RU2665963C1 - Agent, its application and method for improving resistance of mammal organism to supercooling - Google Patents

Abstract

FIELD: pharmaceuticals.SUBSTANCE: group of inventions relates to the development of a therapeutic agent for improving resistance of mammals to supercooling. Agent comprises a pharmaceutical composition of preparations containing 0.78–1.18 wt. % of propranolol, 0.015–0.024 wt. % of reserpine, 0.078–0.12 wt. % of ivabradine, 0.098–0.18 wt. % of diphenhydramine, 0.025–0.035 wt. % of pericyazine, 0.25–0.35 wt. % of serotonin hydrochloride, 0.07–0.12 wt. % of propycil, 0.07–0.16 wt. % of magnesium sulfate, 98–98.61 wt. % of pharmaceutically acceptable solvent. Also provided is a method for improving resistance of a mammalian organism to supercooling, comprising administering a therapeutically effective amount of the agent.EFFECT: technical result is an improved resistance of cells of vital organs and tissues to supercooling.3 cl, 2 dwg, 2 ex

Description

Technical field

The invention relates to the field of medicine, in particular to emergency medicine, anesthesiology / resuscitation, to aviation and space medicine, diving medicine, as well as pharmaceutical technology.

State of the art

The task of preserving the life of mammals, including humans, who find themselves in conditions of low temperatures for survival, is very urgent at the present time. A search is underway for drugs to increase the resistance of the mammalian organism to hypothermia, which should save the lives of victims and reduce the harmful effects of hypothermia.

Known patent of the Russian Federation No. 1520688 [1], in which the purpose of the invention is to lengthen the stay of mammals at low temperatures. To increase the resistance of mammals to general cooling, animals are injected with a 20-50% solution of polyethylene oxide (PEO) mol.m. 15-30 minutes before cooling. 400 or 1500 at a dose of 0.001 to 0.0004 g per 1 g of live weight. The introduction of these solutions does not cause negative effects observed with the introduction of alcohol (impaired coordination of movements, body thermoregulation). The disadvantage of this method is the detected fluctuations in the toxicity of PEO-400 and PEO-1500 [2].

Known RF patent No.2010569 [3] according to which an increase in resistance to hypothermia, in particular, in water is achieved by the introduction of a combination of Relanium 5 mg / kg with sodium hydroxybutyrate 500 mg / kg 30 minutes before cooling. For practical use, a combined oral administration of 10 mg of Relanium with 2 g of sodium oxybutyrate immediately before cooling is recommended. An increase in the body's resistance to hypothermia in water under the action of the agent occurs due to an increase in the resistance of nerve centers to the action of cold; increase in heart resistance to cooling; positive effects on thermoregulatory mechanisms. The disadvantage of this and the following invention relates to high mortality in the process of self-heating.

In the patent of the Russian Federation No. 2268049 [4] there is a similar tool that was used to restore body temperature in the posthypothermic period. The patent contains proposals for the practical use of a pharmacological agent that accelerates the restoration of body temperature and reduces mortality in the posthypothermic period, after cooling the body in cold water. This is achieved by joint ingestion of Relanium with sodium hydroxybutyrate before cooling in water. Doses of both components of the formulation may vary in the therapeutic range.

Known invention (RF patent No. 2270008) [5], which relates to the creation of drugs to increase the resistance of humans and animals to hypothermia. The product contains nicotinic and glutamic acids, riboflavin, ascorbic acid, ubiquinone, succinic acid, polyethylene oxide and water in a certain ratio. 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 aforementioned agent is administered. The research results show that the average cooling time compared to the control of polyethylene oxide mol.m. 400 is better by 1.34 times, the proposed product is 2.25 times, while the average residence time in water is 4.0 ± 0.5 ° C for a person 32.1 minutes. The disadvantage of the composition of the product can be attributed to its effect only on ensuring the maintenance of heat due to the utilization of ATP and stored energy, to ensure the functioning of vital organs and there is no data on the restoration of the body in the posthypothermic period. In addition, judging by its composition, the lack of the mixture can be considered an increase in oxygen consumption, which it should cause, which, ultimately, will lead to even faster energy depletion and overcooling the body [6].

The tasks to which the invention is directed are to create a new tool and its use to increase the resistance of the mammalian body to hypothermia, where the new tool, method and application are free from the above disadvantages, which today is an urgent problem for the treatment of such diseases.

The technical result consists in the fact that the claimed tool allows you to increase the resistance of cells of vital organs and tissues to hypothermia.

SUMMARY OF THE INVENTION A main aspect of the invention is a means for increasing the resistance (resistance) of a mammalian organism to hypothermia. The product contains a pharmaceutical composition of drugs included in the group consisting of an adrenergic blocker (1), a sympatholytic, which depletes and promotes the destruction of the catecholamine depot (2), an antihistamine drug with or without antiemetic effect (3), an If-channel inhibitor of the sinus node (4) , a dose-dependent serotonergic agent (5), an antipsychotic with a hypothermic effect (6), a dose-dependent inhibitory synthesis or the action of the main thyroid hormones (7), a drug containing ions magnesium or other NMDA receptor inhibitors that prevent excitotoxicity (8), wherein the composition further comprises a pharmaceutically acceptable solvent. In this case, the pharmaceutical composition contains the following ratio of components, wt. %:

propranolol beta blocker 0.78-1.18 wt. % sympatholytic reserpine 0.015-0.024 wt. % antianginal drug ivabradine 0.078-0.12 wt. % antihistamine diphenhydramine 0.098-0.18 wt. % hypothermic antipsychotic drug action of pericyazine 0.025-0.035 wt. % serotonergic serotonin hydrochloride 0.25-0.35 wt. % propithyl antithyroid 0.07-0.12 wt. % magnesium sulfate 0.07-0.16 wt. % pharmaceutically acceptable solvent 98-98.61 wt. %

The next aspect of the invention is that the adrenergic blocker is propranolol or its effective analogue, diphenhydramine is used as an antihistamine with an antiemetic effect, ivabradine is used as an inhibitor of the If-channels of the sinus node, serotonin hydrochloride or its effective analogue is selected as a dose-dependent serotonergic agent , as a neuroleptic agent with a hypothermic effect, periciazine is chosen, as a means, I depress dose-dependently its synthesis or the effect of thyroid hormone is selected basic propitsil in selected magnesium sulfate or its analog effective as a means of preventing the excitotoxicity due to hyperactivation of NMDA-receptors.

Another aspect of the invention is a method of increasing the resistance of a mammalian organism to hypothermia, wherein a therapeutically effective amount of the agent is administered once to a mammal in the period before cooling or directly during cooling of the body.

Another aspect of the invention is the use of an agent for increasing the resistance of a mammalian organism to hypothermia.

List of figures

FIG. 1. Verification of the results of using the product on animals immersed in standard model anesthesia that simulates loss of consciousness and is used as a control for the effect of low ambient temperature (0 ° C). The cooling period is indicated by a horizontal line. The effect of the pharmaceutical composition on: A) body core temperature, B) heart rate (HR), C) hemoglobin oxygenation.

FIG. 2. Verification of the results of the use of an agent made on the basis of a pharmaceutical composition to increase the resistance of a mammalian organism to the effect of a reduced ambient temperature (0 ° C). The cooling period is indicated by a horizontal line. The effect of the pharmaceutical composition on: A) body core temperature, B) heart rate (HR), C) hemoglobin oxygenation.

Description of the invention

An approach has been developed aimed at preventing excessively fast hypothermia of a biological object at low temperatures for survival, while maintaining basic vital signs at the level of stable life support.

In the process of developing a tool to increase the resistance of a mammalian organism, including for the prevention or treatment of hypothermia, a composition of the drug was discovered that led to real results: to restore the heart rate (HR), to maintain and subsequently restore the temperature of the mammalian body core, which confirms the effectiveness of a means to increase the resistance of a mammalian organism to hypothermia. This option includes, but is not limited to, the scope of the invention. It includes an agent containing a pharmacological composition of eight drugs used in a therapeutically effective amount.

Moreover, the pharmaceutical composition consisting of eight preparations contains an adrenergic blocker, a sympatholytic, an antihistamine, an inhibitor of If-channels of the sinus node, a serotonergic agent, an antipsychotic agent with a hypothermic effect, an antithyroid drug, a preparation containing magnesium ions.

It is known that the adrenolytic agent propranolol is included in the group of adrenergic blockers, which also includes: cartolol, nadolol, penbutolol, pindolol, propranolol, sotalol, timolol, carvedilol, labetalol, metoprolol, atenolol, esmolol, acebutaloline, and others. selectively inhibiting If-channels of the sinus node, use ivabradine. Diphenhydramine is a member of the group of sedatives that block histamine H1 receptors and cholinergic receptors of autonomic nerve nodes. Propicyl is used as an antithyroid drug that suppresses the intrathyroid peroxidase system. Periciazine is used as a drug with a pronounced antiemetic, anticholinergic, hypothermic and sedative effect, moderately expressed adrenolytic and extrapyramidal effect. The main pharmacological property of reserpine is its sympatholytic effect, due to the effect of depletion of catecholamine depots with their subsequent destruction due to the inactivating effect of monoamine oxidase (MAO). Magnesium sulfate in the composition is used as a non-specific inhibitor of NMDA receptors to prevent excitotoxicity provoked by hyperactivation of these receptors during hypothermia. In this case, the pharmaceutical composition contains the following ratio of components, wt. %:

propranolol beta blocker 0.78-1.18 wt. % sympatholytic reserpine 0.015-0.024 wt. % antianginal drug ivabradine 0.078-0.12 wt. % antihistamine diphenhydramine 0.098-0.18 wt. % hypothermic antipsychotic drug action of pericyazine 0.025-0.035 wt. % serotonergic serotonin hydrochloride 0.25-0.35 wt. % propithyl antithyroid 0.07-0.12 wt. % magnesium sulfate 0.07-0.16 wt. % pharmaceutically acceptable solvent 98-98.61 wt. %

Doses of drugs included in the tool do not go beyond the therapeutic ranges (Mashkovsky M.D., 1985, v. 1). It is advisable to administer the composition to the mammal directly as a prophylactic or during emergency treatment of the mammal from hypothermia. In the proposed tool, instead of the existing and listed drugs, its analogues can be used, both in the pharmacological group and in the effect exerted.

The tool was tested in experiments on 20 white clinically healthy rats of the Wistar strain weighing 200-250 grams, distributed in 2 groups of 10 animals each. The following examples include, but are not limited to, the use of analogues of the active substances that make up the tool.

Examples.

Example 1. Use as control animals with model anesthesia followed by cooling on ice.

In the experiment, Wistar rats weighing 200-250 g were used, native rats, vivarium content under standard conditions. Within 0.5 h, control physiological parameters of temperature (rectally), heart rate, respiratory rate individually in each animal were recorded using the MouseOxPlus device. Check the effect of model anesthesia as a control for hypothermia.

Before cooling, intramuscular injections of zoletil (13 mg / kg) and rometar (7 mg / kg) are performed. They monitor changes in heart rate (HR), mammalian body temperature, record data on hemoglobin oxygenation after drug administration. After that, the rat is laid on ice.

In FIG. 1 shows the results of cooling an animal with model anesthesia.

It was found that when cooling animals in model anesthesia, the temperature drop was rapid (Fig. 1A) and without stopping cooling, i.e. removing from the ice, animals died. The decrease in heart rate was also smooth and occurred simultaneously with a decrease in temperature (Fig. 1B). Saturation indicators were uneven (Fig. 1B).

Example 2. Check the effect of the pharmaceutical composition to increase the resistance of the mammalian organism to hypothermia. A solution of the pharmaceutical composition in a volume of 5 ml is prepared, containing a mixture of eight drugs with a ratio of components: Propranolol - 0.983 wt. %, Ivabradine - 0.098 wt. % Diphenhydramine - 0.118 wt. %, Reserpine - 0.0197 wt. %, Serotonin hydrochloride - 0.295 wt. %, Periciazine - 0.029 wt. %, Propitsil - 0,098 wt. %, Magnesium sulfate - 0.098 wt. % As a pharmaceutically acceptable solvent use physical. solution, Ringer's solution and other balanced saline solutions.

Before cooling, a single intraperitoneal injection of 1 ml of the drug is carried out. After that, the rat is laid on ice. They monitor changes in heart rate (HR), mammalian body temperature, record data on hemoglobin oxygenation after drug administration.

In FIG. 2 shows the results of checking the effects of a pharmacological agent containing a composition of eight drugs. In FIG. 2B is a diagram of heart rate changes after drug administration. Immediately after administration, a rapid decrease in heart rate of approximately 3-4 times (from 400-420 to 100-120 beats / min) is observed, after which the heart rate is maintained at a constant level of about 100-120 beats / min throughout the recording time, as during and after cooling: about 7 hours. In FIG. 2A is a diagram of a change in body core temperature after drug administration when a rat is placed on ice. The measurements were carried out simultaneously with the registration of heart rate shown in FIG. 2B. A gradual decrease in temperature to 18 ° C-19 ° C over 3 hours occurs against a background of significantly reduced heart rate. After cooling to approximately 18 ° C, the animal was removed from the ice and left at room temperature in the mode of self-heating. The cooling did not affect the heart rate and it remained at a significantly reduced stationary level for 2 hours, as did the temperature after the ice was removed, while the temperature in the animal was restored very slowly. In FIG. 2B shows hemoglobin oxygenation data after drug administration. It can be seen from the figure that, compared with model anesthesia, saturation was stable. The averaged data from experiments on ≥5 animals are presented.

The results of the test show that in the treatment of mammals from hypothermia, when hypothermia was introduced, and when hypothermia was exited, results were obtained indicating that, compared to control rats, a once-administered mixture of eight drugs promotes survival received this mixture of animals.

Industrial applicability

The tool described in the invention allows mammals to endure many hours of cooling by moving the body to a stationary state with reduced heart rate and temperature. The developed tool is characterized by the fact that after removal of the cooling source, the body self-heats up with a gradual return to the normothermic state. Common to the invention is the use of the adaptive capabilities of the body to critical influences due to the endogenous mechanisms of thermoregulation. It was established in experiments that the developed tool statistically significantly increases the resistance of the mammalian organism to hypothermia when introduced into a state of hypothermia, and upon exiting a state of hypothermia.

Information sources

1. Mazalov V.K. et al. METHOD FOR IMPROVING LABOR RESPONSIBILITY TO GENERAL COOLING. RF patent No. 1520688 (08.27.1995).

2. Guchok G.M. A comparative study of the toxicity of ethylene glycol, PEO-400 and PEO-1500 for rats and mice in early postnatal ontogenesis. // Cryobiology and cryomedicine. 1980. 7.p. 34-39.

3. Bazhanov N.O. et al. MEANS TO INCREASE ORGANISM RESISTANCE TO HYPOTHERMIA. RF patent No.2010569 (04/15/1994).

4. Bazhanov N.O. MEANS FOR INCREASING THE RESISTANCE OF THE ORGANISM IN THE POST-HYPOTHERMAL PERIOD. RF patent No. 2268049 (01/20/2006).

5. Doronin Yu. K. et al. MEANS AND METHOD FOR INCREASING STABILITY OF HUMAN AND ANIMALS TO HYPOTHERMIA BY ACTIVATION OF Vital IMPORTANT BIOCHEMICAL PROCESSES. RF patent No. 2270008 (02.20.2006).

6. Kulinsky V.I., Olkhovsky I.A. Two adaptive strategies under adverse conditions are resistant and tolerant. The role of hormones and receptors. // Successes of modern biology. 1992.V. 112 (5-6). S. 697-715.

Claims (4)

1. A tool to increase the resistance of the body of mammals to hypothermia, characterized in that it contains a pharmaceutical composition of preparations containing the following ratio of components, wt. %: propranolol beta blocker 0.78-1.18 wt. % sympatholytic reserpine 0.015-0.024 wt. % antianginal drug ivabradine 0.078-0.12 wt. % antihistamine diphenhydramine 0.098-0.18 wt. % hypothermic antipsychotic drug action of pericyazine 0.025-0.035 wt. % serotonergic serotonin hydrochloride 0.25-0.35 wt. % propithyl antithyroid 0.07-0.12 wt. % magnesium sulfate 0.07-0.16 wt. % pharmaceutically acceptable solvent 98-98.61 wt. % 2. A method of increasing the resistance of a mammalian organism to hypothermia characterized in that a therapeutically effective amount of an agent according to claim 1 is administered to the mammal once. 3. The use of the agent of claim 1 as a preparation for increasing the resistance of a mammalian organism to hypothermia.

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