HK1082441B - Peritoneal dialysis method - Google Patents

Description

Peritoneal dialysis method

Technical Field

The present invention relates to a prophylactic/therapeutic agent for peritoneal membrane damage during peritoneal dialysis, a safe peritoneal dialysis solution that does not cause peritoneal membrane damage, and a peritoneal dialysis method using the same.

Background

When renal failure occurs, waste products in the body cannot be sufficiently excreted, and uremic substances such as urinary nitrogen (BUN), creatine lactam (Cr), phosphorus (P), potassium (K), and the like increase in blood concentration, resulting in various symptoms. The symptoms include fatigue, short breath, decreased urine volume, edema, decreased appetite, hypertension, hyperkalemia, anemia, etc. Death if left untreated, therefore, requires hemodialysis, peritoneal dialysis or kidney transplantation for the treatment of uremia.

Among them, peritoneal dialysis has advantages over hemodialysis in that it can be performed without machines and hands, without going to a hospital, and peritoneal dialysis is a slow process, so that it can keep the body condition of a patient stable, does not cause hypotension and fatigue after dialysis, and has no time limitation such as hemodialysis, and thus has been widely used in recent years.

However, since peritoneal dialysis is performed using the peritoneum as a semipermeable membrane by implanting a catheter into the abdominal cavity, introducing a dialysate containing high-concentration glucose into the peritoneal cavity, and draining the dialysate after storing the dialysate for 5 to 6 hours, there is a problem that the peritoneal membrane is hardened by the high-concentration glucose and the peritonitis or the like causes damage to the function of the peritoneum if the peritoneal dialysis is performed for a long period of time.

Disclosure of The Invention

Accordingly, the present invention provides a peritoneal dialysis solution which can be continuously used for a long period of time without causing damage to the peritoneal membrane, and a peritoneal dialysis method using the same.

The present inventors have focused on peritoneal mesothelial cells covering the peritoneal epidermis, found that Adenosine Triphosphate (ATP) or a salt thereof has an effect of preventing damage to peritoneal mesothelial cells, since it is a component capable of preventing damage to peritoneal mesothelial cells generated in the presence of a high concentration of sugar, and found that ATP or a salt thereof is useful as a prophylactic and therapeutic agent for peritoneal damage, and further found that a dialysate capable of performing peritoneal dialysis for a long period of time can be obtained if ATP or a salt thereof is incorporated, and completed the present invention.

That is, the present invention provides a peritoneal dialysis solution containing ATP or a salt thereof.

Further, the present invention provides a prophylactic and therapeutic agent for peritoneal injury comprising ATP or a salt thereof as an active ingredient.

The present invention also provides a therapeutic agent for cell damage caused by a sugar containing ATP or a salt thereof as an active ingredient.

The invention also provides the application of ATP or salt thereof in the preparation of peritoneal dialysis solution.

The invention also provides the use of ATP or a salt thereof in the preparation of a prophylactic or therapeutic agent for peritoneal injury.

The invention also provides the use of ATP or a salt thereof in the preparation of a therapeutic agent for sugar-induced cell damage.

The present invention also provides a peritoneal dialysis method characterized by using a dialysate containing an effective amount of ATP or a salt thereof.

The invention also provides a method of treating peritoneal lesions characterized by administering an effective amount of ATP or a salt thereof.

The present invention also provides a method for treating sugar-induced cell damage characterized by administering an effective amount of ATP or a salt thereof.

The present invention provides a safe peritoneal dialysis solution that does not cause peritoneal membrane damage even after dialysis for a long period of time.

Brief description of the drawings

FIG. 1 shows the effect of ATP on the decrease in cell viability (absorbance) of HPMC caused by glucose (5.8mM, 75mM, 140 mM).

FIG. 2 shows the effect of adenosine on the decrease in cell viability (absorbance) of HPMC with glucose (5.8mM, 75mM, 140 mM).

FIG. 3 shows the results of ATP receptor antagonist (Suramin, Suramin, 10 μ M) affecting the effect of ATP on the decrease in cell viability (absorbance) of HPMC by glucose (5.8mM, 75mM, 140 mM).

FIG. 4 shows the effect of ATP receptor antagonist (Reactive Blue, 2, 30. mu.M) on the decrease in cell viability (absorbance) of HPMC caused by glucose (5.8mM, 75mM, 140mM) by ATP.

FIG. 5 shows the results of ATP receptor antagonist (PPADS, 10. mu.M) affecting the effect of ATP on the decrease in cell viability (absorbance) of HPMC by glucose (5.8mM, 75mM, 140 mM).

Best Mode for Carrying Out The Invention

Adenosine Triphosphate (ATP) used in the present invention is known as an energy source for cell functions, but its effect of preventing damage to cells, particularly peritoneal mesothelial cells, due to high concentrations of sugars, particularly glucose, is completely unknown. Further, as shown in the following examples, if ATP is allowed to act after pretreatment of peritoneal mesothelial cells with an ATP receptor antagonist, no effect of improving damage to peritoneal mesothelial cells is observed. From this, it is known that the cell injury therapeutic action of ATP is not to introduce ATP into the cell to act as an energy source, but to act via an ATP receptor.

The salt of ATP is preferably an alkali metal salt such as a sodium salt, an alkaline earth metal salt such as a magnesium salt or a calcium salt, or the like.

The peritoneal dialysis solution of the present invention contains an effective amount of ATP or a salt thereof. The concentration of ATP or its salt in the peritoneal dialysis solution is 10 to 5000. mu.M, preferably 50 to 3000. mu.M, more preferably 50 to 2000. mu.M.

The peritoneal dialysis solution of the present invention preferably contains glucose and electrolytes in addition to ATP or its salts. The concentration of glucose is 1000-4000mg/dl, particularly preferably 1200 to 3600 mg/dl. In addition, Na can be used as the electrolyte⁺、Ca²⁺、Mg²⁺And Cl^-。Na⁺Preferably 100 to 200mEq/l, Ca²⁺Preferably 4 to 5mEq/l, Mg²⁺Preferably 1 to 2mEq/l, Cl^-Preferably 80 to 120 mEq/l. In addition, it is preferable to incorporate 30 to 50mEq/l of an organic acid such as lactic acid. The osmotic pressure of the peritoneal dialysis solution is preferably adjusted to 300-700 m0 sm/l. The balance being water.

The peritoneal dialysis solution containing ATP or its salt of the present invention can prevent damage to the peritoneum and cell damage, particularly damage to peritoneal mesothelial cells, caused by high concentrations of sugar. Here, the peritoneal injury may be peritonitis, sclerosing cystic peritonitis, intractable delayed peritonitis, diffuse peritonitis, or the like. However, the agent for preventing and treating peritoneal damage and the agent for treating cell damage of the present invention can be used in a form such as oral administration, intravenous administration, intramuscular administration, and topical administration, regardless of the form of the peritoneal dialysis solution. These dosage forms can be prepared by incorporating pharmaceutically acceptable carriers and by conventional formulation methods well known to those skilled in the art.

When preparing a solid preparation for oral administration, an excipient may be added to ATP or a salt thereof, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a corrigent and a deodorant may be added, followed by preparing tablets, coated tablets, granules, powders, capsules and the like by a conventional method. Examples of the additives include lactose, white sugar, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid, etc., examples of the excipient include water, ethanol, propanol, monosaccharide, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, polyvinylpyrrolidone, etc., examples of the disintegrant include dried starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride stearate, lactose, etc., examples of the lubricant include purified talc, stearate, borax, polyethylene glycol, etc., and examples of the taste-improving agent include white sugar, orange peel, citric acid, tartaric acid, etc.

When preparing a liquid preparation for oral administration, a taste-masking agent, a buffer, a stabilizer and a deodorant may be added to ATP or its salt, and an oral solution, syrup, elixir and the like may be prepared by a conventional method. In this case, examples of the taste-modifying agent include vanillin, the buffering agent includes sodium citrate, and the stabilizing agent includes tragacanth, gum arabic, and gelatin.

When preparing an injection, a pH adjuster, a buffer, a stabilizer, an isotonic agent, a anesthetic, and the like may be added to ATP or its salt, and subcutaneous, intramuscular, and intravenous injections may be prepared by a conventional method. Examples of the pH adjuster and the buffer in this case include sodium citrate, sodium acetate, and sodium phosphate. The stabilizer may, for example, be sodium metabisulfite, EDTA, thioglycolic acid or thiolactic acid. Examples of the anesthetic agent include procaine hydrochloride and lidocaine hydrochloride. Examples of the isotonic agent include sodium chloride and glucose.

The amount of the above-mentioned pharmaceutical product (excluding peritoneal dialysis solution) of the present invention varies depending on age, body weight, symptoms, administration method, administration frequency, etc., and it is generally preferable that 1 to 1000mg of ATP is orally or intravenously administered 1 time or several times per 1 day or several times per adult.

When the dialysis is performed using a peritoneal dialysis solution, the dialysis can be performed according to a general peritoneal dialysis method. That is, dialysis is performed by a method of injecting ATP-containing dialysate (usually 1.5 to 2.0L) into the peritoneum of a renal disease patient having a catheter implanted in the abdominal cavity through the catheter, or a method of injecting ATP-containing physiological glucose-concentrated solution and then injecting conventional dialysate (for example, the above-mentioned high-concentration glucose solution), and the resulting solution is stored for about 5 to 6 hours and then drained. Usually, the operation is performed 3 to 5 times in 1 day. Here, the physiological concentration of glucose is 0.08 to 0.16% (w/v).

Examples

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1

Peritoneal Mesothelial Cells (HPMC) were pre-cultured in culture medium (M199) containing ATP (0, 10, 100 and 1000 μ M) for 3 hours. After washing with HPMC medium (physiological saline buffer), it was cultured in medium (M199) containing 3 concentrations (5.8mM, 75mM, 140mM) of glucose for 8 hours, and the cell viability of HPMC was determined by cell counting method (WST-1).

As a result, as shown in FIG. 1, when HPMC was precultured in the ATP-free medium, the cell survival rate decreased with the increase in glucose concentration, whereas when HPMC was precultured in the ATP-containing medium, the decrease in cell survival rate due to the high concentration of glucose was substantially improved.

Example 2

Adenosine, which is a metabolite of ATP, was used instead of ATP, and the effect of adenosine on the reduction of cell survival of HPMC in high glucose concentrations was investigated.

As a result, as shown in fig. 2, adenosine was not confirmed to have an improving effect like ATP on the decrease in cell survival rate of HPMC.

Example 3

HPMC was pre-cultured for 30 minutes using (1) suramin (P2X, P2Y receptor antagonist, 10 μ M), (2) reactive blue 2(P2Y receptor antagonist, 30 μ M) or (3) PPADS (P2X receptor antagonist, 10 μ M) as a selective ATP receptor antagonist before pre-culturing in ATP-containing culture solution of example 1, and then the experiment was performed in the same manner as in example 1.

As a result, as shown in fig. 3, 4 and 5, when an ATP receptor antagonist was allowed to act, no improvement effect of ATP on the decrease in cell survival rate of HPMC was observed.

From the results of example 1, it is understood that ATP has an effect of substantially preventing peritoneal mesothelial cell damage caused by high-concentration glucose. From the results of examples 2 and 3, it is understood that this action of ATP is not an effect produced by introducing ATP into cells to act as an energy source, but acts directly via the P2 receptor.

Example 4

Formula of peritoneal dialysis solution

(1) ATP-containing dialysate

Sodium chloride, sodium lactate, calcium chloride, magnesium chloride, etc. were added to 3 types of glucose-containing dialysate (1.36, 2.27, 3.86%) at the same concentrations as in the conventional one, and ATP was added at a concentration of 50 to 2000 μ M.

(2) ATP-containing physiological glucose concentration solution

Sodium chloride, sodium lactate, calcium chloride, magnesium chloride, etc. are added to a physiological glucose solution (0.1%) so that the concentrations thereof are the same as those of the conventional solutions, and ATP is added so that the concentration thereof becomes 50 to 2000. mu.M.

Claims (8)

1. A peritoneal dialysis solution characterized by containing 50 to 3000 [ mu ] M adenosine triphosphate or a salt thereof.

2. The peritoneal dialysis solution of claim 1, further comprising glucose and an electrolyte, wherein the glucose concentration is 1000-4000 mg/dl, and the electrolyte is Na⁺、Ca²⁺、Mg²⁺Or Cl^-Said Na⁺100 to 200mEq/l, Ca²⁺4 to 5mEq/l, Mg²⁺1 to 2mEq/l, Cl^-Is 80 to 120 mEq/l.

3. A prophylactic/therapeutic agent for peritoneal injury, characterized by comprising 50 to 3000 μ M of adenosine triphosphate or a salt thereof as an active ingredient.

4. A therapeutic agent for peritoneal mesothelial cell injury caused by glucose, characterized by comprising 50 to 3000 μ M adenosine triphosphate or a salt thereof as an active ingredient.

5. Application of adenosine triphosphate or its salt in preparation of peritoneal dialysis solution, wherein the content of the adenosine triphosphate or its salt is 50-3000 μ M.

6. The use of claim 5, wherein the dialysate further comprises glucose and an electrolyte, wherein the glucose concentration is 1000-4000 mg/dl and the electrolyte is Na⁺、Ca²⁺、Mg²⁺And Cl^-Said Na⁺100 to 200mEq/l, Ca²⁺4 to 5mEq/l, Mg²⁺1 to 2mEq/l, Cl^-Is 80 to 120 mEq/l.

7.50-3000 mu M adenosine triphosphate or its salt is used in the preparation of a peritoneal injury prevention and treatment agent.

8.50-3000 mu M adenosine triphosphate or its salt is used in preparation of therapeutic agent for peritoneal mesothelial cell injury caused by glucose.