According to WHO, the acquired secondary form of hematopoietic-depressive states increases the risk of death in people with cancer, infectious, and hormonal diseases. The choice of drugs that stimulate the proliferative activity of bone marrow cells is limited. The stimulus to the search for hematopoietic-stimulating compounds among pyridine derivatives was the manifestation of the activity of the cerebroprotective drug Mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate) to restore the granulocytes and B-lymphocytes homeostasis in clinical practice. The hematopoietic-stimulating activity of the newly synthesized compound Complex of 5-benzyl-7-(o-fluorobenzylidene)-2,3-bis(o-fluorophenyl)-3,3a,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c]pyridine complex with β-cyclodextrin (BIV) was studied on a model of cyclophosphamide-induced myelodepression in C57BL6/J mouse line. The BIV compound demonstrated a stimulating effect on the process of restoring the level of Ly-6G+ Ly-6C+ granulocytes, monocytes/macrophages, CD19+ B-lymphocytes in the bone marrow, exceeding the activity of the reference drug Methyluracil. The BIV compound did not affect on the proliferative activity of c-kit (CD117+)-expressing cells, CD3e+ pre-T-lymphocytic cells and Ter-119+ erythroid cells in the bone marrow. The total number of bone marrow myelokaryocytes in the experimental groups was significantly higher than in the intact group. The pronounced hematopoietic-stimulating effect of the BIV compound gives in the future the prospect of development as a drug used for the treatment of B-lymphocytic and granulocytic-macrophage hematopoietic-depressive states.
According to the WHO, the secondary form of hematopoietic-depressive status increases the risk of death in people with oncological, infectious, and hormonal diseases. The choice of drugs that stimulate the hematopoietic activity of B-lymphopoiesis is limited. The current leucopoiesis drugs have a number of side effects: thymic preparations stimulate the production of PGE2, which causes chronic inflammation and various autoimmune diseases through the differentiation of T helper 1 (Th1) cells, the proliferation of Th17 cells, and the production of IL-22 from Th22 cells through EP2 and EP4 receptors; cytokine preparations can cause uncontrolled immune reactions and impaired contractility of smooth and cardiac muscles; drugs based on nucleic acids can stimulate the division of all cells, including bacterial and cancerous ones. The use of oligonucleotides such as ribozymes and antisense oligodeoxynucleotides (AS-ODNs) shows promise as therapeutic moieties, but faces a number of challenges such as nuclease sensitivity, off-target effects, and efficient delivery. The search for substances that stimulate B-lymphopoiesis among ionic compounds was motivated by the discovery of the unique properties of lidocaine docusate, one of the first ionic liquid forms of the known drugs. The lidocaine docusate (protonated form of lidocaine (2-(diethylamino)-N-(2,6-dimethylphenyl) acetamide + docusate-anion (dioctylsulfosuccinate))) suppresses the division of pheochromocytoma cells and activates immunity in rats. The trimecaine-based ionic compound (TIC) demonstrates high B-lymphopoiesis-stimulating activity. The TIC compound stimulates an increase in the volume of transitional B cells, which play an important role for further differentiation and formation of a sufficient number of mature B1 cells and mature B2 cells, where mature B2 cells make up the bulk of the functional population of B lymphocytes. The TIC compound most strongly stimulated the restoration of the number of marginal zone B cells, follicular B cells, and activated germinal center B cells after the cytotoxic emptying of the follicular centers of the spleen induced cyclophosphamide. It significantly exceeds the activity of the comparison drug methyluracil. The TIC compound does not affect the level of pro-B, pre-B-I, or pre-B-II bone marrow cells, which prevents the risk of the formation of immature functionally defective cells.
1-(2-phenylethyl)-4-ketoxympiperidine o-fluorobenzoic acid hydrochloride, a complex with β-cyclodextrin p-fluorobenzene carbonylamide morpholine, a complex with β-cyclodextrin o-fluorobenzene carbonylamide piperidine had high myelostimulating activity at the level of the comparison drug methyluracil. 1-(3-ethoxypropyl)-4-ketoxympiperidine p-fluorobenzoic acid ester hydrochloride, 1-(2-phenylethyl)-4-ketoxympiperidine m-fluorobenzoic acid ester hydrochloride, 1-(2-phenylethyl)-4-ketoxympiperidine p-fluorobenzoic acid ester hydrochloride did not possess leukopoiesis-stimulating activity, but showed erythropoiesis-stimulating and thrombocytopoiesis-stimulating activity at the level of the comparison drug methyluracil.
The immune system of humans and higher animals performs an important function of maintaining the constancy of the internal environment of the body by detecting and eliminating foreign substances of an antigenic nature, both endogenously created and exogenously penetrating. This function of the immune system is performed by factors of innate and acquired immunity. As the name suggests, immunostimulants are the agents boosting the immune response. The new chemical series of compounds is promising for the search new effective immunostimulating drugs. Acute toxicity and the effect on peripheral blood hemogram parameters and on the subpopulation composition of lymphocytes were determined in the compounds (piperidine-containing derivatives):ethoxyethyl)-4-ethynyl-4hydroxypiperidine) dihydrochloride and, 1:1 complexes of β-cyclodextrin with 1-(2-ethoxyethyl)-4-(2-ethoxyethoxyl)-4-ethynylpiperidine, 1-(2-ethoxyethyl)-4-(2-methoxyethoxyl)-4-ethynylpiperidine, 7-(2-methoxyethyl)-2,2-dimethyl-3-thia-7-azabicyclo[3.3.1]nonane or 3-(2-morpholinoethyl)-7-(3isopropoxypropyl) diazabicyclo[3.3.1] nonane with β-cyclodextrin. Compound ˗ 1-(3-n-butoxypropyl) piperidine-3-methyl-4-spiro-5'-imidazolidine-2',4'-dione, exceeds the immunostimulating activity of the comparison drug of levamizole by 3.1 times and shows low toxicity.
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