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941.
942.
SC Chien FA Wong CL Fowler SV Callery-D'Amico RR Williams R Nayak AT Chow 《Canadian Metallurgical Quarterly》1998,42(4):885-888
The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy male volunteers were investigated in a randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to the treatment (n = 10) or placebo group (n = 6). In study period 1, 750 mg of levofloxacin or a placebo was administered orally as a single dose on day 1, followed by a washout period on days 2 and 3; dosing resumed for days 4 to 10. Following a 3-day washout period, 1 g of levofloxacin or a placebo was administered in a similar fashion in period 2. Plasma and urine levofloxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. Levofloxacin was rapidly absorbed after single and multiple once-daily 750-mg and 1-g doses with an apparently large volume of distribution. Peak plasma levofloxacin concentration (Cmax) values were generally attained within 2 h postdose. The mean values of Cmax and area under the concentration-time curve from 0 to 24 h (AUC0-24) following a single 750-mg dose were 7.1 microg/ml and 71.3 microg x h/ml, respectively, compared to 8.6 microg/ml and 90.7 microg x h/ml, respectively, at steady state. Following the single 1-g dose, mean Cmax and AUC0-24 values were 8.9 microg/ml and 95.4 microg x h/ml, respectively; corresponding values at steady state were 11.8 microg/ml and 118 microg x h/ml. These Cmax and AUC0-24 values indicate modest and similar degrees of accumulation upon multiple dosing at the two dose levels. Values of apparent total body clearance (CL/F), apparent volume of distribution (Vss/F), half-life (t1/2), and renal clearance (CL[R]) were similar for the two dose levels and did not vary from single to multiple dosing. Mean steady-state values for CL/F, Vss/F, t1/2, and CL(R) following 750 mg of levofloxacin were 143 ml/min, 100 liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g dose were 146 ml/min, 105 liters, 8.9 h, and 105 ml/min. In general, the pharmacokinetics of levofloxacin in healthy subjects following 750-mg and 1-g single and multiple once-daily oral doses appear to be consistent with those found in previous studies of healthy volunteers given 500-mg doses. Levofloxacin was well tolerated at either high dose level. The most frequently reported drug-related adverse events were nausea and headache. 相似文献
943.
Fas and Fas-associated death domain (FADD) play a critical role in the homeostasis of different cell types. The regulation of Fas and FADD-mediated cell death is pivotal to many physiological functions. The activation of T lymphocytes by concanavalin A (Con A) inhibited Fas-mediated cell death. We identified that among the several activation signals downstream of Con A stimulation, mitogen-activated protein (MAP) kinase kinase (MKK) was the major kinase pathway that antagonized Fas-triggered cell death. MKK1 suppressed FADD- but not caspase-3- induced apoptosis, indicating that antagonism occurred early along the Fas-initiated apoptotic cascade. We further demonstrated that activation of MKK1 led to expression of FLIP, a specific inhibitor of FADD. MKK1 inhibition of FADD-induced cell death was abrogated if induction of FLIP was prevented, indicating that FLIP mediates MKK1 suppression of FADD-mediated apoptosis. Our results illustrate a general mechanism by which activation of MAP kinase attenuates apoptotic signals initiated by death receptors in normal and transformed cells. 相似文献
944.
Little information is available on the active site structure of the CYP4A family of enzymes or the mechanism by which their omega-hydroxylation regiospecificity is enforced. We report here that the E320A, D323E, and E320/D323E mutations decrease the catalytic rate of CYP4A1 approximately 5-fold and cause up to a 10-fold shift from omega- to (omega-1)-hydroxylation. The decreased catalytic rate is due to an increase in the uncoupled reduction of molecular oxygen. Tighter binding of 1- and 4-substituted imidazoles to the double mutant than to the other proteins suggests that its active site is less constrained. The reaction of these proteins with phenyldiazene causes heme degradation without the detectable formation of a phenyl-iron complex. CYP4A1 and its E320A mutant are not inactivated by 1-aminobenzotriazole (1-ABT), but the D323E and E320A/D323E mutants are inactivated. The resistance of purified CYP4A1 to inactivation by 1-ABT is surprising in view of the fact that 1-ABT causes the loss of the omega-hydroxylase activity both in microsomal preparations and in vivo. Collectively, the results establish that Glu-320, and particularly Asp-323, help to define the active site dimensions, the degree of coupled versus uncoupled versus uncoupled turnover, the omega-versus (omega-1)-hydroxylation regiospecificity, and the susceptibility to inactivation by mechanism-based inhibitors. Furthermore, they provide experimental evidence for a structural analogy between the CYP4A1 and P450BM-3 active sites. 相似文献
945.
G Livesey IT Johnson JM Gee T Smith WE Lee KA Hillan J Meyer SC Turner 《Canadian Metallurgical Quarterly》1993,47(6):419-430
The production of hydrogen from substrates and substrate mixture of sugar alcohols and Polydextrose was determined, both in vivo using the breath hydrogen test, and in vitro, using human faecal microorganisms in anaerobic culture. One objective was to test a previous assumption that the stoichiometry of hydrogen production from different alternative carbohydrates is similar. Another objective was to discover whether hydrogen responses from mixtures of substrates were simply additive, or whether interactions occurred. The breath tests were performed in a 10 subject x 10 substrate factorial design with substrates and substrate mixtures (5-11 g) administered in 42 g chocolate confectionery. Incorporation of the alternative carbohydrates lactitol (L), Isomalt (I) and Polydextrose (P) into otherwise conventional confectionery increased breath hydrogen production by approximately 112, 73 and 11%/g respectively. There was no interaction between L and I or between P and I, but a combination of L and P approximately doubled the breath hydrogen anticipated from their individual contributions (P < 0.05). Anaerobic cultures showed a sixfold range in the efficiency of converting individual substrates and mixtures to hydrogen gas (0.003-0.018 kJ H2 per kJ carbohydrate). The positive interaction between L and P, and the lack of interaction between L and I, and between P and I, found in vivo were reproduced in vitro. The work showed that interpretation of the hydrogen breath test is confounded by differing stoichiometries for hydrogen production, by interaction between substrates and by an uncertain extent to which small intestinal hydrolysis yielding species with a fermentation stoichiometry that differs from the parent substrate. 相似文献
946.
947.
SC Stocks MH Ruchaud-Sparagano MA Kerr F Grunert C Haslett I Dransfield 《Canadian Metallurgical Quarterly》1996,26(12):2924-2932
Neutrophils express several heavily glycosylated carcinoembryonic antigen (CEA)-related glycoproteins (CD66 antigens) which have been implicated in adhesion to E-selectin and as receptors for the lectins galectin 3 and bacterial type-1 fimbriae. The role of the CD66 antigens in neutrophil effector function was examined using non-cross-reacting and cross-reacting domain-mapped CD66 monoclonal antibody (mAb), which recognize epitopes on biliary glycoprotein (BGP; CD66a), CEA gene family member 6 (CGM6; CD66b), nonspecific cross-reacting antigen 90 (NCA90; CD66c) or CGM1 (CD66d). We show that BGP-specific mAb which recognize an AB-domain epitope strongly augment adhesion to fibrinogen by an Fc receptor- and beta2 integrin-dependent mechanism. Co-ligation of BGP with the glycophosphatidylinositol (GPI)-anchored CGM6 and NCA90 also caused increased beta2 integrin-mediated adhesion, receptor clustering and priming of formyl-Met-Leu-Phe (fMLP)-induced oxidant production by neutrophils, but only a small change in expression of L-selectin and CR3 compared to the chemotactic peptide fMLP. Ligation of CGM6 or NCA90 alone did not cause activation of the neutrophil in any of the assays used and did not cause priming of fMLP-induced oxidant production even when a secondary cross-linking reagent was used. We propose that specific cross-linking of neutrophil BGP with CGM6 and NCA90 contributes significantly to the regulation of neutrophil function during neutrophil recruitment. 相似文献
948.
JR Barrio SC Huang DC Yu WP Melega J Quintana SR Cherry A Jacobson M Namavari N Satyamurthy ME Phelps 《Canadian Metallurgical Quarterly》1996,16(4):667-678
PURPOSE: Recent information indicates that large, sustained wall shear stress gradients are a dominant hemodynamic parameter associated with the location and severity of atherosclerosis and myointimal hyperplasia. This study computes the spatial values of wall shear stresses and their gradients for three carotid artery bifurcation geometries. METHODS: A computational fluid dynamics program was used to solve the transient two-dimensional partial differential equations that describe fluid flow. Blood was treated as both a Newtonian and a non-Newtonian incompressible fluid. Solutions for the velocities, wall shear stresses, and wall shear-stress gradients were obtained for three carotid bifurcation geometries: a normal carotid bifurcation (similar to a primarily reconstructed carotid endarterectomy), a patch-reconstructed carotid endarterectomy, and a gradually tapered, low-angle carotid bifurcation (no carotid bulb). RESULTS: Computed velocity profiles closely match published experimental ones. Disturbed flow velocities are largest in the bulb segment of the normal carotid bifurcation. Peak and minimum wall shear stresses and peak shear stress gradients occurred in the lateral internal carotid artery wall. These were binodal in the normal or primarily reconstructed carotid artery, localized at the distal end of the patch-reconstructed carotid bifurcation, and minimal in the smooth, tapered carotid bifurcation. Wall shear stresses and their gradients were slightly higher for non-Newtonian than Newtonian fluids in the normal carotid artery but were similar in the other two geometric configurations. CONCLUSION: These results indicate that flow disturbances in general and wall shear stress gradients in particular are markedly reduced in carotid artery bifurcations that are smooth and gradually tapered and do not have a bulb. Abrupt geometric wall changes such as those occurring in the normal carotid bulb and at the distal end of a patch-reconstruction after carotid endarterectomy are harbingers of disturbed flow and high wall shear stress gradients. These results suggest that carotid endarterectomy reconstruction geometry characterized by a gradually tapered internal carotid artery may minimize the hemodynamically induced component of early myointimal hyperplasia and thrombosis and late atherosclerotic restenosis. 相似文献
949.
950.