Synergetic composition for inhibition of hiv

FIELD: medicine, virology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a synergetic composition comprising azidothymidine and glycyrrhizic acid penta-O-nicotinate - niglizine taken in physiologically blood concentrations: 0.0037-0.0254 mcM for azidothymidine and 0.0052-9.64 mcM for niglizine. Using the proposed composition provides effective inhibition of HIV-1 reproduction and significant reducing consumptions required for treatment. The composition shows high bioavailability and high effectiveness.

EFFECT: improved and valuable medicinal properties of composition.

6 tbl, 1 dwg

 

The invention relates to Virology and medicine, namely to develop a composite preparations on the basis of azidothymidine and derivatives glycyrrhizic acid, can effectively inhibit the reproduction of human immunodeficiency virus at low physiological concentrations of their constituent individual components.

With the spread of the AIDS epidemic problem of treatment of this dangerous disease remains one of the urgent problems of modern medicine. For almost 15 years in clinical practice for the treatment of HIV infection is widely used by azidothymidine (AZT) is an effective inhibitor of viral reverse transcriptase [1]. In recent years due to rapidly developing in the body of HIV-infected patients with resistance azidothymidine [2], and also because of the high toxicity of the drug (including mitochondrial toxicity) [3, 4] its use has been limited. As monotherapy AZT is not currently recommended by the world health organization, since it leads to emergence of resistant to the drug mutants of the virus.

Currently, in most cases, azidothymidine used as a constituent in the so-called "cocktails" in combination with 2-4 other drugs [5, 6], acting on other targets of the cycle of reproduction of the virus. As the rule is, this HIV protease inhibitors or non-nucleoside inhibitors of HIV reverse transcriptase. Despite the effectiveness of some of these "cocktails", there still remains the search for new combinations-combinations of azidothymidine drugs with different nature and a different mechanism of action, quite effective and cheap to manufacture, suitable for the treatment of HIV infection.

One such affordable and cheap drugs is glycyrrhizin acid (ha), mechanism of action which some authors associated with the inhibition of protein kinases, providing phosphorylation T4 receptor is required for binding of the virus [7], others directly blocking the binding of the virus with the cell [8]. Although the mechanism of anti-HIV action of GC remains outstanding until the end, it is clear that it inhibits the reproduction of the virus in the early stages of infection [9] in contrast to azidothymidine.

Study of therapeutic action of GK on the model of chronic HIV infection in monocytes line U937 with long-term cultivation in her presence showed that GL inhibits the production of the virus in the first 4 passages, and then to the 20th passage only 60% reduces virusprotection compared with controls [10]. Using a combination of AZT and GK (1:1000) was more effective: by the 20th passage virousspecificakih protein P24 was not identified what I [10].

The antiviral activity of a series of derivatives of GA has demonstrated the effectiveness of their anti-HIV activities in culture cells [11-13]. Previously it was shown that monoammonium salt of glycyrrhizic acid (glitsiram) is not an antagonist against azidothymidine and in combination with it effectively blocks the reproduction of HIV in cell cultures in both acute and chronic infection with a ratio of AZT:glitsiram=1:10000 [9, prototype]. However, the effective concentrations of AZT and of glycyram are quite high and unacceptable level of an organism.

An object of the invention is to develop a highly effective anti-HIV compositions on the basis of azidothymidine and derivatives glycyrrhizic acid, having a synergetic effect of its components in a physiologically acceptable concentrations in blood.

The problem is solved by the selection and study of antiviral activity of various combinations of AZT and new domestic drug Penta-O-nicotinate glycyrrhizic acid (nigrizia) is an effective inhibitor of HIV [14]. When selecting combinations of the components of the new synergistic composition must take into account the pharmacokinetics of azidothymidine and glycyrrhizic acid, according to which the concentration of AZT should not exceed 0,05-0,1 MK who/ml, and GK - 2-10 µg/ml, which corresponds to the actual concentrations of these compounds in blood [15].

The result of this study shows that AZT and nipidin in combination 1:20, 1:50, 1:100, 1:200 and 1:2000 show a pronounced synergistic effect (table 1). It is important to note that if AZT 50%inhibiting dose in these combinations vary slightly (from 0,0056 to 0.014 μm) and differ little from that of individual of the drug, in case nigrizia they significantly reduced by decreasing its share in combination (from 2,076 to 0,0519 μm).

2,076
Table 1

Quantitative characteristics of inhibition of HIV-1The ECRscombinations of AZT and nigrizia
CombinationID50, mcmFIC
AZTNillesen
The strain of HIV-1The ECRs
Individual medication0,0254for 9.64-
AZT:nillesen=1:200,01240,0520,491
AZT:nillesen=1:500,01420,1480,574
AZT:nillesen=1:2000,010,3860,614
AZT:nillesen=1:20000,00560,435
AZT-resistant mutant HIV-1
Individual medication4,490,134-
AZT:nillesen=1:1000,00370,0740,553
* combinational index (the fractional inhibition concentration)defined according to [16].

Thus, using combinations of AZT with Negotino, you can significantly reduce the effective concentration of individual drugs from 0,0254 to 0,0142 μm, which corresponds to 0,0038 μg/ml and below (up to 0,0037 μm) for AZT and for 9.64 to 0,052 μm (0,07 mg/ml) for nigrizia, well below the physiologically achievable in the blood and non-toxic concentrations of these compounds.

In the experiments, we studied the antiviral activity nigrizia and its combination with AZT against AZT-resistant mutant of HIV-1 obtained in cell culture and characterized by decreased sensitivity to AZT 160 times and the presence of point mutations in the gene pol Asp67→Asn; Lys70→Arg; Leu214→Phe responsible for resistance [17].

Nillesen proved to be more effective against AZT-resistant mutant (ID50=0,134 µm)than those of the wild strain (ID50=for 9.64 μm). Defined for combinations of AZT:nillesen=1:100 Raman FIC index was 0,553 (&t; 1), indicating a synergistic antiviral effect of this combination against AZT-resistant mutant. And 50%inhibiting dose of the drugs in the mixture were significantly lower than for individual compounds: for AZT - 0,0037 μm, and for nigrizia - 0,052 microns.

The efficiency of the combined anti-HIV action of AZT and nigrizia both in terms of the "wild" strain and AZT-resistant mutant shows the viability of using such compositions for the treatment of HIV infection.

The invention is illustrated in the following chart.

Figure 1. The efficiency of inhibition of HIVThe ECRscomposition AZT and nigrizia 1:50 in the culture of cells MT-4.

AZT (µg/ml)Nillesen (µg/ml)Composition 1:50 (µg/ml)
1 -0,0010,050,001:0,05
2 -0,010,50,01:0,5
3 -0,150,1:5
4 -1501:50

For a better understanding of the invention the following specific examples of its implementation.

Example 1. Evaluation of anti-HIV activity of the composition of azidothymidine and nigrizia 1:50.

Anti-HIV-1 Akti is the ability of the composition study on highly sensitive to human immunodeficiency virus culture cells MT-4. Cells MT-4 infect runoff virus (strain HIV-lThe ECRs[18]) with multiplicity of infection of 0.2-0.5 infectious units per cell and incubated at 37°C for 1 hour (adsorption of the virus). Suspension of infected cells plant growth nutrient medium RPMI-1640 containing 10% serum fetal cow company "ICN" (USA), 0,06% L-glutamine, 100 µg/ml gentamicin and 60 μg/ml of lincomycin, before planting a concentration of 0.5×106cells/ml and added to wells of 96-well culture plate. Then in wells make aliquots of serial dilutions of azidothymidine in medium without additives to the final concentrations from 0.1 ng/ml to 1.0 μg/ml (three wells for each concentration), aliquots of serial dilutions nigrizia in DMSO to final concentrations of from 0.05 to 100 μg/ml (three wells for each concentration) and the mixture aliquot of serial dilutions of azidothymidine and nigrizia, final concentration of azalomycin in which from 1.0 ng/ml to 1.0 μg/ml, and nigrizia from 0.05 to 50 μg/ml (three wells for each option). Experimental (drug) and control (without drug) infected cells and uninfected control cells (without drug) were cultured at 37°C and 5% CO2within 4 days. After incubation count the proportion of viable cells in the cell Goryaeva after staining with 0.4%solution of the trip is the new blue and control the level of accumulating virousspecificakih protein P24 by ELISA, as described in [19].

Experimental data is shown in figure 1. On the basis of the obtained in the experiment quantitative data to build a dose-dependent curves that define inhibiting dose ((ID50) - the concentration by 50% reduces the accumulation of viral P24 antigen compared to the control) for individual compounds and for each compound in the mixture. Thus obtained quantitative characteristics is then used to calculate the combination index (FIC), as dened in [16] by the formula:

where And azidothymidine, nillesen.

Quantitative data of inhibition of virus reproduction composition and individual compounds are presented in table 2. Combinational index equal 0,574 (<1), indicating a synergistic anti-HIV effect of azidothymidine and nigrizia in the ratio of 1:50.

Table 2

Quantitative characteristics of inhibition of HIV-1The ECRscomposition AZT and nigrizia (1:50)
MedicationID50, mcmFIC
IndividualIn the mix

0,574
AZT0,02540,0142
iglitzin for 9.640,148

Example 2. Evaluation of anti-HIV activity of the composition of azidothymidine and nigrizia 1:20.

Anti-HIV-1 activity of the composition study on highly sensitive to human immunodeficiency virus culture cells MT-4. Cells MT-4 infect, plant growth nutrient medium prior to seeding concentration and contribute to the wells of the culture of the tablet as described in example 1. Then in wells make aliquots of serial dilutions of azidothymidine in medium without additives to the final concentrations from 0.1 ng/ml to 1.0 μg/ml (three wells for each concentration), aliquots of serial dilutions nigrizia in DMSO to final concentrations of from 0.02 to 100 µg/ml (three wells for each concentration) and the mixture aliquot of serial dilutions of azidothymidine and nigrizia, final concentration of asiamedia, in which from 1.0 ng/ml to 1.0 μg/ml, and nigrizia from 0.02 to 20 mg/ml (three wells for each option). Experimental (drug) and control (without drug) infected cells and uninfected control cells (without drug) were cultured at 37°C and 5% CO2within 4 days. After incubation count the proportion of viable cells in the cell Goryaeva after staining with 0.4%solution Trypanosoma blue and control the level of accumulating virousspecificakih Bel is and P24 by ELISA, as described in [19]. On the basis of the obtained in the experiment quantitative data to build a dose-dependent curves that define inhibiting dose (ID50) and calculate the combination index (FIC), as described above in example 1. Quantitative data of inhibition of virus reproduction composition and individual compounds are presented in table 3. Combinational index equal to 0.56 (<1), indicating a synergistic anti-HIV effect of azidothymidine and nigrizia in the ratio of 1:20.

Table 3

Quantitative characteristics of inhibition of HIV-1The ECRscomposition AZT and nigrizia (1:20)
MedicationID50, mcmFIC
individualin the mix

0,491
AZT0,02540,01235
Nillesenfor 9.640,0519

Example 3. Evaluation of anti-HIV activity of the composition of azidothymidine and nigrizia 1:100 against AZT-resistant mutant of HIV-1.

Anti-HIV-1 activity of the composition study on highly sensitive to human immunodeficiency virus culture cells MT-4. Cells MT-4 infect AZT-resistant mutant of HIV-1 with a plurality of the intrusion of 0.2-0.5 infectious units per cell and incubated at 37° C for 1 hour (adsorption of the virus). Suspension of infected cells plant growth nutrient medium prior to seeding concentration and contribute to the wells of the culture of the tablet as described in example 1. Then in wells make aliquots of serial dilutions of azidothymidine in medium without additives to the final concentrations from 0.1 ng/ml to 0.1 μg/ml (three wells for each concentration), aliquots of serial dilutions nigrizia in DMSO to final concentrations from 0.1 to 100 µg/ml (three wells for each concentration) and the mixture aliquot of serial dilutions of azidothymidine and nigrizia, final concentration of azalomycin in which from 0.1 ng/ml to 0.1 μg/ml, and nigrizia from 1 to 100 µg/ml (three wells for each option). Experimental (drug) and control (without drug) infected cells and uninfected control cells (without drug) were cultured at 37°C and 5% CO2within 4 days. After incubation count the proportion of viable cells in the cell Goryaeva after staining with 0.4%solution Trypanosoma blue and control the level of accumulating virousspecificakih protein P24 by ELISA, as described in [19]. On the basis of the obtained in the experiment quantitative data to build a dose-dependent curves that define inhibiting dose (ID50and raschityvat the t combinational index (FIC), as described above in example 1. Quantitative data of inhibition of reproduction of AZT-resistant mutant HIV-1 composition and individual compounds are presented in table 4. Combinational index equal 0,553 (<1), indicating a synergistic anti-HIV effect of azidothymidine and nigrizia in such a ratio of 1:100.

Table 4

Quantitative characteristics of inhibition of AZT-resistant mutant of HIV-1 by a combination of AZT and nigrizia (1:100)
MedicationID50, mcmFIC
individualin the mix

0,553
AZT4,490,0037
Nillesen0,1340,074

Quantitative characteristics of inhibition of HIV-1The ECRsand AZT-resistant mutant HIV-1 compositions of AZT and nigrizia shown in the summary Table 1.

Example 4. Evaluation of anti-HIV activity of the composition of azidothymidine and nigrizia 1:200.

Anti-HIV-1 activity of the composition study on highly sensitive to human immunodeficiency virus culture cells MT-4. Cells MT-4 infect, plant growth nutrient medium prior to seeding concentration and contribute to the wells of cultures is a high tablet, as described in example 1. Then in wells make aliquots of serial dilutions of azidothymidine in medium without additives to a final concentration of 0.5 ng/ml to 0.5 μg/ml (three wells for each concentration), aliquots of serial dilutions nigrizia in DMSO to final concentrations of from 0.1 to 200 μg/ml (three wells for each concentration) and the mixture aliquot of serial dilutions of azidothymidine and nigrizia, final concentration of azalomycin in which from 0.5 ng/ml to 0.5 μg/ml, and nigrizia from 0.1 to 100 µg/ml (three wells for each option). Experimental (drug) and control (without drug) infected cells and uninfected control cells (without drug) were cultured at 37° and 5% CO2within 4 days. After incubation count the proportion of viable cells in the cell Goryaeva after staining with 0.4%solution Trypanosoma blue and control the level of accumulating virousspecificakih protein P24 by ELISA, as described in [19]. On the basis of the obtained in the experiment quantitative data to build a dose-dependent curves that define inhibiting dose (ID50) and calculate the combination index (FIC), as described above in example 1. Quantitative data of inhibition of virus reproduction composition and individual compounds are presented in t is BL. Combinational index equal 0,614 (<1), indicating a synergistic anti-HIV effect of azidothymidine and nigrizia in the ratio of 1:200.

Table 5

Quantitative characteristics of inhibition of HIV-1The ECRscomposition AZT and nigrizia (1:200)
MedicationID50, mcmFIC
individualin the mix

0,614
AZT0,02540,01
Nillesenfor 9.640,386

Example 5. Evaluation of anti-HIV activity of the composition of azidothymidine and nigrizia 1:2000.

Anti-HIV-1 activity of the composition study on highly sensitive to human immunodeficiency virus culture cells MT-4. Cells MT-4 infect, plant growth nutrient medium prior to seeding concentration and contribute to the wells of the culture of the tablet as described in example 1. Then make holes aliquots of serial dilutions of azidothymidine in medium without additives to a final concentration of 0.5 ng/ml to 0.5 μg/ml (three wells for each concentration), aliquots of serial dilutions nigrizia in DMSO to final concentrations of from 0.1 to 200 μg/ml (three wells for each concentration) and MES aliquot of serial dilutions of azidothymidine and nigrizia, final concentration of azalomycin in which from 0.5 ng/ml to 0.1 μg/ml, and nigrizia from 1 to 200 μg/ml (three wells for each option). Experimental (drug) and control (without drug) infected cells and uninfected control cells (without drug) were cultured at 37°C and 5% CO2within 4 days. After incubation count the proportion of viable cells in the cell Goryaeva after staining with 0.4%solution Trypanosoma blue and control the level of accumulating virousspecificakih protein P24 by ELISA, as described in [19]. On the basis of the obtained in the experiment quantitative data to build a dose-dependent curves that define inhibiting dose (ID50) and calculate the combination index (FIC), as described above in example 1.

Quantitative data of inhibition of virus reproduction composition and individual compounds are presented in table 6. Combinational index equal 0,435 (<1), indicating a synergistic anti-HIV effect of azidothymidine and nigrizia in such a ratio of 1:2000.

Table 6

Quantitative characteristics of inhibition of HIV-1The ECRsthe combination of AZT and nigrizia (1:2000)
MedicationID50,mcm FIC
individualin the mix

0,435
AZT0,02540,0056
Nillesenfor 9.642,076

Thus for the first time it is shown that the proposed composition nigrizia with AZT can effectively suppress the reproduction of a "wild" strain and AZT-resistant mutant HIV-1 in culture-sensitive virus cells, showing a synergistic effect. Given that nillesen is an effective inducer of interferon-gamma [20], we can hope to significantly strengthen its therapeutic potential in the treatment of HIV infection. This allows us to recommend such compositions ("cocktails") for the development of new effective domestic remedies for treatment of HIV infection, which may substantially (about 50 times) to reduce the costs to the community and those patients for treatment.

References

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2. Larder B.A, Kemp S.D. Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). // Science. - 1989. - Vol.246. - P.1155-1158.

3. Chiu D.T. & P.H. Duesberg The toxicity of azidothymidine (AZT) on human and animal cells in culture at concentrations used for antiviral therapy.// Genetica. - 1995 - Vol.95 - P.103-109.

4. Brinkman, K., Hofstede J.M, D.M. Burger Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity ascommon pathway. // AIDS. - 1998. - Vol.12. - P.1735-1744.

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6. Kravchenko A.V. Combination antiretroviral therapy for HIV infection. // Epidemiology and infectious diseases. - 2001. No. 1.- P.59-62.

7. Ito M., Sato, A., Hirabayashi K., Tanabe f, Shigeta, S., Baba, M., De Clercq E., Nakashima, H., Yamamoto N. Mechanism of inhibitory effect of glycyrrhizin on replication of human immunodeficiency virus (HIV) // Antiviral Res. - 1988. - V.10. - P.289-298.

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9. Plyasunov O.A., Egorychev I.N., Fedyk NV and other Studies of anti-HIV activity (3-glycyrrhizic acid // Vopros. - 1992 - No. 5-6 - S-238.

10. Pokrovsky A.G., Plyasunov O.A., Gashnikova NM, Mamaeva O.A., fedyk NV Chronically infected HIV-1 culture human monocytes U937 as a model for evaluating the effectiveness of anti-HIV drugs // Virology. - 2001. No. 6. - Ñ.38-42.

11. Pokrovsky A.G., Plyasunov O.A., Ilichev T.N., Borisov O.A., fedyk NV, Petrenko NI, Petukhova the old Testament, Schulz EE, Tolstikov G.A. Synthesis of derivatives of vegetable triterpenes and the study of their antiviral and immunostimulating activity // Chemistry for sustainable development. - 2001. No. 9. - S-491.

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14. Copyright witness the creation of the USSR №1804848, class. And 61 To 31/705 published BI No. 12, 1993

15. Ilichev T.N., Olkin S.E., fedyk NV, Abdullayev S.M., Schulz EE, Tolstikov G.A., Pokrovsky A.G. Pharmacokinetics of glycyrrhizic acid and its derivatives. // Russian journal of HIV/AIDS and related problems". - 2000. - V.4. No. 1. - 74.

16. Allen L.B., Teepe A.G., Kehoe M.J., C.S. Holland, Me Namara D.J. and Cook P.D. Antiviral and cytotoxicity evaluation of 3-nitro-3-deazauridine // Antiviral Res. - 1989. - V.12. - P.259-268.

17. Pokrovsky A.G., Plyasunov O.A., Kiseleva AU, Gashnikova NM, fedyk NV Comparative study of the emergence of resistance to HIV-1 AZT H-phosphonate AZT in cell culture, " DOKL. - 2002. - T. No. 2. - S-252.

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20. Application for patent of the RF No. 2003134868 (037495), priority from 01.12.2003, "Inducer of IFN-γ".

Synergistic composition for inhibiting HIV, characterized in that it contains azidothymidine and Penta-O-nicotinate glycyrrhizic acid - nillesen, in concentrations that are physiologically achievable in the blood: for azidothymidine 0,0037-0,0254 μm, for nigrizia 0,0052-for 9.64 μm.



 

Same patents:

FIELD: organic chemistry, medicinal virology, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazole of the formula (I-A):

wherein R1 means (C1-C12)-alkyl that can be optionally substituted with 1-3 substitutes taken among fluorine, chlorine and bromine atoms, (C3-C8)-cycloalkyl, phenyl, pyridyl or (C1-C4)-alkyl substituted with phenyl; R2' means optionally substituted phenyl wherein phenyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano- and nitro-group; R3 means (C1-C12)-alkyl or (C1-C4)-alkoxy-(C1-C4)-alkyl; A' means (C1-C4)-alkyl optionally substituted with phenyl or optionally substituted with 4-pyridyl wherein phenyl or 4-pyridyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH2-U-heterocyclyl wherein U represents O, S or NR'' wherein R'' means hydrogen atom or (C1-C4)-alkyl and wherein heterocyclyl means pyridyl or pyrimidinyl that is optionally substituted with 1-2 substitutes taken among (C1-C4)-alkyl, fluorine, chlorine and bromine atoms, cyano-, nitro-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH(OH)-phenyl; or A' means the group CH=CHW wherein W means phenyl; X means S or O, and their pharmaceutically acceptable salts. These compounds are inhibitors of human immunodeficiency virus (HIV) reverse transcriptase and, therefore, can be used in treatment of HIV-mediated diseases. Also, invention relates to a pharmaceutical composition used in treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 5 tbl, 32 ex

FIELD: biology, medicine.

SUBSTANCE: invention proposes the complex anti-HIV compound that comprises polyanionic matrix and chemical bound pseudoligand for HIV-1/2 gp120 that comprises a peptide fragment of HIV-1/2 CCR5 or CXCR4 co-receptor. Polyanionic matrix and bound peptide fragment of HIV-1/2 CCR5 or CXCR4 co-receptor are represented by the general formula:

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EFFECT: improved and valuable medicinal properties of complex compound.

3 cl, 2 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

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EFFECT: improved and valuable medicinal properties of agent.

20 cl, 2 tbl, 2 ex

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EFFECT: increased biological activity of the product.

43 cl, 16 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: the suggested treatment should be performed due to introducing a compound of total formula I.

EFFECT: increased efficiency of therapy.

17 cl, 1 dwg, 7 ex, 8 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

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R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, vitamins, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the formula (I): wherein X means hydrogen atom or hydroxy group; R1 and R2 that can be similar or different mean hydrogen atom, (C1-C4)-alkyl; R3 means hydrogen atom, methyl group, fluorine or chlorine atom. Also, invention relates to its esters able to hydrolysis in vivo in combination with pharmaceutically acceptable acids. Also, invention relates to a pharmaceutical composition eliciting the inhibitory activity with respect to proliferation and promoting differentiation of cells and comprising the effective dose of compound of the formula (I) in common with pharmaceutically acceptable carriers and/or excipients. Also, invention relates to applying compound of the formula (I) for preparing a medicine used in treatment and prophylaxis of disease characterizing by abnormal differentiation of cells and/or proliferation of cells.

EFFECT: valuable medicinal properties of compounds.

13 cl, 3 sch, 3 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: method involves treating hepatitis C virus infection or hepatitis B virus infection by introducing carboxamidine of formula 1 or its pharmaceutically permissible salt at a dose of 0.1-40.0 mg/kg of body mass. Α-interferon is also introduced. Compound of formula 1 is in D-configuration.

EFFECT: enhanced effectiveness of treatment.

7 cl, 5 dwg

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives if azaindole of the formula (I)

or its pharmaceutically acceptable salts wherein the formula is taken among the group consisting of , , and and wherein each among R1, R2, R3 and R4 is taken independently among the group consisting of hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, halogen atom, cyano-group (CN), phenyl, nitro-group, -OC(O)R15, -C(O)R15, -C(O)OR16, -OR19, -SR20 and NR21R22 wherein R15 is taken independently among the group including hydrogen atom (H),(C1-C6)-alkyl and (C2-C6)-alkenyl; each among R16, R19 and R0 is taken independently among the group including hydrogen atom (H), (C1-C6)-alkyl or (C1-C6)-alkyl substituted with from 1 to 3 halogen atoms; each among R21 and R22 is taken among the group including hydrogen atom(H), hydroxy-group (OH), (C1-C6)-alkyl; R5 represents the group (O)m wherein m = 0 or 1; n = 1 or 2; R6 is taken among the group including hydrogen atom (H), (C1-C6)-alkyl, -C(O)R24 and -C(O)OR5 under condition that carbon atoms comprising carbon-carbon double bond of indicated (C3-C6)-alkenyl are not the addition point to nitrogen atom to which R6 is joined; R24 is taken among the group consisting of hydrogen atom (H), and (C1-C6)-alkyl; R25 represents (C1-C6)-alkyl; each among R7, R8, R9, R10, R11, R12, R13 and R14 is taken independently among the group including hydrogen atom (H) and (C1-C6)-alkyl; Ar is taken among the group including:

, and . Compounds of the formula (I) inhibit HIV-1 that allows proposing their applying in medicine.

EFFECT: valuable medicinal and antiviral properties of compounds.

22 cl, 13 sch, 2 tbl

FIELD: medicine, virology, pharmacy.

SUBSTANCE: invention relates to treatment of HIV-infection and AIDS and involves a method for decreasing the content of ceramides in a patient suffering these diseases and a set for its realization. Method involves administration in a patient the medicinal preparation comprising L-carnitine or acyl-L-carnitine wherein a linear or branched acyl group comprises 2-6 carbon atoms, or their pharmacologically acceptable salts in combination with an antiretroviral medicinal preparation taken among the group of nucleoside-like inhibitors of reverse transcriptase, non-nucleoside inhibitors of reverse transcriptase, inhibitors of HIV protease. A set for decreasing the content of the content of ceramides involves an antiretroviral medicinal agent taken among the abovementioned group and enhancing agent taken among the group consisting of L-carnitine or acyl-L-carnitine wherein linear or branched acyl group comprises 2-6 carbon atoms, or their pharmacologically acceptable salts or mixtures. Invention provides enhancing activity of antiretroviral agents and to protect immune system due to decreasing the concentration of ceramides that results to inhibition of HIV expression and cellular apoptosis.

EFFECT: improved and valuable medicinal properties of agent.

20 cl, 2 tbl, 2 ex

The invention relates to the field of medicine

The invention relates to substituted ammonium salts of 5'-H-phosphonate 3'-azido-3'-deoxythymidine General formula (1), where RR'R N are L-alanine, ethanolamine, triethanolamine, 6-aminocaproic acid, pyridoxine or dimethylaminoethanol, which are selective inhibitors of the production of human immunodeficiency virus HIV-1 and HIV-2

The invention relates to pharmaceutical compositions containing two or more compounds having anti-HIV activity

The invention relates to the field of molecular biology, Virology and medicine, namely to the new 2 ,3 dideoxy-2 ,3-didehydrothymidine (d4T) - 2',3'-didehydro-2',3'-dideoxythymidine -5'[(etoxycarbonyl) (ethyl)phosphonate] as an inhibitor of HIV

The invention relates to new antiviral derived 5'-H-phosphonate 3'-azido 3'-deoxythymidine General formula I

< / BR>
where R represents isopropyl, neopentyl or cyclohexyl,

containing pharmaceutical compositions

FIELD: medicine, oncology, pharmacy.

SUBSTANCE: after proving the pleural fluid sterility method involves its exfusion from pleural cavity and administration of antitumor chemopreparations. Firstly, 20 mg of bleomycetin is incubated with 20 ml of autopleural fluid, pleural fluid remained after exfusion is placed into packages "Gemakon" and centrifuged at 2000 rev/min for 60 min and liquid part is frozen. Pleural fluid is removed again as its accumulation and administration of incubated mixture of pleural fluid with bleomycetin is repeated also wherein the bleomycetin dose is increased up to 25 mg. In 2-3 days after removal of pleural liquid chemopreparations incubated with preliminary defrosted liquid part of pleural fluid are administrated each 5-7 days in the following sequence and doses: the first administration - 100 mg of cisplatin; the second administration - 100 mg of cisplatin; third, fourth and fifth administrations - 30 mg of doxorubicin and 1000 mg of cyclophosphan up to the total amount - cisplatin, 200 mg; doxorubicin, 90 mg, and cyclophosphan, 3000 mg. Method provides elimination of pleural fluid in full volume, to compensate loss of liquid, protein and trace elements, to reduce tumor size and to avoid toxic symptoms of chemotherapy. Invention can be used in the presence of exudative pleuritis in patients with lung cancer who can't to be subjected for operative and radiation treatment.

EFFECT: improved treatment method.

2 ex

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