RU2201755C2 - Method for treating uremic syndrome - Google Patents

Abstract

FIELD: medicine, nephrourology. SUBSTANCE: method deals with treating uremia. For this purpose one should introduce gel form of finely divided chitosan either per oral or through a probe per 4 ml/kg body weight in every 3 h. The method leads to efficient detoxication at uremia of different genesis, in incurable patients in case of prolongation of predialysis terms when active methods of therapy are contraindicated, as well. EFFECT: higher efficiency of therapy. 3 dwg

Description

 The invention relates to medicine, namely to neurophysiology.

 The clinical picture and dynamics of the course of acute and chronic renal failure, accompanied by uremia syndrome, are known. In uremia syndrome, the main indicators of intoxication are the concentration of urea (which characterizes the retention of nitrogenous substances in the extracellular fluid) and creatinine (which is highly stable in the blood). [Rodoman V.E., Maksimov V.I. Extrarenal cleansing of the body of nitrogenous toxins in urological diseases accompanied by chronic renal failure, Urology. 1999, 6, p. 51-54]. The effectiveness of treatment of this group of patients largely depends on detoxification methods [Enterosorption / Ed. N.A. Belyakova L. 1991, p. 210-211]. The use of active methods of treating renal failure, primarily hemodialysis, does not solve all medical problems. Therefore, in nephrological and resuscitation practice, the tasks of assisting patients with uremia at the pre-dialysis stage of treatment with the aim of lengthening the pre-dialysis period and helping incurable patients who are contraindicated in active therapy are especially emphasized. The use of the gastrointestinal tract as a vicar (replacement) organ in the removal of uremic toxins and metabolic correction of renal failure has long been known. It has been experimentally and clinically proven that with intestinal dialysis, urea, creatinine and uric acid can be removed from the body [Sparks R.E. - Kidney int., 1975, v. 7, p. S-373-s-376]. Uremic toxins and hormones are spontaneously excreted through the gastrointestinal tract [Zeig S., Friadman E.A. - In: Sordents and Their Clinical Application. Ed. C. Giordano. New York, 1980, p. 275-294]. Conducting intestinal dialysis is achieved by ingestion of sorbents or bacterial enzymes that enhance the processing of nitrogen compounds. To date, solid carbon-containing matrices of enterosorbents and hypertonic solutions for the removal of uremic toxins, the action of which is based on ion exchange, are used in nephrological practice. The disadvantage of solid tablet forms of enterosorbents is low fluidity in the lumen of the intestine, sharply reducing the contact of enterosorbent with toxins, irritating effect on the intestinal mucosa and low ability to bind and remove uremic toxins. The disadvantage of ionic hypertonic solutions is their inability to bind uremic toxins, the ability to cause diarrhea and hypersecretion of toxins into the intestinal lumen, creating an ionic imbalance in the body.

 Known elimination of nitrogenous substances through the gastrointestinal tract using per os solid oxidized starch, which has an affinity for chitosan. The disadvantage of the sorbent is a significant increase in intestinal motility, the appearance of diarrhea. The selective adsorption of urea and ammonia is characteristic, the concentration of creatinine and urea in the blood serum does not decrease. [1) Giordano C., Esposito R., Pluvio M. - Proc. Europ. Dialys Transplant Ass. , 1973, v. 10, p. 136-140. 2) Inoshito, K. - Nephron, 1981, v. 28, p. 305-307. 3) Man N. K., Druenke T., Paris J. et al. - Proc. Europ. Dialis Transplant Ass., 1973, v. 10, p. 143-151].

 To date, the most effective in the removal of uremic toxins has a granular brand of SKN coal in a dose of 0.8-1.5 g / kg (60-120 g / day) per day. For several months, there has been a decrease in the symptoms of uremic gastroenteropathy and a significant decrease in creatinine from 1.02 ± 0.09 mmol / L to 0.81 ± 0.07 mmol / L, which can significantly delay dialysis therapy [Shostak G.D. Ryabov S.I., Lukichev B.G. et al. Oral sorbents in the treatment of chronic renal failure. Therapeutic Archive, Volume LVI, 7, 1984, p. 58-63]. The disadvantage of this sorbent is that when prescribing small doses of the sorbent (30-60 g / day), the latter causes nausea and vomiting, and at high doses (120-150 g / day) leads to constipation and the development of partial intestinal obstruction. It is well known that SKN sorbents practically do not absorb serum urea. [Nikolaev V.G., Strelko V.V. Activated carbon hemosorption. Kiev, 1979].

An experimental study is known in which the simulation of the disease was reproduced by the simultaneous removal of both kidneys, and natural zeolite-containing tufa (clinoptilolite) was used as an enterosorbent [RF patent 94016980, IPC 6 A 61 K 33/00, 05/10/96]. Enterosorbent is administered per os and through a gastric tube in an amount of 500-600 mg / ml. Oral therapy with natural zeolite-containing tuff (clinoptilolite) leads to an increase in the survival of nephrectomized animals by 1.9 times. The disadvantage of using natural zeolite-containing tuff is its low ability to lower the level of creatinine and urea in the blood. Clinical experience shows that enterosorbents should be used even if there is no decrease or stabilization of nitrogen homeostasis in the presence of only positive clinical dynamics [Enterosorption / Ed. N.A. Belyakova. L. 1991, p. 223]
The closest technical solution to reducing uremic toxins is the use of tablets containing chitosan. [Jing SB, Li L., Ji D., Takiguchi Y., Yamaguchi T. Effect of chitosan on renal function in patients with chronic renal failure. J. Pharm. Pharmacol 1997. - Vol. 49. 7. - P. 721-723]. The study was conducted on people suffering from chronic renal failure (CRF) and who are under constant controlled hemodialysis. Patients were divided into 2 groups. In group 1 (control) there were people on the conservative method of treating chronic renal failure. In group 2 (treatment), patients took per os tablets containing chitosan, 450 mg / day. One tablet (140 mg) contains 45 mg of chitosan, 75 mg of dextran, yeast extract and protein. Examination of patients of the two groups was carried out 1 time every 4 weeks. In group 2, after 12 weeks, there was an improvement in appetite, sleep, and physical strength compared with group 1. In the treatment group, after 4 weeks, compared with the control group, there was an increase in hemoglobin from 58.2 ± 12.1 to 69.3 ± 11.3 g / l, a decrease in urea from 79 ± 19 to 54 ± 19 mm, and creatinine from 1.049 ± 0.565 to 0.867 ± 0.261 mm. The disadvantage of this study is the use of a tablet preparation with low fluidity in the lumen of the intestine, a small contact surface with toxins and irritating effect on the intestinal mucosa.

 Search and development of new enterosorbents is one of the fundamental tasks of efferent medicine [Enterosorption / Ed. N.A. Belyakova. L. 1991, p. 336].

 Of greatest interest at present are water-soluble and water-insoluble chitosan preparations that give viscous solutions and gels [Rogozhin S. V., Gamzazade A. I., Sklyar A. M., Leonova E. Yu., Nasibov S. M. Polymer homologues of chitosan and sulfo derivatives based on them, Mater. 1 all-union. scientific and technical conf. : Production and use of chitin and chitosan from krill shell and other crustaceans. Vladivostok, 1983.- S. 58-68; Rogovina S.Z., Akopova T.A., Zelenetskiy S.N. Studying the extrusion grinding of chitosan \ Tez. IV All-Russian. conf. Production and use of chitin and chitosan. - M., 1995. - S. 27-28]. A new direction in the study of chitosan is the production of gels [Moore G.K., Roberts G.A.T. Int. J. Biol. Macromol., 1980. - Vol. 2. - 73. - P. 78], which are formed upon acetylation of chitosan [Hirano S., Ohe Y. Agr. Biol. Chem., 1975 .-- Vol. 39. - P. 1337]. Chitosan as a fiber enhances the passage of food masses through the gastrointestinal tract.

 Morphological and morphometric studies of tissues and internal organs indicate the complete non-toxicity of the chitosan diet for a long time of its use [Petrov VA, Tarasenko GA Toxicological and hygienic assessment of chitosan from the carapace of the king crab in a chronic experiment. Mater. V conf. New perspectives in the study of chitin and chitosan. - M. - Schelkovo, 1999. - S. 179-181].

 The gel treatment of finely divided chitosan uremia syndrome was not found in patent and literature sources.

 Object of the invention: the introduction into clinical practice of a new oral sorbent effective for conservative treatment of uremia of various origins and to assist incurable patients with the aim of lengthening the pre-dialysis period.

 The problem is solved due to the fact that the gel form of finely dispersed chitosan is administered orally or through a probe of 4 ml per 1 kg of body weight every 3 hours.

 Information confirming the possibility of carrying out the invention.

 To reproduce the clinical and laboratory signs of uremia, standard experimental methods were used. Experimental modeling of uremia was performed on white male rats of the Wistar population weighing from 180 to 200 g. The operation was performed under aseptic conditions and consisted of simultaneous bilateral isolated removal of the kidneys through a laparotomy incision under neuroleptanalgesia (intraperitoneal injection of 0.4 ml of ketamine) by applying silk ligatures to vascular legs and ureters. The abdominal wall was sutured tightly with two rows of silk sutures. In the experiment, 30 animals were operated on, of which 3 groups were formed. 1 group (10 individuals) - control: intact animals that are fed on a regular basis; Group 2 (10 individuals) - control over the survival and development of uremic intoxication without the use of enterosorbents; Group 3 (10 individuals) - an experiment on survival during the development of uremic intoxication with the use of the gel form of finely divided chitosan. The therapeutic effect was confirmed by the survival of animals (Fig. 1), the general condition of the animals, signs of uremic gastroenteropathy, hematological blood counts (Fig. 2), biochemical changes in blood serum (Fig. 3), pathomorphological changes in the intestine. In the blood, the number of leukocytes, erythrocytes, and hemoglobin was determined. Serum concentrations of creatinine and urea were determined using standard reagent kits (Olvex). Animals of group 3 during the survival period received gel chitosan (M.M. 180-200 kDa, degree of deacylation of 75%) in a dose of 4 ml / kg every 3 hours. Feeding was carried out by force intragastrically through a tube. The average daily dose of chitosan was 8 ml.

 In animals of group 2, compared with group 1, there was a rapid increase in the external signs of endotoxemia by the end of the first day, manifested by a characteristic smell of urate, decreased motor activity, increased stiffness, brittleness and thinning of the hair. The life span of these animals was 47.2 ± 0.5 hours. When using the gel form of finely dispersed chitosan, external signs of an increase in endotoxemia appeared only at the end of the third day, while the appearance of stiffness and fragility of the hair was not observed. The use of this volume of the drug did not cause stool changes. The external condition of animals of this group indicates a decrease in the release of uremic toxins through the skin. The life span of animals of group 3 was 94.4 ± 0.7 hours.

Objectively: - at autopsy in animals of the 2nd group, compared with the 1st group, free fluid in the peritoneal cavity and low peristaltic activity of the intestine (atony) were noted. When using the gel form of finely divided chitosan, free fluid was absent in the peritoneal cavity. The contents of the intestine compared with group 2 was a liquid consistency with chitosan fibers. Intestinal motility is not impaired. Data from a hematological blood test: in animals of the 2nd group, an increase in leukocytes from 2.0 ± 0.16 • 10 ⁹ / L to 3.4 ± 0.19 • 10 ⁹ / L was observed, in the operated animals, a decrease in the gel form of finely dispersed chitosan occurred white blood cells up to 2.4 ± 0.12 • 10 ⁹ / l compared with group 2. When analyzing red blood cells and hemoglobin in group 2, the erythrocyte count decreased from 6.1 ± 0.16 • 10 ¹² / l to 2, l ± 0.14 • 10 ¹² / l and the amount of hemoglobin from 106 ± 2.4 g / l to 83.7 ± 2.7 g / l, which is typical for uremia syndrome. When using gel forms of finely dispersed chitosan, there was an increase in red blood cells to 3.9 ± 0.07 • 10 ¹² / l and hemoglobin to normal values of 112.2 ± 2.35 g / l, compared with group 2. The biochemical control data showed that the content of toxic metabolites in the blood serum of the operated animals of group 2 is increasing: urea from 7.8 ± 0.48 to 47.2 ± 1.1 mmol / l, creatinine from 0.096 ± 0.007 to 1.05 ± 0.041 mmol / l, which indicates the development of intoxication, characteristic of uremia. In animals of the 3rd group fed by enterosorbent, urea indices in the terminal period were restored to the initial level (7.81 ± 0.52 mmol / L), and creatinine decreased significantly (0.54 ± 0.017 mmol / L).

 Thus, the use of the gel form of finely dispersed chitosan significantly prolongs the life of animals (2 times), showing a therapeutic effect in increasing the amount of hemoglobin, erythrocytes, leukocytes and reducing creatinine and urea of blood serum, which improves the general condition of the experimental animal with experimental uremia syndrome, which makes a positive effect when used. Lengthening life expectancy and removing uremic toxins from the blood when using the gel form of finely divided chitosan as an enterosorbent makes it possible to provide conservative care to patients with uremia at the pre-dialysis stage of treatment and to help incurable patients who are not recommended for active treatment methods.

Claims (1)

 A method of treating uremic syndrome by introducing enterosorbents into the gastrointestinal tract, characterized in that they use the gel form of finely dispersed chitosan orally or through a probe of 4 ml per 1 kg of body weight every 3 hours.

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