JP2016132622A - Sepsis therapeutic or prophylactic nutritional composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a sepsis therapeutic or prophylactic nutritional composition containing amino acid that is effective in septic therapy or prevention, with less concern over side effects compared with existing drugs, such as an antibacterial drug, without causing drug resistance, and further with low cost.SOLUTION: The invention provides a sepsis therapeutic or prophylactic nutritional composition characterized by containing three kinds of amino acids of lysine, histidine, and tryptophan, as well as a pulmonary or hepatic dysfunction therapeutic or prophylactic nutritional composition characterized by containing three kinds of amino acids of lysine, histidine, and tryptophan.SELECTED DRAWING: Figure 2

Description

  The present invention relates to a nutritional composition for treating or preventing sepsis. More specifically, the present invention relates to a nutritional composition for treating or preventing sepsis and organ disorders such as lung, liver and kidney, which contains a combination of three amino acids, lysine, histidine and tryptophan.

Sepsis is a serious disease in which gram-negative bacteria, gram-positive bacteria, etc., which are causative bacteria such as pneumonia, pyelonephritis, and cholecystitis, cause systemic bacterial infection via blood. It is also known to develop when immunity is significantly reduced by anticancer drug treatment, radiotherapy, corticosteroid administration, and the like. Sepsis is not only the main symptom of fever, but also blood pressure drop and disturbance of consciousness (septic shock) may occur, and complications (severe sepsis) may occur in many organs such as lung, liver and kidney. Many.
For the treatment of sepsis, powerful antibacterial drugs are administered, but conventional antibacterial drugs have a low degree of improvement in inflammation, and there is a high risk of becoming serious if the type and timing of administration are not appropriate. Appropriate treatment must also be performed for many organ disorders such as lung, liver and kidney secondary to sepsis.

  Thus, treatment of sepsis requires not only treatment of sepsis but also treatment of organ disorders such as lung, liver and kidney that occur secondary to sepsis. However, if the selection of antibiotics effective for sepsis and the start time of administration are not appropriate, symptoms become serious and mortality increases. Antibacterial drugs also have side effects and drug resistance problems.

Therefore, it is effective not only for the treatment of sepsis but also for prevention, and if an amino acid-containing nutritional composition that is normally ingested can be used, there is less concern about side effects and the start of administration does not become a problem. it is conceivable that.
About the nutrition composition containing an amino acid, the thing for the treatment or prevention of an inflammatory bowel disease is known (patent documents 1-6), However, The amino acid containing nutrition composition for the prevention and treatment of sepsis is still. Absent.

  Under such circumstances, a nutritional composition for treatment or prevention of sepsis containing amino acids, which has excellent therapeutic and preventive effects on sepsis, has no side effects compared to antibacterial drugs, does not cause drug resistance, and is low in cost. Is required.

WO2012 / 133198 Publication JP 2011-121887 A JP 2011-121888 A JP 2011-121889 A JP 2011-144116 A WO2007 / 004613

  The present invention is effective not only for the treatment of sepsis and subsequent organ damage such as lung and liver, but also for prevention, with less side effects and less drug resistance than existing drugs such as antibiotics and synthetic antibacterial agents. An object of the present invention is to provide an amino acid-containing sepsis treatment or prevention nutritional composition that is unlikely to occur and is inexpensive.

  The inventors of the present invention have made extensive studies in order to solve the above-mentioned problems. As a result, by combining three kinds of amino acids, lysine, histidine and tryptophan, an extremely excellent effect can be obtained for the treatment and prevention of sepsis. As a result, the present invention has been completed.

That is, the present invention provides the following nutritional composition for treating or preventing sepsis.
(1) A nutritional composition for treating or preventing sepsis, comprising three amino acids, lysine, histidine and tryptophan.
(2) The nutritional composition for treating or preventing sepsis according to (1) above, wherein the mixing ratio of each amino acid of lysine, histidine and tryptophan is 10 to 80% by weight with respect to the total weight of the three amino acids. .
(3) The nutritional composition for treatment or prevention of sepsis according to (1) or (2), which suppresses IL-6 elevation.
(4) The nutritional composition for treatment or prevention of sepsis according to (1) or (2), which suppresses AST elevation.
(5) The nutritional composition for treating or preventing sepsis according to (1) or (2), which suppresses ALT elevation.
(6) The nutritional composition for treatment or prevention of sepsis according to (1) or (2), which suppresses lung and liver damage.
(7) The nutritional composition for treating or preventing sepsis according to any one of the above (1) to (6), which comprises a total of 5 to 100% by weight of three amino acids of lysine, histidine and tryptophan.
(8) A pharmaceutical or a food or drink containing the nutritional composition for treating or preventing sepsis according to any one of (1) to (7).
(9) A nutritional composition for treating or preventing lung and liver disorders, comprising three amino acids, lysine, histidine and tryptophan.

  The nutritional composition for the treatment or prevention of sepsis of the present invention has a very excellent pharmacological effect for the treatment and prevention of sepsis and organ disorders such as lung and liver that follow it. In addition, the nutritional composition for treating or preventing sepsis according to the present invention has less worry about side effects than existing drugs, does not cause drug resistance, and is low in cost.

4 is a graph showing IL-6 concentrations of various amino acids in Test Example 1. 4 is a graph showing the concentration of IL-6 by the combination of amino acids in Test Example 1. 6 is a graph showing the survival rate of mice in Test Example 2. 10 is a graph showing IL-6 concentration in Test Example 3. 6 is a graph showing enzyme activities of ALT and AST in Test Example 4. (A) shows the enzyme activity of ALT, (b) shows the enzyme activity of AST. 10 is a photograph showing a pathological specimen of liver in Test Example 5. (A) shows the pathological specimen of the liver fed with Casein feed, and (b) shows the pathological specimen of the liver fed with KHW feed. 10 is a photograph showing a lung pathological specimen in Test Example 6. (A) shows the pathological specimen of the lung fed with Casein feed, and (b) shows the pathological specimen of the lung fed with KHW feed.

The present invention will be described in detail below.
The nutritional composition for treating or preventing sepsis of the present invention contains a combination of three amino acids, lysine, histidine and tryptophan. The origin of the three types of amino acids is not limited, and commercially available products may be used.

The mixing ratio of the three amino acids lysine, histidine and tryptophan in the nutritional composition for treating or preventing sepsis according to the present invention is preferably 10 to 80% by weight based on the total weight of the three amino acids. Particularly preferred is 40% by weight of lysine, 40% by weight of histidine and 20% by weight of tryptophan.
These weight ratios indicate the weight of free amino acids, and when a salt or the like is formed, the weight ratio excludes that amount.

The nutritional composition for treating or preventing sepsis according to the present invention is effective for treating or preventing sepsis, and is also effective for preventing and treating disorders that occur in many organs such as lung, liver and kidney.
In the present invention, “sepsis” includes sepsis, severe sepsis, and septic shock.
In addition, the above-mentioned “disorders in many organs such as lung, liver and kidney” include not only organ disorders secondary to sepsis symptoms but also organ disorders not related to sepsis.

The nutritional composition for treating or preventing sepsis according to the present invention suppresses an increase in blood IL-6 (interleukin-6) concentration. IL-6 is a cytokine that is produced in the early stages of inflammation, induces the production of chemokines that induce cell invasion, and induces the expression of adhesion molecules. Therefore, a decrease in the concentration of IL-6 indicates that the production of IL-6 is reduced and inflammation is suppressed (Test Examples 1 and 3).
In addition, the nutritional composition for treating or preventing sepsis of the present invention suppresses an increase in enzyme activity of AST (aspartate aminotransferase) and ALT (alanine aminotransferase) in blood. Since AST and ALT are contained in a large amount in hepatocytes, the value increases as hepatocyte destruction progresses. Therefore, a decrease in these values indicates that liver damage is suppressed (Test Example 4).

The nutritive composition for treating or preventing sepsis of the present invention may be administered as it is, without preparing it, and may be administered with three amino acids of lysine, histidine and tryptophan as they are, or in various forms. In the case of various forms, it can be mixed with excipients, adjuvants, additives and the like.
When the nutritional composition for treatment or prevention of sepsis according to the present invention is blended with excipients, adjuvants, additives, and the like, the types and blending amounts are acceptable in terms of pharmaceutics and food manufacturing. The amount is not limited. Examples of excipients, adjuvants and additives include, for example, gelling agents, thickeners, binders, disintegrants, acidulants, foaming agents, artificial sweeteners, fragrances, lubricants, colorants, Stabilizers, buffers, antioxidants, surfactants and the like can be mentioned, and one or two or more can be appropriately used in an allowable amount.

The nutritional composition for treatment or prevention of sepsis according to the present invention comprises solution preparations such as liquids, gels, jellies, syrups and liquids, dispersion preparations such as emulsions and suspensions, powders, granules and fine granules. It may be in any form such as powder preparations such as powder preparations, capsules, pills, tablets, etc., solid preparations, semisolid preparations, etc., but preferably in the form of powders, liquid preparations, semisolid preparations. .
The nutritional composition for treating or preventing sepsis of the present invention can contain 5 to 100% by weight of three amino acids, lysine, histidine and tryptophan. That is, it may contain only three kinds of amino acids, lysine, histidine and tryptophan, and may contain excipients, adjuvants, additives and the like in addition to any other nutritional ingredients and other active ingredients. Also good.

  The nutritional composition for treating or preventing sepsis of the present invention can also be used as a pharmaceutical product. Although the form in that case is not particularly limited, it is preferable to use a jelly agent, a liquid agent, a powder agent, a solid agent, a semi-solid agent, or the like. In addition, the types and amounts of excipients, adjuvants, additives and the like used for the preparation are not limited. In the case of a pharmaceutical product, only lysine, histidine and tryptophan may be used as active ingredients, but they may be blended as one of a plurality of active ingredients.

Moreover, you may use the nutrition composition for a sepsis treatment or prevention of this invention as food-drinks. When it is used as a food or drink, it can be used as a normal food or beverage by appropriately mixing additives and other nutritional components that are normally allowed.
The nutritional composition for treating or preventing sepsis according to the present invention can contain 5 to 100% by weight of three types of amino acids, lysine, histidine and tryptophan, even when used as a pharmaceutical or a food or drink.

The upper limit of the dosage of the nutritional composition for treating or preventing sepsis according to the present invention is not particularly limited, but it is not more than 5% by weight added to the nutritional balance at the time of mixed diet administration in rodents (edited by the Food Safety Commission) , Food Health Impact Assessment Guidelines for Additives, 2010, p11-16).
The amount of each amino acid in the nutritional composition for treating or preventing sepsis of the present invention is 138 mg / kg body weight, 1630 mg / kg in terms of the respective amounts of lysine, histidine and tryptophan from the viewpoint of the maximum non-toxic amount and the minimum toxic amount per day. It is preferable that the body weight is about 1 kg and about 300 mg / kg body weight.
The administration method is not limited, and oral administration and tube administration are preferred. The frequency of administration can be divided from once a day to an appropriate number of times.

The nutritional composition of the present invention is mixed with lysine, histidine, and tryptophan, so that one of the three types is used alone or two types of the three types are used. The preventive and therapeutic effects are remarkably excellent (Test Example 1).
In addition, the nutritional composition for treatment or prevention of sepsis according to the present invention has significantly fewer side effects, less drug resistance, and high safety compared to existing drugs such as antibiotics, synthetic antibacterial drugs, and corticosteroids. . Furthermore, the nutritional composition for treating or preventing sepsis according to the present invention can be taken orally and is low in cost. In addition, the nutritional composition for treatment or prevention of sepsis according to the present invention contains three kinds of essential human amino acids, and thus contributes to the improvement of nutritional status.

  Hereinafter, the present invention will be described in more detail with reference to test examples and examples. In the test examples and examples, what is simply described as “%” indicates “% by weight”.

(Test Example 1)
-IL-6 production inhibitory effect of various amino acids After isolating macrophages from the abdominal cavity of mice (C57BL / 6, 6 weeks old, male), the concentration of various amino acids shown in FIG. The culture supernatant after 24 hours was collected.
The collected supernatant was screened for amino acids having an anti-inflammatory effect using IL-6 (interleukin-6) as an index. If the concentration of IL-6 is decreased by the addition of amino acids, it is shown that IL-6 production is reduced and inflammation is suppressed. The results are shown in FIG. The numerical value in FIG. 1 shows the ratio (%) of the numerical value of IL-6 with respect to the case where the amount of each amino acid used is 0 mM.
As shown in FIG. 1, as a result of this test, a concentration-dependent IL-6 production decreasing action was observed particularly for lysine, histidine and tryptophan.

-IL-6 production inhibitory effect of lysine, histidine and tryptophan Next, regarding lysine, histidine and tryptophan in which IL-6 production lowering action was recognized as described above, (1) lysine, histidine and tryptophan alone, (2) Three of the three combinations were examined, and (3) the IL-6 production inhibitory effect of the three combinations was examined using intraperitoneal macrophages of mice in the same manner as described above. The results are shown in FIG. The molar concentration of each amino acid was set to be the same in each example. The numerical value in FIG. 2 shows the ratio (%) of the numerical value of IL-6 when each amino acid or a combination thereof is used when the control is 100%.
As shown in FIG. 2, (1) when lysine, histidine and tryptophan are used singly, (2) three combinations of the three types (lysine and histidine, histidine and tryptophan, tryptophan and lysine) (3) When IL-3 was added in combination, the strongest IL-6 production inhibitory effect was observed.
From this, it was found that a remarkable synergistic effect was observed in the IL-6 production-reducing action by combining three kinds of lysine, histidine and tryptophan.

(Test Example 2)
According to the formulation shown in Table 1 below, a normal feed (AIN-93G: manufactured by Oriental Yeast Co., Ltd.) with a casein added to a final concentration of 5% (hereinafter referred to as “Casein”), and the normal feed with lysine A feed (hereinafter referred to as “KHW”) prepared by adding three kinds of amino acids of histidine and tryptophan to a final concentration of 5% by weight was prepared by a conventional method.

Mice (C57BL / 6, 6 weeks old, male) were divided into 2 groups (4 mice per group), and one group was fed with Casein diet and the other group was fed with KHW diet.
Five days after the start of feeding, all mice were subjected to CLP (Cecal Ligation and Puncture) to produce a sepsis model. After CLP, as in the case before CLP, one group was fed with Casein feed and the other group was fed with KHW feed. The survival rate of mice up to 3 days after CLP is shown in FIG.

As apparent from the results shown in FIG. 3, in the group fed with Casein feed, half of the individuals died 3 days after CLP, whereas in the group fed with KHW feed, no dead individuals were seen, 100% of mice survived.
In this test example, feed was given from 5 days before the onset of sepsis, so that administration of lysine, histidine and tryptophan is very effective not only for treatment of sepsis but also for prevention compared to normal feed. It was also found that the survival rate was clearly improved.

(Test Example 3)
Blood IL-6 concentration test After feeding each diet of Test Example 2 to the mouse of Test Example 2, anatomy and blood collection were performed after 3 days, and the concentration of IL-6 (inflammatory index) in the blood was measured . The average value of the measurement results is shown in FIG.
As is clear from the results shown in FIG. 4, IL-6 production was greater in the group of mice fed with the KHW diet supplemented with lysine, histidine and tryptophan compared to the group of mice fed the normal Casein diet. Decreased significantly.
From this, it was found that inflammation due to sepsis is suppressed by administering a combination of three types of amino acids, lysine, histidine and tryptophan, to a sepsis model mouse.

(Test Example 4)
Blood ALT and AST enzyme activity test Blood was collected in the same manner as in Test Example 3, and the enzyme activities of ALT and AST, which are indicators of hepatocyte damage in blood, were measured. The average value of the measurement results is shown in FIG. In FIG. 5, (a) shows the enzyme activity of ALT, and (b) shows the enzyme activity of AST.
As is clear from the results shown in FIG. 5, the group of mice fed with a KHW diet supplemented with a combination of lysine, histidine and tryptophan compared ALT and AST compared to the group of mice fed a normal Casein diet. The enzyme activity was significantly reduced.
From this, it was found that the liver damage secondary to sepsis is markedly suppressed by administering a combination of three kinds of amino acids, lysine, histidine and tryptophan, to a sepsis model mouse.

(Test Example 5)
-Observation of pathological specimen of liver A pathological specimen was prepared by fixing the liver collected at the time of dissection in Test Example 3 with formalin, and HE staining was performed according to a conventional method. A photograph of the pathological specimen is shown in FIG. In FIG. 6, (a) shows the pathological specimen of the liver fed with Casein feed, and (b) shows the pathological specimen of the liver fed with KHW feed.
As is clear from the photograph shown in FIG. 6, the group of mice (b) fed with a KHW diet supplemented with lysine, histidine and tryptophan was compared with the group of mice fed with a normal Casein diet (a). The necrotic site of the liver was small and the degree of liver damage was small.
Thus, administration of a combination of three types of amino acids, lysine, histidine and tryptophan, to a sepsis model mouse significantly suppresses liver damage secondary to sepsis, that is, a combination of the three types of amino acids. Was also found to be effective in severe sepsis.

(Test Example 6)
-Lung pathological specimen observation Lung collected at the time of dissection in Test Example 3 was formalin-fixed to prepare a pathological specimen, and HE staining was performed according to a conventional method. A photograph of the pathological specimen is shown in FIG. In FIG. 7, (a) shows the pathological specimen of the lung fed with Casein feed, and (b) shows the pathological specimen of the lung fed with KHW feed.
As is apparent from the photograph shown in FIG. 7, the group (b) of mice fed with a KHW diet supplemented with a combination of lysine, histidine and tryptophan compared to the group of mice (a) fed a normal Casein diet. In addition, there was little lung cell infiltration, the alveolar structure was clear, and the degree of lung injury was small.
Thus, administration of a combination of three types of amino acids, lysine, histidine, and tryptophan, to a sepsis model mouse significantly suppresses pulmonary damage secondary to sepsis, that is, a combination of the three types of amino acids. Was also found to be effective in severe sepsis.

  In the present invention, a combination of three types of amino acids, lysine, histidine and tryptophan, acts on immune cells and exerts an anti-inflammatory effect, thereby reducing systemic organ damage, sepsis and subsequent organ damage It is thought to improve the disease state and survival rate.

(Manufacture of powder)
Using lysine, histidine and tryptophan (manufactured by Kyowa Hakko Bio Co., Ltd.), a mixture having a weight ratio of 2: 2: 1 was prepared and used as an active ingredient of the powder.
After adding 950 g of conventional nutritional ingredients to 50 g of the obtained active ingredients (lysine 20 g, histidine 20 g and tryptophan 10 g), the mixture is mixed and mixed in a conventional manner so that the daily food intake is 5.0 g. A powder containing the nutritional composition for treatment / prevention of sepsis of the invention was obtained.

  The nutritional composition for treatment or prevention of sepsis of the present invention is very effective for the prevention and treatment of sepsis and many organ disorders that follow. Further, the nutritional composition for treating or preventing sepsis according to the present invention has very few problems of side effects and drug resistance compared to existing drugs, can be administered orally, and can improve nutrition of patients. Furthermore, the nutritional composition for treating or preventing sepsis according to the present invention has a lower cost than existing pharmaceuticals, and thus can contribute to a reduction in medical costs.

Claims (9)

A nutritional composition for treating or preventing sepsis, comprising three amino acids, lysine, histidine and tryptophan. The nutritional composition for treating or preventing sepsis according to claim 1, wherein the mixing ratio of each amino acid of lysine, histidine and tryptophan is 10 to 80% by weight with respect to the total weight of the three amino acids. The nutritional composition for treating or preventing sepsis according to claim 1 or 2, which suppresses IL-6 elevation. The nutritional composition for treating or preventing sepsis according to claim 1 or 2, which suppresses an increase in AST. The nutritional composition for treating or preventing sepsis according to claim 1 or 2, which suppresses ALT elevation. The nutritional composition for treating or preventing sepsis according to claim 1 or 2, which suppresses lung and liver damage. The nutritional composition for treating or preventing sepsis according to any one of claims 1 to 6, comprising 5 to 100% by weight of a total of 3 amino acids of lysine, histidine and tryptophan. The pharmaceutical or food-drinks containing the nutrition composition for a sepsis treatment or prevention in any one of Claims 1-7. A nutritional composition for treating or preventing lung or liver disorders, comprising three amino acids, lysine, histidine and tryptophan.

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