Comparative analysis of metal-complex and aminothiol antihypoxants efficiencies in the experiment

Aim. Comparative analysis of the efficiency of metal-complex (πQ1983, πQ2721) and aminothiol (Amtizole, Sunazole) antihypoxants in experiments on rats exposed to acute hypoxia with hypercapnia. Methods. Experiments performed on 182 male rats of Wistar line weighing 150-170 g. The study of antihypoxic activity of substances was carried out on the model the AH+Hc. The condition of acute hypoxia in rats was formed by placing them in glass airtight containers with a free volume of 1.0 L. Antihypoxic effect was evaluated by the life expectancy of animals in the described conditions. Substances πQ2721, πQ1983, Amtizole and Sunazole was administered once intraperitoneally at doses of 25, 50 and 100 mg/kg. Previously each substance was dissolved in 0.9% NaCl (1.0 ml). Testing the effectiveness of the substances on AH+Hc model was carried out after 1 h after administration of the substances and after 24 h. Animals of control groups were injected with 1.0 ml of 0.9% NaCl. In animals exposed to test AH+Hc in 1 h after administration were performed measurements of the rectal temperature before the experiment and through 1 h after administration, i.e. before AH+Hc. In animals selected for 24-hour observation, rectal temperature was measured before the experiment, and then after 1, 3, 6, 12, 18 and 24 h of observation, after which they were exposed to AH+Hc. Results. The antihypoxic effect of a selenium-containing substance πQ2721 based on Zn2+ was confirmed in experiments on rats. In a number of substances for comparison the πQ2721 proved himself not only as equally effective. It is found that after 1 h after administration at a dose of 50 mg/kg πQ2721 superior to all studied compounds, including antihypoxant with succinate Sunazole. An important advantage of the new promising antihypoxic agent was the preservation of its action for 24 hours after injection. (For citation: Evseev AV, Surmenev DV, Evseeva MA, et al. Comparative analysis of metal-complex and aminothiol antihypoxants efficiencies in the experiment. Reviews on Clinical Pharmacology and Drug Therapy. 2018;16(2):18-24. doi: 10.17816/RCF16218-24).

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II-Valent metals complex compounds and prospects of the acute hypoxia protection

Reviews on Clinical Pharmacology and Drug Therapy ◽

10.17816/rcf17153-56 ◽

2019 ◽

Vol 17 (1) ◽

pp. 53-56

Author(s):

Andrey V. Evseev ◽

Albert E. Belenky ◽

Dmitrij V. Surmenev ◽

Marina A. Evseeva ◽

Denis V. Sosin

Keyword(s):

Protective Effect ◽

Rectal Temperature ◽

Active Substance ◽

Acute Hypoxia ◽

Complex Compounds ◽

Antihypoxic Activity ◽

Reference Substance ◽

Divalent Metals ◽

Hypoxia With Hypercapnia ◽

Antihypoxic Effect

Aim. To find antihypoxic properties in complex compounds of some divalent metals on the model of acute hypoxia with hypercapnia. Methods. In the experiments on mice in acute hypoxia with hypercapnia (AH+Hc), the protective effect of 6 new complex compounds was studied in comparison with the effectiveness of reference antihypoxants. Substances were injected intraperitoneally 60 min before acute hypoxia with hypercapnia in doses of 25 and 50 mg/kg. Antihypoxic effect was compared with their ability to change the rectal temperature. Results. The most active substance πQ-2116 with Nickel as a complexing metal was established. Mice resistance to acute hypoxia with hypercapnia at a dose of 25 mg/kg was increased to 89.5%, at a dose of 50 mg/kg – to 165.8%. The effect was accompanied by serious hypothermia, reaching 28.5 °C. Antihypoxic activity of the substance πQ-2116 is comparable with reference substance πQ-1983 and greater than the effect of aminothiol antihypoxants – Amtizole and Sunazole.

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Testing of new selenium containing metal complex compounds by acute hypoxia-hypercapnia method

Reviews on Clinical Pharmacology and Drug Therapy ◽

10.17816/rcf15446-52 ◽

2017 ◽

Vol 15 (4) ◽

pp. 46-52

Author(s):

Andrey V Evseev ◽

Dmitrij V Surmenev ◽

Edgar A Parfenov ◽

Marina A Evseeva ◽

Denis V Sosin ◽

...

Keyword(s):

Metal Complex ◽

Life Span ◽

Rectal Temperature ◽

Acute Hypoxia ◽

Complex Compounds ◽

Antihypoxic Activity ◽

Positive Interaction ◽

Antihypoxic Effect ◽

The Right ◽

Dose Dependent

Aim. To test the new selenium containing metal complex (Zn2+) compounds by acute hypoxia-hypercapnia method in experiments on mice for antihypoxic effect finding. Methods. The screening of antihypoxants in experiments on mice placed in acute hypoxia-hypercapnia condition (AH + H) among 11 new metal complex selenium containing compounds have been performed. Condition of AH + H in animals was formed by their placing in hermetic glass boxes with 0.25 L free volume. Each substance has been used once by intraperitoneal introduction 60 min. before mice placing in AH + H area in doses 10, 25, and 50 mg/kg. The “life span” parameter was used as a criterion of antihypoxic activity. At the definite steps of investigation all animals where undergone to rectal temperature measuring. Results. The antihypoxic effect was shown by 4 compounds among 11 (πQ2719, πQ2720, πQ2721, πQ2882). The greatest result in life span was found in substance πQ2721. In this case the right positive interaction between doses of substances and results was marked - doses 10, 25 and 50 mg/kg provide life span enlargements to 25.1, 81.7 (р < 0.05), and 186.1% (р < 0.005) in comparison with control groups correspondently. The efficiency of etalon substance πQ1983 was near to that of πQ2721 but in dose 50 mg/kg it becomes weaker in activity than new compound. Conclusion. The test resultant of 11 new metal complex (Zn2+) substance with selenium in structure of ligand in use of acute hypoxia-hypercapnia method shows the πQ2721 as an antihypoxant that was confirmed by significant mice life span enlargement after doses 25 and 50 mg/kg during its action that according with dose-dependent rectal temperature decrease. (For citation: Yevseyev AV, Surmenev DV, Parfenov EA, et al. Testing of new selenium containing metal complex compounds by acute hypoxia-hypercapnia method. Reviews on Clinical Pharmacology and Drug Therapy. 2017;15(4):46-52. doi: 10.17816/RCF15446-52).

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EFFECT OF AMINOTHIOL ANTIHyPOXANTS ON INTERHEMISPHERIC ASyMMETRy OF THE bRAIN

Reviews on Clinical Pharmacology and Drug Therapy ◽

10.17816/rcf10151-53 ◽

2012 ◽

Vol 10 (1) ◽

pp. 51-53

Author(s):

Vladimir Vladimirovich Mihkeev ◽

Vera Vasilievna Marysheva ◽

Boris Nikolaevich Bogomolov ◽

Lubov Vladislavovna Zhukova-Williams

Keyword(s):

Left Hemisphere ◽

Right Hemisphere ◽

Acute Hypoxia ◽

Life Time ◽

Antihypoxic Activity ◽

Interhemispheric Relations ◽

Hypoxia With Hypercapnia ◽

Antihypoxic Effect ◽

The Right ◽

The Brain

The effect of aminothiol antihipoxants amthizol and its analogue VM-606 on the resistance of the SHR mice males to an acute hypoxia with hypercapnia under conditions of isolated functioning of one of the hemispheres of the brain was studied. Antihypoxic agent amthizol 25 mg/kg increases life time of naïve mice by 46.2%. The drug acted on the sham-operated mice more slightly, increasing of their life only on 28.1% (p<0.01). Administration of amthizol under conditions of functioning of the right hemisphere significantly enhanced (+64.8%) the life time of mice. No antihypoxic effect was registered after administration of amthizol to mice with active left hemisphere: the result was the same as in mice without amthizol. Therefore, antihypoxic effect of amthizol was due to its action on the right (but not the left) hemisphere of the brain. VM-606 possessed more antihypoxic activity in comparison with amthizol. After unilateral cortical inactivation, VM-606 increased life time of mice both in active right and active left hemispheres, but in more degree in active right hemisphere. Thus, interhemispheric differences in resistance of mice to hypoxia with hypercapnia were diminished. Therefore, the differences between amthizol and VM-606 are the followings: amthizol inverts interhemispheric relations in hypoxia whereas VM-606 diminishes them.

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Characteristics of external respiration of rats in acute hypercapnic hypoxia and its correction by new metal-complex antihypoxant

Reviews on Clinical Pharmacology and Drug Therapy ◽

10.17816/rcf12236-42 ◽

2014 ◽

Vol 12 (2) ◽

pp. 36-42

Author(s):

Denis Vladimirovich Sosin ◽

Andrey Viktorovich Yevseyev ◽

Vitaliy Andreyevich Pravdivtsev ◽

Petr Dmitriyevich Shabanov

Keyword(s):

Metal Complex ◽

Acute Hypoxia ◽

Antihypoxic Activity ◽

External Respiration ◽

Low Oxygen ◽

Resistance Level ◽

Hypoxia With Hypercapnia ◽

Hypercapnic Hypoxia ◽

Low Oxygen Concentration ◽

Respiration Parameters

Changes of external respiration parameters have been studied in experimental rats after oral introduction of new selenium-containing metal-complex substance πQ1983 in dose 100 mg/kg before and under action of acute hypercapnic hypoxia (AH+Hc). A substance for comparison was metabolic antihypoxant amthizole administered in similar way and dosage. The substances were introduced 90 min before (incubation period) placement of animals into hypoxic chambers with 1.0 L free volume. During each experiment as well as during AH+Hc a respiration curve called pneumobarogramm (PBG) was recorded continually. It has been established that the substance πQ1983 decreases parameters of lungs ventilation in the rats. According to PBG dynamics, rats protected by the substance demonstrated a high resistance level to the aroused acute hypoxia with hypercapnia, that expressed by weakening of early reactions from respiratory system under hypercapnia action, twice longer life span of animals in hypoxic experiment, and by rising of possibility to withstand low oxygen concentration. It has been proved that the substance πQ1983 significantly surpass a substance for comparison amthizole in both antihypoxic activity and influence on external respiration parameters.

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Evaluation of the activity of antihypoxants with an isothiourea structure in a model of hypercapnic hypoxia with a shutdown of the cerebral hemispheres

Reviews on Clinical Pharmacology and Drug Therapy ◽

10.17816/rcf19155-63 ◽

2021 ◽

Vol 19 (1) ◽

pp. 55-63

Author(s):

Vera V. Marysheva ◽

Vladimir V. Mikheev ◽

Petr D. Shabanov

Keyword(s):

Acute Hypoxia ◽

Life Time ◽

The Body ◽

Cerebral Hemispheres ◽

Antihypoxic Activity ◽

Hypoxic Episode ◽

Hypoxia With Hypercapnia ◽

Hypercapnic Hypoxia ◽

Outbred Mice ◽

The Brain

PURPOSE: To study the effect of amtizol, 2-aminobenzthiazole (2-ABT) and 2-amino-4-acetylthiazolo[5,4-b]indole (BM-606) on the resistance of male outbred mice to acute hypoxia with hypercapnia under conditions of isolated functioning of one from the hemispheres, as well as both hemispheres of the brain. METHODS: A model of acute hypoxia with hypercapnia (canned hypoxia) was used in mice of the same mass, the lifespan of all animals was determined. Temporary shutdown of the cortex of one of the hemispheres or both hemispheres was achieved by epidural application of filter paper moistened with 25% potassium chloride solution, creating a spreading depression according to Leao. Amtizol, 2-aminobenzthiazole (2-ABT) and 2-amino-4-acetylthiazolo[5,4-b]indole (BM-606) at equimolar doses of 25, 32.5, and 50 mg/kg, respectively were used as pharmacological analyzers, the compounds were injected intraperitoneally 30 min before the hypoxic episode. RESULTS: It was shown that, in contrast to amtizol, 2-ABT and VM-606 increase the life time of experimental animals when any hemisphere is turned off. The use of drugs when both hemispheres were turned off revealed that amtizol has approximately equal effect on the brain and the rest of the body, in 2-ABT antihypoxic activity is 1/3 associated with the brain, in VM-606 exclusively with the brain. CONCLUSION: The experimental model used in this work makes it possible to quite easily evaluate the effect of either one drug or compare several drugs, their role in the functioning of the cerebral hemispheres, on which part of the sample highly resistant or low resistant to hypoxia they have the greatest effect.

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Acute hypoxia influence on cardio-respiratory system and new possibilities of pharmacological prophylactics of hypoxia in experiment

Reviews on Clinical Pharmacology and Drug Therapy ◽

10.17816/rcf14137-45 ◽

2016 ◽

Vol 14 (1) ◽

pp. 37-45

Author(s):

Andrei V Evseev ◽

Vitaliy A Pravdivtsev ◽

Denis V Sosin ◽

Marina A Yevseyeva

Keyword(s):

Metal Complex ◽

Electrical Activity ◽

Respiratory System ◽

High Resistance ◽

Acute Hypoxia ◽

Cardiorespiratory System ◽

Resistance Level ◽

Hypoxia With Hypercapnia ◽

Hypercapnic Hypoxia ◽

Complex Substance

Cardiorespiratory system activities have been studied on rats in experiment after oral introduction of the new selenium-containing metal-complex substance πQ1983 in dose 100 mg/kg before and under action of acute hypercapnic hypoxia (AH + Hc). The substance was introduced 90 min. before (incubation period) placement of animals into hypoxic chambers with 1.0 L free volume. During each experiment as well as during AH+Hc an electrical activity of myocardium (ECG) and respiration curves called pneumobarogramm (PBG) were recorded simultaneously. It has been established that the substance πQ1983 made cardiodepressive effect and decreases parameters of lungs ventilation in animals. According to ECG and PBG dynamics, rats protected by the substance demonstrated a high resistance level to the aroused acute hypoxia with hypercapnia, that expressed by weakening of early reactions from cardiorespiratory system under hypercapnia action, and by twice longer life span of animals in hypoxic experiment.

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The experimental study of the antihypoxic properties of harmine hydrochloride

Biomeditsina ◽

10.33647/2074-5982-17-2-71-78 ◽

2021 ◽

Vol 17 (2) ◽

pp. 71-78

Author(s):

S. M. Adekenov ◽

V. N. Karkischenko ◽

M. S. Nesterov ◽

D. A. Abaimov ◽

A. K. Sariev

Keyword(s):

Experimental Study ◽

Life Expectancy ◽

Hypobaric Hypoxia ◽

Normobaric Hypoxia ◽

Antihypoxic Activity ◽

Reference Drug ◽

Small Doses ◽

Hypoxia With Hypercapnia ◽

Antihypoxic Effect ◽

Compensatory Effect

A derivative of the beta-carboline alkaloid harmine — the drug harmine hydrochloride was studied for the presence of antihypoxic properties in models of hypobaric hypoxia and normobaric hypoxia with hypercapnia. It was found that harmine hydrochloride does not have a signifi cant compensatory effect in the normobaric hypoxia test with hypercapnia. At the same time, harmine hydrochloride in small doses (2.5 and 5 mg/kg) has antihypoxic activity in the hypobaric hypoxia test, which is expressed in a statistically signifi cant increase in the life expectancy of animals treated with the drug, compared with the control, in conditions of hypoxia. According to the antihypoxic effect, harmine hydrochloride at doses of 2.5 and 5 mg/kg was found to be comparable with the reference drug (mexidol, 100 mg/kg).

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THE COMPARATIVE STUDYING OF ANTI-HYPOXEMIC ACTIVITY OF COMPLEX OF ZINC ACETATE WITH N-PROPARGYLIMIDAZOLE AND 3-HYDROXYPYRIDINE

Medical Journal of the Russian Federation ◽

10.18821/0869-2106-2017-23-3-148-151 ◽

2017 ◽

Vol 23 (3) ◽

pp. 148-151

Author(s):

S. A Shakhmardanova ◽

P. A Galenko-Yaroshevsky ◽

L. N Parshina ◽

B. A Trofimov ◽

V. V Tarasov ◽

...

Keyword(s):

Zinc Acetate ◽

Hypobaric Hypoxia ◽

Large Range ◽

Narrow Range ◽

Acute Hypoxia ◽

Comparative Investigation ◽

Complex Compounds ◽

Control Groups ◽

Acute Hypobaric Hypoxia ◽

Hypoxia With Hypercapnia

The pharmacotherapy of hypoxia is an important task of modern experimental and clinical pharmacology. The medications with anti-hypoxic effect implemented into clinical practice unfortunately do not meet requirements of physicians due to poor efficiency, narrow range of active dosages and undesirable side effects. The complexes of zinc with N-alkenylimidazole demonstrated anti-hypoxic activity at various models of acute hypoxia within large range of dosage. Therefore, further studying of zinc-contained compounds as possible correctors of hypoxia is of particular interest. The experiments with white nonlinear male mice were used for comparative investigation of ant-hypoxic effect of complex compounds of zinc acetate with N-propargylimidazole and 3-hydroxipyridine, including complexes immobilized on sulfated arabinogalaсtan and also well-known anti-hypoxants and/or anti-oxidants: etomerzol, mexidol, nooglutil and hypoxen. It is demonstrated that anti-hypoxic effect of complex of zinc acetate with N-propargylimidazolein conditions of acute hypobaric hypoxia, acute hypoxia with hypercapnia acute hematic hypoxia by width of active dosages (1-100 mg/kg, intraperitoneally) and degree of expression (19-317% in comparison with control groups of animals) excels the similar effect in well-known anti-hypoxants and/or anti-oxidants: etomerzol (25-100 mg/kg, intraperitoneally), mexidol (100 mk per kg, intraperitoneally), nooglutil (25-100 mg/kg, intraperitoneally) and hypoxen (50-150 mg/kg, intraperitoneally). The protective effect of complex of zinc acetate with 3-hydroxipyridine by width of active dosages (25-100 mg/kg, intraperitoneally) and degree of expression (27-167% in comparison with control groups of animals) in conditions of exogenous hypoxia (acute hypobaric hypoxia and acute hypoxia with hypercapnia) excels similar effect of etomerzol and mexidol ans is comparable with effect of nooglutil and hypoxen. The complexes immobilized on sulfated arabinogalactan were ineffective.

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