RU2270008C1 - Agent and method for enhancing human and animal resistance to hypothermia by activation of vital essential biochemical processes - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to the development of medicines used for enhancing resistance of humans and animals to hypothermia. Agent for enhancing resistance of humans and animals to hypothermia comprises nicotinic acid, glutamic acid, riboflavin, ascorbic acid, uniquinone, succinic acid, polyethylene oxide and water taken in the definite ratio. Also, invention proposes a method for enhancing resistance of humans and animals to hypothermia involving administration of the abovementioned agent 30 min before works associated with hypothermia and after its termination for activation of vital essential biochemical processes. Invention provides enhancing resistance to overcooling under extreme conditions and using in surgery practice in cooling organs (in operations in heart and brain).

EFFECT: enhanced effectiveness and valuable medicinal properties of agent.

2 cl, 2 tbl, 1 dwg, 2 ex

Description

The invention relates to the field of creating a means to increase the resistance of humans and animals to hypothermia by activating vital biochemical processes.

Known means of increasing the body's resistance to general cooling.

The closest analogue to the problem being solved is a way to increase the resistance of mammals to general cooling and increase the body's viability under hypothermia by 116.8% by introducing a 30% PEO - 400 solution at a dose of 0.004 g per 1 g of animal weight (SU 1520688). An example of this method is the work of V.I. Lugovoi, V.K. Mazalov, V.V. Chizhevsky, and T.P. Govorukha. On the mechanisms of blood-protective action of polyethylene oxides during deep cooling of a warm-blooded organism. In the journal Problems of Cryobiology, 1996, No. 1.

However, this method does not provide activation or maintenance of the physiological norm of such vital processes as the Krebs cycle, electron transfer in the respiratory chain of a cell, etc.

First of all, there are two aspects of hypothermia: physiological and biochemical.

The physiological understanding of hypothermia is an overload of thermoregulation mechanisms. First, under conditions of hypothermia, thermoregulation processes are turned on at full capacity, but their intensity decreases with decreasing temperature. At a human body temperature of 28-26 ° C, death from cardiac fibrillation may occur. Other consequences of acute hypothermia are respiratory and metabolic acidosis.

Biochemical processes - synthesis reactions, muscle contraction, nerve impulse conduction, active transport - receive energy by chemical conjugation with oxidative reactions. An increase or decrease in free energy is determined by endergonic and exergonic reactions. Impaired conjugation leads to disruption of homeostasis. One of the factors that have a significant impact on these processes is hypothermia.

Low temperatures are known to slow down the rate of chemical and biochemical reactions and, in fact, inhibit the respiratory chain and oxidative phosphorylation. Oxidative phosphorylation is provided in the mitochondrial system, which combines oxidative processes with the generation of a high-energy mediate - ATP.

It is known that all the useful energy released during the oxidation of fatty and amino acids, and almost all the energy of carbohydrate oxidation is used in mitochondria in the form of reducing equivalents. Mitochondria contain several catalysts that form the respiratory chain, ensuring the capture and transfer of reducing equivalents, directing them to react with oxygen, leading to the formation of water. The molecule that captures part of the free energy and is released in the catalytic processes is ADP, which results in the formation of ATP, which supplies free energy further for the implementation of energy-dependent processes. Mitochondria also contain enzyme systems that provide the formation of most reducing equivalents; these are enzymes without oxidation and the citric acid cycle, which is a common metabolic pathway for the oxidation of all major nutrients.

At the initial stage of hypothermia, there is an increase in the level of lipid peroxidation (LP), the activity of the antioxidant systems of the cell changes, which leads to the development of pathological processes.

In this regard, the problem of the restoration of metabolic processes during hypothermia can be solved in the case of cryoprotectants with active components of the respiratory chain, activators of fundamental biochemical processes, such as the citric acid cycle, etc.

Thus, the task was to develop a composite composition with the properties of a cryoprotectant and activator of vital biochemical processes, i.e. increasing the resistance of humans and animals to hypothermia in extreme conditions, and the use in surgical practice for cooling organs, such as, for example, in operations on the heart and brain.

The task is achieved by a group of inventions, united by a single inventive concept.

A tool is proposed for increasing the resistance of humans and animals to hypothermia, containing nicotinic and glutamic acids, riboflavin, ascorbic acid, ubiquinone, succinic acid, polyethylene oxide and water in the following ratio of ingredients, wt.%:

polyethylene oxide 0.5-0.7 a nicotinic acid 0.001-0.0012 glutamic acid 0.005-0.007 riboflavin 0.005-0.007 vitamin C 0.015-0.017 ubiquinone 0,0004-0,0006 succinic acid 0.003-0.005 water rest

A method is also proposed to increase the resistance of humans and animals to hypothermia, which consists in the fact that to activate vital biochemical processes 30 minutes before performing work related to hypothermia, and after their completion, the above agent is administered.

The result of the claimed method is achieved through the use in appropriate proportions of the proposed drug in an aqueous solution, used at the rate of 0.5-0.7 g of polyethylene oxide per 1 kg of mass.

Such a composition with controlled hypothermia provides optimal conditions for the phosphorylating respiratory chain and lipid peroxidation processes.

Pharmacokinetics of the process.

In order for a pair of electrons to produce enough energy to support the synthesis of ATP molecules, the electron must move down with a potential difference of 300 mV. There are three phosphorylating NADH, b-Q, and c sites along the electron pathway. The drawing shows the phosphorylation of the respiratory chain when activated by Cryoplan.

The level of NAD (I) is occupied by a specific flavoprotein that transfers electrons to phosphorylation site 1. For each electron pair entering this level, only three ATP molecules are synthesized. NAD itself serves as an electronic acceptor in the reaction chain.

Level I is provided by nicotinic acid and riboflavin. Niacin is involved in the formation of NAD and NADH.

Riboflavin in tissues by ATP-dependent phosphorylation is converted to FMN and then to FAD, forming riboflavin-dependent dehydrogenases, most of which either participate in the respiratory chain or supply electrons for this chain. Riboflavin is not synthesized in animal tissues.

Level (II) bQ, so named because it contains cytochrome b and coenzyme Q, or ubiquinone, is associated with several FAD-dependent flavoproteins, which serve as entry gates for electrons from metabolic substrates, such as succinic acid, an intermediate Krebs cycle and fatty derivatives of acyl coenzyme A - activated forms of fatty acids. When a pair of electrons arrives at this level, it falls through two consecutive blocks. In this case, two ATP molecules are formed.

Level 2 work is provided by ubiquinone and succinic acid.

Level 3 is provided by the interaction of ascorbic acid with mitochondria, so that one ATP molecule is synthesized for each pair of electrons transferred from ascorbic acid to oxygen. The activity of this level is provided by ascorbic acid.

Glutamic acid is used to maintain heat through the utilization of ATP and stored energy, to ensure the functioning of vital organs.

Violations of general hemodynamics and microcirculation caused by hypoxia of various origins, exogenous and endogenous intoxications, and inflammation are assessed by the most modern technique for the activity of enzymatic antioxidants of superoxide dismutase (SOD).

SOD is an enzyme that catalyzes the dismutation of superoxide radicals O ₂ ^- and H with the formation of hydrogen peroxide and molecular oxygen. It is the main enzyme of intracellular antiradical protection.

SOD induction causes an increase in the concentration of O ₂ ^- and an increase in peroxidation processes, which occurs in various pathological conditions associated with impaired general hemodynamics.

SOD was determined by reagents and according to the method of JBS.

The invention is illustrated by experimental data.

Example 1

Experimental studies were carried out on 60 sexually mature male rats weighing 180-200 g. The animals were divided into three groups of 20 animals each.

Each group of animals was subjected to cooling in water of 0.5 ° C until a rectal temperature of 19 ° C was reached, after which the average time necessary for this was determined.

In animals of each group, the level of SOD and percent survival were determined.

The first group - the control - was exposed to hypothermia without the use of any drugs.

The second group was exposed to hypothermia with preliminary administration 20% before cooling per os of 15% polyethylene oxide: 0.5 g of substance per 1 kg of animal weight.

The third group underwent hypothermia with preliminary administration 20 minutes before cooling of the composite preparation “Cryoplan” per os based on: polyethylene oxide 0.5 g, nicotinic acid 0.001, glutamic acid 0.005 g, riboflavin 0.005, ascorbic acid 0.010 g, ubiquinone - 0.0004 g, succinic acid - 0.004 g per 1 kg of animal weight. After removing the animals from the water, they immediately received Crioplan per os, calculated as: polyethylene oxide 0.5 g, nicotinic acid 0.01 g, glutamic acid 0.007 g riboflavin 0.005, ascorbic acid 0.017 g ubiquinone 0 , 0004 g, succinic acid - 0.004 g, water up to 100 g

The drug is used in the form of an aqueous solution at the rate of 0.5 g of polyethylene oxide per 1 kg of animal weight.

The research data are shown in table 1.

Table 1. Indicators of average cooling time, SOD and percent survival of animals. Groups the control PEO 400 Cryoplan Rectal temperature 19.3 ± 0.7 19.2 ± 0.5 19.2 ± 0.4 The average cooling time to reduce rectal T to 19 ° C (min.) 6.3 8.5 14.2 SOD 48 ± 0.7 27 ± 0.7 11 ± 0.7 Animal survival% 0 12 86

The research results show that the average cooling time in comparison with the control in PEO 400 is 1.34 times better, in Cryoplan 2.25 times. From table 1 it can be seen that the SOD and survival rates in animals of the Cryoplan group significantly exceed the control and PEO 400.

Example 2

Three male groups with an average age of 19-21, 4 people each, consisting of submarine athletes involved in winter swimming, underwent voluntary tests. The weight of each participant was selected within 75-78 kg in order to correctly measure body temperature. Subjects after taking the drug were offered to stay in water until the first signs of hypothermia (chills, tremors, etc.) appeared. Each group, 45 minutes before swimming and immediately after swimming in the hole, was offered per os drug X to improve cold tolerance.

The first group took 200 ml of a 3% glucose solution.

The second group took 200 ml of 15% polyethylene oxide: 0.5 g of substance per 1 kg of body weight.

The third group took the composite preparation "Cryoplan" 200 ml from the calculation: polyethylene oxide 0.5 g, nicotinic acid - 0.001 g, glutamic acid - 0.005 g, riboflavin - 0.007, ascorbic acid - 0.015 g, ubiquinone - 0.0006 g, succinic acid - 0.004 g, water - the rest.

The drug is used at the rate of 0.5 g of polyethylene oxide per 1 kg of body weight with a dilution of up to 200 ml of an aqueous solution.

The research results are shown in table 2.

Table 2. Indicators of average cooling time and SOD by groups Groups one 2 3 Average residence time in water (min) 12.5 17,2 32.1 Rectal temperature (° C) 34.8 35.1 35.8 SOD 16 ± 0.5 14 ± 0.5 11 ± 0.5 Water temperature -4.0 ± 0.5 -4.0 ± 0.5 -4.0 ± 0.5 Air temperature -18.0 ± 0.5 -18.0 ± 0.5 -18.0 ± 0.5

Claims (2)

1. A tool to increase the resistance of humans and animals to hypothermia, characterized in that it contains nicotinic and glutamic acids, riboflavin, ascorbic acid, ubiquinone, succinic acid, polyethylene oxide and water in the following ratio of ingredients, wt.%: Polyethylene oxide 0.5-0.7 A nicotinic acid 0.001-0.0012 Glutamic acid 0.005-0.007 Riboflavin 0.005-0.007 Vitamin C 0.015-0.017 Ubiquinone 0,0004-0,0006 succinic acid 0.003-0.005 Water Rest 2. A method of increasing the resistance of humans and animals to hypothermia, characterized in that to activate the vital biochemical processes 30 minutes before the work associated with hypothermia, and after its completion, the agent according to claim 1 is administered.