bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutant Selection Window in Levofloxacin and Moxifloxacin Treatments of Experimental Pneumococcal Pneumonia in a Rabbit Model of Human Therapy
Authors: Croisier Delphine , Etienne Manuel , Bergoin Emilie , Charles Pierre-Emmanuel , Lequeu Catherine , Piroth Lionel , Portier Henri , Chavanet Pascal 
Published: April 2004

ABSTRACT

For some pneumococci the fluoroquinolone MICs are low but the mutant prevention concentrations (MPCs) are high; this difference defines in vitro the mutant selection window (MSW). We investigated in vivo the bacterial reduction and the occurrence of resistant mutants with moxifloxacin (MFX; 400 mg once daily) or levofloxacin (LVX; 500 mg twice daily) in treatments similar to those in humans with experimental pneumonia due to pneumococci (expPP) exhibiting various MICs and MPCs. The MIC/MPC for MFX and LVX and genotypes were as follows: strain 16089, 0.125/0.125 and 0.5/0.5 (wild type); strain MS1A, 0.25/0.25 and 1/2 (efflux); strain MS2A, 0.25/4 and 1.75/28 (
parC79
); strain MR3B4, 0.25/4 and 2/32 (
parC79
); strain M16, 0.5/2 and 8/32 (
parC83
); strain Gyr-1207, 1.5/3 and 8/16 (
gyrA
); and strain MQ3A, 4/4 and 16/64 (
parC
and
gyrA
). Both drugs were efficient with wild type-expPP, but only MFX was efficient with efflux-expPP. No bacterial reduction was observed for
parC
-expPPs due to mutants observed in 18 to 100% of animals, depending on the strain and the drug tested. These mutants showed unbound area under the concentration-time curve and MICs of from 50 to 164 for MFX. The in vivo pharmacodynamic boundaries of the MSW were different for MFX and LVX. We conclude that, after LVX or MFX treatment, mutants occur in vivo if there is a preexisting
parC
mutation, since the drug concentrations fall below the MPCs of these strains. Since the MPC determination cannot be routinely determined, these phenotypes or genotypes should be detected by simple tests to guide the therapeutic options.
Dose-Dependent Pharmacokinetics of Itraconazole after Intravenous or Oral Administration to Rats: Intestinal First-Pass Effect
Authors: Shin Jee H. , Choi Ka Y. , Kim Yu C. , Lee Myung G. 
Published: April 2004

ABSTRACTThe dose-dependent pharmacokinetics of itraconazole after intravenous (10, 20, or 30 mg/kg) and oral (10, 30, or 50 mg/kg) administration and the first-pass effects of itraconazole after intravenous, intraportal, intragastric, and intraduodenal administration at a dose of 10 mg/kg were evaluated in rats. After intravenous administration at a dose of 30 mg/kg, the area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) was significantly greater than those at 10 and 20 mg/kg (1,090, 1,270, and 1,760 μg · min/ml for 10, 20, and 30 mg/kg, dose-normalized at 10 mg/kg). After oral administration, the AUC0-∞was significantly different for three oral doses (380, 687, and 934 μg · min/ml for 10, 30, and 50 mg/kg, respectively, dose-normalized at 10 mg/kg). The extent of absolute oral bioavailability (F) was 34.9% after an oral dose at 10 mg/kg. The AUC0-∞(or AUC0-8 h) values were comparable between intravenous and intraportal administration and between intragastric and intraduodenal administration, suggesting that the hepatic and gastric first-pass effects were almost negligible in rats. However, the AUC0-8 hvalues after intraduodenal and intragastric administration were significantly smaller than that after intraportal administration, approximately 30%, suggesting that the intestinal first-pass effect was approximately 70% of that of an oral dose of 10 mg/kg. The lowFafter oral administration of itraconazole at a dose of 10 mg/kg could be mainly due to the considerable intestinal first-pass effect.
In Vitro Activity of Expanded-Spectrum Pyridazinyl Oxime Ethers Related to Pirodavir: Novel Capsid-Binding Inhibitors with Potent Antipicornavirus Activity
Authors: Barnard D. L. , Hubbard V. D. , Smee D. F. , Sidwell R. W. , Watson K. G. W. , Tucker S. P. T. , Reece P. A. R. 
Published: April 2004

ABSTRACT

Picornaviruses (PV) include human rhinovirus (HRV), the primary cause of the common cold, and the enteroviruses (EV), which cause serious diseases such as poliomyelitis, meningoencephalitis, and systemic neonatal disease. Although no compounds for PV infections have been approved in the United States, pirodavir was one of the most promising capsid-binding compounds to show efficacy in human clinical trials for chemoprophylaxis of the common cold. Susceptibility to hydrolysis precluded its use as an oral agent. We have developed orally bioavailable pyridazinyl oxime ethers that are as potent as pirodavir. Compounds BTA39 and BTA188 inhibited a total of 56 HRV laboratory strains and three clinical isolates as determined by neutral red uptake assay. At concentrations of <100 nM, BTA39 inhibited 69% of the HRV serotypes and isolates evaluated, BTA188 inhibited 75%, and pirodavir inhibited 59% of the serotypes and isolates. The 50% inhibitory concentrations (IC
50
s) for the two compounds ranged from 0.5 nM to 6,701 nM. The compounds also inhibited EV, including coxsackie A and B viruses (IC
50
= 773 to 3,608 nM) and echoviruses (IC
50
= 193 to 5,155 nM). BTA39 only inhibited poliovirus strain WM-1 at 204 nM, and BTA188 only inhibited poliovirus strain Chat at 82 nM. EV 71 was inhibited by BTA39 and BTA188, with IC
50
s of 1 and 82 nM, respectively. Both compounds were relatively nontoxic in actively growing cells (50% cytotoxic doses, ≥4,588 nM). These data suggest that these oxime ethers warrant further investigation as potential agents for treating selected PV infections.
Mechanism of Increased Fluconazole Resistance in
Candida glabrata
during Prophylaxis
Authors: Bennett John E. , Izumikawa Koichi , Marr Kieren A. 
Published: April 2004

ABSTRACT

Candida glabrata
can become resistant to fluconazole, causing persistent colonization and invasive infection during prolonged exposure to the drug. To determine the mechanism of resistance in this setting, weekly oropharyngeal cultures for
C. glabrata
were obtained over a 2-year period from hematopoietic stem cell transplant recipients who were receiving fluconazole prophylaxis. In 20 patients from whom at least two isolates of the same karyotype were obtained more than two weeks apart, fluconazole MICs doubled every 31 days on average. The mechanism of fluconazole resistance in isolates from the 14 of the 20 patients studied in whom MICs changed at least fourfold was studied. Cellular resistance was accompanied by increased drug efflux as measured by decreased accumulation of fluconazole and rhodamine 6G and increased abundance of transcripts from two drug transporters,
CgCDR1
and
PDH1.
The rapidity and regularity of the rising resistance indicated that
C. glabrata
is able to upregulate drug efflux without losing the ability to maintain colonization.
Membrane Sphingolipid-Ergosterol Interactions Are Important Determinants of Multidrug Resistance in
Candida albicans
Authors: Mukhopadhyay Kasturi , Prasad Tulika , Saini Preeti , Pucadyil Thomas J. , Chattopadhyay Amitabha , Prasad Rajendra 
Published: April 2004

ABSTRACT

In this study, we examined the importance of membrane ergosterol and sphingolipids in the drug susceptibilities of
Candida albicans
. We used three independent methods to test the drug susceptibilities of
erg
mutant cells, which were defective in ergosterol biosynthesis. While spot and filter disk assays revealed that
erg2
and
erg16
mutant cells of
C. albicans
became hypersensitive to almost all of the drugs tested (i.e., 4-nitroquinoline oxide, terbinafine,
o
-phenanthroline, itraconazole, and ketoconazole), determination of the MIC at which 80% of the cells were inhibited revealed more than fourfold increase in susceptibility to ketoconazole and terbinafine. Treatment of wild-type
C. albicans
cells with fumonisin B1 resulted in 45% inhibition of sphingolipid biosynthesis and caused cells to become hypersensitive to the above drugs. Although
erg
mutants displayed enhanced membrane fluidity and passive diffusion, these changes alone were not sufficient to elicit the observed hypersusceptibility phenotype of
erg
mutants. For example, the induction in vitro of a 12% change in the membrane fluidity of
C. albicans
cells by a membrane fluidizer, benzyl alcohol, did not affect the drug susceptibilities of
Candida
cells. Additionally, the surface localization of green fluorescent protein-tagged Cdr1p, a major drug efflux pump protein of
C. albicans
, revealed that any disruption in ergosterol and sphingolipid interactions also interfered with its proper surface localization and functioning. A 50% reduction in the efflux of the Cdr1p substrate, rhodamine 6G, in
erg
mutant cells or in cells with a reduced sphingolipid content suggested a strong correlation between these membrane lipid components and this major efflux pump protein. Taken together, the results of our study demonstrate for the first time that there is an interaction between membrane ergosterol and sphingolipids, that a reduction in the content of either of these two components results in a disruption of this interaction, and that this disruption has deleterious effects on the drug susceptibilities of
C. albicans
cells.
Simple and Inexpensive Fluorescence-Based Technique for High-Throughput Antimalarial Drug Screening
Authors: Smilkstein Martin , Sriwilaijaroen Nongluk , Kelly Jane Xu , Wilairat Prapon , Riscoe Michael 
Published: April 2004

ABSTRACT

Radioisotopic assays involve expense, multistep protocols, equipment, and radioactivity safety requirements which are problematic in high-throughput drug testing. This study reports an alternative, simple, robust, inexpensive, one-step fluorescence assay for use in antimalarial drug screening. Parasite growth is determined by using SYBR Green I, a dye with marked fluorescence enhancement upon contact with
Plasmodium
DNA. A side-by-side comparison of this fluorescence assay and a standard radioisotopic method was performed by testing known antimalarial agents against
Plasmodium falciparum
strain D6. Both assay methods were used to determine the effective concentration of drug that resulted in a 50% reduction in the observed counts (EC
50
) after 48 h of parasite growth in the presence of each drug. The EC
50
s of chloroquine, quinine, mefloquine, artemisinin, and 3,6-bis-ε-(
N
,
N
-diethylamino)-amyloxyxanthone were similar or identical by both techniques. The results obtained with this new fluorescence assay suggest that it may be an ideal method for high-throughput antimalarial drug screening.
Anti-Respiratory Syncytial Virus (RSV) Neutralizing Antibody Decreases Lung Inflammation, Airway Obstruction, and Airway Hyperresponsiveness in a Murine RSV Model
Authors: Mejías Asunción , Chávez-Bueno Susana , Ríos Ana María , Saavedra-Lozano Jesús , Fonseca Aten Mónica , Hatfield Jeanine , Kapur Payal , Gómez Ana María , Jafri Hasan S. , Ramilo Octavio 
Published: April 2004

ABSTRACTNumerous studies have described a strong association between respiratory syncytial virus (RSV) infection in infancy and the development of recurrent wheezing and airway hyperresponsiveness. We evaluated the effect of an anti-RSV neutralizing monoclonal antibody (palivizumab) on different aspects of RSV disease by using a murine model. BALB/c mice were intranasally inoculated with RSV A2. Palivizumab or an isotype-matched control antibody was administered once at 24 h before inoculation, 1 h after inoculation, or 48 h after inoculation. Regardless of the timing of administration, all mice treated with the neutralizing antibody showed significantly decreased RSV loads in bronchoalveolar lavage (BAL) and lung specimens compared with those of infected controls. Pulmonary histopathologic scores, airway obstruction measured by plethysmography, and airway hyperresponsiveness after methacholine challenge were significantly reduced in mice treated with the anti-RSV antibody 24 h before inoculation compared with those for untreated controls. Concentrations of interferon-gamma, interleukin-10, macrophage inflammatory protein 1α, regulated on activation normal T-cell expressed and secreted (RANTES), and eotaxin in BAL fluids were also significantly reduced in mice treated with palivizumab 24 h before inoculation. This study demonstrates that reduced RSV replication was associated with significant modulation of inflammatory and clinical markers of acute disease severity and significant improvement of the long-term pulmonary abnormalities. Studies to determine whether strategies aimed at preventing or reducing RSV replication could decrease the long-term morbidity associated with RSV infection in children should be considered.
Biochemical Characterization of
Streptococcus pneumoniae
Penicillin-Binding Protein 2b and Its Implication in β-Lactam Resistance
Authors: Pagliero Estelle , Chesnel Laurent , Hopkins Julie , Croizé Jacques , Dideberg Otto , Vernet Thierry , Di Guilmi Anne Marie 
Published: April 2004

ABSTRACT

Extensive use of β-lactam antibiotics has led to the selection of pathogenic streptococci resistant to β-lactams due to modifications of the penicillin-binding proteins (PBPs). PBP2b from
Streptococcus pneumoniae
is a monofunctional (class B) high-molecular-weight PBP catalyzing the transpeptidation between adjacent stem peptides of peptidoglycan. The transpeptidase domain of PBP2b isolated from seven clinical resistant (CR) strains contains 7 to 44 amino acid changes over the sequence of PBP2b from the R6 β-lactam-sensitive strain. We show that the extracellular soluble domains of recombinant PBP2b proteins (PBP2b*) originating from these CR strains have an in vitro affinity for penicillin G that is reduced by up to 99% from that of the R6 strain. The Thr446Ala mutation is always observed in CR strains and is close to the key conserved motif (S
443
SN). The Thr446Ala mutation in R6 PBP2b* displays a 60% reduction in penicillin G affinity in vitro compared to that for the wild-type protein. A recombinant R6 strain expressing the R6 PBP2b Thr446Ala mutation is twofold less sensitive to piperacillin than the parental
S. pneumoniae
strain. Analysis of the Thr446Ala mutation in the context of the PBP2b CR sequences revealed that its influence depends upon the presence of other unidentified mutations.
Virulence of Metallo-β-Lactamase-Producing
Pseudomonas aeruginosa
In Vitro and In Vivo
Authors: Aoki S. , Hirakata Y. , Kondoh A. , Gotoh N. , Yanagihara K. , Miyazaki Y. , Tomono K. , Yamada Y. , Kohno S. , Kamihira S. 
Published: April 2004

ABSTRACT

We evaluated the virulence of
Pseudomonas aeruginosa
carrying
bla
IMP
, a metallo-β-lactamase gene, and the efficacy of ceftazidime, imipenem-cilastatin, and ciprofloxacin in the endogenous bacteremia model. The presence of
bla
IMP
did not practically change the virulence of the parent strain, and ciprofloxacin was effective against infection with
P. aeruginosa
carrying
bla
IMP
.
Development of a Liposome Formulation of Ethambutol
Authors: Wiens Theresa , Redelmeier Thomas , Av-Gay Yossef 
Published: April 2004

ABSTRACT
A liposomal formulation capable of encapsulating 76 to 92% of the antimycobacterial drug ethambutol and showing prolonged in vitro release kinetics is described. In vitro efficacy is equivalent to that of the free drug, suggesting that encapsulation of ethambutol has the potential to shorten the current regimens for tuberculosis.
Influence of Cell Opener in High Resilience Molded Polyurethane Foam
Authors: Song Kee-Cheon , Lee Sang-Mok , Lee Dong-Ho 
Published: April 2004

In a chemical method for cell opening of high resilience (HR) molded polyurethane (PU) foam, two types of cell openers, the poly(ester-ether) type, PESE, having ester linkage and hydrophilic polyether segment in the molecule and the conventional polyether type, poly(propylene oxide-ethylene oxide), PPEO, were employed. The influence of structure and concentration of cell opener on the kinetics, stability, open cell content and mechanical properties of molded foam were investigated. The PESE-based formulation exhibited delayed reaction times and good stability compared to the PPEO-based formulation. The open cell content increased with cell opener amount and was independent of the cell opener structure. The mechanical properties clearly depend on the structure of cell opener. The PESE-based formulation had improved mechanical properties such as indentation hardness, tensile strength and tear strength. The increase of PPEO concentration significantly deteriorated the molded foam’s mechanical properties, while the foam with PESE gave less deterioration of mechanical properties up to a specific concentration of the PESE. With the above observations, PESE was found to be a useful cell opener for preparation of HR molded PU foam which has acceptable mechanical properties.
Effect of Filler Size on Cell Nucleation during Foaming Process
Authors: Chen Lee , Blizard Kent , Straff Rich , Wang Xiang 
Published: April 2004

This work concerns the effects of the filler size on cell nucleation during the foaming process. The cell density of foams with fillers of two different sizes has been investigated using the foaming process simulator developed previously. It was found that the cell density is strongly affected by the filler size. Foams with a fine filler show a higher cell density at a high saturation pressure but give a lower cell density at a low saturation pressure. At a certain value of the saturation pressure, cell density becomes similar with both fillers. This transition pressure changes with the foaming condition. It goes down with a higher pressure drop rate. The experimental results have been explained with an analysis off iller particle size distribution. The analysis also recommended a way to select filler size if a high cell density is desired in the foaming process.
The Use of Ethylene/Styrene Interpolymers in Crosslinked Foams for the Footwear Industry
Authors: Dubois Robert , Karande Seema , Wright David P. , Martinez Felipe 
Published: April 2004

Ethylene/Styrene Interpolymers (ESI) currently under development by The Dow Chemical Company can be effectively crosslinked using current commercial equipment to produce extruded sheets, bun foams, and injection molded foams (IMF) for footwear parts providing properties that enhance and/or outperform current foams of crosslinked ethylene vinyl acetate copolymers (EVA). Crosslinked EVA foams with density ranging from 0.12 to 0.35 g/cc are becoming increasingly popular in many athletic, ladies high heel, and casual shoes for the fabrication of insoles, midsoles, and unisoles, where light weight, comfort, aesthetics, low cost, and performance are the key. ESIs can be blended with EVA or used pure to give light weight, softer foams with better compression set while maintaining or improving on resiliency, heat shrinkage, and split tear.
Measurement of High Resiliency Moulded Foam Properties as a Function of Climatic Conditions
Authors: Blair G. R. , Russ A. , Bradt D. E. , Bailey R. J. 
Published: April 2004

High resiliency moulded foam is normally tested under standard laboratory conditions, e.g., 23 2 C, 50 5% RH, but other conditions may be specified. It is well known that critical foam properties such as hardness and resiliency are influencedby environmental changes. This may affect foam performance especially in automotive seating applications. Changes in seating support, durability and comfort may occur and critical safety components such as occupant sensors may be affected. We have measuredproperty changes that result from different climatic conditions from 30 to 95 C and 0–95% RH. A number of foam chemistries both experimental and in worldwide production have been thoroughly examined for property responses after conditioning. Cushion hardness, hysteresis loss and thickness have been shown to change after environmental conditioning. Resiliency as measuredby ball reboundalso responds to climatic changes. We have analysed our extensive data for temperature or relative humidity responses andfor the combinedresponse to both of these variables. Also we are able to demonstrate combined responses of properties that contribute to seating comfort as a function of climatic conditions. Therefore, we are able to demonstrate to automotive seating designers/engineers the temp/RH ranges where an important cushioning parameter such as seating hardness (and hence H-point) is relatively consistent. Thus, important safety components such as occupant seating sensors shouldremain functional over a relatively wide range of climatic conditions. Seating of various constructions, e.g., metal pan, flexible suspension, sinespring wire, have been testedto ascertain foam responses specific to these constructions. Full details of foam seat performance after environmental conditioning will be discussed.
Effect of Nano-and Micro-Silica Fillers on Polyurethane Foam Properties
Authors: Javni I. , Zhang W. , Karajkov V. , Petrovic Z. S. , Divjakovic V. 
Published: April 2004

Two series of rigid and flexible polyurethane foams were prepared with two types of silica fillers. The density of the flexible foams was 60 kg/m 3 and that of rigid 30 kg/m3. The fillers were micro-silica of the average particle size of 1.5 mm and nano-silica of the average particle size of 12 nm. The concentration of fillers varied from 0–20%. The micro-silica filler did not show any significant effect on density of either rigid or flexible foams. Nano-silica increased the density of both types of foams only at concentration above 20%. Nano-silica lowered the compression strength of both types of foams at all concentrations while micro-silica exhibited the same effect at concentrations above 10%. The hardness and compression strength in flexible polyurethane foams with nano-silica was increased and the rebound resilience decreased. Reduced density of foams was not changed by nano-silica concentrations up to 20%. It is assumed that the nano-filler, as an additional physical crosslinker, increased modulus of the flexible segment in the polyurethane matrix, resulting in increased hardness and compression strength. The micro-filler in flexible foams lowered hardness and compression strength, but increased rebound resilience. Wide angle X-ray scattering (WAXS) showed amorphous morphology of both flexible and rigid foams filled with nano-silica. WAXS of the micro-silica filled foams showed the presence of randomly oriented crystalline quartz particles and the amorphous structure of the polymeric matrix.
Effect of Different Nucleating Agents on the Degassing Conditions as Measured by Ultrasonic Sensors
Authors: Tatiboue Jacques , Gendron Richard , Hamel Andre , Sahnoune Abdelhadi 
Published: April 2004

Ultrasonic sensors have proven to provide valuable information on the thermoplastic foaming process in polymers. Measurement of the attenuation of the ultrasonic signal can be easily related to the nucleation process, i.e., the onset of bubble formation in the foam matrix (degassing). The ultrasonic sensors can be installed in-line, on the extrusion line, and thus allow direct access to the prevailing processing conditions. In this work, the degassing conditions (pressure and temperature) of a mixture of polystyrene and a physical blowing agent (PBA), HCFC 142b, are determined for two different nucleating agents as well as in absence of any nucleating agent. The resulting cellular structure of the extruded foams is correlated to the degassing conditions determined by the ultrasounds. The results are discussed in light of other observations on the nucleation process.