Water-soluble polymeric complexes of arbidol

FIELD: medicine.

SUBSTANCE: invention refers to high-molecular compounds for medical purposes. Water-soluble polymeric complexes of antiviral agent arbidol of general formula: are described, where: Arb - arbidol: ethyl ester 6-bromo-4-dimethyl-aminometil-1-methyl-5-oxy-2-feniltiometilindolinil-3-carboxylic acid hydrochloride monohydrate; m1=100-(m2+m3) mol %; m2=(7.6-9.8) mol %; m3=(11.5-13.6) mol %; content of Arb=26.4-32.1 wt %.

EFFECT: obtained water-soluble polymeric complexes of arbidol may find application in pharmacology, as they can serve as basis for new effective and safe antiviral drugs and their dosage forms.

1 cl, 6 ex, 4 tbl, 2 dwg

 

The invention relates to macromolecular compounds for medical purposes, namely, water-soluble polymeric complexes containing drug Arbidol, the General formula

where Arb - Arbidol: ethyl ester of 6-bromo-4-dimethyl-aminomethyl-1-methyl-5-hydroxy-2-phenylthiomethyl-3-carboxylic acid hydrochloride monohydrate;

m1=100-(m2+m3), mol.%;

m2=(7,6-9,8) mol.%;

m3=(11,5-13,6) mol.%

with M.M. (19.000-31.000) Da.

Content Arb 26,4-32,1 wt.%.

In the complexation of Arbidol with polymers having a molecular weight of 19,000-31.000 Da and consisting of copolymers of acrylamide (AA) and 2-acrylamide-2-methylpropanesulphoacid (AMPS), a number of water-soluble derivatives of Arbidol with reduced toxicity compared with Arbidol, increased bioavailability, improved pharmacodynamics, and these polymer complexes retain a high level of biological activity of Arbidol, in particular antiviral activity. The content of Arbidol in the obtained water-soluble polymer complexes is 26.4-32,1 wt.%.

Created a water-soluble polymer complexes Arbidol can find application in pharmacology, as can serve as the basis for new effective and safe antiviral drug is of rest and their dosage forms.

The need to have in the Arsenal of drugs highly effective antiviral drugs with a broad spectrum of activity against influenza viruses a and b and other acute respiratory viral infections (ARVI) leads to a modification of the formulas found in tools.

1. The reason for modification is the high toxicity of many of the drugs used or their insufficient solubility.

Widely used causal antiviral drugs are rimantadine, and the neuraminidase inhibitors - zanamivir and oseltamivir, ribavirin. The use of rimantadine is limited by the lack of activity against influenza b, as well as wide spread in recent years resistant to it of influenza virus strains [CDC Health Alert. CCID.: www.cdc.gov/flu/han011406]. Relative to the neuraminidase inhibitors may be noted that along with the high cost of these drugs to their disadvantages include side effects such as irritation of the nasopharynx at the reception of zanamivir in the form of nausea and vomiting when taking oseltamivir. In addition, they are effective only at the beginning of a viral infection. Often in the treatment of severe forms of cancer are also used ribavirin and its domestic analogue ribamidil. Due to the high toxicity of these drugs are used only in a hospital for persons with a weakened immune system is m [I. Kiselev, Deeva EG, Platonov VG, Ilyenko V. Antivirals // Influenza and other ARVI". - SPb. - 2003. - Pp.96-146].

2. One of the most effective and feasible ways to reduce the toxicity of drugs while maintaining the specific biological activity is their complexation with water-soluble non-toxic ionic polymers-carriers [Petr M., Solowski M.V., Eropkin E.M., Sulava AL a Comparative study of the cytotoxic effect of polymeric derivatives of antibiotics-aminoglycosides // Toxicol. Herald. - 2006. No. 5. - P.18-22]. Polymeric drugs rimantadine (its complex with sodium alginate - allgire and complex with a copolymer of N-vinylamine with vinylimidazole acid - polyrem) have a wider spectrum of antiviral activity compared with rimantadine. An important factor is the prolonged effect of the polymer derivative rimantadine, contributing to prolonged circulation antiviral component in effective therapeutic doses [I. Kiselev, Deeva AG, Merged AV, Platonov VG antivirals for treatment of influenza and acute respiratory infections. The design of drugs based on polymeric carriers. "Time". SPb., 2000].

3. Well-known and widely used as antiviral agents drug Arbidol - ethyl ester 6-bromo-4-dimethylamine is Teal-1-methyl-5-hydroxy-2-phenylthiomethyl-3-carboxylic acid hydrochloride monohydrate, which has a broad spectrum of activity against influenza viruses a and b and other acute respiratory viral infections (ARVI)

Arbidol, in addition to the antiviral action, is an immunomodulator, an inducer of interferon and anti-oxidant properties [Guskov T.A., Glushkov RG Arbidol - immunomodulator, an interferon inducer, an antioxidant. CHLS-UNIFI, M., 1999, 2001]. Virusinghviru action of Arbidol is determined by its ability to inhibit the fusion of the lipid envelope of the virus with the cell membrane of the endosome, occurring inside cells. It is shown that Arbidol has no effect on the adsorption, transcription and translation, as well as neuraminidase activity of influenza virus [Leneva I.A. Mechanism virousspecificakih action of Arbidol. Abstract of Prof. Diss., SPb., 2005]. Currently Arbidol is widely distributed in the national pharmaceutical market and is one of the main causal anti-influenza drugs.

At the same time, a significant disadvantage of the drug is that it is practically insoluble in water, which reduces its bioavailability and limits the possibility of creating new dosage forms based on it (solutions, sprays, ointments, hydrophilic on the base). In addition, Arbidol as a therapeutic drug is effective only what about in the early stages of influenza - not more than 2 days from the onset of the disease [Leneva I.A., Guskova T.A., Glushkov RG Drugs for chemotherapy and chemoprophylaxis of influenza: characteristics of the mechanism of action, efficacy and safety // Chem. Pharm. log. - 2004. No. 11. - P.8-14].

After intragastric application of Arbidol refers to low-toxic drugs [Guskov., Glushkov RG Arbidol - immunomodulator, an interferon inducer, an antioxidant. CHLS-UNIFI, M., 1999, 2001], however, parenteral administration in mice and rats it DL50109 and 140 mg/kg, respectively, allowing it to be classified as moderately toxic drugs [Berezovskaya IV Classification of chemicals according to the parameters of acute toxicity of parenteral routes of administration // Chem.-Pharm. W. - 2003. - T. 37, No. 3. - P.32-34]. When evaluating on cell cultures of its IC50(sredneimportnaja concentration, reduce by 50% cell viability) is 40-60 µg/ml [Leneva I.A. Mechanism virousspecificakih action of Arbidol. Diss. Prof. Biol. of Sciences, St. Petersburg., 2005]. In addition, according to our data, during storage of the drug for about 6 months its cytotoxicity significantly increased (IC50reduced to 20 µg/ml in the cell culture MDCK). While pharmacological index, or index of selectivity (the ratio between the cytotoxic concentration and average Viru is inhibitory concentration) is only 3,75, that is unacceptable for this widely used drug (usually a selectivity index of at least must be greater than 10) [Gabriel RU (as amended). Manual on experimental (preclinical) study of new pharmacological substances. - M., 2005].

4. The technical task and the positive result of the invention is to provide a water-soluble derivatives of Arbidol with reduced toxicity while retaining the wide range and high level of biological activity, in particular antiviral activity.

This task is achieved by complexation of Arbidol with copolymers of acrylamide (AA) and 2-acrylamide-2-methylpropanesulfonate (AMPS), resulting in a gain of polymeric complex

where Arb - Arbidol: ethyl ester of 6-bromo-4-dimethyl-aminomethyl-1-methyl-5-hydroxy-2-phenylthiomethyl-3-carboxylic acid hydrochloride monohydrate;

m1=100-(m2+m3), mol.%;

m2=(7,6-9,8) mol.%;

m3=(11,5-13,6) mol.%

with M.M. (19.000-31.000) Da, and the content of Arbidol (26,4-32,1) wt.%.

5. The essence of the invention is the use for the complexation of Arbidol copolymers of AA with AMPS, resulting in strictly selected proportions of Arbidol and copolymers obtained water-soluble polymer included the si content in them Arbidol from 26.4 to 32.1 wt.%, moreover hydrochloride and monohydrate as part of Arbidol part of the structure of link m2. The content of the links in the polymer chain in molar%: m1(AA)-[100-(m2+m3)], m2(the complex Arb with AMPS) - (11,5-13,6).

Small value (19.000-31.000 Da) molar mass polymers (MM) provide their complete elimination from the body by the mechanism of renal filtration that in the absence sulfacetamide copolymers biological activity results in complex acceptable for the body of the water-soluble form with the preservation of biological activity of Arbidol as such.

Polymeric derivatives of Arbidol and, in particular, the inventive water-soluble polymer complexes are not described in literature.

The choice as modifiers properties of Arbidol copolymers AA-AMPS due to the following reasons:

(a) the copolymers, as with all polymers of acrylamide (AA), have high hydrophilic polymer chain, highly soluble in water.

b) Copolymers contain strongly acidic, sulfopropyl and in aqueous solutions easily form a salt link with primary, secondary and tertiary amines, namely amines include Arbidol.

C) According to the literature [Mveselovski, Moorabbin, Umerica and other Synthesis and properties of low molecular weight copolymers of acrylamide with 2-acrylamide-2-matilal what facility - potential carriers of biologically active compounds // J. of applied chemistry. in 2008, 80. - VIP. - S-1678] copolymers of AA-AMPS (≤ 23 mol.% the sulfo) non-toxic in vitro.

6. Obtaining a polymer carrier and kompleksoobrazovanie with them Arbidol

Polymers-media - copolymers of acrylamide with 2-acrylamide-2-methylpropanesulfonate (AA-AMPS) was prepared by heterophase radical copolymerization with monomers in isopropanol [Mveselovski, Moorabbin, Emergin and other J. of applied chemistry. - 2007. - So 80. - VIP. - S-1678]. The composition of the copolymers AA-AMPS was calculated according to elemental analysis for sulfur content. The molecular weight of the copolymers AA-AMPS determined by viscometric method, using equation Mark-Kuhn-Houwink known for polyacrylamide [encyclopedia of polymers. Publishing house "Soviet encyclopedia". 1972. So 1. - P.30].

The structure of the copolymers was confirmed by titration of sulfo -, and IR spectra, in which, unlike the infrared spectrum of poly-AA, there is a new characteristic absorption bands-SO3H groups in the field 1227 cm-1, 1040 cm-1, 624 cm-1.

Complexation copolymers AA-AMPS with Arbidol was performed in water at room temperature at a mass ratio of copolymer/Arbidol, equal to 2.3-2.5/1. Copolymers of AA-AMPS was dissolved in distilled water is based 3,0-4,0 mg/ml and the solution was added with stirring Arbidol in dry form (26-30 mg). The mixture primatively within 40-60 minutes, with all of Arbidol completely passed into the solution. The reaction mixture was filtered. Polymer complexes was isolated by freeze drying. The content of Arbidol in the resulting polymer complexes was determined by means of UV-spectroscopy. Used intense absorption band of Arbidol with a maximum at 320 nm (ε=13.700 mol-1·cm-1). UV spectra were taken in a mixture of DMF + H2On (volume ratio 1:9). Complexation of copolymers with Arbidol schematically shown in the diagram:

Tests of the obtained complexes was carried out in vitro.

7. Determination of antiviral drugs

Antiviral activity of the synthesized compounds and drugs was determined in relation to the reference strain of the virus of human influenza A/Victoria/35/72 (H3N2). The action of Arbidol and its polymeric complex was evaluated in relation to highly pathogenic strain of avian influenza, allocated and deposited at the research Institute of influenza A/duck/Kurgan/8/05 (H5N1).

The presence of the virus in the incubation medium was determined by micromethods haemagglutination reaction with 0.5%suspension of human erythrocytes I (0) blood group. The titer of the virus was expressed in decimal logarithms in 100 ál (lg50). Antiviral activity of samples was evaluated by the decrease in the titre of virus in the pilot hole square is hatov compared with the control (Δlg 50). Average virusvirus concentration of the sample (VIC50) was calculated based on the cytopathic response of cells under the influence of a specific virus titer, which was evaluated in microtitration test. Micrometrology test (MTT) was performed according to Mosmann [Mosmann T. J Immunol Meth, 1983, v. 65 (1), p.55-63]. Cell cultures grown in 96-well tablets, incubated for 3 h in a solution of MTT (0.5 mg/ml) in buffered physiological solution at 37°C in CO2-incubator. The resulting water-insoluble crystals formazan was extracted with 95° ethanol for 30 min and measured the optical density of the samples at a wavelength of 550 nm on a tablet analyzer "Chameleon" (Hydex, Finland).

The degree of inhibition of viability of cells in culture correlates with the development of viral infection in vitro.

Antiviral activity was evaluated in the case of herpes simplex virus type I HSV1/248/88 and adenovirus type III Ad/3/et/4120 on the culture of cells A-549 (lung carcinoma line person). Preparations were made by the medical scheme for 30 min before introduction into the culture suspension of the virus. Cytopathic response was taken into account after 48 and 72 h according to the degree of degradation of the monolayer (microscopic examination of culture), as well as by the MTT method. In the latter case, to calculate VIC50used regression method.

8. The definition of cytot is sicnosti investigated compounds in vitro

Toxicity Arbidol ("Masterlek", M, capsule form), polymers carrier and polymer complexes of Arbidol was determined by incubation of the cultures of MDCK cells with serial dilutions of drugs in serum-free medium Needle MEME. Standard time of incubation with drugs accounted for 72 hours assessment Methods toxicity in vitro was recovering cells in culture fluorescent dye of resazurin ("Sigma", USA) [R. Clothier, Starzec G., L. Pradel et al. The prediction of human skin responses by using the combined in vitro fluorescein leakage/Alamar blue (resazurin) assay // ATLA. - 2002. - V. 30. - P.493-504] or tetrazolium dye MTT 3-(4,5-dimethylthiazole-2)2,5-diphenyltetrazolium bromide (ICN Pharmaceuticals, USA). Method MTT was performed as described above.

Both methods reflect the integral activity of mitochondrial dehydrogenases and are adequate pokazateli viability of cells in culture and intensity of oxidative processes. Dye resazurin (in English literature - Alamar blue) when you restore it by mitochondrial dehydrogenase is converted into a fluorescent product resorufin (λmaxexcitation = 530 nm, λmaxemission = 590 nm). The method is adapted to a 96-well tablets: the measurements were carried out in tablet analyzer "Chameleon" with the appropriate interference filters for fluorescence. The advantage of the method are the two which is the fact that the measurement of fluorescence is directly in the wells after incubation with the dye without additional extraction, since the reaction product is resorufin freely excreted from the cells into the environment. Cells remain after this viable, and on the same tablet after washing the dye can be another test, such as the binding of neutral red, determination of DNA or protein and other [R. Clothier, Starzec G., L. Pradel et al. The prediction of human skin responses by using the combined in vitro fluorescein leakage/Alamar blue (resazurin) assay // ATLA. - 2002. - V. 30. - P.493-504].

As a criterion of toxicity in both methods took IC50- cytotoxic dose which causes a drop higher than 50% of the control (intact cells), which was calculated by the equations of the linear regression of the dose-effect. Each concentration was taken not less than 4 points with three or more independent repetitions of the experiment. Used two ways of representing values of concentration are linear and logarithmic. Mathematical and statistical processing of data was performed in Excel 2000.

The invention is presented in the examples.

Example 1. 68 mg of the copolymer AA-AMPS containing 19,1 mol.% of sulfo, 19.000 MM Da, was dissolved in 20 ml of distilled water. To the obtained solution under stirring was added to 27.2 mg dry Arbidol. Mass is th ratio of copolymer/Arbidol - a 2.5:1. The mixture was intensively stirred at room temperature for 40 min At this Arbidol completely passed into the solution. The target solution was filtered through a dense filter Shota (40 long). The filtrate was frozen and subjected to freeze drying. Received a 75.1 mg (78,8%) water-soluble polymer containing 28,1 wt.% Arbidol. Composition and biological characteristics of the obtained product are shown in table 1-4 and figures 1 and 2. From table 1 it is seen that the antiviral activity of a complex of Arbidol with the media commensurate with the antiviral activity of unmodified Arbidol against the model strain of influenza A (H3N2), and its toxicity in vitro is approximately 10 times lower than that of unmodified Arbidol (corresponding IC50higher order). According to the data presented in table 2, it follows that Arbidol has in this system, a clear dose-dependent antiviral activity (ΔlogT50>2,0) as regards the model of the influenza A(H3N2), and highly pathogenic strain of avian influenza A(H5N1), the activity of the complex in respect to the latter, substantially higher than unmodified Arbidol. Virus A/duck/Kurgan/8/06 (H5N1)isolated on cell culture MDCK and translated into chicken embryos (S2/E1). Hemagglutinin activity of the virus: 32-128 the GUY/0.2 ml, infectious activity: 6,0 Ted50/0,2 ml

More de the real data on the impact of polymer-modified Arbidol presented in figure 1 and 2. Figure 1 shows the antiviral activity of Arbidol (pectina line) and complex ARB-AA-AMPS (solid line) in relation to highly pathogenic avian influenza A/duck/Kurgan/8/05. The abscissa shows the concentration of Arbidol and complex in μg/ml On the y - axis of the protected area. pl. at 550 nm (MTT). Figure 2 presents the cytotoxicity of Arbidol (dashed line) and complex ARB-AA-AMPS (solid line) on the culture of MDCK cells. Designations are the same as in figure 1.

Δlog50=2.0 for Arbidol at the concentration of 6.25 µg/ml In 10 Ted50viryinia concentration (VIC50) Arbidol was VIC50=5,2 μg/ml intermediate toxicity concentrations of Arbidol in vitro against cells MDCK: IC50=19,5 µg/ml (see page 2). Thus, pharmacological index (index of selectivity of the drug) at 10 Ted50equal to 3.75, which is clearly unsatisfactory for this widely used drug.

At the same time for the polymer-modified Arbidol in equimolar concentration (taking into account the mass content of Arbidol) at 10 Ted50VIC50=12.5 ág/ml and toxicity IC50=190 ág/ml Thus, the index of selectivity for a given drug was in the same conditions, 15,2, which is four times better than the unmodified Arbidol.

Hence we can conclude that the polymer-mod is fitsirovannye Arbidol not only shows a high antiviral activity against highly pathogenic strain of influenza A(H5N1), allocated on the territory of Russia, but has far less toxic and much higher pharmacological index compared to the unmodified Arbidol.

In table 3 presents the antiviral effect of Arbidol and its complex with AA-AMPS (sample No. 1 of table 1) in respect of the herpes simplex virus HSV1/248/88 in culture cells A-549. Has significant antiviral effect of Arbidol and comparable dose-dependent effect of its complex with AA-AMPS against herpes simplex virus type 1. Antiviral activity comparable to those in respect of the virus of human influenza.

In table 4 presents the antiviral effect of Arbidol and its complex with AA-AMPS (sample No. 1 of table 1) in respect of adenovirus And<3/3/EB/4/20 in culture cells A-549. Weak antiviral effect of Arbidol and its polymer-modified derivative on adenoviruses. The concentration dependence of the action of the latter is not observed. The effect of Arbidol in evaluating the two methods coincide, while for polymer derived it below when assessing recovery MTT.

Example 2. In the conditions of example 1 of 68 mg of the copolymer AA-AMPS containing 22,0 mol.% of sulfo, M.M. 31.000 Da and 27.2 mg Arbidol (mass ratio of copolymer/Arbidol 2,5:1) got to 79.2 mg (83,2%) modorator the constituent polymer, containing of 28.6 wt.% Arbidol. Composition and biological characteristics of the obtained product are shown in table 1.

Example 3. In the conditions of example 1 of 68 mg of the copolymer AA-AMPS containing 22,8 mol.% of sulfo, 28.000 MM Da and 27 mg of Arbidol (mass ratio of copolymer/Arbidol 2,5:1) obtained 79,4 mg (83.6 percent) of the water-soluble polymer containing 26,4 wt.% Arbidol. Composition and biological characteristics of the obtained product are shown in table 1.

Example 4. In the conditions of example 1 of 68 mg of the copolymer AA-AMPS containing 22,8 mol.% of sulfo, 28.000 MM Da and 30.4 mg Arbidol (mass ratio of copolymer/Arbidol 2,3:1) got to 88.3 mg (87.9 per cent) of the polymer containing 32,1 wt.% Arbidol. Composition and biological characteristics of the obtained product are shown in table 1. As can be seen from the table, the antiviral activity of all of the polymers obtained in examples No. 1-4, about the same. The corresponding figure (ΔlogT50) exceeds 2.0, indicating a fairly high antiviral activity of the synthesized polymer complexes. Antiviral activity obtained in examples No. 1-4 complexes not statistically different between themselves and the activity of the unmodified Arbidol (nonparametric test Mann-Whitney). The toxicity in vitro of all studied in examples 1-4 complexes also about od is nakova. There is a slight fluctuation of cytotoxicity (statistically insignificant) depending on the content of sulfo. At the same time, the toxicity of all the synthesized polymer complexes is considerably lower toxicity in vitro unmodified Arbidol, determined by us in the same conditions of experience (table 1).

Example 5 (control). In the conditions of example 1 of 68 mg of the copolymer AA-AMPS containing 22,8 mol.% of sulfo, 28.000 MM Da and 22.7 mg Arbidol (mass ratio of copolymer/Arbidol 3,0: 1) received a 76.5 mg (84,4%) water-soluble polymer containing 24,8 wt.% Arbidol. Composition and biological characteristics of the obtained product are shown in table 1.

This complex had a low antiviral activity that corresponds to the lowest mass content of Arbidol in comparison with other complexes (examples 1-4).

Example 6 (control). 70 mg of the copolymer AA-AMPS containing 19,1 mol.% the sulfo with 19.000 MM Da, was dissolved in 20 ml of water. To the resulting solution was added 36 mg of Arbidol (mass ratio of copolymer/Arbidol 1,95:1). This Arbidol is not dissolved in the solution of the copolymer.

Analysis of tabular data allows to draw the following conclusions:

1. Delivered invention the problem is solved by the claimed water-soluble polymer complexes of Arbidol with discobolus the governmental copolymers of acrylamide with 2-acrylamide-2-methylpropanesulphoacid.

2. Antiviral activity of the claimed polymer complexes for all the investigated viruses (virus of human influenza A (H3N2), a highly pathogenic virus of avian influenza a (H5N1)virus, herpes simplex virus type I (HSV1), adenovirus type III) commensurate with the antiviral activity of unmodified Arbidol.

3. Toxicity in vitro stated complexes approximately an order of magnitude lower toxicity in the same conditions unmodified Arbidol.

4. Pharmacological index (index selectivity), calculated for the polymer compound (sample No. 1) against influenza a (H5N1)was 15.2 against 3,75 for unmodified Arbidol. Thus, pharmacological index polymer derived four times higher than unmodified Arbidol.

5. The stated interval parameters are determined by the following factors:

a) the Interval of the molecular masses of the copolymers AA-AMPS 19.000-31.000 Da, firstly, provides solving inventive problems, and secondly, it ensures complete removal of the polymer carrier from the body by the mechanism of renal filtration.

b) the Declared content of Arbidol in the complex (26,4-32,1) wt.% provides solubility of the claimed complexes and their high antiviral activity. When the content of Arbidol in the complex 24,8% (example 5) to the complex is less antiviral activity. Water-soluble complex with the desired content of Arbidol 34% (example 6) cannot be obtained.

Table 3
Antiviral effect of Arbidol and its complex with a copolymer of AA-AMPS (sample No. 1 of table 1) in respect of the herpes simplex virus HSV1/248/88 in culture cells A-549. Preparations were made for 30 min before infection with the virus. Accounting results after 72 hours Assessment cytopathogenic actions (JRC) on the morphological changes of the cells (optical microscopy) and recovery of the dye MTT. Average of 3-4 independent experiments
IndexControlArbidol, 10 mg/mlAr-AA-AMPS, 33* mcg/mlAr-AA-AMPS, 67 mcg/ml
JRS, (lg50), microscopic. assessment of morphologyto 3.671,832,52,13
Antiviral effect on MIC. assessment (ΔlogT50)1,841,171,54
JRS, (lg5o), reset. MTT2,60,550,950,4
Antiviral effect by reset. MTT (Δlg50)2,11,652,2
*- see the caption to table 2.

Table 4
Antiviral effect of Arbidol and its complex with a copolymer of AA-AMPS (sample No. 1 of table 1) in respect of the adenovirus Ad/3/et/4/20 in culture cells A-549. Other conditions as in table 3
IndexPin-roleArbidol, 10 mg/mlARB-AA-AMPS, 33 μg/mlARB-AA-AMPS, 67 mcg/ml
JRS, (log50), microscopic. assessment of morphology3,02,252,132,25
Antiviral effect on MIC. assessment (Δlg50) 0,750,870,75
JRS, (logT50), reset. MTT2,041,31,51,9
Antiviral effect by reset. MTT (Δlog50)0,740,540,14

Water-soluble polymer complexes antiviral drug Arbidol General formula:

where Arb - Arbidol: ethyl ester of 6-bromo-4-dimethyl-aminomethyl-1-methyl-5-hydroxy-2-phenylthiomethyl-3-carboxylic acid hydrochloride monohydrate;
m1=100-(m2+m3) (mol.%;
m2=(7,6-9,8) mol.%;
m3=(11,5-13,6) mol.%;
content Arb=26,4-32,1 wt.%.



 

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1 ex, 2 dwg

FIELD: medicine.

SUBSTANCE: invention concerns medicine, particularly gastroenterology and surgery, and covers prevention of dialysis peritonitis (DP). Therefor, prior to the peritoneal dialysis (PD), a bio-sample from the patient's intestines is analysed for dysbacteriosis by one of the standard methods. If dysbacteriosis is diagnosed, prior to the PD, dysbacteriosis is treated by elimination at the first stage of detected excess conditionally-pathogenic and pathogenic intestinal microflora with antibacterial preparations, taking into account sensitivity thereto of said microflora. The second stage involves compensation of deficiency and restoration of normal intestinal microflora. The restoration of intestinal microflora is followed with the PD.

EFFECT: method provides effective prevention of DP development, eliminating risk of DP development in multiple prolonged courses of the PD.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to immunomodulatory drugs. Application Helepin D or Helepin as an immunomodulatory drug in secondary immunodeficiency states.

EFFECT: Helepin D or Helepin possess effective immunomodulatory action in immunodeficiency states.

1 dwg, 4 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely pulmonology, and can be used for treating community-acquired pneumonia in the patients with mid-severe and severe clinical course involving immunogram abnormalities. That is ensured by antibacterial therapy. In addition, for 3-4 day of treatment, the treatment regimen is supplemented with Polyoxidonium in a dose 6 mg daily intramuscularly within 5 days.

EFFECT: early positive dynamics of the main clinical symptoms of disease and normalisation of immunological indicators which allow reducing treatment time and preventing complications.

1 tbl, 1 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention relates to field of veterinary and deals with mutant virus of bull diarrhea. Essence of invention includes virus of bull diarrhea, containing at least one amino acid mutation of helicase domaine, where mutation in domain NS3 results in loss of recognition by monoclonal antibody, generated against wild type of NS3, but were virus RNA replication and generation of infectious virus are preserved. Second version includes virus of bull diarrhea containing at least one mutation in helicase domain, where mutation is in helicase domain in IGR loop and/or in KHR loop and/or in SES loop.

EFFECT: advantage of invention lies in obtaining mutant virus of bull diarrhea, where virus RNA replication and generation of infectious virus are preserved.

21 cl, 10 ex, 7 tbl, 5 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular to gastroenterology, and deals with application of conjugate of interferon with water-soluble polymer in combination with ribavirin and cyclosporine A for preparation of medication intended for treatment of HCV-induced infection. Invention ensures efficient impact in patients with HCV infection who initially did not respond to monotherapy with pegylated interferon, as well as combination of interferon A with ribavirin or interferon with cyclosporin A.

EFFECT: claimed method of application of cyclosporine and pagylated interferon combination.

14 cl

FIELD: medicine.

SUBSTANCE: invention belongs to medicine, notably to infectious diseases and can be used for treatment of infections, induced by herpes simplex viruses type I and II, cytomegalovirus and Epstein-Barr virus. For treatment are used valacyclovir and human recombinant interferon alpha 2. Valacyclovir via ingestion dose is 500 mg twice a day during 5 -10 days. Three million IU of human recombinant interferon alpha 2, diluted in 5 or 10 ml of 0.9% sodium chloride solution is administered twice a day 3 drops into each nostril during 10 days, then 2 drops during 10 days and 1 drop during 10 days.

EFFECT: regimen of human recombinant interferon alpha 2 and valacyclovir administration and dosing aids in increasing of endogenous interferon production resulting in shorter period of infection active phase and longer remission.

1 ex

FIELD: medicine.

SUBSTANCE: invention belongs to medicine, notably to biguanid compounds, namely Siofor 500, Delagil and 0.5 acetylsalicylic acid administration 1 tablet 3 times a day for plague treatment.

EFFECT: there is offered plague treatment method.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention covers a water-soluble drug based on ionic silver and methylene blue compound, and also a method for preparing thereof. Said method implies synthesis when heating to 90-95°C by mixing the following components: methylene blue - silver chloride - ammonia in the molar ratio 1.06:1:58 to be cooled; a by-product is filtered, steamed in vacuum, washed with acetone and dried in vacuum at room temperature.

EFFECT: prepared drug meets the composition C16H18CI2N3SAg and exhibits antiviral and immunomodulatory action.

2 cl, 2 dwg, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutics and concerns a pharmaceutical composition for treatment and prevention of respiratory syncytial virus (RSV) including the respiratory syncytial virus (RSV) fusion protein and a benzodiazepine derivative capable of inhibiting RSV replication.

EFFECT: compositions have improved therapeutic efficiency.

10 cl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and concerns a composition for treatment or prevention of infection and/or infectious disease of respiratory tracts and the method for application of said composition for specified purposes which involves oral introduction to a mammal of the composition containing a galactose-containing indigestible oligosaccharide and at least 5 wt % of digested galactose saccharide.

EFFECT: invention provides that the active substance is safe and can be included in the dietary intake.

20 cl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention presents the method and composition for treatment and-or prevention of infection, and said method includes oral introduction of the composition to a mammal, and said composition involves galactose-containing indigestible oligosaccharide and immunoglobulin of milk or colostrum of hyperimmunised cows.

EFFECT: development of the effective method for the compositions for treatment and-or prevention of infection.

15 cl, 1 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: medicinal agent with activity of alpha interferon represents a conjugate with a molecule of branched polyethylene glycol of general formula: , where: INF - polypeptide of alpha interferon; R - radicals of 2-aminoethanol -HN-CH2-CH2-O-, 3-aminopropanol -HN-CH2-CH2-CH2-O-, homoserine -HN-CH(COOH)-CH2-CH2-O-; n and n1 - identical or different =50-170, wherein residual branched polyethylene glycol molecular weight 5000-15000 Da are covalently bound with amino groups of polypeptide of alpha interferon.

EFFECT: said agent is an effective antiviral and antiproliferative preparation.

2 cl, 3 tbl, 9 ex

Antiviral agent // 2381807

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, namely to preparation of an antiviral agent of brown algae. The antiviral agent contains fucoidane made of brown aglae fucus or laminaria and representind a salt solution to 30 kDa of vegetative polysaccharide complex concentrated 0.01-15% containing fucoidane, laminarane and alginate made of brown aglae fucus or laminaria, with the salt solution containing a preserving agent from the group: sodium benzoate concentrated 0.01-0.3%, or potassium sorbate concentrated 0.02-0.3% or formaldehyde concentrated 0.01-0.3%, and as a salt solution, it contains an aqueous solution of sodium chloride concentrated 0.85-0.95% - the rest. The vegetative polysaccharide complex contains fucoidane, laminarane and alginate in any ratio, preferentially the vegetative polysaccharide complex contains fucoidane concentrated 10-99.9%.

EFFECT: extended range of antiviral activity with respect to: herpes virus types 1 and 2, cytomegalovirus, adenovirus, hepatitis C virus without expressed by-effects.

3 cl

FIELD: medicine.

SUBSTANCE: novel biomaterials consist of combination of sulphated hyaluronic acid and deacetylated hellane for application as highly efficient barrier for prevention of post-operation commissures in operation in abdominal, pelvic areas and, first of all, on spine.

EFFECT: increase of application efficiency.

16 cl, 1 dwg, 2 tbl, 6 ex

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