Method of treating non-alcoholic liver disease accompanying type 2 diabetes mellitus

FIELD: medicine.

SUBSTANCE: according to a known method of treating the liver disease accompanying type 2 diabetes mellitus involving the baseline therapy of diabetes mellitus and prescribed hepatoprotectors, the above hepatoprotector is presented by Mexicor in a daily therapeutically effective dose of not less than 16 weeks. The therapeutically effective dose of Mexicor makes 100 mg 4 times a day.

EFFECT: higher clinical effectiveness ensured by eliminating the liver disease more prominently, reducing the length of treatment, normalising the liver function test results over a short period of time, and avoiding any side effects.

2 cl, 2 tbl

 

The invention relates to medicine, more precisely to endocrinology, and can be used to treat non-alcoholic fatty hepatosis in diabetes mellitus type 2.

The basis of the formation of non-alcoholic fatty hepatosis in diabetes mellitus type 2 is the phenomenon of insulin resistance, which leads to activation of free radical oxidation, chronic systemic inflammation, disruption of microcirculation, tissue ischemia and impaired metabolism (4) that initiates the dysfunction of hepatocytes, the process of cytolysis, activation fibrogenesis.

Currently, as a hepatotropic funds used drugs of different groups with membrane stabilizing and antioxidant activity (essential phospholipids, vitamin E, essential phospholipids in combination with glycyrrhizic acid, ursodesoxycholic acid, ademethionine) (3). The use of these drugs is focused and corrects only one link in the pathogenesis of non-alcoholic fatty hepatosis in diabetes mellitus type 2.

Closest to the claimed invention is a method of treatment of fatty hepatosis liver when safarnama the type 2 diabetes using mildronata, which is able to improve cellular metabolism and reduce the need for tissue oxygen due to inhibition of p the entry of free fatty acids into the mitochondria in ischemia.

The disadvantage of this method of fatty hepatosis liver using mildronata on the background of basic therapy in diabetes type 2 diabetes is the inability to achieve complete elimination of fatty hepatosis liver, resulting in the inability to normalize liver samples, and the presence of complications such as metabolic disorders of the liver. In addition, in those cases, when therapeutic effect, it requires long term use mildronata.

These shortcomings mildronata, apparently, are explained as follows. The mechanism of hypoxic potential mildronata (trimethylhydrazine propionate (Tgp)), analogue of gamma-butirobetaina is implemented by suppressing gamma butyrobetaine, thus reducing the synthesis of carnitine and transport long-chain fatty acids through the cell membrane, which prevents the accumulation in the cells activated forms of oxygenated fatty acid derivatives acylcarnitine and acylcoenzyme A. by reducing the concentration of carnitine heavily synthesized gamma-butyrobetaine, with vasodilating properties. Positive effects mildronata were demonstrated on the model of cardiomyocytes. When a rat mildronata (50 mg/kg, intraperitoneally, 10 days) the concentration of free carnitine in the myocardium is reduced by 42%, which with the introduction of 150 mg/kg 70%. The concentration of acid-insoluble acylcarnitine in the latter case falls to 84%. In rats contained on the fat diet, the drug inhibits the oxidation14C-palmitic acid 16% and 50%, respectively [Shutenko J. C., simkhovitch B. H., Marina D. C. and other Regulation of carnitine-dependent fatty acid metabolism in the myocardium in rats using 3-(2,2,2-Trimethylhydrazinium)propionate. The matters. the honey. chem. 1989; 35(2):59-64; Shutenko J. C., Prietena I. A., kalvinsh I. J., Lukovic E. J. Impact of structural analogue of gamma-butirobetaina mildronata (3-(2,2,2-Trimethylhydrazinium)propionate) on Chernicinsky metabolism in the dynamics. The matters. the honey. chemistry 1991, 37(3), 24-26]. With the introduction of white rats the drug is almost 2 times increases the concentration of free fatty acids (FFA) in serum, with no impact on their level in the myocardium, which is obviously caused by the limitation of their capture from the blood. The content in the myocardium of triglycerides tends to increase (1.25 times), which can be seen as a compensatory reaction in response to an excess of FFA in terms of the course introduction mildronata [Shutenko J. C., simkhovitch B. H., kalvinsh I. J., Lukevics E. J. Regulation of ketogenesis in rats using 3-(2,2,2,-Trimethylhydrazinium)propionate - mildronata. WPI. Of Latv. SSR. 1988; 11: 117-119]. Application mildronata not accompanied by the accumulation in the heart dinocerata the aqueous acyl-COA and acylcarnitine, that is xed under the action of the derivatives oxirane-2-carboxylic acid [simkhovitch B. Z. Regulation camicissima metabolism and protection of the heart from adrenergic and ischemic injuries: author. dis. Dr. med. Sciences. M., 1988. C. 34]. Preventive long in doses of 50-150 mg/kg introduction mildronata warns caused by izadrina violation of the metabolism of the myocardium (the accumulation of acylcarnitine, the decrease in ATP content) against an even more pronounced fall in the concentration of free carnitine and lack of accumulation of AMP and lactate. Along with this weakened the damaging effect of membrane-products of metabolic activation of fatty acids in hepatocytes and cardiomyocytes. However, according to experimental work Markus Spaniol with co-authors (2003) [Markus Spaniol, Priska Kaufmann, Konstantin Beier, et al. Mechanisms of liver steatosis in rats with systematic carnitine deficiency = MKD due to treatment with trimethylhydraziniumpropionate. Journal of Lipid Research Vol.44, 2003; p.144-153], carnitine deficiency caused by the use of trimethylhydrazine propionate at the level of hepatocytes in the evaluation after 3 and 6 weeks in the group of rats receiving Tgp, soprovozhdalsya decrease metabolism of palmitate in vivo and the development of mixed steatosis of the liver. In rats treated Tgp, hepatic carnitine pool was reduced at both time points at 65-75%.

The content of coenzyme a in the liver increased by 23% after 3 weeks and 40% after 6 weeks of receiving Tgp. To the ome, in rats treated Tgp, has been an improvement in the long-chain acyl-COA in the cytosol, and the content in mitochondria of hepatocytes of rats treated Tgp was decreased, which was comparable with the decrease in the activity of carnitine, Palmitoyl transferase I (CPT I) in vivo. After receiving Tgp after 3 and 6 weeks in rats was observed peroxisome proliferation in hepatocytes and increased concentrations of triglycerides and phospholipids in the composition lonp (VLDL) plasma. Thus, the reduction of the hepatic pool of carnitine may be the main mechanism leading to disturbance of the metabolism of fatty acids in the liver and the development of steatosis in rats receiving Tgp.

The fundamental difference of Mexicor (etilmetilgidroksipiridina succinate) is that antihypoxic action of the drug is due to the presence in its pharmacological formula metabolites of the tricarboxylic acid cycle - succinate, which is able to support the activity succinicacid level of the Krebs cycle, involving the oxidation of glucose, which promotes intracellular accumulation and ATP synthesis. This fact is of fundamental importance, as the FAD-dependent part of the Krebs cycle oppressed during hypoxia and ischemia significantly later compared to the NAD-dependent oxidase and may not be sufficiently long to support the energoproduktsii in the cell subject to the availability of mitochondrial substrate oxidation in this link - succinate (succinic acid) on the one hand, on the other, determines the absence of the possibility of negative effects on the metabolism of free fatty acids in hepatocytes and accumulation of triglycerides with the subsequent formation of steatosis. The connection of succinic acid with emoxipin dramatically improves the permeability of the complex through biomembranes and delivery succinate directly in the mitochondria, as emoxipin not only has antioxidant properties, but also of penetrant.

The technical result of the claimed method is to increase the effectiveness of treatment through achieving a more pronounced eliminate fatty hepatosis liver, reduce treatment time, normalize liver samples in a shorter time, no side effects.

This technical result is achieved by the fact that in the known method of treatment hepatosis in diabetes mellitus type 2, including basic treatment of diabetes and the appointment of hepatoprotectors, as hepatoprotector appoint Mexicor in a daily therapeutically effective dose of at least 16 weeks.

A therapeutically effective dose of Mexicor 100 mg 4 times a day.

The method is as follows.

1. The patient with non-alcoholic fatty hepatosis "per os" assign basic therapy of diabetes type.

2. Additionally, the patient should receive Mexicor in capsules at a dose of 100 mg four times a day for 16 weeks. In the instructions for use of the drug is noted that 1 capsule of Mexicor contains oxitetraciclina succinate 0.1 gram and the excipient is lactose, succinic acid, potato starch, magnesium stearate. When receiving Mexicor inside in the form of capsules the drug is rapidly absorbed in the gastrointestinal tract. Proabably of the drug occurs through 0.08 to 0.1 hour. The maximum concentration of drug in the blood plasma is reached in between 0.46 and 0.5 hours, the Maximum concentration in plasma of 50-100 ng/ml Metabolism of Mexicor in the liver occurs with the formation of phosphate-3-oksipiridina, glycoconjugates hours. The Mexicor excreted by the liver and kidneys. The half-life is 4.7-5.

The action of Mexicor, this energy substrate metabolism or "substrate antihypoxic drug" as he is, is nonspecific: it reduces the level of active oxygen metabolites, increasing the clinical effectiveness of therapy (2). In the instructions for use of the drug manufacturer States that the Mexicor reduces symptoms of oxidative stress, by inhibiting free radical lipid peroxidation and increasing the activity of antioxidant enzymes. The drug improves cleoc the initial energy exchange, activating energosintezirutuyu the function of mitochondria, enhancing compensatory activation of aerobic glycolysis and reducing the degree of inhibition of oxidative processes in the Krebs cycle. Energosintezirutuyu effect of the drug is associated with an increase in the delivery and consumption of cells succinate, implementation of the phenomenon of the rapid oxidation of succinic acid, succinate dehydrogenase, as well as with activation of the mitochondrial respiratory chain. When the dissociation of Mexicor in a cage on succinate and base (derived 3-oksipiridina) base has strong antioxidant effect, stabilizing cell membranes and regenerating the functional activity of cells. The Mexicor reduces the viscosity of the cell membrane, increasing its fluidity and has a modulating effect on membrane-bound enzymes (calcination phosphodiesterase, adenylate cyclase, acetylcholinesterase), ion channels and receptor complexes, including the GABA-benzodiazepine, acetylcholine, which contributes to the preservation of the structural and functional integrity of membranes, improves the transport of neurotransmitters and synaptic transmission.

The method provides a reduction in manifestations of cytolysis and cholestasis under the influence of harmful agents in non-alcoholic fatty hepatosis mediated metabolic syndrome, reducing the Indus the KSA steatosis. The method can improve metabolic lipid and glycemic indexes to reduce the severity of insulin resistance. The method is accompanied by a decrease in the severity of ultrasonic manifestations fatty steatosis.

The purpose of the statistical confirmation of the effectiveness of Mexicor conducted an open, prospective, randomized, 16-week study of the impact of Mexicor on the functional state of the liver, lipid and carbohydrate metabolism, insulinresistance, the severity of ultrasonic manifestations of fatty hepatosis in combined therapy of patients with coronary heart disease and non-alcoholic fatty hepatosis on the background of diabetes mellitus type 2.

The results are presented in table 1 Influence of combined therapy with the inclusion of Mexicor on the functional state of the liver and carbohydrate and lipid metabolism and insulin resistance in patients with nonalcoholic fatty steatosis and type 2 diabetes mellitus (M±m)". The significance of differences compared with baseline (p<0,05); # - the significance of differences between groups (p<0,05).

The studied group included 60 patients aged 45-65 years who had angina FC I-II and CHF I-II functional class according to the classification PRAS (2002). All included in the study is of patients had clinical and ultrasound characteristics of non-alcoholic hepatic steatosis. After randomization into two groups, patients of the 1st main group (30 people) in addition to the basic therapy of diabetes mellitus (biguanide, sulfonylurea derivatives), and ischemic heart disease (angiotensin-converting enzyme inhibitor, beta-blocker, an anti-platelet agent, a statin, the dosage in the study did not changed, if necessary, calcium antagonists, nitrates) were administered Mexicor (CJSC Ecofeminist, Russia) at a dose of 0.4 g/day orally.

The duration of the study was 16 weeks. The main and control (2-I) groups of patients were comparable in age, sex, severity of disease, the nature of the conducted basic therapy.

The results of the study

Laboratory data evaluate the impact of Mexicor in the combination therapy on the functional state of the liver obtained results indicate favorable dynamics of indicators of the functional state of the liver (table.1). The initial increase in the activity of aspartic (ACT) and alanine (ALT) aminotransferase above normal value (but no more than 3N) was observed in 20% of cases in primary and 23.3% in the control group. After 16 weeks of treatment Mexicor in combination therapy in patients with non-alcoholic fatty hepatosis and diabetes mellitus type 2 indicated the disappearance bol the data hyperferritinemia, whereas in the control group in 10% of cases remained increased activity ACT. The difference between groups is statistically significant. Showed a significant decrease in the activity ACT and ALT in patients additionally receiving Mexicor (Δ, % - 39,06 and Δ, % - 26,93 respectively vs Δ, % - 4.1 and Δ, % 0,98 in the control group).

The detected decrease in the activity of alkaline phosphatase (apase) and gammaglutamyltranspeptidase (GGT). The activity of alkaline phosphatase decreased by 22.7% in the core vs 0,34% in the control group (p<0.05), and GGTG on 41,86% vs 6,94 in the main and control group, respectively (p<0,05). In addition, in the group of patients receiving Mexicor, statistically significantly decreased the percentage of patients with hyperferritinemia GGT (from 26.7% to 0%), whereas in the control group increased GGT above 54 u/l in men and more than 35 IU/l in women preserved in 20% of patients. Laboratory findings syndrome hepatic cell failure (the content of total protein and albumin in the blood), and syndrome of mesenchymal inflammation (thymol turbidity test) statistically significant changes were not.

Prothrombin index (PTI) may serve as an early laboratory marker debut fibrosis or cirrhosis of the liver, with its chronic lesions of various etiologies, and its decrease is prognostically unfavorable. In the conducted studies is assured a statistically significant increase in the PTI in the group of patients receiving Mexicor in the combination therapy on the rate of 7.54% vs - 1,04% in the control group (p<0,05). In the main group of patients registered with the disappearance of the patients with initially reduced PETIT (less than 75%) in 3% of cases in the study group, with the continued performance of the control group (PETIT<75%-5%), which can be considered as an additional evidence hepatoprotective antifibrotics steps of Mexicor.

Index of steatosis, calculated according to the formula Lee Jeong-Hoon et al (2010) (5) in the main group of patients statistically significantly decreased by 9,43%, whereas in the control group increased by 2.46%, which may be associated with a decrease in ALT activity and ACT at a constant during the study, the body mass index in both the main and control group.

Revealed a beneficial effect of Mexicor in the combination therapy on metabolic indicators of carbohydrate and lipid metabolism (table.1). The 16-week study of glycosylated hemoglobin in patients receiving Mexicor in combination therapy, decreased by 13,35% (p<0.05) as compared with that in the control group (Δ, % - 0,83, p>0,05). Differences between groups are statistically significant.

The results of this study indicate a significant reduction in severity of insulin resistance in jus the first group of patients, in which the Homa index decreased by 15.5% vs 11.6% in the control group (p<0.05), and the QUICKI index increased by 28,98% (p=0.05) vs -0,69% in the control.

The positive influence of Mexicor in the composition of the combined treatment of non-alcoholic fatty hepatosis in patients with diabetes on lipid profile, first of all, was expressed in a significant decrease in triglycerides (TG) blood in patients of the main group on 25,89% (p<0.05), and also a reduction in the percentage of patients with hypertriglyceridemia more than 2 times - from 56.7% to 26.7 percent. In the control group the level of triglycerides increased by 1.94%, which is of fundamental negative value for this category of patients in connection with the role of excess triglycerides in the formation of non-alcoholic fatty steatosis.

There was a statistically significant decrease in cholesterol, low-density lipoprotein (LDL) in the group of patients additionally receiving Mexicor in combination therapy 9Δ, % -5,84 vs 2,61% in the control, p<0,05.

The change in other lipid spectrum (atherogenic index (IA), cholesterol high density lipoprotein (HDL cholesterol) was statistically insignificant in both the main and control group.

The inclusion of Mexicor in the combination therapy of non-alcoholic fatty hepatosis in patients with diabetes mellitus type 2 was accompanied by statistically dostava is a decrease of the percentage of patients with a higher ultrasound class of structural changes in the liver (score from E. Yilmaz, 1999) (6) - IB, IC and II (76,6%), due to the increase in the percentage of patients with class IA (73,3%). In the control group, these figures are virtually unchanged.

Thus, the above clinical study shows that the use of Mexicor in patients with non-alcoholic fatty steatosis accelerates normalization of laboratory parameters characterizing the functional state of the liver, promotes additional received lipid-reducing effect on the background of the application of statins, reduces insulin resistance, has a positive effect on structural changes in the liver.

Additional studies have been conducted on the impact of mildronata for the treatment of fat hapatsa in diabetes mellitus type 2. Research results are reflected in table 2.

As can be seen from comparing table 1 and table 2, the use of Mexicor for the treatment of fatty hepatosis liver in diabetes mellitus type 2 in comparison with Mildronate provides a normalization of the total bilirubin, activity of GGT, alkaline phosphatase, ALT, ACT much better. Differences in their values through 16 weeks after treatment with both drugs reach tenfold values that clearly shows the advantages of Mexicor before Mildronate.

the main group Triglycerides, mmol/l
Table 1
Indexthe control group
sourceAfter 16 weeksΔ, %sourceAfter 16 weeksΔ, %
The total bilirubin, µmol/l13,8±4,2112,67±4,37-8,05of 13.58±5,3915,44±4,913,7
The activity of GGT, u/l33,8±18,419,67±8,1*#-41,8628,6±11,426,8±9,12-6,94
The activity of alkaline phosphatase, u/l2,2±0,811,71±0,36*#-22,272,9±0,72,89±0,63-0,34
ALT, u/l31,05±5,318,92±8,3*#-39,0627,54±11,5426,41±18,87-4,1
ACT, u/l29,6±11,921,67±4,9*#-26,9320,94±8,420,45±6,30,98
Thymol test, ed1,73±0,981,79±0,543,471,72±0,351,91±0,511,04
Total protein, g/l70,6±6,970,86±to 7.770,3566,93±4,5465,33±5,12-2,39
Albumin, g/l43,32±7,745,16±8,064,2534,8±5,9635,13±4,880,95
PTI, %84,0±9,3190,33±4,3*#7,5483,13±10,882,26±9,92-1,04
Index of steatosis, ed47,4±8,9542,9±5,74*# 40,61±5,07around 41.28±5,442,46
The fasting blood glucose, mmol/l5,8±0,55,59±0,56-3,625,96±0,62,91±0,51-0,83
HbA1c, %? 7.04 baby mortality±1,86,1±1,43*#-13,356,77±0,64to 6.88±0,551,62
The Homa index5,8±1,74,9±0,8*#-15,54,89±1,614,32±1,0-11,6
Index Quicky1,38±0,541,78±0,98*#28,981,44±0,571,43±0,28-0,69
Cholesterol, mmol/l5,5±1,225,24±1,050,955,33±0,9lower than the 5.37±0,650,75
2,24±1,061,66±±0,52*#-25,891,54±0,31,57±0,251,94
LDL cholesterol, mmol/lis 3.08±0,752,9±0,96-5,84#2,68±0,592,75±0,512,61
HDL cholesterol, mmol/l1,14±0,241,19±0,254,391,14±0,171,09±0,15-4,39
The atherogenic indexa 3.87±1,373,56±0,97-8,01#3,7±0,613,97±0,597,29

Table 2
IndexGroup mildronata
sourceAfter 16 weeksΔ, %
The total bilirubin, µmol/l13,8±4,115,7±4,513,77
The activity of GGT, u/l29,3±11,127,4±9,05-6,49
The activity of alkaline phosphatase, u/l2,94±0,642,92±0,58-0,68
ALT, u/l21,6±11,621,8±7,60,93
ACT, u/l21,1±11,720,8±6,41,42
Thymol test, ed1,8±1,31,9±1,035,56
Total protein, g/l67,6±5,966,8±7,27-1,32
Albumin, g/l38,4±5,739,2±7,062,08
PTI, %82,6±8,783,3±6,8of 1.34
Index of steatosis, ed42,9±6,50,7
The fasting blood glucose, mmol/l6,2±0,45,9±0,3-4,8
HbA1c, %7,4±1,76,5±1,4*#-12,1
The Homa index5,5±1,1are 5.36±1,4-2,54
Index Quicky1,52±0,541,69±0,721,12

Continuation of table 2
Cholesterol, mmol/l6,0±0,345,5±0,37-8,3#
Triglycerides, mmol/l2,1±0,211,9±0,28-9,5
LDL cholesterol, mmol/la 3.87±0,243,55±0,35-8,3#
HDL cholesterol, mmol/l0,95±0,251,09±0,16 14,7
The atherogenic index5,3±0,24,8±0,5-9,4#
Note: * - significance of differences in performance (p<0,05); # - significance (p<0,05)

References

1. Kalvinsh I. J. Mildronate - mechanism of action and perspectives of its application. Riga: JSC Grindeks, 2002.

2. Kooka So, The Drugs in the pharmacotherapy of cell pathology. - M., 2007. - 125 S.

3. Acavity S. C., Bezborodko N. N., Ulaczyk, S., Shulenin S. N. Hepatoprotectors. M., 2010. - 109 C.

4. Lam Century, Younossi Z. M. Treatment options for nonalcoholic fatty liver disease. Ther Adv Gastroenterol. 2010; 3(2): 121-137.

5. Lee Jeong-Hoon, Kim Donghe, Kim Jung Hwa, LeeChang-Hoon, et al. Hepatic steatosis index: A simple screening tool reflecting nonalcoholic fatty liver disease. Digestive and Liver Disease 2010; 42(7):503-508.

6. Yilmaz Ergun. The diagnostic role of ultrasonograhyy in liver streatosis. The Turkish Journal of Gastroenterology 1999; 2: 96-100.

1. A method of treating non-alcoholic fatty hepatosis in diabetes mellitus type 2, including basic treatment of diabetes and the appointment of hepatoprotectors, characterized in that as the hepato-designate Mexicor in a daily therapeutically effective dose of at least 16 weeks.

2. The method according to p. 1 wherein therapeutically effective dose of Mexicor 100 mg 4 times a day.



 

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FIELD: medicine.

SUBSTANCE: what is presented is a fused protein that is a Notch1 antagonist, which consists of a human Fc region fused with the EGF-like repeat 1-13 of Notch1 or the EGF-like repeat 1-24 of Notch1. Fc-portion is localised on a carboxy-terminal portion of the EGF-repeat. There are described a pharmaceutical composition for the protein-based Notch signal transmission inhibition and using it for preparing the pharmaceutical composition for treating an individual suffering from: tumour; ovarian cancer; metabolic disorder; vascular proliferative retinopathy. What is presented is using the fused protein for producing the pharmaceutical composition for inhibition: angiogenesis in the individual; physiological lymphangiogenesis or pathological lymphangiogenesis in the individual; tumour deposits in the individual.

EFFECT: using the invention provides the proteins expressed in a supernatant at a level by several times more than the fused protein containing the EGF-like repeats 1-36 of Notch1; they penetrate into the tumour better, maintain a ligand-binding ability with the fused protein containing the repeats 1-24, binds to DLL4 and JAG1, whereas the fused protein containing the repeats 1-13 only binds to DLL4, but not to JAG1 that can find application in therapy of various diseases related to the Notch1 activity.

18 cl, 124 dwg, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (1), which possess an affinity to the µ-opiod receptor and the ORL1-receptor. The invention also relates to the application of the said compounds for obtaining medications, which can be used in treatment of fear, stress and associated with stress syndromes, depressions, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunctions, learning and memory disorders (as nootropic), withdrawal syndromes, alcohol and/or drug abuse and/or abuse of medications and/or alcohol, narcotic and medication addiction, etc. In general formula (1) (1) Y1, Y1', Y2, Y2', Y3, Y3', Y4 and Y4' in each case stand for -H; Q stands for -R0, -C(=O)-R0, -C(=O)OR0, -C(=O)NHR0, -C(=O)N(R0)2 or-C(=NH)-R0; R0 in each case stands for -C1-8-aliphate, -C3-12-cycloaliphate, -aryl, -heteroaryl, -C1-8-aliphate-C3-12-cycloaliphate, -C1-8-aliphate-aryl, -C1-8-aliphate-heteroaryl, -C3-8-cycloaliphate-C1-8-aliphate, -C3-8-cycloaliphate-aryl or -C3-8-cycloaliphate-heteroaryl; R1 and R2 independently on each other stand for -C-1-8-aliphate; R3 stands for -C1-8-aliphate, -aryl, -heteroaryl or -C1-8-aliphate-C3-12-cycloaliphate; n stands for 0; X stands for -NRA-;RA stands for -C1-8-aliphate; RB stands for -C1-8-aliphate; on condition that R1, R2, RA and RB simultaneously do not stand for the non-substituted-C1-8-aliphate.

EFFECT: increased efficiency of the application of the compounds.

9 cl, 11 tbl, 164 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and aims at treating the non-alcoholic fatty liver disease. Increasing a transaminase level to three normal values inclusively requires applying essential phospholipids for 2-3 months twice a year that is followed by using statin 10-20 mg in a combination to ursodeoxycholic acid 15-20 mg/kg for 3-6 months. If the transaminase level exceeds three normal values, the treatment is isolated and includes ursodeoxycholic acid 15-20 mg/kg for 3-6 months.

EFFECT: method enables providing the higher clinical effectiveness of the non-alcoholic fatty liver disease.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to endocrinology, and can be used for treating non-alcoholic liver disease accompanying type 2 diabetes mellitus. The declared preparation Mexicor provides reducing manifestations of cytolysis and cholestasis, decreasing the steatosis index, enables improving metabolic lipid and glycaemic values and reducing insulin resistance. Mexicor is applied in a daily therapeutically effective dose of 100 mg 4 times a day for at least 16 weeks.

EFFECT: high pharmacological activity of Mexicor has been shown by achieving the pronounced and stable elimination of fatty liver disease that enables reducing the length of treatment with no side effects.

2 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to surgery, and describes a method for compensating a disturbed intestinal bile inflow in patients with the external biliary drainage. A method for the deficient bile replacement with the external biliary drainage consists in conducting a background therapy, prescribing a therapeutic formulation containing the following ingredients: ursodeoxycholic acid 12-15 mg/kg/day (up to 20 mg/kg) in 2-3 doses, Eslidin (soya lecithin phospholipids 300 mg; methionine 100 mg, soya oil up to 550 mg) 1 capsule 3 times a day at mealtimes; Milaif 0.2 g 3 times a day.

EFFECT: invention enables improving the patient's health condition and relieving a pain syndrome by a safe and technically easy method.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a novel derivative of N-acylanthranilic acid, represented by the following general formula 1, or to its pharmaceutically acceptable salt, in which R1, R2, R3, X1, X2, X3, X4 and A are determined in the invention formula.

EFFECT: invention relates to an inhibitor of collagen production, a medication for treating diseases, associated with the excessive production of collagen, containing N-acylanthranilic acid derivative Formula 1.

FIELD: chemistry.

SUBSTANCE: hepatoprotective agent based on a lipid fraction from an alcohol extract of perforated thallome ulva - Ulva fenestrate P. et R., containing less than 70% membrane-active lipid components, including not less than 20% essential phospholipids with content of polyunsaturated fatty acids of the n-3 series of not less than 55%.

EFFECT: agent has effective hepatoprotective action, speeds up restoration of stages of metabolic reactions, thereby providing normalisation of biochemical properties of carbohydrate and lipid exchange.

5 tbl

FIELD: biotechnology.

SUBSTANCE: hepatoprotector is used as peptide ACTH (4-7) -PGP (Semax) having the formula Met-Glu-His-Phe-Pro-Gly-Pro.

EFFECT: use of the said peptide with the aim of hepatoprotection under condition of the development of free-radical oxidation of hepatocytes enables to improve the efficiency of treatment of liver diseases accompanied by intensification of free radical oxidation processes.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound of formula [I] or to its pharmaceutically acceptable salt, wherein A represents optionally substituted alkyl, wherein the substitute represents identical or different 1-3 groups specified in aryl optionally substituted by 1-3 groups specified in alkyl, halogen, alkoxy and alkanoyl; cycloalkyl optionally substituted by 1-3 groups specified in alkyl and halogen; hydroxy; alkoxy; halogen; an amino group and oxo; an optionally substituted carbocyclic group specified in a mono- and bicyclic group, wherein an aromatic ring and cycloalkyl are condensed; optionally substituted aryl, an optionally substituted completely saturated 5- or 6-merous monocyclic heterocyclic group each of which contains 1 heteroatom specified in nitrogen and oxygen, wherein the substitute of optionally substituted aryl, the optionally substituted carbocyclic group and the optionally substituted heterocyclic group for A represents identical or different 1-3 groups specified in alkyl, optionally substituted hydroxy, alkoxy, cycloalkyl or halogen; cycloalkyl optionally substituted by alkyl or alkoxy; alkoxy optionally substituted by halogen; halogen; hydroxy; oxo; heterocycle; alkyl sulphonyl; and mono- or dialkylcarbamoyl, optionally substituted amino, wherein the substitute represents identical or different 1 or 2 alkyl or aryl, or optionally substituted carbamoyl, wherein the substitute represents identical or different 1 or 2 alkyls optionally substituted by aryl, X represents optionally substituted methylene or -O-, wherein the substitute of optionally substituted methylene for X represents alkoxy or hydroxy, Q represents N or C-R4, L1 represents a single bond, methylene, -CH=CH-, -O-, -CO-, -NR11-, -NR11CO-, -CONR11- or -CH2NR11-, L2 represents a single bond, -CR6R7- or a bivalent 5- or 6-merous completely saturated monocyclic heterocyclic group each of which contains 1 heteroatom specified in nitrogen and oxygen, R1 and R2 are identical or different, and each represents hydrogen, alkyl or halogen, R3 and R4 are identical or different, and each represents hydrogen, alkyl, alkoxy, cyano or halogen, R1 and R3 are optionally bond thereby forming 5- or 6-merous cycloalkane, or a 5- or 6-merous aliphatic heterocycle containing oxygen atom, R5 represents a carboxyl group, an alkoxycarbonyl group or a bioisosteric group of the carboxyl group, R6 and R7 are identical or different, and each represents hydrogen or alkyl, or R6 and R7 are bond thereby forming cycloalkane, R8 represents hydroxy, alkanoylamino or alkyl sulphonylamino, R9 and R10 represent hydrogen or halogen, and R11 represents hydrogen or alkyl. Besides, the invention refers to specific compounds of formula [I], a drug based on the compound of formula [I], using the compound of formula [I], a method of treating based on using the compound of formula [I], and an intermediate compound of formula [II].

EFFECT: there are prepared new compounds possessing the agonist activity on thyroid hormone β receptor.

18 cl, 36 tbl, 344 ex

FIELD: medicine.

SUBSTANCE: managing pregnancy in females suffering from overweight on their 26-30 weeks of pregnancy involves measuring an S-wave velocity in the hepatic tissue by acoustic pulse-wave elastometry. If an average value is 1.41 ms or more, hepatic protectors are administered.

EFFECT: reducing a rate of obstetric complications in the pregnant women suffering from overweight.

3 ex

FIELD: veterinary medicine.

SUBSTANCE: method comprises complex pathogenetic therapy. Additionally, the specific biological preparation is used. The preparation is prepared according to the principle of production of cytotoxic serum from donor blood by hyperimmunisation of their antigens prepared from liver and spleen tissue. The antihepatotoxic serum and serum antisplenotoxic serum are obtained. They are mixed with sterile saline solution preserved with phenol to 0.5% concentration on the basis of the content in 1.0 ml of 0.9-1.15 its titrated units of antihepatotoxic and antisplenotoxic sera by reaction of binding the complement. The preparation is administered to animals once subcutaneously in the area of the withers at a dose of 0.45-1.1 ml per 1 kg of live weight. The method provides a higher immune status of the animal organism and high efficacy of treatment.

EFFECT: invention enables to improve the efficiency of treatment of liver steatosis in cats.

4 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a therapeutic agent for preventing and treating chronic liver diseases. The above agent represents amaranth oil prepared by cold pressing of amaranth seed kernels and coats, to be used in a dose of 62.5 - 250 mg/kg of body weight.

EFFECT: declared invention provides higher positive effect on biochemical processes in blood and liver tissues in treating toxic hepatitis.

2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to endocrinology, and can be used for treating non-alcoholic liver disease accompanying type 2 diabetes mellitus. The declared preparation Mexicor provides reducing manifestations of cytolysis and cholestasis, decreasing the steatosis index, enables improving metabolic lipid and glycaemic values and reducing insulin resistance. Mexicor is applied in a daily therapeutically effective dose of 100 mg 4 times a day for at least 16 weeks.

EFFECT: high pharmacological activity of Mexicor has been shown by achieving the pronounced and stable elimination of fatty liver disease that enables reducing the length of treatment with no side effects.

2 cl, 2 tbl

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