JPH11209303A - Renal insufficiency therapeutic drug and food for renal insufficient patient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a renal insufficiency therapeutic drug and foods for renal insufficient patients capable of remarkably controlling the progress of renal insufficiency by efficiently decreasing the formation of indoxyl sulfate. SOLUTION: This renal insufficiency therapeutic drug is prepared by including a compound having tryptophanase inhibitory effect, e.g. hydroxyindoryl-L-alanine, 2,3-dihydro-L-tryptophan or the like, as an active ingredient and further foods for renal insufficient patients are obtained by adding it to the prescribed foods.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a remedy for renal insufficiency and food for renal insufficiency patients, a so-called renal insufficiency diet, and more particularly to a drug capable of effectively suppressing the progress of renal insufficiency and a food useful for renal insufficiency patients. It is.

[0002]

BACKGROUND ART At present, there are 167,000 dialysis patients in Japan, and 28,000 new dialysis patients are introduced annually. Thus, in order to suppress such an increase in dialysis patients, it is important to suppress the progress of renal failure, and there is an urgent need to develop drugs for that purpose. By the way, today, as one measure for suppressing the progress of renal failure, an oral adsorbent (trade name: Kremezin) is used.
Has been used, and its mechanism of action is considered to be removal of the substance promoting progression of renal failure in the intestine by adsorption. As a result of various studies, the present inventors have proved that indoxyl sulfate, which is a protein metabolite, is a uremic substance having an effect of promoting progression of renal failure (J. Lab.Clin. Med. 124: 96-104).
, 1994, Am. J. Nephrol. 14: 207-212, 1994, Kidney.
Int. 52 (Suppl. 62): S15-S22, 1997], and clarified that the main mechanism of action of the above-mentioned treatment method using an oral adsorbent is suppression of indoxyl sulfate production.

[0003] For patients with chronic renal insufficiency, a low-protein diet has conventionally been employed in order to suppress the progress of renal insufficiency. And the present inventors, as a mechanism by which this low protein diet suppresses the progression of renal failure, the amount of tryptophan derived from the protein is reduced, so that the production of indole is reduced, and as a result, it has an action to promote renal failure progression It has been shown that indoxyl sulfate production is reduced: Miner. Electrol. Metab., 23: 179-194, 19
97.

[0004] However, even if such oral adsorbents or low-protein diets are used today, their effects are not sufficiently improved, and therefore, drugs and foods that can more effectively suppress the progression of renal failure. The development of is desired.

[0005]

In view of such circumstances, the present inventor has proposed a drug that more effectively reduces indoxyl sulfate production in order to more significantly suppress the progress of renal failure.
Focusing on tryptophanase of enterobacteria (Escherichia coli) that produces indole, a precursor of indoxyl sulfate, based on the finding that it is effective, and administers a compound that inhibits the action of such tryptophanase As a result of various studies on the effectiveness of such a compound, it was found that the effect of suppressing the progress of renal failure of such a compound was extremely remarkable, and a substance having such a tryptophanase inhibitory effect was added to foods. It has been found that by adding, containing and using it as a food for patients with renal failure, it can more effectively reduce the production of indoxyl sulfate and exert a remarkable effect on suppressing the progression of renal failure, and The present invention has been completed based on these findings.

Accordingly, an object of the present invention is to provide an effective therapeutic agent for renal insufficiency and a renal insufficiency patient capable of more efficiently reducing the production of indoxyl sulfate and more remarkably suppressing the progress of renal insufficiency. Food products.

[0007]

According to the present invention, there is provided a remedy for renal failure characterized by containing a compound having a tryptophanase inhibitory activity as an active ingredient. It is an abstract.

[0008] The present invention also provides a food for patients with renal insufficiency characterized in that a compound having a tryptophanase inhibitory action is added to or contained in the food.

In the remedy for renal insufficiency or food for patients with renal insufficiency according to the present invention, the compound having the tryptophanase inhibitory activity is preferably oxyindolyl-L-alanine or 2,3- Dihydro-L-tryptophan is used, and a therapeutic agent for renal failure is advantageously used as an orally administered drug, while in foods for patients with renal failure, a combination with a low protein diet is advantageously employed. .

[0010]

DETAILED DESCRIPTION OF THE INVENTION Indoxyl sulfate, which has an action to promote the progression of renal failure, uses indole in the intestine as its precursor.
It is produced from tryptophan derived from dietary protein by tryptophanase of intestinal bacteria such as Escherichia coli in the intestine. Therefore, in the present invention, the production of indole by such tryptophanase is suppressed or prevented by a compound having a tryptophanase inhibitory action, that is, a tryptophanase inhibitor. In comparison with conventional oral adsorbents, it effectively inhibits the production of indoxyl sulfate,
Thus, the progression of renal failure can be more significantly suppressed.

Further, if the tryptophanase inhibitor according to the present invention is added to a food to be taken by a patient with renal insufficiency and is introduced into the body of a patient with renal insufficiency, the same superior effect as in the case of drug administration can be obtained. In addition, the effect of inhibiting the progression of renal failure can be exerted, and further, a conventional low protein diet, that is, a food in which the amount of protein intake is generally about 0.8 g / day or less per kg of body weight, If the tryptophanase inhibitor according to the present invention is added, the production of indoxyl sulfate will be further reduced, so that a food that can exhibit a more excellent effect of inhibiting progression of renal failure can be obtained. Therefore, as a current low protein diet, although a severe low protein diet with a protein intake of about 0.5 g / kg / day is recommended, a food to which a tryptophanase inhibitor is added according to the present invention is used. For example, even with a milder low protein diet, for example, a protein intake of about 0.8 g / kg / day, the protein intake is 0.5 g / kg / day.
It is possible to obtain an indoxyl sulfate production inhibitory effect and a renal failure progression inhibitory effect, similar to severe low protein diets that result in day.

In addition, indole in the intestine can cause fecal odor. Therefore, according to the present invention, if a tryptophanase inhibitor is administered as a drug or ingested as a food, such indole can be reduced to such a level. Indole production can be effectively reduced by the tophanase inhibitor, so that the effect of suppressing fecal odor can be advantageously exerted.

The tryptophanase inhibitor used in the present invention, in other words, the compound exhibiting a tryptophanase inhibitory action, is a substance (compound) that inhibits the production of indole from tryptophan by tryptophanase of intestinal bacteria. , Any of which can be advantageously used, but typically, oxyindolyl-L
-Alanine (oxindolyl-L-alanine), 2,3-dihydro-L-tryptophan (2,3-dihydro-L-tryptophan)
And the like.

[0014] Such a tryptophanase inhibitor can be used in the form of a crude product or in the form of a mixture with other components, in addition to its use in the form of its purified product. The use form is appropriately selected according to the purpose.

In preparing a drug as a therapeutic agent for renal failure according to the present invention containing such a tryptophanase inhibitor as an active ingredient, a selected form of the tryptophanase inhibitor is used. It will be converted into a drug according to a usual method, in which case, as a component used in a usual pharmaceutical formulation, a binder, an excipient, a lubricant, an emulsifier, a disintegrant, a wetting agent, a preservative, a coloring Agents and the like are blended as necessary, and are made into various conventionally known dosage forms such as tablets, powders, granules, capsules, and liquids.

The remedy for renal failure according to the present invention thus prepared is administered according to a known administration technique in order to effectively suppress the production of indole from protein-derived tryptophan in the intestinal tract. In particular, in the present invention, the compound is advantageously used as an orally administered drug. The dose should be appropriately adjusted depending on the patient's age, body weight, degree of symptoms, and administration route. In the case of oral administration, usually, in an adult, it is an active ingredient per day. 0.001 to 1000 mg, preferably about 0.01 to 100 mg, of the tryptophanase inhibitor according to the present invention will be administered per kg of body weight.

Further, the food for patients with renal failure according to the present invention comprises:
Tryptophanase inhibitors are added to and contained in predetermined foods, and the target foods include various foods used for staple foods, side meals, snack foods, and foods eaten as favorite foods For example, all conventional foods are targeted, and for such foods, a tryptophanase inhibitor is added and contained by an appropriate technique. It is desirable to add a predetermined tryptophanase inhibitor to a low-protein diet conventionally used for patients with renal failure, so that a more effective inhibitory effect on indoxyl sulfate production and renal The effect of suppressing the progress of failure can be obtained.

[0018]

EXAMPLES Hereinafter, some examples of the present invention will be shown to clarify the present invention more specifically. However, the present invention does not impose any restrictions due to the description of the examples. It goes without saying that it is not what you receive. In addition, the present invention, in addition to the following examples, and in addition to the above-described specific description, various changes, modifications, and modifications based on the knowledge of those skilled in the art without departing from the spirit of the present invention. It should be understood that improvements can be made.

Example 1 Oxyindolyl-L-alanine (OA), which is a compound having a tryptophanase inhibitory action, was added to the diet to renal insufficiency rats subjected to 5/6 nephrectomy. Orally administered at a rate of 100 mg / kg / day in the form, serum indoxyl sulfate concentration, serum creatinine concentration, blood urea nitrogen concentration, and creatinine at 2, 4, 6, and 8 weeks later. The clearance was measured, and the effect of oxyindolyl-L-alanine on the progression of renal failure was examined. The measurement result is
It was as follows.

The serum indoxyl sulfate concentration was HPL
On the other hand, the serum creatinine concentration and the blood urea nitrogen concentration were measured according to a normal method using an autoanalyzer, and the creatinine clearance was obtained by calculation from the measured value of the creatinine concentration. . In addition, in this test, all rats with renal failure in each group were given a normal diet (protein content:
2.4 g / animal / day). a) Serum indoxyl sulfate concentration (mg / dl, mean ± SE) OA administration + normal diet group Normal diet group (control) Before administration 1.0 ± 0.08 1.0 ± 0.09 Two weeks later 0.08 ± 0.01 1.1 ± 0.08 After 4 weeks 0.07 ± 0.01 1.2 ± 0.09 After 6 weeks 0.08 ± 0.01 1.3 ± 0.09 After 8 weeks 0. 07 ± 0.01 1.5 ± 0.08 b) Serum creatinine concentration (mg / dl, mean ± SE) OA administration + normal diet group Normal diet group (control) Before administration 1.5 ± 0.2 1.5 ± 0.2 After 2 weeks 1.5 ± 0.3 1.7 ± 0.3 After 4 weeks 1.6 ± 0.2 2.0 ± 0.3 After 6 weeks 1.7 ± 0.3 2. 4 ± 0.3 8 weeks later 1.7 ± 0.2 2.9 ± 0.4 c) Blood urea nitrogen concentration (mg / dl, mean ± SE) OA administration + normal diet group Normal diet group (control) Before administration 86 ± 8 87 ± 9 Two weeks later 85 ± 9 92 ± 94 after 4 weeks 87 ± 7 97 ± 96 after 6 weeks 88 ± 9 102 ± 98 after 8 weeks 88 ± 8 110 ± 10 d) creatinine clearance (ml / min, mean ± SE) OA administration + normal diet Group Normal diet group (control) Before administration 0.64 ± 0.04 0.64 ± 0.03 After 2 weeks 0.64 ± 0.03 0.56 ± 0.03 After 4 weeks 0.63 ± 0.04 0.42 ± 0.04 after 6 weeks 0.60 ± 0.04 0.36 ± 0.04 after 8 weeks 0.59 ± 0.05 0.32 ± 0.04

As is clear from the results obtained above,
By administering oxyindolyl-L-alanine (OA) together with a normal diet to rats with renal failure, it is recognized that the serum concentration of indoxyl sulfate can be reduced, thereby suppressing the progress of renal failure. is there.

Example 2 A low protein diet (protein content: 1.2 g / animal /
day) and a normal diet (protein amount: 2.4 g / animal / day), while renal failure rats were divided into three groups, and OA administration + low protein diet group, low protein diet group, and normal diet group In and
The same measurement as in Example 1 was performed, and the action of suppressing progression of renal failure was examined. The results are shown below. a) Serum indoxyl sulfate concentration (mg / dl, mean ± SE) OA administration + low protein diet group Low protein diet group (control) Normal diet group (control) Before administration 1.0 ± 0.08 1.0 ± 0 0.08 1.0 ± 0.09 After 2 weeks 0.06 ± 0.01 0.08 ± 0.01 1.1 ± 0.06 After 4 weeks 0.05 ± 0.01 0.07 ± 0.01 1.3 ± 0.05 After 6 weeks 0.05 ± 0.01 0.08 ± 0.01 1.4 ± 0.08 After 8 weeks 0.04 ± 0.01 0.08 ± 0.01 4 ± 0.07 b) Serum creatinine concentration (mg / dl, mean ± SE) OA administration + low protein diet group Low protein diet group (control) Normal diet group (control) Before administration 1.5 ± 0.2 5 ± 0.2 1.5 ± 0.2 After 2 weeks 1.5 ± 0.3 1.6 ± 0.3 1.7 ± 0.4 After 4 weeks 1.5 ± 0.2 1.7 ± 0.2 1.9 ± 0.4 After 6 weeks 1.5 ± 0. 1.7 ± 0.3 2.3 ± 0.5 8 weeks 1.6 ± 0.2 1.8 ± 0.2 3.0 ± 0.5 c) blood urea nitrogen concentration (mg / dl, (Mean ± SE) OA administration + low protein diet group Low protein diet group (control) Normal diet group (control) Before administration 86 ± 888 86 ± 886 ± 9 2 weeks later 82 ± 888 86 ± 10 91 ± 94 weeks later 85 ± 88 88 ± 896 ± 96 weeks later 84 ± 8 91 ± 9 100 ± 98 weeks later 83 ± 8 92 ± 8 112 ± 10 d) Creatinine clearance (ml / min, mean ± SE) OA administration + Low protein diet group Low protein diet group (control) Normal diet group (control) Before administration 0.65 ± 0.05 0.65 ± 0.04 0.65 ± 0.03 Two weeks later 0.64 ± 0.03 0.64 ± 0.04 0.55 ± 0.05 After 4 weeks 0.64 ± 0.04 0.61 ± 0.05 0.41 ± 0.066 After 6 weeks 0.64 ± 0.04 0.0. 9 ± 0.05 0.35 ± 0.05 8 weeks after 0.64 ± 0.05 0.59 ± 0.06 0.31 ± 0.06

As is evident from the measurement results, when oxyindolyl-L-alanine was administered to rats with renal insufficiency together with a low protein diet, the serum of indoxyl sulfate was more increased than in the group receiving only the low protein diet. It is observed that the concentration is reduced and the progress of renal failure can be effectively suppressed.

Example 3 As a tryptophanase inhibitor, 2,3-dihydro-
Using L-tryptophan (DT), it was orally administered at a rate of 100 mg / kg / day to a 5/6 nephrectomized renal insufficiency rat in the form of added to the diet, and the normal diet (protein) was added. Dose: 2.4 g / animal / day), and the serum indoxyl sulfate concentration, serum creatinine concentration, blood urea nitrogen concentration and creatinine clearance at 2, 4, 6, and 8 weeks after administration. Each was determined in the same manner as in Example 1, and the following results were obtained. a) Serum indoxyl sulfate concentration (mg / dl, mean ± SE) DT administration + normal diet group Normal diet group (control) Before administration 1.1 ± 0.08 0.9 ± 0.07 Two weeks later 0.07 ± 0.01 1.0 ± 0.06 After 4 weeks 0.06 ± 0.01 1.1 ± 0.08 After 6 weeks 0.08 ± 0.01 1.2 ± 0.08 After 8 weeks 0. 08 ± 0.01 1.4 ± 0.08 b) Serum creatinine concentration (mg / dl, mean ± SE) DT administration + normal diet group Normal diet group (control) Before administration 1.4 ± 0.2 1.4 ± 0.2 After 2 weeks 1.4 ± 0.3 1.7 ± 0.3 After 4 weeks 1.4 ± 0.3 1.9 ± 0.3 After 6 weeks 1.5 ± 0.3 2. 2 ± 0.3 8 weeks later 1.6 ± 0.3 2.7 ± 0.4 c) Blood urea nitrogen concentration (mg / dl, mean ± SE) DT administration + normal diet group Normal diet group (control) Before administration 83 ± 7 84 ± 8 Two weeks later 84 ± 88 ± 9 4 weeks after 84 ± 6 95 ± 8 88 ± 8 108 ± 9 d after 87 ± 9 99 ± 9 8 weeks after 6 weeks) Creatinine clearance (ml / min, mean ± SE) DT administration + normal diet group Normal diet group (control) Before administration 0.62 ± 0.03 0.62 ± 0.04 After 2 weeks 0.63 ± 0.03 0.56 ± 0.03 After 4 weeks 0.63 ± 0.040 0.44 ± 0.03 after 6 weeks 0.61 ± 0.04 0.38 ± 0.04 after 8 weeks 0.60 ± 0.04 0.34 ± 0.03

As is apparent from the measurement results,
3-Dihydro-L-tryptophan, with a normal diet,
When administered to rats with renal failure, it is recognized that the serum concentration of indoxyl sulfate decreases and the progress of renal failure can be suppressed.

Example 4 Rats with renal failure were administered with DT and a low protein diet (protein amount: 1.2
g / animal / day) group, low protein diet group and normal diet (protein amount:
The group was divided into three groups of 2.4 g / animal / day) and evaluated for the effect of inhibiting the progression of renal failure in the same manner as in Example 3, and the following results were obtained. a) Serum indoxyl sulfate concentration (mg / dl, mean ± SE) DT administration + low protein diet group Low protein diet group (control) Normal diet group (control) Before administration 1.1 ± 0.08 1.1 ± 0 0.08 1.1 ± 0.06 After 2 weeks 0.04 ± 0.01 0.09 ± 0.01 1.0 ± 0.02 After 4 weeks 0.04 ± 0.01 0.07 ± 0.01 1.1 ± 0.02 after 6 weeks 0.03 ± 0.01 0.09 ± 0.01 1.1 ± 0.028 after 8 weeks 0.04 ± 0.01 0.08 ± 0.01 0 ± 0.02 b) Serum creatinine concentration (mg / dl, mean ± SE) DT administration + low protein diet group Low protein diet group (control) Normal diet group (control) Before administration 1.4 ± 0.2 1. 4 ± 0.3 1.4 ± 0.2 After 2 weeks 1.4 ± 0.3 1.5 ± 0.3 1.8 ± 0.3 After 4 weeks 1.4 ± 0.3 1.6 ± 0.3 1.9 ± 0.3 After 6 weeks 1.5 ± 0. 1.6 ± 0.2 2.1 ± 0.3 8 weeks 1.6 ± 0.3 1.7 ± 0.4 2.6 ± 0.4 c) blood urea nitrogen concentration (mg / dl, Average ± SE) DT administration + low protein diet group Low protein diet group (control) Normal diet group (control) Before administration 83 ± 88 83 ± 88 83 ± 8 2 weeks later 82 ± 9 87 ± 10 88 ± 94 weeks later 82 ± 6 88 ± 896 ± 96 Week after 82 ± 990 90 ± 9 100 ± 98 Week after 80 ± 8 91 ± 9 106 ± 10 d) Creatinine clearance (ml / min, mean ± SE) DT administration + Low protein diet group Low protein diet group (control) Normal diet group (control) Before administration 0.62 ± 0.03 0.63 ± 0.04 0.63 ± 0.03 Two weeks later 0.63 ± 0.04 0.62 ± 0.06 0.55 ± 0.03 After 4 weeks 0.64 ± 0.04 0.61 ± 0.06 0.47 ± 0.04 After 6 weeks 0.63 ± 0.04 0.0. 1 ± 0.03 0.40 ± 0.04 8 weeks 0.64 ± 0.05 0.60 ± 0.05 0.36 ± 0.04

As is clear from the above results, 2,3-
When dihydro-L-tryptophan is administered to rats with renal insufficiency together with a low protein diet, the serum concentration of indoxyl sulfate is further reduced as compared to the low protein diet group. It is understood that it can be suppressed more effectively.

[0028]

As is apparent from the above description, according to the present invention, a compound having a tryptophanase inhibitory action is used as a therapeutic agent for renal failure containing the compound as an active ingredient or as a food for patients with renal failure. By administration or ingestion, the production of indoxyl sulfate can be more selectively and efficiently inhibited, and a strong inhibitory effect on renal failure progression can be exerted.

Therefore, by realizing such a remedy for renal failure or food for patients with renal failure, the progress of renal failure in patients with renal failure in the preservation stage can be effectively suppressed, thereby suppressing an increase in the number of dialysis patients. And the patient's QO
Contribution to the welfare of patients and improvement of society, such as improvement of L (quality of life) and reduction of medical expenses related to dialysis, can be greatly enhanced. By reducing the fecal odor, nursing becomes easier.

Claims (6)

[Claims] 1. A remedy for renal failure, comprising a compound having a tryptophanase inhibitory action as an active ingredient. 2. The compound having an inhibitory action on tryptophanase is oxyindolyl-L-alanine or 2,3-dihydro-L-tryptophan.
The remedy for renal insufficiency according to the above. 3. The remedy for renal failure according to claim 1, which is used as an orally administered drug. 4. A food for patients with renal failure, characterized in that a compound having a tryptophanase inhibitory action is added to or contained in the food. 5. The compound having an inhibitory action on tryptophanase is oxyindolyl-L-alanine or 2,3-dihydro-L-tryptophan.
The food for renal failure patients described in the above. 6. The food for renal failure patients according to claim 4, wherein the food is a low protein diet.