Agent possessing anti-inflammatory and antifibrotic action in pulmonary tissue, and cytostatic action

FIELD: medicine.

SUBSTANCE: invention refers to the use of reserpine as an agent possessing anti-inflammatory and antifibrotic action in pulmonary tissue, and cytostatic action.

EFFECT: extended range of products used for pharmacological correction of pulmonary inflammation and fibrosis accompanying cytostatics prescribed.

1 dwg, 6 tbl, 1 ex

 

The invention relates to medicine, namely to pulmonology, and can be used for pharmacological correction of inflammation and fibrosis in the lung tissue developing in the appointment of cytotoxic agents.

One of the serious complications of cytotoxic chemotherapy is interstitial pneumonia, which can lead to idiopathic fibrosis of the lungs. Idiopathic pulmonary fibrosis, a chronic progressive disease of unknown etiology, characterized by inflammation, interstitial fibrosis and progressive respiratory failure with adverse outcome [1]. Therapy of pulmonary fibrosis is mainly aimed at the prevention of the rapid progression of the disease, and not on his warning. To do this, currently using corticosteroids, often in combination with cytotoxic agents, antioxidants (N-acetylcysteine), antifibrosis means (D-penicillamine, colchicine) [2].

The problem solved by this invention is the expansion of the means that have anti-inflammatory and antifibrotic action in the lung tissue when cytotoxic effects.

This object is achieved by the use of reserpine as a means possessing anti-inflammatory and antifibrotic action in the lung tissue when qi is staticheskom impact.

New in the present invention is the use of foreign exchange administration of reserpine after administration of cytostatics.

We first identified the ability of reserpine to prevent the development of inflammation and fibrosis in the lung tissue, developing when using cytotoxic drugs.

The use of reserpine on the new appointment was made possible thanks identified by the authors of his new property to prevent the development of inflammation and fibrosis in the lung tissue with the introduction of drugs.

The main pharmacological properties of reserpine is its sympatholytic action. Drug acting on varicose thickening adrenergic nerve endings, is deposited in the membranes of vesicles, violates the entrance of dopamine in vesicles (and, consequently, the synthesis of noradrenaline and noradrenaline reuptake vesicles. The content of noradrenaline in the vesicles decreases, decreases the secretion of norepinephrine at nerve impulses. Due to the sympatholytic action of reserpine reduces the stimulating effect of the sympathetic innervation of the heart and blood vessels [3]. The effect of reserpine spreads to the Central nervous system. Initially, before the advent of modern antipsychotic drug used for the treatment of mental illness. Currently reserpine is used as an antihypertensive is the means in the early stages of arterial hypertension, he is also part of the combined number of drugs and is used as a pharmacological agent in experimental studies [3]. On models neurotic impacts and mielosupressiu shown to be an effective correction by reserpine disorders of hematopoiesis, in particular granulomonocitarnyi and lymphoid sprouts blood [4, 5].

Inflammation and fibrosis of the pulmonary interstice, pneumatic spaces, following the disruption of the structural and functional units of the lung parenchyma lead to the disturbance of gas exchange and the development of respiratory failure [6]. It is believed that the development of pulmonary fibrosis can be caused by abnormally activated alveolar epithelial cells, which produce mediators that stimulate the formation of fibroblasts and myofibroblasts [7]. In the inflammation fibroblasts and myofibroblast produce excessive amounts of collagen, contributing, in turn, scarring and destruction of the lung architecture. Suggest that the adrenergic system can control the synthesis of collagen in the lungs [8]. In addition, it was found that the development of the inflammatory process in the lung tissue during bleomycin-induced pulmonary fibrosis affects the number of adrenergic receptors in the lungs [9].

Distinctive features showed in sawse the second aggregate new properties are not explicitly derived from the prior art in this field and not obvious to the expert. Identical set of features not found in the analyzed patent and medical literature.

The invention can be used to improve the stability of the lung tissue to inflammation and deposition fibrocycstic mass chemotherapy in experiment and clinic.

Based on the foregoing, the claimed invention meets the criteria of patentability "Novelty", "Inventive step" and "Industrial applicability".

The proposed action of reserpine has been studied in experiments on 7-8 weeks mice C57BL/6J in the amount of 155 pieces. Animals of the first category, inbred mice, obtained from the nursery of the Department of experimental biomedical modeling NII pharmacology" SB RAMS (certificate available). The use of animals in experiments justified and agreed with the Commission on control over the content and use of laboratory animals NII pharmacology" SB RAMS.

The invention will be clear from the following description and the attached drawing 1.

Figure 1 depicts a light mouse, staining of lung tissue with hematoxylin and eosin and intact b - treated with bleomycin, - treated with reserpine on the background modeling fibrosis; lung mouse staining of lung tissue by van gieson on connective tissue: Mr. intact is; Dr. treated with bleomycin; e - treated with reserpine on the background modeling fibrosis.

The invention is as follows.

Fibrosis of the lung simulated single intratracheal introduction of 80 μg bleomycin (Bleomycin", JSC "Landfarm", Russia) in 30 µl of saline. The control animals under similar conditions were treated with equivalent volume of saline (control). Bleomycin belongs to the group of antitumor antibiotics. Its mechanism of action is not fully elucidated, although it is known that he is able to inhibit the synthesis of nucleic acids (DNA) and protein. The drug is active against cells in the mitotic cycle, and out of it, but is very active in the phase of G2. The main toxic effect of the cytostatic has on light: causes pneumonia, fibrations changes in the lung parenchyma [3].

Reserpine (Sigma, USA) was injected intraperitoneally at 1-7, 9, 11, 13 days after injection of bleomycin at a dose of 1 mg/kg intraperitoneally. The timing of administration and dose of reserpine chosen experimentally as the most optimal for modeling the depletion depot of catecholamines in the nervous system. The volume of injected solution was 100 µl. Immediately before use, the drug was dissolved in sterile physiological solution. In quality the ve background used intact animals (intact control).

7, 14, 21, 25, and 60 d after injection of bleomycin mice were killed by an overdose of CO2studied the morphological picture of the lungs. For histological examination of the lung slices were fixed in 10% formalin. By standard histological methods did the wiring material filled in the objects of study in paraffin blocks, which did histological sections with a thickness of 5 μm. Dewaxed sections were stained with haematoxylin-eosin and van gieson on connective tissue [10]. With the help of computer graphic analysis on the standard square histological slice measured the area of collagen fibers in the lung tissue. Then calculate the proportion of these indicators from the standard square cut.

7, 14, 21, 25 d after injection of bleomycin in animals were identified peripheral blood and bone marrow hematopoiesis standard hematological methods. Cultural methods in the bone marrow studied the contents of the colonies granulocyte-eritroidnogo-macrophage-megakaryocyte type (SOME GAMM), consisting of 4 different types of hematopoietic cells (eritrotsitov, granulocytes, macrophages and megakaryocytes) and granulocyte associations (CFU-G) [11].

Mathematical processing of the results produced using standard methods of variation statistics. Dostov most of differences was assessed using non-parametric U criterion of Mann-Whitney.

Example.

Staining of lung tissue with hematoxylin and eosin revealed the development of edema millionary walls, infiltration interstitial alveolar neutrophils, lymphocytes, macrophages and plasma cells, which leads to significant disruption of histoarchitecture lung tissue of mice treated with bleomycin (Fig.1b). In the walls of the alveoli occurs venous plethora, and hemorrhage. In the lumen of the alveoli appear plasma cells, neutrophilic and eosinophilic leukocytes, alveolar macrophages, histiocytes. In the Central parts of the body, there are areas where the lung figure is not part of emphysematous alveoli expanded.

When painting the light on van Giesen on connective tissue in the interstitium of the alveoli of mice treated with bleomycin, there is an increased formation of collagen fibers and progressive growth of connective tissue (RISD). On the 7th day of the experiment connective tissue is mainly perivascular and peribronchial, the content of the connective tissue around 1.98±0,28% of the area of lung tissue (table 1). 14, 21 day experience observed diffuse distribution fibrocycstic masses. Painting pneumovirus most pronounced on the 25th day of observation (RISD), when the content of collagen fibers is the 5.45±0,74% of the area of tissue is egcogi (table 1).

Reserpine reduces the intensity of inflammation in bleomycine the lungs of mice throughout the observation period. So, in the conditions of introduction of reserpine swelling of the epithelium and hyperemia of the alveolar walls is reduced, while retaining the lightness of the lung tissue (Resv). Cellular infiltration is mainly peribronchial and perivascular. Unlike mice bleomycine control animals treated with cytostatic and reserpine, a slight release of inflammatory cells in the lumen of the alveoli. Simultaneously with the suppression of the inflammatory response reserpine prevents the spread fibrocycstic masses in the lungs (rice, table 1).

Table 1
The content of connective tissue (% of the area of tissue) in the lungs of C57BL/6J in terms intratracheal injection of bleomycin and course assignments reserpine on the background modeling of pulmonary fibrosis (M±M)
The timeframe of the study dayBleomycinBleomycin + reserpine
Intact control1,03±0,20
71,8±0,26 * 1,33±0,06 *&
143,09±0,23 *2,94±0,27 *
213,02±0,44 *2,75±0,42 *
25the 5.45±0,74 *3,85±0,58 *&
403,47±0,21 *2,58±0,30 *
602,77±0,25 *1,59±0,39 &
Note: the observed accuracy (P<0,05) differences index from the intact control - *bleomycine control &.

Study of the reactions of the blood system when pneumovirus allowed to reveal that along with activation of the inflammatory process in the lung tissue the installation of bleomycin causes leukocytosis in the peripheral blood (3, 14 days). The increase in total number of leukocytes was associated with an increased number of lymphocytes (3 days) and neutrophils (3, 7, 14 days) (table 2). The increase in the content of neutrophilic granulocytes (3, 7, 21, 25 days) and lymphocytes (7, 14, 21 days) registered in the bone marrow (table 4).

Table 2
Dynamics of the content of the total number of leukocytes, neutrophils and lymphocytes (×109cells/l) in the peripheral blood in mice under the conditions of injection of bleomycin
The period of study., dayThe total number of leukocytesNeutrophilic granulocytesLymphocytes
Intact control13,90±1,442,01±0,3510,54±1,25
317,40±1,22 *3,07±0,37 *13,11±1,08 *
714,75±1,343,20±0,57 *or 10.60±0,99
1416,58±1,37 *3.04 from±0,40 *12,3±1,11
2114,40±1,302,01±0,62to 11.61±0,63
2515,20±0,532,97±0,2611,35±0,30
Note: * the validity of the distinctions of the Oia from the intact control (P< 0,05).

Reserpine cancels neutrophilic leukocytosis (3, 7 days) and lymphocytosis (3, 7, 14, 21 days) in the peripheral blood of mice with pneumovirus (table 2, 3). Similarly reserpine acts on bone marrow cells: the drug reduces the number of neutrophils (3, 21, 25 days) and lymphocytes (7, 14, 21 days) to the level of the intact control (table 4, 5).

Pneumovirus accompanied by an increase in the number granulocyte-eritroidnogo-macrophage-megakaryocyte (3 days) and granulocyte (3, 7, 14, 21 days) precursor cells in the bone marrow (table 6). Under the influence of reserpine decreases the content of SOME GAM (3, 7 days) and CFU-G (3, 7, 14 days) compared to animals receiving only bleomycin (table 6).

Table 3
Effect of reserpine on the dynamics of the content of the total number of leukocytes, neutrophils and lymphocytes (×109cells/l) in the peripheral blood in mice under the conditions of injection of bleomycin
The timeframe of the study dayThe total number of leukocytesNeutrophilic granulocytesLymphocytes
Intact control13,9±1,442,01±0,3510,54±1,25
312,40±1,22 &2,30±0,29 &9,03±0,98 &
710,20±0,41 &1,91±0,19 &7,16±0,38 &
1412,70±0,80was 2.76±0,408,66±0,79 &
213,38±1,13 *, &2,20±1,101,16±0,01 *, &
2514,75±2,182,97±0,5810,96±1,73
Note: * reliability of differences from intact controls (P<0,05), & reliability differences in mice under the conditions of injection of bleomycin.

Table 4
Dynamics of the content of the total number of kariolou, neutrophilic granulocytes and lymphocytes in the bone marrow (×106cells/femur) in mice under conditions of weinebene
The timeframe of the study dayThe total number of kariolouNeutrophilic granulocytesLymphocytes
ImmatureMature
Intact control10,10±0,850,65±0,13the 4.29±0,342,55±0,3
314,39±0,55 *1,36±0,19 *7,06±0,14 *2,78±0,23
712,48±1,461,02±0,15 *to 5.21±0,683,47±0,37 *
1414,39±1,18 *0,77±0,075,31±0,484,24±0,53 *
2115,36±0,71 *1,26±0,11 *6,34±0,17 *4,34±0,34 *
2512,29±0,841,11±0,13 *of 5.82±0,49 2,71±0,22
Note: * reliability of differences from intact controls (P<0,05).

Table 5
Effect of reserpine on the dynamics of the content of the total number of kariolou, neutrophilic granulocytes and lymphocytes in the bone marrow (×106cells/femur) in mice under the conditions of injection of bleomycin
The period of study., dayThe total number of kariolouNeutrophilic granulocytesLymphocytes
ImmatureMature
Intact animals10,1±0,850,65±0,13the 4.29±0,342,55±0,3
3to 11.61±0,78 &1,09±0,12of 5.34±0,46 &2,18±0,28
711,44±0,491,02±0,12 2,33±0,23 &
14of 12.76±1,130,64±0,126,53±0,722,22±0,43 &
219,36±0,14 &0,71±0,15 &3,93±0,40 &2,58±0,18 &
2510,44±1,200,68±0,16 &to 4.41±0,982,45±0,86
Note: * reliability of differences from intact controls (P<0,05), & reliability differences in mice under the conditions of injection of bleomycin.

Table 6
Effect of reserpine on the content of SOME GEMM and CFU-G (×105cells) in the bone marrow of mice under the conditions of injection of bleomycin
The timeframe of the study daySOME HAMSOME G
Phys. solutionReserpinePhys. Rast is the PR Reserpine
Intact control2,50±0,432,50±0,431,00±0,261,00±0,26
310,17±0,98 *4,00±0,43 *&was 9.33±1,94 *3,33±0,45 *&
72,00±0,370,67±0,11 *&5,67±0,84 *2,33±0,32 *&
140,83±0,18 *0,17±0,07 *&2,83±0,48 *0,33±0,21 *
213,17±0,312,00±0,466,67±1,36 *7,17±0,88 *
Note: * reliability of differences from intact controls (P<0,05), & reliability differences in mice under the conditions of injection of bleomycin.

Thus, the use of reserpine on the infusion of bleomycin prevents the development of inflammatory reactions in the lung interstitium and deposition fibrocycstic masses. Anti-inflammatory effects associated with ug is emeniem activity of hematopoietic precursor cells granulocyte-eritroidnogo-macrophage-megakaryocyte and granulocyte type.

Literature

1. Ilkovich M., Novikova, L.N., Speranskaya A.A. Idiopathic fibrosing alveolitis // a General practitioner in 2009. No. 6. - P.1-3.

2. Andreeva I.I. Fibrosing alveolitis. In the book: Sappers V.N., Andreeva I.I., Muslimova GG (ed) Practical pulmonology. Cheboksary: Publishing house of the Chuvash. state University; 2007. S-514.

3. Mashkovsky PPM Medicines. Manual for doctors. - 15-ed., Rev., Corr. and extra - M.: "a New wave", the Publisher Merenkov, 2008. - S-454, 1003-1004.

4. Goldberg ED, Digi A.M., Provalov NV, Skurikhin Mrs x, Suslov N. the Role of the nervous system in the regulation of hematopoiesis. - Tomsk: Izd. University, 2004. - P.87-90.

5. Digi A.M., Khmelevskaya Y.S., Skurikhin Mrs x, Pershin O.V., Andreeva, T., N. Ermakova. Peculiarities of regulation of the catecholamine stromal precursors and hematopoietic stem cells by cytotoxic mielosupression // bul. the experimental. Biol. and medicine. - 2011. - C, No. 12. - S-671.

6. Bridge I.D., Caridina B.C., Luchnikov NR. Morphofunctional characteristics of the mucous membrane of the bronchial tree and alveolar tissue in the dynamics of experimental pneumonia // Pacific medical journal. - 2007. No. 1. - P.18-20.

7. King IE, Pardo A. Selman M. Idiopathic pulmonary fibrosis // LANCET. - 2011. - V.378, No. 9807. - P.1949-1961.

8. Berg, R.A., Moss J., B.J. Baum, Crystal R.G. Regulation of Collagen Production by the (β-Adrenergic System // Journal of Clinical Investigation. - 1981. - V.67, May. - P.1457-1462.

9 S.N. Giri, Sanford D.A., Jr., Robinson, T.W., Tyler N.K. in his or her coupled beta-adrenergic receptor and adenylate cyclase system during bleomycin-induced lung fibrosis in hamsters // Exp Lung Res. - 1987. - V.13, №4. - P.401-416.

10. Merkulov, G. A. Course histopathological techniques. - SPb: Medicine, 1969. - P.14, 36-38, 58, 98-100, 163, 170.

11. Goldberg ED, Digi A.M., Shah V.P. Methods of tissue culture in Hematology. - Tomsk, 1992. - 264 C.

The use of reserpine as a means possessing anti-inflammatory and antifibrotic action in the lung tissue with cytotoxic effects.



 

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8 cl, 8 ex, 9 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, namely to oncology, and deals with method of combined treatment of non-small cell lung cancer of II and III stage. Method includes 2 courses of neoadjuvant chemotherapy with application of carboplatin and further radical surgery. Neoadjuvant therapy is carried out by intravenous introduction of vinorelbine in dose 25 mg/ m2 on 1 and 8 days of cycle, on the second day, 20 hours after introduction of vinorelbine carboplatin is introduced intravenously by drop infusion in dose by AUG 6, interval between courses of chemotherapy constitutes 20 days. After that in post-operative period on 14 day additionally carried out is adjuvant chemotherapy in the same regimen, with number of course being 3-4.

EFFECT: invention ensures increased efficiency of treatment of non-small cell lung cancer of II and III stage due to reduction of complications and increase of patients' survival.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly a composition containing a lyophilised salt of vinflunine or vinorelbine stable at room temperature. A pharmaceutical composition containing a water-soluble salt of vinflunine or vinorelbine stable at room temperature where said salt is presented in the lyophilised form prepared in the presence at least of one carbohydrate of specific pH and relation of the water-soluble salt of vinflunine or vinorelbine and carbohydrate.

EFFECT: composition is stable.

9 cl, 2 dwg, 6 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a combination containing the mTOR inhibitor everolimus and vinorelbine applicable for simultaneous, combined, separate or successive introduction.

EFFECT: invention refers to a method for preventing or treating a proliferative disease.

8 cl, 6 dwg, 2 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to traumatology and orthopedics and can be applied in complex treatment of posttraumatic, dystrophic, neurological, degenerative and scar-adhesion processes in joint area, deforming osteoarthrosis of large joints and osteochondrosis. Method of treatment includes introduction of drug mixture by ultraphonoresis for 5 minutes on a field, daily. To obtain said mixture applied are ointment "Indomethacyne", "Chondroxyde", gel "Essaven" in proportion 1:1:1, in dose, expressed in form of 3-10 cm long stripe of each ointment. These components are mixed with 50 mg of medication Karipasim, dissolved in 5 ml of physiological solution and 5 ml 2% solution of Trental. Treatment course includes 15-20 procedures.

EFFECT: method ensures fast achievement of antihydrophic and analgetic effect, reduction of total terms of patients' rehabilitation, increase of disease remission periods.

3 ex, 1 tbl, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline form of vinflunine ditartrate, production method thereof and use thereof in therapy, especially for cancer pathology treatment.

EFFECT: high stability and wide variety of galenic forms.

8 cl, 3 ex, 5 dwg

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

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