CS231084B1 - A complex of amino acids for the treatment of renal failure, in the form of an infusion solution - Google Patents

Abstract

The invention relates to an amino acid complex for the treatment of renal failure, in the form of an infusion solution, with the possible addition of other active and/or auxiliary components, in particular vitamins, cations and anions, energy sources, stabilizers and/or antioxidants; the complex contains L-forms of the following amino acids: valine, leucine, isoleucine, phenylalanine, lysine acetate, methionine, threonine, tryptophan, histidine, arginine hydrochloride, N-acetyl-L-tyrosine, proline and water for injection up to 1,000 ml and has a pH value of 5.0 to 7.0.

Description

The invention relates to an amino acid complex for the treatment of renal failure, in the form of an infusion solution, with the optional addition of other active and/or auxiliary ingredients, in particular vitamins, for example ascorbic acid or B vitamins, cations, for example sodium, potassium or magnesium and anions, phosphate or chloride, energy sources, for example sorbitol or xylitol, stabilizers or antioxidants, for example sodium bisulfite.

Previously known infusion solutions containing amino acids, intended for parenteral nutrition or treatment of liver failure, containing L-forms of amino acids, are contraindicated in renal failure.

The basis of parenteral nutrition in renal failure is the restriction of protein intake, but ensuring their high biological value and with a gradual conversion to a mixture of selected amino acids, which would allow normalization of their spectrum, especially in the case of reduced values, both in the extracellular and intracellular areas, or the use of some of their pharmacodynamic properties. From this point of view, a new formula of an amino acid complex for the treatment of renal failure was developed based on the results of basic experimental work, in the form of an infusion solution, with the possible addition of other active and/or auxiliary components, especially vitamins, for example ascorbic acid or vitamins of group B, cations, for example sodium, potassium or magnesium and anions, for example phosphate or chloride, energy sources, for example sorbitol or xylitol, stabilizers and/or antioxidants, for example sodium bisulfite, according to the invention, the essence of which is that it contains in percentages by weight

231,084

9.24 until 11.29 14.51 until 17.74 9.24 until 11.29 11.89 until 14.53 11.89 until 14.53 11.89 until 14.53 6.61 until 8.08 3.30 until 4.02 5.22 until 6.38 until 4.85 0.93 until 1.14 1.32 until 1.62

and water for injection into

100 wt.

L-valine L-leucine L-isoleucine L-enylalanine L-ljrgin acetate L-methionine L-threonine L-tryptophan L-histidine L-arginine.HCl N-acetyl - L-tyrosine L-proline and has a pH value of 5.0 to 7.0.

To prepare the infusion solution of the amino acid complex according to the invention, either pure L-forms of the individual amino acids or a certain sum obtained by hydrolysis of a suitable protein substrate and supplemented to the required amount with pure amino acids can be used. The solution is usually prepared by dissolving the individual components in no particular order in water for injection at a temperature of at least 80 °C, while stirring with a high-speed stirrer, in a protective nitrogen atmosphere. After dissolving the amino acids, 0.20 g/liter of sodium bisulfite, 25 g/liter of xylitol and 25 g/liter of D-sorbitol are usually added to the resulting solution and, after clarification, it is made up to the final volume with water for injection. The pH value of the solution ranges from 5.0 to 7.0, if necessary, it is adjusted with hydrochloric acid or acetic acid or another pharmaceutically acceptable acid. The solution thus prepared is clarified with activated carbon /5 to 10 g/liter/, filtered through an antimicrobial filter and filled into infusion bottles in a nitrogen atmosphere, under laminar flow at a temperature of 20 to 65 °C. After filling into bottles, the solution is sterilized in an autoclave at a temperature of 120 °C for 25 °C,

The amino acid complex for the treatment of renal failure according to the invention, in the form of the described infusion solution, has been clinically tested and introduced into medical practice. It has demonstrated the possibility of increasing nitrogen intake in patients with renal failure without

- 3,231,084 there was an increase in the level of urea in the plasma and further influence the spectrum of amino acids in the plasma in the sense of normalization, ensure the supply of nitrogen when this fails in an integrated dialysis program and finally postpone the use of an artificial kidney by up to about three years. These four favorably tested properties represent the main advantages of the amino acid complex according to the invention.

The properties of the amino acid complex according to the invention have been demonstrated by the following clinical tests:

1· The patients were transferred to a protein minimum /2.7 g nitrogen/day/ and in the next treatment was supplemented with either the amino acid complex according to the invention or a comparative commercial preparation /containing 8 essential amino acids, did not contain

arginine, proline and tyrosine/. Results are listed in table. Preparation Number of cases N balance g Urea mmol/l Uric acid jumol/l Hb /p CB g/1 /2.7 6 */ period 0 7 - 2.05 19.2 500 89.6 71.2 Complex amino acid tench /2.7 g N ♦ 3.36 g N/ 7 * 2.84 15.2 422 96 74 Commercial/ preparation 7 - 1.4 21.8 465 89.6 71.5

/2.7 gN ♦ g N/ ^x per 1 g N 1856 kJ /445 koal/ was administered

Hb « hemoglobin, CB « total protein.

The best results were found with the amino acid complex according to the invention, which, when evaluating the cumulative balance in 4 days after the addition of 5.36 g of nitrogen in the form of the above solution, showed a positive nitrogen balance, a decrease in plasma urea, a decrease in uric acid, an increase in hemoglobin and total protein. After application of the commercial comparative preparation

- 4,231,084 at a dose of 3.0 g of nitrogen, the nitrogen balance remains negative, the urea level did not decrease, although there was no increase either, the uric acid level decreased much less, the hemoglobin and total protein levels almost did not change.

Average aminogram values in 5 patients on a dialysis program after application of six infusions of the amino acid complex solution according to the invention in the amount of 3-4 g of nitrogen during 14 days: Amino- Norm. Before the dia- After six applications- acid level lysis of the complex ρο< jamol/l ymol/l according to the invention /on an empty stomach/ jumol/l I—valine 259 83 258 I-leucine 160 48 214 1-isoleucine 84 25 70 I-phenylalanine 65 94 104 1-tyrosine 72 38 89 I-lysine 148 230 362 1-threonine 146 217 428 l-methionine 32 5 67 l-tryptophan 60 5 54 L-histidine 93 154 276 E/A x 100 55 33 75 Val/Glyo x 100 94 33 68 Tyr/Phe x 100 110 40 65 Albumin g/l 25 to 50 36.2 38.2 Hb g/1 138 to 172 61.8 76.2 Explanations: E - total amount of essential amino acids-

Val - valine, Glyc - glycine, Tyr - tyrosine, Phe - phenyl-alanine, Hb - hemoglobin

The review shows that the application of the amino acid complex according to the invention led to a large-scale normalization of the amino acid spectrum, especially in the very low levels of the branched-chain amino acids methionine and tryptophan. Also, low indices characterizing the situation in renal failure, such as E/A, Val/Glyc and Tyr/Phe, increased significantly, so that they approached normal values. Also, the protein spectrum, characterized by

- 5,231,084 albumin and hemoglobin, improved. The nutritional status improved by administering the amino acid complex according to the invention is of great importance for the prognosis of the disease*

3* Balance evaluation performed in dialysis patients during the period of anuria. Application of the amino acid complex in a dose of 400 ml/day for 14 days /3.36 g of essential nitrogen with a diet of 100 g of proteins of high biological value with 8,374 kJ /2,000 calories//· Comparison performed with the period without application of the amino acid complex according to the invention /tl - 3/·

Amino acid complex Calculation / from dialysate' g N Calculation from plasma g N Period 0 /without amino acid complex/ /7 days/ - 20.9 - 6.2 Amino acid complex /14 days/ ♦ 28.7 ♦ 23.1 Period 0 /without amino acid complex/ /7 days/ - 3.0"/ - 14.7 "/

x/ cumulative balance for the relevant period xx/ in one patient, positive nitrogen balance persisted for another week

The balance evaluation clearly demonstrates that the amino acid complex according to the invention enables the achievement of a positive nitrogen balance even in completely anuric patients, i.e.* where this is not possible by other means*

4. The following table shows the delay of the start of the dialysis program by one month* Protein-energy provision of 40 g of protein and 28 g of amino acids in the form of an amino acid complex according to the invention and 10,468 kJ /2,500 kcal/ per day* 1 g of N accounts for 962 kJ /230 kcal/.

231,084

Biochemical parameters Patient 1 Patient day 1 Day 30 day 1 Day 30 creatinine imol/l 928 1206 770 1039 creatinine clearance ml/s 0.280 0.163 0.109 0.091 urea mmol/1 30.5 29.0 32 34 prealbumin g/1 0.34 0.36 0.34 0.43 Clinical parameters Nausea present disappearance present disappearance Dyspeptic discomforts yes no yes no Paresthesia present reduced present reduction Weight kg 100 101 63 65

The table shows that patients who would already require dialysis treatment can still be treated with the amino acid complex according to the invention. This therapy not only does not cause deterioration, but on the contrary, some clinical symptoms disappear, weight gain occurs with unchanged urea levels, even though the disease itself has progressed further, as evidenced by a slight increase in creatinine levels. This therapeutic effect also has a significant economic impact, because therapy with the amino acid complex according to the invention is significantly cheaper than very expensive dialysis therapy, which is also limited by the number of devices available.

- 7,231,084

Further details on the possibilities and composition of the amino acid complex according to the invention are illustratively given in the following examples.

Example 1

Weigh the L-forms of pure amino acids and other components according to

following recipes /in g per 1 liter solution L-valine 7.00 L-leucine 11.00 L-isoleucine 7.00 1-phenylalanine 9.00 L-lysine acetate 9.00 1-methionine 9.00 1-threonine 5.00 l-tryptophan 2.50 1-histidine 3.96 1-Arginine Hydrochloride 3.00 N-acetyl-L-tyrosine 0.70 l-proline 1.00 B-sorbitol 25.00 Xylitol 25.00 Electrolytes: Cl” 14.00 mmol OÍ^COO“ 43.00 mmol Sodium disulfide 0.2 Water for injections up to 1 000.00 ml Content of the overall 8.54 nitrogen Energy supply 658 kJ

pf

5.0 to 7.0

The listed components are dissolved in no particular order in redistilled water at a temperature of at least 60 °C, with vigorous stirring and in a nitrogen atmosphere. After dissolution, the solution is clarified twice with the addition of 0.5 to 3 wt. of activated carbon, based on

- 8,231,084 weight of active ingredients. The solution is then filtered through an antimicrobial filter and filled into infusion bottles under laminar flow, in a nitrogen atmosphere, at a temperature of 20 to 65 °C. It is sterilized in an autoclave at 120 °C for 25 min.

Example 2 ' <

As a starting material, 20 to 40% by weight of the required amount of amino acids is taken in the form of a summary obtained by hydrolysis of casein or other protein substrate*. After analysis, the required amounts of individual amino acids are supplemented with pure substances of L-forms, or in the form of acetates, to the amount in the recipe according to example 1. The further procedure is the same as in this example.

Example 3

The procedure is the same as in example 1 or 2, with the difference that either only D-sorbitol or only xylitol is used, or a solution without both of these sugars is prepared for application in pediatric practice.

Example 4

The procedure is the same as in example 1 or 2, except that sodium bisulfite is used as an antioxidant in an amount of 0.2 to 1.00 g/liter.

Example 5

The procedure is the same as in the previous examples, with the difference that the following components are also added /in g per 1 liter of solution/ ascorbic acid ί

inositol nicotinamide

0.4

0.5

0.6

- 9 pyridoxine.HCl 0.04· 231 084 riboflavin-5-phosphate sodium 2.5

Ascorbic acid acts not only as a vitamin, but also as a stabilizer and antioxidant.

Example 6 '

The procedure is the same as in the previous examples, with the difference that the following cations and anions are also added /y mmol per 1 liter of solution/:

To * 48.0 To * 25.0 Mg ** 2.6 Zn** / 8.0 %*° ₄ 9.0 Cl 14.0

Claims (1)

A complex of amino acids for the treatment of renal failure, in the form of an infusion solution, with optional addition of other adjuvants, in particular vitamins such as ascorbic acid or B-group vitamins, cations such as sodium, potassium or magnesium and anions such as phosphate or chloride, energy sources, for example sorbitol or xylitol, stabilizers and / or antioxidants, for example sodium bisulfite, characterized in that it contains in percent by weight 9.24 to 11.29 L-valine 14.51 to 17.74 L-leucine 9.24 to 11.29 L-isoleucine 11.89 to 14.53 L-phenylalanine 11.89 to 14.53 L-lysine acetate li, 89až 14.53 L-methionine 6.61 to 8.08 Of L-threonine 3.30 to 1,02 L-tryptophan 5.22 to 6.38 L-histidine 3.96 to 4.85 L-arginine.HCl 0.93 af 1.14 N-acetyl-L-tyrosine 1.32 to 1.62 L-proline and water for injection to 100 $ wt. and has a pH of 5.0 i Printed by Moravian Printing Works, Price: 2,40 CZK with operation 12, Leninova 21, Olomouc