INTRODUCTION:Tuberculosis (TB) is one of the top ten causes of death worldwide. Improvement of the treatment options via development of new drugs and treatment regimens that would be more convenient for patients is one of key options of improving the effecacy of the TB prevention and careis. Since the creation of new treatment regimens by minimizing the number of the drugs used and reducing the duration of treatment is the most promising and correct direction, macozinone, a new candidate of the benzothiazinone series, can become the basis for development of new chemotherapy regimens for drug-resistant forms of TB including the combination of macozinone with the most effective modern anti-TB drugs. AIM:Comparative evaluation of the pharmacokinetic properties of macozinone capsules 80 mg and the new dosage form a dispersible tablet for preparation of oral solution. MATERIALS AND METHODS:Solubility of the substance macozinone in biorelevant media in vitro, permeability of macozinone in the test Caco-2 in vitro, as well as pharmacokinetics of macozinone in dogs in vivo were evaluated. RESULTS:The solubility assessment in biorelevant media showed that the average limit of macozinone substance dissolution in the pH 5.0 acetate buffer solution was from 6 to 9 mg/l, in FaSSIF medium (fasted) from 2.5 to 4 mg/l, and in FeSSIF medium (after meals) from 16.8 to 29 mg/l. It is established that the cell permeability of the pharmaceutical substance macozinone in the CACO-2 test system is on average 2.510-6cm/s in the forward direction from the apical to basolateral cell membrane, and 1.510-6cm/s in the reverse direction, which corresponds to low permeability. The main pharmacokinetic parameters of macozinone dispersable tablets 160 mg, after dosing with food and on an empty stomach, as well as capsules 80 mg, when administered on an empty stomach in vivo studies in dogs are presented. DISCUSSION:The specific physicochemical properties of macozinone, the problems of developing the new dosage form, as well as ways of solving some of them are presented. CONCLUSION:In the process of new dosage forms development, the existing chemical properties of the macozinone substance should be considered. One of the promising ways of increasing bioavailability and, consiquently, efficacy is development a fundamentally new drug form with modified release within the absorption window.

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.

Background: Plasma apo B-containing lipoproteins of low densities represent a heterogeneous population of particles varying by physicochemical composition, functional activity, and atherogenicity. Aim: To study some peculiarities in low density lipoproteins subfractional distribution in men with coronary atherosclerosis at normolipidemia. Material and methods: Patients with angiographically documented coronary atherosclerosis were included into the study ( n = 177; mean age 62.5 ± 9.3 yrs). Lipoprotein subfractional distribution was analyzed using Lipoprint LDL System (Quantimetrix, USA). Results: Out the total cohort normolipidemic patients (total C < 5,0 mmol/l, TG < 1.7 mmol/l, LDL-C < 2.5 mmol/l) with coronary atherosclerosis were selected and thereafter were split into those without small dense LDL (sdLDL) - group 1, n = 16, and and group 2 with presence of sdLDL ( n = 22). Patients from group 2 had lower portion of IDLB: 7.0 ± 1.2 vs 8.5 ± 1.0 %, IDLА: 7.9 ± 1.7 vs 9.6 ± 2.5 %, and higher LDL2 portion: 7.0 ± 2.0 vs 4.3 ± 1.6 %. In group 2 C level in LDL2 was higher than in group 1 while in IDL B it appeared to be lower. Mean LDL particles size in group 2 was lower as well: 270.7 ± 1.3 и 273.8 ± 0.8 Е. Conclusion. In men with coronary atherosclerosis at normolipidemia two different patterns of subfractional distribution of apo B-containing lipoproteins were detected. Presence of sd LDL associated with decreased LDL size could be regarded as more atherogenic profile even at normal lipid levels.

Aim. To investigate  on  the  presence and  relation characteristics of glycemia  variability (GV) and   vascular   wall  parameters,  chronic inflammation, oxidation status,   telomere  biology in type  2  diabetes patients (DM2). Material and methods . Into the single-movement study, 50 DM2 patients included, with no signs of cardiovascular diseases. All participants  were evaluated on the carbohydrate  metabolism, glycemia variablity, underwent duplex  scan   of  carotid   arteries   with  intima-media  complex  (IMC) measurement, and  assessment for atherosclerotic  plaques;  underwent carotid-femoral pulse wave velocity measurement, endothelium dependent vasodialtion, telomere length measurement and telomerase activity (TA). Results. The parameters of vessel wall, together with the classical CVD risk  factors,   independently   related   with the  various  carbohydrate metabolism parameters: glycated hemoglobin, fasting glucose plasma, HOMA-IR index, C-peptide, immune reactive insulin. The GV of moderate amplitude  of glycemia (MAGE) was related  to IMC increase  in DM2 patients.  There was significant relation of telomere length (TL) not just with a chronic hyperglycemia, but with glucose level fluctuations as well, e.g. with GV standard deviation (SD), MAGE, CONGA (continuous overall net glycemic action), and such relation is higher in the analysis of “the longest”  telomeres.  Relation of TL  and  GV  is not dependent on the cardiovascular risk factors,  chronic inflammation and TA, but depends on fasting plasma glucose.  There was no significant relation of TA with GV in DM2. There was direct correlation of GV CONGA  and oxidative stress marker malonic dialdehyde, and independent negative correlation of GV (MAGE, SD, CONGA) with TL. Conclusion. GV is related  with subclinical atherosclerosis (IMC) and shorter  TL in DM2 patients,  which is mediated  by activated oxidation stress under glycemia fluctuations.

Aim: To reveal whether statin therapy affects subfractional distribution of low densities lipoproteins in men and women with documented coronary atherosclerosis (CA).

Aim. To reveal whether there are differences in subfractional distribution of apo B-containing lipoproteins in men and women with coronary atherosclerosis treated with statins depending on low density lipoprotein (LDL) cholesterol level.Material and methods. Patients aged 33-85 years with angiography documented coronary atherosclerosis were included into the study (n=133): 97 men (mean age 61±9.0 years) and 36 postmenopausal women (mean age 65±9.3 years). Patients were on statin therapy at least 6 months before admission: atorvastatin (10-40 mg/day), simvastatin (20-40 mg/day), rosuvastatin (10-40 mg/day) and pravastatin (20 mg/day). Subfractional apo B-containing lipoproteins distribution was analyzed by electrophoresis in a 3% polyacrylamide gel.Results. Men achieving target LDL cholesterol level (<2.5 mmol/l) as compared with those with higher LDL cholesterol level alongside with decreased proatherogenic lipids and apolipoproteins, had less atherogenic LDL subfractional profile: lower portion of LDL 2 (7.3±3.4 и 9.9±3.9%, p<0.01), small dense LDL 3 (1.3±1.2 и 2.2±2.2%, р<0.05), LDL 4 (0.2±0.2 и 0.3±0.5%, p<0.05), and concentration of cholesterol in this subfrtactions. These differences were associated with elevated mean size of LDL particles (270.8±3.0 vs 268.8±3.9 Å, p<0,01). On the other hand, women, despite achieving target LDL cholesterol level, had elevated apo B level and apo B/AI ratio without any differences in subfractional profile of low densities lipoproteins.Conclusion. In patients with coronary atherosclerosis treated with statins, antiatherogenic shifts in apo B-containing lipoproteins, decrease of cholesterol concentration subfractions coupled by elevation of mean LDL particle size were found only in men who reached target LDL cholesterol level.

Background: Increased arterial stiffness (AS), intima-media thickness (IMT), and the presence of atherosclerotic plaques (PP) have been considered as important aspects of vascular aging. It is well documented that the cardiovascular system is an important target organ for growth hormone (GH) and insulin-like growth factor (IGF)-1 in humans, and GH /IGF-1 deficiency significantly increases the risk for cardiovascular diseases (CVD). The telomere length of peripheral blood leukocytes (LTL) is a biomarker of cellular senescence and that has been proposed as an independent predictor of (CVD). The aim of this study is to determine the role of GH/IGF-1, LTL and their interaction cardiovascular risk factors (CVRF) in the vascular aging. Methods: The study group included 303 ambulatory participants free of known CVD (104 males and 199 females) with a mean age of 51.8 ± 13.3 years. All subjects had one or more CVRF [age, smoking, arterial hypertension, obesity, dyslipidemia, fasting hyperglycemia, insulin resistance—HOMA (homeostatic model assessment) >2.5, or high glycated hemoglobin]. The study sample was divided into the two groups according to age as “younger” (m ≤ 45 years, f ≤ 55 years) and “older” (m > 45 years, f > 55 years). IMT and PP were determined by ultrasonography, AS was determined by measuring the carotid-femoral pulse wave velocity (c-f PWV) using the SphygmoCor system (AtCor Medical). LTL was determined by PCR. Serum IGF-1 and GH concentrations we measured by immunochemiluminescence analysis. Results: Multiple linear regression analysis with adjustment for CVRF indicated that HOMA, GH, IGF-1, and LTL had an independent relationship with all the arterial wall parameters investigated in the younger group. In the model with c-f PWV as a dependent variable, p < 0.001 for HOMA, p = 0.03 for GH, and p = 0.004 for LTL. In the model with IMT as a dependent variable, p = 0.0001 for HOMA, p = 0.044 for GH, and p = 0.004 for IGF-1. In the model with the number of plaques as a dependent variable, p = 0.0001 for HOMA, and p = 0.045 for IGF-1. In the older group, there were no independent significant associations between GH/IGF-1, LTL, HOMA, and arterial wall characteristics. Conclusions: GH/IGF-1, IR, HOMA, and LTL were the important parameters of arterial aging in younger healthy participants.

Aim: CVD remains the main cause of death in the world therefore search for markers identifying coronary atherosclerosis (CA) patients is of crucial interest.

The lipoproteins of low and high density are presented by heterogeneous specter of particles differing by size, density, charge, composition and functional characteristics. The prevalence of small dense particles of lipoproteins of low and high density in blood plasma is associated with higher risk of development of coronary heart disease. The identification of subfractional spectrum of lipoproteins in clinical purposes is complicated because of requirement of expensive equipment and reagents and extended time of implementation. The lipoprint-system (Quantimetrix Lipoprint LDL/HDL System, USA) based on the vertical electrophoresis using 3% polyacrilamid gel, permits shortening time of sub-fractioning of lipoproteins up to three hours. In the spectrum of apoB-containing lipoproteins of very low density, intermediate density, C, B, A, lipoproteins of low density 1 and 2, small dense (lipoproteins of low density 3-7) are singled out. In the spectrum of lipoproteins of high density up to 10 sub-fractions associated in three groups and represented by large (lipoproteins of high density 1-3), intermediate (lipoproteins of high density 4-7) and small (lipoproteins of high density 8-10) particles are singled out. The article describes technique of identification of spectrum of particles of lipoproteins of low and high density in human blood serum. The conditions of implementation of experiments are presented. The advantages and limitations of technique are indicated. The number of examples of application of indices of sub-fractional spectrum of lipoproteins as additional markers of evaluation of aterogenity of lipid profile are presented. The conclusion is made concerning possibility of application of technique in clinical laboratory diagnostic.

Background: Telomerase activity (TA) is considered as the biomarker for cardiovascular aging and cardiovascular diseases (CVDs). Recent studies suggest a link between statins and telomere biology that may be explained by anti-inflammatory actions of statins and their positive effect on TA. Until now, this effect has not been investigated in prospective randomized studies. We hypothesized that 12 months of atorvastatin therapy increased TA in peripheral blood mononuclear cells. Methods: In a randomized, placebo-controlled study 100 hypercholesterolemic patients, aged 35-75 years, free of known CVDs and diabetes mellitus type 2 received 20 mg of atorvastatin daily or placebo for 12 months. TA was measured by quantitative polymerase chain reaction. Results: At study end, 82 patients had sufficient peripheral blood mononuclear cells needed for longitudinal analysis. TA expressed as natural logarithms changed from 0.46 ± 0.05 to 0.68 ± 0.06 (p = 0.004) in the atorvastatin group and from 0.67 ± 0.06 to 0.60 ± 0.07 (p = 0.477) in the control group. In multiple regression analysis, atorvastatin therapy was the only independent predictor (p = 0.05) of the changes in TA independently of markers of chronic inflammation and oxidative stress. Atorvastatin therapy was associated with increases in interleukin-6 within the normal range and a tendency toward reduction in blood urea. Conclusion: These initial observations suggest atorvastatin can act as telomerase activator and potentially as effective geroprotector. Trial registration: The trial was registered in ISRCTN registry ISRCTN55050065.

Aim. To find out, whether there is specifics of subfractional distribution of plasma lipoproteides in men and women depending on coronary atherosclerosis.Material and methods. Totally 310 patients included (203 males, 107 females), underwent coronary arteriography; lesion of artery was assessed with Gensini Score (GS). Subfractional spectrum of plasma lipoproteides was studied via electrophoresis in 3% polyacrylamid gel with Lipoprint system (Quantimetrix Lipoprint System, USA).Results. In the group without lesion (GS =0) gender differences of lipids, apolipoproteides and glucose utilization parameters were absent. Among coronary atherosclerosis patients (GS >0) males had lower concentrations of low and high density cholesterol (LDL, HDL), as Apo A1 and Apo B. Males with GS =0, as with GS >0 differed from females by lower lipoproteides of intermediate density (LID) — LID B and LID A, and higher part of LDL 2 and small dense particles LDL 3, but mean size of LDL particles was smaller. There were no differences in HDL subfractions distribution among men and women, but in men only if coronary atherosclerosis, there were lower cholesterol concentrations found in all HDL subfractions.Conclusion. Gender differences are revealed in subfractional spectrum of LID and LDL: in men regardless coronary atherosclerosis with the same and even lower level of LDL cholesterol there was accumulation of more atherogenic small dense LDL particles. Gender differences in the part of HDL subfractions were not found, but in men concentration of cholesterol in each of subfractions, with coronary lesion, was lower than in women.

Objectives: To study the relationship between apolipoprotein B-containing lipoproteins subfractional distribution and carotid and coronary atherosclerosis.

Telomere length (TL) is a recognized marker of replicative cellular ageing, and related to the ageing of cardiovascular system with the risk of cardiovascular diseases development (CVD). Chronic inflammation and oxidative stress significantly determine the velocity of telomeres shortening, and most of CVD risk factors (RF) closely related to these proceses; and it is possible to suggest that relationship of TL and RF determine CVD risk. However, clinical studies on this processes elaboration are lacking.Aim. To study relation of TL with traditional and some “new” RF in persons of different age without clinical signs of CVD, related to atherosclerosis.Material and methods. Totally, 303 patients included, of the age 25-91 y.o., without signs of CVD and other chronic diseases, not taking regularly and medications. All patients underwent traditional and some “novel” RF. TL was measured via real time polymerase chain reaction.Results. According to the regression model, TL is independently related to age, C-reactive protein (marker of inflammation), urea (oxidative stress maker), and metabolic status markers as waist circumference, insulin resistance index HOMA, fasting glucose level; the most significant predictor is HOMA (p=0,0001). Risk of having shortened telomeres increases 12 times with increased urea, 2,4 times with insulin resistance, 2 times in fasting hyperglycemia.Conclusion. Revealing of the factors that are related to cellular ageing makes it to define the most potentially benefit targets for interventions towards early and effective CVD prevention.

Objectives: Traditional cardiovascular disease (CVD) risk factors, despite high predictive value on population level, fail to fully predict individual risk.

Objectives: Plasma lipoproteins represent a highly heterogeneous population of particles varying in size, composition, and functional activity.

Apolipoprotein (apo)B-containing lipoproteines of low density are heterogeneous by their nature, and differ by their lipid and protein contents, charge, particle size and functional activity. High blood level of small dense particles of low-density lipoproteines (LDL) is related to higher risk of coronary heart disease 3-5 times irrelevant to cholesterol level they contain.Aim. To evaluate and describe the specifics of subfraction spectrum of apo-Bcontaining lipoproteines in patients with lesions in carotid and/or coronary circulation.Material and methods. Totally, 310 patients included (62,5±9,3 year old), underwent duplex scanning of carotid arteries and coronary arteriography (M/F 203/107). Sub fraction spectrum of lipoproteines was assessed with electrophoresis on 3% polyacrylamide gel (Lipoprint system, Quantimetrix Lipoprint LDL System, USA). The level of severity of coronary atherosclerosis lesion was assessed with the Gensini Score (GS).Results. Evaluation of subfractional spread of lipoproteines according to the results of duplex scan showed that in the group of patients with intima-media thickness (IMT) >0,9 mm part of intermediate density lipoproteides (IDL) C is higher (11,0±3,6 vs 9,1±2,8%, р=0,002), and the part of low density lipoproteides (LDL) 1 is lower (16,7±4,1 vs 18,1±3,7%, р=0,047) comparing to the patients with normal IMT. Assessment of the spread of LDL subfractions according to the number of atherosclerotic plaques (AP) and/or lesion of carotid arteries showed that among the patients with ≥3 AP and/or involved carotid arteries for >45%, the part of LDL C decreased (9,9±3,2 vs 11,4±3,7%, р=0,003), but there is increase of intermediate density lipoproteides A (IDL A) (9,3±2,6 vs 8,4±2,5%, р=0,013) and large particles of IDL 1 (17,8±4,0 vs 16,2±4,0%, р=0,005) and comparing to those having <3 AP and/or in lesion ≤45%. With the grading score GS the groups of patients were selected with absence of coronary atherosclerosis (GS =0, n =68) and presence of coronary atherosclerosis (GS >0, n=242). Coronary patients were selected to subgroups with minimal or mild (GS <35, n =81) and severe lesion of coronary arteries (GS ≥35, n=161). In the group of GS >0 part of very low density lipoproteines (VLDL) (21,0±4,1 vs 19,3±4,1%, р=0,004) and IDL (11,4±3,4 vs 10,5±3,3%, р=0,047) were higher, and part of IDL A (8,4±2,5 vs 9,4±2,6%, р=0,006) and large particles IDL 1 (16,8±4,2 vs 18,2±4,2%, р=0,013) lower than group GS =0. In the group GS ≥35 the part of IDL C was significantly higher comparing to those from GS <35 (11,8±3,7 vs 10,8±3,0%, р=0,008). According to multifactor regression, the risk of coronary atherosclerosis is related to higher part of VLDL (OR =1,1, 95% CI 1,0-1,2, р=0,039), small dense particles of LDL 3-6 (OR =1,3, 95% CI 1,0-1,6, р=0,049), and higher part of LDL 2 is associated with the risk of coronary atherosclerosis by 10% GS score (OR =0,9, 95% CI 0,8-1,0, р=0,014). Conclusion. Combination of carotid and coronary arteries is related to the changes of subfractional lipoproteides spectrum (lower part of IDL A and large particles of LDL 1 and higher part of VLDL), characteristic for isolated lesion of coronary arteries regardless its prominence, which probably might be regarded as additional markers of atherogenity of lipid profile in earlier stage carotid and any coronary atherosclerosis.

LDL particles vary in size, density and differ in atherogenic potential. Small dense LDL particles are the most atherogenic and increase risk of CAD.