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N-ALKENYLIMIDAZOLE METAL COMPLEX DERIVATIVES AS EFFECTIVE AGENTS FOR THE HYPOXIC CONDITIONS

The relevance. The therapy of hypoxemic conditions by the substances, which are differing because of their key role in the vital processes of metabolism and also their high pharmacological activity, and which are known to be the regulators of redox systems, can be considered as one of the priority directions of the modern clinical and experimental pharmacology. Metal complexes of essential elements, which are the natural participants of the ligand formation, can be very interesting in this sense. The research goal. Experimental validation of the pharmacological correction of the hypoxic conditions of the N-alkenyl-, N-propargylimidazoles and 3 hydroxypyridine metal complex derivatives. Test compounds and drugs. In comparison with well-known antihypoxants, antioxidants and actoprotectors in animal studies investigated acute toxicity, cytotoxicity, antihypoxic and actoprotective activity, effect on Central nervous system, liver, kidneys, heart, system of blood microcirculation, biochemical and hematological parameters, redox potential, studied the main ways of mechanism of action and the possibility of combined use with drugs of different pharmacological groups of complexes of zinc, cobalt, iron, derivatives of N-alkenyl-, N propargylimidazol and 3-hydroxypiridine. The discussion of the results. The researched drugs are moderately and low toxic, so it proves their safety. The antyhypoxic and actoprotective effect has been shown by the complexes of cobalt (CoALL) and iron (tetravim) and also by the derivatives of N-alkenylimidazole. Hemostimulating effect of CoAll has also been discovered. A possible mechanism of the antihypoxic effect of the test compounds could be attributed to the effect on coupling of oxidation and phosphorylation, maintenance of the mitochondria structure and functions in conditions of oxygen deficiency, elimination of the negative effect of hypoxia on carbohydrate metabolism, improvement of microcirculation and tissue oxygenation parameters and restore of the redox potential at hypoxia exposure. CoALL, probably, activates the key metabolism stages, which are responsible for energy supply by oxidizing organic substrates. The increasing of hematocrit, erythrocyte and hemoglobin levels can also be a protective factor of CoALL in condition of hypoxia. Conclusions. CoALL is promising for the further development as a hemostimulating drug, and CoALL and tetravim as antihypoxic and actoprotective drugs. Redox-regulating activity of metal complexes of the derivatives of N alkenylimidazole offers the opportunities to construct new effective preparations of a wide spectrum of action on their basis.

Иллюстрации

Table 1. N-alkenyl-, N-propargylimidazoles and 3-hydroxypyridine metal complex derivatives.

Figure 1. N-alkenylimidazole general formula.

K – optical density in the control wells;  O – optical density in the studied wells.

Figure 2. Cytotoxic effect of tetravim on MDCK and Vero cell cultures.

Table 2. Effect of N-alkenyl-, N-propargylimidazoles, 3-hydroxypyridine metal complex derivatives and comparison drugs on the mice lifespan during acute hypoxia.

Notice.* – Significant differences compared with control animals at p < 0.05. Data are expressed as M ± m. M – arithmetic mean as % relative to the control group (100%); m – standard error of the mean as % relative to the arithmetic mean. 

 

Table 2 (continueed).

Notice.* – Significant differences compared with control animals at p < 0.05. Data are expressed as M ± m. M – arithmetic mean as % relative to the control group (100%); m – standard error of the mean as % relative to the arithmetic mean. 

Table 2 (continueed).

Notice.* – Significant differences compared with control animals at p < 0.05. Data are expressed as M ± m. M – arithmetic mean as % relative to the control group (100%); m – standard error of the mean as % relative to the arithmetic mean. 

Table 3. Effect of the co-administration of the N-alkenylimidazole metal complexes with different pharmacological classes drugs on the mice lifespan during acute hypoxia.

Тable 4. Effect of the N-alkenylimidazole metal complex derivatives and officinal drugs on the mice physical performance in normal and complicated conditions of hypoxia

Figure 3. The effect of derivatives of N-alkenylimidazole on CPRA on rats

Notice.* – Significant differences compared to control animals at p < 0.05. Data are presented as % relative to the control group (100 %).

Figure 4. The effect of the N-alkenylimidazole derivatives on the volume and structure of behavior of rats in «open space».

Significant differences compared to the control animals at p < 0.05. Data are presented as % relative to the control group (100 %).

Figure 5. The effect of CoALL (25 mg/kg), tetravim (50 mg/kg), AHBH and their combination on blood sugar in rabbits after intravenous administration of galactose (1 mg/kg)

Table 5. The effect of CoALL (25 mg/kg), tetravim (50 mg/kg), acyzol (25 mg/kg), cobazol (50 mg/kg), AHBH and combined on the activity of enzymes of blood serum of mice

Figure 6. Effect of CoALL (25 mg/kg), tetravim (50 mg/kg), 2,4-DNP (5 mg/kg) and combinations thereof on mice oxygen consumption (n = 10)

Figure 7. Effect of CoALL (25 mg/kg), tetravim (50 mg/kg), 2,4-DNP (5 mg/kg) and combinations thereof on mice rectal temperature (n = 10).

Тable 6. The effect of CoALL (25 mg/kg) and tetravim (50 mg/kg) on the oxygen consumption of mice in the early after hypoxic period (n = 10).

Table 7. The effect of CoALL (25 mg/kg), tetravim (50 mg/kg), AHBH and combined on the hemogram

Table 8. Effect of CoALL (25 mg/kg), tetravim (50 mg/kg), AHBH and their combination on microhaemodynamics (n=10)

Table 9. Effect of CoALL (25 mg/kg), tetravim (50 mg/kg), AHBH and their combination on tissue oxygenation (n=10)

Figure 8. Effect of CoALL (25 mg/kg), tetravim (50 mg/kg), AHBH and their combination on erythrocyte concentration (Vr) and EOE (n =10)

Table 10. The effect of tetravim (50 mg/kg), CoALL (25 mg/kg), AHBH and their combination on FOCI and Red-Ox potential (n=8)

DOI: 10.18413/2500-235X-2017-3-1-49-72
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