PCSK9 Antagonists: Clinical Efficacy and Main Trends in the Development of New Medicines

Scientific relevance. Cardiovascular diseases (CVD) are the leading cause of death worldwide. Dyslipidemia, as the pathophysiological basis of atherosclerosis, is the most important cause of CVD. Among the factors that modify this pathology, the World Health Organisation lists statins, which effectively reduce the cholesterol level. However, statin treatment compliance is not sufficient to achieve population-based lipid targets. This is a powerful stimulus for the creation of fundamentally new groups of lipid-lowering agents, in particular, antagonists of proprotein convertase subtilisin/kexin type 9 (PCSK9).Aim. The study aimed to review innovative approaches to developing a new generation of lipid-lowering agents, PCSK9 antagonists, and to evaluate the effectiveness, safety, and clinical potential of these medicines.Discussion. PCSK9 antagonists significantly increase the effectiveness of lipid-lowering therapy when combined with statins and are an effective monotherapy in patients with contraindications for statins. PCSK9 monoclonal antibodies, as well as inclisiran, have a favourable risk–benefit ratio. However, the high cost of commercially available PCSK9 antagonists limits their clinical use. A number of promising directions exist for developing new PCSK9 antagonists that have fundamentally different mechanisms of action, such as adnectins; genome editing with CRISPR/Cas9; combining small molecules with low molecular weight PCSK9 inhibitors; PCSK9 vaccines; and antisense oligonucleotides. Medicinal products from these groups are currently at various stages of preclinical and clinical development.Conclusions. Therefore, new lipid-lowering agents can be developed by synthesising high and low molecular weight PCSK9 ligands and by altering the genetic mechanisms of PCSK9 synthesis. The innovative medicines considered in this review are highly effective, and most have shown no signs of toxicity at the pre-authorisation stage

Genes involved in the regulation of vascular homeostasis determine renal survival rate in patients with chronic glomerulonephritis

In this study, we analyzed association of genes of vascular homeostasis with hypertension and renal survival of CGN patients. The study sample included 238 patients with CGN and 304 healthy subjects of population control. Ten polymorphisms of ten genes of vascular homeostasis were genotyped through polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) analysis and TaqMan assays. Association of the genotypes with renal survival was analyzed by the Kaplan-Meier estimato

Chemokines Genetic Variants are Associated with Parameters of Humoral Immunity of Patients with Chronic Glomerulonephritis

The authors researched associations of chemokines genes polymorphisms with parameters of humoral immunity of 238 patients with chronic glomerulonephritis and 462 individuals of a control grou

The role of chemokine genes in the formation of terminal stage of chronic renal failure

The data on the role of chemokine genes (+1931A/T CCL4, A/G CXCL11 (rs4512021), -403A/G CCL5, C/G CCL2 (rs2857657), -801G/A CXCL12) in the formation of terminal stage of chronic renal failure, in patients with chronic glomerulonephritis, is presented in the work. It was established, that the allele A CXCL11 (rs4512021) (OR = 1.65) was the marker for the development of terminal stage of chronic renal insufficiency, and the genotype GG CXCL11was a protective factor for the development of terminal stage of chronic renal failure (OR = 0.22

Studying the Impact of the genetic polymorphisms of chemokines on the arterial pressure level and kidney function in patient with the chronic glomerulonephritis

It has been established that the genetic marker А I-TAC (rs 4512021) is the risk factor for genesis of the severe arterial hypertension at the chronic glomerulonephritis (OR=1,65) and the genotypes АА and AG I-TAC are the risk factors of depression of the kidney functio

Clinical and genetic research of chronic glomerulonephritis

The paper presents data on interaction of candidate genes (S311C PON2, (-6)A/G AGT, (-1166)A/CAGTR1, (-592)C/A IL-10, VNTR IL-1Ra, T113M IL-9, K198N EDN1, (+46)G/A ADRB2, G/A GNB3 (rs.2301339)) with oligogenic and continuous characters of chronic glomerulonephriti

The effectiveness of glucocorticoid therapy in patients with chronic glomerulonephritis, depending on the polymorphic markers of cytokine genes

The paper presents the results of a study of interrelationships of polymorphic cytokine loci (rs1800629 TNFα, rs909253 Ltα, rs767455 TNFR1 and rs1800469 TGFβ-1) with the features of glucocorticoid therapy in patients with chronic glomerulonephriti

Genetic factors of decreased kidney function in patients with chronic glomerulonephritis

The article presents the results of studying the interaction of polymorphic variants of vascular homeostasis genes (I/D ACE, 4а/4b eNOS, S311C PON2, (-6) A/G AGT, (-1166) A/С AGTR1, G/A GNB3 (rs.2301339), G460W ADD1, (+46) G/A ADRB2, K198N EDN1, (+6986) G/A CYP3A5) with the state of renal function at the onset of chronic glomerulonephriti

Ge-Hg-Rich Sphalerite and Pb, Sb, As, Hg, and Ag Sulfide Assemblages in Mud Volcanoes of Sakhalin Island, Russia: An Insight into Possible Origin

We characterize the mineralogy and geochemistry of Fe, Zn, Pb, Sb, As, Hg, Ag sulfide assemblages from mud masses currently extruded by the onshore South Sakhalin and Pugachev mud volcanoes (Sakhalin Island, Russia). Abundant Tl-rich pyrite in sulfide concentrate samples from the mud volcanoes coexists with common Hg- and Ge-rich sphalerite, as well as with sporadic boulangerite, robinsonite, bournonite, galena, realgar, metacinnabar, cinnabar, acanthite, and chalcopyrite. Sphalerites are remarkably enriched in Hg (locally reaching 27 wt%) and coupled zwith permanent abnormal enrichment in Ge (3008–3408 ppm). According to single-crystal XRD analyses and Raman spectroscopy, both Hg-poor and Hg-rich sphalerites are single-phase (Zn,Hg)Scub compounds. Pyrite is of diagenetic origin, judging by its trace-element chemistry, particular morphology, and heavy S isotope composition. Another assemblage, composed of Pb-Sb-(Hg) sulfide minerals and lesser As, Cu, Ag, and Bi compounds, results from hydrothermal alteration and is genetically related to Neogene volcano-sedimentary rocks found among the ejecta of the mud volcanoes. The composition of impurities in sphalerite from mud masses indicates crystallization at temperatures lower than ~100 °C, under the leaching effect of mud volcano waters

Ge-Hg-Rich Sphalerite and Pb, Sb, As, Hg, and Ag Sulfide Assemblages in Mud Volcanoes of Sakhalin Island, Russia: An Insight into Possible Origin

We characterize the mineralogy and geochemistry of Fe, Zn, Pb, Sb, As, Hg, Ag sulfide assemblages from mud masses currently extruded by the onshore South Sakhalin and Pugachev mud volcanoes (Sakhalin Island, Russia). Abundant Tl-rich pyrite in sulfide concentrate samples from the mud volcanoes coexists with common Hg- and Ge-rich sphalerite, as well as with sporadic boulangerite, robinsonite, bournonite, galena, realgar, metacinnabar, cinnabar, acanthite, and chalcopyrite. Sphalerites are remarkably enriched in Hg (locally reaching 27 wt%) and coupled zwith permanent abnormal enrichment in Ge (3008–3408 ppm). According to single-crystal XRD analyses and Raman spectroscopy, both Hg-poor and Hg-rich sphalerites are single-phase (Zn,Hg)Scub compounds. Pyrite is of diagenetic origin, judging by its trace-element chemistry, particular morphology, and heavy S isotope composition. Another assemblage, composed of Pb-Sb-(Hg) sulfide minerals and lesser As, Cu, Ag, and Bi compounds, results from hydrothermal alteration and is genetically related to Neogene volcano-sedimentary rocks found among the ejecta of the mud volcanoes. The composition of impurities in sphalerite from mud masses indicates crystallization at temperatures lower than ~100 °C, under the leaching effect of mud volcano waters