Vol 17, No 3 (2019)

Eryptosis (quasi-apoptosis) the human red blood cells. Its role in medicinal therapy
Vaschenko V.I., Vil’yaninov V.N.

In the course of circulation erythrocytes can test damages, which compromises their integrity and thus triggers suicidal erythrocyte death or eryptosis. This mechanism is characterised by cell shrinkage, cell membrane blebbing, and cell membrane phospholipid scrambling after phosphatidylserine exposure on the cell surface that is identified by macrophages, which engulf and degrade the eryptotic cells. The term eryptosis also includes typical mechanisms, which contribute to the triggering of this process, such as oxidative stress, Ca2+ entry with an increase in cytosolic Ca2+ activity and the activation of p38 kinase, which is a kinase expressed in human erythrocytes and activated after hyperosmotic shock. Enhanced eryptosis has been observed in several clinical conditions such as diabetes, renal insufficiency, haemolytic uremic syndrome, sepsis, mycoplasma infection, malaria, iron deficiency, sickle cell anaemia, beta-thalassemia, glucose-6-phosphate dehydrogenase (G6PD)-deficiency, hereditary spherocytosis, paroxysmal nocturnal haemoglobinuria, Wilson’s disease, myelodysplastic syndrome, and phosphate depletion. Therefore, eryptosis may be considered as a useful mechanism of removal of defective erythrocytes to prevent haemolysis. Moreover, the clearance of infected erythrocytes in diseases such as malaria may counteract parasitemia. Indeed it is known that sickle-cell trait, beta-thalassemia trait, G6PD-deficiency and iron deficiency confer some protection against a severe course of malaria. Importantly, strategies to control Plasmodium infection by inducing eryptosis are not expected to generate resistance of the pathogen, as the proteins involved in suicidal death of the host cell are not encoded by the pathogen and thus cannot be modified by mutations of its genes. However, excessive eryptosis could compromise microcirculation and lead to anemia. Besides, adhesion of eryptosis erythrocytes to a vascular wall also can lead to microcirculation infringement.Thus, modern representations about eryptosis expand our knowledge about the programmed death of blood cells and is more directed to create new therapeutic schemes of treatment of patients.

Reviews on Clinical Pharmacology and Drug Therapy. 2019;17(3):5-38
Original articles
Influence of l-type slow calcium channels blockers on cardiac, respiratory and motor activity at the intact and poisoned by physostigmine (eserine) of rats during the early ontogeny
Kuznetsov S.V., Kuznetsova N.N., Gaydukova P.A.

The effects of calcium-channel blockers (CCBs) (verapamil, nifedipine) on heart rate, respiration rate and motor activity were studied in 3-30-day-old rats. The role of calcium channels in development of disturbances of a heart and respiratory rhythms after introduction to newborn rats of acetylcholinesterase (AChE) inhibitor of physostigmine was revealed. Parameters of functional activity of heart, respiratory and somatomotor systems in case of blockade of calcium channels were studied also under conditions of the activation of cholinoceptive structures caused by an injection to infant rats of AChE inhibitor after premedication by CCBs. It is shown that use of calcium channels blockers leads to development of bradycardia, and verapamil causes more expressed disturbance of a heart rhythm in rats of younger age, while blockade of dihydropyridinic receptors by nifedipine has no ontogenetic specifics. Similar ontogenetic dynamics concerns also reaction of respiratory system. Verapamil have a detrimental effect on respiration, up to a stop, in 3-7-day-old and to a lesser extent in 16-30-day-old infant rats. Nifedipine slightly reduces a respiration rate at younger infant rats, but raises it at the mature rats. The nifedipine injection more in comparison with verapamil changes the level and a pattern of motor activity. Preliminary blockade of calcium channels does not render significant change of reaction at the subsequent introduction of physostigmin.

Reviews on Clinical Pharmacology and Drug Therapy. 2019;17(3):39-49
Reciprocity between muscarinic and nicotinic cholinoreactive structures of liver tissue in conditions, in substrates and in products of free radical oxidation of liver lipids in 5-day period of cooling in rats
Tikhanov V.I.

The effects of administration of cholinotropic agents (neostigmine, hexamethonium, pilocarpine, atropine, nicotine) on liver tissue after 5-day period of cooling of rats were compared. The analysis of the conditions inducing lipid peroxidation (LPO), the analysis of the substrate components of the LPO in liver, and the evaluation of the LPO products content in 5-day period of cold loads were made. The data obtained indicate on the contradirectory effects when pilocarpine and nicotine were administered to animals, as well as after administration of atropine and hexamethonium to animals. There was the similar effects after administration of both pilocarpine and hexamethonium and both nicotine and atropine in conditions of activated LPO assessed by substrate components of LPO in the liver after 5-day cooling. On the basis of these results, a hypothesis of reciprocity between muscarinic and nicotinic cholinoreceptors located on the plasma membrane of hepatocytes in the LPO processes of the liver during the period of cold loads has been formulated.

Reviews on Clinical Pharmacology and Drug Therapy. 2019;17(3):51-58
Cellular mechanisms of hypoxia development in the tissues of experimental animals under varying characteristics of vibration exposure
Vorobieva V.V., Shabanov P.D.

The aim of the work was to study the primary bioenergetic mechanisms of hypoxia formation in the myocardial tissue of experimental animals depending on the differentiated physical characteristics of vibration (frequency and duration) and their combination. The study of the functional states of native mitochondria in the composition of the tissue homogenate was carried out using the polarographic method and a galvanic-type closed-oxygen sensor in a 1-ml thermostatic cuvette in a salt incubation medium. The metabolic states of the mitochondria of the myocardium of experimental animals were modeled in vitro during the oxidation of endogenous substrates (before and after the administration of inhibitors of different links of the respiratory chain), with varying exogenous energy substrates (before and after the introduction of 2,4-DNP into the cell). In order to ensure synchronism of measurements in a short time, an incomplete cycle of metabolic states “endogenous respiration → rest → activity” was used. The results of multiple comparisons of variations in kinetic parameters revealed a reliable but multidirectional effect of the frequency of vibration on the rate of oxidation of substrates of the mitochondria of the heart of rabbits in different metabolic states. A change in the duration of exposure to vibration showed an increase in the oxidation rate of endogenous substrates and succinic acid at rest to 21–56 sessions by 17% and 24. 4%, respectively, while the oxidation rate of glutamate decreased to 56 sessions by 24. 5%. Comparison of the general variability of kinetic parameters with a combination of frequency and duration of vibration at different levels of variation showed that it was the interaction of factors that made the most important and significant contribution to the intergroup variability of oxidation rates of endogenous and exogenous substrates, identifying signs of the formation of bioenergetic hypoxia and allowing analysis of the primary physical transformation phenomena in the biological effect.

Reviews on Clinical Pharmacology and Drug Therapy. 2019;17(3):59-70
Promising antihypoxant in a range of complex zinc-containing derivatives of nicotinic acid
Gneushev I.M., Pozhilova E.V., Katunina N.P.

The aim of the work was to study the antihypoxic properties of a number of complex zinc-containing compounds of nicotinic acid under the code πQ. The experiments were performed on male mice of the SHR line. Antihypoxic properties of compounds were studied on 4 models of acute hypoxia (hypoxia with hypercapnia, hypobaric, hemic, and histotoxic). It was found that the compound πQ-1043 in the dose spectrum of 10-100 mg/kg effectively increases the life expectancy of animals in all models of acute hypoxia. The compound πQ-1043 at a dose of 25 mg/kg reduces the oxygen consumption and rectal temperature of animals, which can be a key factor in its anti-hypoxic action. The compound does not change glycolytic carbohydrate metabolism in animals under normal conditions, but corrects these changes in acute hypoxia. Substance πQ-1043 maintains a high content in the blood of erythrocytes and hemoglobin under hypoxic conditions. The lethal dose 50 of the compound πQ-1043 applies to moderately toxic chemicals. It is assumed that the complex zinc-containing derivative of nicotinic acid πQ-1043 is a promising compound for the development of an effective drug for the correction of hypoxic states of different genesis.

Reviews on Clinical Pharmacology and Drug Therapy. 2019;17(3):71-78
Lipid-lowering and anti-atherosclerotic activity of the natural original enzyme preparation in the experiment
Okunevich I.V., Klyueva N.N., Parfenova N.S., Belova E.V.

The experimental large-scale investigation in vitro and in vivo is devoted to the results of a long-term study of the biological, lipid-lowering and anti-atherosclerotic activity of the original natural microbial enzyme preparation of cholesterol oxidase (CHO). In chronic experiments (rats, rabbits, dogs), low toxicity, good tolerability, and anti-atherosclerotic activity of the CHO preparation were established. To assess the effect of CHO in conditions of moderate nutritional dyslipoproteinemia, experiments were carried out in 3 species of animals (rats, guinea pigs, rabbits). It was shown the pronounced lipid-lowering effect of CHO in modeling dyslipoproteinemia.

Reviews on Clinical Pharmacology and Drug Therapy. 2019;17(3):79-84
Clinical pharmacology
To the mechanisms for the prevention of postoperative thromboembolic complications using regional methods of anesthesia
Zabrodin O.N., Strashnov V.I.

The article presents data on the mechanisms of development of vascular thrombosis, in particular, thromboembolic complications: 1. endothelial inyury or endothelial dysfunction; 2. slowing the flow of blood and its stagnation; 3. violation of the coagulation and anticoagulation blood systems. In accordance with paragraphs 1–3 the effects of regional anesthesia – epidural anesthesia and spinal anesthesia on the prevention of postoperative thromboembolic complications are considered.

Reviews on Clinical Pharmacology and Drug Therapy. 2019;17(3):85-90

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