- MeSH
- aminoglykosidy aplikace a dávkování škodlivé účinky MeSH
- antibakteriální látky * aplikace a dávkování klasifikace škodlivé účinky MeSH
- endokarditida * etiologie farmakoterapie komplikace patofyziologie MeSH
- gramnegativní bakterie patogenita MeSH
- lidé MeSH
- rifampin aplikace a dávkování MeSH
- vankomycin aplikace a dávkování škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- směrnice pro lékařskou praxi MeSH
Physiology-based pharmacokinetic modeling suggests that rifabutin can out-balance P-glycoprotein (P-gp) induction by concurrent P-gp inhibition. However, clinical or experimental evidence for this Janus-faced rifabutin effect is missing. Consequently, LS180 cells were exposed to a moderately (2 μM) and strongly (10 μM) P-gp-inducing concentration of rifampicin or rifabutin for 6 days. Cellular accumulation of the fluorescent P-gp substrate rhodamine 123 was evaluated using flow cytometry, either without (induction only) or with adding rifamycin drug to the cells during the rhodamine 123 efflux phase (induction + potential inhibition). Rhodamine 123 accumulation was decreased similarly by both drugs after 6-day exposure (2 μM: 55% residual fluorescence compared to non-induced cells, P < 0.01; 10 μM: 30% residual fluorescence compared to non-induced cells, P < 0.001), indicating P-gp induction. Rhodamine 123 influx transporters mRNA expressions were not affected, excluding off-target effects. Acute re-exposure to rifabutin, however, considerably re-increased rhodamine 123 accumulation (2 μM induction: re-increase by 55%, P < 0.01; 10 μM induction: 49% re-increase, P < 0.001), suggesting P-gp inhibition. In contrast, rifampicin only had weak effects (2 μM induction: no re-increase; 10 μM induction: 16% re-increase; P < 0.05). Molecular docking analysis eventually revealed that rifabutin has a higher binding affinity to the inhibitor binding site of P-gp than rifampicin (ΔG (kcal/mol) = -11.5 vs -5.3). Together, this study demonstrates that rifabutin can at least partly mask P-gp induction by P-gp inhibition, mediated by high affinity binding to the inhibitory site of P-gp.
Rifampicin is a model ligand of the pregnane X receptor (PXR), the nuclear receptor involved in the regulation of cytochrome P450 3A4 (CYP3A4). Rifampicin forms several degradation products and metabolites of which 25-desacetylrifampicin is the most abundant in vivo. Here, we aimed to study both the stability and metabolism of rifampicin in media and 2D and 3D primary human hepatocytes (PHHs). Additionally, we analyzed interactions of rifampicin derivatives with PXR. We described that rifampicin gradually degrades by more than 50 % in the medium partly into quinone over 72 h. We observed 25-desacetylrifampicin in 2D PHHs but not in 3D PHHs. Contrary, rifampicin was converted into quinone in a one-direction process in media of 3D PHHs. The potency of rifampicin and its derivatives to activate human PXR was arranged as follows: 3-formylrifamycin SV > rifampicin quinone > rifampicin > rifampicin N-oxide > 25-desacetylrifampicin, respectively, but none activates mouse and rat PXR. The binding differences between rifampicin and 25-desacetylrifampicin were modeled in silico. Finally, we showed that overexpressed uptake organic anion transporting polypeptide 1B1 (OATP1B1) potentiated activation of PXR by rifampicin and rifampicin quinone, but overexpressed efflux multidrug resistance protein 1 (MDR1) decreased PXR activation by all derivatives.
- MeSH
- cytochrom P-450 CYP3A metabolismus MeSH
- hepatocyty * metabolismus MeSH
- kultivované buňky MeSH
- lidé MeSH
- myši MeSH
- pregnanový X receptor * metabolismus MeSH
- rifampin * farmakologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- antituberkulotika * terapeutické užití farmakologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti * MeSH
- multirezistentní tuberkulóza * farmakoterapie diagnóza mikrobiologie MeSH
- Mycobacterium tuberculosis účinky léků genetika MeSH
- rifampin * terapeutické užití farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
- komentáře MeSH
- Geografické názvy
- Evropa MeSH
x
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- MeSH
- amoxicilin aplikace a dávkování terapeutické užití MeSH
- antibakteriální látky terapeutické užití MeSH
- debridement metody MeSH
- infekce spojené s protézou * chirurgie terapie MeSH
- klindamycin aplikace a dávkování terapeutické užití MeSH
- lidé MeSH
- replantace metody MeSH
- rifampin aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- senioři MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
The elimination of most drugs based on liver/renal excretion; making liver and kidneys the commonest target organ for exposure to toxic materials. Long-term use of drugs surpassed the effect and aggravate the toxicity. Tuberculosis (TB) is chronic disease with long-term therapy and the deleterious impact of antitubelculosis is certain. Various pharmacokinetic manoveuors were proposed to avoid the potential harmful effect of TB therapy. The present study aimed at mitigating the destructive effects of TB therapy using propolis. To do so, rats were exposed to isoniazid or rifampicin or a combination of them in groups of 8 rats each for a period of 8-weeks these groups were matched with similar group with a propolis ad-on therapy. These results were compared to propolis-free negative control group and positive propolis-treated group. The histological and laboratory findings confirmed that isoniazid or rifampicin or a combination of them jeopardized hepatorenal function and induced deleterious damage. However, isoniazid has shown more intensive deleterious effect compared to rifampicin. Nonetheless, propolis restore the quasi-equilibrium status for kidney and liver via restoring its normal architecture and functionality. To sum up, the potential defect of anti-TB was restored via using propolis as add-on therapy, we do advise using propolis as an adjuvant TB therapy in critically-ill and clinical cases required long-term TB therapy.
- MeSH
- antituberkulotika antagonisté a inhibitory škodlivé účinky MeSH
- biochemická analýza krve metody přístrojové vybavení MeSH
- biomedicínský výzkum MeSH
- histologické techniky MeSH
- isoniazid antagonisté a inhibitory škodlivé účinky MeSH
- krysa rodu rattus * MeSH
- mikroskopie MeSH
- modely u zvířat MeSH
- nemoci jater prevence a kontrola MeSH
- nemoci ledvin prevence a kontrola MeSH
- nežádoucí účinky léčiv farmakoterapie terapie MeSH
- propolis * farmakologie MeSH
- rifampin antagonisté a inhibitory škodlivé účinky MeSH
- Check Tag
- krysa rodu rattus * MeSH
- Geografické názvy
- Irák MeSH
Rifampicin is a clinically important antibiotic that binds to, and blocks the DNA/RNA channel of bacterial RNA polymerase (RNAP). Stalled, nonfunctional RNAPs can be removed from DNA by HelD proteins; this is important for maintenance of genome integrity. Recently, it was reported that HelD proteins from high G+C Actinobacteria, called HelR, are able to dissociate rifampicin-stalled RNAPs from DNA and provide rifampicin resistance. This is achieved by the ability of HelR proteins to dissociate rifampicin from RNAP. The HelR-mediated mechanism of rifampicin resistance is discussed here, and the roles of HelD/HelR in the transcriptional cycle are outlined. Moreover, the possibility that the structurally similar HelD proteins from low G+C Firmicutes may be also involved in rifampicin resistance is explored. Finally, the discovery of the involvement of HelR in rifampicin resistance provides a blueprint for analogous studies to reveal novel mechanisms of bacterial antibiotic resistance.
- MeSH
- antituberkulózní antibiotika aplikace a dávkování terapeutické užití MeSH
- atypické mykobakteriální infekce * diagnóza farmakoterapie přenos MeSH
- hypotyreóza chemicky indukované MeSH
- lékové interakce MeSH
- lidé středního věku MeSH
- lidé MeSH
- Mycobacterium marinum patogenita MeSH
- nemoci ryb přenos MeSH
- poranění prstů ruky patologie MeSH
- rifampin aplikace a dávkování terapeutické užití MeSH
- thyroxin aplikace a dávkování terapeutické užití MeSH
- zoonózy MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
The emergence and spread of resistant tuberculosis (TB) pose a threat to public health, so it is necessary to diagnose the drug-resistant forms in a clinically short time frame and closely monitor their transmission. In this study, we carried out a first whole genome sequencing (WGS)-based analysis of multidrug resistant (MDR) M. tuberculosis strains to explore the phylogenetic lineages diversity, drug resistance mechanisms, and ongoing transmission chains within the country. In total, 65 isolates phenotypically resistant to at least rifampicin and isoniazid collected in the Czech Republic in 2005-2020 were enrolled for further analysis. The agreement of the results obtained by WGS with phenotypic drug susceptibility testing (pDST) in the determination of resistance to isoniazid, rifampicin, pyrazinamide, streptomycin, second-line injectables and fluoroquinolones was more than 80%. Phylogenetic analysis of WGS data revealed that the majority of MDR M. tuberculosis isolates were the Beijing lineage 2.2.1 (n = 46/65; 70.8%), while the remaining strains belonged to Euro-American lineage. Cluster analysis with a predefined cut-off distance of less than 12 single nucleotide polymorphisms between isolates showed 19 isolates in 6 clusters (clustering rate 29.2%), located mainly in the region of the capital city of Prague. This study highlights the utility of WGS as a high-resolution approach in the diagnosis, characterization of resistance patterns, and molecular-epidemiological analysis of resistant TB in the country.
- MeSH
- antituberkulotika farmakologie terapeutické užití MeSH
- fylogeneze MeSH
- genotyp MeSH
- isoniazid MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- mnohočetná bakteriální léková rezistence genetika MeSH
- multirezistentní tuberkulóza * diagnóza farmakoterapie epidemiologie MeSH
- mutace MeSH
- Mycobacterium tuberculosis * MeSH
- rifampin MeSH
- sekvenování celého genomu metody MeSH
- tuberkulóza * farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
The design of improved biopolymeric based hydrogel materials with high load-capacity to serve as biocompatible drug carriers is a challenging task with vital implications in health sciences. In this work, chitosan crosslinked dialdehyde xanthan gum interpenetrated hydroxypropyl methylcellulose gels were developed for the controlled delivery of different antibiotic drugs including ampicillin, minocycline and rifampicin. The prepared hydrogel scaffolds were characterized by rheology method, FTIR, SEM, TGA and compression analysis. In addition, gelation kinetics, swelling, in vitro degradation and drug release rate were studied under simulated gastrointestinal fluid conditions of pH 2.0 and 7.4 at 37 °C. Results demonstrated the gel composition and structure affected drug release kinetics. The release study showed more than 50% cumulative release within 24 h for all investigated antibiotic drugs. In vitro cell cytocompatibility using mouse embryonic fibroblast cell lines depicted ≥80% cell viability, indicating the gels are non-toxic. Finally, the antibacterial activity of loaded gels was evaluated against Gram-negative and positive bacteria (Escherichia coli, Staphylococcus aureus and Klebsiella pneumonia), which correlated well with swelling and drug release results. Overall, the present study demonstrated that the produced hydrogel scaffolds serves as promising material for controlled antibiotic delivery towards microbial growth inhibition.
- MeSH
- ampicilin farmakologie MeSH
- antibakteriální látky farmakologie MeSH
- bakteriální polysacharidy chemie MeSH
- biokompatibilní materiály chemie MeSH
- buněčné linie MeSH
- chitosan chemie MeSH
- deriváty hypromelózy chemie MeSH
- Escherichia coli účinky léků MeSH
- fibroblasty MeSH
- hydrogely chemická syntéza chemie farmakokinetika toxicita MeSH
- koncentrace vodíkových iontů MeSH
- mikrobiální testy citlivosti MeSH
- mikroskopie elektronová rastrovací MeSH
- minocyklin farmakologie MeSH
- myši MeSH
- nosiče léků chemie MeSH
- reologie MeSH
- rifampin farmakologie MeSH
- spektroskopie infračervená s Fourierovou transformací MeSH
- Staphylococcus aureus účinky léků MeSH
- termogravimetrie MeSH
- uvolňování léčiv MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
