[The main results of clinical trials of the efficacy, safety and pharmacokinetics of the perspective anti-tuberculosis drug makozinone (PBTZ169)].

Tuberculosis is a chronic infectious disease, usually localized in the respiratory system and representing one of the most important global social and biomedical health problems associated with the spread of therapy-resistant forms (multidrug-resistant and extensively drug-resistant tuberculosis). One of the most promising targets for the development of antimycobacterial drugs is the enzyme DprE1, which is involved in the synthesis of the cell wall of mycobacteria. In the series of DprE1 inhibitor drugs, the most advanced drug is PBTZ169 (INN maсozinone). Clinical trials (CT) of the efficacy and safety of macozinone are conducted by the pharmaceutical company LLC NEARMEDIC PLUS in the Russian Federation, and in other countries (Sponsors: Innovative Medicines for Tuberculosis Foundation, cole polytechnique fdrale de Lausanne and Bill and Melinda Gates Foundation). The publication describes results of completed I, IIa and Ib phases CT, conducted in the Russian Federation. AIM: The goal of phase I CT was to assess the safety, tolerability and pharmacokinetics (PK) of PBTZ169, 40 mg capsule, after single and multiple administration under fasting conditions in increasing doses in healthy volunteers. The goal of phase IIa CT was to study the efficacy (in terms of early bactericidal activity EBA), safety and PK of the drug PBTZ169, 80 mg capsules, in various doses, when used as monotherapy in patients with newly diagnosed respiratory tuberculosis with bacterial excretion and retained sensitivity to isoniazid and rifampicin. The purpose of phase Ib CT was to evaluate the safety, tolerability, PK of PBTZ169, 80 mg capsule, after single, double and multiple administration under fasting conditions in increasing doses, as well as the effect of food on its bioavailability in healthy volunteers. MATERIALS AND METHODS: The data of 100 healthy volunteers and 15 patients with newly diagnosed pulmonary tuberculosis, who received the study medication PBTZ169, capsules 40 mg and 80 mg, in the dose range 40 mg 1280 mg of PBTZ169, obtained during phase I, IIa and Ib CTs were analyzed. During I phases CTs, safety, tolerability, and PK of the drug after a single and multiple administration under fasting condition and after meals at rising doses were evaluated. The safety assessment included evaluation of AE/SAE, vital signs, ECG results, and laboratory tests results in the safety population. In the course of phase IIa CT, in addition to safety, tolerance, and PK evaluation, the efficacy of the drug (in terms of EBA) using sputum culture on agar with CFU/ml counting (main method) and quantitative PCR method (auxiliary method) was evaluated. RESULTS: During all CTs, a high safety and tolerability profile was shown, the main PK parameters of the drug and the efficacy were described. PBTZ169 demonstrated linear PK in the dosage range up to 640 mg after single and multiple administration, a statistically significant of EBA of the drug after monotherapy at the dose of 640 mg/day was demonstrate, and it was concluded that the preferred regimen of the drug PBTZ169 intake is administration after meals. Good tolerability and a favorable safety profile of the drug in the studied doses range were demonstrate during all the CTs. CONCLUSION: One of the most promising and currently studied drugs-inhibitors of DprE1, a new target for the cell wall of mycobacteria, is PBTZ169 or macozinone, which is being develop by the Russian pharmaceutical company NEARMEDIC PLUS ltd.

Immunogenic lipid markers of atherosclerosis in type 2 diabetic patients on program haemodialysis.

AIM: Determination of desialized apolipoprotein-B-100 (apoB-100) and lipoprotein-containing circulating immune complexes in patients with chronic kidney disease (CKD) in program hemodialysis with type 2 diabetes mellitus. MATERIALS AND METHODS: We examined 81 patients with CKD (50 men / 31 women) treated with program hemodialysis, of which 36 (17/19) with type 2 diabetes mellitus, 45 (33/12) non-diabetic patients. The levels of total cholesterol, triglycerides and desialylated apoB-100 in blood plasma and lipoprotein-containing circulating immune complexes. A color duplex scan of brachiocephalic arteries was used to assess the extent of development of atherosclerosis with the determination of the thickness of the intima-medial complex. RESULTS: Patients with diabetes had high values of total cholesterol, triglycerides (p<0.05). Duplex scan of brachiocephalic arteries showed an increase in the thickness of intima-medial complex in all patients for program hemodialysis, however, in patients with diabetes, the thickness was 13% higher (p<0.05). In patients with diabetes, plaques with stenosis up to 50% prevail, compared with non-diabetic patients, p<0.05. The incidence was significantly higher for desialized apoB-100 by 46% in patients with diabetes on hemodialysis compared non-diabetic patients (p<0.05). An increase in the level of lipoprotein-containing circulating immune complexes by 39%, (p<0.05) in patients with diabetes mellitus was observed, compared with patients non-diabetic patients. The correlation between desialized apoB-100 and duplex scan of brachiocephalic arteries parameters (r=0.325), as well as between the cholesterol level and stenosis up to 50% (r=0.465) in patients with diabetes mellitus, was found to be of medium strength. The patients with diabetes and CKD, myocardial infarction developed 79% more often than in patients without diabetes (p<0.05). Thus, immunogenic lipid markers of atherosclerosis can be considered both as mechanical factors of atherogenesis and diagnostic and prognostic characteristics in type 2 diabetic patients with impaired renal function and chronic renal insufficiency. CONCLUSION: Accelerated development of atherosclerosis with diabetes and CKD, confirmed with the help of duplex scan of brachiocephalic arteries, may be associated with an increase in the level of modified low density lipoprotein.

Influence of autophagy on the genesis and development of atherosclerosis and its risk factors. / Vliianie autofagii na vozniknovenie i razvitie ateroskleroza i ego faktorov riska.

Autophagy is a highly conservative process of degeneration during which intracellular components including soluble macromolecules (e. g., nucleic acids, proteins, carbohydrates and lipids) and dysfunctional organelles (e. g., mitochondria, peroxisomes, and the endoplasmatic reticulum) are degraded by a lysosome. Autophagy serves as a dynamic system of recycling proving cells with energy and building components. Because of it in cells of an organism new proteins and membranes can form contributing to survival of the individual under starvation conditions. Autophagy plays an important role in the genesis and development of multifactorial pathogenesis including atherosclerosis and its risk factors. The present article examines both a pathogenic and protective role of autophagy in such pathological processes. The article can be useful to molecular biologists and biochemists, as well as to professionals involved in the problems of atherosclerosis and cardiovascular diseases.

Phytoestrogen-Rich Natural Preparation for Treatment of Climacteric Syndrome and Atherosclerosis Prevention in Perimenopausal Women.

The present study evaluated the risks and benefits of phytoestrogen treatment in healthy perimenopausal women in relation to the dynamics of climacteric syndrome and progression of atherosclerosis. Study participants were treated with placebo or phytoestrogen-rich natural preparation Karinat based on grape (Vitis vinifera) seeds, green tea (Camellia sinensis) leaves, hop (Hunulus lupulus) cone powder and garlic (Allium sativum) powder. The dynamics of climacteric syndrome was evaluated by Kupperman Index and Utian Quality of Life Scale. Atherosclerosis progression was evaluated by measuring carotid intima-media thickness. Significant changes of climacteric syndrome's severity in both Karinat and placebo groups (p = 0.005 and p = 0.001) were obtained after 24 months of follow-up. Detailed analysis of Kupperman Index suggested that Karinat possessed a significant effect on nervousness (p = 0.010), weakness (p = 0.020) and formication (p = 0.010). A significant improvement of medical (p = 0.070) and emotional (p = 0.060) components of Kupperman Index and Utian Quality of Life Scale was also observed in Karinat group. However, difference in carotid intima-media thickness between the two groups was not statistically significant at follow-up. A slight positive effect of phytoestrogens on climacteric syndrome manifestations was demonstrated in this study. Karinat can be used for alleviation of climacteric syndrome and cardiovascular disease prevention in perimenopausal women. Copyright © 2017 John Wiley & Sons, Ltd.

[Macrophage activation in atherosclerosis. Message 2. Effects of factors on macrophage activation].

In atherosclerosis, macrophages demonstrate phenotypic plasticity to rapidly adjust to changing microenvironmental conditions. In the plaque, serum lipids, serum lipoproteins and various pro- or anti-inflammatory stimuli such as cytokines, chemokines and small bioactive molecules could greatly influence the macrophage phenotype inducing switch towards more proinflammatory or anti-inflammatory properties. Dynamic plasticity of macrophages is achieved by up-regulation and down-regulation of overlapping set of transcription factors that drive macrophage polarization. Understanding of mechanisms of macrophage plasticity and resolving functional characteristics of distinct macrophage phenotypes should help in the development of new strategies for treatment of chronic inflammation in cardiovascular disease.

[Soluble receptors for tumor necrosis factor and lipid metabolism as potential prognostic factors in patients with prostate cancer].

There was investigated the relationship of lipid metabolism, humoral immunity, high sensitivity C-reactive protein and soluble receptors for TNF-alpha with the presence, severity and prognosis of the disease in 85 patients with morphologically verified diagnosis of prostate cancer. Connection with the dynamics of change in PSA as a major predictor of the disease was observed for concentration sRI and sRII to TNF, PSA baseline, total cholesterol and LDL-cholesterol. During follow-up the relative risk of poor prognosis increased by 3 times, and death-in 8.7 times with increasing concentrations of soluble receptors for TNF. The concentration of soluble receptors for TNF may serve as an additional predictor of the presence and clinical course of disease in patients with prostate cancer.

[LDL oxidation and uptake by monocyte-derived macrophages from blood of patients with ischemic heart disease].

The aim of this study was to test our hypothesis that monocyte-derived macrophages of patients with ischemic heart diseases (IHD, MPIHD) were prestimulated (primed) or stimulated cells whose capacity for LDL oxidation and uptake exceeded that ofmacrophages from healthy donors (MPN). Monocytes were obtained from the blood of 18 healthy donors and 25 IHD patients; plasma LDL--from 16 another group healthy donors (LDLN) and 15 patients with family hypercholesterolemia. Incubation of LDLN or LDLH with MPIHD or MPN was carried out under aerobic and hypoxic conditions. It was shown that incubation of LDLN or LDLH with MPIHD TBARS accumulation, LDL aggregation, apoB fragmentation were observed earlier and proceeded more actively than in the case of incubation with MPN. MPIHD (compared to MPN) more actively uptook LDLH and LDLN as accumulated greater amounts of total cholesterol (TCh) (by a factor of 1.8-2.1; p < 0.05-0.01), and their viability decreased to a markedly greater degree (p < 0.01). MPIHD and MPN also oxidized and took up LDLH with a higher intensity than LDLN, and their capacity for LDL oxidation and uptake increased, under hypoxic condition, compared to those under aerobic conditions. Thus, new experimental results provide direct evidence that macrophages of IHD patients are in vivo priming or stimulated cells and that this stimulation, especially in combination with hypercholesterolemic LDL and hypoxia, is a very strong risk factor that can predispose these patients to the onset or progression of atherosclerosis. Using MPIHD, it was created express-method for evaluation the degree of monocyte/macrophage stimulation in patients with IHD, selection of premedication medicine and new antiatherosclerotic and antiischemic drugs.

Antiatherogenic effect of grape flavonoids in an ex vivo model.

The effects of grape phytoestrogens on cholesterol accumulation were studied in primary culture of human blood monocytes incubated with blood serum from postmenopausal women obtained before and 2, 4, and 6 h after single intake of plant components of grapes. Phytoestrogens from grape seeds, pressed out grapes, and fermented grape ridges prevent cholesterol accumulation in cells and can be regarded as prospective components for the development of natural preparations for the prevention of atherosclerosis in postmenopausal women.

[Hypolipoproteinemia and secondary role of atherosclerosis in the development of ischemic heart disease in patients with polycythemia vera].

Relationship between presence of coronary heart disease (CHD), coronary risk factors (parameters of lipid transport system and hypertension) and disturbances of microcirculation was studied in patients with myeloproliferative blood disease Polycythemia Vera (PV). Probability of tissue (including blood vessel wall) cholesterol accumulation was estimated by measurement of its content in skin surface layers. PV patients (n=55, including 27 patients with CHD) had predominant hypolipoproteinemia with normal proportion of various lipoprotein classes. Absence of substantial increase of skin surface cholesterol content both in patients with and without CHD was considered to be a sign of low probability of the presence of severe atherosclerotic processes. However patients with CHD had substantially more pronounced disturbances of microcirculation. Basing on these data the authors suggest that CHD in PV patients had non-lipoprotein genesis and present discussion of alternative mechanisms of vascular changes.

[Erythrocyte cholesterol content in polycythemia vera: relation to ischemic heart disease]. / Soderzhanie kholesterina v éritrotsitakh pri istinnoi politsitemii: sviaz' s ishemicheskoi bolezn'iu serdtsa.

Relative cholesterol content and its distribution between erythrocytes and plasma were studied in 34 patients with polycythemia vera (PV) both with and without concomitant coronary heart disease (CHD). Deformability of erythrocytes, disturbances of microcirculation (blood flow fragmentation, decrease of capillary density) were also assessed. Erythrocytes cholesterol/phospholipids molar ratios (0.68+/-0.03) in patients was lower than normal value (0.8) in spite of decreased cell deformability. This was associated with some increase of peroxidation products. Blood cholesterol distribution between cell and plasma species had some peculiarities caused by high hematocrit: compared with normal value erythrocytes of patients carried relatively larger portion of total blood cholesterol (23.7+/-0.8% and 27-31%, respectively). However in CHD patients these values were significantly lower with correspondent increase of plasma cholesterol quota. This allowed to suggest possible protective role of blood cholesterol redistribution in polycythemia patients, through erythrocytes trafficking of some part of plasma cholesterol.

Effect of oxidized LDL on hemolytic resistance of erythrocyte.

Using the method of peroxide-induced chemiluminescence we showed that incubation of the whole blood with oxidized LDL or oxidized blood plasma increased plasma hemoglobin concentration, which linearly depended on the degree of LDL oxidation. Similar effects were observed in erythrocyte suspension. Hemolytic activity of oxidized plasma 3-4-fold surpassed that of LDL isolated by ultracentrifugation. LDL capacity to oxidation in the presence of Cu(2+)increased by 50% and osmotic hemolysis of erythrocytes increased by 53% in coronary patients in comparison with healthy donors. These results indicate that oxidized LDL induce erythrocyte hemolysis.

[Characteristics of the lipid transport system in psoriasis]. / Osobennosti lipid-transportnoi sistemy pri psoriaze.

Cholesterol of high density lipoprotein (HDL) subfractions (HDL2 and HDL3), activity of cholesterol ester transport protein (CETP), and standard lipoprotein parameters (cholesterol, triglycerides, HDL cholesterol) were measured in plasma of 192 patients with various psoriasis forms, which included simple "distributed psoriasis", erythrodermic and arthropathic psoriasis. Among psoriatic patients unusually high percent of persons with both hypo- and hyper-cholesterolemia was observed. The same situation was observed with frequency of cases with both low and high plasma HDL cholesterol levels, the distribution being depending from disease severity. In contrast to norm, psoriasis patients had big range not only in HDL2 cholesterol level, but also in HDL3 cholesterol. They also had decreased CETP activity. Data obtained suggest the existence of changes in reverse cholesterol transport system in psoriasis, which may influence skin cell proliferation (via control of cell supply with cholesterol).

[Changes in blood rheological properties and erythrocyte osmotic resistance in activation of free radical processes]. / Izmenenie reologicheskikh svoistv krovi i osmoticheskoi rezistentnosti éritrotsitov pri aktivatsii svobodnoradikal'nykh protsessov.

Relationship between serum oxidation of different degree and micro- and macrorheology of the blood and modification of this relationship in the presence of antioxidant alpha-tocopherol were studied. Lipid peroxidation affects blood rheology and erythrocyte osmotic resistance. Erythrocytes are the first to react to increased activity of free radical oxidation and to exhaust their compensatory potential. Plasma viscosity remains stable in serum oxidation of different degree, and therefore erythrocytes are responsible for changes in blood rheology during intensification of free radical oxidation. Moreover, erythrocytes are functionally resistant to oxidative stress in malonic dialdehyde concentrations under 3.62 +/- 0.41 nM/ml. alpha-Tocopherol increases functional resistance of erythrocytes and maybe of protein components of the plasma to damaging action of free radicals.

Effects of low-density lipoproteins on blood coagulation and fibrinolytic activity.

In vitro experiments showed that copper-oxidized low-density lipoproteins activate factors of the prothrombin complex in the whole blood and inhibit fibrin generation in both blood and plasma. Moreover, oxidized low-density lipoproteins inhibit fibrinolysis and impair the structure of fibrin clot, which results in hypercoagulation.

[New approaches to therapy in glomerulonephritis patients]. / Novye podkhody k terapii bol'nykh glomerulonefritom.

Before starting treatment of chronic glomerulonephritis it is desirable to determine the patient's drug sensitivity in vitro because in the absence of such sensitivity chemotherapy should be preceded by immunomodulation with tactivin or thymalin and 3-5 sessions of plasmapheresis to stimulate drug sensitivity. Further measures include prednisolone or cyclophosphamide intravenously for 3-5 days in a dose 300-500 followed by oral administration. Active treatment lasts for 4-8 weeks. After that the patients receive maintenance for 1-2 years.

[A method of determination of cholesterol contents on the surface of the human skin and prospects of its use. I. Atherosclerosis]. / Metod opredeleniia soderzhaniia kholesterina poverkhnosti kozhi cheloveka i perspektivy ego ispol'zovaniia. 1. Ateroskleroz.

Proceeding from published data on lipid content and composition in human skin and on the possible relationship between cholesterol level in skin biopsy specimens and status of blood vessels, the authors measured cholesterol content in skin layers available for external extraction in patients with atherosclerosis with different types of dyslipoproteinemias. Effective conditions of extraction were developed permitting after external rapid atraumatic treatment extraction of the maximally possible amount of cholesterol, 1.5 to 1.6 mkg from 1 cm2 of the palm skin surface, this being a constant value for each examinee (coefficient of variations after 3-4 repetitions 5%). Though slight, but statistically reliable increase of the amount of surface-extractable cholesterol was observed in atherosclerosis patients. This parameter did not correlate with the blood serum concentration of lipid components. A correlation (r = 0.54, p < 0.001) was observed with an only serum lipoprotein parameter, the so-called dyslipoproteinemia coefficient representing the sum of "atherogenic" parameters (cholesterol+triglycerides) divided by alpha-lipoprotein cholesterol. Measurements of surface-extractable skin cholesterol may be used as an available discriminant of atherosclerosis; the method seems to find application in other diseases as well.

[Comparison of results of the fluorescent method in the determination of atherogenic lipids and the data of biochemical methods]. / Sravnenie rezul'tatov fliuorestsentnogo metoda opredeleniia aterogennykh lipidov s dannymi biokhimicheskikh metodov.

Devices based on assessment of fluorescence of special "probes" incorporated in lipoprotein particles of the blood were developed at Research Institute of Physicochemical Medicine of the Ministry of Health of the Russian Federation. The resultant value is considered to reflect the sum of total cholesterol and triglycerides. The present study was aimed at elucidation of the relationship between the fluorescent and enzymatic methods, the enzymatic method realized by the Centrifikhem autoanalyzer. Coronary angiography during which blood for analysis by the two methods was collected was carried out in 182 patients aged 26 to 68 (mean age 49). Analysis of correlations revealed a direct relationship of the fluorescent value with the sum of total cholesterol and triglycerides, with triglycerides, with total cholesterol, and an inverse relationship with high-density lipoproteins. Using multifactorial regression analysis, the level of fluorescent parameter could be predicted only on the basis of triglyceride level and ratio of total cholesterol to high-density lipoproteins. Using the linear regression equation it is possible, if the fluorescent parameter value is available, to calculate triglyceride level. No relationship of the fluorescent parameter or triglycerides with the dissemination of coronary atherosclerosis, which is characteristic of total cholesterol sum, was detected.

[New findings in the pathogenesis of chronic glomerulonephritis]. / Novoe o patogeneze khronicheskogo glomerulonefrita.

30 untreated patients with membranoproliferative glomerulonephritis (MPGN) with isolated urinary syndrome were examined for cellular and humoral immunity. There was a significant (p < 0.05) reduction of the number of T-helpers/inductors (T4/4B4) and early undifferentiated lymphoid precursors with the marker enzyme. T-lymphocytes with markers T1, T3, T11, T12 as well as T-suppressors/cytotoxic cells (T8/2H4) occurred in normal quantities. IL-1 and IL-2 production was inhibited. Mature T-lymphocytes with markers T11, suppressors T8, early precursors of T-cells (T6) were higher in number in development of dystrophic changes in tubular epithelium. It is suggested that T-cell factor may be involved in nephron impairment observed in MPGN patients. Humoral immunity disorders are of the secondary nature.