Method for treating the cases of chronic diffuse hepatic diseases

FIELD: medicine.

SUBSTANCE: method involves administering hepatoprotector means and transplanting spinal marrow stem cells. The stem cells are selected from aspirated spinal marrow sample taken from the patient. The portion to be introduced is calculated so that the number of CD34-position cells is equal to 40-240x106 cells. Then the portion is divided into two halves of which the first one is intrahepatically introduced, and the second one is intravenously introduced.

EFFECT: enhanced effectiveness of treatment; reduced risk of hepatic cell insufficiency syndrome.

2 cl

 

The present invention relates to medicine, in particular to methods of treatment of chronic diffuse liver diseases, accompanied by the development of hepato-cellular failure, including liver cirrhosis, toxic, viral and mixed etiology, chronic hepatitis, primary sclerosing cholangitis, but not limited to these pathologies. Cause hepatic cell failure in patients with chronic diffuse liver diseases is the loss of hepatocyte toxicity of different agents and the replacement of dead cells by connective tissue. The only effective treatment for end stages of liver cell failure remains liver transplantation. However, the shortage of donor organs is the limiting factor. In this respect, of great interest technology substitution cell therapy, which is an alternative to organ transplantation. It is known that the high regenerative capacity of the liver caused by the proliferation of hepatocytes. Therefore, one of the directions substitution of cell therapy is the transplantation of Mature hepatocytes. Isolated hepatocytes can be injected into subcutaneous tissue, the spleen, the liver parenchyma [1]. At the same time as donor material can ispolzovatsya only hepatocytes adult, but the cells of fetal liver [2, 3].

Thus, a method is described according to which in order to relieve the hepato-cellular failure of autologous hepatocytes isolated from fragments of liver, were injected into the spleen of patients with cirrhosis and chronic hepatitis [4]. Transplantation of hepatocytes was not accompanied by the development of any complications, but due to the use of autologous material and obtain a small number of hepatocytes significant clinical effect were noted. There is also known a method, according to which patients under the capsule of the rectus abdominis muscle was injected allogeneic cells (about a billion cells)obtained from the liver 9-17-week human fetuses of. The introduction of such cells was not accompanied by the development of transplantation reactions in some patients was accompanied by a decrease in the manifestations of hepatic cell failure [5].

The disadvantage of the above methods is that the introduction of hepatocytes allows only temporarily improve liver function, without affecting significantly the repair processes of damaged liver parenchyma. The big problem is the isolation of donor hepatocytes and maintaining their functional activity during storage, the risk of transfer of infection when using allogeneic donor material and an opportunity again in the party transplantation reactions. In the case of cells of the embryonic liver, there are ethical constraints, a high risk of contamination of the material by bacterial and/or viral contamination. In addition, the literature discusses the possibility of malignant transformation of embryonic cells.

Conducted subsequent research has shown that along with hepatocytes important role in liver regeneration, especially in chronic damage of the liver cells, play a stem liver cells, able to differentiate into hepatocytes and cholangiocytes. Thus, a method of obtaining stem cells to the liver for treatment of degenerative liver disease [Patent US 6,129,911, published. 10.10.2000,]. According to this method of liver tissue receives stem cells (SC) or doublets stem cells with hepatocytes, which are administered to patients. Allotment IC includes disaggregatio connective tissue by enzymatic processing, filtering through the pores of the nylon fiber, centrifugation in density gradient percoll, negative selection with magnetic beads, enzymatic treatment with trypsin and the positive selection of cells expressing markers of stem cells - SC, SAM, dipeptidyl-peptidase-4 using magnetic beads or flow cytofluorimetry. Received the stem cells are administered either through p is Stalnoy Vienna, or deposited in the spleen, the pancreas. Source of cells can be native liver tissue obtained by biopsy or partial hepatectomy; cadaveric liver tissue donor; liver tissue of the fruit. Significant disadvantages of this approach are the complexity and high cost of obtaining stem cells of the liver, the limitation in obtaining a sufficient number of autologous stem cells and the lack of an evidence base on the effectiveness of treatment for liver pathology in humans.

Addition of liver stem cells in regeneration of the liver can also participate SC bone marrow. Thus, it was shown that the transplantation of allogeneic bone marrow donors-men in the liver of female recipients is found in liver cells with Y-chromosome [6]. In addition, it is shown that transplantation of bone marrow SC mice in a model of lethal pathology associated with severe liver failure due to a deficiency of the enzyme fumarylacetoacetate hydrolases, accompanied by a survival of 30% of the animals. These data served as the basis for the use of the SC bone marrow to stimulate the regeneration of the liver [7].

So, Goff and Peterson was the method of transplantation of bone marrow cells to stimulate regeneration and repair of liver [Patent # WO 0050048, published. 31.08.2000,]. According to Dan is th way to stimulate regeneration in the body of the recipient is entered cells in the bone marrow dose, sufficient to ensure the formation of new hepatocytes, cholangiocytes and/or oval cells of the liver. As a source of stem cells can also be used enriched fraction oval cells of the liver, isolated using antibodies that recognize Thy 1 antigen. Bone marrow cells or oval cells can be genetically modified to Express the functional active protein, transplanted to the matrix or treated prior to transplantation by growth factors. Before transplantation, the bone marrow cells can be enriched by selection of cells expressing markers of stem cells (Thy 1, CD34, Flt-3 ligand, c-kit), using the methods of separation of magnetic beads, affinity chromatography or flow cytofluorimetry. The appearance in the liver cells (hepatocytes, cholangiocytes, oval cells) donor bone marrow origin was proved in experimental models of rats on the appearance of hepatocytes with markers of the donor's stem cells.

However, a significant drawback of this method is the lack of data on its clinical efficacy in the treatment of liver disease in humans. Not clear how this will affect the appearance of the hepatocytes and bone marrow origin of the pathological process in the liver. Moreover, the damage model is tion of the liver in experimental animals is fundamentally different from the real clinical situation etiological factors, the timing of development of the pathological process and the mechanisms of its formation. Another disadvantage is the lack of data about the volume of bone marrow in humans, sufficient for the generation of new liver cells.

Also known is a method of treatment of chronic hepatitis (application RU # 2003105379 published 20.09.2004,), lies in the hepatoprotective and immunosuppressive effects by introducing Heptral, legalon, LIV-52, prednisolone, azathioprine and amino acid mixtures, as well as the introduction of the cytokine G-CSF, causing the migration of hematopoietic stem cells from the bone marrow to the periphery capable of repopulating liver and differentiate into hepatocytes. However, the introduction of G-CSF in patients with chronic hepatitis, as with other chronic diffuse liver diseases that can lead to activation of the inflammatory process due to the ability of G-CSF to induce increased levels of neutrophils and their products proinflammatory cytokines. In addition, the use of immunosuppressants may, on the one hand, to provoke the activation of viral replication in patients with chronic hepatitis of viral etiology, and on the other hand, reducing the efficiency of the migration of stem cells in the liver and their differentiation in the epithelial cells of the liver. Finally, by definition, method is to treat the HRO is practical hepatitis and does not include the category of patients with outcomes in cirrhosis, when the leading pathogenetic factor is the hepatic cell failure.

The technical task of the present invention is to provide a method for treatment of chronic diffuse liver diseases, including the treatment of a wide range of diseases involving liver cell failure, including cirrhosis of the liver.

The problem is solved through the use of hepatic and transplantation of stem cells directly isolated from the aspirate bone marrow of the patient, which is injected and intrahepatic under ultrasound control, containing the number of CD34-positive cells sufficient to achieve clinical effect.

The use of the claimed method allows to achieve a significant improvement in clinical laboratory parameters by reducing the manifestations of hepatic cell failure in patients with chronic diffuse liver disease, including patients with cirrhosis of the liver toxic and viral etiology. While treatment with use of the proposed method is well-tolerated and does not cause the development of any adverse or toxic reactions.

The method is as follows. The patient receives a course treatment hepatoprotectors in the form of preparations of ursodesoxycholic sour is you (Ursosan or Ursofalk in a dose of 10-15 mg/kg/day and/or Heptral (800 mg, in/in 5-10 injections). After this the patient in the operating conditions under anaesthetic support specialist hematologist is the procedure performs, during which the wing of the Ilium in a sterile bottle with a solution of heparin (10000-15000 Ed) gets aspirate bone marrow in the volume of 200-300 ml laboratory unit vial is incubated at 37°C for 40 minutes After gravity separation of whole bone marrow in a separate vial was going "top" faction, consisting of cells of lykousis, which then centrifugeuse and deposited (1200 rpm, 15 min). Adosados containing autoplaza, collected in separate sterile vial, and the sediment cell lykousis resuspended in 40-50 ml of phosphate-buffered saline containing 10 U/ml heparin (SFR/heparin). Then cells lykousis layered on a density gradient ficoll-urografin (1,078 g/l) and centrifuged for 20 min at 3000 rpm/min Collected from the interphase of bone marrow mononuclear cells (MNCs KM) washed three times in SFR/heparin. With the objective characteristics of the isolated cells and counting hematopoietic stem cells determine the total number of selected MNCs KM, their viability by staining Trifanova blue, and the relative abundance among them CD34+stem cells by the method of protoc the second cytofluorimetry (FACSCallibur, Becton Dickinson). Half selected cells resuspended in 2-3 ml of saline, supplemented with 10% (v/v) autoplasma (the first portion). The other half in 50-100 ml of saline, supplemented with 10% (v/v) autoplasma (the second portion). The first portion is injected intrahepatic 3-5 points from a single injection under ultrasound control. The second portion intravenous drip.

This method of treatment of chronic diffuse liver diseases has been tested in a clinical setting based on immunological clinic of immunology Institute of Clinical immunologists SB RAMS, Novosibirsk. The proposed method was treated 14 patients (8 men and 6 women) aged from 27 to 67 years. According to the histological examination of liver biopsy in all patients were found to have cirrhosis of the liver. According to the classification of child-Pugh a cirrhosis in the stage And was diagnosed in 43% (6/14) of cases in stage b in 50% (7/14)of cases, stage - 7% (1/14). Cause of cirrhosis in 4 patients was toxic hepatitis, 6 - chronic viral hepatitis (b, C, or combined options - b+C, B+D), and 4 had hepatitis mixed etiology (viral+toxic). The amount allocated from the aspirate of bone marrow MNCs ranged from 0.65×109to 5.3×109cells and averaged 1,77±0,2×109. The amount of injected SC in terms of CD34-POS is positive cells averaged 107± 26×106cells, varying in the range of minimum and maximum values from 40 to 240×106cells.

Stem cell transplantation was characterized by good tolerability, in particular the absence of side reactions. Subfebrile temperature was recorded only in 2 of 14 patients. According to a prospective observation, after 1-3 months after transplantation 43% of patients reported subjective improvement in terms of reducing the severity asteno vegetative syndrome, improve health and vitality. Objectively reduction of swelling, pain, dyspeptic and hemorrhagic syndromes were recorded, respectively, at 57; 86; 93 and 43% of cases. According to the biochemical examination within 1-3 months after transplantation increased albumin serum was observed at 64.3% of patients, a reduction ACT and ALT - 71,4% of patients. The deterioration in the form of increase hepatic cell failure 2 months after transplantation were recorded only in 1 patient.

Thus, the proposed method for the treatment of chronic diffuse liver disease with the use of hepatic and transplantation of autologous stem cells from bone marrow that helps achieve positive dynamics of clinical and laboratory parameters, including red eye reduction is of cytolysis and improve protein synthesis of the liver, attesting to the severity of liver cell failure. While treatment with use of the proposed method is well-tolerated and does not cause the development of any adverse or toxic reactions.

Below are clinical examples of this method of treatment in patients with cirrhosis of the liver.

Example 1. Patient A., 41.

Was admitted to the hospital of immunopathology 15.10.2003, with complaints of severe General weakness, decreased performance, heartburn, constant bitter taste in the mouth, vomiting, sometimes with blood, pain, aching character in the right hypochondrium, not associated with food intake, skin itch.

The patient for many years abused alcohol. The diagnosis of cirrhosis was first staged in 1994, when he felt weak, the increase in the abdomen, weight loss, pain in the right hypochondrium and epigastrium. He was then diagnosed with peptic ulcer of the duodenum. Markers for hepatitis b, C and D were always negative. Repeatedly treated in gastroenterology departments.

On examination: the patient is moderate. Skin dry, grayish-yellow, in axillary regions hyperhidrosis. On the skin of the breast of a single spider veins, gynecomastia, paraumbilical area varicose veins of the anterior abdominal wall, n is the existence of Palmar erythema. Tongue moist, "crimson", the root is covered with whitish-yellow coating on the tongue a few small cracks.

Palpation of the abdomen is soft, is palpated increased serving 5 cm liver, the edge of a dense, rounded. The size of the liver by karlovu 14×15,5×16 see Spleen not palpated. Free fluid in the abdominal cavity is not defined. The result of histopathological studies: Chronic hepatitis moderate activity (IGA=18 points), formed cirrhosis of the liver. Analysis: PETIT 84%, platelet count 177 thousand/ál; AST - 0,73 mm/l; ALT - 0,60 mm/l; index De Rytis - 1,2; GGT - 53,3; KFK - 373 U/l; cholesterol - 6,69 mm/l; beta-lipoproteins and 64.5 Units; total protein - 77 g/l, albumin - 49 g/L. According to ultrasound: liver size increased - the right proportion of 14×13 cm, left - 6,0×5,4 cm, spleen S=58 cm2. Echoscopically diffuse changes of a liver, splenomegaly, signs of portal hypertension.

Diagnosis after examination: liver cirrhosis ethanol etiology, active phase, moderate activity. Stage And on the classification of child-Pugh.

The patient received treatment with hepatic (Heptral 400 mg/×5 days). 22.10.03 made the marrow puncture and received 200 ml of aspirate bone marrow from the iliac wing bone from which the selected 650×106OOC containing 60×106CD34+cells. From either the half cells in 2 ml of saline solution was introduced under ultrasound intrahepatic, and the other half in a volume of 50 ml of saline was injected, calello. Stem cell transplantation was not accompanied by the development of side effects. When viewed through the month marked improvement: significant reduction of weakness; the disappearance of pain, heartburn, vomiting was not observed; bitter taste in the mouth is not worried. Upon physical examination the liver size decreased and amounted karlovu 12,5×14×15 cm

Through year - 01.11.2004 was hospitalized at the clinic for examination. Complaints: rarely pains in the right hypochondrium, associated with movement, tendency to constipation. At survey: Palmar erythema is absent, decreased the number of vascular asterisks (there is only one telangiectasia in the neck), there is a decrease in the severity of gynecomastia. Is palpated densified left lobe of the liver, painless. The size of the liver clinically not increased.

According to histopathological studies: chronic hepatitis, mild activity (IGA=10 points). Fibrosis stage 4 (cirrhosis). In blood platelets - 162 thousand/ál; ALT - 0.67 mm/l; AST - 0.46 mm/l; index De Rytis 0,68; albumin - 44 g/l, ck - 307 U/l, cholesterol - 6,12 mm/l; beta-lipoproteins - 60,1 Ed.

The results of ultrasound: liver size normal: right lobe - 12×11 cm, left 7×5.7cm, portal ve is a - 14 mm; spleen - S=50 cm2. Echoscopically diffuse changes of a liver, moderate signs of portal hypertension.

Thus, after 12 months after treatment by the proposed method noted positive dynamics of clinical and laboratory parameters in the form of the disappearance of pronounced weakness, dyspeptic disorders, improve efficiency and tolerance to physical activity, normalization of the liver and spleen, reduce the activity of the inflammatory process from 18 to 10 points according to the results of histological examination of liver biopsy specimens, the improvement of biochemical parameters of blood.

Example 2. Patient A., 36 years.

Was admitted to the hospital of immunopathology, 15.06.2004 with complaints expressed General weakness, increasing the volume of the stomach, swelling of legs and feet, decreased urine output in the days free from diuretics, yellowness of the skin and sclera, dry skin, dry mouth, thirst, loss of appetite and flatulence, pain in the right hypochondrium, shortness of breath with slight exertion, palpitations, subcutaneous hemorrhage on legs and belly.

The patient considers himself since 1994 After surgery "caesarean section" long-continued General weakness, fever. In 1995 came the yellowness and itchy skin. Diagnosed with chronic cholangiohepatitis. The treatment included the hepatoprotectors, infusion therapy, vitamins. In 1999 he became a marked increase in body mass by increasing the volume of the stomach, decreased urine output. At the next survey in 2000 revealed antibodies to HCV, with ultrasound signs of cirrhosis of the liver, ascites, portal hypertension, on the basis of what is diagnosed with liver cirrhosis of viral etiology, chronic viral hepatitis C. Additionally been appointed diuretics with good initial effect is stoped signs of ascites. Since the autumn of 2003, despite the constant diuretics, ascites persisted. After discharge from the hospital almost no improvements were noted in 2004 joined the swelling of the legs. In may 2004, during one hospitalization on FGS showed signs of varicose veins of the esophagus, blood - anemia syndrome of mild severity, hypoproteinemia with hypoalbuminemia, hepatosplenomegaly.

An objective examination of the patient's state of moderate severity, contact, speech somewhat slow. Marked interesest skin and sclera, "raspberry tongue", varicose veins of the anterior abdominal wall, the sharp increase in the volume of the stomach, the tension of the anterior abdominal wall due to ascites. Palpation of the abdomen is moderately painful during bowel swollen. Liver and spleen not palpable, percutane - the size of the liver is reduced, spleno egale.

According to laboratory examinations revealed anemia (Hb=101 g/l), leukopenia (leukocyte 3,2×109/l) and thrombocytopenia (platelets 77 thousand/ál). Total protein - 55.8 g/l; albumin - to 26.2 g/l; thymol turbidity test - 15,7; bilirubin total - 60,6 m/l, ALT - 190 U/l; ACT - 80 U/l; urine was determined by the presence of acetone and urobilin. The ultrasound showed a decrease in the size of the liver, cirrhosis, ascites, portal hypertension, splenomegaly. The results of histopathological studies from 17.06.2004 confirm signs of chronic hepatitis moderate activity, formation of liver cirrhosis. PCR on viral hepatitis in a liver biopsy sample is negative. When x-ray of the chest revealed a right-sided hydrothorax.

Diagnosis after examination: liver Cirrhosis of viral etiology. Chronic viral hepatitis C, active phase (moderate activity). Stage In the classification of child-Pugh. Symptoms of portal hypertension - varicose veins of the esophagus and the anterior abdominal wall. Ascites. Syndrome hepatic cell failure. The syndrome of hypersplenism (cytopenic syndrome). Right-sided hydrothorax.

The patient completed the treatment by hepatoprotectors, including Ursofalk (10 mg/kg/day to 10 days) and Heptral (800 mg/10 days). 26.06.2004, performed the transplantation of autologous stem is o cells. Isolated from the aspirate of bone marrow MNCs containing 240 million CD34+cells entered as two servings - 500 million in volume of 2 ml and intrahepatic 500 million in volume to 50 ml/drip. Adverse reactions with the introduction of stem cells was not observed.

During follow-up after 1 month marked improvement: stoped fatigue, decreased body weight due to the reduction of ascites disappeared swelling in the legs, yellowness of the skin, bloating, bruising on legs, icteric coloration of the sclera. According to laboratory tests: stoped anemia (Hb - 130 g/l), increased the number of platelets to 290 thousand/ál. In the analysis of urine the presence of acetone and urobilin is not selected, ALT - 73 U/l, ACT - 118 units, bilirubin total of 24.8 μm/l, total protein 75 g/l, albumin - 32.1 g/l, thymol test - 12 Unit.

After 3 months, in September 2004 there was a further reduction of body weight by reducing the severity of ascites, mild dyspeptic syndrome. During examination: Hb 120 g/l, leucocytes - 2,8×109/L, platelets - 190 thousand/ál, ALT - 60 U/ml, ACT - 87 IU/ml, bilirubin total of 9 μm/l, total protein 66 g/l, albumin - 30,8 g/l, thymol test - 11,65 Ed. The data obtained indicate that after 1-3 months after treatment under the proposed method, the patient noted the positive dynamics of clinical and laboratory findings in the form with which to achieve the severity asteno vegetative syndrome, ascites, anemia and thrombocytopenic syndromes, improve protein synthetic function of the liver (increased albumin levels), reduced cytolysis (decrease thymol turbidity tests and ALT)normalization, urine analysis (disappearance of acetone and urobilin), which generally indicates a decrease in the severity of liver cell failure.

Thus, validation of the proposed approach in a clinical setting allows us to conclude that this method involving the use of hepatic and transplantation of autologous stem cells from bone marrow allows to achieve a significant improvement in clinical laboratory parameters by reducing the manifestations of hepatic cell failure, primarily syndromes cytolysis, mesenchymal-inflammatory, jaundice, portal hypertension and, to a lesser extent of cholestasis in patients with chronic diffuse liver disease, including patients with cirrhosis of the liver toxic and viral etiology. While treatment with use of the proposed method is well-tolerated and does not cause the development of any adverse or toxic reactions.

Literature

1. Ohashi, K., Park, F., M.A. Kay Hepatocyte transplantation: clinical and experimental application. // J. Mol. Med. - 2001. - Vol.79. - P.617-630.

2. Hagihara, M. et al: Effects of iso and xeno fetal liver fragments transplantation on acute and chronic liver failure in rats. Cel Transplant 3: 283-290, 1994.

3. Sukhikh G.T., this song honoured A.A. Stem cell transplantation for treatment of liver diseases: From biological foundations to clinical experience (Review) // Inter. J. Mol. Med. - 2003. - Vol.11. - P.395-400.

4. Mito M., Kusano m, Kawaura y Hepatocyte transplantation in man. // Transplant Proc. - 1992. - Vol.24. - P.3052-3053.

5. Shumakov V.I., Halperin AI, Neklyudov E.A. liver Transplantation. - M., 1981.

6. Alison MR., Poulsom R, Jeffery R, Dhillon AP., Quaglia, A., Jacob J., Novelli, M., Prentice, G., Williamson J., Wright NA.: Hepatocytes from non-hepatic adult stem cells. Nature. - 2000. - Vol.406. - P.257-260.

7. Lagasse, E., Connors, H., Al-Dhalimy, M., Reitsma, M., Dohse, M., Osbome L., Wang, X., Finegold, M., Weissman I.L., Grompe M. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. // Nat. Med. - 2000. - Vol.6. - P.1229-1234.

1. A method for the treatment of chronic diffuse liver disease, including hepatic and transplantation of stem cells from bone marrow, characterized in that use stem cells directly isolated from the bone marrow aspirate of a patient, a portion of which is calculated so that the number of CD34-positive cells in it have ranged from 40 to 240×106cells, which is divided into two halves, first enter intrahepatic, and the second intravenously.

2. The method according to claim 1, characterized in that the chronic diffuse liver disease is cirrhosis of the liver.



 

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FIELD: pharmaceutical industry, in particular production of ointment having antiinflammation and antimicrobial activity.

SUBSTANCE: method for ointment production includes grinding of plant raw materials namely solid coconut husk up to certain particle size; extraction with chloroform during certain time followed by solvent removing and isolation of lipophilic fraction. Further emulsifier, lipophilic fraction and coconut oil are fused under specific conditions; mixture is cooled to certain temperature and blended with celandine juice heated up to certain temperature.

EFFECT: ointment of increased antiinflammation and antimicrobial activity.

3 tbl, 15 ex

FIELD: medicine.

SUBSTANCE: invention relates to pharmaceutical composition preferably in ointment form for treatment of skin lesions containing as active ingredient dexpanthenol and target additives such as fatty additives, namely solid, soft and liquid additives, emulsifier and water. As emulsifier cetostearyl alcohol is used. Composition of present invention has storage time not less than 2 years.

EFFECT: composition of improved quality and prolonged storage time.

8 cl, 2 tbl, 6 ex

FIELD: medicine, traumatology, orthopedics.

SUBSTANCE: defects of tubular bones should be filled with a transplant, moreover, as a transplant it is necessary to apply autologous thrombocyte-rich plasma at addition of autologous trabecular bone. Then the bone should be fixed. The innovation excludes the application of foreign tissue, shorten therapy terms and decrease the quantity of transplant's detachments in patients.

EFFECT: higher efficiency of therapy.

1 ex

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