The correction method of the blood and increasing the life expectancy of patients with t-lymphoblastic animals

 

(57) Abstract:

The invention relates to medicine, namely to Hematology. A method for inhibition of T-limfoleikoze process in animals, namely, that once in 10-14 days subcutaneously at a dose of 0.2 ml injected mixture containing mmol/kg of body weight: ATP acid - 0.1; adenosine-3', 5'-monophosphine acid - 0.1; oxidized glutathione - 0,05; theophylline - 0.05; Ethylenediamine - 0,01; 2-S-turnieren-1,1-diphosphonic acid - 0,1; 1--D-arabinofuranosylcytosine - 0,17; and all substances dissolved in RPMI medium, adding of 0.2-0.3 n sodium hydroxide to a pH of 5.6 to 6.5, and theophylline and Ethylenediamine is used in the composition of 2.4% aminophylline. The method allows to increase the effectiveness of treatment of T-limfoleikozom. 1 table, 5 Il.

The invention relates to the field of medicine and for the restoration of the life expectancy of patients with T-lymphoblastic animals, recovery to normal number of leukocytes and lymphocytes activation of the blood by introducing substances that induce intracellular regulatory system camp and repair processes on the background of radioprotectors and widely used in oncogenic drugs. Inherent in the present method pregenome. Used in Oncology drugs only increase disorders throughout the body (1,2), resulting in accelerated and amplified without these influences developing leukopenia, anemia, decreased activity of the immune system (3, 4). Therefore, in Oncology, the problem of eradication of the malignant clone is in line with the protection of the systems of immunity and hematopoiesis. On the possibility of resolving these problems and indicates declare us the way.

The most effective way of protecting your systems immunity and blood of cancer patients is the introduction of them after chemotherapy with cytotoxic drugs temporarily closed until the disease autologous bone marrow cells or hematopoietic stem cells. Cryopreservation of cells before the disease for the entire population unreal.

Closest to the claimed method is chemotherapy cytotoxic drugs while maintaining the activity systems of immunity and hematopoiesis by cytokines. It is used in Oncology cytokines include recombinant interleukin IL-1- (5), interferons, taktivin (6), IL-2 (7). However, cytokinemia does not solve one of the most urgent tasks, namely reparation as existing violations slocate the ins short and have only a supporting character.

The aim of the invention is a method of maintaining the number of leukocytes and lymphocytes at the level of norms, activation of erythropoiesis and increase the life expectancy of patients with leukemia.

The inventive method differs from known methods of inhibition of leukemic processes the fact that the basis of the approach is the repair of existing damage in malignant cells and newly arising in any tissue under the influence of practice in Oncology drugs. Induction of reparative processes scheduled radioprotectors in terms of strengthening the coordination of intracellular regulatory systems through the activation of intracellular regulatory systems camp.

Adopted in the present method approach to braking limfoleikoze process proceeds from the obtained data, the almost complete inactivation of the camp system in malignant thymoma cells of mice of the AKR/J with spontaneously developing under the action of retrovirus T-lymphocytic leukemia. The table shows that phosphotransferase activity of camp-dependent protein kinases (PC) in thymoma cells of mice AKR/J does not exceed 5% of the activity of the PC And in the thymocytes of young (3-4 months). even healthy mice of this line. Introduction patients with leukemia mice AK the progress of the activity remains very low on the background activity of PC And thymocytes as young healthy mice AKR/J, and genetically healthy (CBAxC57BL/6)F1hybrids. However, induction, and this residual activity may at least during the injection closer to the normal functioning of cell membranes and their receptors and to ensure more effective integration into the cells of the input substances and their effects. The camp system involved in the coordination of all intracellular regulatory systems; therefore, activation of the camp system on the background of radioprotectors can be expected activation not only of the energy processes under the control of camp, but repair system damage. For cells and tissues that do not undergo malignant transformation, created such conditions can be protected, providing reparation emerging damage under the influence of drugs used in Oncology. These assumptions and underlying inventive mixture similarly developed earlier method of restoring the activity of hematopoietic stem cells after radiation (8).

The method consists in the following. Mice of the AKR/J with spontaneously developing T-lymphocytic leukemia at the age of 10 months and the number of leukocytes in peripheral blood, exceeding 10-12 million in 1 ml of blood (with 7-8 million is the red RPMI following substances, mmol per 1 kg of weight of animal: adenosine triphosphate (ATP) - 0.1; oxidized glutathione - 0.05; adenosine-3',5'-monophosphoryl acid (camp) - 0,1; theophylline (consisting of 2.4% aminophylline) - 0.05; Ethylenediamine (consisting of 2.4% aminophylline) is 0.01; 2-S-turnieren-1,1-diphosphonic acid is 0.05; 5-(2'-pyridyl)-3-thiopental-1,1-diphosphonic acid - 0,1; 1--D-arabinofuranosylcytosine (cytarabine, CA) is 0.17. The solution is neutralized 0,2-0,3 N. Paon to a pH of 5.5 to 6.5.

All components of the mixture is directed to the activation of intracellular systems of regulation and system repair through the induction of the camp system on the background of radioprotectors.

Induction of the camp system is such substances as glutathione oxidized (activator PC), theophylline (an inhibitor of phosphodiesterase camp), camp (an activator of the expression of many functionally important genes), ATP. Glutathione and Ethylenediamine known as radioprotectors, effective with the introduction before irradiation. Substance 2-S-turnieren-1,1-diphosphonic acid and 5-(2'-pyridyl)-3-thiopental-1,1-diphosphonic acid is introduced into the mixture as being able to carry a double function: inhibitor of camp phosphodiesterase (due to the active binding of CA2+and reduce the concentration of the latter in the cell), radioprotectors primarily in actively proliferating cells, including malignant.

Introduced in the mixture of substances known and resolved pharmacology, except for two new substances synthesized in the Institute of chemical kinetics and combustion SB RAS. One of these substances - 2-S-turnieren-1,1-diphosphonic acid described in the patent (8). The method of obtaining another substance is given below. The concentration of introduced substances is selected experimentally.

A new chemical substance is 5-(2'-pyridyl)-3-thiopental-1,1-diphosphonic acid is not described in literature. The method of obtaining this substance based on the reaction of nucleophilic attachment 2-vinylpyridine) - derivatives to 2-mercaptoethylamine-1,1-diphosphonic acid, the method of obtaining which published (9). The reaction proceeds in aqueous solution, slightly alkaline environment (pH 8-9) and gives the target product with the release of close to 70%. The substance is easily excreted from the reaction mixture in the form of sludge.

Obtaining 5'-(2-pyridyl)-3-thiopental-1,1-diphosphonic acid of the formula

< / BR>
1.2 g Triammonium salt 2-mercaptoethylamine-1,1-diphosphonic acid are dissolved in 10 ml of water and passed through a column Packed with resin KU-2 in the N+-form. The eluate pariveda to 10 ml To one stripped off the eluate is added to 10.1 g La prevent oxidation via reaction mixture is passed a weak stream of nitrogen. After 12 h the mixture is cooled, to the mixture is added 10 ml of water and 1 g of potassium carbonate. The mixture is purified by extraction with ethyl ether 4 times. The aqueous phase after removing residual ether is passed through a column of resin KU-2 in the N+-form. The eluate pariveda to 5 ml, and then methanol is added to turbidity. After the beginning of crystallization is added 10 ml of methanol. After 12 h, the precipitate is highlighted by filtration, washed with methanol and dried. Substance precrystallization out of the water. The product yield, 1.2 g (72%).

Data pH-metric titration and elemental analysis.

Found, %: C 32,48; N 4,60; R Is 18.40.

EQ. 325,0.

WITH9H15NP2O6S.

Calculated,%: 32,44; N. Of 4.54; P 18,59.

EQ.327,2.

31P-NMR-spectrum (E2O+K2CO3, pH 7): 18,6 M. D. Rel. 85%H3RHO4during the suppression of the spin-spin interaction.

with1N-singlet.

The toxicity of a given substance does not exceed the toxicity of 2-S-turnieren-1,1-diphosphonic acid (8).

Experiments that reveal the influence of the proposed mixture on life expectancy and on the blood of patients with leukemia animals held namp in the immune system this line of mice determined by phosphotransferase activity PC And thymocytes young healthy animals (3-4 months) and thymoma cells in animals in 10-12 months method (10). The number of leukocytes and erythrocytes in the peripheral blood was determined in the cell Goryaeva. Formula leukocytes were detected by strokes blood stained by Romanovsky-Giemsa. The data are processed by the method of nonparametric statistics Wilkinson. The number of animals in the control and experimental groups of 14 and 17, respectively, in the three experiments.

Example. Once in 10-14 days to mice R/J from the age of 10 months and the number of cells in more than 10 million in 1 ml of peripheral blood (7-8 million in 1 ml of blood in mice of this line in 5 months.) injected (subcutaneously) 0.2 ml of the mixture in the environment RI containing the following substances in concentrations (mmol per 1 kg of weight of animal): ATP - 0,1; camp - 0.1; oxidized glutathione -0,05; theophylline (consisting of 2.4% aminophylline) - 0.05; Ethylenediamine (consisting of 2.4% aminophylline) is 0.01; 2-S-turnieren-1,1-diphosphonic acid is 0.05; 5-(2'-pyridyl)-3-thiopental-1,1-diphosphonic acid - 0,1; cytarabine (CA) is 0.17. The mixture is neutralized 0,2-0,3 N. NaOH to a pH of 5.5 to 6.5. 5-7 days after each injection is determined by the number of leukocytes and erythrocytes in the peripheral blood, leukocyte formula. The number of injections inventive mixture of 15-20.

Data of Fig.1 show that the introduction of the claimed reparation mixture Noah line in 5 months. and genetically healthy (CBAC57BL/6)F1hybrids. The percentage of atypical lymphocytes in the blood of animals on the background of the input inventive mixture (Fig.2) after some hesitation from 20 to 40% decreased to values detected in mice of this line in 5 months (14-15%), with 70% of atypical lymphocytes in the control of leukemic animals without introductions. The data Fig.3 convince activation of the blood of the inventive mixture. Up to 30-40% of patients with T-lymphoblastic mice (Fig.4) in conditions of chronic periodic introduction of the inventive mixture are life expectancy, characterized genetically healthy mice. Their life expectancy exceeds 18 months in 100% loss of control animals to 14-15 months. The photograph confirms the healthy appearance of mice T-limfoleikoze line R/J to the time of life in 25 months in the case of injection repair mixture from the age of 10 months.

The inventive method confirms the effectiveness of the approach adopted for the removal of pathological processes in the body associated with abnormalities in the genome, and first of all malignant. The apparent wide range of applications of the inventive repair mixture. Repair mixture may be urgent for cancer patients as a drug, restoring the blood and lenat H. 1. Genotoxic effects of radiotherapy and chemotherapy on the circulating lymphocytes of breast cancer patient. Chromosme aberrations induced in vivo. Mutat. Res.Toxicol.Test, 1990, v.242, n.1, 17-23.

2. Sadamori n, Isode m, Shimisu S., Yamamory T., Itoyama, T., Ikeda, S., Yamoda Y., M. Ichimaru Relationship between chromosomal breackpoint and molecular rearrangement of T-cell antigen receptors in adult T-cell leukemia. Acta Haematol., 1991, v.86, n.1, 14-19.

3. Anticancer chemotherapy Ed. by N. And. Perevozchikova M., 1986, S. 26.

4. And 61 kastrofylakas k37/36 PCT 91/00103 91.06.16. USA

5. The Gershanovich M. L., S. A. Kitlinski, L. C. Filatov, L. A. Dan, C. O. Korolenko, A. S. Simbirtsev. Stimulating and protective effects of recombinant interleukin-1- (betaleikina) on leucopoiesis chemotherapy of malignant tumors. Questions of Oncology, 1996, T. 42, 6, 13-18.

6. Mahonova L. A., A. C. Kiselev, G. A. Gordin, H., Kadagidze. Interferon and taktivin treatment of non-Hodgkin lymphoma in children in remission. Questions of Oncology, 1995, T. 41, 2, 80-81.

7. Sodel P. M., Kawal H., Wesly O. H. Harnessing graft versus leukemia: implications for 1L-2 treatment. Bone Marrow Transplant., 1992, v.10, Suppl. 1, n.1, 13-15

8. Novikov, C. M. , V. A. Kozlov, I. S. Alferov, N. In. Mihalin. Method of recovery of hematopoietic stem cells in irradiated animals. Patent 2017494 RF // BI 1994, 15.

9. Mihalin N. Century Vinylidenefluoride acid, its synthesis and chemical transformations. ependent histone kinase from pig brain. Purification and some properties of the enzyme. Biochim. Acta, Enzymology, 1975, v.377, n.2, 271-281.

The method of inhibition of T-limfoleikoze process in animals, including the introduction of substances inhibit leukemic process, characterized in that once in 10-14 days subcutaneously at a dose of 0.2 ml injected mixture containing, mmol/kg of body weight:

ATP acid - 0,1

Adenosine-3', 5'-monophosphine acid - 0,1

The oxidized glutathione - 0,05

Theophylline - 0,05

The Ethylenediamine - 0,01

2-S-Turnieren-1,1-diphosphonic acid - 0,1

1--D-Arabinofuranosylcytosine - 0,17

and all substances dissolved in the medium RI, adding of 0.2-0.3 n sodium hydroxide to a pH of 5.6 to 6.5, and theophylline and Ethylenediamine are used in the composition of 2.4% aminophylline.

 

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