Individual substances based on chemical interaction dyslipidaemias peptides derivatives of purine or pyrimidine bases, pharmaceutical compositions and preparations on their basis, and their uses for the treatment of infectious diseases and prevention of complications

 

(57) Abstract:

The invention relates to medicine, namely to the development of new drugs based on the active metabolites of peptide and nucleotide-nucleotide nature. The inventive offers new compounds based on the chemical interaction of oxidized glutathione (GSSG) with derivatives of purine or pyrimidine bases; pharmaceutical compositions and preparations on their basis, which has antiviral, antibacterial, immunomodulatory and hepatoprotective effects; methods of treatment and prevention of infectious diseases. The technical result-the creation of new medicines and the development of methods of their use for the treatment and prevention of infectious diseases of various etiologies. 13 C. and 76 C. p. F.-ly, 42 ill. , 60 PL.

The invention relates to medicine, in particular for anti-infective pharmacology, namely the creation of new medicines on the basis of active metabolites peptide and nucleotide-nucleotide nature, intended for the treatment and prevention of infectious diseases, first of all, viral hepatitis b and C, as well as AIDS and herpes; and also caused the ecene TB malaria, intestinal infections, chlamydia and Mycoplasma infections.

Infections caused by hepatitis b (HBV) and hepatitis C (HCV) prevalence significantly superior to HIV infection. The rate of HBV infection and, especially, the HCV grow with each passing year. In some regions of the world hepatitis C affected more than 10% of the adult population. While HCV is most chronogram potential as the main reason for the formation of the entire spectrum of chronic liver diseases. In particular, the proportion of chronic hepatitis induced by HCV is more than 70%, while the share of cirrhosis is equal to 40%, and cases of hepatocellular carcinoma - 60% [1] . The underlying mechanisms of chronic viral hepatitis, especially hepatitis C, are the mechanisms of escape of the virus from under immune surveillance, as well as in connection with the existence of multiple simultaneously present virus variants with altered, but closely related genome - quasiresonance ("quasisspecies"). Recent studies indicate the presence in the liver cells virousspecificakih T-lymphocytes, which confirms immunopositivity pathogenesis of hepatitis C [2] . Furthermore, it is established dependence is] . Exceptional value represents the T-cell response, the first response of CD4+, CD8+ and SD/56+ NS3 protein of HCV, characterized as vysokoosnaschenny for spontaneous resolution of hepatitis C, as well as for positive results of antiviral therapy [4, 5] .

In turn, it is known that the nature of the immune response depends on the dominant participation of clones of CD4+ T-lymphocyte helper type 1 (Th1) and helper cells type 2 (Th2), which differ by produced by these cytokines and activation of the immune response at the cellular or humoral type. Activation of Th1 producing interferon gamma (IFN-), interleukin 2 (IL-2), tumor necrosis factor alpha and beta (TNF -), leads to the stimulation of the function of T-lymphocytes and resident macrophages, i.e. to the development of the immune response by the cell type that plays a crucial role in defense against viruses. Activation of Th2, which secrete IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13, starts humoral immunity. Hence, the imbalance of cytokine production of Th1/Th2 cells plays a crucial role in the immunopathogenesis of HBV, HCV and HIV infections, and the primary part of cytokines Th2-type is associated with viral persistence and chronicity of. On the contrary, the activation of the production of Th1-related cytokines is on virus elimination from the body and restore the functional capacity of the affected organs [6, 7, 8, 9] .

In this regard, an equally important function of the pleiotropic cytokine IL-12, which is one of the key figures in the regulation of the immune response of the host. Regulating the balance of Th1/Th2, IL-12 modulates the function of macrophages, especially resident macrophages (Kupffer cells) of the liver. In chronic hepatitis C, and chronic hepatitis b, IL-12 activates the secretion of cytokines by Th1 cells, inhibiting the proper function of Th2. Chronization and negative for viral hepatitis is accompanied by a decrease in the level of IL-12 [10] . Thus, it can be argued that determining the course and outcome of HBV and HCV infection and their successful therapy of T-cell immunity suffers functional weakness in the first place, in our opinion, in terms of endogenous production of adequate and wealthy "team" cytokines in response to antigenic factor. It cytokines in the constant race for the speed between the formation of new "quasisspecies and immune reaction of the organism determine its ability to modulate the quality and direction of response of the immune system. Hence, the methods of treatment of viral hepatitis and AIDS must involve the use of immunorehabilitation means being ProE to reproduce their effects in terms of blocking helper and cytotoxic activity), but also selectively inhibiting replicative activity of the virus.

All antiviral medications used to treat viral hepatitis, belong to 3 main groups: 1 - reverse transcriptase inhibitors, including nucleoside analogues, nucleotide analogues and non-nucleoside analogues; 2 - protease inhibitors; 3 - analogues of pyrophosphate. As shown in the scientific literature, hepatitis B (HBV) from products group of nucleoside analogues greatest efficiency has lamivudine, azidothymidine, famciclovir [11, 12] ; hepatitis C (HCV) as a common therapeutic agents used: ribavirin (Rebetol), azidothymidine [11, 13] .

As analogues for use, taking into account the data about the nature of the known antiviral agents and the principal structural formula of these compounds, and to assess their relative effectiveness with this invention of new drugs were selected antiviral drugs 1 group, namely, lamivudine, ribavirin, azidothymidine.

In some studies [14, 15, 16] the nucleoside analogue lamivudine named a promising drug in the treatment of chronic hepatitis C. At the same absence of HbsAg, sustained suppression of HBV DNA and sustainable normalization of the level of alanine aminotransferase.

Despite the lack of data on long-term observation of patients receiving lamivudine, there are many side effects of lamivudine, including: gastro-intestinal tract (vomiting, nausea, darany syndrome); hepato - and nephrotoxicity; from the blood (neutropenia, thrombocytopenia and anemia); have an adverse dermatological reactions (skin rash, alopecia).

Analysis of literature data on the effectiveness of therapy of chronic hepatitis C ribavirin allows to draw the following main conclusion: the use of ribavirin in mono does not provide a satisfactory therapeutic effect; at the same time, the combination of high doses of interferon and ribavirin used for a long period of time - not less than 12 months, is the best therapy that provides a high percentage of sustained response to treatment [17] .

Ribavirin is also not devoid of serious side effects such as bronchospasm, pulmonary edema, hypotension, anemia, skin rashes, fatigue. However, the main drawback of ribavirin JW what about it is important to contain the methodology of management of viral hepatitis.

Drugs AZT group in the recent past were the main drugs for the treatment of AIDS and herpes infections [18] . Their widespread use was hampered by the rapid development (after 2-3 courses of treatment) very severe complications in the form of hemo - and immunosupressed, allergic dermatitis and Candida mucous, which excluded the use of AZT.

Summarizing the prior art, it should be emphasized that at present the main method of treatment of hepatitis b and C are recombinant interferons and nucleoside analogues. Adopted program of combined therapy (3 million IU of interferon 3 times a week for 6 months and ribavirin), until recently, considered the "gold standard", yesterday provided the remission of the disease in more than 30% of patients today - 12-15% of patients. Such negative dynamics of therapeutic efficacy of traditional antiviral combinations due to, among other mechanisms, the fact that the interferon - high molecular weight (large) protein substances that cause the formation of antibodies. Hence, the larger and longer of such therapy within the human population (given the galloping pace of the epidemic viral hepatitits the treatment of viral hepatitis, along with these drugs direct antiviral action, use drugs, have hepatoprotective effects. One of these drugs is Heptral (S-adenosylmethionine). This drug is seen as the analogue of the claimed preparation in terms of hepatoprotective properties.

In this regard, turning to the conceptual model of the present invention, we consider it possible to postulate the potential and priority use of low molecular weight compounds, structural and functional analogues for key cellular regulatory factors (active metabolites), which has antiviral, at the same time immunomodulatory, as well as hepato - and chemoprotective effects.

In the present invention is used as follows, adopted in this area terminology.

The term "metabolism" refers to the sum of all biochemical reactions in the cells of living organisms [19] . Active metabolites, in turn, is a separate biochemical compounds, often short-chain peptides (from 2 to 9 amino acids), the dynamics of the content in the cell determines the direction and activity of those or other metabolites.removing cell death [20, 21, 22] . Mechanisms of apoptosis senescent cells are removed from the body; mechanisms of apoptosis induced cell death during embryogenesis, as well as the death of the "spent" activated immune cells. In the classic definition, thus, apoptosis is defined as a physiological cell death response.

The concept of cytokines, including interleukins (IL), interferons (IFN); factors tumor necrosis (TNF) and other means of regulatory substances of protein nature, produced, as a rule, immunocompetent cells and play a key role in the development of the immune response, hematopoiesis, processes of apoptosis. Hence, the dynamics and content of endogenous cytokine production largely determines the nature and peculiarities of the course of pathogenesis of different, including infectious diseases [20, 23] .

Immunocompetent cells, denoted as: LED3+; CD4+; CD8+; SD/56+ (NK-cells) - these are different types (differencirovanie markers) T-lymphocytes, performs specific to a particular type of cells, their functions, which form the body's immune response to the action of antigens or other pathogenic elements.

The histology activity index of Knodes a (IGA), proletar (hepatocytes), and the nature of the morphological changes of the liver tissue. Index Knodes is used to determine the degree of activity of the hepatic lesion tissue in conventional units - scores for different types of hepatitis, including viral hepatitis b and C. it has been estimated in the range of 1-3 points characteristic of minimal activity; 4-8 - mild; 9-12 - for moderate and 13-18 - expressed, usually observed in the case of cirrhotic changes in the liver.

Polymerase chain reaction (PCR) detects the presence (+) or absence (-) replicative activity of DNA-type or RNA-type viruses, for example, respectively hepatitis b virus (HBV) or hepatitis C virus (HCV). Quantitative PCR allows to determine (measure) the number of viral copies per 1 ml of blood in the human body. Hence, for example, high replicative activity, i.e., the active replication of the virus in the body (high viral load"), will determine the severity of the clinical course of infectious diseases and, on the contrary, the termination of the replicative activity of the virus or its significant reduction shows antiviral activity of the drugs used for the treatment of viral diseases.

The unique properties of oxidized glutathione (GSSG) to stimulate endogenous production of cytokines and hemopoietic factors - established and patented by the authors previously [25] .

Stabilizing disulfide bond GSSG contributes to the prolongation of the residence time introduced exogenous GSSG in biological environments in the oxidized (disulfide) form and essentially increases for the first time established biological and pharmacological effects of GSSG [25, 26] . In biological environments, GSSG is metabolized by the enzyme NADPH+dependent glutathione reductase, which cleaves disulfide bonds GSSG with the formation of two molecules of reduced glutathione (GSH) [25, 26] .

Hence, a new decision on the prolongation of the time "half-life" introduced exogenous GSSG in biological environments in the disulfide form has become a method of obtaining the composite connection GSSG with the SG from the "attack" of NADPH+dependent glutathione reductase, providing this composite connection new as its biological and pharmacological effects, the integrative result of which is the ability to regulate the processes of cell proliferation, differentiation and apoptosis [26] .

In the above patent [26] presented the group of pharmaceutically acceptable substances, containing as active principle derived GSSG in the form of its salts, which provide:

new pharmacokinetics of GSSG in the data derived GSSG;

- targeted delivery of GSSG in a particular organ, i.e. targeted trapnest to various tissues and organs;

- the new content of the basic biological and pharmacological effects GSSG, or rather its structural and functional analogue - Hexapeptide stabilized by a disulfide bond.

Thus, in the patent [26] , as in the closest analogue we have chosen as a prototype of the claimed invention described salts of oxidized glutathione, which are organic salts GSSG produced by the interaction of oxidized glutathione and inorganic bases.

Task to be solved by the present invention is directed, allevamenti dyslipidaemias peptides with purines and pyrimidines, including nitrogenous bases; nucleosides and nucleotides, as well as the development of methods of their use for the treatment of infectious diseases and prevention of complications.

By its nature this:

any organic salt counterions which are GSSG and a nitrogenous base; or GSSG and purine and pyrimidine nucleosides nature;

any new chemical substance, obtained on the basis of the formation of covalent bonds between GSSG and nukleotidfosfatazu.

According to the classification of IUPAC, not to mention the compounds obtained on the basis of the formation of covalent bonds between two substances - organic salt formed based on the formation of ionic bonds between its constituent components is also an individual matter, as strictly defined soleobrazutaya cations and anions.

In the present invention revealed that in case of receipt of a number of organic GSSG salts with nitrogenous bases and/or nucleoside purine and/or pyrimidine nature as anion formed salt is ionized carboxyl group of the glycine residue of a molecule of GSSG, and the cation is protonated nitrogen atom vnuma, inosine or thymidine protonated nitrogen atom of the N1).

At the same time shows the formation of a number of organic salts on the basis of interaction GSSG and nucleotides, for example:

- GSSG and inosinmonofosfata (GSSG-IMP);

- GSSG and urediniospores (GSSG-MFIs).

In the present invention discloses a series of compounds derived from the formation of covalent bonds between GSSG and nukleotidfosfatazu, such as inosine-51-phosphate, uridine-51-phosphate, citizen-51-phosphate, thymidine-51-phosphate, adenosine-51-phosphate and guanosine-51-phosphate. In this case purposefully used education phosphoramides communication between the amino group of sodium or other inorganic salt of GSSG and the remnants of phosphoric acid nukleotidfosfatazu. The formation of the covalent bond develops according to the same scheme of chemical reactions and gives products which formulas are presented in the respective figures.

One of the embodiments of the invention is represented by a number of substances obtained:

a) on the basis of the formation of ionic bonds between the D-form GSSG and nitrogenous bases, between the D-form GSSG and nucleosides, which formulas are presented on sootvetstvovali, formulas are presented in the respective figures.

According to the invention offers organic salts of oxidized glutathione (GSSG), in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and nitrogenous bases, and nucleosides and nucleotides, purine and pyrimidine nature.

According to the invention offers organic salts of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and nitrogenous bases purine or pyrimidine nature.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and adenine.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and guanine.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glottalised organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and cytosine.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and uracil.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in the L-form and 5-methylcytosine.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in the L-form and 4-thiouracil.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and dihydrouracil.

According to the invention offers organic salts of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula which all the amino acids presented the Xia organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and adenosine.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and guanosine.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and inosine.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and citizen.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and uridine.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and where the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and nitrogenous bases or nucleosides or nucleotides purine or pyrimidine nature.

According to the invention offers organic salts of oxidized glutathione (GSSG), the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and nitrogenous bases purine or pyrimidine nature.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and adenine.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and guanine.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are the two who, the remaining amino acids are represented in an L-shape, and thymine.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and cytosine.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and uracil.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in the L-form and 5-methylcytosine.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in L-formoterol counter-ions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and dihydrouracil.

According to the invention offers organic salts of oxidized glutathione (GSSG), in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and the nucleoside purine or pyrimidine nature.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and adenosine.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and guanosine.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized gluta what the notes are presented in an L-shape, and inosine.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and citizen.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and the nuke is uridine.

According to the invention serves organic salt of oxidized glutathione, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and thymidine.

According to the invention offers organic salts of oxidized glutathione (GSSG), in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in the L-form, or oxidized glutathione, in the formula of which two chemically unambiguous amino acids predstavlja, in the formula which ribose is presented in the form of D-ribose or D-deoxyribose.

According to the invention offers organic salts of oxidized glutathione (GSSG), in which the counterions are oxidized glutathione in L - or D-form, and at the same time two nitrogenous bases: one purine and second - pyrimidine nature.

According to the invention offers organic salts of oxidized glutathione (GSSG), in which the counterions are oxidized glutathione in L - or D-form, and at the same time two nucleoside: one purine and second - pyrimidine nature.

According to the invention offers the individual substances which contain organic cations represented by a number of nucleosides or nucleotides and phosphamide derivatives of oxidized glutathione (GSSG), amino acids which is represented in the L-form.

According to the invention offers substance, which as phosphamide derived oxidized glutathione use derivative with monophosphate (AMP).

According to the invention offers substance, which as phosphamide derived oxidized glutathione using production is TBE phosphamide derived oxidized glutathione use derivative with inosinmonofosfata (IMP).

According to the invention offers substance, which as phosphamide derived oxidized glutathione use derivative with citizensinformation (CMP).

According to the invention offers substance, which as phosphamide derived oxidized glutathione use derivative with urediniospores (MFIs).

According to the invention offers substance, which as phosphamide derived oxidized glutathione use derivative with timedimension (TMP).

According to the invention provides compounds where as phosphamide derived oxidized glutathione use derivatives of nucleotides purine or pyrimidine nature, in which the ribose is presented in the form of D-ribose or D-deoxyribose.

According to the invention offers the individual substances which contain organic cations represented by a number of nucleosides or nucleotides and phosphamide derivatives of oxidized glutathione (GSSG), the structure of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in the L-form.

According to the invention otvagnoe with monophosphate (AMP).

According to the invention offers substance, which as phosphamide derived oxidized glutathione use derived from guanosine monophosphate (GMP).

According to the invention offers substance, which as phosphamide derived oxidized glutathione use derivative with inosinmonofosfata (IMP).

According to the invention offers substance, which as phosphamide derived oxidized glutathione use derivative with citizensinformation (CMP).

According to the invention offers substance, which as phosphamide derived oxidized glutathione use derivative with urediniospores (MFIs).

According to the invention offers substance, which as phosphamide derived oxidized glutathione use derivative with timedimension (TMP).

According to the invention provides compounds where as phosphamide derived oxidized glutathione use derivatives of nucleotides purine or pyrimidine nature, in which the ribose is presented in the form of D-ribose or D-deoxyribose.

And according the lnyh and/or transition metals and phosphamide derivatives of oxidized glutathione in L-form or D-form with a number of nucleosides or nucleotides purine or pyrimidine nature, in which ribose is presented in the form of D-ribose or D-deoxyribose.

According to the invention offers substance, which as phosphamide derived oxidized glutathione use derived from two nucleotides, one of which is a purine, and the second - pyrimidine nature.

According to the invention features a pharmaceutical composition exhibiting anti-viral, antibacterial, immunorehabilitation and hepatoprotective activity, containing as active substance at least one of the above-described compounds in an effective amount, as well as pharmaceutically acceptable carrier or excipient.

According to the invention features a pharmaceutical product, which has antiviral, antibacterial, immunorehabilitation and hepatoprotective effect and containing as active substance at least one of the above-described compounds in an effective amount, as well as pharmaceutically acceptable carrier or excipient.

According to the invention proposes a method of preparation of organic salts of oxidized glutathione and inosine, in which (9-D-ribofuranosyl-gipoksantina), characterized in that the solution of the disodium salt of oxidized glutathione under stirring at room temperature was added 1 equivalent of powder inosine and leave until completely dissolved, after which a clear solution is filtered and freeze-dried.

According to the invention proposes a method of obtaining inoil-5-phosphoryl-N-glutathione, which potamianou the relationship between the amino group of glutamic acid in the molecule of oxidized glutathione and a phosphoric acid residue in the molecule inosine-5-monophosphate get in the reaction N-oxysuccinimide activated ether and oxidized glutathione in dimethylformamide at pH 8.0-8.5.

According to the invention proposes a method of exposure to infectious agents (including intracellular localized) and/or stimulation of T-cell and humoral anti-infective immunity along with providing cytoprotective effects, which consists in the introduction to the mammals of an effective amount of the compounds obtained on the basis of chemical interaction dyslipidaemias peptides with nitrogenous bases or nucleosides, or nucleotides purine or pyrimidine nature.

AGM expression inducer of apoptosis, FAS/APO-1 antigen (CD95+) on the membranes virusinfizierovannah cells on the membranes of macrophages containing Mycobacterium tuberculosis, on the membranes of cells infected with Mycoplasma, chlamydia, malaria Plasmodium and other infectionthe, through the introduction in the mammalian organism a pharmaceutical preparation containing an effective amount of the active substance is selected from the group consisting of GSSG, GSSG, GSSG, GSSG, GSSG, GSSG-insimenator, GSSG-brazilianist, GSSG-timeinterest, GSSG-casinodeposit and other compounds based on the interaction of L - or D-forms of oxidized glutathione and its salts with nitrogenous bases or nucleosides or nucleotides purine or pyrimidine nature.

According to the invention it is proposed a method consisting in the introduction in mammals infected with hepatitis C virus, a pharmaceutical preparation containing an effective amount of an active ingredient selected from the group consisting of GSSG, GSSG-insimenator, GSSG-brazilianist and other derivatives of L - or D-forms of oxidized glutathione with components of nucleic acids in order to inhibit ATP-asna/helicases aktivnogo, therapeutic effect.

According to the invention it is proposed a method consisting in preferential inhibition of replicative activity of RNA viruses, in the case of use as active ingredients, compounds derived from the chemical interaction of L - or D-forms of oxidized glutathione and its salts with nitrogenous bases or nucleosides, or nucleotides pyrimidine nature.

According to the invention it is proposed a method consisting in preferential inhibition of replicative activity of DNA-containing viruses, in the case of use as active ingredients of the compounds derived from the chemical interaction of L - or D-forms of oxidized glutathione and its salts with nitrogenous bases or nucleosides, or nucleotides purine nature.

According to the invention proposes a method, which consists in introducing into the mammalian organism a pharmaceutical preparation containing an effective amount of the active substance is selected from the group consisting of GSSG, and other compounds oxidized glutathione with components of nucleic acids, with the aim of preferential activation of the functional is but determines the efficiency of the immune system of mammals in relation to causal factors of infectious diseases.

According to the invention proposes a method, which consists in the introduction into the organism of the patient With viral hepatitis C pharmaceutical preparation containing an effective amount of the active substance is selected from the group consisting of GSSG, and/or GSSG-insimenator, in order to restore the normal ratio of Th1/Th2 cells, therefore, the optimum content of cytokines produced by Th1 and Th2 group of cells, including with the aim of increasing the endogenous production of IL-2, IL-12, IFN -.

According to the invention proposes a method, which consists in the introduction into the organism of the patient with viral hepatitis a, b and/or pharmaceutical preparation containing an effective amount of the active substance is selected from the group consisting of GSSG and other compounds oxidized glutathione, its salts with components of nucleic acids, in order to achieve hepatoprotective effects, including the prevention and/or treatment of complications called chronic viral hepatitis, namely the prevention and treatment of liver cirrhosis and hepatocellular carcinoma.

According to the invention it is proposed a method in which the disease is selected from all kinds of infectious zabolevanii; fungal infections (candidiasis); protozoal infections.

According to the invention it is proposed a method in which substances based on chemical interaction dyslipidaemias peptides with nitrogenous bases, nucleosides and nucleotides, through pharmaceutically acceptable solvents or carriers injected into the infected organism parenterally, orally, in the form of inhalation solutions, solutions for local instillation, eye or intranasal drops, ointments, creams or gels for transdermal application, as well as in the form of suppositories - before reaching therapeutic effect and/or prevention of complications caused by infectionthe in the process of development of infectious diseases.

According to the invention proposes a method of treatment of a subject in need of the termination of the replicative activity of the virus, bacteria or other infectionhow, induction mechanisms of apoptosis of infected cells, restore, and stimulation of anti-infective capable of immunity: T-cell and/or humoral system cytoprotective effects, which consists in the introduction to a subject a pharmaceutical preparation containing a biologically active substance, wybir the I L - or D-forms of oxidized glutathione, its salts with nitrogenous bases or nucleosides or nucleotides purine or pyrimidine nature in a quantity sufficient to achieve a therapeutic effect.

According to the invention the method comprises the treatment of acute, long lasting viral hepatitis, and pharmaceutical drug is chosen from the group consisting of GSSG and GSSG-inosinmonofosfata.

According to the invention the method comprises the treatment of acute viral hepatitis C, and pharmaceutical drug is chosen from the group comprising GSSG, GSSG and GSSG-insimenator.

According to the invention the method comprises the treatment of chronic viral hepatitis, and pharmaceutical drug is chosen from the group comprising GSSG, GSSG, GSSG, GSSG-insimenator and GSSG-timeinterest.

According to the invention the method comprises the treatment of chronic viral hepatitis C, and pharmaceutical drug is chosen from the group comprising GSSG, GSSG, GSSG, GSSG, GSSG-brazilianist, GSSG-casinodeposit, uracil-GSSG-inosine.

According to the invention the method comprises the treatment of chronic viral hepatitis in the cirrhotic stage, and pharmaceutically who/SUB>-GSSG-timeinterest.

According to the invention includes a method of treatment of pulmonary tuberculosis, and pharmaceutical drug is chosen from the group comprising GSSG, GSSG, GSSG-5-methylcytosine, Li2-GSSG-insimenator.

According to the invention the method comprises the treatment of tuberculosis of the genitourinary system and the pharmaceutical drug is chosen from the group comprising GSSG, Na2-GSSG-guanosine monophosphate and uracil-Li2-GSSG-guanosine monophosphate.

According to the invention the method comprises the treatment of AIDS and cytomegalovirus infections and infections caused by virus, Epstein-Barr and/or with this pathogen, and the pharmaceutical drug is chosen from the group comprising GSSG, GSSG, GSSG4-thiouracil, and Zn2-GSSG-timeinterest and Ag2-GSSG-brazilianist and GSSG.

According to the invention the method comprises the treatment of infections caused by herpes viruses, and pharmaceutical drug is chosen from the group comprising GSSG, Li2-GSSG-guanosine monophosphate, and also the D-form Na2-GSSG-casinoniagara and D-form GSSG.

According to the invention the method comprises the treatment of fungal infections (candidiasis), and the pharmaceutical drug is chosen from the group including Uchenie mycoplasmal infections, and pharmaceutical drug is chosen from the group comprising GSSG, GSSG and PA2-GSSG-monophosphate.

According to the invention the method comprises the treatment of chlamydial infections, and pharmaceutical drug is chosen from the group comprising GSSG, GSSG, GSSG, GSSG and Na2-GSSG-guanosine monophosphate.

According to the invention the method comprises the treatment of malaria, leishmaniasis, and pharmaceutical drug is chosen from the group comprising GSSG, and GSSG5-methylcytosine.

According to the invention the method comprises treatment of anaerobic infections, and pharmaceutical drug is chosen from the group comprising D-form GSSG (D-cysteine and D-form GSSG (D-glutamic acid).

According to the invention includes a method of treating viral hepatitis a, dysentery and cholera, and the pharmaceutical drug is chosen from the group comprising GSSG, Li2-GSSG-insimenator and Li2-GSSG-guanosine monophosphate, and also the D-form GSSG (D-glutamic acid).

According to the invention the method comprises the treatment of infectious meningitis, and pharmaceutical drug is chosen from the group comprising GSSG, Li2-GSSG-insimenator, D-shape GSSG includes treatment of especially dangerous infections plague, tularemia and anthrax, and pharmaceutical drug is chosen from the group comprising GSSG, GSSG, GSSG, GSSG5-methylcytosine, GSSG4-thiouracil, D-shape GSSG (D-glutamic acid, D-form GSSG(D-listen), GSSG.

According to the invention the method comprises the treatment of infections caused by prions ("core proteins"), and the pharmaceutical drug is chosen from the group comprising GSSG, GSSG, GSSG, Ag2-GSSG-brazilianist, Ag2-GSSG-timeinterest and brazilianist-Li2-GSSG-insimenator.

According to the invention the method comprises the treatment of influenza and acute respiratory viral infections, and pharmaceutical product selected from

groups, including GSSG, GSSG, GSSG and GSSG,

The invention is illustrated by drawings, which are schematic and were made to represent the structural formulas of new substances. While not every item is labeled in every drawing and not every component of each embodiment of the inventive concept is shown if the illustration is not needed to allow an ordinary person skilled in the art to understand the invention. The presented figures izobrazheniya (GSSG) with adenine.

In Fig. 2 is the structural formula of an organic salt of GSSG with guanine.

In Fig. 3 is a structural formula of an organic salt of GSSG with thymine.

In Fig. 4 is a structural formula of an organic salt of GSSG with uracil.

In Fig. 5 is a structural formula of an organic salt of GSSG with cytosine.

In Fig. 6 is a structural formula of an organic salt of GSSG with 5-methylcytosine.

In Fig. 7 is a structural formula of an organic salt of GSSG and 4-thiouracil.

In Fig. 8 is a structural formula of an organic salt of GSSG with dihydrouracil.

In Fig. 9 is a structural formula of a substance (organic salts), counterions which GSSG and inosine (9--D-ribofuranosylpurine).

In Fig. 10 is a structural formula of a substance (organic salts), counterions which GSSG and thymidine (3--D-2-deoxyribofuranosyl).

In Fig. 11 is a structural formula of a substance (organic salts), counterions which GSSG and uridine (3--D-ribofuranosylpurine).

In Fig. 12 is a structural formula of a substance (organic salts), counterions which GSSG and guanosin, where R is the remainder of the ribose.

In Fig. 13 is a structural formula of a substance (organic salts), counterions which GSSG and adenosine, where R is the remainder of the ribose.2-GSSG, uridine-51-phosphate (MFIs).

In Fig. 15 is a structural formula of a substance, obtained on the basis of the formation of covalent bonds between Na2-GSSG and citizen-51-phosphate (CMP).

In Fig. 16 is a structural formula of a substance, obtained on the basis of the formation of covalent bonds between Na2-GSSG and thymidine-51-phosphate (TMP).

In Fig. 17 is a structural formula of a substance, obtained on the basis of the formation of covalent bonds between Na2-GSSG and adenosine-51-phosphate (AMP).

In Fig. 18 is a structural formula of a substance, obtained on the basis of the formation of covalent bonds between Na2-GSSG and guanosin-51-phosphate (GMP).

In Fig. 19 is a structural formula of a substance, obtained on the basis of the formation of covalent bonds between Zn2-GSSG and thymidine-51-phosphate.

In Fig. 20 is a structural formula of a substance, obtained on the basis of the formation of covalent bonds between Ag2-GSSG, uridine-51-phosphate.

In Fig. 21 is a structural formula of a substance, obtained on the basis of the formation of covalent bonds between Li2-GSSG and guanosin-51-phosphate.

In Fig. 22 is a structural formula of a substance, obtained on the basis of - tructura the formula of a substance, obtained on the basis of the formation of covalent bonds between the D-form of Na2-GSSG (D-cysteine) and CMP.

In Fig. 24 is a structural formula of a substance (organic salts), counterions which D-form GSSG and uracil.

In Fig. 25 is a structural formula of a substance (organic salts), counterions which D-form GSSG and inosine.

In Fig. 26 is a structural formula combined organic salt counterions which are GSSG and nitrogenous bases of purine and pyrimidine nature.

In Fig. 27 is a structural formula combined organic salt counterions which are GSSG and purine and pyrimidine nucleosides nature.

In Fig. 28 is a structural formula of the combined compounds formed on the basis of covalent bonds between the amine groups of the inorganic salt of GSSG and vospalenye groups of purine nucleotides and pyrimidine nature.

Fig. 29 is a structural formula 9--D-ribofuranosyl-5'-phosphoryl-N-bis-(-L-glutamyl)-L-cystinyl-bis-glycine disodium (delitala) salt, obtained on the basis of the formation of covalent bonds between Na2(Li2)-GSSG and inosine-5'-monophosphate (IMP).

Fig. 30 - dynamics clinic - dynamics of clinical, laboratory and morphological characteristics of the patient Z. , received therapy drug GSSG.

Fig. 32 - chest x-ray, the left lung. Before treatment (October 1999 ) (example 16).

Fig. 33 - chest x-ray, the left lung. After treatment (January 2000 ) (example 16).

Fig. 34 - therapeutic effectiveness of the studied hepatoprotective compounds in experimental dichlorethane hepatitis (Example 17).

Fig. 35 - therapeutic effectiveness of the studied hepatoprotective compounds in experimental acetaminophenol hepatitis (Example 17).

Fig. 36 - therapeutic effectiveness of the studied hepatoprotective compounds when combined (dichloromethane+acetaminophen) experimental hepatitis (Example 17).

Fig. 37 - change indicators cytolytic syndrome (ALT, ACT), with the combined experimental hepatitis (dichloromethane+acetaminophen) (Example 17).

Fig. 38 - change in the level of bilirubin in the blood plasma when combined experimental hepatitis (dichloromethane+acetaminophen) (Example 17).

Fig. 39 - the dynamics of immunological parameters in patients with chronic viral hepatitis C before and during treatment In Preah drug GSSG.

Fig. 41 - the level of cytokines in the serum of patients with chronic viral hepatitis C before and during treatment with the drug GSSG.

Fig. 42 is a diagram of the synthesis inoil-5'-phosphoryl - GSSG-PA2.

As a preferred embodiment of the objectives of the invention appears to be a new compound, obtained as an organic salt of oxidized glutathione, in which the cation is a 9--D-ribofuranosylpurine (inosine). The method of obtaining GSSG below its structural formula in Fig. 9.

Methods of preparation of organic salts GSSG

Taken 200 g (0.65 M) of reduced glutathione (GSH) and dissolved in 700 ml of distilled water with constant stirring and the temperature of 12-15oC (ice bath). Added 163 ml (0.65 M) 4N NaOH solution. After complete dissolution slowly entered 295 ml of 3% solution of N2ABOUT2while the solution is in an ice bath and the temperature is maintained at the same level. Stirring is continued for a further 3-4 hours (this time is determined empirically for working with platinum as the catalyst), the temperature of the solution is maintained below the 20oC. After completion of the reaction is carried out HPLC (final content of GSSG - 98% or more). P what is 174.2 g (0.65 M) inosine (in the form of a homogeneous dry powder) and stirring continued at 23-25oWith another 10-12 hours until it dissolves.

The resulting solution is filtered through a filter with pore size of not more than 0.7 microns. The filtered solution should be clear, colorless, not to opalisrobot, pH 5.3+/-0.2. the pH is brought to 6.0 by adding 1-4N NaOH solution. Control - HPLC: peaks GSSG and inosine (Nucleosil 18, MeCN - 0.1% TFA).

The resulting solution liabilitiesa in accordance with the following recommendations (see also the attached diagram lyophilization):

- the shelves are cooled to -20+/-0.2oC;

- place the vessel with the solution on the shelves;

- freeze solution to -35+/-0.2oC;

- frozen solution contains at the same temperature for 3+/-0.5 hours;

- disable shelves;

- to enable the condenser to the cooling -54 to+/-2oWith 15+/-3 min;

- vacuum treatment for 30+/-5 min to achieve 4-6 PA;

- the material is left for 2 hours;

the temperature on the shelves gradually increases until reaching a constant temperature on the shelves and the temperature of the material.

An important element of the claimed new technical solutions to obtain the titled compound (GSSG) is an established fact that is poorly soluble in aqueous solution is determined as being evidence of the formation of ionic bonds between GSSG and inosine, i.e. the formation of a special type of organic salt.

As a preferred embodiment of the invention is to provide a D-shaped GSSG. In this case, in the formula GSSG two chemically unambiguous amino acids (cysteine) is represented in the D-form, and the remaining amino acids in L-form (Fig. 25). At the same time in Fig. 24 presents the formula D-GSSG-uracil, in which the D-form of glutamic acid.

In turn, in the following embodiment of the invention reveals that the pharmaceutical preparation obtained on the basis of GSSG has a unique combination of biological and pharmacological effects, providing a fundamentally new solution to the problem of treatment of viral diseases such as viral hepatitis b and C and their complications; AIDS (see examples of implementation of the invention 5-8, 12-13); herpes and infections (see examples of implementation of the invention 14-15).

It is emphasized that a new level of therapeutic efficacy GSSG, especially in relation to viral hepatitis, due to the fact that the product has three kinds of activity: the antiviral, immunorehabilitation and hepatoprotective.

It is established that each of the three types of pharmacological active the mechanisms of antiviral, antibacterial, immunorehabilitation and hepatoprotective activity GSSG (D-form) and other compounds derived from the interaction dyslipidaemias peptides and purines/pyrimidines.

Regarding antiviral activity shows that these compounds have two systems mechanisms of antiviral action. First, a kind of nonspecific system mechanisms due to the General property of drugs to induce apoptosis mechanisms virusinfizierovannah cells, in particular, due to increased expression of the inducer of apoptosis is FAS/APO-1 receptor (CD95+) (see the example implementation of the invention 3). It is this mechanism leads to high efficiency GSSG and several other compounds (GSSG-IMP, GSSG-UMP, Li2-GSSG-IMP, Zn2-GSSG-TSR) in their application as tools for the treatment of infectious diseases caused by DNA-type and RNA-type viruses.

In particular, the antiviral activity GSSG installed on some models of viral infections, namely: rift valley fever (LDR); the generalized form of herpes infection; Venezuelan encephalomyelitis of horses (VAL); flu (A virus H3N2) (see examples of implementation of the invention 2). traditional antiviral drugs.

In turn, a unique therapeutic efficacy GSSG and other of the considered compounds is demonstrated in the clinic of infectious diseases when using these compounds for the treatment of TB (see examples of implementation of the invention 16); urogenital infections (see examples of implementation of the invention 14-15); AIDS (see examples of implementation of the invention 12-13); acute and chronic hepatitis b (see examples of implementation of the invention 5-8, table. 12-21, Fig. 30 and 31).

Thus, the ability to identify GSSG and consider other compounds to induce apoptosis virusinfizierovannah cells also applies to cells infected with Mycobacterium tuberculosis, chlamydia, Mycoplasma, Ureaplasma, and other infectionthe.

In most examples of the invention demonstrate a new quality of therapeutic solutions listed socially significant diseases, the effectiveness of the proposed in the invention of drugs is compared with the efficiency, featured today's medical practice, preventive and curative medicines. It is shown that therapeutic efficacy, for example, GSSG hepatitis B, defined in terms of normalization of objective indicators of infection processes, such as: the activity of transaminases (ALT and ACT); the content of bilirubin; the content of prothrombin; the content of HbsAg significantly higher therapeutic effectiveness of traditional therapy.

So, in the case of acute hepatitis In traditional therapy provides positive dynamics transaminases activity of bilirubin concentration and HbsAg, usually 50-60 days of treatment. Application GSSG mono - to 14-17 days of treatment (see examples of implementation of the invention 5 and 6, PL. 12-17, Fig. 40).

In the case of chronic hepatitis In key indicators of the effectiveness of therapy are, again, transaminase activity (a measure of the degree of cytolysis of hepatocytes) and replicative activity of the virus determined using a PCR test.

On this main indicator of the effectiveness of treatment of chronic hepatitis b In traditional therapy (recombinant interferon plus nucleoside analogues) reduce the percentage of positive PCR HBV DNA from 100% to no more than 30-40%; i.e. 60-70% of patients the treatment is ineffective. Application GSSG ensures conversion of PCR HBV DNA with Polo is 0 and 31). Restoring the functional capacity of the liver in case of viral and toxic hepatitis, defined by indicators such as protein synthesis and detoxification functions of the liver, is achieved using GSSG 2-3 times more quickly than with traditional therapy, for example, Geptral(S-adenosyl-methionine) or Essentiale(see examples of implementation of the invention 11; 14).

As a preferred embodiment of the invention is the disclosure of specific, i.e. direct antiviral activity GSSG (Molisana), GSSG-IMP and GSSG-UMP, as well as their salts, relative to the hepatitis C virus (HCV RNA), i.e., RNA-containing virus in contrast to DNA-containing hepatitis b virus (HBV DNA). This embodiment of the invention claims a unique property GSSG (Molisana), and GSSG-IMP and GSSG-UMP - the ability to inhibit ATP-asna/heliozoa the activity of regulatory non-structural protein-enzyme (NS3) of hepatitis C virus (see example implementation of the invention 4). The data we have suggests that Zn2-GSSG-IMP, as well as other salt of GSSG-UMP, for example Ag2-GSSG-UMP, have the ability to inhibit the activity of the lightly the practical activity GSSG relatively acute and chronic viral hepatitis; herpes infection and AIDS (see examples of implementation of the invention 5-14) due to a combination of its mediated (the induction of apoptosis virusinfizierovannah cells) and direct antiviral activity (inhibition of ATP-asna/helicase activity of HCV NS3) that defines a new solution treatment and preventive measures for chronic hepatitis C.

At the same time it is shown that in relation to viral infections, especially viral hepatitis, and AIDS - D-form GSSG has greater antiviral activity, ensuring the termination of the high replicative activity of the virus and their elimination from the body (see the example implementation of the invention 12).

Extremely relevant for therapy of chronic viral hepatitis, especially for the treatment of hepatitis C, was vector immunorehabilitation activity GSSG, as the second type of pharmacological activity of this and related compounds.

Characteristics immunorehabilitation efficiency GSSG is:

- normalization of the ratio of the production of cytokines by Th1/Th2 cell types with predominant activation of T-cell immunity;
+; CD8+; SD+/56+; SD+; the increase in the activity of resident macrophages), thereby getting HBV and HCV (hepatitis viruses b and C) under the proper immunological surveillance, and consequently, the elimination of the virus from the body and a favorable therapeutic outcome.

One of the most important mechanisms of therapeutic effect GSSG - induction of the secretion of IL-12, which promotes the stabilization process of the prevalence of Th1 activity group, therefore, the active production of endogenous (native to the body) interferons (see examples of implementation of izobreteniya implements an embodiment of the invention, its hepatoprotective activity, specifically defines a unique protevorevmaticescoe effects GSSG (Molisana).

The very posing of this question is intrinsically linked with one of the main conceptual provisions of the invention is the creation of individual substances, able to implement a fundamentally new solution to the problem of treatment of infectious diseases such as viral hepatitis, especially hepatitis C.

With that said in the introduction that more than 40% of liver cirrhosis and 60% of liver cancer caused by chronic hepatitis C - this means that every design solution therapy of chronic hepatitis C involves both the elimination of the actual virtualdatacenter destruction of the liver tissue and the prevention of processes of fibrosis of the liver, along with the prevention of processes of malignant transformation of hepatocytes.

In the invention presents the rationale protivoaritmicheskih effects obtained in experimental models of cirrhosis of the liver and in the clinic.

In particular, on the model of cirrhosis resulting from chronic introduction experimental animals dimethylnitrosamine (DMNA), it was found that when einternal tissue in the liver by 64% and contributed to the restoration of damaged hepatocytes. When this drug comparison - Heptral (S-adenosyl-methionine) had significantly lower therapeutic effect, reducing the degree of fibrosis of the liver of experimental animals only 35% and not exerting a significant influence on the recovery of functional capacity of the liver (and other protein-synthesizing) (see an example implementation of the invention 29).

Equally convincing results were obtained in the clinic for the treatment of drug GSSG patients with a diagnosis of chronic viral hepatitis b or chronic hepatitis C); cirrhotic stage (PCR HBV+; HCV PCR+), ascites, portal hypertension. The drug GSSG mono for repeated courses provided a unique therapeutic effect, affirm positive dynamics of clinical status and special methods of examination of patients (see Examples of implementation of the invention 8-11).

Thus, treatment of patients with chronic viral hepatitis, especially hepatitis C, with the use of dosage forms of the drug GSSG (Molczan) provides not only the elimination of the actual infection, but also the prevention of complications of viral hepatitis, particularly cirrhosis and liver cancer. Kim to cirrhosis, application GSSG in experiment and clinic demonstrates therapeutic efficacy, unparalleled from the point of view of the appropriate application of the known hepatoprotective drug.

Therefore, the conceptual platform of the invention is to be submitted to the group of the original substances (possible name - tionally) produced (synthesized) as organic GSSG salts with nitrogenous bases and/or nucleosides; and/or as compounds based on the formation of covalent bonds between GSSG and purine nucleotides and pyrimidine nature.

Data for individual substances of the formula in Fig. 1-29) possess a unique combination of biological and pharmacological effects, namely: (a) antiviral action - direct (inhibition of ATP-asna/helicase activity of HCV NS3) and indirect (through the induction of apoptosis virusinfizierovannah cells, including due to the expression of the inducer of apoptosis FAS/APO-1 receptor); b) immunorehabilitation activity; and/system cytoprotective and, especially, specific hepatoprotective effects with the ability to warn cirrhotic changes in the liver and even perform about the ve biologically-active substances are presented in the invention compounds can be used in various pharmaceutical forms for parenteral administration; and (b) receiving per os in capsules and tablets, and in the form of a suppository - rectal and vaginal; g) in the form of eye drops; and d) in the form of creams, gels and ointments for external use.

In this regard, it seems appropriate use of substances as medicines for the treatment of a wide group of infectious diseases and prevention of complications. First of all, it belongs to the group of infectious diseases that are fundamental factors in the etiopathogenesis of chronicity and progression of the disease process are: a) the stage presence of intracellular persistence of infectionthe; b) quasivariational genetic apparatus of infectionthe that allows him to "escape" from the immunological surveillance of host organisms; C) violation suitable from the viewpoint of protection of the organism, the ratio of production of cytokines by Th1/Th2 groups of lymphocytes-helper cells, i.e., the violation of the orientation of an effective immune response of the body; g) system cytopathic, especially hepato-, nephro and gamesituation effects.

In turn, executed and others represent drugs, have a high therapeutic efficacy due to their ability to correct all of these factors of pathogenesis of infectious processes, which allows us to formulate the following medical indications for their use.

First of all, for the treatment of infectious diseases in respect of which the causal factor is an intracellular pathogen, for example: DNA-type and RNA-type viruses, chlamydia, Mycoplasma and Ureaplasma, hence for the treatment of acute and chronic viral hepatitis, AIDS, herpes, Mycoplasma and chlamydia infections.

For the treatment of protozoal infections (malaria, leishmaniasis); for the treatment of infectious diseases caused by fungi (mycoses) and with this pathogen, in combination with traditional antibacterial therapy in the acute phase and mono under maintenance therapy.

For the treatment of infectious diseases caused by gram-positive and gram-negative bacteria, as well as etiology anaerobes, containing in the process of etiopathogenesis stage of intracellular persistence of the pathogen, for example, as is typical for tuberculosis and persistence of mycobacteria in macrophages of the body. This increases the damage of mycobacteria-specific chemotherapy and system of T-cell immunity.

For the treatment of acute viral hepatitis b and C, as well as mixed hepatitis preferably use GSSG and GSSG-inosine-monophosphate, Li2-GSSG-inosinmonofosfata.

For the treatment of chronic hepatitis b and C preferably use GSSG and GSSG-inosine-monophosphate (GSSG-IMP), and GSSG-uracil-monophosphate (GSSG-MFIs).

For the treatment of chronic hepatitis b cirrhotic stage preferably use GSSG and GSSG, GSSG, GSSG and Na2- GSSG-timeintensity (Na2- GSSG-TMP), depending on the peculiarities of the morphological changes in the liver and the degree of violation of its functional capacity.

For the treatment of pulmonary tuberculosis preferably use GSSG, GSSG and GSSG-5-methylcytosine.

In the case of tuberculosis of the genitourinary system preferably application of Na2-GSSG-guanosine monophosphate (Na2-GSSG-FM) and/or uracil-Li2-GSSG-guanosine monophosphate (MFIs-Li2-GSSG-GMF).

For the treatment of AIDS, as well as cytomegaloviruses infection; infections caused by virus Epstein-Barr and/or with this pathogen, preferably using Pinetina, GSSG, and Zn2-GS is the capabilities and availability of Kaposi's sarcoma.

For the treatment of herpetic infections preferable application of Li2-GSSG-GMF, and D-forms of Na2-GSSG-casinodeposit (D-form Na2-GSSG-CMP) and D-forms GSSG.

For the treatment of mycosis preferably use GSSG, GSSG4-thiouracil and Ag2-GSSG-uralmonatsit.

For the treatment of mycoplasmal infections preferably use GSSG, GSSG and PA2-GSSG-monophosphate (Na2-GSSG-AMF).

For the treatment of chlamydial infection preferably use GSSG, GSSG, GSSG and Na2-GSSG-GMF.

To treat infections caused by herpes viruses should preferably use GSSG, Li2-GSSG-guanosine monophosphate, and also the D-form PA2-GSSG-casinoniagara and D-forms GSSG.

For the treatment of viral hepatitis, and intestinal infections (dysentery, cholera) is preferable application of Li2-GSSG-GMF, GSSG and D-forms GSSG (D-glutamic acid).

For the treatment of influenza and other acute respiratory viral infections (ARVI) preferably use GSSG, GSSG, GSSG and GSSG, depending on the type of influenza virus and the viruses that cause colds.

The following examples of the invention demonstrate the possibility of obtaining the above substances, methods for their medical use, as well as therapeutic efficacy of the family developed new pharmaceutical drugs (derived from the presented new individual substances) with respect to their application to a wide range of infectious diseases (Examples of implementation of the invention 1-18).

Example 1

The method of obtaining (synthesis) Insel-5'-phosphoryl-GSSG-Na2< / BR>
I. General characteristics of the drug.

1. Name: 9--D-ribofuranosyl-5'-phosphoryl-N-bis-(-L-glutamyl)-L-cystinyl-bis-glycine disodium (delitala) salt.

2. The structural formula is shown in Fig. 29.

3. Brutto-formula: C36H55N10O19Na2S2P.

4. Molecular weight: 1072,96 (disodium salt).

5. Appearance: white powder, odorless.

6. Solubility: soluble in water, isotonic sodium chloride 0.9% for injection; insoluble in 95% alcohol, chloroform, ether and other organic solvents.

7. The clarity and color of solution: a solution of 0.05 g of the drug in 10 ml of water (a) amino acid analysis (6 n HCl, 110oC, 20 h), (a margin of error of 20% for cysteine 35%), in accordance glycine - 2,0; glutamic acid - 2,0; cysteine - 2,0;

b) NMR(1N) spectroscopy, in accordance "BRUKER AM 500, 500 MHz, D2O (see tab. A);

b) in time of the output corresponds to the standard.

10. Purity (content of the basic substance):

(a) HPLC: not less than 97%

the instrument BECKMAN Gold Nouveau Chromatography Data System Version 1.0, Diod Array Detector Module 126. Sample 20 μl of 0.1% solution of the preparation, chromatography was carried out on a column of ULTRASPERE ODS h,6 mm with reversed WITH18phase in isocratic mode acetonitrile - 0.1% of triperoxonane acid (2: 98); flow rate 1 ml/min, detection at 220 nm, scanning 190-600 nm, PDA functions - Contour Plot, 3D;

b) amino acid analysis 85% (analysis under item 9a with the exact hinge);

C) TLC - homogeneous, the analysis is carried out while applying a strip of 5 μl of 0.1% solution of the drug; plates Kieselgel 60f(Merck) 10x5 cm system: N. butanol - acetic acid - water (4: 1: 1); development of standard methods on - ninhydrin and chlorine/benzidine; Rf= 0,15;

g) sodium (Na) emission spectral method 4,0-4,8%.

11. Found the content elements, mg/g:

Silver (Ag) - < 1,0 (less than 0,0001%)

Aluminum (Al) - 2,0

The
Cobalt (Co) - < 0,5

Chromium (Cr) - 1,7

Copper (Cu) - < 0,5

Iron (Fe) - < 1,0

Potassium (K) - < 2,5

Selenium (Se) - < 2,0

Magnesium (Mg) - < 2,5

Manganese (Mn) - < 0,2

Molybdenum (Mo) - < 0,2

Sodium (Na) - 48 mg/g

Nickel (Ni) - < 0,5

Lead (Pb) - < 0,40

Strontium (Sr) - 1,9

Titanium (Ti) - < 0,5

Vanadium (V) - < 0,5

Zinc (Zn) - 0,65

Antimony (Sb) - < 0,5

The method of determining the

Accurately weighed sample (about 50 mg) was dissolved in 50 ml of bidistilled water and the solution was used for analysis.

The content of platinum was determined quantitatively by the method of mass spectrometry with inductively coupled plasma device model PQe, firms VG Elemental, UK. The relative precision of this assay is 5%.

The content of other elements is determined quantitatively by atomic emission spectrometry with inductively coupled plasma device model 61E TRACE, Thermo Jarrell Ash, USA. The relative precision of this assay is 5%.

12. The mass loss during drying: 10% when dried to constant weight at 100oC in vacuum (1 mm Hg) over CaCl2and R2ABOUT5.

II. Description of methods of synthesis.

13. The chemical scheme for the synthesis (see Fig. 42).

I - inosine-5-monophosphate,

HOSu - ocny ester,

III - inosine-5-monophosphoryl-N-glutathione.

14. Description techniques

Inosine-5-monophosphate (I) is dissolved in dimethylformamide and under stirring and cooling to 0-5oWith type 1 equivalent of N-oxysuccinimide and 1.2 EQ. N, N-dicyclohexylcarbodiimide. Stirred with cooling for 1 h, and then 12 hours at room temperature. Dropped dicyclohexylphosphino filtered off and to the residue add 3 equivalent disodium salt of oxidized glutathione. Stirring at room temperature for 24 hours. Next dimethylformamide evaporated and using preparative HPLC mode described above, the product is subjected to purification. Control UV spectrum absorption band purine bases 260 nm.

Example 2

Antiviral activity of the drug GSSG

1) rift valley Fever (LDR) is an acute febrile disease of viral etiology that affects domestic animals and people. Human disease is characterized by acute onset, rapid development of the febrile symptoms, pain in joints and limbs, eye damage, symptoms of hemorrhagic diathesis. One of the characteristics of LDR in humans and animals is caused by a virus of the liver, resulting in the e leukopenia.

Existing tools and methods etiotropic and pathogenetic therapy LDR is not effective enough. Taking into account the peculiarities of pathogenesis LDR, in particular high tropism of the pathogen to the hepatocytes, it was considered useful to assess in an experimental model of this infection antiviral activity of the drug GSSG.

1. Materials and methods study.

1.1. Animals. In the experiments used adult randombred white of male mice weighing 18-21 g, the set of the kennel "Rapolano RAMS.

1.2. The pathogen. For modeling infection LDR used a strain of virus isolated in Uzbekistan in 1987 from a person who hemorrhagic fever, from the Museum of viral cultures research Institute of military medicine. The inoculum suspension was brain of newborn mice infected intracerebrally specified strain of the pathogen. Infecting dose of virus in the present study were within the range of 1-20 LD50the causative agent was injected intraperitoneally. The period of observation of the animals was 14 days.

1.3. The preparations. GSSG - dosage form for injection (1% and 3%) is used in doses of 3, 10 and 30 mg/kg at an injection. The drug was introduced vnutribrjushinnye (for 4 h before infection and continued to introduce a further 4 days. Thus, the treatment consisted of 6-7 injection GSSG.

Ribamidil - drug comparisons (similar to pulse. virazole, ribavirin), the production of "Olaine" (Latvia), injectable dosage form. Ribamidil is currently one of the most effective antiviral drugs, in particular, in the hemorrhagic fevers. The drug was administered subcutaneously at the optimum, the previously well-established pattern: single (daily) dose was 100 mg/kg, the time of introduction consistent with the time of appointment GSSG.

1.4. The efficacy evaluation. Protective efficacy was evaluated by survival rates (%) and life expectancy (days) animal experimental and control groups.

2. The results of the study

2.1. The effect of monotherapy GSSG on the outcome of infection LDR

In the first series of experiments was conducted to study the efficacy GSSG at his appointment in monotherapy. The drug was introduced to the infected animal pathogen; when one scheme for 48 h before infection, when the other two for 4 h before infection. In General, courses of therapy consisted of 6-7 injection GSSG intraperitoneally in single doses of 3, 10 and 30 mg/kg Ribamidil was introduced after inserting basiony period was 6 days. At the same time, the animals of the experimental groups signs of infection appeared on 2 days later. The final results of this experiment are presented in table 1.

As follows from the presented data, the mortality of the animals of the control group infected with a virus at doses of 10-20 LD50was 100%. When infecting dose, equal to 1-2 LD50killed 67% of the infected mice. Drug comparison ribamidil, taken as positive control, were protected against a lethal outcome approximately one third of the animals infected with a high dose of the virus, and up to 60% of the animals infected with low doses of the pathogen. The drug GSSG in this model, acute generalized viral infection also had a certain protective effect, increasing the survival of animals on 22-59% relative to control, depending on therapeutic dose and severity of infection.

In the second series of experiments evaluated the protective efficacy of the combined application of ribamidil and GSSG. Drugs used in the same doses and for the same schemes as in the first series. The results of this experiment are presented in table. 2. The obtained data suggest that the antiviral effect of combined ispolzuemogo product separately.

In the third series of experiments examined the effect GSSG on the course of infection LDR in terms of survival and the presence of hemorrhage on the surface of the liver in experimental and control mice, revealed in the process of developing this infection.

In the experiment 40 randombred of male mice weighing 18 g, the set of the kennel "Rapolano RAMS. For infection, the virus is taken in a dose of 4 LD50infection was performed intraperitoneally.

GSSG was also administered intraperitoneally in two doses of 3 and 30 mg/kg for 7 days. Start therapy immediately after infection, the animals, and then daily (1 time daily). The observation was carried out for 10 days (table. 3).

It is established that in this scheme the destination GSSG dose of 3 mg/kg had a protective effect against experimental infection in white mice induced by intraperitoneal infection 4 LD50virus rift valley fever, increasing the survival of animals about 2 times (66% vs. 31% in the control). It should be noted that the General condition of the animals of the experimental group was better than control, in particular they are much better consumed food during the whole observation period, while mice in the control group already 5 days after 5 days (early death) and 10 days (end of experiment) observations. For dissection took seemingly healthy mice. The study of dead mice did not. On the 5th day it was opened on 1 animal from each group, 10 - 2 from the experimental group and 3 animals from the control group. During visual inspection of the liver of animals, it was found that the number of hemorrhagic lesions in animals of the experimental groups is smaller than in the control. In the latter case, there were more than 15-20 on every liver, and in animals of the experimental groups 1-3, and a better indicator observed in animals treated with the higher dose GSSG - 30 mg/kg (lesions not identified).

Thus, the new system tittoproject and immunomodulator GSSG has antiviral activity and increases the resistance of mice to the causative agent rift valley fever, causing these animals to lethal generalized infection in the liver and other organs. Introduction GSSG intraperitoneally in single doses of 3, 10, 30 mg/kg for 6 days in experimental LDR white mice infected with 1 -20 LD50virus, can improve the survival rates of animals by 30-60%, and also significantly (2 or more times) to increase their life expectancy. The purpose GSSG in experimental fever in the share of the latter, as evidenced by the increase in survival rates (20%) and life expectancy (2 times) infected mice.

2.2. The influence of the drug GSSG on for generalized herpetic infection in white mice

In the experiments used white randombred of male mice weighing 12-14 g, the set of the kennel "Rapolano RAMS.

For modeling herpes infection used herpes simplex virus, strain L-2 from the Museum of the research Institute of military medicine. Infected animals was intraperitoneally with inoculum, which was an emulsion brain of infected and sick newborn mice.

GSSG was administered daily, 1 time a day at a dose of 30 mg/kg during 5 days; the beginning of the introduction for 2 h before infection.

Herpes infection proceeded against the background of immunodeficiency caused by cyclophosphamide (CPA) - 1 group, hydrocortisone (HC) - group 2, irradiation (Obl)- 3 group.

The product comparison - cycloferon (single dose, 2 h before infection at a dose of 100 mg/kg).

The follow - up period was 14 days.

Results: the results of the experiment showed that GSSG has a protective effect against DNA-containing viruses, including virus p total loss of animals from the control groups (table. 4).

2.3. The influence of the drug GSSG on the course of infection caused by the virus of Venezuelan encephalomyelitis of horses (VAL) in experimental animals

In the experiments used white ainbridge mouse-males weighing 18-20 g, the set of the kennel "Rapolano RAMS. Only in the experiment 144 animals.

The pathogen: virus VAL, strain "TRINIDAD" infecting dose 1 and 2 LD50. The virus was injected subcutaneously.

Study drug: GSSG. The drug was administered intraperitoneally at doses of 3 and 30 mg/kg; dry sample was dissolved in isotonic sodium chloride so that the required dose was contained in a volume of 0.5 ml.

Scheme of administration of the drug: the drug in the dose was administered on 2 circuits and prevention (-72 h, -48 h, -24 h, 0) and extra-preventive(+2, +24, +48, +72, +96, +120 h).

Comparator drug (positive control): the interferon inducer CYCLOFERON (CP) at a dose of 50 mg/kg, was administered for 4 h before infection.

Control of virus: animals infected vaccinated material, the treatment was absent.

The combined use of drugs: in the 2 experimental groups were used combined prophylactic purpose GSSG the day after infection.

The efficacy evaluation: the difference in survival rates (%) and life expectancy (T, d) animal experimental and control groups.

The results obtained are presented in table. 5.

As follows from the obtained data, infecting dose of virus VAL in this experience was even somewhat lower than the calculated, doom 2 LD50the pathogen occurred in 50% of animals in the control group, and from 1 LD50- 33%.

In groups 1, 4 and 9 on the 3rd and 4th day after infection marked nonspecific loss of 1-2 animals, which is usually caused by either toxic drugs or injuries. Specific mortality in VAL white mice normally recorded 5 days after infection.

The product comparison - CYCLOFERON, taken in subtherapeutic dose of 50 mg/kg, at 2LD50protective effect did not possess, and when 1 LD50- protective effect was equal to 33%.

The drug GSSG when used in a dose of 30 mg/kg had an antiviral effect. In the case of the application of preventive schemes: in this case, the protective efficacy was equal to the efficiency of cycloferon (increased survival by 33%, a significant increase in prodolenie drug GSSG as the survival rate (increase in 17-30%), and the value of the index T is life expectancy (an increase of 3 times).

2.4. Antiviral activity of the drug GSSG

In the laboratory of chemotherapy Institute of influenza Ministry of health of Russia (St. Petersburg) have conducted a study on the antiviral activity GSSG against influenza a (NC 2). Antiviral activity was determined by the ability of the test drug to suppress the reproduction of influenza virus on the model experiencing fragments chorioallantoic membrane of chicken embryo (HAO).

Drugs, which caused a reduction in infectious titer in the experiment compared to control (index neutralization) of more than 2.0 lg EID50. considered active; from 1.0 to 2.0 lg EID50- moderately active and less than 1.0 lg EID50- inactive.

Preliminary studies of the toxicity of the drug GSSG showed that even at a concentration of 1 mg/0.5 ml, it did not cause damaging effects on the cells HAO. Thus, the maximum tolerated dose (MTD) 1000 mcg/0.5 ml

The results of the experiments for the study of antiviral activity of samples GSSG in relation to the model of influenza virus a/Hong Kong/1/68 (NC 2) are presented in table. 6.

As brigaut contagious virus.

Thus, the data presented justify the choice of experimental models of toxic hepatitis to study specific pharmacological activity GSSG with subsequent extrapolation of results and viral liver disease.

CONCLUSIONS

1. The new system tittoproject and immunomodulator increases the resistance of mice to the causative agent rift valley fever, causing these animals to lethal generalized infection in the liver and other organs.

2. Introduction GSSG intraperitoneally in single doses of 3, 10, 30 mg/kg for 6 days in experimental LDR white mice infected 1-20 LD50the virus can increase the survival of animals by 30-60%, and also significantly (2 or more times) to increase their life expectancy.

3. The purpose GSSG in experimental rift valley fever in white mice together with the antiviral drug ribamidil allows you to enhance the protective effect of the latter, as evidenced by increased survival rates (20%) and life expectancy (2 times) infected mice.

4. GSSG at a dose of 30 mg/kg when injected into 5 days increases ustoichivosti. Model nairoviruses infection caused by a pathogen Venezuelan encephalomyelitis of horses (VAL). identified antiviral effect of the drug GSSG. Preventive assignment scheme drug GSSG was more effective than extra-care.

6. Study of antiviral activity against influenza virus And showed that the drug GSSG has a pronounced antiviral activity (KTI= 5) and reduce the infectious activity of the virus.

Thus, the unique property GSSG to induce apoptosis mechanisms virusinfizierovannah cells and activate the proliferation and differentiation of normal cells provides high efficiency GSSG against a broad range of viral infections.

Example 3

Increased expression of the inducer of apoptosis is Fas/APO-I receptor (CD95) in virusinfizierovannah hepatocytes drug GSSG

Fas receptor (also denoted as CD95 antigen are the initial link receptor-mediated apoptotic cascade. The liver tissue is rich in these receptors and therefore apoptosis of liver cells is usually implemented through a Fas-dependent mechanism. Activation of Fas-membrane receptors is favourable course of the disease, caused by the hepatitis C virus, shows the accumulation of Fas receptor in virus-infected cells, which contributes to their programmed death and elimination, thus, infected cells from the tissue. The presence of the extracellular part of the Fas-receptor domains that are rich in reactive cysteine, determines its activation when a sudden change in the state of SH-groups in the intercellular environment. This could occur when the change in the ratio of oxidized and reduced glutathione in the treatment of patients with drugs group Glutoxim. In the present study as time and the influence of drug treatment GSSG on the expression of Fas receptor in liver biopsy specimens of these patients.

The formation of groups of patients for examination using liver biopsy was performed depending on the clinical course of the disease, the type of the virus found and used instead of standard drugs drug GSSG. Biopsy was performed in patients only with chronic hepatitis b or C. the First biopsy was performed to assess hepatic lesion tissue before treatment. Re-biopsy was performed in 3 (hepatitis b) or 6 months (hepatitis C) after the commencement of the standard course of therapy or therapy is C. The morphological study of the biopsies they were divided in accordance with the classification by: Knodel. Thus, the Protocol involved patients with moderately severe degree of inflammation in the liver, and with a moderately pronounced symptoms fibrous replacement of the parenchyma. In the blood of patients at the beginning of therapy PCR revealed from 500,000 to 1,000,000 copies/ml viral particles. All were selected 78 patients with hepatitis b and 54 patients with hepatitis C.

In addition to morphological evaluation of fibrotic processes and detection of viral particles was performed immunomorphological analysis of cells containing Fas-receptors, as well as immunochemical method quantitatively determined the content of the Fas-receptors in freshly prepared homogenate of biopsy specimens. For immunomorphological analyses used reagents and antibodies firm DAKO (DENMARK) and immunoassay was performed with a set of firm Oncogene (USA).

Samples fixed tissues from paraffin blocks prepared in the form of a slice thickness of 5 microns, which deparaffinized and dehydrated as described in the Protocol of the firm "DAKO". Monoclonal antibodies against Fas/Apo1 receptor recognize him on the surface. Antibodies were diluted in accordance with the tool is according to the attached letters. Laundered not bound peroxidase antibodies twice in 50 ml of PBS buffer for 2 minutes and then bound peroxidase primary antibody detected with a secondary antibody containing bitenova tag using a set of firm DAKO (DAKO LSAB kit k675). Bound peroxidase Biotin identify streptoavidin-peroxidase conjugate in the presence of a chromogenic substrate, such as diaminobenzidine (DUB), as described in the Protocol. The appropriate components and reagents included in the kit company DAKO. The ratio of cells expressed Fas-receptors to the rest of the cells were carried out in accordance with the Protocol.

Immunoasays Fas-antigen was performed with the lysate of cells svegevigatogo biopsies. Enzymoimmunoassay was performed by the method of "sandwich" using mouse monoclonal antibodies to Fas-squirrel man, immobilized in the wells of 96-hole tablet Oncogene (USA). Incubation of the lysate in an hour causes the binding of the Fas antigen, and subsequent washing associated Fas-antigen remains in the hole. In the washed wells were added other specific biotinylated antibodies to Fas-antigen, and after their binding to Fas-antigen wells are again washed. Next was added conjugate streptavidin with horseradish peroxidase. Streptoavidin with sewn thereto p in the hole. To the wells were added chromogenic substrate tetramethyl benzidine (TMB), which under the action of peroxidase changes from a colorless state to a bright blue colored product, which is registered spectrophotometrically. Used ready-made kits for analysis of Fas-APO-1 firm OncogeneTMResearch Products (USA).

The piece of biopsy material was added to lyse buffer in the ratio of 10: 1 and homogenized. Incubated 30 minutes on ice, shaking occasionally. Remove the cell residues by centrifugation for 5 min, 12000 rpm in appendectomy the centrifuge. Supernatant used immediately or stored at -80oC.

100 μl of the supernatant of cell lysate was made in the wells with immobilized antibodies and incubated for 1 hour at room temperature. Washed 3 times in wash buffer. Was added to each well 100 ál of detection antibody and incubated for another hour at room temperature. Washed 3 times in wash buffer. Bred streptoavidin-peroxidase conjugate 1: 400 and add 100 ál to each well. Incubated for 30 minutes at room temperature. Washed the wells wash buffer. Added 100 μl of a solution of a chromogenic substrate for 30 minutes. Added 100 ál of stop p the immunoassay at a wavelength of 450/540 nm. The measurement was performed no later than 30 minutes after adding the stop solution. The results were compared with a control sample, is applied in the set. It has been shown that in patients with hepatitis b and patients with hepatitis C, a large percentage of cells enriched in Fas-receptors (table. 7, 8).

Determining the content of the Fas-receptor-prepared homogenate part biotopo also testified to the accumulation of Fas receptor in liver tissue after drug treatment GSSG as the hepatitis b and especially when hepatitis C (table. 9). So in the lysate supernatant of homogenate of liver cells from viewsat biopsies content Fas was less than 2 u/mg when compared with Fas standards.

The presence of viral infection resulted in a significant increase in the content of Fas-receptors. When you re-analysis 3 (hepatitis b) or 6 (HCV) months against the standard management of patients content Fas-receptors remained at the same level. On the contrary, when therapy with GSSG content Fas-receptors was significantly increased.

The implementation of Fas-dependent apoptosis is a main pathway of programmed cell death of hepatocytes. Given the presence of the extracellular part of the Fas-reciprical and thus, activation of Fas receptors due to the wave-like changes in the ratio of reduced and oxidized SH-groups in the pool of extracellular glutathione. Moreover, the intracellular cascade of caspases, implementing Fas-dependent signals cell death, which the cysteine proteases, can also be triggered by drug GSSG.

Conclusion: activation of the Fas-dependent apoptosis helps cleanse fabric from virus-infected cells. However, due to Wieruszewski synthesis of inhibitors of apoptosis Fas-induced processes are implemented in full and then virusinfection cells avoid apoptosis. The increase in the concentration and activity of the Fas receptor with drug GSSG provides a more complete elimination of virus-infected cells. These results correlate with a decrease or absence of hepatitis C virus in blood flow after treatment with the drug GSSG.

Example 4

The study of inhibition of ATP-asna/helicase activity of hepatitis C virus GSSG, GSSG-IMP and GSSG-UMP in the culture of normal and virusinfizierovannah cells

Evaluated the ability of the compounds of oxidized glutathione with inosine (GSSG-I), inosinmonofosfata (GSSG-IMP) and urediniospore actulaly incubation of these substances with nuclear lysate of normal lymphocytes, obtained from peripheral blood of healthy donors or homogenate NER-2 cells infected with hepatitis C.

Venous blood from healthy donors was collected in heparinised tubes, tested for the absence of endotoxin. Mononuclear fraction of peripheral blood leukocytes were obtained by centrifugation in a density gradient ficoll-PAC (Pharmacia). The cell concentration was brought to 2106cells in 1 ml complete culture medium (RPMI 1640) containing 20 mm HEPES, 2 mm glutamine, 50 μg/ml gentamicin and 10% fetal calf serum. Cell viability was assessed in test with Trifanova blue. Then the cell suspension was again centrifuged to remove residual Pichola with the environment. The precipitate was suspensively in 1 ml of physiological solution and subjected to lysis with Nonidet 40 for receiving the cell nuclei as described (Maniatis, etc). Then spent the nuclei lysis and lysate were analyzed by changing ATF-asna/helicase activity in the presence of investigated compounds.

To 0.2 ml of the lysate of nuclei was added 0.1 ml, annealed with R32-labeled complementary oligonucleotide (long 42 nucleotides), single-stranded DNA phage M13 mp10. Pre-selected concentration of DNA phage, allowing the Wiik phage, and almost complete separation of the oligonucleotide from the DNA single-stranded form of the M13 phage.

In the incubation mixture also was injected with 0.1 ml of Tris-Hcl buffer solution containing ATP and Mg++. Next, 0.1 ml of physiological NaCl solution or 0.1 ml of physiological solution with the addition of the tested composite to a final concentration of 10, 50 and 100 µg/ml.

After incubation for 30 minutes, 10 μl of the sample was subjected to vertical electrophoresis in 8% polyacrylamide gel. There was division on the high-molecular fraction, representing a hybrid of R32-labeled oligonucleotide associated with DNA phage, and low molecular weight fraction is released from the hybrid under the action of helicase oligonucleotide. The densitometry of the autoradiographs revealed changes in the ratio of bound and released under the action of helicase R32-labeled oligonucleotide.

When evaluating helicase activity in the lysate culture, infected with hepatitis C virus, used the same technique, but instead of lysate used the nuclei lysate of cells to evaluate the contribution of virusinduced proteins in the cytoplasm.

The results are shown in table. 10 and 11. As can be seen from the table. 1,EP donor lymphocytes, whereas at concentrations of 50 and 100 μg/ml significantly suppressed helicase activity of all three tested compounds. GSSG is UMP among them is the greatest inhibition of ATP-asna/helicase activity.

The lysate virusinfizierovannah cells helicina activity above, as unbraiding 90% of double-stranded hybrids, single-stranded DNA of M13 domain with the oligonucleotide was achieved at a concentration of hybrid 20 ISC/ml compared with 5 PCG/ml lysate nuclei of donor lymphocytes. The effect of the studied compounds is also apparent when these higher levels helicase activity. Significant inhibition helicase activity was observed when the concentrations of these substances as 50 and 100 µg/ml, but at a concentration of 100 μg/ml inhibition of ATP-aznoe/helicase activity was expressed to a greater extent. The maximum inhibitory effect on ATP-asnow/helicase activity obtained using connection GSSG-UMP.

Discussion and conclusion:

High helicina activity in cells infected With HCV, compared with donor lymphocytes may be associated not only with proliferative activity and expression of 3rd nonstructural protein of hepatitis C virus, which is the Norsky lymphocytes, but in the lysate virusinfizierovannah cells suggests that the compounds oxidized glutathione with nucleosides (GSSG-I) or nucleotides (GSSG-IMP, GSSG-UMP) suppresses helicase activity nonstructural protein NS3 of hepatitis C virus, which prevents the synthesis virusspecific RNA in infected cells.

Example 5

Treatment of acute viral hepatitis In long lasting drug GSSG

Surname, name, patronymic of the patient: Dr. centuries

Gender: male

Age: 32

History 661

Diagnosis: Acute viral hepatitis b, phase replication (HBV PCR+), a protracted course, a moderately severe degree of activity.

Complaints during the inspection: weakness, heaviness in the right hypochondrium, nausea, sweating.

Medical history: the Sick with 01.10.98 when there are sharp pains in the small joints of the hand, and then pain and redness, swelling of joints. With 09.10.98 - dark urine. Came for treatment in the clinic of viral infections. After the treatment (see below) remains high cytolytic syndrome.

Pre-treatment: a course of detoxification, antispasmodic, antibiotic (kanamycin 0.52 times a day/m is nothin with 29.10.98 on 21.11.98:

0 day

Intramuscularly "GSSG" 1% - 1 ml daily

1-14 day

Intravenous "GSSG" 1% - 1 ml

15-17-19 day

Intravenous "GSSG" 3% - 1 ml

20-24 day

Intramuscularly "GSSG" 1% - 1 ml

The patient's condition after treatment: a Significant improvement, which is expressed in the absence of weakness, nausea, heaviness in temper hypochondrium. The results of the laboratory analyses - see table. 12, 13 and 14.

Conclusion: the course of drug therapy "GSSG" gave positive dynamics of key indicators of the patient's condition, which is expressed in the normalization of biochemical parameters, the cessation of HBV replication, persistence, Hbs Ag, improvement of General condition. Watchful waiting (after 1 and 3 months after end of treatment) showed stabilization of the figures and helped to treat the condition as early convalescence.

Example 6

Treatment of acute viral hepatitis, severe, drug GSSG

Surname, name, patronymic of the patient: A. J. C.

Gender: female

Age: 18

History 6006

Diagnosis: Acute viral hepatitis b, phase replication (HBV PCR+), severe course.

Medical history: the Sick with 12.03.99 when there are sharp pains in the small joints of the hand, and then pain and redness, swelling of joints. With 16.09.99 - dark urine. Received for treatment in 26 Department of the hospital. S. P. Botkin. After the treatment (see below) remains high cytolytic syndrome.

Pre-treatment: a course of massive detoxifying, antispasmodic, antibiotic (gentamicin 40 mg 2 times a day/m N 7), anti-inflammatory (indomethacin in table 1. 3 times per day) therapy.

The course of drug therapy GSSG with 08.04.99 on 02.05.99:

0 day

Intramuscularly "GSSG" 1% - 1 ml

1-14 day

Intravenous "GSSG" 1% - 1 ml

15-17-19 day

Intravenous "GSSG" 3% - 1 ml

20-24 day

Intramuscularly "GSSG" 1% - 1 ml

The patient's condition after treatment: a Significant improvement, which is expressed in the absence of weakness, nausea, heaviness in the right hypochondrium. The results of the laboratory analyses - see table. 15, 16 and 17.

Conclusion: the course of drug therapy "GSSG" gave positive dynamics of objective indicators of the condition of the patient, namely:

a) but the e General condition.

Watchful waiting (1 month after end of treatment) showed stabilization of the figures and helped to treat the condition as early convalescence.

Example 7

Treatment of chronic viral hepatitis In drug GSSG

Surname, name, patronymic of the patient: K. M. D.

Gender: female

Age: 41 year

Diagnosis: Chronic viral hepatitis b (HbsAg+) phase replication (HBV PCR+), moderately severe degree of activity. Comorbidities: chronic cholecystitis, chronic pancreatitis. Obesity class II).

Liver biopsy (background): beam and lobular structure of the liver of the saved. Portal tracts expanded by proliferation of connective tissue with the formation of Porto-portal Sept. In the periportal connective tissue moderate lymph macrophage infiltration (3 points). The inner edge of the plate partially destroyed, step necrosis (2 points). The segments are defined by focal necrosis (1 point). Vnutridolkovom and precentral.net lymphoid infiltration. Vacuolization of the cytoplasm of hepatocytes with degeneration and polymorphism their nuclei. Determined by Matt vitreous hepatocytes. Conclusion: hronicheskimi after the end of treatment): beam and lobular structure of the liver of the saved. Portal tracts are slightly extended due to proliferation of connective tissue. In the periportal connective tissue weak lymph macrophage infiltration (1 point). The inner edge of the plate saved. Minor vnutridolkovom and precentral.net lymphoid infiltration. Conclusion: chronic hepatitis with minimal activity (YOKE Cnodes = 1) and mild fibrosis.

Complaints during the inspection: Weakness, inability to perform normal operation.

Medical history: was at the hospital from 9 to 30.04.97 diagnosed with chronic viral hepatitis C. the Disease was very mild cytolytic syndrome. A course of detoxification therapy. During the treatment, the level of ALT decreased from 620 to 365 u/l, bilirubin level was at the time of discharge is normal.

Pre-treatment: In connection with the replicative activity of the virus (HBV PCR+) were prescribed course of acyclovir with 25.04.97 within 21 days, and then cycloferon with 26.05.97. During the treatment, the ALT levels ranged from 421 to 168 E/L. the Activity of the virus was suspended for 1 month, then again intensified with 15.10.97,

The course of drug therapy "GSSG" with 15.10.97:

0 day

venous "GSSG" 3% - 1 ml

31-90 day

"GSSG" 3% - 1 ml three times per week

The patient's condition after treatment: for the First 7 months of the disease the level of biochemical parameters of blood returned to normal (ALT - 33 u/l, bilirubin - 9.0 µmol/l). The patient feels well, no weakness, appeared normal exercise tolerance. Laboratory values - see table. 18, 19, 20 and Fig. 30.

Conclusion: the course of drug therapy "GSSG provided:

- termination of HBV replication;

- normalization of biochemical parameters;

- normalization of immunological and cytokine status;

- improvement of morphological indicators (decrease index Knodel and fibrosis).

Thus, the drug "GSSG" is an effective medicine for the treatment of chronic viral hepatitis C.

Example 8

Treatment of chronic viral hepatitis, cirrhotic stage, drug GSSG

Surname, name, patronymic of the patient: A. Century. And.

Gender: male

Age: 59 years

Diagnosis: Chronic viral hepatitis, cirrhotic stage (PCR HBV+), ascites, portal hypertension.

MS: for the First time was in the clinic about HUGW, cirrhotic stage, ascites in 1995. Subsequently was treated again in April 1997. This deterioration since the beginning of October: increased shortness of breath and dragging pain in the left hypochondrium and epigastrium. Taking furosemide 2 times a week 1 tablet. Admission: state of moderate severity, pale skin, language, bright, wet, pulse 110 beats per minute, BP 140/90, BH 20 DV/min on the Left lower corner of the scapula dullness of percussion tones, breath held. The abdomen is enlarged (the volume of the abdomen 113 cm) due to ascites. On the shins no edema. He received a course of detoxification, symptomatic treatment with antibiotics. Conducted infusion therapy with diuretic drugs, proteins.

The course of drug therapy GSSG:

1 course with 27.11.97 on 20.12.97 1%/m 3 times a week

2 course 12.01.98 on 06.02.98 1%/m 3 times a week

3 course 11.02.98 on 14.05.98 1%/m 3 times a week

4 course 06.06.98 on 10.07.98 1%/m 3 times a week.

The patient's condition after 1 treatment: a satisfactory Condition. Notes a significant improvement, celebrates the courage, walks. Ascites decreased (the volume of the abdomen 89 cm), adequate diuresis, no pain in the left hypochondrium. Clinical and laboratory data are presented in pozvolili to maintain good health, and stable picture of the clinical and laboratory data (table. 21).

Conclusion: therapy course GSSG provided:

positive correction limfotsitov and thrombocytopenia;

- termination of replication of HCV;

- lack of cytolytic syndrome (normalization of bilirubin concentration and ALT activity);

- reduction of ascites;

- improving the quality of life: improvement of health and its stabilization during 8 months of follow-up, which translates into increased energy, vitality, desire to actively pursue further treatment.

Example 9

Treatment of chronic viral hepatitis, cirrhotic stage, drug GSSG

Surname, name, patronymic of the patient: T. I. N.

Gender: male

Age: 48 years old

Diagnosis:

Primary: Chronic viral hepatitis b (HbsAg+), phase integration (PCR HBV), cirrhotic stage

Companion: Status post cholecystectomy

Complaints at the beginning of treatment: Fatigue, insomnia

Medical history: the First identified chronic hepatitis b in 1999 when the survey about surgical treatment of cholecystitis. After completed in January 2000 cholecystectomy, started therapy Preilu 12 weeks.

Ultrasound: Background from 18.04.00 1344. The liver is normal in size, structure, homogeneous, fine-grained, contours equal, precise vessels visible but the periphery, the structure is sealed. Portal vein 13 mm, v. mesenterica superior 14 mm, choledoch 7 mm, the spleen is normal in size, structure hypoechoic, contours equal, precise. Gall bladder removed. Pancreas: head 22 mm, the body of 16 mm, the tail 20 mm, contours equal, structure homogeneous, fine-grained, echo is equal to the liver. Kidney is normal in size, bobbidee form. concretions no. Conclusion: diffuse changes of a liver.

The patient's condition after treatment: considerable improvement and the ability to perform their professional duties in full force. Completed the treatment improved clinical and laboratory findings and the patient's quality of life (table. 22, 23 and 24).

Conclusion: the course of drug therapy GSSG provided:

- correction of thrombocytopenia;

- termination of cytolytic syndrome (normalization of bilirubin concentration and ALT activity);

- stimulation of cellular immunity (increased levels of CD3+, CD4+, CD16/56);

- improvement of the portal circulation according to doesny hepatitis b drug GSSG

Surname, name, patronymic of the patient: z centuries

Gender: male

Age: 18

History: 1043

Diagnosis: Chronic viral hepatitis C, phase replication (HCV PCR+), moderate level of activity; chronic viral hepatitis b, phase integration (PCR HBV), drug intoxication, drug addiction.

Liver biopsy (background): beam and lobular structure of the liver of the saved. Portal tracts are slightly extended due to proliferation of connective tissue. In the periportal connective tissue moderate lymph macrophage infiltration (3 points). The inner edge of the plate saved. Some segments are defined calf Councilmen (1 point). Vnutridolkovom and pericentral lymphoid infiltration. Vacuolization of the cytoplasm and some nuclei of the hepatocytes. Conclusion: chronic hepatitis with minimal activity (YOKE Cnodes = 4) and mild fibrosis.

Liver biopsy (12 months after treatment): beam and lobular structure of the liver of the saved. Portal tracts are not changed. In the periportal connective tissue weak lymph macrophage infiltration (1 point). The inner edge of the plate saved. In some slices of opredelitelei and some nuclei of the hepatocytes. Conclusion: chronic hepatitis with minimal activity (YOKE Cnodes = 2).

Complaints during the inspection: Weakness, severe pain in the right hypochondrium, knee joints, spine, joints of the hand.

Medical history: have Noticed pain in the joints of the knees, spine in early August 1997. The examination of blood was found increased levels of bilirubin to 34.0 mmol/l and ALT - 86 E/l for stationary examination 15.08.97 were identified anti-HCV IgG and replicative activity of the virus of hepatitis C.

The history of life: to Apply drugs began to apply from the age of 14. Intravenous their introduction spent 17 years. At the time of inspection dose of heroin is about 2 grams per day.

Previous treatment: Not been conducted.

The rate of drug GSSG with 15.08.97:

0 day

Intramuscularly "GSSG" 3% - 1 ml

1-14 day

Intravenous "GSSG" 3% - 1 ml

15-30 day

Intravenous "GSSG" 3% - 1 ml

The course is conducted over 3 months.

The patient's condition after treatment: a satisfactory Condition. Notes a significant decrease in weakness, no pain in the right hypochondrium, in the joints. According to the patient, leaving the state narcotics the indicators and the absence of replicative activity of the virus (see table. 25, 26, 27, and Fig. 31).

Conclusion: the course of drug therapy GSSG provided a positive trend, which is expressed in the normalization of biochemical, serological indicators, and termination of replication of HCV. Immunological indicators and data cytokine status correlate with the reduction of infection and the absence of virus replication. In the study of peripheral blood lymphocytes of the patient by flow cytometry using monoclonal antibodies to FasAg (CD95+) after treatment shows an increase in CD95+cells, indicating that the activation process of programmed cell death virusinfizierovannah cells. When observed in the dynamics of one month and three months after treatment has stabilized in this state. When repeat biopsies at 12 months after treatment there has been a decrease of Knodes and no fibrosis.

Concomitant drug intoxication and withdrawal symptoms when use GSSG were stopped earlier and were smaller for the patient's suffering.

Thus, the course of drug treatment GSSG of chronic hepatitis C with rap is that the centralization of biochemical parameters of blood;

- normalization of hematological parameters;

- the absence of replicative activity of the virus;

- improvement of morphological indicators of hepatic parenchyma;

- normalization of immunological parameters and cytokine status;

the induction of apoptosis virusinfizierovannah cells;

stable therapeutic effect.

Example 11

Treatment of chronic hepatitis C in liver cirrhosis drug GSSG

Surname, name, patronymic of the patient: G. N. Century

Gender: female

Age: 48 years old

Diagnosis: Cirrhosis (child C), chronic viral hepatitis C.

Ascitic syndrome, varicose veins of the esophagus and cardia of the stomach, stage II.

Complaints at the beginning of treatment:

Weakness, insomnia, arthralgia, skin itching, bleeding gums

Medical history: Chronic hepatitis C in cirrhotic stage first identified in 1993 when a random survey. Ascites began to grow in 1999 before therapy GSSG.

The course of drug therapy GSSG.

1% solution 3 times per week for 12 weeks.

The patient's condition after treatment: a satisfactory Condition. Planet who completed the treatment improved clinical and laboratory findings and the patient's quality of life (see table. 28, 29 and 30).

Conclusion: therapy course GSSG provided:

- minimum display ascitic syndrome;

- improvement of the portal circulation according to dopplerography;

- the absence of Doppler indices of portal hypertension (no spleno-renal anastomosis);

- almost complete normalization of the content of lymphocytes and platelets;

- improving the quality of life.

Example 12

therapeutic effects of the drug GSSG in a patient with AIDS

Patient: M. C. M.

Gender: male

Age: 50 years

The primary diagnosis: AIDS. Classification CDC Atlanta: C3.

Diagnosis companion: Kaposi's Sarcoma. Tuberculosis of intrathoracic lymph nodes, cytomegalovirus infection, candidiasis of the oral mucosa, herpes simplex, eczema, neurosyphilis.

HIV infection diagnosed in 1994, the Immunoblotting results in R24, R17, P25, P18, P55, R40, R, R, P34, gp120, gp160.

Initial condition: Heavy, temperature 38.5oWith persisting more than one month, the Karnofsky index - 50, the progressive deterioration of immunological parameters. Sharp leukopenia (1,81012and lymphopenia the drug "GSSG (D-form)":

"GSSG" 3% - 1 ml 3 times a week intramuscularly 12 weeks.

therapeutic effect of month of treatment:

- body temperature of 37.5oC;

- improving the quality of life (Karnofsky index 70;

- there is a tendency to normalization of immunological parameters (the number of lymphocytes increased from 570 to 832, the ratio of CD4+/CD8+increased from 0.71 to 0.84);

- viral load 89000 copies/ml

therapeutic effect after 2 months of treatment:

- body temperature 36,9oC;

- improving the quality of life (Karnofsky index 75;

- the trend towards normalization of immunological parameters (number of lymphocytes 736, the ratio of CD4+/CD8+- 0,87; CD4+- 199; CD8+- 228);

- viral load of 56,000 copies/ml

therapeutic effect at the end of treatment:

- body temperature 36.6oC;

- improving the quality of life (Karnofsky index 90;

- the trend towards normalization of immunological parameters (number of lymphocytes 1350, the ratio of CD4+/CD8+- 0,87; CD4+- 527; CD8+- 608);

- viral load of 10,000 copies/ml

Laboratory values - see table. 31 and 32.

Example 13

therapeutic effect of the n-monophosphate)

Patient: I. O. I.

Gender: female

Age: 40 years

The diagnosis of primary HIV infection in the AIDS stage. Classification CDC Atlanta-C2. Chronic recurrent herpes simplex. Encephalopathy. Chronic viral hepatitis b (HbsAg+) in the stage of integration.

Upon admission to the clinic of infectious diseases 12.03.99 (division of AIDS) complains of weakness, fatigue, increased sweating, especially at night, weight loss, memory loss, pain in the wrist joints, in the popliteal fossa to the left.

Objectively: the patient is in satisfactory Condition. The power is reduced. Pale skin. Cervical and axillary lymph nodes up to 1 cm in diameter. Mucous membranes of the mouth pale. Over light percussion sound is not muted. Auscultation - hard breathing, scattered dry rales. The abdomen is soft, sensitive in the epigastrium, in the right iliac region is defined by the small seal. Notes acrocyanosis bones of the hands. PA lips visible scars from multiple herpetic rash. The Karnofsky Index Of 75.

The course of drug treatment " Zn2-GSSG-IMP" with 26.03.99:

"Zn2-GSSG-IMP" 3% - 1 ml 3 times a week intramuscularly to 8 weeks.

After a course of drug treatment "Zn2-GSSG-IMP": no Complaints. The condition is satisfactory: disappeared sweating, become more energetic. The skin became less pale. Gained weight 2,5 kg Level of lymphocytes in the blood 2295, CD4+- 574, CD8+- 597. The Karnofsky Index 90.

The specific dynamics of immunological indexes and hemogram reflected in the table. 33 and 34.

Conclusions

The course of drug treatment "Zn2-GSSG-IMP" in monotherapy provided:

- a reduction in viral load;

- improving the quality of life of the patient;

- improvement of immunological indices;

- stabilization of the hematological parameters.

Example 14

Therapeutic efficacy GSSG when chlamydia infection

Patient: C. I. M. , 29 years.

The diagnosis of Urogenital chlamydia flowing with systemic manifestations. Chronic vesiculopustular. Chronic synovitis of the right knee joint, chronic blepharoconjunctivitis.

Anamnesis: the Patient within 8.5 years suffer from chronic prostatitis. Was treated 4 times with Ei on the background immunotherapy (Cycloferon, Viferon). In 1999, the last time was treated in the clinic of urology of St. Petersburg honey. University, but after 3 months. developed disease recurrence in acute exacerbation of chronic prostatitis and synovitis of the right knee joint; worried about the pain in the eyes, photophobia, discharge from the eyes after sleep. On this occasion, was treated by an ophthalmologist (ointment tetracycline, erythromycin), but the positive effect was not observed. From March 1992 received: bicillin, kanamycin, doxycycline, tetracycline, trichopol, tinidazole, metatsiklina, Sumamed, cifran, zanocin, abaktal, ruled, cycloferon, Viferon.

In September 2000, the patient on the recommendation of the military specialists of the clinic of traumatology and orthopedics of the SCA was sent for consultation to the clinic of infectious diseases, military medical Academy, where it was carried out an in-depth examination and comprehensive therapy using drug GSSG + antibiotics. Etiotropic therapy was carried out after determining the antibiotic susceptibility of chlamydia allocated to culture cells from semen and synovial fluid of the joint.

Turning: satisfactory condition, complaints about General weakness, malaise, long (more than 1.5 months. ) low-grade fever. intermittent the Islands in the joint.

Secret of the prostate - symptoms of chronic prostatitis. When the puncture of the right knee joint received 8 ml of turbid synovial fluid. After the puncture the swelling has decreased slightly.

Direct immunofluorescence method (PIFM) in the prostate fluid and synovial fluid found reticular and elementary bodies of C. Trachomatis in a considerable amount. The antibody titer in the serum to C. trachomatis (NIFM indirect immunofluorescence method) is equal to 1: 128 in synovial fluid - 1: 64. The culture of the pathogen was isolated in pure culture cells from ejaculate and synovial fluid, susceptibility to antibiotics.

Dynamics of basic laboratory parameters are presented in table. 35.

Conclusion: the use of the drug GSSG according to the scheme: 1 ml of 3% R-RA 1 2 times a day for 10 days (5 injections) prior antibiotic therapy and likewise in the course of antibiotic therapy (8 days - maxaquin and 8 days - vilprafen) - provided a stable clinical and bacteriological effect. Readjustment of the organism from chlamydia installed on the main indicators directly after treatment, and according to PCR after 3 months after therapy. GSSG contributed).

Example 15

Therapeutic efficacy GSSG when mixed infection: herpes and chlamydia

Patient: Mr. M. M

The Diagnosis Of Chlamydia. Genital herpes. Chronic pyelonephritis

History: In the course of 5 years suffer from chronic pyelonephritis and chlamydial herpes infection. Treated with all kinds of antibiotics (fluoroquinolones, macrolides, tetracyclines), including accompanied with drugs type Roferon, cycloferon. The application of cold has caused toxic manifestations in the form of fever (t 40oC), alopecia, skin rash. In 1996, was treated in the urology Department of the Central Medical unit 122 regarding the exacerbation of chronic pyelonephritis.

For 5 years of continuous treatment, the titer of antibodies to chlamydia specific antibody in the sample was reduced to 64. One month after the end of each treatment was increased above 150.

From December 1993 to August 1997 he received the following drugs:

Trichopol, Tinidazole, Bicillin, Timogen, Sumamed, Metatsiklina, Dalacin, Marvelon, Doxycycline, Cifran, Zanocin, Macropen, Clotrimazole, Reaferon, Abaktal, Rovamycin, Tarivid, Ruled.

In April 1999, the patient was referred for treatment at the café the parathas GSSG in combination with antibiotic therapy.

The state of turning satisfactory, complaints of weakness, recurrent pain in the knee joints and the lumbar region, highlighting whiter.

In urine weak leukocyturia. In the blood are detected autoantibodies to the tissues of the kidneys in titer of 1: 4 (Reaction of complement fixation "cold" by C. I. Ioffe and K. M. Rosenthal).

Dynamics of peripheral blood are presented in table. 36.

Treatment Protocol:

2 courses of antibiotic therapy (doxycycline 0.1 g 2 times a day for 10 days 3-12 days of treatment; klacid 0.25 to 2 times a day for 10 days 21-30 days of treatment);

- drug GSSG scheme (1-30 days of treatment).

After a month of treatment: good Condition. No complains. The blood and urine in norm.

Conclusion: the use of the drug GSSG provided:

- clinical recovery of the patient;

- absence of signs of chlamydia and herpes on laboratory data (bacteriological analysis, PCR, serology);

- the absence of antibodies to the tissues of the kidneys, the normalization of indicators of urine.

Example 16

therapeutic effects of the drug Li2-GSSG-IMP) in the TB patient'or is tratively tuberculosis of the upper lobe of the left lung in the phase of decay and contamination, Bq(+).

The concomitant diagnosis: Chronic bronchitis in acute phase.

History: Tuberculosis of the lungs revealed in prison in may 1998, the Treatment in the prison hospital from may to August 1998 without effect, the process has progressed. After the liberation in August 1998 continued treatment in the tuberculosis hospital in St. Petersburg. However, the improvements could not be achieved, and in October 1998, he survived a massive smear-positive increased cavity decay in the lung tissue. Set the resistance of tubercle bacilli to streptomycin and isoniazid.

Initial state: moderate, evening temperature 37.5oWith, night sweats, weakness, cough with discharge of purulent sputum, Karnofsky index - 50, the progressive deterioration of immunological parameters. Leukocytopenia, lymphocytopenia, monocytosis, stab shift of neutrophils. Sputum Bq (+) by microscopy to 100 in the field of view. Radiographically in the upper lobe of the left lung - infiltration with the cavity decay 4x3 cm and foci of dropouts in the lower lobe of the left lung.

The course of drug treatment "Li2-GSSG-IMP" as support of anti-TB chemotherapy (isoniazid, ri is the course duration is 3 months.

therapeutic effect of month of treatment:

- normalization of body temperature;

- the disappearance of night sweats;

- improving the quality of life (Karnofsky index 70;

- the patient has gained weight 4 kg;

- improvement of hematological parameters, there is a tendency to increase the level of IL-12, normalization ratio Th1/Th2;

- decreased the bacterial excretion (Bq+ 2-4 in the field of view by microscopy, sputum acquired severe character.

therapeutic effect after 2 months of treatment:

- body temperature of 36.7oC;

- improving the quality of life (Karnofsky index 75;

- the trend towards normalization of immunological indices;

- smear conversion (BC-by microscopy).

therapeutic effect at the end of treatment:

- body temperature 36,6oC;

- improving the quality of life (Karnofsky index 90;

- normalization of immunological parameters;

- the absence of bacteria (three-BK-flotation);

- radiographically: closing disintegration cavity in the upper lobe of the left lung with the outcome in a linear scar (see Fig. 31 and 32).

Change the main laboratory parameters pringaroni therapy within 3.5 months provided:

- smear conversion;

- healing disintegration cavity in the lung tissue;

overcoming drug resistance of Mycobacterium tuberculosis.

These effects were not achieved prior conventional chemotherapy for 6 months of treatment.

Example 17

Hepatoprotective efficacy

Experimental investigation of hepatoprotective activity of the drug GSSG

The study of hepatoprotective activity of the drug GSSG conducted on available and replicable models of toxic hepatitis, since it is known that the mechanisms of hepatotoxicity - inflammation, cytolysis and cholestasis - generic and are not specific regardless of the agent inducing liver damage. Were used for comparison is known hepatoprotectors "Essentiale" (Essentiale, Rhone-Poulenk Rorer) and "Legalon" (Legalon, Madaus).

When modeling toxic hepatitis was used dichloroethane and acetaminophen. Both compounds were injected into the stomach of rats-males standard mass (160-170 g) through the metal atraumatic probe at doses of 500 and 400 mg/kg, respectively, 1 time a day for 4 days in a mixture of olive oil (1: 1). In addition, used combined the s animals on morphological picture of the liver confirmed the presence of toxic hepatitis. Since that time, over 10 days experimental animals were administered 1 time per day GSSG (5 mg/kg, I/m) and Comparators: Essentiale-ampoules (1 ml/kg into the tail vein) and Legalon (silymarin) (100 mg/kg/W).

The effectiveness of treatment was assessed by clinical picture, the dynamics of body weight, relative liver weight, the content of bilirubin, transaminase activity, phosphatase, the level of ceruloplasmin, total protein, serum lipids, glycogen content, glutathione, SH-groups of cytochromes in the liver, load the samples (geksenalovy test bromsulphalein test) and histological picture of the liver.

It is established that the dependence on the type of toxicant, the death of experimental animals to the 20th day of the experiment ranged from 40% (in the group inoculated dichloroethane) to 80% (in the group of animals subjected to combined effects of dichloroethane and acetaminophen) (Fig. 34, 35 and 36). The most pronounced liver damage was observed in the combined toxicity of two of the above chemical agents, which is confirmed by changes in the biochemical indices of the functional state of hepatocytes: the increase of transaminase activity, phosphatase, lactate dehydrogenase, decreased content with what azmina, significant slowing excretion bromsulphalein.

The presence of toxic hepatitis was confirmed by morphological studies of liver tissue.

In animals, dead or attenuirovannogo after 1 day after oral administration of dichloroethane, there were signs of acute toxic hepatitis. Microscopic examination revealed: the cytoplasm of hepatocytes densely filled with small and large drops of fat. Fatty degeneration of the liver were of diffuse nature, was observed vacuolization of the cytoplasm of hepatocytes, swelling of the cell phone

A similar pattern was observed with the introduction of acetaminophen. In the case of combined lesions of the morphological picture of the liver biopsy specimens were more pronounced and total character. In addition to the above changes in the liver parenchyma was observed foci of lobular colliquation necrosis.

When using the combined model intoxication of animals in the liver more significantly decreased glycogen stores, reduced glutathione levels detoxifying cytochrome. The liver lesion was characterized by the reduction of its functional activity in a reduction of the decomposition rate geksenala and excretion bromal is S="ptx2">

Drug use GSSG has greatly improved the General condition of the animals, prevented their death and has a positive effect on morphometric, biochemical and functional indicators reflecting the state of the metabolism of the liver tissue.

The drug GSSG provided 100% survival rate of experimental animals at 80% loss in control; 45% mortality in the group treated with legalon, and 30% in the treatment of Essentiale (Fig. 36).

In the study of biochemical parameters were determined explicitly reliable signs of liver problems: violation of the protein-synthesizing and lipidcontaining functions, activation of cytolytic syndrome and cholestasis in the formation of toxic hepatitis when combined with the influence on the organism of the above toxicants - dichloroethane and acetaminophen. therapeutic use of the drug GSSG contributed to the restoration of the main functions of the liver and normalizing all major indicators of toxic liver damage (see tab. 38, 39).

The indicators that are directly the state of the metabolism of the liver (glycogen, the level of glutathione, the activity of microsomal the new values (see table. 40).

Thus, the presented results suggest that the drug GSSG is effective hepatoprotector. During the course of the 10-day application in rats at a dose of 5 mg/kg of the drug exerted a pronounced therapeutic effect when combined liver dichloroethane and acetaminophen, normalizing negative changes in biochemical status and morphological parameters of the liver. The medical use of the drug GSSG provided 100% survival rate of experimental animals at 80% loss in control; 45% of the deaths of the animals treated with legalon, and 30% mortality on the background of the introduction of Essentiale (see tab. 38, 39 and 40).

Example 18

Therapeutic efficacy GSSG in experimental toxic liver cirrhosis

In the experiments used a nonlinear white rats-males weighing 180-240 g, the set of the kennel "Rapolano RAMS, for a total of 60 animals.

To obtain experimental cirrhosis of the liver in albino rats applied method Jezequel, A. M. et al. (1989) [27] , according to which the animals were injected intraperitoneally 1% solution dimethylnitrosamine (DMNA) in a dose of 1.0 ml/kg for 3 consecutive days, followed by 4-bottom of the rose liver was enough to hold 4 cycle injection.

For histological studies in animals after attanasio under General anesthesia was dissected samples of liver tissue from the Central and right lateral lobes. Pieces of liver were fixed with a mixture of formalin, alcohol and acetic acid. Prepared paraffin sections 4 µm thick, which were stained with haematoxylin-eosin and van Gison.

The purpose of objectification assess the impact of the studied drugs on the development of connective tissue in the liver in experimental toxic injury of the DMNA conducted measuring the area occupied by connective tissue, within 5-7 liver slices 6 slices of liver. Morphometrics were subjected to drugs, painted by van Gison, in which collagen fibers were dyed red. Using computer processing of the scanned image slice of the liver with increasing h subjected to binarization color emitting red collagen fibers. The number of pixels forming the selected objects, expected relative area occupied in the liver tissue developed collagen (connective tissue).

The measurement results were subjected to statistical analysis. The significance of differences of average samples assests rowdily on drugs with "blind" marking, reducing the risk of aggravate results of the experiment.

The presence of the pathological process and the efficacy was assessed by clinical signs (weight of animals, eating food, appearance, presence of ascites, motility, death), and pathomorphological signs at autopsy of animals and subsequent histological study of the liver drugs.

After the formation of the pathological process, i.e. after 4 weeks. after the beginning of the introduction of DMNA, all animals were randomly divided into 4 groups of 12 animals. Animals of group 1 received no treatment, the animals of group 2 - received saline, 3 - GSSG, 4 - product comparison - Heptral. Group 5 (12 animals) was intact animals of the same population for morphometric studies.

Each group of animals was divided into two subgroups, one of them the drugs were injected for 3 weeks, after which assessed the effectiveness of the morphological method; animals of the second subgroup was treated for 6 weeks. The drugs were injected through the day intramuscularly in the thigh muscle.

The results obtained indicate the following.

The first experimental group (12 rats) amounted to individuals, no recip is the 3-4 weeks they were sedentary, bad eating food was dull and matted coat. The morphological and histological study after 3 weeks after stopping the introduction of DMNA (6 animals), these individuals noted the presence of ascites and signs of portal hypertension. The study of drugs, painted by van Gison, allowed to determine the maturation of the connective tissue in saptah which was acquired regular structure. Glimpses of Central veins, located in the nodes of cept, were often occluded and replaced by connective tissue. Collateral circulation was carried out at the advanced modified sine concluded in an orderly regular fiber backbone Sept. Liver cells have undergone degenerative changes. In preparations stained with hematoxylin-eosin, revealed a large number of cells with signs of severe protein-hydropic dystrophy. Nuclei of hepatocytes were partially pinatibay, and in some cases - lysed.

Compared with the above changes, the corresponding 3-week period after the introduction of a toxic agent, observing animals (6 animals) for 6 weeks. helped to establish the absence of spontaneous reenie DMNA marked thickened connective tissue septa with dilated venous collaterals, filled with blood. When painting the hematoxylin-eosin shows the conservation of the intensity of dystrophic changes in the liver in the form of granular and protein-hydropic degeneration of hepatocytes.

The second control group (12 rats) were animals treated with saline. Daily observation of the animals of this group showed that they like the animals of group 1, in the long term (3-4 weeks) after injection of DMNA badly eaten food, was underweight, had a bad appearance - stringy dirty hair; they were sluggish, sedentary. The morphological and histological study found that a 3-week introduction of 0.9% solution of sodium chloride had no effect on the formation of pseudopolis. Despite the appointment of saline solution, developed bleeding from dilated microvessels, leading to disruption of the structure of the lobules, degeneration and death of hepatocytes with lysis of the nuclei of cells. Even with a 6-week introduction of 0.9% sodium chloride solution clearly remained Centro-Central connective tissue septa limiting portal lobules. In Siptah and places destroyed Central veins were visible dilated venous, collater what ivala process fibrogenesis.

The treatment of animals of group 3 (12 rats) drug GSSG lead to a rapid improvement in their condition. Daily observation already after 7 days after initiation of therapy with this drug increased physical activity, increased feed intake, improved appearance, increased weight gain of almost all experimental rats of this group. On histological preparations of liver of rats that received GSSG within 3 weeks, a marked reduction in the number of connective tissue septae, collagen fibers were distributed mainly perisinusoidal in the form of thin fibers and in the periportal area of the slices. At colouring preparations hematoxylin-eosin showed a significant reduction in the number of cells with protein and hydropic degeneration. Macrophage cells were significantly activated. The introduction of the drug GSSG within 6 weeks was accompanied by a significant reduction in the number of connective tissue. Signs intraorganelle roundabout circulation was absent. When this treatment on preparations stained with hematoxylin-eosin, there was a statistically significant decrease in the number of degenerative changes in hepatocytes and cells lysed nuclei. Dystrophic the betrayal of the drugs was observed resorption connective tissue septae activated phagocytes. The number of lymphocytes in the connective tissue was increased.

Observation of the animals of group 4 (12 rats) treated with Heptral, testified that in a long time (3 weeks from start of therapy), their condition did not improve: they bad eaten food, not gaining weight, had a bad appearance, were sedentary. The morphological and histological study found that after a 3-week course of therapy, the severity of acute-phase inflammation in portal tracts was at the level of the control (treated with saline). The drugs were clearly visible pseudodevice limited connective tissue septa containing small collaterals Central veins, anastomoziruet between them and forming a connection with the vessels of the portal tract. Hepatocytes underwent profound degenerative changes, and most significantly manifested protein and hydropic degeneration. Only purpose of Heptral for 6 weeks resulted in some positive effect, although lower than in the treatment GSSG, decreased the percentage of collagen in the liver, decreased the severity of inflammatory changes in the structure of the connective t is can be noted that there are a significant number of cells, with hydropic changes. All this testified to insufficiently high efficacy of experimental cirrhosis by Heptral.

For an objective assessment of the relative content of connective tissue in the liver of rats experimental and control groups was performed morphometry toxinotyping (i.e., connective tissue, collagen) fibers on the slices of liver. The data obtained are presented in table. 42. It is established that the treatment of toxic liver cirrhosis drug GSSG for 3 weeks accompanied by a decrease in the number of

collagen in the liver by 1.6 times compared with the control saline; at the same time, the use of Heptral was accompanied by a reduction of collagen in the liver only 1.1 times. At 6-week course of therapy, the difference in the effect was even more pronounced: Pinnothin reduced the amount of connective tissue in 3,27 times, and Heptral - 1.7 times. All this allows to conclude that the purpose GSSG promotes involution of connective tissue and liver cirrhosis. All this allows to conclude that the purpose GSSG promotes involution of connective tissue and liver cirrhosis.

Thus, a high therapeutic effect GSSG on m is the situation for experimental animals and confirmed by histological studies. On the preparations of liver of rats of the control group (DMNA without treatment) clearly followed the plots of the death of hepatocytes, the development of inflammation in the walls of the small Central veins, the formation of connective tissue septae. Hepatocytes underwent degenerative changes, to the greatest extent was expressed protein and hydropic degeneration. The use of saline had no effect in a positive way to the development of liver damage in this case on histological preparations were visible Mature connective tissue septa and degenerative changes of hepatocytes formed pseudomales. Treatment Heptral caused only a small reduction in the number of connective tissue and the severity of acute-phase inflammation in portal tracts and dystrophic changes in the liver cells, and the positive effect of therapy Heptral installed only at a 6-week course of therapy. On the contrary, in animals that received GSSG, already after 3 weeks from the start of treatment there was a significant decrease in the number of connective tissue, is even more significant in therapy for 6 weeks. Histological examination of the liver drugs from these animals marked by only a few IU is Titov not identified, that allows you to judge fairly high hepatoprotective action of this drug.

Conclusion: the use of the drug GSSG at a dose of 10 mg/kg 3 times a week for 6 weeks in experimental cirrhosis of the liver in albino rats caused by dimethylnitrosoamine directly correlated with the involution of connective tissue in the body, and also contributed to the restoration of damaged hepatocytes. The product comparison - Heptral (S-adenosyl-methionine) - had significantly lower therapeutic effect.

Example 19

Clinical and experimental efficiency GSSG, GSSG and GSSG5-methylcytosine in the treatment of especially dangerous infections: tularemia and melioidosis

Assessment of therapeutic efficacy GSSG, GSSG and GSSG5-methylcytosine were performed on white mice, which were immunized virulent culture of the pathogen melioidosis, chemical, and live tularemia vaccine.

In the experiments used adult randombred of male mice weighing 18-21 g, the set of the kennel "Rapolano RAMS. For immunization used commercial preparations. To study the effect of GSSG nonspecific resistance to melioidosis drug rntne culture of the pathogen melioidosis strain 59361, then determined the mortality rates of animals (the percentage of dead animals, life expectancy - ALE) during the observation period of 1 month.

The study of the effects GSSG nonspecific resistance of mice to live tularemia vaccine (ITV) GSSG was administered intraperitoneally at a dose of 2 mg/mouse (0.5 ml) for 6 h prior to subcutaneous inoculation of animals IT in various doses with subsequent determination of LD50 ITV in the control and experimental groups.

The study of the effects GSSG5-methylcytosine on protectionist "C-complex", isolated from tularemia (provisionally designated us "chemical tularemia vaccine" - HTV), this "vaccine" was injected into mice subcutaneously in different doses without GSSG5-methylcytosine and in conjunction with him. After 21 days the animals were infected by the virulent strain of the pathogen melioidosis (10 LD50), and others ITV in lethal dose (4106m CL ). For urgent prophylaxis of tularemia GSSG5-methylcytosine entered once for 6 h prior to vaccination HTV, and to improve the immunity to melioidosis twice: for 6 h prior to vaccination and for 6 h before infection.

The results of the experiments were evaluated statistically.

It is established that 18 days after infection, animals 300 LD50 virulent the observations marked decrease in the number of surviving animals to 17%, at the same time, there is significant increased mean life span (p<0,05) dead mice treated GSSG. Most active in the protection melioidosis was dose GSSG 2.5 mg, introduced animals at 1, 6, 12 or 18 h before infection.

The results of the experiment is to study therapeutic properties GSSG in respect of tularemia are presented in table. 56.

It is shown that the introduction of animals GSSG increased their resistance to IT; LD50 JTV for mice, which were injected GSSG, was 4 times higher than in intact animals.

Also examined the ability GSSG5-methylcytosine to increase the immunogenicity of HTV against pathogens of melioidosis and tularemia. HTV used simultaneously as a non-specific protective factors against melioidosis infection.

It is noted that vaccination of mice ITV doses of 10, 50 and 250 μg defended from death to 25% of animals, while ALE fallen mice only slightly exceeded the similar indicator in the control group of intact animals (p>0,05). Two introduction GSSG5-methylcytosine (for 6 h prior to vaccination HTV and for 6 h before infection) contributed to the increased survival of the animals (12%) and suscestvennoj for mice: 12 animals vaccinated this dose, killed 8, while in the group of animals treated with 250 µg HTV 2 mg GSSG5-methylcytosine, from 12 mice before infection survived 11.

When studying the possibilities GSSG5-methylcytosine to enhance specific immunity to tularemia has been shown that a single injection GSSG5-methylcytosine for 6 h prior to vaccination 25-100 µg HTV increased immunogenic properties of this drug, which was reflected in the increase of the survival rate of animals (14-17%) and a significant increase (p<0.05) of the terms ALE when infected with a lethal dose of IT (PL. 58).

Studies have shown the ability of drugs group GSSG to increase the body's resistance to melioidosis and tularemia. An important feature of the drug is immunomodulatory, and cytoprotective system and, especially, a hepatoprotective effect. The data obtained on substantial reductions in toxicity dose HTV 250 mg for mice using GSSG5-methylcytosine, introduced for 6 hours prior to vaccination, evidence of its antibacterial and cytoprotective action.

Thus, the new derivatives of oxidized glutathione and elements of nucleic acids using specific methods provide dignity of the EU", that can be used to create comprehensive preventive and therapeutic drugs.

Simultaneously, these data suggest that the investigated drugs are effective for infections caused by prions.

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19. Robert C. Bohinski "Modern Concepts in Biochemistry", 4thedition, 1987.

20. Harrison''s Principles of Internal Medicine, 14thedition, p. 511, 1998.

21. Apoptosis: a role in neoplasia, C. D. Gregory, 1996.

22. The Molecular Biology of Apoptosis, D. L. Vaux, A. Strasser; Proc. Natl. Acad. Sci. USA 93 (1996).

23. Cytokines in Hematology, L. Grachev A. , Moscow, 1996.

24. Paola Galinari et al. Multiple enzymatic activities associated with recombinant NS3 protein of hepatitis With virus. J. Virol. , August 1998, p. 6758-6769, Vol. 72, No. 8.

25. RF patent 2089179, MKI a 61 K 38/00, 1997.

26. RF patent 2153350, MKI a 61 K 38/00, 38/06, 33/00, 1999.

27. Jezequel, A. M. et is Aly on experimental and clinical study of new drugs. Parts 1 and 3 (Official edition). Pharmacological Committee, M. , 1975, 1981.

29. Requirements for pre-clinical study of the General toxic action of new pharmacological substances (Interim guidelines). Pharmacological Committee. M. , 1985 and the Rules of preclinical safety assessment of pharmacological agents (GLP). RD 64-126-91. M. , 1992.

1. Organic salt of oxidized glutathione (GSSG), characterized in that it is counter-ions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape and a nitrogenous base or nucleoside, or nucleotide purine and pyrimidine nature.

2. Organic salt under item 1, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and a nitrogenous base is a purine or pyrimidine nature.

3. Organic salt under item 2, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and adenine.

4. Organic salt under item 2, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and guanine.

5. Organic Sol is Lena in an L-shape, and thymine.

6. Organic salt under item 2, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and cytosine.

7. Organic salt under item 2, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and uracil.

8. Organic salt under item 2, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in the L-form and 5-methylcytosine.

9. Organic salt under item 2, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in the L-form and 4-thiouracil.

10. Organic salt under item 2, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and dihydrouracil.

11. Organic salt under item 1, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and nucleoside purine or pyrimidine nature.

12. Organic salt on p. 11, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in the tion, in the formula which all amino acids are represented in an L-shape, and guanosine.

14. Organic salt on p. 11, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and inosine.

15. Organic salt on p. 11, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and citizen.

16. Organic salt on p. 11, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and uridine.

17. Organic salt on p. 11, in which the counterions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, and thymidine.

18. Organic salt of oxidized glutathione (GSSG), characterized in that it is counter-ions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and a nitrogenous base or nucleoside, or nucleotide purine or pyrimidine nature.

19. Organic salt p. 18, in which the counterions are oxidized glutathione, in the formula kotorogo, and a nitrogenous base is a purine or pyrimidine nature.

20. Organic salt p. 19, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape and adenine.

21. Organic salt p. 19, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and guanine.

22. Organic salt p. 19, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and thymine.

23. Organic salt p. 19, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and cytosine.

24. Organic salts on p. 19, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form and the rest aminutza oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in the L-form and 5-methylcytosine.

26. Organic salt p. 19, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in the L-form and 4-thiouracil.

27. Organic salt p. 19, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and dihydrouracil.

28. Organic salt p. 18, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and nucleoside purine or pyrimidine nature.

29. Organic salt p. 28, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and adenosine.

30. Organic salt p. 28, in which proabley in D-form, and the remaining amino acids are represented in an L-shape, and guanosine.

31. Organic salt p. 28, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and inosine.

32. Organic salt p. 28, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and citizen.

33. Organic salt p. 28, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and uridine.

34. Organic salt p. 28, in which the counterions are oxidized glutathione, in the formula of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids are represented in an L-shape, and thymidine.

35. Organic salt of oxidized glutathione, characterized in that it is counter-ions are oxidized glutathione, in the formula which all amino acids are represented in an L-shape, realnye amino acids are represented in the L-form, and nucleoside purine or pyrimidine nature, in the formula which ribose is presented in the form of D-ribose or D-deoxyribose.

36. Organic salt p. 35, in which the counterions are oxidized glutathione in L - or D-form, and at the same time two nucleoside, one of which is a purine, and the second - pyrimidine nature.

37. Organic salt of oxidized glutathione, characterized in that it is counter-ions are oxidized glutathione in L - or D-form and two nitrogenous bases: one purine and second - pyrimidine nature.

38. Individual-based substance fosfamida derivatives of oxidized glutathione, characterized in that it contains organic cations represented by a number of nucleosides or nucleotides and phosphamidon derived oxidized glutathione, amino acids which exist in the L-form.

39. Substance on p. 38, characterized in that as phosphamide derived oxidized glutathione use derivative with monophosphate (AMP).

40. Substance on p. 38, characterized in that as phosphamide derived oxidized glutathione use derived from guanosine Lenogo use of glutathione derivative with inosinmonofosfata (IMP).

42. Substance on p. 38, characterized in that as phosphamide derived oxidized glutathione use derivative with citizensinformation (CMP).

43. Substance on p. 38, characterized in that as phosphamide derived oxidized glutathione use derivative with urediniospores (MFIs).

44. Substance on p. 38, characterized in that as phosphamide derived oxidized glutathione use derivative with timedimension (TMP).

45. Substance on p. 38, characterized in that as phosphamide derived oxidized glutathione use derivatives of nucleotides purine or pyrimidine nature, in which the ribose is presented in the form of D-ribose or D-deoxyribose.

46. Individual-based substance fosfamida derivatives of oxidized glutathione, characterized in that it contains organic cations represented by a number of nucleosides or nucleotides and phosphamidon derived oxidized glutathione, the structure of which two chemically unambiguous amino acids are represented in the D-form, and the remaining amino acids in L-form.

47. Substance on p. 46, characterized in that as FOSFA is 48. Substance on p. 46, characterized in that as phosphamide derived oxidized glutathione use derived from guanosine monophosphate (GMP).

49. Substance on p. 46, characterized in that as phosphamide derived oxidized glutathione use derivative with inosinmonofosfata (IMP).

50. Substance on p. 46, characterized in that as phosphamide derived oxidized glutathione use derivative with citizensinformation (CMP).

51. Substance on p. 46, characterized in that as phosphamide derived oxidized glutathione use derivative with urediniospores (MFIs).

52. Substance on p. 46, characterized in that as phosphamide derived oxidized glutathione use derivative with timedimension (TMP).

53. Substance on p. 46, characterized in that as phosphamide derived oxidized glutathione use the derived nucleotide purine or pyrimidine nature, in which the ribose is presented in the form of D-ribose or D-deoxyribose.

54. Individual substance, based on fosfamida derivatives of oxidized glutathione, characterized in that izvozna oxidized glutathione in L-form or D-form, with a number of nucleosides or nucleotides purine or pyrimidine nature, in which the ribose is presented in the form of D-ribose or D-deoxyribose.

55. The substance according to p. 54, characterized in that as phosphamide derived oxidized glutathione use derived from two nucleotides, one of which is a purine, and the second - pyrimidine nature.

56. The pharmaceutical composition exhibiting anti-viral, antibacterial, immunorehabilitation and hepatoprotective activity, containing as active substance, at least one of the compounds according to paragraphs. 1-55 in an effective amount and a pharmaceutically acceptable carrier or excipient.

57. Pharmaceutical drug, which has antiviral, antibacterial, immunorehabilitation and hepatoprotective activity, containing as active substance, at least one of the compounds according to paragraphs. 1-55 in an effective amount and a pharmaceutically acceptable carrier or excipient.

58. The method of preparation of organic salts of oxidized glutathione and inosine, in which the quality of the anion molecule is oxidized glutathione, and the quality is disodium salt of oxidized glutathione under stirring at room temperature was added 1 equivalent of powder inosine and leave to dissolve, after which a clear solution is filtered and freeze-dried.

59. The method of obtaining inoil-5-phosphoryl-N-glutathione, namely, that potamianou the relationship between the amino group of glutamic acid in the molecule of oxidized glutathione and a phosphoric acid residue in the molecule inoil-5-monophosphate get in the reaction N-oxysuccinimide activated ether and oxidized glutathione in dimethylformamide at pH 8.0 to 8.5.

60. The method of exposure to infectious agents body of the patient, including intracellular localized, and/or stimulation of T-cell and humoral anti-infective immunity, along with providing cytoprotective effects, which consists in the introduction to the mammals of an effective amount of a pharmaceutical preparation obtained on the basis of chemical interaction dyslipidaemias peptides with nitrogenous bases or nucleosides or nucleotides purine or pyrimidine nature.

61. The method according to p. 60, which consists in the induction of apoptosis mechanisms, including through expression inducer of apoptosis, FAS/APO-1 antigen (CD95+) on the membranes of virus-infected cells, macrophage membranes the applications by Plasmodium and other infectionthe, through the introduction in the mammalian organism a pharmaceutical preparation containing an effective amount of the active substance is selected from the group consisting of GSSG, GSSG, GSSG, GSSG, GSSG, GSSG-insimenator, GSSG-brazilianist, GSSG-timeinterest, GSSG-casinodeposit and other compounds derived from the interaction of L - or D-forms of oxidized glutathione and its salts with nitrogenous bases or nucleosides or nucleotides purine or pyrimidine nature.

62. The method according to p. 60, consisting in the introduction in mammals infected with hepatitis C virus, a pharmaceutical preparation containing an effective amount of an active ingredient selected from the group consisting of GSSG, GSSG-insimenator, GSSG-brazilianist and derivatives of L - or D-forms of oxidized glutathione and components of nucleic acids in order to inhibit ATP-asna/helicase activity of NS3 of hepatitis C virus to stop replicative activity and elimination of hepatitis C virus, therefore, achieve a therapeutic effect.

63. The method according to p. 60, consisting in preferential inhibition of replicative activity of RNA-containing viruses, istia L - or D-forms of oxidized glutathione and its salts with nitrogenous bases or nucleosides or nucleotides pyrimidine nature.

64. The method according to p. 60, consisting in preferential inhibition of replicative activity of DNA-containing viruses, in the case of use as an active substance, compounds derived from the chemical interaction of L - or D-forms of oxidized glutathione and its salts with nitrogenous bases or nucleosides or nucleotides purine nature.

65. The method according to p. 60, which consists in introducing into the mammalian organism a pharmaceutical preparation containing an effective amount of the active substance chosen from the group containing GSSG and other compounds oxidized glutathione with components of nucleic acids with the aim of preferential activation of the functional activity of Th1-group of T cells or Th2-group of T cells, or their adjustable ratio, which differentially determines the efficiency of the immune system of mammals in relation to causal factors of infectious diseases.

66. The method according to p. 60, which consists in the introduction into the organism of the patient With viral hepatitis C pharmaceutical preparation containing an effective amount of the active substance is selected from the group consisting of GSSG and/or GSSG-insimenator for ugamak Th1 and Th2 dysbalance groups of cells, and also to increase the endogenous production of IL-2, IL-12, IFN -.

67. The method according to p. 60, which consists in the introduction into the organism of the patient with viral hepatitis a, b and/or pharmaceutical preparation containing an effective amount of the active substance is selected from the group consisting of GSSG and other compounds oxidized glutathione, its salts, with the components of nucleic acids to achieve the hepatoprotective effects, including the prevention and/or treatment of complications of chronic viral hepatitis, namely the prevention and treatment of liver cirrhosis and hepatocellular carcinoma.

68. The method according to p. 60, in which the disease is selected from all kinds of infectious diseases, including viral and bacterial infections, including anaerobic infections; chlamydia and Mycoplasma infections; fungal infections (candidiasis); protozoal infections.

69. The method according to p. 60, in which the pharmaceutical preparation according to p. 57, injected into the infected organism parenterally, orally, in the form of inhalation solutions, solutions for local instillation, eye or intranasal drops, ointments, creams or gels for transdermal application, as well as in the form of suppositories, to achieve therapeutic effect and/or /P> 70. The method of treatment of a subject in need of the termination of the replicative activity of the virus, bacteria, or other infectionhow, induction mechanisms of apoptosis of infected cells, restore, and stimulation of anti-infective capable of immunity: T-cell and/or humoral system cytoprotective effects, which consists in the introduction to a subject a pharmaceutical preparation containing the active substance, selected from the group consisting of biologically active compounds derived from the chemical interaction of L - or D-forms of oxidized glutathione, its salts with nitrogenous bases or nucleosides or nucleotides purine or pyrimidine nature in a quantity sufficient to achieve a therapeutic effect.

71. The method according to p. 70, in which the disease is acute with a prolonged course of viral hepatitis b, and pharmaceutical drug is chosen from the group consisting of GSSG and GSSG-inosinmonofosfata.

72. The method according to p. 70, in which the disease is acute viral hepatitis C, and pharmaceutical drug is chosen from the group comprising GSSG, GSSG and GSSG-insimenator.

73. The method according to p. 70, in which the disease is Zin, GSSG, GSSG, GSSG-insimenator and GSSG-timeinterest.

74. The method according to p. 70, in which the disease is chronic viral hepatitis C, and pharmaceutical drug is chosen from the group comprising GSSG, GSSG, GSSG, GSSG, GSSG-brazilianist, GSSG-casinodeposit, uracil-GSSG-inosine.

75. The method according to p. 70, in which the disease is chronic viral hepatitis b cirrhotic stage, and pharmaceutical drug is chosen from the group comprising GSSG, GSSG, GSSG, Li2-GSSG-insimenator and Na2-GSSG-timeinterest.

76. The method according to p. 70, in which the disease is pulmonary tuberculosis, and pharmaceutical drug is chosen from the group comprising GSSG, GSSG, GSSG-5-methylcytosine, Li2-GSSG-insimenator.

77. The method according to p. 70, in which the disease is tuberculosis of the genitourinary system and the pharmaceutical drug is chosen from the group comprising GSSH, Na2-GSSG-guanosine monophosphate and uracil-Li2-GSSG-guanosine monophosphate.

78. The method according to p. 70, in which the disease is AIDS and cytomegalovirus infection, infection caused by virus, Epstein-Barr and/or uracil, and Zn2-GSSG-timeinterest and Ag2-GSSG-brazilianist and GSSG.

79. The method according to p. 70, in which the disease is an infection caused by herpes viruses, and pharmaceutical drug is chosen from the group comprising GSSG, Li2-GSSG-guanosine monophosphate, and also the D-form Na2-GSSG-casinoniagara and D-form GSSG.

80. The method according to p. 70, in which the disease is a fungal infection (candidiasis), and the pharmaceutical drug is chosen from the group consisting of GSSG, GSSG4-thiouracil and Ag2-GSSG-brazilianist.

81. The method according to p. 70, in which the disease is Mycoplasma infection, and pharmaceutical drug is chosen from the group comprising GSSG, GSSG and Na2-GSSG-monophosphate.

82. The method according to p. 70, in which the disease is chlamydia infection, and pharmaceutical drug is chosen from the group comprising GSSG, GSSG, GSSG, GSSG and Na2-GSSG-guanosine monophosphate.

83. The method according to p. 70, in which the disease is malaria, leishmaniasis, and pharmaceutical drug is chosen from the group comprising GSSG, GSSG and GSSG5-methylcytosine.

84. The method according to p. 70, in which the disease Stein) and D-form (D-glutamic acid).

85. The method according to p. 70, in which the disease is selected from the group consisting of viral hepatitis a, dysentery and cholera, and the pharmaceutical drug is chosen from the group comprising GSSG, Li2-GSSG-insimenator and Li2-GSSG-guanosine monophosphate, and also the D-form GSSG (D-glutamic acid).

86. The method according to p. 70, in which the disease is infectious meningitis, and pharmaceutical drug is chosen from the group comprising GSSG, Li2-GSSG-insimenator, D-shape GSSG (D-glutamic acid), GSSG5-methylcytosine, Ag2-GSSG-brazilianist.

87. The method according to p. 70, in which the disease is chosen from a group of especially dangerous infections, consisting of plague, tularemia and anthrax, and pharmaceutical drug is chosen from the group comprising GSSG, GSSG, GSSG, GSSG5-methylcytosine, GSSG4-thiouracil, D-shape GSSG (D-glutamic acid, D-form GSSG, (D-cysteine), GSSG.

88. The method according to p. 70, in which the disease is an infection caused by prions ("mad cow disease"), and the pharmaceutical drug is chosen from the group comprising GSSG, GSSG, GSSG, Ag2-GSSG-brazilianist, Ag2-GSSG-timeinterest and brazilianists of influenza and acute respiratory viral infections and pharmaceutical drug is chosen from the group comprising GSSG, GSSG, GSSG and GSSG.

 

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