Vol 10, No 5 (2022)
- Year: 2022
- Articles: 7
- URL: https://journals.eco-vector.com/2307-9266/issue/view/7506
REVIEWS
Molecular mechanisms defining application of glycine and zinc combination in correction of stress and anxiety main manifestations
Abstract
The aim of the work was to carry out a systematic analysis of the molecular mechanisms that determine the possibility of a combined use of amino acid glycine and zinc compounds for the treatment of patients with manifestations of stress and anxiety.
Materials and methods. Information retrieval (Scopus, PubMed) and library (eLibrary) databases were used as research tools. In some cases, the ResearchGate application was applied for a semantic search. The analysis and generalization of references was carried out on the research topic, covering the period from 2000 to the present time.
Results. It has been shown that amino acid glycine, along with gamma-aminobutyric acid (GABA), is a key neurotransmitter that regulates physiological inhibition processes in the central nervous system (CNS) by increasing transmembrane conductance in specific pentameric ligand-gated ion channels. The introduction of zinc ions can potentiate the opening of these receptors by increasing their affinity for glycine, resulting in an inhibitory processes increase in CNS neurons. The replenishment of the glycine and zinc combined deficiency is an important element in the correction of a post-stress dysfunction of the central nervous system. A balanced intake of zinc and glycine is essential for most people who experience daily effects of multiple stresses and anxiety. This combination is especially useful for the people experiencing a state of chronic psycho-emotional stress and maladaptation, including those who have a difficulty in falling asleep.
Conclusion. A balanced maintenance of the zinc and glycine concentration in the body of a healthy person leads to the development of a stable anti-anxiety effect, which is accompanied by the normalization of the sleep-wake rhythm, which makes it possible to have a good rest without any loss of working efficiency after waking up.
404-415
Conventional approaches to the therapy of hereditary myopathies
Abstract
The aim of the work was to analyze the available therapeutic options for the conventional therapy of hereditary myopathies.
Materials and methods. When searching for the material for writing a review article, such abstract databases as PubMed and Google Scholar were used. The search was carried out on the publications during the period from 1980 to September 2022. The following words and their combinations were selected as parameters for the literature selection: “myopathy”, “Duchenne”, “myodystrophy”, “metabolic”, “mitochondrial”, “congenital”, “symptoms”, “replacement”, “recombinant”, “corticosteroids”, “vitamins”, “tirasemtiv”, “therapy”, “treatment”, “evidence”, “clinical trials”, “patients”, “dichloracetate”.
Results. Congenital myopathies are a heterogeneous group of pathologies that are caused by atrophy and degeneration of muscle fibers due to mutations in genes. Based on a number of clinical and pathogenetic features, hereditary myopathies are divided into: 1) congenital myopathies; 2) muscular dystrophy; 3) mitochondrial and 4) metabolic myopathies. At the same time, treatment approaches vary significantly depending on the type of myopathy and can be based on 1) substitution of the mutant protein; 2) an increase in its expression; 3) stimulation of the internal compensatory pathways expression; 4) restoration of the compounds balance associated with the mutant protein function (for enzymes); 5) impact on the mitochondrial function (with metabolic and mitochondrial myopathies); 6) reduction of inflammation and fibrosis (with muscular dystrophies); as well as 7) an increase in muscle mass and strength. The current review presents current data on each of the listed approaches, as well as specific pharmacological agents with a description of their action mechanisms.
Conclusion. Currently, the following pharmacological groups are used or undergoing clinical trials for the treatment of various myopathies types: inotropic, anti-inflammatory and antifibrotic drugs, antimyostatin therapy and the drugs that promote translation through stop codons (applicable for nonsense mutations). In addition, metabolic drugs, metabolic enzyme cofactors, mitochondrial biogenesis stimulators, and antioxidants can be used to treat myopathies. Finally, the recombinant drugs alglucosidase and avalglucosidase have been clinically approved for the replacement therapy of metabolic myopathies (Pompe’s disease).
416-431
Current aspects of etiotropic COVID-19 therapy
Abstract
Since the beginning of the pandemic, repeated attempts have been made to develop etiotropic therapy for a novel coronavirus infection. Hydroxychloroquine, lopinavir/ritonavir, etc. derivatives were used as antiviral agents, however, they demonstrated a low efficiency and an insufficient safety. In this connection, other groups of drugs with a more effective and safe pharmacological profile are currently being actively used.
The aim of the study was to analyze the literature references on the efficacy and safety of antiviral drugs for the COVID-19 treatment.
Materials and methods. When searching for the materials for the review article writing, such abstract databases as PubMed, Google Scholar, e-Library were used. The search was carried out on publications for the period from January 2020 to September 2022. The key queries were: COVID-19, etiotropic therapy; immunological drugs; antiviral drugs; interferons.
Results. Currently, there are various degrees of effective etiotropic drugs for the treatment of COVID-19 patients. The review has considered a few groups of drugs that are of interest from the point of view of etiotropic therapy: immunological drugs (anticovid plasma, the drugs based on antiviral antibodies, the drugs of recombinant interferons-α2 and -β1, as well as interferon inducers, i.e., the drugs based on double-stranded RNA sodium salt, and others); drugs that block the penetration of the virus into the cell (umifenovir); the drugs that disrupt the process of the viral replication (favipiravir, remdesivir, molnupiravir, nirmatrelvir/ritonavir).
Conclusion. Synthetic antivirals, in particular favipiravir, molnupiravir, remdesivir, and nirmatrelvir/ritonavir, have the largest evidence base for their efficacy and safety. The search for new effective and safe etiotropic drugs for the treatment of COVID-19, as well as the collection and analysis of post-registration data on the drugs already used in clinical practice, continues.
432-445
ORIGINAL ARTICLES
Consumption details of systemically acting antiviral and antimicrobial preparations in period of novel coronavirus infection spread in retail sector of Samara region pharmaceutical market
Abstract
An analysis of the medicinal preparation consumption structure in the period of the COVID-19 pandemic in the pharmacy network reflects the existing outpatient practice and makes it possible to draw generalized conclusions about its compliance with the pharmacotherapy standards.
The aim. Comparative analysis of population consumption of antimicrobial and antiviral medicines sold in the retail pharmacies of the Samara region in 2015–2021.
Materials and methods. The study was conducted in the retail sector of the Samara region pharmaceutical market. The material of the study was the information on the list of items and dispensing volumes of antibacterial and individual antiviral drugs during the novel coronavirus infection spread (in 2020) in the network of the Samara region pharmacies. The data are compared with the indicators of the drug sales in 2015–2019. Methods of retrospective, comparative, graphical, methodological, content analyzes and statistical methods of analyses were used.
Results. The authors have established a significant distortion in the consumption of systemic antimicrobial preparations in the Samara region pharmacy segment in the period of 2015–2019 with the predominance of the ATC (Anatomical Therapeutic Chemical Classification System) J01D group, primarily cephalosporins (38%), mainly by the parenteral administration route. The share of macrolides (J01F) consumption in volume terms was 14.9%, of fluoroquinolones (J01M) – 11.3%, beta-lactam antibiotics with beta-lactamase inhibitors – 10.7%, beta-lactam antibiotics penicillins (J01C) – 8.1%. Compared to 2019, in 2020, under the conditions of the COVID-19 pandemic, the total consumption of AMPs increased by 2.1 times. In the “Other beta-lactam antibiotics” group with a predominant proportion of cephalosporins, there was an increase by 3.2 times, in the “Macrolides and lincosamides” group – by 3.5 times, in “Quinolone derivatives” – by 2.6 times. The noted facts should be assessed as the phenomenon that can have a direct impact on the growth of an antibiotic resistance on a population scale. Among antivirals, the largest consumption increase was noted for oseltamivir and rimantadine. In absolute terms, the volume of antiviral preparations consumption in 2020 increased by 2.4 times, which was accompanied by an increase in the cost of one package by 55.8%.
Conclusion. In the period of spreading a novel coronavirus infection, a significant increase in the consumption of antimicrobial and antiviral preparations (up to 20 times for certain pharmacotherapeutic groups and names) was notified, which may negatively affect the growth of the antibiotic resistance in the population.
446-459
Characteristics of olokizumab pharmacokinetics in patients with novel coronavirus infection COVID-19
Abstract
The aim of the article is to study pharmacokinetic characteristics of intravenous olokizumab in patients with moderate COVID-19 to relieve a hyperinflammation syndrome.
Materials and methods. The pharmacokinetic study was conducted as a part of a phase III clinical study (RESET, NCT05187793) on the efficacy and safety of a new olokizumab regimen (intravenous, at the doses of 128 mg or 256 mg) in COVID-19 patients. Plasma concentrations of olokizumab were determined by the enzyme immunoassay. The population analysis was performed using a previously developed pharmacokinetic model based on a linear two compartment.
Results. The pharmacokinetic analysis included the data from 8 moderate COVID-19 patients who had been administrated with olokizumab intravenously at the dose of 128 mg. According to the analysis results in this population, there was an increase in the drug clearance, compared with the data obtained in healthy volunteers and the patients with rheumatoid arthritis: 0.435, 0.178 and 0.147 l/day, respectively. The parameters analysis within the framework of a population pharmacokinetic model showed that the main factors for the increased olokizumab clearance are a high body mass index. In addition, the presence of COVID-19 itself is an independent factor in increasing the drug clearance.
Conclusion. After the intravenous olokizumab administration, an increase in the drug clearance is observed in moderate COVID-19 patients against the background of the disease course. The main contribution to the increased clearance is made by the characteristics of the population of COVID-19 patients associated with the risk of a severe disease and inflammation. When administered intravenously at the dose of 128 mg, a therapeutically significant olokizumab level was maintained throughout the acute disease phase for 28 days.
460-471
Hemostimulating properties of the conjugates of granulocyte-macrophage colony stimulating factor with alendronic acid
Abstract
The aim of the work is to evaluate the hemostimulating activity of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) conjugates with alendronic acid (ALN) in the model of cytostatic myelosuppression and the dynamics of rhGM-CSF accumulation as a part of the conjugate in the bone tissue and bone marrow of mice.
Materials and methods. The conjugates obtained by a solid-phase synthesis using 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide or periodate oxidation, were used. A hemostimulating activity was evaluated in a model of a cytostatic myelosuppression induced by the administration of cyclophosphamide to CBA/Calac mice. RhGM-CSF preparations were injected subcutaneously for 4-5 days at the dose of 90 µg/kg. After the injections cycle had been completed, the total leukocyte and segmented neutrophil counts were carried out in the blood samples, and the total karyocyte count was carried out in the bone marrow samples.
The tissue distribution of rhGM-CSF preparations was assessed in outbred CD-1 mice after a single intravenous administration at the effective dose. The content of rhGM-CSF in blood, femoral tissue and bone marrow was determined by enzyme immunoassay.
Results. RhGM-CSF conjugates with ALN have been shown to retain the ability of the original protein to increase the number of leukocytes, segmented blood neutrophils, and bone marrow karyocytes under the action of conjugates. The stimulation of the neutrophil production used to be observed at earlier times than in the case of rhGM-CSF. The increase in the total number of bone marrow cells after the introduction of all three conjugates was more pronounced compared to the original protein (by 34%). The increased hemostimulatory effect of the AEG conjugate was accompanied by a more intense accumulation of rhGM-CSF in the bone tissue and bone marrow of mice. The rhGM-CSF introduced into the conjugate was detected in the bone tissue for 24 h and it circulated in the bloodstream for a longer time compared to the original protein.
Conclusion. The data obtained make it possible to conclude that further work on the development of effective hemostimulating drugs based on rhGM-CSF conjugates with ALN, is promising.
472-482
В6.А-Dysfprmd/GeneJ mice as a genetic model of dysferlinopathy
Abstract
The aim of the work was behavioral and pathomorphological phenotyping of the mice knockout for the DYSF gene, which plays an important role in the development and progression of dysferlinopathy.
Materials and methods. A B6.A-Dysfprmd/GeneJ (Bla/J) mice subline was used in the work. During the study, a muscle activity was determined basing on the following tests: “Inverted grid”, “Grip strength”, “Wire Hanging”, “Weight-loaded swimming”, Vertical Pole”. Histological and immunofluorescent examinations of skeletal muscles (m. gastrocnemius, m. tibialis) were performed. The presence and distribution of the dysferlin protein was assessed, and general histological changes in the skeletal muscle characteristics of mice at the age of 12 and 24 weeks, were described. A morphometric analysis with the determination of the following parameters was performed: the proportion of necrotic muscle fibers; the proportion of fibers with centrally located nuclei; the mean muscle fiber diameter.
Results. The “Grip strength” test and the “Weight-loaded swimming” test revealed a decrease in the strength of the forelimbs and endurance in the studied mice of the Bla/J subline compared to the control line. The safety of physical performance was checked using the “Wire Hanging” test and the “Vertical Pole” test, which showed a statistically significant difference between the studied mice and control. The coordination of movements and muscle strength of the limbs examined in the “Inverted Grid” test did not change in these age marks. Decreased grip strength of the forelimbs, decreased physical endurance with age, reflects the progression of the underlying muscular disease. Histological methods in the skeletal muscles revealed signs of a myopathic damage pattern: necrotic muscle fibers, moderate lympho-macrophage infiltration, an increase in the proportion of fibers with centrally located nuclei, and an increase in the average fiber diameter compared to the control. The dysferlin protein was not found out in the muscle tissues.
Conclusion. Taking into account the results of the tests performed, it was shown that the absence of Dysf-/- gene expression in Bla/J subline mice led to muscular dystrophy with the onset of the development of phenotypic disease manifestations at the age of 12 weeks and their peak at 24 weeks. Histopathological phenotypic manifestations of the disease are generally nonspecific and corresponded to the data of intravital pathoanatomical examination in diferlinopathy patients. The mice of the studied subline Bla/J are a representative model of dysferlinopathy and can be used to evaluate new therapeutic agents for the treatment of this disease.
483-496
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