V článku je popsán současný vývoj mikrochirurgických operačních technik mikrochirurgické operace varikokély a mikrochirurgického odběru zárodečné tkáně z varlat (microTESE). U operace varikokély přinesl vývoj peroperační mikrovaskulární Dopplerovskou diagnostiku, trojrozměrné zvětšení a bezesvorkovou metodu ligatury spermatických žil při prezervaci spermatických arterií. U microTESE je přínosem možnost předoperační triplexní mikrovaskulární Dopplerovské diagnostiky, hydrodisekce kanálků testis a vysoké zvětšení ("high power") kanálků in vivo s možností mikrometrie kanálků, selekce odběru kanálků s vyšší pravděpodobností přítomnosti spermií a vysoký stupeň ochrany ostatní tkáně testis. Postupy jsou demonstrovány ve fotodokumentaci.
The article deals with the recent developments in microsurgical techniques for microscopic varicocele surgery and microdissection testicular sperm extraction (microTESE). In varicocele surgery, recent developments have led to intraoperative microvascular Doppler diagnosis, three-dimensional magnification, and clipless ligation of the spermatic veins with preservation of the spermatic arteries. In microTESE, the benefits include preoperative triplex microvascular Doppler diagnosis, hydrodissection of testicular tubules and high magnification of the tubules in vivo with possible micrometry of the tubules, selection of tubule collection sites with a greater likelihood of sperm presence, and a high degree of protection of surrounding testicular tissue. The procedures are demonstrated in the photo documentation.
- Klíčová slova
- mikrovaskulární Doppler, micro TESE, hydrodisekce, optoelektronická mikrometrie kanálků testes,
- MeSH
- lidé MeSH
- ligace metody MeSH
- mikrochirurgie * metody MeSH
- varikokéla * chirurgie MeSH
- zobrazování trojrozměrné MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- komentáře MeSH
Tuberculosis remains a serious killer among infectious diseases due to its incidence, mortality, and occurrence of resistant mycobacterial strains. The challenge to discover new antimycobacterial agents forced us to prepare a series of N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)(hetero)aryl-2-carboxamides 1-19 via the acylation of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol with various activated (hetero)arylcarboxylic acids. These novel compounds have been tested in vitro against a panel of clinically important fungi and bacteria, including mycobacteria. Some of the compounds inhibited the growth of mycobacteria in the range of micromolar concentrations and retained this activity also against multidrug-resistant clinical isolates. Half the maximal inhibitory concentrations against the HepG2 cell line indicated an acceptable toxicological profile. No growth inhibition of other bacteria and fungi demonstrated selectivity of the compounds against mycobacteria. The structure-activity relationships have been derived and supported with a molecular docking study, which confirmed a selectivity toward the potential target leucyl-tRNA synthetase without an impact on the human enzyme. The presented compounds can become important materials in antimycobacterial research.
- MeSH
- amidy chemie farmakologie MeSH
- aminoacyl-tRNA-synthetasy * MeSH
- antibakteriální látky farmakologie MeSH
- antiinfekční látky * farmakologie MeSH
- antituberkulotika farmakologie MeSH
- houby MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium tuberculosis * MeSH
- simulace molekulového dockingu MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb), each year causing millions of deaths. In this article, we present the synthesis and biological evaluations of new potential antimycobacterial compounds containing a fragment of the first-line antitubercular drug pyrazinamide (PZA), coupled with methyl or ethyl esters of selected amino acids. The antimicrobial activity was evaluated on a variety of (myco)bacterial strains, including Mtb H37Ra, M. smegmatis, M. aurum, Staphylococcus aureus, Pseudomonas aeruginosa, and fungal strains, including Candida albicans and Aspergillus flavus. Emphasis was placed on the comparison of enantiomer activities. None of the synthesized compounds showed any significant activity against fungal strains, and their antibacterial activities were also low, the best minimum inhibitory concentration (MIC) value was 31.25 μM. However, several compounds presented high activity against Mtb. Overall, higher activity was seen in derivatives containing ʟ-amino acids. Similarly, the activity seems tied to the more lipophilic compounds. The most active derivative contained phenylglycine moiety (PC-ᴅ/ʟ-Pgl-Me, MIC < 1.95 μg/mL). All active compounds possessed low cytotoxicity and good selectivity towards Mtb. To the best of our knowledge, this is the first study comparing the activities of the ᴅ- and ʟ-amino acid derivatives of pyrazinamide as potential antimycobacterial compounds.
- MeSH
- aminokyseliny chemie farmakologie MeSH
- antibakteriální látky farmakologie MeSH
- antituberkulotika farmakologie MeSH
- Aspergillus flavus účinky léků MeSH
- buňky Hep G2 MeSH
- Candida albicans účinky léků MeSH
- chromatografie kapalinová MeSH
- koncentrace vodíkových iontů MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium smegmatis účinky léků MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- optická otáčivost MeSH
- plynová chromatografie s hmotnostně spektrometrickou detekcí MeSH
- Pseudomonas aeruginosa účinky léků MeSH
- pyrazinamid chemie farmakologie MeSH
- Staphylococcus aureus účinky léků MeSH
- tuberkulóza farmakoterapie MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
We prepared a series of substituted N-(pyrazin-2-yl)benzenesulfonamides as an attempt to investigate the effect of different linkers connecting pyrazine to benzene cores on antimicrobial activity when compared to our previous compounds of amide or retro-amide linker type. Only two compounds, 4-amino-N-(pyrazin-2-yl)benzenesulfonamide (MIC = 6.25 μg/mL, 25 μM) and 4-amino-N-(6-chloropyrazin-2-yl)benzenesulfonamide (MIC = 6.25 μg/mL, 22 μM) exerted good antitubercular activity against M. tuberculosis H37Rv. However, they were excluded from the comparison as they-unlike the other compounds-possessed the pharmacophore for the inhibition of folate pathway, which was proven by docking studies. We performed target fishing, where we identified matrix metalloproteinase-8 as a promising target for our title compounds that is worth future exploration.
- MeSH
- antiinfekční látky chemická syntéza chemie farmakologie MeSH
- antituberkulotika chemická syntéza chemie farmakologie MeSH
- chemické jevy MeSH
- mikrobiální testy citlivosti MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- sulfonamidy chemická syntéza chemie farmakologie MeSH
- techniky syntetické chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
Flubendazole (FLU), an anthelmintic drug of benzimidazole type, is now considered a promising anti-cancer agent due to its tubulin binding ability and low system toxicity. The present study was aimed at determining more information about FLU reduction in human liver, because this information has been insufficient until now. Subcellular fractions from the liver of 12 human patients (6 male and 6 female patients) were used to study the stereospecificity, cellular localization, coenzyme preference, enzyme kinetics, and possible inter-individual or sex differences in FLU reduction. In addition, the risk of FLU interaction with other drugs was evaluated. Our study showed that FLU is predominantly reduced in cytosol, and the reduced nicotinamide adenine dinucleotide phosphate (NADPH) coenzyme is preferred. The strict stereospecificity of FLU carbonyl reduction was proven, and carbonyl reductase 1 was identified as the main enzyme of FLU reduction in the human liver. A higher reduction of FLU and a higher level of carbonyl reductase 1 protein were found in male patients than in female patients, but overall inter-individual variability was relatively low. Hepatic intrinsic clearance of FLU is very low, and FLU had no effect on doxorubicin carbonyl reduction in the liver and in cancer cells. All these results fill the gaps in the knowledge of FLU metabolism in human.
- Publikační typ
- časopisecké články MeSH
We report the design, synthesis, and in vitro antimicrobial activity of a series of N-substituted 3-aminopyrazine-2-carboxamides with free amino groups in position 3 on the pyrazine ring. Based on various substituents on the carboxamidic moiety, the series is subdivided into benzyl, alkyl, and phenyl derivatives. The three-dimensional structures of the title compounds were predicted using energy minimization and low mode molecular dynamics under AMBER10:EHT forcefield. Compounds were evaluated for antimycobacterial, antibacterial, and antifungal activities in vitro. The most active compound against Mycobacterium tuberculosis H37Rv (Mtb) was 3-amino-N-(2,4-dimethoxyphenyl)pyrazine-2-carboxamide (17, MIC = 12.5 μg/mL, 46 μM). Antimycobacterial activity against Mtb and M. kansasii along with antibacterial activity increased among the alkyl derivatives with increasing the length of carbon side chain. Antibacterial activity was observed for phenyl and alkyl derivatives, but not for benzyl derivatives. Antifungal activity was observed in all structural subtypes, mainly against Trichophyton interdigitale and Candida albicans. The four most active compounds (compounds 10, 16, 17, 20) were evaluated for their in vitro cytotoxicity in HepG2 cancer cell line; only compound 20 was found to exert some level of cytotoxicity. Compounds belonging to the current series were compared to previously published, structurally related compounds in terms of antimicrobial activity to draw structure activity relationships conclusions.
- MeSH
- antibakteriální látky chemická syntéza chemie farmakologie MeSH
- antifungální látky farmakologie MeSH
- Bacteria účinky léků MeSH
- buněčná smrt účinky léků MeSH
- buňky Hep G2 MeSH
- houby účinky léků MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- molekulární konformace MeSH
- pyraziny chemická syntéza chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
