DE2013026A1 - Amino acid compsn against liver diseases - Google Patents

Abstract

Medicament for treating and preventing liver diseases and muscular insufficiency contains at least two of the aminoacids leucine, isoleucine, lysine, phenylalanine and tryptophane, isolated or protein-bound. A pref. form also contains ubiquinones (tetra-substd. p-benzoquinones) with opt. additions of vitamin B12, K and/or E.

Description

Preparations in particular for the treatment and prevention of liver diseases and muscular insufficiency The invention relates to an agent for treatment and Prevention of liver diseases, especially hepatitis, liver necrosis and liver cirrhosis, and von'muscular insufficiency, such as a weak tone in bladder diseases. In addition, however, the agent according to the invention is also used for treatment and Prevention of dysproteinemia and as an antioxidant, such as for prevention a-s degradation of Vitasin E in the organism, suitable.

In Proc, Soc, Exper. Biol. Med. 77, page 818 (1951) was published by K. Schwarz stated that cystine has a protective effect against liver diseases. Even it's from J. Nutrit. 63, page 399 (1957) known that methionine has a similar Should have protective effect, the specified protective dose for both of the compounds between 0.5 and 1.0% as a feed component of various Diets fluctuates. With a daily feed intake of 5 to 10 g in rats, the daily amount is of these two described amino acids at s up to 100 mg. Had attempts on with artificially produced liver necrobiosis, however, showed that the two amino acids mentioned neither individually nor in combination with one another have an influence on the disturbed enzyme system of the liver and therefore not suitable for the treatment of liver diseases are.

In J. Biol. Chem. 217, page 829 (1955), there is also information on liver treatment Cytidine and in advance. Protein Chem. 12, page 134, (1954) the use of cytosine described. According to L.

Wagner, R. Hörhammer and R. Münster, Drug Research 18, page 688 (1968) is said to be used against liver diseases and, according to Int. Z. f. Clin. Pharm., Therefore. and Tox. 1, page 319 (1968) and Med. Klin. 62, page 609 (1967) Xant-inol-nicstinat are given. In addition, Acta.chem. Scand. 12, page 1330 (1958), spring. Proc. 17, page 1929 (1958) and J. Biol. Chem. 233, page 245 (1958), to use selenium and selenium compounds for liver therapy, as these have hepatropic functions can be attributed. All of these above-described agents for treating liver diseases however, did not result in any in rats with artificially produced liver necrobiosis either or no significant reduction in the symptoms of the disease. Also need selenium and selenium compounds as substances having a toxic effect on the liver pulp wheel and the toxicity of these compounds is manifested in neuritis and paralysis a short time after their administration.

The object of the invention was therefore to find new means for treatment and Prevention of liver disease and muscular insufficiency to get the one hand do not act toxic in the required dosages and on the other hand a better one Have an effect than the already known means. In particular, the new Means according to the invention for curing and preventing hepatitis and Bebernecrobiosis and cirrhosis of the liver and have additional areas of application.

The agents according to the invention, in particular for treatment and contraception of liver diseases and muscular insufficiency, with an amino acid content are -there characterized in that they contain at least two of the amino acids leucine, isoleucine, lysine, Phenylalanine and tryptophan in isolated form - or bound in a protein contain.

Depending on whether this means to cure an acute illness or serve to prevent such a disease, it may be sufficient in individual cases, to administer only two of the amino acids mentioned with the agent according to the invention or to give a combination of several or all of these five amino acids. It is useful that the agent is a combination of leucine, isoleucine, lysine, Phenylalanine and tryptophan in the form of the isolated amino acids or in one Includes bound protein. A suitable protein that contains these amino acids, is egg albumin, or fractions of egg albumin can also be used instead that these amino acids contain. These are to be mentioned preferably the. Ovalbumin fraction and / or the globulin fractions of egg albumin.

The administration of egg albumin or its appropriate fractions is particularly useful because it also contains the amino acids arginine, histidine, Threonine, valine, tyrosine, nathionine and cystine are included, which are preferred administered in combination with the above five amino acids. Of these Additional amino acids are made with the above five essential amino acids expediently combined above all methioni and cystine.

The ratio of the amino acids to each other can be varied to a large extent Range can be varied, omitting one or more amino acids the above combination of five by using larger amounts of the remaining Amino acids can be balanced. Appropriately, the weight ratio is the Amine acids with one another in each case in the range between 1: 7 and 7: 1. Particularly cheap Amount ratios for leucine, isoleucine, lysane, phenylalanine and tryptophan are at about 6.4: 4.4: 4.0: 3.7: 0.9. An optimal amino acid sequence for the invention Average is about 4.4 parts by weight isoleucine, 6.4 parts by weight leucine, 4.0 Parts by weight of leucine, 3.7 parts by weight of phenylamine, 0.9 parts by weight of tryptophan, 4.8 parts by weight of arginine, 1.2 parts by weight of histidine, 4.0 parts by weight of methionine, 3.0 parts by weight treonine, 3.6 parts by weight valine, 2.3 parts by weight Cystine and 4.8 parts by weight of tyrosine.

It is particularly preferred to use the above-mentioned amino acid combinations or proteins with the amino acid sequences mentioned, such as egg albumin or its Fractions combined with ubiquinones to be administered. The ubiquinones are tetra-substituted p-Benzo-quinones with one methyl, two methoxy and one polyisoprenoid substituent. So far, at least for-n! Ubiquinones are known that correspond to the carbon atoms are designated in the polyisoprenoid side chain with C30 to C50. So far has been the group of ubiquinones subsumed under the term coenzyme Q (Nature, London 172, page 716 (1953).

The production of the Ubiquinone is for example in the German latentsohrifte 1 103 868 and 1 223 794 as well as in the German Offenlegungsschrift 1 442 124. Although all ubiquinones for the remedy according to the present In accordance with the invention, ubiquinone 50 is suitable for reasons of economy with 50 carbon atoms in the polyisoprenoid side chain particularly preferred, because it is currently the cheapest to produce.

It also proved useful in addition to the above Substances vitamin 3129 vitamin K and / or vitamin E in the agent according to the invention to incorporate.

By the means according to the invention, the regeneration process in the liver cell can be initiated therapeutically. The at Liver necrobosis, For example, a disruption in the enzyme system caused by a high supply of carbohydrates and protein synthesis is regulated by the means according to the invention, since these Means contain substances which, as has now been established, are in the structure of the liver tissue resemble. The albumen with its protein fractions apparently provides the liver protein structure important reactive compounds for synthesis. So contains the conalbumin with a molecular weight of 87,000 as the terminal amino acid alanine, and ovomucoid With a molecular weight of 27,000, phenylalanine is carboxyl terminated Amino acid and alanine as an amino terminal compound.

Ubiquinones could be detected in the mitochondria of the animal cell will. The mitochondria have a double lipoprotein membrane, and that is what it is 80% protein and 20% phospholipoid. The ubiquinones are capable of the important process of electron transfer, which is essential for the cell physiological process Processes is necessary to initiate and carry out.

Thus, the means of the invention are suitable by constructing To normalize cellular functions that are disturbed by protein and enzyme synthesis or prophylactically to prevent the disruption of cell functions. While for the Prophylaxis and the administration of the above for weak diseases Amino acid combinations are sufficient in the treatment of acute liver diseases and muscular insufficiency usually useful, a combination of amino acids in isolated form or bound in a protein substance, as a precaution Egg albumin or these fractions, to be administered in combination with the ubiquinones, The agents according to the invention can be used in any conventional manner, such as orally, administered parenterally or rectally. Except as a means of treatment or They are the prevention of liver diseases and muscular insufficiency at the same time also used to treat or prevent dysproteinemia and as antioxidants, for example suitable for preventing a breakdown of vitamin E.

The dosages are very much dependent on whether one of the invention Means used prophylactically or for the treatment of acute diseases. The quantity ratio from amino acids or proteins, such as egg albumin, to ubiquinones in the remedies According to the invention can expediently 9m range from 91 g to 25 g of amino acids or Egg albumin range from 1 to 75 mg ubiquinone.

The following examples serve to further illustrate the invention.

Albino rats were used as experimental animals, and those with the help a diet high in carbohydrates causes artificial liver necrobiosis X This Idinstilohe lebernorobiosis was caused o1gende-Oßen: 33 young resentful jump Dawlav albino rats with an average weight from 37.0 g received a diet of 10% dry beer yeast for 60 days, 76, 'sucrose, 7% palmin, 2% cod liver oil, 4% minerals and 1% vitamin mixture, the animals were they were housed in individual cages, and the diet and water were available to them ad libitum to disposal. The average weight after this period was 45 g, the weight gain 8 g per animal during the 60 days.

With this diet there was a reduction in the overall metabolism, the growth effect was small. It is to be assumed that the high carbohydrate supply blocks protein and nucleic acid synthesis. The is also about substitute reactions growing organism with this carbohydrate oversupply not enabled.

The general approach corresponds to the course of the weight curve of animals affected. Death often occurs in a convulsive state, being the cause of death is an acute hepatic insufficiency. Those found in the histological examination Findings give the picture of a necrobiese of the Laber. This Laber cell change is clearly pronounced in all animals after a diet given for 60 daysq example 1 boy Botton with an average weight of 35 to 40 g received daily the above-mentioned diet and at the same time 50, 100 or 200 milligrams of egg albumin (daily dose pre tier). The reindeer albumin used was free of selenium and heavy metals.

When 50 mg was administered to 16 test animals in 100 Days a mean weight gain of 33 g per animal.

The experiment with 100 mg of egg albumin resulted in 13 animals in 100 days a mean weight gain of 55 g and the experiment with 200 mg of egg albumin 30 test animals a mean weight gain of 72 g per animal in 100 days.

Example 2 Three groups of 10 each of the albino rats weighing from 42 to 46 g received the diet described above and in the kuraein test from 13th day 200 mg egg albumin and the following vitamin supplements. The duration of the search was 260 days.

Received upon administration of 200 mg of egg albumin and 10 IU of vitamin A. a mean weight gain of 110 g per animal.

With an administration of 200 mg of egg albumin, 10 IU of vitamin A and 10 μg of vitamin B12, the weight gain per animal was 125 g.

With the administration of 200 mg egg albumin, 10 IU vitamin A, 1Q IU vitamin K and 10 / u g of vitamin B12 would result in a weight gain of 131 g of the animal.

In all three groups there were still detectable in 50 to 50% of the animals necrobiotic foci, in some cases small droplets and large droplets Fat infiltration of the liver.

Experiments 1 and 2, however, indicated that egg albumin was one significant influence on the active metabolic function of the nutritionally damaged Liver cell owns. The combination of egg albumin with vitamins A, K and B12 did not lead to any significant improvement in liver cell metabolism.

Example 3 Six test groups of 10 each of the albino rats were fed with the diet described above. The test animals were also given daily assistance with the help of a pharyngeal tube 20 resp.

40 / u g ubiquinone 30, in groups 3 and 6 in combination with vitamin A, K and B12. The six test groups received the following daily allowance: I. 100 mg egg albumin + 20 / u g ubiquinone II. 150 mg egg albumin + 40 1u g ubiquinone III. 150 mg egg albumin + 20 / u g ubiquinone, 10 IU vitamin A, 10 IU vitamin K and 101u g vitamin B12 IV. 200 mg egg albumin + 20 / u g ubiquinone V. 200 mg egg albumin + 40, u g ubiquinone VI. 200 mg egg albumin + 20 / u g ubiquinone, 10 IU vitamin A, 10 IU vitamin K and 10 Xu g vitamin B12.

The evaluation showed that the growth efficiency was at its optimum after 100 days at the groups with 200 mg egg albumin + 20 resp.

40µg ubiebinon is, with the vitamin addition no noteworthy additional Effect is attributable. The histological examination of the liver of some vermin after 100 days, no pathological findings were found in any group.

These experiments show that the combination of egg albumin with ubiquinone suitable is. Prevent Necrobinse's Life.

Comparative Example 1 15 of the albino rats with a medium weight of 37 g was placed on the above-described diet for 55 days, face gain averaged 15.0 g. The animals then received daily in addition to the diet 5 mg cystine and 5 mg methionine, after 40 days the weight gain was The autopsy findings of 5.0 g per animal showed mecrobiosis of the liver tissue.

In parallel experiments, the dose for cystine and methionine became essential elevated. One test group received 50 mg of cystine, a second test group 100 mg cystine, a middle test group 50 mg methionine and a fourth test group 50 mg cystine and 50 mg mathionine. Obtained from the two next Veruchzgruppen an increase in weight of 43 to 51 over a period of 100 or 152 days G. but in the praphylactic aunt the formation of necrobiotic areas in the boar of the Verenchstienen did not prevent it. Even with the third and fourth Trial group necrobiotic areas developed in the liver.

The administration of cytidine in a daily dose of 10 resp. 20 mg per animal resulted in the curative test, which was only detectable after occurrence necrobiotic changes the test substance was administered over a period of time from 20 to 30 days to the death of the animals with the development of liver recrobiosis.

Daily doses of 10 or 20 mg of cytosine resulted in unge after 21 days severe liver changes in rats. The weight gain ranged from 3.0 to 5.0 g per animal.

Daily doses of 10 and 15 mg silymarin resulted in on 15th day the picture of liver necrobiosis.

Daily doses also occurred when xantinol nicotinate was administered of 30 or 60 mg for the development of liver necrobioses with fresh bleeding. One Weight gain did not occur.

Comparative Example 2 To investigate the effect of selenium and selenium compounds after 75 days of normal diet, rats received the above-described diet from day 76 as well as selenium in different dosages and administration. The evaluation took place with groups of 10 test animals each.

The daily dose of selenium in group 1 was 5 mg, selenium / kg diet, for group 2 25 mg selenium / kg diet, for group 3 10µg.

Selenium dioxide daily per animal (gastric tube) and 100 µ g for group 4 Selenium dioxide daily per animal (stomach tube). With a daily feed intake of 5 to 10 g per animal, the daily selenium intake was 25 to 50 µg.

In the first test group, pebbles after 30 days of selenium administration found no significant weight gains, and the general findings of the animals was reduced From the 30th day 50 mg beer yeast per rat were added daily, but this supplement did not lead to any activation of the metabolism. During a total of 75 Days there was no increase in weight, but rather weight loss of 10 g. All animals died of liver scrobioee.

Increasing the dose also resulted. in the second experimental group to no growth effect. From the 30th day the tienes also healed daily 75 mg dry beer yeast per animal. After 65 days the weight gain was 1g, all Animals died due to liver scrobiosis.

Administration of selenium dioxide resulted in the third experimental group Despite daily administration of vitamin B12, only one garing from the 30th day of the experiment Weight gain of 6.0g. The Tera died of Leher insufficiency during the stay and prone to liver recrobiosis in histological picture.

When adding 100 μg of selenium dioxide in the fourth test group the average survival time was not more than 20 days, although from the 10th On the 2nd day, the animals were given 100 mg of dry beer yeast daily. All animals showed evidence of liver ecrobiosis.

Comparative Example 3 In the curative and prophylactic test Test groups of 10 albino rats each with dry beer yeast in daily doses of 8 mg, 10 mg, 50 mg, 75 mg, 100 mg and 150 mg are administered in addition to the diet described above. In all animals the typical developed in a period of 25 to 95 days Image of Labernacrobiose Also the combination of 150 mg of dry beer yeast uit 50 mg of methionine failed to prevent liver necrobiosis from developing, though slight weight gains were recorded.

In the cuiven test, in further test groups of 10 boys each received Albino rats the test animals 100 ig, 150 mg or.

200 ig whole milk powder as a daily dose. For all three groups is the maximum survival time was 30 days, the weight curve showed one slight increase. All Tiera show nacrobiotic hyperchanges.

The comparative experiment shows that proteins that are not under d.n Subject of the invention fall, were unable to necrobiosis prophylactic to prevent or cure.

Claims (1)

Claims 1. Means, especially for the treatment and prevention of liver diseases and muscular insufficiency, with an amino acid content, characterized that there are at least two of the amino acids leucine, isoleucine, cystine, and phenylalanine Contains tryptophan in isolated form or bound in a protein. 2. Means according to claim 1, characterized in that there is a combination of leucine, isoleucine, lysine, phenylalanine and tryptophan. 3. Means according to claim 1 and 2, characterized in that it is additionally one or more of the amino acids arginine, histidine, threonine, valine and tyrosine, preferably methionine and cystine. +. Agent according to Claims 1 to 3, characterized in that it is used as the amino acids egg albumin containing protein in bound form or containing amino acids Contains fractions of the same. 9. Composition according to claim 4, characterized in that it is the ovalbumin fraction and / or contains the globulin fractions of egg albumin. 6. Means according to claim 1 to 5, characterized in that it de Amino acids in a weight ratio of 1: 7 to 7: 1 contains. 7. Composition according to claim 6, characterized in that it is leucine, Isoleucine, Lysine, Phenylalanine and Tryptophan in a weight ratio of about 5.2 to 7.6 parts by weight of leucine, 3.5 to 5.3 parts by weight of isoleucine, 3.2 to 4.8 parts by weight of lysine, 3.0 to 4.4 parts by weight of phenylalanine and 0.7 to 1.1 Contains parts by weight of tryptophan. 8. Means according to claim 7, characterized in that it is additionally 3.8 to 5.8 parts by weight arginine, 1.0 to 1.4 parts by weight histidine, 2.2 to 4.8 Parts by weight methionine, 2.4 to 3.6 parts by weight threonine, 2.9 to 4.3 parts by weight Valine, 1.9 to 2.7 parts by weight of cystine and 3.8 to 5.8 ge. contains important parts of tyrosine. 9. Means according to claim 8, characterized in that it is about 6.4 Parts by weight of leucine, 4.4 parts by weight of isoleucine, 4.0 parts by weight of lysine, 3.7 Parts by weight phenylalanine, 0.9 parts by weight tryptophan, 4.8 parts by weight arginine, 1.2 parts by weight of histidine, 4.0 parts by weight of methionine, 3, Q parts by weight of threonine, 3.6 parts by weight valine, 3.3 parts by weight cystine and 4.8 parts by weight tyrosine contains. 10. Means naoh claim 1 to 9, characterized in that it additionally contains at least one ubiquinone, preferably ubiquinone 50. 11. Composition according to claim 1 to 10, characterized in that it additionally contains vitamin B12, K and / or E.