Oral bioequivalence of three ciprofloxacin formulations following single-dose administration: 500 mg tablet compared with 500 mg/10 mL or 500 mg/5 mL suspension and the effect of food on the absorption of ciprofloxacin oral suspension.
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The oral bioequivalence and tolerability of two ciprofloxacin formulations (tablet and suspension) and the effect of food on the absorption of ciprofloxacin oral suspension were investigated. Sixty-eight young, healthy male subjects participated in two separate, randomized, crossover studies. In study 1, ciprofloxacin as a single 500 mg tablet or as 500 mg/10 mL oral suspension was administered in a fasted state on day 1. In study 2, subjects participated in a three-way crossover study in which ciprofloxacin suspension was administered as 500 mg/10 mL in a fasted state, or 500 mg/10 mL with food, or 500 mg/5 mL in a fasted state. Plasma ciprofloxacin concentrations were measured by high-performance liquid chromatography. Standard pharmacokinetic parameters were estimated using non-compartmental methods. In study 1, geometric mean Cmax values of ciprofloxacin following the single 500 mg tablet and 500 mg/10 mL suspension doses were 2.36 and 2.18 mg/L, respectively; corresponding geometric mean t(max) values were 1.1 and 1.6 h, respectively. Geometric mean AUC(0-infinity) values were 12.0 and 11.8 mg x h/L, respectively. In study 2, geometric least squares mean Cmax values following ciprofloxacin 500 mg/10 mL and 500 mg/5 mL suspension during fasted conditions were 1.54 and 1.59 mg/L, respectively. Corresponding geometric least squares mean AUC(0-infinity) values were 7.3 and 8.0 mg x h/L. Administration of ciprofloxacin 500 mg/10 mL suspension, in either a fasted or fed state, was not associated with significant changes in Cmax (1.54 mg/L for fasted vs 1.37 mg/L for fed) or AUC(0-infinity) values (7.28 mg x h/L for fasted vs 8.19 mg x h/L for fed). Each ciprofloxacin formulation was well tolerated for the duration of each study. These studies demonstrated bioequivalence between ciprofloxacin 500 mg tablet and two strengths of ciprofloxacin suspension (500 mg/10 mL and 500 mg/5 mL). Bioavailability was unaltered by food. (+info)
Modulation of vascular cell growth kinetics by local cytokine delivery from fibrin glue suspensions.
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PURPOSE: Fibrin glue (FG) has been used as a delivery system for bioactive agents on grafts and angioplasty sites. Reports from two different institutions suggest that heparin concentrations of 500 U/mL in FG inhibit smooth muscle cell (SMC) proliferation, but do not effect endothelial cell (EC) proliferation. The purposes of this study were to (1) quantify the diffusive release of fibroblast growth factor-1 (FGF-1) and heparin from FG; (2) determine the effect of heparin and FGF-1 on SMC proliferation when the cells are immediately plated on the FG; and (3) by means of the diffusive release data, design a new in vitro model that may differentiate the effect of FG-incorporated FGF-1 and heparin, rather than the released, solubilized components of these two factors, on SMC and EC proliferation. METHODS: 125I-FGF-1 or 3H-heparin release from FG into the overlying media was measured serially in a 96-hour period, either with or without cells. SMCs were immediately plated on FG containing various concentrations of FGF-1 and heparin. SMCs or ECs were plated on identical groups of FG containing FGF-1 and heparin 24 hours after the FG was made to exclude the effect on cell growth of the initial release of FGF-1 into the media. RESULTS: In the first 24 hours, 70% +/- 1% of the FGF-1 and 59% +/- 2% of the heparin in the FG was released into the overlying media, with minimal release occurring thereafter. The cell type or absence of cells did not affect release, but there was five times more FGF-1 and four times more heparin in the media at 72 hours for the immediate plating versus the delayed plating because of a diffusive release primarily in the first 24 hours. A heparin concentration of 500 U/mL inhibited SMC proliferation, as compared with 5 U/mL heparin, only when immediate plating of SMCs was used. Comparing immediate versus delayed SMC plating, at equivalent FGF-1 and heparin doses, immediate plating induced greater proliferation than delayed plating; this was likely caused by the higher soluble FGF-1 concentration. Heparin doses as high as 500 U/mL had little effect on SMC proliferation. In contrast, ECs died with delayed plating on FG containing 500 U/mL heparin, and their growth was inhibited at 50 U/mL heparin, as compared with 5 U/mL heparin. CONCLUSION: The differences in SMC proliferation when comparing immediate versus delayed plating are likely caused by diffusive release of heparin and FGF-1 into the media. Our ongoing work uses an optimized in vitro FG system that minimizes the effects of soluble factors. This is an important distinction, because the cytokines that are released in vivo will be removed by blood flow and, thus, may not exert an effect unless they are contained within the FG. (+info)
The effects on intragastric acidity of per-gastrostomy administration of an alkaline suspension of omeprazole.
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BACKGROUND: It may be difficult to administer proton pump inhibitors via gastrostomy. Previous studies have examined the effect of intact proton pump inhibitor granules in orange juice. This study examined the effect of an alkaline suspension of omeprazole (simplified omeprazole suspension (SOS)) on 24-h intragastric acidity. METHODS: Six men with an established gastrostomy had a baseline 24-h intragastric pH study using methodology we have previously described. They then received 20 mg SOS o.d. for 7 days and had a repeat pH study at the end of this period. Four of the patients then received 20 mg SOS with 30 cc of liquid antacid (Mylanta) per gastrostomy o.d. for a further 7 days and then underwent a third pH study. RESULTS: SOS raised mean pH from 2.2 to 4.1. Intragastric pH was above 3, 4 and 5 for 35, 28 and 17% of the 24-h period at baseline, respectively; corresponding values after SOS were 63, 51 and 39%, respectively. Addition of liquid antacid to SOS did not further increase its pH-controlling effect. CONCLUSIONS: We found a statistically significant effect of o.d. SOS on intragastric pH when administered via gastrostomy. We found no additional benefit of administering SOS with liquid antacid. (+info)
Simultaneous reduction of nitrate and selenate by cell suspensions of selenium-respiring bacteria.
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Washed-cell suspensions of Sulfurospirillum barnesii reduced selenate [Se(VI)] when cells were cultured with nitrate, thiosulfate, arsenate, or fumarate as the electron acceptor. When the concentration of the electron donor was limiting, Se(VI) reduction in whole cells was approximately fourfold greater in Se(VI)-grown cells than was observed in nitrate-grown cells; correspondingly, nitrate reduction was approximately 11-fold higher in nitrate-grown cells than in Se(VI)-grown cells. However, a simultaneous reduction of nitrate and Se(VI) was observed in both cases. At nonlimiting electron donor concentrations, nitrate-grown cells suspended with equimolar nitrate and selenate achieved a complete reductive removal of nitrogen and selenium oxyanions, with the bulk of nitrate reduction preceding that of selenate reduction. Chloramphenicol did not inhibit these reductions. The Se(VI)-respiring haloalkaliphile Bacillus arsenicoselenatis gave similar results, but its Se(VI) reductase was not constitutive in nitrate-grown cells. No reduction of Se(VI) was noted for Bacillus selenitireducens, which respires selenite. The results of kinetic experiments with cell membrane preparations of S. barnesii suggest the presence of constitutive selenate and nitrate reduction, as well as an inducible, high-affinity nitrate reductase in nitrate-grown cells which also has a low affinity for selenate. The simultaneous reduction of micromolar Se(VI) in the presence of millimolar nitrate indicates that these organisms may have a functional use in bioremediating nitrate-rich, seleniferous agricultural wastewaters. Results with (75)Se-selenate tracer show that these organisms can lower ambient Se(VI) concentrations to levels in compliance with new regulations proposed for release of selenium oxyanions into the environment. (+info)
Structure of the glycosylphosphatidylinositol anchor of an arabinogalactan protein from Pyrus communis suspension-cultured cells.
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Arabinogalactan proteins (AGPs) are proteoglycans of higher plants, which are implicated in growth and development. We recently have shown that two AGPs, NaAGP1 (from Nicotiana alata styles) and PcAGP1 (from Pyrus communis cell suspension culture), are modified by the addition of a glycosylphosphatidylinositol (GPI) anchor. However, paradoxically, both AGPs were buffer soluble rather than membrane associated. We now show that pear suspension cultured cells also contain membrane-bound GPI-anchored AGPs. This GPI anchor has the minimal core oligosaccharide structure, D-Manalpha(1-2)-D-Manalpha(1-6)-D-Manalpha(1-4)-D-GlcN -inositol, which is consistent with those found in animals, protozoa, and yeast, but with a partial beta(1-4)-galactosyl substitution of the 6-linked Man residue, and has a phosphoceramide lipid composed primarily of phytosphingosine and tetracosanoic acid. The secreted form of PcAGP1 contains a truncated GPI lacking the phosphoceramide moiety, suggesting that it is released from the membrane by the action of a phospholipase D. The implications of these findings are discussed in relation to the potential mechanisms by which GPI-anchored AGPs may be involved in signal transduction pathways. (+info)
Preparation of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic efficacy in murine Mycobacterium avium infection.
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Clofazimine nanosuspensions were produced by high pressure homogenization and the formulation was optimized for lyophilization. Characterization of the product by photon correlation spectroscopy, laser diffraction and Coulter counter analysis showed that the clofazimine nanosuspensions were suitable for iv injection with a particle size permitting passive targeting to the reticuloendothelial system. Following iv administration to mice of either the nanocrystalline or a control liposomal formulation at a dose of 20 mg clofazimine/kg bodyweight, drug concentrations in livers, spleens and lungs reached comparably high concentrations, well in excess of the MIC for most Mycobacterium avium strains. When C57BL/6 mice were experimentally infected with M. avium strain TMC 724, nanocrystalline clofazimine was as effective as liposomal clofazimine in reducing bacterial loads in the liver, spleen and lungs of infected mice. Nanocrystalline suspensions of poorly soluble drugs such as riminophenazines are easy to prepare and to lyophilize for extended storage and represent a promising new drug formulation for intravenous therapy of mycobacterial infections. (+info)
beta1 integrins regulate keratinocyte adhesion and differentiation by distinct mechanisms.
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In keratinocytes, the beta1 integrins mediate adhesion to the extracellular matrix and also regulate the initiation of terminal differentiation. To explore the relationship between these functions, we stably infected primary human epidermal keratinocytes and an undifferentiated squamous cell carcinoma line, SCC4, with retroviruses encoding wild-type and mutant chick beta1 integrin subunits. We examined the ability of adhesion-blocking chick beta1-specific antibodies to inhibit suspension-induced terminal differentiation of primary human keratinocytes and the ability of the chick beta1 subunit to promote spontaneous differentiation of SCC4. A D154A point mutant clustered in focal adhesions but was inactive in the differentiation assays, showing that differentiation regulation required a functional ligand-binding domain. The signal transduced by beta1 integrins in normal keratinocytes was "do not differentiate" (transduced by ligand-occupied receptors) as opposed to "do differentiate" (transduced by unoccupied receptors), and the signal depended on the absolute number, rather than on the proportion, of occupied receptors. Single and double point mutations in cyto-2 and -3, the NPXY motifs, prevented focal adhesion targeting without inhibiting differentiation control. However, deletions in the proximal part of the cytoplasmic domain, affecting cyto-1, abolished the differentiation-regulatory ability of the beta1 subunit. We conclude that distinct signaling pathways are involved in beta1 integrin-mediated adhesion and differentiation control in keratinocytes. (+info)
Some observations on the effects produced in white mice following the injection of certain suspensions of corroding bacilli.
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Strictly anaerobic and facultatively anaerobic strains of "corroding bacilli" failed to produce any pathological symptoms when injected into white mice and no viable organisms could be recovered after 7 days. However, when these same strains were coupled with certain other living bacteria or certain sterile bacterial extracts, lesions developed from which corroding bacilli could be isolated even after 21 days. (+info)