For the treatment and prevention of pathological proliferation of connective tissue in parenchymatous organs

 

(57) Abstract:

The invention relates to the field of medicine. Perfluorocarbon compounds proposed as a means for the prevention and treatment of pathological proliferation of connective tissue in parenchymatous organs. This tool can be used for cirrhosis, liver fibrosis, pneumosclerosis, amyloidosis, nodular goiter and other diseases. The proposed tool more effectively. 1 C.p. f-crystals.

The invention relates to medicine, namely to the prevention and treatment of pathological proliferation of connective tissue in parenchymatous organs.

The predominant use of the invention: termination and prevent future development of connective tissue degeneration of parenchymatous organs, in particular the treatment of patients with cirrhosis of the liver.

Description we have performed on the example of cirrhosis of the liver, which is, we believe, correctly, as the pathological features of diseases associated with fibrations degeneration of parenchymatous organs such as the spleen, kidneys (amyloidosis), lung (pneumosclerosis, bronchiectasis), mammary gland (matapedia)) are similar to those of assistanee connective tissue.

Treatment of cirrhosis of the liver is the actual problem, not solved till now.

Cirrhosis (a chronic progressive sclerosing hepatitis) is a severe disease with a high percentage of mortality (Tareev E. M., 1956). According to M. P. Pavlovsky (1959), 9435 autopsies in 0,62% of cases the cause of death was cirrhosis of the liver. The main cause of this disease is considered a disease Hungary, on the ground of which cirrhosis develops in 53-80% of cases (Tareev E. M., 1956, Shubladze A. K., 1955; Mussabayev, I. K., 1961; Krutskikh E. C. 1976).

A. S. Loginov et al. (1987) indicates that from the point of view of the morphologist cirrhosis is the final stage of the evolution of numerous inflammatory-necrotic and degerativnye necrotic pathological processes parenchyma or biliary system of the liver, characterized by regenerative and fibrational rebuilding structures and vascular system of the body. Abnormal reconstruction of lobular architecture, related to cirrhosis of the liver can be caused by long-term recurrent small or krupnooptovyh necrosis of the liver parenchyma, or as a result of slowly progressive active fibrosis extending from the center and the periphery of the city of pécs is alchnyh ducts with long-term intra - or extrahepatic obstruction of the flow of bile. The most important condition for the formation of pseudopolis parcels parenchyma, completely or partially surrounded by a connective tissue layers, is the development of active (i.e., active fibrogenesis) and passive (i.e., the result of collaborative of connective tissue fibers in the zone parasitoses necrosis) of the fibrous septae between the Central veins and portal tracts.

The formation of such cept prevents ordered regenerative process by restoring the normal structure of the lobules. Regenerative growth of surviving islets between the septa leads to the formation of cirrhotic pseudomales. Compression regenerative cirrhotic nodules of the terminal branches of the hepatic veins and branches of the portal vein in portal tracts is the main cause of portal hypertension. The prognosis of cirrhosis of the liver largely determined by the severity and rate of progression of inflammatory and necrotic processes in the liver parenchyma and accompanying fibrosing reaction, i.e., the degree of activity of cirrhotic process (Loginov, A. C. et al., 1987).

As pointed out by N. X.Abdullaev (1968), the formation of connective tissue with necrosis of pechanec the Kani liver arise inflammatory and proliferative processes, accompanied by repair of liver cells and enhanced vascularization of tissue; a major role in the formation of fibrosis played by cells of the reticuloendothelial system. The above processes are accompanied gistologicheskoe hypoxia (respiratory depression, liver tissue), including after 20-40 days after cessation of exposure to the pathogen (CCl4). At the same time proliferative processes, replaced dystrophic after the abolition of the pathogen, begin to dominate, that is, begins to form itself cirrhosis of the liver.

According to the Rules of application for the invention (section 12.4.2), "if the invention relates to the use of previously known ... substances ... for a new purpose, then the analogues of known ... substances ... the same destination.

A. S. Loginov et al. (1987) reported the successful application of cirrhosis colchicine (1 mg per day, cycles for 5 days a week for 5 years. This drug is primarily used as antitumor and and antimitoticescoy effect, i.e. suspends the division of all cells in the body, including fibrous.

According to E. C. Krutskikh (1976) and A. S. Loginov et al. (1987), treatment with corticosteroids is about the Oia was anti-inflammatory, anti-allergic and anti-toxic effect, inhibition of the formation of fibrous tissue, suppression of immunological processes (formation of antibodies and autoantibodies), acceleration of protein synthesis, as well as a strong diuretic effect.

Because corticosteroid funds are the only known means used for inhibiting abnormal proliferation of connective tissue in the area of inflammation, that is the main pathogenetic start corrosione liver, their use for the treatment of cirrhosis of the liver we have chosen as a prototype of the claimed invention.

The prototype of the invention is the use of hormonal drugs (corticosteroids) to prevent proliferation of connective tissue in the liver parenchyma in her cirrhotic degeneration (Krutskikh E. C., 1976; Loginov, A. C. et al., 1987).

The essential features of the prototype:

1. Method of application prototype

Corticosteroids (prednisone, for example) when diagnosed with cirrhosis of the liver injected parenterally in a maintenance dose of 5-15 mg per day for 6-38 months (Krutskikh E. C., 1976; Loginov, A. C. et al., 1987).

2. Histological data when application is/100 g of body weight within 40-60 days), starting with a 60-day, in the liver parenchyma (along with displays relating to the direct action of the poison - ed.) some increase has arisen before the phenomenon of proliferation of connective tissue with proliferation of the bile ducts. The author further indicates that "... the Introduction of the 65-th day after the cessation of the poisoning CCl4on the 80th day of prednisolone, unlike control ... only slightly reduces the severity of morphological changes. In both groups of experiments are indicated some disconnecktie liver cells, distinct hydropic degeneration, significant proliferation kupperbusch cells, change tinctorially properties of hepatocytes and proliferation of connective tissue fibers. The difference with the introduction of prednisolone during repair ... is only to a lesser severity of the above changes.

The signs consistent with the essential features of the claimed invention.

1. The prototype is used for inhibition of connective tissue degeneration of the liver when it is corrosione.

2. The prototype is used when diagnosed with cirrhosis of the liver.

Criticism of the prototype.

The question of how desensibiliziruyuschee and protivovesa cirrhosis of the liver, remains debatable (Krutskikh E. C., 1976); information about their effectiveness varied.

According to one source, when using prednisolone described by way of the three-year survival rate is about 60%, without its use is about 20% (Krutskikh E. C., 1976; Loginov, A. C. et al., 1987).

However, according to other researchers, improvement in clinical and biochemical parameters in patients with active liver cirrhosis treated with prednisolone, is not accompanied by cessation of progression of the disease and does not extend lifespan, even cutting them with decompensated cirrhosis (Dalgat, D. M., 1974; Loginov, A. C., 1987).

Researchers have also pointed to numerous complications associated with steroid therapy: drug overdose due to impaired liver function; neuropsychiatric disorders, pain in the heart, increase blood pressure, osteoporosis, edema, lesions of the lung tissue, steroid diabetes, peptic ulcer disease (L. I. Egorova, 1969; Dalgat, D. M., 1974; Loginov, A. C. et al., 1987).

From our point of view, the most significant drawback of the application of the prototype is the inability to stop or apparent slowing of proliferation of connective tissue (i.e. progredient eroticheskoe degeneration of the liver (Abdulaev, N. X., 1968, 1989).

The disadvantage of the prototype can be considered as the need for long-term use and the inability preventive of its application, i.e. application if required (for example, after viral hepatitis or poisoning by carbon tetrachloride) will occur connective tissue pererozhdenie body.

Thus, some funds intended for the prevention and cessation of connective tissue degeneration of the liver, are not sufficiently effective.

The aim of the invention is to stop and prevent further connective tissue degeneration of parenchymatous organs when they are reliably diagnosed or suspected lesions, in particular the treatment of patients with chronic progressive sclerosing hepatitis (cirrhosis), pneumosclerosis, bronchiectasis disease, nodular goiter, breast, renal amyloidosis and other diseases with similar photomorphogenesis.

This goal is achieved by the fact that in contrast to the method of the prototype at reliably diagnosed or suspected connective tissue degeneration of parenchymatous organ (primer, through the blood stream periodically introduces product containing perfluorocarbons in the form of an emulsion; however, the preferred perfluorocarbons with possible long half-life (months, not days and weeks) and perhaps a greater ability to absorb oxygen and carbon dioxide.

The frequency and dose of the drug should depend

a) from half of his parenchymal organ (depending on the time of elimination of the drug from the time of elimination of macrophages and disappearance of secondary granulomas);

b) the General condition of the patient;

c) on the activity of the pathological process in the body (which is detected instrumental methods of research, in particular, anoscopy and biopsy).

For example, when diagnosed with cirrhosis of the liver, which developed after viral hepatitis, with intact its functions and the absence of obstructive jaundice, we believe shows the annual introduction of perfluorocarbon emulsion compounds containing perfluorocarbons with a very long half-life (of the time-tested and destroyed in the clinical application of this may be percocetmedicinedeliveredcod included in official medicine " the (claimed) of the drug may not be introduced because of the small (7 days) half-life and his unfitness, consequently, to carry out the declared purposes of the invention.

Information confirming the possibility of carrying out the invention.

Known function and properties of perfluorocarbon compounds.

Perfluorocarbon compounds (PFOS) are used in emulsified form as synthetic carriers of oxygen and carbon dioxide in the bloodstream and are used in the treatment of:

a) blood loss [Golubev, A. M., 1993, Ivanitsky, R., 1983;. Krylov N. P., 1983; Kuznetsova, I. N., 1993);

b) brain injury (Usenko L. C., 1993),

c) myocardial infarction (Golubev, A. M., 1993; Krylov, L. N., 1994);

(d) violations of cerebral circulation (Century. And. Vorobiev et al., 1993);

e) purulent wounds and rinsing of body cavities (C. I. Vorobiev et al., 1993);

f) viral hepatitis (Svetlov Century. N. et al., 1995);

g) other diseases associated with impaired organ microcirculation and peripheral circulation, changes in tissue metabolism and gas exchange (septic condition, infection, etc.) (Century. And. Vorobiev et al., 1993);

h) for anti-ischemic protection of donor organs (C. I. Vorobiev et al., 1993).

In clinical practice has already been applied perftoran, one of the drugs g the cases (Krylov, L. N., 1994, 1995).

Research aimed at the study of the chemical, physical and biological properties of PFOS, are carried out in many laboratories of the world (Ivanitsky, R., 1983; Krylov N. P., 1983, 1994, 1995).

In 1981, developed a drug "FeRAM" based emulsion of perpendicular/performability (PFTB). This emulsion has improved stability and longer stay in the bodies due to the presence of PTBA.

Consider the well-known function and properties of perfluorocarbon compounds on the example of perftoran (Ivanitsky, R., 1983; Krylov N. P., 1983).

Perftoran (and its analogues containing PF) was created and was used as chromosonal, i.e. the substance that manifests its therapeutic function when injected into the blood vessels and stay in the bloodstream (Ivanitsky, R., 1983).

Therapeutic functions of perftoran its developers and experts who have studied various aspects of clinical and experimental applications (C. I. Vorobiev et al., 1993), belong

a) transmission function (vector CO2and O2) from the bloodstream into the tissues and from the tissues into the blood stream;

b) rheological function (i.e. a means of reducing the viscosity and aggregation is Rozinov to osmotic and acid hemolysis;

d) a decrease in coronary vascular resistance;

e) improvement of cardiac output;

f) the impact on the blood flow in the great vessels, reduce resistance;

g) increasing the charge on the surface of cell membranes.

Developers indicate that ... "Perfluorocarbon compounds have on the body two effects. On the one hand, they improve the gas dynamics in systems of exchange of oxygen for carbon dioxide (Ivanitsky, R., 1983); ... "on the other part, being dissolved in the membranes of cells and organelles, temporarily change their viscoelastic properties, thereby ensuring the preservation of organs, protecting them from destructive ischemic damage." Perfluorocarbons well dissolved gases from 50 vol.% O2and up to 200% CO2but in the dynamics of their bad give, therefore, the main problem of engineering gas emulsions on the PFC is not only how to inject oxygen into the bloodstream, and how to make perfluorocarbon emulsion effective to give, ensuring its distribution to all systems of the body without distortion of the phase portrait of their interaction (Ivanitsky, R., 1993).

However, it is known that although the introduction of perftoran su is in tissue oxygen tension increases significantly (30-40%), because physically dissolved in the perftoran oxygen (unlike chemically bound to hemoglobin is almost completely absorbed by the tissues (Krylov N. P., 1983). Submicron size particles of perftoran allows him (unlike red blood cells) it is easy to penetrate in areas with impaired circulation, effectively transport oxygen and remove actively adsorbed in these zones of carbon dioxide (Ronkina T. I., 1993.) These same authors reported the ability of macrophages phagocytose perforadora connection with the formation of clusters.

The reaction of the tissues and organs in the introduction emulsions of PFOS, the first reaction of the liver, requires separate consideration.

According to A. M. Golubeva (1993)..."disposable intravenous emulsions of PFOS in the modeling of acute toxicity leads to the appearance in the cytoplasm of hepatocytes and Kupffer cells of small vacuoles. Their appearance is logged in a day after the introduction of the emulsion. After 5-7 days vacuoles disappear. Unchecked education macrophage (primary) granulomas. The functional value of the cells of immune system in conditions of introduction of emulsions of PFOS in animals is pursuing the ranks of granulomas. Macrophages (white blood cells) carry out phagocytosis of particles PFOS mainly in the first days of the experiment, participate in the formation of cellular responses to injury. The lymphocytes that form rosettes around macrophages, phagocytophila PFOS, participate in the formation of secondary granulomas, respond to stimulation "B" dependent areas of the follicles of the spleen and lymph nodes; there is an exit of lymphocytes from the cortical layer of the thymus gland. At certain stages of existence macrophages, phagocytophila PFOS, there are some differences of enzyme activity. During phagocytosis is some increase in the activity of redox enzymes, providing energy processes, indicating that activation of macrophages and phagocytosis of particles of PFOS. In these terms is not marked increase in the activity of hydrolytic enzymes, indicating chemical inertness perfluorinated hydrocarbons. In subsequent in macrophages increases the amount of glycogen, RNA; particles of PFOS localized in the cytoplasm of macrophages, have sudaniya. Transformed macrophages (epithelioid cells) secondary granulomas are characterized by significant aktivnosti, this is due to the formation of local immune reactions in connection with the elimination of the components of the dying macrophages primary granulomas.

Morphogenesis of granulomas formed by macrophages, phagocytophila PFOS , includes several phases. Primary granulomas consisting only of macrophages, phagocytophila PFOS, are formed in the liver, spleen, lymph nodes, bone marrow, adrenal glands, lungs, thymus gland during the first week after a massive intravenous PFOS. In the next 2-4 months primary granulomas are replaced by lymphocytes and transformed macrophages, which do not contain vacuoles in the cytoplasm, identified using a light microscope. It should be noted that this process is more pronounced when using emulsions, prepared on the basis of PFMSP, PFD/PFMRP, and sluggish secondary granulomatous is logged in the application PFTB. Gradually epithelioid cells completely replace the primary granuloma, with the formation of secondary granulomas, which are subject to recourse. Important is the fact that in place of the secondary granulomas is not formed connective tissue, almost no granuloma fibroblasts, is not observed education mentaly. Regressing secondary granulomas have been gradually replaced elements parenchymal (hepatocytes in the liver, lymphocytes in the spleen, lymph nodes, thymus gland). This unique biological response likely reflects the unique chemical inertness performancesin compounds. It should be noted that in one and the same body, you can see girolami, in various stages of development... . Note that A. M. Golubev (1993) describes the emergence of secondary granulomas with reduced formation of areas with reduced collagen disorders in almost all parenchymatous organs (lung, liver, thymus gland, adrenal glands, lymph nodes, spleen, etc.).

About the ability of macrophages phagocytose perforadora connection with the formation of clusters in the parenchymatous organs also tells And. So Rankin (1993).

Due to its recent development PFOS range of applications is still not fully investigated and expands with approbation.

In particular, previously no one had investigated the use of PFOS as a means of correction of the pathological processes in connective tissue degeneration of parenchymatous organs and, in particular, cirrhosis of the liver.

Temperature, has been used exclusively as a dynamic vector of oxygen, i.e. as (a) moving with the blood flow; b) outside the cell.

Before you point to the novelty of the use of PFOS for the aforementioned purpose, it is necessary to mention the principal difference of this method of application of PFOS and our (this does not apply to distinctive features of the prototype characteristics, but it is necessary for the reasoning of the fact that previously known substance is used for a new purpose).

Researchers (researchers and clinicians) as a side effect of the use of emulsions of perfluorocarbons found, as mentioned above, emulsified perfluorocarbons (particles smaller than a micron) has the ability for a long time to kumulirovat in parenchymatous organs, being incorporated in the phagocytes (macrophages) (Golubev, A. M., 1993; Rankin I. T., 1993).

It is also known that macrophages at the same time aggregations ("secondary granuloma" - [Golubev, A. M., 1993]), around which even in 2-4 months is not formed connective tissue (Golubev, A. M., 1993).

It is also known that when the necrosis of cells of any organ around areas of necrosis over time develops ucam (in a period of about 1-2 months) in connective tissue. This primarily refers to postnecrotic cirrhosis of the liver (Abdulaev, N. X., 1968; Loginov, A. C. et al., 1987).

However, anyone not previously declared and not used the use of perfluorocarbon compounds for the prevention of pathological proliferation of connective tissue, with targeted use of the ability of particles PF to be favoritemovie macrophages, with the formation of primary and secondary macrophage granulomas (see the Description of the prototype). This property PF was negative, and the developers wanted to get rid of it.

So, Sedov L. A. et al. (1993) did not recommend the repeated application of the PF-drugs because of their accumulation in the RES and in the tissues.

G. R. Ivanitskii et al. (1993) as a positive research result indicates creation of PF-second-generation drugs with a shorter half-life (based performancebased) than the previous drugs (perftoran, based performanceline); however, the presence of the drug "perftoran" in addition to performanceline (half-life 7 days) percocetmedicinedeliveredcod (half-life period of 90 days) they are considered a necessary evil with which it measures the same reduction of toxicity emulsion.

Moreover, researchers are trying to deal with the absorption of particles PF macrophages, to increase the circulation time of the emulsion PF in the blood. So, because of Putyatin (1993) recommends that to prevent absorption RES particles PF to apply the preliminary introduction of the fat emulsion, such as lipofundin.

In the well-known and available to us literature, as indicated above, did not specify anything about the purposeful use of PFOS for the formation of secondary granulomas consisting of phagocytophila particles PFOS macrophages, parenchymatous (pid) (in particular, in the liver), to prevent their connective tissue degeneration.

However, the positive effect from the use of a known substance (emulsion PFOS) for a new purpose due to this effect. Its implementation requires the following factors.

1. The presence in the body area of chronic inflammation (particularly in parenchymatous organs).

2. The presence in the body of phagocytes (such as macrophages), with the ability to phagocytose emulsified particles of PFOS.

3. The body's ability to make (including in the area of chronic inflammation) of the primary, and most importantly, the secondary is I.

The ability of particles PFOS possible long term stay in phagocytes, with education in the area of granulomas sites with independent gas exchange at the cellular and intracellular level (exchange of O2CO2), a kind of microclimate zones around the granuloma, which leads, as mentioned above, to the termination and inhibition of abnormal growth of connective tissue in the parenchyma of the organs.

Thus, the claimed invention differs from the known fact that for the first time in the practice formerly known substance is used for a new purpose.

Distinguishing features of the claimed invention from the prototype.

1. The invention is more efficient than the prototype, prevents further connective tissue degeneration of parenchymatous organs when they diagnosed the lesion, in particular, in the treatment of chronic progressive sclerosing hepatitis (cirrhosis).

2. The claimed invention is less harmful than the prototype.

3. The principle of the invention is totally different from the principle of the prototype.

4. The invention is simpler to use than the prototype, can be used in lesser periods.

To test the effectiveness of perfluorocarbon compounds to halt and prevent further connective tissue regeneration (corrosione) liver, we performed the experiment in vivo.

The experimental procedure.

In the experiments used 30 white nonlinear rats (females). Animals were divided into 3 groups.

During the preliminary stage of the experiments in groups 1-2 were established model of liver cirrhosis by daily subcutaneous injection of CCl4at a rate of 0.1 ml per 100 g weight (Lopukhin Y. M., 1971). Group 3 (intact animals, which did nothing) was used for comparative control groups 1 - 2.

2, 3 and 4 months since the beginning of the simulation cirrhosis in four different animals from groups 1 - 2 via laparotomy climbed sampling liver morphological study (performed by van gieson to identify soedinitelnoj tissue (Volkova, O. C., 1971)). At the same time, during laparotomy was performed macroscopic examination of the organs of the abdominal cavity.

At the same time performed the behavior, appearance and General condition of the animals, these data were compared with data intact healthy is spent regeneration of the liver tissue (postnecrotic cirrhosis of the liver) in animals 1 - 2 group moved to the main stage of the experiment.

The main phase of the experiment lasted 4 months.

Animals of the primary (first) group in the tail vein injected with a perftoran rate of 8 ml per 1 kg of body weight (lower regulatory clinical dose as krovozamenitel and desegregate (Krylov N. P., 1994)). The introduction of perftoran in this dose was repeated three times with an interval of 30 days.

The condition of the animals of all three groups and laboratory findings were recorded every 4 weeks and vzaimozacitivalis. At the same time via laparotomy climbed the biopsies biscuits (two different animals every 4 weeks) with subsequent morphological study. When laparotomy was registered with the state of the organs of the abdominal cavity.

30 days after the last injection of perftoran and 120 days after the beginning of the main phase of the experiment the animals were taken out of their experience by the introduction of excessive doses of calypsol/m, was executed by macro - and microscopic examination of the internal organs. At the same time out of the experience of animals in the control group.

On the basis of macro - and microscopic examination of internal organs, as well as data General state of Sadovaya.

1. The results of observations during simulation of cirrhosis of the liver.

After 1 week of modeling material changes to the status of animals not identified, except for some decrease in motor activity and food intake.

After 2 weeks the signs of intoxication increased somewhat, food consumption decreased by about 10%, defense reflex decreased from 5 animals, they became degchi to vyderzhivatjsya coat.

After 3 weeks data external examination without changes. At laparotomy macroscopically the abdominal cavity without pathology, liver and spleen not changed. The liver was taken for histological examination.

Histological examination of the liver was observed obesity hepatocytes, cloudy swelling of their protoplasm, noted connective tissue layer within lobules and periportal.

A month after the beginning of the experiment, the observed decrease in motor activity and defensive reflex of most animals. The appetite of animals has decreased, the average weight decreased by 10% from the original.

Histological examination of the liver was observed atrophic changes, growth soedinitel the Agen maceration around the urethra. At laparotomy macroscopically the abdominal cavity without pathology, the spleen is not changed. Liver lighter norms, marked the appearance of graininess (bumps on liver pinkish-yellow color D 0.2 mm), taken for histological examination.

Histological examination of the liver significantly expressed in the phenomenon of necrosis and necrobiosis of individual liver cells. Around the veins of a large number of large cells with muddy protoplasm and pinnatisectum core. Saved periportal connective tissue proliferation.

After 9 weeks the condition of the animals still, half of them expressed maceration around the urethra. If laparatomy macroscopically the abdominal cavity without pathology, the spleen is not changed. The liver is lighter than the norm, has become more friable and edematous, easy screamed. Occurrence of graininess (bumps on liver pinkish-yellow Zeta 02 D, mm) taken for histological examination.

After 12 weeks, the animal still. At laparotomy macroscopically the abdominal cavity without pathology, the spleen is not changed, no ascites. The liver is lighter than the norm, has become more friable and edematous, easy screamed. Occurrence of graininess (bumps on liver ro the Institute of liver installed, what dystrophic changes in the liver cells continue to be, dominated by the phenomenon of proliferation of connective tissue, are found in a number of large binucleate cells.

3 months after the beginning of the simulation cirrhosis rats of the first and second groups have the following differences from intact (group 3).

1. Reduced appetite (about 20%).

2. Constantly gather together, in spite of the heat (in the laboratory of the 25oC).

3. Do not fight and do not play with each other.

4. Coat half tousled, unkempt. They also expressed maceration of the skin around the urethra; they are also the most sluggish, defensive reflex is reduced.

5. The average weight of the rats decreased by 20% from the original.

6. The majority of rats with monotonous food since the beginning of the experiment, the color of feces was lighter and ranges from light brown to dark yellow (normal dark brown to black).

At laparotomy macroscopically the abdominal cavity without pathology, the spleen is not changed, no ascites. The liver is swollen, thick, easy screamed, has a whitish tubercles (D=0,2-0,3 mm), and whitish spots 1-3 mm, more at the edges.

When GIS is and with the gradual restructuring of the architecture of the liver due to proliferation of connective tissue.

After 4 months the condition of the animals has somewhat deteriorated in comparison with the data of the third month; became more sluggish, defensive reflex mild, color of feces from light yellow to dark yellow.

At laparotomy macroscopically the abdominal cavity without pathology, the spleen is not changed, no ascites. The liver is lighter than normal, became more dense, smaller, easy screamed. Grain became more pronounced (bumps on liver yellowish-whitish D=0.3 to 0.4 mm), whitish spots become more and more.

Histological examination of the liver along with the above changes were observed thickening of the Central veins, the narrowing of their lumen and around the veins were detected foci of desolation.

2. The results of the main stage of experiments.

4 weeks after the introduction of perftoran first became apparent differences between the animals of groups 1 and 2.

The status of all zhivotnyh group 1 was better than all the animals of group 2, the behavior of their more active defensive reflex is more pronounced eaten the food is 20% higher than in group 2 and than a month ago; the hair was smooth and shiny; it's not going together, began to play and fight each ruchnoy cavity liver several smaller than normal, normal color; at the edges of the liver stored grain size D= 0.1-0.2 mm; whitish spots no; other organs revealed no pathology.

Histological examination of the liver connective tissue layer, as is within the segments, and periportal were presented in the form of narrow bands; gross violations of the architectonics of the liver were not found.

The condition of the animals of group 2 was better than a month ago; but worse than in groups 1 and 3, is still reduced defensive reflex and appetite, hair unkempt and disheveled; sluggish.

Histological examination of the liver of the phenomenon of proliferation of connective tissue become more apparent as periportal, so in the zone "false lobules"; hepatic cells in a state of fatty degeneration; in General, there were all the signs of developing cirrhosis of the liver.

2 months after the beginning of the second phase difference in the condition of the animals first and second groups became apparent.

The General condition of the animals of the second group remained virtually unchanged, except that the hair became smoother; defensive reflex and appetite is still reduced. During the inspection of the abdominal cavity, the liver reduced m the study in this group are morphologically showed signs of emerging cirrhosis - saved disturbance architectonics liver tissue, along with areas of regeneration of liver cells there are signs of strain them portal vein; saved rude and deforming the growth of connective tissue periportal in areas of necrosis.

However, the condition of the animals of the first group was still not distinguishable from the state of the intact animals. Upon examination of abdominal cavity organs - the liver is somewhat reduced in size, color normal, there is a small grain size, a little condensed, but less than in group 2. Other abdominal organs without pathology. Histological examination of liver sections of fatty liver were less common and pronounced than the month before, noted that regenerative rebuilding the liver has evolved preservation and restoration of the original architecture; connective tissue fibers became more gentle and not deformed portal tracts.

3 months after the second stage of the condition of the animals first and second groups remained without significant changes, preserving the same differences that and the month before.

During the inspection of the abdominal cavity of the animals of the second group susistence have become smaller in size, the edge of the liver is more pointed, she became more dense. Other abdominal organs without pathology. Histological examination of the liver is also significant changes in the morphological status is not marked, except for some increase in areas with fatty degeneration. In General, the morphological picture is regarded as the well-established and progressive postnecrotic cirrhosis of the liver.

During the inspection of the abdominal cavity of the animals of the first group of liver differences from animals of group 3 (control laparotomy three animal groups 3) is not revealed, except for the presence on the surface of the liver of animals of the first group of small grain sizes (d=0.05 to 0.1 mm). Other abdominal organs without pathology. Histological examination of the liver morphological picture is regarded as residual effects of postnecrotic liver fibrosis, in General, in comparison with the previous data, the positive dynamics in the areas of fatty degeneration unit, the architectonics of the liver close to normal.

4 months after the start of the second phase of the experiment all the animals of the first and second groups, and 2 rats in the third group are derived from the experience of the introduction and the second group has stabilized completely, in some animals showed increase in physical activity, appetite, excitement defensive reflex.

Upon examination of the thoracic cavity pathology in all three groups were not found. During the inspection of the abdominal cavity of the animals of the first group of liver sealed and has more brick hue, and the edge is more pointed than in the intact group, small grain size on the surface of the liver and the "oiliness" of the liver was preserved, although these symptoms have decreased slightly compared to the three-month period. In the rest of the abdominal organs without pathology. Histological examination of the liver morphological pattern is still consistent with the developing postnecrotic cirrhosis of the liver.

During the inspection of the abdominal cavity of the animals of the second group compared with the intact group noted only the presence of small grain in some places hepatic lobe and inaccurate reduction of share; the rest of the abdominal organs without visible pathology. Histological examination of the liver of a registered separate areas of fatty liver, interspersed with areas of the liver with clear signs of regeneration of hepatocytes with full Voss is ri comparison of the collagen structures of the parenchyma. If in the control group of connective tissue proliferation in the liver parenchyma was sitting in the portal venules and veins, forming the classic "false wedges", which was generally characterized as postnecrotic cirrhosis of the liver, in the experimental group connective tissue was presented in the form of delicate fibers around the hepatocytes and along the portal tracts and parcels of fatty degeneration; architectonics liver testified adequate regeneration and the possibility of further normal operation.

The characteristic of a medical and economic efficiency.

The results obtained during the experiments, allow us to recommend the use of the invention for preventing and/or termination of connective tissue degeneration of parenchymatous organs, that is, diseases that are considered pathogenetically incurable; in particular the treatment of patients with cirrhosis and fibrosis of the liver.

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1. The use of perfluorocarbon compounds as a means for the prevention and treatment of pathological proliferation of connective tissue in parenchymatous organs.

2. The use of perfluorocarbon compounds on p. 1, as a means for the treatment of connective tissue degeneration of the liver.

 

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FIELD: medicine, surgical stomatology.

SUBSTANCE: in case of patient's average-severe or severe state before surgical interference or at satisfactory state - after surgical interference one should intravenously once introduce perfluorane at the dosage of 1-3 ml/kg body weight followed by daily treatment of the wound with perfluorane, washing and introducing perfluorane-impregnated gauze tampons till the end of exudation phase. The method enables to widen the number of preparations to treat odontogenic phlegmons of oral area, simplify therapeutic technique due to excluding the work with patient's blood, accelerate the process of purification and regeneration of soft tissues in the region of inflammation and shorten therapy terms.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: medicine.

SUBSTANCE: method involves introducing perfluoran bubbled with ozone-and-oxygen mixture with given ozone concentration of 3000 mkg/l during 15 min.

EFFECT: restricted peritoneal inflammation.

FIELD: medicine.

SUBSTANCE: the present innovation deals with treating different wounds. The suggested perfluorocarbon emulsion is being used as the medium in case of ultrasound treatment of wounds. Moreover, the enhancement of reparative processes is observed in the wound along with accelerated wound healing due to development of perfluorophages in area of inflammatory process and to higher gas saturation of perfluorocarbon emulsion against other media applied before. The emulsion under the action of low-frequency ultrasound obtains other properties (increased specific weight, increased fluidity, higher wettability of purified surface, the presence of abrasive properties) necessary for achieving technical result. All these measures, thus, enhance reparative processes in the wound because low-frequency ultrasound raise to a higher power the action of perfluorocarbon emulsion both regarding ultrasound purification and its curative action upon wound.

EFFECT: higher efficiency.

5 dwg, 1 ex

FIELD: cosmetology, dermatology.

SUBSTANCE: the present innovation deals with applying preparations affecting the values of blood microcirculation in skin. The suggested preparation is the emulsion of perfluorocarbons that increases skin resistance to negative impacts and favorably affects microcirculation by steadily increasing its total level that enables to improve the state of microcirculatory canal of skin.

EFFECT: higher efficiency.

6 dwg

FIELD: medical engineering.

SUBSTANCE: method involves exposing an intraocular neoplasm after vitrectomy and retinotomy, smoothening retina with perfluororganic compound later substituted with silicon oil. After having removed the neoplasm, intravenous 10% Perfluorane emulsion transfusion is carried out at a rate of 60 drops per 1 min in the amount of 80-100 ml. Next to it, photosensitizer is intravenously drop-by-drop introduced into cubital vein of the same arm. Laser irradiation of blood is carried out with power of 20-50 mW through laser light guide set in advance into cubital vein of the other arm in 5-15 min after starting introducing Perfluorane. When applying 0.1-1% water solution of Khlorine as photosensitizer at a dose of 0.2-0.5 mg/kg, irradiation is carried out at wavelength of 630-633 nm during 10-45 min. The treatment is administered twice with 5 days long pause.

EFFECT: enhanced effectiveness of treatment; reduced risk of tumor cells dissemination and metastases formation.

3 cl

FIELD: medicine.

SUBSTANCE: the suggested emulsion contains quickly excreting perfluoroorganic compounds as perfluorodecalin and perfluorooctylbromide, perfluoroorganic additive and phospholipids in the form of dispersion prepared due to homogenization at pressure of not less than 100 atm. in water-saline medium. Perfluoroorganic additive is being the mixture of perfluorated tertiary amines - perfluorotripropylamine and its co-products: cis- and trans-isomers of perfluoro-1-propyl-3.4-dimethylpyrrolidone and perfluoro-1-propyl-4-methylpiperidine. The method to obtain the emulsion deals with obtaining the dispersion of phospholipids due to homogenization at pressure of not less than 100 atm. in water-saline medium followed by thermal sterilization, then comes homogenization at pressure of the mentioned perfluoroorganic compounds in dispersion of phospholipids and thermal sterilization of the ready-to-use emulsion. The latter is indicated to treat blood losses, hypoxic and ischemic states, improve oxygen supply by blood and keep isolated perfused organs and tissues. In accordance to the present innovation stability of emulsion has been increased and its qualities have been improved. Storage period of emulsion in its unfrozen state at +4 C corresponds to 12 mo, not less, moreover, biocompatibility of emulsion with biological medium (blood, plasma or serum)has been kept.

EFFECT: higher efficiency of application.

20 cl, 13 ex, 21 tbl

FIELD: cosmetology, dermatology.

SUBSTANCE: the suggested aqueous emulsion of perfluorocompounds contains perfluorocompounds, water and emulsifier, additionally it may contain emulsion wax, moreover, as an emulsifier it contains block-copolymer of ethylene oxides and propylene, components should be taken at certain ratio. Method for obtaining aqueous emulsion deals with mixing aqueous solution of emulsifier and emulsion wax while heating in necessary quantities, cooled mass should be supplemented with perfluorocompounds at constant mixing with ultra-mixer at the rate of 15000 rot./min to homogenize then the mixture obtained, one should perform 3-5 cycles at pressure not exceeding 600 bar. The suggested method enables to obtain the emulsion of high stability and obtain wide-range spectrum of products for cutaneous application.

EFFECT: higher efficiency of application.

3 cl, 1 dwg, 6 ex, 2 tbl

FIELD: infectious diseases and surgery.

SUBSTANCE: wound surface is covered with perfluorane porcine spleen perfusate. Application is repeated daily over a period of 4-12 days depending on the wound surface area and virulence of causative agent. Perfluorane porcine spleen perfusate is prepared by passing perfluorane through spleen vessels at velocity 20-40 ml/min and total volume up to 1 L. Perfusate is used in amount 0.5-0.7 ml per 1 cm2 wound surface area.

EFFECT: activated local immunity and tissue oxygenation.

2 ex

FIELD: medicine, anesthesiology, resuscitation.

SUBSTANCE: under conditions of artificial pulmonary ventilation at positive pressure at the end of expiration one should set the level of positive pressure at the end of expiration being above against pre-chosen optimal one for 4-8 cm water column. About 10-15 min later one should introduce perfluorocarbon as aerosol with the help of nebulizer for 10-15 min. The innovation enables to introduce perfluorocarbons without depressurization of respiratory contour, decreases damaging impact upon pulmonary parenchyma and, also, reduce invasiveness of the method and decrease expenses of perfluorocarbons.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: medicine, traumatology.

SUBSTANCE: one should puncture the wound with perfluorane at the dosage of 30 ml, not more/kg affected area once daily for 14 d, not more. The present innovation provides prophylaxis of reperfusion and purulent-necrotic complications in case of gunshot wounds and that of anaerobic infection due to oxygen supply to ischemized wound tissues at adequate quantity during pre-hospital period.

EFFECT: higher efficiency of therapy.

1 ex

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