JPH1059851A - Guanidino compound reducing agents and water and potassium ion adsorbents - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicine effective for patients with acute and chronic renal insufficiency, receiving hemodialysis and reduced in liver function, having a new action, by using a specific resin as an active ingredient. SOLUTION: This reducing agent comprises an acrylic water-absorbing resin as an active ingredient. An alkaline earth metal acrylate- or methacrylate-based polymer or a self cross-linking type metal acrylate-based polymer is preferable as the acrylic water-absorbing resin. Preferably, these metal salts comprise at least partially a calcium ion (with the proviso that a potassium salt is omitted in the case of a potassium ion adsorbent). The medicine reduces a guanidine compound accumulated in the body of a patient, discharges the compound out of the body together with water accumulated in the body without by hemodialysis and also potassium ion accumulated in the body.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a guanidino compound-lowering agent, and more particularly, to patients with acute or chronic renal failure who are undergoing hemodialysis, or who have not yet undergone hemodialysis, but who have lost water due to renal dysfunction. Orally administered to a patient who is restricted, reduces the guanidino compound accumulated in the body of the patient, together with the water accumulated in the body,
The present invention relates to a guanidino compound-lowering agent having a new action capable of removing potassium ions which are excreted from the body without hemodialysis and accumulated in the body.

[0002]

2. Description of the Related Art Acrylic water-absorbing resins such as sodium polyacrylate have been used as sanitary products such as sanitary products, diapers, disposable rags, food additives, agricultural and horticultural products, and the like. It can be used as a therapeutic agent for peptic ulcer (German Patent No. 2412090), a hemostatic and wound protective agent (Japanese Patent Application Laid-Open No. 62-70318), an agent for preventing sickness (Japanese Patent Application Laid-Open No. 1-153643), etc. It has been known.

[0003] On the other hand, renal function is reduced, and substances to be excreted in urine such as nitrogen, metabolic waste products and water are accumulated in the living body. Although renal transplantation and CAPD (portable peritoneal dialysis) are also known, there are too few renal donors in renal transplantation and CAPD
At present, he currently mainly relies on hemodialysis because of the drawback that peritonitis tends to occur.

[0004] The number of patients with renal disease in Japan is said to be 500,000 to 600,000, and the Japan Statistical Investigation Committee for Dialysis Therapy reported that the number of chronic dialysis patients in Japan as of the end of 1994 was 143709, which was 9411 compared to the previous year. Reports that it has increased.

[0005] Patients in the preservation period who have not yet undergone such dialysis patients and hemodialysis, but who have the same restriction of water intake as dialysis patients due to renal function deterioration, have a problem of water and the like due to renal function deterioration. Since it is said that extracorporeal discharge is impossible or difficult, and angina in dialysis patients is likely to appear during dialysis, and it is said that seizures are likely to be induced even when the volume of fluid immediately before dialysis is maximized. The amount is severely restricted. The daily allowable water intake is set to be within about 1 liter, and the allowable water intake of the dialysis patient until the next hemodialysis is restricted to about 4 to 5% of the body weight. In the current situation. Thus, this allowable water intake is equivalent to about half of the amount of water normally taken by a healthy person. This prolonged stringent water management can cause dialysis patients significant mental and physical distress,
This is one of the most serious adverse effects of hemodialysis.

[0006] The hemodialysis time of the above-mentioned dialysis patient is, for example, about 3 hours in the case of removing 2 liters of water and metabolic wastes, and more time is required to remove more water. Since patients need to repeat such hemodialysis about two or three times a week, it is difficult to return to society in terms of time.

As described above, hemodialysis currently applied to patients with renal insufficiency is indispensable for maintaining the life of the patient, but involves a great deal of mental distress and the like, and has a long treatment time. Therefore, the development of a new technology capable of reducing such a problem is awaited.

Further, in renal failure patients such as dialysis patients, guanidino compounds such as methylguanidine, guanidinopropionic acid and guanidinobutyric acid, which are regarded as one of the causative substances of uremia, are accumulated in the body. There are evils. In addition, methylguanidine has cytotoxicity, guanidinopropionic acid has a hemolytic effect, guanidinobutyric acid has a central nervous system dysfunction, and according to their respective accumulation in the body, there is a risk of illness of various diseases. .

[0009] Of these, methylguanidine can be reduced in blood concentration by hemodialysis, but the concentration in organs is not easily reduced by hemodialysis. In addition, guanidinopropionic acid and guanidinobutyric acid can hardly reduce the blood and organ concentrations by hemodialysis.

As described above, hemodialysis is performed for the purpose of removing metabolic wastes, toxic substances, etc., in addition to removing water. However, depending on the type of toxic substances accumulated in the body, such dialysis is not sufficient. It is also desired to develop a technology that cannot be removed and that can replace or supplement this.

In addition, in general, in hemodialysis patients,
When fever, infection, poor eating, etc. occur, potassium ions migrate to the outside of the cell due to the breakdown of cytoplasm and self-protein, and hyperkalemia is easily induced without oral potassium intake, and limbs Paresthesia, vomiting, diarrhea, oliguria,
It is known that symptoms such as muscle weakness, flaccid muscle paralysis, metabolic acidosis, respiratory muscle paralysis, dyspnea, and arrhythmia may occur. Therefore, conventionally, to such dialysis patients, administration of potassium adsorbent is often performed,
Known potassium adsorbents have the disadvantage of constipation as a side effect, and their improvement is also required.

[0012]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a new method for excreting water taken in by a hemodialysis patient or the like, guanidino compounds and potassium ions accumulated in the body without using hemodialysis. It is an object of the present invention, in particular, to provide an orally-administered drug which enables such extracorporeal excretion.

The present inventors have conducted intensive studies for the above purpose, and as a result, when a certain kind of water-absorbing resin conventionally used in sanitary goods and the like is orally ingested by patients, it has been accumulated in the body. It lowers the guanidino compound, and also adsorbs potassium ions at the same time as water, exhibits an action capable of being excreted outside the body, and found that oral administration at a dose exhibiting the above action is excellent in safety, Here, the present invention has been completed.

[0014]

According to the present invention, there is provided a guanidino compound lowering agent comprising an acrylic water-absorbing resin as an active ingredient, particularly a guanidino compound lowering agent, a water adsorbent and a guanidino compound lowering agent. , Moisture and potassium ion adsorbents are provided.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION One preferable example of the acrylic water-absorbing resin as an active ingredient in the reducing and adsorbent of the present invention is a compound represented by the following general formula: CH ₂ = CR ¹ COOR ² [where R ¹ is hydrogen An atom or a methyl group, R ² represents a hydrogen atom or a metal atom. And a crosslinked product of the polymer containing the acrylic monomer represented by the formula (1) as an essential constituent unit.

Examples of the metal forming the metal salt include alkali metals such as sodium, potassium and lithium, and alkaline earth metals such as calcium and magnesium.

The preferred acrylic water-absorbing resin includes:
An acrylic acid-based polymer, a metal acrylate-based polymer, a methacrylic acid-based polymer and a metal methacrylate-based polymer are included, and each of these polymers may be a crosslinked type thereof.
Among them, a crosslinked product of polyacrylic acid or an alkali metal salt of polyacrylic acid is preferable, and a crosslinked product in which a part of the crosslinked product has a form of a calcium salt is most preferable.

The above-mentioned cross-linked products include self-cross-linked products obtained without using any cross-linking agent and cross-linked products obtained by cross-linking with various commonly used cross-linking agents according to a conventional method.

As the crosslinking agent, various ones such as polyhydric allyls, polyhydric vinyls, polyhydric epoxies, haloepoxys, polyhydric alcohols, polyhydric amines and hydroxyvinyls can be used. it can. The following can be exemplified as typical crosslinking agents.

Polyvalent allyls: N, N-diallylacrylamide and N, N-diallylmethacrylamide (these are referred to as "N, N-diallyl (meth) acrylamide", the same applies hereinafter), diallylamine, diallylmethacrylamine And polyvalent allyl compounds such as diallyl phthalate and diallyl malate.

Polyvalent vinyls: divinylbenzene, N,
N'-methylenebis (meth) acrylamide, ethylene glycol di (meth) acrylate and polyethylene glycol di (meth) acrylate (these are referred to as "(poly) ethylene glycol di (meth) acrylate", the same applies hereinafter), (poly ) Polyvalent vinyl compounds such as propylene glycol di (meth) acrylate and trimetalol propane triacrylate.

Polyhydric epoxies: (poly) ethylene glycol diglycidyl ether, (poly) propylene glycol diglycidyl ether, glycerin-1,3-diglycidyl ether, trimethylolpropane triglycidyl ether, (poly) glycerin polyglycidyl ether And other polyepoxy compounds.

Haloepoxys: epichlorohydrin, α
-Methyl chlorohydrin and the like.

Polyhydric alcohols: (poly) glycerin,
(Poly) ethylene glycol, trimethylolpropane, pentaerythritol and the like.

Polyvalent amines: ethylenediamine and the like.

The above-mentioned acrylic acid polymer, metal acrylate polymer, methacrylic acid polymer and metal methacrylate polymer include, in addition to the homopolymers of acrylic acid and methacrylic acid, And copolymers of each monomer with other monomers copolymerizable with them and a graft-polymerizable polymer. Such a copolymer may be a random polymer, a block polymer, a graft polymer, or the like. It may be united.

The other monomers copolymerizable with (meth) acrylic acid include, for example, hydroxyethyl (meth) acrylate, (methoxy) polyethylene glycol (meth) acrylate, glycerin (meth) acrylate, and glycosylethyl (meth) acrylate. ) Alkyl (meth) acrylates such as acrylates; acrylamide compounds such as N, N-dimethylacrylamide and acrylamide; carboxylic acid compounds such as maleic acid and its metal salts, itaconic acid and its metal salts; 2-acrylamide-2
Sulfonic acid compounds such as -methylpropanesulfonic acid and its metal salt, vinylsulfonic acid and its metal salt, styrenesulfonic acid and its metal salt; and N-vinylpyrrolidone.

Examples of the polymer that can be graft-polymerized with (meth) acrylic acid include starch, carrageenan,
Examples include hydrophilic polysaccharides such as agarose and carboxymethyl cellulose.

Some of the above-mentioned various water-absorbing resins are commercially available, and can be produced by a usual method. As a general production method, for example, a method of polymerizing a monomer in an aqueous monomer solution (aqueous solution polymerization), a method of preparing a suspension of an aqueous monomer solution in a non-aqueous organic solvent and polymerizing the suspension (reverse phase suspension polymerization) A method of cross-linking a polymer aqueous solution using a cross-linking agent (polymer cross-linking method) and the like are known, and the water-absorbing resin used in the present invention may be any of these methods.

In particular, a self-crosslinking alkali metal acrylate polymer, which is one of the preferred active ingredients of the present invention, is prepared by using a water-soluble radical polymerization initiator to prepare a highly concentrated aqueous solution of an alkali metal acrylate. It is preferably produced by suspending and dispersing in an organic solvent to carry out polymerization (reverse phase suspension polymerization) (for example, see Japanese Patent Publication No. 54-30710).

A self-crosslinkable metal acrylate polymer in which part of an alkali metal atom is substituted with calcium, which is one of the particularly preferable active ingredients of the present invention, is, for example, an alkali metal acrylate and an acrylic acid. A high-concentration aqueous solution of a calcium acid salt is suspended and dispersed in an organic solvent and polymerized, or more preferably, a calcium chloride aqueous solution is gradually added to a water-swelled polymer of a self-crosslinkable alkali metal acrylate obtained according to the above method. In addition to the above, it can be produced by performing counter ion exchange.

Thus, an acrylic water-absorbing resin which can be used as an active ingredient of the guanidino compound-lowering agent of the present invention can be produced.

As the acrylic resin particularly suitable for the present invention, for example, a physiological saline absorption capacity (absorbed amount of physiological saline per 1 g (ml)) is about 5 to 100, more preferably about 15 to 70. Can be exemplified.

The guanidino compound-reducing agent of the present invention can be prepared by converting the acrylic water-absorbing resin obtained as described above into a usual form, for example, powder, powder, fine powder, bead, flake, gel, etc. It can be orally administered to patients in need of reducing the guanidino compound, adsorbing and removing water and potassium ions in the form of a drug, etc. It can also be used by shaping it into an appropriate form such as a tablet, granule, capsule or the like using a carrier.

The dose can be arbitrarily determined according to the amount of water taken by the hemodialysis patient to whom it is administered and the patient in the preservation period, and is not particularly limited. For example, 70
When the reducing agent of the present invention is applied to a patient who has taken 0 ml of water, the amount of the active ingredient is preferably in the range of about 5 to 20 g per day. The guanidino compound can be excreted out of the body by adsorbing and holding, and at the same time, the guanidino compound accumulated in the body can be reduced and potassium ions can be adsorbed and held and excreted out of the body.

Of course, the above-mentioned active ingredient has a safety with substantially no toxicity even when applied to a living body, as conventionally proposed as a therapeutic agent for peptic ulcer or a hemostatic agent. In addition, even by the oral administration according to the present invention, it is not substantially absorbed into the body, and thus the safety by its application is guaranteed.

Thus, according to the use of the guanidino compound-lowering agent of the present invention, the water management of the above-mentioned hemodialysis patients and the like can be facilitated, and the hemodialysis time can be shortened. It can greatly reduce the target and mental distress.

[0038]

EXAMPLES Hereinafter, in order to explain the present invention in more detail, a method for producing a water-absorbing resin used as an active ingredient in the present invention will be described as a production example, and then a formulation example of the guanidino compound-lowering agent of the present invention and the use of the same Test examples are given.

[0039]

[Production Example 1] Production of crosslinked sodium polyacrylate Cyclohexane 1 was placed in a 5000 ml four-necked flask equipped with a stirrer, a reflux condenser, a dropping funnel, and a nitrogen gas inlet tube.
600 ml and sorbitan monostearate 16.32 g
, And the temperature was raised to 75 ° C. while purging dissolved oxygen by blowing nitrogen gas.

In another flask, 80% acrylic acid 510
g while cooling from the outside, and adding 30% NaOH aqueous solution 5
44 g was added to neutralize, then potassium persulfate 1.6
After dissolving 2 g, nitrogen gas was blown in to remove oxygen dissolved in the aqueous solution.

The contents of the flask were added dropwise to the above four-necked flask over a period of one hour, and a polymerization reaction was carried out. The cyclohexane was distilled off under reduced pressure, and the remaining swollen polymer was
Dry under reduced pressure at １００100 ° C. Cyclohexane 300
The collected crosslinked polymer was washed twice using ml to remove sorbitan monostearate.

The water-absorbing capacity of physiological saline with respect to 1 g of the crosslinked polymer thus obtained was 53 (g). Hereinafter, this polymer is referred to as “polymer A”.

Similarly, a polymer (Polymer B) having a physiological saline absorption capacity of 48 (g) and a polymer (Polymer C) having a capacity of 58 (g) per 1 g of the crosslinked polymer were obtained.

[0044]

[Production Example 2] Production of crosslinked polyacrylic acid 50 g of sodium polyacrylate obtained in Production Example 1
Was added to 15 liters of an aqueous solution of 77.5 g of hydrochloric acid while stirring, and then allowed to stand for 2 days to replace sodium ions with hydrogen ions. The obtained polymer was collected by filtration, washed with ion-exchanged water, added to 3 liters of ion-exchanged water to form a slurry, and water and hydrochloric acid were distilled off from the slurry to obtain a dried polymer. . This is designated as “Polymer D”.

The Na content in the obtained polymer was 530
ppm, and the sodium acrylate in the polymer is
More than 99% was converted to acrylic acid.

The physiological saline absorption capacity was 1 (g).

[0047]

[Production Example 3] Production of crosslinked calcium polyacrylate 100 g of sodium polyacrylate obtained in Production Example 1
Into 5 liters of ion-exchanged water to absorb water,
2.4 L of a 0.2 M aqueous solution of calcium chloride was added dropwise thereto with stirring to obtain a desired polymer. This is designated as “Polymer E”.

The polymer E is obtained by converting 90% or more of sodium acrylate in the raw material polymer to calcium acrylate, and has a physiological saline absorption capacity of 1%.
8.5 (g).

[0049]

[Production Example 4] Production of crosslinked polysodium methacrylate In Production Example 1, 70% was used instead of 80% acrylic acid.
Using 714 g of methacrylic acid, while cooling this, 30
% NaOH in an aqueous solution of 544 g, then dissolving 0.04 g of methylenebisacrylamide (crosslinking agent) and 1.63 g of potassium persulfate, and then blowing in nitrogen gas to remove oxygen dissolved in the aqueous solution. The same operation was performed to obtain a desired polymer. This is designated as “Polymer F”.

The physiological saline absorption capacity of this was 47 (g).
Met.

[0051]

[Production Example 5] Production of crosslinked polymethacrylate In the same manner as in Production Example 2, except that 55 g of the crosslinked sodium polymethacrylate obtained in Production Example 4 was used instead of the crosslinked sodium polyacrylate, Was obtained. This is designated as “Polymer G”.

The physiological saline absorption capacity of this product was 31 (g).
Met.

[0053]

[Production Example 6] Production of crosslinked polycalcium methacrylate In Production Example 3, except that 110 g of the crosslinked polysodium methacrylate obtained in Production Example 4 was used instead of the crosslinked sodium polyacrylate, The desired polymer was obtained. This is designated as “Polymer H”.

The water absorption capacity of physiological saline was 20 (g).
Met.

[0055]

Production Example 7 Production of Crosslinked Sodium Polyacrylate + Calcium (Na / Ca = 3/1) Instead of neutralizing with 544 g of a 30% aqueous NaOH solution in Production Example 1, 408 g of a 30% aqueous NaOH solution was used.
And a desired polymer was obtained in the same manner except that neutralization was performed with a suspension composed of 126 g of Ca (OH) 2 and 150 g of ion-exchanged water. This is designated as “Polymer I”.

The calcium substitution degree was 25%, and the physiological saline absorption capacity was 43 (g).

[0057]

Formulation Example 1 Production of Capsules A self-crosslinked product of sodium polyacrylate (degree of neutralization: 72%, water absorption capacity: 53, polymer A) obtained in Production Example 1 as an active ingredient is orally having desired dimensions. Gelatin capsules for administration were filled to prepare 1,000 hard gelatin capsules containing 250 mg per capsule.

[0058]

Formulation Example 2 Production of Capsules Uniformly the polymer A and the self-crosslinked body of calcium polyacrylate obtained in Production Example 3 (neutralization degree: 70%, water absorption capacity: 18.5, polymer B) were used as active ingredients. Mixing and filling into gelatin capsules for oral administration with desired dimensions,
1000 hard gelatin capsules containing 150 mg of polymer A and 150 mg of polymer B per capsule, respectively, were prepared.

[0059]

[Pharmacological Test Example 1] Seven-week-old male SD rats (Charles River Japan) were divided into groups of 6 to 8 rats, and a total kidney excision operation was performed on all rats in the morning of the first day. That is, under Nembutal anesthesia, the hair on both sides of the rat was removed,
A ventral incision was made in the abdominal wall at the rib edge. The kidney wrapped in adipose tissue was pulled out, and the renal artery and the renal vein were ligated. Then, the kidney was excised, and the incision in the abdominal wall and the skin was closed.

Polymer A as a reagent was suspended in commercially available perilla oil to prepare a 300 mg / ml administration solution.
One dose was 1 ml. Dosing 8 pm on day 1
In total, 10 ml of water and then 1 ml of the above-mentioned reagent were suspended at 8:00 am on the second day, 2:00 pm, 8:00 pm on the second day, and 8:00 am on the third day in total, using a gastric tube. Performed orally. After the final administration, each rat was sacrificed, and blood was collected and then dissected (experimental group).

Further, a control group consisting of the above nephrectomized rats to which 10 ml of water was ingested, and then 1 ml of perilla oil containing no reagent was similarly administered instead of the suspension of the reagent was prepared.

Further, normal rats (rats who had not undergone nephrectomy) were allowed to freely ingest water, and then, instead of the suspension of the above-mentioned reagent, only perilla oil containing no reagent was used.
A reference group to which the same amount was administered was provided.

During the experimental period, rats in each group were allowed to freely feed, but the amount of water consumed was only the amount of the above-mentioned oral administration.

In the above experiment, the body weight of each group of rats before the experiment (before the administration of the suspension) and after the end of the experiment (2 pm on the third day)
At the time of the last administration and before the autopsy), the body weight was measured. The moisture content in the body was measured by the following method.

That is, after completion of the experiment, each rat was sacrificed, and after collecting blood, the visceral organs, fat and digestive tract were excised, and the rat weight (mostly composed of bone, muscle and skin, hereinafter referred to as “weight before drying”) ), Then dried at 70 ° C for one week,
The weight (hereinafter referred to as “weight after drying”) is measured, and the value obtained by subtracting the weight after drying from the above weight before drying is defined as the amount of water accumulated in the body. It was calculated as a rate.

Further, serum sodium, potassium and chlor ion concentrations of the collected blood (serum) were measured by an ion electrode method.

Each measurement value was analyzed by the Dunnett-Two Ta
Statistical processing was performed by the il method, and the test was performed.

The results (mean ± SE) obtained are shown in FIG. 1 (weight change), FIG. 2 (moisture content in the body), and Table 1 (serum sodium, potassium and chlor ion concentrations).

In each figure, (1) represents a control group (n = 8).
(2) is the experimental group (n
= 7), (3) shows the reference group (n = 6),
In the figure, black stars indicate p <0.01 with respect to the control group (1) by the statistical processing.

[0070]

[Table 1]

The following is clear from the above results.

That is, from FIG. 1, the average weight gain of about 30 g was observed in the control group (1).
In the experimental group (2) administered at a dose of 00 mg / dose, the weight gain
g, which is almost the same as Reference Group (3).

According to FIG. 2, the control group (1) had an average water content of 0.709, whereas the control group (1) had 300 m
The average in the g / dose experimental group (2) was 0.691, which means that it significantly (p <0.01) significantly suppressed the accumulation of water in the body as compared with the control group.

Further, according to Table 1, by nephrectomy,
It can be seen that the serum potassium concentration is significantly higher than that of normal rats, while the serum sodium and chlor concentrations are significantly lower (comparison between the reference group (3) and the control group (1)).

The reagent 300 according to the present invention, however,
It is clear that the remarkable increase in serum potassium concentration and decrease in serum sodium concentration observed in the control group (1) can be remarkably suppressed in the mg / dose experimental group (2).

[0076]

[Pharmacological Test Example 2] Eight-week-old Wistar male rats (produced by Charles River Japan) were used in groups of eight rats (grouped according to the weight of each rat). Total nephrectomy was performed. That is, the hair on both sides of the rat was shaved under Nembutal anesthesia, and the abdominal wall was incised dorsoventrally at the rib edge. Pull out the kidney wrapped in adipose tissue, ligate the renal artery, renal vein ureter, resect the kidney,
The incision in the abdominal wall and skin was sutured.

As reagents, sodium polyacrylate (food additive grade, manufactured by Wako, hereinafter referred to as “polymer J”), and polymers B, C, D and E were each suspended in commercially available perilla oil. 250 mg / ml and 1
A solution of 00 mg / ml was prepared. One dose is 1
ml. Administration is at 9 pm on the first day and 9 am on the second day
A total of three times at 9:00 pm and 9:00 pm, each time, 15 ml of water and then 1 ml of the suspension of the above-mentioned reagent were orally administered using a gastric tube. After the final administration, each rat was sacrificed, and after blood collection,
Dissected (experimental group).

In addition, a control group consisting of the above nephrectomized rats to which 1 ml of perilla oil alone and 15 ml of water which did not contain the reagent was administered in the same manner as the suspension of the reagent was prepared.

As a reference group, in place of the above-mentioned nephrectomy, a rat in which the abdominal wall was incised and the incised portion was sutured without nephrectomy to limit water absorption in the same manner as described above (reference I group) ) And a group with free access to water (reference
II group).

During the experimental period, the rats of each group were allowed to eat freely, but the amount of water consumed was only the amount of the above-mentioned oral administration.

In the above experiment, the body weight of each group of rats before the experiment (before the suspension administration) and after the end of the experiment (9 am on the third day)
Before dissection at the time) body weight was measured respectively. The moisture content in the body was measured by the following method.

That is, after completion of the experiment, each rat was sacrificed, and after collecting blood, the internal organs, fat and digestive tract were excised, and the rat weight (mostly composed of bone, muscle and skin, hereinafter referred to as “weight before drying”) ), Then dried at 70 ° C for one week,
The weight (hereinafter referred to as “weight after drying”) is measured, and the value obtained by subtracting the weight after drying from the above weight before drying is defined as the amount of water accumulated in the body. It was calculated as a rate.

Further, serum sodium, potassium, chlor and magnesium ion concentrations of the collected blood (serum) were measured by an ion electrode method.

For plasma, the guanidino compound separated with a strongly acidic cation exchange resin was reacted with ninhydrin under alkaline conditions, and the resulting fluorescence intensity was measured to quantify each guanidino compound [Hiraga, Y. et. a
. l, J. Chematography, 22 6 , 43-51 (1981): Sasaki et al., Japan clinical, 47,1989 extra number, 397-401 (198
9)].

[0086] Each measured value was analyzed by the Dunnett-Two Ta
Statistical processing was performed by the il method, and the test was performed.

The obtained results (mean ± SD) are shown in FIG.
(Amount of change in body weight), FIG. 4 (moisture content in the body), Table 2 (concentration of serum potassium and magnesium ions) and FIG. 5 (concentration of guanidino compound in blood).

In each of the figures and tables, (1) indicates the reference group, (2) indicates the reference group, (3) indicates the control group, (4) indicates the polymer J administration experimental group, and (5) indicates the reference group. The experimental group administered with polymer B, (6) represents the experimental group administered with polymer C, (7) represents the experimental group administered with polymer E, and (8) represents the experimental group administered with polymer D.

In each of the experimental groups in FIGS. 3 and 5, open bars indicate the case where the reagent was administered at 100 mg / ml, and solid bars indicate the case where the agent was administered at 250 mg / ml. Is 250 mg / m
1 is the result of administration.

The asterisk indicates p <0.05 relative to the control group (3) by statistical processing.

[0090]

[Table 2]

The following is clear from the above results.

That is, from FIG. 3, the control group (3) showed an average weight gain of about 25 g, whereas the experimental groups (4), (5) and (6) administered 250 mg of the reagent of the present invention. )
The weight increase was about 10 to 15 g, and a statistically significant (p <0.05) difference was observed as compared with the control group (3).

According to FIG. 4, the control group (3) had an average water content in the body of 0.710, whereas the control group (3) administered 250 mg of the test agent of the present invention (4), (5), In (6) and (8), significant (p <0.0) as compared to the control group (3).
It is clear that the accumulation of water in the body was suppressed in 5).
In addition, in the experimental group (7) to which the polymer E was administered, although no statistically significant difference was observed, it is clear that the accumulation of water in the body tends to be suppressed.

According to Table 2, it was confirmed that the serum potassium ion concentration was higher than that of normal rats (reference group) by nephrectomy (see control group). On the other hand, in the experimental groups (4), (5) and (6) to which the reagent of the present invention was administered at 250 mg / ml, no remarkable increase in serum potassium ion as observed in the control group was observed. , Significantly (p <0.05), that is, an increase in potassium ion concentration can be significantly suppressed.

Further, according to FIG. 5, the reference I group and the reference II
Guanidino compound (guanidinobutyric acid (G
BA), guanidinopropionic acid (GPA) and methylguanidine (MG)) concentrations are all below the detection limit, whereas according to total nephrectomy, the concentrations of these guanidino compounds are significantly increased. And is stored in the blood (see the control group (3)).

In the experimental groups (4), (5), (6), (7) and (8) administered with 250 mg of the reagent according to the present invention, the blood guanidino compound concentration found in the control group (3) It was found that a marked rise (retention in blood) can be suppressed.

[Brief description of the drawings]

FIG. 1 is a graph showing changes in body weight of test animals measured according to Pharmacological Test Example 1.

FIG. 2 is a graph showing the water content in the body of a test animal measured according to Pharmacological Test Example 1.

FIG. 3 is a graph showing changes in body weight of test animals measured according to Pharmacological Test Example 2.

FIG. 4 is a graph showing the water content in the body of a test animal measured according to Pharmacological Test Example 2.

FIG. 5 is a graph showing the blood guanidino compound concentration of a test animal measured according to Pharmacological Test Example 2.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Kenji Hashimoto 83rd east of Kitahama-Ju, Nadu-cho, Naruto-shi, Tokushima Prefecture (72) Inventor Eiji Sakashita 42-45 72) Inventor Hideaki Kori 85-23, Ichimachi, Kitamura, Kitajima-cho, Itano-gun, Tokushima Pref. (23) Inventor Akihiro Kondo 1334 Minato, Wakayama-shi, Wakayama Pref. 1334 Minato, Wakayama, Japan Kao Research Laboratory

Claims (7)

[Claims] 1. A guanidino compound lowering agent comprising an acrylic water-absorbing resin as an active ingredient. 2. A guanidino compound lowering agent and a moisture adsorbent, comprising an acrylic water-absorbing resin as an active ingredient. 3. A guanidino compound lowering agent, water and potassium ion adsorbent, comprising an acrylic water-absorbing resin (excluding potassium salt) as an active ingredient. 4. The reducing or adsorbing agent according to claim 1, wherein the active ingredient is an acrylic acid or alkali metal methacrylate polymer. 5. The reducing or adsorbing agent according to claim 1, wherein the active ingredient is an acrylic acid or alkaline earth metal methacrylate polymer. 6. The reducing or adsorbing agent according to claim 1, wherein the active ingredient is a self-crosslinkable metal acrylate polymer. 7. The reducing or adsorbent according to claim 6, wherein at least a part of the metal salt is a calcium salt.