- Publikační typ
- abstrakt z konference MeSH
In this paper we have compiled and summarized the steps which manufacturers and clinical investigators need to undertake to perform a target population definition during the Health technology assessment process of medical device, namely external cardio stimulator (pacemaker). Based on available data using top-down approach we have defined target population for external cardiostimulator and estimated, that the size of the target population for external pacing will not exceed 16000 patients per year in the Czech Republic and is of comparable size with other states in the region.
Objective: Medical device development, from the product's conception to release to market, is very complex and relies significantly on the application of exact processes. This paper aims to provide an analysis and summary of current research in the field of medical device development methodologies, discuss its phases, and evaluate the associated legislative and risk aspects. Methods: The literature search was conducted to detect peer-reviewed studies in Scopus, Web of Science, and Science Direct, on content published between 2007 and November 2019. Based on exclusion and inclusion criteria, 13 papers were included in the first session and 11 were included in the second session. Thus, a total of 24 papers were analyzed. Most of the publications originated in the United States (7 out of 24). Results: The medical device development process comprises one to seven stages. Six studies also contain a model of the medical device development process for all stages or for just some of the stages. These studies specifically describe the concept stage during which all uncertainties, such as the clinical need definition, customer requirements/needs, finances, reimbursement strategy, team selection, and legal aspects, must be considered. Conclusion: The crucial factor in healthcare safety is the stability of factors over a long production time. Good manufacturing practices cannot be tested on individual batches of products; they must be inherently built into the manufacturing process. The key issues that must be addressed in the future are the consistency in the classification of devices throughout the EU and globally, and the transparency of approval processes.
- Publikační typ
- systematický přehled MeSH
The purpose of this study was to identify new small molecules that possess activity on human toll-like receptor 4 associated with the myeloid differentiation protein 2 (hTLR4/MD2). Following current rational drug design principles, we firstly performed a ligand and structure based virtual screening of more than 130 000 compounds to discover until now unknown class of hTLR4/MD2 modulators that could be used as novel type of immunologic adjuvants. The core of the in silico study was molecular docking of flexible ligands in a partially flexible hTLR4/MD2 receptor model using a peta-flops-scale supercomputer. The most promising substances resulting from this study, related to anthracene-succimide hybrids, were synthesized and tested. The best prepared candidate exhibited 80% of Monophosphoryl Lipid A in vitro agonistic activity in cell lines expressing hTLR4/MD2.
- MeSH
- buněčné linie MeSH
- knihovny malých molekul chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- molekulární struktura MeSH
- počítačová simulace * MeSH
- preklinické hodnocení léčiv MeSH
- racionální návrh léčiv * MeSH
- simulace molekulového dockingu MeSH
- toll-like receptor 4 antagonisté a inhibitory MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
In order to identify novel lead structures for human toll-like receptor 4 (hTLR4) modulation virtual high throughput screening by a peta-flops-scale supercomputer has been performed. Based on the in silico studies, a series of 12 compounds related to tryptamine was rationally designed to retain suitable molecular geometry for interaction with the hTLR4 binding site as well as to satisfy general principles of drug-likeness. The proposed compounds were synthesized, and tested by in vitro and ex vivo experiments, which revealed that several of them are capable to stimulate hTLR4 in vitro up to 25% activity of Monophosphoryl lipid A. The specific affinity of the in vitro most potent substance was confirmed by surface plasmon resonance direct-binding experiments. Moreover, two compounds from the series show also significant ability to elicit production of interleukin 6.
- MeSH
- adjuvancia imunologická chemie metabolismus farmakologie MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- inhibiční koncentrace 50 MeSH
- interleukin-6 krev MeSH
- lidé MeSH
- ligandy MeSH
- počítačová simulace MeSH
- povrchová plasmonová rezonance MeSH
- rychlé screeningové testy metody MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- toll-like receptor 4 agonisté metabolismus MeSH
- tryptaminy chemie MeSH
- vakcíny MeSH
- vazebná místa MeSH
- vztahy mezi strukturou a aktivitou * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Vaccination is defined as the administration of an antigenic material in order to stimulate the immune system, leading to the development of adaptive immunity to a pathogen. Vaccines can prevent or reduce morbidity from a vast number of infections. This manuscript presents an analysis of vaccine types and vaccine substances, concentrating on individual components including the active ingredient, adjuvants, preservatives, stabilizers, inactivators, antibiotics, diluents and other substances. While many papers have been published on individual vaccine components, this review provides detail on a wide range of the most commonly-used vaccine ingredients and components that have been tested in clinical trials.
- MeSH
- adjuvancia imunologická MeSH
- antigeny imunologie MeSH
- imunitní systém imunologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- vakcinace MeSH
- vakcíny chemie imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
In this study, we have carried out a combined experimental and computational investigation to elucidate several bred-in-the-bone ideas standing out in rational design of novel cationic surfactants as antibacterial agents. Five 3-hydroxypyridinium salts differing in the length of N-alkyl side chain have been synthesized, analyzed by high performance liquid chromatography, tested for in vitro activity against a panel of pathogenic bacterial and fungal strains, computationally modeled in water by a SCRF B3LYP/6-311++G(d,p) method, and evaluated by a systematic QSAR analysis. Given the results of this work, the hypothesis suggesting that higher positive charge of the quaternary nitrogen should increase antimicrobial efficacy can be rejected since 3-hydroxyl group does increase the positive charge on the nitrogen but, simultaneously, it significantly derogates the antimicrobial activity by lowering the lipophilicity and by escalating the desolvation energy of the compounds in comparison with non-hydroxylated analogues. Herein, the majority of the prepared 3-hydroxylated substances showed notably lower potency than the parent pyridinium structures, although compound 8 with C12 alkyl chain proved a distinctly better antimicrobial activity in submicromolar range. Focusing on this anomaly, we have made an effort to reveal the reason of the observed activity through a molecular dynamics simulation of the interaction between the bacterial membrane and compound 8 in GROMACS software.
- MeSH
- antibakteriální látky chemie farmakologie toxicita MeSH
- Bacteria účinky léků MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- houby účinky léků MeSH
- hydrofobní a hydrofilní interakce MeSH
- křečci praví MeSH
- kvantitativní vztahy mezi strukturou a aktivitou * MeSH
- molekulární konformace MeSH
- pyridiny chemie farmakologie toxicita MeSH
- simulace molekulární dynamiky * MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
In the present paper, we describe the synthesis of a new group of 5-hydroxyisoquinolinium salts with different lengths of alkyl side-chain (C10-C18), and their chromatographic analysis and biological assay for in vitro activity against bacterial and fungal strains. We compare the lipophilicity and efficacy of hydroxylated isoquinolinium salts with the previously published (non-hydroxylated) isoquinolinium salts from the point of view of antibacterial and antifungal versatility and cytotoxic safety. Compound 11 (C18) had to be excluded from the testing due to its low solubility. Compounds 9 and 10 (C14, C16) showed only moderate efficacy against G+ bacteria, notably with excellent potency against Staphyloccocus aureus, but no effect against G- bacteria. In contrast, non-hydroxylated isoquinolinium salts showed excellent antimicrobial efficacy within the whole series, particularly 14 (C14) against G+ strains and 15 (C16) against fungi. The electronic properties and desolvation energies of 5-hydroxyisoquinolinium and isoquinolinium salts were studied by quantum-chemistry calculations employing B3LYP/6-311++G(d,p) method and an implicit water-solvent simulation model (SCRF). Despite the positive mesomeric effect of the hydroxyl moiety reducing the electron density of the quaternary nitrogen, it is probably the higher lipophilicity and lower desolvation energy of isoquinolinium salts, which is responsible for enhanced antimicrobial versatility and efficacy.
- MeSH
- antibakteriální látky chemická syntéza farmakologie MeSH
- antifungální látky chemická syntéza farmakologie MeSH
- gramnegativní bakterie účinky léků růst a vývoj MeSH
- grampozitivní bakterie účinky léků růst a vývoj MeSH
- houby účinky léků růst a vývoj MeSH
- isochinoliny chemická syntéza farmakologie MeSH
- kvantová teorie MeSH
- mikrobiální testy citlivosti MeSH
- molekulární modely MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Alzheimerova choroba (AD) je jedním z nejzávažnějších onemocnění moderní doby. Vzrůstající průměrný věk společně s vysokou prevalencí a incidencí AD v seniorské populaci, společně s vysokými náklady na péči o pacienty s AD z ní činí jednu z finančně nejnáročnějších diagnóz vůbec. Vakcinace je dlouhodobě označována za nákladově nejefektivnější formu terapeutické intervence, proto není divu, že do imunoterapeutických přístupů k terapii AD jsou vkládány veliké naděje. V tomto přehledovém článku bychom rádi shrnuli dosavadní imunologické přístupy v terapii AD a prezentovali současné trendy výzkumu, které by v dohledné době mohly přinést posun v terapii nebo prevenci AD.
Alzheimer's disease (AD) is one of the plagues of modern era. Increasing mean age of a population in combination with the overall high prevalence and incidence of AD in elderly population and very high both direct and indirect health care costs of the disease, makes AD one of the most expensive diagnosis in the developed countries. Vaccination is one of the best cost effective approaches of the therapeutic interventions. Progresses in immunotherapeutic approaches in AD therapy are watched with great anticipations both by healthcare professionals and general population. In this review we would like to summarize up-to date immunotherapeutic approaches in clinical development and to present current research trends that could lead to the breakthrough in AD therapy or prevention.
- MeSH
- aktivní imunoterapie metody MeSH
- Alzheimerova nemoc * etiologie farmakoterapie imunologie prevence a kontrola MeSH
- amyloidní beta-protein imunologie metabolismus MeSH
- amyloidní plaky MeSH
- histokompatibilita - antigeny třídy I MeSH
- imunoterapie * metody MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- monoklonální protilátky terapeutické užití MeSH
- neurofibrilární klubka MeSH
- pasivní imunizace MeSH
- proteiny tau MeSH
- protilátky terapeutické užití MeSH
- receptory Fc MeSH
- senioři MeSH
- stárnutí MeSH
- vakcíny proti Alzheimerově nemoci * terapeutické užití MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
- tabulky MeSH
To predict unknown reactivation potencies of 12 mono- and bis-pyridinium aldoximes for VX-inhibited rat acetylcholinesterase (rAChE), three-dimensional quantitative structure-activity relationship (3D QSAR) analysis has been carried out. Utilizing molecular interaction fields (MIFs) calculated by molecular mechanical (MMFF94) and quantum chemical (B3LYP/6-31G*) methods, two satisfactory ligand-based CoMFA models have been developed: 1. R(2)=0.9989, Q(LOO)(2)=0.9090, Q(LTO)(2)=0.8921, Q(LMO(20%))(2)=0.8853, R(ext)(2)=0.9259, SDEP(ext)=6.8938; 2. R(2)=0.9962, Q(LOO)(2)=0.9368, Q(LTO)(2)=0.9298, Q(LMO(20%))(2)=0.9248, R(ext)(2)=0.8905, SDEP(ext)=6.6756. High statistical significance of the 3D QSAR models has been achieved through the application of several data noise reduction techniques (i.e. smart region definition SRD, fractional factor design FFD, uninformative/iterative variable elimination UVE/IVE) on the original MIFs. Besides the ligand-based CoMFA models, an alignment molecular set constructed by flexible molecular docking has been also studied. The contour maps as well as the predicted reactivation potencies resulting from 3D QSAR analyses help better understand which structural features are associated with increased reactivation potency of studied compounds.
- MeSH
- acetylcholinesterasa chemie MeSH
- aktivace enzymů MeSH
- chemické bojové látky chemie MeSH
- cholinesterasové inhibitory chemie MeSH
- GPI-vázané proteiny agonisté antagonisté a inhibitory chemie MeSH
- kinetika MeSH
- krysa rodu rattus MeSH
- kvantitativní vztahy mezi strukturou a aktivitou MeSH
- kvantová teorie MeSH
- ligandy MeSH
- organothiofosforové sloučeniny chemie MeSH
- oximy chemie MeSH
- pyridinové sloučeniny chemie MeSH
- reaktivátory cholinesterázy chemie MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- termodynamika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
