CS203420B1 - Infusion solution for treatment and nourishment of patients with the liver failure and hyperamonemic condition - Google Patents

Description

The invention relates to an infusion solution for the treatment and nourishment of patients with hepatic failure and hyperammonaemic conditions, optionally containing other drugs, vitamins, energy sources, physiologically needed cations and anions. and preservatives and / or stabilizers. This solution is prepared from pure L-forms of amino acids or from a mixture of amino acids, obtained by hydrolysis of suitable protein substrates, supplemented with pure L-forms of amino acids and L-form of malic acid.

The use of pure L-forms of amino acids for the preparation of infusion solutions for the treatment of hyperammonaemic conditions and liver failure is known. Many of these solutions with different compositions have been developed but are not usually optimal. All known solutions contain L-arginine and other amino acids such as L-glutamic acid, L-aspartic acid and L-ornithine, also DL- or L-malic acid. Combination with L-lysine has not been described so far in any known solution, nor has any combination with some essential amino acids limiting tryptophan entry into the brain.

Further progress in this field is the infusion solution for the treatment and nourishment of patients with hepatic failure and hyperammonemia.

0.670 g of L-valine; 0.710 g L-Ieucine, 0.450 g L-isoleucine, 0.600 g L-methionine, 0.280 g L-threonine, 12.500 g L-arginine, 5.120 g L-lysine hydrochloride, 7,100 g L-glutamic acid, 1,000 g L-aspartic acid and 1.250 g of L-ornithine hydrochloride and water for injections up to 1000 ml, having a pH of 5.0 to 7.0 and containing, optionally, vitamins, energy sources, physiologically needed cations and anions, preservatives and / or stabilizers, according to the invention, containing 3,500 g of L-malic acid.

Malic acid. it is a part of a wide range of infusion solutions, both nutritionally and some specialty, used in the treatment of hyperammonaemic conditions, especially in liver failure. So far, the D, L-form has been used in these cases, difficult to use by the organism, as is the case with DL-forms of amino acids, in most cases utilizable only as a source of non-specific nitrogen, since only L-forms are present in proteins. The use of D-forms has a high energy burden on the organism, they are not nutritionally full-valued and therefore they were mostly abandoned.

L-malic acid is present in plants, both free and in salts and malts. In the human body, 203420 ⁸ to L-malic acid is normally present in whole blood in an average of 0.46 mg /% 0.24-0.75 mg /% JP Hummel, J. Biol. Chem. 180, 1225 (1949)]. It is part of the Krebs cycle of tricarboxylic acids and is a source of carbon dioxide, thus increasing alkaline. reserve organism. Its main significance lies in detoxifying ammonia and obtaining ATP.

The mechanism of action of L-malic acid in the body is as follows: the removal of ammonia in the body varies in three consecutive steps. It first undergoes an oxidation process by the action of malate dehydrogenase on oxalacetic acid. The D-form requires an acidic D-α-hydroxydehydrogenase for its oxidation, ie in the first phase its metabolism is completely different (R). Nordman: Hyperammonia. Infusionstherapie, Anaesthesiologie und Wiederbelebung, Vol.

13, page 107; Berlin-Heidelberg-New York, 1966]. When oxidizing the L-form, NAD ⁺ is converted to a reduced form of NADH2. In the second step, oxaleacetic acid is reacted with glutamic acid under the action of glutamate oxaleacetic transaminase to produce β1-ketoglutaric acid and L-aspartic acid. In the third step, the ω-ketoglutaric acid is reacted with

Dose 600 mg / kg

The form of LT50 malic days limits the reliability with ammonia under the catalytic action of glutamate dehydrogenase to produce glutamic acid. NADH2 is also involved in this reaction to form NAD ⁺ . The result of this three-step reaction is the formation of aspartic acid from malic acid and ammonia. Aspartic acid is then involved in the urinary cycle. A portion of L-malic acid is oxidized in the tricarboxylic acid cycle to form ATP. Thus, the administration of L-malic acid results in the removal of elevated ammonia levels, which ultimately takes place via the urinary cycle, but is also a source of ATP, a source of energy. These are the main two reasons for its administration.

Since malic acid is produced in the DL-form in the synthesis, it has also been used in this form. However, significant initial toxicity of DL-malic acid was found during initial tests, so some manufacturers have stopped adding this form to infusion solutions. In separate pharmacological testing of the DL- and L-forms of malic acid, the original assumptions were confirmed, as can be seen from the LT50 value table:

LT50 days

Dose 300 mg / kg confidence limits

DL- 3,5 2,6—

L- 5,2 3,2—

The table shows that the difference at 300 mg / kg body weight is twice as high in survival as the L-form. In clinical consequences, this means a reduction in the toxicity of the product, which is very important when used in terminal stages of liver failure and means an increase in the therapeutic breadth of the product, a reduction in the risk of overdose and the possibility of increasing the effective dose in exceptional cases.

The infusion solution of the invention containing L-malic acid has been well tolerated in clinical application. After 5,000 doses, no adverse reaction was noted, the preparation was completely stable.

Clinical results have shown exceptional efficacy of the solution. Experimentally, 11 patients were treated with liver failure, x served to improve the patient's nutritional status. In all cases, liver failure was clinically corrected. In the laboratory findings, mainly the level of ammonia in the blood was evaluated. The decrease was in the range of 50 to 152 gamma ° / o, ie an average of 106 gamma ° / o. When using the product as a nutrient solution, there was no increase in ammonia levels, and the product was well tolerated as in the treatment of liver failure.

With the infusion solution composition below 4.7 4.9 2.8-8.4

7.7 9.8 4.6-15.2 according to the invention was based both on the knowledge of individual amino acids and on the author's own experimental work, which made it possible to select the optimal combination from many combinations, even in comparison with some commercial preparations.

In addition to these components, the solution may contain magnesium, sodium and chlorides. Mostly it does not contain potassium, which is expected to be added individually, as needed by the patient, as a source of calories sorbit can be delivered, which is a sugar that can be utilized in liver damage.

The originality of the solution results from its composition, which does not contain any known solution, and from experimental works that demonstrate its optimal effectiveness. Three tests were used for this demonstration. The first test evaluates the effect of L-malic acid solution on the ammonia level in rat blood after administration of ammonium carbonate, the second test evaluates the LD50 effect on ammonium carbonate after infusion in mice and the third test the effect of premedication of infusion solution on convulsions administration of ammonium bicarbonate in rats. A total of 21 different combinations of solutions, including commercial solutions, were evaluated by these tests. In all three tests, the solution according to the invention showed the best performance. Correspondingly, clinical results show that the solution very well lowers ammonia levels; in the blood and is very effective in liver failure, especially where portocaval anastomosis has already been performed. The solution was well tolerated, even with very rapid administration in patients, without symptoms of pyrogenic reactions, as mentioned above.

The infusion solution of the invention may be prepared either from pure L-forms of individual amino acids or from a complex source of amino acids supplemented with pure amino acids. The preparation of the solution is simple, the individual components are dissolved without special order in redistilled water at a temperature of at least 80 ° C, using a high-speed stirrer and under a protective nitrogen atmosphere. The solution is clarified twice by filtration with activated carbon in an amount of 0.5 to 1% by weight, based on the active substance content. Next, the solution is filtered through an antimicrobial filter, for example a membrane filter. They are then filled into a sterile infusion bottle under a nitrogen atmosphere and at a laminar flow, typically at a temperature of about 50-60 ° C. The bottles are sealed with a sterile rubber stopper and secured with a metal cap. The solution is sterilized at 120 ° C for 25 minutes. Before filling into infusion bottles, the pH of the solution should be checked and optionally adjusted to a pH of 5.0 to 7.0, for example with hydrochloric acid, sodium, potassium or magnesium acetate or acetic acid or another pharmaceutically acceptable acid.

The invention is further illustrated by the following examples.

Examples

He did

Weigh the pure L-forms of amino acids in this amount (in gj anginine (base) 12,500 lysine (hydrochloride) 5,120 glutamic acid 7,100 aspartic acid 1,000 valine 0,670 leucine 0,710 isoleucine 0,450 methionine 0,600 threonine 0,280 ornithine (HCl) 1,250 malic acid 3,500

Mg ⁺⁺ 5'mval

Na ⁺ 35 mval

Clm 35 malate malate 26 mval sodium bisulphite 0.100 sorbitol 100,000 water for injections to 1000.0 ml pH 5.0 to 7.0 and dissolve in redistilled water at a temperature of at least 80 ° C, under a nitrogen atmosphere, in a special order stirring. Then the solution is clarified twice with 0.5 to 1 wt. activated carbon, filtered through an antimicrobial filter and at a temperature of 50 to 60 ° C, under a nitrogen atmosphere and under laminar flow. they are filled into sterile infusion bottles or plastic (disposable) bottles.

Example 2 t

The amount of ingredients is the same as in Example 1, except that xylitol or mixtures of both sugars can be used in the same ratio instead of sorbitol.

Example 1 a d 3

The amount of the components is the same as in Example 1 or 2, but the mineral feed, i.e. Na ⁺ , K ⁺ and Mg ⁺⁺ , is omitted and 0.2 to 1 g of sodium or potassium pyrosulphite is used as the antioxidant. It is also possible to use sodium bisulfite in the same dose or a combination of both to a dose of 1 g.

Claims (1)

Subject Solution for infusion for the treatment and nourishment of patients with hepatic failure and hyperammonaemic conditions, consisting of 0.670 g of L-valine, 0.710 g of L-leucine, 0.450 g of L-isoleucine, 0.600 g of L-methionine, 0.280 g of L-threonine, 12,500 g of L-arginine, 5,120 g of L-lysine hydrochloride, 7,100 g of L-glutamic acid, 1,000 g of L-aspaNYNALEZ ragic acid and 1,250 g of L-ornithine hydrochloride and water for injections up to 1 000 ml, pH 5.0 to 7 And optionally containing vitamins, energy sources, physiologically needed cations and anions, preservatives and / or stabilizers, characterized in that it contains 3,500 g of L-malic acid.