MXPA98005326A - Compositions for the treatment of renal failure, comprising l-carnosine - Google Patents

Abstract

Methods and compositions for treating renal failure patients are provided. Pursuant to the present invention, a renal failure patient is provided with an intravenous or dialysis solution that includes a therapeutically effective amount of L-carnosine. In part, the L-carnosine will prevent the renal failure patient from developing L-carnosine deficiency.

Description

METHOD AND COMPOUNDS FOR THE TREATMENT OF KIDNEY FAILURES BACKGROUND OF THE INVENTION The present invention relates in general to the treatment of diseases. The invention relates more specifically to methods and compounds for the treatment of kidney diseases. Of course, a kidney failure can occur in a patient due to a variety of diseases and injuries. An acute renal failure can result from: a direct renal tubular lesion; renal ischemia; and intra-tubular obstruction. Renal failure causes decreased glomerular filtration and reduced secretion of waste metabolic products, water and electrolytes. The resulting fluid overload, electrolyte imbalance and uraemic syndrome can create organ failure, leading to death. It is known to use dialysis to support a patient in whom renal function is reduced to the extent that the kidneys do not function sufficiently. Dialysis provides a method to supplement and replace renal function in certain patients. Two main methods of dialysis are used: dialysis hemodialysis and peritoneal dialysis. In hemodialysis, the patient's blood is passed through an artificial kidney dialysis machine. A membrane in the machine works like an artificial kidney to cleanse the blood. Because it is an extracorporeal treatment that requires special machines, hemodialysis has certain inherent disadvantages.

To overcome the disadvantages associated with hemodialysis, peritoneal dialysis was developed. Peritoneal dialysis uses the patient's own peritoneum as a semipermeable membrane. The peritoneum is the lining membranes of the abdominal cavity, which due to the large number of blood vessels and capillaries, is able to act as a natural semi-permeable membrane. In peritoneal dialysis, a dialysis solution is introduced into the peritoneal cavity using a catheter. After a sufficient period of time, an exchange of solutes between the dialysate and the blood is achieved. The removal of fluids is achieved by providing an adequate osmotic degree of the blood to the dialysate to allow the effusion of water from the blood. This allows the acid base of the proper electrolyte and the fluid balance to be returned to the blood and the dialysis solution is simply drained from the body cavity through the catheter. Although the use of dialysis and other treatment methods for patients with kidney diseases provide treatments that allow patients to survive, the compounds and methods used today can not provide all the therapeutic agents necessary to combat kidney failure.

BRIEF DESCRIPTION OF THE FIGURES Figures 1A and 1B graphically illustrate the levels of L-carnosine in the dialysis solution with the passage of time for a dialysis solution containing L-carnosine at 8 mmol / L.

Figures 2A and 2B graphically depict plasma carnosine levels over time in two rats infused with the dialysis solution of Figures 1A and 1B. Figures 3A and 3B graphically illustrate the levels of L-carnosine in the dialysis solution with the passage of time for a dialysis solution containing L-camosine at 16 mmol / L. Figures 4A and 4B graphically illustrate plasma carnosine levels over time in two rats infused with the dialysis solution of Figures 3A and 3B.

DETAILED DESCRIPTION OF THE PREFERRED INCORPORATIONS The present invention provides improved methods and compounds for the treatment of renal failure. According to the present invention, patients with renal failure are provided, by means of a dialysis solution or intravenously, with a source of L-carnosine. It has been found that L-carnosine can prevent and / or treat L-carnosine deficiency. In this aspect it has surprisingly been found that L-carnosine can be effectively transferred from a peritoneal dialysis solution into the peritoneum of the patient, until the plasma so that later it is used by the tissue. The dipeptide L-carnosine (β-alanila-L-histidine) is one of the major non-protein-nitrogenous constituents of the skeletal muscles. It seems that in the skeletal muscles, L-carnosine functions as an intracellular stop. Additionally, L-carnosine is an ATP activator and a body reserve of histidine. It has recently been shown that L-carnosine acts as a natural antioxidant. In this aspect, the L-camosina cleanses free radicals, decreases the lipid oxidation of the membrane and gradually extracts the effects of membrane protection and adaptation of immunity. It has been found that in patients with chronic renal failure, the intracellular muscle L-carnosine concentration is significantly reduced. For example, in patients with hemodialysis, the concentration of intracellular muscle L-carnosine is reduced by approximately 46% (see Experiment No. 1 below). The inventor hypothesizes that the reduction of L-carnosine and the reduced cap capacity and other metabolic effects caused by such reduction can cause muscle fatigue, decreased immunological response, increased lipid peroxidation and the risk of contracting atherosclerosis. It has been surprisingly found that L-carnosine levels in plasma can be increased through the transfusion of L-camosin from a peritoneal dialysis solution containing plasma to both the plasma and the plasma to the muscle tissues. Accordingly, and consequently to the present invention, patients with renal failure are provided with intravenous, or peritoneal dialysis solutions a therapeutically effective amount of L-carnosine.

In an embodiment of the present invention, a patient receiving L-carnosine is infused with a patient receiving peritoneal dialysis. As has been noted above, it has been found that when L-carnosine is added to a dialysis fluid, it is absorbed from the peritoneal cavity. As noted below, in hemodialysis patients and other patients with renal failure without dialysis treatments, L-camosin can be administered intravenously with or without other nutrients. In accordance with the present invention, in a peritoneal dialysis solution there will preferably be present approximately 1. 0 to 40.0 mmol / L of L-carnosine. In accordance with the present invention, any of a variety of peritoneal dialysis solutions may be used, as long as they contain L-carnosine. For example, the peritoneal dialysis solution may contain any known osmotic agent (dextrose, glycerol, polyglucose or amino acids). In one embodiment, the peritoneal dialysis solution contains: approximately 100 to 150 mEq / L sodium; approximately 70 to 140 mEq / L of chlorid; approximately 0.0 to 45.0 mEq / L bicarbonate; approximately 0.0 to 45.0 mEq / L of calcium; approximately 0.0 to 4.0 mEq / L of magnesium; approximately 1.0 to 40.0 mmol / L of L-camosine; and approximately 0.0 to 300 mmol / L dextrose. In another embodiment, the peritoneal dialysis solution contains: approximately 100 to 150 mEq / L sodium; approximately 70 to 140 mEq / L of chlorid; approximately 0.0 to 45.0 mEq / L lactate; approximately 0.0 to 45.0 mEq / L bicarbonate; approximately 0.0 to 4.0 mEq / L of calcium; approximately 0.0 to 4.0 mEq / L of magnesium; approximately 1.0 to 40.0 mmol / L of L-camosine; and approximately 0.0 to 300 mmol / L of some other osmotic agent.

As can be seen from the foregoing, it is also possible to practice the present invention by administering to a patient with renal failure an intravenous solution containing L-carnosine. In such an intravenous solution, the solution will preferably include about 1.0 to 80 mmol / L of L-carnosine. The solution would be administered approximately 1 to 3 times per day. Examples of intravenous solutions containing L-camosine include: about 1 to 80 mmol / L of L-carnosine; approximately from 0 to 200 mEq / L of sodium; approximately from 0 to 100 mEq / L of potassium; about 0 to 300 mEq / L of chlorid; approximately 0 to 10 mEq / L of calcium; approximately 0 to 10 mEq / L of magnesium; approximately 0 to 20 mEq / L of phosphate; approximately 0 to 100 mEq / L bicarbonate; approximately from 0 to 100 mEq / L of lactate; approximately from 0 to 100 mEq / L of lactate; approximately from 0 to 150 g / L of amino acids; approximately from 0 to 100 g / L of dipeptides; and approximately from 0 to 300 g / L of lipids.

For example means, and not limitation, experiments will be given below with respect to the present invention; Experiment 1 Levels (sampled by percutaneous needle biopsy of quadriceps femoris, HPLC analysis) of carnosine were taken (CARN) and muscle histidine (HIS) (m-) and plasma HIS (p-) in 9 hemodialysis patients, before and after the correction of acidosis during a period of 6 months and in 15 healthy controls. The patients were in good health and had no symptoms of malnutrition. The results are presented in averages ± S.D. St. HC03 P-HIS m-HIS m-CARN (mmol / L) (μmmol / L) (μmmol / L) (μmmol / L i.c. H20) Before 20.3 ± 1.3 86 ± 22 467 ± 171 to 4697 ± 1681 a After 25.9 ± 1.8 65 ± 7 a, b 522 ± 169 6122 ± 2408 a, b Control 81 ± 8 628 ± 138 8621 ± 1707 a = significant difference of controls, b = significant difference before-after Sampling showed that concentrations of muscle carnosine, which in the acedotic pill, were reduced by 46% compared to the control. Although these concentrations increased significantly after the acedotic correction, they did not reach normal levels. The plasma HIS fell after the acedotic correction and the histidine grade i.c./e.c. it increased from 5.4 ± 1.8 to 7.9 ± 1.8.

The observations suggest that acidosis has an impact on the metabolism of histidine and carnosine in uremia. The inventor speculates that muscle carnosine decreases with the ability to top i.c. reduced can be involved in muscle dysfunctions of uremia patients and that acidosis may have a role in this context. Experiment 2 The object of the study was to test in pilot experiments the taking of L-carnosine from the plasma dialysis fluid in rats. Experimental animals: male Sprague-Dawley rats, weighing approximately 300 g. Peritoneal dialysis solutions used: I.- Dianeal ® 1.36% (accessible from Baxter healthcare of Deerfield, IL.) + 8 mmol / L L-camosine. II.- Dianeal ® 1.36% (accessible from Baxter healthcare of Deerfield, IL.) + 16 mmol / L of L-carnosine. Volume of intraperitoneal filling: 25ml. Dialysate samples: (0.2 ml.); 0, 60, 120, 240 min. Analysis: L-camosin and L-histidine in dialysate and plasma. Results: Figures 1A, 1B, 2A and 2B graphically illustrate the results in rats A and B, which receive 25 ml. of peritoneal dialysis solution containing 8 mmol / L of L-carnosine. There was a rapid decrease in the concentration of L-carnosine in the dialysate, together with a constant increase in the concentration of L-histidine to a level of 213 μmol / L. At the end of this state (240 min.) The concentration of L-carnosine in the dialysate was approximately 10% of the original concentration.

Plasma L-carnosine levels increased from 0 to 432-677 μmol / L after 60 min., Then gradually fell to 113 and 224 μmol / L after 240 min. The plasmid L-histidine increased from 72 and 80 μmol / L to 182 and 166 μmol / L after 120 min. and 146 and 160 μmol / L respectively after 240 min. Figures 3A, 3B, 4A and 4B graphically illustrate the results in rats C and D, which receive 25 ml. of peritoneal dialysis solution containing 16 mmol / L of L-camosin. The model was similar to that of rats A and B, with a rapid initial decrease in L-camosin concentration. At the end of this state, the concentration was less than 10% of the original concentration. The dialysate L-histidine gradually increased to reach 297 μmol / L. The concentration of plasmatic L-carnosine was approximately twice that of the concentration of rats A and B, and they were also higher (233 and 245 μmol / L) at the end of the state. The plasmid L-histidine increased and remained at around 230-270 μmol / L. It was determined that the L-carnosine in the peritoneal dialysis fluid is absorbed by up to 90% or more. Of approximately 360 μmol / L absorbed from a solution containing L-carnosine 16 mmol / L, only a small part (<5%) accumulates in extracellular fluid (which is assumed to be 20% of body weight). The increase of L-histidine in dialysate and plasma indicates that L-camosin is metabolized to its constituent amino acids. However, since the increase in histidine concentration is small, the results suggest that most of the absorbed L-carnosine is used without modification by the skeletal muscles and other body cells. Therefore, it should be feasible to correct the depletion of intracellular L-carnosine by adding L-camosine to the dialysis fluid. It should be understood that changes and modifications varied to the preferred embodiments herein, which are described herein, will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and object of the present invention, and without diminishing its servant advantages. Therefore, it is intended that such changes and modifications be covered by the appended claims.

Claims (16)

CLAIMS •

1. A method for the treatment of patients with chronic renal failure, comprising the step of providing a therapeutically effective amount of a composition containing L-camosin through a non-oral method.

2. The method described in claim 1 wherein the composition is administered to the patient intravenously.

3. The method of claim 1 wherein the composition is administered to the patient through the peritoneal cavity.

4. The method of claim 1 wherein the composition contains a source of amino acids.

5. The method of claim 1 wherein the composition includes carbohydrates.

6. The method of claim 1 wherein the composition includes fats.

7. A method for treating patients receiving dialysis comprising the steps of administering to the patient a therapeutically effective amount of a composition containing L-carnosine.

8. The method of claim 7 wherein the composition is administered to the patient parenterially.

The method of claim 7 wherein the composition is administered to the patient through the peritoneal cavity.

10. The method of claim 7 wherein the patient is receiving hemodialysis.

The method of claim 7 wherein the patient is receiving peritoneal dialysis.

The method of claim 7 wherein the patient is receiving a peritoneal dialysis solution containing an osmotic agent chosen from the group consisting of dextrose, amino acids, polypeptides, polyglucose and glycerol.

13. A peritoneal dialysis solution containing a therapeutically effective amount of L-carnosine.

The peritoneal dialysis solution of claim 13 wherein the solution contains approximately 1.0 to 40 mmol / L of L-carnosine.

15. The peritoneal dialysis solution of claim 13 including an osmotic agent chosen from the group consisting of dextrose, amino acids, polypeptides, polyglucose and glycerol.

16. The peritoneal dialysis solution of claim 13 including: about 100 to 150 mEq / L sodium; approximately 70 to 140 mEq / L of chlorid; approximately 0.0 to 45.0 mEq / L lactate; approximately 0.0 to 45.0 mEq / L bicarbonate; approximately 0.0 to 4.0 mEq / L of calcium; and approximately 0.0 to 4.0 mEq / L of magnesium. The peritoneal dialysis solution of claim 15 wherein the osmotic agent comprises up to 300 mmol / L of the solution. 18 A peritoneal dialysis solution comprising: about 1.0 to 40 mmol / L of L-camosine; approximately 0.0 to 300 mmol / L dextrose; approximately 100 to 150 mmol / L of sodium; approximately 70 to 140 mEq / L of chlorid; approximately 0.0 to 45 mEq / L lactate; approximately 0.0 to 45 mEq / L of B-carbonate; approximately 0.0 to 4.0 mEq / L of calcium; and approximately 0.0 to 4.0 mEq / L of magnesium. 19 An intravenous solution for treating patients with chronic renal failure comprising: L-carnosine; approximately from 0 to 200 mEq / L of sodium; approximately from 0 to 100 mEq / L of potassium; about 0 to 300 mEq / L of chlorid; approximately 0 to 10 mEq / L of calcium; approximately 0 to 10 mEq / L of magnesium; about 0 to 20 mmol / L of phosphate; approximately 0 to 100 mEq / L bicarbonate; approximately from 0 to 100 mEq / L of lactate; approximately from 0 to 100 mEq / L of acetate; approximately from 0 to 150 g / L of amino acids; approximately from 0 to 100 g / L of dipeptides; and approximately from 0 to 300 g / L of lipids. The intravenous solution of claim 19 wherein the solution contains approximately 1 to 80 mmol / L of L-carnosine.