RU2538221C1 - Method of treating non-alcoholic liver disease accompanying type 2 diabetes mellitus - Google Patents

Abstract

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

Description

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

The formation of non-alcoholic fatty hepatosis in type 2 diabetes is based on the phenomenon of insulin resistance, the implementation of which leads to the activation of free radical oxidation, chronic systemic inflammation, impaired microcirculation, tissue ischemia and impaired energy exchange (4), which initiates hepatocyte dysfunction, their cytolysis processes, activation of fibrogenesis .

Currently, drugs of various groups with membrane-stabilizing and antioxidant activity (essential phospholipids, vitamin E, essential phospholipids in combination with glycyrrhizic acid, urodesodeoxycholic acid, ademethionine) are used as hepatotropic drugs (3). The use of these drugs is narrowly targeted and corrects only one of the links in the pathogenesis of non-alcoholic fatty hepatosis in type 2 diabetes mellitus.

Closest to the claimed invention is a method of treating fatty liver hepatosis in type 2 diabetes mellitus with mildronate, which is able to improve cellular energy metabolism and reduce tissue oxygen demand by inhibiting the flow of free fatty acids into mitochondria under ischemic conditions.

A disadvantage of the known method of hepatic fatty liver with mildronate in the background of basic therapy for type 2 diabetes is the inability to fully eliminate fatty liver hepatosis, which is expressed in the impossibility of normalizing liver samples, as well as the presence of complications in the form of impaired liver metabolism. In addition, in those cases when the therapeutic effect is achieved, it requires long periods of use of mildronate.

These deficiencies of mildronate are apparently explained by the following. The mechanism of the antihypoxic potential of mildronate (trimethylhydrazinium propionate (THP)), an analog of gamma-butyrobetaine, is realized by suppressing gamma-butyrobetaine hydroxynase, while carnitine synthesis and transport of long-chain fatty acids through cell membranes are reduced, which prevents the accumulation of activated neocis acylcarnitine and acylcoenzyme A. As a result of a decrease in carnitine concentration, gamma-butyrobetaine with vasodilating properties is intensely synthesized Twami. The noted beneficial effects of mildronate have been demonstrated on a cardiomyocyte model. With the introduction of mildronate in rats (50 mg / kg, intraperitoneally, 10 days), the concentration of free carnitine in the myocardium decreases by 42%, and with the administration of 150 mg / kg - by 70%. The concentration of acid-insoluble acylcarnitine in the latter case drops by 84%. In rats kept on a fat diet, the administration of the drug inhibits the oxidation of ¹⁴ C-palmitic acid by 16% and 50%, respectively [Zhutenko Zh.V., Simkhovich BZ, Meirena DV et al. Regulation of carnitine-dependent metabolism of fatty acids in the myocardium in rats using 3- (2,2,2-trimethylhydrazinium) propionate. Q. honey. Chem. 1989; 35 (2): 59-64; Shutenko Zh.V., Priedena I.A., Kalvins I.I., Lukevits E.Ya. The effect of the structural analogue of gamma-butyrobetaine mildronate (3- (2,2,2-trimethylhydrazinium) propionate) on the dynamics of carnitine-dependent metabolism. Q. honey. Chemistry 1991, 37 (3), 24-26]. When administered to white rats, the drug almost 2 times increases the concentration of free fatty acids (FFA) in the blood serum, without affecting their level in the myocardium, which is obviously due to the limitation of their capture from the blood. The content of triglycerides in the myocardium tends to increase (1.25 times), which can be considered as a compensatory reaction in response to an excess of FFA in the course of the course administration of mildronate [Shutenko Zh.V., Simkhovich BZ, Kalvinsh I.Ya. , Lukevich E.Ya. Regulation of ketogenesis in rats using 3- (2,2,2, -trimethylhydrazinium) propionate - mildronate. Izv. Academy of Sciences of Latvia. SSR. 1988; 11: 117-119]. The use of mildronate is not accompanied by the accumulation in the heart of long-chain acyl-CoA and acylcarnitine, which is fixed by the action of derivatives of oxiran-2-carboxylic acid [Simkhovich B.Z. Regulation of carnitine-dependent metabolism and protection of the heart from adrenergic and ischemic injuries: Author. dis. Dr. med. sciences. M., 1988. S. 34]. Prophylactic prolonged administration of mildronate in doses of 50-150 mg / kg prevents isadrin-induced myocardial metabolism disturbance (accumulation of acylcarnitine, decrease in ATP) against the background of an even more pronounced drop in the concentration of free carnitine and the lack of accumulation of AMP and lactate. Along with this, the damaging effect of membranotropic products of the metabolic activation of fatty acids on hepatocytes and cardiomyocytes is weakened. However, according to experimental work by Markus Spaniol et al. (2003) [Markus Spaniol, Priska Kaufmann, Konstantin Beier, et al. Mechanisms of liver steatosis in rats with systematic carnitine deficiency due to treatment with trimethylhydraziniumpropionate. Journal of Lipid Research Vol. 44, 2003; p.144-153], carnitine deficiency caused by the use of trimethylhydrazinium propionate at the hepatocyte level after 3 and 6 weeks in the group of rats treated with THP, accompanied by a decrease in palmitate metabolism in vivo and the development of mixed liver steatosis. In rats treated with THP, the hepatic pool of carnitine was reduced at both time points by 65-75%.

The content of coenzyme A in the liver increased by 23% after 3 weeks and by 40% after 6 weeks of taking TGP. In addition, rats treated with THP showed an increase in the level of long-chain acyl-CoA in the cytosol, and the content of rat hepatocytes treated with THP in the mitochondria decreased, which was comparable with a decrease in the activity of carnitine palmitoyl transferase I (CPT I) in vivo. After taking TGP after 3 and 6 weeks in rats, peroxisome proliferation in hepatocytes and an increase in the concentration of triglycerides and phospholipids in VLDL (very low density lipoproteins) plasma were observed. Thus, a decrease in the hepatic pool of carnitine may be the main mechanism leading to a violation of the metabolism of fatty acids in the liver and the development of steatosis in rats receiving THP.

The principal difference between mexicor (ethylmethylhydroxypyridine succinate) is that the antihypoxic effect of the drug is due to the presence in its pharmacological formula of a metabolite of the tricarboxylic acid cycle - a succinate, which is able to maintain the activity of the Krebs cycle succinate oxidase link, involving glucose into the oxidation process and contributes to the accumulation of glucose and glucose. ATP. This fact is of fundamental importance, since the FAD-dependent link of the Krebs cycle is inhibited during hypoxia and ischemia much later than NAD-dependent oxidases and can maintain energy production in the cell for a sufficiently long time, provided that mitochondria have an oxidation substrate in this link - succinate (amber acids), on the one hand, on the other hand, determines the absence of the possibility of a negative effect on the exchange of free fatty acids in hepatocytes and the accumulation of triglycerides in them with the subsequent formation of steat oz of the liver. The combination of succinic acid with emoxipin can dramatically increase the permeability of the complex through biomembranes and the delivery of succinate directly to the mitochondria, since emoxipin has not only antioxidant, but also penetrant properties.

The technical result of the claimed method is to increase the effectiveness of treatment by achieving a more pronounced elimination of fatty liver hepatosis, reducing treatment time, achieving normalization of liver samples in a shorter time, and the absence of side effects.

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

The therapeutically effective dose of Mexico is 100 mg 4 times a day.

The method is as follows.

1. The patient with non-alcoholic per os non-alcoholic fatty hepatosis is prescribed basic treatment for type 2 diabetes.

2. Additionally, the patient is prescribed Mexico in capsules at a dose of 100 mg four times a day for 16 weeks. In the instructions for use of the drug, it is noted that 1 capsule of Mexico contains oxymethylethylpyridine succinate 0.1 grams and excipients - milk sugar, succinic acid, potato starch, magnesium stearate. When Mexico is taken orally in the form of capsules, the drug is rapidly absorbed in the gastrointestinal tract. Half-absorption of the drug occurs after 0.08-0.1 hours. The maximum concentration of the drug in plasma is reached after 0.46-0.5 hours. The maximum concentration in the blood plasma is 50-100 ng / ml. Mexicor metabolism in the liver occurs with the formation of phosphate-3-hydroxypyridine, clock glucoconjugates. Mexico is excreted by the liver and kidneys. The half-life is 4.7-5.

The action of Mexico, this substrate of energy metabolism or the “substrate antihypoxant”, which it is, is non-specific: it reduces the level of active oxygen metabolites, increasing the clinical effectiveness of therapy (2). The instructions for use of the manufacturer's drug indicate that Mexico reduces the manifestations of oxidative stress, inhibiting the free radical peroxidation of lipids and increasing the activity of enzymes of the antioxidant system. The drug improves cellular energy metabolism by activating the energy synthesizing functions of mitochondria, enhancing the compensatory activation of aerobic glycolysis and reducing the degree of inhibition of oxidative processes in the Krebs cycle. The energy-synthesizing effect of the drug is associated with increased delivery and consumption of succinate by the cells, the realization of the phenomenon of the rapid oxidation of succinic acid by succinate dehydrogenase, as well as the activation of the mitochondrial respiratory chain. When mexicor is dissociated in a cell into succinate and a base (a derivative of 3-hydroxypyridine), the base exhibits a powerful antioxidant effect that stabilizes cell membranes and restores the functional activity of cells. Mexico reduces the viscosity of the cell membrane, increases its fluidity and has a modulating effect on membrane-bound enzymes (calcium-independent phosphodiesterase, adenylate cyclase, acetylcholinesterase), ion channels and receptor complexes, including GABA-benzodiazepine, acetylcholine, which contributes to the preservation of the biological integrity neurotransmitter transport and synaptic transmission.

The method provides a reduction in the manifestations of cytolysis and cholestasis under the influence of damaging agents in non-alcoholic fatty hepatosis mediated by metabolic syndrome, a decrease in the index of steatosis. The method allows to improve metabolic lipid and glycemic indices, reduce the severity of insulin resistance. The method is accompanied by a decrease in the severity of ultrasonic manifestations of fatty steatosis.

In order to statistically confirm the effectiveness of mexicor, an open, prospective, randomized 16-week study was conducted to study the effect of mexicor on the functional state of the liver, lipid and carbohydrate metabolism, insulin resistance, the severity of ultrasound manifestations of fatty hepatosis as part of combination therapy for patients with coronary heart disease and non-alcoholic fatty hepatosis background of type 2 diabetes.

The results are presented in table 1 "The effect of combination therapy with the inclusion of mexicor on the functional state of the liver and indicators of carbohydrate and lipid metabolism, insulin resistance in patients with non-alcoholic fat steatosis and diabetes mellitus 2 (M ± m)". Significance of differences compared with baseline (p <0.05); # - significance of differences between groups (p <0.05).

The study group included 60 patients aged 45-65 years who had angina of exertion I-II FC and CHF I-II of a functional class according to the classification of OSCH (2002). All patients included in the study had clinical and ultrasonic signs of non-alcoholic liver steatosis. After randomization to two groups, patients of the 1st main group (30 people) in addition to basic therapy for diabetes mellitus (biguanides, sulfonylurea derivatives), and coronary heart disease (angiotensin converting enzyme inhibitor, beta-blocker, antiplatelet agent, statin, the dose of which is the study did not change, if necessary, calcium antagonists, nitrates) was prescribed mexicor (ZAO Ekofarminvest, Russia) at a dose of 0.4 g / day orally.

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

Research results

According to laboratory data, evaluating the effect of Mexico as part of combination therapy on the functional state of the liver, results are obtained that indicate favorable dynamics of indicators reflecting the functional state of the liver (Table 1). Initially, an increase in the activity of aspartic (ACT) and alanine (ALT) aminotrasferases above normal (but not above 3N) was observed in 20% of cases in the main group and in 23.3% in the control group. After 16 weeks of treatment with mexicor as part of combination therapy in patients with non-alcoholic fatty hepatosis and type 2 diabetes mellitus, the disappearance of patients with hyperfermentemia was noted, while in the control group an increase in the level of ACT activity remained in 10% of cases. The difference between the groups is statistically significant. A significant decrease in the activity of ACT and ALT was noted in the group of patients taking mexicor additionally (Δ,% - 39.06 and Δ,% - 26.93 vs vs Δ,% - 4.1 and Δ,% 0.98 in the control group) .

A decrease in the activity of both alkaline phosphatase (ALP) and gamma glutamyl transpeptidase (GGTP) was found. Alkaline phosphatase activity decreased by 22.7% in the main vs 0.34% in the control group (p <0.05), and GGTG by 41.86% vs 6.94 in the main and control group, respectively (p <0.05 ) In addition, in the group of patients receiving Mexico, the percentage of patients with GGTP hyperfermentemia decreased statistically significantly (from 26.7% to 0%), while in the control group the increase in GGT was higher than 54 units / L in men and more than 35 units / L in women survived in 20% of patients. Laboratory indicators of hepatic cell deficiency syndrome (total protein and albumin in the blood), as well as mesenchymal inflammation syndrome (thymol test) did not undergo statistically significant changes.

The prothrombin index (PTI) can serve as an early laboratory marker for the debut of fibrosis or cirrhosis of the liver with its chronic lesions of various etiologies, and its decline is prognostically unfavorable. The study revealed a statistically significant increase in IPT in the group of patients taking mexicor as part of combination therapy by 7.54% vs - 1.04% in the control group (p <0.05). In the main group of patients, the disappearance of patients with initially reduced IPT (less than 75%) was recorded in 3% of cases in the main group, while the indices of the control group remained (IPT <75% -5%), which can be regarded as additional evidence of the hepatoprotective antifibrotic effect of Mexico.

The liver steatosis index calculated according to the formula Lee Jeong-Hoon et al (2010) (5) in the main group of patients statistically significantly decreased by 9.43%, while in the control group it increased by 2.46%, which may be associated with a decrease in ALT and ACT activity indicators with a constant body mass index during the study, both in the main and in the control group.

The beneficial effect of Mexico as a part of combination therapy on metabolic parameters characterizing carbohydrate and lipid metabolism was revealed (Table 1). By the 16th week of the study, glycosylated hemoglobin in patients receiving mexicor as part of combination therapy decreased by 13.35% (p <0.05) compared with that in the control group (Δ,% - 0.83, p> 0 , 05). Differences between groups are statistically significant.

The results of the study indicate a significant decrease in the severity of insulin resistance in the main 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 effect of Mexico in the combined treatment of non-alcoholic fatty hepatosis in patients with diabetes mellitus on the lipid profile was primarily expressed in a significant decrease in the level of triglycerides (TG) in blood of patients of the main group by 25.89% (p <0.05), and also a decrease in the percentage of patients with hypertriglyceridemia by more than 2 times - from 56.7% to 26.7%. In the control group, the level of TG increased by 1.94%, which is fundamentally negative for this category of patients due to the role of excess TG in the formation of non-alcoholic fat steatosis.

There was a statistically significant decrease in low-density lipoprotein cholesterol (LDL cholesterol) in the group of patients taking mexicor as part of combination therapy 9Δ,% -5.84 vs 2.61% in the control, p <0.05.

Changes in other indicators of the lipid spectrum (atherogenicity index (IA), high density lipoprotein cholesterol (HDL cholesterol) were statistically insignificant in both the main and control groups.

The inclusion of Mexico in the combination therapy of non-alcoholic fatty hepatosis in patients with type 2 diabetes mellitus was accompanied by a statistically significant decrease in the percentage of patients with a higher ultrasound class of structural changes in the liver (assessment by E. Yilmaz, 1999) (6) - IB, IC and II (76.6%), due to an increase in the percentage of patients with IA class (73.3%). In the control group, these indicators remained virtually unchanged.

Thus, the above clinical study shows that the use of Mexico in patients with non-alcoholic fatty hepatosis accelerates the normalization of laboratory parameters characterizing the functional state of the liver, contributes to an additional lipid-lowering effect against the use of statins, reduces insulin resistance, and has a positive effect on liver structural changes.

Additionally, studies have been conducted on the effect of mildronate on the treatment of fatty hapatosis in type 2 diabetes. The results of the study are shown in table 2.

As can be seen from the comparison of table 1 and table 2, the use of mexicor for the treatment of hepatic fatty liver disease in patients with type 2 diabetes mellitus compared with mildronate ensures the normalization of total bilirubin, the activity of GGTP, alkaline phosphatase, ALT, ACT is much better. Differences in their values after 16 weeks after treatment with both drugs reach tenfold values, which indicates the clear advantages of Mexico over mildronate.

Table 1 Indicator main group control group initially After 16 weeks Δ,% initially After 16 weeks Δ,% Bilirubin total, μmol / l 13.8 ± 4.21 12.67 ± 4.37 -8.05 13.58 ± 5.39 15.44 ± 4.9 13.7 GGTP activity, units / 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, units / l 2.2 ± 0.81 1.71 ± 0.36 ^{* #} -22.27 2.9 ± 0.7 2.89 ± 0.63 -0.34 ALT, units / l 31.05 ± 5.3 18.92 ± 8.3 ^{* #} -39.06 27.54 ± 11.54 26.41 ± 18.87 -4.1 ACT, units / l 29.6 ± 11.9 21.67 ± 4.9 ^{* #} -26.93 20.94 ± 8.4 20.45 ± 6.3 0.98 Thymol test, units 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 ± 7.77 0.35 66.93 ± 4.54 65.33 ± 5.12 -2.39 Albumin, g / l 43.32 ± 7.7 45.16 ± 8.06 4.25 34.8 ± 5.96 35.13 ± 4.88 0.95 PTI,% 84.0 ± 9.31 90.33 ± 4.3 ^{* #} 7.54 83.13 ± 10.8 82.26 ± 9.92 -1.04 Steatosis index, units 47.4 ± 8.95 42.9 ± 5.74 ^{* #} -9.43 40.61 ± 5.07 41.28 ± 5.44 2.46 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 ± 1.8 6.1 ± 1.43 ^{* #} -13.35 6.77 ± 0.64 6.88 ± 0.55 1,62 Homa Index 5.8 ± 1.7 4.9 ± 0.8 ^{* #} -15.5 4.89 ± 1.61 4.32 ± 1.0 -11.6 Quicky Index 1.38 ± 0.54 1.78 ± 0.98 ^{* #} 28.98 1.44 ± 0.57 1.43 ± 0.28 -0.69 Cholesterol, mmol / L 5.5 ± 1.22 5.24 ± 1.05 0.95 5.33 ± 0.9 5.37 ± 0.65 0.75 Triglycerides, mmol / L 2.24 ± 1.06 1.66 ± den 0.52 ^{* #} -25.89 1.54 ± 0.3 1.57 ± 0.25 1.94 LDL cholesterol, mmol / l 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 Atherogenic index 3.87 ± 1.37 3.56 ± 0.97 -8.01 ^# 3.7 ± 0.61 3.97 ± 0.59 7.29

table 2 Indicator Mildronate Group initially After 16 weeks Δ,% Bilirubin total, μmol / l 13.8 ± 4.1 15.7 ± 4.5 13.77 GGTP activity, units / l 29.3 ± 11.1 27.4 ± 9.05 -6.49 The activity of alkaline phosphatase, units / l 2.94 ± 0.64 2.92 ± 0.58 -0.68 ALT, units / l 21.6 ± 11.6 21.8 ± 7.6 0.93 ACT, units / l 21.1 ± 11.7 20.8 ± 6.4 1.42 Thymol test, units 1.8 ± 1.3 1.9 ± 1.03 5.56 Total protein, g / l 67.6 ± 5.9 66.8 ± 7.27 -1.32 Albumin, g / l 38.4 ± 5.7 39.2 ± 7.06 2.08 PTI,% 82.6 ± 8.7 83.3 ± 6.8 1.34 Steatosis index, units 42.6 ± 8.95 42.9 ± 6.5 0.7 Fasting blood glucose, mmol / L 6.2 ± 0.4 5.9 ± 0.3 -4.8 HbA1c,% 7.4 ± 1.7 6.5 ± 1.4 * # -12.1 Homa Index 5.5 ± 1.1 5.36 ± 1.4 -2.54 Quicky Index 1.52 ± 0.54 1.69 ± 0.72 1.12

Continuation of table 2 Cholesterol, mmol / L 6.0 ± 0.34 5.5 ± 0.37 -8.3 # Triglycerides, mmol / L 2.1 ± 0.21 1.9 ± 0.28 -9.5 LDL cholesterol, mmol / l 3.87 ± 0.24 3.55 ± 0.35 -8.3 # HDL cholesterol, mmol / l 0.95 ± 0.25 1.09 ± 0.16 14.7 Atherogenic index 5.3 ± 0.2 4.8 ± 0.5 -9.4 ^# Note: * - significance of differences in indicators (p <0.05); # - reliability (p <0.05)

Bibliography

1. Calvins I.Ya. Mildronate - mechanism of action and prospects for its application. Riga: PJSC Grindeks, 2002.

2. Kozhoka T.G. Medicines in the pharmacotherapy of cell pathology. - M., 2007 .-- 125 p.

3. Okovity S.V., Bezborodkina N.N., Uleichik S.G., Shulenin S.N. Hepatoprotectors. M., 2010 .-- 109 s.

4. Lam V., 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 Hwa Jung, 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.

Claims (2)

1. A method for the treatment of non-alcoholic fatty hepatosis in type 2 diabetes mellitus, which includes the basic treatment of diabetes mellitus and the appointment of hepatoprotectors, characterized in that Mexico is prescribed as a hepatoprotector in a daily therapeutically effective dose of at least 16 weeks. 2. The method according to claim 1, characterized in that the therapeutically effective dose of Mexico is 100 mg 4 times a day.