Balanced infusion solution
SUBSTANCE: invention represents a balanced infusion solution containing sodium, potassium and magnesium chlorides, a solvent and sodium L-arginine succinate of formula: Na+[NH=C(NH2)NH(CH2)3CH(NH2)COOH]+[OOC(CH2)2COO]2-. The ingredients in the solution are found in certain proportions, wt %.
EFFECT: invention provides enhanced detoxification activity, low toxicity and wide range of clinical applications.
11 tbl, 6 ex
Area of technology.
The invention relates to medicine and pharmacology, namely to saline infusion solution, with a detoxifying effect, and can be used in the treatment of diseases and conditions associated with intoxication of the organism of varying severity.
In medical practice widely used saline infusion solutions on the basis of salts of succinic acid.
For example, registered polyionic solution based on sodium succinate - "Regimen" (Registration certificate of the Republic of Belarus RU 12/12/2047 from 04.12.12), used as anti-hypoxic and means of detoxification in acute endogenous and exogenous intoxications of various etiologies and for the correction of water-salt balance in the body, containing the following components: sodium succinate hexahydrate 7.5 g/l, sodium chloride 4.0 g/l, potassium dihydrogen phosphate 1.4 g/l, magnesium chloride hexahydrate 0.02 g/l, glucose 50 g/l and has the following ionic composition: sodium 161 mmol/l, potassium 10,2 mmol/l, magnesium 1.1 mmol/l, chlorides 70,5 mmol/l phosphate (calculated as phosphorus) of 10.0 mmol/l (instructions for medical use, the Ministry of health of the Republic of Belarus No. 1515 dated 26.12.12)
It must be emphasized that this solution is not balanced in the main vital �Onam and contains an excess of sodium (10%), the excess of potassium ions (250% of normal), and lack of chlorine ions (30%), which creates problems of correction of water-salt metabolism in patients.
Furthermore, it is known that the combination of glucose with low molecular weight dicarboxylic acids (in this case with succinic acid) creates a risk of formation of dangerous for the health of patients impurities (furfural) in the production and storage of the drug (Encyclopedia of Pharmaceutical technology. Third Edition, 2006).
Also known drug "Succinea 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 1l) and has the following ionic composition: sodium 142 mmol/l, potassium 4.0 mmol/l, magnesium 1.1 mmol/l, chloride 114 mmol/l proposed as remedies for the treatment of critical conditions and, also containing in its composition as an active ingredient succinic acid. "Succinea" improves blood circulation, activates energy metabolism, restores hemodynamic parameters and cardiac muscle function in various pathological conditions (patent UZ 4106 In from 21.04.1994, RUz 10/140/3 from 11.05.10, Levin GS, Shevchenko LI, Gubaev SA. Comparative evaluation of the effects of crystalloid solutions containing sodium lactate and sodium succinate on the hemodynamic indicators in different types of hemorrhage, Gematol Transfuziol. 1991 Feb; 36 (2): 25-8., PMTO:2055408).
Known solutions �of uccinate in combination with a complex of vitamins and metabolic components. Thus, the known drug "Cytoflavin" (Registration number of the Russian Federation PN 00313/1 from 21.10.2004) containing succinic acid as sodium meglumine succinate, in combination with inosine, nicotinamide and Riboflavin, possess cytoprotective action (patent EA 001099).
In clinical practice polyionic recovery solution "Reamberin" (Registration number of the Russian Federation №99/363/2 08.10.1999), containing succinic acid as sodium meglumine succinate and balanced set of macro salts of potassium, magnesium, sodium, and used as a detoxifying medicines (patent EA 000879) and recovery solution, "Remaxol" (Registration number of the Russian Federation LSR-009341/09 19.11.2009) containing succinic acid as sodium meglumine succinate in combination with inosine, nicotinamide and methionine, possessing hepatoprotective action (patent EA 007865).
The closest analogue of the claimed invention on the pharmacological action and composition is a saline infusion solution "Reamberin" (patent EA 000879), selected as a prototype. The drug is balanced by the ion composition and has detoxifying properties due to the normalization of water-electrolyte balance, antihypoxic and antioxidant effects.
However, carrying�of atra that there is a high therapeutic effect, known to the infusion solution has a key pharmacological disadvantage, due to the peculiarity of the active component meglumine sodium succinate, the cation of which (methylglucamine) is practically not metabolized in the human body and quick utilization of anion - monosubstituted sodium succinate is able to accumulate in the body and lead to significant alkalization of the blood (alkalosis), and urine, as noted in the instructions for medical use of the prototype (Registration number of the Russian Federation №99/363/2 08.10.1999). The corrected state is difficult and especially dangerous in patients with reduced buffer capacity of the blood and renal insufficiency with severe critical conditions such as polytrauma, sepsis, frostbite organs and tissues, liver failure, and other conditions associated with activation of catabolic processes in the body.
In this regard, the high content of sodium meglumine succinate in the prior art, limits the maximum daily amount of this drug 800 ml, which is insufficient for infusion therapy of a number of critical conditions (acute blood loss, sepsis, polytrauma, hepatic encephalopathy), requiring the administration of large amounts (up to 10 litres a day).
In addition, alkalization of urine, typical when applying proto�IPA and due to the excretion of an organic base methylglucamine through the kidneys, can be dangerous for patients with nephrolithiasis. This is due to the solubilization ability of urates and oxalates of calcium under the influence of methylglucamine that 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 specific groups of patients, which significantly narrows the scope of its application.
Brief description of the invention.
The object of the invention is to create a new balanced infusion solution having a high detoxifying activity, low toxicity and providing a wide range of clinical applications.
The problem is solved in that a balanced infusion solution containing the chlorides of sodium, potassium and magnesium, the solvent and the biologically active component according to the invention, as a biologically active component contains sodium L-arginine succinate of the formula:
with the following ratio of components, mass.%;
|Magnesium chloride hexahydrate||0,015-0,030|
|Sodium L-arginine succinate||1,400-1,700|
|Water for injections||Else|
Inventive infusion solution contains sodium chloride, magnesium chloride hexahydrate and potassium chloride in a certain proportion, providing a physiologically acceptable, the content of inorganic ions sodium, potassium, magnesium and chlorine (the Magician Lee, Basic skills in interpreting laboratory data., 4thed.).
As a biologically active component of the inventive balanced infusion solution contains a new chemical compound of sodium L-arginine succinate of the formula:
Physico-chemical properties of sodium L-arginine succinate are shown in table 1:
Good solubility in water and physiologically acceptable pH value of aqueous solutions (7,0-7,2) sodium L-arginine succinate, makes it suitable for the production of parenteral pharmaceuticals.
It is known that salts of succinic acid in the composition with the conditionally essential amino acid L-arginine are used as ingredients in medicinal drugs with stabilizing and buffer properties. For example, the known composition and�of hibitor way of tissue factor and L-arginine succinate (patent EP 1602667), for preservation of solutions of antibodies (application US 20100239567, patent JP 2009-108040, the application US 20120121581) and as a detergent skin care product (application JP 2001-081025).
Described complex compositions comprising L-arginine and succinic acid for the treatment and prevention of hepatic encephalopathy in the form of effervescent tablets, used as food additives (application RU 2011109884/15).
In scientific literature described in the cardioprotective effect of mono - and di-argininosuccinate - different combinations of succinic acid from L-arginine.
Thus, the effect of L-arginine monoacrylate as a potential cardioprotective drug (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 Belarusian state medical University, No. 4, Pp. 51-53).
On the basis of diergeneeskunde registered drug "Carcinosin" (THAT BY 100185198.112-2009, registration number 027761 from 09.12.2009) containing the active substance in the form of a 5% aqueous solution applied as a means for the treatment of acute myocardial infarction.
In a number of inventions proposed combined medications for the treatment of cardiovascular� diseases on the basis of a combination of arginine succinate with arginine aspartate in the form of solution for oral parenteral use (UA patents No. 36998, 37388, 39095, 90368).
In the available scientific literature are not described infusion solutions containing as an active ingredient of sodium L-arginine succinate of formula (1).
In the present invention it was shown that the new chemical compound of the formula (1) can be used as a biologically active component 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 with the prototype.
As a result of the experiments on the choice of a balanced composition of the inventive infusion solution revealed that the solutions obtained in the range of sodium content of L-arginine succinate from 14 to 17 g/l, are theoretical (calculated) the 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 315-324 mmol/kg for the inventive infusion solution is optimal, since the received data on the pharmacokinetics showed that in vivo sodium L-arginine succinate quickly penetrates into the cells and metabolized to osmotically inactive carbonic ha�and water reduced to physiological osmolality values.
These characteristics allow to balance the composition of the inventive infusion solution and enter it without significant restrictions in the volume, which expands the area of clinical application due to the exclusion of a number of contraindications associated with alkalization of the blood and urine.
Detailed description of the invention
In the inventive infusion solution ratio of components, providing balance to the composition, chosen empirically.
Thus, the introduction of the inventive infusion solution of cations of potassium and magnesium are encouraged by the addition of potassium chloride at concentrations of 0.025-0,040 g/l, and magnesium chloride hexahydrate at concentrations of 0.015-0.030 g/l, providing a physiologically acceptable ions of potassium 3,4-5,3 mmol/l and magnesium is 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, adding sodium chloride at a concentration of 8.6 g/l allows to obtain a physiologically acceptable cations of sodium 147 mmol/L. thus, the content of chlorine anions resulting from the dissociation of sodium chloride, potassium chloride and magnesium chloride hexahydrate will be about 153 mmol/l, significantly higher than the normal physiological value (May Lee, Basic skills in interpreting laboratory data., 4thed.).
In the present invention it is proposed to align the content of chlorides to physiological norm (97-110 mmol/l) by the substitution in the composition of the inventive infusion of a solution of parts of sodium chloride (NaCl) new biologically active substance. However the content of the drug in concentrations ranging from 14 to 17 g/l provides physiological chloride content without disturbing the content of sodium cations.
The invention is as follows.
Example. At the first stage receive a new biologically active ingredient - sodium L-arginine succinate of formula (1).
To obtain the sodium of L-arginine succinate take 52,80 kg of succinic acid (CAS Number 110-15-6); 77,89 kg L-arginine (Eur. Ph.); 17,88 kg of sodium hydroxide (Eur. Ph.) and dissolved in 500 l of water. Thus formed aqueous 28% solution new substance sodium L-arginine succinate according to the chemical reaction:
The resulting solution was spray dried sodium and secrete L-arginine succinate in the amount of 134,9 kg (yield 96%) as a white amorphous powder, physico-chemical properties of which correspond to the data given in table 1. Further, the powder of sodium L-arginine succinate packaged in sealed primary packaging materials with high barrier properties against water vapor and sour�ode, and then in the secondary packaging.
At the second stage have claimed recovery solution.
To do this, take the powder of sodium L-arginine succinate in the amount of 14,052 kg and dissolved in 500 l of water for injection, to the solution was added 6.0 kg of sodium chloride (Eur. Ph.), 0,244 kg of magnesium chloride and 0.3 kg of potassium chloride (Eur. Ph.) and bring the volume of the solution up to 1000 liters of water for injection (Eur. Ph.). Then the solution was filtered, poured into a glass or plastic packaging, sealed and sterilized using standard mode (maintained at a temperature of 121°C for at least 15 minutes).
Manufactured according to the example of the infusion solution has the following composition:
Study of the safety and biological activity of the claimed balanced infusion solution obtained in example of preparation carried out in comparison with the prototype - drug "Reamberin", solution for infusion of 1.5%, in a series of experimental studies on animals (experiments 1-6).
Experience 1. The study of the acute toxicity of the inventive infusion solution
The experiments were performed on white outbred rats of both sexes. To determine the rates of acute toxicity of the test solution was administered intravenously in accordance with the intended method of use in clinical practice to rats of both sexes in�trustusa doses according to the Litchfield-Wilkinson and possible for an acute injection volumes. Control animals received 0.9% sodium chloride solution in a volume of 20 ml/kg (ICH M 3(R2) Guidance of Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals, Current Step 4 version dated 11 June 2009).
In the study of acute toxicity of the inventive infusion solution revealed that the introduction of the drug in the highest possible dose 8175 mg/kg in terms of active substance mortality in the group of animals was not observed. While the toxicity of the solution prototype amounted LD50=5600 mg/kg of body weight of the animal in terms of the active substance.
Thus, in conditions of acute experience, claimed recovery solution less toxic than the prototype, is not mutagenic, teratogenic, embryotoxic, allergenic and immunotoxic effect.
Experience 2. Study of the effect on mortality of the inventive infusion solution in a model of acute endotoxemia induced by lipopolysaccharide from Salmonella enterica
The test was conducted on 200 standard Wistar rats of the age of 17-18 weeks and weighing 180-210 g. All animals received standard food and water.
Lethal endotoxic modeled by the introduction of bacterial endotoxin - lipopolysaccharide of Salmonella enterica serotype enteritidis (SIGMA-ALDRICH). Endotoxin was injected intravenously (tail vein) once in 0.2 ml water for injection. Experimentally matched doses of endotoxin, causing�ment pyrogenic reaction and 50 and 100% mortality of animals from toxic shock, that was 5 µg/kg and 25 μg/kg of endotoxin, respectively. Pyrogenic reactions recorded by measuring rectal temperature (Filkins JP, Di Luzio NR, Endotoxin induced hypothermia and tolerance in the rat. Proc. Soc. Exp. Biol. Med. 1968 Dec, 129 (3): 724-6; Utili R, Abernathy CO, Zimmerman HJ. Endotoxin effects on the liver. Life Sci. 1977 Feb 15, 20 (4): 553-68; M. Banet, Fever and survival in the rat. The effect of enhancing fever, Pflugers Arch. 1979 Jul, 381 (1): 35-8.).
For the study was drawn into eight groups of experimental animals (25 rats each: 2 control group - no treatment, experimental group 2 animals, which were injected with 0.9% solution of sodium chloride at a dose of 20 ml/kg, experimental group 2 animals, which were injected with a prototype at a dose of 20 ml/kg, experimental group 2 animals, which were injected with a new infusion solution at a dose of 20 ml/kg. the study drugs were administered intravenously once after 2 h after injection of lipopolysaccharide. Evaluation of the efficacy of drugs was assessed by the mortality rate in groups for seven days after administration of lipopolysaccharide (PL. 2).
In animals of the control groups during the first seven days after the administration of LPS at doses of 5 and 25 mg/kg developed toxic shock hyperthermia, decreased motor activity, decreased muscle tone, food refusal, diarrhea, and death.
Maintenance of endotoxin at a dose of 5 mg/kg resulted in 60% mortality.
Conducting the standard therapy formed the toxic�th shock with 0.9% solution of sodium chloride, reduced mortality of animals in 1,5 times (from 60% to 40%). The use of the prototype reduced mortality compared to control animals, 1.88 times (from 60% to 32%), as compared with the group receiving sodium chloride in 1.25 times.
By using the inventive solution decreased mortality within seven days of the experiment compared with control in 2,5 times in comparison with therapy with sodium chloride at a rate of 1.67 times, and in comparison with the prototype - 1.33 times (from 32% to 24%).
The increase in administered to laboratory animals a single dose of endotoxin to 25 µg/kg resulted in a weighting of the flow of toxic shock and 100% mortality within seven days of observation.
Conducting the standard therapy with 0.9% solution of sodium chloride at a dose of 20 ml/kg, reduced the mortality of animals in group b of 1.39 times (from 100% to 72%).
The use of the prototype reduced mortality compared with the control group already at 1.47 times, as compared with the group receiving sodium chloride at 1,06 times.
The use of the claimed solution shows a more significant reduction in mortality within seven days of the experiment compared with control in at 1.67 times compared to therapy with sodium chloride - 1.2 times, as compared with the prototype of 1.13 times (from 68% to 60%).
Thus, testing of the inventive infusion solution on the model �oxycoccos shock, showed its high detoxifying activity at various doses of endotoxin Salmonella enterica.
Experience 3. A study of the effectiveness of the inventive infusion solution on the model of acute toxic hepatitis
Studies of the claimed solution was carried out in comparison with the prototype on rats the males of the breed "Wistar" weighing 180-200 g. the experiment was carried out on 90 for the animals which formed 6 groups: intact animals (n=15); control group (n=15) animals were injected with 0.9% solution of sodium chloride at a dose of 20 ml/kg; experimental group 1 (n=15) and # 2 (n=15) animals, which were injected with the prototype in doses of 10 ml/kg and 20 ml/kg, respectively;
experimental group No. 3 (n=15) and 4 (n=15) animals, which were injected with the inventive infusion solution in doses of 10 ml/kg and 20 ml/kg, respectively.
For the formation of acute toxic hepatitis in animals of control and test groups once intraperitoneally administered phenylhydrazine sulfate at a dose of 50 mg/kg, and then after 24 h was administered intragastrically 50% oil solution of carbon tetrachloride in a dose of 3 ml/kg of body weight. After 2 h in the experimental groups began conducting fluid therapy study solutions. Therapy was conducted for 2 days consecutively. At the end of the treatment was assessed markers of intoxication: the activity of the enzymes alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, u�dairy phosphatase, the bilirubin level and the indicators of hemostasis: the prothrombin time, activated partial thrombi plastikowe time, thrombin time (Heimberg M, Watkins ML, R. Tooker Carbon tetrachioride hepatotoxicity: the direct action of CCl4on the liver Pharmacol. Exp. Ther. 1964 Jul 145: 92-101; Plaa GL, Larson RE, CCl4induced liver damage. Current concept regarding the mechanism of action. Arch Environ. Health., 1964 Oct. (9), 536-43; Bruckner JV, Mac Kenzie WF, Muralidhara S, Luthra R, Kyle GM, Acosta D. Oral toxicity of carbon tetrachloride: acute, subacute, and subchronic studies in rats. Fundam. Appl. Toxicol. 1986 Jan. 6 (1): 16-34).
In the control group noted the signs of toxic hepatitis: cytolysis syndrome, impaired detoxication of the liver with the increase of enzyme activity of alkaline phosphatase, aspartate aminotransferase, bilirubin level, the "failure" of alanine aminotransferase and tended to increase the activity of lactate dehydrogenase (p=0,222 compared with the group of intact animals) (tab.3).
Infusion therapy the prototype contributed to the limitation of cytolysis syndrome the effect on the activity of alanine aminotransferase and aspartate aminotransferase, but did not affect activity of the marker of cholestasis, alkaline phosphatase and bilirubin levels. The action of the inventive solution, unlike the prototype, was characterized by a significant decrease of bilirubin level (p=0.032) and alkaline phosphatase activity (p>0.05 compared with the group of intact animals). However, in�revealed changes were mixed (table. 4).
Positive changes during therapy with the prototype and to a greater extent the claimed solution was expressed in the reduction of pathologically increased activated partial thromboplastin time (the internal path of coagulation and thrombin time. On the background of therapy the inventive solution it was found a significant normalizing effect on activated partial thromboplastin time and thrombin time (p=0.009 and 0.05) compared with those in therapy the prototype in the equivalent volume dose.
After analyzing the data, we can conclude that the proposed infusion solution has a significantly more pronounced hepatoprotective effect in the model of acute toxic hepatitis than the prototype.
Experience 4. A study of the effectiveness of the inventive infusion solution on the model of poisoning with ammonium carbonate
The experiments were carried out at 150 outbred white rats-males weighing 170-180 g at the age of 13-14 weeks. All were formed into 5 experimental groups: 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 intoxicatie� and introduction of saline (n=30); experimental group 3 - animals with intoxication and the introduction of the prototype (n=30).
Toxicity ammonium carbonate were created by introduction of an aqueous 10% solution intragastrically using a noninvasive probe in a dose of 250 mg/kg (LD50). The clinical picture with the introduction of the toxicant was accompanied by the initial physical arousal, vocalization, followed expressed General toxic effect is a substantial reduction in activity, muscle tone, response to painful stimuli on the background of ataxia and development soporous condition. Some animals have been observed lateral position, and seizures. These acid-base balance of the blood of animals (tab.5) showed the character of the convulsions. These acid-base balance of the blood of animals (tab. 5) showed a characteristic picture of the development of metabolic alkalosis under the influence released from the ammonium carbonate of ammonia (Karr NW, Hendriks EL. The toxicity of intravenous ammonium compounds. Am. J. Med. Sci. 1949 Sep. 218 (3): 302-7; Ting YC. The toxicity of ammonia. Science. 1950 Jul 21, 112 (2899): 91-2; Warren KS, The differential toxicity of ammonium salts. J. Clin. Invest. 1958 Apr. 37 (4): 497-501; Handford SW, An experimental study of ammonium intoxication. Gastroenterology. 1959 Jun; 36 (6): 770-9.).
Compare the solutions were introduced intravenously 1 h after the development of symptoms of intoxication in the tail vein at a dose of 20 ml/kg for 3 days. The effectiveness of the treatment was judged by the clinical picture, l�of mentality, indicators of the oxygen budget and the acid-base balance: FNL3- the bicarbonate of the blood plasma; RSO2- partial pressure of carbon dioxide; pO2- partial pressure of oxygen; BB - excess grounds blood; BE - a shortage of buffer bases plasma; BE ecf - excess grounds extracellular fluid. In addition, we evaluated the renal function in kidney weight, daily urine output, protein and chloride in the urine, density and pH of urine.
After 4 h after administration of the investigated solutions of 10 animals from each group were subjected to decapitation, took a mixed blood and measured the parameters of the oxygen budget and the acid-base balance (table.5)
Application of the proposed solution has allowed to reduce the excess buffer bases of blood plasma, to maintain an alkaline pH, SR2unlike the prototype, which, on the contrary, contributed to raise the pH. With the inventive solution, in General, contributed to a more effective reduction of symptoms of alkalosis and hypoxia.
Third day of observation the mortality in the control group consisted of 15 of the 20 animals (75%). Surviving animals worse gained weight, were less active in comparison with the animals of the experimental groups.
The use of saline (Experimental group 2) reduced the mortality to 60% (killed 12 now�tion 20), and the prototype (Experimental group 3) - up to 20% (killed 4 of 20). Treatment of the inventive infusion solution (Experimental group 1) resulted in a lack of lethality.
Objective condition of the animals was better in the application of the proposed solution and the prototype (table. 6).
In animals of the control group showed a significant decrease in daily urine output and increasing the amount of protein and pH in urine. The use of the claimed solution to the prototype and sodium chloride had diuretic activity: increased daily urine and the content of chlorides in the urine. However, the diuretic effect of the claimed solution was more pronounced than that of the prototype and saline solution.
The results indicate high efficiency of the inventive infusion solution in comparison with the prototype in the treatment of conditions accompanied by alkalosis. Thus, the claimed recovery solution contributes to the normalization of metabolic abnormalities in the body caused by alkalosis, decreases severity of hypoxia, which positively affects the kidney and the state of the organism as a whole.
Experience 5. The effectiveness of the inventive infusion solution in a model of acute ethanol poisoning
The experiments were performed on 105 male rats. For each experimental model f�was morowali in 7 groups of animals (n=15).
To form acute poisoning animals once intraperitoneally administered about 40. % solution of ethanol at a dose of 8 ml/kg of body weight. After 2 h in all experimental animals began conducting fluid therapy study solutions. Therapy was performed for 2 days consecutively. The solutions were injected three times a day with intervals of 2 hours because of restrictions maximum single volume for insertion into a vein of the rats. New infusion solution was administered in the following doses: 10 ml/kg 20 ml/kg 30 ml/kg 40 ml/kg, and a prototype in effective according to the literature, a dose of 20 ml/kg per day (Di Luzio NR, A mechanism of the acute ethanol-induced fatty liver and the modification of liver injury by antioxidants. Am. J. Pharm. Sci. Support Public Health, 1966 Jan; 15: 50-63; Acute ethanol intoxication and liver lipid metabolism. Nutr Rev. 1965 Nov, 23 (11): 338-40; Kalant H, Mons W, Mahon MA, Acute effects of ethanol on tissue electrolytes in the rat. Can J Physiol. Pharmacol. 1966 Jan, 44 (1): 1-12.).
At the end of the treatment was assessed the mortality of animals in groups during 24 and 48 hours, and in the blood of survivors was determined markers of intoxication (the activity of the enzymes alanine aminotransferase, levels of glucose, lactate, pyruvate, products of lipid peroxidation, diene conjugates, klodiana conjugate of trienol and Schiff bases.
The death of animals occurred within the first 2 days and was associated with hypothermia, collapse and General intoxication, provided the long-term interference animal unconscious (IO�tosem) state.
Thus, in the control group during the first day killed 3 rats (20%), which after ethanol induction of coma did not come out of a pathological condition, and showed a sympathetic reflex response to painful and visual stimuli. Then during the second day killed 3 animals with signs of acute fulminant hepatitis with hyperthermia (marble liver at autopsy the abdominal cavity), while total mortality was 40%.
On the first day, the best effect was observed after the introduction of the proposed solution in doses of 20 and 30 ml/kg in the groups of animals were observed death. In groups of animals treated with the inventive solution in doses of 10 (low therapeutic dose) and 40 mg/kg (overload circulating blood volume), were killed by one animal (6, 7%) as in the group treated with the prototype (6, 7%).
On the second day of the experiment revealed the deterioration of rats in all experimental groups. In groups of animals treated with the inventive solution in doses of 10, 20, 30 and 40 mg/kg died by one individual, the total mortality amounted to 13,3%, 6,7%, 6,7%, 13,3% accordingly, in the group treated with the prototype, two individuals (20,0%) (tab. 7).
Positive developments on the background of therapy the prototype was expressed in the normalization of alanine aminotransferase and glucose. Activity Apartamentos�erase, the levels of lactic and pyruvic acids, thus, remained elevated and significantly different values from those of rats from positive control group (tab. 8).
In the analysis of the dose dependence of the effects of the proposed solution revealed a positive impact on all key indicators. The transition from a dose of 10 ml/kg to a dose of 20 and 30 ml/kg of the inventive solution gave a significant leap in the form of increased positive effect on transaminase activity and indicators of energy metabolism (tab. 8). In the process the effectiveness of the doses of 20 and 30 ml/kg were almost equivalent and average therapeutic dose was within the specified range (estimated average dose 25 ml/kg).
Indicators of lipid peroxidation (table. 9) on the background of acute ethanol poisoning has varied largely in the form of increasing the level of Schiff bases, reaction products of aldehydes with amino groups of proteins and amino acids. Thus the inventive infusion solution at a dose of 30 ml/kg exceeds the prototype for efficiency.
Experience 6. The effectiveness of the inventive infusion solution in a model of acute poisoning cytostatic cyclophosphamide
Detoxifying action of the solutions studied in a model of toxicity induced ciclope�fan on mice-females weighing 20-22 g BDF1 hybrid lines. Study drugs were administered for 14 days after exposure to cyclophosphamide.
To assess the detoxifying action of the inventive solution is formed into 5 experimental groups of animals: group 1 (n=50) animals once was intravenously administered cyclophosphamide in cytotoxic dose of 450 mg/kg (LD50), group 2 (n=50) and group 3 (n=50) animals for 14 days was administered intraperitoneally, the inventive solution in a daily dose of 40 ml/kg and 20 ml/kg, respectively, group 4 (n=50) animals within 14 days were injected intraperitoneally prototype at a dose of 20 ml/kg; group 5 (n=9) - intact animals (Chave Cytotoxic effects of the cyclophosphamide. An experimental study. Arch Ital Patol Clin Tumori. 1967 Jul-Dec; 10 (3): 223-34; Koss LG, Lavin P, Effectsof a single dose of cyclophosphamide on various organs in the rat. 3. Electron microscopic study of the liver, Am. J. Pathol. 1971 Feb, 62 (2): 159-68).
Recorded death of animals and biochemical indicators of blood of survivors. The material was taken at 3, 7 and 14 days after administration of cyclophosphamide. Biochemical blood analysis included determination of the activity of aspartate aminotransferase and alanine aminotransferase, urea concentration, creatinine, content of total bilirubin in the serum of experimental animals. The most pronounced cyclophosphamide hepatotoxicity is characterized by degenerative and destructive changes in the liver.
The introduction of cyclophosphamide (group 1) when�Odilo to 45% death of the animals, the death of animals began with 4 days after exposure and continued for 5 days (table. 10).
The introduction of the proposed solution in daily doses of 40 ml/kg and 20 ml/kg on the background of administration of cytostatic contributed to a statistically significant decrease in the toxic effects of cyclophosphamide - death of animals in these groups of animals was 10% and 5% respectively.
In the 3rd group, where the background of the introduction of cyclophosphamide was used as a prototype, there was a 35% mortality caused by toxic action of cyclophosphamide (table. 10), i.e. by the integral indicator of the death of animals" of the inventive solution exhibits a more pronounced ability to detoxify than the prototype.
The laboratory analysis of blood parameters of experimental animals (group 1) showed that leading to the toxic action of cyclophosphamide hepatotoxicity is. During 7 days of observation after the administration of cyclophosphamide in animals showed a statistically significant increase in the activity of the enzyme alanine aminotransferase, and on the 3rd day of observation - a statistically significant increase in the activity of aspartate aminotransferase and concentration of total bilirubin (table. 11) relative to intact animals. It is characteristic that the same transient increase of 3 days of activity of aspartamine�ransferase changed to 7 days, a statistically significant decrease of enzyme activity compared with the level in intact animals. This is due, apparently, the development of animal liver by the type of cytolysis.
The results of biochemical studies have confirmed a statistically significant reduction in the intensity of the toxic reactions of cyclophosphamide with the introduction of the proposed solution in daily doses of 40 ml/kg and 20 ml/kg. Its application leads to the relief of hepatotoxic action of cyclophosphamide: values of biochemical parameters remained normal throughout the observation time for the animals with the introduction of the proposed solution in both doses. For example, with the introduction of the inventive solution in a daily dose of 40 ml/kg at 3 days after administration of the cytostatic activity of the enzymes aspartate aminotransferase and alanine aminotransferase were 138±21 40±4 IU/l, respectively, and with the introduction of the inventive solution in a daily dose of 20 ml/kg - 146±17 40±5 IU/l respectively, while in the group of cyclophosphamide - 219±14 326±33 IU/l (normal: aspartate aminotransferase - 136±5 IU/l, alanineaminotransferase - 42±2 IU/l). A similar pattern was observed on 7th day of observation.
The concentration of total bilirubin also remained at a normal level in contrast to the index in animals treated only with cyclophosphamide, which on the 3rd day the concentration was 13.1�1,4 mmol/l (norm of 6.4±1.0 µmol/l, table.11).
The effectiveness of the prototype has also been expressed in maintaining the activity of the enzymes alanine aminotransferase and aspartate aminotransferase and concentration of total bilirubin to normal levels in all the observation periods.
Thus, the detoxifying activity of the inventive infusion solution in respect of cyclophosphamide at different doses was not inferior to the prototype, there was recorded a significant difference in mortality in the groups of application of the inventive solution in the various doses (10% and 5%) and the prototype (35%).
The experiments proved the power of using the inventive infusion solution as a detoxifying drugs through the use of new biologically active ingredient - sodium L-arginine succinate of formula (1).
The inventive balanced infusion solution promotes rapid reduction of hypoxic processes in organs and tissues, excretion of oxidized products of cell activity, activation of energy metabolism, normalization of water-electrolyte balance and acid-base balance of all biological liquids of an organism.
In addition, a balanced infusion solution significantly reduces the alkalinity of the blood and urine, characteristic of the prototype, due to the lower values of p� sodium L-arginine succinate, what appears to be preferential for certain groups of patients.
Thus, the claimed balanced infusion solution has a high detoxifying activity, low toxicity and can be used in treating a wide range of diseases and conditions associated with intoxication of the organism of varying severity.
A balanced infusion solution containing the chlorides of sodium, potassium and magnesium, the solvent and the biologically active compound, characterized in that as biologically active component it contains sodium L-arginine succinate of the formula:
with the following ratio of components, wt.%:
|Magnesium chloride hexahydrate||0,015-0,030|
|Sodium L-arginine succinate||1,400-1,700|
|Water for injections||Else|
SUBSTANCE: body weight, physiological requirements and degree of disease severity are determined. That is followed by calculating an infusion therapy extent by formula: V=Ce×BW+PR+300 ml 5% glucose, wherein V is the infusion therapy extent, ml; Ce is an encephalopathy coefficient: 0.02 in prodromal period, 0.03 in manifested psychosis, 0.04 in chronic alcoholic encephalopathy; BW is patient's body weight, gram; PR are the physiological requirements for one day, ml.
EFFECT: method provides the effective infusion therapy in the given category of patients by the accurate determination of the therapy extent caused by taking into account the stages of alcoholic encephalopathy development.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to medicine and consists in a pharmaceutical substance, representing an instantly soluble in water powder of a crystalline chemical compound of dextrose with sodium chloride - (C6H12O6)2·NaCl·H2O, which has a specific rotation of a polarised light plane initial at 113°, equilibrium at 52.9°, constant of the mutarotation rate of 6.7·10-3 and moisture content of not more than 4.3%. The invention also relates to a method of obtaining the pharmaceutical substance.
EFFECT: pharmaceutical substance has stable quality, is easily packaged, it is possible to prepare a solution for injections from it in a fast and easy way, its storage and transportation are considerably more simple.
2 cl, 1 ex
SUBSTANCE: invention refers to medicine, namely to anaesthetics, and can be used for the prevention of spinal headache during spinal or combined spinal epidural anaesthesia in bone marrow exfusion. That is ensured by an intravenous infusion of 6% hydroxyethylstarch 500 ml 30 minutes before the subarachnoid puncture and the spinal and combined spinal epidural puncture or for the first 30 minutes of the anaesthesia.
EFFECT: invention provides preventing postoperative spinal headache in this group of patients.
1 dwg, 1 tbl, 4 ex
SUBSTANCE: invention refers to medicine, namely to cardiovascular surgery, and concerns preventing a diffuse intra- and postoperative blood loss in surgery of abdominal aorta. To this effect, performing the aortoiliac operations is combined with measuring preoperative antithrombin III; if the measured value is less than 87±3%, a thromboelastography is performed from the moment of an anaesthetic support started with determining a coagulation index. If the coagulation index is less than 2.89±0.25 as early as at the start of the stage of approaching the abdominal aorta, before any surgically significant blood loss, fresh-frozen plasma of the identical group in a min. amount of 600 ml is administered into the patient. If the following dynamic control shows a decrease of the coagulation index below 1.10±0.28, at least 600 ml of fresh-frozen plasma is additionally administered, providing thereby the coagulation index by the end of the operation not less than 0.52±0.27.
EFFECT: method provides effective prevention of intra- and postoperative blood loss by prevention of intraoperative homeostatic disorders.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to a concentrated acidic component for producing a hemodialysis solution. The acidic component contains the following ingredients in an amount of producing 1 litre of the solution in water purified for hemodialysis: 204.7-215.0 g of sodium chloride NaCl, 6.2-9.0 g of calcium chloride CaCl2*2H2O, 3.56-7.12 g of magnesium chloride MgCl2*6H2O, 5.22-10.44 g of potassium chloride KCl, 0.021-6.28 g of acetic acid and 0.02-6.2 g of succinic acid. Also, the invention refers to the hemodialysis solution containing the above concentrated acidic component, water purified for hemodialysis, and bicarbonate component. The invention also refers to a method for producing the hemodialysis solution with the method involving supplying the concentrated acidic component into a hemodialysis apparatus, diluting with water purified for hemodialysis, and mixing with bicarbonate component. What is also declared is a kit for producing the concentrated acidic component containing sodium chloride, calcium chloride, magnesium chloride, potassium chloride, succinic acid in the form of dry agents and acetic acid in the form of a liquid agent.
EFFECT: invention provides higher effectiveness by a biochemical compatibility with blood plasma of the hemodialysis solution.
36 cl, 18 tbl, 16 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to a composition, adapted for intravenous introduction, intended for the treatment or prevention of pathological processes of crystallisation or calcification in a person, subjected to dialysis. The composition contains inositol phosphate and/or its pharmaceutically acceptable salt, with a dose of inositol phosphate and/or its salt constituting from 1 nmol/kg to 0.1 mil/kg. The invention also relates to a combined method of treatment, including the intravenous introduction of the said composition of the dialysis liquid simultaneously.
EFFECT: method is intended for the treatment or prevention of pathological processes, associated with an impairment of the regulation of physiologically adequate levels of inositol phosphate in blood plasma of the person, subjected to dialysis.
10 cl, 4 dwg, 1 tbl, 9 ex
SUBSTANCE: what is declared is an infusion solution for filling the deficiency and meeting the physiological needs for water and basic electrolytes, which contains the following ingredients: sodium (Na+) - 27.72-28.28 mmole/l; fumarate(H2C4O4 2-) - 13.86-14.14 mmole/l; potassium (K+) - 18.61-18.99 mmole/l; calcium (Ca2+) - 3.56-3.64 mmole/l; magnesium (Mg2+) - 2.18-2.22 mmole/l; chlorine (Cl-) - 30.0-30.6 mmole/l; glucose (C6H12O6) - 189.1-192.9 mmole/l, water for injections.
EFFECT: solution contains the basic electrolyte concentration balanced for meeting the physiological needs; it is safe for the clinical application and can be used in diseases of various aetiology for patients of any age.
1 tbl, 2 ex
SUBSTANCE: invention refers to medicine and aims at intraoperative and early postoperative infusion therapy. A method involves administering a crystalloid balanced solution of sterofundin iso and a balanced colloidal solution of tetraspan. In the intraoperative period, sterofundin is administered with tetraspan in the volume ratio 3:1. In the early postoperative period, for the first day, sterofundin and tetraspan are administered in the volume ratio 6:1.
EFFECT: method is simple, safe, enables effectively correcting aqueous electrolyte disorders, stabilising systemic hemodynamic parameters, causing no negative effect on haemostasis and electrolyte composition of the blood serum.
1 ex, 1 tbl
SUBSTANCE: invention relates to a concentrated acid component for bicarbonate hemodialysis. The acid component includes sodium (Na+) in an amount of 2450.0-4550.0 mEq/l, chlorine (Cl-) in an amount of 2453.5-4553.5 mEq/l, hydrogen H+ (hydrochloric acid), succinate and citrate, each in an amount of 3.5-98.0 mEq/l. The invention also relates to a diluted acid component for bicarbonate hemodialysis, which includes sodium chloride 70.0-130.0 mEq/l, hydrochloric acid 0.1-2.8 mEq/l, succinic acid 0.1-2.8 mEq/l, and citric acid 0.1-2.8 mEq/l. The invention also relates to a concentrate for preparation of the acid component, which contains hydrochloric acid in a liquid form, and all other components in a dry form, as well as to a method of obtaining the acid component, which includes dissolution of dry chemical reagents from the said concentrate in water and addition of liquid reagents.
EFFECT: invention ensures obtaining a solution for dialysis, applied in case of acute and chronic renal failure.
14 cl, 1 tbl, 3 ex
SUBSTANCE: before transfusion, a preserved blood sample of 2 ml is mixed with an ozonised solution of 0.9% sodium chloride with the ozone concentration of 2 mg/l in the equivalent volume. The 15-minute exposition is followed by evaluating the 2,3 diphosphoglycerate concentration in the prepared packed red cell suspension. The 2,3 diphosphoglycerate concentration in the packed red cell suspension more than 6 mcmole/l testifies to the high effectiveness of planned hemotransfusion.
EFFECT: using the invention provides higher accuracy of determining the suitability of the preserved packed red cells for transfusion that ensures higher clinical effectiveness in the severe patients by fast and stable correction of oxygen delivery and consumption preferentially by functionally adequate red cells.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to pharmaceutical industry, namely to production of medications for treating dermatosis. Medication according to invention, made in form of cream, contains mometasone furoate, preservative, hydrophilic no-aqueous solvent, emulsifying agent of 1st kind, emulsifying agent of 2nd kind, emollient, disodium edetate (trilon B), pH-regulating agent, and purified water in quantities, given in invention formula.
EFFECT: invention can be applied for treating inflammatory diseases and itching in case of dermatosis, yielding to glycocorticosteroid therapy.
9 cl, 3 tbl, 3 ex
SUBSTANCE: invention relates to medicine, namely to cardiac surgery, and represents cardioplegic solution, which contains sodium chloride - 3.41-3.62, potassium chloride - 1.092-1.156 g, magnesium chloride - 3.190-3.485 g, calcium gluconate - 0.0105-0.0130 g, mannite - 4.365-4.520 g, L-carnosine - 20.1504-24.1650 g, N-acetylcarnosine - 8.056-11.032 g, L-histidine - 0.705-0.820 g, water for injections to 1000 ml.
EFFECT: invention ensures prevention of reduction of amplitude, speed of front and speed of pulse-wave reduction, as well as increase of diastolic pressure in left heart ventricle during reperfusion with preservation of buffer capacity and osmolarity of cardioplegic solution with physiological pH parameters.
4 tbl, 2 ex
SUBSTANCE: composition has an action of the central nervous system; it is presented in the form of a solution, contains glycine, glycerol, a preserving agent and water. The invention also concerns a therapeutic agent and a biologically active addition based on the above composition.
EFFECT: group of inventions provides high bioavailability as the composition is presented in the liquid and ease of dosing.
12 cl, 2 tbl, 3 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutics, namely represents pharmaceutical formulations containing 9-cis-retinyl esters in a lipid excipient. The pharmaceutical formulations containing 9-cis-retinyl esters are described to be applicable in a retinoid replacement therapy for treating retinal degenerations in individuals.
EFFECT: using the formulations for the retinoid replacement therapy for treating retinal degenerations in individuals.
73 cl, 14 dwg, 2 tbl, 6 ex
SUBSTANCE: group of inventions refers to medicine. What is described is a method for preparing a high-purity drug preparation for treating degenerative-dystrophic diseases of peripheral synovial joints and spinal column. The method provides introducing L-proline, an amino acid in an amount of 10-70 g/l into aqueous chondroitin sulphate solution containing no more than 11.5% of an active ingredient, and filtering the solution at temperature 20-50°C through ZetaCarbon (Cuno) R54SLP, R51SLP, R53SLP or AKS (Pall) - AKS 1, 2, 6, 7 filters.
EFFECT: method provides preparing the high-grade 99% pure liquid or lyophilised chondroprotective preparation stabilised with L-proline with the residual content of organic purities: protein - no more than 0,2%, lipids (per 1mg of chondroitin sulphate) - no more than 0,05 mcg, bacterial endotoxins (per 1mg of chondroitin sulphate) - no more than 0,05 EU.
6 cl, 3 tbl, 2 ex
SUBSTANCE: invention refers to a method for Helicobacter pylori eradication of a gastroduodenal zone by a silver nitrate monotherapy consisting in administering an electrolyte solution of silver ions in the concentration of 300 mcg/l in a daily volume of 960 ml, for the first three days - in an amount of 120 ml every 3 h, 160 ml - every 4 hours and for the following three days - every 6 hours in an amount of 240 ml.
EFFECT: achieving the stable eradication of the vegetative and coccal forms of Helicobacter pylori, reducing the length of treatment by the early recovery of the involved gastric and duodenal mucosa.
FIELD: medicine, pharmaceutics.
SUBSTANCE: object of the invention is a method and a pharmaceutical composition in the form of a water-alcohol solution of ethanol 30-60° and water 40-70%, wherein at least one hypoglycaemic active substance is stably and completely dissolved, to be used by administering through the oral mucosa as a therapeutic agent in accurate treatment of postprandial hyperglycemia accompanying type II diabetes mellitus in a human or animal; wherein the water-alcohol solution in the composition has a volume of less than 2 ml, wherein an amount of 250mg or less of the above active substance is stably and completely dissolved, while the hypoglycaemic active substance is specified in lipophilic or amphiphilic active substances, such as gliclazide, glinides, incretins and glyphins. The invention also refers to a method for preparing this dosage form.
EFFECT: preparing the therapeutic agent for treating postprandial hyperglycemia accompanying type II diabetes mellitus.
9 cl, 20 ex
FIELD: chemistry, pharmaceutics.
SUBSTANCE: invention relates to method of treating proliferative disease in subject, including introduction to subject of (a) therapeutically effective quantity of AC220 or its salt in dose from approximately 27 to 1000 mg/day, and of (b) second agent, selected from azacitidine, cytarabinum, etoposide, daunorubicin, cladribine, where azacitidine is introduced in dose 50-100 mg/m2/day, cytarabinum is introduced in dose from 5 mg/m2/day to 3 mg/m2/day, etoposide is introduced in dose 10-150 mg/m2/day and daunorubicin is introduced is dose 10-60 mg/m2/day.
EFFECT: invention makes it possible to extend arsenal of medications for treating proliferative diseases, including cancer.
39 cl, 10 dwg, 26 tbl, 9 ex
SUBSTANCE: invention represents a liquid dosage form of a hopantenic acid calcium salt possessing nootropic activity, containing an effective amount of the hopantenic acid calcium salt and additive agents. It represents drops, and as additive agents, it contains benzoic acid, sodium saccharinate, an orange flavour, hydrochloric 1M, Trilon B and water.
EFFECT: higher active substance content by improving its organoleptic properties and reducing a viscosity of the liquid dosage form by reducing the content of viscosity-enhancing agents and increasing the water content.
2 cl, 4 ex
SUBSTANCE: method involves performing the following stages: - treating a nerve canal with sodium hypochlorite in the concentration of 0.5-5.25 wt %, in an amount of 1-20 ml for one root canal and activating with ultrasound at frequency 20-40 kHz; both one-stage activation with ultrasound accompanying the treatment, and alternating the sodium hypochlorite treatment and activation with ultrasound every 3-5 sec are possible, - treating with ozonised normal saline in the ozone concentration of 10 mcg to 60 mg per one litre, in an amount of 1-20 ml per 1 root canal and activating with ultrasound at frequency 20-40 kHz, - treating with aqueous chlorhexidine in the concentration of 0.12-2 wt %, in an amount of 1-20 ml per one root canal and activating with ultrasound at frequency 20-40 kHz; the above stages are intermitted with time intervals of no more than 3 minutes, and each stage lasts for 3 to 15 minutes.
EFFECT: high quality of treatment by preventing a post-filling aggravation and reducing the length of periodontal tissue regeneration; the method is easy-to-implement and efficient.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to the pharmaceutical industry and represents a formulation specially adapted for insulin transformation into the aerosol state, containing insulin in water from 100 IU/ml to 1,200 IU/ml and 2 to 4 Zn2+ ions per the insulin hexamer, wherein the formulation is preservative-free and wherein the formulation is able to transform into the aerosol state as an aerosol spray when using a holed vibration plate with no foaming of the formulation, when the formulation is kept on a back surface of the holed plate by gravity, and the spray is ejected from the front surface of the holed plate entirely by vibrating the holed plate.
EFFECT: invention provides reducing the foaming of the formulation, the time of transformation into the aerosol state and providing the more effective administration of an insulin dose.
19 cl, 5 dwg