Enterosorbent for the treatment of renal failure

 

(57) Abstract:

The invention relates to medicine, in particular to Nephrology. The objective of the invention is the formation of a range of chelators, effective for the conservative therapy of acute, progressive, and chronic renal failure of different etiologies. Natural zeolite tuff (clinoptilolite) was proposed as such enterosorbent. 2 C.p. f-crystals, 6 ill., 5 table.

The invention relates to medicine, in particular to Nephrology, and can be used as detoxifying and protective remedy in acute and chronic renal failure (CRF) of various etiologies.

Known clinical picture and the dynamics of the course of acute and chronic renal failure (CRF), accompanied by uremia. The treatment of this category of patients is largely dependent upon the effectiveness of the methods of detoxification (Enterosorption. /Ed. by N. A. Belyakov. L. S. 1991 210 211). The use of active methods of treatment of renal and first of all hemodialysis does not solve all medical and ethical issues, so in Nephrology practice are highlighted tasks assist ESRD patients on dovalina stage of treatment with the aim of lengthening modelinga p CLASS="ptx2">

Well-known role of the gastrointestinal tract (GIT) in the elimination of uremic toxins and metabolic correction of renal failure. Detoxification of the body through the digestive tract is possible in three ways:

intestinal dialysis;

the ingestion of sorbents (oral sorbents, sorbents);

bacterial enzymes that enhance the processing of nitrogenous compounds (Chronic renal failure in children. /Ed. by M. S. Ignatova, P. M. Grossman. M. Leipzig, 1986, S. 153.)

Substantiated experimentally and clinically confirmed the appropriateness of the number of carbon enterosorbents as nonspecific components of comprehensive treatment of renal failure (Enterosorption./ Ed. by N. A. Belyakov. L. 1991, S. 210 224).

Optimal physical and chemical characteristics (grain size, sufficient mechanical strength, high sorption capacity, lack of adhesion to the mucosa) is granulated charcoal brand SKN, tested in the clinic, which shows its high efficiency in the treatment of uremia [Shostka D. Ryabov S. I. Lukichev B., Oral sorbents in the treatment of chronic renal failure.// Ter. are 60 to 90 g/day for several months observed the reduction of symptoms of uremic gastroenteropathy, a significant decrease in serum creatinine of 20% urea, 25% and a slight increase in diuresis, which allowed to significantly delay dialysis therapy.

Clinical experience shows that it is necessary to apply chelators even in the absence of a decrease or stabilization indicators of nitrogen homeostasis in the presence of only positive clinical dynamics (Enterosorption. /Ed. by N. A. Belyakov. L. 1991, S. 223).

However, the known range of chelators specified action narrow, limited, mostly synthetic materials, to the same therapeutic tolerability and clinical effectiveness of their individual at different stages of development of acute and chronic kidney disease. Therefore, the finding of new chelators, which increases the possibility of conservative treatment of renal failure, acute need for clinical practice.

The task of the invention is the formation of a range of chelators, effective for the conservative therapy of renal failure (expanding Arsenal of technical means).

The problem is solved by use of natural zeolite tuff (clinoptilolite) as such enterosorbent.

Known natural tseolitsoderzhashchikh zeolite tuffs typically contain from 30 to 90% of clinoptilolite (Chelishchev N. F. and other Zeolites new type of mineral raw materials. - M. Nedra, 1987), which determines the similarity of geochemical, adsorption and ion exchange properties of different varieties of zeolite tuffs (e.g., PL.1. Feeding the animals and zeolites: guidelines for the study of natural zeolites in the feeding of farm animals. Kemerovo, 1990, S. 5 of 6).

A unique combination of zeolite raw material sorption, catalytic, ion exchange, screening and other properties provides a wide range of industrial and agricultural applications.

Known natural zeolite-containing tuffs as a potential medical chelators (Enterosorption / Ed. by N. A. Belyakova, L. 1991, S. 14).

However, in clinical practice, none of them have not yet entered. Theoretical and experimental study of the effectiveness of tuffs in the treatment of renal failure in the prior art are also missing.

The invention is illustrated in Fig. 1 6. In Fig. 1 shows a curve of survival in acute renal failure; Fig. 2 survival curve in the rapidly progressive renal failure; Fig. 3 - status of fur in rats, selectedcategory; in Fig. 5 heart, renal failure, 2 months, interstitial edema, significant lymphohistiocytic infiltration, necrotic changes in individual myocytes, x 100, hematoxylin-eosin; Fig. 6 heart, renal failure, 2 months, Sorption therapy, moderate lymphocytic infiltration, the formation of the lesion necrosis soedinitelnotkannyh structures, x 100, hematoxylin-eosin.

Used in the work of the zeolite tuff (clinoptilolite) various domestic deposits: Chivyrkuyskogo (Chita region), Golynskogo (Buryat Republic), Hangaroo (Republic of Sakha). For medical purposes used pure homogeneous mineral with Tonino grinding of 0.1 mm

For playback of clinical and laboratory signs of acute, rapidly progressive, and chronic renal failure used standard experimental methods. The experiments were performed at the laboratory of Mature rats male Wistar rats weighing 200 to 250 g All surgical interventions performed surface of ether anesthesia.

To confirm therapeutic effect was monitored survival of animals, signs of uremic gastroenteropathy, biochemical change Enza and hemodynamic changes, pathomorphological changes in the heart, lungs, intestines and other organs.

Example 1. The use of natural zeolite tuff (clinoptilolite) as enterosorbent: acute renal failure.

Acute renal failure was reproduced simultaneously removing both kidneys. In the experiment operated 25 sexual maturity of male rats weighing 160 to 190 g of which formed 3 groups:

10 individuals control for survival against the standard laboratory diet;

10 individuals control for survival against the background of enterosorption;

5 individuals overseeing the development of uremic toxicity: rats scored 2 days after surgery, the serum was determined by the concentration of creatinine and urea using standard reagent kits (Biotest LACHEMA, CREAT 100, UREA 150).

In the period of survival benefaction animals were fed once a day via a stomach tube. Enterosorbent was introduced in the amount of 500 to 600 mg in 1 ml of distilled water. After 15 to 20 minutes after this was introduced 1,0 1,5 ml thick nutrient mixture consisting of pounded and boiled barley and oat grain with the addition of milk powder "Baby".

PE is th. The data of biochemical control (group 3) showed that the content of toxic metabolites in the blood of the operated animals grows: urea with 7,820,47 to 51,023,93 mmol/l, creatinine with 0,0860,009 to 0,581 0,064 mmol/l, which indicates the development intoxication phenomena characteristic of acute renal failure (Shostka, D. Ryabov S. I. Lukichev B., Ter. archive. 1984. N7, S. 58 63).

The criterion of adequacy of therapy is actuarially survival of operated animals. Almost twice (1,9) increased duration of survival benefaction animals on the background of enterosorption: the average duration of life of the patients (untreated) animals was 2,300,41 day, with the use of enterosorption 4,320,74 day; maximum lifespan in the first group of 3.75 days (Fig. 1, control), the second 6,38 day (Fig. 1, experience). 4 days later, when operated control animals have all died in the treated group remained more than half of the rats (57%).

Curve survival of treated rats over the canopy. This suggests that morphological and functional disturbances, leading to a fatal outcome, has been slower. In clinical variant of acute renal failure is equally possible is their tuff (clinoptilolite) rats after benefactee resulted in a statistically significant increase in survival nephrectomised animals that proves held therapeutic effect in the most severe, end-stage renal failure at very high levels of creatinine and urea in the blood.

Example 2. The use of natural zeolite tuff (clinoptilolite) as enterosorbent: rapidly progressive renal failure (end-stage).

The experiment was performed in 15 sexually Mature rats-male weighing 200 - 250 g Animals were divided into two groups: control and experimental. The condition is rapidly progressive renal failure played a phased full nephrectomy scheme Platt, Roscole, Smith (Kidney./ Ed. by F. K., Mostafa, D. E. Smith. M. 1972, S. 252]

The first operation is the removal of the upper and lower pole of the left kidney, the stump of the body was a kidney plate thickness 2 to 4 mm

A week after the first operation, all experimental animals were operated again.

The second operation complete removal of the right kidney. After the second surgery the animals were no more than 15% of renal tissue.

The third operation one week after the second surgery carried out the complete removal of the stump of the left kidney.

Since the completion of tretheway and the third operation were kept on a standard laboratory diet, access to food and water was free. During this period, the animals of the experimental group sorbent was injected via a stomach tube at a dose of 500 600 mg in 1 ml of distilled water daily, starting the day after the first operation. After the third surgery because of the severity of the condition of all the animals began to feed through a tube under the scheme of example 1.

The average life expectancy of animals of the control group is 1,650,86 day (Fig. 2, control), the maximum lifetime of 2.5 days, significantly less than in the control group with acute renal failure (Fig. 1, control). This is due to the fact that the development of the pathological process begins with the first operation, and the timing survival we started since complete removal of the kidney (third operation), by this time the animals had expressed signs of renal failure (before the third operation, the concentration of urea in serum - 31,63,94 mmol/l, creatinine 0,2590,044 mmol/l as compared with intact, neopoznannymi animals, in which the concentration of urea and creatinine respectively 7,94 0,46 and 0,0780,009 mmol/l

Sorption therapy, which began with the first days of the development of renal failure, leads to an increase in sright. The curve of the survival of the treated animals (Fig. 2, experience) extends: through three days after the third operation, when in the control group, all animals died in the experimental group were alive 83% of rats.

Therapy enterosorbent is more efficient with rapidly progressive renal failure than acute. Probably, when phased in over three weeks) the destruction of renal tissue, leading to progression of renal failure develops compensatory hypertrophy of the urinary system, the gastrointestinal tract and toxins begin to actively be released in the intestinal lumen, where effectively communicate enterosorbent that reduces the intoxication of the organism and increases the lifetime of the animal.

Thus, a significant elongation of the life time of the treated animals in end-stage renal disease confirms the effectiveness of therapeutic effects of the zeolite tuff (clinoptilolite) and rapidly progressive renal failure.

Example 3. The use of natural zeolite tuff (clinoptilolite) as enterosorbent: chronic renal insufficiency.

In the experiment used in the scheme, described in example 2, i.e., not performed a third surgery. After the second surgery the animals were no more than 15% of renal tissue. Evaluation A. B. Morrison (the Kidneys./ Ed. by F. K., Mostafa, D. E. Smith. M. 1972, S. 252) this experimental model of CRF adequately reproduces the real pathological process: it was revealed the presence of progressive acidosis and other metabolic abnormalities found in chronic renal failure in humans.

therapeutic effect of the zeolite tuff detected in the result of the comparison of clinical and laboratory parameters among the three groups of animals:

1st group intact (standard laboratory diet);

2nd group operated (standard laboratory diet);

3rd group operated (standard laboratory diet, enteral introduction of enterosorbent).

All animals were kept under identical conditions. In the morning feeding the rats were given a thick porridge, in which animals of the 3rd group as a dietary Supplement drove sorbent based 3,5 5,0% of the wet weight of feed. On average, each animal in this group received 500 to 600 mg of the enteric daily, beginning with the first day after the first operation. After you complete eating the daytime observation. Weekly performed biochemical control of blood on the content of toxins, ballast metabolites and other components.

For the development of pathological functional manifestations of CRF animals of the 2nd and 3rd groups were followed for 2 months, then all surviving animals were killed and morphological examination of the internal organs (heart, lungs, intestines).

On the visually observable features animals operated groups are easily distinguishable. By the end of the second month of development in untreated CRF rats marked diffuse thinning of the coat (the coat of uneven length), partial restoration of hair in the area of the wound, which is a consequence of the reduction in the regenerative capacity of the skin (Fig. 3).

When sorption therapy such painful manifestations are absent. The fur of the animal is healthy, shiny, uniform length, including in the area of the wound (Fig. 4).

Survival and biochemical parameters of blood.

In animals, prepared for surgery (2nd and 3rd groups) in the blood was determined by the initial urea concentration. The concentration of the metabolite in these groups of animals in the preoperative period, practically the 2-nd group (untreated) 30% in the 3rd group (treated) 15% Concentration of urea in all operated animals increased sharply and was in the 2nd group 31,63,9 mmol/l, in the 3rd group 42,13,9 mmol/l In the 3rd group was twice higher animals with high levels of urea (83 versus 43% in rats of the 2nd group). Then there are signs of renal failure were expressed more sharply in the 3rd group treated enterosorbent. It is clear: in the 3rd group were killed in two times less than animals, that is, survived and were taken into account in the statistical treatment of rats with a high renal toxicity.

Further observation of the operated animals showed that the General condition of the rats of the 2nd group on the past 2 months has not improved: not decreased the concentration of urea in blood and number of animals with urea concentration above 30 mmol/l, was high mortality of animals (two months killed 70% of the operated rats).

Animals of the 3rd group on the background of enterosorption noted inverse dynamics (PL. 2), which was reflected in a significant (1.5 times) the reduction of urea in the blood, a sharp decline in the relative number of animals with high levels of urea (from 83% to 30% by the end of the second month of observation), the mortality rate was significantly lower.

therapeutic effect of the enteric show and other biochemical parameters (table. 3). An important poach animals grew at 12.8 times, but against the background of enterosorption only 6.8 times and further decreased.

In the blood serum of the operated animals to 9th days of increased glucose concentrations, high concentrations of which was maintained during the 2-month follow-up. In the group treated rats, the glucose concentration in the blood was significantly lower than in untreated animals, as on the 9th day, and 2 months after surgery. It is known that the glucose content in the blood increases when different stress and pathological processes. The normalization of this index indicates an improvement in the General condition.

Under the influence of enterosorbent increased the concentration of total protein serum operated animals, this indicates activation of synthetic and reparative processes in clinical variant is extremely important, for example, for incurable patients.

Interesting changes observed in the protein spectrum of blood. In untreated animals observed abrupt changes in the fractions of globulins: disappears fraction1-globulin and 1.54 times increases the fraction-globulin. Under the influence of enterosorbent positive changes of the protein spectrum already on the 9th day after surgery: n is e same occurs.

Therapy complications CHRI

The hemostatic system

The state of hemocoagulation level of hemostasis studied twice: after 2 and 6 weeks after the last operation. Determination was carried out on coagulogram " H 333 (Wetmaker U. A. Tolstojeva I. A. and other Laboratory work. 1969. N 8, c. 469 472; ibid., No. 9, S. 543 547). The rat in the waking state has put in place the body of the camera, gave her time to relax (animal began to wash), the tail was dipped for 3 to 5 minutes in a bath with water temperature 40-45oC and the tip of the tail was cut off by a sharp blade. Collected freely flowing blood in the Teflon cell to its full completion. Immediately began the recording of coagulation. The speed of movement of the paper tape 60 cm/h

Was calculated the following indices of coagulation:

T1the beginning of coagulation;

T2end of coagulation;

T duration of coagulation;

T3the beginning of the retraction and fibrinolysis;

Amaxthe maximum pulse amplitude (mm) at the beginning of the recording, it depends on the dense phase of the blood and is the reciprocal of the hematocrit;

A0minimum amplitude (mm) minimum pulse is inversely proportional to the density of blood clot;

A1amplitude while roaming in the formula

< / BR>
In animals with CRF contained on a normal diet, there are phase changes of hemostasis (table. 4). In the initial period (2 weeks after the last operation) observed phenomena hypercoagulable:

reduced the start time and end clotting;

shortened time of the formation of a clot;

increased hematocrit, indicating a thickening of the blood (decreased Amax);

density increases clot (reduced A0);

sharply reduced fibrinolytic activity of blood.

In the second phase (6 weeks after the last operation) disappear signs of hypercoagulability and evolving phenomenon gipokoagulyatsii:

thinning the blood (an increase of Amax);

the decrease of the density of the clot (an increase of A0);

accelerates the onset of retraction and fibrinolysis.

Such phase changes in the coagulation characteristic of DIC (disseminated intravascular coagulation) (Laboratory methods of hemostasis/Ed. by B. N., Baluda and other Tomsk, 1980, S. 47]

DIC threatening complication of ESRD when you are sick at this development stage CRF immediately transferred to hemodialysis.

When sorbtion, close to the norm, the development of DIC is not diagnosticums throughout the study period. In clinical variant that contributes to the lengthening dialitnow stage CRF in this clinical indicator.

Cardiovascular system

Electrocardiographic studies

The ECG recording from anesthetized animals performed on the electrocardiograph of ECG-1 using needle electrodes.

In rats with CRF after 5 weeks after the last operation is detected, the following changes of the ECG as compared with intact neopoznannymi animals (PL. 5):

increased heart rate;

reduced the duration of P wave, the amplitude of the wave slightly increased its shape is pointed;

there is a rotation of the electric axis of the heart to the right.

These ECG changes indicate the development of sinus tachyarrhythmias against the backdrop of concerns hyperkaliemia:

increased the duration of the segment PQ, reflecting the slow atrioventricular conduction;

reduced voltage of the R-wave, indicating severe diffuse changes of the heart (Myasnikov A. L. Propaedeutics of internal diseases. M. S. 232 235)

Such changes in ECG in nelec brianna therapy zeolite tuff effectively normalizes all ECG parameters (table. 5), indicating a protective effect of enterosorbent on the cardiovascular system.

Morphological studies. Pathological changes in the heart were observed in animals in the state 2-month development of ESRD.

Collected samples were exempted from the adjacent fatty tissue and in planes perpendicular to clinico body, dissected into fragments of thickness up to 2 to 3 mm From each organ from its various departments randomly selected 3 5 fragments, which are fixed initially in the 9% alcohol-formula, and after 24 h in 70% ethyl alcohol. Histological specimens were prepared in accordance with the scheme paraffin fill. The slicing thickness up to 5 MMK painted hematoxylin-Sosina and selectively by van Gison. From each tissue block was cut at 3 to 6 slices at several levels.

In patients operated on untreated animals (group 2) histopathological changes in the myocardium correspond to different stages of the developing pathological process.

In all cases, there was necrosis of individual myocytes, small necrosis, symptoms of varying severity perivascular edema and lymphohistiocytic infiltration, and (Fig. 5) Separate myocardiocytes are in accordance hypertrophy. Destructive changes are more expressed in the right ventricle. There is a picture of toxic cardiomyopathy, which is manifested on the ECG sinus tachyarrhythmia.

In rats with chronic kidney disease on the background of enterosorption myocardium exposed to less destructive changes at all stages of developing pathological processes: phenomena of alteration is expressed in the myocardium to a lesser extent, and effects of repair and replacement of damaged structures more pronounced (Fig. 6).

Thus, comparative morphological pattern indicates a pronounced protective effect of enterosorbent on the cardiovascular system.

Such sacrificial orientation of therapeutic effect of clinoptilolite exhibits in relation to the lungs and intestines, it means the ability to reduce drug component in the complex of measures traditionally used in clinical practice for the prevention and treatment of medical complications of ESRD, and thereby avoid adverse reactions (toxic, allergic, nephrotoxic), caused by the characteristics of drug therapy in the reduction of kidney function (Chronic the military enclose, what zeolite tuff (clinoptilolite) can be effectively used as enterosorbent in the conservative treatment of various forms of renal failure and, in particular, for prolonging the current CRF in any phase modelinga period.

1. The use of zeolite varieties of natural zeolite tuff as enterosorbent for the treatment of renal failure.

2. Application under item 1, characterized in that clinoptilolite varieties is hangarin zeolite tuff deposits of Hangaroo.

3. Application under item 1, characterized in that clinoptilolite varieties is RIVERTWIN zeolite tuff Chivyrkuyskogo field.

 

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