UA126123U - METHOD OF CORRECTION OF ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH NON-ALCOHOLIC STEATOGEPATITIS AND CHRONIC DISEASE DISEASE - Google Patents

Abstract

Method for correction of endothelial dysfunction in patients with non-alcoholic steatohepatitis and chronic kidney disease by using complex etiopathogenetic treatment, additionally prescribing vasonate (meldonium) 250 mg 1 capsule 2 times a day and agent preparation (S-adenosine 400 L) mg 2 times a day - to obtain clinical effect.

Description

The useful model belongs to the field of medicine, namely internal medicine and gastroenterology, and can be applied to correct endothelial dysfunction in patients with non-alcoholic steatohepatitis and chronic kidney disease.

The problem of diagnosing and predicting the course of non-alcoholic fatty liver disease (NAFLD) is one of the important problems of internal medicine and has general medical and social significance. Among the forms of NAFLD, steatosis of the liver 60-70 9o is most often formed, non-alcoholic steatohepatitis (NASH) (30-40 Fo), cirrhosis of the liver is less common. The first place among the causes of the development of NASH is occupied by the syndrome of insulin resistance, which occurs against the background of obesity and type 2 diabetes.

An important problem of internal medicine is chronic kidney disease (CKD), which is accompanied by increasing endotoxicosis, an increase in the systemic circulation of products of nitrogenous metabolism against the background of hypoalbuminemia, hyper- and dyslipidemia, activation of oxidative and nitrosative stress against the background of significant inhibition of the antioxidant defense system and natural detoxification system , inhibition of erythrocytopoiesis, dysfunction of the endothelium, significant disorders of peripheral and organ (liver, kidney, myocardium) blood circulation, activation of the connective tissue system. All these links of the pathogenesis of CKD, at the same time, can be pathogenetic links of NAFLD. Especially if they are caused by diabetes mellitus (DM) type 2 With the development of diabetic nephropathy and chronic pyelonephritis, the influence of metabolic syndrome with the development of hyperuricemia and gouty nephropathy, hyperaldosteronemia, as well as drug-induced NAFLD under the influence of repeated courses of antibiotics, uroseptics - in the treatment of CKD (pyelonephritis), immunosuppressive therapy (steroid hormones, cytostatics) - in the treatment of glomerulonephritis, allopurinol with hepatotoxic properties in the treatment of gouty nephropathy, and in general chronic antibiotic-induced colon dysbiosis (which is an important etiological factor of NAFLD). Endothelial dysfunction (ED) plays an important role in many diseases of internal organs, in particular, in nonalcoholic steatohepatitis (NASH) (O.S. Khukhlina, 2007), which is caused by a violation of the ability of the endothelium to synthesize nitric oxide (NO), which, in turn, inhibits adhesion , activation and aggregation of platelets, preventing intravascular thrombus formation. However, at present, the degree of these disorders in the comorbid period of NAFLD and CKD depends on the forms

NAFLD and stages of CKD were not studied.

An analogue of a useful model is a method of correcting endothelial dysfunction in non-alcoholic steatohepatitis combined with chronic obstructive pulmonary disease depending on gene polymorphism (Method of correcting endothelial dysfunction in non-alcoholic steatohepatitis combined with chronic obstructive pulmonary disease depending on gene polymorphism): pat. 94389 Ukraine. MO and 201406041; statement 02.06.2014; published 10.11.2014, Bull. Mo 21), in which I-arginine (tivortin) is prescribed depending on the level of nitrites/nitrates in the blood and polymorphism of the 18940 gene of endothelial MO-synthase; and with a normal concentration of nitrites/nitrates or with their slight increase and in the presence of genotype 894032 4.2 95 tivortin solution is prescribed in a dose of 100 ml once a day intravenously for 7 days with the transition to oral administration of tivortin aspartate in a dose of 5 ml day during the month; when genotype 89421 or 89417 is detected, tivortin is prescribed under the control of the nitrite/nitrate level; and if their level is low, the dose and duration of tivortin treatment are doubled (intravenously 100 ml once a day for 14 days, then 5 ml 6 times a day for 2 months).

The disadvantages of the analog-method are that when using the indicated method, combined comorbid pathology and possible side effects of Tivortin are not taken into account, namely general disorders: hyperthermia, feeling of heat, aches in the body; from the musculoskeletal system: pain in the joints; from the digestive tract: dry mouth, nausea, vomiting; from the side of the skin and subcutaneous tissue: changes at the injection site, including hyperemia, a feeling of itching, paleness of the skin, up to acrocyanosis; from the immune system: hypersensitivity reactions, including rash, urticaria, angioedema; from the side of the cardiovascular system: fluctuations in blood pressure, changes in heart rhythm, pain in the area of the heart; laboratory indicators: hyperkalemia.

The closest analog of a 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 0200911219; application 05.11.2009; publ. 25.03.2010, Bull. Mo 6), 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 analog-method are that when using the indicated method, the achievement of stable remission of NAST is noted, and at the same time, stabilization of liver fibrosis is achieved only in half of patients with NAST, which occurs against the background of obesity, while in the other part of patients with NAST there is or active NASH, or unstable remission of steatohepatitis.

The useful model is based on the task of improving the method of correcting endothelial dysfunction in patients with nonalcoholic steatohepatitis and chronic kidney disease by prescribing a combination of Agepta (5-adenosyl-i-methionine) and vasonate (meldonium) drugs in addition to complex etiopathogenetic treatment.

Common features of the useful model and the prototype are the use of complex etiopathogenetic treatment.

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 (Zadenosyl!-methionine) sublingually 400 mg 2 times a day - until clinical effect

Theoretical prerequisites for the implementation of a useful model.

Agepta (5-adenosyl!-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.

Zo Vasonate (meldonium) is a precursor of carnitine, a structural analog 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 in cells of a strong detergent - activated forms of underoxidized

C5 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 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. In somatic cells, in response to irritation, new GBB molecules are synthesized again, ensuring the spread of the signal.

Therefore, in a useful model, the sublingual form of the drug Agepta (5-adenosyl-p-methionine) is included as an antioxidant, membrane stabilizer and hepatoprotective agent, which inhibits the progression of liver fibrosis, and vasonate (meldonium), which regulates the processes of P-oxidation of free fatty acids, capable of positively affect the dysfunction of the endothelium and, accordingly, contribute to the normalization of vascular tone.

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, which can contribute to the development of steatogenic liver cirrhosis.

Chronic kidney disease is a disease that is characterized by long-term (at least 3 months) structural and/or functional renal changes according to clinical, laboratory, instrumental, and morphological studies, which at the same time provide grounds for excluding the acute nature of the pathological process in the kidneys.

Agepta (5-adenosyl-methionine) is a hepatoprotective drug.

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

A useful model is implemented as follows.

A patient with nonalcoholic steatohepatitis and chronic kidney disease is prescribed complex etiopathogenetic treatment and additional vasonate (meldonium) 250 mg 1 capsule 2 times a day and Agepta (5-adenosyl-i-methionine) sublingual 400 mg 2 times a day - until clinical effect.

Examples of the use of a useful model.

Patient M., 57 years old. Diagnosis: Non-alcoholic steatohepatitis, moderately active. ХХН 18:

Chronic glomerulonephritis, mixed form, exacerbation phase. He complained of discomfort and periodic aching pain in the right subcostal region, nausea, decreased appetite, general weakness, sleep disturbances, and rapid fatigue.

He has been sick for years. He was periodically treated at his place of residence. The patient underwent a number of examinations, including 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), γ-glutamyltransferase (γ-GT), blood urea, creatinine. A comprehensive ultrasound 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 (VioRédisimée, France).

Endothelial function was investigated by a non-invasive method by determination

From endothelium-dependent vasodilation (ESVD) of the brachial artery (PA), using a sample with reactive hyperemia. At the same time, the AGOKA-4000 system (Japan) was used, equipped with a linear sensor with a frequency of 7.5 MHz in triplex mode. Measurements were carried out three times according to the standard method of Seyepta|eyi 0.5. and co-author Adequate reaction was considered to be vasodilatation by 10 95 or higher from the initial value of the diameter of the vessel. Smaller values or paradoxical vasoconstriction is a pathological response to this stimulus and indicates the presence of endothelial dysfunction (ED). The functional state of the endothelium was also studied by the content of stable metabolites of nitrogen monoxide (NO) (nitrites, nitrates) in the blood using the method

G.S. Stgeep with co-authors, the content of endothelin-1 (ET-1) (EN-1) in the blood by enzyme-linked immunosorbent assay (ELISA), determination of the number of desquamated endothelial cells (ESD).

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 - 169 cm. Weight - 72 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 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) 86/min., 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.

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. In order to further examine the liver, the following tests were performed: viral hepatitis B and C markers were negative.

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 dyspeptic syndrome subsided, the bitterness in the mouth disappeared, and the general well-being improved.

Table

Indicators of the functional state of the endothelium in patients with nonalcoholic steatohepatitis depending on the presence of comorbid chronic kidney disease in the dynamics of treatment (Mat)

Indicators, unit measurement of PZO, n-50 Before treatment After 30 days

MO of blood, μmol/l 15.3251.225 32.49--1.3187 21.51-11.173 7/7

ET-1, pmol/l 6.17-0.854 10.25:0.4577 9.8320.559 5/7

EZVD PA, 9o 15,1021,153 14,52520,729 14,4750,3287/7

KDEH107/l 3.0320.204 3.85:0.123 7 3.80520.12777/

Notes: x is the probability of a difference in indicators compared to the PZO group (p<0.05); "х" is the probability of a difference in indicators compared to patients after 30 days (p>0.05).

Therefore, the proposed method of correction of endothelial dysfunction in patients with nonalcoholic steatohepatitis and chronic kidney disease contributes to the rapid elimination of hepatomegaly, reduction of the degree of steatosis of hepatocytes, inhibition of fibrosis of liver tissue, functional state of the endothelium, indicators of the platelet link of hemostasis and stability of red blood cell membranes. In comparison with the prototype, the claimed method leads to the probable elimination of risk factors for the development of non-alcoholic steatohepatitis in a patient with chronic kidney disease and eliminates the threat of complications.

Technical result. The proposed method allows effective treatment of endothelial dysfunction in patients with nonalcoholic steatohepatitis and chronic kidney disease by eliminating signs of exacerbation of clinical syndromes of this pathology.

Claims (1)

USEFUL MODEL FORMULA The method of correction of endothelial dysfunction in patients with non-alcoholic steatohepatitis and chronic kidney disease by using complex etiopathogenetic treatment, which is distinguished by the fact that vasonate (meldonium) 250 mg per 1 capsule 2 times a day and the agent preparation (5-adenosyl-i-methionine ) sublingually at 400 mg 2 times a day - until the clinical effect is obtained.