Populační farmakokinetika je oblast farmakologie, jejímž cílem je tvorba matematického modelu popisujícího farmakokinetiku léčiva v populaci včetně její variability. Tento článek přináší vhled do této problematiky a osvětluje terminologii pro lepší orientaci ve studiích. V úvodu je představena metoda v rámci farmakologie jako celku s důrazem na farmakokinetiku a využití statistických modelů pro optimální dávkování. Další část je rychlým shrnutím historie farmakokinetiky po vytvoření programu NONMEM s navázáním na počítačové zpracování dat v současnosti. Následující část je zaměřena na tvorbu modelu, různé přístupy odhadu parametrů včetně Bayesovské metody, na to navazují metody validace, a dále krátká část týkající se kovariance parametrů. V závěru jsou shrnuty přínosy a pozitiva populační farmakokinetiky a diskuse o jejích limitacích a perspektivách.
Population pharmacokinetics is a field of pharmacology that aims to create a mathematical model describing the pharmacokinetics of a drug in a population, including its variability. This article provides an insight into this field and explains the terminology to better understand the studies. The method is introduced in the context of pharmacology as a whole, with an emphasis on pharmacokinetics and the use of statistical models for optimal dosing. The next section is a quick summary of the history of pharmacokinetics after the creation of NONMEM with a follow-up on computerized data processing today. The following section focuses on model building, various approaches to parameter estimation including the Bayesian method, and continues with validation methods, followed by a short section on parameter covariance. Finally, the benefits and positives of population pharmacokinetics are summarized and a discussion of its limitations and perspectives is provided.
- Klíčová slova
- farmakokinetická analýza, populační farmakokinetika,
- MeSH
- Bayesova věta MeSH
- farmakokinetika * MeSH
- farmakologie metody přístrojové vybavení MeSH
- léčivé přípravky aplikace a dávkování MeSH
- lidé MeSH
- software MeSH
- statistické modely * MeSH
- statistika jako téma MeSH
- validace softwaru MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Considering its very short elimination half-life, the approved oxacillin dosage might not be sufficient to maintain the pharmacokinetic/pharmacodynamics (PK/PD) target of time-dependent antibiotics. This study aimed to describe the population pharmacokinetics of oxacillin and to explore the probability of PK/PD target attainment by using various dosing regimens with oxacillin in staphylococcal infections. Both total and unbound oxacillin plasma concentrations retrieved as a part of routine therapeutic drug-monitoring practice were analyzed using nonlinear mixed-effects modeling. Monte Carlo simulations were used to generate the theoretical distribution of unbound oxacillin plasma concentration-time profiles at various dosage regimens. Data from 24 patients treated with oxacillin for staphylococcal infection have been included into the analysis. The volume of distribution of oxacillin in the population was 11.2 L, while the elimination rate constant baseline of 0.73 h-1 increased by 0.3 h-1 with each 1 mL/s/1.73 m2 of the estimated glomerular filtration rate (eGFR). The median value of oxacillin binding to plasma proteins was 86%. The superiority of continuous infusion in achieving target PK/PD values was demonstrated and dosing according to eGFR was proposed. Daily oxacillin doses of 9.5 g, 11 g, or 12.5 g administered by continuous infusion have been shown to be optimal for achieving target PK/PD values in patients with moderate, mild, or normal renal function, respectively.
- Publikační typ
- časopisecké články MeSH
DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) is a pattern recognition receptor expressed on immune cells and involved in the recognition of carbohydrate signatures present on various pathogens, including HIV, Ebola, and SARS-CoV-2. Therefore, developing inhibitors blocking the carbohydrate-binding site of DC-SIGN could generate a valuable tool to investigate the role of this receptor in several infectious diseases. Herein, we performed a fragment-based ligand design using 4-quinolone as a scaffold. We synthesized a library of 61 compounds, performed a screening against DC-SIGN using an STD reporter assay, and validated these data using protein-based 1H-15N HSQC NMR. Based on the structure-activity relationship data, we demonstrate that ethoxycarbonyl or dimethylaminocarbonyl in position 2 or 3 is favorable for the DC-SIGN binding activity, especially in combination with fluorine, ethoxycarbonyl, or dimethylaminocarbonyl in position 7 or 8. Furthermore, we demonstrate that these quinolones can allosterically modulate the carbohydrate binding site, which offers an alternative approach toward this challenging protein target.
- Publikační typ
- časopisecké články MeSH
In this work, we report two concepts of drug delivery based on small-molecule drug conjugates with the ability of specific targeting and drug release monitoring via ratiometric fluorescence. The functionality of these concepts has been verified by two model systems consisting of three parts: (i) fluorescent aminoBODIPY for real-time detection of conjugate cleavage, (ii) a c(RGDfK) peptide specific for αvβ3 integrin receptors targeting angiogenesis in most solid tumors or redBODIPY for conjugate cleavage monitoring via FRET, and (iii) pegylated-2-phenyl-3-hydroxy-4(1H)-quinolinone (3HQ) as a model drug. The model drug release is based on a self-immolative disulfide linker sensitive to environments containing thiols, especially glutathione, which is overexpressed in cancer cells. The results show effective thiol-mediated cleavage of the fluorescent reporter and the subsequent liberation of the drug in a tube. The conjugate with c(RGDfK) was confirmed to penetrate the cells via interaction with integrin receptors. Drug release from this conjugate is possible to monitor inside the cells. Further, the synthetic approach to the conjugates and the method of fluorescence monitoring of the drug release have also been described.
- MeSH
- fluorescence MeSH
- fluorescenční barviva chemie MeSH
- glutathion metabolismus MeSH
- HeLa buňky MeSH
- hydroxychinoliny aplikace a dávkování farmakokinetika MeSH
- integrin alfaVbeta3 metabolismus MeSH
- lidé MeSH
- nosiče léků chemie farmakologie MeSH
- oligopeptidy chemie farmakologie MeSH
- sloučeniny boru chemie MeSH
- uvolňování léčiv MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We have synthesized a series of 2-phenyl-3-hydroxy-4(1H)-quinolinone derivatives substituted with one or more fluorine atoms on the quinolone backbone as well as on phenyl ring. The derivatives bearing more fluorine atoms were subjected to modification by nucleophilic substitutions by thiophenol, morpholine, and piperazine derivative. We have tested the prepared compounds in cytotoxic activity assay against cancer cell lines. Four derivatives exhibited micromolar values of IC50 against some of the cancer cell lines, and we have subjected them to cell cycle analysis on CCRF-CEM. Moreover, most active 7-fluoro-3-hydroxy-2-phenyl-6-(phenylthio)quinolin-4(1H)-one inhibits mitosis progression. Cell cycle analysis, in vitro tubulin polymerization assay, and tubulin imaging in cells indicated that the anticancer activity of thiophenol derivative is associated with its ability to inhibit microtubule formation.
- MeSH
- chinolony chemická syntéza chemie farmakologie MeSH
- halogenace MeSH
- HCT116 buňky MeSH
- lidé MeSH
- modulátory tubulinu chemická syntéza chemie farmakologie MeSH
- molekulární struktura MeSH
- polymerizace účinky léků MeSH
- tubulin metabolismus MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The village and street dogs represent a unique model of canine populations. In the absence of selective breeding and veterinary care, they are subject mostly to natural selection. Their analyses contribute to understanding general mechanisms governing the genetic diversity, evolution and adaptation. In this study, we analyzed the genetic diversity and population structure of African village dogs living in villages in three different geographical areas in Northern Kenya. Data obtained for neutral microsatellite molecular markers were compared with those computed for potentially non-neutral markers of candidate immunity-related genes. The neutral genetic diversity was similar to other comparable village dog populations studied so far. The overall genetic diversity in microsatellites was higher than the diversity of European pure breeds, but it was similar to the range of diversity observed in a group composed of many European breeds, indicating that the African population has maintained a large proportion of the genetic diversity of the canine species as a whole. Microsatellite marker diversity indicated that the entire population is subdivided into three genetically distinct, although closely related subpopulations. This genetical partitioning corresponded to their geographical separation and the observed gene flow well correlated with the communication patterns among the three localities. In contrast to neutral microsatellites, the genetic diversity in immunity-related candidate SNP markers was similar across all three subpopulations and to the European group. It seems that the genetic structure of this particular population of Kenyan village dogs is mostly determined by geographical and anthropogenic factors influencing the gene flow between various subpopulations rather than by biological factors, such as genetic contribution of original migrating populations and/or the pathogen-mediated selection. On the other hand, the study of oldest surviving dogs suggested a biological mechanism, i.e. a possible advantage of the overal heterozygosity marked by the the microsatellite loci analyzed.
- MeSH
- analýza hlavních komponent MeSH
- fenotyp MeSH
- genetická variace * MeSH
- genetické lokusy MeSH
- genetické markery MeSH
- haplotypy genetika MeSH
- heterozygot MeSH
- hlavní histokompatibilní komplex genetika MeSH
- imunita genetika MeSH
- jednonukleotidový polymorfismus genetika MeSH
- jezera MeSH
- mikrosatelitní repetice genetika MeSH
- populační genetika * MeSH
- psi genetika imunologie MeSH
- software MeSH
- zeměpis MeSH
- zvířata MeSH
- Check Tag
- psi genetika imunologie MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Evropa MeSH
- Keňa MeSH
Here, we have identified the interaction site of the contraceptive drug gamendazole using computational modeling. The drug was previously described as a ligand for eukaryotic translation elongation factor 1-α 1 (eEF1A1) and found to be a potential target site for derivatives of 2-phenyl-3-hydroxy-4(1 H)-quinolinones (3-HQs), which exhibit anticancer activity. The interaction of this class of derivatives of 3-HQs with eEF1A1 inside cancer cells was confirmed via pull-down assay. We designed and synthesized a new family of 3-HQs and subsequently applied isothermal titration calorimetry to show that these compounds strongly bind to eEF1A1. Further, we found that some of these derivatives possess significant in vitro anticancer activity.
- MeSH
- antitumorózní látky chemická syntéza farmakologie MeSH
- chinolony chemická syntéza farmakologie MeSH
- elongační faktor 1 biosyntéza účinky léků MeSH
- indazoly metabolismus MeSH
- lidé MeSH
- ligandy MeSH
- molekulární konformace MeSH
- molekulární modely MeSH
- nádorové buněčné linie MeSH
- vazebná místa účinky léků MeSH
- výpočetní biologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The proposed HPLC method using solely or nearly 100% aqueous mobile buffer as mobile phase offers fast determination of dissociation constant for compounds in relatively wide range of lipophilicity (log P from -2.26 to 2.26). The dissociation constant value for simpler chemical compounds can be determined via only 8 chromatographic runs. The number of needed chromatographic separations depends on the structural complexity of the tested compound. Moreover, the proposed method does not require a measurement of Yasuda-Shedlovsky extrapolation that includes several pKa determinations in solutions with different methanol content which speeds up considerably the procedure. The methodology is suitable for evaluation of large series of drug candidates, which can be present as complex mixtures and in small amounts.
2-Aminoquinolin-4(1H)-one was reacted with various primary/secondary amines and paraformaldehyde under Mannich reaction conditions. In the case of secondary amines, the reaction in N,N-dimethylformamide yielded expected Mannich products accompanied with 3,3'-methylenebis(2-aminoquinolin-4(1H)-one). Except these main products, the pyrimido[4,5-b]quinolin-5-one derivative was also identified as co-product. The reaction with primary amines led to the formation of pyrimido[4,5-b]quinolin-5-ones. The Mannich reaction products were thermally unstable and afforded a mixture of bis-(2-aminoquinolin-4(1H)-one) and tris-(2-aminoquinolin-4(1H)-one) derivative, probably via reactive methylene species. This retro-Mannich reaction was tested in reaction with indole and thiophenole as nucleophilles, and appropriate conjugates were formed. The mechanism of above discussed reactions in which 2-aminoquinolinone displays the nucleophilicity on C3 carbon as well as N2 nitrogen is discussed.
- MeSH
- aminochinoliny chemie MeSH
- Mannichovy báze chemie MeSH
- Publikační typ
- časopisecké články MeSH
Derivatives of 3-methyl-3,6-dihydro-2H-1,2-oxazine-6-carboxylic acid prepared by regioselective hetero Diels-Alder reaction of arylnitroso compounds with sorbic acid were used for solid-phase synthesis of a library of derivatives that included modification of carboxylic group, dihydroxylation of double bond and cleavage of N-O bond. Derivatives of 2,3,4-trihydroxyhexanoic acid obtained from 3,6-dihydro-2H-1,2-oxazines after double bond dihydroxylation and N-O cleavage were used for simple and stereoselective formation of chiral lactones derived from 3,4-dihydroxydihydrofuran-2(3H)-one. The final compounds obtained as a mixture of stereoisomers were analyzed with use of chiral HPLC and SFC. HPLC analyses were not successful for all derivatives or required lengthy chromatography. On the other hand SFC afforded much shorter analyses and was effective for all studied derivatives. The method of synthesis and analysis is thus suitable for future study of stereoselective synthesis of lactones and other derivatives from single oxazine derivatives and application of high-throughput synthesis on solid-support and combinatorial chemistry.
- MeSH
- cykloadiční reakce MeSH
- hmotnostní spektrometrie MeSH
- laktony chemická syntéza chemie MeSH
- magnetická rezonanční spektroskopie MeSH
- oxaziny chemická syntéza chemie MeSH
- stereoizomerie MeSH
- techniky syntézy na pevné fázi MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- Publikační typ
- časopisecké články MeSH
