The experimental study of the antihypoxic properties of harmine hydrochloride

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).

Improving the efficiency of gas exchange during alimentary biocorrection of the nutritional status of students and teachers of an engineering university

The results of studies of alimentary correction of the efficiency of gas exchange in the lungs by the example of students and teachers of an engineering university with daily use of foods with known bio-correcting properties: 3.5 g of wheat germ oil (WGO), 50 g of wheat germ meal cake (WGMC), are presented 6.5 g of concentrated tissue fish oil (CTFO) and their combinations with the biomass of the consortium of lacto- and bifidobacteria (10 g). The efficiency of gas exchange processes was evaluated based on the analysis of the respiratory coefficient, the concentration of carbon dioxide (CO2) and oxygen (O2) in the exhaled gas mixture was determined using a TESTO-310 gas analyzer, an MDG-1201 capnograph, the values of which were recorded before and after daily use of the studied products during 30 days. The experimental group consisted of volunteers – teachers and university students aged 16 to 65 years, divided into 3 age groups: 16-24, 25-44 and 45-65 years old. It was established that the most effective antihypoxic drug is WGMC, in all age groups, the increase in average RR values amounted to 0.041 units, and 4.8% relative to the initial values. When using WGO, the change in RC was 0.032, an increase compared to baseline – 3.7%. In the 1st, 2nd and 3rd age groups, the average change in RC was: 0,031, 0,036 and 0,043 units, relative to the initial indicators, the increase was 3.5, 4.2 and 5.0%, respectively. It is proved that the combination of the studied biocorrector with the active forms of probiotic microorganisms provides a more active antihypoxic effect for all the studied products in all age groups. The effectiveness of the WGO was increased, the increase in RC was 0.049 units, for CTFO – 0.024 units. The growth of RC relative to the initial values was 5.7 and 2.9%, respectively. The synergism of the action of biocorrectors in combination with probiotics, by age groups amounted to – 0.035, 0.033 and 0.038 units, which is 4.1, 3.8 and 4.5% relative to the initial indicators.

Mitochondrial dysfunctions and antihypoxants

Mitochondrial dysfunctions (an impaired energy metabolism in the mitochondria) are essential in a pathogenesis of many diseases. Aim. The analysis of various mitochondrial dysfunction (MD) type study, as well as evaluation of drugs with an antihypoxic effect in their treatment. Methods. Collection, systematization and analysis of experimental and clinical data of current scientific research about the problem. Results. The mitochondrial dysfunctions can be caused by genetic disorders of the mitochondrial or nuclear genome (the primary MD or the mitochondrial diseases), as well as structural, functional and biochemical defects of mitochondria caused by other diseases (the secondary MD). MD are characterized by impaired tissue respiration, ATP synthesis deficiency and decreased energy metabolism. The clinical implications of MD are polysystemic and polymorphic. One of the biochemical sign of MD is the lactic acidosis. There are certain difficulties with the early diagnosis of primary MD. It is suggested to use complete exome sequencing among patients with a clinical suspicion on mitochondrial disease. The energotropic pharmacotherapy including drugs with an antihypoxic effect is used for MD treatment. It is more rational to use the drug combination that influences different stages of energy production. The combinations of L-carnitine, coenzyme Q10, cytochrome C and succinate-containing drugs are frequently used for MD. However, the usage of energotropic and antihypoxic drugs is not able to cure the patients and stop the progression of all disease displays. Conclusion. MD are a multidisciplinary problem, therefore, doctors of any speciality must be competent in the MD diagnosis and treatment. The use of energotropic agents in the MD treatment requires further research. Numerous issues remain open (daily drug doses choice, treatment duration, rational combinations). The phenotype variability and the uniqueness of diagnosed cases, clinical and genetic differences between patient groups with mitochondrial diseases fail to create homogeneous samplings for therapy effectiveness and safety analysis. The literature data are the results of different degrees of reliability. The international efforts are needed to unify studies of related mitochondrial disorders, which, in combination with a constant improvement of MD pathogenesis knowledge will allow to develop more effective treatment regimens.

INVESTIGATION OF THE ANTIHYPOXIC PROPERTIES OF NEW NICOTINIC ACID DERIVATIVES

Two of the five new nicotinic acid derivatives proved to have the antihypoxic properties in tests with mice exposed to acute normobaric hypoxic hypoxia with hypercapnia. Specifically, LKhT 4–19 (100 mg/kg) extended lifetime of the animals by 11 %; LKhT 6-19 doses of 50 and 100 mg/kg extended lifetime by 23 and 34 %, respectively. The antihypoxic effect of LKhT 6–19 (50 mg/kg) outperformed in 1.2 times mexidol (substance of comparison) at the similar dose and was highly competitive at the dose of 100 mg/kg. For reference, mexidol is a 3-hydroxypyridine derivative (ethylmethylhydroxypyridine succinate incorporating, similar to the substances in question, the pyrydine heterocycle). Besides, LKhT 6–19 (100 mg/kg) outperformed mexidol at the similar dose in 1.1 times.

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

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.

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).

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

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).