JPH08295633A - Complication-preventing agent for patient in high protein catabolismic state - Google Patents

Abstract

PURPOSE: To obtain a complication-preventing agent for patients in high protein catabolismic state, containing glutamine dipeptide as an effective component. CONSTITUTION: This complication-preventing agent for patients in high protein catabolismic state contains at least one kind of glutamine peptides (e.g.; L- alanyl-L-glutamine) as an effective component and is formulated in an injection solution form such as infusion, etc. The concentration of the glutamine dipeptide in an aqueous solution is 5-50wt.%. This complication-preventing agent can be preferably used for patients under a centralized treatment by nutritional control through a middle cardiac vein and is effective for preventing infectious diseases such as bactermia, septicemia, etc., acute respiratory insufficiency syndrome and acidosis. The daily dose is 0.2-1.5 mili mole/kg based on the glutamine dipeptide as the effective component. The high protein catabolismic state of a patient who has been suffering from a surgical invasion is normalized and evil influences such as migration of intesinal bacteria into the body due to the atrophy of intestine mucous membrane caused by nutrition control depending only on a high calorie infusion are improved.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a preventive agent for complications in a patient with a high degree of protein catabolism, and particularly to prevent complications occurring in a patient under intensive care (ICU) and undergoing central parenteral nutrition (TPN). About new drugs to do.

[0002]

2. Description of the Related Art Patients who have undergone a high degree of surgical invasion such as postoperative patients with esophageal cancer and patients with serious trauma are usually managed under intensive care. In addition, such patients often cannot take oral nutrition, and in that case, nutritional management is performed by high calorie infusion from the central vein.
Patients under such special circumstances are often known to cause complications. More specifically, the complications include, for example, infectious diseases such as bacteremia and sepsis, inflammation such as pneumonia and bronchitis, organ failure such as renal failure and liver failure, acute respiratory failure syndrome and acidosis. To be done.

Various studies have been carried out on the cause of the onset of complications, and at present, the onset of the above complications is that protein catabolism is promoted due to invasiveness, resulting in abnormal immune function or impaired microcirculation. Against the background of occurrence, transfer of intestinal bacteria from the intestinal mucosa atrophied by high-calorie infusion into the body, invasion of bacteria from the central venous catheter site, etc.,
It has been found that the decrease in organ blood flow and tissue oxygen concentration, the retention of toxic substances in organs, etc. are the triggers.

By the way, the above-mentioned complications have been mainly treated with drugs, and especially for the above-mentioned infectious diseases, antibacterial agents such as antibiotics are exclusively administered. However,
Side effects are inherent in the treatment with drugs, and in particular, since patients are under special circumstances, side effects are likely to occur. In addition, the antibacterial agent has a disadvantage that the effective bacteria are limited depending on its type, and also has a problem that drug-resistant bacteria are generated.

More importantly, the causes of the above-mentioned complications are closely related, and even if the bacteria causing the infection could be eradicated, they are expected to be due to other causes. There are many cases where the therapeutic effect cannot be obtained. In other words, drug treatment is only symptomatic treatment and does not fundamentally improve the cause of complications in patients under special circumstances.

On the other hand, although various prescriptions for high calorie infusions have been studied in order to maintain the nutritional status of patients more normally, changes in high calorie infusion prescriptions are sufficient for preventing the above complications. No cases have been reported yet.

[0007]

[Means for Solving the Problems] The present inventors have focused on the fact that the causes of the above-mentioned complications are concentrated in “promoted protein catabolism” and “adverse effects of high-calorie infusion”, In order to eliminate the above causes and prevent complications by devising, day and night studies were repeated. As a result, it was found that administration of glutamine dipeptide as a part of the nutritional source suppresses the harmful effects of protein catabolism and high-calorie infusion, and thus can prevent the above-mentioned complications, leading to the completion of the present invention. .

That is, according to the present invention, there is provided a complication preventive agent for patients with advanced protein catabolism, which comprises at least one glutamine dipeptide as an active ingredient.

The preventive agent for complications of the present invention is preferably used particularly for patients under centralized parenteral nutrition and under intensive care. Among the above-mentioned complications, infectious diseases such as bacteremia and sepsis, and It is highly effective in preventing acute respiratory failure syndrome and acidosis.

In the preventive agent for complications of the present invention, the glutamine dipeptide used as an active ingredient may be any of various peptide conjugates of glutamine and other amino acids. Specific examples thereof include L-alanyl-L-glutamine, glycyl-L-glutamine,
L-glutaminyl-L-alanine, L-glutaminyl-
Glycine, L-glutaminyl-L-glutamine and the like can be exemplified, and among these, L-alanyl-L-
Glutamine, glycyl-L-glutamine and L-glutaminyl-L-alanine are preferred, and especially L-alanyl-L-glutamine is more preferred.

The above-mentioned dipeptides used in the present invention are not only in the free form but also in their pharmacologically acceptable salts, for example, metal salts with sodium, potassium, etc., mineral salts with hydrochloric acid, sulfuric acid, etc., acetic acid. It may be in the form of a salt such as an organic acid salt with lactic acid or the like, and these salts are also included in the active ingredients of the preventive agent for complications of the present invention.

The preventive agent for complications of the present invention comprises a glutamine dipeptide such as L-alanyl-L-glutamine described above,
It can be prepared in various forms according to various general methods. A typical example of the above form is a liquid form for injection such as infusion. As an example of the preparation to the form, for example, a method of dissolving an appropriate amount of the above dipeptide in water for injection and adjusting the pH value to an appropriate value by using a pH adjusting agent such as sodium hydroxide or hydrochloric acid as required can be exemplified. . The concentration of glutamine dipeptide in the aqueous solution obtained here can be appropriately determined and is not particularly limited, but is usually about 5 to 50% by weight, preferably about 8 to 40% by weight. The aqueous solution prepared above can be sterilized or the like according to a conventional method to give a desired product. For example, this is 0.45
After filtration using a membrane filter of μm, etc., it is filled in an appropriate container such as a glass bottle or a plastic container and sealed,
By high-pressure steam sterilization or hot water sterilization, a desired injectable liquid form product (aqueous solution product for intravenous administration) can be obtained.

The agent for preventing complications of the present invention in the form of an injectable liquid prepared as described above may be contained in a high calorie infusion preparation in advance, or may be administered alone from a peripheral vein or a central vein. May be.

The dose of the preventive agent for complications of the present invention is generally 0.2 to 15 mmol / kg / day, preferably 0.5 to 7.5 mmol / kg / day, using glutamine dipeptide as an active ingredient. Is appropriate. For example, in the case of pre-administration in a high-calorie infusion preparation, the complication preventive agent of the present invention is added to 100 ml of 10% amino acid infusion in an amount of about 1.5 to 9.0 g in terms of free equivalent glutamine amount. It may be administered.

Thus, the administration of the preventive agent for complications of the present invention corrects the highly catabolic state of patients undergoing severe surgical invasion, atrophies the intestinal mucosa and transfers intestinal bacteria into the body. The adverse effects of nutritional management due to only high calorie infusion are improved, and infections such as bacteremia and sepsis, inflammation such as pneumonia and bronchitis, organ failure such as renal failure and liver failure, acute respiratory failure syndrome, acidosis, etc. , The complications peculiar to this kind of patients are prevented.

[0016]

EXAMPLES In order to explain the present invention in more detail, preparation examples of the preventive agent for complications of the present invention will be given as examples, and then test examples carried out on the preventive agent will be given. The percentage in each example is based on the weight.

[0017]

Example 1 45 g of L-alanyl-L-glutamine was dissolved by heating in water for injection to a total volume of 200 ml. This aqueous solution was filtered through a 0.45 μm membrane filter, sealed in a glass bottle in an amount of 100 ml, and sterilized under high pressure steam at 110 ° C. for 40 minutes to obtain a product of the present invention having a concentration of 22.5% and a pH of about 5.6.

[0018]

Example 2 Using 20 g of L-alanyl-L-glutamine, the same operation as in Example 1 was carried out to obtain a concentration of 10%, p
The product of the present invention having H of about 5.6 was obtained.

[0019]

Example 3 Using 30 g of glycyl-L-glutamine,
The same operation as in Example 1 was performed to obtain the product of the present invention having a concentration of 15% and a pH of about 5.6.

[0020]

[Example 4] Using 30 g of L-glutaminyl-L-alanine, the same operation as in Example 1 was carried out to obtain a concentration of 15%.
The product of the present invention having a pH of about 5.6 was obtained.

[0021]

Example 5 Using 40 g of L-glutaminyl-L-alanine, the same operation as in Example 1 was conducted to obtain a concentration of 20%.
The product of the present invention having a pH of about 5.6 was obtained.

[0022]

[Test Example 1] Six-week-old Wistar male rats were anesthetized with Nembutal under a Nembutal anesthesia with a hot water bath on the back of the rat to reduce the body surface area to about 1
A 2% burn was created. Then, a silicone rubber catheter was inserted and placed at the origin of the superior vena cava from the external jugular vein, and a microtube pump was operated so that continuous infusion without restriction was possible. Immediately thereafter, TPN was performed for 5 days. The TPN was performed in the following two groups.

That is, the first group was Amiparene (registered trademark: Otsuka Pharmaceutical Co., Ltd.) with a nitrogen content of 1.4 g / kg / day and a total heat content of 2
Standard TP dosed at 70 kcal / kg / day
Group N (control group), the other group is the above-mentioned amiparene with the product of the present invention prepared in Example 1 at 30 mmol / k.
The amount of nitrogen added is 2.7 g / kg / day,
It is an L-alanyl-L-glutamine group (hereinafter referred to as AG group) that was administered so that the total amount of heat would be 298 kcal / kg / day. The composition of the infusion solution administered in each group is shown in Table 1 below.

[0024]

[Table 1]

The dose on the day of the burn load was half the daily dose, and the entire dose was administered from the next day.

After performing the TPN for 5 days, the test animals in each group were subjected to laparotomy under Nembutal anesthesia, and mesenteric lymph nodes were collected. After measuring this weight, put it in a sterilized Spitz tube, add 9 volumes of Heart Infusion Broth (Nissui Pharmaceutical Co., Ltd.), grind with a Teflon homogenizer,
A sample solution for determining the viable cell count was prepared. The diluted sample solution was used to culture in MacConkey agar medium (Nissui Pharmaceutical Co., Ltd.) at 35 ° C. for 24 hours, and the viable cell count of Enterobacteriaceae was examined. Then, it is assumed that 50 cfu / g or more of the tissue is positively transferred to the mesenteric lymph node of the Enterobacteriaceae,
The transition rate was calculated.

As a result, the transfer rate of Enterobacteriaceae to the mesenteric lymph nodes was 87% in the control group (41 out of 47 cases).
66% in the AG group (2 out of 44 cases)
9 cases) and the frequency was significantly low (p <0.05; χ2 test).

From the above, it was revealed that the administration rate of the preventive agent of the present invention reduces the rate of transfer of intestinal bacteria to the mesenteric lymph nodes, and that the onset of infectious diseases can be prevented.

Claims (8)

[Claims] 1. A prophylactic agent for complications in patients with advanced protein catabolism, which comprises at least one glutamine dipeptide as an active ingredient. 2. The preventive agent for complications in a patient with advanced protein catabolism according to claim 1, which is used for a patient under intensive care under central parenteral nutrition management. 3. A glutamine dipeptide is L-alanyl-L.
The prophylactic agent for complications in a patient with advanced protein catabolism according to claim 2, which is at least one selected from the group consisting of: glutamine, glycyl-L-glutamine, and L-glutaminyl-L-alanine. 4. A glutamine dipeptide is L-alanyl-L.
-Glutamine, a prophylactic agent for complications in a patient with advanced protein catabolism according to claim 3. 5. The preventive agent for complications in patients with advanced protein catabolism according to claim 1, wherein the complication is an infectious disease. 6. The preventive agent for complications in patients with advanced protein catabolism according to claim 1, wherein the complication is acute respiratory failure syndrome. 7. The method according to claim 1, wherein the complication is acidosis.
A prophylactic agent for complications in a patient with a high degree of protein catabolism according to any one of 1. 8. The preventive agent for complications in a patient with advanced protein catabolism according to any one of claims 1 to 7, which is in the form of an injectable solution.