SK283178B6 - Mixture of amino acids intended for treating metabolic breakdown in post-operative states, polytraumas and sepsis - Google Patents

Abstract

The mixture, aimed particularly at nutritional support and solving the metabolic breakdown in post-operative states, polytraumas and sepsis, contains L-alanyl-L-glutamine dipeptide and L-forms of the following amino acids: leucine, isoleucine, valine, methionine, phenylalanine, threonine, tryptophan, lysine, alanine, arginine, cystine, glycine, histidine, proline, serine and tyrosine.

Description

The present invention relates to novel amine solutions enriched with glutamine and intended, in particular, for the nutritional support and solution of metabolic breakdown in severe catabolic states.

BACKGROUND OF THE INVENTION

Parenteral and enteral nutrition, designed to ensure a positive nitrogen, energy, water and mineral balance, is elaborated in detail and widely and routinely used in a well-run healthcare facility. The effect of a well and systematically carried out nutritional support by pharmaceutical preparations has, besides a major effect on the course of the disease, also economic consequences, which translate into reduced treatment time and reduced costs, especially in the treatment of complications.

In addition to ensuring anabolic balance of the body, proteosynthesis and regeneration, modern artificial nutrition products also have a significant pharmaceutical effect. Nutrients with a characteristic and well-defined pharmacological action are chemically very different and act by different metabolic mechanisms. This group of substances and the derived nutritional products derived therefrom include e.g. some amino acids or their metabolites (arginine, glutamine, dipeptides, d-ketoglutarate). These components, which have a specific organ or therapeutic effect, are contained in artificial nutrition in pharmacological doses that are many times higher than those normally found in food.

In the field of amino acid solutions for parenteral nutrition, a new trend in the use of substrates is currently emerging. These are synthetic di-eventual tripeptides, prepared enzymatically from pure forms of L-amino acids. These are dipeptides of those amino acids that are necessary for the organism but are either unstable in solution (glutamine) or sparingly soluble (tyrosine, purity, branched amino acids).

In recent years, a number of studies have shown that peptides have significantly higher solubility and stability compared to free amino acids. The bioavailability of amino acids from dipeptides and hence their utility in the body has been shown to be very good (Proceedings of the Nutrition Society 49, 1990, pp. 343-359, Furst P. et al .: "Dipeptides in clinical nutrition"; Clin. Sci., 76, 1989, pp. 643-648, Albers S. et al .: "Availability of amino acids supplied by constant intravenous infusion of synthetic dipeptides in healthy man"; Metabolism 1986, pp. 830-836, Adibi SA et al .: "Influence of molecular structure on half life and hydrolysis of dipeptides in plasma: importance of glycine as N-terminal amino acid residue"). Thus, it is possible to increase the supply of the necessary amino acids into the body without the need to simultaneously supply an increased amount of fluid and thereby disproportionately burden the body.

To date, the amino acid glutamine, a specific nutritional substrate for the intestinal mucosa having a particular role in maintaining the intestinal barrier and immune function, has not been added to amino acid solutions due to its instability in aqueous solutions (JPEN 14, 1990, 56S to 62S, Häussinger D .: Liver) glutamine metabolism ').

The application of glutamine in the form of alanyl-glutamine has significant effects on its stability in infusion solutions, and the solubility of the dipeptide is 16 times higher than that of free glutamine (W. Zuckschwerdt Verlag Munich - Bern - Wien - S. Francisco, 1991, Stehle P .: Das Synthetic Dipeptide L-alanyl-L glutamine ').

Polytrauma state and postoperative state are characterized by increased values of branched amino acids in the amino acid spectrum (due to leaching of these substances from proteins, especially muscle), furthermore elevated amino acid levels characterizing the course of liver functions are evident, documenting permanent liver load due to catabolism (JPEN) 10 (5), 1986, pp. 446-452, Brennan MF et al .; "Raport of Research Workshop: Branched-Chain Amino Acids in Stress and Injury"; JPEN 9/2/1985, pp. 133-138, Gimmon Z. et al: "The optimal branched-chain to total amino acid ration in the injury - adapted amino acid formulation", JPEN 10/6 /, 1986, pp. 574 to 577, Kirvela O. at: "Postoperative parenteral nutrition with high supply of branched-chain amino acids ”), protoesynthesis is permanently blocked. The aminograms of these patients are characterized by an increase in phenylalanine, alanine, proline or methionine. Phenylalanine - tyrosine and methionine - cysteine are blocked. The sudden rise of lysine is a sign of blockade of proteosynthesis (JPEN 9/2 /, 1985, pp. 133-138, Gimmon Z. et al .: "The optimal branching chain-total amino acid ratio in the injury - adapted amino acid formulation") .

The solution to this is to exploit the pharmacodynamic properties of branched amino acids; however, these are achieved by applying high doses of these substances, which means a high water load on the patient at risk of circulatory failure. The application of branched-chain amino acids alone does not further address the need for some of the other essential amino acids required for proteosynthesis (JPEN 13/3/1989, pp. 223-227, Hubcrstone DA et al .: "Relative importance of amino acid infusions of sparing protein in surgical patients" ).

The branched-chain amino acid fortification should be carried out in an amount corresponding to about 45% of the total amount of amino acids added.

A similar situation to that of polytraumas is in dealing with the metabolic breakdown of septic conditions (Ann. Sugr. 190: 571-576, 1979, Freund H. et al .: "Plasma amino acids as predictors of the severity and outeome of sepsis"; AM. 53, 1991, pp. 143-148, Arnold J. et al .: Lipid infusion inereases of oxygen consumption similarly in septic and nonseptic patients').

Significantly increased proteolysis is an important feature of sepsis. The daily nitrogen loss can reach more than 30 to 50 g (corresponding to catabolism of 250 to 300 g of protein), (Zuckschwerdt, Munchen 1980, Schuster HP: Emission at Sepsis: in Peter, Schmitz (eds), Sepsis and Metabolism, pp. 125 to 144).

It is characterized in the amino acid spectrum by low doses of branched-chain amino acids and by leaching of aromatic and sulfur-containing amino acids and, of course, by blockade of proteosynthesis. Changes in liver amino acids are not comparable to changes in skeletal muscle, in contrast to the increasing flux of gluconeogenetic amino acids from muscle to liver, these acids are not accumulated in the liver (Nutrition, vol. 8, No. 4, 1992. 237-244, Jimenez FJJ et al .: "Variations in plasma amino acids in septic patients subjected to parenteral nutrition with a high proportion of branched-chain amino acids").

The metabolic response of the organism to sepsis is determined by several hormones. Since the 1970s, it has been known that in the case of damage, and in particular sepsis, regulatory hormones, namely adrenaline from the adrenal gland, glucagon from the pancreas, and corticosteroids from the adrenal cortex, have been washed away. This neuroendocrine

The response seemed to be largely responsible for increasing proteolysis in the muscles, which, in conjunction with proteosynthesis less than normal, led to the breakdown of muscle proteins with leaching and the transfer of amino acids to the liver. Hepatic secretion of acute phase proteins, lack of structural protein synthesis, hepatic insufficiency, underlying multiorgan insufficiency syndrome (Surgery 86, 163-192, 1979, Siegel HH et al., "Physiological and Metabilistic Correlations in Human Seppsis") JPEN 12/3 /, 1988, pp. 244-249, Hasselgren PO et al .: "Infusion of a branched-chain amino acid enriched solution and d-catoisocaproic acid in septic rats: effect or nitrogen balance and sceletal muscle protein turnover ").

It is now known that in addition to the hormone activity mentioned above, a series of macrophage and lymphocyte products, such as interleukins and cachectins, i.e., cytokines, are involved in the acute phase response, which induce protein redistribution in the body. Amino acids released from the connective tissue muscle serve as a material to provide defense responses (synthesis of acute phase proteins in the liver, accelerated maturation of leukocytes in the bone marrow, activation of phagocytic cells of the reticuloendothelial system (RES), antibody formation). A part of the amino acids is also used as a substrate for gluconeogenesis, or is utilized directly in cells where proteolysis takes place. In sepsis, fatty acids and ketone bodies are the main endogenous energy source. Glucose gradually ceases to serve as a fuel and is increasingly acting as a carrier of amino groups, respectively. non-oxidized hydrogen between peripheral tissues and the liver. Amino acids cease to serve as a substrate for proteoanabolic events in the liver and RES, and some of them, especially branched-chain amino acids, are increasingly utilized directly in peripheral tissues (Clin. Nutr. 10,1991, sl to 9, Fischer JE: "A teleological view of sepsis ").

Nutritional support for septic patients should also be based on these relationships. Here again, the application of branched-chain amino acids, valine, leucine and isoleucine can be utilized again in an amount corresponding to about 45% of the total amount of essential and assisting amino acids (JPEN 12/3/1988, pp. 244-249, Hasselgren PO et al. : "Infusion of a branched-chain amino acid enriched solution and a - ketoisocaproic acid in septic rats: effect of nitrogen balance and sceletal mucle protein tumover"). The situation with the supply of water when using a combination of upcoming solutions is the same as with polytrauma. The amino acid composition of septic patients is also prognostic. Surviving patients have higher plasma concentrations of branched-chain amino acids and lower aromatic and sulfur-containing amino acids, and proline levels also play a role in the prognosis.

SUMMARY OF THE INVENTION

Nutritional status in stress is characterized by a pronounced catabolic reaction with a negative nitrogen balance and increased energy consumption. Proteosynthesis is permanently blocked. To improve proteosynthesis, the pharmacodynamic properties of branched amino acids can be utilized to enrich the mixture in an amount corresponding to about 45% of the total amount of amino acids in the solution. However, the application of branched amino acids alone does not address the need for some of the other essential amino acids required for proteosynthesis.

The addition of the alanyl-glutamine dipeptide makes it possible for the first time to enrich the amino acid solution with glutamine to approach the balance between increased consumption and glutamine output in catabolic states, which has not been possible to date due to the volatility of aqueous glutamine solutions.

L-leucine L-isoleucine L-valine L-methionine L-phenylalanine L-threonine L-tryptophan L-lysine.HCl L-alanine L-arginine L-arginine.HCl L-histidine glicin L-proline N-acetyl-L- tyrosine

L-cystine L-serine L-alanyl-L-glutamine

The present invention provides a mixture of essential and non-essential amino acids enriched with a glutamine-containing dipeptide in the following proportions suitable for severe catabolic conditions: 14.62-17.86 wt. 7.52 to 9.19 wt. 9.64 to 11.78 wt. 1.90 to 2.32 wt. 2.54 to 3.10 wt. 2.12 to 2.59 wt. 0.85 to 1.04 wt. 4.02 to 4.92 wt. 5.51 to 6.73 wt. % 1.06 to 1.29 wt. 4.74 to 5.82 wt. 1.27 to 1.55 wt. 4.45 to 5.44 wt. 4.87 to 5.95 wt. 0.69 to 0.84 wt. 0.16 to 0.19 wt. 2.86 to 3.49 wt. 21.18 to 25.88 wt.

Individual substances are dissolved in hot, pyrogen-free water. Make up the volume and measure the pH of the solution. Aseptic filtration is performed by pressure through membrane filters (membranes with porosity of 0.45 µm and 0.2 µm). The solution is filled under a laminar flow of air into the infusion bottles. The bottles are closed with a special rubber stopper and the stopper is secured with a cap. The bottles were autoclaved at 120 ° C for 20-25 minutes.

The amino acid mixture of the invention was subjected to pharmacological monitoring. To assess their biological effect, a single-dose test for mice and guinea pigs, a three-month chronic toxicity study in rats, and pyrogenicity in rabbits were determined. The specific effect of the new solutions on the level of amino acids in the rat serum was demonstrated in a polytrauma model.

In a clinical trial, a range of examinations were monitored according to a predetermined protocol: fluid intake and weight, body weight, electrolyte balance and acid-base balance, nitrogen balance, urea, creatinine, glycemia, liver tests, blood count, resp. preferably an aminogram of serum amino acids. After administration (always very severe patients in ARO and JIS) many patients improved their nitrogen balance and reversed the catabolic state. Patients were well tolerated, with no undesirable symptoms. All investigators evaluated the formulation as a suitable extension of the range of amino acid solutions.

Production technology guarantees two-year stability without loss of chemical identity of contained substances.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Weigh the L-forms of amino acids, the L-alanyl-L-glutamine dipeptide and the other ingredients according to the following recipe in grams per liter of solution.

L-Leucine 13.80 g / L

L-Isoleucine 7.10 g / L

L-valine 9.10 g / l

L-methionine 1.80 g / l L-phenylalanine 2.40 g / l L-threonine 2.00 g / l L-tryptophan 0.80 g / l L-lysine HCl 3.80 g / l L-alanine 5.20 g / l L-arginine 1.00 g / l L-arginin.HCl 4.50 g / l L-histidine 1.20 g / l glycine 4.20 g / l L-proline 4.60 g / l N-acetyl-L-tyrosine 0.65 g / l L-cystine 0.15 g / l L-serine 2.70 g / l L-alanyl-L-glutamine 20.00 g / l Sodium bisulfite 0.20 g / l Water for injection make up to 1000,00 mi Example 2

0.16 to 0.19 wt.

2.86 to 3.49 wt.

21.18 to 25.88 wt.

L-cystine

L-serine L-alanyl-L-glutamine

End of document

The procedure is the same as in Example 1 except that d-sorbitol is added in an amount of 100 g per liter of solution, so that the solution now also contains the energy component.

Example 3

The procedure is the same as in Examples 1 and 2, except that the vitamin components in grams per liter of solution are additionally added:

ascorbic acid 0,4000g / 1 inosites 0,5000g / 1 nicotinamide 0,0600g / 1 pyridoxilium chloride 0,0400g / 1 5-riboflavin phosphoric acid sodium salt 0,0025g / 1 thiaminium dichloride 0,2000g / 1

Example 4

The procedure was the same as in Example 1 except that the glycyl-L-glutamine dipeptide was used instead of L-alanyl-L-glutamine.

Industrial usability

The amino acid mixture according to the invention serves in parenteral nutrition especially in severe catabolic states with the need for glutamine amino acid.

Claims (4)

A mixture of amino acids intended to address metabolic breakdown in postoperative conditions, polytrauma and sepsis, characterized in that it comprises: 14.62 to 17.86 wt. % L-leucine 7.52 to 9.19 wt. % L-isoleucine 9.64 to 11.78 wt. 1.27 to 1.55 wt. 4.45 to 5.44 wt. % 1.06 to 1.29 wt. 4.74 to 5.82 wt. 1.90 to 2.32 wt. 2.12 to 2.59 wt. 0.85 to 1.04 wt. 4.02 to 4.92 wt. 5.51 to 6.73 wt. L-valine L-methionine L-phenylalanine L-threonine L-tryptophan L-lysine.HCl L-alanine 2.54 to 3.10 wt. 4.87 to 5.95 wt. 0.69 to 0.84 wt. L-arginine L-arginine.HCl L-histidine glicin L-proline N-acetyl-L-tyrosine