RU2440128C1 - Method of complex pathogenetic therapy of acute forms of viral hepatitis b and mixed hepatites (b+c, b+d, b+c+d) - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to treating infectious diseases, and can be used in treating patients with acute forms of viral hepatitis B and mixed hepatites (B+C, B+D, B+C+D). A method involves basic therapy consisting of a protected mode, diet No.5, plenty drink 2-3 l/day, drug-induced therapy including administration of polyvitamins, intravenous injections of 5% glucose, Ringer's solution 500-1000 ml/day with Riboxinum 5 ml, hemodesis or neo-hemodesis 200-400 ml/day, 10-20% albumin 50-100 ml/day. The basic therapy is added with a complex of drugs to suppress viral replication and inflammatory reaction of macrophages, specifically chloroquines cyclosporine A, heparin, novocaine, mexidol, ascorbic acid, a-tocopherol, unitiol, N-acetylcystein, retinol, sodium thiosulphate, vitamin D₃.

EFFECT: use of the invention allows providing higher clinical effectiveness in patients with acute forms of viral hepatitis B and mixed hepatites (B+C, B+D, B+C+D).

3 cl, 8 tbl, 2 ex

Description

The invention relates to medicine, namely the treatment of infectious diseases of adults, and can be used to treat patients with acute forms of viral hepatitis B and mixed hepatitis (B + C, B + D, B + C + D).

Viral hepatitis is one of the most widespread infections of our time. Some experts believe that we live in a period of a pandemic of viral B and C hepatitis [1, 2]. According to WHO, the problem of viral hepatitis is a public health problem on a global scale: there are about 2,000 million people infected with hepatitis B virus in the world, of which more than 350 million are chronically infected and between 500,000 and 700,000 die each year from hepatitis B virus infection. 57% of cases of liver cirrhosis and 78% of cases of primary liver cancer are caused by infection of hepatitis B or C virus [3, 4]. Up to 200 million people are chronically infected with hepatitis C virus [2]. Hepatitis of viral etiology are among the ten diseases that determine mortality in the United States [5]. In the first decade of the twenty-first century, the incidence of viral hepatitis in Russia as a whole and in its individual regions continued to remain high. The incidence of viral hepatitis with a parenteral mechanism of transmission is associated with the prevalence of intravenous drug abuse in the country. It is also significant that the number of forms of diseases that are difficult to respond to traditional therapy caused by two to three viruses (mixed hepatitis), as well as combined liver damage (viral + toxic), is growing. Often the disease acquires a protracted course.

The treatment of viral hepatitis is far from resolved. For many years, therapeutic measures have been largely preserved unchanged and are still largely consistent with outdated ideas about the essence of pathological processes developing in viral hepatitis and ways to correct them. In this regard, the development of effective methods for the treatment of liver diseases of viral etiology, which reduce the time and improve the quality of treatment, is urgently needed [6].

Pathogenetic therapy of acute forms of viral hepatitis is carried out in the following areas: non-specific detoxification, hepatoprotection, immunocorrection, vitamin therapy, as well as the use of antihypoxic and antihemorrhagic agents.

Methods of treating various forms of viral hepatitis in our country are regulated by orders of the Minister of Health of the USSR in 1989 No. 408, Ministry of Health and Social Development of the Russian Federation in 2004 No. 260, 2005 No. 618, 621, 634, 2006 No. 571 [7-12]. According to regulatory documents, treatment of acute viral hepatitis should be carried out in a hospital setting and consist in the appointment of basic therapy for all patients, consisting of a protective regime, diet No. 5, heavy drinking (2-3 liters per day), multivitamins. Treatment of mild forms of acute viral hepatitis is limited to basic therapy.

In moderate to severe cases of acute viral hepatitis B, antiviral therapy with interferon (reaferon) preparations is indicated, 1 million DBs twice a day intramuscularly for 5-6 days, then 1 million units once a day for another 5 days. In the absence of interferon preparations, riboxin is prescribed orally at 0.2 g four times a day for 10 days, cytochrome C at 10 mg / day intramuscularly, quercetin inside at 0.04 g three times a day for 10-14 days. Basic therapy is enhanced by intravenous infusions of 5% glucose solution, Ringer's solution of 500-1000 ml / day with 10 ml of 5% ascorbic acid solution, hemodesis 200-400 ml / day, 10-20% albumin solution of 50-100 ml / day At the same time, the length of stay of patients with severe forms of viral hepatitis in the intensive care unit (ICU) is from 7 to 20 days or more, and the average duration of treatment in a hospital is 60-85 days. The economic costs per hospital patient with this nosological form in December 2009 prices are approximately 120,000 rubles (data from the St. Petersburg City Hepatology Center).

Known methods of treating severe forms of viral hepatitis, the main content of which is to carry out non-specific detoxification: through the introduction of crystalloid and colloidal plasma substitutes, albumin, plasma (1.5-3 l / day); the appointment of enterosorbents; the implementation of oxygenobaro-therapy sessions, efferent therapy (hemosorption, plasmapheresis, plasmosorption, ultrafiltration); the use of glucocorticoids, riboxin, essentials, vitamins [13-17].

Known methods for the treatment of liver diseases of viral etiology by using compounds with hepatoprotective action. The main active components of these formulations are various amino acids and their derivatives: a composition comprising L-aspartic acid, L-arginine and a carbohydrate (eg, sorbitol) [18]; formulations containing derivatives of hydroxyproline [19], orotic acid [20], valine, leucine, isoleipine (Volkamin preparation) [21]; mixtures of amino acids, nucleotides, and an enzyme [22]. The hepatoprotective activity of ursodeoxycholic acid [23], the precursors of the amino acid L-cysteine [24], the choline ester of thioctic acid [25], and human alpha-fetoprotein [26] is known and used.

Common shortcomings of the listed formulations and hepatoprotective drugs proposed for the treatment of viral hepatitis are their lack of antiviral effects, insufficient anti-inflammatory activity and low efficiency. Some of these drugs are not registered in the Russian Federation as medicines.

Known methods of etiotropic treatment of viral hepatitis, consisting in monotherapy with interferon or interferon and ribavirin, the clinical efficacy of which is verified [27-35]. Of all interferons, the most widely used drug is interferon alfa [36]. However, the high cost of drugs along with insufficient efficacy and an abundance of side effects (fever, leukopenia, neutropenia, thrombocytopenia, anemia, myalgia, autoimmune syndrome, dyspeptic symptoms and depression), which enhance typical immunological reactions in acute viral hepatitis [37], limit their use in clinical practice [38].

In the treatment of viral hepatitis, drugs with immunocorrective action are widely used: interferon inducers [39]; agents stimulating humoral immune responses [40]; drugs that increase the functional and metabolic activity of macrophages [41] and stimulate the production of antibodies [42]. Common disadvantages of these drugs with immunocorrective activity used in the treatment of viral hepatitis is their low efficiency, the frequent occurrence of side effects.

Oxidative stress plays a significant role in the formation of the cytolytic syndrome in acute viral hepatitis [43]. The processes of non-enzymatic oxidation are most intense during HBV infection [44]. And the iron ions released from transferrin and ferritin during inflammatory damage to hepatocytes act as a factor catalytically multiplying the production of free radicals [45, 46]. In the presence of metal ions of variable valency, antioxidants (α-tocopherol, ascorbic acid) turn into producers of a hydroxyl radical, participating in the reduction of hydrogen peroxide (Fenton reaction) [47] and hypochlorite (Osipov reaction) [48]. Iron ions not only stimulate free radical damage to hepatocytes, but also significantly accelerate the replication of hepatitis B and C viruses [49-51], and determine the effectiveness of interferon therapy [52]. In order to correct these pathogenetically significant processes in the treatment of viral hepatitis, antioxidants [53] and iron complexones are prescribed [54]. However, the effectiveness of these appointments is low, and iron ions in the composition of the used complexones do not lose catalytic activity [55].

A means is known, which is an emulsion of perfluorocarbons (perftoran), used as a blood substitute with gas transport function, used to treat and prevent pathological proliferation of connective tissue in parenchymal organs [56], in the conservative treatment of thrombophlebitis of the saphenous limbs [57], in the treatment of acute pancreatitis [58].

As a prototype, a method for treating complicated forms of viral hepatitis with an emulsion of perfluorocarbons perftoran [59, 60] was chosen as the closest in technical essence (providing modulation of the functional activity of hepatic resident macrophages [61]). The disadvantage of the prototype method is its relatively low efficiency.

The purpose of the invention is to increase efficiency, reduce the treatment time for patients with acute forms of viral hepatitis B and mixed hepatitis (B + C, B + D, B + C + D) and reduce the economic costs of treating this category of patients.

The purpose of the invention is achieved by the fact that against the background of basic therapy, patients with acute forms of viral hepatitis B and mixed hepatitis (B + C, B + D, B + C + D) are prescribed a complex of drugs that suppress the replication of viruses and the inflammatory response of macrophages.

Hepatitis B, C and D viruses (HBV, HCV and HDV) have different toxonomic affiliations:

- HBV - DNA-containing virus from the family of hepatadaviruses;

- HCV - RNA-containing virus from the flavivirus family;

- HDV is an RNA-containing subvirus satellite of hepatitis B virus that does not belong to any of the known families of animal viruses [62–64]. The parenteral mechanism of infection, the mandatory circulation of viral particles in the blood, tissue tropism and the absence of a pronounced direct cytopathic effect are common to them. The damaging effects of hepatitis viruses on liver tissue are immune-mediated.

Hepatitis B and C viruses penetrate cells after interaction with receptor molecules localized on the cytoplasmic membrane of hepatocytes through endocytosis [65, 66]. These receptor molecules determine the tissue tropism of hepatitis viruses [67, 68]. From the endosomes in the cytosol of hepatocytes, the virus genome is isolated in a pH-dependent manner, transposed into the cell nucleus, and thus the replication mechanism is triggered. In infected hepatocytes, infection-activated Kupffer cells and lymphocytes, expression of tumor necrosis factor (TNF-α) [69], various chemokines and cytokines is induced [70, 71]. Interferons (IFN-γ), pro-inflammatory cytokines (IL-1, IL-2, IL-6) and tumor necrosis factor (TNF-α) induce expression of cell death receptors (Fas receptor, TNF-R1, TNF-R2, DR -3 and others) on the cytoplasmic membrane of infected hepatocytes [72, 73].

In infections with hepatotropic viruses, the cause of cytolysis is most often not the direct cytotoxic effect of the virus, but the immune response of NK and T lymphocytes to viral antigens expressed on the cytoplasmic membrane of infected hepatocytes, realized through cell death receptors [74]. The death of hepatocytes is accompanied by the destruction of their mitochondria and the release of intracellular contents into the extracellular environment. If cytolysis is quite massive, if intramitochondrial macromolecules are released into the extracellular medium, then the course of the infectious process can acquire a qualitatively new content.

Mitochondria are intracellular organelles (each human cell contains from several hundred to several thousand of these formations [75, 76]), which are descendants of ancient endosymbiont bacteria [77], bearing generic signs of prokaryotes. In particular, mitochondrial DNA, like bacterial DNA, has unmethylated sequentially located nitrogen bases cytosine and guanine (CpG sequences) [78]. In contrast, the cytosine of CpG dinucleotides is usually methylated in the eukaryotic genome [79]. The presence of DNA fragments with unmethylated CpG sequences in mammalian biological media is recognized by TLR9 receptors (located in the cytosol in lysosome membranes [80]) of phagocytes, which is perceived as the presence of bacteria and is accompanied by their activation [81].

Formyl peptides are other structural components of mitochondria that are not found under physiological conditions in the cytosol of eukaryotic cells and biological media of multicellular organisms, which are characteristic only of bacteria. Translation (protein synthesis) in mitochondria, like all prokaryotes, always starts with a special, modified amino acid - N-formylmethionine. In eukaryotic cells, this amino acid is not used in the synthesis of polypeptide chains. Therefore, the presence of N-formylmethionine at the end of the polypeptide chain is a reliable indicator of the presence of bacteria. N-formyl peptides are recognized by the cytosolic receptor FPR1 (Formyl Peptide Receptor 1 - FPR1) of immunocompetent cells (phagocytes), which sharply stimulates their activity [82, 83].

The liver, the largest parenchymal organ of the human body, consists of 80% of parenchymal cells (hepatocytes) [84] and 15% of Kupffer cells (3% of the mass of the organ) [85]. Kupffer cells are resident "professional" macrophages localized in the hepatic sinusoidal capillaries. Kupffer cell activation is a two-step process. The first stage is to stimulate hepatic macrophages with cytokines (IFN-γ, IL-1, IL-4, IL-6, IL-10, TGF-β) [86]. Thus stimulated hepatic macrophages become able to present antigens to T-lymphocytes. The fully activated Kupffer cells become influenced by bacterial antigens (lipopolysaccharide, N-formyl peptides, TLR9 ligands). Activated hepatic macrophages lose their antigen-presenting ability and become producers of cytolytic substances: cytolytic proteinases, TNF-α and other cytokines, eicosanoids (prostanoids and leukotrienes), partially reduced forms of oxygen and nitrogen [87, 88].

One of the prooxidants generated by Kupffer cells is the superoxide radical anion. The superoxide radical in relation to organic and inorganic chemical compounds, depending on the chemical nature, is able to play the role of both an oxidizing agent (E ₀ O ₂ ^- / H ₂ O ₂ = + 0.89 V) and a reducing agent (E ₀ O ₂ / O ₂ ^- = -0.33 V) [89]. The restorative properties of the superoxide radical produced in pessimal quantities in viral hepatitis in the inflammation zone are realized, in particular, in the restorative release of iron ions from their complexes with biomacromolecules. For example, in the composition of transferrin and ferritin, iron is present only in the form of Fe ³⁺ ions which, under the influence of the superoxide anion radical, are reduced to Fe ²⁺ and leave the above proteins [90, 91].

In the presence of iron ions and partially reduced forms of oxygen, a peculiar catalytic “reactor” of redox-catabolic production of prooxidants and, in particular, an extremely toxic hydroxyl radical is formed [92]. This is an extremely dangerous state of the biological system. Removing free iron ions from the body’s biological environment is a matter of life and death in viral hepatitis. Attempts to use complexon (desferroxamine) for binding iron ions in viral inflammatory diseases not only did not have a positive effect on the course of the pathological process, but, contrary to expectations, increased mortality [93]. This paradox is explained by the fact that iron ions chelated with desferroxamine do not seem to lose their catalytic activity, i.e. do not lose their ability to undergo redox transformations and thus participate in the implementation of the reactions of Fenton and Osipov. Therefore, to remove iron ions from the body’s biological environment, it is advisable to use such complexones that deprive the ions of this metal of the transition valency of catalytic activity (in particular, mexidol as a precursor of phosphorylated derivatives of 3-hydroxypyridine - iron ion chelators).

A modern understanding of the main pathogenetic mechanisms of the infectious and inflammatory process in viral hepatitis with all the certainty makes it obvious that the pharmacological correction of this pathology requires the implementation of a comprehensive program of therapeutic measures. Therapy of viral hepatitis should provide an effect both on the process of multicyclic replication of viruses, and on the formation of an inadequate inflammatory response of the patient's body, induced by cytolysis.

In clinical practice, as a safe, effective and affordable medicine, chloroquine (Chloroquine) is widely used:

- for the prevention and treatment of malaria [94, 95];

- in the treatment of leprosy [96];

- as an anti-inflammatory agent in the treatment of rheumatoid arthritis [97, 98];

- in the treatment of metabolic syndrome and inflammatory diseases of bacterial etiology [99, 100];

- as a means of sensitization in the treatment of neoplasms [101, 102];

- in the treatment of amoebic hepatitis [103];

- as a treatment for HIV-infected patients [104, 105];

- to suppress the replication of hepatitis A virus [106, 107], hepatitis C virus [108] and hepatitis B virus [109]. Chloroquine has proven to be an effective therapeutic agent in the treatment of acute and chronic forms of viral hepatitis B and C [110];

- as a treatment for autoimmune hepatitis [111].

In terms of the manifestations of the antiviral activity of chloroquine, it is significant that this drug is able to block hepatitis virus endocytosis, inhibit endosome / lysosome acidification, inhibit lysosomal proteinase activity, and intercalate HBV DNA polymerase [110, 112]. An important aspect of the physiological activity of chloroquine is that the drug is recognized as a reference inhibitor of TLR9 [113] and is able to inhibit a number of other Toll-like receptors (TLR3, TLR7 and TLR8) [114, 115]. In addition, chloroquine suppresses the secretion of pro-inflammatory cytokines (TNFα, IL-1, IL-6, IL-10, IL-12) by cells of the immune system, inhibits the activation of nuclear transcription factors (NF-kB, AP-1) and the expression of Toll-like receptors (TLR9, TLR4), inhibits the activity of the proapoptotic enzyme caspase-3, which significantly reduces the severity of the inflammatory reaction and is manifested by cytoprotective effects [113, 115]. It is also significant in the formation of manifestations of the physiological activity of chloroquine that, in the micromolar range of concentrations, this drug exhibits the properties of an phospholipase A2 inhibitor and slow plasma Ca ²⁺ channels [116, 117]. It should be emphasized that there is convincing evidence of the safety of a long (for two years) daily intake of the drug in a dose of 250 mg [111].

The spectrum of physiological effects of chloroquine, proposed for use in the complex pathogenetic therapy of acute forms of viral hepatitis, is successfully supplemented by the pharmacological activity palette of cyclosporin A (a cyclic peptide containing 11 amino acid residues), which has:

- a powerful blocking effect on the ryanodine receptors (RyRs) of the endoplasmic reticulum, which protects cells from overload by calcium ions [118-120];

- a pronounced inhibitory effect on the intracellular formyl peptide receptor 1 (FPR1) [121, 122];

- the ability to suppress the replication of hepatitis viruses by inhibiting cyclophilin [123-125];

- the effect of a suppressor of the expression of phospholipase A2 induced by pro-inflammatory cytokines [126-128];

- direct inhibitory effect on the activity of calcineurin [128], which, among other things, prevents dephosphorylation-activation of constitutive isoforms of NO synthases [129, 130];

- the effect of suppressing the expression of inducible and constitutive isoforms of NO-sitases [131, 132];

- a property of the reference mitochondrial pore inhibitor of transit permeability, manifested by pronounced cytoprotective activity [133-135].

The ability of cyclosporin A to modulate the most important biochemical mechanisms of homeostatization of cytosolic calcium levels, inhibit the effects of proinflammatory cytokines and block the formation of mitochondrial pores in transit permeability, allows us to consider this pharmacological drug as a cytoprotective agent in critical conditions, including and in viral hepatitis (including fulminant forms) [136, 137]. In clinical trials of the efficacy and safety of cyclosporin A twice daily for three days in the dose range of 1.25-5 mg / kg / day as a cytoprotector in patients with severe traumatic brain injury, a significantly beneficial effect of the drug on the formation of injury outcomes was established in the absence of adverse effects [138]. The efficacy and safety of the use of cyclosporin A (at an initial dose of 3 mg / kg / day, followed by a decrease) is shown both for the example of fulminant forms of viral hepatitis [137] and for long-term administration (from 20 to 100 weeks) in the dose range of 2-15 mg / kg / day for the treatment of viral hepatitis C [139].

With the combined use of chloroquine and cyclosporine A, the complementary pleiotropy of the physiological effects of the drugs allows you to positively affect most of the pathogenetic mechanisms of the formation of an inadequate inflammatory response in viral hepatitis.

Xanthine oxidoreductase [140] plays an important role in the formation of the symptom complex of the manifestations and complications of viral hepatitis, the expression level of which in hepatocytes can increase by an order of magnitude during viral infection [141] under the influence of pro-inflammatory cytokines [142, 143]. Xanthine oxidoreductase is a cytosolic enzyme [144], which is released from the cells into the blood under pathophysiological conditions (the oxidase form of the enzyme [145] predominates as a result of proteolytic modification of the enzyme induced by pro-inflammatory cytokines [142]) and is fixed on the cytoplasmic membrane of endotheliocytes in the inflammation zone via chemical interaction with glycosaminoglycans [146]. Xanthine oxidoreductase localized on the cytoplasmic membrane of endotheliocytes and Kupffer cells [147], during the purine oxidation, produces a superoxide radical anion and can simultaneously reduce nitrite and nitrate anions to nitric oxide (NO) at another site (FAD-dependent) [148] , i.e. recycle this vasodilating agent. The production of prooxidants (O ₂ ^- , H ₂ O ₂ , NO, ONOO ^- ) with xanthine oxidoreductase is potentially very dangerous, since it can be accompanied by alteration of the liver parenchyma and adverse changes in the blood coagulation system. Attempts to use the allopurinol xanthine oxidoreductase inhibitor (allopurinol is a non-metabolizable hypoxanthine isomer competitively inhibiting the oxidative transformation of hypoxanthine and xanthine at the molybdopterin-containing enzyme site [149, 150]) have been unsuccessful in the therapeutic range of 5 mg / 50 mg / day. Allopurinol had no effect on the course and outcome of viral infection [151]. The absence of a therapeutic effect in this case is explained by the fact that upon inhibition of the (Mo-Co) -containing center of the enzyme with allopurinol, NADH oxidase and nitrite, nitrate reductase activities of xanthine oxidoreductase are realized, which are realized on the FAD-dependent domain of the enzyme [152-154]. Since there are no drugs among pharmacological agents capable of inhibiting the FAD-dependent activity of xanthine oxidoreductase, it is advisable to ensure desorption of this prooxidant enzyme from the cytoplasmic membrane of endotheliocytes and Kupffer cells (using heparin) in the treatment of patients with acute forms of viral hepatitis [147].

In addition to the direct damaging effect on bimacromolecules, intracellular prooxidants, forming a shift of the redox potential towards oxidative values, act as a regulatory stimulus modulating gene expression of an early inflammatory reaction [155]. Under conditions of oxidative stress, neutrophil hematractant expression is stimulated by Kupffer [147], TNFα, IL-1β [156], IL-6 [157], IL-8 [158], metalloproteinases (MMP-1, MMP-2, MMP-9 cells) ) [159-161] through redox activation of the nuclear transcription factor NF-kB [162]. Similarly, prooxidants stimulate the activity of other transcription factors: AP-1 (Activated Protein-1 - AP-1) [163], HDF-1α (Hypoxia-Inducible transcription Factor-la - HIF-1α) [164] and CREB ( cAMP-Responsive Element-Binding protein - CREB) [165]. The role of peroxynitrite in the induction of gene expression of an early inflammatory response is also very significant [166-171]. Therefore, it is not surprising that antioxidants have a pronounced anti-inflammatory effect [172-175].

It is known that pharmacological correction of the manifestations of oxidative stress is effective only with the integrated use of water-, fat-soluble antioxidants that restore their thiols and chelators of variable valence metals [176-178]. Based on the provisions of this concept, in the treatment of viral hepatitis, it is advisable to use ascorbic acid, α-tocopherol, unitiol as the thiol that restores them, and the amino acid precursor N-acetylcysteine to replenish the pool of endogenous glutathione. In the protection of biological membranes from the damaging effect of prooxidants, in cooperation with α-tocopherol (forming dynamic sensory-conducting complexes in the lipid bilayer of the membranes, each of which protects 300-500 phospholipid molecules [179]), retinol (vitamin A) also takes part, enhancing antioxidant effects of vitamin E [180]. In addition, in the presence of vitamin A, the bioconversion of arachidonic acid into pro-inflammatory eicosanoids is significantly inhibited [181], which is manifested, in particular, by inhibition of penetrating radiation-induced pulmonitis [182]. It is advisable to use sodium thiosulfate to immediately change the redox state of the biological environment of the body in order to block the transduction of signals of pro-inflammatory cytokines and stoichiometric quenching of reactive oxygen and nitrogen metabolites, regardless of the state of the antioxidant systems of the body. An integral part of the antioxidant complex in the treatment of viral hepatitis is emoxipin succinate (mexidol), as a precursor compound of phosphorylated derivatives of 3-hydroxypyridine, which are effective complexes of iron ions [183, 184]. Mexidol has the ability to inhibit the free radical stages of the synthesis of eicosanoids [185, 186]. The need for intensive antioxidant therapy for viral hepatitis is also due to the fact that prooxidants stimulate the influx of calcium ions into the cytosol of phagocytes, ensuring the maintenance of activated polymorphonuclear neutrophils [187].

Interferon is a physiological protein factor of antiviral protection of eukaryotic organisms used for the prevention [188, 189] and the treatment of viral infections [190-192]. However, the high cost of the drug and the abundance of side effects when using it (fever, leukopenia, neutropenia, thrombocytopenia, anemia, myalgia, autoimmune syndrome, dyspeptic symptoms and depression) limit the use of interferon in clinical practice [193]. Therefore, it is advisable to use effective interferon inducers, in particular novocaine (β-diethyl-aminoethyl ether of para-aminobenzoic acid) as antiviral agents in the treatment of viral hepatitis. Novocain is a drug characterized by good tolerance, mild antispasmodic action, relatively high hydrolysis rate in the body’s biological environment with the release of para-aminobenzoic acid, which has a powerful interferon-inducing effect [194, 195].

Only in recent years has the immunomodulating effect of 1,25-dihydroxyvitamin D ₃ (the active form of vitamin D ₃ ) begun to attract attention. The immunomodulatory activity of vitamin D _{3 is} mediated by specific receptors and transcription factors NF-AT and NF-kB, or is realized when it directly interacts with vitamin D ₃ receptor elements of the promoter regions of the genes (expression of at least several hundred genes is controlled by vitamin D ₃ ) [ 196]. In terms of the issue under consideration, it is significant that in the presence of the active form of vitamin D _{3 the} expression of pro-inflammatory cytokines is suppressed [197]. Considering the prevalence of hypovitaminosis D ₃ among the population of temperate latitudes [198], in the treatment of viral hepatitis it is advisable to prescribe it in a physiological daily dose (1500-2000 ED).

The possibility of achieving the objective of the invention is proved by the results of experimental studies on acute hepatitis and clinical trials of the method in the treatment of patients with acute forms of viral hepatitis B and mixed hepatitis (B + C, B + D, B + C + D), presented in the following examples .

Example 1. Experimental studies to determine the applicability of the proposed method for the treatment of hepatitis were performed on white outbred rats weighing 180-200 g. Two models of acute hepatitis were used: toxic and autoaggressive.

Acute toxic hepatitis was reproduced by a single intragastric administration to rats of 1% allyl alcohol at a dose of 15 ml / kg.

Acute autoaggressive hepatitis was reproduced by consecutive intravenous administration to rats, first 1 ml of suspension of the three-day-old culture of Propyonibacterium acnes (10 ¹⁰ CFU / ml of isotonic sodium chloride solution), and after 6 days typhoid endotoxin ty-446 series 158 produced by the St. Petersburg Research Institute of Vaccines and 1.5 mg / kg.

The introduction of drugs in the treatment of acute hepatitis was carried out in the following order:

- chloroquine was administered intragastrically at a dose of 15 mg / kg;

- cyclosporin A was administered intragastrically at a dose of 10 mg / kg;

- heparin was administered intraperitoneally at a dose of 200 IU / kg;

- Novocaine was administered intragastrically at a dose of 1.5 mg / kg;

- Mexidol was administered intragastrically at a dose of 10 mg / kg;

- N-acetylcysteine was administered intragastrically at a dose of 10 mg / kg;

- sodium thiosulfate was administered intragastrically at a dose of 50 mg / kg together with novocaine, mexidol and N-acetylcysteine 20-30 minutes after administration of chloroquine and cyclosporin A;

- retinol was administered intragastrically at a dose of 25 mg / kg 30 minutes after the appointment of a mixture of novocaine-mexidol-N-acetylcysteine-sodium thiosulfate;

- vitamin D ₃ was administered intragastrically at a dose of 30 IU / kg together with retinol;

- ascorbic acid was administered subcutaneously at a dose of 30 mg / kg;

- unitiol was administered intramuscularly at a dose of 50 mg / kg;

- α-tocopherol was administered intramuscularly at a dose of 25 mg / kg.

The drugs began to be administered one day after the poisoning of the animals and was carried out once a day. Their introduction was carried out for three days. The dosage of antioxidants has been optimized in preliminary full-factor experiments [174].

The effectiveness of the pharmacological correction of the manifestations of acute forms of hepatitis during therapy according to the prototype method and the claimed method was evaluated by the activity of alanine transaminase (ALT) in the blood serum of animals 1, 3 and 6 days after drug administration. Enzyme activity was determined using a Spectrum biochemistry analyzer. The data obtained are presented in table 1.

As can be seen from the data presented, the treatment by the claimed method provides a more rapid normalization of the level of ALT in the blood serum of animals in both toxic and autoaggressive hepatitis.

In the above periods, an assessment was also made of the intensity of lipid peroxidation processes in rat liver by the level of activity of prooxidant enzymes: xanthine oxidase (CSR), myeloperoxidase (MP) of Kupffer cells and some indicators of the state of the antioxidant system: content of reduced glutathione (GSH), catalase activity (K ), glucose-6-phosphate dehydrogenase (G-6-FDG) in the liver tissue.

Xanthine oxidase activity (CSR) was evaluated spectrophotometrically by the rate of change in the concentration of uric acid in the incubation medium and expressed as μM uric acid / mg protein per 1 minute.

Myeloperoxidase (MP) activity was determined by the histochemical method in cryostatic (-20 ° С) sections of the liver with a thickness of 15 μm and expressed in arbitrary units.

The concentration of reduced glutathione (GSH) was determined photocolorometrically by a method based on the reduction of sodium nitroprusside by glutathione in an alkaline medium to form a colored compound, and expressed in μM GSH / g liver tissue.

Catalase activity was measured spectrophotometrically by the rate of decrease of hydrogen peroxide in the incubation medium and expressed in μM H ₂ O ₂ / mg protein per 1 minute.

Evaluation of the activity of glucose-6-phosphate dehydrogenase (G-6-FDH) was also performed spectrophotometrically by the rate of change of the NADPH content in the incubation medium. Enzyme activity was expressed as μM NADPH / mg protein per minute.

The results were subjected to statistical processing. The significance of differences between groups was evaluated by t-student test.

The results of experimental studies are presented in tables 2, 3 and 4.

As can be seen from the data presented, the dynamics of the manifestations of toxic and autoaggressive hepatitis developed in parallel with an increase in the activity of xanthine oxidase and myeloperoxidase in the liver tissue. In groups of experimental animals, the treatment of which was carried out by the claimed method, a significantly faster normalization of the activity indicators of these enzymes was observed.

The opposite picture is noted from the side of indicators of the state of bioantioxidants. In the midst of experimental hepatitis, a decrease in the content of reduced glutathione, the activity of catalase and glucose-6-phosphate dehydrogenase in the liver tissue of animals was observed. Treatment by the claimed method provided a more rapid restoration of these indicators of the antioxidant system in animals with both variants of experimental hepatitis.

Thus, experimental studies have shown the feasibility and advisability of using the proposed method of treatment in a clinic for the treatment of acute forms of viral hepatitis.

Example 2. Clinical studies on the basis of the St. Petersburg city hepatological center and 442 district clinical military hospital of the Leningrad military district (St. Petersburg).

The treatment by the claimed method was carried out in the treatment of 21 patients with a diagnosis of Acute hepatitis B (9 people), acute mixed hepatitis B + D (3 people), acute mixed hepatitis B + C (7 people), acute mixed hepatitis B + C + D (2 people).

The treatment according to the prototype method was carried out in the treatment of 19 patients with a diagnosis of Acute hepatitis B (6 people), acute mixed hepatitis B + D (2 people), acute mixed hepatitis B + C (10 people), acute mixed -Hepatitis B + C + D (1 person).

A control group of 15 people received only basic therapy, which consisted of a protective regimen, diet No. 5, heavy drinking (2-3 l / day), multivitamins, intravenous infusions of 5% glucose solution, Ringer's solution of 500-1000 ml / day with 5 ml of riboxin, hemodesis or neohaemodesis, 200-400 ml / day, 10-20% albumin solution, 50-100 ml / day.

All patients are men from 17 to 40 years old. The composition of the groups is identical in diagnosis and age. All patients had an icteric form with cholestatic syndrome, a severe course.

When implementing the treatment according to the prototype method, patients in addition to basic therapy (protective regimen, diet No. 5, heavy drinking (2-3 l / day), drug exposure involving multivitamins, intravenous infusion of 5% glucose solution, Ringer's solution of 500- 1000 ml / day with 5 ml of riboxin, hemodesis or neogemodesis of 200-400 ml / day, 10-20% albumin solution of 50-100 ml / day) received perfluorane, which was administered intravenously in a dose of 400 ml 1-2 times per day for 2-3 days. The dose of perftoran was regulated depending on body weight and severity of the patient's condition and was 800-1200 ml per course.

During the treatment of the claimed method, patients in addition to basic therapy (protective mode, diet No. 5, heavy drinking (2-3 l / day), medication, including multivitamins, intravenous infusion of 5% glucose solution, Ringer's solution of 500-1000 ml / day with 5 ml of riboxin, hemodesis or neohaemodesis of 200-400 ml / day, 10-20% albumin solution of 50-100 ml / day) received:

- chloroquine in the form of a 5% solution at a dose of 10 ml intravenously drip twice a day on the first day after the start of therapy and at a dose of 5 ml intravenously drip twice a day on subsequent days;

- cyclosporin A intravenously drip for 2-3 hours twice a day based on the daily dose of 3.5-4.0 mg / kg;

- heparin intravenously for 3-4 hours once a day at a dose of 5000 ME on the first day after the start of therapy and at a dose of 5000 ME under the skin around the navel once a day on the following days (under the control of the blood coagulation system);

- novocaine in the form of a 0.25% or 0.5% solution intravenously once a day, based on a daily dose of 1.5 mg / kg;

- Mexidol (emoxipin succinate) in the form of a 5% solution at a dose of 2 ml intravenously twice a day;

- ascorbic acid in the form of a 5% solution in a dose of 2 ml intramuscularly twice a day;

- α-tocopherol in the form of a 10% oil solution at a dose of 1 ml intramuscularly twice a day;

- unitiol in the form of a 5% solution in a dose of 5 ml intramuscularly twice a day;

- N-acetylcysteine at a dose of 10 mg / kg orally twice a day;

- Retinol 5000 IU orally in capsules after meals, twice a day;

- sodium thiosulfate in the form of a 30% solution in a dose of 5 ml intravenously twice a day on the first day after the start of treatment and once a day on subsequent days;

- Vitamin Ds 1000 IU orally twice a day.

Chloroquine, cyclosporin A, heparin, unitiol and sodium thiosulfate were prescribed for 2-4 days, and the rest of the listed drugs for 10 days.

The effectiveness of the proposed method for the treatment of acute forms of viral hepatitis was evaluated by the content in the blood serum of patients with bilirubin and the activity of alanine transaminase (ALT) 3, 6 and 12 days after the start of therapy. ALT activity was determined by the standard Reitman-Frenkel dinitrophenylhydrazine method.

The initial indicators of bilirubin content and ALT activity, at which treatment was prescribed by the claimed method, were 461 ± 31 μM / L and 30.4 ± 3.1 mm / hour · L, respectively, with a norm of up to 20 μM / L and 0.68 mm / hour.l respectively.

The dynamics of these indicators under the influence of the treatment of the claimed method in patients with acute forms of viral hepatitis in comparison with a similar group of patients who received treatment according to the prototype method, are presented in table 5.

As can be seen from the data presented, the claimed method of treatment of acute forms of viral hepatitis contributes to a significantly faster normalization of the level of bilirubin and transaminase activity in the blood serum of patients.

In order to prove the antioxidant effectiveness of the proposed method for the treatment of acute forms of viral hepatitis, we studied its effect on the intensity of peroxidation processes in terms of myeloperoxidase activity in peripheral blood neutrophil granulocytes, the content of reduced glutathione, catalase activity and glucose-6-phosphate dehydrogenase in red blood cells using the above methods. In acute hepatitis, the dynamics of the state of neutrophil prooxidant systems reflects that of Kupffer cells, and the dynamics of erythrocyte antioxidant systems in general corresponds to that of hepatocytes [199].

The results are presented in tables 6, 7 and 8.

As can be seen from the data presented, the implementation of the proposed method for the treatment of acute forms of viral hepatitis is accompanied by distinct antioxidant effects, which are expressed in a significantly faster decrease in the activity of the neutrophil myeloperoxidase prooxidant enzyme and the erythrocyte antiradical factors stimulation (the content of reduced glutathione, the activity of catalase and -6-phosphate dehydrogenase).

The term of treatment in ICU for patients with acute forms of viral hepatitis who underwent treatment by the claimed method was 4.1 ± 0.3 days against 6.2 ± 0.5 days in the treatment according to the prototype method (p <0.05), and the duration of further treatment in the hospital decreased from 27.2 ± 3.5 days (prototype method) to 14.7 ± 3.0 days (the claimed treatment method) (p <0.05). As a result of treatment of acute forms of viral hepatitis by the claimed method, the economic costs per patient decreased by thirty-eight thousand rubles.

Thus, the use of the proposed method for the treatment of acute forms of viral hepatitis in the medical practice of infectious hospitals will ensure high efficiency in the treatment of patients with acute forms of viral hepatitis B, mixed hepatitis (B + C, B + D, B + C + D) and significantly reduce material costs.

The claimed invention meets the criterion of "novelty", since for the first time for the treatment of acute forms of viral hepatitis B and mixed hepatitis (B + C, B + D, B + C + D), complex pathogenetic therapy using pharmacological agents with a pronounced modulating effect is recommended on key pathogenetic mechanisms of pathology formation during viral infectious process.

The claimed invention meets the criterion of "inventive step", since the previously known properties of the pharmacological agents used do not imply the feasibility of their complex use for modulating effects on various pathogenetic links in the formation of an inadequate inflammatory response in acute forms of viral hepatitis B and mixed hepatitis (B + C, B + D, B + C + D), that is, the possibility of their use in the complex pathogenetic therapy of acute forms of viral hepatitis B and mixed hepatitis (B + C, B + D, B + C + D).

Compliance with the criterion of "industrial applicability" is proved by the fact that all drugs used in the implementation of the proposed method for the complex pathogenetic treatment of acute forms of viral hepatitis B and mixed hepatitis (B + C, B + D, B + C + D) are produced by industry in ready-to-use form and are widely used in clinical practice in the treatment of various categories of patients. The possibility of using the proposed method of complex pathogenetic therapy of acute forms of viral hepatitis B and mixed hepatitis (B + C, B + D, B + C + D) in clinical practice is proved by the above results of experimental studies and clinical trials.

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Table 1 The dynamics of the activity of alanine transaminase (ALT) in the blood serum of rats with experimental hepatitis under the influence of treatment according to the prototype method and the claimed method Groups of animals Method of treatment ALT activity (u / l) Time after starting treatment 1 day 3 days 6 days 1. Control (n = 8) - 63.0 ± 12.7 2. Toxic hepatitis (n = 17) 1077.9 ± 112.3 234.8 ± 22.6 83.7 ± 19.2 3. Toxic hepatitis (n = 17) Prototype method 758.0 ± 92.4 82.3 ± 16.8 54.3 ± 13.5 4. Toxic hepatitis (n = 16) The inventive method 410.5 ± 45.6 * 58.5 ± 9.4 55.7 ± 8.2 5. Autoaggressive hepatitis (n = 14) - 1174.5 ± 125.9 376.6 ± 13.4 140.4 ± 20.5 6. Autoaggressive hepatitis (n = 13) Prototype method 1015.4 ± 94.8 223.5 ± 20.6 66.2 ± 14.0 7. Autoaggressive hepatitis (n = 17) The inventive method 472.2 ± 57.3 ** 81.9 ± 6.7 ** 56.6 ± 8.3 * - differences between groups 3 and 4 are significant (p <0.05)
** - differences between groups 6 and 7 are significant (p <0.05)

table 2 The dynamics of the content of reduced glutathione (GSH) in rat liver tissue during experimental hepatitis under the influence of treatment by the prototype method and the claimed method Groups of animals Method of treatment GSH Content (μM / g) Time after starting treatment 1 day 3 days 6 days 1. Control (n = 8) - 4.82 ± 0.32 2. Toxic hepatitis (n = 17) 2.32 ± 0.19 3.05 ± 0.24 4.60 ± 0.27 3. Toxic hepatitis (n = 17) Prototype method 2.77 ± 0.20 3.42 ± 0.30 5.23 ± 0.28 4. Toxic hepatitis (n = 16) The inventive method 4.21 ± 0.31 * 4.92 ± 0.36 * 6.54 ± 0.33 * 5. Autoaggressive hepatitis (n = 14) - 2.06 ± 0.12 2.72 ± 0.26 4.02 ± 0.32 6. Autoaggressive hepatitis (n = 13) Prototype method 2.14 ± 0.15 3.04 ± 0.23 5.34 ± 0.34 7. Autoaggressive hepatitis (n = 17) The inventive method 3.75 ± 0.18 ** 4.33 ± 0.29 ** 6.71 ± 0.35 * * - differences between groups 3 and 4 are significant (p <0.05)
** - differences between 6) and 7 groups are significant (p <0.05)

Table 3 The dynamics of the activity of xanthine oxidase (KCO) and myeloperoxidase (MP) in rat liver tissue during experimental hepatitis under the influence of treatment by the prototype method and the claimed method Groups of animals Method of treatment KCO activity (μM / mg protein per minute) MP activity (Conventional units) Time after starting treatment 1 day 3 days 6 days 1 day 3 days 6 days 1. Control (n = 8) - 0.280 ± 0.036 0.178 ± 0.030 2. Toxic hepatitis (n = 17) - 0.752 ± 0.092 0.424 ± 0.036 0.315 ± 0.034 0.390 ± 0.040 0.288 ± 0.025 0.190 ± 0.013 3. Toxic hepatitis (n = 17) Prototype method 0.523 ± 0.079 0.352 ± 0.031 0.268 ± 0.027 0.285 ± 0.031 0.193 ± 0.019 0.165 ± 0.014 4. Toxic hepatitis (n = 16) Declare. way 0.304 ± 0.032 * 0.241 ± 0.020 0.223 ± 0.021 0.194 ± 0.019 * 0.167 ± 0.015 0.122 ± 0.012 5. Autoaggressive hepatitis (n = 14) 0.920 ± 0.111 0.577 ± 0.053 0.391 ± 0.038 0.630 ± 0.051 0.415 ± 0.042 0,304 ± 0,031 6. Autoaggressive hepatitis (n = 13) Prototype method 0.876 ± 0.098 0.456 ± 0.044 0.295 ± 0.025 0.611 ± 0.048 0.326 ± 0.028 0.213 ± 0.018 7. Autoaggressive hepatitis (n = 17) Declare. way 0.405 ± 0.053 ** 0.285 ± 0.029 0.220 ± 0.021 ** 0.359 ± 0.038 ** 0.204 ± 0.018 0.155 ± 0.016 ** * - differences between groups 3 and 4 are significant (p <0.05)
** - differences between groups 6 and 7 are significant (p <0.05)

Table 4 The dynamics of the activity of catalase (K) and glucose-6-phosphate dehydrogenase (G-6-FDH) in rat liver tissue during experimental hepatitis under the influence of treatment by the prototype method and the claimed method Groups of animals Method of treatment Activity K (μM / mg protein per minute) The activity of G-6-FDG (μm / mg protein per minute) Time after starting treatment 1 day 3 days 6 days 1 day 3 days 6 days 1. Control (n = 8) - 0.199 ± 0.021 54.4 ± 5.2 2. Toxic hepatitis (n = 17) - 0.124 ± 0.011 0.142 ± 0.018 0.184 ± 0.016 36.2 ± 5.8 41.6 ± 5.9 53.8 ± 4.7 3. Toxic hepatitis (n = 17) Prototype method 0.155 ± 0.012 0.157 ± 0.021 0.228 ± 0.016 42.4 ± 5.8 45.4 ± 5.5 69.2 ± 5.1 4. Toxic hepatitis (n = 16) The inventive method 0.231 ± 0.019 * 0.238 ± 0.021 * 0.283 ± 0.024 60.9 ± 5.9 65.9 ± 5.8 78.3 ± 5.3 5. Autoaggressive hepatitis (n = 14) - 0.095 ± 0.009 0.130 ± 0.014 0.157 ± 0.013 28.8 ± 4.6 30.8 ± 4.4 45.1 ± 4.8 6. Autoaggressive hepatitis (n = 13) Prototype method 0.112 ± 0.017 0.161 ± 0.02 0.295 ± 0.025 26.6 ± 4.0 37.2 ± 5.0 67.2 ± 5.2 7. Autoaggressive hepatitis (n = 17) The inventive method 0.198 ± 0.018 ** 0.256 ± 0.027 ** 0.271 ± 0.021 44.3 ± 4.1 ** 67.5 ± 5.9 ** 89.4 ± 6.3 ** * - differences between groups 3 and 4 are significant (p <0.05)
** - differences between groups 6 and 7 are significant (p <0.05)

Table 5 The dynamics of the content of bilirubin and the activity of atanine transaminase (ALT) in the blood serum of patients with acute forms of viral hepatitis under the influence of treatment according to the prototype method and the claimed method Patient groups The content of bilirubin (μm / l) ALT activity, (mm / hour · l) Time after the start of intensive care 0 days 3 days 6 days 12 days 0 days 3 days 6 days 12 days 1. Control (basic therapy)
(n = 15) 450 ± 12 414 ± 21 347 ± 18 254 ± 12 28.9 ± 5.6 23.8 ± 3.3 16.8 ± 3.5 10.2 ± 2.7 2. Therapy according to the prototype method
(n = 15) 452 ± 35 285 ± 28 198 ± 20 82 ± 13 28.6 ± 7.4 19.6 ± 4.0 9.4 ± 2.3 5.6 ± 1.0 3. Therapy of the claimed method (n = 18) 461 ± 31 167 ± 15 * 86 ± 9 * 21 ± 5 * 30.4 ± 3.1 8.7 ± 1.9 * 4.9 ± 1.1 2.9 ± 0.6 * * - differences between groups 2 and 3 are significant (p <0.05)

Table 6 The dynamics of the activity of myeloperoxidase neutrophilic granulocytes of peripheral blood in patients with acute forms of viral hepatitis under the influence of treatment according to the prototype method and the claimed method Patient groups Myeloperoxidase activity (arbitrary units) Time after the start of intensive care 0 days 3 days 6 days 12 days 1. Healthy faces (n = 8) 0.475 ± 0.017 2. Control (basic therapy) (n = 5) 0.693 ± 0.123 0.671 ± 0.098 0.625 ± 0.077 0.551 ± 0.045 3. Therapy according to the prototype method (n = 9) 0.688 ± 0.108 0.582 ± 0.081 0.534 ± 0.060 0.464 ± 0.036 4. Therapy of the claimed method (n = 12) 0.701 ± 0.117 0.315 ± 0.022 * 0,307 ± 0,042 * 0.283 ± 0.027 * * - differences between groups 3 and 4 are significant (p <0, <05)

Table 7 The dynamics of the content of reduced glutathione (GSH) in peripheral blood erythrocytes in patients with acute forms of viral hepatitis under the influence of treatment according to the prototype method and the claimed method Patient groups GSH Content (μM / g Hb) Time after the start of intensive care 0 days 3 days 6 days 12 days 1. Healthy faces (n = 8) 14.0 ± 4.1 2. Control (basic therapy) (n = 5) 7.2 ± 2.4 8.1 ± 2.6 8.9 ± 3.0 9.5 ± 2.8 3. Therapy according to the prototype method (n = 9) 7.0 ± 2.5 9.3 ± 2.8 12.2 ± 3.1 13.5 ± 3.3 4. Therapy of the claimed method (n = 12) 7.2 ± 2.3 19.8 ± 2.9 * 24.7 ± 3.5 * 26.8 ± 4.4 * * - differences between groups 3 and 4 are significant (p <0.05)

Table 8 The dynamics of the activity of catalase (K) and glucose-6-phosphate dehydrogenase (G-6-FDH) in peripheral blood red blood cells in patients with acute forms of viral hepatitis under the influence of treatment by the prototype method and the claimed method Patient groups Activity K (μM / g Hb · min) The activity of G-6-FDG (μm / g Hb · min) Time after the start of intensive care 0 days 3 days 6 days 12 days 0 days 3 days 6 days 12 days 1. Healthy faces (n = 8) 38.5 ± 3.8 34.8 ± 4.4 2. Control (basic therapy) (n = 5) 20.3 ± 3.3 22.7 ± 3.1 25.5 ± 3.3 28.2 ± 2.8 16.7 ± 3.4 18.8 ± 2.6 21.5 ± 2.9 24.6 ± 3.6 3. Therapy according to the prototype method (n = 15) 19.7 ± 3.0 26.8 ± 2.9 33.2 ± 3.4 36.6 ± 3.1 17.2 ± 3.0 25.3 ± 2.8 31.4 ± 3.5 33.2 ± 3.4 4. Therapy of the claimed method (n = 12) 17.9 ± 3.2 39.4 ± 3.5 * 46.9 ± 3.9 * 42.5 ± 2.9 17.8 ± 3.2 39.7 ± 4.2 * 52.8 ± 4.2 * 47.5 ± 3.8 * * - differences between groups 3 and 4 are significant (p <0.05)

Claims (3)

1. The method of complex pathogenetic therapy of acute forms of viral hepatitis B and mixed hepatitis B + C, B + D, B + C + D, including basic therapy, characterized in that the basic therapy consists of a protective regimen, diet No. 5, heavy drinking 2-3 l / day, medication, including multivitamins, intravenous infusion of 5% glucose solution, Ringer's solution of 500-1000 ml / day with 5 ml of riboxin, hemodesis or neohaemodesis 200-400 ml / day, 10- 20% albumin solution of 50-100 ml / day, in addition to basic therapy, a set is prescribed Exx of drugs that suppress the replication of viruses and the inflammatory response of macrophages, namely chloroquine, cyclosporin A, heparin, novocaine, mexidol, ascorbic acid, α-tocopherol, unitiol, N-acetylpistein, retinol, sodium thiosulfate, vitamin D ₃ . 2. The method of complex pathogenetic therapy of acute forms of viral hepatitis B and mixed hepatitis B + C, B + D, B + C + D according to claim 1, characterized in that drugs that suppress the replication of viruses and the inflammatory response of macrophages are prescribed the following doses and with the following modes of administration:
- chloroquine in the form of a 5% solution at a dose of 10 ml intravenously drip twice a day on the first day after the start of therapy and at a dose of 5 ml intravenously drip twice a day on subsequent days;
- cyclosporin A intravenously for 2-3 hours twice a day based on a daily dose of 3.5-4.0 mg / kg;
- heparin intravenously for 3-4 hours once a day at a dose of 5000 ME on the first day after the start of therapy and at a dose of 5000 ME under the skin around the navel once a day on the following days (under the control of the blood coagulation system);
- novocaine in the form of a 0.25% or 0.5% solution intravenously once a day, based on a daily dose of 1.5 mg / kg;
- Mexidol in the form of a 5% solution in a dose of 2 ml intravenously twice a day;
- ascorbic acid in the form of a 5% solution in a dose of 2 ml intramuscularly twice a day;
- α-tocopherol in the form of a 10% oil solution at a dose of 1 ml intramuscularly twice a day;
- unitiol in the form of a 5% solution in a dose of 5 ml intramuscularly twice a day;
- N-acetylcysteine at a dose of 10 mg / kg orally twice a day;
- Retinol 5000 IU orally in capsules after meals, twice a day;
- sodium thiosulfate in the form of a 30% solution in a dose of 5 ml intravenously twice a day on the first day after the start of treatment and once a day on subsequent days;
- Vitamin D ₃ at 1000 ME orally twice a day. 3. The method of complex pathogenetic therapy of acute forms of viral hepatitis B and mixed hepatitis B + C, B + D, B + C + D according to claim 1, characterized in that chloroquine, cyclosporin A, heparin, unitiol and sodium thiosulfate are prescribed in for 2-4 days, and novocaine, mexidol, ascorbic acid, α-tocopherol, N-apetildistein, retinol and vitamin D ₃ are prescribed for 10 days.