INTRODUCTION: The real-world effectiveness of the efmoroctocog alfa (recombinant FVIII Fc fusion protein, a rFVIIIFc) has been investigated in numerous studies, however, currently, there exists no comprehensive collection of the existing real-world evidence (RWE) on the performance of prophylactic use of rFVIIIFc. AIM: The aims of this systematic literature study were to identify, review, evaluate and collate the RWE of prophylactic rFVIIIFc for patients with haemophilia A reported in Europe. METHODS: We searched Medline and Embase from 2014 to February 2022 to identify publications reporting the effectiveness of rFVIIIFc in patients with haemophilia A. The outcomes of interest were annualised bleeding rates (ABR, AjBR, AsBR), injection frequency, factor consumption, adherence, development of inhibitors and quality-of-life measures. RESULTS: 46 eligible publications (eight full-text articles) were included. rFVIIIFc showed a low ABR in patients with haemophilia A. Studies assessing treatment switching from a standard half-life (SHL) treatment to rFVIIIFc found that the ABR and consumption were reduced in most patients. Studies assessing rFVIIIFc effectiveness reported a median ABR between 0.0 and 2.0 with median injections per week ranging between 1.8 and 2.4 and median doses between 60 and 105 IU/kg/week. Of the studies assessing inhibitor development, only one study reported an incidence of a low titre inhibitor, and no patients developed clinically significant inhibitors. CONCLUSION: rFVIIIFc prophylaxis treatment results in a low ABR across studies in patients with haemophilia A in a European real-world setting, which correlates with findings from clinical trials assessing the efficacy of rFVIIIFc in patients with haemophilia A.

• Klíčová slova
• Elocta, efmoroctocog alfa, haemophilia A, prophylaxis, rFVIIIFc, real-world evidence, systematic review,
• MeSH
• faktor VIII terapeutické užití   MeSH
• hemofilie A * farmakoterapie   prevence a kontrola   MeSH
• imunoglobuliny - Fc fragmenty terapeutické užití   MeSH
• lidé MeSH
• poločas MeSH
• rekombinantní fúzní proteiny terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• systematický přehled MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• faktor VIII MeSH
• imunoglobuliny - Fc fragmenty MeSH
• rekombinantní fúzní proteiny MeSH

Vancomycin is frequently used in haemodialysis (HD) patients but generally accepted target serum ranges and dosing strategy are still lacking in this group. Based on retrospective analysis of data from 118 HD patients treated with vancomycin the interdialytic elimination constant (Ke), apparent volume of distribution (Vd) and dialysis efficacy were calculated. The influence of possible clinical variables on the pharmacokinetic parameters of vancomycin have been tested. The median of Ke in interdialytic periods, corresponding half-life and Vd were 0.0073 h-1, 95.0 h and 0.87 L/kg, respectively. We found significant positive correlation between time in dialysis program and Ke. The Vd correlated best with lean body mass (LBM). For high- and low flux membrane HD of 4 hours duration the decline in vancomycin levels was 20.88% and 12.86%, respectively. Based on these data loading dose for vancomycin in HD patient should be calculated as 24.483 × LBM (kg) + 455 mg. The utility of this equation for entire HD population should be also verified prospectively.

• Klíčová slova
• Vancomycin, dosing, haemodialysis, pharmacokinetics, therapeutic drug monitoring,
• MeSH
• antibakteriální látky MeSH
• dialýza ledvin MeSH
• lidé MeSH
• monitorování léčiv * MeSH
• poločas MeSH
• retrospektivní studie MeSH
• vankomycin * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky MeSH
• vankomycin * MeSH

INTRODUCTION: For children with haemophilia, early initiation of prophylaxis is crucial to prevent life-threatening bleeds and maintain joint health throughout life. Options for prophylaxis have recently increased from replacement therapy with standard or extended half-life coagulation factor products to include other haemostasis products, such as the non-replacement therapy emicizumab. AIM: To review key factors that determine the choice of prophylaxis in young children. METHODS: Key clinical questions on the implementation of prophylaxis for haemophilia in children were identified and PubMed was searched for evidence supporting guidance on the implementation of prophylaxis. RESULTS: The results of the literature search and the practical experience of the authors were used to build consensus on when to start prophylaxis, the pros and cons of the products available to guide the choice of product, and practical aspects of starting prophylaxis to guide the choice of regimen. CONCLUSIONS: In this era of increasing therapeutic choices, available information about the range of treatment options must be considered when initiating prophylaxis in young children. Parents or care givers must be sufficiently informed to allow informed shared decision making. Although plentiful data and clinical experience have been gathered on prophylaxis with clotting factor replacement therapy, its use in young children brings practical challenges, such as the need for intravenous administration. In contrast, our relatively brief experience and limited data with subcutaneously administered non-replacement therapy (i.e., emicizumab) in this patient group imply that starting emicizumab prophylaxis in young children requires careful consideration, despite the more convenient route of administration.

• Klíčová slova
• EHL factor concentrate, arthropathy, children, haemophilia, non-replacement therapy, prophylaxis,
• MeSH
• dítě MeSH
• faktor VIII terapeutické užití   MeSH
• hemofilie A * farmakoterapie   MeSH
• hormonální substituční terapie MeSH
• koagulační faktory terapeutické užití   MeSH
• krvácení MeSH
• lidé MeSH
• poločas MeSH
• předškolní dítě MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• faktor VIII MeSH
• koagulační faktory MeSH

The SARS-CoV-2 virus is highly contagious to humans and has caused a pandemic of global proportions. Despite worldwide research efforts, efficient targeted therapies against the virus are still lacking. With the ready availability of the macromolecular structures of coronavirus and its known variants, the search for anti-SARS-CoV-2 therapeutics through in silico analysis has become a highly promising field of research. In this study, we investigate the inhibiting potentialities of triazole-based compounds against the SARS-CoV-2 main protease (Mpro). The SARS-CoV-2 main protease (Mpro) is known to play a prominent role in the processing of polyproteins that are translated from the viral RNA. Compounds were pre-screened from 171 candidates (collected from the DrugBank database). The results showed that four candidates (Bemcentinib, Bisoctrizole, PYIITM, and NIPFC) had high binding affinity values and had the potential to interrupt the main protease (Mpro) activities of the SARS-CoV-2 virus. The pharmacokinetic parameters of these candidates were assessed and through molecular dynamic (MD) simulation their stability, interaction, and conformation were analyzed. In summary, this study identified the most suitable compounds for targeting Mpro, and we recommend using these compounds as potential drug molecules against SARS-CoV-2 after follow up studies.

• Klíčová slova
• MD simulation, SARS-CoV-2, docking, drug, main protease, triazole,
• MeSH
• antivirové látky chemie   metabolismus   terapeutické užití   MeSH
• benzocyklohepteny chemie   metabolismus   MeSH
• chemické databáze MeSH
• COVID-19 virologie   MeSH
• farmakoterapie COVID-19 MeSH
• inhibitory proteas chemie   metabolismus   terapeutické užití   MeSH
• koronavirové proteasy 3C antagonisté a inhibitory   metabolismus   MeSH
• kvantitativní vztahy mezi strukturou a aktivitou MeSH
• lidé MeSH
• ligandy MeSH
• poločas MeSH
• SARS-CoV-2 enzymologie   izolace a purifikace   MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• triazoly chemie   metabolismus   terapeutické užití   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 3C-like proteinase, SARS-CoV-2 MeSH Prohlížeč
• antivirové látky MeSH
• bemcentinib MeSH Prohlížeč
• benzocyklohepteny MeSH
• inhibitory proteas MeSH
• koronavirové proteasy 3C MeSH
• ligandy MeSH
• triazoly MeSH

Tacrine is a classic drug whose efficacy against neurodegenerative diseases is still shrouded in mystery. It seems that besides its inhibitory effect on cholinesterases, the clinical benefit is co-determined by NMDAR-antagonizing activity. Our previous data showed that the direct inhibitory effect of tacrine, as well as its 7-methoxy derivative (7-MEOTA), is ensured via a "foot-in-the-door" open-channel blockage, and that interestingly both tacrine and 7-MEOTA are slightly more potent at the GluN1/GluN2A receptors when compared with the GluN1/GluN2B receptors. Here, we report that in a series of 30 novel tacrine derivatives, designed for assessment of structure-activity relationship, blocking efficacy differs among different compounds and receptors using electrophysiology with HEK293 cells expressing the defined types of NMDARs. Selected compounds (4 and 5) potently inhibited both GluN1/GluN2A and GluN1/GluN2B receptors; other compounds (7 and 23) more effectively inhibited the GluN1/GluN2B receptors; or the GluN1/GluN2A receptors (21 and 28). QSAR study revealed statistically significant model for the data obtained for inhibition of GluN1/Glu2B at -60 mV expressed as IC50 values, and for relative inhibition of GluN1/Glu2A at +40 mV caused by a concentration of 100 μM. The models can be utilized for a ligand-based virtual screening to detect potential candidates for inhibition of GluN1/Glu2A and/or GluN1/Glu2B subtypes. Using in vivo experiments in rats we observed that unlike MK-801, the tested novel compounds did not induce hyperlocomotion in open field, and also did not impair prepulse inhibition of startle response, suggesting minimal induction of psychotomimetic side effects. We conclude that tacrine derivatives are promising compounds since they are centrally available subtype-specific inhibitors of the NMDARs without detrimental behavioral side-effects.

• Klíčová slova
• Acetylcholinesterase, Electrophysiology, Glutamate receptor, Ion channel, Pharmacology, QSAR, Tacrine, in vivo,
• MeSH
• acetylcholinesterasa chemie   genetika   metabolismus   MeSH
• butyrylcholinesterasa chemie   metabolismus   MeSH
• cholinesterasové inhibitory chemie   metabolismus   farmakologie   MeSH
• hematoencefalická bariéra účinky léků   metabolismus   MeSH
• krysa rodu Rattus MeSH
• kvantitativní vztahy mezi strukturou a aktivitou MeSH
• lidé MeSH
• lokomoce účinky léků   MeSH
• membránové potenciály účinky léků   MeSH
• myši inbrední ICR MeSH
• myši MeSH
• poločas MeSH
• potkani Wistar MeSH
• psi MeSH
• racionální návrh léčiv MeSH
• receptory N-methyl-D-aspartátu antagonisté a inhibitory   genetika   metabolismus   MeSH
• rekombinantní proteiny biosyntéza   chemie   MeSH
• takrin chemie   metabolismus   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• receptory N-methyl-D-aspartátu MeSH
• rekombinantní proteiny MeSH
• takrin MeSH

Membrane-tethered signalling proteins such as TNFα and many EGF receptor ligands undergo shedding by the metalloproteinase ADAM17 to get released. The pseudoproteases iRhom1 and iRhom2 are important for the transport, maturation and activity of ADAM17. Yet, the structural and functional requirements to promote the transport of the iRhom-ADAM17 complex have not yet been thoroughly investigated. Utilising in silico and in vitro methods, we here map the conserved iRhom homology domain (IRHD) and provide first insights into its structure and function. By focusing on iRhom2, we identified different structural and functional factors within the IRHD. We found that the structural integrity of the IRHD is a key factor for ADAM17 binding. In addition, we identified a highly conserved motif within an unstructured region of the IRHD, that, when mutated, restricts the transport of the iRhom-ADAM17 complex through the secretory pathway in in vitro, ex vivo and in vivo systems and also increases the half-life of iRhom2 and ADAM17. Furthermore, the disruption of this IRHD motif was also reflected by changes in the yet undescribed interaction profile of iRhom2 with proteins involved in intracellular vesicle transport. Overall, we provide the first insights into the forward trafficking of iRhoms which is critical for TNFα and EGF receptor signalling.

• Klíčová slova
• ADAM17, Ectodomain shedding, Growth factors, TNF, iRhom, iRhom homology domain,
• MeSH
• aminokyselinové motivy MeSH
• buněčné linie MeSH
• epidermální růstové faktory metabolismus   MeSH
• lidé MeSH
• malá interferující RNA metabolismus   MeSH
• membránové proteiny genetika   metabolismus   MeSH
• mutageneze MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• poločas MeSH
• protein ADAM17 chemie   metabolismus   MeSH
• proteinové domény MeSH
• RNA interference MeSH
• signální transdukce MeSH
• TNF-alfa metabolismus   MeSH
• transport proteinů MeSH
• transportní proteiny antagonisté a inhibitory   genetika   metabolismus   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• epidermální růstové faktory MeSH
• iRhom1 protein, mouse MeSH Prohlížeč
• iRhom2 protein, mouse MeSH Prohlížeč
• malá interferující RNA MeSH
• membránové proteiny MeSH
• protein ADAM17 MeSH
• TNF-alfa MeSH
• transportní proteiny MeSH

Histone deacetylase 6 (HDAC6) is a promising therapeutic target for the treatment of neurodegenerative disorders. SW-100 (1a), a phenylhydroxamate-based HDAC6 inhibitor (HDAC6i) bearing a tetrahydroquinoline (THQ) capping group, is a highly potent and selective HDAC6i that was shown to be effective in mouse models of Fragile X syndrome and Charcot-Marie-Tooth disease type 2A (CMT2A). In this study, we report the discovery of a new THQ-capped HDAC6i, termed SW-101 (1s), that possesses excellent HDAC6 potency and selectivity, together with markedly improved metabolic stability and druglike properties compared to SW-100 (1a). X-ray crystallography data reveal the molecular basis of HDAC6 inhibition by SW-101 (1s). Importantly, we demonstrate that SW-101 (1s) treatment elevates the impaired level of acetylated α-tubulin in the distal sciatic nerve, counteracts progressive motor dysfunction, and ameliorates neuropathic symptoms in a CMT2A mouse model bearing mutant MFN2. Taken together, these results bode well for the further development of SW-101 (1s) as a disease-modifying HDAC6i.

• MeSH
• acetylace MeSH
• benzamidy chemie   metabolismus   MeSH
• Charcotova-Marieova-Toothova nemoc farmakoterapie   metabolismus   patologie   MeSH
• chinoliny chemie   metabolismus   terapeutické užití   MeSH
• fenotyp MeSH
• histondeacetylasa 6 antagonisté a inhibitory   metabolismus   MeSH
• inhibitory histondeacetylas chemie   metabolismus   terapeutické užití   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• poločas MeSH
• protein - isoformy antagonisté a inhibitory   metabolismus   MeSH
• simulace molekulového dockingu MeSH
• tubulin metabolismus   MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• 1,2,3,4-tetrahydroquinoline MeSH Prohlížeč
• benzamidy MeSH
• chinoliny MeSH
• histondeacetylasa 6 MeSH
• inhibitory histondeacetylas MeSH
• protein - isoformy MeSH
• SW-100 MeSH Prohlížeč
• tubulin MeSH

The inhalation of metal (including lead) nanoparticles poses a real health issue to people and animals living in polluted and/or industrial areas. In this study, we exposed mice to lead(II) nitrate nanoparticles [Pb(NO3)2 NPs], which represent a highly soluble form of lead, by inhalation. We aimed to uncover the effects of their exposure on individual target organs and to reveal potential variability in the lead clearance. We examined (i) lead biodistribution in target organs using laser ablation and inductively coupled plasma mass spectrometry (LA-ICP-MS) and atomic absorption spectrometry (AAS), (ii) lead effect on histopathological changes and immune cells response in secondary target organs and (iii) the clearance ability of target organs. In the lungs and liver, Pb(NO3)2 NP inhalation induced serious structural changes and their damage was present even after a 5-week clearance period despite the lead having been almost completely eliminated from the tissues. The numbers of macrophages significantly decreased after 11-week Pb(NO3)2 NP inhalation; conversely, abundance of alpha-smooth muscle actin (α-SMA)-positive cells, which are responsible for augmented collagen production, increased in both tissues. Moreover, the expression of nuclear factor κB (NF-κB) and selected cytokines, such as tumor necrosis factor alpha (TNFα), transforming growth factor beta 1 (TGFβ1), interleukin 6(IL-6), IL-1α and IL-1β , displayed a tissue-specific response to lead exposure. In summary, diminished inflammatory response in tissues after Pb(NO3)2 NPs inhalation was associated with prolonged negative effect of lead on tissues, as demonstrated by sustained pathological changes in target organs, even after long clearance period.

• Klíčová slova
• LA-ICP-MS imaging, clearance, inhalation, lead nanoparticles, toxicity,
• MeSH
• aktiny agonisté   genetika   imunologie   MeSH
• alveolární makrofágy účinky léků   imunologie   patologie   MeSH
• aplikace inhalační MeSH
• biologická dostupnost MeSH
• dusičnany farmakokinetika   toxicita   MeSH
• exprese genu MeSH
• inhalační expozice analýza   MeSH
• interleukin-1alfa agonisté   genetika   imunologie   MeSH
• interleukin-1beta agonisté   genetika   imunologie   MeSH
• interleukin-6 agonisté   genetika   imunologie   MeSH
• játra účinky léků   imunologie   patologie   MeSH
• kovové nanočástice aplikace a dávkování   toxicita   MeSH
• látky znečišťující vzduch farmakokinetika   toxicita   MeSH
• myši inbrední ICR MeSH
• myši MeSH
• NF-kappa B agonisté   genetika   imunologie   MeSH
• olovo farmakokinetika   toxicita   MeSH
• plíce účinky léků   imunologie   patologie   MeSH
• poločas MeSH
• spektrofotometrie atomová MeSH
• tkáňová distribuce MeSH
• TNF-alfa agonisté   genetika   imunologie   MeSH
• transformující růstový faktor beta1 agonisté   genetika   imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aktiny MeSH
• alpha-smooth muscle actin, mouse MeSH Prohlížeč
• dusičnany MeSH
• Il1a protein, mouse MeSH Prohlížeč
• IL1B protein, mouse MeSH Prohlížeč
• interleukin-1alfa MeSH
• interleukin-1beta MeSH
• interleukin-6, mouse MeSH Prohlížeč
• interleukin-6 MeSH
• látky znečišťující vzduch MeSH
• lead nitrate MeSH Prohlížeč
• NF-kappa B MeSH
• olovo MeSH
• Tgfb1 protein, mouse MeSH Prohlížeč
• TNF-alfa MeSH
• transformující růstový faktor beta1 MeSH

The time course of 137Cs activity in general population of the Czech Republic has been systematically followed since the Chernobyl accident in 1986. Either whole body counting or the determination of 137Cs content in 24-hour urine samples were used as a method of determination of body activity. Environmental and effective half-lives were calculated from the data. In the time period from 1986 to 1990 the effective half-life was 1.3 years; since 1990 up to present the half-life is 15 years. The older data on whole body activity of 137Cs from 1965 to 1985 were compiled and are presented as well. Apart from the general population, a group of people who have special dietary habits in terms of increased game meat consumption, namely wild boar meat, has been monitored since 2000. In this group, the body content of 137Cs is about two orders of magnitude higher than in the general population.

• MeSH
• celotělové počítání MeSH
• černobylská havárie MeSH
• dieta MeSH
• dospělí MeSH
• elektrárny MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské tělo MeSH
• maso * MeSH
• mladý dospělý MeSH
• monitorování radiace MeSH
• obsah radioaktivních látek v organizmu MeSH
• poločas MeSH
• prasata MeSH
• radioaktivní látky znečišťující půdu analýza   MeSH
• radioaktivní spad analýza   MeSH
• radioizotopy cesia analýza   moč   MeSH
• senioři MeSH
• Sus scrofa MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Ukrajina MeSH
• Názvy látek
• Cesium-137 MeSH Prohlížeč
• radioaktivní látky znečišťující půdu MeSH
• radioaktivní spad MeSH
• radioizotopy cesia MeSH

The genome sequence of Pyrobaculum calidifontis contains two open reading frames, Pcal_0144 and Pcal_0970, exhibiting homology with L-asparaginases. In search of a thermostable L-asparaginase with no glutaminase activity, we have cloned and expressed the gene encoding Pcal_0970 in Escherichia coli. Recombinant Pcal_0970 was produced in insoluble and inactive form which was solubilized and refolded into enzymatically active form. The refolded Pcal_0970 showed the highest activity at or above 100 °C. Optimum pH for the enzyme activity was 6.5. Addition of divalent metal cations or EDTA had no significant effect on the activity. The enzyme was capable of hydrolyzing D-asparagine with a 20% activity as compared to 100% with L-asparagine. Pcal_0970 did not show any detectable activity when L-glutamine or D-glutamine was used as substrate. Pcal_0970 exhibited a Km value of 4.5 ± 0.4 mmol/L and Vmax of 355 ± 13 μmol min-1 mg-1 towards L-asparagine. The activation energy, from the linear Arrhenius plot, was determined as 39.9 ± 0.6 kJ mol-1. To the best of our knowledge, Pcal_0970 is the most thermostable L-asparaginase with a half-life of more than 150 min at 100 °C and this is the first report on characterization of an L-asparaginase from phylum Crenarchaeota.

• MeSH
• asparaginasa izolace a purifikace   metabolismus   MeSH
• glutamin metabolismus   MeSH
• glutaminasa metabolismus   MeSH
• kinetika MeSH
• klonování DNA MeSH
• koncentrace vodíkových iontů MeSH
• poločas MeSH
• Pyrobaculum enzymologie   genetika   MeSH
• rekombinantní proteiny genetika   metabolismus   MeSH
• stabilita enzymů MeSH
• substrátová specifita MeSH
• teplota MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• asparaginasa MeSH
• glutamin MeSH
• glutaminasa MeSH
• rekombinantní proteiny MeSH