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991.
Appolonova SA Baranov PA Mesonzhnik NV Brazhnikova DO Rodchenkov GM 《Drug testing and analysis》2011,3(10):717-723
A method is described for the determination of mesocarb abuse in equestrian sport by combining gradient liquid chromatography and electrospray ionization tandem mass spectrometry. Mesocarb was administrated orally to two horses at a dose of 50 µg/kg. Urine samples were collected up to 120 h post administration. Hydrolyzed and conjugated urine fractions were handled using liquid‐liquid extraction (LLE). The identity of the parent drug and metabolites was confirmed using liquid chromatography combined with tandem mass spectrometry (MS/MS). Mesocarb and seven metabolites were detected in horse urine. Mono‐ and two di‐hydroxylated metabolites were the main metabolites observed in horse urine samples. Based on the differences in MS/MS spectra it was supposed that these metabolites were been formed by the hydroxylation of the phenylisopropyl moiety of mesocarb whilst the main process of hydroxylation of mesocarb in human occurred in the phenylcarbamoyl moiety. The main metabolites were almost completely glucuroconjugated. Minor metabolites such as p‐hydroxymesocarb and three di‐hydroxylated metabolites together with parent mesocarb were also presented in the free urine fraction. This study has shown that two mono‐ and two di‐hydroxylated metabolites are useful for controlling the abuse of mesocarb in horses. Copyright © 2011 John Wiley & Sons, Ltd. 相似文献
992.
Makarieva TN Tabakmaher KM Guzii AG Denisenko VA Dmitrenok PS Shubina LK Kuzmich AS Lee HS Stonik VA 《Journal of natural products》2011,74(9):1952-1958
New unusual polycyclic guanidine alkaloids monanchocidins B-E (2-5) along with monanchocidin A (1), which we recently described, were isolated from the Far-Eastern marine sponge Monanchora pulchra. Their structures were established using spectroscopic data and chemical transformations. Compounds 1-5 show potent cytotoxic activities against HL-60 human leukemia cells with IC50 values of 540, 200, 110, 830, and 650 nM, respectively. 相似文献
993.
Kateina Brtov Klra Hilscherov Pavel Babica Blahoslav Marlek Ludk Blha 《Environmental toxicology》2011,26(6):641-648
Oxidative stress is one of the biochemical mechanisms involved in toxicity of cyanobacterial toxins microcystins (MC), but its role in the effects of complex water blooms is elusive. The aim of this study was to investigate effects of pure MCs and different complex mixtures of cyanobacterial metabolites on the growth and biochemical markers of oxidative stress and detoxification in green alga Pseudokirchneriella subcapitata. Pure MCs at high concentrations (300 μg/L) had no effects on the growth of P. subcapitata (up to 10 day exposures) but stimulated activity of glutathione reductase (GR) after short 3 and 24 h exposures. Other biomarkers (levels of glutathione, GSH, and activities of glutathione‐S‐transferase, GST, and glutathione peroxidase, GPx) were not affected by pure MCs). Crude extract of the laboratory culture of cyanobacteria Microcystis aeruginosa (containing 300 μg/L of MCs) had no effects on algal growth or any of the biomarkers. Weak growth stimulations after 4–7 days were observed after exposures to the growth‐spent medium of the M. aeruginosa culture, which also inhibited activities of GST after prolonged exposures. Other investigated parameters (reduced GSH and activity of GPx) were not affected by any of the cyanobacterial samples. The results were compared with effects of model oxidative stressor herbicide paraquat, which exhibited variable effects on both algal growth and biomarkers (decrease in reduced GSH, stimulations of GR). Taken together, although pure MCs induce oxidative stress in green alga, the effects of cyanobacterial mixtures, which are more relevant to the natural situation, are more complex and they differ from the pure toxin. High variability in the biochemical responses to the oxidative stress makes the interpretation of results complicated, which limits the use of these biomarkers as early warnings of toxicity under natural conditions. © 2010 Wiley Periodicals, Inc. Environ Toxicol, 2011. 相似文献
994.
995.
Kollar P Závalová V Hošek J Havelka P Sopuch T Karpíšek M Třetinová D Suchý P 《International immunopharmacology》2011,11(8):997-1001
The cytotoxicity and in vitro effects of six variously modified types of cellulose (OC--oxidized cellulose, NaOC--oxidized cellulose sodium salt, DAC--dialdehyde cellulose, CMC--carboxymethyl cellulose, MFC--microfibrilated cellulose, and MCC--microcrystalline cellulose) on the inflammatory response in macrophage-like THP-1 cells were examined, with special focus on their ability to influence gene expression and the production of TNF-α. The study provides evidence that DAC exerts a marked effect on the induction of TNF-α gene expression and its subsequent production in human macrophages. Thus, the use of DAC for anti-hemorrhagic or wound-healing therapy should be considered carefully with regard to its pro-inflammatory activity. On the contrary, MCC showed significant anti-inflammatory effects in the LPS-induced conditions, which might be beneficial for the treatment of non-healing chronic wounds, e.g., diabetic or venous ulcers. 相似文献
996.
Nadine Beetz Michael D. Harrison Marc Brede Xiangang Zong Michal J. Urbanski Anika Sietmann Jennifer Kaufling Stefan Lorkowski Michel Barrot Mathias W. Seeliger Maria Augusta Vieira-Coelho Pavel Hamet Daniel Gaudet Ondrej Seda Johanne Tremblay Theodore A. Kotchen Mary Kaldunski Rolf Nüsing Bela Szabo Howard J. Jacob Allen W. Cowley Jr. Martin Biel Monika Stoll Martin J. Lohse Ulrich Broeckel Lutz Hein 《The Journal of clinical investigation》2011,121(1):454
997.
Savechenkov PY Zhang X Chiara DC Stewart DS Ge R Zhou X Raines DE Cohen JB Forman SA Miller KW Bruzik KS 《Journal of medicinal chemistry》2012,55(14):6554-6565
We synthesized 5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl)barbituric acid (14), a trifluoromethyldiazirine-containing derivative of general anesthetic mephobarbital, separated the racemic mixture into enantiomers by chiral chromatography, and determined the configuration of the (+)-enantiomer as S by X-ray crystallography. Additionally, we obtained the (3)H-labeled ligand with high specific radioactivity. R-(-)-14 is an order of magnitude more potent than the most potent clinically used barbiturate, thiopental, and its general anesthetic EC(50) approaches those for propofol and etomidate, whereas S-(+)-14 is 10-fold less potent. Furthermore, at concentrations close to its anesthetic potency, R-(-)-14 both potentiated GABA-induced currents and increased the affinity for the agonist muscimol in human α1β2/3γ2L GABA(A) receptors. Finally, R-(-)-14 was found to be an exceptionally efficient photolabeling reagent, incorporating into both α1 and β3 subunits of human α1β3 GABA(A) receptors. These results indicate R-(-)-14 is a functional general anesthetic that is well-suited for identifying barbiturate binding sites on Cys-loop receptors. 相似文献
998.
M Ehrlichová I Ojima J Chen R Václavíková V Němcová-Fürstová J Vobořilová P Simek S Horský P Souček J Kovář M Brabec I Gut 《Naunyn-Schmiedeberg's archives of pharmacology》2012,385(10):1035-1048
Resistance of tumours to taxanes causes chemotherapy failure in numerous patients. Resistance is partly due to the low tumour uptake of taxanes and their rapid metabolism. Structural modifications of taxanes can reduce their P-glycoprotein-related efflux or decrease metabolism and consequently increase taxane efficiency. This study compared cytotoxicity and effects of the cell cycle, transport and metabolism of novel taxanes SB-T-1102, SB-T-1103, SB-T-1214 and SB-T-1216, fluorinated SB-T-12851, SB-T-12852, SB-T-12853, SB-T-12854 and IDN5109 with paclitaxel in paclitaxel-sensitive (MDA-MB-435) and paclitaxel-resistant (NCI/ADR-RES) human cancer cells. We have shown before that NCI/ADR-RES cells were 1,000-fold less sensitive to paclitaxel than MDA-MB-435 cells in correspondence to P-glycoprotein overexpression and up to 20-fold lower uptake of the drug in the resistant cells. The uptake of novel taxanes was 1.2 to 3.8 times lower than that of paclitaxel in the MDA-MB-435 cells, but 1.5 to 6.5 times higher in NCI/ADR-RES cells. NCI/ADR-RES cells were correspondingly only 2- to 6.6-fold less sensitive than the MDA-MB-435 cells to novel taxanes. Both cell lines showed minimal metabolism of the novel taxanes which was therefore not responsible for their different sensitivity, the observed differences in their individual efficiency and higher effects than paclitaxel. All novel taxanes caused G(2)/M block of the cell cycle similar to paclitaxel, but lower at concentrations by order of magnitude. Thus, structural modifications of taxanes resulting in their decreased P-glycoprotein-related transport probably caused their higher efficiency than paclitaxel in multidrug-resistant NCI/ADR-RES tumour cells. 相似文献
999.
Zachařová A Siller M Spičáková A Anzenbacherová E Skottová N Anzenbacher P Večeřa R 《Xenobiotica; the fate of foreign compounds in biological systems》2012,42(8):731-736
The aim was to investigate whether rosuvastatin affect rat cytochrome P450 (CYP) 2C11 and CYP2C6. CYP2C11 and CYP2C6 are considered as counterparts of human CYP2C9, which metabolizes many drugs including S-warfarin, diclofenac or ibuprofen. The male Wistar rats were fed standard laboratory diet (STD) or high cholesterol diet (HCD, 1% of cholesterol, 10% of lard fat) for 21 days. Rosuvastatin administration in STD (0.03% w/w) resulted in decreased mRNA expression of CYP2C11 as well as of CYP2C6 (here significant) and in a significant decrease of the respective protein expression as well as of the enzyme activity of both CYP2C forms. When rosuvastatin was administered in the HCD, the mRNA expression of both CYP2C forms was significantly lowered; the protein and activity parameters did not show significant changes. These results suggest that CYP2C11 as well as CYP2C6 expression and activity are negatively affected by rosuvastatin and may be modulated by high cholesterol high fat diet. Therefore, it should be taken into consideration that drugs metabolized by CYP2C9 in human could interact with rosuvastatin, as it has been already suggested for warfarin (rosuvastatin has increased its anticoagulant effect in human), and for telmisartan, sildenafil and glimepiride. 相似文献
1000.
Kašnar-Šamprec J Ratkaj I Mišković K Pavlak M Baus-Lončar M Kraljević Pavelić S Glavaš-Obrovac L Žinić B 《Investigational new drugs》2012,30(3):981-990
New N-1-sulfonylpyrimidines showed potent growth inhibitory activity against human and mouse tumour cells of different origin. 1-(p-toluenesulfonyl)cytosine (TsC) and 1-(p-toluenesulfonyl)cytosine hydrochloride (TsC × HCl) inhibited the growth of human cervical carcinoma cells (HeLa), and had no significant cytotoxic effects on normal human foreskin fibroblasts (BJ). TsC and TsC × HCl interfered with the HeLa cell cycle progression bringing about the accumulation of G1 phase cells and the induction of apoptosis. Antiproliferative effects of TsC and TsC × HCl were additionally confirmed by investigating de novo synthesis of RNA, DNA and proteins in HeLa cells. Monitoring gene expression using DNA Chip Analysis and quantitative PCR showed that TsC × HCl affects the expression of several cell-cycle regulating genes implying that cell cycle arrest and DNA damage-induced apoptosis might account for the observed cellular effects. In vivo experiments revealed low toxicity of TsC × HCl, as demonstrated by unaltered haematological and metabolic blood parameters. In conclusion, potent antitumour efficacy and low toxicity of new compounds in comparison with the common chemotherapy drug 5-FU make them promising anticancer agents. Additional pre-clinical and clinical studies are warranted to illuminate the mode of action of these newly synthesized compounds in vivo, which would lay the groundwork for their further optimization. 相似文献