Influence of exogenous lactoferrin on the oxidant/antioxidant balance and molecular profile of hormone receptor-positive and -negative human breast cancer cells in vitro.

AIM: To investigate the mechanisms of cytotoxic activity and pro-/antioxidant effect of lactoferrin on hormone receptor-positive and receptor-negative breast cancer cells in vitro. MATERIALS AND METHODS: The study was performed on receptor-positive (MCF-7, T47D) and receptor-negative (MDA-MB-231, MDA-MB-468) human breast cancer cell lines. Immunocytochemical staining, flow cytometry, low-temperature electron paramagnetic resonance, and the Comet assay were used. RESULTS: Upon treatment with lactoferrin, the increased levels of reactive oxygen species (ROS) (p < 0.05), NO generation rate by inducible NO-synthase (p < 0.05) and the level of "free" iron (p < 0.05) were observed. Moreover, the effects of lactoferrin were more pronounced in receptor-negative MDA-MB-231 and MDA-MB-468 cells. These changes resulted in increased expression of proapoptotic Bax protein (p < 0.05), reduced expression of the antiapoptotic Bcl-2 protein (p < 0.05) and level of not-oxidized mitochondrial cardiolipin (1.4-1.7-fold, p < 0.05). This, in turn, caused an increase in the percentage of apoptotic cells (by 14-24%, p < 0.05). Cytotoxic effects of lactoferrin were accompanied by an increase in the percentage of DNA in the comet tail and blocking cell cycle at G2/M phase, especially in receptor-negative cell lines. CONCLUSION: The study showed that exogenous lactoferrin causes a violation of an antioxidant balance by increasing the level of ROS, "free" iron and NO generation rate, resalting in the blocking of cell cycle at G2/M-phase and apoptosis of malignant cells.

[Experimental study of the influence of recombinant human lactoferrin on the levels of androgens and basic parameters of lipid and protein metabolism]. / Éksperimental'noe issledovanie vliianiia rekombinantnogo laktoferrina cheloveka na urovni androgenov i osnovnye pokazateli lipidnogo obmena.

System administration of human recombinant lactoferrin per os to rats for 2,5 months increased serum and testicular levels of total testosterone. The data correlated with the increase in free testosterone levels. These changes were accompanied by an increase of concentrations of steroidogenesis substrates (cholesterol, progesterone, and 17-OH progesterone) and a decrease of the estradiol content in blood serum. This resulted in the 3.6-3.8-fold increase of the testosterone/estradiol index. Basic parameters of lipid and protein were also studied. Results of this study suggest that lactoferrin administration causes activation of androgen synthesis and lipid metabolism.

Modifying effects of lactoferrin in vitro on molecular phenotype of human breast cancer cells.

AIM: To assess the role of endogenous lactoferrin (LF) in the formation of the molecular phenotype of human breast cancer (BC) cell lines with varying degrees of malignancy, including cisplatin/doxorubicin resistant cell lines, and identify possible impact of exogenous LF. MATERIALS AND METHODS: 5 breast cell lines of different origin - MCF-10 A, MCF-7, including doxorubicin/cisplatin resistant ones, T47D, MDA-MB-231, and MDA-MB-468. Immunocytochemistry: expression of LF, Ki-67, adhesion molecules E- and N-cadherin, CD44, CD24 rating the invasive potential of cells. RESULTS: Expression of LF in human BC cell lines varies. It is associated with the heterogeneity of molecular profiles of cell lines in terms of adhesion. A link has been established between the level of LF expression in the resistant cell line MCF-7/CP and MCF-7/Dox, features of their molecular profile and invasive properties. Exogenous LF was shown to be capable of modifying the molecular profile and invasive properties of all the studied cell lines including resistant ones (MCF-7/CP and MCF-7/Dox). CONCLUSIONS: The sensitivity of cytostatic-resistant cell lines (MCF-7/CP and MCF-7/Dox) tends to increase under the influence of exogenous LF. It is likely that this effect is due to LF-mediated inhibition of the expression of proteins associated with drug resistance.

Cardiovascular and heart failure safety profile of vildagliptin: a meta-analysis of 17 000 patients.

AIMS: To report the cardiovascular (CV) safety profile and heart failure (HF) risk of vildagliptin from a large pool of studies, including trials in high-risk patients with type 2 diabetes mellitus (T2DM), such as those with congestive HF and/or moderate/severe renal impairment. METHODS: We conducted a retrospective meta-analysis of prospectively adjudicated CV events. Patient-level data were pooled from 40 double-blind, randomized controlled phase III and IV vildagliptin studies. The primary endpoint was occurrence of major adverse CV events (MACEs; myocardial infarction, stroke and CV death). Assessments of the individual MACE components and HF events (requiring hospitalization or new onset) were secondary endpoints. The risk ratio (RR) of vildagliptin (50 mg once- and twice-daily combined) versus comparators (placebo and all non-vildagliptin treatments) was calculated using the Mantel-Haenszel (M-H) method. RESULTS: Of the 17 446 patients, 9599 received vildagliptin (9251.4 subject-years of exposure) and 7847 received comparators (7317.0 subject-years of exposure). The mean age of the patients was 57 years, body mass index 30.5 kg/m(2) (nearly 50% obese), glycated haemoglobin concentration 8.1% and T2DM duration 5.5 years. A MACE occurred in 83 (0.86%) vildagliptin-treated patients and 85 (1.20%) comparator-treated patients, with an M-H RR of 0.82 [95% confidence interval (CI) 0.61-1.11]. Similar RRs were observed for the individual events. Confirmed HF events were reported in 41 (0.43%) vildagliptin-treated patients and 32 (0.45%) comparator-treated patients, with an M-H RR 1.08 (95% CI 0.68-1.70). CONCLUSIONS: This large meta-analysis indicates that vildagliptin is not associated with an increased risk of adjudicated MACEs relative to comparators. Moreover, this analysis did not find a significant increased risk of HF in vildagliptin-treated patients.

Efficacy and safety of vildagliptin in patients with type 2 diabetes mellitus inadequately controlled with dual combination of metformin and sulphonylurea.

AIM: The broadly used combination of metformin and sulphonylurea (SU) often fails to bring patients to glycaemic goal. This study assessed the efficacy and safety of vildagliptin as add-on therapy to metformin plus glimepiride combination in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control. METHODS: A multicentre, double-blind, placebo-controlled study randomized patients to receive treatment with vildagliptin 50 mg bid (n = 158) or placebo (n = 160) for 24 weeks. RESULTS: After 24 weeks, the adjusted mean change in haemoglobin A1c (HbA1c) was -1.01% with vildagliptin (baseline 8.75%) and -0.25% with placebo (baseline 8.80%), with a between-treatment difference of -0.76% (p < 0.001). Significantly more patients on vildagliptin achieved the HbA1c target <7% (28.3% vs. 5.6%; p < 0.001). The difference in fasting plasma glucose reduction between vildagliptin and placebo was -1.13 mmol/l (p < 0.001). In subgroup of patients with baseline HbA1c ≤8%, vildagliptin reduced HbA1c by 0.74% from baseline 7.82% (between-treatment difference: -0.97%; p < 0.001) with significantly more patients achieving the HbA1c target <7% (38.6% vs. 13.9%; p = 0.014). Vildagliptin was well tolerated with low incidence of hypoglycaemia, slightly higher than with placebo (5.1% vs. 1.9%) and no clinically relevant weight gain. CONCLUSIONS: Vildagliptin significantly improved glycaemic control in patients with T2DM inadequately controlled with metformin plus glimepiride combination. The addition of vildagliptin was well tolerated with low risk of hypoglycaemia and weight gain. This makes vildagliptin an attractive treatment option for patients failing on metformin plus SU particularly in patients with baseline HbA1c ≤8%.

Improved glycaemic control with vildagliptin added to insulin, with or without metformin, in patients with type 2 diabetes mellitus.

AIM: The aim of this study is to assess the efficacy and safety of vildagliptin 50 mg bid as add-on therapy to insulin in type 2 diabetes mellitus (T2DM). METHODS: This is a multicentre, double-blind, placebo-controlled, parallel group, clinical trial in T2DM patients inadequately controlled by stable insulin therapy, with or without metformin. Patients received treatment with vildagliptin 50 mg bid or placebo for 24 weeks. RESULTS: In all, 449 patients were randomized to vildagliptin (n = 228) or placebo (n = 221). After 24 weeks, the difference in adjusted mean change in haemoglobin A1c (HbA1c) between vildagliptin and placebo was -0.7 ± 0.1% (p < 0.001) in the overall study population, -0.6 ± 0.1% (p < 0.001) in the subgroup also receiving metformin and -0.8 ± 0.2% (p < 0.001) in the subgroup without metformin. Vildagliptin therapy was well tolerated and had a similarly low incidence of hypoglycaemia compared with placebo (8.4 vs. 7.2%, p = 0.66) in spite of improved glycaemic control, and was not associated with weight gain. (+0.1 vs. -0.4 kg). CONCLUSIONS: Vildagliptin 50 mg bid added to insulin significantly reduced HbA1c in patients with T2DM inadequately controlled by insulin, with or without metformin. Vildagliptin was well tolerated, with a safety profile similar to placebo. These results were achieved without weight gain or an increase in hypoglycaemia incidence or severity in spite of improved glycaemic control.

[Certain aspects of combined vibration training for the treatment of neurological manifestations of osteochondrosis in the lumbar spine region].

The physical rehabilitation of the patients presenting with neurological manifestations of osteochondrosis in the lumbar spine region remains a challenging problem due to the high prevalence of this condition. Vibration training in the form of graduated vibration impacts was shownto induce muscular stimulation, activate metabolic processes by promoting microcirculation, stimulate operation of the complex proprioceptive apparatus with a rise in the energy level of the gamma-system, and lead to the development of long-term post-activation alterations in the muscular fibers. These observations give reason to consider vibration therapy as a most promising method for the combined treatment of a variety of diseases affecting human subjects. We have developed a set of exercises for the vibration platform training consisting of three main parts (preparative, basic, and concluding components).

[Using vibration training for the treatment of neurological manifestations of osteochondrosis in the lumbar spine region].

The physical rehabilitation of the patients presenting with neurological manifestations of osteochondrosis in the lumbar spine region remains a challenging problem due not only to the high prevalence of this condition but also to its substantial financial burden. Vibration training provides be a promising tool to address this problem. We studied 50 patients with neurological manifestations of osteochondrosis in the lumbar spine region recommended vibration training as a rehabilitative treatment. The objective assessment of its outcome was made based on the results of biokinematic videoanalysis of the movements and the scales for the evaluation of pain syndrome intensity. This approach allowed the clinical efficacy of vibration training following the recommended schedule to be verified.

One-year safety, tolerability and efficacy of vildagliptin in patients with type 2 diabetes and moderate or severe renal impairment.

AIM: Assess long-term safety and efficacy of the dipeptidlyl peptidase-4 (DPP-4) inhibitor vildagliptin in 369 patients with type 2 diabetes mellitus (T2DM) and moderate or severe renal impairment (RI). METHODS: Double-blind, randomized, parallel-group, 52-week clinical trial comparing safety and efficacy of vildagliptin (50 mg qd, n = 216) and placebo (n = 153) added to ongoing stable antihyperglycaemic treatment, in patients with T2DM and moderate or severe (glomerular filtration rate [GFR] ≥ 30 to <50 ml/min/1.73 m(2) and < 30 ml/min/1.73 m(2) ) RI. RESULTS: The study population comprised 122 and 89 patients with moderate RI and 94 and 64 patients with severe RI randomized to vildagliptin and placebo, respectively, with the majority of patients receiving background insulin therapy (72% and 82% for moderate and severe RI, respectively). After 1 year, the between-treatment difference in adjusted mean change in A1C was -0.4 ± 0.2% (p = 0.005) in moderate RI (baseline = 7.8%) and -0.7 ± 0.2% (p < 0.0001) in severe RI (baseline = 7.6%). In patients with moderate RI, similar proportions of patients experienced any adverse event (AE) (84 vs. 85%), any serious adverse event (SAE) (21 vs. 19%), any AE leading to discontinuation (5% vs. 6%) and death (1% vs. 0%) with vildagliptin and placebo, respectively. This was also true for patients with severe RI: AEs (85% vs. 88%), SAEs (25% vs. 25%), AEs leading to discontinuation (10% vs. 6%) and death (3% vs. 2%). CONCLUSIONS: In patients with T2DM and moderate or severe RI, vildagliptin added to ongoing antidiabetic therapy had a safety profile similar to placebo during 1-year observation. Furthermore, relative to placebo, a clinically significant decrease in A1C was maintained throughout 1-year treatment with vildagliptin.

Safety and efficacy of vildagliptin versus placebo in patients with type 2 diabetes and moderate or severe renal impairment: a prospective 24-week randomized placebo-controlled trial.

AIM: Assess safety/tolerability and efficacy of the DPP-4 inhibitor vildagliptin in 515 patients with type 2 diabetes mellitus (T2DM) and moderate or severe renal impairment (RI). METHODS: Double-blind, randomized, parallel-group, placebo-controlled, 24-week clinical trial assessing safety and efficacy of vildagliptin (50 mg qd) added to current antidiabetic therapy, in patients with T2DM and moderate or severe RI (GFR ≥ 30 to <50 or <30 ml/min/1.73 m(2) ). RESULTS: The study population comprised of 165 and 129 patients with moderate RI and 124 and 97 patients with severe RI randomized to vildagliptin and placebo, respectively, with most patients receiving background insulin therapy (68 and 81% for moderate and severe RI, respectively). After 24 weeks, the between-treatment difference in the adjusted mean change in A1C was -0.5 ± 0.1% (p < 0.0001) in moderate RI (baseline A1C = 7.9%) and -0.6 ± 0.1% (p < 0.0001) in severe RI (baseline A1C = 7.7%). In patients with moderate RI, similar proportions of those receiving vildagliptin or placebo experienced any AE (68 vs. 73%), any SAE (9 vs. 9%), any AE leading to discontinuation (3 vs. 5%) or death (1 vs. 1%). This was also true for patients with severe RI: AEs (73 vs. 74%), SAEs (19 vs. 21%), AEs leading to discontinuation (9 vs. 6%) and death (2 vs. 4%). CONCLUSIONS: In this 24-week study of 515 patients with T2DM and moderate or severe RI, vildagliptin added to ongoing antidiabetic therapy had a safety profile similar to placebo. Further, relative to placebo, vildagliptin elicited a statistically and clinically significant decrease in A1C in patients with moderate or severe RI.

[The video motion analysis as a method of the diagnosis of the basal ganglion lesion in Parkinson's disease].

Movement disturbances in patients with Parkinson's disease (PD) are one of the most important clinical symptoms. Locomotion analysis systems are one of perspective directions of instrumental diagnosis of movement disturbances. We studied 113 patients, including 53 patients with PD (18 with the tremor type, 25 with rigid type), and 60 healthy volunteers. Indices of purposeful and no-purposeful movements and useful movements' coefficient were specified in the motion analysis software V&A. The index of no-purposeful movements can be used as a reliable marker of side-dependent clinical symptoms in the rigid PD type.

[Dynamics of postural dysfunction in patients with Parkinson's disease under the action of vibrational therapy].

This experimental study was designed to reveal changes of the postural function in patients with Parkinson's disease (PD) under the action of vibrational therapy. It was shown that application of classical passive vibrostimulation employed under clinical conditions can be recommended to patients presenting with the rigid-trembling form of Parkinson's disease owing to the fact that their system of regulation of the vertical posture readily responds to vibration loading. This effect is attributable to low muscular activity.

[Serological evidence of Lassa virus circulation in the Republic of Guinea]. / Serologicheskie dokazatel'stva tsirkuliatsii virusa Lassa v Gvineiskoi Respublike.

Seroepidemiological investigations in Guinea were carried out to estimate the areas of Lassa virus circulation. The recombinant protein of Lassa virus nucleocapsid was used as the antigen to analyse blood sera by ELISA. In some regions, from 30 to 54.9% of the population had antibodies to Lassa virus, but in others only 6-7%.