Anti-influenza Drugs Research Articles

Pathophysiological effects\xa0of Tamiflu on liver and kidneys of male rats

BackgroundTamiflu/oseltamivir phosphate (OP), an anti-influenza drug, has a highly doubted safety especially after many cases of abnormal behaviour and deaths reported after being used. Such controversy was also locally and globally generated, especially after being heavily used in COVID-19 treatment protocol. This study was designed to evaluate the effect of three different doses of OP on the liver and kidneys of male adult albino rats through histological approaches, measuring their DNA integrity and biochemical analyses. Different doses of Tamiflu applied to humans were converted to rats, then observed their effects on the liver and kidneys. Rats were divided into four groups. G1: considered as control group. The rest of the three treated groups were received the same calculated dose of Tamiflu (6.75 mg/kg b.w.) in three different durations. G2, G3 and G4 represented the animals orally received OP, in which the rats received OP twice for 5 consecutive days, once for 10 and 45 days, respectively.ResultsOur data showed numerous deleterious necrotic and fibrotic histopathological changes in the liver, and kidneys; as well as necrotic DNA smears, by using electrophoresis, in OP-treated rats of G2 and G4. In addition, OP significantly increased the serum cellular hepatic/renal toxicity markers (ALT, AST, ALP, GGT, indirect bilirubin, urea, creatinine, uric acid, & Na+). Also, it showed a reduction in the levels of serum total protein, albumin and K+ ions in rats of G2 and G4 compared with G1. In G3, OP treatment did not significantly alter hepatic/renal histological, DNA integrity and biochemical analyses in rats. ConclusionsThe therapeutic and long-term prophylactic doses of OP most likely cause structural and functional hepato- and nephrotoxicity in experimentally subjected rats. So, caution must be taken during Tamiflu treatment, and not used for long durations and/or with repetitive doses (time- and/or accumulative-dose-dependent); especially with patients suffer from liver and/or kidney dysfunction, while the short-term prophylactic dose of OP appears to be relatively safe and could be explored for oral medications.Graphical

Synthesis and antiviral activity of formycin derivatives with anti-influenza virus activity

In a screening using our unique natural product library, the C-nucleoside antibiotic formycin A, which exerts strong anti-influenza virus activity, was rediscovered. Aiming to develop a new type of anti-influenza virus drug, we synthesized new derivatives of formycin and evaluated its anti-influenza virus activity. Structural modifications were focused on the base moiety and sugar portion, respectively, and >40 novel formycin derivatives were synthesized. Modification of the C-7 position of the pyrazolopyrimidine ring strongly contributed to improve the activity. In particular, excellent anti-influenza virus activity was observed in the NHMe (10), SMe (12), and SeMe (15) derivatives, in which heteroatoms were introduced. In addition, in the modification of the sugar moiety, the presence of a hydroxyl group and its stereochemistry greatly affected both the expression and intensity of the activity. Furthermore, the evaluation results of the 7-SEt derivative (29) and the 2′-modified derivative (59) suggested that structural modifications may reduce cytotoxicity.

A Comparison for Time for Drug Administration Guidance and Patient’s Pharmacy Stay between Anti-influenza Drugs in Insurance Pharmacies

A Comparison for Time for Drug Administration Guidance and Patient’s Pharmacy Stay between Anti-influenza Drugs in Insurance Pharmacies

The MEK1/2-inhibitor ATR-002 efficiently blocks SARS-CoV-2 propagation and alleviates pro-inflammatory cytokine/chemokine responses

Coronavirus disease 2019 (COVID-19), the illness caused by a novel coronavirus now called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to more than 260 million confirmed infections and 5 million deaths to date. While vaccination is a powerful tool to control pandemic spread, medication to relieve COVID-19-associated symptoms and alleviate disease progression especially in high-risk patients is still lacking. In this study, we explore the suitability of the rapid accelerated fibrosarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase (Raf/MEK/ERK) pathway as a druggable target in the treatment of SARS-CoV-2 infections. We find that SARS-CoV-2 transiently activates Raf/MEK/ERK signaling in the very early infection phase and that ERK1/2 knockdown limits virus replication in cell culture models. We demonstrate that ATR-002, a specific inhibitor of the upstream MEK1/2 kinases which is currently evaluated in clinical trials as an anti-influenza drug, displays strong anti-SARS-CoV-2 activity in cell lines as well as in primary air–liquid-interphase epithelial cell (ALI) cultures, with a safe and selective treatment window. We also observe that ATR-002 treatment impairs the SARS-CoV-2-induced expression of pro-inflammatory cytokines, and thus might prevent COVID-19-associated hyperinflammation, a key player in COVID-19 progression. Thus, our data suggest that the Raf/MEK/ERK signaling cascade may represent a target for therapeutic intervention strategies against SARS-CoV-2 infections and that ATR-002 is a promising candidate for further drug evaluation.

Functional Analysis of Sulfatide in Influenza A Virus Infection and Replication.

3-O-sulfation synthesizes sulfatide in the galactose moiety of galactosylceramide. Sulfatide is expressed in many organs such as the gastrointestinal tract, trachea, kidney, and central nervous system. Influenza A virus binds not only to glycoconjugates terminally containing sialic acid as a viral binding receptor but also to sulfatide not containing sialic acid. On the surface of infected cells, the envelope glycoprotein hemagglutinin of influenza A virus interacts with sulfatide. This interaction enhances the nuclear export of viral ribonucleoprotein complexes, resulting in efficient progeny viruses. Inhibiting this interaction would be a new potent anti-influenza drug that suppresses the progeny virus production in the infected cells.

Creation of a model for studying the antiviral effect of small interfering RNAs in vitro

Influenza is a widespread respiratory infection, accompanied by damage to the lower respiratory tract of a person, and can lead to severe complications, up to a fatal outcome. Currently existing therapeutic agents and vaccines do not provide fully effective protection against influenza viruses. The development and creation of drugs based on the mechanism of RNA interference in the context of this problem is a promising direction. The aim of this study is to select and experimentally substantiate cellular target genes for miRNAs whose knockdown suppresses viral reproduction. A549 cells (human lung adenocarcinoma) were transfected with small interfering RNAs. After 4 hours, the transfected cells were infected with the influenza virus pri MOI = 0.1; 0.01 and 0.001. The virus-containing liquid was sampled within three days from the moment of transfection and the intensity of the dynamics of viral reproduction was assessed by the CPD titration method. The use of all small interfering RNAs at MOI = 0.1 resulted in a significantly significant decrease in the viral titer relative to non-specific control. Similar results were obtained at MOI = 0.01 and 0.001. The most effective siRNA ISSINUP98, since when using it, at MOI = 0.1, the viral titer values decreased by 1.7 lg TCD50/ml and by 3 lg TCD50/ml at MOI = 0.01 on the third day. The results showed that miRNAs directed to human cellular genes FLT4, Nup98 and Nup205, whose derivatives play an important role in the life cycle of the influenza virus, effectively reduce its reproduction in vitro. Thus, the studied genes and their products are potential targets for the development of anti-influenza drugs.

Creation of a model for studying the antiviral effect of small interfering RNAs in vitro

Influenza is a widespread respiratory infection, accompanied by damage to the lower respiratory tract of a person, and can lead to severe complications, up to a fatal outcome. Currently existing therapeutic agents and vaccines do not provide fully effective protection against influenza viruses. The development and creation of drugs based on the mechanism of RNA interference in the context of this problem is a promising direction. The aim of this study is to select and experimentally substantiate cellular target genes for miRNAs whose knockdown suppresses viral reproduction. A549 cells (human lung adenocarcinoma) were transfected with small interfering RNAs. After 4 hours, the transfected cells were infected with the influenza virus pri MOI = 0.1; 0.01 and 0.001. The virus-containing liquid was sampled within three days from the moment of transfection and the intensity of the dynamics of viral reproduction was assessed by the CPD titration method. The use of all small interfering RNAs at MOI = 0.1 resulted in a significantly significant decrease in the viral titer relative to non-specific control. Similar results were obtained at MOI = 0.01 and 0.001. The most effective siRNA ISSINUP98, since when using it, at MOI = 0.1, the viral titer values decreased by 1.7 lg TCD50/ml and by 3 lg TCD50/ml at MOI = 0.01 on the third day. The results showed that miRNAs directed to human cellular genes FLT4, Nup98 and Nup205, whose derivatives play an important role in the life cycle of the influenza virus, effectively reduce its reproduction in vitro. Thus, the studied genes and their products are potential targets for the development of anti-influenza drugs.

Enzymatic Substrates and Fluorescence Imaging of Influenza Virus Sialidase.

Immunostaining with an antiviral antibody is usually performed to visualize virus-infected cells. In contrast, this study established an easy method for fluorescence (FL) imaging of cells infected with influenza A and B viruses and some paramyxoviruses without the need for cell fixation and an antiviral antibody. These viruses and the cells they have infected express the viral surface enzymes "neuraminidase" or "hemagglutinin-neuraminidase," which show sialidase activity. Sialidase activity is fluorescently visualized by using a sialidase fluorogenic probe developed in our previous study. The probe enables histochemical FL imaging of the virus-infected cells and applies to virus isolation and detection of an influenza virus resistant to sialidase inhibitors anti-influenza drugs.

Способность экстрактов некоторых съедобных грибов подавлять репродукцию вируса гриппа

In this work, extracts from the mycelium of some xylophytic fungi: Pleurotus eryngii, Auricularia auriculajudae, Tremella fuciformis were obtained, the toxicity of the obtained extracts was evaluated, and the antiviral activity was researched. The influenza virus was grown in the allantois cavity of chicken embryos. The infectious titer of the influenza virus was determined by titration on chicken embryos. The presence of the virus was judged by the reaction of hemagglutinating activity. The virus infectivity titer was calculated using the Reed-Muench method. The hemagglutinating activity of viruses was determined by a standard method using 0.75 % suspension of chicken red blood cells. The main criterion for studying the specific antiviral effect of compounds was the CTI (chemical-therapeutic index), that is determined by the ratio of the average toxic concentration of the substance (TC50) to the average effective viral inhibitory concentration (EC50). The antiviral activity of the obtained extracts was studied on a model of human, animal and bird influenza viruses, in the dose range from 0.025 mcg/ml to 1.25 mcg/ml using the methodological recommendations of the “Guidelines for conducting Preclinical studies of medicines”. While studying the acute toxicity of 3 obtained fungi extracts, it was found that all studied fungi compounds with a single intragastric injection to white mongrel mice, did not show a toxic effect in the studied dose range. During the study of the ability to suppress the reproduction of various strains of the influenza virus, it was found that extracts of the fungi Auricularia auricula-judae and Tremella fuciformis have possessed antiviral properties, and extracts exceed in terms of CTI to commercial anti-influenza drugs.

Comparison of the incidence of bleeding between baloxavir marboxil and other anti‐influenza drugs among outpatients with influenza virus infection: A retrospective cohort study using an employment‐based health insurance claims database in Japan

PurposeAlerts for bleeding events are included in the Japanese package inserts of some anti‐influenza drugs, including baloxavir marboxil and oseltamivir. However, there are few reports on the incidence of bleeding events during treatment with anti‐influenza drugs. This large‐scale quantitative assessment compared the incidence of bleeding events in influenza patients treated with baloxavir and other anti‐influenza drugs and in untreated patients.MethodsThis retrospective cohort study used a large‐scale Japanese employment‐based health insurance claims database provided by JMDC Inc. and included outpatients diagnosed with influenza between October 1, 2018 and April 11, 2019. Bleeding events were identified by International Classification of Diseases 10th revision codes. Incidences were compared between patients treated with baloxavir or neuraminidase inhibitors and untreated patients. Odds ratios were calculated after exact matching to adjust for potential confounders.ResultsAmong 529 201 influenza episodes, 30 964 were untreated and 498 237 were treated with anti‐influenza drugs: baloxavir, 207 630; oseltamivir, 143 722; zanamivir, 28 208; peramivir, 5304; laninamivir, 113 373. Crude incidence proportions for total bleeding up to 20 days after influenza diagnosis were similar among treated groups, with a slightly higher value for peramivir (0.21% vs. 0.19% for baloxavir, oseltamivir, zanamivir, and laninamivir), and 0.30% in untreated patients. After exact matching, the incidence of bleeding for baloxavir was similar to that for other anti‐influenza treatments (odds ratios for baloxavir were 0.90–0.99 compared to other therapies).ConclusionsBased on real‐world observation using a large‐scale claims database, a similar incidence of bleeding events was observed in recipients of the different anti‐influenza drugs.

Drug Repurposing for Influenza Virus Polymerase Acidic (PA) Endonuclease Inhibitor.

Drug repurposing can quickly and effectively identify novel drug repurposing opportunities. The PA endonuclease catalytic site has recently become regarded as an attractive target for the screening of anti-influenza drugs. PA N-terminal (PAN) inhibitor can inhibit the entire PA endonuclease activity. In this study, we screened the effectivity of PAN inhibitors from the FDA database through in silico methods and in vitro experiments. PAN and mutant PAN-I38T were chosen as virtual screening targets for overcoming drug resistance. Gel-based PA endonuclease analysis determined that the drug lifitegrast can effectively inhibit PAN and PAN-I38T, when the IC50 is 32.82 ± 1.34 μM and 26.81 ± 1.2 μM, respectively. Molecular docking calculation showed that lifitegrast interacted with the residues around PA or PA-I38 T’s active site, occupying the catalytic site pocket. Both PAN/PAN-I38T and lifitegrast can acquire good equilibrium in 100 ns molecular dynamic simulation. Because of these properties, lifitegrast, which can effectively inhibit PA endonuclease activity, was screened through in silico and in vitro research. This new research will be of significance in developing more effective and selective drugs for anti-influenza therapy.

Effectiveness of Chinese patent medicine in the treatment of influenza: A protocol for systematic review and meta-analysis.

Background:Western medicine mainly uses antiviral drugs to treat influenza. However, anti-influenza virus drugs have been reported to have high levels of drug resistance and varying degrees of adverse reactions. In addition, Western medicine uses vaccination to prevent influenza, but vaccination cannot ensure complete prevention. Vaccines have a certain lag and cannot prevent the constantly mutating influenza virus. At present, there are still certain limitations in the prevention of influenza. In recent years, traditional Chinese medicine has been used more and more widely in the prevention and treatment of influenza and improvement of influenza-like symptoms, and related clinical efficacy control studies have reached a certain number. Therefore, the purpose of this study is to systematically evaluate the effectiveness of Chinese patent medicine in the treatment of influenza.Methods:Computer search of PubMed, Cochrane Library, Embase, CNKI, Wangfang and VIP database, search for randomized controlled trials of Chinese patent medicines therapy on influenza, the search time limit is to build the database until October 2021. Two researchers screened the retrieved literature and collected relevant patient information and data. The final included literature was meta analyzed by Rev man5.4 software.Results:The effectiveness and safety of Chinese patent medicines in the treatment of patients with influenza will be systematically evaluated.Conclusion:Systematic collection and analysis of clinical randomized controlled trials of Chinese patent medicines for the treatment of influenza, with a view to providing basic information for clinical decision-making and related research.Registration number:INPLASY2021100064 (https://inplasy.com/inplasy-2021- 10-0064/).

Molecular Docking and Virtual Screening of an Influenza Virus Inhibitor That Disrupts Protein-Protein Interactions.

Influenza is an acute respiratory infection caused by the influenza virus, but few drugs are available for its treatment. Consequently, researchers have been engaged in efforts to discover new antiviral mechanisms that can lay the foundation for novel anti-influenza drugs. The viral RNA-dependent RNA polymerase (RdRp) is an enzyme that plays an indispensable role in the viral infection process, which is directly linked to the survival of the virus. Methods of inhibiting PB1–PB2 (basic polymerase 1–basic polymerase 2) interactions, which are a key part of RdRp enzyme activity, are integral in the design of novel antiviral drugs, a specific PB1–PB2 interactions inhibitor has not been reported. We have screened Enamine’s database and conducted a parallel screening of multiple docking schemes, followed by simulations of molecular dynamics to determine the structure of a stable ligand—PB1 complex. We also calculated the free energy of binding between the screened compounds and PB1 protein. Ultimately, we screened and identified a potential PB1–PB2 inhibitor using the ADMET prediction model.

Design and Synthesis of Oleanolic Acid Trimers to Enhance Inhibition of Influenza Virus Entry.

Influenza is a major threat to millions of people worldwide. Entry inhibitors are of particular interest for the development of novel therapeutic strategies for influenza. We have previously discovered oleanolic acid (OA) to be a mild influenza hemagglutinin (HA) inhibitor. In this work, inspired by the 3D structure of HA as a homotrimeric receptor, we designed and synthesized 15 OA trimers with different linkers and central region via the copper-catalyzed azide-alkyne cycloaddition reaction. All of the OA trimers were evaluated for their antiviral activities in vitro, and 12c, 12e, 13c, and 13d were observed to exhibit robust potency (IC50 in the submicromolar range) against influenza A/WSN/33 (H1N1) virus that was stronger than that observed with oseltamivir. In addition, these compounds also displayed strong biological activity against A/Hong Kong/4801/2014 and B/Sichuan/531/2018 (BV). The results of hemagglutination inhibition assays and surface plasmon resonance binding assays suggest that these OA trimers may interrupt the interaction between the HA protein of influenza virus and the host cell sialic acid receptor, thus blocking viral entry. These findings highlight the utility of multivalent OA conjugates to enhance the ligand-target interactions in anti-influenza virus drug design and are also helpful for studying antiviral drugs derived from natural products.

Single and multiple dose pharmacokinetics and safety of ZSP1273, an RNA polymerase PB2 protein inhibitor of the influenza A virus: a phase 1 double-blind study in healthy subjects

ABSTRACT Background Influenza is an acute respiratory illness. Treating with antiviral drugs can decrease the duration of illness and serious complications . ZSP1273 is a small-molecule anti-influenza drug targeting the RNA polymerase PB2 subunit of the influenza virus. The aim of this clinical trial was to evaluate the safety and pharmacokinetics (PKs) of ZSP1273 in healthy subjects. Research design and methods This was a double-blind, placebo-controlled phase 1 study consisting of three parts. 100 volunteers were enrolled and randomized to receive either single or multiple doses of ZSP1273 or placebo. Results A total of 31 (31.0%) subjects experienced at least one mild or moderate adverse event. The linear regression relationship between dose and plasma Cmax, AUC0-t, and AUC0-∞ showed an increasing trend and rapid absorption of ZSP1273. A high-fat diet had little effect on the PKs. The plasma concentration of ZSP1273 reached steady state on day 5 without drug accumulation. Conclusions ZSP1273 was safe in healthy volunteers. Based on the preclinical resuilts, safety profile and PK characteristics of ZSP1273, the dose of ZSP1273 (≥200 mg) may be used for future clinical trials in influenza patients. Trial Registration The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03679143).

Association of bleeding symptoms during influenza infection and administered drugs.

On March 1, 2019, the Ministry of Health, Labour and Welfare added bleeding symptoms to adverse reaction package inserts as a possible adverse event for a new anti-influenza drug, baloxavir marboxil, because 13 patients with bleeding symptoms were identified among influenza patients taking the drug. Nevertheless, aspects of the epidemiology of bleeding symptoms among influenza patients remain unclear. This study elucidated bleeding symptoms among influenza patients and hospitalized patients as severe cases. A survey was administered to all physicians in Japan during the 2019-2020 season for reporting of bleeding symptoms in influenza patients. The survey elicited information about outcomes, assuming associated underlying diseases and drugs in addition to administered drugs including acetaminophen and anti-influenza (antiviral) drugs. We received reports of 63 cases with bleeding symptoms, including 5 cases of hospitalized patients. Among all patients, 54% had been administered oseltamivir; 10% had been administered baloxavir marboxil. Among hospitalized patients, all had been administered acetaminophen; 40% of them had been administered oseltamivir, and one patient had been administered baloxavir marboxil. Accumulation of bleeding symptom cases is expected to be necessary to evaluate the association.

Antiviral Activity and Underlying Action Mechanism of Euglena Extract against Influenza Virus.

It is difficult to match annual vaccines against the exact influenza strain that is spreading in any given flu season. Owing to the emergence of drug-resistant viral strains, new approaches for treating influenza are needed. Euglena gracilis (hereinafter Euglena), microalga, used as functional foods and supplements, have been shown to alleviate symptoms of influenza virus infection in mice. However, the mechanism underlying the inhibitory action of microalgae against the influenza virus is unknown. Here, we aimed to study the antiviral activity of Euglena extract against the influenza virus and the underlying action mechanism using Madin–Darby canine kidney (MDCK) cells. Euglena extract strongly inhibited infection by all influenza virus strains examined, including those resistant to the anti-influenza drugs oseltamivir and amantadine. A time-of-addition assay revealed that Euglena extract did not affect the cycle of virus replication, and cell pretreatment or prolonged treatment of infected cells reduced the virus titer. Thus, Euglena extract may activate the host cell defense mechanisms, rather than directly acting on the influenza virus. Moreover, various minerals, mainly zinc, in Euglena extract were found to be involved in the antiviral activity of the extract. In conclusion, Euglena extract could be a potent agent for preventing and treating influenza.

Drug repositioning of Clopidogrel or Triamterene to inhibit influenza virus replication in vitro.

Influenza viruses cause respiratory tract infections and substantial health concerns. Infection may result in mild to severe respiratory disease associated with morbidity and some mortality. Several anti-influenza drugs are available, but these agents target viral components and are susceptible to drug resistance. There is a need for new antiviral drug strategies that include repurposing of clinically approved drugs. Drugs that target cellular machinery necessary for influenza virus replication can provide a means for inhibiting influenza virus replication. We used RNA interference screening to identify key host cell genes required for influenza replication, and then FDA-approved drugs that could be repurposed for targeting host genes. We examined the effects of Clopidogrel and Triamterene to inhibit A/WSN/33 (EC50 5.84 uM and 31.48 uM, respectively), A/CA/04/09 (EC50 6.432 uM and 3.32 uM, respectively), and B/Yamagata/16/1988 (EC50 0.28 uM and 0.11 uM, respectively) replication. Clopidogrel and Triamterene provide a druggable approach to influenza treatment across multiple strains and subtypes.

135 YEARS OF HISTORY AND MODERNITY OF THE STATE INSTITUTION «I. I. MECHNIKOV INSTITUTE OF MICROBIOLOGY AND IMMUNOLOGY OF THE NATIONAL ACADEMY OF MEDICAL SCIENCES OF UKRAINE»

The article is devoted to the results of a retrospective study of the historical path of formation and development of scientific research in State Institution «I. I. Mechnikov Institute of Microbiology and Immunology of the NAMS of Ukraine». The Institute as a scientific institution of anti-epidemic profile was founded in May 1886. At the beginning of the last century, the Institute turned into a major scientific and practical center of pre-revolutionary Russia for the fight against infectious diseases. Already in 1913-1914 the Institute produced 6 types of sera and 7 vaccines. In 1920 the Institute was nationalized, became a state institution and received the name of the Bacteriological Institute, and in 1922 – the First Ukrainian Sanitary-Bacteriological Institute. The Institute was the first in the Soviet Union to begin the production of BCG and became one of the pioneers of the introduction of bacteriophage in the treatment and prevention of intestinal infections: dysentery, typhoid fever, cholera. From 1921 to 1940, the Institute produced more than 40 names of various drugs in an amount exceeding the previous 20 years by more than thirty times. In addition, the Institute currently produces the following serum: diphtheria, scarlet fever, dysentery, meningococcal, pneumococcal, streptococcal, staphylococcal, tetanus, botulinum and 4 gangrenous sera. Since the beginning of the war, the Institute has been evacuated first to Stalingrad and then to Chkalov. During the evacuation, the Institute continues to produce bacteriological preparations. From 1941 to 1945 the release of vaccines and serums amounted to 400% of the pre-war level, only in 1942 110 thousand wounded soldiers received serum against gas gangrene, more than 120 thousand soldiers received tetanus serum. After re-evacuation to Kharkiv, the Institute continued to work on the production of vaccines and serums and, starting in 1944, began the production of smallpox detritus, measles serum and typhus vaccine. At that time, in the laboratory of V. S. Derkach, the antibiotic pyocyanin (or sanazine) was studied and a method for its biosynthesis was developed, and together with the Academy of Sciences of the Ukrainian SSR, its new homologues were synthesized. Also in the laboratory after the war, neocide a drug against cancer was created. The problems of epidemiology at the Institute were developed by the outstanding microbiologist V. M. Zhdanov. From 1946 to 1950 V. M. Zhdanov headed the virological laboratory, and since 1948 – the Kharkov Institute of Microbiology and Epidemiology named I. I. Mechnikov. In 1950, a laboratory for the production of anti-influenza drugs was organized, and a year later, the study and improvement of dry polytype therapeutic and prophylactic anti-influenza serum began. The collection of mycobacterial phages, collected by Professor L. A. Kosobutsky, Doctor of Medical Sciences, was one of the three largest in the world. At the Institute, on the basis of fish oil, the drug «ektericide» was developed. V. L. Nadtoka became the founder of a new scientific direction for the development and use of antimicrobial preparations of plant origin. Under the leadership of V. L. Nadtoka developed dosage forms of the drug chlorophyllipt, which are introduced into production and clinical practice in Ukraine. Now the Institute is a methodological center for the development of theoretical provisions and practical use of laboratory diagnostic methods, anti-epidemic measures, treatment and prevention of infectious diseases, advanced training of bacteriologists, virologists, epidemiologists and other specialists. Currently, on the basis of the Institute, there are a number of divisions of industry-wide importance that coordinate scientific and methodological work in important areas of infection control: the Center for Specific Indication of Biological Pathogenic Agents, the Republican Reference Laboratory of Pathogens of Anaerobic Infections, the Laboratory of New and Little-Studied Infectious Diseases. In general, the staff of the Institute over the years of its existence has developed and introduced into production about 60 different vaccines, sera and other therapeutic and diagnostic immunobiological preparations. The Institute has developed drugs against 21 infections. In addition to immunobiological drugs, the Institute has developed and introduced a number of antimicrobial drugs, among which the most famous are chlorophyllipt, decamethoxin, ektericide, eucavan and others. Keywords: history of science, I.Mechnikov Institute of Microbiology and Immunology, bacteriological preparations, vaccines, serums, bacteriophages, antimicrobial agents, chlorophylipt

Effect of oxidative stress response in acute respiratory distress syndrome caused by influenza

Influenza virus is one of the common pathogens causing acute respiratory infectious diseases, and is easy to cause acute respiratory distress syndrome (ARDS) after infecting human body, which is an important cause of death of influenza patients. Influenza-induced ARDS results from a combination of overwhelming inflammation and immune response, causing tissue damage and apoptosis. Furthermore, virus-mediated oxidative stress is another important mechanism. Viral infection can produce excessive reactive oxygen species, which damage the epithelial-endothelial barrier with pulmonary edema. In this content, numerous studies have highlighted the importance of antioxidants as a new therapy aimed at blocking both viral replication and virus-induced inflammation. Therefore, this paper summarizes the epidemiology and mechanisms of influenza-induced ARDS, the role of oxidative stress in the occurrence and development of influenza-related ARDS and the role of antioxidants in anti influenza virus infection, in order to provide reference for effective treatment of influenza patients, reducing mortality, developing new anti influenza drugs and preventing and controlling influenza epidemic.