CH642541A5 - ESSENTIAL SOLUTION CONTAINING AMINO ACIDS FOR ADMINISTRATION TO CANCER PATIENTS. - Google Patents

Description

The invention will now be explained in more detail with the aid of a few examples. The values given in brackets correspond to the conversion results from amino acids in salt form to free acids.

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The amino acids contained in the amino acid solutions according to the invention are preferably the crystalline

example 1

The following amino acids were dissolved in the specified 65 concentrations (mg / 100 ml) in sterile water, so that an amino acid solution according to the invention could be formulated. The solution obtained is then sterilized at 110 ° C. for at least 10 minutes.

642 541

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mg /

100ml

Leucine Valine Isoleucine Lysine HCl

Phenylalanine threonine tryptophan arginine HCl

Histidine-HCl-2H20

Glycine

410 200 180 620 (496) 290 180 60 270 (223.3) 130 (88.7) 340

Total amino acids Total free amino acids Total nitrogen

2680 mg / 100ml 2480 mg / 100ml 0.397 g / 100ml

Examples 2 to 6

The following amino acid solutions were prepared in accordance with Example 1:

Composition (mg / 100ml)

Components

Example 2

Example 3

Example 4

Example 5

Example 6

Leucine

410

410

1090

267

175

Valine

200

200

960

198

175

Isoleucine

180

180

960

192

189

Lysine HCl

620

620

963

189

330

(500)

(500)

(770)

(151)

(264)

Phenylalanine

290

290

640

138

175

Threonine

180

180

646

138

180

Tryptophan

60

60

320

48

45

Arginine HCl

-

270

830

147

165

(220)

(686.4)

(121.6)

(136.5)

Histidine-HCl-2H20

-

130

370

-

143

(252.3)

(97.5)

Glycine

-

-

1490

-

236

Alanine

-

-

-

81

150

Aspartic acid

- -

-

-

246

240

Glutamic acid

-

-

-

600

300

Proline

-

-

-

222

143

Serine

-

-

171

150

Tyrosine

-

-

165

5

In the following, experimental investigations and clinical tests are described which explain the use of the amino acid solutions according to the invention.

Experimental investigation Donryu and Wistar rats, each with a live weight of 150 to 160 g, were provided with a catheter which allowed a continuous infusion into the animals. The animals were acclimated to the catheter for 3 days.

An infusion pump is connected to the catheter via a three-way valve. The pump used was the "Bio-Canulla" from Bio Medica Ltd., Japan. During the three-day acclimatization mentioned, the animals were given the Pan-Amin infusion solution by Otsuka

55 Pharm. Co., Ltd., Japan, hereinafter referred to as “PA”. Said PA solution was introduced at a continuous administration rate of 1.5 ml / h, the animals having free access to water and to a protein-free diet. The PA solution had the following composition (data in mg / 100 ml):

Leucine 410

Valine 200

Isoleucine 180

Phenylalanine 290

Threonine 180

Tryptophan 60

Arginine • HCl 270

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642 541

Histidine • HCl • 2H20

Methionine

Glycine

130 240 340

The composition of the protein-free diet food was as follows:

a-starch sucrose vitamin mixture1 salt mixture2 cereal oil cellulose «Chocola A» 3 choline chloride

47.83 g 23.92 g 1.0 g 5.0 g 5.0 g 2.0 g 0.05 ml 0.20 ml

The vitamin mixture 1 had the following composition (data in weight per volume%):

Thiamine • HCl

Riboflavin

Nicotinic acid

Calcium pantothenate

Pyridoxine HCl

Menadione

Biotin

Folic acid

Vitamin BJ2

Inositol

Ascorbic acid

Lactic acid

0.059 0.059 0.294 0.235 0.029 0.006 0.001 0.002 0.0002 1.176 0.588 97.551

The salt mixture 2 had the following composition (data in weight per volume%):

CaCO

29.29

CaHP04 • 2H20

0.43

kh2po4

34.31

NaCl

25.06

MgS04 • 7H20

9.98

Fe (C6H507) • 6H20

0.623

CuS04 • 5HzO

0.156

MnSO * • H20

0.121

ZnCl2

0.02

(NH +) 6Mo704 • 4H20

0.0025

Potassium iodide

0.005

“Chocola A” 3 is a trademark of Eisai Co., Ltd., Japan and contains a palmitic acid ester of vitamin A with 30,000 international units / ml vitamin A (20 mg / ml retinol palmitate).

Detection of the inhibitory effect on solid tumors

After the acclimation period described above, various animals were prepared with tumor cells. The Donryu rats were administered 2.7 x 10 "cells ml Yoshida Sar-coma cells and 9x10® cells ml AH 130, the Wistar rats 1 x 107 cells / ml Walker Sarcoma cells and Rhodamine Sarcoma cells in one amount of 0.2 ml as tumor cell porridge The tumor cells were transplanted subcutaneously into the left groin area of the animals. As shown in Table 1 below, the rats with the same tumor cells and rats without tumor cells were divided equally into 12 groups. The groups Al and A-4, only the amino acid solution according to the invention as described in Example 1 was given below, AO-30, and groups A-2 and A-5 were given both AO-30 and Mitomvcin-C.

groups A-3 and A-6 were given AO-30, MMC and diet, and, as a control, groups PI and P-4 were given only PA, groups P-2 and P-5 PA and MMC and the groups P-3 and P-6 s PA, MMC and diet administered together. Each group consisted of 6 rats. AO-30 and PA were administered continuously at an infusion rate of 1.5 ml / h. MMC is administered intraperitoneally in a dose of 0.1 mg / kg body weight and day, the administration being started 24 hours after the implantation of the tumor cells. The diet is a protein-free diet as described above.

In Table 1, the sign "+" means the fact

that the rats got tumor cells implanted i5 or that they got MMC or diet. The sign "-" means no tumor cell implantation, no administration of MMC or no diet.

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Table 1

20th

Group implantation of MMC

Tumor cells

diet

30th

35

Control

P-l

-

-

P-2

-

+

P-3

-

+

P-4

+

-

P-5

+

+

P-6

+

+

invention

A-l

-

-

A-2

-

+

A-3

-

+

A-4

+

-

A-5

+

+

A-6

+

+

+

+

+

The Yoshida tumors and the AH 130 are removed from the animals on the 12th day after the transplantation and the Walker tumors and rhodamine tumors on the 15th day after the transplantation. The removed tumors are then weighed. The corresponding measurement results are summarized in Tables 2 to 5. The mean tumor weights C from the tumor-infested group P-4, which contained only PA, are then calculated. The mean weight T of the tumors of groups P-5, P-6, A-4 and A-6 is also calculated. Tables 2 to 5 show the T / C ratios obtained. The values obtained are said to be effective if T / C is less than 0.50, weakly effective if the ratio is between 0.5 and 0.7 and ineffective if the ratio mentioned is greater than 0.7.

The average value of the weighed tumors in Tables 2 to 5 is the average of the maximum and minimum tumor weight in the 6 rats of the group examined. The mean «+» the scatter gives the maximum, the mean «-» the scatter the minimum weight.

Table 2 (Yoshida tumor)

group

Tumor weight (mg)

T / C

65 P-l

P-2 P-3 P-4

2689 + 588

642 541

Table 2 (continued)

6

Table 4 (continued)

Group Tumor Weight (mg) T C

P-5 1860 ± 814 0.69

P-6 - 1865 ± 678 0.69

A-1-A-2

A-3 -

A-4 1720 + 960 0.64

A-5 1135 + 265 0.42

A-6 II 26 ± 324 0.42

Table 2 clearly shows that the administration of the amino acid infusion solution AO-30 according to the invention alone (group A-4) brings about a reduction in the tumor weight up to 1/3 of the untreated tumor. The solution AO-30 therefore shows a tumor-inhibiting effect. Furthermore, the T / C ratio of group A-4 - the corresponding value is 0.64 - indicates that the stated effect is at least as great or even higher than the corresponding effect when MMC alone is administered (group P-5 ) or with administration of MMC and diet (group P-6). Group A-5 with administration of AO-30 and MMC and group A-6 with administration of AO-30, MMC and diet show T / C values of 0.42. This means effective treatment activities. This also proves that the joint administration of the A0-30 solution according to the invention and MMC increases the tumor-inhibiting effect of the individual substances.

Table 3 (Walker tumor)

group

Tumor weight (mg)

T / C

P-l

P-2

P-3

-

P-4

5010 ± 1311

P-5

2783 + 1001

0.56

P-6

2712 ± 873

0.54

A-l

_

A-2

-

A-3

-

A-4

1816+ 878

0.36

A-5

1198+ 522

0.24

A-6

1262 + 375

0.25

The information in Table 3 also shows that the use of the A0-30 solution according to the invention (group A-4) leads to a reduction in the tumor weight corresponding to approximately 1/3 of the untreated tumor (P-4). Likewise, the administration of AO-30 together with MMC or together with MMC and the diet gives even better results.

Table 4 (AH-130)

Group Tumor Weight (mg) T / C

PI

P-2 - -P-3

P-4 8005 + 2891

P-5 4883 ± 1460 0.61

P-6 5046 ± 1100 0.63

Group Tumor Weight (mg) T / C

A-1

A-2 - -

A-3 - -

A-4 4642 ± 910 0.58

A-5 2275 ± 1518 0.28

A-6 2300 ± 1005 0.29

Table 4, like tables 2 and 3 above, also shows that the amino acid solutions according to the invention show effective results.

Table 5 (Rhodamine tumor)

Group Tumor Weight (mg) T / C

P-l

P-2 - -

P-3 - -

P-4 1007 ± 508

P-5 567 ± 416 0.56

P-6 500 ± 143 0.50

A-l A-2 A-3

A-4 513 ± 171 0.51

A-5 268 ± 82 0.27

A-6 294 ± 46 0.29

The values in Table 5, as already in Tables 2 to 4, show the effect of the amino acid infusion solutions according to the invention.

Investigations regarding extension of the lifespan

In Donryu rats, 1.7 x 105 cells / ml of Yos hida tumor cells or 1.1 x 106 tumor cells / ml of AH 130 were transplanted, in Wistar rats, 1.0 x 105 cells / ml of Walker tumor. In each of these studies, an infusion solution of AO-30 (or PA in the corresponding control group) was administered, which also contained glucose, electrolytes and vitamins. The nutrient solution was administered by means of the so-called total parenteral nutrition (hereinafter referred to as the "TPN method").

The composition of the infusion solution is as follows:

Components Control solution according to the invention

solution

amino acids

AO-30 16.1 g / l

PA 175 g / 1

glucose

200 g / 1

200 g / 1

Well +

53 mAeq / 1

53 mAeq / 1

K +

25 mAeq / 1

25 mAeq / 1

he

53 mAeq / 1

53 mAeq / 1

hpo42 "

25 mAeq / 1

25 mAeq / 1

ch3ch (oh) -

48 mAeq / 1

48 mAeq / 1

cocr

Vitamin B,

0.1 mg / animal and day

0.1 mg / animal / day

Vitamin B2

0.01 mg / animal / day

0.01 mg / animal / day

Vitamin B6

0.02 mg / animal / day

0.02 mg / animal / day

Vitamin C

0.5 mg / animal, day

0.5 mg / animal / day

Nicotinic acid

0.2 mg / animal day

0.2 mg / animal / day

Panthenol

0.02 mg animal day

0.02 mg / animal / day

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(Continuation)

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Table 7

642 541

Components Control solution according to the invention

Nutritional value 206 cal / kg and day 208 cal / kg and day

Dose 240 ml / kg 240mg / kg

Body weight and body weight and

Day day

NPC / N * 337 317

Infusion rate 1.5 ml / 150 g 1.5 ml / 150 g speed body weight and body weight and

Hour hour

* NPC / N stands for protein-free calories / nitrogen

As the following Table 6 shows, the rats with the same tumor cells are now divided into 4 groups of 10 animals each: Group A-1 'only receives AO-30, group A-2' receives both, namely AO-30 and MMC. The control group P-1 'only receives PA and the group P-2' receives both, namely PA and MMC. MMC is again infused intraperitoneally as above with an infusion rate of 0.1 mg / kg body weight and day.

In Table 6, the designation "+" means groups with inoculation or MMC and the designation "-" groups without inoculation or MMC.

Table 6

Group inoculation with MMC infusion

Tumor cells

Control group

P-l '+

P-2 '+ +

invention

A-l '+

A-2 '+ +

The lifespan of the animals in the various test groups was now determined 30 days after inoculation with tumor cells. The average survival time (hereinafter referred to as "MST") is calculated according to the following equation:

In the above formula:

n for the number of animals examined f for the number of animals that died on day t and t for the number of survival days after the transplant.

The effect on life is also determined based on the T / C ratio. In this case, T / C means the ratio of the average lifespan of each group having tumor cells to the survival time C of the group P-1 'which receives PA as the amino acid infusion solution. The result is said to be effective if T / C is higher than 1.25 and ineffective if the ratio is less than 1.25.

Table 7 shows the compilation of the various results obtained:

tumor

group

MST (day)

T / C

Yoshida-

P-l '

11.9

-

tumor

P-2 '

15.9

1.34

A-l '

15.0

1.26

A-2 '

19.9

1.67

AH-130

P-l '

13.6

-

P-2 '

> 21.6

1.59

A-r

18.0

1.32

A-2 '

> 25.1

1.85

Walker tumor p-r

14.7

-

P-2 '

> 22.7

1.54

A-r

> 22.4

1.52

A-2 '

> 26.9

1.82

The values in Table 7 show that the infusion solution according to this invention brings about an increase in survival by factors of 1.3 to 1.5 in each of the tumors examined. Likewise, the administration of the amino acid solution according to the invention together with MMC increases the survival time by even higher factors (groups A-2 ').

Survival rates are not shown in Table 7. They are for groups P-2 'and A-2', when inoculated with AH-130.40 and 60%, respectively. This value applies to the point in time 30 days after the inoculation. The corresponding value for group P-2 'with Walker tumor cells is 20%, while group A-2' with the same inoculation had a survival rate of up to 50%.

The results shown show that the amino acid solution according to the invention, which is free of methionine, both alone and increasingly together with chemotherapeutic agents, is effective in the treatment of Yoshida tumors, Walker tumors, AH-130 and rhodamine. Tumors. The growth of the corresponding tumor cells is inhibited. Likewise, if the solution mentioned is administered as the only nitrogen source using the TPN method, a noticeable extension of the service life is achieved.

Clinical description 1

The patient, a 54 year old male with peritonitis car cinomatosa, 2 years after total gastrectomy. A new relapse could be remedied by repeated abdominal surgery. Now the patient complained of vomiting, which was due to carcinomatous intestinal constriction. The man was very weak. The patient was now administered a daily dose of 500 ml / day of an amino acid infusion solution AO-30 according to Example 1 using the TPN method. Administration continued for 4 weeks. In addition to the amino acid solution, the patient received MMC, 5-fluorouracil (hereinafter referred to as “5FU” and neocarzinostatin (hereinafter referred to as “NCS”). MMC was administered intravenously in a dose of 10 mg / cm2 of the tumor area, once a day. This agent was administered for the first 4 days and then again only after a 2-week interruption, again for 4 days.5FU was injected intravenously at a dose of 10 mg / kg of body weight, also once a day during the first 5 days and then again after 5 weeks of interruption for 5 days

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642 541

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also injected intravenously in a dosage of 2000 units once a day for 4 weeks. 4 weeks after the start of the infusion, the patient began to eat food and was subsequently cured and released.

Clinical Description 2 The patient, a 39 year old male, was re-hospitalized for hepatic metastasis with jaundice 1 year after total gastrectomy. The patient had hepatoma, phlebism in the abdominal wall, ascites, and edema in the lower half of the body. He was in critical conditions. As in clinical description 1, the patient was administered the amino acid solution AO-30 according to example 1 using the TPN method. He was also treated with MMC, 5FU and NCS. The dose administered, schedules, etc. were the same as in clinical case 1. However, the duration of the administration of the amino acid solutions and the NCS was 5 weeks. Hepatoma and phlebism were no longer detectable 5 weeks after the start of the infusion. The other symptoms were also greatly reduced. The patient nevertheless died of intestinal bleeding. The subsequent biopsy demonstrated that the wounds were due to extensive histological destruction of the tissue.

s

Claims (5)

642 541 2nd PATENT CLAIMS 1. A solution containing essential amino acids for administration to cancer patients, characterized in that it contains no methionine. 2. Solution according to claim 1, containing, in 1 liter of solution: 1.4 to 14.0 g leucine, 1.4 to 10.0g valine, 1.6 to 10.0 g isoleucine, 1.5 to 14.9 g lysine, 1.0 to 9.4 g phenylalanine, 1.0 to 6.7 g threonine and 0.4 to 4.0 g tryptophan, but no methionine. 3. Solution according to claims 1 and 2, characterized in that it further contains at least one non-essential amino acid from the group arginine, histidine, glycine, alanine, aspartic acid, glutamic acid, proline, serine, tyrosine and ornithine. 4. Solution according to claim 1, containing, in 1 liter of solution: 1.5 to 14.7 g lysine, 1.0 to 6.4 g phenylalanine, 1.3 to 6.7 g of threonine, 0.4 to 3.5 g tryptophan, 1.0 to 13.2 g arginine, 0.9 to 3.0 g of histidine, 2.3 to 15.0 g glycine, 0 to 4.8 g of alanine, 0 to 2.5 g aspartic acid, 0 to 6.0 g of glutamic acid, 0 to 2.3 g proline, 0 to 1.8 g serine, 0 to 1.7 g tyrosine and 0 to 5.0 g ornithine, but no methionine. 5. Solution according to claim 1, containing, in 1 liter of solution: 4.1 g leucine, 2.0 g valine, 1.8 g isoleucine, 5.0 g lysine, 2.9 g phenylalanine, 1.8 g threonine, 0.6 g tryptophan, 2.2 g arginine, 0.9 g of histidine and 3.4 g glycine, but no methionine. The invention described here relates to solutions containing essential amino acids for administration to cancer patients. If it is not possible to give food to patients by oral or intestinal route, the patient is usually fed parenterally or otherwise non-intestinally. This is the case, for example, in postoperative conditions, where it is very important that the patient's physical condition is at least maintained if any improvement is to be made. For this purpose, various compositions consisting mainly of amino acid solutions are known and used worldwide. Such known amino acids, which by definition are intended for parenteral nutrition, are all essentially the same in terms of amino acid composition. Depending on the intended use, they correspond to the amino acid compositions of human milk, chicken eggs, the albumin of human serum, etc. This means that the nutrient solutions mentioned contain all the amino acids essential for the nutrition of the human body. In other words: the known solutions contain all eight essential amino acids, since these are considered to be indispensable for the above-mentioned purpose. In the course of studies regarding amino acid solutions especially for cancer patients, it has now unexpectedly been found that the amino acid solutions known per se, but without methionine, can reduce or even eliminate cancer cells. The nutritional effect of the solution is not affected in any way. It is therefore an object of this invention to provide an amino acid solution which has inhibitory or reducing effects on tumor cells and at the same time continues to serve as a nutrient solution. Another object of this invention is to provide an amino acid solution which, when administered with known anti-tumor chemotherapeutic agents, remarkably increases its effect. These and other purposes of this invention will become more apparent in the following description. The solution containing essential amino acids for administration to cancer patients is defined in claim 1. The amino acid solution according to the invention exhibits the effect indicated above in a manner which is completely unexpected in relation to the effect of the known amino acid solutions. As mentioned, the solution according to the invention inhibits the growth and spread of tumor cells, and the nutritional effect of the solution is thus all the better. The consequence of the administration of the solution according to the invention is therefore an increase in the lifespan and a maintenance and even improvement of the physical living conditions. If the solution according to the invention is administered in combination with known chemotherapeutic agents for tumor, the solution increases its effectiveness. Examples of such chemotherapeutic agents are mitomycin-C, 5-fluorouracil, neocarzinostatin or bischloroethyl nitro urea. So far, nothing has become known of side effects in the administration of the solution according to the invention. The solution according to the invention thus makes it possible to improve the treatment methods against tumor. The unexpected and very important effects of the solution according to the invention were absolutely unexpected due to the known properties of nutrient solutions based on essential amino acids. The known nutrient solutions strengthened the patient in his physical condition; they also presumably nourished and strengthened the tumor cells in the patient's body. This type of diet only contributed to slowing down the patient's body weight reduction as much as possible, without however having any effect on the disease itself. The patient's body weight was also increased by the known, known nutritional method. In contrast to this, the solutions according to the invention selectively inhibit the growth of tumor cells in the patient's body, both increasing the body weight and regression of symptoms. The amino acid solutions according to the invention can have similar compositions to the known amino acid solutions, with the exception that the new solutions contain no methionine. The composition of the solutions according to the invention can be designed according to the desired purpose, it can also be based on the 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 3rd 642 541 Symptoms of the patient are adapted as well as to the duration of administration etc. Essentially, the amino acid solutions according to the invention comprise the seven essential amino acids apart from methionine, namely leucine, valine, isoleucine, lysine, phenylalanine, threonine and tryptophan. The solutions according to the invention preferably contain the amino acids mentioned in the following proportions (data in g / liter solution): Leucine 1.4-14.0 Valine 1.4-10.0 Isoleucine 1.6-10.0 Lysine 1.5-14.9 Phenylalanine 1.0-9.4 Threonine 1.0-6.7 Tryptophan 0.4-4.0 In addition to the seven essential amino acids mentioned, the solution may contain non-essential amino acids. Examples of such non-essential amino acids are: argenin, histidine, glycine, alanine, Aspartic acid, glutamic acid, proline, serine, tyrosine, ornithine, etc. Preferred among these amino acids are arginine, histidine and glycine. These unnecessary amino acids can be contained in the following content limits in the solutions according to the invention (data in g / liter Solution): Arginine 0-13.2 Histidine 0- 6.0 Glycine 0-18.0 Alanine 0- 5.0 Aspartic acid 0- 6.0 Glutamic acid 0- 9.0 Proline 0- 9.0 Serine 0- 6.0 Tyrosine 0- 2.0 Ornithine 0- 6.0 The solvents according to the invention preferably contain solutions, if they include both essential and non-essential amino acids, the components within the following salary limits (data in g / liter solution): Leucine 1.7-14.0 Valine 1.7-9.5 Isoleucine 1.8-9.6 Lysine 1.5-14.7 Phenylalanine 1.0- 6.4 Threonine 1.3-6.7 Tryptophan 0.4-3.5 Arginine 1.0-13.2 Histidine 0.9-3.0 Glycine 2.3-15.0 Alanine 0 - 4.8 Aspartic acid 0-2.5 Glutamic acid 0 - 6.0 Proline 0-2.3 Serine 0 - 1.8 Tyrosine 0 - 1.7 Ornithine 0 - 5.0 According to the invention, all of the above examples contain none Methionine. 10th pure amino acids present. These can exist in both their D and L form; however, mixtures of the two forms can also be used. However, the L-shape is generally preferred. The amino acids are preferably used as free acids. However, this is not mandatory. Their pharmacologically acceptable salts can also be used. Preferred acid addition salts are the hydrochlorides, the acetates and the like. In addition to the actual amino acids, the amino acid solutions according to this invention can also contain various additives as are known for the various fields of application. Examples of such additives are: car bohydrates, vitamins, fats, electrolytes, antiseptics, stabilizers, etc. Special forms of the examples mentioned are therefore starch, sucrose, glucose, maltose, fructose, sorbitol, xylitol, ascorbic acid, nicotinic acid, pantothenic acid , Thiamine, riboflavin, pyridoxine, menadione, biotin, folinic acid, vitamin Bi2, inositol, sodium bisulfite, phosphoric acid, 20 etc. The amino acids according to this invention, like the known amino acid preparations, are based on sterile water and are administered as infusions parenterally or non-intestinally, for example in the form of intravenous injections or drops. The solutions can also be administered orally or interally, provided that this is possible. The dose can be varied according to the symptoms the patient is showing. In general, the amount administered is intended to serve the patient's 30 diet. For example, daily doses of approximately 100 to 1500 ml per patient, preferably approximately 500 to 1500 ml per patient, are administered. As stated, the amino acid solutions according to the invention can be administered together with known chemotherapeutic agents against tumors. If e.g. B. a patient with gastric tumor only 5-fluorouracil as a chemotherapeutic agent, in combination with an amino acid solution according to the invention, the same is administered dropwise intravenously. The dose is 15 mg / kg body weight and day, for 5 consecutive days. The dose is then reduced to 7.5 mg / kg body weight per day. The active ingredient can also be administered intra-arterially; the corresponding doses are then: 5 to 10 mg / kg body weight and day, for 10 to 20 days. When using mitomycin-C together with the solutions according to the invention - still in a patient with gastric tu-mor - the active substance is injected intravenously once or twice a week, namely in a dose of 8 to 10 mg / kg body weight in each Injection. The amino acid solutions according to the invention are advantageously used in patients with tumors in the stomach, colon, rectum, esophagus, with pancreatic tumor, 55 with colangioma, hepatoma and various other tumors.