9 research outputs found
Analysis of The Use of PCSK9 Inhibitors in Clinical Practice
Aim. The analysis of the experience of using PCSK9 inhibitors (alirocumab) in patients with very high cardiovascular risk, аccording to long observations in real clinical practice.Material and methods. In study evaluated the data for 31 people (23 men and 8 women, the average age of those surveyed was 59.4±5.8 years) of very high cardiovascular risk with atherogenic dyslipidemia and no achievement of the target lipid levels. Alirokumab was administered in a dose of 150 mg subcutaneously once every 2 weeks in the day hospital of a multidisciplinary clinic. The primary endpoint was reached the target level of low density lipoprotein cholesterol (HS-LDL) level and/or reduce HS-LDL levels by 50% or more. Liver tests, level of creatinine and glycemia were studied to assess safety; side effects studied/Results. The long-term use of alirocumab (on average 7,5±2,3 months) is well tolerated without adverse reactions and withdrawal syndrome, in the day hospital of a multidisciplinary clinic. 90% of patient have achieved either a target level of HS-LDL less than 1.4 mmol/l or a reduction in HS-LDL by 50% or more. The remaining third of patients achieved both target levels. It can be distinguished a group of patients with a good response to the medication, in the first months of administration of alirokumab.Conclusion. The results of conducting an efficiency assessment for use of the alirocumab in a dose of 150 mg subcutaneously within two weeks showed that this therapy has the high efficacy and good tolerability without any adverse reactions, in the day hospital of a multidisciplinary clinic
The Synthesis and Properties of a New Carrier for Paclitaxel and Doxorubicin Based on the Amphiphilic Copolymer of N-vinyl-2-pyrrolidone and Acrylic Acid
Antimicrobial Activity and Immunomodulatory Properties of Acidocin A, the Pediocin-like Bacteriocin with the Non-Canonical Structure
Pediocin-like bacteriocins are among the natural antimicrobial agents attracting attention as scaffolds for the development of a new generation of antibiotics. Acidocin A has significant structural differences from most other members of this subclass. We studied its antibacterial and cytotoxic activity, as well as effects on the permeability of E. coli membranes in comparison with avicin A, the typical pediocin-like bacteriocin. Acidocin A had a more marked tendency to form an alpha-helical structure upon contact with detergent micelles, as was shown by CD spectroscopy, and demonstrated considerably less specific mode of action: it inhibited growth of Gram-positive and Gram-negative strains, which were unsusceptible to avicin A, and disrupted the integrity of outer and inner membranes of E. coli. However, the peptide retained a low toxicity towards normal and tumor human cells. The effect of mutations in the pediocin box of acidocin A (on average, a 2–4-fold decrease in activity) was less pronounced than is usually observed for such peptides. Using multiplex analysis, we showed that acidocin A and avicin A modulated the expression level of a number of cytokines and growth factors in primary human monocytes. Acidocin A induced the production of a number of inflammatory mediators (IL-6, TNFα, MIG/CXCL9, MCP-1/CCL2, MCP-3/CCL7, and MIP-1β) and inhibited the production of some anti-inflammatory factors (IL-1RA, MDC/CCL22). We assumed that the activity of acidocin A and similar peptides produced by lactic acid bacteria might affect the functional state of the human intestinal tract, not only through direct inhibition of various groups of symbiotic and pathogenic bacteria, but also via immunomodulatory effects
Design of Protegrin-1 Analogs with Improved Antibacterial Selectivity
Protegrin-1 (PG-1) is a cationic β-hairpin pore-forming antimicrobial peptide having a membranolytic mechanism of action. It possesses in vitro a potent antimicrobial activity against a panel of clinically relevant MDR ESKAPE pathogens. However, its extremely high hemolytic activity and cytotoxicity toward mammalian cells prevent the further development of the protegrin-based antibiotic for systemic administration. In this study, we rationally modulated the PG-1 charge and hydrophobicity by substituting selected residues in the central β-sheet region of PG-1 to design its analogs, which retain a high antimicrobial activity but have a reduced toxicity toward mammalian cells. In this work, eight PG-1 analogs with single amino acid substitutions and five analogs with double substitutions were obtained. These analogs were produced as thioredoxin fusions in Escherichia coli. It was shown that a significant reduction in hemolytic activity without any loss of antimicrobial activity could be achieved by a single amino acid substitution, V16R in the C-terminal β-strand, which is responsible for the PG-1 oligomerization. As the result, a selective analog with a ≥30-fold improved therapeutic index was obtained. FTIR spectroscopy analysis of analog, [V16R], revealed that the peptide is unable to form oligomeric structures in a membrane-mimicking environment, in contrast to wild-type PG-1. Analog [V16R] showed a reasonable efficacy in septicemia infection mice model as a systemic antibiotic and could be considered as a promising lead for further drug design