Method of predicting disease course in children in case of acute respiratory viral infections

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely, to immunology and clinic laboratory diagnostics, and can be used to predict course of acute respiratory viral infections (ARVI) in children in the first days of disease and timely administration of immunomodulating medications. For this purpose by means of ELISA immunologic indices of spontaneous and induced interferon-γ in vitro (IFH-γ) are determined. Index of interferon-γ stimulation (IS IFH-γ) is calculated by division of index of induced level by index of spontaneous level of interferon-γ. Also carried out is calculation of lymphocyte activation index (LAI IFH-γ) per 1000 lymphocytes by division of index of induced interferon-γ by absolute number of patient's lymphocytes. Additionally in blood plasma determined is content of interleukin-10 (IL-10). If values of IS IFH-γ are higher than 3, LAI IFH-γ equals or is higher than 40, IL-10 is from 30 to 60 pg/ml favourable outcome of disease is predicted with therapeutic treatment which does not include immunomodulators. If IS IFH-γ is lower than 3, LAI IFH-γ is lower than 40, IL-10 is from 60 to 100 pg/ml, predicted are severe course of disease and development of complications, which requires urgent treatment by immunomodelling therapy. If IS IFH-γ is lower than 3, LAI IFH-γ is lower than 30, IL-10 is higher than 100 pg/ml, predicted are severe course of disease with development of bronchopulmonary complications and possible chronisation of pathologic process and recurrent ARVD, which requires additional introduction of immunomodelling medications.

EFFECT: increase of accuracy of early prediction of disease course severity and development of complications in children with ARVI, including those from 1 month old, which makes it possible to carry out necessary anti-viral and immunomodelling therapy, aimed at strengthening immunity cell responses, in due time.

3 tbl, 3 ex

 

The invention relates to medicine, namely to immunology and the clinical laboratory. It can be used to predict the course of disease, such as acute respiratory viral infection (ARVI)in children aged 1 month to 18 years. The invention allows to predict the development of complications in children and at an early stage of the disease to prescribe therapeutic drugs that prevent unfavorable course of the disease, in particular to choose the best together with immunomodulating therapy.

The invention is based on the method of estimating the total immunoreactivity of the organism of children in individual indicators interferonalpha (IFN) status and content of interleukin-10 (IL-10) in blood plasma of the patient in the early days (1st, 2nd day) of SARS.

Factors determining the severity of disease, the characteristic clinical manifestations and outcome of acute respiratory viral infections, in addition to the properties of the pathogen, are characteristics of the immune system to adequately respond to infectious antigen. Acute inflammatory process, usually accompanied by disturbances in the immune system, which in most cases reversible. However, complications may be associated with an initial defect in the immune system or deficiency of macrophage functions and immune cells.

In the diagnosis and prognosis of t is the treatment of diseases changes in cytokine production are used extensively.

Famous work:

Pitkäranta A., Nokso-Koivisto j, Jäntti V., A. Takala, Kilpi T., Hovi T. Lowered yields of virus-induced interferon production in leukocyte cultures and risk of recurrent respiratory infections in children. Journal of Clinical Virology. Volume 14, Issue 3, December 1999, P. - 199-205.

It is characterized as reducing the production of interferon by leukocytes in vitro increases the risk of recurrent respiratory infections in children. The disadvantage of this method of forecasting is the complexity of the method using cell cultures and the test virus.

Known RF patent 2159936, G01N 33/68, Marinenko RU, Anikin V.B. have been, iovlev VI, Malinovskaya CENTURIES, the method of selecting the type of immunomodulatory therapy and determine the prognosis of disease outcome based on the analysis of interferon status of the patient.

This invention relates to a method of selection of immunomodulatory therapy and prognosis of the disease on the basis of interferon status of the patient. The method includes the determination of the activity of total serum interferon (S-IFN), production by leukocytes in vitro interferon-α and interferon-γ.

The determination is carried out in samples of whole blood incubated in medium RPMI-1640, 100 µl, with the addition of Newcastle disease virus (NDV) and phytohemagglutinin (PHA) for the induction of IFN-α and IFN-γ respectively. It is carried out by titration of the samples in cell culture followed by incubation with the virus of vesicular with whom matita. Using transplantable culture, sensitive to the action of IFN. This method allows to predict the course of the disease, however, is time-consuming, labor-intensive and requires specialized equipment and skills of the contractor, tcherepanova work with tissue culture and viruses.

Known RF patent №2169923, G01N 33/53, Senko O.V. a method for predicting the frequency of recurrent infections of the respiratory tract and durability of the effect of rehabilitation in preschool children.

The authors propose a method for predicting the possible frequency of recurrent infections of the respiratory tract using a range of biochemical parameters. The method includes evaluating the quality and quantity correlation between these laboratory values.

Known RF patent №2008686, G01N 33/53, Sizechina L.P., Chernyshov, VN, Andreeva I.I., Bolgarinov NICHOLAS a method for predicting the development of complications in children with ARVI.

This method is based on the definition in the early period of the disease the number of neutrophils in peripheral blood expressing receptors for Fcj fragment of immunoglobulin G (Fc jP) in response rosethorne with sheep erythrocytes. In the case of increasing the percentage of neutrophils with FcjP above 58% predict the development of complications.

Known RF patent №2297003 G01N 33/68, Useynov N.N., SHOVKUN VA, Miz is Ricky UL A method for predicting the recurrence of the disease in infants suffering from acute respiratory diseases.

The method was carried out as follows: the patient in the morning on an empty stomach made the sampling of venous blood (5 ml, was isolated mononuclear cells and were cultured for 24-48 hours at 37°C in the presence of 5% CO2 in culture medium RPMI1640 with 10% inactivated calf serum, 5×10,5 M2-mercaptoethanol, 2 mm glutamine, 10 mm HEPES buffer, 50 μg/ml gentamycin with the addition of mitogens (LPS-for the induction of tumor necrosis factor-alpha and formalistic acetate for the induction of interferon-gamma). In parallel was determined spontaneous products by adding equal volume of culture medium. The level of cytokines in supernatant were determined by ELISA kits company "Protein path. Expected index is the ratio of induced and spontaneous production of these cytokines and when the index value ratios for tumor necrosis factor alpha below 0,85, and interferon gamma below 0,45 determine the possibility of repeated respiratory diseases. Here we are speaking only about the predisposition to re ARD.

The prototype of the claimed invention is the method described in thesis Exemplary E.V. "the Drugs interferon and its Indus the Torah in the treatment of influenza and acute respiratory viral infections in children" (abstract. Diss. Kida. the honey. Sciences. - St. Petersburg, 2007. - 23 (C).

The method includes determination of spontaneous and induced production by leukocytes in vitro IFN-α and IFN-γ according to the method SIG. On the basis of the results calculate the index ratio between induced and spontaneous production of these cytokines is the stimulation index (IP) IP IFN-α or-γ, the index of lymphocyte activation (ial group) - ial group of IFN-α or-γ.

These figures give an idea about the activity of immune cells (KIC), which characterizes the spare capacity interferoninducible cells. This allowed the author to develop criteria for the appointment of the drugs interferon and its inducers at different period of ARVI in children.

The system of interferon (IFN) provides nonspecific antiviral resistance of the body and affects the full range of its specific and nonspecific immune response.

A reflection of the functional state of the system IFN is IFN status which is being evaluated by several well-known figures [Issues of General Virology, Ed. by Ohikysupiv, 2007, St. Petersburg], the main of which are:

1. The number of circulating blood IFN-α and-γ (serum IFN).

2. The level of IFN-α production by cells (or lymphocytes) in vitro at his induction viral inducers.

3. Level production of IFN-γ Le is kazetami (or lymphocytes) - during its induction by mitogens in vitro.

The task of the invention is to develop a method of predicting the course of viral respiratory infections in children at the earliest stages of the disease by identifying indicators of immunoreactivity of patient, practical and cost-effective.

According to the results of diagnostic perspective direction of therapy is complicated and protracted course of acute respiratory viral infections is the use of methods of immunotherapy aimed at strengthening the cellular immune reactions, in addition to a comprehensive therapeutic treatment.

The proposed method for predicting easily reproducible, does not require special conditions (e.g., sterile boxes)related to working with tissue culture and test viruses for the study. It is less time-consuming by the number of actions in the analysis. The advantage is that research does not require serum that allows you to take blood in a smaller scale, and it is essential in the examination of young children: from 1 month.

Goal - an early prediction of the severity of the disease and its complications in children with ARVI and simplification of the diagnostic method.

From large enough clinical material were selected the most informative indicators adequately assess the ü functional state of the immune system of the sick child, namely interferon-gamma and interleukin-10. Earlier in this combination, these indicators are not used.

When determining the change in selected indicators can assess the severity of the pathological process and the possibility of complications of SARS, and the percentage of forecast accuracy is improved compared with known combinations of other indicators of immunoreactivity of the child.

The essence of the invention is the establishment of digital patterns in the values determined in vitro spontaneous and induced phytohemagglutinin production by leukocytes of IFN-γ to calculate the stimulation index (IP), index lymphocyte activation (ial group), as well as bringing in the accuracy of the prediction values of the levels of Il-10 in plasma. The account of the interdependence of all of these metrics allows you to assign adequate therapeutic treatment, preventing possible complications.

The authors have shown the possibility of using only data SP IFN-γ and IP IFN-γ in vitro. Additional definition of the level of IL-10 in plasma allows to estimate the direction and intensity of the immune response of the organism of children with ARI.

IL-10 is produced by T-helper 2-type responsible for switching on humoral antigen-specific immune response, and plays the role of an antagonist of a number of cytokines, including interface, the she-gamma. This fact may be a negative feature, as it is associated with manifestations of immunosuppression in the form of suppression of the proliferative response of T-lymphocytes and consequently less effective protection in case of viral infections [Children's infections. 2003. No. 3. p.58-61].

It is known that interferon system belongs to the early cytokine responses during infection. INF-γ is produced mainly T-helper type I and cytotoxic lymphocytes, is a powerful immune stimulator and inducer of non-specific protection, stimulates phagocytosis, as well as the activity of neutrophils and natural killer cells, promotes adhesion of granulocytes to endothelial cells and regulates the strength of the immune response [Immunology. 2002. No. 2. - p.77-80].

Increased spontaneous production of interferon-gamma occurs when the development of inflammatory processes in the upper respiratory tract (Acta Paediatrica. - 2008. - Volume 74. - Issue 1, p - 118-121).

For diagnosis and prognosis in contrast to the prototype method was carried out only study induced phytohemagglutinin (PHA) and spontaneous production (SP) of IFN-γ in vitro. For this analysis, patients in the morning on an empty stomach took a blood from a vein or finger in a volume of 1.0 ml in a test tube with heparin is 10-15 units/ml Selected so the blood can be stored for 5-6 hours at +4°C without losing all the required properties.

The remaining is the Yuexiu blood was centrifuged and plasma was determined by the level of interleukin-10. The determination was performed by ELISA standard sets of production of LLC "Cytokine", SPb.

Further analysis was performed automatically using the reader for ELISA analysis at a wavelength of 490 nm. The level of IFN in the analyzed sample is determined using a calibration curve depending on the optical density. This allows to obtain reproducible results.

The authors used a metric called - index stimulate production of IFN-γ (IP IFN-γ), which gives an idea about the degree of activity of the KIC, about their ability to answer the synthesis of IFN-γ on the introduction of the inductor characterizing backup capabilities interferon-producing cells. IP IFN-γ was determined by dividing the level induced production of FE IFN-γ on the value of the spontaneous products of the JV IFN-γ:

Due to the fact that there are age-related features of the content interferoninducible cells, such as lymphocytes, was introduced the following index - the index of lymphocyte activation (ial group IFN) - an indicator that provides information about individual IFN-producing activity of lymphocytes (in terms of thousand lymphocytes), which is private from division of ti measure IFN-γ on the absolute number of lymphocytes of the patient:

Statistical processing of the obtained results showed a certain regularity. In 36 healthy children were received levels of SP IFN-γ 10-50 PG/ml, IFN-γ - inlet 150 up to 450 PG/ml IP IFN-γ=9-45. Ial group IFN-γ>40. The level of IL-10=2 to 50 PG/ml

At Ari with no complications most often at the beginning of the disease met the patients with high levels of SP IFN (61.6% of the cases). In children with initially low levels of SP IFN-γ and IP IFN-γ, when the level of IL-10>60 PG/ml, more often than in other groups, met patients with pneumonia and bronchitis, while high JV IFN-γ (>50 PG/ml) and IP IFN-γ (>4,0), the level of IL-10<50 PG/ml in 90,9% of cases met the children with ARVI without bronchopulmonary lesions and only 9.1% - was diagnosed bronchitis.

The highest level JV IFN-γ in the blood (58,3±4,3 PG/ml) and IP IFN-γ>4, when the level of IL-10<50 PG/ml were detected in children with ARVI without complications, and lowest for pneumonia (39,0±5,4 PG/ml, IP IFN-γ<3 when the level of IL-10>60 PG/ml), differences in performance are statistically significant (p<0,05).

PI IFN-γ, and ial group of IFN-γ were significantly lower in children carrying SARS with lesion of lower respiratory tract, indicating a reduced ability of the body to counteract the pathogen, i.e., the level of destruction of the respiratory tract to a certain extent depends on the activity of the KIC of the patient. The content And the -10 in the blood plasma in patients with severe disease SARS and presence of complications were significantly higher than in children over medium gravity and without complications.

When activity is low ICC (low SP IFN and low IP) occurs more often protracted course of the disease than at higher activity of the KIC. The presence of high interferoninducible activity of the cells, even in those with low SP IFN reduces the duration as the intoxication syndrome and disease in General (Table 1).

Table 1
The prognostic value of two methods of predicting the level of destruction of the respiratory tract in children with ARVI
IndexIP IFN-γIL-10The claimed method IP IFN-γ + IL-10 (abs./%)The prototype method is IP IFN-α + IP IFN-γ (abs./%)
≤2,0; >50>2,0; ≤50≤2,0; ≤2,0>2,0; >2,0
ORI, n=2984,5±0,430,5±1,356/19,0242/81,071/24,0 227/76,0
Acute respiratory infections, bronchitis, + complications, n=932,6±0,7*55,9±2,1*81/87,0#12/24,0#32/34,061/66,0
ARI, pneumonia, prolonged period, n=421,2±0,4*76,4±1,9*37/88,0#5/12,0#27/64,015/36,0
* - p<0,05 - against the ORI without bronchopulmonary lesions
# - p<0,05 - in relation to the method prototype

The sensitivity of the inventive method is 87%, which is significantly higher than that of the prototype method - 66,0%.

The specificity of the claimed method 81,0%, and the prototype method - 76,0%.

Thus, the claimed method is much more accurately predicts the development of complications and a prolonged course of the disease SARS in children, which will promptly appoint together with immunomodulating therapy with regard to the immune response of the patient.

The dependence of IFN-producing activity of the KIC patients from the content they have absolute number of lymphocytes and their ability to produce IFN-γ (Table 2).

Table 2
Description ial group of IFN-γ in children with ARVI depending on the level of lesion of respiratory tract
IndexIal group IFN-γ (abs.%)
≤30,0, n=118>30,0, n=294
ORI, n=31769/21,8248/78,2#
Acute respiratory infections, bronchitis, n=7335/47,938/52,1
ARI, pneumonia, n=2214/63,6*8/36,4*
Abs. the number of lymphocytes, 109/l4,6±0,52,5±0,3#
Ial group IFN-γ (10-3PG)21,1±1,251,1±2,9#
*p<0,05 - against the ORI without bronchopulmonary lesions
# to children with ial group IFN-γ≤30,0·10-3PG

When the content of the absolute number of lymphocytes in the blood >2,0×109/l in children, ial group IFN-γ>30.0 disease occurs more easily with a significant reduction in duration of febrile period and intoxication syndrome, less razvivaetsyavsesezonny.

The nature of the disease also depends on the individual interferoninducible activity of the KIC. So, the protracted course of the disease most often occurs in patients with low ial group IFN-γ (≤30 PG 10-3).

According to the method claimed in the invention, were surveyed 578 children from 1 month to 18 years. The reliability of the results and conclusions are shown in table 3.

Conclusions:

The regularities in combination indicators of immunoreactivity in the different characters of the disease statistically significant.

Thus, when defining the venture IFN-γ and IP IFN-γ in the early days of SARS, calculating IP IFN-γ and ial group of IFN-γ by determining the level of interleukin-10 in plasma, it is possible to correctly estimate the state of the immunoreactivity of the body of a sick child and with a sufficient degree of confidence to predict the nature of the disease.

The authors first established, what is the minimum characteristics of immunity is necessary and sufficient for an adequate assessment of the immune response of children with ARI.

Variants of the immune response are inextricably linked with the clinical features of the disease. The authors used a set of indicators of immunity has a high degree of accuracy to 87%, for short-term forecasting is complicated and Agnolo current SARS.

The determination in plasma IL-10 contributes to a more accurate and early assessment of severity of disease, complications, and possible recurrent disease SARS.

If children healthy levels of SP IFN-γ 10-50 PG/ml, IFN-γ-inlet 150 up to 450 PG/ml, IP IFN-γ=9-45, ial group IFN-γ>40, the level of IL-10=2 to 50 PG/ml, when the disease SARS in the establishment of the following indicators - SP IFN-γ=50-75 PG/ml, PI IFN-γ≥150 PG/ml, IP IFN-γ>3, and ial group IFN-γ≥40, the level of IL-10=30-60 PG/ml predicts favorable outcome of the disease.

When JV IFN-γ=50-75 PG/ml, PI IFN-γ=90-100 PG/ml, IP IFN-γ≤3, and ial group IFN-γ≤40, the level of IL-10=60-100 PG/ml predict a severe course and the development of complications requiring immunogenetically therapy.

When JV IFN-γ=20-35 PG/ml, PI IFN-γ=60-100 PG/ml and IP IFN-γ<3, and ial group IFN-γ≤30, the level of IL-10>100 PG/ml predicted a protracted course with the development of bronchopulmonary complications and possible chronic pathological process and re-infection.

The real way to measure the immune response of patients diagnosed with SARS allows to predict the development of long and complicated course of the disease and time to make the necessary antiviral and together with immunomodulating therapy aimed at enhancing the cellular immune reactions. The method can be used in the work of the departments of children's infectious is olenic.

Clinical example.

1. Girl Feet, 5,7, formalized map of survey No. 152, examined for admission to the first day of the infectious diseases of the respiratory tract.

JV IFN-γ - 55 PG/ml; PI IFN-γ - 190 PG/ml; leukocyte count (absolute number) of 5.8×109/l; lymphocytes - 45%. IP IFN-γ=3,5, ial group IFN-γ=72,9; IL-10=32,4 PG/ml, these figures suggest a smooth course of the disease, which further confirmed the clinical and laboratory data. Diagnosed with SARS. Length of illness was 6 days. Moderate changes in immunological parameters corresponded to rapid clinical recovery from SARS and confirmed the accuracy of prognosis and selection of treatment methods.

2. Boy And., 4,6, formalized survey map No. 120, examined for admission to the first day of the infectious diseases of the respiratory tract.

JV IFN-γ - 50 PG/ml; PI IFN-γ - 90 PG/ml; leukocyte count (absolute number) of 7.4×109/l; lymphocytes - 36%. IP IFN-γ=1,8, ial group IFN-γ=33,8; IL-10=73,6 PG/ml of the Obtained result suggests a protracted course with the development of complications that have been confirmed clinical and laboratory data. Diagnosed with acute bronchitis. In addition to symptomatic was appointed substitution therapy with interferon (Viferon or analogues). Duration of illness of 10 days.

3. Boy, 6,5, formalized survey map No. 128, examined for admission to the first day of the infectious diseases of the respiratory tract. History of frequent acute respiratory infections.

JV IFN-γ - 35 PG/ml; PI IFN-γ - 70 PG/ml; leukocyte count (absolute number) of 5.2×109/l; lymphocytes - 36%. IP IFN-γ=2.0, the ial group IFN-γ=37,4; IL-10=138,5 PG/ml, these figures suggest a protracted course with the development of complications that have been confirmed clinical and laboratory data. Diagnosed with pneumonia, right catarrhal otitis. Conclusion: low immune reactivity, poor prognosis of the disease. Additionally, he was appointed immunomodulatory therapy. The disease duration of 16 days. Thus, the preliminary forecast after conducting laboratory tests of the proposed method was correct.

A method for predicting the clinical course in children with acute respiratory viral infections (ARVI) in the first days of the disease, including the determination of enzyme-linked immunosorbent assay immunological parameters of spontaneous and induced interferon-γ in vitro (IFN-γ) and calculate the stimulation index (IP IFN-γ) by dividing the indices of the induced level of spontaneous, the index calculation lymphocyte activation (ial group IFN-γ) 1000 lymphocytes, by dividing the index and dozirovannogo interferon γ on the absolute number of lymphocytes of the patient (ial group IFN-γ), wherein the plasma further define the content of interleukin 10 (IL-10), and then make a conclusion: when IP IFN-γ is greater than 3, ial group IFN-γ is equal to or greater than 40, IL-10 from 30 to 60 PG/ml predicts favorable outcome in therapeutic treatment without including immunomodulators; IP IFN-γ is less than 3, ial group IFN-γ is less than 40, IL-10 from 60 to 100 PG/ml predict a severe course of the disease and the development of complications requiring urgent treatment by immunogenetically therapy; and when IP IFN-γ is less than 3, ial group IFN-γ is less than 30, IL-10 greater than 100 PG/ml predicted a protracted course with the development of bronchopulmonary complications and possible chronic pathological process and re-ARI, which requires the addition of immunomodulatory drugs.



 

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4 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is application of CCR5 antagonist maraviroc or its pharmaceutically acceptable salt (solvate) for increasing number of cells CD4, or CD8, or both CD4, and CD8 in HIV-infected patient, as well as application of maraviroc for increasing number of cells CD4, or CD8, or both CD4 and CD8 in patient with HIV, infected by virus population, using CXCR4. It is demonstrated that maraviroc in addition to earlier known inhibition of HIV penetration in patients, enhanced immunorestorative therapy in treatment of HIV-associated opportunistic patient/s states with impaired immune status.

EFFECT: invention also makes it possible to treat with CCR5 antagonist maraviroc of patients, which has virus population, using CXCR4, as for such patients increase of their CD4 and/or CD8cells will be also useful.

13 cl, 2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, namely, to method of obtaining preparation, which has immunomodulating, anti-inflammatory and wound-healing action, which lies in crushing preparation components dog rose fruit and/or ambrosia, drying to 10% humidity, freezing ambrozia and/or dog rose fruit separately to temperature 40-60°C with further impact on each component in jet mill by air jet under pressure 0.6-0.8 MPa until particles with size not more than 500 nm are obtained.

EFFECT: method ensures high productivity and good preservation of material properties.

2 tbl, 9 ex, 2 cl

FIELD: chemistry.

SUBSTANCE: invention describes ergoline derivatives of formula (I), in which each of R1 and R2 independently denotes H; optionally R10 and/or R11-substituted phenyl or -phenyl C1-C4alkyl; optionally R10 and/or R11-substituted heteroaryl or -heteroaryl C1-C4alkyl; optionally R10 and/or R11-substituted N-oxide heteroaryl; optionally R10-substituted C1-C8alkyl; optionally R10-substituted C2-C8alkenyl; optionally R10-substituted C2-C8alkynyl; optionally R10-substituted C3-C8cycloalkyl; or optionally R10-substituted C4-C8cycloalkenyl; or r1 and r2 together with the nitrogen atom to which they are bonded optionally form R10-substituted 3-8-member ring, which, in addition to the nitrogen atom, contains up to 2 heteroatoms independently selected from a group comprising N, O and S; R3 denotes H; OR1; CH2R1R2; (CH2)1-2NR1R2; CH2-CH2-OR1; CH2-CO-NR1R2; or CO-CH2R1R2; R4 denotes F; CI; Br; I; OR1, NR1R2 or assumes one of the values given for R1; and R5 assumes one of the values given for R1, in free form or in form of a salt for preventing or treating disorders or diseases mediated by interactions between chemokine receptors and their ligands.

EFFECT: high effectiveness of the compounds.

14 cl, 99 ex, 8 tbl

FIELD: medicine.

SUBSTANCE: Lactobacillus salivarius CNCM I 1794 and Lactobacillus paracasei CNCM I 1688 strains either separately or combined are applied for preparing a composition effective for immune system stimulation in the diseases associated with immune changes. The composition represents an oral composition, a dietary composition, a food composition or a nutritious composition containing salubrious additives.

EFFECT: invention enables certain immune system stimulation by making it stimulating more actively.

14 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a mixture of sodium laquinimod crystal particles wherein 10% or more of total volume of sodium laquinimod particles are sized more than 40 micron. Also, the invention refers to the mixture of sodium laquinimod crystal particles of tap density at least 0.6 g/ml, to a pharmaceutical composition, to a composition, to a method of sodium laquinimod recrystallisation, as well as to a method for preparing the pharmaceutical composition.

EFFECT: preparation of the new biologically active compounds used for treatment of disease caused by autoimmune or pathological inflammation.

39 cl, 17 ex, 5 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new cyclic peptide compound or its pharmaceutically acceptable salt which shows a hepatitis C virus activity based on an inhibiting activity of RNA replication of a hepatitis C virus replicon, to a method of producing it involving regrouping in a soft acid medium followed by amino acid exchange reactions, to a pharmaceutical composition containing said compound.

EFFECT: preparation of the drug exhibiting the anti-HCV activity.

16 cl, 44 tbl, 228 ex

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