RU2703535C1 - Combination of antiviral agents for treating influenza viral pneumonia and use thereof - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to a combination of antiviral agents for treating viral influenza pneumonia, as well as to using a combination of riamilovir and oseltamivir. Combination of antiviral agents consists of riamylovir (methylthionenitrooxodihydrotriazolo-triazinide sodium) and oseltamivir ((3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester, phosphate), taken in the following ratios, mg/kg/day: riamilovir – 12.5 or 25.0, oseltamivir – 5.0.

EFFECT: implementation of the invention will make it possible to increase clinical effectiveness of anti-influenza preparations riamilovir and oseltamivir of influenza virus pneumonia, as well as to reduce duration of the main symptoms of the disease.

3 cl, 6 dwg, 3 tbl

Description

The claimed invention relates to the pharmaceutical industry, and in particular to antiviral pharmaceutical combinations for the treatment of viral influenza pneumonia.

One of the approaches to increasing the effectiveness of a chemotherapy drug against a viral infection is its use in combination with another drug. The advantages of combination therapy are the use of lower doses of drugs, which, in turn, can increase the effectiveness of their use, as well as reduce side effects (Govorkova E.A., Webster RG Combination chemotherapy for influenza. Viruses. 2010 Aug; 2 (8 ): 1510-29 - [1]).

In addition, the use of combination therapy is one of the possible ways to prevent the emergence of drug-resistant strains of the virus.

A combination of oseltamivir ((3R, 4R, 5S) -4- (Acetylamino) -5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ether), rimantadine (alpha-methyltricyclo, is known in the art) [3.3.1.13,7] decan-1-methanamine (as hydrochloride) and ribavirin (1- (3-0-ribofuranosyl-1 H-1,2,4-triazole-3-carboxamide) in cell culture, effective in against rimantadine and oseltamivir resistant influenza strains (Nguyen JT, Hoopes JD, Le M.N. et al. Triple combination of amantadine, ribavirin, and oseltamivir is highly active and synergistic against drug resistant influenza virus strains in vitro. PLoS One 2010; 5 (2): e9332 - [2]). This combination was successfully applied in the treatment of severe cases of influenza caused by the pandemic H1 influenza virus strains.

The synergistic effect of the combination of umifenovir (6-bromo-5-hydroxy-1-methyl-4-dimethylaminomethyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (in the form of a monohydrate hydrochloride) with rimantadine and oseltamivir has been shown to be effective in cell culture. such a combination was confirmed in clinical studies (Leneva IA Medical agent for treating viral infections. Patentlnternational Pub. No. WO / 2007/075102: International Application No .: PCT / RU2005 / 000677, 2007 - [3]; Leneva I.A., Fedyakina IT, Guskova TA, Glushkov RG Sensitivity of various strains of the influenza virus to arbidol. Study of the effect rbidola on the reproduction of influenza A virus in combination with various therapeutic antivirals file 2005, №8 pp 84-88 -.. [4]).

It is shown that the best results are obtained by a combination of drugs with a different mechanism of action [1].

The target for zanamivir and oseltamivir preparations used in chemotherapy for influenza virus is the surface glycoprotein neuraminidase, the function of which these drugs inhibit.

Known riamilovir (methylthionitrooxodihydrotriazolotriazinide sodium, "Triazavirin®") is a preparation of the azoloazine family, an analogue of purine nucleoside (guanosine), which is an inhibitor of viral RNA synthesis and replication of genomic fragments (Chupakhin O.K., Kiselev O.Kavir, editors. new generation drug.Monograph, 2016 - [5]), which has a wide spectrum of antiviral activity and is effective for a number of acute respiratory viral infections (Tikhonova EP, Kuzmina T.Yu., Andronova NV, Tyushevskaya .A., Elisshratova T.A., Kuzmin A.E. Study of the effectiveness of antiviral drugs (umifenovir, triazavirin) in relation to acute respiratory viral infections (Kazan Medical Journal, 2018, Volume 99, No. 2 - [6]), including influenza A and B, as in cell culture (Loginova S.Ya., Borisevich S.V., Maksimov V.A. et al. Study of the antiviral activity of triazavirin against the causative agent of influenza A (H5N1). Antibiotics and chemotherapy. 2007.V. 52.No11-12. P. 18-20 - [7], and in the model of secondary pneumonia of mice after influenza infection (Leneva I. A., Falynskova I. N, Makhmudova NR, Glubokova EA, Kartasheva NP, Leonova EI, Mikhailova NA, Shestakova IV Effect of triazavirine on the outcome of a lethal influenza infection and secondary bacterial pneumonia following influenza in mice. Microbiology Independent Research (MIR) journal. Volume 4, Number 1, 2017. P. 52-57 - [8]).

Triazavirin is included in the clinical guidelines for the treatment of influenza in adults (Federal Clinical Recommendations edited by the International Association of Specialists in the Field of Infections (ISSAI) "Adult Influenza", 2017. P. 32 - [9]; Clinical Recommendations of the National Scientific Society of Infectious Diseases ”And“ All-Russian Public Organization Russian Scientific Medical Society of Therapists ”, 2017, p. 29 - [10].

It has been established that the use of riamilovir in the etiotropic treatment of influenza reduces the duration of the main symptoms of the disease, such as fever intoxication, catarrhal symptoms, and also significantly reduces the incidence of complications and the volume of symptomatic therapy.

Current data indicate its pleiotropicity. However, the main mechanism of riamilovir, in all likelihood, is the inhibition of viral RNA synthesis and replication of genomic fragments (Triazavirin (Triazavirin) Instructions for use, registration number LP-002604 - [11]).

The technical result aimed at achieving the invention proposed for protection is to increase the effectiveness of treatment with influenza drugs riamilovir and oseltamivir of viral influenza pneumonia, reducing the duration of the main symptoms of the disease.

The specified technical result is achieved in that the combination of antiviral agents for the treatment of influenza virus pneumonia according to the invention consists of riamilovir (sodium methylthionitrooxodihydrotriazolotriazinide) and oseltamivir ((3R, 4R, 5S) -4-acetylamino-5-amino-3- (1-ethylpropoxy ) -1-cyclohexene-1-carboxylic acid ethyl ether, phosphate) taken in the following ratios, mg / kg / day:

Riamilovir - 12.5 or 25.0

Oseltamivir - 5.0

The use of a combination of antiviral agents consisting of riamilovir (sodium methylthionitrooxodihydrotriazolotriazinide) and oseltamivir ((3R, 4R, 5S) -4-acetylamino-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester, phosphate), for the treatment of viral influenza pneumonia according to the first embodiment, in which the daily dose of rialomivir is 12.5 mg / kg / day, and oseltamivir is 5.0 mg / kg / day.

The use of a combination of antiviral agents consisting of riamilovir (sodium methylthionitrooxodihydrotriazolotriazinide) and oseltamivir ((3R, 4R, 5S) -4-acetylamino-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester, phosphate), for the treatment of viral influenza pneumonia according to the second option, in which the daily rialomivir is 25.0 mg / kg / day, and oseltamivir is 5.0 mg / kg / day.

The invention is illustrated by drawings, where

FIG. 1 is a graph of the survival of mice treated with riamilovir, oseltamivir and their combinations in a model of influenza pneumonia in mice infected with a low dose (MLD90) of influenza virus (experiment I);

FIG. 2 is a graph of the change in body weight of mice during treatment with riamilovir, oseltamivir and their combinations on the model of influenza pneumonia in mice infected with a low dose (MLD90) of influenza virus (experiment I);

Figure 3 is a graph of the survival of mice treated with riamilovir, oseltamivir and their combinations in a model of influenza pneumonia in mice infected with a high (10 MLD50) dose of the influenza virus (experiment II);

FIG. 4 is a graph of the change in body weight of mice treated with riamilovir, oseltamivir and their combinations on the model of influenza pneumonia in mice infected with a high (10 MLD50) dose of the influenza virus (experiment I);

FIG. 5 - distribution of foci of pneumonia on total sections of the lungs of mice of experimental groups, where Gr. 1 - control group; Gr. 2 - group receiving 12.5 mg / kg of riamilovir; Gr. 3 - group receiving 25.0 mg / kg of riamilovir; Gr. 4 - group receiving 5 mg / kg of oseltamivir; Gr. 5 - a group receiving a composition containing oseltamivir 5 mg / kg and riamilovir 12.5 mg / kg;

FIG. 6 - a histogram of the magnitude - the dependence of the volume fraction of inflammatory infiltrate on the drug used and its dose.

The implementation of the invention is confirmed by examples of specific performance.

A study was made of the combined effect of riamilovir with the anti-influenza drug neuroaminidase inhibitor oseltamivir in two series of independent experiments using different doses of virus infection - low MLD90 (MLD - mouse lethal doses) and high 10 MLD50. To determine the dose of the virus containing MLD90 and 10 MLD50, groups of animals were infected with the obtained whole allantoic virus with successive 10-fold dilutions thereof. According to the data indicating the death of mice, the necessary doses of the virus were calculated.

To simulate influenza pneumonia in mice, the influenza virus strain A / California / 04/2009 (PNM H1N1 2009) was used, obtained from the World Health Organization (WHO) and adapted to mice. To prepare the infectious material, the mice were infected intranasally with the allantoic virus. After the manifestation of the signs of the disease under sterile conditions, a homogenate of lung tissue was obtained, which was then used to infect 10-day-old chicken embryos intended for cultivation of the allantoic virus. After determining the infectious activity of the virus, it was used to infect animals. In both experiments, one of which involved infecting with a low dose (MLD90) of the influenza virus, the other with high dose infection (10 MLD50) of the virus, aliquots of one pool of the virus were used, which were frozen and stored at a temperature of - 70 ° С.

Substance of riamilovir (methylthionitrooxodihydrotriazolo-triazinide, Triazavirin) provided by the manufacturer, Medsintez Plant LLC, and oseltamivir dosage form in the form of Tamiflu capsules manufactured by Hoffmann-La Roche Ltd were used as medications.

Before the experiment, the preparations were dissolved in distilled water in order to prepare solutions for their subsequent administration to animals.

Doses of oseltamivir were prepared and subsequently indicated based on the calculation of the content of pure substance in the dosage form.

The substances were weighed to the nearest 0.1 mg on an analytical balance. Doses of drugs were calculated in relative weight units — mg / kg body weight of animals (mice) per day.

The solutions of each of the preparations, as well as their combinations, were orally administered to animals in a total volume of 200 μl.

The following doses were taken as the studied doses: riamilovir - 12.5 and 25.0 mg / kg / day; oseltamivir - 5.0 mg / kg / day; as well as combinations thereof containing riamilovir 12.5 or 25.0 mg / kg / day and oseltamivir 5.0 mg / kg / day.

Nonlinear mice - females weighing 12-14 g, were kept on a standard diet in vivarium. The keeping of animals corresponded to the rules for the design, equipment and maintenance of experimental biological clinics (vivariums). The animals were fed with briquetted feed in accordance with the approved standards. Animals had free access to water. Marking of animals according to the experimental groups was carried out by coloring the surface of the body with various dyes.

All experiments were carried out in accordance with the rules of humane treatment of animals and approved by the Ethics Committee of the Scientific Research Institute of Vaccines and Serums named after I.I. Mechnikov, Moscow.

Experience I.

A study of the effect of a combination of riamilovir and oseltamivir on a mouse influenza pneumonia model induced by a low (MLD90) dose of influenza virus compared with a single use of riamilovir or oseltamivir.

When determining the effectiveness of treatment with riamilovir, the following treatment regimen was used: the drug was administered 24 hours before infection, 4 hours before and 4 hours after infection, and then the drug was administered 2 times a day for 5 days.

When treating animals with oseltamivir alone, the following regimen was used: the drug was administered 1 hour before infection, then 8 hours after infection, and then twice a day for 5 days.

The combination of riamilovir and oseltamivir was used according to the treatment regimen of oseltamivir.

For oral administration of drugs, a disposable insulin syringe with a probe for feeding animals was used.

All animals were divided into five groups, each of which included 18 individuals.

Pre-weighed mice were infected intranasally under anesthesia with influenza virus A / California / 04/09 at a dose of MLD90.

In this case, animals of the control group infected with the influenza virus did not receive any treatment, except for orally administered distilled water in a volume of 200 μl, according to the scheme of using a combination of antiviral agents.

All animals receiving and not receiving treatment were monitored daily. The first five days after infection with the low-dose influenza virus, the mice were weighed every day, and then weighed after one to two days.

The chemotherapeutic activity of drug compounds in a mouse viral influenza pneumonia model was evaluated according to the following criteria: animal survival, increased average life expectancy, and reduced weight loss in groups of animals treated with drugs compared to the control group not treated. The average life expectancy of mice was calculated by the formula: MSD = Σf (d-1) / n, where the f-number of mice died on day d, the surviving mice are also included in f and d in this case is 16, the n-number of mice in the group. The decrease or increase in weight was calculated separately for each mouse and expressed as a percentage, while the weight of the animal before infection was taken as 100%. For all mice of the same group, the average percentage loss or weight gain was determined.

On the fourth day after infection with a low dose of influenza virus, 3 animals were killed in the lungs to determine the titer of the virus, and 5 were scored for morphological studies. Thus, 10 animals remained in each group.

After killing in each group of 3 mice, their lungs were removed under sterile conditions. After washing in phosphate-buffered saline (PBS), the lungs were homogenized and resuspended in 1 ml of cold sterile PBS. The suspension was clarified from cell debris by centrifugation at 2000 g for 10 min. and then the supernatant was used to determine the infectious titer of the virus in an MDCK cell culture (Madin-Darby Canine Kidney - Dog Kidney Cell Culture).

After killing in each group of 5 mice, 1 ml of 10% buffered formalin was injected into each animal through a trachea using a syringe. After inflating the trachea with a surgical instrument, the sternum was opened, the lungs were removed and placed in a glass container with formalin.

Lungs of mice were performed using ascending alcohol solutions and xylenes in a Tissue-Tek VIP5Jr apparatus. Dehydrated samples were poured into histomyx on a Tissue-Tek TEC apparatus. Total stepwise sections of the lungs with a thickness of 4-6 μm were made on a Microm HM340E model microtome, dewaxed and stained with hematoxylin and eosin.

To quantify the prevalence of inflammatory changes in the lungs, stepwise total sections (3 levels) were scanned and combined into a single image using an Axioplan 2 Imaging Carl Zeiss microscope. Then, using the computer program Adobe Photoshop, the areas of inflammatory infiltration in the obtained images were circled with a light pen and painted in red. The remaining sections of the sections, without signs of an inflammatory process, were outlined and stained blue. Area measurements were carried out using Image-Pro Premier 3D 9.1 Media Cibernetics Inc. morphometric software. Bulk density (P / p), the fraction of the area of the infiltrate of the total cut-off area, was calculated.

The obtained digital data were subjected to statistical processing using a computer program, for example, “Statistica 8.0”. Since the number of animals in the groups was small and the distribution did not obey the normal distribution law, methods of nonparametric statistics were applied. At the same time, the central trends were calculated as the median of both the lower (25%) and upper (75%) quartiles, and the comparison of the data obtained for all groups was carried out using the Kruskal-Wallis test multiple comparisons method.

Comparison of survival rates in groups of animals was carried out using one-way analysis of variance (ANOVA) in the computer program "Statistica 8.0".

For a graphical representation of the obtained data, the Kaplan-Meier method was used.

When comparing the weight changes of mice, we used a one-way analysis of variance for non-linear models, as well as a four-parameter log-logistic model. Data analysis was performed in the R-Studio application (Version 1.0.136), the 'drc' package (C. Ritz, 2016).

In the control group of animals infected with a low dose of influenza virus and not receiving any treatment, from the fourth day, the death of mice was observed, and by the 16th day of observation only 1 out of 10 mouse survived (Fig. 1).

The average life expectancy in this group was 9.5 days (Table 1).

Analysis of changes in body weight of animals showed that in the control group of mice that did not receive treatment, there was a maximum decrease in body weight, reaching about 15% by the 7th day of observation (Fig. 2).

Treatment with riamilovir alone reduced the mortality of animals and increased their average life expectancy at doses of 12.5 and 25.0 mg / kg / day, however, these effects were not statistically significant. In these groups, a lower weight reduction was also noted compared with the control group (Fig. 2).

Treatment with oseltamivir alone at a dose of 5.0 mg / kg / day was similar in effectiveness to treatment with riamilovir at doses of 12.5 and 25.0 mg / kg / day, protecting 40% of infected animals, increasing their average life expectancy (Fig. 1, 2), while weight loss in this group was not observed.

The use of combinations of riamilovir in two doses of 12.5 and 25.0 mg / kg / day with oseltamivir at a dose of 5.0 mg / kg / day was more effective than treatment with each of the drugs separately, statistically significantly reducing the death of mice, preventing loss weight and increasing the average life expectancy of infected and treated animals. With a combination of riamilovir with oseltamivir, increasing the dose of riamilovir from 12.5 to 25 mg / kg / day did not lead to an increase in the effectiveness of treatment in all respects.

The results of a virological study of the lungs of the animals studied confirmed clinical efficacy data. Separate treatment with riamilovir in all doses studied, as well as with oseltamivir alone at a dose of 5.0 mg / kg / day, about the same, by 1.0-1.33 lg TTsID50 (tissue cytopathic infectious dose 50) inhibited the titer of the virus, but this inhibition was not statistically significant. With the combined use of rialomivir and oseltamivir preparations, the inhibition of virus reproduction in the lungs of animals is statistically significant and amounts to 3.5-3.67lg TTsID50 (Table 1).

Experience II

Study of the combined effect of riamilovir with oseltamivir on a model of influenza pneumonia in mice induced by a high (10 MLD50) dose of influenza virus compared with a separate use of riamilovir or oseltamivir

In the second series of experiments, a high dose of infection with 10 MLD50 mice was used, which caused a more acute course of infection and the death of all animals in the viral control group.

In the control group of animals infected with influenza virus at a dose of 10 MLD50 and not receiving treatment, in accordance with the dose of infection, starting from day 5, death was observed, which took place in two days, i.e. by the 7th day of observation reached 100% (Fig. 3). The average life expectancy in this group was 5.5 days.

By the day of the complete death of the mice of the control group, treatment as a separate riamilovir in two studied doses of 12.5 and 25.0 mg / kg / day and separately oseltamivir at a dose of 5.0 mg / kg / day, as well as their combinations almost completely prevented the death animals. Treatment of the highest studied doses of riamilovir protected one third of the animals from mortality, while the weight loss of animals from influenza virus pneumonia was comparable with the viral control group (Table 2, Fig. 4).

Upon further observation of the animals, it was noted that death was observed in all groups of treated animals. By the end of the observation period, it turned out that treatment with only riamilovir at doses of 12.5 and 25.0 mg / kg / day was similar in effectiveness to treatment with oseltamivir at a dose of 5.0 mg / kg / day and protected 40-50% of animals from mortality , increasing their life expectancy by 1.6-2 times and reducing weight loss.

Treatment with a combination of riamilovir at doses of 12.5 and 25.0 mg / kg / day with oseltamivir at a dose of 5.0 mg / kg / day was more effective than treatment with each of the drugs in appropriate doses individually. This treatment led to protection from mortality of 70-77% of animals, an increase in their life expectancy by more than 2 times, and to almost complete prevention of weight loss (Fig. 3, 4).

Treatment with all drugs separately inhibited the reproduction of the virus in the lungs of animals (table 1).

The most clinically effective treatment with combinations of drugs completely suppressed the reproduction of the virus in the lungs: the virus in the lungs of such animals was not determined.

In all groups in the lungs of mice infected with the influenza virus, extensive foci of bronchopneumonia were detected, the lumens of the alveoli were filled with lymphocytes, macrophages, erythrocytes and neutrophils. In bronchi of different orders, exudate was determined from neutrophils, lymphocytes, macrophages, the epithelium was focally desquamated (Fig. 5). In the lungs of mice treated with riamilovir alone at a dose of 12.5 mg / kg / day, no differences from the control group were found.

In groups of mice treated with riamilovir at a dose of 25.0 mg / kg / day, oseltamivir at a dose of 5 mg / kg / day, a combination of riamilovir at a dose of 12.5 mg / kg / day and oseltamivir at a dose of 5 mg / kg / day , the foci of pneumonia were clearly defined and located mainly peribronchial, while the hemorrhagic component was less pronounced in them.

In addition to a qualitative histological study of the lungs of animals, a quantitative morphometric analysis was performed. Data on a quantitative assessment of the prevalence of the inflammatory process in the lungs of mice after infection with influenza viruses and treatment with antiviral drugs are presented in a histogram (Fig. 6).

Table 3 presents the confidence level of the results of digital data comparison.

Gr. 1: - control; Gr. 2: riamilovir -12.5 mg / kg; Gr. 3: riamilovir - 25.0 mg / kg;

Gr. 4: oseltamivir - 5.0 mg / kg; Gr. 5: oseltamivir 5.0 mg / kg + riamilovir 12.5 mg / kg;

According to morphometric estimates, riamilovir in doses of 12.5 and 25.0 mg / kg did not have a therapeutic effect. The introduction of the drug oseltamivir in a dose of 5.0 mg / kg had a therapeutic effect - the bulk density P / r of the foci of inflammatory infiltration was reduced by 53% compared with the mice of the control group.

The combination of oseltamivir at a dose of 5.0 mg / kg and riamilovir at a dose of 12.5 mg / kg had a noticeable therapeutic effect, while the bulk density P / p of inflammatory infiltrate was reduced by 60%, compared with the lungs of untreated mice, as well as compared with a group of animals treated with riamilovir alone at a dose of 12.5 mg / kg. Thus, a histological study of the lungs fully confirmed the data obtained by clinical signs and in the virological study of the lungs of mice.

Studies on a model of influenza pneumonia in mice showed that a combination of riamilovir at doses of 12.5 or 25.0 mg / kg / day with oseltamivir at a dose of 5.0 mg / kg / day can increase the effectiveness of treatment compared to the treatment efficiency of each from drugs taken in the appropriate dose and taken according to the appropriate scheme. This treatment in a model of influenza pneumonia in mice statistically significantly reduced the death of animals, prevented their loss of body weight and increased life expectancy compared with the control group of untreated animals.

These combinations of drugs when infected with a low dose of the virus reduced the reproduction of the virus in the lungs of animals, and at a high dose of infection, the reproduction of the virus was completely suppressed. In addition, treatment with a combination of riamilovir at a dose of 12.5 mg / kg / day with oseltamivir had an effect on the state of the lungs of animals, reducing the area of the foci of pneumonia. This study confirmed that the combined effect of drugs is more effective than the action of each of the drugs separately. Previous studies have shown that riamilovir in the mouse influenza pneumonia model has a narrow therapeutic window, that is, a concentration range at which it is effective.

In the studies conducted, the combination of riamilovir with oseltamivir reduced the concentration of riamilovir without reducing its effectiveness. Currently, strains resistant to riamilovir have not been identified in either experimental or clinical practice. Resistance to oseltamivir during its clinical use is detected in 1.5-2.5% of adult patients and reaches a higher percentage in children (18%), as well as patients suffering from impaired immune systems [Hurt A.S. The epidemiology and spread of drug resistant human influenza viruses. Curr Opin Virol. 2014; 8: 22-29. - [12].

The use of a combination of riamilovir with oseltamivir for the treatment of viral influenza pneumonia also reduces the risk of resistance to oseltamivir. The data obtained are the basis for the optimization of regimens and doses of treatment with influenza drugs riamilovir and oseltamivir of influenza virus pneumonia.

Claims (4)

1. The combination of antiviral agents for the treatment of viral influenza pneumonia according to the invention consists of riamilovir (sodium methylthionitrooxodihydrotriazolotriazinide) and oseltamivir ((3R, 4R, 5S) -4-acetylamino-5-amino-3- (1-ethylpropoxy) -1-cyclohex -1-carboxylic acid ethyl ether, phosphate) taken in the following ratios, mg / kg / day: Riamilovir - 12.5 or 25.0 Oseltamivir - 5,0 2. The use of a combination of antiviral agents consisting of riamilovir (sodium methylthionitrooxodihydrotriazolotriazinide) and oseltamivir ((3R, 4R, 5S) -4-acetylamino-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ether, phosphate), for the treatment of viral influenza pneumonia, in which the daily dose of rialomivir is 12.5 mg / kg / day, and oseltamivir is 5.0 mg / kg / day. 3. The use of a combination of antiviral agents consisting of riamilovir (sodium methylthionitrooxodihydrotriazolotriazinide) and oseltamivir ((3R, 4R, 5S) -4-acetylamino-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ether, phosphate), for the treatment of viral influenza pneumonia, in which the daily dose of rialomivir is 25.0 mg / kg / day, and oseltamivir is 5.0 mg / kg / day.

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