RU2696100C1 - Use of xenon immobilized in carrier in agent for increasing body resistance to hypoxia - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to emergency medicine, and can be used for increasing body resistance to hypoxia. That is ensured by using an agent in the form of xenon gas immobilized in a carrier, wherein said agent additionally contains a mixture of preparations consisting of: beta-blocker of propranolol 0.09 wt. %, respatolitic reserpine 0.020 wt. %, antagonist H1 of histamine receptors of diphenhydramine 0.099 wt. %, antianginal preparation with anti-ischemic effect of ivabradine 0.099 wt. %, serotonergic agent serotonin hydrochloride 0.099 wt. %, neuroleptic agent with pericyazin hypothermic effect 0.079 wt. %, an antithyroid agent for propicyl 0.099 wt. %, a preparation containing magnesium-magnesium sulphate ions 0.593 wt. %, the rest being a pharmaceutically acceptable solvent. Carrier is 20 % fat emulsion of lipofundin, wherein 1 ml of lipofundin contains 0.54 to 2.2 ml of xenon.

EFFECT: application of the agent allows to prolong the stable life-support of the organism in a medium with low oxygen level till the moment of providing the corresponding state of professional medical care while maintaining the possibility of reversible recovery of all functions of a mammal with increase of oxygen level in the environment.

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Description

Technical field

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

State of the art

An important and urgent task is to preserve the lives of patients (mammals) in case of injuries, transportation, accidents, disasters in conditions of severe hypoxia associated with low oxygen levels in the environment. New solutions are needed for the development of hypoxia prophylaxis and the controlled maintenance of the body's viability in a given period of time with the subsequent complete restoration of life-supporting functions.

Known technical solutions that are intended for the treatment of cardiovascular diseases, blood circulation, brain diseases and other dysfunctions in which drugs act on the body as antihypoxants.

Existing antihypoxants are chemically synthesized compounds, amino acids and polypeptides, drugs that are isolated from medicinal plants, gas mixtures that increase the body's resistance to hypoxia.

Known drugs of various chemical structures and mechanisms of action, which have a protective effect against harmful factors of hypoxia.

A known patent of the Russian Federation No. RU 2485953 [1], which describes a drug with antihypoxic and adaptogenic effects with pharmacological properties similar to EMHPS (Mexidol, Mexidant, Mexiphin, Medomexi, Mexico, Mexiprim) and meldonium. The drug is convenient for preparing finished dosage forms and comprehensively affects the body. The preparation was obtained by synthesis of a complex of 3- (2,2,2-trimethylhydrazinium) propionate-2-ethyl-6-methyl-3-hydroxypyridine disuccinate.

The USSR author's certificate No. SU 1832499 [2] is known, in which an agent with antihypoxic and antihyperthermic properties is achieved by using the compound 1-2-ethyl-6-methyl-3-hydroxypyridine succinate.

In the patent of the Russian Federation No. RU 2232576 [3] proposed funds with antihypoxic properties. As such they use:

- N- isopropylamide 2- (1-phenyl-ethyl) aminoethanesulfonic acid;

- N- isopropylamide 2- (1-methyl-2-phenyl-ethyl) aminoethanesulfonic acid, or N-isopropylamide 2- (benzyl) aminoethanesulfonic acid.

Known applications for inventions in China, which protects anti-hypoxic drugs isolated from medicinal plants. Application for invention No. CN 106265636 [4] discloses the use of the antihypoxic drug Linderolide N. The results show that Linderolide H can provide significantly increased survival and survival time for mice with suffocating hypoxia and acute decompression hypoxia and alleviate cardiac injury. The drug is isolated from the roots of binder a strychnifolia. Application for invention No. CN 106265646 [5] discloses the use of the antihypoxic drug Ternatusine A, which is isolated from the roots of Ranunculus ternatus Thunb. The application for invention No. CN 105412119 [6] describes the antihypoxic effect of Astataricusones D. The results show that Astataricusones D isolated from the roots and rhizomes of Aster tataricus L can significantly improve the survival and survival time of mice with asphyxia hypoxia and acute decompression hypoxia.

As follows from the texts of the descriptions of inventions, known antihypoxants have a fairly narrow spectrum of effects and do not carry a systemic effect on the body.

Treatment of hypoxic conditions is carried out, including using gas mixtures.

International application No. WO 2017027810 [7] describes methods for treating or preventing mitochondrial dysfunction disorders and oxidative stress disorders. The method comprises administering to the subject, by inhalation, a therapeutically effective amount of a therapeutic gas containing from 20 to 70% xenon. Therapeutic gas is administered to the subject continuously for three minutes to 24 hours.

US Pat. No. 9,326,996 [8] describes the use of xenon in the manufacture of a medicament for preventing and / or alleviating one or more neurological deficits caused by anesthesia in a neonatal subject. The product contains 10-20% xenon and additionally contains 0.67% -4% GABAergic agent. Where the GABAergic agent is selected from the group of isoflurane, sevoflurane, or desflurane, which are used in medicine as an inhaled anesthetic to induce and maintain general anesthesia.

In the application of Germany No. DE 19933704 [9] for the treatment of neurodegenerative diseases it was proposed to use a liquid composition containing xenon gas.

Known hypoxia treatments are mainly used in situations where hypoxic conditions are formed. It is important to develop a tool that would not only affect the treatment of hypoxia in individual mammalian organs, but would be systemic in nature and affect the whole organism. It should be noted that none of the means known from the prior art was used for preliminary prophylaxis and to increase the body's resistance in the formation of hypoxic conditions.

One of the problems to which the invention is directed is to use an agent containing a mixture of drugs and the active agent xenon immobilized in a carrier to prevent and increase the body's resistance to hypoxia in conditions of insufficient oxygen content in the environment.

The technical result is that the claimed agent containing xenon allows you to increase the body's resistance to hypoxia.

SUMMARY OF THE INVENTION

One aspect of the invention is the use of an agent comprising xenon immobilized in a carrier as an active agent, as well as a mixture consisting of beta-blockers, sympatholytics with adrenolytic action, an H1 histamine receptor antagonist, an antianginal drug with anti-ischemic effect, a serotonergic agent, a neuroleptic agent with hypothermic effect, antithyroid drug, a preparation containing magnesium ions to increase the body's resistance to hypoxia

Another aspect of the invention is that the composition of the mixture includes:

propranolol beta blocker 0.079-0.119 mass. % sympatholytic reserpine 0.016-0.024 mass. % antianginal drug ivabradine 0.079-0.119 mass. % antihistamine diphenhydramine 0.079-0.119 mass. % antipsychotic drug periciazine 0.063-0.095 mass. % serotonergic serotonin hydrochloride 0.079-0.119 mass. % propithyl antithyroid 0.079-0.119 mass. % magnesium sulfate 0.474-0.711 mass. % pharmaceutically acceptable solvent 98-99 mass. %

Another aspect of the invention is that the carrier in which xenon gas is immobilized is a fat emulsion selected from the group consisting of lipofundin, cmoflipid, interlipid.

Another aspect of the invention is that a 20% lipofundin emulsion is used in the composition of the agent, while the ratio of the volumes of the solution of the pharmaceutical composition to the volume of the solution of the carrier is 1 to 1.

Another aspect of the invention is that in 1 ml of a fat emulsion, when saturated at a pressure of 2 atm, it contains between 0.54 and 2.2 ml of xenon in 1 ml of a 20% fat emulsion.

A further aspect of the invention is that for the prevention of a hypoxic condition in mammals, a therapeutically effective amount of the agent is administered to the mammal once.

List of figures

In FIG. 1 shows the results of changes in body temperature and heart rate (HR) in control rats under hypoxia.

In FIG. 2 shows the results of changes in body temperature and heart rate (HR) in experimental rats under hypoxia.

In FIG. 3 shows data on the survival of rats under hypoxia. A - change in oxygen concentration in the hypoxic chamber. B - survival functions of Kaplan-Mayer rats that received an intravenous injection of FP8 + LPF + Xe 1.5-2.0 hours before the start of the decrease in oxygen concentration (1) and control rats (2).

Description of the invention

In the process of developing tools for prolonging the “golden hour” in patients who have fallen as a result of catastrophes in conditions causing hypoxic reactions of the body to low oxygen levels in the environment or when cardiac arrest occurs and the first stage of clinical death occurs, it was found that the use of an active agent xenon gas immobilized in the carrier makes it possible to develop a means of increasing the body's resistance to hypoxia. Moreover, this tool provides a sustained release of the specified active agent into the body of a mammal. The specified tool additionally contains a pharmaceutical mixture that contains eight drugs: adrenergic blocker, sympatholytic, histamine H1 receptor antagonist, If-channel inhibitor of the sinus node, serotonergic agent, antipsychotic agent with hypothermic effect, antithyroid drug, 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. This embodiment of the composition includes, but is not limited to, the scope of the invention.

A carrier in which xenon gas is immobilized is a fat emulsion, which is selected from the group consisting of lipofundin, cmoflipid, interlipid.

Use solutions of emulsions in a concentration of from 10% to 20%. The ratio of the volumes of the solution of the drug composition and the volume of the solution of the carrier is 1 to 1.

The concentration of inert gas xenon in the solution of the fat emulsion is from 0.54 ml to 2.2 ml. xenon in 1 ml of a 20% fat emulsion. As pharmaceutical acceptable additives, solvents of the components of the composition are used. They may include physical. solution, Ringer's solution and other balanced saline solutions.

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 when it becomes necessary to save the body’s energy resources. 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 clinically healthy white Wistar rats weighing 200-250 grams, distributed in groups of 6 animals each. The following examples include, but are not limited to, the use of analogues of the active substances that make up the tool. Before the experiment, control physiological parameters were recorded for 0.5 h. Rats were measured rectal temperature (T _p ) and heart rate (HR), which averaged T _p = 36-38 ° C and heart rate of 370-450 beats / min.

Examples

Example 1. Verification of the use of funds to increase nonspecific resistance of the body and the prevention of hypoxia.

Verification of the use of the active agent in the form of xenon gas immobilized in the carrier is carried out in an agent comprising a pharmaceutical composition and a lipofundin carrier.

The experiment uses rats of the Wistar strain, weighing 200-250 g, rats native, the content in standard conditions of vivarium. The control and experimental rats a day before the experiment, a catheter is implanted in the jugular vein in accordance with the standard operating procedure developed in the laboratory. Within 0.5 h, control physiological parameters of rectal temperature, heart rate, respiratory rate and blood saturation are recorded individually for each animal with the MouseOxPlus device. Metabolism of oxygen consumption is recorded using the MMS-100 device. Rats are given a single intravenous injection of a mixture containing drug options, including a pharmaceutical composition of eight drugs in combination with a carrier based on a fat emulsion saturated with an inert gas.

The product includes a pharmaceutical composition containing a mixture of eight drugs in the following ratio of components: Propranolol (Anaprilin) - 5 mg / kg, Ivabradine (Coraxan) - 5 mg / kg, Diphenhydramine (Diphenhydramine) - 5 mg / kg, Reserpine - 1 mg / kg, Serotonin hydrochloride - 5 mg / kg, Periciazine - 4.0 mg / kg, Propicyl - 5 mg / kg, magnesium sulfate - 30 mg / kg. Prepare a 20% solution of lipofundin. As pharmaceutical acceptable additives use physical. solution, Ringer's solution and other balanced saline solutions. To protect against hypoxia, a single intravenous administration of 1 ml of the drug is carried out, in which 0.5 ml of a solution of the composition and 0.5 ml of lipofundin fat emulsion saturated with the active agent, xenon. Saturation is carried out at a pressure of 2 atm.

In FIG. 1 shows the results of changes in body temperature and heart rate (HR) in control rats under hypoxia. Before the experiment, the animal was injected intravenously with meldonium (MD) and rometar (PMT). Rats are placed in a hypoxic chamber (HA), where they gradually reduce the oxygen content from 21% (normal in the atmosphere) to 3.5% (acute hypoxia), and then within a few minutes, often at the stages of changing the gas composition (from 5% to 3.5% oxygen) was observed death of the animal (Gib).

In FIG. 2 shows the results of changes in body temperature and heart rate (HR) in experimental rats under hypoxia

Before the experiment, animals were injected intravenously with xenon-saturated lipofundin (FP8 + PSL + Xe), while the temperature of the animals gradually decreased by at least 10 ° C. Then after 1.5-2 hours the animals are placed in a hypoxic chamber (HA), where the oxygen content is gradually (over 25-30 minutes) reduced from 21% (normal in the atmosphere) to 3.5% (acute hypoxia). Under these conditions, a further gradual decrease in body temperature (by 2-4 ° C) and heart rate occurred and the animal had a longer life than in the control (up to 1 hour).

In FIG. Figure 3 shows the survival of rats under hypoxia. A - change in oxygen concentration in the hypoxic chamber. B - survival functions of Kaplan-Mayer rats that received an injection of FP8 + LPF + Xe 1.5-2 hours before the oxygen concentration level decreased (Group 1) and control rats (Group 2).

As shown in FIG. 3, in the experimental group, 50% of animals die 38 minutes after reaching an oxygen concentration of 3.5% and the cumulative probability of survival of animals after being in hypoxia (3.5%) for 60 minutes is 0.22 (22%).

In the control group, 50% of the animals die within 1.5 minutes before reaching an oxygen concentration of 3.5%, which corresponds to the moment of reaching an oxygen concentration of 3.7%. The last rat in the control group dies 18 minutes after reaching an oxygen level of 3.5%. Thus, no animal remains viable for 60 minutes at an oxygen concentration of 3.5%. From the data obtained it follows that the Cox risk coefficient (risk of death in control / risk of death in experience): r = 9.3654. This means that the risk of death of control animals kept for 60 minutes at an oxygen concentration of 3.5% is 9.3654 times higher than the risk of death of animals after injection of FP8 + PSL + Xe.

These examples include, but are not limited to, the scope of the invention.

Industrial reproducibility

The invention may find application in medicine for the prophylactic protection of people from the threat of acute hypoxia and oxygen deficiency.

The invention allows for the threat of fatal hypoxia and oxygen deficiency to transfer mammals to an energy-saving mode with a primary decrease in heart rate and a subsequent decrease in core temperature with a general decrease in oxygen consumption. This allows you to maintain the life support of the body in critical, life-threatening conditions while reducing oxygen levels in the environment.

The use of an active agent, in the form of xenon gas immobilized in the carrier as a drug to increase the body's resistance to hypoxia, allows you to extend the stable life support of the body in an environment with low oxygen levels until professional medical care is provided or during complex surgical operations. At the same time, it remains possible for the reversible restoration of all functions of the mammal with an increase in the level of oxygen in the environment.

Sources of information 1. Engashev SV COMPLEX 3- (2,2,2-TRIMETHYLHYDRAZINIA) PROPIONATE 2-ETHYL-6-METHYL-3-HYDROXYPYRIDINE DISUCCINATE, POSSESSING ANTIGYPOXIC AND ADAPTOGENIC ACTION, AND METHOD. RF patent No. 2485953 (06/27/2013).

2. Bobkov Yu.G. and others. SUBSTANCE, MANIFESTING ANTI-HYPOXIC AND ANTI-HYPOTHERMIC PROPERTIES. USSR copyright certificate No. SU 1832499 (05/27/1995).

3. Sapronov N.S. and other AGENTS WITH ANTI-HYPOXIC PROPERTIES. RF patent No. 2232576 (07/20/2004).

4. TIAN LIHUA Application of Linderolide H in preparation of anti-hypoxic drug. China Application No. CN 106265636 (2017-01-04).

5. TIAN LIHUA Application of Ternatusine A in preparation of anti-hypoxic drugs. China Application CN 106265646 (2017-01-04).

6. TIAN LIHUA Application of Astataricusones D in preparing anti-hypoxic drugs. China Application No. CN 105412119 (2016-03-23).

7. MOOTHA VAMSI K et.al. COMPOSITIONS AND METHODS THAT PROMOTE THE HYPOXIA RESPONSE FOR TREATMENT OF MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS DISORDERS. International Application No. WO 2017027810 (2017-03-16).

8. FRANKS N.P. et.al USE OF XENON AS NEUROPROTECTANT IN A NEONATAL SUBJECT. U.S. Patent No. US 9326996 (2016-05-03).

9. GEORGIEFF MICHAEL Use of liquid preparations containing lipophilic gases such as xenon for neuroprotection or neuroregeneration e.g. in cases of cerebral hypoxia and ischemia. German application No. DE 19933704 (2001-01-25).

Claims (6)

1. The use of an agent comprising xenon immobilized in a carrier as an active agent, as well as a mixture consisting of beta-blockers, sympatholytics with adrenolytic action, an H1 histamine receptor antagonist, an antianginal drug with anti-ischemic effect, a serotonergic agent, a neuroleptic agent with a hypothermic effect, antithyroid drug, a preparation containing magnesium ions, to increase the body's resistance to hypoxia, and the tool itself is characterized by the fact that in go composition include, wt.%: propranolol beta blocker             0,099 sympatholytic reserpine                                                 0,020 antianginal drug ivabradine                         0,099 antihistamine diphenhydramine             0,099 antipsychotic drug periciazine                         0,079 serotonergic serotonin hydrochloride 0,099 propithyl antithyroid                         0,099 magnesium sulfate                                                             0.593 pharmaceutically acceptable solvent             98,813 2. The use according to claim 1, characterized in that the carrier in which xenon gas is immobilized is a lipofundin fat emulsion. 3. The use according to claim 1, characterized in that the composition of the product uses a 20% lipofundin emulsion, the ratio of the volumes of the solution of the pharmaceutical composition and the volume of the solution of the carrier being 1: 1. 4. The use according to claim 1, characterized in that 1 ml of a fat emulsion contains from 0.54 to 2.2 ml of xenon in 1 ml of a 20% fat emulsion. 5. The use according to claim 1, characterized in that for the prevention of a hypoxic state in mammals, a therapeutically effective amount of the agent is administered to the mammal once.

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