[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.

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.

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.

[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.

[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.

Modulation of TXA2 generation of platelets by human lipoproteins.

The lipoprotein (LP) fractions VLDL, LDL, HDL2 and HDL3 were prepared by ultracentrifugation of plasma from healthy volunteers and from patients with coronary heart disease (CHD). We investigated the capacity of platelets from healthy volunteers and patients with atherosclerosis to generate thromboxane A2 (TXA2) during spontaneous clotting of whole blood under the influence of the lipoprotein fractions. In our experiments the serum concentration of TXB2, reflecting the capacity of platelets to generate TXA2 during clotting, depends on several factors: the type of LP fraction used, the blood used for generation of TXA2, and for the same LP fraction whether it was taken from plasma of healthy volunteers or patients with CHD. VLDL prepared from plasma of healthy volunteers inhibited but VLDL prepared from plasma of patients with CHD enhanced the TXA2 formation of platelets from healthy volunteers (p less than 0.05, resp.). LDL from CHD patients inhibited the TXA2 formation of platelets from atherosclerotic patients (p less than 0.01). The HDL subfractions HDL2 and HDL3 from healthy volunteers inhibited TXA2 formation by platelets from healthy volunteers as well as those from atherosclerotic patients (p less than 0.05; p less than 0.01, respectively). HDL2 from patients with CHD inhibited only the TXA2 formation of platelets from healthy volunteers (p less than 0.01), whereas HDL3 from CHD patients inhibited only the TXA2 formation of platelets from atherosclerotic patients (p less than 0.01).

[Indicators of the atherogenic properties of plasma lipoproteins and coronary atherosclerosis (selective angiography data)]. / Pokazateli aterogennosti lipoproteidov plazmy krovi i koronarnyi ateroskleroz (po dannym selektivnoi angiografii).

A combined study of possible atherogenic factors was carried out in 213 males subjected to clinical investigation including selective angiography of the heart's coronary arteries. Two sets of biochemical tests were used: the routine set including the measurement of the plasma lipid spectrum, and a more sophisticated procedure (93 cases) where plasma apoproteins A1 and B, and high-density lipoprotein phospholipid composition were assessed as well. A correlation of biochemical disorders to coronary atherosclerosis could be demonstrated in 68% of cases, using the first set, and in 98% with the second set. Abnormal apoprotein levels and high-density lipoprotein phospholipid composition were found to contribute significantly to lipoprotein atherogenesis even in cases of normolipidemia.

[First-onset stenocardia: indices of the atherogenicity of the blood plasma lipoprotein system and the coronary angiographic data]. / Vpervye voznikshaia stenokardiia: pokazateli aterogennosti sistemy lipoproteidov plazmy krovi i dannye koronarnoi angiografii.

Coronary angiography and the assessment of blood lipoproteins were carried out in 43 patients with recent (not more than three months old) angina. A rise in cholesterol above 270 mg/dl and/or triglycerides above 200 mg/dl was demonstrated in 19. The level of alpha-cholesterol was below 35 mg/dl in 11 of 24 normolipidemic patients. The apoprotein B/apoprotein AI ratio was above 1.0 in 7 of 13 patients with normal cholesterol levels. Plasma phospholipid composition was disturbed in 4 of 6 patients with normal apoprotein B/apoprotein AI rations. Therefore, atherogenic changes in plasma lipoprotein composition were found in 95% of patients with recent angina.

[Atherogenic properties of sera from patients with ischemic heart disease demonstrated in vitro]. / Aterogennye svoistva syvorotok bol'nykh ishemicheskoi bolezn'iu serdtsa, proiavliaiushchiesia in vitro.

The sera of coronary patients with angiographically-documented stenosis of 1 to 3 coronary arteries caused a two-to-fivefold accumulation of intracellular cholesterol in intact human aortic intimal cell culture. This property, qualified as "atherogenic", was exhibited by the sera of 90% of the coronary patients examined (97 males and females, aged 29 to 55 years). Only 20% of normal subjects revealed atherogenic properties in cell cultures. The capacity of the sera to accumulate intracellular cholesterol was unrelated to the levels of total cholesterol, high density lipoprotein cholesterol, apo-B or apo-AI, taken separately, but showed a weak correlation to the apo-B/apo-AI ratio. The sera of coronary patients caused lipid accumulation in human aortic medial smooth-muscle cells and blood mononuclear cells, in human and mouse peritoneal macrophages, but never in human aortic or umbilical vein endothelial cells, nor human embryo fibroblasts.

[A trial of the clinical use of the Russian hypocholesterolemic preparation fenbutol--an analog of probucol]. / Opyt klinicheskogo primeneniia otechestvennogo gipokholesterinemicheskogo preparata fenbutola--analoga probukola.

Phenbutol, a Russian analogue of probucol, was studied by the single blind method by using placebo in 30 patients aged 36 to 65 years whose total serum cholesterol levels were more than 250 mg/dl after a month placebo therapy. The patients were divided into two groups: (1) 15 patients on placebo and (2) 15 patients on phenbutol, 500 mg twice a day for 5 months. Blood lipid parameters were monthly determined. The findings are in agreement with the data on the effects of probucol on lipids and its adverse effects. During the follow-up, phenbutol showed 17%, 14% and 10% decreases in total cholesterol and low density lipoprotein cholesterol and high density lipoprotein cholesterol, respectively, as compared with the baselines. These changes were greater than those in patients on placebo. In the first week of therapy with phenbutol, vomiting, appetite decrease, digestive disturbances were observed in 73% of patients. These adverse reactions did not require its withdrawal. Resting ECG Q-T interval became prolonged in 7 out of 15 patients receiving phenbutol (maximum 500 msec).

[Study of low density lipoproteins in hyperlipoproteinemia by the method of double immunodiffusion]. / Issledovanie lipoproteidov nizkoi plotnosti pri giperlipoproteidemii metodom dvoinoi immunodiffuzii.

By way of gel double immunodiffusion a certain heterogeneity of low density lipoproteins was observed to manifest itself in an additional band of immunoprecipitation. The incidence of this additional band does not exceed 1/3 of the cases of low density lipoproteins studies in normal individuals, while in those with ischaemic heart disease the additional band is found twice-thrice as often, the highest incidence being noted in patients with ischaemic heart disease and Type IIb hyperlipoproteinemia (93% of cases). The revealed immunochemical heterogeneity of low density lipoproteins was shown to be not connected with the appearance of any new, additional antigen in their structure. Most probably it is attributable to the presence of lipoprotein particles with a quantitatively different protein and lipid composition, probably of intermediate lipoprotein metabolites in blood plasma, or conformation changes in the structure of low density lipoproteins.

[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.

[Isolation and quantitative determination of apoprotein C-11 in the blood using rocket immunoelectrophoresis]. / Vydelenie apoproteina C-11 i kolichestvennoe opredelenie ego v plazme krovi metodom raketnogo immunoélektroforeza.

Apoprotein C-II was isolated from human blood plasma by means of column chromatography-gel filtration and DEAE ion exchange chromatography by modified method of Brown et al (1969). Production of antiserum to apoprotein C-II as well as a procedure for rocket immunoelectrophoresis are described for estimation of the apoprotein in blood plasma of men and women of various age, exhibiting different lipid spectra. Content of the apoprotein C-II in blood plasma, estimated by the immunoelectrophoretic procedure, was higher in men as compared with women and correlated with concentration of triglycerides in blood plasma.

[Change in the apoproteins of very low density lipoproteins in the blood in hypertriglyceridemia]. / Izmenenie apoproteinov lipoproteidov ochen' nizkoi plotnosti plazmy krovi pri gipertriglitseridemii.

Some properties of very low density lipoproteins were studied under conditions causing an increase of their concentration in blood plasma. Content of high molecular apolipoprotein B and low molecular lipoproteins were estimated after fractionation using column chromatography and selective precipitation with tetramethylurea. In 216 men (40-59 years old) with hypertriglyceridemia the increase in content of particles of very low density lipoproteins was accompanied by simultaneous alteration in their composition in blood plasma: content of low molecular polypeptides, triglycerides and cholesterol was increased per a weight unit of apoprotein B. At the same time, the absolute concent of apoprotein B and of low molecular apoproteins of very low density lipoproteins was increased in blood plasma. The most distinct alteration in the ratio of apolipoproteins to very low density lipoproteins was observed, if content of testosterone--activator of lipoprotein lipase--was decreased in blood plasma.

[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.

[Preparative subfractionation of high-density lipoproteins in dysalphalipoproteinemias]. / Preparativnoe subfraktsionirovanie lipoproteidov vysokoi plotnosti pri disal'falipoproteidemiiakh.

A new modified procedure is described for preparative production of three subfractions of high density lipoproteins (HDL) by means of salt density gradient developed in ultracentrifugation. Concentrations of cholesterol, phospholipids and apoprotein A-1 in both subfractions HDL2b and HDL2 alpha were found to alter simultaneously with the level of HDL cholesterol in blood plasma of the patients with low, normal and increased content of HDL cholesterol (10 men in each group), thus suggesting the alteration of the particles amount in both these subfractions. In hyperalphacholesterolemia the level of all the components studied was unaltered as compared with normal state, and in hypoalphacholesterolemia only cholesterol containing in HDL3 was decreased due to diminished loading of the particles with cholesterol, as calculated per a unit of apoprotein A-1. The data obtained suggest that alterations in amount of both HDL2b and HDL2a particles depended on intensity of lipid binding, especially of cholesterol, to particles of the HDL3 subfraction, which plays an important role in various physiological and pathological states.

[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.

[Incidence among men of atherogenic potential of the serum detected in a culture of mouse peritoneal macrophages]. / Rasprostranennost' sredi muzhchin aterogennogo potentsiala syvorotki krovi, vyiavliaemogo v kul'ture peritoneal'nykh makrofagov myshi.

Blood serum of 63 persons out of 191 men examined, randomly selected among non-organized population, caused in primary culture of mice peritoneal macrophages the 1.3-4-fold increased accumulation of intercellular cholesterol. Blood serum of other 128 men studied did not exhibit any atherogenic properties in the culture. The atherogenic potential of blood serum did not correlate with content of blood serum lipids, apolipoproteins B and A-I, while it correlated with the ratio apo B/apo A-I in blood serum and with one of ischemic heart disease risk factors--increased arterial pressure. Blood serum atherogenic potential, detected in experimental model, appears to be involved in development of human atherosclerosis.