Brief insight into the in silico properties, structure-activity relationships and biotransformation of fruquintinib, an anticancer drug of a new generation containing a privileged benzofuran scaffold.

Current trends in drug design notably consider so-called privileged scaffolds as the core structural fragments with decisive impact on affinity to properly chosen biological targets, potency, selectivity and toxicological characteristics of drugs and prospective drug candidates. Fruquintinib (1) is a novel synthetic selective inhibitor of vascular endothelial growth factor receptor (VEGFR) isoforms, i.e., VEGFR-1, VEGFR-2 and VEGFR-3. The therapeutic agent (1) consists of a flat bicyclic heteroaromatic ring, in which two nitrogens are suitablyincorporated, a core bicyclic heteroaromatic ring - privileged (substituted) benzofuran scaffold, and a pair of hydrogen bond (H-bond) donor and acceptor group, i.e., amide functional moiety. Fruquintinib (1) was first approved in China for the treatment of metastatic colorectal cancer, a severe malignant disease with a high mortality rate. The review article offered a brief insight into the topic of privileged structures, their drug- -like ranges of several parameters, pharmacodynamic characteristics of fruquintinib (1) and various in silico descriptors characterizing drug's structural and physicochemical properties (molecular weight, number of heavy atoms, number of aromatic heavy atoms, fraction of sp3 C-atoms, number of H-bond acceptors, number of H-bond donors, total polar surface area, molar refractivity, molecular volume as well as parameters of lipophilicity and solubility). Some of these descriptors were related to pharmacokinetics and distribution of fruquintinib (1), and, in addition, might help predict its ability to cross passively the blood-brain barrier (BBB). Moreover, a possible connection between the induction potential on cytochrome P450 isoenzymes (CYP1A2 and CYP3A4) and passive transport of a given drug into the central nervous system via BBB was investigated. Current clinical experience and future directions regarding of fruquintinib (1) were also briefly outlined.

The efficacy of triazavirin (riamilovir)-based treatment for coronavirus disease 2019 (COVID-19) in clinical trials and preliminary practical experiences.

Coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has plagued the human population as 2019 turned into 2020, when first cases were confirmed to be infected with the pathogen in Wuhan City, the largest mega-city and capital of Hubei Province in Central China. Since this time, many pharmacotherapeutic modalities were suggested and used to treat the patients suffering from COVID-19. Triazavirin (TZV; riamilovir) is a synthetic non-toxic broad-spectrum antiviral drug belonging into an azolotriazine class. Several hypotheses and suggestions based on the knowledge about morphology, structure of virion, genome, replication cycle and functions of particular proteins within SARS-CoV-2 as well as in silico analyzes were published aiming to employ TZV for the treatment of COVID-19. Results and conclusions from a well-known randomized controlled trial registered under the Registration No. ChiCTR2000030001, which was carried out in China in 2020, indicated not only the anti-SARS-CoV-2 efficacy of given aza analogue of guanine but also some limitations of these outcomes in the context of their general interpretability and applicability. Thus, a primary aim of this review article was to provide more complex view on pharmacotherapeutic interventions based on TZV against COVID-19/SARS-CoV-2. The focus was on relevant results and conclusions from clinical trials as well as practical experiences with given antiviral agent considering not only real benefits of chosen therapeutic strategies but also several obstacles connected with them.

Telacebec (Q203): Is there a novel effective and safe anti-tuberculosis drug on the horizon?

High prevalence and stronger emergency of various forms of drug-resistant tuberculosis (DR-TB), including the multidrug-resistant (MDR-TB) as well as extensively drug-resistant (XDR-TB) ones, caused by variously resistant Mycobacterium tuberculosis pathogens, make first-line anti-tuberculosis (anti-TB) agents therapeutically more and more ineffective. Therefore, there is an imperative to develop novel highly efficient (synthetic) agents against both drug-sensitive-TB and DR-TB. The exploration of various heterocycles as prospective core scaffolds for the discovery, development and optimization of anti-TB drugs remains an intriguing scientific endeavour. Telacebec (Q203; TCB), a molecule containing an imidazo[1,2-a]pyridine-3-carboxamide (IPA) structural motif, is considered a novel very promising anti-TB agent showing a unique mechanism of action. The compound blocks oxidative phosphorylation by inhibiting a mycobacterial respiratory chain due to interference with a specific cytochrome b subunit (QcrB) of transmembrane bc1 menaquinol-cytochrome c oxidoreductase as an essential component for transporting electrons across the membrane from menaquinol to other specific subunit, cytochrome c (QcrC). Thus, the ability of mycobacteria to synthesize adenosine-5´-triphosphate is limited and energy generating machinery is disabled. The TCB molecule effectively fights drug-susceptible, MDR as well as XDR M. tuberculosis strains. The article briefly explains a mechanism of an anti-TB action related to the compounds containing a variously substituted IPA scaffold and is focused on their fundamental structure-anti-TB activity relationships as well. Special consideration is paid to TCB indicating the importance of particular structural fragments for maintaining (or even improving) favourable pharmacodynamic, pharmacokinetic and/or toxicological properties. High lipophilicity of TCB might be regarded as one of the key physicochemical properties with positive impact on anti-TB effect of the drug. In January 2021, the TCB molecule was also involved in phase-II clinical trials focused on the treatment of Coronavirus Disease-19 caused by Severe Acute Respiratory Syndrome Coronavirus 2.

Pretreatment Levels of Chromogranin A and Neuron-specific Enolase in Patients With Gastroenteropancreatic Neuroendocrine Neoplasia.

BACKGROUND/AIM: Chromogranin A (CgA) and neuron-specific enolase (NSE) are applied in the diagnosis of neuroendocrine neoplasms (NENs), especially non-functional ones. The aim of this study was to investigate the predictive values of CgA and NSE in long-term survival. PATIENTS AND METHODS: Our retrospective analysis included 65 patients with histologically verified gastroenteropancreatic NEN between 2005 and 2019. We performed bivariate and multivariable analyses to evaluate the relationship between CgA and NSE values before histological assessment and overall survival. Distribution of time-to-event was analyzed using Kaplan-Meier survival curves and modelled by Cox regression models. RESULTS: Elevated NSE levels prior to histology were significantly associated with worse survival (HR=1.13, p=0.004) and were associated with low-differentiated NENs (rs=0.321, p=0.0338). CgA was associated with well-differentiated tumors (rs=0.233), but not significantly. CONCLUSION: Pretreatment serum levels of NSE can serve as a valuable additional predictor of long-term survival in patients with NEN.

A proposed Common Training Framework for Specialists in Laboratory Medicine under EU Directive 2013/55/EC (The Recognition of Professional Qualifications).

European Union (EU) Directive 2013/55/EC (The Recognition of Professional Qualifications) allows Member States to decide on a common set of minimum knowledge, skills and competences that are needed to pursue a given profession through a Common Training Framework. To be adopted the framework must combine the knowledge, skills and competences of at least one third of the Member States. Professionals who have gained their qualifications under a Common Training Framework will be able to have these recognised automatically within the Union. The backbone of the European Federation of Clinical Chemistry and Laboratory Medicine's (EFLM) proposed Common Training Framework for non-medical Specialists in Laboratory Medicine is outlined here. It is based on an Equivalence of Standards in education, training, qualifications, knowledge, skills, competences and the professional conduct associated with specialist practice. In proposing the recognition of specialist practice EFLM has identified 15 EU Member States able to meet Equivalence and in whom the profession and/or its training is regulated (an additional EU Commission requirement). The framework supports and contributes to the Directive's enabling goals for increasing professional mobility, safeguarding consumers and ensuring a more equitable distribution of skills and expertise across the Member States. It represents EFLM's position statement and provides a template for professional societies and/or competent authorities to engage with the EU Commission.

Telacebec (Q203): Is there a novel effective and safe anti-tuberculosis drug on the horizon?

High prevalence and stronger emergency of various forms of drug-resistant tuberculosis (DR-TB), including the multidrug-resistant (MDR-TB) as well as extensively drug-resistant (XDR-TB) ones, caused by variously resistant Mycobacterium tuberculosis pathogens, make first-line anti-tuberculosis (anti-TB) agents therapeutically more and more ineffective. Therefore, there is an imperative to develop novel highly efficient (synthetic) agents against both drug-sensitive-TB and DR-TB. The exploration of various heterocycles as prospective core scaffolds for the discovery, development and optimization of anti-TB drugs remains an intriguing scientific endeavour. Telacebec (Q203; TCB), a molecule containing an imidazo[1,2-a]pyridine-3-carboxamide (IPA) structural motif, is considered a novel very promising anti-TB agent showing a unique mechanism of action. The compound blocks oxidative phosphorylation by inhibiting a mycobacterial respiratory chain due to interference with a specific cytochrome b subunit (QcrB) of transmembrane bc1 menaquinol-cytochrome c oxidoreductase as an essential component for transporting electrons across the membrane from menaquinol to other specific subunit, cytochrome c (QcrC). Thus, the ability of mycobacteria to synthesize adenosine-5´-triphosphate is limited and energy generating machinery is disabled. The TCB molecule effectively fights drug-susceptible, MDR as well as XDR M. tuberculosis strains. The article briefly explains a mechanism of an anti-TB action related to the compounds containing a variously substituted IPA scaffold and is focused on their fundamental structure-anti-TB activity relationships as well. Special consideration is paid to TCB indicating the importance of particular structural fragments for maintaining (or even improving) favourable pharmacodynamic, pharmacokinetic and/or toxicological properties. High lipophilicity of TCB might be regarded as one of the key physicochemical properties with positive impact on anti-TB effect of the drug. In January 2021, the TCB molecule was also involved in phase-II clinical trials focused on the treatment of Coronavirus Disease-19 caused by Severe Acute Respiratory Syndrome Coronavirus 2.

Ingavirin might be a promising agent to combat Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2).

The Severe Acute Respiratory Coronavirus 2 (SARS--CoV-2) and Coronavirus Disease-19 (COVID-19) pandemic, caused by the virus, have changed the world in just half a year. Lack of effective treatment, coupled with etiology of COVID-19, has resulted in more than 500,000 confirmed deaths at the time of writing, and the global economy is at an unseen unprecedented low level with unknown near- and long-term consequences. Ingavirin has been considered a non-toxic broad-spectrum antiviral with a complex mechanism of action. The molecule was originally designed for the prophylaxis and treatment of flu caused by both Influenza A and B viruses and for the treatment of viral causes of acute respiratory illness. The article hypothesized that the efficiency of given 1H-imidazol-4-yl heterocyclic scaffold-containing compound against SARS-CoV-2 might be connected with its ability to interfere with specific heterogeneous nuclear ribonucleoproteins (A1, for example). These specific cellular RNA-binding proteins showed affinity to Severe Acute Respiratory Coronavirus (SARS-CoV) nucleocapsid (N) protein, which shared high homology with the N protein of SARS-CoV-2 and the fact was expressed by a sequence identity of 90.52%. Impairing of the interactions between nuclear ribonucleoproteins and nucleocapsid (N) protein of SARS-CoV-2 might result in the inhibition of a viral replication cycle. Additional immunomodulating properties of ingavirin could be favorable for induction of adaptive immunity of host cells.

The European Federation of Clinical Chemistry and Laboratory Medicine syllabus for postgraduate education and training for Specialists in Laboratory Medicine: version 5 - 2018.

Although laboratory medicine practise varies across the European Union's (EU) member states, the extent of overlap in scope is such that a common syllabus describing the education and training associated with high-quality, specialist practise can be identified. In turn, such a syllabus can help define the common set of skills, knowledge and competence in a Common Training Framework (CTF) for non-medical Specialists in Laboratory Medicine under EU Directive 2013/55/EU (The recognition of Professional Qualifications). In meeting the requirements of the directive's CTF patient safety is particularly enhanced when specialists seek to capitalise on opportunities for free professional migration across EU borders. In updating the fourth syllabus, the fifth expands on individual discipline requirements, new analytical techniques and use of statistics. An outline structure for a training programme is proposed together with expected responsibilities of trainees and trainers; reference is provided to a trainee's log book. In updating the syllabus, it continues to support national programmes and the aims of EU Directive 2013/55/EU in providing safeguards to professional mobility across European borders at a time when the demand for highly qualified professionals is increasing in the face of a disparity in their distribution across Europe. In support of achieving a CTF, the syllabus represents EFLM's position statement for the education and training that underpins the framework.

Lipid levels and their genetic regulation in patients with familial hypercholesterolemia and familial defective apolipoprotein B-100: the MEDPED Slovakia Project.

We examined, from a cohort of 165 families, 529 individuals for familial hypercholesterolemia (FH). Utilising clinical criteria for diagnosis, we identified 122 patients (n=41 families) as having FH. With PCR testing, 31 individuals (n=12 families) were found to have familial defective Apo B-100 (FDB). From the cohort, 102 normolipidemic (NL) individuals served as a control group. Patients with FH had the highest levels of total cholesterol (TC), LDL-cholesterol (LDL-C) and apolipoprotein B (Apo B), followed by FDB patients and the normolipidemic relatives had the lowest levels (P<0.0001 for all parameters). We did not find any effect of Apo E genotypes on lipid levels in the NL or FH group. Therefore, other genetic and/or environmental factors may be responsible for the diversity in the clinical expression in these populations.