EA024426B1 - Balanced infusion solution - Google Patents

Abstract

The invention relates to medicine and pharmacology, namely to the saline infusion solutions having a detoxifying effect and can be used for treating diseases and conditions associated with organism intoxications of varying severity. The task of the invention is to provide a novel balanced infusion solution having enhanced detoxicating activity, low toxicity and wide clinical application. The set task is solved by that the balanced infusion solution comprising sodium, potassium and magnesium chlorides, a solvent and a biologically active component, according to the invention as a biologically active component comprises sodium L-arginine succinate of formula Na[NH=C(NH)NH(CH)CH(NH)COOH][OOC(CH)COO]in the following component ratio, mass %: sodium chloride 0.540-0.600, magnesium chloride 0.015-0.030, potassium chloride 0.025-0.040, sodium L-arginine succinate 1.400-1.700, water for injections the rest.

Description

The invention relates to medicine and pharmacology, in particular to saline infusion solutions with a detoxifying effect, and can be used in the treatment of diseases and conditions associated with intoxication of the body of varying severity.

State of the art

In medical practice, salt infusion solutions based on succinic acid salts are widely used.

For example, a polyionic solution based on sodium succinate Reogemin was registered (registration certificate of the Republic of Belarus RU 12/12/2047 of 12/04/12), used as an antihypoxic and detoxifying agent for acute endogenous and exogenous intoxications of various etiologies and for correcting the water-salt balance in an organism 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 ion 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 (Instructions for medical use, order of the Ministry of Health of the Republic of Belarus No. 1515 dated 12/26/12).

It must be emphasized that this solution is not balanced for 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 chlorine ions (by 30%), which creates problems for the correction of 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 with succinic acid) poses a risk of impurities (furfurols) hazardous to the health of patients during the manufacture and storage of the drug (Epsus lorea rb Pattaseysa lucopoda, Tyut Eyup, 2006).

Also known is the drug Succinasol containing sodium chloride - 6.2 g; potassium chloride - 0.3 g; calcium chloride - 0.082 g; magnesium chloride - 0.1 g; succinic acid - 2.0 g; sodium bicarbonate - 3.0 g; water for injection - up to 1 l and having the following ionic composition: sodium - 142 mmol / l, potassium - 4.0 mmol / l, magnesium - 1.1 mmol / l, chlorides - 114 mmol / l, proposed as a means for treatment of critical conditions and also containing succinic acid as an active component. Succinasol improves blood microcirculation, activates energy metabolism, restores hemodynamic parameters and function of the heart muscle in various pathological conditions (patent υζ 4106 В from 04/21/1994, RU 10/140/3 from 05/11/10, Leus C8, 8 Neus Nepko L, CuLaeu 8L. Sotratayue eu1ia1yup oG Yue eGGes15 oG tapping 8OlOi88Uaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa!

Succinate solutions are known in combination with a complex of vitamins and metabolic components. So, the drug Cytoflavin is known (registration number of the Russian Federation ΡΝ 00313/1 dated October 21, 2004) containing succinic acid in the form of sodium meglumine succinate, in combination with inosine, nicotinamide and riboflavin, which has a cytoprotective effect (patent EA 001099).

In clinical practice, Reamberin polyionic infusion solution (registration number of the Russian Federation P No. 99/363/2 10/08/1999) is used, which contains succinic acid in the form of sodium meglumine succinate and a balanced set of macrocells of potassium, magnesium, sodium salts and is used as detoxifying drug (patent EA 000879) and Remaxol infusion solution (registration number of the Russian Federation LSR009341 / 09 of 11/19/2009) containing succinic acid in the form of sodium meglumine succinate in combination with and ozinom, nicotinamide and methionine having hepatoprotective action (patent EA 007865).

The closest analogue of the claimed invention in pharmacological action and composition is the Reamberin salt infusion solution (patent EA 000879), selected as a prototype. The drug is balanced in ionic composition and has detoxifying properties due to the normalization of water-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, whose cation (methyl glucammonium) practically does not metabolize in the human body and, when the anion is used, monosubstituted sodium succinate is able to accumulate in the body and cause significant alkalization of blood (alkalosis) and urine, as noted in the instructions for medical use of the prototype (register ion of the Russian Federation No. P № 99/363/2 08.10.1999). This condition is difficult to correct and is especially dangerous in patients with reduced blood buffer capacity and renal failure in case of serious critical conditions, such as polytrauma, sepsis, frostbite of organs and tissues, liver failure, and other conditions associated with activation of catabolic processes in the body.

In this regard, the high sodium meglumine succinate in the prototype limits the maximum 1,024,426 daily volume of administration of this drug to 800 ml, which is insufficient for infusion therapy of a number of critical conditions (acute blood loss, sepsis, polytrauma, and hepatic encephalopathy) requiring the introduction of large volumes (up to 10 l day).

In addition, alkalization of urine, characteristic of the use of the prototype 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 calcium urate and oxalate under the influence of methylglucammonium, which can initiate the migration of kidney stones and blockage of the ureters.

All of 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.

SUMMARY OF THE INVENTION

The objective of the invention is to create a new balanced infusion solution with increased detoxifying activity, low toxicity and providing a wide area of clinical application.

The problem is solved in that a balanced infusion solution containing sodium, potassium and magnesium chlorides, a solvent and a biologically active component according to the invention contains sodium L-arginine succinate of the formula Να ⁺ [ΝΗ = 0 (ΝΗ2) ΝΗ2 (ΟΗ2 ^{) 30Η (ΝΗ2) ΟΟΟΗ] +} [ 000 (ΟΗ2) _2000] ^2- in the following ratio, wt.%:

Sodium chloride

0.540-0.600

0.015-0.030

0,025-0,040

1,400-1,700

Rest.

Magnesium Chloride Hexahydrate Potassium Chloride

Sodium L-Arginine Succinate Water for Injection

The inventive infusion solution contains sodium chloride, magnesium chloride hexahydrate and potassium chloride in a certain quantitative ratio, which provides a physiologically acceptable content of inorganic ions of sodium, potassium, magnesium and chlorine (Maguie, Wams kkLk ίη 1 ет рг рг рг рг § а а! 4. eb.).

As a biologically active component of the inventive balanced infusion solution contains a new chemical compound of sodium b-arginine succinate of the formula \ η ⁺ [ΝΗ = Ο (ΝΗ2) ΝΗ2 (СН2) 3CH (% H2) COOH] ⁺ [OOS (CH2) ₂ CCU] ^g ' (one)

Physico-chemical properties of sodium L-arginine succinate are given in table. one.

Table 1

Parameter Value Appearance White amorphous hygroscopic substance Solubility It is soluble in water, dimegylformamide, dimethyl sulfoxide, slightly soluble in alcohols, insoluble in acetone, ether, benzene, chloroform pH of aqueous solutions 7.0-7.2 Melting point, ° С 214-215 with decomposition Infrared spectrometer 3400 (ΝΗ ₂ ), 1630 (ΝΗ ₃ ⁺ ), 1570 (COO '), 1400 (COO) 1Н NMR spectra (О ₂ О) 13С (О ₂ О) 15Ν (Ο ₂ Ο) 1.55-1.61 (CH ₂ ); 1.77-1.80 (CH ₂ ); 2.29 (CH ₂ ); 3.11-3.14 (CH ₂ ); 5.64-3.67 (CH) 23.86 (CH ₂ ); 27.54 <CH ₂ ); 34.14 (CH ₂ ); 40.07 (CH ₂ ); 54.28 (CH); 156.78 (C = OH); 174.42 (COOH); 182.35 (COOH) 83.45 (ΝΗ ₂ ); 70.17 (ΝΗ); 39.35 (ΝΗ ₂ ) Gross formula Elemental analysis Calculated,% C 38.22; H 6.09; N, 17.83; About 30.55, Νη 7.32 Found,%: C 38.65; H, 6.18; N, 17.30; About 30.52; Yah 7.35 Molecular mass Calculated 314.27 Found: 306.81 (mass spectroscopy)

The good solubility in water and the physiologically acceptable ρΗ value of aqueous solutions (7.07.2) of sodium L-arginine succinate makes it suitable for the preparation of parenteral drugs.

It is known that salts of succinic acid in the composition with the conditionally essential amino acid Larginine are used as components of drugs with stabilizing and buffering properties. For example, a composition of a tissue factor pathway inhibitor and L-arginine succinate is known (patent EP 1602667), for preservation of antibody solutions (application I8 20100239567, patent 1P 2009-108040, application I8 20120121581) and as a detergent treatment cosmetic product (application 1P 2001-08102525 )

- 2,024,426

Complex compositions are described, which include L-arginine and succinic acid, for the treatment and prevention of hepatic encephalopathies in the form of effervescent tablets used as biological food additives (KI application 2011109884/15).

The scientific and technical literature describes the cardioprotective effect of mono- and diargininosuccinates - various combinations of succinic acid with b-arginine.

Thus, the effect of L-arginine monosuccinate as a potential cardioprotective drug was established (B.V. Dubovik, A.A. Zhdanov, D.I. Romanovsky, Comparative cardioprotective efficacy of arginine hydrochloride and arginine succinate in ischemic reperfusion injury of myocardium in rats, 2005, Medical Journal of the Belarusian State Medical University No. 4, pp. 51-53).

On the basis of diargininosuccinate, the drug Cardinosin was registered (TU ΒΥ 100185198.1122009, registration number 027761 dated 12/09/2009) containing the active substance in the form of a 5% aqueous solution, used as an agent for the treatment of acute myocardial infarction.

In a number of inventions, combined drugs have been proposed for the treatment of cardiovascular diseases based on a combination of arginine succinate and arginine asparaginate in the form of a solution for oral parenteral administration (patents IA No 36998, 37388, 39095, 90368).

The available scientific and technical literature does not describe infusion solutions containing succinate of formula (1) as the active component of sodium L-arginine.

The present invention is the first to show that a new chemical compound of formula (1) can be used as a biologically active component of a detoxifying infusion solution.

In particular, the authors found that the introduction of sodium L-arginine succinate in the composition of the inventive infusion solution increases its detoxifying properties and reduces toxicity compared to the prototype.

As a result of experiments on the selection of a balanced composition of the proposed infusion solution, it was found that solutions obtained in the range of sodium L-arginine succinate from 14 to 17 g / l have a theoretical (calculated) osmolarity of 350 to 360 mmol / l and practical (physiological) osmolality 315-324 mmol / kg, respectively. It is known that the actual osmolality of blood plasma is 286 ± 5 mmol / kg. However, the osmolality in the range of 315-324 mmol / kg for the inventive infusion solution is optimal, since the pharmacokinetic data showed that ίη νίνο sodium L-arginine succinate quickly penetrates the cells and metabolizes to osmotically inactive carbon dioxide and water, which reduces it osmolality to physiological values.

These characteristics make it possible to balance the composition of the claimed infusion solution and introduce it without significant volume restrictions, which expands the scope of clinical use by eliminating a number of contraindications associated with alkalization of blood and urine.

DETAILED DESCRIPTION OF THE INVENTION

In the inventive infusion solution, the ratio of the components ensuring the balance of the composition was selected empirically.

So, the introduction of potassium and magnesium cations to the composition of the claimed infusion solution is proposed by adding potassium chloride in concentrations of 0.025-0.040 g / l and magnesium chloride hexahydrate in concentrations of 0.015-0.030 g / l, providing a physiologically acceptable potassium ion content of 3.45.3 mmol / l and magnesium 0.7-1.5 mmol / l, respectively.

Introduction to the composition of the inventive infusion solution of sodium ions is proposed by adding sodium chloride. For example, the addition of sodium chloride at a concentration of 8.6 g / l makes it possible to obtain a physiologically acceptable content of sodium cations of 147 mmol / l. The content of chlorine anions formed by the dissociation of sodium chloride, potassium chloride and magnesium chloride hexahydrate, around 153 mmol / l, which significantly exceed the physiological norm (Mage Lee, Va81S kkyk ίη IegrgeOpd 1aotaYutu ba1a .. 4 ^'1' ee). .

The present invention proposes to bring the chloride content to a physiological norm (97-110 mmol / l) by replacing part of the inventive infusion solution of a portion of sodium chloride (No. 0) with a new biologically active substance. At the same time, its content in the preparation in concentrations from 14 to 17 g / l provides the physiological content of chlorides without violating the content of sodium cations.

The invention is as follows.

Example. At the first stage, a new biologically active component is obtained - sodium L-arginine succinate of the formula (1).

To obtain sodium L-arginine succinate, 52.80 kg of succinic acid are taken (CAgLitbeg 11015-6); 77.89 kg of L-arginine (Eig. Pb.); 17.88 kg of sodium hydroxide (Eig. Pb.) And dissolved in 500 l of water. In this case, an aqueous 28% solution of the new sodium substance L-arginine succinate is formed according to the chemical reaction

- 3,024,426

NOOS (CH ₂ ) ₂ COOH + ΝαΟΗ + HH = C (W ₂ ) MH (CH ₂ LCH (OH ₂ ) COOH

I

Ca ⁺ [da = C (HH2) CHN2 (CH2) 3CH (KH2) COOH] ⁺ [OOS (CH2) ₂ COO] ² · + H ₂ O

The resulting solution was spray dried and sodium b-arginine succinate was isolated in an amount of 134.9 kg (96% yield) as a white amorphous powder, the physicochemical properties of which corresponded to the data given in table. 1. Subsequently, the powder of sodium L-arginine succinate is packaged in a sealed primary packaging with high barrier properties with respect to water vapor and oxygen, and then in the secondary packaging.

At the second stage receive the claimed infusion solution.

To do this, take a powder of sodium L-arginine succinate in an amount of 14,052 kg and dissolve it in 500 l of water for injection, add 6.0 kg of sodium chloride to the solution (Eig. PH.). 0.244 kg of magnesium chloride and 0.3 kg of potassium chloride (Eig. PH.) And adjust the volume of the solution to 1000 l with water for injection (Eig. PH.). Then the resulting solution is filtered, poured into a glass or plastic bag, sealed and sterilized using the standard mode (kept at a temperature of 121 ° C for at least 15 minutes).

The infusion solution made according to the example has the following composition:

Component: _ (wt.%):

Sodium chloride Magnesium Chloride Hexahydrate Potassium chloride Sodium, L-Arginine Succinate Water for injections 0.6000 0.0244 0.0300 1.4000 up to 1 liter Ionic composition: mmol / l: Sodium 147 Potassium 4.0 Magnesium 1,2 Chloride 109

A study of the safety and biological activity of the inventive balanced infusion solution obtained in the preparation example was carried out in comparison with the prototype drug Reamberin, a solution for infusion of 1.5%, in a series of experimental studies on animals (experiments 1-6).

Experience 1. The study of acute toxicity of the inventive infusion solution.

The experiments were performed on white outbred rats of both sexes. To determine indicators of acute toxicity, the test solution was administered intravenously in accordance with the planned method for the use in clinical practice of rats of both sexes in increasing doses according to Litchfield Wilcoxon and in the maximum volumes possible for acute administration. The control animals were injected with a 0.9% sodium chloride solution in a volume of 20 ml / kg (1CH M 3 (K2) Sbbaise οί Νοη-Οίη®; · ι1 8aGe1u δΙυΠίοκ ίοτ : 81er 4, left δίοη ba! Eb 11. Type 2009).

When studying the acute toxicity of the proposed infusion solution, it was found that when the drug was administered at the maximum possible dose of 8175 mg / kg, calculated as the active substance, no mortality was observed in the group of animals, while the toxicity of the prototype solution was LI ₅₀ = 5600 mg / kg body weight animal in terms of active substance.

Thus, in the conditions of acute experience, the claimed infusion solution is less toxic than the prototype, does not have mutagenic, teratogenic, embryotoxic, allergenic and immunotoxic effects.

Experience 2. The study of the effect on mortality of the proposed infusion solution on a model of acute endotoxemia induced by a lipopolysaccharide from 8a1tοηe11a eShepsa.

The experiment was carried out on 200 standard Wistar rats aged 17-18 weeks and weighing 180-210 g. All animals received standard food and water.

Lethal endotoxemia was modeled by the administration of a bacterial endotoxin, the lipopolysaccharide δ-1tοηе11а eShepsa serotype eSepNb18 (ZUMA-AYISN.). Endotoxin was administered intravenously (in the tail vein) once in 0.2 ml of water for injection. Doses of endotoxin, causing a pyrogenic reaction and 50 and 100% mortality of animals from toxic shock, which were 5 and 25 μg / kg of endotoxin, respectively, were experimentally selected. The pyrogenic reaction was recorded by measuring rectal temperature (T1, K8, TR,, ί-υζίο Ν.Κ., Εη6οΐοχ тη tbiseb NuroίNe ^ t ^ and aib U1egaise Нη 1Not so Rtos. 8ο ^ Exp. ΒίοΙ. Meb. 1968. 1968. : 724-6; TIN K., ANETA1Nu S.O., ΖίιηπκΓπκ · ιη N.T. Εη6οΙοχπι eGGes (8 οη (Not Nuet. November 8, 1977 ReN 15, 20 (4): 553-68; Vaiye (M., AIB 8HU1ua1 ίη 1Ne ha1 is operating. THe eEpc (ίί eiNaistd Geuet, RG1ideg8 AgsN. 1979 bi1, 381 (1): 35-8).

For the study, eight groups of experimental animals were formed, 25 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, which introduced a prototype at a dose of 20 ml / kg, 2 experimental groups of animals that were injected with a new infusion solution at a dose of 20 ml / kg. The studied drugs were administered intravenously once 2 hours after the administration of lipopolysaccharide. Evaluation of the effectiveness of the drugs was evaluated by the mortality rate in the groups within seven days after the administration of lipopolysaccharide (table. 2).

In the animals of the control groups, during the first seven days after the administration of lipopolysaccharide at doses of 5 and 25 mg / kg, toxic shock developed - 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.

Conducting standard therapy of the formed toxic shock with 0.9% sodium chloride solution reduced animal mortality by 1.5 times (from 60 to 40%). The use of the prototype reduced mortality compared with the control group of animals by 1.88 times (from 60 to 32%), and compared with the group receiving sodium chloride, by 1.25 times.

When using the inventive solution, there was a decrease in mortality during the seven days of the experiment compared with the control by 2.5 times, compared with sodium chloride therapy - by 1.67 times, and compared with the prototype - by 1.33 times (from 32 to 24%).

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

table 2

The effect of infusion solutions on the lethality of animals with endotoxicosis caused by lipopolysaccharide

Dose endotoxin Experimental groups Exodus- share pace ratrata Measure nation temperature on the first day Mortality in groups on the third day "rats (%) Lethality in groups on the fourth day, rats (%) Mortality in groups on the fifth day, rats (%) Total mortality in flow seven days rats <%) Lipopolnsa haritz ZDPyuvetsa epTeps 5 mcg / kg Without treatment 36.9 * 0.3 + 1.9 * 0.2 1 (4) 2 (8) 12 (48) 15 (60) 0.9% sodium chloride solution 20 ml / kg (control troupe) 37.6 * 0.9 + 1.5 * 0.3 1 (4) 1 (4) 8 (32) 10 (40) Prototype 20 ml / kg 36.8 * 0.8 + 1.6 * 0.6 - 1 (4) 7 (28) 8 (32) The inventive solution 20 ml / kg 37.1 * 0.5 + 1.1 * 0.5 - 1 (4) 5 (20) 6 (24) Lipopolnosa charide 5a1tooe 25 mcg / kg Without treatment 37.4 * 0.6 + 2.1 * 0.3 2 (8) 11 (44) 13 (52) 25 (100) 0.9% sodium chloride solution 20 ml / kg (control troupe) 36.4 * 0.8 + 2.4 * 0.4 2 (8) 7 (28) 9 (36) 18 (72) Prototype 20 ml / kg 36.6 * 0.6 + 2.1 * 0.5 2 (8) 7 (28) 8 (32) 17 (68) The inventive solution 20 ml / kg 37.4 * 0.8 + 1.9 * 0.5 2 (8) 5 (20) 8 (32) 15 (60)

Conducting standard therapy with a 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 prototype reduced mortality compared with the control group by 1.47 times, and compared with the group receiving sodium chloride, by 1.06 times.

The use of the proposed solution shows a more significant decrease in mortality during the seven days of the experiment compared with the control by 1.67 times, compared with sodium chloride therapy - by 1.2 times, and compared with the prototype 1.13 times (from 68 to 60%).

Thus, testing the inventive infusion solution in a toxic shock model showed its high detoxifying activity at various doses of endotoxin 8a1topope11a step.

Experience 3. The study of the effectiveness of the proposed infusion solution on a model of acute toxic hepatitis.

Studies of the inventive solution were carried out in comparison with the prototype in rats of male Wistar breed with a body weight of 180-200 g. The experiment was conducted on 90 animals, of which 6 groups were formed: intact animals (n = 15); control group (n = 15), animals were injected with 0.9% sodium chloride solution at a dose of 20 ml / kg; experimental groups No. 1 (n = 15) and No. 2 (n = 15) animals, which were introduced the prototype in doses of 10 and 20 ml / kg, respectively; experimental groups No. 3 (n = 15) and No. 4 (n = 15) animals that were injected with the inventive infusion solution in doses of 10 and 20 ml / kg, respectively.

To form acute toxic hepatitis, the animals of the control and experimental groups were once intraperitoneally injected with phenylhydrazine sulfate at a dose of 50 mg / kg, and then after 24 hours a 50% oil solution of carbon tetrachloride at a dose of 3 ml / kg of body weight was administered intragastrically. After 2 hours in the experimental groups, infusion therapy with the studied solutions was started. The therapy was carried out for 2 days sequentially. At the end of the treatment, intoxication markers were evaluated: the activity of the enzymes alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase 5,024,426, the level of bilirubin and hemostasis: prothrombin time, activated partial platelet-thrombotic time, thrombin time (thrombin time 5). .B., Tookeg K. Satjoi (e (GasN1opbe Hera1o1oh1C11u: (Not bp (asbop οί CC1 ₄ op (Do not Nuet Rnattaso1. Exp. Tn. 1964 1i1145: 92-101; P1aa O.I., Butkop K.E. , CC1 ₄ shbiseb Nuet batade. Siggep! sopser !, tedatbshd tesNayzt og asbop. AgsN Epubop. not NN., 1964 Os !. (9), 536-43; Vgiskpeg EU., Mas Kep / 1е ν.Ρ., MitNbNaga 8., Lynta K., Ku1e OM, Asocha со. : aci! e, 8baci1e, apb kiSntoshs 81ib1e8 shai Ripbat. Arr1. Toh1so1. 1986 1ap. 6 (1): 16-34).

In the control group, signs of the development of toxic hepatitis were noted: cytolysis syndrome, impaired liver detoxifying function with increased activity of alkaline phosphatase enzymes, aspartate aminotransferase, bilirubin level, failure of alanine aminotransferase activity and a tendency to increase lactate dehydrogenase activity (p = 0.222 compared to the group of intact animals) (table. 3).

Table 3

The effect of infusion therapy on rat blood biochemical parameters in a model of acute toxic hepatitis

Experimental groups, n = 15 The studied indicators, M ± t alanine mi- notransfe times A piece of chalk aspartate mi- notransfe times A piece of chalk alkaline phosphatase U / L lactate hydrogen per, A piece of chalk bilirubin, μmol / l Intact animals 24.5 * 1.1 115.8 * 3.3 333.1 * 27.4 3060 * 265 10.3 * 0.1 Control group Without treatment 6.8 * 2.4 p] = 0.009 340.2 * 38.6 Ρι = 0.009 761.0 * 120.6 Ρι = 0.009 4281 * 602 51.9 * 6.8 Ρι = 0.008 Experimental group No. 1 Prototype, 10 ml / kg 30.1 * 2.2 Rg = 0.009 294.8 * 63.3 p, = 0.047 610.8 * 100.4 Ρι = 0,028 3285 ± 790 58.4 * 17.1 Ρι = 0.008 Experimental group No. 3 of the inventive solution, 10 ml / kg 18.4 * 4.7 p2 = 0.047 188.7 * 48.2 Ρϊ = 0,047 699.3 * 54.2 p 1 = 0.009 3177 * 446 56.0 * 13.1 ρι = 0.007 Experimental group No. 2 Prototype, 20 ml / kg 22.3 ± 2.8 0.016 331.8 * 81.9 599.4 * 49.7 Ρι = 0.009 3781 * 1019 64.8 * 7.0 Ρι = 0.009 Experimental group No. 4 of the inventive solution, 20 ml / kg 34.8 * 6.8 pg = 0.016 439.8 * 39.6 ρι = 0.009 556.5 * 122.6 2846 * 359 35.2 * 6.6 Ρι = 0.008 p _} = 0.032

Prototype infusion therapy helped to limit cytolysis syndrome by its effect on the activity of alanine aminotransferase and aspartate aminotransferase, but did not affect the activity of the alkaline phosphatase cholestasis marker and bilirubin level. The action of the proposed solution, in contrast to the prototype, was characterized by a significant decrease in the level of bilirubin (p = 0.032) and alkaline phosphatase activity (p> 0.05 compared with the group of intact animals). However, the identified changes were multidirectional (Table 4).

Table 4

The effect of infusion therapy on biochemical parameters of rat hemostasis in a model of acute toxic hepatitis

Experimental groups, I = 15 The studied indicators, M ± W prothrombin time sec activated partial thromboplastin time, sec thrombin time, sec Intact animals 24.08 * 0.70 15.42 * 0.79 60.32 * 5.02 Control group Without treatment 26.22 * 3.45 40.60 * 19.86 Ρι = 0.009 99.08 ± 12.81 Ρι = 0,026 Experimental group No. 1 Prototype 10 ml / kg 26.10 * 3.63 60.48 * 24.36 p, = 0.027 67.82 * 4.66 Experimental group No. 3 of the inventive solution, 10 ml / kg 31.12 * 2.63 34.82 * 4.95 Ρι = 0.009 78.48 * 5.09 Ρι = 0.009 Experimental group No. 2 Prototype, 20 ml / kg 28.76 * 4.51 30.08 * 6.49 p, = 0.009 96.00 * 14.78 Experimental group No. 4 of the inventive solution, 20 ml / kg 28.6 * 4.97 16.34 * 1.0 pg = 0.009 pz = 0.009 p5 = 0.009 61.76 * 3.73 Ρ2 = 0,044 pg = 0.047

Positive changes during therapy with the prototype and, to a greater extent, the claimed solution

- 6,024,426 expressed in a decrease in pathologically increased activated partial thromboplastin time (internal coagulation pathway) and thrombin time. At the same time, against the background of therapy with the claimed solution, a significant normalizing effect was revealed in relation to the activated partial thromboplastin time and thrombin time (p = 0.009 and 0.05) compared with those of the prototype in a dose equivalent in volume.

Analyzing the data obtained, it can be concluded that the claimed infusion solution has a significantly more pronounced hepatoprotective effect in the acute toxic hepatitis model than the prototype.

Experience 4. The study of the effectiveness of the proposed infusion solution on the model of poisoning with ammonium carbonate.

The experiments were performed on 150 outbred white male rats weighing 170-180 g at the age of 13-14 weeks. A total of 5 experimental groups were formed: intact animals (n = 30); control group - animals with intoxication without treatment (n = 30); experimental group 1 - animals with intoxication and the introduction of the inventive infusion solution (n = 30); experimental group 2 - animals with intoxication and the introduction of physiological saline (n = 30); experimental group 3 - animals with intoxication and the introduction of the prototype (n = 30).

Ammonium carbonate intoxication 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 the toxicant was accompanied by initial motor excitement, vocalization, followed by a pronounced general toxic effect - a significant decrease in activity, muscle tone, reaction to pain irritation against the background of ataxia and the development of a soporous state. Some animals showed lateral position and cramps. The data of the acid-base balance of animal blood (Table 5) showed a characteristic picture of the development of metabolic alkalosis under the action of ammonia released from ammonium carbonate (Kagg Ν.Α., Nepbpkh E.B. 8s1. 1949 8p. 218 (3): 302-7; Tshd, W.S. 8a118. 1. SPb 1pu§1. 1958 Arg. 37 (4): 497-501; NapbGogb Z.A., Ap ehrepteya1 81ibu oG attopst Yohuayop. Sa81goep1egoda. 1959 1ip; 36 (6): 770-9. .

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

4 hours after the administration of the test solutions, 10 animals from each group were decapitated, mixed blood was taken, and the parameters of the oxygen budget and acid-base balance were measured (Table 5)

Table 5

Indicators of the state of the oxygen budget and acid-base balance in rats 4 hours after the start of treatment, (M ± t)

Exponential Experimental groups Iptactic, p-10 The control, p-10 Experimental group 1 p = 10 Experimental group 2 n = 10 Experimental group 3 p => 10 pH 7.27 ± 0.02 8.26 ± 0.03 * 7.35 ± 0.01 7.63 ± 0.05 * 8.47 ± 0.03 * pCO3, mmH £ 40.3 ± 0.5 52.6 ± 0.9 * 41.3 ± 2.6 49.7 ± 0.8 * 47.4 ± 2.8 pO ₂ , mmH 45.7 ± 0.8 23.2 ± 0.5 * 38.1 ± 0.5 * 25.4 ± 1.5 * 35.4 ± 0, b * WB, mmol / l -1.0 ± 0.3 1.5 ± 0.1 * -2.3 ± 0.2 1.0 ± 0.1 * 0.8 ± 0.1 * BE ec £, mmol / l -1.5 ± 0.5 3.5 ± 0.3 -0.5 ± 0.1 2.5 ± 0.4 * 0.5 ± 0.2 BB, mmol / l 45.8 ± 3.0 64.7 ± 2.5 * 49.5 ± 2.4 60.2 ± 2.1 * 58.3 ± 2.9 * НСОз, mmol / l 18.4 ± 1.0 27.3 ± 1.5 * 23.7 ± 1.3 29.4 ± 1.3 * 29.2 ± 1.7 *

* - significant differences from intact animals at p <0.05.

The use of the proposed solution allowed to reduce the excess of buffer bases of blood plasma, to normalize the pH level, pCO ₂ in contrast to the prototype, which on the contrary contributed to an increase in the pH level. Moreover, 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 15 out of 20 animals (75%). Surviving animals gained weight worse, were less active compared with animals of the experimental groups.

The use of physiological saline (experimental group 2) reduced mortality to 60% (12 animals died 20), and the prototype (experimental group 3) - up to 20% (4 animals out of 20 died). Treatment with the claimed infusion solution (experimental group 1) led to the absence of mortality.

The objective condition of the animals was better when using the inventive solution and prototype (table. 6).

Table 6

Mortality, body weight, biochemical and functional indicators of the kidney condition of experimental animals with intoxication with ammonium carbonate after the use of the compared drugs on the 3rd day of treatment (M ± t)

Indicators Experimental groups Intact p-20 The control, n = 5 Experimental group 1 p-20 Experimental group 2 Experimental group 3 p “1st Mortality,% 0 75 0 60 twenty Body weight g 187 ± 6 174 ± 4 * 189 ± 6 176 ± 3 182 ± 4 Relative kidney mass, g / kg body weight 7.5 ± 0.3 9.6 ± 0 6 * 7.3 ± 0.4 8.b ± O.Z * 7.4 ± 0.5 Daily diuresis, ml 4.1 ± 0.1 1.3 ± 0.1 * 5.1 ± 0.2 * 4.4 ± 0.3 4.8 ± 0.5 * Urine protein, mg / ml 3.8 ± 0.2 5.4 ± 0.7 * 3.4 ± 0.4 3.9 ± 0.2 3.8 ± 0.3 Urine Chloride, mg / ml 3.4 ± 0.2 2.7 ± 0.2 * 4.4 ± 0.5 * 5.1 ± 0.2 * 4.3 ± 0.1 * Urine density 1.011 ± 0.002 1.009 ± 0.003 1.017 ± 0.006 1.010 ± 0.003 1.010 ± 0.007 urine pH 6.3 ± 0.3 9.4 ± 0.2 * 6.5 ± 0.3 7.2 ± 0.3 * 8.6 ± 0.4 *

* - significant differences from intact animals at p <0.05

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

The results indicate a high efficiency of the proposed infusion solution in comparison with the prototype in the treatment of conditions accompanied by alkalosis. So, 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 positively affects the function of the kidneys and the state of the body as a whole.

Experience 5. The effectiveness of the proposed infusion solution on the model of acute ethanol poisoning.

The experiments were performed on 105 male rats. For each experimental model, 7 groups of animals were formed (n = 15).

To form acute poisoning, the animals were injected once intraperitoneally with a 40 vol.% Ethanol solution at a dose of 8 ml / kg body weight. After 2 hours, all experimental animals started the infusion therapy with the studied solutions. The therapy was carried out for 2 days sequentially. The solutions were administered three times a day with an interval of 2 hours due to the limitation of the maximum single volume for administration to rat veins. The new infusion solution was administered in doses of 10, 20, 30, 40 ml / kg, and the prototype in an effective literature dose of 20 ml / kg per day (Όί Ειιζζο Ν.Κ., and TESHAB8T OL 1NS ASHE SHAPOYPBISEB Tabu 1 run apb 1be toblsabop All the shield for the bw apbh1bap18. Att. 1. Pbt. δα. 8irrob Pbbc Nebb, 1966 1bp; 15: 50-63; : 338-40; Ka1ap1 N., Mop8 DO., MAbop M.A., Acrye elss® ol e1bap1 op i88ie e1ec1go1u1e8 w 1b e ga Cap 1, Pbu8u1. Pbactaco. 1966 1ap, 44 (1): 1-12).

At the end of therapy, mortality of animals in the groups was assessed for 24 and 48 hours, and intoxication markers were determined in the blood of survivors (activity of alanine aminotransferase enzymes, levels

- 8,024,426 glucose, lactate, pyruvate, lipid peroxidation products, diene conjugates, ketodienes of conjugated trienes and Schiff bases.

The death of animals occurred during the first 2 days and was associated with hypothermia, collapse, and general intoxication, provided the animal was in an unconscious (coma) state for a long time.

So, in the control group, on the first day, 3 rats died (20%), which after induction of ethanol coma did not go out of the pathological state and did not show a reflex response to pain and light stimuli. Then, during the second day, 3 more animals died with signs of acute fulminant hepatitis with hyperthermia (marble liver when opening the abdominal cavity), with a total mortality rate of 40%.

On the first day, the best effect was observed with the introduction of the inventive solution in doses of 20 and 30 ml / kg - in groups of animals there was no death. In groups of animals that received the claimed solution in doses of 10 (low therapeutic dose) and 40 mg / kg (overload of circulating blood volume), one animal died (6.7%), as in the group that received the prototype (6.7% )

On the second day of the experiment, deterioration of rats was revealed in all experimental groups. In groups of animals that received the claimed solution in doses of 10, 20, 30 and 40 mg / kg, one individual died, with a total mortality rate of 13.3%, 6.7%, 6.7%, 13.3%, respectively , in the group receiving the prototype, two more individuals (20.0%) (table. 7).

Table 7

The effect of the drug on mortality in rats with acute ethanol poisoning

Experimental groups, p — 15 Mortality (dead / total) The total mortality of individuals /% 24 hours 48 hours Intact animals 0/15 0/15 0 (0%) Control group (without treatment) 3/15 3/12 6 / (40.0%) Prototype 20 ml / kg 1/15 2/14 3 / (20.0%) The inventive solution, 10 ml / kg 1/15 1/14 2 / (13.3%) The inventive solution, 20 ml / kg 0/15 1/15 1 / (6.7%) The inventive solution, 30 ml / kg 0/15 1/15 1 / (6.7%) The inventive solution, 40 ml / kg 1/15 1/14 2 / (13.3%)

Positive changes during prototype therapy were expressed in normalization of alanine aminotransferase activity and glucose level. The activity of aspartate aminotransferase and the level of lactic and pyruvic acids remained elevated and significantly different from those in rats from the positive control group (Table 8).

Table 8

The effect of infusion therapy on rat biochemical parameters

Experimental groups, n = 5 The studied indicators, M ± W Alanya notransfe times A piece of chalk Asiartataminogransferase, ME / L Glucose, mmol / l Dairy acid, mmol / l Pyruvic acid, mmoy / l Intact animals 31.8 * 5.9 127.9 * 6.9 5.1 ± 0.2 1.7 * 0.2 0.13 * 0.01 Control group (without treatment) 109.7 * 6.9 * 333.9 * 61.8 * 3.1 ± 0.5 * 8.8 * 1.2 * 0.17 * 0.01 * Prototype 20 ml / kg 41.4 * 13.7 ** 169.5 * 29.2 ** 5.2 ± 0.2 ** 5.7 ± 0.5 * / ** 0.20 * 0.02 * The inventive solution, 10 ml / kg 47.5 * 5.3 ** 158.0 * 10.0 * / ** 4.1 ± 0.3 * & 7.0 ± 0.1 * 0.20 * 0.02 * The inventive solution, 20 ml / kg 29.1 ± 4.4 ** # 133.3 * 11.6 ** 3.8 ± 0.3 * & 5.1 ± 0.5 0.16 * 0.02 The inventive solution, 30 ml / kg 28.5 ± 2.5 ** # 118.4 * 11.0 ** 4.4 ± 0.3 4.0 ± 0.2 * / ** # 0.15 * 0.01 The inventive solution, 40 ml / kg 39.3 * 4.6 ** 138.1 * 14.6 ** 3.8 ± O, 2 * & 5.0 * 0.6 * / * * # 0.18 * 0.02

Notes:

* - differences are significant in comparison with intact animals, p <0.05;

** - differences are significant compared with the control group, p <0.05;

& - differences are significant compared to the prototype group, p <0.05;

# - differences are significant compared with the group receiving the claimed solution at a dose of 10 ml / kg, p <0.05.

- 9,024,426

When analyzing the dose dependence of the effects of the claimed solution, a positive effect was revealed on all the main indicators. The transition from a dose of 10 ml / kg to a dose of 20 and 30 ml / kg of the claimed solution gave a significant leap in the form of an increase in the positive effect on transaminase activity and energy metabolism (Table 8). Moreover, in terms of their effectiveness, the doses of 20 and 30 ml / kg were almost equivalent, and the average therapeutic dose was within the specified range (calculated average dose of 25 ml / kg).

Table 9

Influence of infusion therapy on rat LPO

Experimental groups, n = 5 The studied indicators, M ± ha ketodienes of conjugated trienes, y, e. / ml Schiff's base, cu / ml Intact animals 6.33 ± O, 18 0.57 ± 0.03 Control group (without treatment) 7.55 ± 0.58 1.37 ± 0.07 * Prototype 20 ml / kg 7.64 ± 0.28 1.17 ± 0.09 * The inventive solution, 10 ml / kg 7.74 ± 0.45 0.97 ± 0.07 * / ** The inventive solution, 20 ml / kg 6.71 ± 0.48 0.95 ± 0.10 * / ** The inventive solution, 30 ml / kg 6.84 ± 0.49 0.86 ± 0.1 ** The inventive solution, 40 ml / kg 7.33 ± 0.27 1.04 ± 0.09 * / **

Notes:

* - differences are significant compared with the group of intact animals, p <0.05; ** - differences are significant compared with the control group, p <0.05.

Lipoperoxidation indices (Table 9) against the background of acute ethanol poisoning changed mainly in the form of an increase in the level of Schiff bases, the products of the interaction of aldehydes with amino groups of proteins and amino acids. At the same time, the claimed infusion solution in a dose of 30 ml / kg exceeds the prototype in terms of effectiveness.

Experience 6. The effectiveness of the proposed infusion solution on the model of acute cytostatic poisoning with cyclophosphamide.

The detoxifying effect of the solutions was studied on the model of toxicosis induced by cyclophosphamide in female mice weighing 20-22 g of the линии1 hybrid line. The studied drugs were administered within 14 days after exposure to cyclophosphamide.

To assess the detoxifying effect of the claimed solution, 5 experimental groups of animals were formed: group 1 (n = 50); the animals were once intravenously injected with cyclophosphamide in a cytotoxic dose of 450 mg / kg (LI ₅₀ ); Group 2 (n = 50) and group 3 (n = 50) animals were injected intraperitoneally with a daily dose of 40 and 20 ml / kg for 14 days, respectively, group 4 (n = 50) animals were injected intraperitoneally a prototype for 14 days at a dose of 20 ml / kg; 5th group (n = 9) - intact animals (Causus Su-сοΐοχίο cGGss® οί 1Pc ss1orBo8pbash1. Raush R., EGGss1kOG and khd1s yoks oG suOorNokrNaiys op uapoik dobpk sh 1ps gag 3. E1ss1gop tyugoksoryu k! Uyu gG 1ps Psg At. 1. Ra11yu.1. 1971 Psb, 62 (2): 159-68.

The death of animals and the biochemical blood parameters of the surviving animals were recorded. The material was taken on the 3rd, 7th and 14th day after cyclophosphamide administration. A biochemical blood test included determining the activity of aspartate aminotransferase and alanine aminotransferase, the concentration of urea, creatinine, and the content of total bilirubin in the blood serum of experimental animals. In cyclophosphamide, hepatotoxicity is most pronounced, characterized by degenerative and destructive changes in the liver.

The introduction of cyclophosphamide (group 1) led to 45% death of animals, the death of animals began from 4 days after exposure and lasted for 5 days (Table 10).

The introduction of the inventive solution in daily doses of 40 and 20 ml / kg against the background of cytostatic administration contributed to a statistically significant decrease in the toxic effects of cyclophosphamide - the death of animals in these groups of animals was 10 and 5%, respectively.

In group 3, where a prototype was used against the background of cyclophosphamide administration, a 35% mortality rate was observed due to the toxic effect of cyclophosphamide (Table 10), that is, according to the integral indicator of animal death, the claimed solution shows a more pronounced detoxification ability than the prototype.

- 10,024,426

Table 10

The effect of a new infusion solution on the toxic effects of cyclophosphamide

Group number Impact Mortality,% one Control group (without treatment) 45 2 The inventive solution (40 ml / kg) 10* 3 The inventive solution (20 ml / kg) 5* 4 Prototype (20 ml / kg) 35 5 Intact animals 0

* - statistically significant difference from the group of animals without exposure (p <0.05).

Analysis of laboratory blood parameters of experimental animals (group 1) showed that hepatotoxicity is leading in the toxic effect of cyclophosphamide. During the 7 days of observation after administration of cyclophosphamide in animals, a statistically significant increase in the activity of the enzyme alanine aminotransferase was noted, and on the 3rd day of observation, a statistically significant increase in the activity of aspartate aminotransferase and the concentration of total bilirubin (Table 11) relative to indices in intact animals. It is characteristic that the transient increase on the 3rd day of aspartate aminotransferase activity also changed on the 7th day with a statistically significant decrease in enzyme activity compared with the level in intact animals. This is apparently due to the development in animals of liver damage by the type of cytolysis.

Table 11

Biochemical blood parameters of animals in dynamics after exposure to cyclophosphamide

No. groups Impact Biochemical parameters 3 7 14 Alanine aminotransferase. A piece of chalk one Control group (without treatment) 326 ± 33 * 381 ± 15 * 62 ± 31 2 The inventive solution (40 ml / kg) 40 ± 4 ** 50 ± 5 ** 44 ± 3 3 The inventive solution (20 ml / kg) 40 ± 5 ** 58 ± 12 ** 54 ± 1O 4 Prototype (20ml / kg) 42 ± 2 ** 47 ± 8 ** 4 & Η1 5 Intact animals 42 ± 2 Aspartate aminotransferase. A piece of chalk one Control group (without treatment) 219 ± 14 * 62 ± 15 * 106 ± 15 2 The inventive solution (40 ml / kg) 138 ± 21 ** 181 ± 15 ** 15O ± 18 3 The inventive solution (20 ml / kg) 146 ± 17 ** 173 ± 20 ** 158 ± 14 4 Prototype (20ml / kg) 156 ± 20 ** 173 ± 23 ** 13b ± 5 5 Intact animals 136 ± 5 Total bilirubin, µmol / l one Control group (without treatment) 13.1 ± 1.4 * 8.1 ± 0.4 8.0 ± 2.0 2 The inventive solution (40 ml / kg) 7.3 ± 0.3 ** 7.9 ± 0.7 6.0 ± 1.8 3 The inventive solution (20 ml / kg) 7.2 ± 1.7 ** 7.3 ± 0.4 4,5 ± 1,2 4 Prototype (20ml / kg) 6.6 ± 0.4 ** 7.6 ± 0.5 7.8 ± 1.2 5 Intact animals 6.4 ± 1.0 Creatinine, μmol / L one Control group (without treatment) 36 ± 1 24 ± 5 25 ± 3 2 The inventive solution (40 ml / kg) 32 ± 3 23 ± 4 33 ± 6 3 The inventive solution (20 ml / kg) 33 ± 7 25 ± 3 37 ± 2 4 Prototype (20ml / kg) 35 ± 3 24 ± 3 35 ± 5 5 Intact animals 36 ± 4 Urea, mmol / L one Control group (without treatment) 6.7 ± 0.5 4.7 ± 0.4 4.7 ± 0.6 2 The inventive solution (40 ml / kg) 7.7 ± 1.1 5.2 ± 0.5 5.6 ± 0.7 3 The inventive solution (20 ml / kg) 6.6 ± 0.2 5.6 ± 1.5 4.9 ± 0.8 4 Prototype (20ml / kg) 4.0 ± 0.4 4.7 ± 0.7 b, 4 ± 0.3 5 Intact animals 5.1 ± 1.4

* statistically significant difference from the group of animals without exposure (p <0.05), ** - statistically significant from the group of animals that received only the cytostatic cyclophosphamide (p <0.05).

The results of biochemical studies confirmed a statistically significant decrease in the intensity of toxic reactions of cyclophosphamide with the introduction of the inventive solution in daily doses of 40 and 20 ml / kg Its use leads to the relief of the hepatotoxic effect of cyclophosphamide:

- 11 024426 values of biochemical parameters were maintained at a normal level during the entire time of observation of animals with the introduction of the inventive solution in both doses. For example, with the introduction of the inventive solution in a daily dose of 40 ml / kg on the 3rd day after the administration of the cytostatic agent, the activity of the enzymes aspartate-notransferase and alanine aminotransferase was 138 ± 21 and 40 ± 4 IU / L, respectively, and with the introduction of the inventive solution in a daily dose of 20 ml / kg - 146 ± 17 and 40 ± 5 IU / L, respectively, while in the cyclophosphamide group - 219 ± 14 and 326 ± 33 IU / L (normal: aspartate aminotransferase - 136 ± 5 IU / L, alanine aminotransferase - 42 ± 2ME / L). A similar picture was observed on the 7th day of observation.

The concentration of total bilirubin also remained at a normal level, unlike in animals receiving only cyclophosphamide, in which on the 3rd day the concentration was 13.1 ± 1.4 μmol / L (normal 6.4 ± 1.0 μmol / L, tab. . eleven).

The effectiveness of the prototype was also expressed in maintaining the activity of the enzymes alanine aminotransferase and aspartate aminotransferase and the concentration of total bilirubin at a normal level for all periods of observation.

Thus, the detoxifying activity of the inventive infusion solution in relation to cyclophosphamide in various doses was not inferior to the prototype, while there was a significant difference in mortality in the groups of application of the inventive solution in various doses (10 and 5%) and prototype (35%).

The experiments performed show the wide possibilities when using the inventive infusion solution as a detoxifying drug due to the use of a new biologically active component - sodium L-arginine succinate of the formula (1).

The inventive balanced infusion solution contributes to the rapid reduction of hypoxic processes in organs and tissues, the removal of under-oxidized waste products of cells, activation of energy metabolism, normalization of water-electrolyte balance and acid-base balance of all body fluids.

In addition, a balanced infusion solution significantly reduces the alkalization of blood and urine, characteristic of the prototype, due to the lower pH of sodium L-arginine succinate, which seems to be advantageous for certain groups of patients.

Thus, the inventive balanced infusion solution has increased detoxifying activity, low toxicity and can be used in the treatment of a wide range of diseases and conditions associated with intoxication of the body of varying severity.

Claims (1)

CLAIM A balanced infusion solution containing sodium, potassium and magnesium chlorides, a solvent and a biologically active compound, characterized in that it contains sodium L-arginine succinate of the formula as a biologically active component Ia ⁺ [II = C (IN2) IN2 (CH2) 3CH (IN2) COOH] ⁺ [OOS (CH2) ₂ COO] ² in 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 injection - the rest.