UA126122U - METHOD OF TREATMENT OF INSULIN RESISTANCE IN PATIENTS WITH TYPE 2 DIABETES WITH SUB-ALCOHOLIC STEATOGEPATITIS - Google Patents

Abstract

Method of treating insulin resistance in patients with type 2 diabetes mellitus with concomitant non-alcoholic steatohepatitis by using complex treatment with metformin at a dose of 500 mg 2 times a day, and additionally appoint vasonate (meldonium) 250 mg per 1 capsule and 2 capsules (S-adenosyl-L-methionine) was sublingually 400 mg 2 times a day until clinical effect was obtained.

Description

The useful model belongs to the field of medicine, namely internal medicine and gastroenterology, and can be applied to the treatment of insulin resistance in patients with type 2 diabetes mellitus with concomitant non-alcoholic steatohepatitis.

According to the literature, non-alcoholic fatty liver disease (NAFLD) when progressing leads to the development of both liver cirrhosis and hepatocellular carcinoma, the incidence of which on the background of NAFLD significantly exceeds the rates in the population. There are numerous attempts by scientists to find new probable biochemical markers of the intensity of fibrosis, to increase the diagnostic value, sensitivity and specificity of existing methods, and to develop methods of influence in order to inhibit these processes.

Schematically, the development of non-alcoholic steatohepatitis (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 various pathological processes in internal organs that occur, NASH is the most common disease, but 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 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. Me Sh200911219; application. 05.11.2009; publ. 25.03.2010, bull. Mo b ) in which complex etiopathogenetic treatment is carried out, 3 with the addition of hepatoprotective drugs, in particular antral, and the combined herbal preparation hepalin is additionally administered.

The disadvantages of the analog-method are that when using the specified method, the achievement of stable remission of non-alcoholic steatohepatitis 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 in the other part of patients with NASH there is or active NASH or unstable remission of steatohepatitis and there are clearly expressed shifts in the exchange of protein-protein components of the extracellular matrix and their regulation, in particular, a significantly increased level

From pro-inflammatory cytokines (I-1p, I--2, TNFs, etc.), which can contribute to further progression

NASH to liver cirrhosis.

The closest analogue of a useful model is the method of treatment of insulin resistance in patients with type 2 diabetes mellitus with accompanying nonalcoholic steatohepatitis (Method of treatment of insulin resistance in patients with type 2 diabetes mellitus with accompanying nonalcoholic steatohepatitis: patent 70026 Ukraine. Mo 20031212151; application. 12.23.2003; publ. . 15.09.2004, Bull. Mo 9), in which metformin is prescribed in a dose of 500 mg 2 times a day, in addition to the complex of basic treatment, glutargin is included in the case of a low degree of activity of steatohepatitis in 50 ml 4 95 solution intravenously by drip in 200 ml 0.9 95 sodium chloride solution for 5 days, with a moderate degree of activity of steatohepatitis - for 10 days, and then - enterally 2 tablets (500 mg) 2 times a day for 2 months.

The disadvantages of the analog-method are that when using the specified method, side effects of glutargin may be noted, namely general disorders: shortness of breath, pain behind the sternum, increased body temperature, chills, changes in the injection site, phlebitis; from the side of the cardiovascular system: atrial fibrillation, a decrease in blood pressure, tachycardia; from the side of the digestive system: nausea, pain in the epigastric area; from the immune system: hypersensitivity reactions, including skin rashes, itching, hyperemia, urticaria, angioedema.

The useful model is based on the task of improving the method of treatment of insulin resistance in patients with type 2 diabetes with accompanying non-alcoholic steatohepatitis by prescribing metformin in combination with agepta (5-adenosyl-!-methionine) and vasonate (meldonium) in addition to the basic treatment.

Common features of the useful model and the closest analogue are the use of a complex of basic treatment with the appointment of metformin at a dose of 500 mg 2 times a day.

Distinctive features of a useful model from the closest analogue are that they additionally prescribe vasonate (meldonium) 250 mg 1 capsule 2 times a day and the drug agepta (5-adenosyl-ii-methionine) sublingually 400 mg 2 times a day - until obtaining clinical effect

Theoretical prerequisites for the implementation of a useful model.

Metformin (metformin hydrochloride) is an antidiabetic drug of the group of biguanide derivatives, which reduce fasting and postprandial glucose concentrations. Does not stimulate insulin release, therefore does not cause hypoglycemia. Metformin hydrochloride has three mechanisms of antidiabetic action: it reduces the production of glucose in the liver by inhibiting gluconeogenesis and glycogenolysis; increases insulin sensitivity in muscles, increasing glucose uptake and demand of peripheral tissues; reduces the absorption of glucose in the intestinal tract.

Metformin hydrochloride stimulates intracellular synthesis of glycogen; reduces the transport capacity of all types of transport systems that transport glucose through the cell membrane; has a positive effect on lipid metabolism. In controlled medium- and long-term clinical studies, it has been proven that metformin in therapeutic doses reduces the concentration of total cholesterol, fractions of cholesterol I 0. and three glycerides.

Agepta (5-adenosyl-i!-methionine) is a natural amino acid that is present in almost all tissues and liquid environments of the body. Ademethionine, first of all, acts as a coenzyme and metal 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.

Vasonate (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, reversibly 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 of a strong detergent in cells - activated forms of underoxidized fatty acids. Therefore, damage to cell membranes is prevented. In turn, with an increase in the biosynthesis of the carnitine precursor, that is, 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 resumes

Zo increases and the number of fatty acids gradually increases in the cells. 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. In somatic cells, in response to irritation, new GBB molecules are synthesized again, ensuring the propagation of the signal.

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

GBB can perform the functions of "mediator". In contrast, GBB-hydroxylase "does not recognize" meldonium, so the concentration of carnitine does not increase, but decreases. Thus, meldonium, replacing the "mediator" and contributing to an increase in the concentration of GBB, 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).

So, in a useful model, the drug agepta (5-adenosyl-!-methionine) is prescribed as an antioxidant, membrane stabilizer and hepatoprotective agent, which inhibits the progression of liver fibrosis, and the drug vasonate (meldonium), which regulates the B-oxidation of free fatty acids, reduces the degree insulin resistance, activates the energy supply processes of hepatocytes due to aerobic glycolysis.

Definition of terms used when describing a utility 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, which can contribute to the development of steatogenic liver cirrhosis.

Metformin (metforin hydrochloride) is an antidiabetic drug from the group of biguanide derivatives.

Agepta (5-adenosylch-i-methionine) is a hepatoprotective drug.

Vasonate (meldonium) is a precursor of carnitine, a structural analog of gamma-buterobetaine (GBB).

A useful model is implemented as follows.

A patient with nonalcoholic steatohepatitis and type 2 diabetes is prescribed complex etiopathogenetic treatment, which includes metformin (metformin hydrochloride) in a dose of 500 mg 2 times a day, vasonate (meldonium) 250 mg in 1 capsule 2 times a day, agepta (5Z-adenosyl -th -methionine) sublingually 400 mg 2 times a day - until the clinical effect is obtained.

Examples of the use of a useful model.

Patient B., 43 years old. Diagnosis: Non-alcoholic steatohepatitis, moderately active. Type 2 diabetes, moderate, subcompensated. She complained of discomfort and periodic aching pain in the right subcostal region, nausea, decreased appetite, bitterness in the mouth, general weakness, and rapid fatigue.

He has been ill for 5-6 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, gram a protein, coagulogram, blood lipid spectrum, blood amylase activity, electrolytes, activity of enzymes: alanine and notransferase (AlAT), aspartate aminotransferase (AST), alkaline phosphatase (AL), γ-glutamyltransferase (γ-GT), blood urea, creatinine. A complex 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 SteatotTest (VioRgedissime, France).

Objective examination data: The general condition is conditionally satisfactory. Consciousness is clear. The body structure is correct. 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. Both halves of the chest take equal part in the act of breathing. The type of breathing is mixed, with an advantage

From December The frequency of respiratory movements is 18 per minute. Vesicular breathing is heard over the lungs, side breath sounds are not 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. Heart rate (HR) -- 76/min, pulse rhythmic, of satisfactory properties, blood pressure 120/80 mm Hg. 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.

Ultrasound examination of abdominal organs. The liver was examined completely from the right hypochondrium, in the supine position. Dimensions: left lobe: front-back - 83 mm (enlarged), vertical 94 mm (enlarged); tail lobe: thickness - 33 mm (enlarged); right lobe: front-back - 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 the purpose of further examination of the liver, the following studies were performed: glycosylated Hb (NBAIS) - 7.8 bo; 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: occupied dyspepsia syndrome, abdominal pain syndrome in the right hypochondrium, appetite recovery, bitterness in the mouth disappeared.

Therefore, the proposed method allows reducing 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 comorbid diseases (diabetes mellitus, normoglycemia, reduction of 95 glycosylated hemoglobin), rapid reduction of the degree of steatosis of hepatocytes, inhibition of liver tissue fibrosis, improvement of hepatic blood circulation: reduction of hemodynamic parameters indicating the pressure in the portal vein system.

Table

Indicators of glycemia and insulin homeostasis in patients with nonalcoholic steatohepatitis, type 2 diabetes in the dynamics of treatment, (Mat)

PZO, p-50 After 30 days | After 90 days

БЛ1жЖОм2 5.85ж0.167 5.66:0.147 5.420107 7.45:0.31 9.830.227 8.86520.32 7 8.3950.28 7 mmol/l

Insulin, micro units/ml 9.90522.32 22.552.38 7 19.7g-2.03 17.3:21.227

NOMA IR 1.2920.13 2.9650.14 2.5850.177 2.2550.17/

Notes: " - the difference is probable in comparison with the indicator in the PZ (p« e0.05); "x - the difference is probable in comparison with the indicator before treatment (p« 0.05);

I - the difference is probable compared to the indicator after treatment in patients of group 1 (p<0.05).

In comparison with the closest analogue, the proposed method 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.

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

Claims (1)

USEFUL MODEL FORMULA The method of treatment of insulin resistance in patients with type 2 diabetes mellitus with accompanying non-alcoholic steatohepatitis by using a complex of basic treatment with the appointment of metformin at a dose of 500 mg 2 times a day, which differs in that vasonate (meldonium) 250 mg per 1 capsule 2 times a day is additionally prescribed day and the drug Agepta (5- adenosyl-i-methionine) sublingually 400 mg 2 times a day - until the clinical effect is obtained.