Method for stimulating excised liver regeneration with l-norvaline

FIELD: medicine.

SUBSTANCE: stimulating the excised liver regeneration is ensured by a 70% hepatectomy into a laboratory animal on the second day of the experiment. A liver regeneration stimulator is presented by L-norvaline administered intragastrically in a daily dose of 10.0 mg/kg every 46 hours for the first 7 days of the experiment.

EFFECT: method provides the effective stimulation of the excised liver regeneration evidenced by reducing the animals' lethality, improved hepatic microcirculation, reduced manifestation of cytolysis and enhanced synthetic function of the liver.

2 tbl, 1 ex

 

The invention relates to medicine, in particular to experimental pharmacology and experimental surgery, and can be used to stimulate the regeneration of resected liver.

Closest to the claimed solution is the Method of post-resection liver regeneration in the experiment" S. P. Chikoteev. RU 2232550. In this solution, conduct a preliminary xenotransplantation of cryopreserved isolated hepatocytes pigs subcutaneously into the anterior abdominal wall. The procedure was carried out for 48 hours before surgery. Then intraoperatively immediately after resection of 90% of liver perform transplantation of such cells under the capsule of the spleen.

The disadvantages of this method are: the complexity of the technical performance and high probability of development of complications of xenotransplantation. In addition, a 100% mortality of rats of control group makes it difficult to experiment because of the impossibility of comparison of the experimental and control groups of animals. According to most researchers, the most optimal for the study of liver regeneration in rats is resection of 70% of the body.

In every living organism possesses a complex mechanisms of self-preservation and restoration. The task of modern medicine to study and find ways to activate them. In this regard, the phenomenon ishemicheskogo� preconditioning deserves detailed study. Effects of preconditioning - cytoprotective and neoangiogenesis underpinning restorative processes important in surgery. The introduction of pharmacological agents, contributing to the activation and extension of this natural protective mechanism, will greatly improve the results of treatment. Many researchers are inclined to consider as a humoral agent erythropoietin preconditioning. However, it is a hormone protein preparation and there are a number of contraindications for its use, namely, hypertension, and cancers. Furthermore, the known methods of activation of the process of preconditioning the direct stimulation of the main effector component of ATP dependent potassium channels. It is certainly relevant is the study of drugs that are able to activate the various stages of the process of preconditioning.

The most promising for the study, from this point of view, we considered L-Norvaline. Moreover, the drug was administered every 46 hours, given that by this time the effect of reconditionable weakens, the first 7 days of the experiment, as it is at this stage the most effective activation of reparative processes.

The main advantage of the proposed method is the ease of execution, and application� drug minimal dose not causing side effects.

The technical result of the invention is to provide a method of stimulating regeneration of resected liver with L-Norvaline. The technical result is achieved by resection of 70% of the liver on the second day of the experiment laboratory animal administered L-Norvaline intragastrically in a daily dose of 10.0 mg/kg every 46 hours the first 7 days of the experiment.

The METHOD IS AS follows

Experiments carried out on albino Wistar rats weighing 210-220.

Liver resection is performed on the second day in a volume of 70%.

The condition of the liver is assessed according to the mortality rate of animals, the level of microcirculation, the severity of cytolysis, the synthetic indicators of liver function and the results of morphological analysis in the group of intact animals, lonaprisan with liver resection, and in the group of animals with resection of the liver who were administered L-Norvaline.

The case-fatality rate is estimated in the experimental groups of animals in the first 10 days after surgery.

The level of microcirculation in the liver is determined by the equipment manufacturing company Biopac systems: the polygraph MP 100 module with laser Doppler flowmetry LDF100C and surface sensor TSD 140. Registration and processing of the results of laser Doppler flowmetry (LDF) proizvodite� the program AcqKnowledge version 4.2, the values of microcirculation expressed in perfusion units (PUS). The entry level of the microcirculation is carried out sequentially on the surface of the liver, then calculate average value. The registration level of the microcirculation was performed on the 2nd, 7th, 14th, 21st and 28th day after the operation.

The severity of cytolysis appreciate the levels of Alt, AST and LDH in the blood of experimental animals on the 2nd, 7th, 14th, 21st and 28th day after operation. Indicators measured the UV kinetic method for AU5800 automated system (Beckman Coulter, USA).

Sinteticas liver function is assessed by indicators of coagulation (APTT, MHO, fibrinogen) on the 7th, 14th, 21st and 28th day after operation on the analyzer CS-2000i (Sysmex, Japan).

Morphological study is performed on the material standard sections of liver taken after the exclusion of animals from the experiment. Processing of the material produced according to the standard procedure with fixation in formalin, pouring in paraffin, stained with hematoxylin and eosin. Obamaholics and morphometric studies performed with the use of a system for scanning and archiving images MiraxDesk.

L-Norvaline administered intragastrically in a daily dose of 10.0 mg/kg every 46 hours the first 7 days of the experiment.

Statistical processing of the data calculate the mean value, the standard value�th deviation. Differences considered significant at p<0,05.

An EXAMPLE of a SPECIFIC IMPLEMENTATION

Experimental animals were divided into following groups:

1) intact animals (n=20);

2) linopirdine animals (n=20);

3) liver resection (n=50);

4) liver resection + L-Norvaline (n=50).

Liver resection was performed in laboratory animals on the second day of the experiment in the amount of 70%. Rats were anesthetized by intraperitoneal injection of a combination of chloral hydrate and zoletil. After anesthesia, the rat was fixed in the supine position. The hair on the abdomen was carefully cut off, the skin was treated with a solution of 70% ethyl alcohol. Median laparotomy was performed from the xiphoid process length 4 cm Liver was mobilized by crossing cords. Remove the left and medial lobe after preliminary ligation of the vessels. Open hole sutured after sanation of abdominal cavity and hemostasis control layers nodal seam.

Stimulation of liver regeneration was performed in animals of the 4th group by intragastric administration of L-Norvaline in a daily dose of 10.0 mg/kg every 46 hours the first 7 days of the experiment.

The case-fatality rate was evaluated in experimental groups of animals in the first 10 days after surgery. In the group of animals with liver resection it was 40%, in the group of animals with liver resection and the administration of L-nor�Alina 12%.

The level of microcirculation in the liver were determined using the equipment manufactured by the company Biopac systems: the polygraph MP100 module with laser Doppler flowmetry LDF100C and surface sensor TSD 140 on the 2nd, 7th, 14th, 21st and 28th day after operation. Registration and processing of the results of laser Doppler flowmetry (LDF) was performed using AcqKnowledge version 4.2, the values of microcirculation was expressed in perfusion units (PUS). The entry level curve of the microcirculation was performed on the entire surface of the liver for 30 seconds at each point. From the obtained values deduced average, which contributed to the Protocol and adopted at the level of microcirculation in the liver from this animal. From the obtained values we calculated the average, which was hosted at the level of microcirculation in the group of animals at this time.

In the group of intact animals the level of microcirculation in the liver was 877±17 NE. The results of the assessment of the level of the microcirculation in animals of the experimental groups are presented in table 1.

The average value level of the microcirculation in the liver lonaprisan animals in all periods has no significant differences from that of intact rats.

After resection of liver damage is reduced by 50% and remained at the same level the first 14 days. 21 days until�athel begins to grow, however, at 28 days mean value of the level of microcirculation in the resected liver of rats significantly lower than that in intact animals.

The introduction of L-Norvaline contributed to the preservation of blood flow in the resected liver at a fairly high level (figure falls to 15%) and restore it on the up to 21 days after resection.

The severity of cytolysis was assessed by the levels of Alt, AST and LDH in the blood of experimental animals on the 2nd, 7th, 14th 21st 28th day after the operation. The indicators were determined by UV kinetic method for AU5800 automated system (Beckman Coulter, USA).

Alt in the control group on the 2nd day 108±4 IU/l, decreased to normal values by 21 days - 38±2 IU/l in the group with L-Norvaline for 2 days and 68±2 IU/l, normal at 7 days and remained within normal values in all other periods of the experiment.

AST in the control group on the 2nd day 184±7 IU/l, decreased to normal values by 21 days, in a group with L-Norvaline for 2 days - 87±3 IU/l, normal on the 14th day and remained within normal values in all other periods of the experiment.

LDH in the control group on the 2nd day 564±3 IU/l, decreased to normal values on the 28th day of 250±6 U/l in the group with L-Norvaline for 2 days - 311±8 IU/l, normal at 7 days and remained within the normal W�of acini at all other periods of the experiment.

Sinteticas liver function was assessed by the indices of coagulation (APTT, MHO, fibrinogen) on the 7th, 14th, 21st and 28th day after operation on the analyzer CS-2000i (Sysmex, Japan).

On the 7th day after liver resection decreased synthetic function, manifested by lengthening of APTT to 60±1 h, increasing to 4 MHO±0,2, decreased fibrinogen level to 1.7±0,002 g/l. the Greatest changes of the indicators identified in 21 days (APTT - 75±1 h, MHO - 6±0,1, fibrinogen 0,9±0.003 g/l). On the 28th day, noted a slight recovery (APTT - 55±1 h, MHO - 4±0,1, fibrinogen 1,2±0,002 g/l). Correction of L-Norvaline contributed to the less pronounced decrease in synthetic function of the liver after resection. The most pronounced changes in the indices were registered on the 7th day (APTT - 42±1 h, MHO - 2,8±0,02, fibrinogen 1,0±0.01 g/l). To 14-day counts have recovered and remained in the normal range on all other terms of the experiment.

Morphological study was carried out on material standard sections of liver taken after the exclusion of animals from the experiment. Processing of the material produced according to the standard procedure with fixation in formalin, pouring in paraffin, stained with hematoxylin and eosin. Obamaholics and morphometric study was performed using the system to scan and archive images MiraxDesk.

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Weight of the liver of intact animals were 9.2±0.002 g In the group lonaprisan animals indicator has no significant differences from that of intact animals. Liver weight directly after resection of 2.8±0,003 g. the Average weight of the liver of animals of experimental groups at different stages of the experiment are presented in table 2.

In the group of animals with liver resection liver weight in 2 days is increased in comparison with the mass directly after resection almost in 2 times, 7 days decreases, then begins to increase, however at 28 days after resection was significantly lower liver weight in intact rats. In the group of animals with liver resection and the introduction of L-Norvaline liver weight in 2 days increases exactly 2 times, continuing to grow and reaching the masses in intact animals by 21 days.

Microscopy - to long-run terms in the control group remained uneven blood vessels of all types, was observed foci of granular dystrophy of hepatocytes foci of sclerosing and inflammatory infiltration of the portal tracts. Restoration of hepatic tissue was attributed to hypertrophy of mononuclear hepatocytes, polyploidy and mitoticheskogo division binuclear hepatocytes. In the group with the introduction of erythropoietin in long-run terms of violations �microcirculation and signs of damage to the hepatocytes is not revealed, is determined uniformly expressed hypertrophy of the cytoplasm and nuclei of hepatocytes. Restoration of hepatic tissue was due to polyploidy, mitoticheskogo division binuclear hepatocytes and mitotic division of mononuclear hepatocytes, i.e. were involved in all kinds of liver regeneration. The main burden fell on mononuclear hepatocytes with a kernel size of 9 μm for 2 and 7 days, indicating that stimulation of the genetic apparatus of the cell.

The results obtained allow us to state the possibility of stimulation of regeneration of the resected liver of rats with L-Norvaline.

A method of stimulating regeneration of resected liver, characterized in that the resection of the liver carry out a laboratory animal on the second day of the experiment in the amount of 70%, L-Norvaline administered intragastrically in a daily dose of 10.0 mg/kg every 46 hours the first 7 days of the experiment.



 

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