Method of cadmium nephropathy prevention in experimental animals suffering from chronic poisoning

FIELD: medicine; veterinary science.

SUBSTANCE: method consists in introduction to an experimental animal of Acyzol 30 mg/kg once a day combined with daily subcutaneous introduction of cadmium sulphate solution in a dose 0.1 mg/kg.

EFFECT: prevention of cadmium toxic effect in chronic poisoning in experimental animals.

2 cl, 1 tbl, 1 ex

 

The invention relates to ecology, medicine, toxicology, experimental biology and can be used to study the mechanisms of prevention of toxic effects of heavy metals, particularly cadmium.

The enrichment of the natural environment by cadmium in recent decades takes rampant. Excessive intake and accumulation of cadmium in the body leads to various disorders of metabolism: uncoupling of oxidative phosphorylation (Acacac et al., 2004; S.Jimi et al., 2004), competitive substitution of zinc in some metalloenzymes and changes in their activity (M.R.Fox, 1976); the increased activity of lipid peroxidation (Vincenta et al., 2000; F. Casalino et al., 2002); the metabolic vital electrolytes, particularly calcium (Evecutive et al., 1987; Katsuta O. et al., 1994; Ohta N., Ymauchi Y. et al. 2000). Ultimately all this leads to the development of severe acute and chronic conditions, the defeat of almost all organs and systems. Due to the high krovosnabjaemah and specificity of the functions associated with the excretion of xenobiotics, the kidneys are one of the main authorities on the level which manifests the damaging effect of cadmium (Fukumoto M. et al., 2001; Tang W., Z.A. Shaikh, 2001; L Azou B. et al., 2002; L.J.Stinson et al., 2003; M. Trzcinka-Ochocka et al., 2004, etc).

Given the above and the high cumulative SV is istwa cadmium efficient process half-life equal to 140±20 days (MA Bogomazov et al. 1984) to 10 years (I.Franchini et al., 1990), it is important to create and develop ways to prevent cadmium nephropathy and its toxic effects of the compounds on the body.

There are plenty of detoxicants able to reduce the toxic effect of heavy metals on the body. These include thiol compounds tetatsin calcium, unithiol, sodium thiosulfate, various complexing compounds pentatsin, the disodium salt of ethylenediaminetetraacetic acid, deferoxamine, penicillamine, etc (Mashkovsky PPM Medicines: in 2 volumes. Vol.2. - Kharkov "Torching", 1998. S-220). Use, especially long-term, these synthetic drugs can cause various side effects: gastrointestinal disorder, allergic reaction, anemia, leukopenia, thrombocytopenia, acute necrosis of the proximal tubules of the nephrons, etc. along with the toxins they are able to excrete minerals and essential ions like iron, calcium, zinc, etc. and cause a violation of metabolic processes, which makes them long and prophylactic use.

Known also funds reduce the nephrotoxic effect of heavy metals, including cadmium, for example Califon and succimer (Mashkovsky PPM Medicines: in 2 volumes. Vol.2. - Kharkov "Torching", 1998. S-20).

The disadvantage of this method is that the drugs cause side effects, and prevention of their impact has not been studied at all. Succimer (unithiol) along with side effects (see above) may have membranotoksicheskoe effect, resulting in limited ability of its long-term prophylactic use. Xidian with long-term use may alter the exchange of vital electrolytes such as calcium and magnesium, the balance of which in the body and without changes in cadmium intoxication.

A special place in the complex detoxification measures is the use of antidotes. The antidote, according to the definition of the International Program of Chemical Safety who is a drug that has the ability to eliminate or weaken specific effects of the xenobiotic. In modern pharmacology, intensive research scientists focused primarily on the search for medicines, approaching the mechanism of action of natural compounds. For these purposes promising metal complexes of a number of vital elements on the basis of azole ligands, are actively involved in various enzymatic processes and the binding of trace elements in living organisms. Data coordination compounds, with a wide range of directional ways is owing to stabilization of homeostasis low toxicity, easy dosing, and most importantly, highly effective.

In Irkutsk Institute of chemistry SB RAS in the result of years of research in the field of directed synthesis of biologically active compounds found high pharmacological activity of the metal complex salt of zinc with 1-vinylimidazole, based on drug "Aziza". The drug Arizol" is the most powerful and unique in the world antihypoxic agent. Azizol, being highly efficient antihypoxic drug is able to protect the organism at low partial pressure of oxygen and insufficient oxygenation of hemoglobin, reducing the body's need for oxygen. The drug helps increase resistance to hypoxia bodies that are sensitive to lack of oxygen. Also contained in Anisole zinc, eliminating its deficit in the body, normalizes the cascades of metabolic processes, work-related zinc-dependent enzyme systems. In this regard, Azizol can be used in the treatment of zinc-deficient state (illness Prasad, immunodeficiency, allergic and other).

The claimed invention is directed to the solution of this problem involves the development of a way to prevent cadmium nephropathy in chronic poisoning.

The solution to this problem provides significant SN is laid on the toxic effects of cadmium on the kidney in chronic poisoning by reducing the damaging effects of cadmium on cell due to cytoprotective actions based on preventing the development of hypoxia cells and reduce the activity of enzyme systems, due to the competition between ions of cadmium and zinc in the area of linking them into the molecule of the enzyme.

To achieve this, the technical result of the claimed invention, a method of prevention of cadmium nephropathy in experimental animals with chronic poisoning has the following distinctive features: animals daily enter azizol at a dose of 30 mg/kg through a tube into the stomach at the same time with a daily injection of a solution of cadmium sulfate subcutaneously at a dose of 0.1 mg/kg

Azizol introduced at the same time (which means the introduction within a period of 2 months.) sulfate cadmium, which allows to evaluate the prophylactic effect of chronic intoxication. Aziza has a combined beneficial effect in chronic cadmium intoxication - is a powerful antihypoxic drug and aid donor ions of zinc.

Preventive daily administration of alzola through a tube into the stomach in a dose of 30 mg/kg simultaneously with the introduction of a solution of cadmium sulfate subcutaneously leads to the reduction of the pathological effects of heavy metal in experimental animals. The claimed method is efficient, cost effective and easily reproducible.

According to the authors of the information is the third set of essential features, characterizing the essence of the claimed invention, is not known, which allows to make a conclusion about conformity of the invention, the criterion of "novelty".

According to the authors, the essence of the claimed invention should not be for experts explicitly known level of medicine, since it is not detected above indicated the possibility of obtaining a way to prevent cadmium nephropathy in experimental animals with chronic poisoning, characterized in that the animals daily enter azizol at a dose of 30 mg/kg through a tube into the stomach at the same time with a daily injection of a solution of cadmium sulfate subcutaneously at a dose of 0.1 mg/kg, which allows to conclude that the criterion of "inventive step".

The set of essential features that characterize the invention, in principle, can be repeatedly used in medicine with the result, consisting in an effective and easily reproducible method of prevention cadmium nephropathy by reducing the toxic effects of cadmium in chronic poisoning, which allows to make a conclusion about conformity of the invention, the criterion of "industrial applicability".

This method is as follows.

To obtain a toxic substance cadmium sulfate dissolved in sterile distilled water so th is per unit of solution, equal to 1 ml, accounting for 0.1 mg of cadmium (in terms of metal). For every 100 g weight rats injected subcutaneously with 0.1 ml of the toxic solution that is not excessive water stress on the organism of experimental animals. By dissolving 30 g of alzola in 1 liter of 0.5% solution of acetic acid obtained a strong solution of alzola with the content of 30 mg in 1 ml Solution alzola introduced through a tube into the stomach using a syringe with a specially curved needle, which put the probe in an amount of 0.1 ml per 100 g, which is also not excessive water stress on the organism of experimental animals.

At the end of the first and second month of the experiment was determined indicators photoelectrochemically renal function.

For histological examination of tissue samples (liver, kidney, heart) were fixed in 10% neutral formalin, and then was subjected to fill in paraffin and subsequent preparation of slices of a thickness of 7-8 microns. Sections were stained with hematoxylin and eosin. The study sections were performed in transmitted light using a microscope Micmed-1 under the magnification of 80×200×400.

The essence of the method is confirmed morphologically, in which figure 1 is marked histological changes in animals with isolated introduction of sulfate cadmium, presents manifestations of degeneration, necrosis, dyscirculatory processes and Vespa is sustained fashion reaction. Dystrophic processes presents hydropic degeneration, symptoms which range from partial vacuolization cytoplasm of tubules epithelium and capillary endothelium to total colliquation necrotic cells (A). Necrosis is manifested by the presence of groups of cells occupying places in the entire field of view. Places such changes have captured not only the epithelium of the tubules, but the glomerulus. Alterative changes occur predominantly in the cortical substance. Due to dystrophic and necrotic changes in the lumen of the tubules for the most part of otsutstvuet places lumen of the tubules vacuolation (B), the glomeruli swollen in places yalnizyan. Collective tubules in the medulla in the lumen with protein mass, intensively stained with eosin. Inflammation is an extremely scarce mixed perivascular infiltrates, rare on the drug (In). Dyscirculatory change presents a plethora of vessels, predominantly cortical substance. Vessels with thickened edematous wall places yalnizyan.

The morphological differences between groups with isolated introduction of salts of cadmium and concomitant introduction of sulfate cadmium and Alzola (figure 2) consist in reducing the severity of manifestations of all of the above mentioned pathological processes. The number is the creation of neprocital with signs of karyolysis compared with the group with isolated introduction of a cadmium salt, a small (And). The number yalnizyan glomeruli and glomeruli with severe hydropic degeneration of endothelial cells is extremely low. A reduced number of cells of the epithelium of the tubules, in which hydropic degeneration reaches the transition in total colliquation necrosis (B). The number of tubules with saved lumen are also considerably higher than in the group with isolated introduction of cadmium sulfate (In).

Example 1. Two groups of male rats (No. 1 control # 2 - experience with Etizolam) Wistar rats weighing 200-300 g were injected subcutaneously solution of cadmium sulfate in a dose of 0.1 mg/kg every day for two months.

Azizol was injected through a tube into the stomach daily in a dose of 30 mg/kg group No. 2. After 1 month and after 2 months was identified some indicators photoelectrochemically renal function in spontaneous the six-hour diuresis: the level of diuresis, glomerular filtration, tubular reabsorption, the level of excretion of sodium, potassium, calcium, magnesium, phosphorus; also determined the concentration of protein in the urine.

Analysis of the data showed (table), that subcutaneous administration of cadmium sulfate leads to increased spontaneous six-hour diuresis after 1 month of intoxication due to the substantial reduction of tubular reabsorption, trends, at the end of the second month, to the reduction of glomerular filtration. After 1 month and another big degree after 2 months increased excretion of calcium in urine, as phosphorus. The excretion of sodium ions and magnesium increased significantly after 2 months of the experiment. The concentration of protein in the urine increased after 1 month of introduction of the salts of cadmium, in 2 months it has increased by almost five times. In group 2, the background of the simultaneous introduction of Alzola observed a less pronounced increase in spontaneous diuresis with decreased tubular reabsorption, but with a simultaneous increase in glomerular filtration rate.

Prophylactic use of Alzola led to a significantly lesser extent growth excretion of calcium ions (only 2 months) and phosphorus and significantly lower concentrations of protein in the urine after 2 months.

Preventive effect of Arizola on indicators elektrootopitelnoe renal function after subcutaneous administration of cadmium sulfate in a dose of 0.1 mg/kg (M±m)
DiuresisFiltresRehabsCalciumSodiumPotassiumMagnesiumPhosphorusProtein
0,116± 10,5±98,86±0,106±11,78±to 6.19±1,189±3,11±2,59±
Background0,0060,700,0760,0060,450,350,040,160,26
Cadmium,0,146±9,35±to 98.4±0,196±13,0±6,20±1,24±4,42±6,86±
1 month0,004*0,2440,045*0,006*0,580,400,030,28*0,51*
Cadmium,0,17±9,14±98,12±025± 17,01±6,06±1,79±8,05±14,03±
2 months0,004*0,20*0,037*0,009*0,56*0,330,056*0,45*0,57*
Cadmium+0,18±12,97±98,60±0,11±14,08±5,81±1,19±3,86±6,16±
Azizol,0,006*0,34*0,042*0,0060,52*0,350,0650,32*0,52*
1 month*)*)*)
Cadmium+0,223±12,30±98,18±0,15±17,66±5,94±1,799±6,82±8,73±
Azizol,0,009*0,49*0,046*0,012*0,75*0,430,10*0,24*0,82*
2 months*)*)*)*)
*) - p relative experience

Revealed histological changes show a decrease in the manifestations of cadmium nephropathy in animals with prophylactic use of Alzola compared with rats with isolated introduction of cadmium sulfate.

From the foregoing it can be seen that the prophylactic administration of Alzola is an effective way to reduce and correct the toxic effects of cadmium in chronic poisoning its compounds.

The way to prevent cadmium nephropathy in experimental animals with chronic poisoning, characterized in that the animals injected azizol once daily at a dose of 30 mg/kg through a tube into the stomach at the same time with a daily injection of a solution of cadmium sulfate subcutaneously at a dose of 0.1 mg/kg



 

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