Cytokine and hemopoietic factor endogenous production enhancer and methods of use thereof

Abstract

A method of stimulating endogenous production of cytokines and hemopoietic factors by introducing to a mammalian body in need of stimulation of cytokines or hemopoietic factors or both, an effective amount of oxidized glutathione and/or its therapeutically beneficial salts, and/or its therapeutically beneficial derivatives, for a period of time to stimulate said endogenous production to obtain a therapeutic effect. Oxidized glutathione with or without extenders are used in drug forms.

What is claimed is:  
     
         1 . A method of stimulating endogenous production of cytokines and hemopoietic factors comprising introducing to a mammalian body in need of stimulation of cytokines or hemopoietic factors or both, an effective amount of an oxidized glutathione form selected from the group consisting of oxidized glutathione, a pharmaceutically acceptable oxidized glutathione salt, a pharmaceutically acceptable glutathione derivative or mixtures thereof, for a period of time to stimulate said endogenous production to obtain a therapeutic effect.  
     
     
         2 . A method in accordance with the method of  claim 1 , wherein said glutathione form is introduced parenterally.  
     
     
         3 . A method in accordance with the method of  claim 1 , wherein said glutathione form is introduced topically.  
     
     
         4 . A method in accordance with the method of  claim 1 , wherein said glutathione form is introduced along with an extender of the half life of said oxidized glutathione and/or its pharmaceutically acceptable salt form, and/or its pharmaceutically acceptable derivative.  
     
     
         5 . A method in accordance with the method of  claim 1 , wherein said glutathione form is introduced along with an enhancer/beneficial modulator of the biological or therapeutical effects of said glutathione form.  
     
     
         6 . A method in accordance with the method of  claim 4 , wherein said extender is selected from the group consisting of pro-oxidant compounds, agents capable of forming weak ionic or coordinating links stabilizing the GSSG molecule, materials which are competitors of NADP_-H-dependent reduction of GSSG into GSH catalyzed by glutathione reductase, compounds capable of producing reversible inhibition of reduction of NADP+ into NADP-H catalyzed by glucose-6-phosphate-dehydrogenase or by other NADP_H-dependent enzymes, or mixtures thereof.  
     
     
         7 . A method in accordance with the method of  claim 6 , wherein said extender is peroxide.  
     
     
         8 . A method in accordance with the method of  claim 6 , wherein said extender is ascorbic acid.  
     
     
         9 . A method in accordance with the method of  claim 9 , wherein said extender is dimethylsulfoxide.  
     
     
         10 . A method in accordance with the method of  claim 6 , wherein said extender is inosine  
     
     
         11 . A method in accordance with the method of  claim 6 , wherein said cystamine.  
     
     
         12 . A method in accordance with the method of  claim 5 , wherein said enhancer/beneficial modulator is selected from the group consisting of methyl moiety donators, and representatives of intracellular redox-oxidative pairs, or mixtures thereof.  
     
     
         13 . A method in accordance with the method of  claim 12 , wherein said enhancer/beneficial modulator is choline-chloride.  
     
     
         14 . A method in accordance with the method of  claim 12 , wherein said enhancer/beneficial modulator is S-adenosyl-methionine.  
     
     
         15 . A method in accordance with the method of  claim 12 , wherein said enhancer/beneficial modulator is lipoic acid.  
     
     
         16 . A method in accordance with the method of  claim 12 , wherein said enhancer/beneficial modulator is folic acid.  
     
     
         17 . A method in accordance with the method of  claim 2 , wherein said glutathione form is introduced at a dose of from 0.01 to 0.5 Mg of GSSG base per kilogram of body weight for GSSG base and GSSG salts (from 0.01 to 1.0 mg per kg for GSSG derivatives) at least one time each 24 hour period until said desired therapeutic effect is obtained.  
     
     
         18 . A method in accordance with the method of  claim 17 , wherein said glutathione form is introduced parenterally in a pharmaceutically acceptable solution at a concentration of from 0.01 to 2.0% by weight of oxidized glutathione base for GSSG base and GSSG salts (from 0.01 to 4.0% by weight for GSSG derivatives).  
     
     
         19 . A method in accordance with the method of  claim 18 , wherein said solution further includes, or is administered in a combination with an extender selected from the group consisting of 0.03% to 0.0003% (v/v) hydrogen peroxide, 0.1% to 10% (w/v) ascorbic acid, 0.1% to 30% (v/v) dimethylsulfoxide, 0.1% to 5% (w/v) inosine, 0.1% to 3% (w/v) cystamine, or mixtures thereof.  
     
     
         20 . A method in accordance with the method of  claim 1 , wherein said mammalian body is in need of stimulation of cytokine or hemopoietic factor production to treat a condition selected from the group consisting of neoplastic, infectious, hematoilogic, immunologic (ischemic, diastrophic, degenerative) and other diseases.  
     
     
         21 . A method in accordance with the method of  claim 20 , wherein said disease is infectious.  
     
     
         22 . A method in accordance with the method of  claim 20 , wherein said disease is hematologic.  
     
     
         23 . A method in accordance with the method of  claim 20 , wherein said disease is unmunologic.  
     
     
         24 . A method in accordance with the method of  claim 20 , wherein said disease is neoplastic.  
     
     
         25 . A method in accordance with he method of  claim 20 , wherein said disease is selected from the group consisting of AIDS, hepatitis, herpes, tuberculosis, meningitis, peritonitis, sepsis, and purulent postoperative complications caused by infection.  
     
     
         26 . A method in accordance with the method of  claim 20 , wherein said disease is selected from a group consisting of immunodepression, multiple sclerosis, alzheimer sclerosis, neurogenerative diseases, amyotrophic lateral sclerosis, glomerulonephirits, collagenosis, rheumatoid arthritis, lupus, psoriasis, diabetes mellitus and allergic disease.  
     
     
         27 . A method in accordance with the method of  claim 20 , wherein said disease is selected from the group consisting of metastatic spreading, hemobastosis, malignant tumors, lumphogranulomatous and lymphomas, immunodeficiency caused by radioactive or chemical affliction.  
     
     
         28 . A method in accordance with the method of claims  1 ,  2 , 3 ,  4 , or  5  wherein said oxidized glutathione is in a salt form.  
     
     
         29 . A method in accordance with the method of  claim 1 , wherein said salt is the disodium salt.  
     
     
         30 . A method in accordance with the method of  claim 1 , wherein said salt is the dilithium salt.  
     
     
         31 . A method in accordance with the method of  claim 1 , wherein said salt contain one or more atoms of potassium.  
     
     
         32 . A method in accordance with the method of  claim 1 , wherein said salt contain one or more atoms of calcium.  
     
     
         33 . A method in accordance with the method of  claim 1 , wherein said salt contain one or more atoms of zinc.  
     
     
         34 . A method in accordance with the method of  claim 1 , wherein said salt contain one or more atoms of molybdenum.  
     
     
         35 . A method in accordance with the method of  claim 1 , wherein said salt contain one or more atoms of vanadium.  
     
     
         36 . A method in accordance with the method of  claim 1 , wherein said salt contain one or more atoms of fluoride.  
     
     
         37 . A method in accordance with the method of claims  1 ,  2 ,  3 ,  4  or  5  wherein a pharmaceutically acceptable derivative of oxidized glutathione is introduced to a mammalian body in need of stimulation of cytokines or hemopoietic factors or both.  
     
     
         38 . A method in accordance with the method of  claim 1 , wherein said oxidized glutathione derivative is GSSG is covalently bound to cysteamine (S-thioethylamine-glutathione disulfide).  
     
     
         39 . A method in accordance with the method of  claim 1 , wherein said oxidized glutathione derivative is GSSG is covalently bound to lipoic acid(bis-[6,8-thiooktanil].glutathione disulfide).  
     
     
         40 . A method in accordance with the method of  claim 1 , wherein said oxidized glutathione derivative is GSSG is covalently bound to a member of the group consisting of carnosine ([b-alanyl-hystidil].glutathione disulfide) and adenosine ([9-β-D-ribofuranosyladenil].glutathione disulfide).  
     
     
         41 . A method in accordance with the method of  claim 1 , wherein said oxidized glutathione derivative is GSSG is covalently bound to methionine (bis-[2-amino-4-[methylthio]butanoil].glutathione disulfide).  
     
     
         42 . A therapeutic agent for treating neoplastic, infectious, hematologic, immunologic and other diseases in which stimulation of the endogenous cytokine and hemopoietic factor production is considered beneficial, said therapeutic agent comprising an effective amount of oxidized glutathione, and/or a pharmaceutically acceptable salt, and/or a pharmaceutically acceptable derivative, said oxidized glutathione, a tripeptide, γ-glutamyl-cysteinyl-glycine, where two molecules of the tripeptide are linked via covalent disulfide bond between the cysteine residues, as an active substance, along with a pharmaceutically acceptable excipient.  
     
     
         43 . The therapeutic agent of  claim 42 , wherein said substance is formulated in the form of a sterile injectable solution of oxidized glutathione, and/or a pharmaceutically acceptable salt, and/or a pharmaceutically acceptable derivative, in pharmaceutically acceptable solvent.  
     
     
         44 . A therapeutic agent of  claim 43 , in a combination with a pharmaceutically acceptable extender capable of enhancing and prolonging a therapeutic effect of said agent by increasing the half-life of oxidized glutathione.  
     
     
         45 . A therapeutic agent in accordance with  claim 44 , wherein said extender is hydrogen peroxide.  
     
     
         46 . A therapeutic agent in accordance with  claim 44 , wherein said extender is ascorbic acid.  
     
     
         47 . A method in accordance with the method of  claim 44 , wherein said extender is dimethyl sulfoxide.  
     
     
         48 . A therapeutic agent in accordance with  claim 44 , wherein said extender is inosine.  
     
     
         49 . A therapeutic agent in accordance with  claim 44 , wherein said extender is cystamine.  
     
     
         50 . A therapeutic agent of  claim 43 , in a combination with a pharmaceutically acceptable enhancer/beneficial modulator capable of enhancing and/or altering beneficially a therapeutic effect of said agent by mechanisms other than increasing the half-life of oxidized glutathione.  
     
     
         51 . A therapeutic agent in accordance with  claim 50 , wherein said enhancer/beneficial modifier is choline-chloride.  
     
     
         52 . A therapeutic agent in accordance with  claim 50 , wherein said enhancer/beneficial modifier is S-adenosyl-methionine.  
     
     
         53 . A therapeutic agent in accordance with  claim 50 , wherein said enhancer/beneficial modifier is lipoic acid.  
     
     
         54 . A therapeutic agent in accordance with  claim 50 , wherein said enhancer/beneficial modifier is folic acid.  
     
     
         55 . A method of enhancing and prolonging the ability of oxidized glutathione, and/or its pharmaceutically acceptable salt, and/or its pharmaceutically acceptable derivative to stimulate endogenous production of cytokine and hemopoietic factor wherein oxidized glutathione, and/or its pharmaceutically acceptable salt, and/or it pharmaceutically acceptable derivative is either used in a pharmaceutical composition containing at least one additional pharmaceutically acceptable components, or administered in combination with such component, 
 said method comprising obtaining a solution of oxidized glutathione, and/or its pharmaceutically acceptable salt, and/or its pharmaceutically acceptable derivative, and intermixing therewith an extender, said extender being selected from the group consisting of a donor of reactive oxygen intermediates, agent capable of forming weak ionic and/or coordinating links stabilizing the GSSG molecule, hypoxanthine derivatives, a reversible inhibitor of pentose phosphate pathway of glucose oxidation, or mixtures thereof.    
     
     
         56 . A method in accordance with the method of  claim 55 , wherein said extender is hydrogen peroxide.  
     
     
         57 . A method in accordance with the method of  claim 55 , wherein said extender is ascorbic acid.  
     
     
         58 . A method in accordance with the method of  claim 55 , wherein said extender is dimethyl sulfoxide.  
     
     
         59 . A method in accordance with the method of  claim 55 , wherein said extender is inosine.  
     
     
         60 . A method in accordance with the method of  claim 55 , wherein said extender is cystamine.  
     
     
         61 . A method of enhancing and/or beneficially modulating the ability of oxidized glutathione and/or its pharmaceutically acceptable salt, and/or its pharmaceutically acceptable derivative to stimulate endogenous production of cytokine and hemopoietic factor wherein oxidized glutathione and/or its pharmaceutically acceptable salt, and/or its pharmaceutically acceptable derivative is either used in a pharmaceutical composition containing at least one additional pharmaceutically acceptable component other than that prolonging the half-life of oxidized glutathione or administered in combination with such component, 
 said method comprising obtaining a solution of oxidized glutathione and/or its pharmaceutically acceptable salt, and/or its pharmaceutically acceptable derivative and intermixing therewith or administration in a combination with an enhancer/beneficial modulator, said enhancer/beneficial modulator being selected from the group consisting of a methyl moiety donator, representative of intracellular redox-oxidative pairs, or mixtures thereof.    
     
     
         62 . A method in accordance, with the method of  claim 61 , wherein said extender/beneficial modifier is choline-chloride.  
     
     
         63 . A method in accordance with the method of  claim 61 , wherein said extender/beneficial modifier is S-adenosilmethionine.  
     
     
         64 . A method in accordance with the method of  claim 61 , wherein said extender/beneficial modifier is lipoic acid.  
     
     
         65 . A method in accordance with the method of  claim 61 , wherein said extender/beneficial modifier is folic acid.  
     
     
         66 . A method of utilizing oxidized glutathione and/or its pharmaceutically acceptable salt, and/or its pharmaceutically acceptable derivative, said oxidized glutathione being a darner of reduced glutathione, a tripeptide with structure γ-glutamyl-cysteinyl-glycine, where two molecules of the tripeptide are linked via covalent disulfide bond between the cystein residues, as a stimulator of endogenous production of cytokine and/or hemopoietic factors for preparation of pharmaceutical drugs for treating neoplastic, infectious, hematologic, immunologic and other diseases in which stimulation of the endogenous cytokine and/or hemopoietic factor production is considered beneficial.  
     
     
         67 . A method of stimulating production of cytokine and hemopoietic factors comprising introducing to mammalian cells in need of stimulation of cytokine or hemopoietic factors or both, an effective amount of oxidized glutathione and/or a pharmaceutically acceptable salt, and/or a phamaceutically acceptable derivative, for a period of time to stimulate said endogenous production to obtain a therapeutic effect.  
     
     
         68 . A method in accordance with the method of  claim 67 , wherein said cells are in a mammalian body and said oxidized glutathione and/or its pharmaceutically acceptable salt, and/or its pharmaceutically acceptable derivative is introduced into said body at a rate of from 0.01 to 0.5 mg of GSSG base per kg of body weight for GSSG base and GSSG salts (with 0.01 to 1.0 mg/kg for GSSG derivatives), at least one time a day for at least one day.  
     
     
         69 . A method in accordance with the method of  claim 68 , wherein said drug is introduced into said body in an injectable solution form, wherein said oxidized glutathione and/or a pharmaceutically acceptable salt, and/or a pharmaceutically acceptable derivative is present in such solution at a concentration of from 0.01 to 2.0% of GSSG base by weight for GSSG base and GSSG salts (with 0.01 to 4.0% for GSSG derivatives).  
     
     
         70 . A method in accordance with the method of  claim 69 , wherein said injectable drug solution comprises an extender selected from the group consisting of hydrogen peroxide, ascorbic acid, dimethyl sulfoxide, inosine, and cystamine; or such an extender is administered separately.  
     
     
         71 . A method in accordance with the method of  claim 69 , wherein said injectable drug solution comprises an enhancer/beneficial modulator selected from the group consisting of choline-chloride, S-adenosilmethionine, lipoic or folic acid; or such an enhancer/beneficial modulator is administered separately.  
     
     
         72 . A method in accordance with the method of  claim 67 , wherein said cells are in a mammalian body and said oxidized glutathione or/and its pharmaceutically acceptable salt, and/or its pharmaceutically acceptable derivative is introduced topically to a topical area at a dose of from 0.01 to 0.5 mg of GSSG base per square meter of topical area for GSSG base and its salts (with 0.01 to 1.0 mg per square meter for GSSG derivatives)