JPH059121A - Intestinal mucosal atrophy inhibitor - Google Patents

Abstract

(57) [Summary] [Structure] The present invention uses inosine: cytidine: in a relative molar ratio.
5'-GMP salt: uridine: thymidine = 4: 4: 4:
The present invention provides an intestinal mucosal atrophy inhibitor under total parenteral nutrition (TPN), which comprises a nucleic acid component in an amount of 3: 1 as an active ingredient. [Effect] The intestinal mucosa atrophy inhibitor of the present invention has a remarkable inhibitory effect on intestinal mucosa atrophy caused by TPN implementation, and is useful as a new intestinal mucosa atrophy inhibitor.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an intestinal mucosal atrophy inhibitor, and more particularly to a new drug having an action of suppressing intestinal mucosal atrophy in a patient under total parenteral nutrition (TPN).

[0002]

2. Description of the Related Art In general, peripheral veins are apt to cause phlebitis or thrombosis even with a normal non-hypertonic infusion solution, and cannot withstand administration of hypertonic high-calorie nutrition infusion solution. The infusion solution is usually administered by the TPN method. Here, the TPN method is a method in which a catheter is inserted into a central vein such as a subclavian vein, and an energy source of about 500 to 2000 calories per day is administered and supplied as a nutritional infusion through the catheter. However, the TPN method is used when digestive tract nutrition is impossible, for example, when gastrointestinal malabsorption is incomplete, after abdominal surgery trauma, or consciousness disorder,
It is performed when it is necessary to avoid gastrointestinal nutrition such as preoperative preparation, and the duration is usually several hours to several weeks, but it may be several months depending on the patient.

However, according to the above-mentioned TPN method, side effects due to large dose administration of acids, bases, sugars, etc., such as hyperglycemia,
In addition to increased urinary sugar, acid-base balance disorder, hypernitrogenemia, etc., the cause has not yet been clarified, but various causes of intestinal mucosal atrophy have been reported. The atrophy of the intestinal mucosa during TPN administration has disadvantages such as a decrease in normal intestinal function, making oral nutrition intake in patients after TPN administration difficult, and significantly delaying the recovery period of patients. Although development of a suppressive means for prevention is desired, such suppressive means is not known at present, and a suppressive agent for that purpose is not developed at all.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a new drug which suppresses intestinal mucosal atrophy observed when TPN is performed.

In view of the above situation, the inventors of the present invention have conducted extensive studies on intestinal mucosa atrophy measures that are observed during TPN, and as a result, certain nucleic acid component compositions are known to have their original pharmacological activity. We obtained the surprising finding that it exerts an intestinal mucosal atrophy inhibitory action, which is different from the disease treatment action and cannot be predicted from other actions at all, and thus completed the present invention which meets the above object.

[0006]

According to the present invention, there is provided an intestinal mucosal atrophy inhibitor under complete parenteral nutrition, which comprises as an active ingredient a nucleic acid component in an amount having the following composition in a relative molar ratio. To be done.

Inosine 4 cytidine 45 5'-GMP salt 4 uridine 3 thymidine 1 In the above, as the salt of 5'-GMP (guanosine-5'-monophosphate), various pharmacologically acceptable salts, for example, It may be any of alkali metal salts such as sodium and potassium, especially disodium salt (5'-GMP-2
Na) is preferred.

Each nucleic acid component and its composition used as an active ingredient of the intestinal mucosa atrophy inhibitor of the present invention are already known, and for example, "Ayumi no Kiso", Vol. 135, No. 6, 437-44.
P. 2, 1985.

However, it was first discovered by the present inventors that the nucleic acid component composition has an action of suppressing intestinal mucosal atrophy and is effective as an inhibitor of the intestinal mucosal atrophy observed when TPN is performed. , Not known at all.

The intestinal mucosa atrophy inhibitor of the present invention comprises the nucleic acid component of the above composition as an active ingredient, and is used together with an appropriate diluent and other additives to prepare an injection formulation. The prepared agent for suppressing intestinal mucosa atrophy of the present invention may be directly intravenously administered alone, or may be intravenously administered as a mixed injection with a high-calorie nutritional infusion solution.

The intestinal mucosa atrophy inhibitor of the present invention is prepared as an injectable composition by previously mixing and dissolving the active ingredients in the amounts described above with any of the usual infusion components such as amino acids, sugars and electrolytes. It can also be used.

To prepare an injection, an effective amount of each nucleic acid component having the above composition is dissolved in a diluent such as distilled water, physiological saline, Ringer's solution, etc., and if necessary, sodium salicylate and sodium acetate. , Solubilizing agents such as mannitol, buffers such as sodium citrate and glycerin, isotonic agents such as glucose and invert sugar, stabilizers such as sodium bisulfite and polyethylene glycol, and further benzyl alcohol, benzalkonium chloride and the like. Add preservatives, soothing agents such as glucose, calcium gluconate, procaine chloride, etc., and appropriate additives such as pH regulators such as hydrochloric acid, acetic acid, citric acid, sodium hydroxide, etc. It can be carried out after sterilization by the above.

The dose of the intestinal mucosal atrophy inhibitor of the present invention thus obtained is generally such that the amount of the active ingredient is preferably in the range of about 0.02 g to 1.6 g per adult per day. The dose can be appropriately increased or decreased according to the pathological condition, nutritional condition, age, body weight of the patient to be treated, the concomitant drug with the inhibitor of the present invention, and the like.

The intestinal mucosa atrophy inhibitor of the present invention is usually TPN.
A prescribed amount can be administered to a patient in need thereof at the time of administration or before and after the administration by various administration routes in the above-mentioned various formulation forms. It is suitable to administer it as a mixed injection or to administer the effective amount of the same alone through a peripheral vein at the same time as the administration of the high calorie infusion, whereby the desired excellent effect of suppressing intestinal mucosal atrophy can be achieved. In addition, administration after TPN administration can also exert an effect of improving intestinal mucosal atrophy. In addition, the intestinal mucosa atrophy inhibitor of the present invention can be used in combination with other agents that are said to have an intestinal mucosa atrophy inhibitory action such as glutamine (alanylglutamine) and EGF, and when it is more effective There is.

[0015]

INDUSTRIAL APPLICABILITY The agent for suppressing intestinal mucosal atrophy of the present invention has an effect of effectively preventing atrophy of intestinal mucosa in patients under TPN administration. Can maintain the function of the intestinal tract, and TP
It facilitates oral nutrition intake in patients after N administration, and can significantly shorten the recovery period of patients.

[0016]

EXAMPLES In order to explain the present invention in more detail, preparation examples (formulation examples) of the intestinal mucosa atrophy inhibitor of the present invention and pharmacological test examples conducted using the same will be given below.

[0017]

[Formulation Example 1] Inosine 0.80% by weight, cytidine 0.7
The pure crystals of each nucleic acid component were weighed so as to be 3% by weight, 1.22% by weight of 5'-GMP-2Na, 0.55% by weight of uridine, and 0.18% by weight of thymidine, and the mixture was diluted with distilled water for injection. (The total amount is 1 liter) and stirred, and then the solution pH is adjusted to about 7.5 using sodium hydroxide as a pH adjuster.
The resulting aqueous solution was aseptically filtered, filled in a 200 ml glass vial, replaced with nitrogen, the container was closed, and sterilized in an autoclave at 105 ° C. for 40 minutes to obtain the intestinal mucosa atrophy inhibitor of the present invention ( Total free nucleic acid component concentration 3.4 w / v
%) 50 were prepared.

[0018]

[Pharmacological test example 1] Wistar rat (body weight: about 200 g)
Using 6 animals per group (control group and experimental group), first, a continuous infusion route for TPN was created from the right internal jugular vein in each group of rats.

Immediately after the above route was prepared, control TPs having the composition shown in Table 1 below were prepared for the control group rats.
The N composition liquid was administered at a rate of 120 ml / kg / day on the first day and 240 ml / kg / day from the second day.

In the experimental group, the nucleic acid components having the composition shown in Table 2 below according to the invention were added to the control TPN composition solution at 2.5%.
It was added so that it became ml / kg / day, and was similarly administered to rats. There is no difference in the total administered calories and total amino acid amount between the two groups.

[0021]

[Table 1]

[0022]

[Table 2]

On the 8th day after the catheter was placed, the rats in each group were weighed and then sacrificed to release the small intestine (the ileocecal terminal from the ligament of Treitz). The mesenteric adipose tissue was removed from this sample, 10 g of tension was applied to the ileocecal region, and a jejunum sample (5 to 25 cm distal to the ligament of Treitz) and an ileum sample (22 to 2 cm proximal to the terminal ileum) were prepared. It was collected. After washing them with cold saline, they were inverted and scraped on an ice-cooled petri dish with a slide glass to obtain mucous membranes. The total wet weight, mucosal wet weight, and mucosal protein content of each specimen were measured, and a histological search (villi height and crypt depth) was performed.

The results obtained in jejunum are shown in FIGS.

From each figure, it is clear that in the experimental group, administration of the intestinal mucosal atrophy inhibitor of the present invention can markedly suppress mucosal atrophy in the jejunum.

A similar tendency was observed in the ileum.

From the above, it is clear that the intestinal mucosal atrophy inhibitor of the present invention significantly suppresses intestinal mucosal atrophy caused by TPN.

[Brief description of drawings]

FIG. 1 is a graph showing the results of measuring the total wet weight of jejunum according to the pharmacological test example of the present invention.

FIG. 2 is a graph showing the results of measuring the wet weight of jejunal mucosa according to the pharmacological test example of the present invention.

FIG. 3 is a graph showing the results of measuring the amount of mucosal protein in the jejunum according to the pharmacological test example of the present invention.

FIG. 4 is a graph showing the results of measuring the height of villi of the jejunum and the depth of the crypt according to the pharmacological test example of the present invention.

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] October 29, 1991

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0017

[Correction method] Change

[Correction content]

[0017]

[Formulation Example 1] Inosine 0.80% by weight, cytidine 0.7
The pure crystals of each nucleic acid component were weighed so as to be 3% by weight, 1.22% by weight of 5'-GMP-2Na, 0.55% by weight of uridine, and 0.18% by weight of thymidine. (The total amount is 11) and stirred, and then the solution pH is adjusted to about 7.5 using sodium hydroxide as a pH adjuster.
The resulting aqueous solution is aseptically filtered, filled in a 20 ml glass vial, purged with nitrogen, the container is closed, and the container is sterilized in an autoclave at 105 ° C. for 40 minutes to obtain an intestinal mucosa atrophy inhibitor of the present invention. (Total free nucleic acid component concentration 3.4 w / v
%) 50 were prepared.

 ─────────────────────────────────────────────────── (72) Inventor Akitaka Ogawa 2-11-20 Tomimatsucho, Amagasaki City, Hyogo Prefecture (72) Inventor Shohei Iijima 1-1-15 Kokubunji, Kita-ku, Osaka City, Osaka Elvenom Sakura Building 15 No. 1104 (72) Inventor Taro Honma 5-2-20 Midorigaoka, Toyonaka-shi, Osaka (72) Inventor Masaki Sakagami 1-8 Nishiomitabicho, Suita-shi, Osaka St. Polia Kita-Osaka (No. 2) No. 804 (72) Invention Person Mori Takesada 2-19-512 Ryodocho, Nishinomiya-shi, Hyogo

Claims (1)

Claims: 1. An agent for suppressing intestinal mucosa atrophy under complete parenteral nutrition, which comprises, as an active ingredient, an amount of a nucleic acid component having the following composition in a relative molar ratio. Inosine 4 Cytidine 45 5'-GMP salt 4 Uridine 3 Thymidine 1