RU2586283C1 - INJECTION OR INFUSION SOLUTION OF L-ARGININE SALT OF 5-METHYL-6-NITRO-1,2,4-TRIAZOLO[1,5-a] PYRIMIDIN-7-ONE MONOHYDRATE FOR THERAPY OF INFLUENZA AND OTHER VIRAL INFECTIONS - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: disclosed are compositions for injection and infusion solutions of antiviral preparation wide range of action - L-arginine salt of 5-methyl-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-one monohydrate, including auxiliary components. Infusion and injection solutions of L-arginine salt of 5-methyl-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-one monohydrate are based on use of solubilisers of Glutamine type, which increases solubility of main medicinal component and its bioavailability in tissues in a vascular bed. Introduction of Glutathione and Carnosine is linked with their ability to stabilise cell metabolism of Z-arginine salt of 5-methyl-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-one monohydrate and increasing viability of infected cells.

EFFECT: injection and infusion forms of antiviral preparation based on L-arginine salt of 5-methyl-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-one monohydrate are intended for treating severe forms of viral infections in accordance with pharmacological profile of antiviral activity and primarily complicated by influenza.

2 cl, 2 ex, 2 tbl, 1 dwg

Description

The invention relates to the development of new injection or infusion solutions of the antiviral compound L-arginine salt of 5-methyl-6-nitro-1,2,4-triazolo [1,5-a] pyrimidin-7-one monohydrate (NTP) for the treatment of viral infections .

Triazolopyrimidines were synthesized as compounds close to triazolo-triazines, many of which exhibit a wide spectrum of antiviral activity [T.P. Kofman, T.A. Uvarova, G.Yu. Kartseva, T.L. Assumption 6-Nitro- and 6-bromo derivatives of 4,7-dihydro-1,2,4-triazolo [1,5-a] pyrimidin-7-one, Journal of Organic Chemistry, 1997, v. 33, no. 12, p. 1784-1793]. Compounds - 5-methyl-6-nitro-1,2,4-triazolo [1,5-a] pyrimidin-7-one sodium salt, dihydrate [Chupakhin ON, Rusinov VL, Ulomsky E.N ., Charushin V.N., Petrov A.Yu., Kiselev O.I. 5-methyl-6-nitro-1,2,4-triazolo [1,5-a] pyrimidin-7-one sodium salt, dihydrate. RF patent 2 330036 dated 07/27/2008], L-arginine salt of 5-methyl-6-nitro-1,2,4-triazolo [1,5-a] pyrimidin-7-one, monohydrate [Chupakhin ON, Charushin V.N., Rusinov V.L., Ulomsky E.N., Kotovskaya S.K., Kiselev O.I., Deeva E.G. Savateev K.V., Borisov S.S., 5-Methyl-6-nitro-7-oxo-1,2,4-triazolo [1,5-a] pyrimidinide L-arginine, monohydrate, Positive decision to grant a patent from 06/20/2014 by application 2013116765 from 04/15/2013]. Triazolopyrimidines differ from the well-known drug Triazavirin, a representative of triazolotriazines, both in the synthesis method and in several key structural elements, they have a number of advantages in physicochemical properties and exhibit a wide spectrum of antiviral activity. Moreover, these compounds are closer to natural nitrogen bases due to the inclusion of the pyrimidine ring instead of the triazine in the structure.

Unlike the sodium salt of 2-methylthio-6-nitro-1,2,4-triazolo [5,1-s] -1,2,4-triazin-7 (4H) -one (Triazavirin) [Chupakhin O.N. ., Rusinov V.L., Ulomsky E.N., Charushin V.N., Petrov A.Yu., Kiselev O.I. Sodium salt of 2-methylthio-6-nitro-1,2,4-triazolo [5,1-s] -1,2,4-triazin-7 (4H) -one, dihydrate having antiviral action, RF Patent 2294936 from 03/10/2007], L-arginine salt of 5-methyl-6-nitro-1,2,4-triazolo [1,5-a] pyrimidin-7-one, monohydrate [Chupakhin ON, Charushin VN , Rusinov V.L., Ulomsky E.N., Kotovskaya S.K., Kiselev O.I., Deeva E.G. Savateev K.V., Borisov S.S., 5-Methyl-6-nitro-7-oxo-1,2,4-triazolo [1,5-a] pyrimidinide L-arginine, monohydrate, Positive decision to grant a patent dated 06/20/2014 according to the application 2013116765 dated 04/15/2013] (NTP) lacks the S-methyl group in the 1,2,4-triazole ring, but at the same time retains the nitro group in the pyrimidine ring (analogue of the 1,2,4-triazine ring ) This makes the compound more stable and not prone to oxidation at one of the side substituents. In this case, the basic structure of the compound, including the reactive nitro group, is retained.

Compounds based on azoloazines exhibiting antiviral activity are slightly soluble in water. Therefore, when solving the problem of obtaining dosage forms in the form of injection or infusion solutions, it is necessary to increase the solubility and bioavailability of the drugs selected for these purposes.

The use of salts of NTP based on arginine, in addition to increasing solubility [Kiselev OI, Chupakhin ON, Rusinov VL, et al. Triazavirin injection and infusion solution for the treatment of viral infections. The application for a patent of the Russian Federation, 2013146452/15 (072136) from 10.16.2013] has an additional goal - improving the pharmacological properties of this antiviral agent in the form of an injection or infusion solution. In particular, an additional property of L-arginine is its ability to participate as a substrate of NO synthetase as an NO donor, which is necessary to enhance the antibacterial protection associated with viral infections and increase solubility [Chupakhin ON, Charushin VN, Rusinov V.L., Ulomsky E.N., Kotovskaya S.K., Kiselev O.I., Deeva E.G., Savateev K.V. 5-Methyl-6-nitro-7-oxo-1,2,4-triazolo [1,5-a] pyrimidinide L-arginine monohydrate, per. No. 2013116765 dated 04/15/2013; Sasaki S., Miura T., Nishikawa S., et al. Protective Role of Nitric Oxide in Staphylococcus aureus Infection in Mice. Infection and Immunity. 1998, Vol. 66, p. 1017-1022; Bogdan C. Nitric oxide and the immune response. Nature Immunology 2001, Vol. 2, p. 907-916].

A comparison of the structure of Triazavirin and NTP is presented in FIG. one.

The nitro group in heterocyclic compounds is known to exhibit pharmacological activity against functional drug targets important for cells and viruses [Hoffstrom B.G., Kaplan A., Letso R., Schmid R.S., Turmel G.J., Lo D.C., Stockwell B.R. Inhibitors of protein disulfide isomerase suppress apoptosis induced by misfolded proteins. Nature Chemical Biology, 6, 900-906, (2010), doi: 10.1038 / nchembio.467; Gallina A., Hanley T.M., Mandel R., Trahey M., Broder C.C., Viglianti G.A., Ryser H. J.-P. Prevent HIV-1 Entry Receptor-bound Glycoprotein 120 and Prevent Cleavage of Disulfide Bonds in Inhibitors of Protein-Disulfide Isomerase. doi: 10.1074 / jbc.M204547200 originally published online September 5, 2002. J. Biol. Chem. 2002, 277: 50579-50588]. Therefore, its preservation in the structure of scientific and technical progress is of fundamental importance.

Known infusion and injection solution of an antiviral drug with a wide spectrum of action of Triazavirin, described in the patent application [Kiselev OI, Chupakhin ON, Rusinov VL, et al. Triazavirin injection and infusion solution for the treatment of viral infections. Application for a patent of the Russian Federation, 2013146452/15 (072136) from 10.16.2013], in which injection and infusion solutions for the treatment of severe forms of viral infections were developed for the first time for this class of compounds.

Infusion and injection solutions of Tamiflu (Oseltamivir) and Peramivir [http://www.biocryst.com/peramivir] are also known. A characteristic feature of drugs from the group of neuraminidase inhibitors is a decrease in their therapeutic efficacy in the treatment of influenza pneumonia, accompanied by the development of pulmonary distress syndrome [Short K.R., Veldhuis Kroeze E.J.B., Fouchier R.A.M., Prof Kuiken T. Pathogenesis of influenza-induced acute respiratory distress syndrome. The Lancet Infectious Diseases, Volume 14, Pages 57-69, January 2014. doi: 10.1016 / S1473-3099 (13) 70286-XCite or Link Using DOI; Nakajima N., Sato Y., Katano H. et al. Histopathological and immunohistochemical findings of 20 autopsy cases with 2009 H1N1 virus infection. Modern Pathology (2012) 25, 1-13; doi: 10.1038 / modpathol.2011.125; published online 26 August 2011]. This may be due to increased metabolism of drugs with a high level of reactive oxygen species. The generation of reactive oxygen species (from singlet oxygen to hydroxonium and peroxynitrite) accompanies the processes of pulmonary hypoxia in respiratory failure and distress syndrome. On the other hand, the mechanism of action of neuraminidase inhibitors alone is not perfect enough. In fact, neuraminidase inhibitors block the budding of mature viral particles, disrupting their release from the cells, that is, in other words, the dissemination of a viral infection, which is no longer essential for such serious complications as pulmonary distress syndrome, pulmonary edema, or sepsis.

It is known that pathogenic influenza viruses with high tropism to the lungs cause alveolitis, that is, dispersed small focal lesion of the lung tissue [Jakab GJ, Astry CL, Warr GA. Alveolitis induced by influenza virus. Am Rev Respir Dis. 1983 Oct; 128 (4): 730-9; Jeffery K. Taubenberger J.K., Morens D.M. The Pathology of Influenza Virus Infections. Annu Rev Pathol. 2008; 3: 499-522]. Therefore, it makes no sense to rely on the fact that the blockade of the release of a virus that is budding on pneumocytes will lead to a stop of the interstitial spread of the infection. Thus, in the late stages of infection, when the dissemination of the virus in organs and tissues, and, first of all, in the lungs, the blockade of budding of the virus by neuraminidase inhibitors no longer leads to the expected therapeutic results [Kiselev O.I. Chemotherapy and chemotherapy against the flu. SPb. Ed. "Rostock". 2012. S. 269]. Constructive imperfection, starting with the idea of creating neuraminidase inhibitors, is gradually recognized in the world literature and therefore attempts are being made to create complex drugs that to some extent eliminate the disadvantages of these drugs [Zasloff M., Formulations component aminosterols. US 8623416 B2]. Aminosteroids in combination with Tamiflu are used to reduce the destructive processes in the lung tissue. In the cited patent, it is noted that this group of drugs can reduce the adverse effect of the antiviral drug on the state of the lung tissue.

At the same time, the concept of complex treatment of influenza is much wider. This ideology is the basis of the Russian practice of treating influenza [Kiselev O.I. Chemotherapy and chemotherapy against the flu. SPb. Ed. "Rostock". 2012].

The growing interest in injectable and infusion solutions of influenza drugs relates to the period of the “swine” influenza A (H1N1) pandemic when the intravenous drug Peramivir was created in accelerated mode [http://www.biocryst.com/peramivir; Goldbach P., Grassmann O., Sauer I. Polymorphic forms of oseltamivir phosphate. US Patent, 8,334,319 B2. 2012; Zasloff M., Formulations comprising aminosterols. US 8623416 B2; Babu Y.S., Chand P., Arnold S., Kilpatrick J.M. Intramuscular antiviral treatments. Patent Application Publication (10) Pub. No .: US 2011/0015264 A1; Hilfinge J., Amidon G. Prodrugs of neuraminidase inhibitors. WO2009129305 A2; Kohno S. Kida H., Mizuguchi M., Shimada J. for the S-021812 Clinical Study Group. Efficacy and Safety of Intravenous Peramivir for Treatment of Seasonal Influenza Virus Infection. Antimicrob. Agents Chemother. 2010, p. 4568-4574 Vol. 54, No. eleven].

Peramivir is used in the form of a NaCl solution at a concentration of 0.9 or 0.45% without the accompanying additional components [Kohno S., Kida N., Mizuguchi M., et al. Efficacy and Safety of Intravenous Peramivir for Treatment of Seasonal Influenza Virus Infection. Antimicrob. Agents & Chemother. 2010, Vol. 54, p. 4568-4574; Louie JK, Yang S, Yen C, Acosta M, Schechter R, et al. (2012) Use of Intravenous Peramivir for Treatment of Severe Influenza A (H1N1) pdm09. PLoS ONE 7 (6): e40261. doi: 10.1371 / journal.pone.0040261].

Given the increased level of threat of spread of new strains of pathogenic influenza viruses and, first of all, virus A (H7N9), studies are being conducted to study the effectiveness of intravenous dosage forms of Peramivir. The results allow us to recommend this drug for the treatment of severe cases of influenza caused by the virus A (H7N9) [http://www.chinanews.com/jk/2013/04-06/4705205.shtml].

However, all the above costs of using such a therapeutic approach remain, given that the most serious complication of this type of flu is severe acute respiratory distress syndrome.

It was previously found that the L-arginine salt of 5-methyl-6-nitro-1,2,4-triazolo [1,5-a] pyrimidin-7-one monohydrate has a wide spectrum of antiviral activity.

Injectable forms of antiviral drugs can solve several problems:

- actually antiviral therapy,

- combination with systemic anti-inflammatory therapy,

- detoxification problems with influenza and other infections.

The invention is directed to the development of a medicinal composition for injectable or infusion forms of NTP preparations, which provides increased therapeutic efficacy in the treatment of influenza pneumonia and complicated forms of influenza due to the high metabolic stability and bioavailability of the compound while limiting the amount of fluid introduced into the patient's body. Also expanded the range of pharmacological activity of NTP.

The objectives of the invention are solved as follows:

- using the antiviral compound L-arginine salt of 5-methyl-6-nitro-1,2,4-triazolo [1,5-a] pyrimidin-7-one, monohydrate (NTP) with high solubility and high bioavailability compared to triazavirin and the absence of easily oxidizable substituents and, in particular, the S-methyl group in the second position of the triazole ring;

- the introduction of additional compounds in the form of components that form salts with NTP, providing an expansion of the spectrum of pharmacological activity of NTP;

L-arginine salt of 5-methyl-6-nitro-1,2,4-triazolo [1,5-a] pyrimidin-7-one, monohydrate (NTP) differs from Triazavirin in higher solubility, which makes it possible to prepare solutions with concentrations up to 8 and more percent. In this regard, when using them, it is possible to reduce the amount of fluid introduced to a patient with influenza in conditions that threaten the development of pulmonary edema.

Injection and infusion solutions according to the invention contain the biologically active substance L-arginine salt of 5-methyl-6-nitro-1,2,4-triazolo [1,5-a] pyrimidin-7-one, monohydrate (NTP) [Chupakhin O. N., Charushin V.N., Rusinov V.L., Ulomsky E.N., Kotovskaya S.K., Kiselev O.I., Deeva E.G. Savateev K.V., Borisov S.S., 5-Methyl-6-nitro-7-oxo-1,2,4-triazolo [1,5-a] pyrimidinide L-arginine, monohydrate, Positive decision to grant a patent from 06/20/2014 by application 2013116765 from 04/15/2013].

Additional substances can be introduced into the composition, for example, an auxiliary substance - reduced glutathione (Glu-Cis-Gly tripeptide) in an amount of 2.0% and carnosine in an amount of 2.0%.

In the case of severe viral infection caused by pathogenic flu and complicated by the development of the “cytokine storm”, it is necessary to use antioxidants (ascorbic acid, sulfite compounds, L-cysteine, N-acetylcysteine, thiodipropionic acid, thiolactic acid, monothioglycerol, propyl gallate, etc.). In some cases, there is a need to add local anesthetics to the solutions according to the invention, such as procaine hydrochloride, lidocaine hydrochloride, as well as anticonvulsants, Nf-kB inhibitors, tumor necrosis factor, endothelial and vascular projectors [Short K., Veldhuis Kroeze EJB, Fouchier RAM, Kuiken T. Pathogenesis of influenza-induced acute respiratory distress syndrome. Lancet.com.infection. 2014, Vol. 14 p. 57-69]. A combination with acids, for example succinic acid, sugars, including glucose, mannose, alcohols, for example mannitol or sorbitol, is possible. To accelerate dissolution, the solution is heated in a water bath to 50-60 ° C. Immediately after receiving the salt, the remaining components are dissolved in the composition with stirring before or after cooling, or introduced into it. After adding the rest of the solvent, the composition is sterilized by filtration through a bacterial filter and / or by heating.

The invention is implemented as follows.

Example 1. Obtaining solutions of the L-arginine salt of 5-methyl-6-nitro-1,2,4-triazolo [1,5-a] pyrimidin-7-one, monohydrate (NTP)

In the preparation of injection and infusion solutions were guided by the following conditions.

1. The determination of the solubility threshold to achieve the optimal concentration of injection and infusion solution.

2. Determining the conditions for increasing solubility, bioavailability and metabolic stability.

3. Achievement of the conditions of combination with other substances required to increase the therapeutic antiviral efficacy of the drug NTP.

The study of the solubility of NTP was carried out in the following way. An anchor of a magnetic stirrer, 100 g of water (by weight), 8 g of the preparation, and 8 g of the mixture were stirred at room temperature for 8 h in a suspended glass with a volume of 250 ml. The measurement limit of the weights was 0.2 g. After stirring, the mixture was filtered in a device consisting of a weighed round-bottom flask with a volume of 250 ml, a transition with a tap and a weighed funnel with a thin section. After filtration, the filtrate and the wet cake were weighed separately. The precipitate was allowed to dry, the filtrate was evaporated from the flask completely on a rotary evaporator at a residual pressure in the device of 10–15 mm Hg, the temperature in the bath was 40–50 ° C and also left to dry overnight at room temperature. It was found that the mass of the solution before evaporation was 106.2 g, the mass of the dry preparation was 6.2 g; thus, the solubility of NTP in water was about 6.0% [Kiselev OI, Chupakhin ON, Rusinov V .L. et al. Injection and infusion solution of triazavirin for the treatment of viral infections. Application No. 2013146452/15 (072136) from 10.16.2013].

Example 2. The study of the toxicity of solutions of NTP with intravenous administration

In experiments on rabbits and rodents, the acute toxicity of NTP substance samples was studied [Chupakhin ON, Charushin VN, Rusinov VL, Ulomsky EN, Kotovskaya SK, Kiselev OI, Deeva E.G. Savateev K.V., Borisov S.S., 5-Methyl-6-nitro-7-oxo-1,2,4-triazolo [1,5-a] pyrimidinide L-arginine, monohydrate, Positive decision to grant a patent from 06/20/2014 according to the application 2013116765 from 04/15/2013], synthesized at the Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences.

According to a study of acute and chronic toxicity of NTP in rodents, the average lethal dose of NTP with intraperitoneal administration to rats is> 5000 mg / kg. After oral administration of NTP to rats inside, animals transferred the drug in doses up to 40,000 mg / kg without any visible signs of intoxication. According to studies conducted at St. Petersburg Institute of Pharmacy CJSC, when administered orally to rats, the LD ₅₀ was more than 40,000 mg / kg.

It was established that the nature of the toxic effect is similar in studies in mice and rats, i.e. toxic changes in organs and tissues were practically absent.

In experiments, it was impossible to establish the LD ₅₀ values due to the absence of animal death in the experimental groups with both routes of administration. Therefore, in terms of acute toxicity, the substance NTP can be attributed to class VI relatively harmless substances according to the classification of Hodge and Sterner [Hodge N. et al., 1975].

In acute experiments on rabbits, the toxicity and tolerance of the substance of NTP during the intravenous route of administration were studied. NTP solutions, like Triazavirin, for intravenous administration were prepared using a bipolar solvent of dimethyl sulfoxide (DMSO) and a 0.9% solution of sodium chloride, heated to a temperature of 38-39 °. The need to use DMSO is due to the limited solubility of NTP, like most representatives of the triazolo-triazine and triazolo-pyrimidine compounds. So, at room temperature, the solubility of NTP in water is 8%.

The study of acute toxicity of NTP with the intravenous route of administration was carried out on rabbits with a body weight of 2.5 kg to 3.5 kg contained in the vivarium of the research institute of influenza. NTP was administered in increasing dosages from 700 mg / kg to 1500 mg / kg. The death of animals was not observed. In accordance with the established standards in the experiments, NTP was administered intravenously by both a jet and a drop method in a volume of 100 ml, which is 5 times the recommended volume. At the same time, a dose of 1500 mg / kg was administered. Observation of animals during the week did not allow to reveal changes in their behavior, intensity and nature of motor activity, coordination of movements, consumption of food and water.

NTP as well as the drug Triazavirin [Kiselev OI, Chupakhin ON, Rusinov V.L. et al. Injection and infusion solution of triazavirin for the treatment of viral infections. Application No. 2013146452/15 (1072136) dated 10.16.2013] can be classified as a practically non-toxic compound and is characterized by higher solubility, which makes it possible to prepare more concentrated injection and infusion solutions of the drug and, therefore, to avoid excessive liquid administration.

The injection (infusion) dosage form of the NTP preparation should correspond to a concentration of a substance solution of at least 0.5%, which in a certain volume of administration will ensure its effective concentration in the blood, namely 0.5-10 μg / ml, preferably 2-4 μg / ml . In severe flu, you can increase the dose and reach a concentration of the drug up to 20 μg / ml.

The range of effective doses for humans with a parenteral route of administration is 5.0-25 mg / kg. Therefore, the optimal release form for NTP infusion solutions are 50-100 ml bottles with a content of NTP substance up to 500 mg / vial or 5-10 mg / ml. For the treatment of clinically severe forms of influenza with the development of influenza pneumonia and the threat of pulmonary edema, it is recommended that the drug be administered up to 3 times a day in 1 vial with a dose of 500 mg per intravenous administration. For injection, 5-10 ml solutions with a concentration of 20 to 50 mg can be recommended.

As already mentioned, for the treatment of influenza during the 2009/11 pandemic caused by the “swine” strain of virus A (H1N1) in the USA, the injection and infusion preparation Peramivir (http://www.biocryst.com/peramivir) was registered. The drug is used in an aqueous solution in doses of 6 to 10 mg / kg and is available in powder form in 300 or 600 mg vials to dissolve 0.9 or 0.45% sodium chloride in a solution. Practice has shown that the optimal rate of administration is 40 mg / min. NTP is also well soluble in physiological solutions of sodium chloride. At the same time, Mexidol is more adequate in this case in relatively small volumes, which can be compatible with NTP infusions and serve as an additional detoxification tool by reducing the generation of oxygen free radicals [Kalyanaraman B. Teaching the basics of redox biology to medical and graduate students : Oxidants, antioxidants and disease mechanisms. Redox Biology. 2013, Vol. 1, p. 244-257, Zimniak P. Relationship of electrophilic stress to aging. Free Radical Biology and Medicine. 2011, Vol. 51, p. 1087-1105].

However, the most optimal is the combination of NTP with known antioxidants and drugs that restore and stabilize the redox potential of infected cells. Therefore, the following examples provide compositions of NTP infusion solutions based on these findings and known recommendations for the treatment of emergency conditions in infectious disease clinics [http://www.drrobertamorgan.com/intravenous-therapies-and-infections.htm].

Example 3. The composition of the injection or infusion solutions of the drug

The following are compositions of injection and infusion solutions containing NTP as the main antiviral component. The choice of compositions was carried out on the basis of the following principles.

1. Water-salt composition, ensuring the maintenance of water-salt balance and not interfering with the action of NTP.

2. Solutions containing reduced Glutathione - the Glu-Cis-Gly tripeptide, which is the main component of the redox system of cells. Glutathione in combination with carnosine [Koen R., Yamamoto Y., Cundy K.C., Ames B.N. Antioxidant activity of carnosine, homocarnosine, and anserine present in muscle and brain. Proc. NatI. Acad. Sci. USA 1988, Vol. 85, pp. 3175-3179] is an active protector against the destructive effect of reactive oxygen species, which protects tissues from oxidative stress [Bae O.-N., Serfozo K., Baek S.-H., et. al. Safety and Efficacy Evaluation of Carnosine, an Endogenous Neuroprotective Agent for Ischemic Stroke. Stroke. 2013; 44: 205-212; Ditte Z., Ditte P., Labudova M., Simko V., et al. Carnosine inhibits carbonic anhydrase IX-mediated extracellular acidosis and suppresses growth of HeLa tumor xenografts. BMC Cancer. 2014 May 22; 14: 358. doi: 10.1186 / 1471-2407-14-358], associated with inflammatory processes. Carnosine under hypoxia significantly increases the expression level of the HIF-lα gene, a hypoxia-induced factor, providing a protective effect in conditions of acidosis and oxygen deficiency. It should be added that Glutathione is a participant in reactions with proteins known as S-glutathione, which play an important role in the regulation of enzyme functions and the control of viral reproduction [Palamara AT, Brandi G., Rossi L. New synthetic glutathione derivatives with increased antiviral activities. Antivir. Chem. Chemother. 2004 Mar; 15 (2): 83-91 .; Ma H-C, Liu Y, Wang C., Strauss M., Rehage N., et al. (2014) An Interaction between Glutathione and the Capsid Is Required for the Morphogenesis of C-Cluster Enteroviruses. PLoS Pathog 10 (4): e1004052. doi: 10.1371 / journal.ppat. 1004052].

For the study of antiviral activity, various NTP compositions with compounds approved for clinical use and capable of enhancing the general and specific therapeutic effect of the antiviral preparation were used.

The compositions had the following composition:

1. NTP - 500 mg, Sodium chloride - 900 mg, Water d / injection. up to 100 ml, pH 5.5-7.2.

2. NTP - 500 mg, Gluconolactone - 2000 mg, Glutamic acid - 2000 mg, Carnosine - 2000 mg, Sodium sulfite - 100 mg, Water d / injection. up to 100 ml, pH 5.2-6.5.

3. NTP - 500 mg, Glutathione (reinst.) - 2000 mg, Carnosine - 2000 mg, Water d / injection. up to 100 ml, pH 6.8-7.25.

A study of the antiviral activity of the obtained preparations was carried out on a standard model of fatal influenza infection in mice using a strain of influenza virus A / Aichi / 2/68 A (H3N2) adapted to mice [Kiselev OI, Chupakhin ON, Rusinov V.L. ., Charushin V.N., Deeva E.G. Conjugates of 2-methylthio-6-nitro-1,2,4-triazolo [5,1-s] -1,2,4-triazin-7 (4I ′) - it is with glutathione and other peptides with antiviral activity. Patent for invention RUS 2516936 04/27/2012]. Outbred white mice were infected with a 1- or 10-fold lethal dose of the virus, the drug was administered simultaneously with infection, and the protective effect was determined by the number of surviving mice treated with the drug. Data protective effect are presented in table 2.

Thus, all compositions showed a high level of antiviral activity against the remantadine-sensitive strain of the influenza virus A / Aichi / 2/68 A (H3N2). Depending on the dynamics of the infectious process, the administration of certain compositions of NTP solutions can be carried out. Glutathione and Carnosine compositions (2 and 3) have preferences in severe conditions associated with impaired redox balance.

From the above compositions it follows that the quantitative content of the components corresponds to the claimed content in the claims.

Claims (2)

1. Injection or infusion solution for the treatment of influenza, containing a biologically active substance - an antiviral component and physiological solution, characterized in that as an antiviral component contains L-arginine salt of 5-methyl-6-nitro-1,2,4-triazolo [ 1,5-a] pyrimidin-7-one monohydrate, which is a triazolo-pyrimidine at a concentration of 0.5%, based on the total weight of the solution, and as physiological solution - sodium chloride in an amount of 0.9%, water for injection up to 100 ml 2. An injection or infusion solution according to claim 1, characterized in that it additionally contains auxiliary substances — reduced glutathione (Glu-Cis-Gly tripeptide) in an amount of 2.0% and carnosine in an amount of 2.0%.

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