Method for accompanying treatment of lymphoblast leucosis

FIELD: medicine, oncology, hematology.

SUBSTANCE: method involves the complex using symptomatic, antibacterial, general tonic agents and nonspecific immunomodulating therapy. For this aim, lysozyme hydrochloride powder is given orally in the daily dose 500-1800 mg, 2 times per a day, every day for 20-30 days in combination with dosing sodium nucleinate in the daily dose 100-1500 mg, 2 times per a day, for 20-30 days by oral or sublingual route, and lactulose given orally in the dose 2.5-5 ml, 1-2 times per a day, every day for 10-30 days. Lysozyme hydrochloride is given 0.5-1 h before eating, sodium nucleinate is given after intake of lysozyme hydrochloride directly and lactulose is given 20-30 min before eating, or before eating immediately, or in 3-4 h after intake of lysozyme hydrochloride and sodium nucleinate. Method provides the complex correction of nonspecific resistance of body in patients suffering from leukosis and involving maintenance of immune homeostasis, plasma proteolysis, intestine microecology and reparative processes and improved tolerance of scheduled polychemotherapy.

EFFECT: improved method of treatment.

 

The invention relates to medicine and can be used in Oncology for supporting the treatment of patients with acute lymphoblastic leukemia, including children.

The most important achievements of clinical Oncology XX century include advances in the treatment of acute lymphoblastic leukemia (ALL) in children associated with the use of rigid programs of polychemotherapy (PCT), reducing or eliminating the population of tumor cells in the bone marrow. However, there is still a problem side effects of chemotherapy, which is always accompanied by a deep mielo and immunosuppression, mielotoksicskie agranulocytosis, anemia, that causes the development of opportunistic infections [1]. Neutropenia develops a soft PCT of hematological malignancies in children, almost 100% of cases, the degree and duration of suppression of neutrophils directly associated with impaired cellular and humoral immunity. The duration of neutropenia 7-14 days the risk of infectious complications increases to 41%, and mortality from infectious complications during neutropenia during chemotherapy varies from 5 to 20%.

The most dangerous complications of hematological diseases in children include: septic shock, "ciezarowe" easy", hemorrhagic and DIC, as well as neutropenics enterocolitis (necrotizing enterocolitis or necrotize the General enteropathy), also consider the consequence of cytotoxic therapy, leukemic infiltration of the bowel wall and the action of bacterial endotoxins, in particular enterotoxin Clostridia difficile [2]. Medication and specific leukemic shock syndrome inevitably accompanied by violations of the barrier function and the colonization resistance of the mucous membrane of the intestine, suppression of the leading factors of local immunity. This leads to the development of dysbiosis of the gut, characterized by suppression of the normal microflora and the activation of "opportunistic" microorganisms (staphylococci, enterococci, Pseudomonas aeruginosa and Escherichia coli, Klebsiella, Candida), increased frequency of viral infections and high risk of endogenous infection [3]. With the development of infectious diseases, destructive and hemorrhagic complications arises the need to interrupt specific treatment of acute leukemia, does not follow the timing of the stages of the software chemotherapy, which reduces its effectiveness.

Currently, when software anticancer chemotherapy in patients with acute leukaemia make a cover treatment, which, along with the use of symptomatic drugs (drugs that improve impaired function of internal organs, erythropoiesis, hemostasis, hemodynamics and metabolism), a component of the blood or blood substitutes, for the prevention and treatment of infectious complications in episodes of febrile neutropenia use of selective decontamination and antimicrobial therapy with broad-spectrum antibiotics, antiviral and antifungal drugs [2].

Antibacterial therapy during chemotherapy of acute leukemia is carried out with the observance of the General principles of rational antibiotic therapy, taking into account the sensitivity of pathogens and features of the immunological reactivity of the organism. In acute leukemia in children use β-lactam antibiotics, Cefazolin, cephalosporins generations III and IV (Fortum, maxipime), "protected" penicillins a wide spectrum (tazuoqin), and carbapenems (Meronem, Tienam); evidence used vancomycin or clindamycin activity against clostridia, and aminoglycosides with minimal nephrotoxicity (amikacin, netromycin). "Big" antibiotic therapy is usually combined with antifungal therapy with nizoral, diflucan (Mycosyst), early childhood - leporinum. To prevent recurrent bacterial infections in immunodeficient patients on the background and after a long chemotherapy is recommended fluoroquinolones (ciprofloxacin), macrolides, and Biseptol, zyvox and others; in the treatment of herpes virus infection in children with acute leukemia usually apply the zovirax [4].

However, many antimicrobial drugs are broad-spectrum antibiotics have side effects and exacerbate induced by cytostatics secondary immunodeficiency States and dysbiotic disorders. Their application does not allow you to restore suppressed cytostatics cellular and humoral mechanisms of anti-infection resistance and immune homeostasis, reduce toxic effects of drugs in relation to the immune, hematopoietic, excretory, cardiovascular, endocrine and other systems of the body.

In recent years, to improve efficiency and reduce adverse immunosuppressive action of cytotoxic drugs in the accompanying therapy in patients with leukemia increasingly applied immunotherapy, which aims to help the immune system to attack the tumor, to stimulate antitumor immunity [5].

Known methods of treatment of leukemia and other neoplastic diseases of the hematopoietic tissue, based on the use of high technologies using molecular methods, including bone marrow transplantation, LAK cells, hematopoietic stem cells [6].

The leading direction of immunotherapy currently is the use of endogenous modulators of cytokines: interleukins IL-1, IL-2, when adnych and recombinant interferon-α , tumor necrosis factor and others [7].

There is a method of treatment of acute lymphoblastic leukemia in children using drugs α-interferon [8]. Application reaferona or Giverola in the acute period of the disease even without cytotoxic therapy exerts antitumor cytotoxic effect contributes to the reduction in the number of blast cells and the number of megakaryocytes in the bone marrow, the development of neutropenia. These effects alpha interferons are accompanied by activation of the immune system (increasing the total number of T-lymphocytes, equalize immunoregulatory T lymphocytes, increased expression of receptors for IgG and IgM). Their use increases the effectiveness of subsequent inductive chemotherapy with earlier onset of remission than in the comparison group. However, the application of reaferona and human leukocyte interferon in remission at the same time with supportive therapy in some patients induces erythropenia and neutropenia, reaction temperature, headache, vomiting [8].

There are also known methods of treatment of hematological malignancies, including the use of drugs recombinant hematopoietic factors such as granulocyte-colony stimulating factor (filgrastim, Neupogen), intended to reduce neutropenia after high-dose chemotherapy [5, 9].

To fault the m drugs, cytokines, including interferons, applies significant side effects. They are usually parenterally in the form of heavy toxic hemorrhagic, septic conditions, complicating radio - and chemotherapy of tumors. Cytokines, as well as new technologies transplantation components of the bone marrow, while very expensive and used only in a clinical setting, usually in large regional centres [6, 9].

In order to reduce immune disorders and increase the effectiveness of specific treatment of acute leukemia and its complications is known to use in the accompanying combined treatment of patients immune disorders [1]. Sequential or simultaneous application of several immunomodulating agents with different mechanisms of action, is intended to provide a comprehensive approach to immune disorders, including enhancement of nonspecific resistance of the organism to infectious and toxic effects and correction of broken links of immune protection without the risk of reducing the effectiveness of the drugs. This approach requires careful selection of immunomodulators and development of algorithms for their application taking into account the properties of the modulators, their interaction with cytotoxic drugs, the individual characteristics of immunobiological reactivity of the organism of the patient.

Many carried ecificatio immunomodulators, usually used in supportive care of cancer, do not have independent antitumor activity or it is poorly expressed. However, the modulators can increase the effectiveness of treatment as due to the enhancement of antitumor activity and selectivity of action of cytotoxic drugs, and thanks to the enhancement of nonspecific resistance of the organism.

Among the natural immunomodulators that enhance the body's resistance and nonspecific affecting the activity of cytotoxic agents, a special place belongs to lysozyme.

As the closest analogue accepted way of accompanying therapy of acute lymphoblastic leukemia [10], including the commonly used complex therapy with symptomatic, antibacterial, detoxifying, a tonic funds. Additionally the non-specific immunomodulatory therapy by intramuscular injection of lysozyme in daily doses of 200-300 mg for 10-12 days to enhance the antibacterial activity of antibiotics and increasing anti-infective resistance of the organism.

The disadvantages of this method are: the invasiveness of the method of application of lysozyme (intramuscularly); the dosage of the drug is insufficient to enhance the antitumor activity of qi is Ostrikov; the absence of direct effect of lysozyme on the mucous membrane of the digestive tract and its cellular elements, which does not ensure effective correction of the damaged PCT units of local immunity of the gastrointestinal tract and microecology of the intestine; the probability of sensitization of the organism in case of repeated parenteral administration of lysozyme, especially when repeated courses of the drug. This method does not allow for a comprehensive corrective effect on such important parts of the immunological reactivity of the organism, as the functional status of T-lymphocytes, leucopoiesis, antitumor immunity, microbiocenosis of intestines. In addition, in the present method cannot be applied in clinical practice, since discontinued production of injection of lysozyme by domestic producers of medicines.

The objective of the invention is to provide a non-invasive and more effective way to cover the treatment of acute lymphoblastic leukemia, especially in children, in order to enhance the treatment and prevention induced by cytostatics secondary immunodeficiencies, reduce toxic side and dysbiotic effect of chemotherapy on the body.

The invention consists in that way supporting the treatment of acute limp the blast leukemia, integrated use of symptomatic, antibacterial, tonic funds and non-specific together with immunomodulating therapy by introduction of lysozyme, lysozyme be administered orally in the form of a powder lysozyme hydrochloride in a daily dose of 500-1800 mg 2 times a day for 20-30 days, against which impose additional immunomodulator sodium nukleinat in the form of powder or tablets by ingestion or sublingually in a daily dose of 100-1500 mg 2 times a day for 20-30 days, and the prebiotic lactulose in the form of a drug or dietary Supplement orally at a daily dose of 2.5-5.0 ml 1-2 times a day every day for 10-30 days; lysozyme hydrochloride used for 0.5-1 hour before a meal, sodium nukleinat - at the same time, immediately after intake of lysozyme hydrochloride, and lactulose - for 20-30 minutes before a meal or before meal, after 3-4 hours after administration of lysozyme hydrochloride and sodium nucleinate.

The use of the invention allows to obtain the following technical result.

The method provides a pronounced positive clinical effect, which is characterized by:

reducing the severity of chemotherapy-induced secondary immunodeficiencies, comprehensive correction of cellular and humoral immune homeostasis, the drive including: an increase in the content of b-lymphocytes (CD 20+) and activated CD38, especially against the background of severe inhibition of B-cell component of the immune system with long-term chemotherapy (more than 3-4 months); the increased levels of NK-cells (CD 16) - natural killer cells, carrying out the first line of anticancer defenses; the higher initial reduced level of endogenous lysozyme; a decrease in the degree of inhibition of immunoglobulin Ig G, Ig M, Ig and imbalances in blood serum;

reduced side toxic effects of chemotherapy, such as the weakening of the intoxication syndrome, reduction of anemia and neutropenia; improvement of the functional status of neutrophils in the peripheral blood; the lower the frequency and decrease the severity of intestinal syndrome;

the reduction of the destructive potential of the plasma by reducing the high activity of granulocyte elastase and improve balance proteinases and antiproteinases activity;

the reduced severity of dysbiotic disorders microflora and gut function due to the compensation of the deficit of endogenous lysozyme, a more effective elimination of conditionally pathogenic microorganisms, improvement or stabilization of the level of bifidobacteria, lactobacilli and full of Escherichia coli;

improve portability of software chemotherapy, which ensures the timeliness of its stages.

The method provides comprehensive is orecchio nonspecific anti-infective and anti-toxic resistance of the organism, reduces induced by chemotherapy in patients of ALL violations of the cellular and humoral factors of maintenance of immune status, haematopoiesis and intestinal microbiocenosis.

The method is non-invasive and easy to use, which is especially important when it is used in children for whom oral route of administration in the body of lysozyme, which is included in the composition of breast milk, and nucleic acids is physiological.

The developed method differs from the known fact that for the first time in the diagram accompanying the treatment of acute leukemia at the stages of chemotherapy or in remission entered the complex immunomodulatory therapy using oral physiological and harmless immunomodulators wide spectrum of biological action of lysozyme hydrochloride in high doses and sodium nucleinate increasing anti-infective and anti-toxic resistance of the organism, and their background introduction the prebiotic lactulose, which allows to increase the antitumor body's resistance and improve intestinal microbiocenosis.

The technical result is achieved by rst proposed by authors use when accompanying the treatment of acute lymphoblastic leukemia schema complex immune disorders, including oral administration of lysozyme hydrochloride in high doses and its background - BB is Denia sodium nucleinate and lactulose.

Lysozyme protein chicken eggs (enzyme EC 3.2.1.17, N-acetyl-muramic-glucanohydrolase, = muramidase) is used in medical practice in the form of high-purity inject drugs, and pharmaceuticals; lysozyme hydrochloride is widely used in the composition of biologically active additives (BAA) and baby food.

It is known that lysozyme is constantly present in the vast majority of the tissues and fluids of living organisms, including human milk, is a multifunctional factor nonspecific protection and has a unique combination of enzymes, antibacterial, biocorrosion, anti-inflammatory, antioxidant, anti-anemic, and many other valuable properties. Endogenous lysozyme is considered as an additional factor antitumor immunity, and its depletion assign an important role in the pathogenesis of many, including cancer [11, 12].

The proximity of the antigenic structure of exogenous and endogenous lysozyme, a common way their metabolism and excretion in the body condition and low sensitizing properties of exogenous lysozyme, its physiology and innocence, which is especially important for use in children.

Known antitumor activity of homologous and heterologous lysozyme when the number ofóradionuclide and metastatic is puchala. Oral use in adults lysozyme in a daily dose of about 2 grams (dose rate of about 40 g) may enhance the antitumor immune response contributes to the suppression of chemotherapy-growth of carcinoma of the lung, decrease of pain syndrome in some Córadionuclide malignant tumors, provides improvement of the patients with shingles, complicating the course of oncological diseases [11-12]. However, in the global and domestic literature data are not available for clinical use in patients with acute leukaemia drugs oral lysozyme in doses adequate used withóradionuclide tumors.

Sodium nukleinat - sodium salt ribonucleic acid isolated from Baker's yeast, is a nonspecific immunomodulator. The drug for more than 30 years applied in our country to improve anti-infective and anti-toxic resistance, stimulation of leucopoiesis in a wide range of pathological conditions involving secondary immunodeficiency of various origins, including leukopenia, agranulocytosis, lymphocytopenia on the background and after radiotherapy and chemotherapy, some cancer. Sodium nukleinat is a classic stimulator of T-cell immunity in its oppression. The advantages of the drug Rel which relates its ability to quickly raise antitoxic resistance of the organism (tachyphylaxis) and good compatibility with other drugs, including antibiotics, corticosteroids, cytostatics [13]. Data on the use of sodium nucleinate in acute leukemia in the literature are missing.

To stimulate anaerobic normoflora bowel and motor function in medicine, medical and dietary widely used prebiotic lactulose in the form of drugs (normase, duphalac), biologically active additives "Lactusan", is found in some foods [14]. Lactulose is a synthesized from lactose oligosaccharide (disaccharide), which serves as a food substrate and stimulates the growth of bifidobacteria and lactobacilli in the colon. The metabolic products of these representatives of the indigenous microflora - unsaturated fatty acids stimulate bowel motility, create conditions for the elimination of opportunistic and enteropathogenic microorganisms bind ammonia and removal of other toxic products of their metabolism. Thanks lactulose is used in hepatic encephalopathy, reduces morphological and functional disorders of the liver, kidneys, heart, intestines in ethanol and drug toxicity, improving the absorption of trace elements and eliminate their imbalance [14]. Antitumor activity of lactulose has not been studied. There are few details about who is agnosti get a specific protective effect of lactulose, aimed at the prevention of colon cancer [15].

Information about applying combinations of lysozyme hydrochloride with sodium nukleinat and probiotics in acute leukemia in the available literature could not be found.

The authors first shown in experiment and clinic that lysozyme hydrochloride high dose sodium nukleinat and lactulose oral combined application have complementary corrective factors for maintenance of immune homeostasis, plasma proteolysis, microecology of the intestine and reparative processes, ensuring the correction of impaired cellular and humoral factors of anti-infective and anti-toxic resistance: increased decreased number of b-lymphocytes (CD20+), activated T - and b-lymphocytes (HLA-DR and CD38+), natural cytotoxic killer cells (NK cells CD16+); correction of functional state of granulocytes (decrease high apoptosis of neutrophils, their degranulation activity and hyperproductive active oxygen radicals); restoring balance proteinases (anastasopoulou), antiproteinases (α-1-proteinase inhibitor) activity and levels of endogenous lysozyme in the serum; the improvement microbiocenosis and morphofunctional state of the intestine.

The mechanism of action proposed combined the I is in the complementary effects of drugs: immunokorrigiruyuschy, Antianemic, antitoxic action of lysozyme hydrochloride and sodium nucleinate, their ability to enhance cell regeneration processes, reduce side effects of drug therapy, to improve oxygen metabolism faguoqitirute cells (neutrophils, macrophages) and haematopoiesis. While lysozyme stimulates mainly erythropoiesis, has a corrective effect on b-cell immunity, normalizes morphofunctional state of phagocytes and is involved in the degradation of circulating immune complexes, whereas sodium nukleinat is a classic stimulant of leucopoiesis and T-cell immunity, strengthens the corrective effect of lysozyme against oxygen metabolism and functional activity of neutrophils.

Lysozyme hydrochloride in combination with sodium nukleinat contribute to a more effective correction activity of leukocyte elastase and its inhibitor due to different mechanisms of their action. It is known that the activity of leukocyte elastase reflects degranulation activity of neutrophilic granulocytes, and its high level may indicate their hyperactively or death. The appearance in the blood of free elastase in high concentrations in the deficit α-1-proteinase inhibitor (α-1-PI) is considered as an important (albeit nonspecific) atipat the genetic sign of acute and chronic inflammation, DIC, multiple organ failure and other emergency conditions, when developing cytostatic therapy. According to our data, nukleinat sodium is able to directly inhibit free the leukocyte elastase, whereas lysozyme acts indirectly reduces the release of elastase from leukocytes, reducing the intensity of their degranulation due to membrane action, you should take into account the presence of lysozyme antihistamine properties, expressed anti-inflammatory action and the ability to increase the resistance of hepatocytes (which are producers α-1-PI) to the toxic effects. Obviously, matters identified reducing the high apoptosis of neutrophils in children with ALL treated with chemotherapy, under the influence of the accompanying therapy with the use of a combination of lysozyme hydrochloride, sodium nucleinate and lactulose.

Fundamentally new data on the effect of lysozyme hydrochloride and its combination with sodium nukleinat and lactulose obtained by the authors in an experimental model of murine T-cell lymphoma EL-4. Lysozyme hydrochloride with long-term oral administration at a high dose (100 mg/kg) in polusemeynyh conditions increased the antitumor activity of cyclophosphamide, which was administered once intraperitoneally at low (immunomodula the ment) dose of 50 mg/kg Sodium nukleinat at a dose of 100 mg/kg daily orally for 20 days did not affect the protective effect of cyclophosphamide, but in some cases increased potentiating effect of lysozyme hydrochloride in relation to antitumor activity of cytostatic agents. The combined use of lactulose dose of 125 mg/kg lysozyme hydrochloride in these conditions significantly increased its potentiating effect on the antitumor activity of cytostatic agents on survival rates and life expectancy of animals, increased antitumor resistance of spleen cells of animals and anti-relapse effect of cyclophosphamide: more effectively prevented the generalization of lymphoma cells in the tissue of the spleen, heart and intestines, had a cardioprotective effect, accelerated the recovery of damaged cytostatic intestinal epithelium and associated with intestinal lymphoid tissue, contributed to the restoration of the level of bifidobacteria and lactobacilli in the colon of mice.

In patients with acute lymphoblastic leukemia oral administration of lysozyme hydrochloride and its background sodium nucleinate and lactulose on the proposed scheme provides a complete clinical and laboratory effect on stages of chemotherapy and remission periods, providing immunocorrigirutee action when violations immunodeficiency, the nogo status and microecology of the intestine, and when applied in the early stages of chemotherapy slows down the formation of immunodeficiency.

Lysozyme hydrochloride in the proposed doses when administered for 0.5-1 hour before meals in patients receiving cytotoxic therapy, a high concentration in the lumen of the digestive tract and in serum that provides optimal conditions for antibacterial action of lysozyme against opportunistic (mainly aerobic) organisms, including with the antilysocyme activity, overcoming the threshold of resistance to lysozyme and used his background to antibiotics. In addition, it implements its enzymatic properties, improving the process of digestion; promotes stimulation of erythropoiesis and antitumor immunity in their oppression; reduces degranulation activity of neutrophils, contributing to the reduction of the high activity of granulocyte elastase, reduction of the deficit of endogenous lysozyme and α1 PI; contributes to the elimination of circulating immune complexes. While using sodium nucleinate with lysozyme hydrochloride is mutual complement and strengthen their immunokorrigiruyuschy effects. The use of sodium nucleinate in the age dosage has immunocorrigirutee effect on phagocytic and T-cellular components of the immune system, provide Ecevit stimulation of leucopoiesis and reparative processes, and detoxifying effect. Lactulose is used as a prebiotic, providing bifidogenic and lactogenic effect on the indigenous anaerobic microflora, thereby facilitating the displacement of Candida; however, it enhances the detoxifying effects of lysozyme hydrochloride and sodium nucleinate and can potentiate the anti-leukemia effect of lysozyme against drugs.

In the available literature there is no any information about the use of this combination of immunomodulators in the accompanying treatment of patients with acute lymphoblastic leukemia.

The method is as follows:

Accompanying the treatment of acute leukemia can be conducted in the Oncology and Hematology clinic or (in remission) in the outpatient setting. The treatment of patients with acute leukemia at the stages of chemotherapy is carried out in the hospital, where after diagnosis is assigned adequate software PCTs and comprehensive accompanying therapy, depending on the results of hematological, clinical, immunological examination, determine the form of leukemia risk group, presence of complications and other

To cover treatment for patients of ALL use common symptomatic, antibacterial, tonic, if necessary, desintoxicacion is completely desensitized therapy, diet therapy. In the presence of immunodeficiency, neutropenia, anemia at any stage of software chemotherapy or in remission in the accompanying treatment additionally include a comprehensive nonspecific immunotherapy by oral combined use of physiological immunomodulators and prebiotic: in the body of the patient administered orally lysozyme hydrochloride in powder form in a daily dose of 500-1800 mg (25-30 mg/kg) for 2 doses, usually in the morning and evening for 0.5-1 hour before meals, daily for 20-30 days. Immediately after lysozyme hydrochloride using sodium nukleinat in the form of tablets or powder, by ingestion or sublingually, in daily doses of 100-1500 mg (depending on age), in 2 doses daily for 20-30 days. In children older than 3 years old and adults over 3-4 hours after administration of immunomodulators prescribed lactulose in the form of drugs (for example, duphalac, normase) or dietary supplements (eg lactusan) at a daily dose of 2.5-5 ml 1-2 times a day for 10-30 days. Lactulose is inside just before second Breakfast or lunch during normal bowel function or for 20-30 minutes before meals with constipation.

The technique is applied in a clinical setting in 12 of the 30 children with acute lymphoblastic leukemia (ALL)treated with chemotherapy according to the international programme for ALL IC-BFM 2002 (proto is ol I-I, I-II, mM, and HR (I). The age of the children ranged from 3.5 to 14 years, disease duration from 1 month. up to 3 years.

The application of the proposed scheme accompanying therapy helped to improve the original lower content of b-lymphocytes (CD 20+), and in the subgroup of children with the most significant inhibition of b-cell level (8 persons) this figure increased more than 3 times (from 1.3±0.5% to 5,6±0,9%), and less pronounced or less than doubled (from 2.5±0.1% to 4,2±1,9%). Examination within 10 days after completion of the course the use of a combination of lysozyme hydrochloride with sodium nukleinat found in all children the increase in the serum content of endogenous lysozyme from an average of 1.88±0.16 g/ml up to 2.67±to 0.21 g/ml (p<0.05), whereas after chemotherapy without immunocorrection its level decreased to 1.1±0.15 ug/ml compared with baseline levels has doubled the number of neutrophils, approaching the lower limit of the norm, almost normalized intensity of production by neutrophil reactive oxygen radicals in terms of chemiluminescence induced simhasanam. In 8 children with high initial level of apoptosis of neutrophils (22,38±0.59% and the rate of 8-15%) after applying this method, accompanying therapy showed a significant decrease of this index.

Improvement of the functional status of neutrophils PE fericelli blood under the influence of the proposed method of treatment was accompanied by a reduction of excessively high activity of leukocyte elastase. Out of the 30 surveyed children with ALL in 80% of cases of high initial level elastase activity, which averaged at the time of hospitalization of 3.25±0,23 u/ml in the first month of chemotherapy - 2,98±of 0.44 u/ml and in 3-4 months. - 3,35±at 0.42 u/ml at norm 2,42±0,255 U/ml in 40% of cases revealed a profound deficit α-1-PI OF 9.5 TO 19.5 S/ml at the rate of 29.9±1,2 IE/ml).

In children treated with accompanying treatment by the proposed method in 50% of cases decreased to normal activity of leukocyte elastase (average of 3.25±0,49 u/ml to 2.28±of 0.25 u/ml), while the average α-1-PI were close to normal (28,98±2,18 IE/ml), indicating a marked tendency to restore balance proteinases and antiproteinases activity of blood plasma. In the comparison group changes anastasopoulou and antiproteinase activity were false.

Bacteriological studies of intestinal (faecal) microflora showed that the proposed method prevented the decrease in the content of bifidobacteria, lactobacilli and full of Escherichia coli, with 3 out of 4 children showed an elimination hemolyticuremic strains of Staphylococcus aureus and 2 children - Klebsiella. In only one case failed to provide for the elimination of hemolytic Escherichia coli, and 2 children with complicated course of illness the project marked its appearance. Ongoing immunotherapy practically no influence on the content of Candida and prevent their occurrence in 2 children; elimination of Candida was observed in 2 of 4 patients receiving antifungal drugs.

The method provided an opportunity for full and timely implementation stages, software chemotherapy, helped to avoid the development of serious complications of cytotoxic therapy - ulcerative-necrotic enteropathy, hemorrhagic syndrome, the occurrence of endogenous infection. Identified good tolerability used immunomodulators and lactulose.

By the end of the course biocorrection was stopped all symptoms of intestinal dysfunction. During biocorrection in 11 of the 12 children did not develop intestinal syndrome, not marked intestinal bleeding. Only 1 child with ALL on the 15th day of application of the drug combinations are marked by the appearance of liquid stools up to 4 times a day, but after 3 days the intestinal function is normalized without antibiotics.

The developed method differs from previously used methods by the fact that for the first time in the diagram accompanying the treatment of acute lymphoblastic leukemia in children entered combination oral immunomodulators lysozyme hydrochloride in high doses and sodium nucleinate in combination with the prebiotic lactulose.

Thus, profitability analysis of the application of the method of supporting the treatment of acute lymphoblastic leukemia with the use of combination oral nonspecific immunomodulators lysozyme hydrochloride in high doses, sodium nucleinate and prebiotic lactulose is evidence of its effectiveness. Apply this combination on the stages of the software PCTs and/or in the period of remission in patients with severe immunodeficiency States, high risk of infectious and destructive complications, intestinal dysbiosis allows you to provide a more rapid improvement in the immunological reactivity of the organism (normalization of the level of endogenous lysozyme, reducing the high activity of leukocyte elastase and improving balance elastase and antiproteinase activity of blood plasma, the improvement of the functional status of neutrophils peripheral blood, reducing anemia), thereby reducing the frequency and severity of infection, destructive and dysbiotic complications of chemotherapy and improve its portability.

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Method cover the treatment of acute lymphoblastic leukemia, including the integrated use of symptomatic, antibacterial, tonic funds and non-specific together with immunomodulating therapy by introduction of lysozyme, wherein the lysozyme is administered orally in the form of a powder lysozyme hydrochloride in a daily dose of 500-1800 mg 2 times a day for 20-30 days, against which impose additional sodium nukleinat by ingestion or sublingually in a daily dose of 100-1500 mg 2 times a day for 20-30 days, and lactulose oral 2.5-5 ml 1-2 times a day daily for 10-30 days; lysozyme hydrochloride is administered for 0.5-1 h before a meal, sodium nukleinat - immediately after taking the lysozyme of hydrochloride and lactulose for 20-30 minutes before meals, or just before eating, or after 3-4 h after administration of lysozyme hydrochloride and sodium nucleinate.



 

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SUBSTANCE: invention relates to a method for chemotherapy of acute leucosis. Method involves isolation of blast cells and interphase cells from marrow puncture sample leukocyte fraction of blood of a patient subjected for chemotherapy. Then cells are deposited by centrifugation in medium 199 and their concentration is brought about to the level (2-3) x 106 cells/ml. Then isolated cells are incubated with each chemotherapeutic drug chosen from the following group: dexamethasone, cyclophosphanum, vincristine, teniposide, etoposide, citarabinum that are diluted preliminary with isotonic solution to the concentration 1:1000. Then cells treated with chemotherapeutic drugs are centrifuged repeatedly in medium 199 followed by carrying out the annexin test. In the schedule treatment drugs that showed the maximal percent of cells apoptosis are used. Method provides maximal decreasing adverse and toxic effects of chemotherapeutic drugs and to enhance apoptosis of tumor cells based on individual selection of chemotherapeutic drugs for a patient, to prolong remission period and to exclude using additional curative effects.

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2 ex

FIELD: organic chemistry, medicine, oncology, pharmacy, biochemistry.

SUBSTANCE: invention relates to amide derivative represented by the following formula [1]:

in any of the following cases (A) or (B), or its salt. In the case (A) R1 represents 5-7-membered saturated cyclic group comprising 1-2 nitrogen atoms as atom forming cycle (saturated cyclic amino-group can be substituted with 1-3 similar or different substitutes chosen from group consisting of (C1-C10)-alkyl, (C1-C10)-alkoxycarbonyl), mono-(C1-C10)-alkylamino- or di-(C1-C10)-alkylamino-group; R2 represents (C1-C10)-alkyl, halogen atom, halogen-(C1-C10)-alkyl, (C1-C10)-alkoxy-group, (C1-C10)-alkoxycarbonyl, nitro-group, mono-(C1-C10)-alkylcarbamoyl, di-(C1-C10)-alkylcarbamoyl or cyano-group; R3 represents hydrogen atom, halogen atom or (C1-C10)-alkoxy-group; Het1 represents any of the following formulae: [2] , [3] , [4] , [5] , [6] , [7] and [8] ; Het2 represents pyridyl, pyrimidinyl, pyrazinyl or 1,2-dihydropyridazinyl (wherein Het2 can be substituted with 1-3 similar or different substitutes chosen from halogen atom) but except for compound wherein R1 means (i) pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl and each of them can be substituted with 1-3 similar or different substitutes chosen from group consisting of alkyl, alkoxycarbonyl, halogen atom, halogenalkyl, hydroxyalkyl, amino-, monoalkylamino-, dialkylamino-group, carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl; (ii) monoalkylamino-group, or (iii) dialkylamino-group; Het1 means group of the formula [6], and Het2 means pyrazinyl or pyridyl and each of them can mean a substituted alkyl. In case the (B) R1 represents 4-methylpiperazin-1-yl, 1-pyrrolidinyl, piperidino-group, 4-ethylpiperazin-1-yl, 4-n-propylpiperazin-1-yl, cis-3,5-dimethylpiperazin-1-yl, morpholino-, dimethylamino- or diethylamino-group; R2 represents methyl, halogen atom, trifluoromethyl, methoxy-group, methoxycarbonyl, nitro-group, dimethylcarbamoyl or cyano-group; R3 represents hydrogen atom, bromine atom or methoxy-group; Het1 represents compound of the formula [6]; Het2 represents 3-pyridyl. Invention relates to a pharmaceutical composition possessing inhibitory activity with respect to BCR-ABL tyrosine kinase comprising amide derivative of the formula (I) or its salt as active component and a pharmaceutically acceptable nontoxic and inert carrier. Also, invention relates to BCR-ABL tyrosine kinase inhibitor, therapeutic agents comprising amide derivative of the formula (I) or its salt and, optionally, a pharmaceutically acceptable nontoxic and inert carrier used in treatment of chronic myelogenous leukemia, acute lymphoblast cell leukemia, acute myelogenous leukemia. Invention provides and proposes amide derivative inhibiting activity of BCR-ABL tyrosine kinase.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 2 tbl, 83 ex

FIELD: medicine, oncology, pharmacy.

SUBSTANCE: invention proposes a pharmaceutical composition that contains compounds of chlorogenic acid isolated from Piper betel leaves extract or from any other part of plant Piper betel and a pharmaceutically acceptable excipient. Invention provides enhanced effectiveness of treatment of such diseases as acute and chronic myeloid leucosis and lymphoid leucosis and absence of its effect on normal cells. Invention can be used in treatment of patients suffering from acute and chronic myeloid and lymphoid leucosis.

EFFECT: enhanced and valuable medicinal properties of pharmaceutical composition.

32 cl, 4 tbl, 4 dwg, 11 ex

FIELD: organic chemistry, pharmacy, veterinary science.

SUBSTANCE: invention relates to compound comprising 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-4-amine or pharmaceutically acceptable salt of this compound and pharmaceutical composition used for stimulation of biosynthesis of cytokine based on abovementioned compound Also, invention claims a method for stimulation of biosynthesis of cytokines in animal body involving administration in animal body of above described compound or its salt. Invention provides preparing a novel compound possessing useful biological properties.

EFFECT: valuable biological properties of compound and pharmaceutical composition.

3 cl, 12 tbl, 213 ex

FIELD: medicine, peptides.

SUBSTANCE: invention relates to osteogenic growth oligopeptides used as stimulators of hemopoiesis. Invention proposes using an oligopeptide of molecular mass in the range from 200 to 1000 Da, comprising one of the following sequence: Tyr-Gly-Phe-Gly-Gly, Met-Tyr-Gly-Phe-Gly-Gly used in preparing a pharmaceutical composition and enhancing mobilization of hemopoietic stem cells from many differentiation line into peripheral blood, in particular, CD34-positive hemopoietic stem cells. Advantage of the invention involves expanding field in using oligopeptides used in stimulation of hemopoiesis.

EFFECT: enhanced and valuable properties of oligopeptides.

34 cl, 2 tbl, 7 dwg, 4 ex

FIELD: oncology.

SUBSTANCE: invention characterizes compositions, their employment, and embodiments of a method of treatment of B-cellular lymphomas, leucosis, and other malignant tumors CD40+. Principal active therapeutical agent is anti-CD40L antibody or another CD40L antagonist inhibiting CD40-CD40L intermediate. In combination or composition with indicated CD40L antagonist any one or several of the following components can be additionally used: anti-CD20 antibody, a chemotherapeutical agent or a combination thereof, and radiotherapy.

EFFECT: enhanced mechanisms of apoptosis of tumor CD40+ cells due to sensitization of these earlier destruction-resistant cells.

88 cl, 4 dwg, 6 tbl, 8 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I)

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

24 cl, 3 sch, 166 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: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new inhibitors of farnesyltransferase of the formula (I):

wherein R1 means hydrogen atom (H), group of the formula R5C(O)- wherein R5 means phenyl, pyridyl or N-methylpiperidine; R2 means hydrogen atom (H), isopropyl, cyclopentyl or N-methyltetrahydropyridyl; R3 means hydrogen atom (H), halogen atom; R4 means hydrogen atom (H), halogen atom; L means -CH2-Z- wherein Z means NH; Y means sulfur atom (S), S(O) or S(O)2; or its salt. Compounds of the formula (I) inhibit activity of enzyme, farnesyl(protein)transferase, that allows their using in pharmaceutical composition in cancer treatment.

EFFECT: valuable medicinal properties of inhibitors.

18 cl, 3 tbl, 3 sch, 6 ex

FIELD: medicine, oncohematology.

SUBSTANCE: the present innovation deals with treating elderly patients with chronic lympholeukosis accompanied with cardiovascular failure. The method deals with applying chemopreparations and cytoprotector. Moreover, 1 wk before the onset of chemotherapeutic therapy one should prescribe preductal at the dosage of 105 mg daily. At this background one should sample blood out of elbow vein at the volume of 200 ml into a vial with glugicir to centrifuge it, isolate plasma, divide into two portions, add into the 1st vial - cyclophosphan 600-800 mg/sq. m, vincristin 1.4 mg/sq. m, into the 2nd vial - adriamycin 50 mg/sq. m to be incubated for 30 min at 37 C and intravenously injected by drops for patients. Simultaneously, the intake of prednisolone should be prescribed at the dosage of 60 mg/sq. m since the 1st d and during the next 5 d and preductal at the dosage of 105 mg daily during a week, and then 2 wk more at the dosage of 60 mg daily. All the procedures should be repeated in above-mentioned sequence 4-6 times. The method enables to decrease toxic manifestations of chemotherapy while applying adequate dosages of cytostatics, anthracycline antibiotics, among them, at no great manifestations of their toxicity due to preductal's cardioprotective action.

EFFECT: higher efficiency of therapy.

1 ex, 5 tbl

FIELD: medicine.

SUBSTANCE: method involves treating trabecule zone with laser radiation of 532 nm wavelength. Laser radiation treatment is carried out with unit pulses of 3 ns duration in the amount of 40-50 per trabecular network of temporal or nasal segment spread over 180°. Pulse energy is equal to 0.8-1.5 mJ. Focal spot diameter is 300-400 mcm. Then, medical mixture is introduced into lymphatic orbit region. The mixture contains lidocaine 50-100 mg; histochrome 10-20 mg; Euphillin 12-24 mg; Glutoxim 5-10 mg; Lidase 16-32 U. The mixture is introduced daily by doing pterygopalatine blocks on injured eye side in 3-5 blocks long course.

EFFECT: enhanced effectiveness of treatment; reduced risk of adverse side effects.

FIELD: medicine, obstetrics.

SUBSTANCE: additionally to iron preparations which should be prescribed by taking into consideration the values of serumal iron and those of ferritin of blood serum one should introduce ceruloplasmin, its daily dosage being 100 mg. It should be injected intravenously, by drops, for the period of 5 d. Due to applying ceruloplasmin at the dosages declared and at a certain mode of injection the present innovation provides the adequacy and safety of therapy both for mother and for fetus, at severe form of iron deficiency anemia and, also, anemia of redistributed genesis that leads to decreased frequency of pathology during pregnancy, in the course of delivery and perinatal pathology at the absence of side effects of therapy conducted.

EFFECT: higher efficiency of therapy.

1 ex, 4 tbl

FIELD: biotechnology.

SUBSTANCE: disclosed are peptides derived from proenzyme forms of matrix proteinases which represent inhibitors of matrix proteinases. Amino acid sequence is disclosed in description. Described are composition for stimulation of healthy skin formation, containing therapeutically effective amount of peptides. Also disclosed are dressing for wounds, method for stimulation of healthy skin formation and wound healing. Disclosed is using of composition in production of drug for wound healing.

EFFECT: new anti-aging and wound-healing agents.

15 cl, 28 dwg, 6 tbl, 7 ex

FIELD: medicine, in particular bioactive polymeric composition and items based on the same.

SUBSTANCE: claimed composition contains plyoxybutirate, biocompatible chloroform-soluble polymer in plyoxybutirate/structure-forming agent of (65-40):(35-60) and as pharmaceutical agents it contains proteolytic enzyme and/or anti-microbial substance. Said composition is useful in surgery and treatment of various wounds.

EFFECT: non-toxic biocompatible composition with anti-microbial and/or proteolytic activity.

1 tbl, 9 ex

FIELD: medicine, experimental oncology.

SUBSTANCE: the present innovation deals with introducing ribonuclease, moreover, as ribonuclease one should apply pancreatic RNase A at concentration of (3.5-7.0)10-4 mg/kg animal body weight. Pancreatic RNase A should be injected intramuscularly, daily, about 8-10 injections/course. The innovation enables to considerably decrease the dosage of ribonuclease and exclude side complications.

EFFECT: higher efficiency of therapy.

5 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: method involves opening pyo-inflammatory focus. Rexod is introduced in addition to basic therapy. Rexod is introduced during the operation or immediately after the operation and then every day once a day intravenously in bolus dose. The drug is introduced during 4-5 days in physiologic saline or in 5% glucose solution at a dose of 0.2 mcg/kg of patient body weight.

EFFECT: enhanced effectiveness of treatment; improved general health state within a short period; reduced oxidation stress; prevented secondary active oxygen forms production.

3 tbl

FIELD: medicine.

SUBSTANCE: method involves administering immunity correction treatment. Wobenzyme is used as immunocorrecting agent at a dose of 7 tablets 3 times a day during 1 month and intramuscular 40 mg of Triamcinolon is additionally applied every other day. 0.1% Indocollir solution 1 drop three times a day combined with Vidisic 1 drop twice a day as are applied on the background of mentioned therapy course.

EFFECT: stable blood circulation normalization in retinal blood vessels; reduced proliferation process intensity.

FIELD: molecular biology, biochemistry, microbiology.

SUBSTANCE: invention relates to using adenylcyclase toxin from microorganisms of genus Bordetella in producing protein vectors used in targeting a molecule to cell expressing CD11b. This molecule is chosen from the following group comprising peptides, glycopeptides, lipopeptides, polysaccharides, oligosaccharides, nucleic acids, lipids and chemicals. Molecule shows antigenic properties, it is targeted and translocated to cytosol in cells expressing CD11b. Also, invention relates to using immunogenic composition based on adenylcyclase from microorganism of genus Bordetella as a vaccine for preparing the immunotherapeutic composition. Invention describes a protein vector comprising adenylcyclase from microorganism of genus Bordatella for targeting to cells expressing CD11b, in particular, to cytosol of these cells directly. Invention provides agents that can target molecules in vivo specifically to definite populations of pAPC for providing possibility for stimulation of the immune system.

EFFECT: valuable biological properties of vectors.

56 cl, 60 dwg, 1 tbl, 1 ex

FIELD: medicine, surgery.

SUBSTANCE: invention describes an agent used in topical treatment of suppurative sluggish vast surface wounds that comprises boric acid, pepsin and sorbent based on highly-dispersed silica in the following ratio of components, g: boric acid, 5; pepsin, 10, and sorbent based on highly-dispersed silica, 20. Using the proposed agent provides reducing cleansing and epithelization of wound and treatment period of a patient in hospital.

EFFECT: improved and valuable medicinal properties of agent.

2 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with treating wide variety of diseases accompanied with increased DNA content in extracellular spaces of human tissues and organs such as: proliferative, for example, tumoral and hyperplastic processes; diseases of infectious origin; diseases being the result of atrophic, degenerative and inflammatory alterations in organs and tissues, for example, systemic lupus erythematosus. The method for therapy includes enteral introduction of DNAase enzyme at the dosages ranged 2000 up to 500000 Kunz U/kg body weight daily. Medicinal preparation for realization of this method contains DNAase enzyme the content of which in a single dosage corresponds to 50000 up to 5000000 Kunz U. It has been first established that enteral introduction of such high dosages of DNAase provides absorption of catalytically valuable quantities of this enzyme into the blood at significant increase of DNA-hydrolytic activity of the enzyme.

EFFECT: higher efficiency of therapy.

13 cl, 12 ex, 6 tbl

FIELD: biotechnology, medicine, proteins.

SUBSTANCE: invention proposes chimeric polypeptide that comprises cell-specific targeting moiety and granzyme. Polypeptide prepared by recombinant way is used for inducing apoptosis in target-cell. Invention provides carrying out the effective treatment of malignant neoplasms by directed lysis of tumor cells. Invention can be used in therapy of hyperproliferative disorders.

EFFECT: valuable medicinal properties of agents.

24 cl, 3 tbl, 35 dwg, 41 ex

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