Detoxifying infusion solution

 

(57) Abstract:

The invention relates to medicine, namely to multicomponent infusion solutions with detoxification, hepatoprotective effect, and can be used in the intoxication of the organism of various severity. The objective of the invention is to provide an infusion solution with enhanced detoxifying activity due choleretic action and effectively to treat diseases associated with severe liver damage. Detoxifying infusion solution containing the chlorides of sodium, magnesium and potassium, biologically active ingredient - sodium, N-methylglucamine succinate and the solvent is water for injection, further comprises as biologically active components - Riboxin, methionine and nicotinamide, in the following ratio, wt.%: sodium chloride is 0.4 to 0.6; magnesium chloride 0,011-0,013; potassium chloride 0,027-0,033; sodium N-methylglucamine succinate 1,40-1,60; Riboxin 0,15-0,25; methionine 0,06-0,08; nicotinamide 0,02-0,04; water for injection else. 6 table.

The invention relates to medicine, namely to multicomponent infusion solutions with detoxification, hepatoprotective the diseases, accompanied by the liver.

Known multicomponent infusion solutions, having the effect of detoxification, containing a biologically active substance succinic acid and its derivatives (succinate), as well as vitamins and mineral salts.

Thus, in the patent of Russian Federation №2039556 ("Pharmaceutical composition protivoallergennogo, stimulating energy metabolism, acid-forming and secretory function of gastric mucosa, radioprotective and cholera steps, the method of prevention and treatment of alcohol intoxication and alcohol withdrawal syndrome, the method of stimulation and diagnosis of acid-forming and secretory function of the gastric mucosa and the way to protect against radiation damage of warm-blooded animals", a 61 K 31/19, priority from 07.07.1993 g) described composition, which contains a mixture of succinic and citric acids or their pharmaceutically acceptable salts, and as a pharmaceutical solvent is water or an alkaline mineral water.

The composition has a alcohol detoxifying effect, stimulates energy metabolism, acid-forming and secretory function of gastric mucosa and is used in acute ALC is, what about it has no effect on the recovery of liver function, impaired when alcohol poisoning, which reduces the effectiveness of treatment of disease.

Known drug "Cytoflavin" for injection (EA patent No. 001099, priority from 10.06.99 And 61 To 31/708), which consists of biologically active components: metabolites sodium salt of succinic acid and Riboxin, and coenzymes - nicotinamide and Riboflavin, and as a solubilizer - N-methylglucamine.

This composition has a pronounced antihypoxic and antioxidant, metabolic activity, and is used in diseases of the liver, including hepatic toxicity of varying severity.

Detoxication effect of this drug is achieved through stimulation of the processes of energy metabolism and recovery of cellular respiration, which are accompanied by active utilization of glucose, while its synthesis, especially in the liver cells, is quite slow. As a result, there is a lack of balance between spending and utilization of energy resources of the cell, which leads to degenerative changes in vital organs, especially the liver.

aktivnosti treatment and longer recovery period.

Also known infusion solution "Reamberin" (EA patent No. 000879, priority from 02.12.1998, And 61 To 31/194), which is a comprehensive drug and contains the chlorides of sodium, potassium and magnesium, the biologically active ingredient - sodium, N-methylglucamine succinate and the solvent in the following ratio, wt.%:

Sodium chloride 0,4-0,6

Magnesium chloride 0,011-0,013

Potassium chloride 0,027-0,033

Sodium, N-methylglucamine succinate 1,40-1,60

Water for injections the Rest

This drug is selected as a prototype.

Infusion solution "Reamberin" detoxifies, antihypoxic effect, promotes utilization of fatty acids and glucose, restores energy potential of cells due to activation of aerobic intracellular processes, normalizes the acid-base balance and gas composition of the blood.

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

However, the effectiveness of this medication decreases in the treatment of diseases involving significant damage to the liver.

Due to the impact of endogenous and exogenous toxins is opinie bile, that not only makes it difficult to remove toxins from the body, but also affects the patient's condition due to a poisoning of the body of bile acids.

In addition, some bile acids, having a pronounced surface-active properties, accumulate, can cause damage, degeneration and necrosis of liver cells (hepatocytes), which leads to irreversible changes in the liver, further weakening its functions and disturbance of the overall regulation of the activity of the organs and body systems.

Thus, detoxifying activity known infusion solution is reduced in cases involving severe liver disease, due to the weakening of the liver, and disorders of the process of detoxification of bile, which reduces the effectiveness of therapeutic action of the drug.

The objective of the invention is to provide an infusion solution with enhanced detoxifying activity due choleretic action and effectively to treat diseases associated with severe liver problems.

The problem is solved by the fact that detoxification infusion solution containing the chlorides of sodium, magnesium, and it is according to the invention additionally contains as a biologically active components Riboxin, methionine and nicotinamide, in the following ratio, wt.%:

Sodium chloride 0,4-0,6

Magnesium chloride 0,011-0,013

Potassium chloride 0,027-0,033

Sodium, N-methylglucamine succinate 1,40-1,60

Riboxin 0,15-0,25

Methionine 0,06-0,08

Nicotinamide 0,02-0,04

Water for injections the Rest

In the composition of the inventive infusion solution is known composition containing the chlorides of sodium, magnesium, potassium and sodium, N-methylglucamine succinate as the active ingredient, which stimulates energy metabolism and recovery of cell respiration, helps increase the energy potential of the damaged cells, organs and tissues and does not have a choleretic effect.

Declare detoxifying infusion solution further comprises a biologically active components Riboxin, methionine and nicotinamide.

It is known that Riboxin activates tissue regeneration as a result of improved blood flow and has a positive effect on metabolic processes in the myocardium.

It is known that the methionine is an aliphatic amino acid, necessary for poderiam component nicotinamide coenzymes, participates in redox reactions and affects the normalization of energy metabolism.

The manifestation of the Riboxin, methionine and nicotinamid choleretic properties is not known.

The authors of the present invention first shown that the proposed infusion solution in General, due to the additional introduction into the composition of Riboxin, methionine and nicotinamide, choleretic drug and increased detoxifying activity.

Increase 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 of bile acids. This results in intense detoxification of bile and toxic damage of the liver is largely reduced. As a result, liver function impaired as a result of intoxication, restored, which has a positive effect on the General regulation of the activity of the organs and body systems.

Thus, the infusion solution of the inventive composition has a high detoxifying activity due to the choleretic activity, which helps to increase the efficiency of therapeutic action Priya), as well as in the treatment of liver diseases (acute and chronic hepatitis).

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

The invention is as follows.

One of the active components of the inventive infusion of a solution of sodium N-methylglucamine succinate is obtained directly in the process of preparing an infusion solution by dissolving the calculated quantities of succinic acid, sodium hydroxide and N-methylglucamine in water for injection. To a solution of a mixed salt of succinic acid is added the estimated number of Riboxin, methionine, nicotinamide and stirred to obtain a homogeneous transparent solution. Then to the resulting solution was added the calculated amount of salts of magnesium, potassium and sodium and again stirred until complete dissolution.

For example, take 5,28 g of succinic acid, 8,73 g of N-methylglucamine, 1,79 g of sodium hydroxide and dissolved in 900 ml of water. This forms a solution of the active substance is sodium, N-methylglucamine succinate.

To this solution was added 2.0 g of Riboxin, 0.75 g of methionine and stirred until complete dissolution. Then bring the volume of the solution to 1000 ml with water for injection.

The solution is filtered through a sterilizing filter type “Sartorius” and poured into a sealed container with a volume of 200 or 400 ml.

The resulting solution contains 1.50 wt.% sodium, N-methylglucamine succinate, 0.6 wt.% sodium chloride, a 0.012 wt.% magnesium chloride, 0.03 wt.% potassium chloride, 0.2 wt.% Riboxin, of 0.075 wt.% methionine, of 0.025 wt.% nicotinamide, and water for injection to 100 wt.% and has an osmolarity of $ 353 Mosmol/L.

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

In table.1 shows the results of studies of acute toxicity of the proposed solution.

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

In table.3 shows the results of experimental studies of the choleretic action of the proposed solution.

In table.4 shows the results of experimental studies of the detoxifying activity of the inventive infusion.

In table.5 and 6 presents the results of the clinical effectiveness of the inventive infusion.

Experience 1. A study on "Wistar" from the kennel Rapolano RAMS by a standard method. The experiment was determined lethal dose LD16, LD50and LD84when intravenous drugs to animals.

The research results presented in table.1, show that the acute toxicity of the proposed preparation is practically equivalent to the acute toxicity of the drug, selected as a prototype.

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

The selection of an effective dose of the inventive infusion solution was implemented experimentally.

Experience 2. Limits effective dose of the inventive infusion solution, minimum and maximum tolerated daily dose installed on a model of acute toxic poisoning.

The experiment was carried out on 200 rats-males obtained from the kennel RAMS “Rapolano”, which was introduced natural toxins produced by toxic mushrooms. In the experiment were used mushroom pale grebes, obtained from the Voronezh region in 1999 and caused severe poisoning in humans. Chemical analysis of these fungi showed the presence of the following toxins: -amanitin - 396,3 µg/ml-amanitin - 172,6 ate toxicometric options - lethal doses of extracts of fungi, which amounted to: LD16=0,33±0,21 ml/10g, LD50=0,67±0,21 ml/10g, LD84=1,37±0,21 ml/10g.

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

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

In each group of animals was infected several lethal doses equal LD50, LD50and LD50respectively.

Investigational dose of the inventive infusion solution was injected to rats 30 minutes after administration of an extract of mushrooms, one in the tail vein, using the infusion, at a rate of 10 ml/h

Limits effective dose of the inventive infusion solution was determined by the clinical picture of intoxication and total mortality of animals was characterizability physical inactivity, the slow, vzieroshenii wool and slovenliness animals. Overall mortality in this group was the largest. The death of animals came amid convulsions and paralysis within 6-24 hours.

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

In the 3rd and 4th groups were observed minimum mortality with the introduction of toxins of poisonous mushrooms. The survival of animals in these groups compared to the control increased by 33.3-41.7 per cent in LD50, 25.0-33.3% of at LD50and 16.7-25.0% of at LD50.

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

Thus, the effective dose of the inventive infusion solution is 10-20 ml per animal per day, which corresponds to a dose of 400-800 ml of this solution are introduced to a person with an average weight of 70 kg (Prozorovsky Century B. a Practical guide to speeding up the definition of medium affectionado steps of the inventive infusion was performed in 12 dogs breed "Beagle", weighing 10-12 kg, obtained from the suburban nursery RAMS. The animals were kept in standard vivarium conditions.

After a transaction overlap bile duct and sewing special fistula according to standard procedures in animals were daily determined the amount of released bile.

For research choleretic action of the inventive infusion solution, in comparison with the infusion solution chosen for the prototype, was formed three groups of animals 4 animals each.

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

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

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

In all groups the drugs were injected with 1 to day 5 after surgery, once per day, intravenously, via infusion, at a rate of 100 ml/h

The results of the study are given in table.3, show that the average amount of bile released through the fistula animals of the 2nd group, 34.9 and 55.7% exceeded this target in animals 1 (control) group. In the 3rd group of animals with the introduction of the prototype, the average number of excreted bile Cstout about what is claimed infusion solution has a strong choleretic action.

Experience 4. Detoxifying activity of the inventive infusion solution was evaluated on the model of obstructive jaundice.

Modeling of mechanical jaundice in experimental animals was carried out by bandaging and compression of the common bile duct by a standard method. The violation of the outflow of bile is the stagnation of bile acids and poisoning of the body by bilirubin, which is absorbed into the blood through the extrahepatic ducts, due to the development of obstructive jaundice.

The study was carried out at 60 the female-female rats of Wistar breed, divided into three groups of 20 animals each.

In the 1st (control) group animals were untreated.

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

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

The study drugs were administered to rats daily, once in the tail vein with the help of infusion, at a rate of 10 ml/h, within five days after the operation.

Detoxifying activity of the infusion solutions were evaluated by clinical and deregulate of the study are presented in table.4.

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

In the 2nd group of animals as a result of introducing the proposed solution has been a significant improvement of the clinical picture. On the fifth day survived 15 animals (75%), whereas in the 3rd group (prototype) survived 8 animals (40%).

Biochemical analysis of blood showed that on the fifth day of the 3rd group of animals, the level of total bilirubin in serum decreased 2.9 times compared with the control group, whereas in the 2nd group, this figure decreased to 11.1 times.

The increase in survival and a significant reduction in total bilirubin in the 2nd group (declare infusion solution) testifies to the active elimination of toxins from the organism.

In addition, in animals that were administered the inventive infusion solution, normalized indicators of the degree of the damage of hepatocytes and liver function. So, in the 2nd group and alkaline phosphatase. Time geksenalovy sleep in the 2nd group of animals has decreased by 1.6 times, and the 3rd group is 1.2 times as compared with the control group; thymol turbidity tests in the 2nd group decreased 3.7 times, and in the 3rd group - 2.1 times as compared with the control group.

The data show that with the defeat of hepatocytes, bile acids, hepatoprotective effect of the inventive infusion solution is higher than the infusion solution chosen for the prototype, which demonstrates the functional recovery of the liver cells.

Thus, increasing the detoxifying activity of the inventive infusion solution is achieved through stimulation of the outflow of bile acids, increased excretion of toxins from the body and restore liver function.

Therapeutic effectiveness of the proposed infusion solution has been evaluated in the treatment of severe forms of acute icteric viral hepatitis in the phase of intoxication 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 treatment was carried out by the claimed preparation in the control group of pooka.

Therapeutic efficacy was assessed by the dynamics of clinical and biochemical parameters in patients at their admission to the intensive care unit and on the sixth day of treatment.

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

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

Thus, in the experimental group, the duration of icteric period and headaches was 2 times smaller, the duration of weakness, pain in the right hypochondrium and skin itching - 1,78 times less duration of anorexia, nausea, dizziness and sleep disturbance is 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.

Analysis of the dynamics of biochemical indicators of liver injury, showed (table.6) that the treatment claimed the drug is a decrease in the levels of bilirubin, ACT, ALT, alkaline phosphatase, creatinine and cholesterol levels to normal values.

Thus, the results of the treatment in the experimental group patients were better than in the control group. The use of the inventive PR is on biochemical parameters and shortening the treatment time, which indicates the efficiency of the treatment of acute viral hepatitis in the phase of intoxication.

Infusion solution of the inventive composition is a drug that has increased detoxifying activity due choleretic action, and allows you to effectively treat a disease associated with severe liver problems.

Detoxifying infusion solution containing the chlorides of sodium, magnesium and potassium, biologically active ingredient - sodium, N-methylglucamine succinate and the solvent is water for injection, characterized in that it further comprises a biologically active components - Riboxin, methionine and nicotinamide in the following ratio, wt.%:

Sodium chloride 0,4-0,6

Magnesium chloride 0,011-0,013

Potassium chloride 0,027-0,033

Sodium, N-methylglucamine succinate 1,40-1,60

Riboxin 0,15-0,25

Methionine 0,06-0,08

Nicotinamide 0,02-0,04

Water for injections the Rest



 

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