RU2796724C1 - Multicomponent infusion solution of electrolytes in combination with biologically active components for intravenous administration - Google Patents

Abstract

FIELD: medicine; pharmacology.

SUBSTANCE: invention is a multicomponent infusion solution that can be used in the treatment of diseases and conditions associated with the need to correct hypovolemia, hypoxia, shock, electrolyte disturbances, intoxication, acidosis, and ketosis. The solution consists of the following components (in wt.%): sodium L-arginine succinate — 1.500, xylitol — 10.000, sodium acetate — 1.500, sodium chloride — 0.600, potassium chloride — 0.300, magnesium chloride — 0.200, calcium chloride — 0.100, water for injections — the rest.

EFFECT: use of the proposed infusion solution allows, due to the selected ingredients of the composition and their ratio, as a result of the effect of mutual supplementation and potentiation of each other's action, to obtain the following effects: hemodynamic, detoxification, antihypoxic, antioxidant, energy, antiketogenic effect, as well as neutralization of metabolic acidosis, restoration of microcirculation, perfusion tissues and rheological properties of blood with low-volume administration.

1 cl, 2 tbl, 9 ex

Description

The invention relates to medicine and pharmacology, and is a multicomponent infusion solution that can be used in the treatment of diseases and conditions associated with the need to correct hypovolemia, hypoxia, shock, electrolyte disturbances, intoxication, acidosis, ketosis, that is, it has a complex multifunctional effect.

Currently, there have been significant changes in the standards of emergency care. Hydroxyethyl starch solutions are banned or severely restricted due to the risk of kidney damage and increased mortality. The drug "HyperHaes", which was widely used as a drug for low-volume resuscitation in the treatment of cerebral edema of various origins, was discontinued. Due to the pronounced side effects, the use of "Neogemodez" is simply inhumane. The rejection of hydroxyethyl starches and other synthetic colloids is in favor of albumin preparations, which, due to their deficiency, does not contribute to solving the problem. To restore hemodynamics in shock, it is recommended to use crystalloids. To reduce the effects of intoxication, Ringer's lactate solution is most often used. High doses of this drug are necessary for adequate detoxification, but when using high doses, undesirable side effects associated with the introduction of a large volume of fluid occur. The drug widely used to improve microcirculation and rheology is Reopoliglyukin, but dextrans are foreign substances. Given the macromolecular structure, dextrans are only partially filtered through the basement membrane of the endothelium of the glomerular capillaries of the kidneys and are hardly available for metabolism in the liver. They partially block the function of the reticuloendothelial system and give side effects in the form of "dextran syndrome". In addition, it inhibits the use of Ringer lactate and Reopoliglyukin and their monodirectionality. To eliminate acidosis and restore microcirculation and rheological disorders, one has to combine them with other drugs, and the practitioner is interested in drugs that have a complex effect.

In the context of a constant shortage of blood plasma preparations and albumin reserves, there is a need to create an innovative drug that, not inferior in plasma-substituting effect to albumin or dextrans, would become available not only for medicine in general, but also for military medical purposes. At the same time, practical medicine is interested in drugs that have a complex multifunctional effect, which, when administered, provides a set of effects that potentiate each other and lead to a rapid correction of all disorders. In addition, medicine, especially emergency and especially military field surgery, needs such drugs that would be able to provide the necessary clinical effect with a small amount of administration.

A large number of infusion preparations are known from the prior art.

For example, a polyionic solution based on sodium succinate - "Reogemin" (Registration certificate of the Republic of Belarus RU 12/12/2047 dated 04.12.12) is known, used as an antihypoxic and detoxifying agent for acute endogenous and exogenous intoxications of various etiologies and for correction water-salt balance in the body, containing the following components:

Sodium succinate hexahydrate 7.5 g/l, Sodium chloride 4.0 g/l, Potassium dihydrogen phosphate 1.4 g/l, Magnesium chloride hexahydrate 0.02 g/l, glucose 50 g/l

and has the following ionic composition:

Sodium 161 mmol/l, Potassium 10.2 mmol/l, Magnesium 1.1 mmol/l, chlorides 70.5 mmol/l, Phosphates (in terms of phosphorus) 10.0 mmol/l

(Instruction for medical use, order of the Ministry of Health of the Republic of Belarus No. 1515 dated 12/26/12).

However, this solution is not balanced in terms of the main vital ions and contains an excess of sodium (by 10%), an excess of potassium ions (by 250% of the norm) and a lack of chloride ions (by 30%), which creates problems for correcting water-salt metabolism. in patients.

In addition, it is known that the combination of glucose solutions with low molecular weight dicarboxylic acids (in this case, succinic acid) creates a risk of the formation of impurities (furfurals) hazardous to the health of patients during the manufacture and storage of the drug (Encyclopedia of Pharmaceutical technology. Third Edition, 2006).

From the prior art also known saline infusion solution "Reamberin" (patent EA 000879 B1, 26.06.2000). The drug is balanced in ionic composition and has detoxifying properties due to the normalization of water and electrolyte balance, antihypoxic and antioxidant effects.

However, despite the presence of a high therapeutic effect, the known infusion solution has a key pharmacological drawback due to the peculiarity of the active component of meglumine sodium succinate, the cation of which (methylglucammonium) practically does not metabolize in the human body and, with the rapid utilization of the anion - monosubstituted sodium succinate - is able to accumulate in the body and lead to significant alkalization of the blood (alkalosis) and urine, which is noted in the instructions for its medical use (Registration number of the Russian Federation R No. 99/363/2 08.10.1999). This condition is difficult to correct and is especially dangerous in patients with reduced blood buffer capacity and kidney failure in serious critical conditions such as polytrauma, sepsis, frostbite of organs and tissues, liver failure and other conditions associated with the activation of catabolic processes in the body.

In this regard, the maximum daily volume of administration of this drug is limited to 800 ml, which, according to its composition, is insufficient for the infusion therapy of a number of critical conditions (acute blood loss, sepsis, polytrauma, hepatic encephalopathy) that require the administration of large volumes. In addition, alkalization of urine, characteristic of the drug, and due to the excretion of the organic base of methylglucammonium through the kidneys, can be dangerous for patients with nephrolithiasis. This is due to the possibility of solubilization of urates and calcium oxalates under the action of methylglucammonium, which can initiate the migration of kidney stones and blockage of the ureters. The above disadvantages of the known infusion solution limit its clinical use in high doses and for certain groups of patients, which significantly narrows the scope of its application.

при следующем соотношении компонентов, мас. %:The closest to the proposed one is the composition described in the source RU 2549448 C1, 04/27/2015, which reveals the well-known balanced infusion solution containing sodium, potassium and magnesium chlorides, a solvent and a biologically active compound, while the solution contains sodium L as a biologically active component -arginine succinate formulas:

with the following ratio of components, wt. %:

sodium chloride 0.540-0.600 Magnesium chloride hexahydrate 0.015-0.030 potassium chloride 0.025-0.040 Sodium L-arginine succinate 1,400-1,700 Water for injections rest.

However, this composition also has a number of disadvantages: The qualitative composition of the solution does not contain a substance that provides the effect of neutralizing metabolic acidosis. The electrolyte complex does not include calcium chloride, which does not ensure the balance of the solution for the electrolyte composition of the blood plasma. The quantitative composition of the composition does not provide an increased osmolarity and, in practical application, requires significant volumes of solution, which is not always shown or possible.

The aim of the invention is to create a multicomponent polyfunctional infusion preparation based on natural metabolites with proven clinical efficacy, which has a complex multifunctional effect with low volume administration.

The objective of the invention: the creation of a drug with hemodynamic, detoxification, antihypoxic, antioxidant, energy effects, neutralization of metabolic acidosis, antiketogenic action, restoration of microcirculation, tissue perfusion and blood rheology.

The technical result of using the proposed composition lies in the possibility, due to the selected ingredients of the composition and their ratio, as a result of the effect of mutual complementation and potentiation of each other's action, to obtain all the necessary effects, namely: hemodynamic, detoxification, antihypoxic, antioxidant, energy, antiketogenic effect, as well as neutralization metabolic acidosis, restoration of microcirculation, tissue perfusion and rheological properties of blood with low-volume administration.

The low volume of administration and potentiation of the effect of the components are achieved due to the fact that the use of the composition quickly leads to the restoration of the physiological balance of the endogenous fluid as a result of its movement from the interstitial tissue into the vascular bed, due to the increased osmolarity of the composition, and the increased osmolarity is achieved precisely due to the selected composition, as in quantitatively as well as qualitatively. Withdrawal of any of the components or a quantitative change in the composition of the composition will lead to the impossibility of achieving such an effect. In addition, a quantitative change in the components of the composition will make it impossible for them to provide all other effects - from restoring the electrolyte balance (in case of a change in the components that carry sodium, calcium, potassium, chlorine ions) to detoxifying properties (in the case of a change in the quantitative content of sodium L - arginine succinate, sodium acetate, xylitol), antiketogenic (in case of changes in the quantitative content of xylitol, sodium L-arginine succinate, etc.) and other effects. That is, each of the components of the composition, which in itself has a number of effects, together, precisely in the quantitative and qualitative composition selected within the framework of the present invention, has the necessary pronounced and rapid effect and provides a small amount of administration to achieve the result.

This technical result allows to significantly expand the scope of clinical application of the proposed drug. The quantitative and qualitative composition of the complex infusion solution ensures its widest application for patients with polytrauma, in shock conditions, with blood loss, burns and intoxication, especially with mass lesions, in military field medicine (MO) and in various disasters in disaster medicine (Ministry of Emergency Situations). ), infectious epidemics (including in the treatment of moderate forms of Covid-19), as well as in emergencies and intoxications (including alcohol and drugs) in emergency medicine and in practical medicine in general (perioperative management of patients and much more). Distinctive positive features of the proposed infusion solution are its universal multifunctionality and low volume necessary to obtain a clinical result, which, in the conditions of military field medicine and in cases of urgent care of emergency conditions, is an undeniable advantage in comparison with other solutions.

The specified technical result is achieved through the use of a composition with the following characteristics:

Calculation of the theoretical osmolarity of the components that make up the solution:

Theoretical osmolarity of the solution:

R _{osm (drug)} \u003d 657.25 + 95.45 + 365.720 + 102.669 + 8.048 + 6.303 + 2.701 \u003d 1238 mOsm / l

The concentration of potassium ions in the solution is:

KCl=K ⁺ +Cl ^-

n(K ⁺ )=n(KCl)

m(KCl)=n(KCl)×M(KCl)

Where:

n is the amount of substance (ions), mol;

m is the mass of the substance in 1 liter of solution, g;

M is the molecular weight of the substance, g/mol.

The concentration of calcium ions in solution is:

CaCl ₂ \u003d Ca ²⁺ + 2Cl ^-

n(Ca ²⁺ )=n(CaCl ₂ )

m(CaCl ₂ )=n(CaCl ₂ )×M(CaCl ₂ )

The concentration of magnesium ions in the solution is:

MgCl ₂ \u003d Mg ²⁺ + 2Cl ^-

n(Mg ²⁺ )=n(MgCl ₂ )

m(MgCl ₂ )=n(MgCl ₂ )×M(MgCl ₂ )

The concentration of sodium ions in the solution is:

NaCl=Na ⁺ +Cl ^-

n(Na ⁺ )=n(NaCl)

m(NaCl)=n(NaCl)×M(NaCl)

CH ₃ COONa \u003d Na ⁺ + CH ₃ COO ^-

n(Na ⁺ )=n(CH ₃ COONa)

m(CH ₃ COONa)=n(CH ₃ COONa)×M(CH ₃ COONa)

The total concentration of Na ⁺ ions in the preparation is:

102.7+182.26=285 mmol/l

The concentration of Cl ions ^- in the preparation is:

Solution preparation technology:

At the first stage, a biologically active component is obtained - sodium L-arginine succinate. To obtain sodium L-arginine succinate take 52.80 kg of succinic acid (CAS Number 110-15-6); 77.89 kg L-arginine (Eur. Ph.); 17.88 kg of sodium hydroxide (Eur. Ph.) and dissolved in 500 liters of water. In this case, an aqueous 28% solution of the new sodium substance L-arginine succinate is formed according to the chemical reaction:

The resulting solution was spray dried and sodium L-arginine succinate was isolated in an amount of 134.9 kg (96% yield) as a white amorphous powder.

At the second stage, an infusion solution is obtained. To do this, take a powder of sodium L-arginine succinate in an amount of 15.0 kg and dissolve it in 500 liters of water for injection. Xylitol - 100.0 kg, sodium acetate - 15.0 kg, sodium chloride - 6.0 kg, potassium chloride - 3.0 kg, magnesium chloride - 2.0 kg, calcium chloride - 1.0 kg are added to the solution and the volume of the solution is adjusted to 1000 l with water for injection. Then the resulting solution is filtered, poured into plastic packaging, hermetically sealed and sterilized, keeping at a temperature of 121°C for at least 15 minutes.

The prepared infusion solution has the following composition (wt %):

Sodium L-arginine succinate 1,500 Xylitol 10,000 Sodium acetate 1,500 Sodium chloride 0.600 Potassium chloride 0.300 Magnesium chloride 0.200 calcium chloride 0.100 Water for injections rest.

The mechanism of action of the drug is based on the redistribution of endogenous fluid volumes from the interstitial tissue into the vascular bed due to the increased osmolarity of the drug. This, combined with the optimal ionic composition, as well as a certain amount of such components in solution as xylitol, sodium acetate, calcium chloride, provides a small amount of administration to achieve the desired clinical effect.

The study of the safety and biological activity of the proposed infusion solution was carried out in a series of experimental studies on animals (examples 1-3).

Example 1. Study of acute toxicity of the proposed infusion solution

The experiments were performed on white outbred rats of both sexes. To determine the indicators of acute toxicity, the test solution was administered intravenously in accordance with the planned method of application in clinical practice to rats of both sexes in increasing doses according to Litchfield-Wilcoxon and in the maximum volumes possible for acute administration. Control animals were injected with 0.9% sodium chloride solution in a volume of 20 ml/kg (ICH M 3(R2) Guidance of Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals, Current Step 4, version dated 11 June 2009).

When studying the acute toxicity of the proposed infusion solution, it was revealed that when the drug was administered at the maximum possible dose of 10 ml/kg, lethality was not observed in the group of animals.

Thus, under conditions of acute experience, the inventive infusion solution is non-toxic, does not have an allergenic and immunotoxic effect.

Example 2. Study of the effect on lethality of the proposed infusion solution in the model of acute endotoxicosis induced by lipopolysaccharide from Salmonella enterica

The experiment was carried out on 60 standard Wistar rats aged 17-18 weeks and weighing 180-210 g. All animals received standard food and water.

Lethal endotoxicosis was modeled by the introduction of bacterial endotoxin - lipopolysaccharide Salmonella enterica serotype enteritidis (SIGMA-ALDRICH.). Endotoxin was injected intravenously (in the tail vein) once in 0.2 ml of water for injection. Experimentally selected doses of endotoxin, causing a pyrogenic reaction and 50 and 100% mortality of animals from toxic shock, which amounted to 5 μg/kg and 25 μg/kg of endotoxin, respectively. Pyrogenic reaction was recorded by measuring rectal temperature (Filkins JP, Di Luzio NR, Endotoxin induced hypothermia and tolerance in the rat. Proc. Soc. Exp. Biol. Med. 1968 Dec, 129 (3): 724-6; Utili R, Abernathy CO, Zimmerman HJ Endotoxin effects on the liver Life Sci 1977 Feb 15, 20 (4): 553-68 Banet M Fever and survival in the rat The effect of enhancing fever Pflugers Arch 1979 Jul 381(1): 35-8.).

For the study, six groups of experimental animals were formed, 10 rats each: 2 control groups - without treatment, 2 experimental groups of animals that were injected with 0.9% sodium chloride solution at a dose of 20 ml / kg, 2 experimental groups of animals that a new infusion solution was administered at a dose of 3 ml/kg. The study drugs were administered intravenously once 2 hours after the administration of lipopolysaccharide. Evaluation of the effectiveness of the drugs was assessed by the mortality rate in the groups within seven days after the administration of lipopolysaccharide.

During the first seven days after the administration of lipopolysaccharide at doses of 5 and 25 mg/kg, animals of the control groups developed toxic shock - hyperthermia, decreased motor activity, decreased muscle tone, refusal to eat, diarrhea and death.

Administration of endotoxin at a dose of 5 mg/kg resulted in 60% mortality.

Carrying out standard therapy of formed toxic shock with 0.9% sodium chloride solution reduced the mortality of animals by 1.5 times (from 60% to 40%).

When using the proposed solution, there was a decrease in mortality during the seven days of the experiment compared with the control by 2.8 times, compared with sodium chloride therapy - by 1.9 times.

An increase in a single dose of endotoxin administered to laboratory animals up to 25 μg/kg led to an aggravation of the course of toxic shock and 100% mortality within seven days of observation.

Carrying out standard therapy with 0.9% sodium chloride solution at a dose of 20 ml/kg reduced the mortality of animals in the group by 1.39 times (from 100% to 72%).

The use of the proposed solution shows a more significant reduction in mortality during the seven days of the experiment in comparison with the control by 1.8 times, compared with sodium chloride therapy - by 1.4 times.

Thus, testing the proposed infusion solution on a toxic shock model showed its high detoxifying activity with low-volume administration at various doses of Salmonella enterica endotoxin.

Example 3. The study of the effectiveness of the proposed infusion solution on the model of poisoning with ammonium carbonate

The experiments were carried out on 40 outbred white male rats weighing 170-180 g at the age of 17-18 weeks. A total of 5 experimental groups were formed: intact animals (n=10); control group - animals with intoxication without treatment (n=10); experimental group 1 - animals with intoxication and the introduction of the proposed infusion solution (n=10); experimental group 2 - animals with intoxication and the introduction of saline (n=10).

Intoxication with ammonium carbonate was created by introducing its aqueous 10% solution intragastrically through an atraumatic probe at a dose of 250 mg/kg (LD50). The clinical picture with the introduction of a toxicant was accompanied by initial motor excitation, vocalization, followed by a pronounced general toxic effect - a significant decrease in activity, muscle tone, response to pain irritation against the background of ataxia and the development of a soporous state. Data on the acid-base balance of animal blood showed a characteristic picture of the development of metabolic alkalosis under the action of ammonia released from ammonium carbonate (Karr NW, Hendriks EL. The toxicity of intravenous ammonium compounds. Am. J. Med. Sci. 1949 Sep. 218 (3): 302-7 Ting YC The toxicity of ammonia Science 1950 Jul 21 112 (2899): 91-2 Warren KS The differential toxicity of ammonium salts J Clin Invest 1958 Apr 37(4) : 497-501 Handford SW, An experimental study of ammonium intoxication Gastroenterology 1959 Jun 36(6):770-9.

Comparable solutions were started to be administered intravenously 1 hour after the development of severe symptoms of intoxication into the tail vein. Physiological solution at a dose of 20 ml/kg, claimed - 3 ml/kg for 3 days. The effectiveness of treatment was judged by the clinical picture, mortality, indicators of acid-base balance: HCO ₃ - plasma bicarbonate; pCO ₂ - partial pressure of carbon dioxide; pO ₂ - partial pressure of oxygen; BB - excess of blood bases; BE - deficiency of plasma buffer bases; BE ecf - extracellular fluid base excess. In addition, kidney function was assessed by kidney weight, daily diuresis, protein and chloride content in urine, urine density and pH.

The use of the claimed solution made it possible to reduce the excess of buffer bases in blood plasma, normalize the pH level, pCO ₂ , unlike sodium chloride, while the claimed solution as a whole contributed to a more effective reduction in the manifestations of alkalosis and hypoxia.

By the third day of observation, mortality in the control group was 75%. The surviving animals gained weight worse, were less active compared to the animals of the experimental groups.

The use of saline reduced mortality to 60%.

Treatment with the inventive infusion solution resulted in no lethality.

In animals of the control group, a significant decrease in daily diuresis and an increase in the amount of protein and urine pH were observed. The use of the proposed solution and sodium chloride had a diuretic effect: increased daily diuresis and chloride content in the urine. However, the diuretic effect of the proposed solution was more pronounced than that of saline.

The results obtained indicate the high efficiency of the proposed infusion solution in the treatment of conditions accompanied by alkalosis. Thus, the claimed infusion solution contributes to the normalization of metabolic disorders in the body caused by alkalosis, reduces the severity of manifestations of hypoxia, which has a positive effect on kidney function and the state of the body as a whole.

The possibility of using an infusion solution in clinical practice, as well as achieving the claimed effect from its use, is also demonstrated by the following examples:

Example 4. As part of the study of the claimed composition, called "Aquitasol", its effect was studied in polytrauma and hypovolemia phenomena. In the study group, there were hemodynamic, microcirculatory disorders and intoxication syndrome. After the introduction of the composition, there was a rapid stabilization of hemodynamic parameters, effective elimination of the intoxication syndrome and restoration of the acid-base balance. The studied composition has proven itself well when used in resuscitation of shocks of various origins. Compared with the use of monodirectional drugs, the studied composition is the most effective both in terms of the speed of obtaining the effect and in terms of its multifunctionality. In addition, it allows you to achieve the effect with low-volume administration. So in all cases of use, a pronounced clinical effect was achieved when using 5-10 ml / kg once and repeatedly during the day, while standard therapy for shock and hypovolemia involves the use of 2 to 5 liters of colloid and crystalloid solutions during the day, depending on the amount of blood loss. In the process of application, the studied composition showed high efficiency and no side effects. The absence of side effects allows you to avoid the appointment of additional drugs.

Example 5. As part of the study of the composition "Aquitasol", its use in the treatment of neurosurgical pathology, including pathology of the brain of vascular, tumoral and traumatic genesis, was studied. In neurosurgical pathologies, the existing standards for the treatment of cerebral edema provide for the use of osmodiuretics (mannitol, urea, glycerin), but their use is highly likely to develop the “rebound” phenomenon. In this case, "Lasix" and potassium preparations are additionally used. When using the composition "Aquitasol", there was a rapid decrease in the signs of increased intracranial pressure and the absence of the "rebound" syndrome. There was no need to use Lasix and potassium preparations, because "Aquitasol" showed a good osmodiuretic effect and is a potassium-containing drug. Also, compared with "Mannitol", "Aquitasol" has other advantages associated with the ability to eliminate metabolic acidosis and maintain the electrolyte composition of the blood. "Aquitasol" is an osmodiuretic and effectively reduces ICP. The presence of a balanced electrolyte composition reduces the loss of electrolytes and eliminates the "rebound" phenomenon. The action of the drug in restoring microcirculation, removing toxic metabolites and effectively stopping cerebral edema can be considered as neuroprotective. Antihypoxic, antioxidant, antiketogenic and energy effects have also been noted. In all cases of use, the volume of the administered composition was significantly less than the volume of administration of drugs, the use of which is the standard. In the treatment of neurosurgical conditions, including cerebral edema, in order to reduce the volume of infusion therapy, the use of a 7.5% solution of sodium chloride and voluven is sometimes practiced, however, even these solutions are used in an amount of 20 ml per kg of body weight, while Aquitasol - 5-10 ml per kg of body weight. In addition, when using hypertonic sodium chloride solution, side effects occur in the form of hypernatremia and hyperchloremia. When using Aquitasol, no side effects were detected.

Example 6 As part of the study of the claimed composition, its use in infusion therapy for Covid-19 was studied. The drug has demonstrated the possibility of achieving a pronounced effect with minimal volumes of injected fluid. The effect of "Aquitasol" on conditions (including infectious-toxic shock) accompanied by intoxication syndrome, hemodynamic and microcirculatory disorders was investigated. The study demonstrated the effective elimination of the intoxication syndrome, which alleviates the severity of the disease, restores the acid-base balance, microcirculation and blood rheology. The introduction of the solution contributes to the rapid stabilization of hemodynamic parameters. Laboratory data, including hematocrit, glycemia, blood diastase, approached the reference values after 24-48 hours from the start of use. The complex composition provides multifunctionality of action and avoids polypharmacy. In addition, all of these effects were achieved with low-volume administration compared to standard therapy. On average, Aquitasol was used in an amount of 5 ml per kg of body weight (about 400 ml in total), which was sufficient to achieve a clinical effect. While the standard infusion therapy for Covid-19 uses 1500 ml (average 2400-2800 ml). Side effects or allergic reactions have not been recorded.

Example 7. As part of the study of the claimed composition, its use in infusion therapy during abdominal surgical interventions for the prevention and treatment of intestinal paresis in the early postoperative period was studied. The drug, having a complex

multifunctional action, in addition to hemodynamic, detoxifying, diuretic action and neutralization of metabolic acidosis, restores microcirculation and perfusion of tissues and due to increased osmolarity and movement of endogenous fluid from interstitial tissue to vessels, quickly eliminates edema of the mesentery and intestines, gently restoring intestinal motility. Unlike standard therapy with cholinomimetics, prescribed due to their aggressive action and the threat of rupture of intestinal sutures on the 3-4th day after abdominal interventions, Aquitasol infusion solution can be administered in the preoperative period for prevention and in the first hours after surgery for the treatment of intestinal paresis . After the introduction of the infusion solution, the first signs of a mild recovery of peristalsis were observed within two hours after surgery. During the first day, peristalsis was restored by 60%, on the 2nd day - by 90%. The drug did not cause a sharp increase in peristalsis. The drug effectively eliminated the intoxication syndrome, which facilitated the severity of the postoperative period. There was a rapid stabilization of hemodynamic parameters and restoration of acid-base balance. No side effects have been identified.

Example 8. The use of the composition "Aquitasol" was studied as part of the complex therapy of moderate and severe alcohol and drug intoxication as the main infusion solution with a complex multifunctional effect

After the introduction of the solution, there was a rapid normalization and stabilization of hemodynamic parameters (BP and pulse). Due to the osmodiuretic effect, the drug effectively eliminated the intoxication syndrome, restored the acid-base balance and microcirculation. Edema, nausea and vomiting, sweating, tremors objectively disappeared. The drug has proven effective in the treatment of withdrawal symptoms. Compared with the use of monodirectional drugs, the solution allows you to achieve the effect with a small amount of administration. So, with alcohol intoxication, the use of various monodirectional solutions in a total amount of up to 40-50 ml per kg of body weight (metadoxil in 500 ml of isotonic solution, 500 ml of hemodez with isotonic solution in a ratio of 1 to 1, potassium chloride, magnesia, up to 1000 ml 4% sodium bicarbonate, etc.). The claimed composition allows to achieve the effect when it is used in the amount of 5-10 liters per kg of weight once and repeatedly during the day. The complex composition provides multifunctionality of action and avoids polypharmacy. Side effects and allergic reactions were not recorded.

Example 9. The use of the claimed composition "Aquitasol" in coronary heart disease (CHD), myocardial infarction was studied. Intravenous infusion of the drug provided a positive hemodynamic effect without adversely affecting the systolic-diastolic function of the left ventricular myocardium. There was an effective restoration of microcirculation. Due to the multifunctionality of the drug, the restoration of hemodynamics and microcirculation occurs with small volumes of solution administration, which is especially important for patients with a cardiological profile. The drug effectively relieved the symptoms of intoxication and restored the acid-base balance. An improvement in the rheological properties of blood was noted. After infusion, there was a decrease in hematocrit, a decrease in blood and plasma viscosity. No changes in the indicators of the functional state of erythrocytes were observed. Side effects in the application of "Akvitasol" were not noted.

Currently, studies are ongoing on the use of the claimed infusion solution in order to develop recommendations on its dosage and rate of administration for each of the possible nosologies, however, the absence of toxicity and the possibility of achieving the technical result specified in the application with a low-volume administration has been proven by previous studies both on adequate models and within the scope of testing.

Claims (3)

Multicomponent infusion solution for intravenous administration with hemodynamic, detoxifying, antihypoxic, antioxidant, energizing, antiketogenic effects, neutralizing metabolic acidosis, restoring microcirculation, tissue perfusion and blood rheology, including xylitol, sodium acetate, sodium, potassium, calcium, magnesium chlorides , as well as sodium L-arginine succinate formula Na ⁺ [NH=C(NH ₂ )NH ₂ (CH ₂ ) ₃ CH(NH ₂ )COOH] ⁺ [OOC(CH ₂ ) ₂ COO] ^2- , in the following ratio, wt.%: Sodium L-arginine succinate 1.50 Xylitol 10.00 Sodium acetate 1.50 Sodium chloride 0.60 Potassium chloride 0.30 Magnesium chloride 0.20 calcium chloride 0.10 Water for injections rest