The pregnane X receptor (PXR) is a ligand-activated nuclear receptor controlling hepatocyte expression of numerous genes. Although expression changes in xenobiotic-metabolizing, lipogenic, gluconeogenic and bile acid synthetic genes have been described after PXR activation, the temporal dynamics of their expression is largely unknown. Recently, 3D spheroids of primary human hepatocytes (PHHs) have been characterized as the most phenotypically relevant hepatocyte model. We used 3D PHHs to assess time-dependent expression profiles of 12 prototypic PXR-controlled genes in the time course of 168 h of rifampicin treatment (1 or 10 μM). We observed a similar bell-shaped time-induction pattern for xenobiotic-handling genes (CYP3A4, CYP2C9, CYP2B6, and MDR1). However, we observed either biphasic profiles for genes involved in endogenous metabolism (FASN, GLUT2, G6PC, PCK1, and CYP7A1), a decrease for SHP or oscillation for PDK4 and PXR. The rifampicin concentration determined the expression profiles for some genes. Moreover, we calculated half-lives of CYP3A4 and CYP2C9 mRNA under induced or basal conditions and we used a mathematical model to describe PXR-mediated regulation of CYP3A4 expression employing 3D PHHs. The study shows the importance of long-term time-expression profiling of PXR target genes in phenotypically stable 3D PHHs and provides insight into PXR function in liver beyond our knowledge from conventional 2D in vitro models.
Flowability is among the most important properties of powders, especially when fine particle size fractions need to be processed. In this study, our goal was to find a possibly simple but accurate mathematical model for predicting the mass flow rate for different fractions of the pharmaceutical excipient sorbitol for direct compression. Various regression models derived from the Jones-Pilpel equation for the prediction of the mass flow rate were investigated. Using validation with experimental data for various particle and hopper orifice sizes, we focused on the prediction accuracy of the respective models, i.e., on the relative difference between measured and model-predicted values. Classical indicators of regression quality from statistics were addressed as well, but we consider high prediction accuracy to be particularly important for industrial processing in practice. For individual particle size fractions, the best results (an average prediction accuracy of 3.8%) were obtained using simple regression on orifice size. However, for higher accuracy (3.1%) in a unifying model, valid in the broad particle size range 0.100-0.346 mm, a fully quadratic model, incorporating interaction between particle and orifice size, appears to be most appropriate.
- Publikační typ
- časopisecké články MeSH
Spontaneous preterm birth is a serious medical condition responsible for substantial perinatal morbidity and mortality. Its phenotypic characteristics, preterm labor with intact membranes (PTL) and preterm premature rupture of the membranes (PPROM), are associated with significantly increased risks of neurological and behavioral alterations in childhood and later life. Recognizing the inflammatory milieu associated with PTL and PPROM, here, we examined expression signatures of placental tryptophan metabolism, an important pathway in prenatal brain development and immunotolerance. The study was performed in a well-characterized clinical cohort of healthy term pregnancies (n = 39) and 167 preterm deliveries (PTL, n = 38 and PPROM, n = 129). Within the preterm group, we then investigated potential mechanistic links between differential placental tryptophan pathway expression, preterm birth and both intra-amniotic markers (such as amniotic fluid interleukin-6) and maternal inflammatory markers (such as maternal serum C-reactive protein and white blood cell count). We show that preterm birth is associated with significant changes in placental tryptophan metabolism. Multifactorial analysis revealed similarities in expression patterns associated with multiple phenotypes of preterm delivery. Subsequent correlation computations and mediation analyses identified links between intra-amniotic and maternal inflammatory markers and placental serotonin and kynurenine pathways of tryptophan catabolism. Collectively, the findings suggest that a hostile inflammatory environment associated with preterm delivery underlies the mechanisms affecting placental endocrine/transport functions and may contribute to disruption of developmental programming of the fetal brain.
- MeSH
- biologické markery MeSH
- lidé MeSH
- metabolické sítě a dráhy MeSH
- náchylnost k nemoci MeSH
- placenta metabolismus MeSH
- předčasný porod diagnóza etiologie metabolismus MeSH
- regulace genové exprese MeSH
- rizikové faktory MeSH
- stanovení celkové genové exprese MeSH
- těhotenství MeSH
- transkriptom * MeSH
- tryptofan metabolismus MeSH
- výpočetní biologie metody MeSH
- výsledek těhotenství MeSH
- zánět komplikace etiologie MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Albeit the preparation of liquisolid systems represents an innovative approach to enhance the dissolution of poorly soluble drugs, their broader utilization is still limited mainly due to the problematic conversion of the liquid into freely flowing and readily compressible powder. Accordingly, the presented study aims to determine the optimal carrier/coating material ratio (R value) for formulations based on magnesium aluminometasilicate (NUS2) loaded with polyethylene glycol 400. Four commercially available colloidal silica were used as coating materials in nine different R values (range of 5 - 100). The obtained results suggested that the higher R value leads to the superior properties of powder mixtures, such as better flowability, as well as compacts with higher tensile strength and lower friability. Moreover, it was observed that the type of coating material impacts the properties of liquisolid systems due to the different arrangement of particles in the liquisolid mixture. To confirm the noted dependency of R value and coating material type, the one- and two-way ANOVA, linear regression and principal component analysis (PCA) techniques were performed. In addition, a comparison of results with the properties of loaded NUS2 itself revealed that LSS with sufficient properties may be prepared even without the coating material.
- MeSH
- hořčík * MeSH
- oxid křemičitý * MeSH
- prášky, zásypy, pudry MeSH
- příprava léků MeSH
- rozpustnost MeSH
- tablety MeSH
- Publikační typ
- časopisecké články MeSH
Aim: We studied the influence of coffee consumption on the therapeutic effect of methotrexate (MTX) in patients with rheumatoid arthritis (RA) sorted according to ADORA2A genotypes. Patients & methods: 82 RA patients were dichotomized according to caffeine intake with a threshold of 700 mg/week. Disease activity score 28 (DAS28) was applied (>3.2: high; <3.2: low or remission). Patients were genotyped using quantitative PCR allelic discrimination. Results: We found significantly higher risk of RA in patients with higher caffeine intake and the CT genotype of ADOARA2A rs2298383, rs3761422 and rs2267076 SNPs. The CC genotype of ADORA2A rs2236624 SNP in patients with lower caffeine intake treated with MTX is significantly protective. Conclusion:ADORA2A genotypes and coffee intake influence risk of RA and efficacy of it MTX treatment.
- MeSH
- adenosin genetika metabolismus MeSH
- antirevmatika metabolismus terapeutické užití MeSH
- dospělí MeSH
- jednonukleotidový polymorfismus genetika MeSH
- káva škodlivé účinky metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- methotrexát metabolismus terapeutické užití MeSH
- průřezové studie MeSH
- receptor adenosinový A2A genetika MeSH
- revmatoidní artritida farmakoterapie genetika metabolismus MeSH
- signální transdukce účinky léků fyziologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
This pilot prospective study verified the hypothesis that use of computer-assisted therapeutic drug monitoring of aminoglycosides by pharmacists leads to better safety therapeutic outcomes and cost avoidance than only concentration measurement and dose adjustments based on a physician's experience. Two groups of patients were enrolled according to the technique of monitoring. Patients (Group 1, n=52) underwent monitoring by a pharmacist using pharmacokinetic software. In a control group (Group 2, n=11), plasma levels were measured but not interpreted by the pharmacist, only by physicians. No statistically significant differences were found between the groups in factors influenced by therapy. However, the results are not statistically significant but a comparison of the groups showed a clear trend towards safety and cost avoidance, thus supporting therapeutic drug monitoring. Safety limits were achieved in 76 % and 63 % of cases in Groups 1 and 2, respectively. More patients achieved both concentrations (peak and trough) with falling eGFR in Group 1. In present pilot study, the pharmacist improved the care of patients on aminoglycoside therapy. A larger study is needed to demonstrate statistically significantly improved safety and cost avoidance of aminoglycoside therapy monitoring by the pharmacist using pharmacokinetic software.
- MeSH
- amikacin aplikace a dávkování MeSH
- aminoglykosidy aplikace a dávkování škodlivé účinky farmakokinetika MeSH
- antibakteriální látky aplikace a dávkování MeSH
- bezpečnost MeSH
- farmaceuti * MeSH
- gentamiciny aplikace a dávkování MeSH
- lidé středního věku MeSH
- lidé MeSH
- monitorování léčiv ekonomika metody MeSH
- náklady a analýza nákladů MeSH
- nemoci ledvin chemicky indukované MeSH
- pilotní projekty MeSH
- počítačová farmakoterapie metody MeSH
- prospektivní studie MeSH
- senioři MeSH
- výpočet dávky léku * MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
The pregnane X receptor (PXR) is a drug/xenobiotic-activated transcription factor of crucial importance for major cytochrome P450 xenobiotic-metabolizing enzymes (CYP) expression and regulation in the liver and the intestine. One of the major target genes regulated by PXR is the cytochrome P450 enzyme (CYP3A4), which is the most important human drug-metabolizing enzyme. In addition, PXR is supposed to be involved both in basal and/or inducible expression of many other CYPs, such as CYP2B6, CYP2C8, 2C9 and 2C19, CYP3A5, CYP3A7, and CYP2A6. Interestingly, the dynamics of PXR-mediated target genes regulation has not been systematically studied and we have only a few mechanistic mathematical and biologically based models describing gene expression dynamics after PXR activation in cellular models. Furthermore, few indirect mathematical PKPD models for prediction of CYP3A metabolic activity in vivo have been built based on compartmental models with respect to drug⁻drug interactions or hormonal crosstalk. Importantly, several negative feedback loops have been described in PXR regulation. Although current mathematical models propose these adaptive mechanisms, a comprehensive mathematical model based on sufficient experimental data is still missing. In the current review, we summarize and compare these models and address some issues that should be considered for the improvement of PXR-mediated gene regulation modelling as well as for our better understanding of the quantitative and spatial dynamics of CYPs expression.
- MeSH
- genové regulační sítě * MeSH
- lidé MeSH
- pregnanový X receptor MeSH
- steroidní receptory genetika metabolismus MeSH
- systém (enzymů) cytochromů P-450 genetika metabolismus MeSH
- teoretické modely * MeSH
- zpětná vazba fyziologická MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND AND AIMS: Increased plasma levels of soluble endoglin (sEng) were detected in patients with endothelial dysfunction-related disorders and hypercholesterolemia. In this study, we hypothesized that high levels of sEng accompanied by mild hypercholesterolemia could aggravate endothelial and vessel wall dysfunction and affect endoglin/eNOS signaling in mouse aorta. METHODS: Three-month-old female transgenic mice on CBAxC57BL/6J background, with high levels of sEng (Sol-Eng+high HFD), and their littermates with low levels of sEng (Sol-Eng+low HFD), were fed a high fat diet for six months. Plasma samples were used for biochemical, ELISA and Luminex analyses of total cholesterol, sEng and inflammatory markers. Functional parameters of aorta were assessed with wire myograph 620M. Western blot analyses of membrane endoglin/eNOS signaling and endothelial dysfunction/inflammation markers in aorta were performed. RESULTS: Functional analysis of aorta showed impaired KCl induced vasoconstriction, endothelial-dependent relaxation after the administration of acetylcholine as well as endothelial-independent relaxation induced by sodium nitroprusside in the Sol-Eng+high HFD group compared to the Sol-Eng+low HFD group. Ach-induced vasodilation after administration of l-NAME was significantly higher in the Sol-Eng+high HFD group compared to the Sol-Eng+low HFD group. The expression of endoglin, p-eNOS/eNOS, pSmad2/3/Smad2/3 signaling pathway was significantly lower in the Sol-Eng+high HFD group compared to the Sol-Eng+low HFD group. CONCLUSIONS: The results indicate that long-term hypercholesterolemia combined with high levels of sEng leads to the aggravation of endothelial and vessel wall dysfunction in aorta, with possible alterations of the membrane endoglin/eNOS signaling, suggesting that high levels of soluble endoglin might be considered as a risk factor of cardiovascular diseases.
- MeSH
- aorta metabolismus patologie patofyziologie MeSH
- ateroskleróza genetika metabolismus patologie patofyziologie MeSH
- cévní endotel metabolismus patologie patofyziologie MeSH
- dieta s vysokým obsahem tuků MeSH
- endoglin genetika metabolismus MeSH
- fosforylace MeSH
- hypercholesterolemie komplikace etiologie MeSH
- lidé MeSH
- mediátory zánětu metabolismus MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši inbrední CBA MeSH
- myši transgenní MeSH
- nemoci aorty genetika metabolismus patologie patofyziologie MeSH
- protein Smad2 metabolismus MeSH
- protein Smad3 metabolismus MeSH
- signální transdukce MeSH
- synthasa oxidu dusnatého, typ III metabolismus MeSH
- upregulace MeSH
- vazodilatace MeSH
- vazokonstrikce MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Non-prescription access to antimicrobials is common, and self-prescribing is increasingly popular in Russian society. The aim of this study was to assess the attitudes of community pharmacists regarding antibiotic use and self-medication. METHODS: We conducted a cross-sectional study from September-December 2015 of community pharmacists in the Saint-Petersburg and Leningrad region, Russia. A self-administered questionnaire was used to assess antibiotic use and self-medication practices. The data were analysed using logistic regression and Pearson chi-squared tests. RESULTS: Of the 316 pharmacists (77.07%) who completed the questionnaire, 230 (72.8%) self-medicated with antibiotics. Antibiotics were mostly used to self-treat upper (53.3%) and lower respiratory tract infections (19.3%), relying on their own knowledge (81.5%), previous treatment experience (49%) and patients' prescriptions (17%). The most commonly used antibiotics were macrolides (33.2%). Characteristics such as age, education and experience were related to antibiotic use and self-medication. CONCLUSIONS: The study confirmed that self-prescription of antibiotics is a common practice amongst pharmacists in Saint Petersburg and also identified personal and professional characteristics of pharmacists strongly associated with self-medication.
- MeSH
- antibakteriální látky aplikace a dávkování MeSH
- dospělí MeSH
- farmaceuti psychologie normy trendy MeSH
- lékárny normy trendy MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- postoj zdravotnického personálu * MeSH
- průřezové studie MeSH
- samoléčba psychologie normy trendy MeSH
- zpráva o sobě MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Rusko epidemiologie MeSH
