Method of treating breast cancer

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely oncology, and can be used in treating patients with breast cancer. A method involves chemotherapy, and 30 minutes prior to cytostatics infusion on autologous liquid tissue - autoblood, autoplasma, with a disposable syringe, 1% ATP 2 ml is introduced in a mammary gland in a peritumour area, 0.5 ml in 4 various points which are changed before the next infusions of chemopreparations with covering the whole perimetre of a tumour.

EFFECT: use of the invention allows intensifying a damaging effect of chemotherapy ensured by uncoupling of cell respiration processes in a tumour and a perifocal zone, by temporary hypoxia of tissues and activation of necrosis processes in a tumour enabled by action of diphenhydramine.

6 dwg, 3 ex

 

The invention relates to medicine, namely to Oncology, and can be used for the treatment of locally advanced and disseminated breast cancer cytotoxic agents.

Known "Method of treatment of breast cancer" (patent No. 2178294, published in Bulletin No. 3 of 20.01.2002), including autohemotherapy parallel with peritumoral the introduction of rihanana, methotrexate and diclofenac, we have chosen as equivalent.

The method gives the possibility to influence peripheral to the tumor area drug immune correcting action (rihlokain), contributing to a more pronounced immune response on the part of regional lymph nodes, which contributes to the implementation of the anti-tumor effect.

However, the local introduction of cytostatic methotrexate can have marked the damaging effect not only in relation to the tumor and cause irreversible changes in the healthy tissue perifocal zone. This method does not allow to influence the mechanisms of regulation of cellular metabolism in the perifocal area of the tumor.

A known method of treating breast cancer - autolackiererei (patent No. 2158588 from 10.11.2000. B. I. No. 31), we have chosen as a prototype, including intravenous drip of anticancer chemotherapy, before artelino incubated with autoplasma, characterized in that the patient from a peripheral vein take 250 ml of autologous blood into the vial with geoconservation "Gleyzer", sedimentation method or by centrifugation separated into a liquid fraction and cellular elements, take the resulting autoplaza, mixed with chemicals and incubated at t 37°C for 40 min: vincristine 1 mg, methotrexate 30 mg, fluorouracil 750 mg, cyclophosphamide 800 mg / 1; 8 days of treatment, doxorubicin 30 mg 1, 3, 5, 8, 10, 12 days. Cellular elements diluted with saline solution and is re-infused to the patient.

There is a method of breast cancer treatment is applied during the entire course of treatment with the use of autoplasma for drug administration. This method increases the effectiveness of treatment due to the binding of drugs to plasma proteins, which, in turn, contributes the most complete delivery of drugs to organs-targets and the implementation of best clinical effect. However, this method of treatment does not give the opportunity to affect peripheral to the tumor area, which is important for the implementation of the anti-tumor effect.

The aim of the invention is the simulation of the development of short-term tissue hypoxia in the peritumoral area to activate the processes of apoptosis and necrosis when conducting systematic hee is iotherapy.

This objective is achieved in that 30 minutes before the infusion of cytotoxic drugs on a standard solvent or autologous liquid tissue (autologous blood, autoplasma) disposable syringe produce vnutrikabinnoe introduction 2 ml of 1% R-RA diphenhydramine (demerol) in peritumoral area of 0.5 ml at 4 different points, which before the next infusion of chemotherapy drugs are changed in order for chemotherapy to cover the impact of the entire perimeter of the tumor. Confirm the development of tissue hypoxia in the impact zone puncture breast cancer before the introduction of diphenhydramine (demerol) and 30 minutes after administration by comparative cytochemical analysis of key dehydrogenases of the Krebs cycle - dehydrogenase (LDH) and alpha glitserofosfatdegidrogenazy (a-GPDH) in lymphocytes punctate and identify the effect of inhibition of the enzymatic activity of LDH, shift activity predominance of a-GPDH, indicating a slowing down of the Krebs cycle and the development of tissue hypoxia.

The invention of "a Method for the treatment of breast cancer" is new, because it is not known in medicine for the treatment of locally advanced and disseminated breast cancer cytotoxic means modeling short-term tissue hypoxia in the peritumoral area to stimulate the process and what optase and necrosis in malignant tumors of the breast.

The novelty of the invention lies in the fact that in the perifocal use diphenhydramine (demerol) in the area of the lesion nizkolegirovannoj mitochondria status is compounded by the limited speed of electron transfer in the respiratory chain. Since the rate of electron transfer in the respiratory chain of mitochondria functionally connected with the conversion of adenine dinucleotide (NAD-NADH), retinopathia straddle the process action Dimedrol determines hypoxic cells exacerbates low energizerbunny mitochondria, the rate of which is the reduction in the activity of LDH. When filled acceptor system and high polarization of tumor cells surrounded by a ring, temporarily shielding it from external influences, which could stimulate the functioning of the Krebs cycle, primarily from endogenous succinic acid, activating SDG in lymphocytes. Inhibition of LDH activity in lymphocytes punctate perifocal zone of the tumor indicates the formation of tissue hypoxia, reinforcing the damaging effect of drugs on tumor cells.

The invention involves an inventive step, as for a specialist oncologist-medical physicist is not obvious from the level of medicine in the treatment of breast cancer.

Offer is "a Method of treating breast cancer" original, not obvious, not obvious from the level of medicine in the field of Oncology is the treatment of locally advanced and generalized breast cancer - either in CIS or in Russia or abroad.

The invention is industrially applicable as it can be used in health care during chemotherapy for breast cancer in various medical institutions, especially cancer, Oncology, oncologic dispensaries.

theoretical rationale local use diphenhydramine for dissociation processes of tissue respiration.

The development of tissue hypoxia and the accompanying biochemical processes and mitochondrial dysfunction, including complete inhibition of the respiratory chain may lead to activation of the regulatory cascade of necrosis as a result of violations of the membrane permeability and ion transport, mitochondrial swelling, free-radical processes leading to the destruction of lysosomes, autolysis, autocycling.

To get the desired effect, namely the dissociation processes of cellular respiration possible by local application of biochemical and pharmacological agents that block at various stages of the process of oxidative phosphorylation, in particular, diphenhydramine (diphenhydramine), blocking on retinopathia the action of oxidative FOSFA melirovanie at the stage of conversion of adenine dinucleotide (NAD⇄NADH).

Modeling of local tissue hypoxia in the body-ofwholesale on the background for systemic chemotherapy opens new prospects for cancer treatment. Peritumoral injection of disconnector processes of cellular respiration and oxidative phosphorylation in tumor and perifocal zone creates a temporary tissue hypoxia, i.e. biochemical conditions that define a trigger role for the mechanism of necrotic changes in the tumor, which, in turn, enhances the damaging effects of chemotherapy.

This approach does not violate the blood circulation to the body, but lets be administered to a tumor, the dose of the cytostatic under conditions of artificially created short-term tissue hypoxia, which allows for repeated treatments and clinical effect.

It is important when conducting neoadjuvant chemotherapy for breast cancer, in the complex, including organochromium the treatment as a mandatory component requires the use of systemic chemotherapy exposure (Agarunov N.A., 1992; Moiseyenko VM, Semiglazov V.F. et al., 1997; Poddubnaya I.V., 1998).

Specific implementation

"Method of treatment of breast cancer".

30 minutes before infusion of cytotoxic drugs on a standard solvent or autologous liquid TKA and (autologous blood, autoplasma and the like) using a disposable syringe is vnutrikabinnoe introduction 2 ml of 1% R-RA diphenhydramine (demerol) in peritumoral area of 0.5 ml at 4 different points. Before the next infusion point of introduction of diphenhydramine (demerol) are changed in order for chemotherapy to cover the impact of the entire perimeter of the tumor.

Previously, the patient produces the fence autologous blood in quantities of 200 to 250 ml in a sterile vial geoconservation "Gleyzer", precipitated at t +4-8°C for 2-3 hours or centrifuged at νabout1500 rpm for 30 min, take the supernatant plasma in another sterile bottle with geoconservation, cellular precipitate is re-infused. Cytostatics in single doses mixed with autoplasma, incubated at 37°C for at least 30 minutes and is administered to the patient intravenously.

Combination chemotherapy CAMF is designed for 2 weeks and entered mode: methotrexate 15 mg/m2in the 1st and 8th days, doxorubicin 15 mg/m2, 5-fu 250 mg/m2, cyclophosphamide 100 mg/m2in 1, 3, 5, 8, 10, 12 days of treatment with intravenous drip. The total course dose is methotrexate 50-60 mg, doxorubicin - 120-180 mg, 5-fluorouracil - 2500-3000 mg, cyclophosphamide - 1000-1200 mg

After introductions observe the General condition of patients, perform laboratory monitoring: complete blood count 2 times the week, biochemical blood analysis, urinalysis 1 time per week, electrocardiogram, ultrasound and x-ray examination of the breast and lymph nodes before and after treatment.

To confirm development of the state of tissue hypoxia in the impact zone is the puncture of the breast and a swab is taken of the blood of breast tissue before the introduction of diphenhydramine (demerol) and 30 minutes after injection before infusion drugs for cytochemical determination of the level of activity of key enzymes of the Krebs cycle.

The laboratory results of the application of the Method for the treatment of breast cancer".

Studied the activity of key dehydrogenases of the Krebs cycle, are in a reciprocal relationship: dehydrogenase (LDH) and α-glitserofosfatdegidrogenazy (α-GPDH). Enzyme activity was determined by quantitative methodology Repartissons in blood lymphocytes taken from the peritumoral area, and expressed in the number of granules formazan (GRP.) MCP±m. Changes resulting from the introduction of a pharmacological agent, were evaluated at 30 minutes after administration of the drug according to the following criteria:

- the average activity of LDH in the granules formazan MCP±m;

- the average activity of α-GPDH granules of formazan MCP±m.

Changes in these indicators are tracked throughout the all courses of chemotherapy.

Monitoring the change in the activity of dehydrogenases was carried out individually for each patient taking into account the individual activity of the enzymes at the beginning of chemotherapy. In our proposed tests assess the development of tissue hypoxia were examined 8 patients with injection of demerol. Around the breast Dimedrol led to a decline in activity of LDH in 30 minutes after injections in 57,9% of cases with a simultaneous increase in the activity of α-GPDH in 41.6% of cases.

During two courses of neoadjuvant chemotherapy was dominated by the reduction in the activity of LDH in 75% of cases, indicating that the preferential development of tissue hypoxia in the perifocal area of the tumor.

Clinical results of the application of the Method for the treatment of breast cancer".

Treatment was subjected to primary patients with cytologically verified diagnosis of breast cancer St IIB-IV (T2-4N0-3M1, where M1 tumor spread beyond the breast, the germination of the skin, chest muscles), which was done 2 courses of neoadjuvant autolackiererei scheme. CMFA, vlychada on a course of cyclophosphamide at a dose of 800 mg/m2, methotrexate 30 mg/m2, fluorouracil - 2000 mg/m2, doxorubicin - 80 mg/m2on the background of peritumoral introduction diphenhydramine.

From April to August 2009 treatment was subjected to 16 patients aged at to 66 years, the average age 48,2 year, having a hub or a hub with secondary edema disease. Evaluated after 2 courses of neoadjuvant objective antitumor effect was an 81.25% (13), of whom of 18.75% (3) showed complete clinical regression and 62.5 percent (10 - partial, of 18.75% (3) marked stabilization process. Morphological study of distant tumors in cases of registration objective antitumor effect in those patients who had to undergo surgical stage of complex treatment (5 people), revealed a 3-4 degree of therapeutic pathomorphosis in 3 cases.

Of the side effects it should be noted soreness 1-2 tbsp. in the area of local administration of drugs in 86,75% (11) patients, the complication wore short character and were stopped on their own without the introduction of additional analgesics. In the rest of the hematological and not hematological toxic manifestations of chemotherapy was just an ordinary character, the most frequently mentioned emetogenic effect 1-3 degrees - of 50.0% (8) leukopenia grade 2 - 25% (4) and stomatitis is 12.5% (2).

Specific examples of the application of the Method for the treatment of breast cancer".

Observation 1.

Patient R., age 64, IB No.-u, was admitted to the Department chorionic gonadotropin, RNII in April 2009 with a diagnosis of breast Cancer, nodular form with secondary edema, St IIIB (T4N1M0), clinical group II. The tumor is in the left breast was discovered in April 2009, immediately I went to the doctor. Ultrasound 22.04.09 - diffuse changes of a liver, hepatomegaly. Chest x-ray 22.04.09 - metastases were not detected. Mammography 22.04.09 - ninananajna quadrant of the left breast tumor diameter of 5 cm

Diagnosed cytologically verified with biopsy of the tumor and lymph nodes. CA No. 9522-25 from 24.04.09 - infiltrative ductal cancer.

When receiving a satisfactory condition. The left breast is deformed, ninananajna quadrant tumor by palpation with a diameter of 6 cm, swelling of the skin, nipple retracted. Right breast without features. In the axillary region to the right l up to 2 cm, flat. Supraclavicular l/do not clearly palpable. Other l/not palpable.

25.04-12.05.09 held the 1st neoadjuvant course APT with pre peritumoral the introduction of 1% R-RA diphenhydramine (demerol). A total dose of drugs was as follows: 50 mg of methotrexate, 3000 mg of 5-fluorouracil, 1200 mg of cyclophosphamide, 180 mg of epirubicin. Of the complications noted nausea 2 degrees. Local complications in the introduction Dimedrol not marked.

After 1 year decrease in tumors up to 4 cm in diameter, axillary lymph nodes up to 1 cm

After the 2nd similar neoadjuvant course APT with pre peritumoral the introduction of diphenhydramine (demerol) tumor in the breast palpation was determined, nipple axillary move not even royalty. From complications nausea 1 degree.

When mammography "in the left mammary gland tumor is not clearly defined". In figure 1, 2 presents mammogram patient R. (1 - before treatment, 2 - after treatment).

The level of activity of succinate dehydrogenase (LDH), determined by the number of granules formazan (GRP.) in lymphocytes taken from the peritumoral area, prior to the introduction of diphenhydramine was 25.1±2,31 GRP., after 30 minutes of 14.5±2,5 GRP., the level of α-glitserofosfatdegidrogenazy (α-GPDH) prior to the introduction of diphenhydramine was 1.4±0,5 GRP., after 30 minutes of 5.7±1,9 GRF. The changes reflect the development of local tissue hypoxia in peritumorally zone.

16.07.2009. Radical mastectomy on the left. Microreport: in the breast after treatment, the tumor in the lymph collectors metastases not identified. Geetanjali No. 46005-20/09 - infiltrating ductal MF, MTS no, pathomorphosis of III degree". Healing by primary intention. After surgery, the patient underwent a remote gemmoterapii on the path of lymphatic drainage from the breast, SOD 40 G, 6 courses of adjuvant APT scheme CAMF. Signs of the activation process is not observed.

Observation 2.

Patient L., 68, IB No.-u, was admitted to the Department chorionic gonadotropin, RNII in may 2009 with a diagnosis of breast Cancer, nodular form with secondary edema, St IIIB (T4N1M0), Klinicheskaya group II. The tumor in the left breast was discovered in April 2009, immediately turned to the doctor.

Ultrasound 01.04.09 by place of residence - diffuse changes of a liver. FLO chest 22.04.09 by place of residence revealed no pathology.

Mammography 7.05.09 - in the left breast of the Central tumor with a diameter of 4 cm, the nipple is fixed.

When needle biopsy CA No. 10079-80 - moderately differentiated carcinoma.

When applying the General condition is satisfactory. The left breast is swollen, at the bottom of brightly hyperemic. In the center of the tumor with a diameter up to 6 cm in the Right breast without features. In the axillary region to the left lymph node up to 2 cm, offset. Supraclavicular l/do not clearly palpable. Other lymph nodes are not palpable. 14-21.05.09 held the 1st neoadjuvant course APT with pre peritumoral the introduction of 1% R-RA diphenhydramine (demerol). A total dose of drugs was as follows: 50 mg of methotrexate, 3000 mg of 5-fluorouracil, 1200 mg of cyclophosphamide, 180 mg of epirubicin. Of the complications noted nausea 2 degrees, stomatitis 2 degrees. Local complications in the introduction Dimedrol not marked.

After 1 year earlier palmirapalace a tumor with a diameter up to 6 cm currently not palpated. Right breast without features. In the axillary region to the right lymph node is not clearly palpable. Supraclavicular lymph nodes are clear is not palpable.

After the 2nd similar neoadjuvant course APT with pre peritumoral the introduction of diphenhydramine (demerol) 8-19.06.09 tumor in the mammary gland by palpation was not determined, axillary move not even royalty. From complications nausea 2 degrees.

When mammography "in the Central regions of the left breast tumor is not defined". Figure 3, 4 presents mammogram patient L. (3 - before treatment, 4 - after treatment).

The level of activity of succinate dehydrogenase (LDH), determined by the number of granules formazan (GRP.) in lymphocytes taken from the peritumoral area, prior to the introduction of diphenhydramine was 18.7±1,4 GRP., after 30 minutes of 9.7±1,8 GRP., the level of α-glitserofosfatdegidrogenazy (α-GPDH) prior to the introduction of diphenhydramine was 5.2±1,6 GRP., after 30 minutes of 13.3±1,5 GRF. The changes reflect the development of local tissue hypoxia in peritumorally zone.

20.07.09 performed a radical mastectomy on the left. Microreport: in the breast after treatment, the tumor is not detected in the lymph collectors metastases not identified. HA No. 46523-28/09 from 24.07.09 - "after XT pronounced stromal sclerosis, single hyperchromic cells, like tumor in the tissue and l/MTS no - pathomorphosis IV degree. Healing by first intention.

After surgery, the patient underwent a remote gemmoterapii to put the lymph drainage from the breast SOD 40 G, 6 courses of adjuvant APT scheme CAMF. Signs of the activation process is not observed.

Observation 3.

Patient A., 61, IB No.-u, was admitted to the Department chorionic gonadotropin, RNII in may 2009 with a diagnosis of Cancer of the right breast St IIIC (T4N3Mx), clinical group II.

The tumor in the right breast found 4-5 months ago, was observed in the polyclinic of the Ministry of internal Affairs.

Ultrasound 7.05.09 - diffuse changes of a liver, pancreas, XP. cholicistitus, microlites left kidney.

Chest x-ray 7.05.09 - metastases were not detected. Mammography - tumor nizhnemartynova quadrant of the right breast, a metastasis in the axillary lymph nodes. When needle biopsy CA No. 10456-59 (tumor, lymph node) - moderately differentiated carcinoma.

MRI of the chest 8.05.09 - tumor breast cancer metastases subscapularis supraclavicular lymph nodes on the right. When receiving a satisfactory condition. In ninananajna quadrant of the right breast tumor to 4 the Left breast is without features. In the right axillary area impacted conglomerate l/y with an external component 5 cm beneath the pectoral muscle. Supraclavicular l/do not clearly palpable. Other l/not palpable. 15-29.05.09 held the 1st neoadjuvant course APT with pre peritumoral the introduction of 1% R-RA diphenhydramine (demerol) - in the area of the tumor and under rincavage conglomeration of lymph nodes. A total dose of drugs was as follows: 50 mg of methotrexate, 3000 mg of 5-fluorouracil, 1200 mg of cyclophosphamide, 180 mg of epirubicin. Of the complications noted nausea 2 degrees. Local complications in the introduction Dimedrol not marked.

After the 2nd similar neoadjuvant course APT with pre peritumoral the introduction of diphenhydramine (demerol) 19-24.06.09 tumor in the mammary gland by palpation was not determined, axillary conglomeration of lymph nodes was reduced to 2 cm, was shifting. From complications nausea 1 degree.

In mammography, "in verhnovodjane quadrant of the left breast tumor with a diameter of 1 cm, axillary lymph node, 2 cm in diameter". Figure 5, 6 presents mammogram patient A. (5 - before treatment, 6 - after treatment).

The level of activity of succinate dehydrogenase (LDH), determined by the number of granules formazan (GRP.) in lymphocytes taken from the peritumoral area, prior to the introduction of diphenhydramine was 16.3±1,8 GRP., after 30 minutes of 7.5±1,15 GRP., the level of α-glitserofosfatdegidrogenazy (α-GPDH) prior to the introduction of diphenhydramine was 2.4±0,65 GRP., after 30 minutes of 4.3±1,3 GRF. The changes reflect the development of local tissue hypoxia in peritumorally zone.

24.07.09 cytoreductive mastectomy with axillary-if the lad on the right (residual substrate in the axillary region). HA No. 48042 - 46/09 - filterui ductal cancer, the stromal sclerosis, metastases in all reservoirs, pathomorphosis of III degree". The partially healing by second intention.

The specified diagnosis (after surgery): Cancer of the right breast after complex treatment (T2N3Mx, 24.07.09 cytoreductive mastectomy with axillary-if the lad on the left (residual substrate in the axillary region, pT1N3M1) St IV clinical group II.

After surgery, the patient underwent a remote gemmoterapii on the path of lymphatic drainage from the breast, SOD 40 G, 6 cycles of postoperative chemotherapy in the treatment regime under the old scheme CMFE. Signs of the activation process is not observed.

Technical and economic efficiency "method of treatment of breast cancer" is that local injection of diphenhydramine, promoting the dissociation processes of cellular respiration in tumor and perifocal zone, creates a temporary tissue hypoxia, contributes to the activation of the processes of necrosis in the tumor, which, in turn, enhances the damaging effects of chemotherapy. This allows you to increase the effectiveness of neoadjuvant treatment of localized and locally advanced breast cancer: to achieve a rapid decrease in the size of the tumor and lymph nodes and to transfer patients from inoperable to operable condition, to perform ablative surgery, increasing to the quality of life of the respective patients.

A method of treating breast cancer, including chemotherapy, characterized in that for 30 minutes before infusion of cytotoxic drugs on autologous liquid fabric - autologous blood, autoplasma disposable syringe produce vnutrikabinnoe introduction 2 ml of 1%aqueous solution of diphenhydramine in the peritumoral area of 0.5 ml at 4 different points, which before the next infusion of chemotherapy vary, covering for chemotherapy entire perimeter of the tumor.



 

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13 cl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention relates to indole and indazole compounds of formula in which n equals a whole number from 1 to 3, m equals 0 or 1, A denotes phenyl, X denotes C or N, R1 denotes hydrogen, alkyl, -(CH2)rNR7R8, where r equals a whole number from 1 to 5, and R7 and R8 independently denote hydrogen, alkyl or alkylcarbonyl, or can together form an optionally alkyl-substituted alkylene chain, where optionally one methylene is substituted with a N atom, R2 denotes hydrogen, halogen, cyano, nitro, hydroxy, alkyl, alkoxy or trialkylsilyl, denotes -(CH2)pCO2R7, -(CH2)pOR7, -(CH2)pNR7R8, -NHR10, -N(H)S(O)2R7, -NHC(O)R10, -(CH2)pS(O)2R7 or (CH2)p-heterocycle-R10, where p equals a whole number from 0 to 3, R7 and R8 are as defined above, R10 denotes hydrogen, oxo, alkylsulphonyl, alkylcarbonyl, alkyloxycarbonyl, alkoxy, alkyl or heterocycle, R3 denotes hydrogen, cyano, halogen, alkyl or phenyl, or denoes -(CH2)n-heterocycle or -(CH2)n-aryl, where n equals a whole number from 0 to 3, provided that R3 denotes phenyl when X denotes C and m=0, R4 denotes -YR11, where Y denotes a direct bond or -(CR7R8)pY′-, where p equals a whole number from 0 to 3, R7 and R8 are as defined above, Y′ is selected from a group consisting of -O-, -S-, -NR12-, -NR12C(O)-, -C(O)-, -C(O)O-, -C(O)NR12-, -S(O)q- and -S(O)qNR12-, where R12 denotes hydrogen, alkyl, aryl or heteroaryl, q equals a whole number from 0 to 2, R11 is selected from a group consisting of hydrogen, cyano, halogen, hydroxy, thiol, carboxy, alkyl and -(CH2)tB-R13, where t equals a whole number from 0 to 3, B denotes heterocycle, heteroaryl or aryl, R13 denotes hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy, carboxyalkyl, alkylcarbonyloxy, alkyl, alkoxy, alkylthio, alkylcarbonyl or alkylsulphonyl, R5 denotes hydrogen, alkyl, cycloalkyl, heterocycle or heterocyclylalkyl, R6 denotes (CR7R8)p-Z-D-W-R14, where Z denotes a direct bond, or is selected from a group consisting of -C(O)-, -C(O)O, -C(O)NR12- and -S(O)y-, y equals a whole number from 1 or 2, D denotes a direct bond, or denotes cycloalkyl, heteroaryl or heterocycle, W denotes a direct bond, or denotes -NR -, -C(O)-, -C(O)O-, -C(O)NR12-, -S(O)y-, -S(O)yNR12- or -NR12S(O)y, wherein R14 denotes hydrogen, hydroxy, alkyl, alkoxy, heterocycle, heteroaryl, aryl or aralkyl, R5 and R6 together denote an alkylene chain, provided that R6 denotes cycloalkyl or heterocyclyl when X denotes N, where the heteroaryl is a 5-6-member aromatic ring containing 1-2 heteroatoms selected from N, O and S, the heterocycle is a 3-8-member ring containing 1-3 heteroatoms selected from N, O and S, where the alkyl, alkoxy, aryl, cycloalky, heterocycle and heteroaryl can be optionally substituted, and the substitutes, one or more, are selected from a group consisting of hydroxy, halogen, nitrile, amino, alkylamino, dialkylamino, carboxy, alkyl, alkoxy, carboxyalkyl, alkylcarbonyloxy, alkylthio, alkyloxycarbonyl, alkylaminocarbonyl, arylalkoxy and oxo, and pharmaceutically acceptable salts or stereoisomers thereof. The invention also relates to a composition, as well as a method of preparing said composition.

EFFECT: obtaining novel biologically active compounds for preventing or treating necrosis and necrosis-associated diseases.

40 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula where: R1 denotes COORa1, CONRa2Ra2', CONRa4ORa4', where: each of Ra1 and Ra4 denotes a hydrogen atom; each of Ra2 and Ra2' denotes a hydrogen atom; Ra4' denotes a lower alkyl; or R1 denotes a heterocyclic group selected from the following groups, where Y2 denotes a hydrogen atom or a lower alkyl: R2 denotes O, S, SO, SO2; R3 denotes a phenyl which is substituted with 2 substitutes selected from halogen, CF3; X2 denotes CH or N; W denotes the following residue: where: W1 denotes CH or S; W2 denotes CH; W3 denotes C or N; and at least one of W1, W2 and W3 denotes a carbon atom; or pharmaceutically acceptable salt or ester thereof. The invention also relates to a pharmaceutical composition having Avrora A selective inhibitory action, which, along with a pharmaceutically acceptable carrier or diluent, contains at least one compound of formula I a an active ingredient.

EFFECT: aminopyridine or aminopyrazine derivatives which inhibit growth of tumour cells based on Avrora A kinase selective inhibitory action.

11 cl, 3 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention comprises the following steps: a) reaction of a compound of formula V with zinc and acetic acid to obtain a compound of formula VI b) reaction of the compound of formula VI with an acid to obtain a compound of formula VIA and c) reaction of the compound of formula VIA with di-tert-butyldicarbonate to obtain docetaxel. The invention also relates to methods of producing crystalline forms I, II, III, IV, V of docetaxel, crystalline forms I, II, III, IV, V, VI, VII, VIII, IX of docetaxel, methods of producing solid amorphous docetaxel, a method of producing crystalline form I of amorphous docetaxel, as well as a method of producing crystalline form II of docetaxel.

EFFECT: obtaining docetaxel and polymorphs thereof with desired purity and output by using improved synthesis methods, which are simple, environmentally safe, cheap, reliable and well suited for use on an industrial scale.

27 cl, 18 ex, 31 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology, also can be used in treating patients with solid tumours. For this purpose, 1-2 days prior to the initiation of chemotherapeutic procedures, a preparation of marrow mesenchymal stem cells coated with perfluorocarbon nanoparticles produced by incubation in a medium containing a pharmaceutically acceptable aqueous perfluorocarbon nanoemulsion of a particle diameter 300 nm and less is introduced to a patient intravenously in dose 0.5-10·106 cell/kg. Then the chemotherapeutic procedures follow with underlying oxygenated gas mixture inhalations at normal or high pressure.

EFFECT: method provides effective growth inhibition and reduced tumour size, including ensured by increasing tumour cell sensitivity to chemopreparations.

9 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to field of medicine and pharmaceutics. As antagonist of neuropiline-2 applied is antibody against Nrp2B, or its antigen-binding fragment, which contains sequences of areas, which define complementarity, (CDR) of variable domains of light and/or heavy chain of antibody YW68.4.2 or antibody YW68.4.2.36, or version of claimed antibody or claimed antigen-binding fragment, where amino acid sequence Fab of YW68.4.2 of antibody fragment is shown in figure 10A and amino acid sequence Fab of YW68.4.2.36 of antibody fragment is shown in figure 10B.

EFFECT: group of inventions makes it possible to increase efficiency of prevention and treatment of tumour metastases.

21 cl, 13 dwg, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to field of medicine. Claimed is method of chemical-therapeutic treatment of locally spread unresectable glandular cancer of pelvis minor organs. Introduction of medication, containing 5-fluorouracil, metronidazole water for injections, low molecular polyethylene, emulsifier T-2, olive oil, lutrol F127 and cremofor RH40 is performed in dose 1 ml into cellular spaces, surrounding organ, ligaments and under serous membrane of organs in area of cancer tumour. Single introduction must not exceed 5.0 g of chemical preparation.

EFFECT: application of invention insures creation of prolonged to 4 weeks local depot of antitumor medication, what results in reduction of intoxication and reduction of medication dose.

2 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of veterinary. Method includes introduction of antibiotic lymphotropically. Preliminarily injected are medications which enhance lymph flow. Preliminarily prepared is mixture, consisting of half of daily antibiotic dose per 1.0 ml of 2% lidocaine solution and 1.0 ml per 10 kg of animal weight of heparinised blood autoplasm. Mixture is introduced into subcutaneous cellular tissue indenting 1-2 cm rightward or leftward from medial raphe of perineum one time per day during 5 days.

EFFECT: method makes it possible to increase efficiency of antibiotic therapy, reduce unfavourable impact of antibiotics on animal organism due to reduction of daily dose of preparation, time of its application and its targeted action on pathologic focus, increase immunologic activity of organism, accelerate recovery.

2 tbl, 1 ex

FIELD: veterinary science.

SUBSTANCE: method to extract gonadotropin from pregnant horses blood serum (PHS), including fractional deposition of ballast substances and extraction of hormonally active fraction PHS by isopropanol, besides, to deposit ballast substances at concentration of PHS gonadotropin dissolubility, and to extract hormonally active fraction of PHS at concentration of gonadotropin insolubility, the extracted preparation of PHS gonadotropin is preserved in ethanol solution with concentration of the latter that ensures preparation sterility.

EFFECT: method makes it possible to increase purity of produced preparation without loss of its hormonal activity.

1 ex

FIELD: medicine.

SUBSTANCE: in order to obtain gel used is platelet-rich plasma, which is prepared by centrifugation of autoblood in centrifuge with vertical axis of rotation. Autoblood is placed into cylindrical cup of centrifuge, which has pocket-trap. In process of centrifugation turbulence of autoblood and its separation into components with their separate simultaneous accumulation: erythrocytes - on cup bottom, and rich and poor in platelets plasma - in pocket-trap. Centrifugation is performed at rate, reducing each three minutes, whose value is selected successively from the following ranges, rot/min.: 4500-3500, 2500-1500, 1200-800.

EFFECT: method makes it possible to increase treatment quality and reduce its terms due to gel base quality - in fact admixture-free plasma, rich with viable platelets, containing great number of growth factors.

6 cl, 4 dwg

FIELD: medicine.

SUBSTANCE: after operation a section of tumour is taken from patient, placed into diffusion chamber together with solution of chemical preparation, chamber is placed into peritoneal cavity of rat for 1 week. After that animals are removed from experiment, fixation, staining and light microscopy of filter from chamber are performed, sensitivity of tumour to said chemical preparation is determined by presence or absence of tumour cell growth. After that, since the eighth day after operation patient is subjected to intraperitoneal autoplasmachemical therapy for 5 days with the preparation to which tumour is sensitive.

EFFECT: increase of anti-tumour action of intraperitoneally introduced cytostatics, incubated on autoplasma, due to individual selection of chemical preparation.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to a set for hypogalactia prevention in women with thyroid diseases. The set for hypogalactia prevention in women with thyroid diseases which includes the preparations: aminophylline; no-spa; a preparation improving blood rheology specified in the group: rheopolyglucinum, fresh frozen plasma, a microdose of aspirin; an energy preparation specified in the group: glucose, actovegin; amino acid specified in the group: methionine, glutamic acid, galascorbinum; antioxidants, a ferriferous preparation specified in the group: Sorbifer Durules, tardiferon; and a vitamin complex containing vitamins A, E, C.

EFFECT: set reduces rate and severity of lactation disorders in women with a thyroid pathology and improves breast milk quality.

2 cl

FIELD: medicine.

SUBSTANCE: invention relates to method of biological material disinfection. Method of removing trialkylphosphate solvent and detergent, which represents polyoxiethylene ether, from mixture of plasma, trialkylphosphate solvent and said detergent, where solvent and detergent were used for virus plasma inactivation, include treatment with synthetic hydrophobic adsorbent from polystyrene and divinylbenzole copolymer in ratio 1 g of adsorbent per 1-8 ml of plasma for 30-60 min at 20-30°C, and collection of treated plasma, where both solvent and detergent are removed by one-stage processing by hydrophobic interaction.

EFFECT: invention ensures safe, efficient and economical method of removing viricidal preparations, that is solvent and detergent from virus-inactivated joined in pool plasma by means of hydrophobic interaction chromatography.

9 cl, 7 tbl, 1 dwg, 9 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to oncology, and can be used in treatment of mammary gland cancer (MGC). Method is realised in the following way. After confirmation of malignant character of tumour tissue in patient sampling of 200 ml of blood from peripheral vein into reservoir with hemopreservative is carried out, after that it is centrifuged with separation of plasma, which is combined with cyclophosphane in amount 400 mg/m2, doxorubincin in dose 40 mg/m2 is introduced into erythrocyte mass; both reservoirs are incubated in thermostat for 30 minutes at temperature 37°C. After that, sucking of blood from the place of tumour tissue sampling is carried out with further introduction into it of 200 mg of cyclophosphane diluted in 5 ml of physiological solution. Tissue of mammary gland around tumour is infiltrated with incubated plasma with cyclophosphane, and erythrocyte mass with doxorubicin is introduced intravenously by drop infusion.

EFFECT: application of the invention makes it possible to increase efficiency of MGC treatment due to creation of maximal concentration of chemical preparations in leision focus and prevention of tumour process dissemination.

1 ex

FIELD: medicine.

SUBSTANCE: autoblood plasma components are fractionated. The autoblood plasma components are exposed to anion-exchange chromatography. The components sorbed on an anion exchanger are recovered. The recovered components are lyophilised. The components are introduced in the ratio 3:1000 in a skin penetrating composition of ointment consistency. The composition is applied in the form of applications on a body surface in a projection of a zone of regenerated bone formation.

EFFECT: method allows to reduce injures and to extend indications for administration.

1 ex, 3 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to anesthesiology and resuscitation, and can be used in states accompanied by massive blood loss. For this purpose, 5 and 3 days prior to a surgery, autoblood is sampled in amount 10 % of circulating blood volume (CBV) in each sampling to be divided on plasma and erythrocyte concentrate. For 5 preoperative days, iron preparations are administered in a therapeutic dose. Also, the surgery is preceded with analysing patient's fluid deficiency. 40 minutes prior to the surgery, 12.5 % dicynone 500 mg, one volume of autoplasma are introduced, and infusion of a rated dose of 5 % glucose and 6 % hydroxyethyl starch (HES) 500 ml is started. If the intraoperative blood loss is suggested to be 15-30 % of the CBV, additionally 6 % HES 250 ml, prednisolone in dosage 2-4 mg/kg of body weight and one volume of erythrocyte concentrate are administered. If the estimated intraoperative blood loss exceeds 30 % of the CBV, the second volumes of autoplasma and erythrocyte concentrate, another introduction of dicynone in the same dosage, 6 % HES 250 ml, prednisolone in dosage 7 - 10 mg/kg of body weight are required. Within 30 and 60 minutes after the surgery, dicynone is injected in the same dosage. 5 hours after the surgery, filter drainage fluid is returned. 6 hours after the surgery, coagulation time is determined, and if observing no hypocoagulation, Clexane is introduced in a preventive dose.

EFFECT: method allows to provide early activation of erythropoiesis combined with improved erythrocyte morphology and blood haemostatic function, considerably reduced risk of complications connected with massive transfusion of donor blood products, as well as prevented edema of interstitial spaces and development of multiple-organ-failure syndrome due to maintained effective transcapillary exchange.

5 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely, to anesthesiology and resuscitation science, and can be used in necessity of anesthesia before surgery, during it and after it. For this purpose 10-15 minutes before incision 0.75% ropivacaine solution in volume 3.0-4.0 ml is introduced between spinous processes Th2-Th3 and 4.0-5.0 ml between spinous processes Th6-Th7. During narcosis anesthesia is supplemented with introduction of 3-5 mg of morphine hydrochloride solution. In resuscitation department between spinous processes Th6-Th7 0.2% ropivacaine solution is introduced at rate 4.0-6.0 ml per hour during 3-4 days, and between spinous processes Th2- Th3 0.2% ropivacaine solution is introduced in dose 3.0-4.0 ml up to three times per day during 3-4 days. Anesthesia is supplemented by introduction of 3-5 mg of morphine hydrochloride solution. After transferring patient to surgery department, anesthesia is carried out by constant introduction at the same levels of 0.2% ropivacaine solution at rate 6.0-8.0 ml per hour during 3-4 days, also introducing morphine hydrochloride solution in dose 3-5 mg per day.

EFFECT: method allows to ensure adequate anesthesia at all stages of treatment due to continuous and prolonged dosing of medications.

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology, also can be used in treating patients with solid tumours. For this purpose, 1-2 days prior to the initiation of chemotherapeutic procedures, a preparation of marrow mesenchymal stem cells coated with perfluorocarbon nanoparticles produced by incubation in a medium containing a pharmaceutically acceptable aqueous perfluorocarbon nanoemulsion of a particle diameter 300 nm and less is introduced to a patient intravenously in dose 0.5-10·106 cell/kg. Then the chemotherapeutic procedures follow with underlying oxygenated gas mixture inhalations at normal or high pressure.

EFFECT: method provides effective growth inhibition and reduced tumour size, including ensured by increasing tumour cell sensitivity to chemopreparations.

9 cl, 4 ex

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