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Jeroen Kool Sebastiaan M van Liempd Huub van Rossum Danny A van Elswijk Hubertus Irth Jan N M Commandeur Nico P E Vermeulen 《Drug metabolism and disposition》2007,35(4):640-648
A high resolution screening (HRS) technology is described, in which gradient high-performance liquid chromatography (HPLC) is connected on-line to three parallel placed bioaffinity detection systems containing mammalian cytochromes P450 (P450s). The three so-called enzyme affinity detection (EAD) systems contained, respectively, liver microsomes from rats induced by beta-naphthoflavone (CYP1A activity), phenobarbital (CYP2B activity), and dexamethasone (CYP3A activity). Each P450-EAD system was optimized for enzyme, substrate, and organic modifier (isopropyl alcohol, methanol, and acetonitrile) in flow injection analysis mode. Characteristic P450 ligands were used to validate the P450-EAD systems. IC(50) values of the ligands were measured and found to be similar to those obtained with conventional microtiter plate reader assays. Detection limits (n = 3; signal-to-noise ratio = 3) of potent inhibitors ranged from 1 to 3 pmol for CYP1A activity, 4 to 17 pmol for CYP2B activity, and 4 to 15 pmol for CYP3A activity. The three optimized P450-EAD systems were subsequently coupled to gradient HPLC and used to screen compound mixtures for individual ligands. Finally, to increase analysis efficiency, a HRS system was constructed in which all three P450-EAD systems were coupled on-line and in parallel to gradient HPLC. The triple parallelized P450-EAD system was shown to enable rapid profiling of individual components in complex mixtures for inhibitory activity to three different P450s. 相似文献
3.
Andrea von Berg Renate Engelstätter Predrag Minic Miodrag Sréckovic Maria Luz Garcia Garcia Tadeusz Lato Jan H. Vermeulen Stefan Leichtl Stefan Hellbardt Thomas D. Bethke 《Pediatric allergy and immunology》2007,18(5):391-400
Ciclesonide is an onsite-activated inhaled corticosteroid (ICS) for the treatment of asthma. This study compared the efficacy, safety and effect on quality of life (QOL) of ciclesonide 160 microg (ex-actuator; nominal dose 200 microg) vs. budesonide 400 microg (nominal dose) in children with asthma. Six hundred and twenty-one children (aged 6-11 yr) with asthma were randomized to receive ciclesonide 160 microg (ex-actuator) once daily (via hydrofluoroalkane metered-dose inhaler and AeroChamber Plus spacer) or budesonide 400 microg once daily (via Turbohaler) both given in the evening for 12 wk. The primary efficacy end-point was change in forced expiratory volume in 1 s (FEV1). Additional measurements included change in daily peak expiratory flow (PEF), change in asthma symptom score sum, change in use of rescue medication, paediatric and caregiver asthma QOL questionnaire [PAQLQ(S) and PACQLQ, respectively] scores, change in body height assessed by stadiometry, change in 24-h urinary cortisol adjusted for creatinine and adverse events. Both ciclesonide and budesonide increased FEV1, morning PEF and PAQLQ(S) and PACQLQ scores, and improved asthma symptom score sums and the need for rescue medication after 12 wk vs. baseline. The non-inferiority of ciclesonide vs. budesonide was demonstrated for the change in FEV1 (95% confidence interval: -75, 10 ml, p = 0.0009, one-sided non-inferiority, per-protocol). In addition, ciclesonide and budesonide showed similar efficacy in improving asthma symptoms, morning PEF, use of rescue medication and QOL. Ciclesonide was superior to budesonide with regard to increases in body height (p = 0.003, two-sided). The effect on the hypothalamic-pituitary-adrenal axis was significantly different in favor of ciclesonide treatment (p < 0.001, one-sided). Both ciclesonide and budesonide were well tolerated. Ciclesonide 160 microg once daily and budesonide 400 microg once daily were effective in children with asthma. In addition, in children treated with ciclesonide there was significantly less reduction in body height and suppression of 24-h urinary cortisol excretion compared with children treated with budesonide after 12 wk. 相似文献
4.
Pharmacokinetics of orally administered hexobarbital in plasma and saliva of healthy subjects 总被引:1,自引:0,他引:1
M van der Graaff N P Vermeulen P Heij J K Boeijinga D D Breimer 《Biopharmaceutics & drug disposition》1986,7(3):265-272
Hexobarbital (HB) concentrations were determined in plasma and saliva of 8 healthy subjects, following oral administration of 500 mg HB-Na. Mean plasma half-lives were 3.2 +/- 0.1 h, and salivary half-lives 3.3 +/- 0.2 h. Mean plasma clearance was 22.9 +/- 2.3 1 h-1. There was a linear relationship between HB concentrations in saliva and plasma (r = 0.92). Mean salivary levels were 34 per cent of plasma levels. Salivary pH was constant throughout the experiment, 7.06 +/- 0.09. There was an inconsistent tendency of the saliva over plasma ratios to increase as a function of time. The percentage of protein binding calculated from saliva over plasma ratios was in reasonable agreement with in vitro data of equilibrium dialysis, 64.1 +/- 2.6 per cent and 65.9 +/- 0.8 per cent, respectively. The experiment was repeated in 4 subjects, and considerable intraindividual differences were shown to exist in saliva over plasma ratio, half-lives, and protein binding. It was concluded that HB elimination half-lives can relatively accurately be determined from salivary concentrations. Oral plasma clearance can only be estimated if the individual saliva over plasma ratios are known; this would require the taking of at least one blood sample during the experiment. When employing HB as a model substrate for drug metabolizing enzyme activity in vivo, the determination of its pharmacokinetic parameters, particularly oral plasma clearance as a reflection of cytochrome P-450 activity, cannot be achieved by taking saliva samples only. 相似文献
5.
Kranendonk M.; Commandeur J.N.M.; Laires A.; Rueff J.; Vermeulen N.P.E. 《Mutagenesis》1997,12(4):245-254
MX100 is an Escherichia coli K12 genotoxicity tester strain,especially developed for mechanistic studies of chemical mutagensand carcinogens. For the study of the role of specific enzymesin the bioactivation and bioinactivation of carcinogens, itis necessary to characterize MX100 as far as its metabolic bio(in)activationcapacities are concerned. In this study such a characterizationis performed in two types of cell-free lysates, one derivedfrom stationary phase cells, grown in rich medium (SR-lysates)and one from exponentially growing cells (log phase), culturedin minimal medium (LM-lysates). Six Phase I enzyme activitiesof aromatic NADPH hydroxylase, NADH hydroxylase, flavin-containingmonooxygenase (FMO), nitroreductase, DT-diaphorase and NADPHferredoximoxidoreductase were determined. Activities of sixPhase II enzymes glutathione S-transferases (GSTs), N-aryl acetyltransferase(NAT), arylamine sulphotransferase, UDPglucuronyltransferaseand epoxide hydratase and of the Phase III enzyme cysteine conjugate(J-lyase were subsequently assessed. In addition, five antioxidantenzymes: superoxide dismutase (SOD), catalase, glutathione (GSH)-reductase,GSH-peroxidase and alkyl hydroperoxide reductase; as well asconcentrations of glutathione (GSH) and its disulphide (GSSG),were measured. The activity parameters of all enzymes were comparedwith those obtained in similar lysates of the Salmonella strainTA100 and in rat liver preparations. The results indicate thatMX100 as well as TA100 contain relatively low oxidative buthigh reductase Phase I activities. Both strains demonstratedlow activities for the Phase II conjugation enzymes except forGSTs. In MX100, relatively high activities were detected forall antioxidative enzymes, activities which were lower in TA100.Significant differences in activities were observed betweenthe SR-lysates derived from stationary phase/rich medium andLM-lysates from log phase/minimal medium cells for nitroreductase,GST, SOD, catalase, NADPH ferredoxin: oxidoreductase as wellas in GSH content. In general, we described for the first timea metabolic characterization of the E.coli tester strain MX100and the Salmonella typhimurium strain TA100 and discussed theresults in terms of its significance for carcinogen bioactivationand bioinactivation capacities.
4To whom correspondence should be addressed 相似文献
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J P Muizelaar M Vermeulen H van Crevel A Hijdra J van Gijn G M Teasdale K W Lindsay G D Murray 《Clinical neurology and neurosurgery》1988,90(3):203-207
The outcome at three months after aneurysmal SAH in a group of older patients and a group of younger patients is compared. The patients were admitted within 72 hours of their SAH. Of 61 patients 66 years of age and older, comprising 13% of the whole patient group, 52% died, 12% remained dependent and 36% became independent. In the younger group, 55% had an independent outcome (p less than 0.01). In contrast to what we expected in the older patient group, not extracranial, but intracranial events (re-bleeds, infarcts, hydrocephalus) were by far the most frequent cause of deterioration. 相似文献
8.
Michael J. Schull MD MSc Therese A. Stukel PhD Marian J. Vermeulen MHSc Astrid Guttmann MDLM MSc Merrick Zwarenstein MD PhD 《Academic emergency medicine》2006,13(11):1228-1231
Background Current influenza pandemic models predict a surge in influenza‐related hospitalizations in affected jurisdictions. One proposed strategy to increase hospital surge capacity is to restrict elective hospitalizations, yet the degree to which this measure would meet the anticipated is unknown. Objectives To compare the reduction in hospitalizations resulting from widespread nonurgent hospital admission restrictions during the Toronto severe acute respiratory syndrome (SARS) outbreak with the expected increase in admissions resulting from an influenza pandemic in Toronto. Methods The authors compared the expected influenza‐related hospitalizations in the first eight weeks of a mild, moderate, or severe pandemic with the actual reduction in the number of hospital admissions in Toronto, Ontario, during the first eight weeks of the SARS‐related restrictions. Results Influenza modeling for Toronto predicts that there will be 4,819, 8,032, or 11,245 influenza‐related admissions in the first eight weeks of a mild, moderate, or severe pandemic, respectively. In the first eight weeks of SARS‐related hospital admission restrictions, there were 3,654 fewer hospitalizations than expected in Toronto, representing a modest 12% decrease in the overall admission rate (a reduction of 1.40 admissions per 1,000 population). Therefore, influenza‐related admissions could exceed the reduction in admissions resulting from restricted hospital utilization by 1,165 to 7,591 patient admissions, depending on pandemic severity, which corresponds to an excess of 0.44 to 2.91 influenza‐related admissions per 1,000 population per eight weeks, and an increase of 4% to 25% in the overall number of admissions, when compared with nonpandemic conditions. Conclusions Pandemic modeling for Toronto suggests that influenza‐related admissions would exceed the reduction in hospitalizations seen during SARS‐related nonurgent hospital admission restrictions, even in a mild pandemic. Sufficient surge capacity in a pandemic will likely require the implementation of other measures, including possibly stricter implementation of hospital utilization restrictions. 相似文献
9.
Youji He Theodorus B M Hakvoort Jacqueline L M Vermeulen Wouter H Lamers Maria A Van Roon 《Developmental dynamics》2007,236(7):1865-1875
Glutamine synthetase (GS) is expressed in a tissue-specific and developmentally controlled manner, and functions to remove ammonia or glutamate. Furthermore, it is the only enzyme that can synthesize glutamine de novo. Since congenital deficiency of GS has not been reported, we investigated its role in early development. Because GS is expressed in embryonic stem (ES) cells, we generated a null mutant by replacing one GS allele in-frame with a beta-galactosidase-neomycine fusion gene. GS(+/LacZ) mice have no phenotype, but GS(LacZ/LacZ) mice die at ED3.5, demonstrating GS is essential in early embryogenesis. Although cells from ED2.5 GS(LacZ/LacZ) embryos and GS(GFP/LacZ) ES cells survive in vitro in glutamine-containing medium, these GS-deficient cells show a reduced fitness in chimera analysis and fail to survive in tetraploid-complementation assays. The survival of heavily (>90%) chimeric mice up to at least ED16.5 indicates that GS deficiency does not entail cell-autonomous effects and that, after implantation, GS activity is not essential until at least the fetal period. We hypothesize that GS-deficient embryos die when they move from the uterine tube to the harsher uterine environment, where the embryo has to catabolize amino acids to generate energy and, hence, has to detoxify ammonia, which requires GS activity. 相似文献
10.
Quantitative relationship between capsular content and killing of K1-encapsulated Escherichia coli. 总被引:7,自引:7,他引:7 下载免费PDF全文
Since there are conflicting reports in the literature on a possible relationship between the K1 capsular polysaccharide (CP) content of Escherichia coli and its susceptibility to killing, we reexamined this issue in a strain that had a smooth lipopolysaccharide (LPS) phenotype (E. coli O18:K1:H7 Bort) and in a strain with a deep rough LPS phenotype (E412, spontaneously agglutinable: K1:H-). When cell-associated K1 capsular content was greater than 90 micrograms of K1 polysaccharide per 10(10) CFU, neither strain was lysed by 20% normal human serum. In contrast, at equivalent but lower levels of K1 CP content, E412 but not strain Bort was lysed by normal human serum. Thus, LPS phenotype is an additional surface determinant that affects bacterial susceptibility to killing. Organisms obtained from very early log phase, when cell-associated K1 CP is greatest, were significantly more virulent for mice than were bacteria harvested in stationary phase, when cell-associated K1 polysaccharide is lowest. We conclude that (i) there is a threshold level of K1 CP needed to confer protection from lysis by serum, and this is usually exceeded under standard growth conditions; (ii) at a given level of K1 CP the LPS phenotype is an important determinant of bacterial killing; and (iii) the loss of capsule at low pH may be an additional mechanism by which hosts defend against invasive infection by K1-encapsulated E. coli. 相似文献