UA120212U - METHOD OF TREATMENT OF PATIENTS WITH NON-ALCOHOLIC STEATOGEPATITIS AND TYPE 2 DIABETES - Google Patents

Abstract

A method of treating patients with non-alcoholic steatohepatitis and type 2 diabetes mellitus involves prescribing complex etiopathogenetic treatment. In this case, ademetionine 400 mg 3 times daily sublingually and at the same time meldonium 250 mg 1 capsule 2 times daily for 30 days are administered until clinical effect is obtained.

Description

The utility model belongs to medicine, namely internal medicine and gastroenterology, and can be applied to the treatment of non-alcoholic steatohepatitis in patients with type 2 diabetes and obesity.

The problem of diagnosis and treatment of non-alcoholic steatohepatitis (NASH) is one of the important problems of internal medicine and has general medical and social significance. NASH is a disease that is characterized by the accumulation of fat in more than 5 95 hepatocytes, which occurs in the absence of regular consumption of toxic doses of alcohol (more than 40 g per day for men and more than 20 g per day for women), contamination with hepatitis B, C viruses , O or any other specific liver damage, with the formation of inflammation against the background of diffuse steatosis of hepatocytes. There are cases of primary and secondary NASH (Mozeieu V.N., 2003). Primary NASH is most often associated with endogenous disorders of lipid and carbohydrate metabolism (obesity, diabetes (especially insulin resistance syndrome), hyperlipidemia). Secondary NASH is induced by external influences and develops as a result of some metabolic disorders (drugs: amiodarone, glucocorticoids, synthetic estrogens, tamoxifen, tetracycline, non-steroidal anti-inflammatory drugs, nifedipine, diltiazem, etc.), malabsorption syndrome (as a result of ileojejunal anastomosis, biliary- pancreatic stoma, gastroplasty for obesity, extended small bowel resection, etc.), rapid weight loss, long-term (more than 2 weeks) parenteral nutrition (especially fat-free or unbalanced in terms of carbohydrates and fats), mixed disorders (syndrome excessive bacterial insemination of the intestine: on the background of diverticulosis of the small intestine, etc.), lipodystrophy of the extremities, William-Christian disease, Konovalov-Wilson disease) genetic factors (Kravchenko N.A., Vinogradova S.V., 2005).

Schematically, the development of NASH can be presented in several stages: fatty infiltration of the liver, oxidative stress, TME/endotoxin - mediated damage. NASH is accompanied by different stages of liver fibrosis (FP), ranging from its absence (EO stage) to liver cirrhosis (CP) (E4 stage). Despite the fact that among the various pathological processes in internal organs that occur - NASH is the most common disease, it remains a significant problem today and requires sufficient study. Due to the multifactorial, heterogeneous nature of non-alcoholic fatty liver disease, therapeutic approaches should also be complex.

An analogue of a useful model is the method of treatment of patients with NASH (Method of treatment of patients with non-alcoholic steatohepatitis combined with type 2 diabetes mellitus: pat. 58755 Ukraine. Mo. 201011372; application. 09.24.2010; publ. 04.26.2011, Bull. Mo. 8 .), in which essential phospholipids are administered, in particular Essentiale forte H, a combination of metabolically active antihomotoxic drugs, namely Heparcompositum and Lymphomyozot, are additionally administered.

The disadvantages of the analog-method are that insufficient influence is exerted on the pathogenetic links of the development of NASH, in particular, the correction of G-carnitine metabolism and hyperhomocysteinemia associated with a violation of methionine synthesis, folic acid deficiency, correction of lipotoxic stress and, as a result, the development of hypoxia of hepatocytes and their apoptosis

The closest analogue of the useful model is the method of treatment of patients with non-alcoholic steatohepatitis combined with obesity (Method of treatment of patients with non-alcoholic steatohepatitis combined with obesity: pat. 48702 Ukraine. Mo ts200911219; application 05.11.2009; publ. 25.03.2010, Bull. Mo 6.|І, in which complex etiopathogenetic treatment is carried out, which includes the administration of hepatoprotective drugs, in particular antral, and additionally hepaline is administered.

The disadvantages of the closest analogue are that when using it, a stable remission of NASH is noted, and at the same time, stabilization of liver fibrosis is achieved only in half of patients with NASH, which occurs against the background of obesity, while the other part of patients with NASH has either active NASH or unstable remission of steatohepatitis, and clearly expressed shifts in the exchange of protein-protein components of the extracellular matrix and their regulation remain, in particular, a significantly increased level of pro-inflammatory cytokines (I-1p, 1/-2, TNFα, etc.), which can contribute to the further progression of NASH to liver cirrhosis.

The basis of the useful model is the task of improving the treatment of patients with non-alcoholic steatohepatitis and type 2 diabetes by prescribing meldonium and ademethionine.

The task is solved by the fact that in the method of treatment, which includes complex etiopathogenetic treatment, according to a useful model, as a complex etiopathogenetic treatment, ademetionine 400 mg is prescribed sublingually 3 times a day and simultaneously meldonium 250 mg 1 capsule 2 times a day for 30 days - until obtaining a clinical effect.

Theoretical prerequisites for the implementation of a useful model.

Meldonium is a precursor of carnitine, a structural analogue of gamma-buterobetaine (GBB), in which one carbon atom is replaced by a nitrogen atom. Meldonium, by inversely inhibiting gamma-buterobetaine hydroxylase, reduces the biosynthesis of carnitine and therefore prevents the transport of long-chain fatty acids through cell membranes, thus preventing the accumulation in cells of a strong detergent of activated forms of underoxidized fatty acids. Therefore, damage to cell membranes is prevented.

When the concentration of carnitine is reduced in conditions of ischemia, beta-oxidation of fatty acids is delayed and oxygen consumption in cells is optimized, glucose oxidation is stimulated and transport of ATP from the sites of its biosynthesis (mitochondria) to the sites of consumption (cytosol) is restored. Essentially, the cells are supplied with nutrients and oxygen, and the consumption of these substances is optimized.

In turn, with an increase in the biosynthesis of the carnitine precursor, i.e. GBB, endothelial MO-synthase is activated, as a result of which the rheological properties of blood improve and the peripheral resistance of blood vessels decreases. When the concentration of meldonium decreases, the biosynthesis of carnitine increases again and the amount of fatty acids in the cells gradually increases.

It is believed that the basis of the effectiveness of meldonium is increased tolerance to glucose and increases its cellular utilization with deposition in the form of glycogen (with a change in the amount of fatty acids). In the body, there is a system of transmission of neuronal signals - the GBB-ergic system, which ensures the transmission of nerve impulses between cells. The mediator of this system is the last precursor of carnitine - GBB-ester. As a result of the action of GBB-esterase, the mediator gives an electron to the cell, thus transferring an electrical impulse, turns into a hydrolyzed form of GBB, which is actively transported to the liver, kidneys and ovaries, where it is converted into carnitine. New molecules are synthesized again in somatic cells in response to irritation

GBB, providing signal propagation. When the concentration of carnitine decreases, the synthesis of GBB is stimulated, as a result of which the concentration of GBB ester increases.

Meldonium, as mentioned earlier, is a structural analogue of GBB and can perform the functions of a "mediator". In contrast, GBB-hydroxylase "does not recognize" meldonium, so the concentration of carnitine does not increase, but decreases. Thus, meldonium, replacing "mediator" and

By contributing to the increase in the concentration of GBB, it leads to the development of the appropriate reaction of the body. As a result, general metabolic activity also increases in other systems, such as the central nervous system (CNS).

Z-adenosyl-i-methionine (ademethionine) is a natural amino acid that is present in almost all tissues and fluid environments of the body. Ademethionine, first of all, acts as a coenzyme and methyl group donor in many transmethylation reactions, which is an important metabolic process in humans and animals. Transfer of methyl groups (transmethylation) of ademethionine is also an important metabolic process in building the phospholipid membrane of cells and plays a role in membrane fluidity.

Ademethionine is able to penetrate through the blood-brain barrier. High concentrations of ademetionine affect transmethylation processes, which are very important in brain tissue, due to the effect on the metabolism of catecholamines (dopamine, epinephrine, norepinephrine), indoleamines (serotonin, melatonin) and histamine.

Ademethionine is a precursor in the formation of physiological sulfur compounds (cysteine, taurine, glutathione, coenzyme A, etc.) in transsulfuration reactions. Glutathione, the most powerful antioxidant, is an important component of the second phase of liver detoxification.

Ademethionine increases the level of glutathione in patients with liver damage of both alcoholic and non-alcoholic origin.

Therefore, ademethionine is prescribed as an antioxidant, membrane stabilizer, hepatoprotector, a means that inhibits the progression of liver fibrosis, and meldonium is a structural analog of gamma-buterobetaine (GBB), which regulates the processes of HD oxidation of free fatty acids, reduces the degree of insulin resistance, and activates the energy supply processes of hepatocytes due to aerobic glycolysis, improves microcirculation in the myocardium, liver, kidneys and vessels of the lower extremities.

Definition of terms used when describing a useful model.

Nonalcoholic steatohepatitis (NASH) is an independent nosological unit characterized by an increase in the activity of liver enzymes in the blood and morphological changes in liver biopsies, similar to changes in alcoholic hepatitis - fatty dystrophy and an inflammatory reaction, but patients with

NASH do not drink alcohol in quantities that can cause liver damage. The term "non-alcoholic" emphasizes the separation of this nosological unit from alcoholic disease.

Steatohepatitis - inflammatory infiltration of the liver against the background of fatty dystrophy of hepatocytes and fibrosis, 60 which can contribute to the development of steatogenic liver cirrhosis.

Ademethionine is a hepatoprotective agent.

Meldonium is a precursor of carnitine, a structural analogue of gamma-buterobetaine.

A useful model is implemented as follows.

A patient with non-alcoholic steatohepatitis and type 2 diabetes as a complex etiopathogenetic treatment is prescribed ademetionine 400 mg 3 times a day sublingually and at the same time meldonium 250 mg 1 capsule 2 times a day for 30 days - until the clinical effect is obtained.

Examples of the use of a useful model.

Patient N., 43 years old. Diagnosis: Non-alcoholic steatohepatitis of moderate activity. Type 2 diabetes, moderate, subcompensated. ХХН I! Art. Diabetic nephropathy.

Chronic bilateral pyelonephritis, remission. She complained of discomfort and periodic aching pain in the right subcostal region, nausea, decreased appetite, bloating, bitterness in the mouth, inability to perform usual physical activity, sleep disturbance.

He has been ill for 4-5 years. She was periodically treated at her place of residence. The patient underwent a series of examinations, which included clinical blood and urine tests, biochemical tests (total bilirubin, conjugated and unconjugated bilirubin content, thymol test, proteinogram, coagulogram, blood lipid spectrum, blood amylase activity, electrolytes, enzyme activity: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AL), y-glutamyltransferase (y-G7T), blood urea, creatinine. A comprehensive ultrasonographic examination (US) was performed on an ultrasound scanner "AO-4 Idea" (Vioteadisa , Italy).The stage of liver tissue fibrosis was studied using the FibrotTest, the degree of fatty liver dystrophy was studied using the SteatoTest (EVioRédisimée, France).

Objective examination data: The general condition is conditionally satisfactory. Consciousness is clear. The position in bed is active. The body structure is correct. The constitution is asthenic. Height - 170 cm. Weight - 76 kg. The skin is pale, inelastic, without rashes, dry. Mucous membranes are pale pink in color, without rashes and hemorrhages. Subcutaneous adipose tissue has reduced nutrition and is underdeveloped. Muscles are poorly developed, their tone is reduced. Swelling on the right and left leg is moderately pronounced. Both halves of the chest take equal part in the act of breathing. The type of breathing is mixed, with a predominance of thoracic. The frequency of respiratory movements is 18 per minute. Above the lungs

A vesicular breath is heard; no secondary respiratory sounds are heard. The area of the heart has not changed, the pulsation of the vessels of the neck is noticeable, the jugular veins are not swollen in a sitting position.

The tones of the heart are clear, rhythmic. The vascular bundle does not extend beyond the sternum. The waist of the heart in the form of a right angle. Heart rate (HR) - 86 bpm, pulse rhythmic, satisfactory properties, blood pressure 130/70 mm. mercury Art. The abdomen is soft on palpation, sensitive in the right hypochondrium.

Liver "3 cm from the edge of the costal arch. The edge is rounded, sensitive to palpation.

According to the laboratory and instrumental examination data indicated in the following table, the following is observed (only pathological changes): blood glucose 6.7 mmol/l; AlAT 110 units. (M to 41 units); ASAT 64 units. (M to 37 units); total cholesterol 7.33 mmol/l; triglycerides 2.7 mmol/l (M up to 2.3 mmol/l); LLIVSH - 0.97 mmol/l (M from 1.45 mmol/l); LLDNSHTC 5.37 mmol/l (M up to 2.59 mmMmol/l); very low density lipoproteins (VLDL) - 0.99 mmol/l (M up to 1.0 mmol/l); coefficient of atherogenicity 6.56 (M to 3.0).

Ultrasound examination of abdominal organs. The liver was examined completely from the right hypochondrium, in the supine position. Dimensions: left lobe: anterior-posterior 82 mm (enlarged), vertical 95 mm (enlarged); tail lobe: thickness 33 mm (enlarged); right lobe: anterior-posterior 132 mm, vertical 178 mm (enlarged). The contour of the liver is even, indistinct, the lower edge is rounded, the capsule is not changed. The echo structure of the parenchyma of increased echogenicity with an indistinct granular pattern is heterogeneous. The sound conductivity of the tissue is significantly reduced (dorsal attenuation of the ultrasound signal). The vascular pattern is impoverished. For further examination of the liver, the following studies were performed: glycosylated I ate (NBAIs) 7.8 95; NOMA index - 2.92 (insulin resistance determination index, M up to 2.5); viral hepatitis B and C markers are negative; degree of saturation of transferrin with iron (diagnosis of hemochromatosis) 28 95.

In this regard, treatment was prescribed according to the proposed method. The patient was comprehensively examined after treatment and after 12 weeks, examined every 2 weeks.

After the treatment, the patient's condition improved: the combined dyspepsia syndrome, abdominal pain syndrome in the right hypochondrium, recovery of appetite, bitterness in the mouth disappeared.

Therefore, the proposed method allows to reduce the intensity of progression of non-alcoholic steatohepatitis by eliminating the signs of exacerbation of clinical syndromes of this pathology: correction of the main clinical and biochemical syndromes of the main and ventricular septal diseases (diabetes mellitus, normoglycemia, reduction of 95 glycosylated hemoglobin), rapid reduction of the degree of steatosis of hepatocytes, inhibition of hepatic fibrosis tissues, improvement of hepatic blood circulation: reduction of hemodynamic parameters indicating the pressure in the portal vein system. In comparison with the closest analogue, the method claimed leads to the probable elimination of risk factors for the development of non-alcoholic steatohepatitis in patients with type 2 diabetes and eliminates the threat of complications.

Table

Indicators of the functional state of the liver, the degree of steatosis and fibrosis of the liver tissue, the state of hepatic blood circulation in patients with nonalcoholic steatohepatitis in the dynamics of treatment with ademethionine and meldonium

Eirgo Gezvi, Acting 0.18:0.01 0.30-0.02 7 0.2750.01 7 zivayutevzvi, u.o. 0.1920.02 0.38-0.037 0.25:20.02 /x

Diameter of the portal vein (Ov.v.), tt. 9,450.51 11.6:20.347 10.5:50.15x

Portal vein congestive index (PI) 0.02320.0019 0.032-0.0037 | 0.02920.002 77/77

Collagenolytic activity of blood plasma

Ki Ki (KLA), µM/lhh 0.84-0.016 0.6820.029 0.86--0.017

AlAT, μmol/lhh 2552.5 46.22.97 20.55-1.277

Indirect bilirubin, 14.7-0.43 233.74" 152.08: μmol/l

Total bilirubin, μmol/l 19.22-1.15 3552.317 21.33 7

Direct bilirubin, 4.5x0.27 121.42 IU μmol/l

Note: 7 - the difference in the indicators is likely compared to the indicator in the PZO (p«e0.05); "x - the difference in indicators is probable in comparison with the indicator before treatment (p" 0.05).

Technical result. The proposed method makes it possible to effectively treat patients with non-alcoholic steatohepatitis in comorbidities with type 2 diabetes by eliminating signs of exacerbation of the clinical syndromes of this pathology.

Claims (1)

USEFUL MODEL FORMULA The method of treatment of patients with non-alcoholic steatohepatitis and type 2 diabetes mellitus, which includes the appointment of a complex etiopathogenetic treatment, which differs in that ademetionine 400 mg is prescribed sublingually once a day and simultaneously meldonium 250 mg in 1 capsule 2 times a day for 30 days - before obtaining a clinical effect.