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Disposition of Posaconazole following Single-Dose Oral Administration in Healthy Subjects. Philip Krieter, 2004.Posaconazole is a potent, broad-spectrum triazole antifungal agent currently in clinical development for the treatment of refractory invasive fungal infections . Eight healthy male subjects received a single 399-mg (81.7 µCi) oral dose of [14C]posaconazole after consuming a high-fat breakfast . Urine, feces, and blood samples were collected for up to 336 h postdose and assayed for total radioactivity; plasma and urine samples were also assayed for parent drug . Posaconazole was orally bioavailable, with a median maximum posaconazole concentration in plasma achieved by 10 h postdose . Thereafter, posaconazole was slowly eliminated, with a mean half-life of 20 h . The greatest peak in the radioactivity profile of pooled plasma extracts was due to posaconazole, with smaller peaks due to a monoglucuronide, a diglucuronide, and a smaller fragment of the molecule . The mean total amount of radioactivity recovered was 91.1%; the cumulative excretion of radioactivity in feces and in urine was 76.9 and 14.0% of the dose, respectively . Most of the fecal radioactivity was associated with posaconazole, which accounted for 66.3% of the administered dose; however, urine contained only trace amounts of unchanged posaconazole . The radioactivity profile of pooled urine extracts included two monoglucuronide conjugates and a diglucuronide conjugate of posaconazole . These observations suggest that oxidative (phase 1) metabolism by cytochrome P450 isoforms represents only a minor route of elimination for posaconazole, and therefore cytochrome P450-mediated drug interactions should have a limited potential to impact posaconazole pharmacokinetics . Compost-Induced Suppression of Pythium Damping-Off Is Mediated by Fatty-Acid-Metabolizing Seed-Colonizing Microbial Communities. Mary E. McKellar, 2003.Leaf composts were studied for their suppressive effects on Pythium ultimum sporangium germination, cottonseed colonization, and the severity of Pythium damping-off of cotton . A focus of the work was to assess the role of fatty-acid-metabolizing microbial communities in disease suppression . Suppressiveness was expressed within the first few hours of seed germination as revealed by reduced P . ultimum sporangium germination, reduced seed colonization, and reduced damping-off in transplant experiments . These reductions were not observed when cottonseeds were sown in a conducive leaf compost . Microbial consortia recovered from the surface of cottonseeds during the first few hours of germination in suppressive compost (suppressive consortia) induced significant levels of damping-off suppression, whereas no suppression was induced by microbial consortia recovered from cottonseeds germinated in conducive compost (conducive consortia) . Suppressive consortia rapidly metabolized linoleic acid, whereas conducive consortia did not . Furthermore, populations of fatty-acid-metabolizing bacteria and actinobacteria were higher in suppressive consortia than in conducive consortia . Individual bacterial isolates varied in their ability to metabolize linoleic acid and protect seedlings from damping-off . Results indicate that communities of compost-inhabiting microorganisms colonizing cottonseeds within the first few hours after sowing in a Pythium-suppressive compost play a major role in the suppression of P . ultimum sporangium germination, seed colonization, and damping-off . Results further indicate that fatty acid metabolism by these seed-colonizing bacterial consortia can explain the Pythium suppression observed . Escherichia coli Ghost Production by Expression of Lysis Gene E and Staphylococcal Nuclease. W. Haidinger, 2003.The production of bacterial ghosts from Escherichia coli is accomplished by the controlled expression of phage  X174 lysis gene E and, in contrast to other gram-negative bacterial species, is accompanied by the rare detection of nonlysed, reproductive cells within the ghost preparation . To overcome this problem, the expression of a secondary killing gene was suggested to give rise to the complete genetic inactivation of the bacterial samples . The expression of staphylococcal nuclease A in E . coli resulted in intracellular accumulation of the protein and degradation of the host DNA into fragments shorter than 100 bp . Two expression systems for the nuclease are presented and were combined with the protein E-mediated lysis system . Under optimized conditions for the coexpression of gene E and the staphylococcal nuclease, the concentration of viable cells fell below the lower limit of detection, whereas the rates of ghost formation were not affected . With regard to the absence of reproductive cells from the ghost fractions, the reduction of viability could be determined as being at least 7 to 8 orders of magnitude . The lysis process was characterized by electrophoretic analysis and absolute quantification of the genetic material within the cells and the culture supernatant via real-time PCR . The ongoing degradation of the bacterial nucleic acids resulted in a continuous quantitative clearance of the genetic material associated with the lysing cells until the concentrations fell below the detection limits of either assay . No functional, released genetic units (genes) were detected within the supernatant during the lysis process, including nuclease expression .
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