the onset of liver damage. [0004] While it is hypothesised that the level of T-cell activation, the responding cell phenotype, and the pattern of cytokine secretion following exposure to ethanol may all play a role in alcohol-associated liver disease, it is noted that such diseases are complex in nature. As such m,any other as yet unidentified factors are likely to contribute to the presentation of the disease. Thus, further research is necessary to elucidate the precise cellular and biochemical mechanisms and interactions involved in the initiation and progression of the disease. Further, it is noted that the precise cellular and biochemical mechanisms and interactions involved in alcohol-induced hepatitis are likely to be different to the precise mechanisms involved in pathogen-mediated hepatitis, such as hepatitis C, and auto-immune hepatic disorders. [0005] Treatment for many hepatic disorders is clearly unsatisfactory and there is an urgent need for improved therapeutics. Consequently there is also a need for suitable methods and in particular animal models to predict the therapeutic value of potentially useful compounds. [0006] It is an object of the present invention to provide an animal model, methods and therapeutic compounds which may overcome or substantially ameliorate at least some of the deficiencies of the prior art, or will provide a useful alternative. SUMMARY OF THE INVENTION [0007] It has been found that mammals administered alcohol and an agent such as concanavalin A (Con A) are useful as a model for identification of therapeutic substances designed to treat hepatic disorders. [0008] It has also been found that the Chinese herb CH-100 is particularly useful in the treatment of alcohol-induced hepatitis. [0009] According to a first aspect the invention provides a method of identifying a compound useful in the prophylactic or therapeutic treatment of a hepatic disorder in a mammal comprising: [0010] (a) administration to the mammal of an agent or agents known to induce a hepatic disorder; [0011] (b) administration to a mammal of a potentially therapeutic compound. [0012] (c) comparison of the effects of the compound on the development of the hepatic disorder with a predetermined standard. [0013] According to a second aspect, the invention provides a method of identifying a compound useful in the prophylactic or therapeutic treatment of a hepatic disorder in a mammal comprising: [0014] (a) administration to the mammal of alcohol; [0015] (b) administration to the mammal of a potentially therapeutic compound; [0016] (c) administration to the mammal of an agent known to induce a hepatic disorder; and [0017] (d) comparison of the effects of the compound on the development of the hepatic disorder with a predetermined standard. [0018] According to a third aspect, the invention provides a method of identifying a compound useful in the prophylactic or therapeutic treatment of T cell-mediated liver damage in a mammal comprising: [0019] (a) administration to the mammal of an agent or agents known to induce T cell-mediated liver damage; [0020] (b) administration to the mammal of a potentially therapeutic compound; [0021] (c) comparison of the effects of the compound on the development of the liver damage with a predetermined standard. [0022] According to a fourth aspect, the invention provides a method of identifying a compound useful in the prophylactic or therapeutic treatment of T cell-mediated liver damage in a mammal comprising: [0023] (a) administration to the mammal of alcohol; [0024] (b) administration to the mammal of a potentially therapeutic compound; [0025] (c) administration to the mammal of a T cell activating agent; and [0026] (d) comparison of the effects of the compound on the development of the hepatic disorder with a predetermined standard. [0027] According to a fifth aspect, the invention provides a method of identifying a compound useful in the prophylactic or therapeutic treatment of T cell-mediated liver damage in a mammal comprising: [0028] (a) administration to a donor mammal of alcohol; [0029] (b) administration to a donor mammal of a T cell-activating agent; [0030] (c) administration of a potentially therapeutic compound to a recipient mammal; [0031] (d) isolation of intrahepatic T cells from the donor mammal and delivery to the recipient; and [0032] (e) comparison of the effects of the compound on the development of T cell-mediated liver damage in the recipient mammal with a predetermined standard. [0033] According to a sixth aspect, the invention provides a method of identifying a compound useful in the prophylactic or therapeutic treatment of T cell-mediated liver damage in a mammal comprising: [0034] (a) administration to a donor mammal of alcohol; [0035] (b) administration to a donor mammal of a T cell-activating agent; [0036] (c) isolation of intrahepatic T cells from the donor mammal and delivery to a recipient; [0037] (d) administration of a potentially therapeutic compound to the recipient mammal; and [0038] (e) comparison of the effects of the compound on the development of T cell-mediated liver damage with a predetermined standard. [0039] The recipient mammal may also be administered a T cell-activating agent after transfer of T cells from the donor, if this is required. [0040] Preferably the mammal referred to herein is a rodent and most preferably the rodent is a rat. However, it will be appreciated by those of ordinary skill in the art that various other mammals may be used in the present invention. [0041] Preferably the hepatic disorder is induced by migration of T lymphocytes to the liver. More preferably, the hepatic disorder is alcoholic hepatitis. [0042] Preferably the T lymphocytes secrete TNF.alpha.. [0043] Where referred to herein the agents known to induce hepatic disorder preferably include alcohol and a cofactor. Preferably, said cofactor is a T cell activating agent. In the case where alcohol is specifically administered first in the method the mentioned agent known to induce a hepatic disorder subsequently administered is a T cell activating agent. [0044] Where alcohol is used in the methods of the present invention, the alcohol is preferably administered as a solution of ethanol in water. Preferably the solution contains 2 to 40% ethanol (v/v). Most preferably the solution contains 5 to 40% ethanol (v/v). Preferably the mammals are fed increasing concentrations of ethanol over a period sufficient to allow adaptation to the ethanol. Preferably the concentration of alcohol ranges from approximately 5% ethanol in water (v/v) to approximately 40% ethanol in water (v/v) over the period of adaptation. Preferably the period of adaptation is approximately seven weeks. [0045] Where a cofactor is referred to herein it is preferably a T cell activator. Preferably the T cell activators referred to herein are concanavalin A (Con A). However, it will be clear to the skilled addressee that other compounds may also be useful eg. endotoxin. Continue reading about Method of identifying therapeutic compounds for a treatment of hepatic disorders... 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