Method for treating cholelithiasis patients for hypercholesterolemia states by administering hepatosan preparation accelerating cholesterol oxidation in liver

FIELD: medicine.

SUBSTANCE: method involves per os administering Hepatosan at a dose of 0.8 g/day. The total treatment course is 2 months long.

EFFECT: high activity of 7-α hydroxylase; no adverse side effects observed.

3 tbl

 

The invention relates to medicine, namely cardiology and gastroenterology, and can be used for the correction of lipid metabolism.

It is known that a number of pathological conditions accompanied by increased levels of cholesterol (LDL) in the blood - hypercholesterolemia (GHS). It can be a result of excess cholesterol (accelerate intestinal absorption and activation synthesis in the liver, the intestinal wall and other tissues), and slowing down the excretion of cholesterol from the body (metabolism in the liver, adrenal glands and gonads, as well as the excretion of bile and through the sebaceous gland).

The major route of elimination of cholesterol from the body is the oxidation of bile acids (LC), which takes place in the liver. The key enzyme of this process is the cholesterol-7α-hydroxylase, localized in the endoplasmic reticulum and related to the superfamily of cytochromes. The enzyme activity is controlled by many factors, including the concentration of themselves LCD (back negative correlation). Primary LCD cholic and chenodeoxycholic, including introduced into the diet, have a 7α-hydroxylase inhibitory activity, and a decrease in revenues of FA in the liver (for example, when the drainage of the bile duct or the use of binding resins) stimulates the enzyme [Jelinek, D., Andersso S., Slaughter, S., Russell D. Cloning and regulation of cholesterol 7ahydroxylase, the rate-limiting enzyme in bile acid biosynthesis // J. Biol. Chon. - 1990. - V.265. - P.8190-8197.]. The increased expression of 7α-hydroxylase methods of gene therapy leads to a significant reduction of plasma cholesterol level in mice (Izzat NN, Deshazer ME, Loose-Mitchell SL. New molecular targets for cholesterol lowering therapy. The Journal of Pharmacology and Experimental therapeutics. 2000; 293(2):315-320). At the same time protection from GHS by induction 7α-hydroxylase and accelerate gelegenes expressed in rats and dogs, as in humans and in rabbits is missing. Because of pendulumeca enzyme nutrient loading cholesterol in humans does not increase synthesis LCD and, accordingly, accompanied by a rise in the level of cholesterol in the blood.

Such peculiarities of regulation of cholesterol homeostasis in hepatocytes were taken into account when creating pharmacological agents that reduce the level of cholesterol in the blood. These include statins, competitive depressing a key enzyme in cholesterol synthesis - HMG-COA-reductase, fibrates, inhibitors of cholesterol absorption (ezetimibe), airing LCD (colestimide and colesevelam) and others (Klimov A.N. //Preventive cardiology. - M., 1977. - P.260-321; Money A.V. Hyperlipidemia - modern state of the problem and methods of its correction.// RMJ. - t. No. 5. - 2003 - p.28-32). Unfortunately, these drugs, in addition to their high cost, and have some drawbacks, manifested by prolonged l the treatment. This chronic constipation, muscle pain, clouding of the eye lens (cataract), toxic effects on the liver, impotence and other Widely used at present, statins have a pronounced hematopoiesis action, until the development of "Statesboro hepatitis", and therefore is contraindicated in active liver disease.

The prototype of the present invention is a specific direction in the treatment of hypercholesterinemia - stimulation of the synthesis of LC and their subsequent evacuation through the intestine, which is accompanied by increased consumption of cholesterol for these purposes and reducing its plasma level, which is achieved, for example, oral administration of cholestyramine (Lopukhin, Y.M., Archakov A.I. Vladimirov, Y.A. Kogan AM Cholesterins. - M., 1983). Know effects of sequestrants LCD linking them in the gut and prevents reabsorption, which leads to the reduction of the pool of FA in hepatoenteric circulation and accelerate their tumors by activating the oxidation of cholesterol in the liver and, thus, its increased consumption (Reihnir E., Angelin Century, Rudling M., Ewerth s, Bjorkhem I, Einarsson K. Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG-CoA reductase activity and low density lipoprotein receptor expression in gallstone patients // J. Lipid Res. - 1990. - V.31. - P.2219-2226).

However, this method has some significant drawbacks. The use of these drugs is accompanied by severe adverse what known as dyspepsia, nausea, upset his chair, and violation of digestion and absorption of lipids, including fat-soluble vitamins and polyunsaturated fatty acids, due to binding in the intestine LCD as emulsifying agents. Airing LCD are taken at fixed doses, they cannot be combined with other drugs.

Additional possibilities for the treatment GHS can open the detection of specific inducers 7α-hydroxylase hepatocytes. They also must be accompanied by increased consumption of cholesterol and reducing its plasma level, but without the side effects typical of the airing of the LCD.

The technical result is the acceleration of the oxidation of cholesterol in the liver cells by increasing the activity of the enzyme 7-alpha hydroxylase, an expansion of the means hypocholesterolemia actions.

The proposed method of treatment is as follows: patients with HHS on the background of a confirmed diagnosis of gallstone disease (GCB) with biliary sludge for the correction of biliary insufficiency and achievements hypocholesterolemic effect impose cellular drug "Hepatosis" in a dose of 0.8 g per day (2 capsules 2 times a day) for 2 months. The product is a mixture of freeze-dried cells of the donor pig liver and has been proposed previously for the correction of hepatic deficiencies is knosti for liver diseases of various origins [Biliary insufficiency diseases of the digestive system. Wasabimon, Alernative, Cemtral, Sdereliev, Aggelika, Siebenten, Sentinentov. Materia Medica Newsletter for pharmacists №3 (39)): 2003 - s].

In the available sources of scientific, technical and patent information by the authors was not found a way to treat GHS in patients with GCB and biliary sludge through the use of activators oxidation of cholesterol in the liver. Thus, the claimed method meets the criterion of "Novelty."

To determine the effect of the drug "Hepatosis" compared to other drugs on the activity of 7α-hydroxylase hepatocytes authors conducted a series of experiments on 48 outbred white rats-males weighing 180-200 g, contained in standard vivarium conditions. In animals caused GHS by oral administration of a solution of cholesterol in vegetable oil. In the future, rats received medical therapy hepatozoon, Kars, anteroinen and allohol, and in the control group - water. At the end of the experiment, animals were scored, we determined the mass of the liver and was calculated weighting factor, and defined the concentration of malondialdehyde in the liver homogenate (Steel, Garishvili) and the level of cholesterol in the serum cholesterol-oxidase method (A.I. Andreev, Kozhemyakin L.A., Kiskun A.A. Modification method determination of lipid peroxides in the test with thiobarbiturate acid // lab. Affairs is - 1988. No. 41. - p.41-46).

To determine the activity of the hydroxylase liver used XC, labeled with tritium in 7α-position. The principle of the method is based on the fact that in the reaction of oxidation (hydroxylation) XC one atom of tritium enters the composition of the water. Thus, the radioactivity of tritium water (3H2O) in the urine reflects the rate of hydroxylation of cholesterol in the microsomal system of the liver (Vphotoshop, You, Fsearch and co., auth. mon. SU 1476380 A1). Labeled cholesterol firm Amersham was administered to rats intravenously in the form of an emulsion with 10% albumin on the eve of the experience, on the 17th day of cholesterol diets and on the 21st day after the beginning of drug therapy. The animals were then collected daily urine and determined it β-activity on scintillation counter (with conversion to 1 ml of urine).

In groups of animals treated with medical therapy hepatozoon, Kars, anteroinen and allohol, was observed unidirectional changes in the form of increased radioactivity in urine, i.e. there were additional acceleration hydroxylation of cholesterol in the liver. Increased activity 7-α-hydroxylase on the background of treatment with hepatozoon was maximum and amounted to 137% of control. Kars was in second place, enteresan - third. In the group of animals treated allohol, increasing the activity of the enzyme was not observed

Similar tendents and was noted in the effect of drugs on serum cholesterol level. On the background of the cholesterol load its content in the blood plasma of animals was more than 10 mmol/l (1,95 mmol/l in control); when treating hepatorenal the cholesterol level decreased to 3.7 mmol/l, Kars - to 6.9 mmol/l, enteresan - to 7.9 mmol/l, allohol to 9.1 mmol/L.

Thus, the action of drugs is accompanied by an additional induction of microsomal cholesterol-hydroxylase, are activated when GHS, and corrective effect, which decreases in the row hepatosis - Kars - enteresan.

Using the proposed method allows correction GHz with the exception of the side effects of currently used lipid-lowering drugs and significantly expand the group of patients with HHS, which can be applied hepatosis, in the absence of contraindications for its use.

As shown in the conducted experimental studies on animal drug hepatosis also has hypocholesterolemic activity and acts by activating 7α-hydroxylase hepatocytes, which meets the criterion of "Inventive step".

The Clinic bgmu and RSC them. Kuvatova the study included 60 patients with a diagnosis of JCB I senior(biliary sludge) and stage II (Ilchenko A.A. Biliary sludge as the initial stage of gallstone disease //Consilium Medicum - volume 6 /number 6/ 2004). Was diagnostically clinical, instrumental and laboratory data, including ultrasonography of the abdominal cavity, duodenal intubation, biochemical analysis of blood (lipid profile, liver function tests). For the correction of biliary insufficiency in patients with dyslipidemia and altered lipid profile was appointed hepatosis at a dose of 0.8 g per day for 2 months. Hepatosis is a mixture of lyophilized cells of donor liver pig, which consists of 17 essential and nonessential amino acids, minerals, vitamins, phospholipids, redox enzymes. Analysis of duodenal contents after a course of hepatosan revealed the decrease lithogenic properties of bile by increasing the pool of bile acids, phospholipids, cholatocholesterol and postliberalisation coefficients. As a result of the treatment we are also registered positive atherogenic orientation changes of the lipid profile in patients with a tendency to decrease elevated levels of plasma cholesterol and low density lipoprotein (LDL), increased levels of high density lipoprotein (HDL).

The proposed method is illustrated by the following clinical examples:

Example 1. Patient A. 44 years were hospitalized in the Clinic of bgmu diagnosed with gallstone disease stage. The patient complained of feeling pain and discomfort in the right hypochondrium of different intensity and duration, mainly associated with food intake, periodically - a feeling of bitterness in the mouth.

According to the U.S.: is defined gipergenny fine structure of the liver with hypoechoic areas 5-6 segments in diameter from 9 to 17 mm, smooth vascular pattern; ducts not dilated, choledoch - 8 mm, free. The gallbladder is curved, the curve, the walls are thickened to 4.2 mm in its cavity is defined by the thick bile at 1/4 volume. The size of the pancreas 24-19-20 mm, contours equal, structure is homogeneous, the densified

Blood biochemical parameters: XC of 6.20 mmol/l, HDL-cholesterol - 1.10 mmol/l, ACT 16 units/l, ALT 11 u/l, triglycerides 1,51 mmol/l, total bilirubin to 10.8 mmol/l, CRP negative, alkaline. phosphatase 160 units/l, γ - GGT 14,6 units/L. In the analysis of duodenal contents into the bile into the portion identified In the lower level holeva acid to 14.1 mmol/l (norm or 18.6 mmol/l)phospholipids to 2,98 mmol/l (normal 3.58 mmol/l) and high cholesterol to 11,64 mmol/l (norm-8.9 mmol/l).

Similar changes were observed in portions: cholic acid - 2,99 mmol/l (norm - 3,49 mmol/l), phospholipids is 0.37 mmol/l (norm 0.40 mmol/l), cholesterol - is 3.08 mmol/l (norm of 2.38 mmol/l).

The patient for the correction GHz in the standard treatment would be the included hepatosis 2 capsules 2 times a day 30 minutes before meals for 2 months. After treatment, the patient noted improvement in health as the disappearance of pain, feeling of heaviness in the right hypochondrium, bitter taste in the mouth.

When repeated ultrasound examination, the patient noted a decrease in hyperechogenic liver, restore the size of the body to normal and the disappearance of biliary sludge in the gall bladder.

Biochemical analysis showed positive changes in the lipid spectrum in the direction of lowering cholesterol 5,20 to mmol/l, LDL - up to 3.10 mmol/l, triglycerides - to 1.49 mmol/l, GGT gamma - 142 units/l, raising HDL - up to 1.50 mmol/l In bile was observed unidirectional changes of cholesterol in the direction of its reduction to 9.00 mmol/l and up to 2.36 mmol/l in the portions b and C, respectively, and increased levels of bile acids to 18.1 mmol/l and to 3.49 mmol/l in the portions b and C and level phospholipids up to 3.36 mmol/l and 0.44 mmol/l in the portions b and C.

Example 2. Patient C. 35 years was hospitalized in the Clinic of bgmu diagnosed with neurocirculatory dystonia syndrome false angina. During the survey it was identified clinically latent cholelithiasis initial stage in the form of mist hyperechoic particles. In the anamnesis the patient noted the long-term use of birth control pills. Complaints of dyspepsia biliary type is not present.

According to the U.S.: opredeliaetsia hypoechoic structure of the liver; ducts not dilated, choledoch - 7 mm-free. Gall bladder - curved, walls thickened to 4.1 mm in its cavity on the rear wall is defined hyperechoic inclusions without echotin. The size of the pancreas 25-20-23 mm, contours equal, structure homogeneous, hyperechoic.

Blood biochemical parameters: XC - 6,40 mmol/l, HDL-LDL - of 1.30 mmol/l, ACT - 13 IU/l, ALT - 16 units/l, triglycerides of 1.46 mmol/l, total bilirubin -11,8 mmol/l, CRP neg., GGT is 15.6 units/L.

In the analysis of duodenal contents into the bile into the portion identified In the lower level holeva acid to 13.4 mmol/l of phospholipids to 2.39 mmol/l and cholesterol to 10.4 mmol/L. Similar changes were observed in portions: cholic acid - 2.48 mmol/l phospholipids to 0.39 mmol/l, cholesterol - 3.11 mmol/L.

The patient for the correction GHS in the treatment algorithm was included hepatosis 2 capsules 2 times a day 30 minutes before meals for 2 months.

After treatment with repeated ultrasound examination, the patient revealed a homogeneous echogenicity of the liver and the disappearance of ehouses in the gall bladder.

Biochemical analysis showed positive changes in the lipid spectrum in the direction of lowering cholesterol to 5,49 mmol/l, triglycerides - to 1.31 mmol/l, LDL - up 3,21, Alp up to 64 units/l, gamma GT - to 13.1 units/l, ACT and ALT - up to 7% and 9%, respectively, of the bilirubin - is about to 10.7 mmol/l, increase HDL - up was 1.69 mmol/L.

In bile was observed unidirectional changes of cholesterol in the direction of its reduction to 8,76 mmol/l and to 2.39 mmol/l in the portions b and C, respectively, and increased levels of bile acids to 79,45 mmol/l and of 3.28 mmol/l in the portions b and C; phospholipids - 2.68 mmol/l and 0.51 mmol/L.

Typical laboratory examination of patients who were treated by hepatozoon in the Appendix. The proposed method of treatment is more cost-effective compared to other lipidemias means, gives a pronounced clinical effect, has no side effects and contraindications. Can be used in any clinical setting, and, thus, meets the criterion of "Industrial applicability".

The method of treatment hypercholesterinemia States in patients with gallstone disease by the use of the drug "Hepatosis"accelerating the oxidation of cholesterol in the liver

Table 1
Biochemical composition of bile in patients on background treatment with hepatozoon (mmol/l)
N=1Gallbladder bile
Cholic acidCholesterolHHKFL FHK
Before the treatment14,111,641,222,980,26
After the treatment18,109,002,013,360,37
N=1Hepatic bile
Cholic acidCholesterolHHKFLFHK
Before the treatment2,90is 3.080,940,370,12
After the treatment3,492,361,480,440,18

Table 2
Biochemical composition of bile, the patient "In" on the background of treatment with hepatozoon (mmol/l)
N=1Gallbladder bile
Cholic acidCholesterolHHKFLFHK
Before the treatment13,40the 10.401,292,390,23
After the treatment17,458,761,992,680,31
N=1Hepatic bile
Cholic acidCholesterolHHKFLFHK
Before the treatment2,483,110,790,390,12
After the treatment3,282,391,370,510,21

Table 3
Biochemical parameters of blood in patients JCB stage I-II (mmol/l)
GroupThe concentration of lipids, mmol/l
XCHDLLDLTGLonpALT (IU)ACT (ed)
Patient "A" before the treatment6,201,10to 4.411,510,69of 17.016,0
Patient"And"after treatment5,201,503,101,320,6016,011,0
Patient "b" to the treatment6,401,304,401,460,6616,013,0
Patient "B" after the treatment5,491,693,211,310,597,09

A method of treating hypercholesterolemia in patients with gallstone disease by oral administration of a drug, wherein introducing hepatosis containing a mixture of dried liver hepatocytes pigs at a dose of 0.8 g per day for 2 months.



 

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2 cl, 1 dwg

FIELD: agriculture, veterinary science.

SUBSTANCE: the present innovation deals with normalizing the flow of coupling, mating and lambing, the rate of growth for preventing and treating acute and chronic diseases of etiology in animals. One should prepare a tissue preparation due to applying cow's ovaries without yellow bodies, thyroid and parathyroid glands, thymus, pancreas and liver of cattle up to 4-yr-aged terms. The organs mentioned should be separately kept for 9-10 d in a fridge to be separately reduced thrice with a meat chopper, diluted with fresh running water at 1:2 ratio, extracted for 4 h in glassware at room temperature, thoroughly mixed every 10-15 min, treated in water bath for 1 h at 58-59 C, separately filtered through double-layered sterile gauze to keep a filtrate 4 times at 1-d-long interval in water bath at 58-59 C for 1 h. Components should be mixed so, that their ratio in preparation should be, weight%: ovarian tissue emulsion 10.3, thyroid and parathyroid emulsion 10.3, that of thymus 10.3, that of pancreas 17.2, that of liver 20.6, ACD f-2 10.3, formalin 0.4, natural bee honey 20.6. Before injection the preparation should be mixed and introduced per 1/2 dosage into dorsal lumbar muscles at 0.02-0.04 ml/kg animal body weight. The innovation provides complex biostimulation, activation of hormonal regulation of animal body.

EFFECT: higher efficiency of prophylaxis and therapy.

1 tbl

FIELD: veterinary medicine.

SUBSTANCE: the present innovation deals with methods to activate the activity of protective mechanisms and organs of hormonal regulations. One should introduce a tissue preparation for an animal, moreover, to obtain it is necessary to apply 2.5 g pregnant or postpartum uterus, per 1.5 g thyroid, parathyroid and thymus glands, 2.0 g pancreas, 2.5 g liver all purified against spare tissues from clinically and hematologically healthy animals from cattle group up to 4-6-yr-aged period. The organs mentioned should be reduced, then tissue mixture obtained should be mixed with fresh running water at 1:2 ratio to obtain emulsion to be thermally treated in water bath at 58-59 C. After cooling emulsion should be supplemented with formalin, ACD f-2 and natural bee honey to obtain the following ratio of components in ready-to-use product: tissue emulsion 10 g, 68.7%; ACD f-2 1.5 g, 10.3%; formalin 0.006 g, 0.4%; natural bee honey 3.0 g, 20.6%. Before being introduced for an animal one should carefully mix preparation to detect its dosage at 0.02-0.5 ml/kg animal body weight to be then introduced per Ѕ parts from the right and from the left into dorsal lumbar muscles either once or twice at interval of 7-9 d. The method enables to perform complex biostimulating and hormonal impact upon animal body due to keeping active substances of tissue preparation being obtained due to above-mentioned technique.

EFFECT: higher efficiency of prophylaxis and therapy.

FIELD: medicine.

SUBSTANCE: method involves introducing bio-organic preparation into patient organism. The preparation is introduced at a daily dose of 2 ml intramuscularly during 3-4 weeks.

EFFECT: enhanced effectiveness of treatment.

2 dwg

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