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351.
L. Sasongko I. Ramzan K. M. Williams A. J. McLachlan 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2001,754(2):357
A reliable high-performance liquid chromatographic method has been validated for determination of gallamine in rat plasma, muscle tissue and microdialysate samples. A C18 reversed-phase column with mobile phase of methanol and water containing 12.5 mM tetrabutyl ammonium (TBA) hydrogen sulphate (22:78, v/v) was used. The flow-rate was 1 ml/min with UV detection at 229 nm. Sample preparation involved protein precipitation with acetonitrile for plasma and muscle tissue homogenate samples. Microdialysate samples were injected into the HPLC system without any sample preparation. Intra-day and inter-day accuracy and precision of the assay were <13%. The limit of quantification was 1 μg/ml for plasma, 1.6 μg/g for muscle tissue and 0.5 μg/ml for microdialysate samples. The assay was applied successfully to analysis of samples obtained from a pharmacokinetic study in rats using the microdialysis technique. 相似文献
352.
The in vitro human serum albumin binding characteristics of the enantiomers of the major metabolites of warfarin [6-hydroxywarfarin (6-HW), 7-hydroxywarfarin (7-HW), (S)-warfarin alcohols [(S,S)- and (S,R)-WA], and (R,S)-warfarin alcohol [(R,S)-WA]] have been studied, using a stereospecific HPLC assay. Warfarin metabolites are less bound both within plasma and a 40 g/liter solution of human serum albumin than the enantiomers of warfarin. The reduced warfarin metabolites have a lower fraction unbound [1.33% for (S,R)-WA, 2.09% for (S,S)-WA, and 1.04% for (R,S)-WA] than hydroxylated metabolites [3.24% for (R)-6-HW, 4.26% (S)-6-HW, 4.49% for (R)-7-HW and 4.27% for (S)-7-HW] to HSA. Phenylbutazone produced a concentration-dependent increase in the unbound fraction of all metabolites. It was possible to predict the unbound fraction of warfarin metabolites based on the unbound fraction of warfarin enantiomers. © 1993 Wiley-Liss, Inc. 相似文献
353.
Hydroxychloroquine, a slow acting antirheumatic drug, is administered as the racemic mixture. Blood concentrations of the two enantiomers of hydroxychloroquine were measured in two studies, one study of eight patients, in whom blood and urine concentrations were measured during the first 6 months of therapy with rac-hydroxychloroquine, and one of 43 patients who had received rac-hydroxychloroquine therapy for at least 6 months. In the latter study rheumatoid disease activity was also measured. The pharmacokinetics of hydroxychloroquine were found to be enantioselective. The concentrations of (?)-(R)-hydroxychloroquine were higher than those of the (+)-(S)-antipode in all patients at all time points, although the ratios of the two enantiomers did display a two to three fold variability between patients. Both total and renal clearance were greater for the (+)-(S)-enantiomer. From the observational, cross-sectional study design used, it was not possible to differentiate concentration–effect relationships of the two enantiomers. The 11-fold range of drug concentrations swamped any effect of variability between patients in enantiomer proportions. Blood concentrations of both enantiomers were significantly higher in groups of patients with less active disease. © 1994 Wiley-Liss, Inc. 相似文献
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355.
Hiroshi Fukamachi John A. McLachlan 《In vitro cellular & developmental biology. Animal》1991,27(12):907-913
Summary The effects of different substrata and estradiol-17β(E2) on proliferation and differentiation of mouse uterine epithelial cells was examined in a serum-free primary culture system.
When cultured on rat-tail collagen gels, the epithelial cells rapidly increased in number to form a simple squamous cell layer
that exhibited a relatively undifferentiated state (a few short microvilli, no secretory granules, and poorly developed endoplasmic
reticulum). Addition of E2 into the culture medium did not affect the proliferation of epithelial cells on collagen gel. Uterine epithelial cells grown
on a reconstituted basement membrane-like substratum (Matrigel) formed a simple columnar/cuboidal cell layer exhibiting fully
developed characteristics (many long microvilli, many secretory granules, and fully developed endoplasmic reticulum). Examination
of epithelial proliferation by counting substratum-attached cell number revealed only a slow increase in cell growth on Matrigel,
and E2 did not significantly affect it. However, measurement of proliferating cells by labeling cells with 5-bromo-2′-deoxyuridine
revealed that cells on Matrigel were replicating and that E2 (10−7 to 10−11
M) actually significantly suppressed epithelial proliferation. However, there was not an effect of E2 on total cell number, indicating that the cells in control medium replicate faster and detach more readily from the substratum
than those in E2-supplemented medium on Matrigel. Thus, it is probable that E2 significantly reduces the rate of cell detachment from the substratum, which may mimic the in vivo condition where significant
decrease in apoptosis or cell death is induced by E2. 相似文献
356.
Mizutori Y Chen CR McLachlan SM Rapoport B 《Molecular endocrinology (Baltimore, Md.)》2008,22(5):1171-1182
The glycoprotein hormone receptor hinge region connects the leucine-rich and transmembrane domains. The prevalent concept is that the hinge does not play a significant role in ligand binding and signal transduction. Portions of the hinge are redundant and can be deleted by mutagenesis or are absent in certain species. A minimal hinge will be more amenable to future investigation of its structure and function. We, therefore, combined and progressively extended previous deletions (Delta) in the TSH receptor (TSHR) hinge region (residues 277-418). TSHRDelta287-366, Delta287-371, Delta287-376, and Delta287-384 progressively lost their response to TSH stimulation of cAMP generation in intact cells, consistent with a progressive loss of TSH binding. The longest deletion (TSHRDelta287-384), reducing the hinge region from 141 to 43 amino acids, totally lost both functions. Surprisingly, however, with deletions extending from residues 371-384, constitutive (ligand-independent) activity increased severalfold, reversing the suppressive (inverse agonist) effect of the TSHR extracellular domain. TSHR-activating point mutations I486F and I568T in the first and second extracellular loops (especially the former) had reduced activity on a background of TSHRDelta287-371. In summary, our data support the concept that the TSHR hinge contributes significantly to ligand binding affinity and signal transduction. Residues within the hinge, particularly between positions 371-384, appear involved in ectodomain inverse agonist activity. In addition, the hinge is necessary for functionality of activating mutations in the first and second extracellular loops. Rather than being an inert linker between the leucine-rich and transmembrane domains, the TSHR hinge is a signaling-specificity domain. 相似文献
357.
358.
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360.
One of the most rapid responses to aluminum (Al) stress in plants is enhanced synthesis and deposition of 1,3-beta-D-glucans (callose) in root tips. Ironically, Al-induced synthesis and deposition of callose occurs in vivo, despite evidence from in vitro systems that suggests that Al is a powerful inhibitor of 1,3-beta-D-glucan synthase. We set out to test the hypothesis that an Al-induced increase in the activity of free calcium in the cytoplasm ([Ca(2+)](cyt)) is the trigger for enhanced synthesis of callose in in vivo systems, an effect that would not be observed in in vitro systems. Root tips of an Al-sensitive cultivar of Triticum aestivum were treated with Al (0-100 microM) or the Ca ionophore A23187 (0-3 micro M) for 3-24 h, and the effects on [Ca(2+)](cyt) and synthesis of callose were measured using confocal laser scanning microscopy. Treatment with Al induced a rapid increase in both [Ca(2+)](cyt) (4.7-fold) and synthesis of callose (30-fold). Treatment with the Ca ionophore, A23187, also elicited an increase in [Ca(2+)](cyt) (6.6-fold). Despite a greater increase in [Ca(2+)](cyt) in the presence of A23187, this increase was accompanied by a smaller increase in callose deposition (11-fold) than was observed in the presence of Al. These data suggest that an increase in [Ca(2+)](cyt) is not the only factor modulating increases in callose synthesis and deposition in the presence of Al. 相似文献