Hepatoprotector for treating non-alcoholic liver disease in type 2 diabetes mellitus
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
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 for liver diseases are the 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 the use of pfox inhibitor mildronata, which can also improve cellular metabolism and reduce the need for tissue oxygen due to braking admission free LM is different acids to the mitochondria in ischemia.
However, the feature of biochemical pathways implementation antihypoxic potential mildronata does not allow to consider it as the drug of choice for the correction of disorders of energy metabolism in hepatocytes (1), because this tool does not provide the desired therapeutic effect.
A disadvantage of the known tools is the inability to achieve the elimination of fatty hepatosis liver, the inability to normalize liver samples, the presence of complications such as metabolic disorders of the liver.
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) concentration of free carnitine is in the myocardium is reduced by 42%, and 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 is not accompanied by the accumulation is in the heart of long-chain 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, accompanied by a reduction in the 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, has declined, 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 technical result of the claimed invention is higher pharmacological activity of the claimed preparation, due to achieve more intense and more persistent elimination of fatty hepatosis liver, providing a reduction of treatment time, normalize liver samples in a shorter time, no side effects.
This technical result is achieved by the fact that as hepatoprotector for the treatment of fatty hepatosis in diabetes mellitus type 2 use Mexicor.
The Mexicor used in a daily therapeutically effective dose of 100 mg 4 times a day for at least 16 weeks.
The use of Mexicor as the protector is as follows.
The patient with non-alcoholic fatty hepatosis ”per os” assign basic therapy of type 2 diabetes. 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 grams and excipients - say what CNY sugar, 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 cellular metabolism, 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 leccami 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 drug reduces the manifestations of cytolysis and cholestasis under the influence of harmful agents in non-alcoholic fatty hepatosis, mediated metabolic syndrome, reducing the index of steatosis. It allows you to improve metabolic lipid and glycemic indexes to reduce the severity of insulin resistance. The drug is accompanied by a decrease in the severity of ultrasonic manifestations fatty steatosis.
The purpose of the statistics the ski confirm 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 No. 1 "the Effect 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 patients had clinical and ultrasound characteristics of non-alcoholic hepatic steatosis. After randomization into two groups, the patients of the 1st main group (30 people) in addition to the basic therapy of diabetes mellitus (biguanide, sulfonylurea derivatives) and coronary heart disease (angiotensin-converting enzyme inhibitor, beta-blocker, an anti-platelet agent, a statin, the dosage in the study did not change when the mu is a necessity - 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 of patients with 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 the as 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 . In the study revealed 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%) that can RASC Nivat as additional evidence hepatoprotective antifibrotics steps of Mexicor.
Index of steatosis, calculated by 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, both in main and in the 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) in comparison 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 the main group of patients in which the index Note 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 per cent 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 basically the 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 a statistically significant reduction in 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 I And class (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 hepato the om 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. For objectifying study we have assessed the influence mildronata on the functional state of the liver in patients with chronic heart failure and diabetes mellitus type 2. This assessment was carried out in the framework of the parallel studies in comparable clinical and demographic and age group of patients. The results obtained are presented 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.
|Index||The main group||The control group|
|Source||After 16 weeks||Δ, %||Source||After weeks||Δ, %|
|The total bilirubin, µmol/l||13,8±4,21||12,67±4,37||-8,05||of 13.58±5,39||15,44±4,9||13,7|
|Activity HTTP, u/l||33,8±18,4||19,67±8,1*#||-41,86||28,6±11,4||26,8±9,12||-6,94|
|The activity of alkaline phosphatase, u/l||2,2±0,81||1,71±0,36*#||-22,27||2,9±0,7||2,89±0,63||-0,34|
|Thymol test, ed||1,73±0,98||1,79±0,54||3,47||1,72±0,35||1,91±0,5||11,04|
|Total protein, g/l||70,6±6,9||70,86±to 7.77||0,35||66,93±4,54||65,33±5,12||-2,39|
|Index of steatosis, ed||47,4±8,95||42,9±5,74*#||-9,43||40,61±5,07||around 41.28±5,44||2,46||The fasting blood glucose, mmol/l||5,8±0,5||5,59±0,56||-3,62||5,96±0,62||,91±0,51||-0,83|
|HbA1c, %||? 7.04 baby mortality±1,8||6,1±1,43*#||-13,35||6,77±0,64||to 6.88±0,55||1,62|
|The Homa index||5,8±1,7||4,9±0,8*#||-15,5||4,89±1,61||4,32±1,0||-11,6|
|Cholesterol, mmol/l||5,5±1,22||5,24±1,05||0,95||5,33±0,9||lower than the 5.37±0,65||0,75|
|Triglycerides, mmol/l||2,24±1,06||1,66±0,52 *#||-25,89||1,54±0,3||1,57±0,25||1,94|
|LDL cholesterol, mmol/l||is 3.08±0,75||2,9±0,96||-5,84#||2,68±0,59||2,75±0,51||2,61|
|HDL cholesterol, mmol/l||1,14±0,24||1,19±0,25||4,39||1,14±0,17||1,09±0,15||4,39|
|The atherogenic index||a 3.87±1,37||3,56±0,97||-8,01#||3,7±0,61||3,97±0,59||7,29|
|Source||After 16 weeks||Δ, %|
|The total bilirubin, µmol/l||13,8±4,1||15,7±4,5||13,77|
|The activity of GGT, u/l||29,3±11,1||27,4±9,05||-6,49|
|The activity of alkaline phosphatase, u/l||2,94±0,64||2,92±0,58||-0,68|
|Thymol test, ed||1,8±1,3||1,9±1,03||5,56|
|Total protein, g/l||67,6±5,9||66,8±7,27||-1,32|
|Index of steatosis, ed||42,6±8,95||42,9±6,5||0,7|
|The fasting blood glucose, mmol/l||6,2±0,4||5,9±0,3||-4,8|
|The Homa index||5,5±1,1||are 5.36±1,4||-2,54|
|LDL cholesterol, mmol/l||a 3.87±0,24||3,55±0,35||-8,3#|
|HDL cholesterol, mmol/l||0,95±0,25||1,09±0,16||14,7|
|The atherogenic index||5,3±0,2||4,8±0,5||-9,4#|
|Note: * - significance of differences compared with baseline (p<0,05); # - the significance of differences between groups (p<0,05)|
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 B, Younossi ZM. 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. Yılmaz Ergun. The diagnostic role of ultrasonograhyy in liver streatosis. The Turkish Journal of Gastroenterology 1999; 2: 96-100.
1. The use of Mexicor as hepatoprotector the La treatment of non-alcoholic fatty hepatosis in diabetes mellitus type 2.
2. Application under item 1, characterized in that the Mexicor used therapeutically effective dose of 100 mg 4 times a day.
FIELD: medicine, pharmaceutics.
SUBSTANCE: pharmaceutical composition contains aleglitezar or its sodium salt in a dose of 0.01 to 0.9 mg.
EFFECT: pharmaceutical composition of aleglitezar is used for treating or preventing type II diabetes mellitus or cardiovascular diseases.
32 cl, 3 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to field of biotechnology. Characterised is application of therapeutically efficient quantity of peptide GGF2, which contains domain, similar to epidermal growth factor (EGF-like), in treatment or prevention of heart failure in mammal by injection of said peptide every 48 hours in dose, which constitutes from approximately 0.001 mg/kg to approximately 10 mg/kg.
EFFECT: invention improves therapeutic effect with introduction of neuroregulin with minimisation of any potential side effects.
14 cl, 15 dwg, 11 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to phenol derivatives of formula (1), wherein R1 represents C1-C6 alkyl group, C1-C6 alkynyl group, C1-C6 halogen alkyl group, C1-C6 alkyl sulphanyl group or a halogen atom, R2 represents a cyano group or a halogen atom, R3 represents a hydrogen atom, and X represents -S(=O)2. Besides, the invention refers to a drug preparation containing a compound of formula (I) as an active ingredient.
EFFECT: phenol derivatives of formula (1) characterised by the high urine concentration of the permanent compound, and possess the uricosuric action.
11 cl, 1 dwg, 2 tbl, 42 ex
SUBSTANCE: invention relates to compositions containing vasoactive intestinal peptide (VIP) or its fragments, and to application of such compositions in treatment of aorta fibrosis.
EFFECT: group of inventions is effective in treatment and prophylaxis of aorta fibrosis.
10 cl, 4 dwg, 2 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to pharmaceutics and represents a pharmaceutical composition for parenteral administration containing sub-micron particles of dosocahexaenoic acid ester dispersed in a water phase with the use of mixture of at least two surfactants specified in a) at least one fatty acid polyoxyethylene ester and b) at least one phospholipide derivative, as well as a method for preparing the above pharmaceutical composition.
EFFECT: invention provides higher pharmacological activity.
14 cl, 3 dwg, 3 tbl, 2 ex
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
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
SUBSTANCE: invention relates to bi- and polycyclic substituted isoquinoline and isoquinolinones of formula (I), or to its stereoisomeric and/or tautomeric forms and/or to its pharmaceutically acceptable salts, where R1 represents OH; R3, R4, R5 and R8 represents H; R7 represents halogen or (C1-C6) alkyl; R6 represents one (C1-C4)alkylene, bound to a cycloalkyl ring, in which (C1-C4)alkylene forms the second bond with the other carbon atom of the cycloalkyl ring with the formation of a bicyclic ring system, where in the bicyclic ring system one carbon atom is substituted with a group, independently selected from O, S or SO2; and if m and s equal 2 or m equals 3 and s equals 1, R6 represents a group CH2-CH-(CH2)2, which via one group CH2 is bound to the cycloalkyl ring, and two other CH2 groups are bound to different carbon atoms of the cycloalkyl ring, and if m equals 3 and s equals 3, R6 represents two methylene groups, bound to different carbon atoms of the cycloalkyl ring, where the methylene groups or group CH2-CH-(CH2)2 are bound to the carbon atoms of the cycloalkyl ring and form an adamantane system of formula (XX) , where L can be bound to any secondary or tertiary carbon atom, or R6 together with R11 and an N atom form (C5) heterocycloalkyl, bound with the cycloalkyl residue in the form of a spirocyclic ring system, where the bicyclic ring system, or the adamantane system, or a ring system, containing (C5) heterocycloalkyl, represent non-substituted or optionally substituted with substituent R9; R9 represents (C1-C6)alkyl, (C2-C6)alkenyl, (C6)aryl or cyclopropyl R11 and R12 independently on each other represent H or (C1-C6)alkylene-(C6)aryl; n equals 0 or 1; m equals 2 or 3; s equals 1, 2 or 3; L represents O; its stereoisomeric and/or tautomeric forms and/or its pharmaceutically acceptable salts. The invention also relates to the application of a formula (I) compound.
EFFECT: novel bi- and polycyclic isoquinoline and isoquinolinone derivatives, useful as inhibitors of Rho-kinase, are obtained.
22 cl, 22 ex
SUBSTANCE: peptide is characterised with sequence Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ ID NO: 16). The invention also relates to peptide/lipid complex based on the above peptide, in which phospholipid represents one or more of sphingomyelin, DPPC and DPPG, a pharmaceutical composition that contains it, and treatment methods of dyslipidemia, cardiovascular disease, endothelial malfunction, macrovascular illnesses and microvascular illnesses using it.
EFFECT: invention allows obtaining ApoA-I mimetic that is more stable in comparison to ApoA-I and that is easy to obtain.
14 cl, 21 dwg, 14 tbl, 24 ex
SUBSTANCE: on the first experimental day, cardiopathy is simulated by a single subcutaneous administration of equally portioned mixture of native egg albumin and Freund's complete adjuvant in rats. The mixture is administered at 0.2 ml of the mixture into 5 injection points: abdominally, into inguinal and axillary regions on the left and right. The cardiopathy is prevented by daily gastric administration of succinic acid 1.5 mmole/kg for 60 days through a probe.
EFFECT: higher clinical effectiveness.
2 dwg, 1 tbl, 1 ex
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.
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.
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.
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
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.
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.
SUBSTANCE: method involves simulating hepatitis by 7-day alcoholisation in female rats. A hepatoprotective agent is presented by an api-phytocomposition in the form of an aqueous suspension of honey, lecithin and licorice root extract in the ratio of 10:2:1. The composition is introduced twice a day intragastrically before feeding in a dose of 200 mg/kg of body weight 5 days before ethanol introduction and for 7 days one hour before ethanol introduction.
EFFECT: effective treatment of hepatitis with no side effects.
1 ex, 1 tbl, 1 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: claimed invention relates to a pharmaceutical, dietary, nutritional orally soluble composition for peroral intake, which contains at least one S-adenosylmethyonine (SAMe) salt in a combination with physiologically acceptable excipients and optionally other active ingredients. The physiologically acceptable excipients include light magnesium oxide.
EFFECT: compositions of the claimed invention have high taste qualities, which provides easier peroral introduction The compositions by the invention are characterised by the higher systemic bioavailability of S-adenosylmethyonine.
15 cl, 2 dwg, 13 ex
SUBSTANCE: therapeutically effective amount of ethyl methyl hydroxypyridine succinate and calcium atorvastatin, as well as additives in the form of lactose and magnesium stearate are encapsulated in gelatine. Ethyl methyl hydroxypyridine succinate and magnesium stearate is placed into an inner smaller gelatine capsule inside a main outer gelatine capsule containing atorvastatin, lactose and magnesium strearate. The ingredient ratio in the inner capsule makes, wt %: Ethyl methyl hydroxypyridine succinate 96.2-98.6; magnesium stearate 1.4-3.8, and the ingredient ratio in the outer capsule makes, wt %: calcium atorvastatin 10.0-45.0; lactose 52.0-89.0; magnesium stearate 1.0-3.8.
EFFECT: method enables providing the higher pharmaceutical effectiveness of the preparation and prolonging the shelf-life by preventing atorvastatin degradation.
3 cl, 3 tbl