CZ288396B6 - Mixture of amino acids intended for treating metabolic disruption of postoperative states, polytraumas and sepsis - Google Patents

Abstract

The present invention relates to a novel amino acid mixture being enriched with L-alanyl-L-glutamine dipeptide, a source of needful glutamine that was so far missing in parenteral nutrition due to its instability in a solution. The mixture, being intended particularly for nutrition support and treatment of metabolic disruption of postoperative states, polytraumas and sepses 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

Technical field

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

BACKGROUND OF THE INVENTION

Parenteral and enteral nutrition, designed to ensure 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 fundamental effect on the course of the disease, also economic consequences, which are reflected in 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 effect are chemically very different and act by different metabolic mechanisms. Some of the amino acids or their metabolites (arginine, glutamine, dipeptides, and - ketoglutarate) belong to this group of substances and derived nutritional products derived therefrom. These components, which have a specific organ or therapeutic effect, are contained in artificial nutritional doses in pharmacological doses which are many times higher than those normally found in the diet.

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

Numerous studies in recent years have shown that peptides have significantly higher solubility and stability compared to free amino acids. The bioavailability of amino acids of peptides and hence their utility in the body has been shown to be very good (Proceedings of the Nutrition Society 49, 1990, pp. 343-359, Fiirst 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 ifusion 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.

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

The administration 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 München - Bern - Wien - S. Francisco, 1991) L-alanyl-L glutamine).

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Polytrauma status and postoperative status is characterized in the amino acid spectrum by elevated values of branched amino acids (due to the leaching of these substances from proteins, mainly muscle), further increased levels of amino acids characterizing the course of liver 5 functions, documenting permanent liver load as a result of catabolism ( JPEN 10/5/1986, pp. 446-452, Brennan MF et al .: Raport of Research Workshop: Branchedchain Amino Acids in Stress and Injection, 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. 574-577, Kirvela O. et al .: Postoperative parenteral nutrition with high supply of branched-chain 10 amino acids). Proteosynthesis is permanently blocked. The aminograms of these patients are characterized by an increase in phenylalanine, alanine, proline or methionine. Phenylalanine - tyrosine and methionine - cysteine pathways are blocked. The sudden rise in lysine is a sign of blockade of proteosynthesis (JPEN 9/2 /, 1985, pp. 133-138, Gimmon Z. et al .: The optimal branchedchain to total amino acid ratio in the injected amino acid formulation).

The solution to this condition is to utilize the pharmacodynamic properties of branched-chain amino acids, but these are achieved by applying high doses of these substances, which means a high water load of the patient at risk of circulatory failure. The application of branched-chain amino acids themselves does not further address the need for some of the other essential amino acids necessary for proteosynthesis 20 (JPEN 13/3 /, 1989, pp. 223-227, Huberstone DA et al .: Relative importance of amino acid infusions as a means of sparing protein in surgical patients).

Branched amino acid fortifications should be performed in an amount corresponding to about 45% of the total amount of amino acids added.

A similar situation to that of polytrauma is also found in the treatment of metabolic breakdown in septic conditions (Ann. Sugr. 190: 571-576, 1979, Freund H. et al., Plasma Amino Acids and Predictors of Severity and Outcome of Sephis, Am. 53, 1991, pp. 143-148, Arnold J. et al .: Lipid infusion increases oxygen consumption similarly in septic and nonseptic patients).

A marked feature of sepsis is the markedly increased proteolysis. The daily loss of nitrogen may be more than 30 to 50 g (corresponding to catabolism of 250 to 300 g of protein), (Zuckschwerdt. Miinchen 1980, Schuster P. P .: Emahrung bei Sepsis: in Peter, Schimtz (eds), Sepsis und Metabolism, pp. 125-144).

Sepsis in the amino acid spectrum is characterized by low doses of branched amino acids and 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, despite the increasing flux of gluconeogenetic amino acids from muscle to liver, these 40 acids do not accumulate in the liver (Nutrition, vol. 8, No 4, 1992, 237-244, Jimenez F. J. J. 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 body to sepsis is determined by several hormones. It has been known since the 45s that, in damage and especially sepsis, regulatory hormones, namely adrenaline from the adrenal gland, glucagon from the pancreas, and corticosteroids from the adrenal skin, have been washed away. This neuroendocrine response appeared to be mostly responsible for increasing proteolysis in the muscles, which, in conjunction with less than normal proteosynthesis, led to the breakdown of muscle proteins with leaching and the transfer of amino acids to the liver. In the liver, 50 acute phase proteins are secreted, structural protein synthesis is lacking, insufficiency is underlying the multi-organ deficiency syndrome (Surgery 86: 163-192, 1979, Siegel H.H. et al .: Physiological and Metabilistic Correlations in Human sepsis, JPEN 12/3 /, 1988, pp. 244-249, Hasselgren PO et al: Infusion of a branched-chain amino acid enriched solution and a - catoisocaproic acid in septic rats: effect or nitrogen balance and sceletal muscle

-2C 288396 B6 protein tumover). It is now known that in addition to the activity of hormones, a series of macrophage and lymphocyte products such as interleukins and cachectins, that is, 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 for defense reactions (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), production of antibodies). A part of amino acids is also used as a substrate for gluconeogenesis, or is utilized directly in cells where proteolysis occurs. In sepsis, the main endogenous energy source is fatty acids and ketone bodies formed therefrom. 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, mainly branched-chain amino acids, are increasingly utilized directly in peripheral tissues (Clin. Nutr. 10,1991, s 1 to 9). of sepsis).

Nutritional support for septic patients should also be based on these relationships. Here again, the application of branched 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 - catoisocaproic acid in septic rats: effect of nitrogen balance and sceletal mucle protein tumover). The situation with water supply when using a combination of existing solutions is the same as for polytrauma. The amino acid composition of septic patients is also prognostic. Surviving patients have higher plasma concentrations of branched amino acids and lower aromatic and sulfur-containing amino acids, and the proline level also plays a role in the prognosis.

SUMMARY OF THE INVENTION

The nutritional state 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 necessary for proteosynthesis.

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

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 to 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.

4.76 to 5.82 wt.

1.27 to 1.55 wt.

L-leucine

L-isoleucine

L-valine

Of L-methionine

L-phenylalanine L-threonine L-tryptophan L-lysine hydrochloride L-alanine

L-arginine L-arginine hydrochloride L-histidine

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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.

glycine

L-proline of N-acetyl-L-tyrosine

L-cystine

L-serine

L-alanyl-L-glutamine

The 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 between 0.45 and 0.2 µm). The solution is filled under the laminar air flow 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 15 of their biological effects, a single-dose tolerance test was conducted in mice and guinea pigs, a three-month chronic toxicity study in rats, and a pyrogenicity assessment in rabbits. The specific effect of the new solutions on the serum levels 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, 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 (they were always very severe patients in ARO and JIP units) in many patients the nitrogen balance improved and the catabolic state reversed. Patients were well tolerated, with no undesirable symptoms. All investigators evaluated the preparation as a suitable extension of the range of amino acid solutions.

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

DETAILED DESCRIPTION OF THE INVENTION

Weigh the L-forms of amino acids, L-alanyl-L-glutamine dipeptides and other ingredients according to the following formulation 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 hydrochloride 3.80 g / l L - alanine 5.20 g / l L-arginine 1.00 g / l L - arginine hydrochloride 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

-4GB 288396 B6

L - alanyl - L - glutamine Water for injections supplement to

20.00 g / l

1000,00 ml

Industrial applicability

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

Claims (1)

PATENT CLAIMS A mixture of amino acids intended for the solution of 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. L-valine 1.90 to 2.32 wt. Of L-methionine 2.54 to 3.10 wt. L-phenylalanine 2.12 to 2.59 wt. Of L-threonine 0.85 to 1.04 wt. L-tryptophan 4.02 to 4.92 wt. L-lysine hydrochloride 5.51 v az 6.73 wt. L-alanine 1.06 to 1.29 wt. L-arginine 4.76 to 5.82 wt. L-arginine hydrochloride 1,27 to 1.55 wt. L-histidine 4.45 to 5.44 wt. glycine 4.87 to 5.95 wt. Of L-proline 0.69 to 0.84 wt. N-acetyl-L-tyrosine 0.16 to 0.19 wt. L-cystine 2.86 to 3.49 wt. L-serine 21.18 to 25.88 wt. L-alanyl-L-glutamine. End of document