Early associations with food in anorexia nervosa patients and obese people assessed in the affective priming paradigm.

Two experiments are reported that used the affective priming paradigm (Fazio, R. H., Sanbonmatsu, D. M., Powell, M. C., & Kardess, F. R. (1986). On the automatic activation of attitudes. Journal of Personality and Social Psychology, 50, 229-238) to uncover associations with food at a relatively automatic level. Experiment 1 tested the hypothesis that anorexia nervosa (AN; n=22) patients would show less sensitivity to the palatability of foods than unrestrained lean controls (n=27). Results indeed suggested that AN patients did not display a liking of palatable foods over unpalatable foods, whereas unrestrained controls did. Experiment 2 tested the hypothesis that obese people (n=27) would show more sensitivity to the palatability of (high-fat) palatable foods than unrestrained lean controls (n=27) would. However, results suggested that the priming effect was based on health concerns, in that participants showed a preference for low-fat palatable foods over high-fat palatable foods. Average speed of responding and context are discussed as variables influencing the affective priming effect. Taken together, results suggest that food evaluations at a relatively automatic level are controlled by an interaction between participant characteristics, stimuli characteristics, and the specific context.

Carbon-carbon-linked (pyrazolylphenyl)oxazolidinones with antibacterial activity against multiple drug resistant gram-positive and fastidious gram-negative bacteria.

In an effort to expand the spectrum of activity of the oxazolidinone class of antibacterial agents to include Gram-negative bacteria, a series of new carbon-carbon linked pyrazolylphenyl analogues has been prepared. The alpha-N-substituted methyl pyrazole (10alpha) in the C3-linked series exhibited very good Gram-positive activity with MICs

Linezolid, critical characteristics

In spite of a constantly expanding information base with the oxazolidinones generally and linezolid specifically, we have elected here to focus on the key characteristics of linezolid. Linezolid is the first member of a new class of antimicrobial agents, the oxazolidinones, to be tested in humans in Phase I, Phase II and Phase III clinical trials. The oxazolidinones have a novel mechanism of action in that they inhibit initiation complex formation in bacterial protein synthesis and, consistent with a novel mechanism of action, they do not exhibit cross-resistance with existing antibacterial agents. Importantly, resistance development as measured in the laboratory occurs very slowly, there is no evidence of rapid resistance development. The spectrum of oxazolidinone activity is principally gram-positive and in vitro studies demonstrate that linezolid is equivalent to vancomycin in vitro. Linezolid is orally as well as intravenously active and orally administered linezolid is as efficacious in mouse models of bacterial disease as is subcutanously administered vancomycin against appropriate pathogens. The exceptional oral behavior of linezolid in mouse models is readily explained by the observation that oral linezolid is 100% bioavilable and that administration of 400- and 600-mg doses of linezolid in humans results in blood level curves which predict that linezolid will be very well suited for bid dosing. Additionally, the blood level concentrations are in significant and very comfortable excess of the MIC90 concentrations for the important gram-positive pathogens for the bulk of the dosing interval.

Substituent effects on the antibacterial activity of nitrogen-carbon-linked (azolylphenyl)oxazolidinones with expanded activity against the fastidious gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis.

A series of new nitrogen-carbon-linked (azolylphenyl)oxazolidinone antibacterial agents has been prepared in an effort to expand the spectrum of activity of this class of antibiotics to include Gram-negative organisms. Pyrrole, pyrazole, imidazole, triazole, and tetrazole moieties have been used to replace the morpholine ring of linezolid (2). These changes resulted in the preparation of compounds with good activity against the fastidious Gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis. The unsubstituted pyrrolyl analogue 3 and the 1H-1,2,3-triazolyl analogue 6 have MICs against H. influenzae = 4 microgram/mL and M. catarrhalis = 2 microgram/mL. Various substituents were also placed on the azole moieties in order to study their effects on antibacterial activity in vitro and in vivo. Interesting differences in activity were observed for many analogues that cannot be rationalized solely on the basis of sterics and position/number of nitrogen atoms in the azole ring. Differences in activity rely strongly on subtle changes in the electronic character of the overall azole systems. Aldehyde, aldoxime, and cyano azoles generally led to dramatic improvements in activity against both Gram-positive and Gram-negative bacteria relative to unsubstituted counterparts. However, amide, ester, amino, hydroxy, alkoxy, and alkyl substituents resulted in no improvement or a loss in antibacterial activity. The placement of a cyano moiety on the azole often generates analogues with interesting antibacterial activity in vitro and in vivo. In particular, the 3-cyanopyrrole, 4-cyanopyrazole, and 4-cyano-1H-1,2,3-triazole congeners 28, 50, and 90 had S. aureus MICs

Oxazolidinones: new antibacterial agents.

The oxazolidinones are a new chemical class of synthetic antibacterial agents that are active orally or intravenously against multidrug-resistant Gram-positive bacteria. Their unique mechanism of action and activity against bacteria that pose therapeutic problems in hospital and community treatments make them promising candidates for antimicrobial agents.

In vivo activities of U-100592 and U-100766, novel oxazolidinone antimicrobial agents, against experimental bacterial infections.

The Upjohn oxazolidinones, U-100592 and U-100766, are orally bioavailable synthetic antimicrobial agents with spectra of activity against antibiotic-susceptible and -resistant gram-positive pathogens. In several mouse models of methicillin-resistant Staphylococcus aureus infection, U-100592 and U-100766 yielded oral 50% effective doses (ED50) ranging from 1.9 to 8.0 mg/kg of body weight, which compared favorably with vancomycin subcutaneous ED50 values of 1.1 to 4.4 mg/kg. Similarly, both compounds were active versus a Staphylococcus epidermidis experimental systemic infection. U-100592 and U-100766 effectively cured an Enterococcus faecalis systemic infection, with ED50 values of 1.3 and 10.0 mg/kg, and versus a vancomycin-resistant Enterococcus faecium infection in immunocompromised mice, both drugs effected cures at 12.5 and 24.0 mg/kg. Both compounds were exceptionally active in vivo against penicillin- and cephalosporin-resistant Streptococcus pneumoniae, with ED50 values ranging from 1.2 to 11.7 mg/kg in systemic infection models. In soft tissue infection models with S. aureus and E. faecalis, both compounds exhibited acceptable curative activities in the range of 11.0 to 39.0 mg/kg. U-100766 was also very active versus the Bacteroides fragilis soft tissue infection model (ED50 = 46.3 mg/kg). In combination-therapy studies, both U-100592 and U-100766 were indifferent or additive in vivo against a monomicrobic S. aureus infection in combination with other antibiotics active against gram-positive bacteria and combined as readily as vancomycin with gentamicin in the treatment of a polymicrobic S. aureus-Escherichia coli infection. U-100592 and U-100766 are potent oxazolidinones active against antibiotic-susceptible and -resistant gram-positive pathogens in experimental systemic and soft tissue infections.

Establishment of an experimental model of a Staphylococcus aureus abscess in mice by use of dextran and gelatin microcarriers.

Staphylococcus aureus UC 9271 mixed with dextran or gelatin microcarrier beads and injected subcutaneously into mice resulted in the formation of reproducible, sustained abscesses with as few as 2 x 10(3) cfu. Without microcarrier beads, 4 x 10(7) cfu were required to produce an abscess. The abscesses that developed with microcarriers attained a diameter of up to 1.5 cm and persisted for several days before discharging through the skin. The pH of the abscesses fell from 7.1 to 6.6 within 24 h. Histological and microscopic examination of the abscesses revealed an influx of phagocytic cells, mostly polymorphonuclear leucocytes, within 1-2 h after injection. Cell debris accumulated and the abscess became encapsulated 24-48 h after infection. Enzymatic digestion of the abscess contents allowed analysis of the host and bacterial cell populations and treatment with lysostaphin permitted differentiation between phagocytosed and free bacterial populations of S. aureus. Phagocytosed but viable S. aureus comprised c. 50% of the total bacterial population after 24 h; however, by 96 h the phagocytosed population was only 1-5% of the total population, primarily because of an increase in extracellular bacterial numbers. Prevention of abscess formation by antibiotic treatment based upon the minimal inhibitory concentration (MIC) of an antibiotic for S. aureus was not always predictable. Tetracycline did not prevent abscess formation even though it possessed a low MIC for S. aureus; methicillin had a borderline MIC value but was quite active. However, the MIC values were quite predictive of antibiotic cures in a systemic-lethal S. aureus infection in mice.