DE1923167A1 - Amino acid solution for intravenous nitrogen supply in uremic conditions and process for their production - Google Patents

Description

Priority! v. May 9, 1968 in Sweden Note No. 6259/68

The present invention relates to infusion solutions intended for intravenous nitrogen supply and in where the nitrogen source consists of important amino acids, which may contain certain semi-important amino acids are combined, such as with! -arginine and! -histidine. The invention also encompasses a method of dividing such nutrient solutions and a method of treating uremia caused by renal insufficiency

It has been proposed to deliver different types of food by intravenous administration, and it has also been suggested to put nitrogen on this

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Manner to be administered. The one for the nitrogen supply so far used infusion solutions had the disadvantage, however, that they were unsuitable for use in patients with acute renal insufficiency or under suffered from very decreased kidney function.

Attempts have also been made to carry out nitrogen nutrition in uremic patients with the help of a special diet. According to the last-mentioned proposals, important amino acids were administered to uremic patients as the sole source of nitrogen in addition to dietary nitrogen. During this treatment the patients received amino acid nitrogen in rather small doses, since there are considerable difficulties associated with the oral administration of the important amino acids, due to their terrible taste, which, even when incorporated into tablets and coated with chocolate or the like, is not sufficient for oral administration Way could be revised. When the taste was masked with a coating, the number of tablets became uncomfortably large, since in such a case the material of the coating became the main component in the tablet. Indeed, the difficulties with this route of administration were so important that the treatment had to be interrupted and the patients taking part in the experiments had to be given siproteins corresponding to essentially the same amount of nitrogen. During this treatment a certain reduction in blood urea was obtained -

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Nitrogen, but only a small one was achieved positive nitrogen balance, which is at most the value of Ig Nitrogen accumulation per day. The result and the effects of this previous treatment method were such It was bad that in different cases the patients had to be treated simultaneously on dialysis.

According to the present invention, it is possible to administer nitrogen intravenously to those patients who suffer from urinary insufficiency or from a very reduced kidney function. At the same time, a considerable reduction in the biourea nitrogen content is obtained in connection with a self-positive nitrogen balance, ie a very considerable nitrogen accumulation. This nitrogenization can reach about 6 g or more per day *, and one of the most important advantages of the junino acid yellow sungon according to the present invention is that such an important reduction in blood urea nitrogen is achieved in combination with a positive nitrogen accumulation, so that it is possible to a certain extent to switch off or delay the patient's dialysis treatment, which was inevitable according to previous methods with various types of kidney disease of the types discussed here. These effects must be regarded as surprising and represent a very important medical advance in terms of brief resuscitation of hospital beds and the great need for action.

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treatment required.

Another advantage obtained by using the amino acid solution of the invention is that there is a marked improvement in the general condition of the patient with a decrease in the concentration of accumulated protein deposition products. Another surprising advantage of using the Solutions according to the invention is that the improvement of the general condition of the patient even after the interruption treatment continues. This is a very important advantage as it is beneficial with previously known means and treatment methods is not achieved. The amino acid solutions according to the present invention preferably contain about 2.5 to 15.0J per liter of nitrogen derived from important and semi-important amino acids. The solutions contain a mixture of important amino acids in approximately the following proportions:

0.0130-0.0850 moles of 1-phenylalanine 0.0165-0.1050 moles 1-leucine 0.0145-0.0900 moles 1-methionine 0.0025-0.0200 moles of 1-tryptophan 0.0105-0.0700 moles of 1-isoleiicin 0.0110-0.0700 moles of 1-lysine

0.0080-0.0550 moles of 1-threonine and ^BAD

0.0135-0.0850 moles of 1-valine per liter

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It is also possible to use 0.0125-0.0800 moles

1-arginine and 0.0070-0.0 ^ 50 mol! -Histidine per liter

to incorporate.

According to a preferred method of the present invention, solutions are prepared with the following molar contents Liters

0.0375-0.0675 moles! -Phenylalanine

0.0500-0.0850 moles! -Leucine

0.0425-0.0750 moles! -Methionine

0.0075-0.0125 moles of 1-tryptophan

0.0300-0.0550 moles of 1-isoleuoin

0.0325-0.0575 moles of 1-lysine

0.0225-0.0425 moles of 1-threonine and

0.0 ^ 00-0.0700 moles of 1-valine

and also these solutions can "inen content of 0.0375 -0.0650 mol of 1-arginine, and 0.0200 - O containing 0375 liters of solution ₁ mole of 1-histidine ever. 1-histidine is preferably the only semi-null amino acid added.

The pH of the solutions is adjusted to fall within the range of 4.9 to 7.0 by adding a pharmaceutically acceptable acid. According to one embodiment of the invention, the pH Vfrt on k, from 9 to 5.1 adjusted by zfcgab · hydrochloric acid. However, in certain disease conditions it may be inopportune to »add further acidifying agents. In these cases, it is preferred to add acids that

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are decomposed by the body to water and carbonic acid, that is, organic acids containing only carbon, oxygen and hydrogen, such as acetic acid, lactic acid, etc., whereby the pH range can be extended up to 7 »0, and preferably the pH Value is set to 6.0 to 7> 0 and is thus more compatible with the physiological pH value. The preferred acid for adjusting the pH.W _e RTEs is .Essigsäure.

The preparations according to the invention are mainly intended for the treatment of those uremic conditions which are associated with kidney damage or decreased kidney function, but of course they can also affect others Conditions used where a nitrogen diet by intravenous administration of nitrogenous compounds, such as in catabolism.

The invention is further developed by the following examples explained.

example 1

A mixture of 1-arginine,! -Phenylalanine, 1-histidine, 1-iaoleucine, 1-leucine, 1-lysine,! -Methionine, 1-threonine, ! -Tryptophan and 1-valine in amounts corresponding to a final hall; of 0.0375 moles of 1-arginine, 0.0400 moles of 1-phenylalanine, 0.0215 moles 1-hiatidine »0.0320 moles! -Isoleucine, 0.0505 moles ! -Leucine, 0.0330 Mo! 1-Lyein, 0.0 ^ 5 MoX! -Methionine, 0.0255 moles 1-threonine, 0.0075 moles! -Tryptophan and 0.04l5 mol! -Valin j · liter was poured into 50 liters with stirring

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sterile! vials, sterile water up to about 90 liters were added and the pH was adjusted to 50 by adding 5 η hydrochloric acid. The volume the solution was then added by adding sterile water made up to 100 liters, and finally sterile filtered nitrogen was bubbled through the solution to remove it get rid of oxygen. The solution thus obtained becomes filtered and placed in infusion bottles under a nitrogen atmosphere filled, whereupon the bottles are sterilized by heating in an autoclave to 120 C for about 10 minutes became.

Example 2

JSin Mixture of 1-arginine, 1-phenylalanine, 1-IIistidine, 1-isoleucine, 1-leucine, 1-lysine, 1-methionine, 1-threonine, 1-tryptophan and 1-valine in amounts corresponding to a final content of 0, 0630 moles of 1-arginine, 0.0665 moles of 1-phenylalanine, 0.0355 moles of 1-histidine, 0.0535 moles of 1-isoleucine, 0.0840 moles of 1-leucine, 0.0550 moles of 1- lysine, 0.07 ^ 0 mol of 1-methionine, 0.0420 mol of 1-threonine, 0.0110 mol of 1-tryptophan and 0.0685 mol of 1-valine per liter were dissolved in 50 liters of sterile water with stirring, after which sterile water up to about 90 liters was added and the pH of the solution was adjusted to 6 to 6.5 by adding concentrated acetic acid. The "volume of the solution was then made up to 100 liters by the addition of sterile water, and finally sterile, filtered nitrogen was bubbled through the solution to make it free of oxygen.

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The third solution was filtered and placed under a nitrogen atmosphere filled into infusion bottles, whereupon the Bottles by heating in an autoclave to 20 C 15 Minutes have been sterilized.

Example 3

Example 2 was repeated, but using 1-arginine the solution was omitted. In this way a solution was obtained which only had 1-histidine as half-important Amino acid contained.

Clinical trials

In a kidney clinic, a number of patients were treated with an amino acid solution prepared according to Example 1. The treatment was carried out in such a way that, for a period of four days, the patients received a standard low-nitrogen diet which contained 2.7 g of protein nitrogen. In most cases the patients carefully ate all of the food given, but in some cases the patients did not eat all of the food given. In some cases, the patients also exceeded the certain amount. The deviations were observed precisely so that an excess or deficiency of nitrogen could be measured precisely. After four days of the standard diet, the patients were treated every other day with one intravenous infusion of an amino acid solution according to Example 1 and in a volume of 1 liter. The infusion was given for h to 6 hours. During the entire treatment

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During this period, patients received the standard diet and treatment was continued for a period varying from one week to one month, and in some cases repeated after some time interval. During the entire treatment period, the nitrogen balance was determined by analyzing the urinary nitrogen and analyzing the urea, amino acids, creatinine and ammonia in the urine. The blood urea nitrogen content and the serum creatinine were also determined. The patient's weight was checked at short intervals. All patients showed subjective improvement in association with amino acid treatment, but three of the patients who were in a band stage died after discontinuing treatment. All patients were uremic and had been referred to the hospital for dialysis treatment. After treatment with the amino acid solution for some time, some of the patients were able to leave the hospital without requiring any dialysis treatment, but for comparison one of the cases was dialyzed in a later treatment period. The number of patients subjected to this careful observation was 1h. The blood urea nitrogen concentration in certain cases fell during the diet period preceding the amino acid treatment, but whether or not diet was able to decrease it, the amino acid treatment of the present invention could further decrease it. In contrast to treatments with previously known

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Preparations and methods, the nitrogen balance during the treatment with the amino acid solutions after the finding was staik positive in all cases with a nitrogen accumulation, which could amount to 6 g per day. In all cases the balance became more positive or remained more positive the longer the treatment was carried out. If treatment was interrupted, or during the days between infusions, the nitrogen balance became negative again, but nitrogen losses during the intervening days decreased the longer the treatment lasted. The total accumulation of nitrogen after complete treatment was in many cases quite large, in one case even up to 73 g. The table shows the results of the treatment in compressed form for 5 of the treated patients. The table is to be understood that by treatment with amino acid solutions according to the invention a very important reduction in blood urea nitrogen concentration obtained ird i *, and that at the same time the nitrogen balance is strongly positive.

bad uHinihiA ^

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diagnosis Time in Ta ^ en Blood urea stick after
diet
alone after
DiUt +
Amino
acids Serum.Creatine ir after
diet
alone ι m ^ / lOOml patient only
diet DiUt +
Amino
acids st off content in / 100 ml 130 73 12.2 No. chronic
Pyelonephri
tis with
Prairie 4th 26th before
the
Authority 96 70 VOX "
the
Authority 12.8 after
Diet +
Amino
acids 1 chronic
Glomerulo-
nephritis 4th 4th 155 94 55 15.5 11.5 10.5 2 chronic
Glomerulo-
nephritis 4th 7th 114 . 122 78 11.8 9.9 11.7 I. 2 chronic
Pyelons
phritis with
Uremia 4th 10 108 88 39 10.0 11.8 it
I.
11.5 3 innate
Cystnias 4th 20th 156 TO O -j.
CO 4th 100 12.5 io, o cn

(Continued)

(Continued)

CQ O CO

Patient no. accumulated
N-gloss Diet +
Amino
acids before the
Treat. Gexvicht after diet +
amino acids 1
2
2
3
4th diet only +74.04
+13.50
+23.47
+ 9.38
+51.6 55.5
54.7
55.3
44.9
48.0 after diet
alone 55.9
57.5
58.9
44, p
48.3 - 4.32
-12.33
- 0.16
-17.24
-10.13 56.0
56.4
57.0
44.8
48.5

Patient No.2 was examined on two occasions.

2 D

O Q

CO

CO -Jk.

σ>

It should be noted that the reported cases are patients with serious kidney damage that were based on previous experience with known treatment methods and means the proposed mixture of amino acids or other nitrogenous substances not without increased discomfort and could get kidney damage intravenously.

! His further patient number was with a considerable
treated good effect. In these cases only the Dluthurea Nitrogen Concentrate! on and the serum creatinine level continuously registered.

Sowix'd according to the present invention of medicine
A new preparation made available, which makes it possible to switch off dialysis in uremic patients, which is otherwise necessary as a result of impaired kidney function, or which in particularly serious cases enables the time between dialysis treatments to be extended considerably.

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Claims (1)

Pa t e n t a η s ρ r ti c h ο 1.) Infusion solution for intravenous nitrogen supply, thereby characterized in that they are in aqueous solution 0.0130-0.0850 moles of 1-phenylalanine, 0.0165-0.1050 moles of 1-leucine, 0.0145-0.0900 moles of 1-methionine, 0.0025-0.0200 moles of 1-tryptophan, 0.0105-0.0700 moles of 1-isoleucine, 0.0110-0.0700 moles of 1-lysine, 0.0080-0.0550 moles of 1-threonine and 0.0135-0.0850 moles! -Valin O is adjusted | per liter of the solution contains and the PLL ¥ _e rt the solution by the addition of hydrochloric acid or a pharmaceutically acceptable organic acid, which is constructed only of carbon, hydrogen or oxygen, to 4.9 to 7 2.) Infusion solution according to claim 1, characterized in that "{characterize t, that they additionally contain 0.0125 to 0.0800 Hol 1-arginine and Contains 0.0070 to 0.0450 moles of 1-histidine per liter. 3.) Infusion solution according to claim 1, characterized {jekennzeichno t, that they additionally 0.0070 to Ο, θ45Ο mol l-IIistidine each contains. - 15 - 909847/1038 BATH h.) Infusion solution according to claim 1, characterized in that they 0.0375-0.0075 moles! -Phenylalanine, 0.0500-0.0 '; 50 moles 1-leucine, 0.0 * 125-0.075O moles 1-ilethionine, 0.0075-0.0125 moles 1 tryptophan, from 0.0300 to 0.0550 mole -isoleucine, 0.03-5 - 0.0575 mol of 1-I.ysin, 0,0.725 - O, O * t25 Get threonine and 0.0 * 100! - 0.0700 moles of 1-valine contains per liter of solution. 5.) Infusion solution according to claim k, characterized in that it additionally contains 0.0375 to 0.0050 mol! -Arginine and 0.0200 to 0.0375 mol of 1-histidine per liter. 6.) Infusion solution according to claim **, characterized in that that it additionally contains 0.0200 to 0.0375 mol of 1-histidine per liter. 7.) Infusion solution according to claim 1 to 6, characterized in that that the pH ¥ ert adjusted to a range from * f, 9 to 5> 1 by adding hydrochloric acid is ο 8.) Infusion solution according to claim 1 to 6, characterized in that the pH Vert a by adding acetic acid 909847/1038 - ₁₆ - BATH ORIGINAL Do ro i from (>, 0 to 7 | O ciiifjosf olJ.t is !>") 1 nfus i on?:. L iisuii; j according to claim 1 to I-, thereby gekcnn-, ■ ('ichnoi, d.'L'i pin by Ei'hitzon L in an autoclave to U'O C - Külurcnd is sterilized for about a quarter of a century. BATH ORIGINAL 909847/1038