RU2354376C1 - Preparation preventing development of depression of erithroid hematopoiesis shoot with introduction of cytostatic - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: claimed is preparation for pharmacological correction of erythropoiesis disturbances, developing under cytostatic influence, - cyproheptadine. Said antiserotin preparation was introduced 30 minutes before cytostatic 5-fluoruracyl. This resulted in formation of additional areas of erytyhroid and mixed hematopoiesis.

EFFECT: cyproheptadine increased number of eryth-rocariocytes in bone marrow and reticulocytes in peripheral blood.

5 tbl, 1 ex

Description

The invention relates to medicine, specifically to hematology, and can be used for pharmacological correction of disorders in the blood system, developing with cytostatic effects.

One of the main pathological syndromes caused by polychemotherapy is depression of the erythroid germ of hematopoiesis, which limits the duration of the use of cytostatics during chemotherapy. In order to correct erythropoiesis disorders caused by cytostatics, nucleic acid precursors, B vitamins, zymosan, recombinant erythropoietin, immunomodulators, and others are used [1]. However, these pharmacopoeial preparations have not found wide application in clinical practice, since they are not very effective in case of deep erythron depression and themselves have side effects.

The problem solved by this invention is to prevent depression of the erythroid germ of hematopoiesis, developing against the background of the use of cytostatics.

The task is achieved by the use of the antiserotonin drug cyproheptadine as a means that can prevent bone marrow erythropoiesis depression that develops with cytostatic myelosuppression.

New in the invention is the use of the drug cyproheptadine 30 minutes before the administration of the cytostatic drug.

We first revealed the ability of cyproheptadine to prevent the development of depression of the erythroid germ of hematopoiesis, which develops with cytostatic myelosuppression.

The use of cyproheptadine for a new purpose has become possible due to the new property identified by the authors to modulate the erythroid germ in cytostatic myelosuppression.

Cyproheptadine (peritol) belongs to the pharmacological group of histamine H1 receptor blockers (registration number P No. 012084/02), in addition, it exhibits antiserotonin and M-anticholinergic activity. The drug is used for allergic diseases, migraines, it has a pronounced sedative effect [2]. The ability of cyproheptadine, administered intraperitoneally at a dose of 30 mg / kg, to block postsynaptic serotonin C ₂ receptors is known [3].

Severe anemic conditions that develop in cancer patients during polychemotherapy, according to most researchers, are associated with a high sensitivity of the erythron to the toxic effect of cytostatic drugs [4]. A prominent representative of the group of cytostatics is fluoropyrimidine antimetabolite 5-fluorouracil, which is actively used in chemotherapy of malignant tumors. Moreover, today there is no doubt that the inhibition of hematopoiesis when various cytostatic drugs act on the body is caused not only by their direct toxic effect on hematopoietic cells and stromal elements, but also by a violation of the functions of the system of local regulation of hematopoiesis [5]. It can be assumed that the correction by an antiserotonin drug cyproheptadine of erythropoiesis disorders during cytostatic exposure will be relevant.

Distinctive features showed in the inventive combination of new properties that are not explicitly derived from the prior art in this field and are not obvious to a specialist. An identical set of features was not found in the analyzed patent and medical literature.

The method can be used to increase the effectiveness of drug chemotherapy in an experiment and clinic. Based on the foregoing, the claimed invention meets the criteria for patentability of the invention of "Novelty", "Inventive step" and "Industrial applicability".

The proposed method was studied in experiments on male mice of the CBA / CaLac line in the amount of 360 pieces, weighing 20-22 g. Animals of the first category, conventional linear mice, were obtained from the nursery of the experimental biomedical modeling department of the Research Institute of Pharmacology of the Siberian Branch of the Russian Academy of Medical Sciences (certificate is available).

The method is as follows.

In a laboratory animal (mouse), cytostatic myelosuppression was modeled by a single intraperitoneal injection of fluoropyrimidine antimetabolite 5-fluorouracil (76 mg / kg) in 1/3 of the MPD. 30 minutes before the cytostatic effect, the animals of the experimental groups were once intraperitoneally injected with the antiserotonin preparation cyproheptadine (Serwa, Germany) at a dose of 30 mg / kg. Immediately before use, the preparation was dissolved in sterile physiological saline. The control animals in all series of experiments under similar conditions were injected with an equivalent volume of physiological saline (0.2 ml). Intact animals were used as background.

On the 1st – 7th days after cytostatic exposure, the parameters of peripheral blood and bone marrow hematopoiesis were determined in animals using standard hematological methods, the structural and functional organization of bone marrow was studied by enzymatic isolation of hematopoietic islets and subsequent assessment of their quantitative and qualitative composition [6].

The results were processed by the method of variation statistics using the nonparametric Wilcoxon-Mann-Whitney U-test.

Example.

In the course of studies, it was found that 5-fluorouracil significantly reduces the content of immature and mature neutrophilic granulocytes, lymphocytes and erythrokaryocytes in the bone marrow throughout the study period, and causes the development of reticulocytopenia in the peripheral blood on the 1st-5th day of the experiment (Tables 1, 3 ) The indicated changes in the erythroid germ of hematopoiesis are associated with severe violations of the structural and functional organization of the bone marrow in mice after cytostatic exposure. So, on the 1-6th day of the study, there was a suppression of the yield of cell complexes associated with macrophage elements (up to 30-55%, P≤0.001). The study of cytological preparations revealed during this period a statistically significant decrease in the number of erythroid and erythrogranulocytic (mixed) hematopoietic islets (Table 4).

Preliminary administration of cyproheptadine prevents the development of depression of the erythroid germ of hematopoiesis, suppressed by 5-fluorouracil. This is evidenced by a statistically significant increase in the bone marrow cellularity of mice on the 4th, 5th day of the experiment in the experimental group compared to that in the cytostatic control (Tables 1, 2). The stimulating effect of cyproheptadine at the indicated time is based on an increase (P <0.01) in the number of immature and mature forms of neutrophilic granulocytes, lymphocytes and erythrokaryocytes in the bone marrow.

Under the influence of cyproheptadine, a statistically significant increase in the content of reticulocytes in peripheral blood was observed over the entire period of the study above the level noted in the control (without the drug) (Table 3).

The ability of the antiserotonin preparation to restore the structural and functional integrity of the bone marrow in mice treated with 5-fluorouracil was shown. So, in the experiment, on the 2-3rd day of the study, an increase in the number of cell complexes associated with macrophage elements is observed up to 186-190% compared with the cytostatic control (Tables 4, 5). However, by 6-7 days, under the influence of cyproheptadine, a decrease in GO with a centrally located macrophage element is noted. The study of cytological preparations revealed the stimulation of the formation of erythroid and erythrogranulocytic (mixed) hematopoietic islands on days 2-4 of the study in the experiment. Moreover, the content of cell complexes did not differ from the initial control. As can be seen, an increase in the number of erythrokaryocytes in the bone marrow and reticulocytes in the peripheral blood under the influence of cyproheptadine in animals treated with 5-fluorouracil was preceded by the organization of additional foci of erythroid and mixed blood formation.

Thus, the introduction of cyproheptadine before modeling cytostatic myelosuppression prevents the destruction of the structural and functional integrity of the hematopoietic tissue and the development of depression of the erythroid germ of hematopoiesis, and also helps to normalize the content of reticulocytes in peripheral blood.

Literature

1. Vorobyov P.A. Anemic syndrome in clinical practice. - M.: Newdiamed, 2001 .-- S.28-35.

2. Mashkovsky M.D. Medicines - 15th ed., Rev. and add. - M .: "New Wave", 2006. - P.293.

3. Peroutka S.J., Lebovitz R.M., Snyder S.H. Two distinct central serotonin receptors with different physiological functions // Science. - 1981. - Vol. 212, No. 4496. - P.827-829.

4. Red blood cells and malignant neoplasms / Novitsky VV, Stepovaya EA, Goldberg V.E. et al. - Tomsk: "STT", 2000. - S.171-217.

5. Goldberg E.D., Dygay A.M., Zhdanov V.V. The role of the hematopoiesis-inducing microenvironment in the regulation of hematopoiesis in cytostatic myelosuppression. - Tomsk: STT, 1999. - P.33-84.

6. Goldberg E.D., Dygay A.M., Shakhov V.P. Methods of tissue culture in hematology. - Tomsk, 1992 .-- S.172-173, 208.

Claims (1)

The use of cyproheptadine as an agent that prevents the development of depression of the erythroid germ of hematopoiesis with the introduction of cytostatics.