EA007865B1 - Disintoxicating infusion solution - Google Patents

Abstract

The invention relates to medicine, in particular, to multicomponent infusion solutions eliciting disintoxicating and hepatoprotective effect and can be used in body intoxications of different severity degree and for the treatment of diseases accompanying damages of liver. The invention relates to the development of infusion solution eliciting the enhanced detoxicating activity due to cholagogic effect and allows carrying out effectively treatment of diseases accompanying heavy damages of liver. Disintoxicating infusion solution containing sodium chloride, magnesium chloride and potassium chloride, N-methylglucamine succinate sodium as a biologically active component and water for injection as a solvent comprises additionally riboxin, methionine and nicotinamide as biologically active components taken in the following ratio of components, wt.-%::sodium chloride, 0.4-0.6;magnesium chloride, 0.011-0.013;potassium chloride, 0.027-0.033;N-methylglucamine succinate sodium, 1.40-1.60;riboxin, 0.15-0.25;methionine, 0.06-0.08;nicotinamide, 0.02-0.04;water for injection, the balance.

Description

The invention relates to medicine, namely to multicomponent infusion solutions with detoxification, hepatoprotective effect, and can be used for intoxication of the body of various severity, as well as in the treatment of diseases accompanied by liver damage.

Known multicomponent infusion solutions with a detoxifying effect, containing as a biologically active substance succinic acid and its derivatives (succinates), as well as vitamins and mineral salts.

So, in the patent of the Russian Federation No. 2039556 (pharmaceutical composition of anti-alcohol, stimulating energy metabolism, acid-forming and secretory function of the gastric mucosa, radioprotective and anti-cholera effects, a method for the prevention and treatment of intoxication and alcohol withdrawal syndrome, a method for stimulating and diagnosing acid-forming and secretory functions of the gastric mucosa and A method of protection against radiation damage to warm-blooded animals, A 61K 31/19, priority from 07/07/1993) describes a composition that contains a mixture of succinic and citric acids or their pharmaceutically acceptable salts, and as a pharmaceutical solvent, water or alkaline mineral water.

The composition has an alcohol detoxifying effect, stimulates energy metabolism, acid-forming and secretory function of the gastric mucosa and is used during an exacerbation of alcoholism.

However, since this drug does not have a hepatoprotective effect, it does not affect the restoration of liver functions impaired by alcohol poisoning, which reduces the effectiveness of the treatment of the disease.

Known drug Citoflavin for injection (EA patent No. 001099, priority 10.06.99, A 61K 31/708), which includes biologically active components: metabolites sodium salt of succinic acid and riboxin, as well as coenzymes nicotinamide and riboflavin, and сол-methylglucamine as a solubilizer.

This composition has a pronounced antihypoxic, antioxidant, metabolic activity and is used for liver diseases, including toxic liver lesions of varying severity.

The detoxifying effect of this drug is achieved by stimulating the processes of energy metabolism and restoration of cellular respiration, which are accompanied by active utilization of glucose, while its synthesis, especially in liver cells, occurs rather slowly. As a result, there is an imbalance between the expenditure and replenishment of the energy resources of cells, which leads to dystrophic changes in vital organs, especially the liver.

Thus, a disadvantage of the known drug is its depleting effect on the liver, which reduces the effectiveness of treatment and lengthens the recovery period.

Also known is the Reamberin infusion solution (EA patent No. 000879, priority 02.12.1998, A 61K 31/194), which is a complex drug and contains sodium, potassium and magnesium chlorides, the biologically active component is sodium Ν-methylglucamine succinate and a solvent at the following ratio of components, wt.%:

Sodium Chloride 0.4-0.6

Magnesium Chloride 0.011-0.013

Potassium Chloride 0.027-0.033

Sodium No. methylglucamine succinate 1.40-1.60

Water for injection Else

This drug is selected as a prototype.

The Reamberin infusion solution has a detoxifying, antihypoxic effect, promotes the utilization of fatty acids and glucose, restores the energy potential of the cell by activating aerobic intracellular processes, and normalizes the acid-base balance and blood gas composition.

This infusion solution is used for acute intoxications of various etiologies.

However, the effectiveness of this drug is reduced in the treatment of diseases accompanied by significant liver damage.

Due to the effects of endogenous and exogenous toxins on the liver, its functions are impaired. In particular, with a violation of the metabolism of bile acids in the liver, bile accumulates, which not only complicates the removal of toxins from the body, but also worsens the patient's condition due to poisoning of the body with bile acids.

In addition, some bile acids with pronounced surface-active properties, accumulating, can cause damage, degeneration and necrosis of liver cells (hepatocytes), which leads to irreversible changes in the liver, further weakening of its functions and disruption of the general regulation of the organs and systems of the body.

Thus, the detoxifying activity of the known infusion solution is reduced in diseases accompanied by severe liver damage due to a weakening of ne

- 1 007865 chenia and violations of the process of eliminating toxins with bile, which leads to a decrease in the effectiveness of the therapeutic effect of the drug.

The objective of the invention is the creation of an infusion solution with increased detoxifying activity due to the choleretic effect and allows you to effectively treat diseases accompanied by severe liver damage.

The problem is solved in that a detoxification infusion solution containing sodium, magnesium and potassium chlorides, a biologically active component - sodium Ν-methylglucamine succinate and a solvent - water for injection, according to the invention additionally contains, as biologically active components, riboxin, methionine and nicotinamide, in the following ratio of components, wt.%:

Sodium chloride 0.4-0.6 Magnesium chloride 0.011-0.013 Potassium chloride 0.027-0.033 Sodium Ν-methylglucamine succinate 1.40-1.60 Riboxin 0.15-0.25 Methionine 0.06-0.08 Nicotinamide 0.02-0.04 Water for injections Rest

The composition of the claimed infusion solution includes a known composition containing sodium, magnesium, potassium and sodium Ν-methylglucamine succinate chlorides as an active component that stimulates energy metabolism and restores cellular respiration, improves the energy potential of damaged cells of organs and tissues, and does not have choleretic action.

The inventive detoxification infusion solution additionally contains as biologically active components riboxin, methionine and nicotinamide.

It is known that riboxin activates tissue regeneration as a result of improving their blood supply and has a positive effect on metabolic processes in the myocardium.

It is known that methionine is an aliphatic amino acid necessary to maintain the growth and nitrogen balance of the body.

It is also known that nicotinamide is a structural component of nicotinamide coenzymes, participates in redox reactions and affects the normalization of energy metabolism.

The manifestation of choleretic properties by riboxin, methionine and nicotinamide is not known.

The authors of the present invention for the first time showed that the claimed infusion solution, in general, due to the additional introduction of riboxin, methionine and nicotinamide into the composition, has a pronounced choleretic effect and increased detoxifying activity.

An increase in the detoxifying activity of the infusion solution is achieved by stimulating the outflow of bile acids, which prevents stagnation of bile and poisoning of the body with bile acids. In this case, intensive elimination of toxins with bile occurs and toxic damage to the liver is significantly reduced. As a result, liver functions, impaired as a result of intoxication, are restored, which positively affects the overall regulation of the activity of organs and systems of the body.

Thus, the infusion solution of the claimed composition has increased detoxifying activity due to the choleretic effect, which allows to increase the effectiveness of the therapeutic effect of the drug during intoxications, accompanied by severe liver damage (alcohol and chemical poisoning), as well as in the treatment of liver diseases (acute and chronic hepatitis).

The quantitative composition of the infusion solution was experimentally selected so that its osmolarity did not change the rheological properties of the blood when using therapeutic doses of the drug.

The invention is as follows.

One of the active components of the inventive sodium infusion solution of Ν-methylglucamine succinate is obtained directly during the preparation of the infusion solution by dissolving the calculated amounts of succinic acid, sodium hydroxide and Ν-methylglucamine in water for injection. The calculated amounts of riboxin, methionine, nicotinamide are added to the solution of the mixed salt of succinic acid and mixed until a uniform transparent solution is obtained. Then, the calculated amounts of magnesium, potassium and sodium salts are added to the resulting solution and mixed again until complete dissolution.

For example, take 5.28 g of succinic acid, 8.73 g of Ν-methylglucamine, 1.79 g of sodium hydroxide and dissolve in 900 ml of water. In this case, a solution of the active substance is formed - sodium Ν-methylglucamine succinate.

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2.0 g of riboxin, 0.75 g of methionine and 0.25 g of nicotinamide are added to this solution. After dissolution, 6.0 g of sodium chloride, 0.3 g of potassium chloride and 0.12 g of magnesium chloride are added and stirred until complete dissolution. Then the volume of the solution was adjusted to 1000 ml with water for injection.

The solution is filtered through a Sartorius type sterilizing filter and poured into sealed containers of 200 or 400 ml.

The resulting solution contains 1.50 wt.% Sodium Ν-methylglucamine succinate, 0.6 wt.% Sodium chloride, 0.012 wt.% Magnesium chloride, 0.03 wt.% Potassium chloride, 0.2 wt.% Riboxin, 0.075 wt. .% methionine, 0.025 wt.% nicotinamide, water for injection - up to 100 wt.% and has an osmolarity of 353 Mosmol / L.

In the table. 1-6 presents the results of experimental and clinical studies of the inventive infusion solution.

In the table. 1 shows the results of a study of acute toxicity of the claimed solution.

In the table. 2 shows data on the selection of an effective dose of the inventive infusion solution.

In the table. 3 shows the results of an experimental study of the choleretic action of the inventive solution.

In the table. 4 shows the results of an experimental study of the detoxifying activity of the inventive infusion solution.

In the table. 5 and 6 present the results of the therapeutic efficacy of the claimed infusion solution.

Experience 1. The study of the acute toxicity of the proposed infusion solution compared with the prototype was performed on 100 rats of the Wistar breed from the Rappolovo nursery RAMS according to standard methods. In the experiment, lethal doses of LD ₁₆ , LD 5 ₀ and LD _{84 were} determined with intravenous administration of drugs to animals.

The research results presented in table 1 show that the acute toxicity of the claimed drug is almost equivalent to the acute toxicity of the drug selected as a prototype.

The inventive infusion solution does not have mutagenic, teratogenic, embryotoxic, allergenic and immunotoxic effects.

The choice of an effective dose of the inventive infusion solution was carried out experimentally.

Experience 2. The limits of the effective dose of the proposed infusion solution - the minimum and maximum tolerated daily dose are set on the model of acute toxic poisoning.

The experiment was performed on 200 male rats obtained from the Rappolovo RAMS nursery, which were injected with natural toxins produced by poisonous mushrooms. In the experiment, pale toadstool mushroom extracts obtained from the Voronezh region in 1999 and causing severe poisoning in humans were used. Chemical analysis of these fungi showed the presence of the following toxins in them: α-amanitine - 396.3 μg / ml, β-amanitine - 172.6 μg / ml, phallocidin - 193.4 μg / ml, phalloidin - 101.8 μg / ml.

Previously, on 20 rats, the main toxicometric parameters were determined - lethal doses of mushroom extracts, which were: LD ₁₆ = 0.33 ± 0.21ml / 10g, LD ₅₀ = 0.67 ± 0.21ml / 10g, LD ₈₄ = 1.37 ± 0.21ml / 10g.

The remaining animals were divided into five groups of 36 animals each.

In the 1st (control) group, animals were injected with mushroom extract without treatment. In the 2nd group, the animals were injected with mushroom extract and the claimed infusion solution in a dose of 5 ml per animal. In the 3rd group, the animals were injected with mushroom extract and the claimed infusion solution in a dose of 10 ml per animal. In the 4th group, the animals were injected with mushroom extract and the claimed infusion solution in a dose of 20 ml per animal. In the 5th group, the animals were injected with an extract of mushrooms and the claimed infusion solution in a dose of 30 ml per animal.

Moreover, in each group of animals were infected with several lethal doses equal to 1LD50,2LD50 and 3LD50, respectively.

The studied doses of the claimed infusion solution were administered to rats 30 minutes after administration of the mushroom extract, once, in the tail vein, using an infusomat, at a rate of 10 ml / h.

The effective dose limits of the claimed infusion solution were determined by the clinical picture of intoxication and total mortality of animals within 48 hours after administration of the mushroom extract.

In the 1st (control) group of rats, the clinical picture was characterized by physical inactivity, lethargy, ruffled hair and untidiness of animals. Overall mortality in this group was the highest. The death of animals occurred against the background of seizures and paralysis for 6-24 hours.

In the 2nd group, the overall mortality was less, the survival rate of animals, compared with the control group, increased by an average of 8.3%.

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In the 3rd and 4th groups, minimal mortality was observed with the introduction of toxin poisonous fungi. The survival of animals in these groups, compared with the control, increased by 33.3 41.7% at 1LD50, by 25.0-33.3% at 2LD50 and by 16.7-25.0% at 3LD ₅₀ .

In the 5th group, with the introduction of a higher dose of the inventive infusion solution - 30 ml per animal, survival decreased. This is due to an increase in the concentration of toxins in the bloodstream due to the deterioration of the hydrodynamic properties of the blood (the effect of cell dehydration) with the introduction of a large dose of the drug.

Thus, the effective dose of the proposed infusion solution is 10-20 ml of the drug per animal per day, which corresponds to a dose of 400-800 ml of this solution, administered to a person with an average weight of 70 kg (Prozorovsky V.B., Practical Guide for Accelerated Determination of Average Effective doses and concentrations of biologically active substances, Baikalsk, 1994, p. 80).

Experience 3. The study of the choleretic effect of the proposed infusion solution was carried out on 12 Beagle dogs, weighing 10-12 kg, obtained from the RAMS kennel near Moscow. Animals were kept under standard vivarium conditions.

After the operation of blocking the bile duct and suturing of a special fistula according to the standard method, the amount of bile released was determined daily in animals.

To study the choleretic action of the claimed infusion solution in comparison with the infusion solution selected for the prototype, three groups of animals were formed, 4 animals each.

In the 1st (control) group, animals were injected with 100 ml of sodium chloride solution.

In the 2nd group, animals were injected with 100 ml of the inventive infusion solution.

In the 3rd group, animals were injected with 100 ml of Reamberin infusion solution.

In all groups, drugs were administered from 1 to 5 days after the operation, once a day, intravenously, using an infusomat, at a rate of 100 ml / h.

The results of the study, shown in table 3, show that the average amount of bile secreted through the fistula in animals of the 2nd group exceeded this indicator in animals of the 1st (control) group by 34.9-55.7%. In the 3rd group of animals, with the introduction of the prototype, the average amount of secreted bile was 10.9-11.6% more than in the control group.

Thus, the presented results indicate that the claimed infusion solution has a pronounced choleretic effect.

Experience 4. The detoxifying activity of the proposed infusion solution was evaluated on a model of obstructive jaundice.

Modeling of obstructive jaundice in experimental animals was carried out by ligation and compression of the common bile duct according to standard methods. In violation of the outflow of bile, stagnation of bile acids occurs and the body is poisoned with bilirubin, which is absorbed into the blood through the extrahepatic ducts, as a result of which obstructive jaundice develops.

Studies were performed on 60 female Wistar rats, divided into three groups of 20 animals each.

In the 1st (control) group, the animals were without treatment.

In the 2nd group, animals were injected with 10 ml of the inventive infusion solution.

In the 3rd group, animals were injected with 10 ml of Reamberin solution (prototype).

The studied drugs were administered to rats daily, once, in the tail vein using an infusomat at a rate of 10 ml / h for five days after surgery.

The detoxifying activity of infusion solutions was evaluated by the clinical picture and the dynamics of biochemical parameters in three groups of animals from the first to the fifth day after the operation.

The results of the study are presented in table 4.

The clinical picture in the 1st group of rats with obstructive jaundice without treatment was characterized by yellowness of the mucous membranes, inhibition of movements, and refusal to eat. On the fifth day, out of 20 animals, 5 individuals survived (25%). At autopsy, a picture of organ damage by bile acids was observed in dead animals.

In the 2nd group of animals, as a result of the introduction of the inventive solution, there was a significant improvement in the clinical picture. On the fifth day, 15 animals survived (75%), while in the 3rd group (prototype) 8 animals survived (40%).

A biochemical blood test showed that on the fifth day in the 3rd group of animals, the level of total bilirubin in the blood serum decreased by 2.9 times, compared with the control group, whereas in the second group this indicator decreased by 11.1 times.

The increase in survival and a significant decrease in the level of total bilirubin in the 2nd group (the claimed infusion solution) indicates the active elimination of toxins from the animal organism.

In addition, in animals that were injected with the inventive infusion solution, normalized indicators characterizing the degree of damage to hepatocytes and the functional state of the liver. So, in the 2nd group to a greater extent than in the 3rd group, the levels of alanine aminotransferase (ALT) decreased

- 4 007865 aspartate aminotransferase (AST) and alkaline phosphatase. Hexenal sleep time in the 2nd group of animals decreased 1.6 times, and in the 3rd group - 1.2 times compared with the control group; the turbidity of the thymol test in the 2nd group decreased by 3.7 times, and in the 3rd group - 2.1 times compared with the control group.

The data show that when hepatocytes are affected by bile acids, the hepatoprotective effect of the claimed infusion solution is higher than the infusion solution selected for the prototype, which indicates the restoration of liver cell function.

Thus, an increase in the detoxifying activity of the inventive infusion solution is achieved by stimulating the outflow of bile acids, more active elimination of toxins from the body and restoration of liver functions.

The therapeutic efficacy of the proposed infusion solution was evaluated in the treatment of severe icteric acute viral hepatitis in the intoxication phase in 200 patients on the background of standard antiviral therapy with recombinant interferon.

All patients were divided into experimental and control groups. In the experimental group, the treatment was carried out by the claimed drug, in the control group - the drug selected for the prototype. The drugs were administered intravenously, drip, once a day at a dose of 800 ml per person.

The therapeutic efficacy of drugs was evaluated by the dynamics of clinical and biochemical parameters in patients upon admission to intensive care and on the sixth day of treatment.

The results of the examination of patients are presented in table. 5, 6.

Clinical indicators presented in table 5, indicate an improvement in the condition of patients in the experimental group in a shorter time than in the control.

So, in the experimental group, the duration of the icteric period and headaches was 2 times less, the duration of weakness, pain in the right hypochondrium and skin itching was 1.78 times less, the duration of anorexia, nausea, dizziness and sleep disturbance was 1.5 times less than in the control group. The number of bed days in the experimental group decreased by 1.8 times and averaged 16.2 days.

An analysis of the dynamics of biochemical parameters characterizing liver lesions showed (Table 6) that during treatment with the claimed drug, there is a decrease in the levels of bilirubin, AST, ALT, alkaline phosphatase, creatinine and cholesterol to normal values.

Thus, the treatment results in the experimental group of patients were better than in the control group. The use of the claimed drug contributed to a significant improvement in the clinical picture of the disease, confirmed by normalization of biochemical parameters, and a reduction in treatment time, which indicates an increase in the effectiveness of treatment of acute viral hepatitis in the intoxication phase.

An infusion solution of the claimed composition is a drug with increased detoxifying activity due to choleretic action, and allows you to effectively treat diseases accompanied by severe liver damage.

Table 1

table 2

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Table 3

Group Injectable drug The average amount of excreted bile (ml), through 1 day 2 days 3 days 4 days 5 days 1 Sodium Chloride 60.6 + 2.3 54.3 + 1.7 48.1 + 1.4 45.9 + 1.1 42.3 + 1.9 2 The inventive infr.r 87.4 + 4.2 80.3 + 4.6 74.9 + 3.0 66.2 + 3.4 57.1 + 2.2 3 Inf. Reamberin 68.8 ± 3.4 61.2 + 2.8 55.8 + 2.1 50.2 + 2.3 47.8 + 1.8

Table 4

Indicator Groups of animals 1 day after ligation of the common bile duct 5 days after ligation of the common bile duct 1 (without treatment) 2 (declared drug) 3 (prototype) 1 (without treatment) 2 (declared drug) 3 (prototype) The number of surviving animals, individuals 18 20 20 5 fifteen 8 Total bilirubin, mmol / l 3.2 + 0.2 3.0 + 0.1 3.2 + 0.2 68.9 + 4.7 * 6.2 + 0.2 24.1 + 0.1 * ALT, mkkat / l 0.33 + 0.03 0.26 + 0.02 0.29 + 0.04 4.62 + 0.11 * 2.32 + 0.03 * 3.78 + 0.06 * AST, mkkat / l 0.99 + 0.06 0.74 + 0.04 0.81 + 0.09 1.88 + 0.18 * 0.92 + 0.06 * 1.28 + 0.15 Alkaline phosphatase, mkkat / l 0.89 + 0.10 0.72 + 0.12 0.69 + 0 .11 3.43 + 0.09 * 0.73 + 0.08 0.96 + 0.14 * Hexenal sleep, min 25.3 + 1.7 15.4 + 1.1 24.0 + 1.6 76.4 ± 2.9 * 47.0 + 1.6 65.8 + 1.8 * Thymol test, units turbidity 1.44 + 0.05 1.49 + 0.14 1.41 + 0.12 12.13 + 0.98 * 3.29 + 0.28 5.69 + 0.24 *

Note: * - significant differences from intact animals at p <0.05. Table 5

Clinical indicator Group experienced control Frequency% Duration, days Frequency% Duration, days Jaundice 100 5.3 ± 0.6 100 10.5 ± 0.9 Weakness 98 3.2 + 0.2 94 5.7 + 0.6 Itchy skin 98 3.2 ± 0.2 100 5.7 ± 0.6 Anorexia 94 3.2 + 0.2 96 4.8 ± 0.5 Pain in the right hypochondrium 87 3.2 + 0.2 81 5.7 + 0.6 Nausea 68 1.5 ± 0.4 76 2.3 + 0.3 Sleep disturbance 56 5.8 + 0.6 46 8.6 + 0.5 Headache 24 1.3 ± 0.5 28 2.7 ± 0.1 Dizziness 10 1.2 ± 0.1 12 1.7 ± 0.1 Number of beds / days 16.2 + 1.4 29.3 ± 0.6

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Table 6

Biochemical indicator Group Normal value experienced control before treatment after treatment before treatment after treatment Bilirubin, μmol / L 258 + 16 26 + 8 231 ± 13 64 ± 12 3.7-17.1 AST, μmol / L 0.87 + 0.10 0.31 + 0.09 0.71 ± 0.12 0.51 ± 0.10 0.06-0.46 ALT, micromol / l 1.08 ± 0.12 0.59 + 0.08 0.98 + 0.11 0.76 + 0.12 0.12-0.68 Creatinine, μmol / L 189 + 11 92 ± 5 164 ± 13 111 ± 11 44.2-106.0 Alkaline phosphatase, units / l 205 + 17 108 ± 9 216 ± 14 146 ± 12 Up to 120 Cholesterol, mmol / L 3.7 + 0.3 4.2 ± 0.5 s, s ± o, s 3.9 + 0.2 Up to 7.2 Thymol test, units turbidity 5.8 1.9 4.1 3.2 Up to 2.5

CLAIM

Claims (1)

CLAIM A detoxification infusion solution containing sodium, magnesium and potassium chlorides, a biologically active component - sodium Ν-methylglucamine succinate and a solvent - water for injection, characterized in that it additionally contains riboxin, methionine and nicotinamide as biologically active components, in the following ratio of components , wt.%: Sodium chloride 0.4-0.6 Magnesium chloride 0.011-0.013 Potassium chloride 0.027-0.033 Sodium Ν-methylglucamine succinate 1.40-1.60 Riboxin 0.15-0.25 Methionine 0.06-0.08 Nicotinamide 0.02-0.04 Water for injections Rest Eurasian Patent Organization, EAPO